north dakota essential evidence topics 2014 · understand the evidence behind the fda approved uses...

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Essential Evidence Topics 2014

NDAFP 59th Annual Meeting and Scientific Assembly

Learning Objective

Discuss recent research important to family physicians for updating their diagnostic and treatment approaches to selected issues in cardiovascular disease, diabetes, mens health and sports medicine. Objectives for each presentation are listed at the beginning of each talk.

Faculty John Hickner, MD, MSc. is Professor and Head of Family Medicine at the University of Illinois at Chicago and Editor in Chief of the Journal of Family Practice. His research centers on patient safety, especially testing safety and medication safety in primary care practice. After receiving his medical degree from Indiana University School of Medicine, Dr. Hickner completed his residency in family medicine at the Medical University of South Carolina and received a master’s degree in Biostatistics and Research Design from the University of Michigan School of Public Health. Gary Ferenchick, MD, MS. is Division Chief, General Internal Medicine, and Professor of Medicine at Michigan State University College of Human Medicine. He earned his master’s degree in human nutrition and medical degree from Michigan State University. He completed his residency training in internal medicine at Michigan State University College of Human Medicine. Dr. Ferenchick is a Past-President of the Clerkship Directors in Internal Medicine. His research interest is the interface between medical education and information technology. Speaker and Faculty Disclosures John Hickner, MD, MSc disclosed no relevant financial relationship or interest with a proprietary entity producing health care goods or services. Gary Ferenchick, MD disclosed no relevant financial relationship or interest with a proprietary entity producing health care goods or services. “Essential Evidence” and all content in this handout is copyright by John Wiley and Sons, Inc, 2014. This syllabus may not be reproduced without permission from the publisher. http://www.essentialevidence.com

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Information Mastery Key Points Objectives

1. Learn the importance of patient oriented evidence for interpretation of research studies. 2. Learn an efficient way to use PubMed to search for information

Usefulness of medical information = (relevance x validity) / work Relevance is a continuum: Rat studies Surrogates Disease-specific All-cause mortality/QOL Validity is a continuum:

Case study Case-control Cohort RCT Systematic review Patient oriented evidence: anything that helps patients live a longer or better life.

Disease oriented evidence: everything else; surrogate or physiologic markers POEMs (Patient Oriented Evidence that Matters): a study that addresses a common or important condition, demonstrates improved patient oriented outcomes, and matters because it would change what we do.

Evidence-based sources to explore: � Essential Evidence: www.essentialevidence.com � Clinical Evidence: www.clinicalevidence.com � Cochrane Library: www.cochrane.org � DynaMed: www.dynamicmedical.com � TRIP Database: www.tripdatabase.com � Bandolier: www.medicine.ox.ac.uk/bandolier/ � National Guidelines Clearinghouse: www.guidelines.gov

Search hints

• Use Clinical Queries at the PubMed site • Select “Narrow” filter • Use quotes to narrow search to only those words appearing next to each other,

i.e. “acute bronchitis” eliminates “acute exacerbation of chronic bronchitis” • Combination of drug and disease is useful: “acute bronchitis” azithromycin;

“infectious mononucleosis” corticosteroid; influenza osletamivir • Optionally, “See all” and then add additional limits (English, abstract, human) • Use “Not” terms to exclude groups of articles • Then, select “Related articles” once you have a good hit.

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ANTICOAGULATION UPDATE: 2014 NEW AGENTS Gary Ferenchick MD

Objective 1. Understand the evidence behind the FDA approved uses of newer oral anticoagulants (i.e. NOAs) including dabigatran and apixaban and rivaroxaban What is the role of newer anticoagulants in the prevention of thromboembolic disease?

Some of the difference between the newer anticoagulants and the “older” anticoagulants, such as warfarin and heparin, is that the new agents target a single enzyme within the coagulation pathway (e.g. thrombin [aka activated factor IIa] or factor Xa); whereas warfarin inhibits the synthesis of factors II, VII, IX, and X, and heparin increases the activity of antithrombin (AT) which exerts an inhibitory effect on factor Xa, thrombin and other factors.

Additionally the “newer” agents have a more rapid onset of action than warfarin, lack the need for bridging anticoagulation and have fewer dietary and drug restrictions and possess a predictable anticoagulant effect limiting the need for routine monitoring protocols.

The development of thrombus is a fast process, taking < 5 minutes from the activation of the clotting cascade to the development of clot. Factor Xa is located at the convergence point of both the intrinsic and extrinsic pathways and has proven to be an effective target for anticoagulation. Note that one molecule of factor Xa catalyzes the formation of ~ 1000 molecules of thrombin.

The oral direct Xa inhibitors, rivaroxaban, apixaban and edoxaban, inhibit both free and bound factor Xa, whereas the indirect factor Xa inhibitor is fondaparinux, which is given subcutaneously and acts by enhancing the activity of AT, only inhibits free factor Xa.

The direct thrombin inhibitor dabigatran inhibits thrombin (thus preventing fibrin formation) and thrombin-mediated activation of several clotting factors (V, VIII and XI) along with inhibiting thrombin mediated platelet activation.

Dabigatran was the first new oral anticoagulant to become available in 50 years and directly inhibits thrombin (see figure). In 2011 the American College of Cardiology and the American Heart Association published an update on the management of patients with atrial fibrillation with a focus on dabigatran. They issued a new recommendation that endorsed dabigatran (with a Class I recommendation, meaning the treatment should be administered) as a useful alternative "... to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL/min), or advanced liver disease (impaired baseline clotting function)." The recommendation also states that “… patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran”. (Circulation 2011;123:1144-1150) Additionally, as of January of 2014 edoxaban, this directly inhibits factor Xa, is awaiting FDA approval for stroke prophylaxis in patients with atrial fibrillation among other indications.

As a general rule for patients with non-valvular atrial fibrillation, aspirin in doses 75 – 325 mg decreases the combination of CVA, MI and vascular death by about 29% compared to placebo in primary prevention trials; and oral anticoagulants

Am J Emerg Med 2012;30:2046

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(warfarin) decreases the risk of stroke and other major vascular events by another 33% compared to aspirin, and by about 64% in those with atrial fibrillation and a history of a TIA.

Drug (Trade Name) Mechanism FDA Approved Indication(s) General Dosing DDIs

Apixaban (Eliquis) Factor Xa inhibitor Nonvalvular atrial fib 2.5 – 5.0 mg bid itraconazole, clarithromycin among others

Rivaroxaban (Xarelto) Factor Xa inhibitor Nonvalvular atrial fib Treatment of DVT and/or PE Prevent of recurrent DVT and PE following initial 6 months treatment for DVT and/or PE Prevention of DVT/PE in pts undergoing knee or hip replacement surgery

Dosing more complex: AF: 15 – 20 mg with evening meal for AF (depending on creatinine clearance) Rx DVT/PE: 15 bid with food for 21 days, then 20 mg daily with food Prevent DVT/PE recurrence: 20 daily with food DVT prophylaxis with hip and knee surgery: 10 mg once daily for 12 (knee) or 35 (hip) days

(DDI major = amiodarone diltiazem, verapamil, felodipine, azithromycin among others)

Edoxaban (Savaysa) Factor Xa inhibitor Seeking approval for

Non-valvular atrial fibrillation (NVAF)

The treatment of DVT/PE

The prevention of recurrence of symptomatic venous thromboembolism

Dabigatran (Pradaxa) Direct thrombin inhibitor

Nonvalvular atrial fib 75 – 150 mg bid depending on Cr Clearance

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Drug Major studies supporting FDA

approval FDA approved indications

Rivaroxaban (Xarelto) ROCKET AF Treatment non valvular AF

EINSTEIN DVT EINSTEIN PE Treatment of DVT, PE AND Reduction of the risk of recurrence of DVT and PE

RECORD1-4 Prevention of DVT in patients undergoing knee or hip replacement surgery

Apixiban (Eloquiis) ARISTOTLE, AVERROES Treatment of non-valvular atrial fib

Dabigitran (Pradaxa) RE-LY Treatment of non valvular as Oct 2010

According to the FDA “Specific antidotes” or “reversal agents” for all of the above are not available

Note also many other studies from the manufacturers are on-going in an attempt to expand indications for their drugs

Note most of these newer anticoagulants have renal cautions; both in initiating the drugs and a caution to “Periodically assess renal function”

Atrial Fibrillation

#1: Dabigatran reduces risk of stroke and embolism in patients with AF (RE-LY) Clinical question: Is dabigatran more safe and effective than warfarin for the prevention of complications of atrial fibrillation? Study design: Randomized controlled trial (single-blinded) Setting: Outpatient (any) Synopsis: Dabigatran etexilate is an oral alternative to warfarin that directly inhibits thrombin. In this study, patients were randomized to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin targeted to an INR between 2.0 and 3.0. Although patients and physicians were masked to the dose of dabigatran, they were not masked to the choice of dabigatran or warfarin. However, outcome assessors were masked to both, which is more important. The researchers enrolled 18,113 patients, with a mean age of 71 years. Groups were balanced at the start of the study, analysis was by intention to treat, and patients were followed up for a median of 2 years. Only 20 patients were lost to follow-up. In general, clinical outcomes were similar between the 110 mg dose of dabigatran and the warfarin. When compared with warfarin, the 150 mg dose of dabigatran was associated with a lower risk of stroke and death from vascular causes, but a slightly higher risk of myocardial infarction. Major bleeding was less common with the 110 mg dose than with warfarin (but not with the 150 mg dose). On balance, the net benefit was similar between the 2 doses of dabigatran; the lower risk of ischemia with the higher dose was balanced by a lower risk of bleeding with the higher dose. All-cause mortality was 3.75% in the 110 mg dose group, 3.64% in the 150 mg dose group, and 4.13% in the warfarin group. The comparison between dabigatran 150 mg and warfarin was of borderline statistical significance (P = .051, NNT = 200 for 2 years). Using the CHADS score as a measure of risk of stroke, only patients with a score of 3 or higher benefited from the lower dose, while all patients benefited from the higher dose. Bottom line: Dabigatran was slightly more effective than warfarin at preventing stroke and embolism, especially the dosage of 150 mg given twice daily, and may reduce all-cause mortality (number needed to treat [NNT] = 200 over 2 years). It will be important to balance efficacy with the higher cost but greater convenience of dabigatran when comparing it with standard warfarin therapy. Reference: Connolly SJ, Ezekowitz MD, Yusuf S, et al, for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139-1151.

#2: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. (ROCKET AF)

BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03;

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P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov.number, NCT00403767.). Reference: Patel MR, Mahaffey KW, Garg J, Pan G, et al. ROCKET AF Investigators. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638.

#3: Apixaban slightly more effective and safe than warfarin, but more expensive (ARISTOTLE) Clinical question: Is apixaban safer and more effective than warfarin for patients with atrial fibrillation? Study design: Randomized controlled trial (double-blinded). Funding source: Industry. Allocation: Concealed. Setting: Outpatient (any) Synopsis: This study of apixaban, an oral factor Xa inhibitor, included patients with atrial fibrillation or flutter and at least one risk factor for stroke (aged 75 years or older, previous stroke, transient ischemic attack, systemic embolism, heart failure, diabetes mellitus, or hypertension). Patients with recent stroke, mitral stenosis, prosthetic heart valve, need for aspirin, or renal insufficiency (serum creatinine > 2.5 mg/dL or 221 umol/L) were excluded. Patients (N = 18,201) were randomized with concealed allocation to receive apixaban 5 mg twice daily or matching placebo; patients older than 80 years, those who weighed less than 60 kg, and those with serum creatinine levels of less than 1.5 mg/dL (133 umol/L) received a dose of 2.5 mg twice daily. Patients also received warfarin adjusted to an INR of 2.0 to 3.0, or matching placebo with sham adjustments. Thus, half of patients got apixaban twice daily plus sham warfarin, while half got placebo twice daily plus real warfarin. The mean age of participants was 70 years, 35% were women, and 85% had persistent or permanent atrial fibrillation (as opposed to paroxysmal). Patients were followed up for a median of 1.8 years, which is somewhat short for a study of a chronic disease. The primary efficacy outcome was the rate of stroke (ischemic, hemorrhagic, or uncertain) or systemic embolism, which occurred in 1.3% of patients receiving apixaban and 1.6% receiving warfarin (absolute risk reduction = 0.3%; number needed to treat [NNT] = 333/year; P = .01). When you look at the individual end points, the only one that improved was hemorrhagic stroke (0.24% vs 0.47%; P < .001; NNT = 434/year). Death from any cause was marginally less likely with apixaban (3.52% vs 3.94%; P = .047; NNT = 238/year), and major bleeding was also slightly less likely with apixaban (2.13% vs 3.09%/year; P < .001; NNT = 105). There was no difference between groups regarding liver function or hepatic outcomes, and there was no difference regarding the likelihood of myocardial infarction, pulmonary embolism, or deep vein thrombosis. Bottom line: In low-risk patients with atrial fibrillation, apixaban (Eliquis) was associated with a slightly lower risk of stroke or venous thromboembolism, as well as a slighly lower risk of major bleeding. It is more convenient than warfarin (as an oral drug that does not require regular INR testing) but is more expensive. Although pricing has not been established, it is likely to be similar to that for Pradaxa: approximately $200 per month. Of course, this higher drug cost has to be balanced against the costs of monitoring for warfarin and the slightly higher risk of stroke and bleeding with warfarin; an objective cost-effectiveness analysis is needed to help sort this out. Reference: Granger CB, Alexander JH, McMurray JJ, et al, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981-992.

#4: Edoxaban noninferior to warfarin for atrial fibrillation BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.). REFERENCE: Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104.

#5: Apixaban versus warfarin in nonvalvular atrial fibrillation: warfarin naïve vs warfarin experienced patients

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BACKGROUND: Patients with atrial fibrillation who are vitamin K antagonist (VKA)-naive may have a higher risk of thrombosis and/or bleeding than VKA-experienced patients.

METHODS AND RESULTS: Using data from ARISTOTLE, we assessed baseline characteristics and the treatment effect of apixaban versus warfarin in the VKA-naive and VKA-experienced cohorts. We compared rates of study drug discontinuation and time-in-therapeutic range. Overall, 7,800 (43%) were VKA naive, and 10,401 were VKA experienced. At baseline, both groups were similar with respect to age and congestive heart failure, hypertension, age, diabetes, stroke score (CHADS2). Fewer VKA-naive patients had a history of prior stroke (18% vs 21%) or prior bleeding (10% vs 22%) and were more often female (39% vs 33%). The effect of apixaban on the primary efficacy and safety outcomes was similar in VKA-naive (stroke/systemic embolism: hazard ratio [HR] 0.86, 95% CI 0.67-1.11 and major bleeding: HR 0.73, 95% CI 0.59-0.91) and VKA-experienced populations (stroke/systemic embolism: HR 0.73, 95% CI 0.57-0.95, P value for interaction = 0.39 and major bleeding: HR 0.66, 95% CI 0.55-0.80, P value for interaction = 0.50). Permanent study drug discontinuation was numerically less likely in patients receiving apixaban whether they were VKA naive (HR for discontinuation: 0.87, 95% CI 0.79-0.95) or VKA experienced (HR for discontinuation: 0.93, 95% CI 0.85-1.02). Among patients receiving warfarin, the mean/median times in therapeutic range were lower in the VKA-naive group (VKA-naive: 57.5/61.4, VKA-experienced: 66.0/69.1, P < .001). CONCLUSION: The treatment effects of apixaban (vs warfarin) were not modified by VKA naivety. The rates of stroke/systemic embolism and major bleeding were numerically lower among the patients assigned to apixaban, irrespective of prior VKA use. REFERENCE: Garcia DA, Wallentin L, Lopes RD, et al. Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Am Heart J. 2013 Sep;166(3):549-58. #6: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation: warfarin naïve vs warfarin experienced patients

BACKGROUND: In ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), a large randomized, clinical trial, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation. OBJECTIVE: To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)-naive and VKA-experienced patients. DESIGN: Prespecified subgroup analysis. (ClinicalTrials.gov: NCT00403767). SETTING: Global. PATIENTS: 14,264 persons with atrial fibrillation. MEASUREMENTS: Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKA-naive and VKA-experienced patients. RESULTS: Overall, 7897 (55.4%) patients were VKA-experienced and 6367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKA-experienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003). LIMITATION: The trial was not designed to detect differences in these subgroups. CONCLUSION: The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial. There were more bleeding events within 7 days of study drug initiation with rivaroxaban, but after 30 days, rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients. This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy. PRIMARY FUNDING SOURCE: Johnson & Johnson and Bayer HealthCare. REFERENCE: Mahaffey KW, Wojdyla D, Hankey GJ, ET AL. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013 Jun 18;158(12):861-8.

VTE Treatment/Prophylaxis

#7: Rivaroxaban effective for acute DVT (EINSTEIN DVT)

Clinical question: Is rivaroxaban safe and effective for the treatment of acute deep vein thrombosis? Study design: Randomized controlled trial (single-blinded). Funding source: Industry. Allocation: Concealed. Setting: Outpatient (any). Synopsis: Rivaroxaban is a direct inhibitor of coagulation factor Xa, and is given orally either once or twice a day. In this industry-sponsored study, patients with acute proximal DVT and no evidence of pulmonary embolism were randomized (allocation concealed) to receive either rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily) or standard therapy (enoxaparin 1 mg/kg twice a day, followed by warfarin titrated to an international normalized ratio of between 2.0 and 3.0). The duration of therapy was based on a risk factor assessment and was determined by the treating physician. Analysis was by intention to treat, groups were balanced at the start of the study, and outcomes were adjudicated by a central committee masked to treatment assignment. The mean age of the 3449 participants was 56 years, and the intended duration of therapy was 6 months for 63%, 12 months for 25%, and 3 months for 12%. Outcomes favored rivaroxaban: recurrent venous thromboembolism occurred less often (2.1% vs 3.0%; P < .001; number needed to treat [NNT] = 111), largely due to fewer episodes of DVT (14 vs 28). There was no difference in episodes of major bleeding between groups (14 for rivaroxaban vs 20 for standard therapy) and no difference in all-cause mortality (38 vs 49). In a second phase of the trial, the researchers enrolled 1196

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patients who were felt to be at equipoise for continued anticoagulation after 6 months to 12 months (ie, their physician believed it was a toss-up whether they needed continued anticoagulation). In this phase, the patients were randomized in double-blind fashion to receive continued rivaroxaban or placebo and were followed up for up to 1 year. During that time, the combined outcome of major bleeding or recurrent VTE occurred in 2.0% in the rivaroxaban group and 7.1% in the placebo group (P < .001; NNT = 20). There was no evidence of hepatic toxicity, which was seen with an earlier factor Xa inhibitor. Bottom line: Rivaroxaban provides an oral alternative to warfarin for patients with acute deep vein thrombosis (DVT). The risk of major bleeding during a 1-year follow-up was approximately 0.7%, which is similar to that seen in other studies of long-term anticoagulant use. Although rivaroxaban is more convenient than warfarin, the cost is certain to be much higher. Reference: The EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363(26):2499-2510.

#8: Oral rivaroxaban as effective as standard therapy for treatment of acute PE. (EINSTEIN PE)

Clinical question: Is rivaroxaban as effective as enoxaparin plus an adjusted-dose vitamin K antagonist for the treatment of symptomatic pulmonary embolism? Study design: Randomized controlled trial (nonblinded). Funding source: Industry. Allocation: Concealed. Setting: Inpatient (any location) with outpatient follow-up

Synopsis: In this open-label study, rivaroxaban was compared with enoxaparin plus a vitamin K antagonist for the treatment of PE. Adult patients with acute symptomatic PE were enrolled. Those with clinically significant kidney disease or liver disease were excluded. In the rivaroxaban group (n = 2419), patients received oral rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily. In the standard therapy group (n = 2413), patients received enoxaparin at a dose of 1 mg per kg twice daily along with either warfarin or acenocoumarol. Enoxaparin was discontinued after at least 5 days or after a therapeutic international normalized ratio (INR) was achieved. Duration of anticoagulation of 3, 6, or 12 months was determined by the treating physician prior to randomization. Almost 90% of the included patients were hospitalized and the majority was diagnosed with an unprovoked PE. It is noted that the use of nonsteroidal anti-inflammatory drugs and antiplatelet agents was discouraged, and if used, doses were limited to 100 mg of aspirin and 75 mg of clopidogrel. However, no data regarding these characteristics amongst the study population was reported. The primary efficacy analysis was by intention to treat, while the safety analysis included patients who received at least one dose of the study drug. For the primary outcome of symptomatic recurrent venous thromboembolism, there was no difference between rivaroxaban and standard therapy (50 events vs 44 events). For the primary safety outcome, there was no significant difference in the rates of overall clinically relevant bleeding between the 2 groups (10.3% in the rivaroxaban group vs 11.4% in the standard therapy group). However, the rivaroxaban group did have a lower rate of major bleeding events (1.1% vs 2.2%; hazard ratio = 0.49; 95% CI, 0.31-0.79; number needed to treat = 90). Bottom line: For patients with acute symptomatic pulmonary embolism (PE), oral rivaroxaban was shown to be noninferior to standard therapy (enoxaparin and a vitamin K antagonist) in preventing recurrent venous thromboembolism. Although there is no significant difference in overall clinically relevant bleeding rates between the 2 groups, the rivaroxaban group had fewer major bleeding events. We would have to treat 90 people with rivaroxaban instead of standard therapy to prevent 1 major bleed. Reference: EINSTEIN-PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366(14):1287-1297.

#9: Apixaban for VTE Clinical question: Is apixaban safer and more effective than conventional anticoagulation for venous thromboembolism? Bottom line: Apixaban (Eliquis) is no more effective than conventional anticoagulation for the treatment of venous thromboembolism. There is a small benefit in terms of reducing major bleeds in critical sites (approximately 1 fewer for every 270 patients given apixaban), but it is not clear whether this benefit is cost-effective. If apixaban costs $100 more per month than conventional therapy, then the cost per prevented critical site bleed is well over $150,000 for 6 months. A full cost-effectiveness analysis could better clarify the balance of benefits, harms, and costs. It is likely that this drug is a good choice for selected patients (those who may have difficulty complying with warfarin and international normalized ratio (INR) monitoring, or those who have higher bleeding risk), but is unlikely to be cost-effective for many others. (LOE = 1b) Study design: Randomized controlled trial (double-blinded) Funding source: Industry Allocation: Concealed Setting: Outpatient (any) Synopsis: Apixaban is an oral factor Xa inhibitor given twice daily. In this trial, 5395 adults with venous thromboembolism (n = 3532), pulmonary embolism (n = 1359), or both (n = 477) were randomized to receive apixaban or usual therapy with enoxaparin 1 mg per kg every 12 hours for at least 5 days, and then warfarin for 6 months at a target range INR of 2.0 to 3.0. Apixaban was given in a dosage of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months. The groups were balanced at the beginning of the study: mean age 57 years, 58% male, and a median of 5 days from onset of symptoms to randomization. Patients were followed up for 6 months by telephone or in the clinic, and outcomes were assessed by committee members masked to treatment assignment. The authors excluded patients with active bleeding, anemia, impaired renal function, or cancer, and those who were taking aspirin. They also excluded patients who had a clear cause for the clot that could be removed (for example, a postoperative or travel-related clot, which is often treated with only 3 months of anticoagulation). Major bleeding occurred more often in the conventional therapy group (1.8% vs 0.6%; P < .001; number needed to treat = 83). Critical site bleeds -- a subset of major bleeds that included intracranial, retroperitoneal, intrathoracic, intraocular, and intraarticular bleeds -- were also somewhat less common (4 vs 14), but a test of statistical significance is not provided. If we assume that it is significant, that is approximately 1 fewer critical site bleed for every 270 patients

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given apixaban instead of conventional therapy. There was no difference in the likelihood of death or recurrent venous thromboembolism. Approximately half of the recurrences and major bleeds occurred during the first month of therapy for both groups. Reference: Agnelli G, Buller HR, Cohen A, et al, for the AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369(9):799-808. #10: Dabigatran for prevention of VTE recurrence BACKGROUND: Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. METHODS: In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. RESULTS: In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. CONCLUSIONS: Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. (Funded by Boehringer Ingelheim; RE-MEDY and RE-SONATE ClinicalTrials.gov numbers, NCT00329238 and NCT00558259, respectively.). REFERENCE: Schulman S(1), Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):709-18.

#11: Edoxaban for prevention of VTE recurrence BACKGROUND: Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear. METHODS: In a randomized, double-blind, noninferiority study, we randomly assigned patients with acute venous thromboembolism, who had initially received heparin, to receive edoxaban at a dose of 60 mg once daily, or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or to receive warfarin. Patients received the study drug for 3 to 12 months. The primary efficacy outcome was recurrent symptomatic venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: A total of 4921 patients presented with deep-vein thrombosis, and 3319 with a pulmonary embolism. Among patients receiving warfarin, the time in the therapeutic range was 63.5%. Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, which occurred in 130 patients in the edoxaban group (3.2%) and 146 patients in the warfarin group (3.5%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.70 to 1.13; P<0.001 for noninferiority). The safety outcome occurred in 349 patients (8.5%) in the edoxaban group and 423 patients (10.3%) in the warfarin group (hazard ratio, 0.81; 95% CI, 0.71 to 0.94; P=0.004 for superiority). The rates of other adverse events were similar in the two groups. A total of 938 patients with pulmonary embolism had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent venous Thromboembolism in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group (hazard ratio, 0.52;95% CI, 0.28 to 0.98). CONCLUSIONS: Edoxaban administered once daily after initial treatment with heparin was noninferior to high-quality standard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism. (Funded by Daiichi-Sankyo; Hokusai-VTE ClinicalTrials.gov number, NCT00986154.). REFERENCE: Hokusai-VTE Investigators, Büller HR, Décousus H, ET AL. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15.

#12: Meta-analysis: Warfarin more effective but has higher bleeding risk vs newer agents in secondary VTE prevention

OBJECTIVE: To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand. REVIEW METHODS: Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms.

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RESULTS: 12 articles met our inclusion criteria, with 11,999 patients evaluated for efficacy and 12,167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available. CONCLUSIONS: All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding. REFERENCE: Castellucci LA, Cameron C, Le Gal G, et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ. 2013 Aug 30;347

The following is one of the four RECORD trials on the use of rivaroxaban in THROMBOPROPHYLAXIS in THR and TKR patients.

#13: Oral rivaroxaban for thromboprophylaxis in THR patients. (RECORD 1)

BACKGROUND: This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. METHODS: In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. RESULTS: A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). CONCLUSIONS: A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. REFERENCE: Eriksson BI, Borris LC, Friedman RJ, et al. RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75.

#14: Clinical benefits of newer agents for thromboprophylaxis are marginal

BACKGROUND: Pharmacologic thromboprophylaxis reduces the risk for venous thromboembolism after total hip replacement (THR) or total knee replacement (TKR). New oral anticoagulants (NOACs), including direct thrombin inhibitors and factor Xa inhibitors, are emerging options for thromboprophylaxis after these procedures. PURPOSE: To compare the benefits and risks of NOACs versus standard thromboprophylaxis for adults having THR or TKR. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from January 2009 through March 2013. STUDY SELECTION: English-language systematic reviews. DATA EXTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin,aspirin, or unfractionated heparin. LIMITATIONS: Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice. CONCLUSION: New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding. REFERENCE: Adam SS, McDuffie JR, Lachiewicz PF, et al. Comparative effectiveness of new oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review. Ann Intern Med. 2013 Aug 20;159(4):275-84. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Safety issues

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The following 3 abstracts remind us that if an anticoagulant is safe and effective for one indication, it does not follow that is safe to stretch the indications nor that the new drug is effective for non-approved indications. Therefore pay attention to FDA approved indications

#15: Dabigatran is neither safe nor effective for anticoagulation with mechanical heart valves Clinical question: Is dabigatran a safe and effective anticoagulant for patients with mechanical heart valves? Bottom line: Warfarin is a safer and more effective alternative than dabigatran for anticoagulation of patients with a mechanical heart valve. (LOE = 1b) Study design: Randomized controlled trial (single-blinded) Funding source: Industry Allocation: Concealed Setting: Outpatient (specialty) Synopsis: The authors identified adults undergoing implantation of a mechanical valve for the aortic or mitral valve (or both), as well as patients who had received a mechanical valve at least 3 months previously. Patients were randomized with concealed allocation to receive either dabigatran or warfarin. Dabigatran was initially dosed in a range from 150 mg twice daily to 300 mg twice daily (depending on renal function), and the dose was adjusted to maintain a level of at least 50 ng/mL. Warfarin was dosed to maintain an international normalized ratio (INR) between 2.5 and 3.5 for those with a mechanical aortic valve and additional risk factors for thromboembolism and for those with a mitral valve; patients with an aortic valve and no risk factors were maintained at an INR range of 2.0 to 3.0. A total of 252 patients, with a mean age of 56 years, were randomized; 68% had a mechanical aortic valve, 28% a mitral valve, and 4% both. This was an open-label trial, but with masked outcome assessment and appropriate concealment of allocation. Patients were followed up for 12 weeks, and at that time could choose whether or not to continue to take the assigned study drug as part of an extension trial. A total of 168 patients participated in the extension trial (99 in the dabigatran group, 59 in the warfarin group), with a median duration of treatment between 136 days and 152 days, depending on the study drug and population. The study was terminated prematurely because of an excess of strokes (5% in the dabigatran group vs 0% in the warfarin group), major bleeding (4% vs 2%) and any bleeding (27% vs 12%). Although only the difference in any bleeds was statistically significant, the weight of the evidence led the researchers to discontinue the trial. The major bleeds were all pericardial. Reference: Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206-1214.

#16: Dabigatran associated with increased risk of coronary events

Clinical question: Does the use of dabigatran increase the risk of acute coronary events? Bottom line: The increased risk of myocardial infarction (MI) or acute coronary syndrome (ACS) associated with dabigatran is small, but statistically significant. You would have to treat 250 patients with dabigatran to cause one additional acute coronary event. Study design: Meta-analysis (randomized controlled trials) Funding source: Unknown/not stated Setting: Various (meta-analysis)Synopsis” The original RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, comparing dabigatran with warfarin for stroke prophylaxis in atrial fibrillation, revealed a slightly higher risk of MI with dabigatran (Connolly et al; Daily POEM, 11/9/09). To investigate the association of dabigatran and acute coronary events, these authors searched PubMed, Scopus, and the Web of Science and selected 7 randomized controlled trials (N = 30,514) that evaluated the efficacy of dabigatran for different indications, including stroke prophylaxis for atrial fibrillation, treatment of acute venous thrombembolism, and deep venous thrombosis prophylaxis in joint replacement patients. All of the included trials also reported on secondary outcomes of MI or ACS. One author independently extracted data, which was then reviewed by the second author. Study quality was assessed using the Jadad scale. Of note, the 7 included studies were all industry funded. Pooled together, the data showed that dabigatran is associated with a higher risk of MI or ACS than warfarin, enoxaparin, and placebo (1.19% vs 0.79%; odds ratio = 1.33; 95% CI, 1.03-1.71; P = .03). The RE-LY study, which comprised 59% of the cohort for this meta-analysis, had the largest effect on the result. This risk remained high when using the revised data from RE-LY that added previously unreported events, including 4 clinical MIs and 28 silent MIs. Data from the 6 trials that reported on mortality showed that dabigatran was associated with a lower risk of death than the control group (4.83% vs 5.02%; P = .04). However, this was not the primary outcome studied in this meta-analysis. Furthermore, given the different disease processes represented, there was significant heterogeneity across studies in the measure of absolute risk reduction for mortality. Reference: Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events. Arch Intern Med 2012;172:397-402.

#17 Apixaban increases bleeding with no benefit in high-risk patients with ACS

Clinical question: Does the use of apixaban along with standard antiplatelet therapy decrease recurrent ischemic events following acute coronary syndrome? Bottom line: Apixaban added to standard antiplatelet therapy in high-risk patients with recent acute coronary syndrome (ACS) increases bleeding without significantly reducing recurrent ischemic events, such as stroke, myocardial infarction, or death. Study design: Randomized controlled trial (double-blinded). Funding source: Industry. Allocation: Concealed. Setting: Inpatient (any location) with outpatient follow-up. Synopsis: Apixaban, an oral direct factor Xa inhibitor, can be used to prevent venous thromboembolism in patients undergoing orthopedic surgery and thromboembolic events in patients with atrial fibrillation. This study examined the effect of apixaban in preventing ishcemic events in high-risk patients with ACS. Using concealed

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allocation, investigators randomized 7392 patients with ACS within the previous 7 days to receive apixaban 5 mg twice daily or placebo. Patients were also receiving standard treatment with aspirin alone or aspirin and clopidogrel. In addition, eligible patients had 2 or more high-risk factors, such as older age, diabetes, peripheral vascular disease, heart failure, history of stroke, renal dysfunction, or lack of revascularization after the index event. At baseline, patients in both groups were well matched with similar comorbidities. The authors performed both intention-to-treat and on-treatment analyses. Because of an excess of clinically significant bleeding events, the trial was stopped early. For the composite outcome of cardiovascular death, myocardial infarction, or ischemic stroke, there was no difference detected between the apixaban and the placebo groups. This was true in patients receiving aspirin alone and in patients receiving both aspirin and clopidogrel. Bleeding, however, was more prominent in the apixaban group; major bleeding, including fatal and intracranial bleeding, was found in 1.3% of patients taking apixaban compared with 0.5% of patients taking placebo (hazard ratio = 2.59; 95% CI, 1.50-4.46; P = .001).Reference: Alexander JH, Lopes RD, James S, et al, for the the APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; Jul 24.

#18: ICH risk with newer anticoagulants 0.6% vs 1.2% with warfarin/ASA

Clinical question: Are the newer anticoagulants less likely to cause intracranial hemorrhage than warfarin or aspirin? Bottom line: This meta-analysis of randomized trials comparing newer anticoagulants against warfarin or aspirin for patients with atrial fibrillation (AF) showed that patients in the treatment groups had fewer intracranial hemorrhages (ICHs) than those in the control groups. It remains to be seen if this result will hold up with longer duration of use in patients less selected than those enrolled in clinical trials. (LOE = 1a) Study design: Meta-analysis (randomized controlled trials) Funding source: Unknown/not stated Setting: Various (meta-analysis) Synopsis: The newer anticoagulants dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) are marketed heavily as not needing frequent laboratory monitoring, and the manufacturers claim greater effectiveness than warfarin. Although anticoagulants can prevent ischemic stroke in patients with AF, they also cause ICH, a catastrophic event. These authors searched multiple databases, conference abstracts, references of included papers, and a clinical trials registry to identify randomized trials of newer anticoagulants against any comparison intervention in preventing stroke in patients with nonvalvular AF. Two authors independently determined study inclusion and assessed study quality. For these elements, they don't say how disagreements were handled. Additionally, 2 authors independently extracted the data and resolved any discrepancies through consensus. In addition to the usual statistical methods used in meta-analyses, these authors did a whole bunch of additional nerdy stuff (Bayesian analyses, Monte Carlo simulation, Gibbs sampling) to obfuscate their real intent. Ultimately, they included 6 studies with more than 57,000 patients. Five studies compared the new agent against warfarin (target INR = 2.0 - 3.0) and one compared them against aspirin (81 - 325 mg/day). Five studies went beyond 1 year and one was only 12 weeks’ duration. Needless to say, all the included studies were industry sponsored. The authors, however, reported no conflicts of interest. If you ignore all the nerdy stuff and just look at the raw data, the rate of ICH in each of the included studies was lower in the patients receiving the newer agents, although the confidence intervals were enormous in most studies and not statistically significant in 3 studies. When you pool the data, the rate of ICH in patients treated with newer agents was 0.6% compared with 1.2% in the comparison groups (number needed to treat to prevent 1 ICH = 154; 95% CI, 123 - 203). So, this is a good example of how reducing by half the rate of a bad event can sound good until you realize the event rate is rare. Keep in mind that industry-sponsored studies, while having decent internal validity, are designed to weed out those patients who are unlikely to respond and who are among the healthiest. When we try to use these products in the real world, where we stretch the eligibility and give them to our frailest patients, we often find that our patients don't have the same experiences as did those in the studies. Perhaps the only important outcome from all the other analyses was that, indirectly, no newer agent appeared any safer than the rest. Reference: Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013;70:1486-1490.

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Bottom Lines

1. The three newer oral anticoagulants (dabigatran and apixaban and rivaroxaban) have all been approved for the treatment of non-valvular atrial fibrillation. Whether these drugs should be used in place of warfarin for this indication is still undetermined. The NNTs for differences in clinical outcomes between these drugs and warfarin are between 100 and 200.

2. Rivaroxaban has also been FDA approved for the treatment of VTE and prophylaxis of VTE in patients undergoing THR and TKR.

3. Note which drugs have which indications, as extrapolating from one indication to another indication may be unsafe.

4. Newer drugs and studies on broader indications are in the “pipeline” so stay tuned!

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Appendix: Data tables from the 3 major studies on the newer oral anticoagulants vs

warfarin

Table 1

Data from the RE-LY Study on dabigatran vs warfarin for atrial fibrillation. N Engl J Med 2009;361(12):1139-1151.

Warfarin Dabigatran 150 bid ∆* NNT

All CVA or systemic emboli per year (%)

1.69 1.11 0.58% (p=.001) 172

Major bleeding per year (%)

3.36 3.11 0.25% (p=.31) 400

Intracerebral hemorrhages per year (%)

0.38 0.10 0.28% (p=.001) 357

Dyspepsia (% of patients) 5.8 11.3 5.5% (p=.001) 18

MI (% of patients) 0.53 0.74 0.21% (p=.048) 476

Mortality (%) – all cause 4.13 3.64 0.49% (p=.051) 204

Mean follow up duration was 2 years No difference in mortality between groups Shaded = favoring dabigitran Not shaded = favoring warfarin Dabigatran 150 bid was superior to warfarin in primary outcome Note there is no specific antidote to dabigatran, its half-life is 12 – 17 hours (major hemorrhage treatment is supportive, and transfusions and surgery if needed The FDA approved dabigatran in October of 2010 at a dose of 150 mg bid if the GFR is > 30, and 75 bid if the GFR is < 30 but > 15; there are no dosing recommendations for patients with a GFR < 15 or on dialysis The 110 mg dose was not approved

Table 2

Data from the Rocket AF. Rivaroxaban vs Warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365):883-891

Warfarin Rivaroxaban ∆* NNT


2.2 1.7 0.5% (p=.001) 200


3.4 3.6 0.2% (p=.58) 500


0.7 0.5 0.2% (p=.02) 500

MI (% of patients) 1.1 0.9 0.2% (p=.12) 500


Mean follow up duration was ~ 2 years No difference in mortality between groups Shaded = favoring rivaroxaban Not shaded = favoring warfarin Rivaroxaban was “non inferior” to warfarin in primary outcome Note there is no specific antidote to rivaroxaban (major hemorrhage treatment is supportive, and transfusions and surgery if needed

Table 3

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Data from Aristotle. Apixiban vs Warfarin in patients with atrial fibrillation. N Engl J Med 2011;365):981-92

Warfarin Apixaban ∆*


1.27 1.6 0.33% (p=.01) 303


3.09 2.13 0.96% (p=.001) 104


0.80 0.33 0.47% (p=.001) 212

MI (% of patients) .61 0.53 0.09% (p=.37) 1111


Mean follow up duration was 1.8 years Shaded = favoring Apixaban Not shaded = favoring warfarin Apixaban was “non inferior” and “superior” to warfarin in primary outcome Note there is no specific antidote to apixiban (major hemorrhage treatment is supportive, and transfusions and surgery if needed

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Table 4

Comparisons between warfarin and 4 NOAs for atrial fibrillation

Table 5

Comparisons between warfarin and 4 NOAs for VTE

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Table 6

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Men’s Health: Low T, Andropause, ED, BPH Steve Brown, MD and John Hickner, MD, MSc Objectives

1. Review BPH diagnostic criteria and effective treatments. 2. Discuss the effectiveness of PDE-5 inhibitors for erectile dysfunction and the limited role of

testosterone in treatment. 3. Review the limited role of testosterone therapy despite the strong marketing emphasis on

“Low-T.”

Diagnosing benign prostatic hyperplasia

Source: auanet.org “Guidelines,” “Management of BPH 2003.” The AUA recommends treatment at score of >7, but patient preferences should be considered. One study showed “patients were only discouraged from performing normal daily activity when the symptom score exceeded 20.” (J Urol 2001;166(2)563).

What medications are effective for BPH?

Medications for BPH Alpha-1 blockers 5-alpha reductase inhibitors

Alfuzosin (Uroxatral) Dutasteride (Avodart) Doxazosin* (Cardura) Finasteride* (Proscar) Prazosin* (Minipress) Silodosin# (Rapaflo)

Tamsulosin*# (Flomax) Terazosin* (Hytrin)

*generic available #selective alpha 1a blockers

#1: Cochrane: Terazosin for benign prostatic hyperplasia Background: Lower urinary tract symptoms associated with benign prostatic obstruction (BPO) occur in up to 70% of men over the age of 60 years. To relieve these bothersome symptoms, treatment options include alpha-antagonists, also know as alpha-blockers.

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Objectives: We conducted a systematic review to evaluate the effectiveness and adverse effects of the alpha-blocker, terazosin, for treatment of urinary symptoms associated with BPO. Main results: Seventeen studies involving 5151 subjects met inclusion criteria (placebo-controlled (n = 10); alpha-blockers (n = 7); finasteride alone or in combination with terazosin as well as placebo (1); microwave therapy (TUMT) (1). Study duration ranged from 4 to 52 weeks. Mean age was 65 years and 82% of men were white. Baseline urologic symptom scale scores and flow rates demonstrated that men had moderate BPO. Efficacy outcomes were rarely reported in a fashion that allowed for data pooling but indicated that terazosin improved symptom scores and flow rates more than placebo or finasteride and similarly to other alpha antagonists. The pooled mean percentage improvements for the Boyarsky symptom score was 37% for terazosin versus 15% for placebo (n = 4 studies). The mean percentage improvement for the American Urological Association symptom score (AUA) was 38% compared to 17% and 20% for placebo and finasteride, respectively (n = 2 studies). The pooled mean improvement in the International Prostate Symptom Score (IPSS) (40%) was similar to tamsulosin (43%). Peak urine flow rates improved greater with terazosin (22%), than placebo (11%) and finasteride (15%) but did not differ significantly from the other alpha-blockers. The percentage of men discontinuing terazosin was comparable to men receiving placebo and finasteride but was greater then with other alpha-antagonists. Adverse effects were greater than placebo and included dizziness, asthenia, headache, and postural hypotension. Authors' conclusions: The available evidence suggests that terazosin improves urinary symptoms and flow measures associated with BPO. Effectiveness is superior to placebo or finasteride, similar to other alpha-blockers but less than TUMT. Adverse effects were generally mild but more frequent than other alpha-blockers and associated with between a two-to-four fold increase in treatment discontinuation. Wilt, Timothy; Howe, R William; Rutks, Indy; MacDonald, Roderick; Wilt, Timothy. Terazosin for benign prostatic hyperplasia (Cochrane Review). In: The Cochrane Library 2008 Issue 4. Chichester, UK: John Wiley and Sons, Ltd. #2: Cochrane: Tamsulosin for benign prostatic hyperplasia Background: Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate which can result in bothersome lower urinary tract symptoms. The treatment goal for men with BPH is to relieve these bothersome symptoms. Objectives: This systematic review assessed the effects of tamsulosin in the treatment of lower urinary tract symptoms (LUTS) compatible with BPH. Main results: Fourteen studies involving 4122 subjects met inclusion criteria. Study duration ranged from 4 to 26 weeks, and no placebo-controlled study lasted longer than 13 weeks. The mean age of subjects was 64 years. Baseline symptom scores and urine flow rates demonstrated that men had moderate LUTS. Tamsulosin improved symptoms and peak urine flow relative to placebo. The weighted mean differences (WMD) for mean change from baseline for the Boyarsky symptom score for 0.4 mg and 0.8 mg doses of tamsulosin relative to placebo were -1.1 points (95% CI = -1.49 to -0.72; 12% improvement) and -1.6 points (95% CI = -2.3 to -1.0; 16% improvement), respectively. The WMD for mean change from baseline in peak urine flow were 1.1 mL/sec (95% CI = 0.59 to 1.51) and 1.1 mL/sec (95% CI= 0.65 to 1.48) for 0.4 mg and 0.8 mg, respectively. Tamsulosin (0.2 mg to 0.4 mg) was as effective as other alpha antagonists and the phytotherapeutic agent Permixon® in improving symptoms and flow rates though the doses of all alpha-antagonists studied may not have been optimal. Discontinuations from treatment for any reason and discontinuations "due to adverse events" were similar in the low dose tamsulosin (0.2 mg) and placebo groups but increased to 16% in trials utilizing a 0.8 mg dose of tamsulosin. Low dose tamsulosin was generally well tolerated although not all the trials reported specific adverse events. The most frequently reported adverse events that were significantly greater than placebo included dizziness, rhinitis and abnormal ejaculation. Adverse effects increased markedly as tamsulosin dosing increased, and were reported in 75% of men receiving the 0.8 mg dose. Men receiving a 0.2 mg dose tamsulosin were less likely to discontinue treatment compared to men receiving terazosin. Authors' conclusions: Tamsulosin provided a small to moderate improvement in urinary symptoms and flow compared to men receiving placebo in men with BPH. Effectiveness was similar to other alpha antagonists and increased only slightly with higher doses. Long term effectiveness and ability to reduce complications due to BPH progression could not be determined. Adverse effects were generally mild but their frequency, including withdrawals, increased substantially with the higher doses that are generally available for treatment. Wilt, Timothy; MacDonald, Roderick; Rutks, Indy; Wilt, Timothy. Tamsulosin for benign prostatic hyperplasia (Cochrane Review). In: The Cochrane Library 2008 Issue 4. Chichester, UK: John Wiley and Sons, Ltd. #3: Cochrane: Finasteride modestly effective for benign prostatic hyperplasia Background: Benign prostatic hyperplasia (BPH), a non-malignant enlargement of the prostate in aging men, can cause bothersome urinary symptoms (intermittency, weak stream, straining, urgency, frequency, incomplete emptying). Finasteride, a five-alpha reductase inhibitor (5ARI), blocks the conversion of testosterone to dihydrotestosterone, reduces prostate size, and is commonly used to treat symptoms associated with BPH. Objectives: To compare the clinical effectiveness and harms of finasteride versus placebo and active controls in the treatment of lower urinary tract symptoms (LUTS). Main results: Finasteride consistently improved urinary symptom scores more than placebo in trials of > 1 year duration, and significantly lowered the risk of BPH progression (acute urinary retention, risk of surgical intervention, = 4 point increase in the AUASI/IPSS). In comparison to alpha-blocker monotherapy, finasteride was less effective than either doxazosin or terazosin, but equally effective compared to tamsulosin. Both doxazosin and terazosin were significantly more likely than finasteride to improve peak urine flow and nocturia, versus finasteride. Versus tamsulosin, peak urine flow and QoL improved equally well versus finasteride. However, finasteride was associated with a lower risk of surgical intervention compared to doxazosin, but not to terazosin, while finasteride and doxazosin were no different for risk of acute urinary retention. Two small trials reported no difference in urinary symptom scores between finasteride and tamsulosin. Finasteride + doxazosin and doxazosin monotherapy improved urinary symptoms equally well (= 4 point improvement). For finasteride, there was an increased risk of ejaculation disorder, impotence, and lowered libido, versus

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placebo. Versus doxazosin, finasteride had a lower risk of asthenia, dizziness, and postural hypotension, and versus terazosin, finasteride had a significant, lower risk of asthenia, dizziness, and postural hypotension. Authors' conclusions: Finasteride improves long-term urinary symptoms versus placebo, but is less effective than doxazosin. Long-term combination therapy with alpha blockers (doxazosin, terazosin) improves symptoms significantly better than finasteride monotherapy. Finasteride + doxazosin improves symptoms equally - and clinically - to doxazosin alone. In comparison to doxazosin, finasteride + doxazosin appears to improve urinary symptoms only in men with medium (25 to < 40 mL) or large prostates (= 40 mL), but not in men with small prostates (25 mL).Comparing short to long-term therapy, finasteride does not improve symptoms significantly better than placebo at the short term, but in the long term it does, although the magnitude of differences was very small (from < 1.0 point to 2.2 points). Doxazosin improves symptoms better than finasteride both short and long term, with the magnitude of differences ~2.0 points and 1.0 point, respectively. Finasteride + doxazosin improves scores versus finasteride alone at both short and long term, with mean differences ~2.0 points for both time points. Finasteride + doxazosin versus doxazosin improves scores equally for short and long term.Drug-related adverse effects for finasteride are rare; nevertheless, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder, versus placebo. Versus doxazosin, which has higher rates of dizziness, postural hypotension, and asthenia, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder. Finasteride significantly reduces asthenia, postural hypotension, and dizziness versus terazosin. Finasteride significantly lowers the risk of asthenia, dizziness, ejaculation disorder, and postural hypotension, versus finasteride + terazosin. Tacklind, James; Fink, Howard A; MacDonald, Roderick; Rutks, Indy; Wilt, Timothy J; Tacklind, James. Finasteride for benign prostatic hyperplasia (Cochrane Review). In: The Cochrane Library 2010 Issue 10. Chichester, UK: John Wiley and Sons, Ltd.

#4: Finasteride + doxazosin effective for selected BPH patients Clinical question: Is the combination of finasteride and doxazosin more effective than either drug alone? Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (any) Synopsis: Doxazosin is an alpha-blocker that reduces smooth muscle tone in the prostate and bladder neck; finasteride is a 5-alpha-reductase inhibitor that reduces prostate volume. Although it makes sense that there may be greater benefit to the combination of both than each alone, short-term studies have not demonstated this. In this study, men with BPH were randomized (allocation concealed) to either doxazosin (4 mg to 8 mg, as tolerated), finasteride (5 mg orally each day), both, or neither. A total of 3047 men were recruited at 17 centers, all with an American Urological Association (AUA) score of at least 8, where 0 = no symptoms and 35 = severe symptoms. Groups were balanced at the start of the study, and analysis was by intention to treat. Men with hypotension, a PSA higer than 10 ng/mL, or previous prostate surgery were excluded. The primary outcome was the worsening in the AUA score of at least 4 points, acute urinary retention, renal insufficiency, recurrent urinary tract infection, and urinary incontinence. At the end of the 4-year study, the primary outcome was significantly less likely in the combination therapy group (5%) than in the groups getting either drug alone (10% each) or no drug at all (17%). You would have to treat 20 patients with combined therapy instead of doxazosin or finasteride alone for 4 years to prevent 1 from having a progression of their BPH. Most adverse events were more common in the combination therapy group, although this difference was only significant for abnormal ejaculation, peripheral edema, and dyspnea. The benefit of combination therapy was greatest in patients with a prostate volume greater than 40 mL and a PSA higher than 4 ng/mL. Bottom line: Combination therapy with finasteride (Proscar) and doxazosin (Cardura) for at least 4 years reduces the risk of clinical progression of benign prostatic hyperplasia (BPH). However, long-term finasteride use is also associated with an increase in the risk of high-grade prostate cancer (N Eng J Med 2003; 349:215-24). (LOE = 1b) McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349:2387-98. #5: PubMed: Alpha-adrenergic blockers and vascular-related events Objectives: To evaluate the safety profile and efficacy of alpha1-adrenergic receptor blockers (A1Bs) currently prescribed for benign prostatic hyperplasia (BPH). Data sources: A systematic literature search of MEDLINE, the Cochrane Database and the Food and Drug Administration Web site through December 2006 identified double-blinded, prospective, placebo-controlled trials, evaluating agents commercially available by prescription for the symptomatic treatment of BPH. Results: Of 2389 potential citations, 25 were usable for evaluation of safety data, 26 for efficacy. A1B use was associated with a statistically significant increase in the odds of developing a vascular-related event [odds ratio (OR) 2.54; 95% confidence interval (CI): 2.00-3.24; p < 0.0001]. The odds of developing a vascular-related adverse event were: alfuzosin, OR 1.66, 95% CI: 1.17-2.36; terazosin, OR 3.71, 95% CI: 2.48-5.53; doxazosin, OR 3.32, 95% CI: 2.10-5.23 and tamsulosin, OR 1.42, 95% CI: 0.99-2.05. A1Bs increased Q(max) by 1.32 ml/min (95% CI: 1.07-1.57) compared with placebo. Difference from placebo in American Urological Association symptom index/International Prostate Symptom Score was -1.92 points (95% CI: -2.71 to -1.14). Conclusions: Alfuzosin, terazosin and doxazosin showed a statistically significant increased risk of developing vascular-related events compared with placebo. Tamsulosin showed a numerical increase that was not statistically significant. All agents significantly improved Q(max) and symptom signs compared with placebo. Nickel JC, Sander S, Moon TD. A meta-analysis of the vascular-related safety profile and efficacy of alpha-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract. 2008 Oct;62(10):1547-59. #6: High-dose saw palmetto no better than placebo for BPH symptoms Clinical question: Is high-dose saw palmetto effective in reducing lower urinary tract symptoms associated with benign prostatic hyperplasia?

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Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (any) Synopsis: These investigators identified 369 healthy men, 45 years or older, meeting criteria for clinically significant lower urinary tract symptoms using a standard BPH symptom scoring tool. Exclusion criteria included recent treatment with an alpha-blocker or 5-alpha-reductase inhibitor, and coagulopathy or use of anticoagulants. Patients randomly received (concealed allocation assignment) standardized saw palmetto fruit extract beginning at 320 mg per day with dose escalation to double and triple dose at 24 and 48 weeks, respectively, or identical placebo. Study participants unaware of treatment group assignment self-assessed outcomes. Complete follow-up occurred for 97% of patients at 72 weeks. Using modified intention-to-treat analysis including participants who took at least 1 dose of study medication and with at least 1 follow-up visit, the proportion of patients achieving a predetermined clinically relevant improvement was similar in the saw palmetto and placebo groups (42.6% vs 44.2%, respectively). An analysis of dose response also showed no difference between the saw palmetto and placebo groups. A per-protocol analysis, including only participants compliant with all doses and all visits, similarly found no differences between the saw palmetto and placebo groups. There were also no differences between the treatment groups in any of the secondary outcomes including nocturia; global assessment of quality of life, including sexual function; sleep quality; or prostatitis symptoms. Adverse events were minimal and similar in both groups. The study was 90% powered to detect a clinically relevant difference. Bottom line: Saw palmetto extract -- given in doses up to 3 times the standard recommended daily dose -- was no more effective than placebo in improving lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH). Reference: Barry MJ, Meleth S, Lee JY, et al, for the Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms. A randomized trial. JAMA 2011;306(12):1344-1351. #7: Oral desmopressin effective for nocturnal polyuria in men with BPH Clinical question: Is oral desmopressin an effective and safe treatment of nocturnal polyuria in men with benign prostatic hyperplasia? Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (specialty) Synopsis: The long-term efficacy and safety of oral desmopressin in the treatment of nocturnal polyuria in elderly men with BPH is unknown. These investigators identified 126 men, aged 65 years or older, meeting standard criteria for BPH and nocturia with an average of 2 or more voids nightly. Patients randomly received (uncertain allocation concealment) oral desmopressin (0.1 mg) at bedtime or placebo. Individuals masked to their treatment group assignment self-assessed outcomes using daily voiding diaries. Follow-up occurred for more than 99% of patients after 12 months. Although the authors don't specifically state their mode of analysis, it appears they used an intention-to-treat analysis. A clinically significant response (decrease in nightly voids by 2 or more compared with baseline) occurred significantly more often in patients receiving desmopressin than in those receiving placebo (61.4% vs 13.8%, respectively; number needed to treat= 2.6; 95% CI,1.9-4.7). Similarly, a quality of life index score using standard tools was significantly increased in patients receiving desmopressin than in those receiving placebo. Adverse events occurred similarly in both treatment groups. Interestingly, asymptomatic hyponatremia, a reported concern with desmopressin, occurred in 10 patients in the placebo group and in 9 in the desmopressin group. Bottom line: In this study, oral desmopressin was effective and well tolerated as a treatment of nocturnal polyuria in older men with benign prostatic hyperplasia (BPH). Asymptomatic hyponatremia occurred with equal frequency in both the desmopressin group and the control group. (LOE = 1b-) Reference: Wang CJ, Lin YN, Huang SW, Chang CH. Low dose oral desmopressin for nocturnal polyuria in patients with benign prostatic hyperplasia: A double-blind, placebo controlled, randomized study. J Urology 2011;185(1):219-223. #8: PubMed: Sildenafil improves ED and BPH symptoms PURPOSE: We evaluated sildenafil for erectile dysfunction and lower urinary tract symptoms in men with the 2 conditions. MATERIALS AND METHODS: This was a 12-week, double-blind, placebo controlled study of sildenafil in men 45 years or older who scored 25 or less on the erectile function domain of the International Index of Erectile Function and 12 or greater on the International Prostate Symptom Score. Men with confirmed or suspected prostate malignancy, or prostate specific antigen 10 ng/ml or more were excluded. End points were changes in International Index of Erectile Function domain scores, International Prostate Symptom Score (irritative, obstructive and quality of life), the Benign Prostatic Hyperplasia Impact Index, the Self-Esteem And Relationship questionnaire and Erectile Dysfunction Inventory of Treatment Satisfaction Index Score. RESULTS: The 189 men receiving sildenafil had significant improvements in erectile function domain score vs the 180 on placebo (9.17 vs 1.86, p<0.0001) and on all other International Index of Erectile Function domains. In men on sildenafil vs placebo significant improvements were observed in International Prostate Symptom Score (-6.32 vs -1.93, p<0.0001), Benign Prostatic Hyperplasia Impact Index (-2.0 vs -0.9, p<0.0001), mean International Prostate Symptom Score quality of life score (-0.97 vs -0.29, p<0.0001) and total Self-Esteem And Relationship questionnaire scores (24.6 vs 4.3, p<0.0001). There was no difference in urinary flow between the groups (p=0.08). Significantly more sildenafil vs placebo treated patients were satisfied with treatment (71.2 vs 41.7, p<0.0001). Sildenafil was well tolerated. CONCLUSIONS: Improved erectile dysfunction and lower urinary tract symptoms with sildenafil in men with the 2 conditions were associated with improved quality of life and treatment satisfaction. Daily dosing with sildenafil may improve lower urinary tract symptoms. However, the lack of effect on urinary flow rates may mean that a new basic pathophysiology paradigm is needed to explain the etiology of lower urinary tract symptoms. Citation: McVary KT, et al. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract smptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol. 2007 Mar;177(3):1071-7.

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What works for erectile dysfunction? #9: PubMed: PDE-5 inhibitors improve erectile dysfunction BACKGROUND: Erectile dysfunction (ED) is a common male sexual disorder. The relative benefits and harms of pharmacologic therapies for ED, as well as the value of hormonal testing in men with ED, are uncertain. PURPOSE: To evaluate the efficacy and harms of oral phosphodiesterase-5 (PDE-5) inhibitors and hormonal treatments for ED and assess the effect of measuring serum hormone levels on treatment outcomes for ED. DATA SOURCES: English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, AMED, and SCOPUS through April 2009. Trial reference lists also were scanned. STUDY SELECTION: Randomized, controlled trials (RCTs) of oral PDE-5 inhibitors and hormonal treatment for ED, and observational studies reporting measurement of serum hormone levels, prevalence of hormonal abnormalities, or both in men with ED. DATA EXTRACTION: Two independent reviewers abstracted data on study, participant, and treatment characteristics; efficacy and harms outcomes; and prevalence of hormonal abnormalities. DATA SYNTHESIS: Data, primarily from short-term trials (<or=12 weeks), indicate that PDE-5 inhibitors were more effective than placebo in improving sexual intercourse success (69.0% vs. 35.0%). The proportion of men with improved erections was significantly greater among those treated with PDE-5 inhibitors (range, 67.0% to 89.0%) than with placebo (range, 27.0% to 35.0%). The PDE-5 inhibitors were associated with increased risk for any adverse events compared with placebo (for example, relative risk with sildenafil, 1.72 [95% CI, 1.53 to 1.93]). In 4 head-to-head RCTs comparing sildenafil, vardenafil, and tadalafil, improvement of ED and adverse events did not differ among treatments. Results from 15 RCTs evaluating hormonal treatment of ED were inconsistent on whether treatment improved outcomes. Evidence was insufficient regarding whether men with ED had a higher prevalence of hypogonadism than men without ED. LIMITATIONS: Many RCTs were of low methodological and reporting quality, particularly those involving hormonal treatments or directly comparing different PDE-5 inhibitors. Most RCTs provided only short-term efficacy and harms data. CONCLUSION: Oral PDE-5 inhibitors improved erectile functioning and had similar efficacy and safety profiles. Results on the efficacy of hormonal treatments and the value of hormone testing in men with ED were inconclusive. Citation: Tsertsvadze A, et al. Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann Intern Med. 2009 Nov 3;151(9):650-61. #10: Sildenafil does not interact with alcohol Clinical question: Should men avoid drinking alcohol while taking sildenafil? Study design: Cross-over trial (randomized) Setting: Other Synopsis: It's not too big a stretch of the imagination to believe that men will often take sildenafil (Viagra) after they have had alcohol. Since both are vasodilators, the researchers of this preliminary study determined the degree of potentiation between the 2 drugs. The authors enrolled 8 healthy college students to participate in this crossover trial. On separate occasions, every subject received, in a randomized manner, either (1) sildenafil 100 mg, (2) red wine, (3) red wine and sildenafil, or (4) double placebo (a sugar pill and a nonalcoholic bottle of wine). When the combination was studied, each participant in the group drank 1 full bottle of wine over 1 hour, beginning 1 hour after sildenafil administration. Cardiac index, heart rate, and mean arterial pressure were determined every 15 minutes for 3 hours. The study design is fairly artificial and may not reflect typical use, since the men were young and were not exercised following administration. Sildenafil given alone reduced mean arterial pressure 7% and peripheral vascular resistance by a maximum of 24% with no effect on heart rate or cardiac index. Red wine increased heart rate by 27% and cardiac index by a maximum of 15%, with an initial small (6%) rise in blood pressure followed by a small (7%) fall. When given together, there was no difference in heart rate, mean arterial pressure, cardiac index, or peripheral vascular resistance as compared with alcohol given alone. This study did not evaluate the effect of the wine on sexual function, which, to quote Shakespeare, "provokes the desire, but takes away the performance." Bottom line: Drinking alcohol following a dose of sildenafil (Viagra) has no more affect on young men's cardiovascular parameters than alcohol alone. Although we need more research in more men -- especially older men who are exercising -- this preliminary information tells us we don't need to caution men not to drink alcohol if they plan to take sildenafil. (LOE = 2b) Reference: Leslie SJ, Atkins G, Oliver JJ, Webb DJ. No adverse hemodynamic interaction between sildenafil and red wine. Clin Pharmacol Ther 2004; 76:365-70. #11: Dietary supplements for ED may contain sildenafil or tadalafil Clinical question: Do dietary supplements marketed for the treatment of erectile dysfunction contain phosphodiesterase type 5 inhibitors (eg, sildenafil [Viagra] or tadalafil [Cialis])? Study design: Descriptive Synopsis: These investigators purchased 7 different brands of dietary supplements for the treatment of erectile dysfunction, including 6 via the Internet and 1 from a local health food specialty store. All products underwent high performance liquid chromatography analyses for the presence of phosphodiesterase type 5 inhibitors. Individuals blinded to product brand names performed the analyses. Two products (Super-X and Stamina-RX) contained significant amounts of sildenafil (Viagra, 30 mg) and tadalafil (Cialis, 20 mg), respectively.

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Bottom line: At least some natural products marketed for the treatment of erectile dysfunction are adulterated with phosphodiesterase type 5 inhibitors. Many of these products claim to be free of adverse effects but in truth may be potentially fatal to patients concomitantly using nitrates. (LOE = 4) Reference: Fleshner N, Harvey M, Adomat H, et al. Evidence for contamination of herbal erectile dysfunction products with phosphodiesterase type 5 inhibitors. J Urology 2005; 174:636-41. #12: ACP Guideline: Hormonal testing and pharmacologic treatment of erectile dysfunction DESCRIPTION: The American College of Physicians developed this guideline to present the available evidence on hormonal testing in and pharmacologic management of erectile dysfunction. Current pharmacologic therapies include phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil, vardenafil, tadalafil, mirodenafil, and udenafil, and hormonal treatment. METHODS: Published literature on this topic was identified by using MEDLINE (1966 to May 2007), EMBASE (1980 to week 22 of 2007), Cochrane Central Register of Controlled Trials (second quarter of 2007), PsycINFO (1985 to June 2007), AMED (1985 to June 2007), and SCOPUS (2006). The literature search was updated by searching for articles in MEDLINE and EMBASE published between May 2007 and April 2009. Searches were limited to English-language publications. This guideline grades the evidence and recommendations by using the American College of Physicians' clinical practice guidelines grading system. RECOMMENDATION 1: The American College of Physicians recommends that clinicians initiate therapy with a PDE-5 inhibitor in men who seek treatment for erectile dysfunction and who do not have a contraindication to PDE-5 inhibitor use (Grade: strong recommendation; high-quality evidence). RECOMMENDATION 2: The American College of Physicians recommends that clinicians base the choice of a specific PDE-5 inhibitor on the individual preferences of men with erectile dysfunction, including ease of use, cost of medication, and adverse effects profile (Grade: weak recommendation; low-quality evidence). RECOMMENDATION 3: The American College of Physicians does not recommend for or against routine use of hormonal blood tests or hormonal treatment in the management of patients with erectile dysfunction (Grade: insufficient evidence to determine net benefits and harms). Citation: Qaseem A, et al. Hormonal testing and pharmacologic treatment of erectile dysfunction: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2009 Nov 3;151(9):639-49. Low testosterone: The hype and the reality. Who might really be helped by testosterone supplementation? “A man on TV is selling me a miracle cure that will keep me young forever. It’s called Androgel…for treating something called Low T, a pharmaceutical company–recognized condition affecting millions of men with low testosterone, previously known as getting older.” - The Colbert Report,1 December 2012 USA Today: Popular 'low T' therapy divides the medical field Some doctors say men benefit from treatment, others say only the drugmakers profit. They seem to be everywhere — drug ads warning aging men about low testosterone, with "symptom quizzes" asking: Are you sad or grumpy? Is your work suffering? Has your strength or sex drive waned? It's a powerful marketing campaign that is driving men to doctors in droves for testosterone-replacement therapy. A study this month in the journal JAMA Internal Medicine said the percentages of men 40 and older being treated for "Low T" more than tripled from 2001 to 2011. A study this spring in Nature Review Endocrinology said prescription sales of testosterone nationally reached $1.6 billion in 2011, up from about $18 million in 1988. Laura Ungar, The (Louisville, Ky.) Courier-Journal June 12, 2013 #13: PubMed: Androgen prescriptions have increased markedly From 2001 through 2011,androgen use among men 40 years or older increased more than 3-fold, from 0.81% in 2001 to 2.91% in 2011. The increase was seen in all age groups. By 2011, 2.29% of men in their 40s and 3.75% of men in their 60s were taking some form of ART. Of the 4 formulations examined, topical gel demonstrated the highest rate of overall use and the highest rate of increase—more than 5-fold. Among all new androgen users (2001-2011), only 74.72% had had their testosterone level measured in the prior 12 months. Common diagnoses in the year prior to ART initiation were hypogonadism (50.58%), fatigue (34.49%), erectile dysfunction (31.88%), and psychosexual dysfunction(11.75%). Baillargeon J, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013 Aug 12;173(15):1465 #14: PubMed: Low “T” as in “Template:” How to sell a disease “The Low T campaign provides a template for understanding how disease awareness campaigns work. Like other campaigns (eg, Bipolar Disorder and Restless Legs Syndrome), the Low T campaign uses 3 basic strategies: lower the bar for diagnosis (turning ordinary life experiences into conditions that require medical diagnoses), raise the stakes so that people want to get tested, and spin the evidence about drug benefits and harms. Before anyone makes millions of men aware of Low T, they should be required to do a large-scale randomized trial to demonstrate that testosterone therapy for healthy aging men does more good than harm.” Scwartz LM, Woloshin S. Low “T” as in “Template: How to sell a disease. JAMA Intern Med 2013;173(15.)

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• In 2012 Androgel was the 17th most prescribed drug by unit, with sales at $1.7 billion. • Androderm costs $377 for a one month supply (30 patches) • Androgel costs $384 for a 75g 1.62% gel pump (generic expected after August 2015)

#15: Total testosterone measurement to predict male hypogonadism Clinical question: How accurate is the measurement of total testosterone for predicting hypogonadism in men? Study design: Cohort (retrospective) Setting: Outpatient (specialty) Synopsis: Male hypogonadism affects an estimated 5% to 10% of men older than 30 years. The measurement of free testosterone level, considered the reference standard for the biochemical diagnosis of hypogonadism (< 34 pg/mL), is costly and time consuming and so it's not often used in clinical practice. These investigators reviewed the medical records of all 3672 men, aged 20 years to 90 years, who were evaluated for possible hypogonadism at a Veterans Administration health system from 1997 through 2007. All patients were tested for total testosterone (TT), sex hormone-binding globulin (SHBG), albumin, and calculated free testosterone (cFT). Approximately one third of the men had diabetes mellitus and nearly half were obese (BMI > 30 kg/m2). One individual abstracted and recorded all data. The prevalence of low cFT was 15.2%. The sensitivity of TT (lower limit of normal = 280 ng/dL) to identify a low cFT was 91% and the specificity was 73.7%. The positive predictive value (the likelihood that a positive result, meaning abnormally low TT, is truly positive) was 38.3% (false positive rate = nearly 62%). The negative predictive value (the likelihood that a negative result, meaning a TT > 280 ng/dL, is truly negative) was 97.9% (false negative rate = 2.1%). The positive likelihood ratio for hypogonadism, defined as a low cFT, was greater than 10 (which is considered moderately to strongly clinically useful) only when the TT level was less than 200 ng/dL. The negative likelihood ratio of a TT level 280 ng/dL or greater was 0.12, which is considered moderately useful. A more useful clinical decision rule which will calculate posttest prevalence for individual levels of TT will be available later this summer in Essential Evidence Plus. Bottom line: A total testosterone level of 280 ng/dL or higher is fairly accurate in ruling out hypogonadism in men, with a false negative rate of only 2.1%. A low total testosterone level (< 280 ng/dL) is only moderately useful in predicting hypogonadism (false positive rate = nearly 62%). (LOE = 1b) Reference: Anawalt BD, Hotaling JM, Walsh TJ, Matsumoto AM. Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism. J Urol 2012;187(4):1369-1373. #16: Testosterone does not improve sildenafil effectiveness Clinical question: Does testosterone supplementation improve the response to sildenafil in men with erectile dysfunction and low testosterone levels? Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (any) Synopsis: These researchers identified, through advertisements and through referrals from specialty clinics, 140 men with ED and low serum testosterone levels, either a total testosterone level of less than 330 ng/dL (11.45 mmol/L) or a free testosterone level of less than 50 pg/mL (173.35 pmol/L). The men, aged 40 years to 70 years, were tested to find the optimum dose of sildenafil before being randomized, using concealed allocation, to receive either testosterone 1% gel or placebo gel, in addition to continuing sildenafil. Testosterone levels were tested 2 weeks after the start of treatment and the dose was titrated up or down to achieve normal levels. Sildenafil, used alone, improved erectile function in men in both groups. Both intention-to-treat and on-protocol analyses found that the addition of testosterone did not significantly improve erectile function as compared with the placebo. Testosterone did not affect the frequency of sexual encounters, percentage of sexual intercourse, sexual desire, quality-of-life scores, or marital intimacy scores. Bottom line: Boosting low testosterone levels into the normal range did not further improve the effectiveness of sildenafil (Viagra) in men with erectile dysfunction (ED). The researchers did not determine whether testosterone replacement alone is as effective as sildenafil for the treatment of ED. (LOE = 1b) Reference: Spitzer M, Basaria S, Travison TG, et al. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction. A parallel, randomized trial. Ann Intern Med 2012;157(10):681-691. #17: PubMed: Small improvements in erectile dysfunction and moderate improvement in libido with testosterone OBJECTIVE: : To conduct a systematic review and meta-analysis of randomized placebo-controlled trials to measure the effect of testosterone use on sexual function in men with sexual dysfunction and varying testosterone levels. METHODS: Librarian-designed search strategies were used to search the MEDLINE (1966 to October 2004), EMBASE (1988 to October 2004), and Cochrane CENTRAL (inception to October 2004) databases. The MEDLINE search was rerun in March 2005. We also reviewed reference lists from included studies and content expert files. We selected randomized placebo-controlled trials of testosterone vs placebo that enrolled men with sexual dysfunction and measured satisfaction with erectile function and libido and overall sexual satisfaction. RESULTS: We included 17 trials (N = 862 participants) in this review. Trials that enrolled participants with low testosterone levels showed (1) a moderate nonsignificant and inconsistent effect of testosterone use on satisfaction with erectile function (random-effects pooled effect size, 0.80; 95% confidence interval [CI], -0.10 to 1.60), (2) a large effect on libido (pooled effect size, 1.31; 95% CI, 0.40 to 2.25), and (3) no significant effect on overall sexual satisfaction. Trials that enrolled patients with low-normal and normal testosterone levels at baseline showed testosterone that caused (1) a small effect on satisfaction with erectile function (pooled effect size, 0.34; 95% CI, 0.03 to 0.65), (2) moderate nonsignificant effect on libido (pooled effect size, 0.41; 95% CI, -0.01 to 0.83), and (3) no significant effect on overall sexual satisfaction.

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CONCLUSION: Testosterone use in men is associated with small improvements in satisfaction with erectile function and moderate improvements in libido. Unexplained inconsistent results across trials, wide CIs, and possible reporting bias weaken these inferences. Citation: Boloña ER, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007 Jan;82(1):20-8. #18: Testosterone does not improve function or cognition in elderly men Clinical question: Is supplemental testosterone useful in improving functional mobility or cognition in elderly men with low normal testosterone levels? Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (any) Synopsis: Previous studies have not shown a benefit of testosterone supplementation for elderly men with low testosterone levels. These investigators identified 237 eligible healthy men with a serum testosterone level below the 50th percentile (less than 13.7 nmol/L). Participants randomly received (concealed allocation assignment) either testosterone undecenoate (80 mg twice daily) or matched placebo. Individuals masked to treatment group assignment assessed multiple outcomes using previously validated assessment tools. Complete follow-up occurred for 87% of study patients for 6 months. Analyses were performed using intention to treat. At the end of 6 months, no significant differences were detected between the 2 groups in cognitive function. Although lean body mass increased and fat mass decreased significantly more in the testosterone group than in the placebo group, there were no significant differences detected in functional ability or muscle strength. Quality of life measures were also not significantly different between the 2 groups. The study was 80% powered to detect a 15% to 20% difference in cognitive function between the 2 treatment groups. Bottom line: Supplemental testosterone for 6 months did not significantly improve functional mobility or cognition compared with placebo in elderly men with low normal (below 50th percentile) testosterone levels. (LOE = 1b) Reference: Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men. A randomized controlled trial. JAMA 2008:299(1):39-52. #19: Testosterone supplementation greatly increases cardiovascular events Clinical question: Is testosterone supplementation safe in frail older men? Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (any) Synopsis: Sometimes the title of a study just says it all. These researchers identified men 65 years and older with limited mobility (difficulty walking 2 blocks on the level or 10 steps climbing, plus a low to moderate score on a physical performance score) who also had a low testosterone level. Low as defined as a free testosterone level greater than 50 pg/mL (173 pmol/L) or a total testosterone level of between 100 ng/dL and 350 ng/dL (3.5 - 12.1 nmol/L). Exclusion criteria included uncontrolled hypertension, unstable cardiovascular disease, cancer, sleep apnea, steroid use, a glycohemoglobin level greater than 8.5%, or morbid obesity. At baseline, the mean age was 74 years, the mean blood pressure was 137/76, and 25% of patients had diabetes. Patients were randomly assigned to receive testosterone in a transdermal gel (100 mg; Testim 1%) applied once daily for 6 months or matching placebo gel. Two weeks after randomization, the dose was adjusted to half the dose if the testosterone level was too high or twice the dose if it was still too low. Groups were similar at baseline, and analysis was by intention to treat for safety and by modified intention to treat of those with at least one postrandomization evaluation for efficacy. Although the researchers intended to enroll 252 men in the study, by the time 209 were enrolled a safety monitoring board concluded that the risk was too great for men in the intervention group, and recruitment was terminated. Men in the testosterone group were much more likely to experience serious adverse events than those in the placebo group, including adverse cardiac events (10 vs 1), more atherosclerotic events (7 vs 1), and more cardiovascular events in general (23 vs 5). There was a dose-response relationship between testosterone levels and cardiovascular risk (hazard ratio = 2.4 for highest quartile vs other 3 quartiles; P = .05). The adjusted odds ratio for cardiovascular adverse events was 5.8 (95% CI, 2.0 - 16.8), although this combined outcome was admittedly quite diverse and included things like edema and ectopy on electrocardiogram. On the bright side, those men not felled by heart attack or stroke did have better results on the tests of leg strength, stair climbing, and gait speed. Bottom line: This study found serious risks to testosterone supplementation in frail older men. Although there may be men for whom the risk:benefit ratio is acceptable, we should not screen for and treat "low T" in older men until we have more data. We don't know whether the results will be similar in younger or less frail men. (LOE = 1b) Reference: Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363(2):109-122. #20: Testosterone therapy increases risk of non-fatal myocardial infarction Background: An association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly. Methods: We conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation. Results: In all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged 75 years (ptrend= 0.03), while no trend was seen for

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PDE5I (ptrend= 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11). Discussion: In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased. Reference: Finkle, Greenland, Ridgeway, et al. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLOS One 2014; E 9(1): e85805. doi:10.1371/journal.pone.0085805 #21: Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. OBJECTIVE: Our objective was to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. CONCLUSIONS: We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and, in some men in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected by measurement of free or bioavailable testosterone level, using validated assays. We recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African-Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score above 19, or uncontrolled or poorly controlled heart failure. When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored using a standardized plan. Citation: Bhasin S, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59. Bottom Lines

1. The AUA BPH symptom score should be used to diagnose and follow treatment for BPH. 2. Medications alone and in combination are modestly effective for BPH symptoms. 3. Medications used for BPH have significant side effects. 4. PDE-5 inhibitors are useful for erectile dysfunction in most clinical situations. Testosterone therapy has

minimal, if any, effect on ED. 5. Despite the effort to expand treatment indications for “Low T,” androgens may be harmful and have

minimal benefit in most patients.

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Hyperlipidemia: The New Approach

Gary Ferenchick, MD Objective

1. To review the new ACC/AHA guideline on the treatment of blood cholesterol In late 2013, the ACC/AHA issued "2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults". This was originally going to be the ATP IV guideline, but was transitioned to the ACC/AHA working group; these guidelines (like the JNC 8) are less comprehensive than their prececessor reports (ATP III and JNC 7), a result of primarily focusing on evidence from RCTs (or meta-analyses of RCTs, no observational studies) focusing on clinical outcomes (e.g. acute coronary syndromes, MI, angina, revascularization, strike TIA or PAD) not DOEs (e.g. Disease Oriented Evidence). #1: New Cholesterol Guidelines Clinical question: What are the new cholesterol guidelines from the 2013 American College of Cardiology/American Heart Association task force? Bottom line: Strengths of this protocol include a more evidence-based approach and a move away from specific cholesterol targets, a practice never supported by clinical trial evidence. Concerns include extensive industry connections among half of the guideline panel, a calculator that does not reliably predict risk, a low 10-year-risk cutoff (7.5%) for treatment with a statin, and a failure to clearly communicate the absolute risks and harms of treatment, especially for those at low risk. Although most would not argue with giving a statin to someone with known heart disease, diabetes, or very elevated low-density lipoprotein (LDL) cholesterol, rigorously following this guideline would give statins to many low-risk adults who would experience only a small potential net benefit (67 would have to take a statin for 10 years to prevent a single cardiovascular event, and hundreds would have to take a statin to prevent a single cardiovascular death). (LOE = 1a-) Study design: Practice guideline Funding source: Other Setting: Various (guideline) Synopsis: The National Cholesterol Education Program Adult Treatment Protocol 3 was last updated in 2003. Work began on "ATP 4" in 2008, and after 5 years of underfunded effort, the National Institutes of Health decided to punt the guideline to the American College of Cardiology and the American Heart Association. The chair of the panel had extensive industry ties, but severed those ties when he took over leadership of the panel. A co-chair and 6 other members (of a total 16) continued to accept industry money while serving on the panel, although they state that they recused themselves from votes in which a conflict of interest may have occurred. These persistent ties to industry are one source of controversy for these new guidelines. To their credit, this panel used a more evidence-based approach not unlike that of the United States Preventive Services Task Force (USPSTF) when crafting their guideline: they developed a series of key questions, commissioned systematic reviews of clinical trials to answer those questions, and rated the strength of evidence from A to I. Unlike the USPSTF, most of the panelists were subspecialists, there was no draft recommendation or opportunity for public comment, the full systematic review and evidence summary has not been published, and as noted above the panel had extensive conflicts of interest. The core of the recommendations is as follows. First, the task force divided statins into moderate intensity (enough medication to lower LDL cholesterol by between 30% and 50%) and high intensity (reducing LDL cholesterol by more than 50%). Gone are targets for cholesterol; the focus is now on identifying persons at increased risk and giving them an appropriate-intensity statin. Anyone 75 years or younger with known atherosclerotic cardiovascular disease (ASCVD; history of myocardial infarction, ischemic stroke, coronary artery disease, or peripheral artery disease) and anyone with an LDL cholesterol level of greater than 190 mg/dL should receive a high-intensity statin. Anyone who is older than 75 years and has known ASCVD, and any patients with diabetes, should receive a moderate-intensity statin. A (controversial new) risk calculator is provided to determine the 10-year risk of having an ASCVD event. It is recommended for use for patients with diabetes and by everyone else who doesn't fall into one of the previous risk groups. If the patient with diabetes has a 10-year risk of at least 7.5%, they should instead be given a high-intensity statin. If any patient without diabetes has a 10-year risk of an ASCVD event greater than 7.5%, they should receive a moderate-intensity or high-intensity statin. The risk calculator is controversial because it appears to consistently overestimate the risk of ASCVD events, leading to considerable overprescribing. Another problem is the selection of a relatively low 7.5% risk cutoff, compared with the 20% cutoff used by some other national guidelines including those from the United Kingdom (http://www.nice.org.uk/nicemedia/live/11982/40675/40675.pdf). Since statins are associated with an approximately 20% reduction in the likelihood of a cardiovascular event (Lancet. 2008 Jan 12;371(9607):117-25. doi: 10.1016/S0140-6736(08)60104-X), a patient with a 20% baseline risk has that reduced to 16% with a statin. This 4% absolute risk reduction corresponds to a number needed to treat of 25 persons taking a statin for 10 years to prevent one event. On the other hand, with a 7.5% baseline risk, taking a statin reduces it to 5%, for a 1.5% absolute risk reduction. This corresponds to a NNT of 67 persons taking a statin for 10 years to prevent one event. The risk calculator would also place all men over age 70 years of age on a statin, and any African-American man over age 65 years, despite normal cholesterol and normal blood pressure. Reference: Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2013 Nov 12. [Epub ahead of print]

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The primary CHANGE in this guideline is a SWITCH of treatment strategies which in the past 10 years has focused on LDL TARGETS (e.g. treat to < 130 mg/dL, < 100 mg/dL, < 70 mg/dL etc), to a strategy focusing on the INTENSITY OF STATIN THERAPY (high-intensity = lowering LDL by > 50%; vs moderate intensity = lowering LDL by 30 – 50%) as the primary therapeutic targets. (Table 1) According to the guideline, evidence was reviewed to determine who should get which therapy at what intensity. Four major statin benefit groups exist for whom the ASCVD risk reduction with a statin, “clearly outweighs the risk of adverse events”.

1. Individuals with clinical ASCVD 2. Individuals with primary elevations of LDL–C =190 mg/dL 3. Individuals 40 to 75 years of age with diabetes with LDL-C 70-189 mg/dL 4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL-C 70 - 189

mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. More below (Appendix) Several potential nuanced points (many ver batim) related to this report have the potential to change our practice include:

A. Lifestyle remains the “foundation” for ASCVD risk reduction (diet, exercise, tobacco, weight) B. Initiation of statin therapy based on estimated 10-year ASCVD risk is recommended regardless of sex,

race or ethnicity C. Age: No primary prevention RCT data were available for individuals 21 to 39 years of age and few data

were available for individuals >75 years of age D. Saftey recommendations:

I. Recommend against routine measurement of CK in individuals recieveing statin therapy a. Obtain a baseline CK in high risk patients (e.g. personal or family hx of statin intolerance or

muscle disease, or drug therapy that might increase likelihood of myopathy) and in those with muscle symptoms (muscle weakness, fatigue, aching, pain, tenderness, cramping or stiffness)

b. Myopathy occurs in ~0.01 excess case per 100. II. Obtain an ALT level before initiating statin therapy.

a. There is no recommendation to monitor transaminase (ALT) level. i. ALT monitoring was performed in the RCTs and there was no significant difference

between placebo groups and statin treatment groups in the rates of ALT elevations. ii. The FDA has indicated that if the baseline hepatic transaminases are normal, further

hepatic monitoring is not needed. III. Statins modestly increase the risk of type-2 diabetes in individuals with risk factors for diabetes.

a. Risk is low: ~ 0.1 (moderate-intensity statins) to 0.3 (high-intensity statins) excess case of diabetes per 100 statin-treated individuals per year.

i. The long-term adverse effects of statin associated cases of diabetes over a 10-year period are unclear and are unlikely to be equivalent to an MI,stroke, or ASCVD death.

IV. Hemorrhagic stroke (~0.01 excess case per 100) makes a minimal contributions to excess risk from statin therapy (statin use in combo with other lipid lowering drugs might require more intensive monitoriing

E. Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD.

i. AIM-HIGH demonstrated the futility of adding niacin in individuals with low HDL–C and high triglycerides, and ACCORD demonstrated the futility of adding fenofibrate in persons with diabetes.

F. A high level of RCT evidence supports the use of an initial fasting lipid panel (total cholesterol,triglycerides, HDL–C, and calculated LDL–C), followed by a second lipid panel 4 to 12

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weeks after initiation of statin therapy, to determine a patient’s adherence. Thereafter, assessments should be performed every 3 to 12 months as clinically indicated.

G. BIOMARKERS: Treatment decision in patients not included in the 4 stain gorups may be informed by

other factors, (e.g. statin therapy is otherwise unclear), including primary LDL–C ≥160 mg/dL or other evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first degree male relative or <65 years of age in a first degree female relative, high-sensitivity C-reactive protein >2 mg/L, CAC score ≥300 Agatston units or ≥75 percentile for age, sex, and ethnicity, ankle-brachial index <0.9, or elevated lifetime risk of ASCVD. Additional factors may be identified in the future

ASCVD events are reduced by using the maximum tolerate statin intensity in high risk groups. Using LDL targets may result in under-treatment with evidence-based statin therapy or overtreatment with non-statin therapy that have not been shown to decread ASCVD events. 1. Patients < 75 years old with clinical ASCVD. Use high intensity statin therapy; use moderate intensity if

high intensity is contra-indicated or not tolerated. (A Grade) a. Note: In patients > 75 it is reasonable to evaluate the potential of statins for risk reduction. (E

Grade) i. Clinical ASCVD = ACS, hx of MI, stable angina, Hx of revascularization, TIA or PAD (? Vasc

dz identified on imaging studies) a. Note: No recommendation is made for initiating or maintaining statin therapy in patients with NYHA

class II-IV ischemic systolic heart failure or in maintainence hemodialysis. Two RCTs for each condition failed to demonstrate ASCVD reduction woith statin therapy. (N Grade)

2. Individuals > 21 years of age with primary elevations of LDL–C ≥190 mg/dL, high-intensity statin therapy preferred, otherwise use maximum tolerated statin intensity. (B Grade)

a. Note: evaluate such patients for secondary causes of hyperlipidemia if LDL > 190 OR TG’s > 500. (B Grade)

3. Individuals 40 to 75 years of age with diabetes with LDL-C 70-189 mg/dL, use moderate intensity statin. (A Grade)

a. Note: High intensity statin is “reasonable” for adults 40 – 75 years old with a calculated 10-year risk of 7.5%. (E Grade)

b. Note: In adults with DM aged < 40 or > 75, it is reasonable to evaluate the potential of statins for risk reduction. (E Grade)

4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL-C 70- 189 mg/dL with an estimated 10-year ASCVD risk of 7.5% or higher initiate high-intensity or moderate intensity statin therapy (A Grade)

a. Use the Pooled Cohort Equaton to estimate 10-year ASCVD risk. (Grade E) b. Note: stain therapy reduces ASCVD events across the spectrum of baseline LDL levels > 70 mg/dL c. Note: For patients with a 5 – 7.5% 10-year risk, it is reasonable of offer moderate intensity statin

therapy (C Grade) i. ASCVD = nonfatal MI, CHD death, CVA – fatal and nonfatal.

d. Note: If a treatment decision is uncertain after risk based treatment decision is additional factors “may” be considered to inform treatment decisions. (E Grade)

i. Such factors may include: LDL > 160 mg/dL; family hx of ASCVD < 55 (male) or < 65 (female) first degree relative; hsCRP > 2 mg/L; CAC score > 300 or > 75th percentile age, sex and ethnicity; ABI < 0.9.

No recommendation for statins is made for heart failure and hemodialysis (NYHA class II- IV ischemic HF or patients on maintenance hemodialysis). (N Grade)

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USPSTF Recommendations (2008) Screening Men

• The U.S. Preventive Services Task Force (USPSTF) strongly recommends screening men aged 35 and older for lipid disorders. Grade: A recommendation.

• The USPSTF recommends screening men aged 20 to 35 for lipid disorders if they are at increased risk for coronary heart disease. Grade: B recommendation.

Screening Women at Increased Risk

• The USPSTF strongly recommends screening women aged 45 and older for lipid disorders if they are at increased risk for coronary heart disease. Grade: A recommendation.

• The USPSTF recommends screening women aged 20 to 45 for lipid disorders if they are at increased risk for coronary heart disease. Grade: B recommendation.

Screening Young Men and All Women Not at Increased Risk

• The USPSTF makes no recommendation for or against routine screening for lipid disorders in men aged 20 to 35, or in women aged 20 and older who are not at increased risk for coronary heart disease.Grade: C recommendation.

Increased risk, for the purposes of this recommendation, is defined by the presence of any one of the risk factors listed below. The greatest risk for CHD is conferred by a combination of multiple listed factors. While the USPSTF did not use a specific numerical risk to bound this recommendation, the framework used by the USPSTF in making these recommendations relies on a 10-year risk of cardiovascular events

• Diabetes. • Previous personal history of CHD or non-coronary atherosclerosis (e.g., abdominal aortic aneurysm,

peripheral artery disease, carotid artery stenosis). • A family history of cardiovascular disease before age 50 in male relatives or age 60 in female relatives. • Tobacco use. • Hypertension. • Obesity (BMI ≥30)

#2: Different CV risk calculators are inconsistent in classifying risk for the same patients

Clinical question: How often do different cardiovascular risk calculators agree with one another? Bottom line: The use of risk calculators is increasingly common, but many calculators still use data gathered in older, homogeneous populations that predate the modern era of statins, aspirin, and antihypertensives. This article serves as a warning that we need to carefully choose which calculator to use with which population, and we need to make sure that the calculators are regularly updated and appropriately calibrated. Study design: Cross-sectional. Funding source: Government. Setting: Population-based. Synopsis: Practice guidelines are increasingly based on cardiovascular risk factors, because overall risk is critical for determining how much a patient will benefit from a preventive medication such as aspirin or a statin. These authors identified 25 such calculators, and created 128 imaginary patients, each with a different combination of 7 cardiovascular risk factors (diabetes mellitus, age, sex, tobacco use, blood pressure, and HDL and total cholesterol levels). They determined whether each risk calculator placed each patient in a low-, moderate- or high-risk category. They then compared each calculator with each other calculator and determined the percentage of times that the calculators' results agreed with one another. For example, if the calculators both placed 20 patients in the low-risk group, 22 patients in the moderate-risk group, and 22 patients in the high-risk group, but disagreed about the other 64 patients, they would have 50% agreement. Agreement varied, with the average agreement generally in the 60% to 70% range (mean = 67%). The Progetto Cuore score (average agreement = 46%) and 2 scores based on the United States National Cholesterol Education Program guidelines (55.4% and 56.2% agreement) were noticeably worse. For 41% of the 128 imaginary patients, at least one calculator put them in the low-, moderate-, and high-risk groups. Only 28% of patients were assigned to the same risk group by all 25 calculators. Reference: Allan GM, Nouri F, Korownyk C, Kolber MR, Vandermeer B, McCormack J. Agreement among cardiovascular disease risk calculators. Circulation 2013;127(19):1948-1956.

#3: Statins for the primary prevention of cardiovascular disease

Background: Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of coronary heart disease (CHD) is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease. The case for primary prevention, however, is less clear.

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Objectives: To assess the effects, both harms and benefits, of statins in people with no history of CVD. Search strategy: To avoid duplication of effort, we checked reference lists of previous systematic reviews. We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007). There were no language restrictions. Selection criteria: Randomised controlled trials of statins with minimum duration of one year and follow-up of six months, in adults with no restrictions on their total low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD, were included. Data collection and analysis: Two authors independently selected studies for inclusion and extracted data. Outcomes included all cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), change in blood total cholesterol concentration, revascularisation, adverse events, quality of life and costs. Relative risk (RR) was calculated for dichotomous data, and for continuous data pooled weighted mean differences (with 95% confidence intervals) were calculated. Main results: Fourteen randomised control trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR 0.83, 95% CI 0.73 to 0.95) as was combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79). Benefits were also seen in the reduction of revascularisation rates (RR 0.66, 95% CI 0.53 to 0.83). Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life. Authors' conclusions: Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of cancers or muscle pain among people without evidence of cardiovascular disease treated with statins.Â Other potential adverse events were not reported and some trials included people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk. Citation: The Cochrane Library 2011 Issue 5. Chichester, UK: John Wiley and Sons, Ltd.

#4: What percentage of statin intolerant patients can resume statins?

BACKGROUND: Statin therapy is a proven effective treatment of hyperlipidemia. However, a significant number of patients cannot tolerate statins. This study was conducted to review treatment strategies for patients intolerant to statin therapy with a focus on intermittent statin dosing. METHODS AND RESULTS: We performed a retrospective analysis of medical records of 1,605 patients referred to the Cleveland Clinic Preventive Cardiology Section for statin intolerance between January 1995 and March 2010 with at least a 6-month follow-up. The changes in lipid profile, achievement of low-density lipoprotein cholesterol (LDL-C) goals, and statin tolerance rate were analyzed. Most (72.5%) of patients with prior statin intolerance were able to tolerate a statin for the median follow-up time of 31 months. Patients on intermittent statin dosing (n = 149) had significantly lower LDL-C reduction compared with daily dosing group (n = 1,014; 21.3% ± 4.0% vs 27.7% ± 1.4%, P < .04). However, compared with the statin discontinued group (n = 442), they had a significantly higher LDL-C reduction (21.3% ± 4.0% vs 8.3 ± 2.2%, P < .001), and a significantly higher portion achieved their Adult Treatment Panel III goal of LDL-C (61% vs 44%, P < .05). There was a trend toward a decrease in all-cause mortality at 8 years for patients on daily and intermittent statin dosing compared with those who discontinued statin (P = .08). CONCLUSIONS: Most patients with previous statin intolerance can tolerate subsequent trial of statin. A strategy of intermittent statin dosing can be an effective therapeutic option in some patients and may result in reduction in LDL-C and achievement of LDL-C goals. REFERENCE: Mampuya WM(1), Frid D, Rocco M, Huang J, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J. 2013 Sep;166(3):597-603. #5: Statins not associated with cognitive decline in dementia patients Clinical question: Among elders without dementia, are statins associated with cognitive decline? Study design: Cohort (prospective) Funding source: Government Setting: Outpatient (specialty) Synopsis: These researchers serially assessed approximately 3500 elderly patients for 3.4 years. The elders did not have dementia at baseline and approximately one third were using a statin. The investigators performed multiple tests of cognitive performance and appropriately adjusted their threshold for statistical significance to reduce the probability of finding random associations. At baseline, the statin users were more likely to have heart disease, diabetes, hypertension, and strokes. Statin users also had slightly worse scores on one of the dementia rating scales at baseline. The investigators tried to take into account these baseline differences as well as education level, recent depression treatment, and family history of dementia. The average age at baseline was 73 years. After 3.4 years of follow-up, the rate of cognitive decline among statin users was comparable with that of nonusers. Keep in mind that cohort studies are unable to account for 2 important phenomena: the healthy-user effect and reverse causality. The healthy-user effect, the primary explanation for older theories of the "benefits" of hormone replacement, refers to the observation that healthy people are more likely to use preventive measures and that the outcomes are due to good health, not the intervention. In reverse causality, we find that patients in declining health stop using treatments because they no longer perceive a potential benefit. It takes a randomized trial to overcome these phenomena. Bottom line: Even well-conducted cohort studies, such as this one, must be interpreted with caution. Three years of statin use is not associated with cognitive decline among elders without dementia. Furthermore, among those patients with no evidence of cognitive impairment, statin use was associated with a slower decline in cognitive measures. Randomized controlled trials on this subject have been limited to patients with Alzheimer’s disease and with high-risk cardiovascular profiles. (LOE = 2b)

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Reference: Steenland K, Zhao L, Goldstein FC, Levey AI. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc 2013;61(9):1449-55.

#6: Dietary advice for reducing cardiovascular risk works in modifying risk Background: Changes in population diet are likely to reduce cardiovascular disease and cancer, but the effect of dietary advice is uncertain. This review is an update of a previous review published in 2007. Objectives: To assess the effects of providing dietary advice to achieve sustained dietary changes or improved cardiovascular risk profile among healthy adults. Search methods: We searched the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects (DARE) and the HTA database on The Cochrane Library (Issue 4, 2010). We searched MEDLINE (Ovid) (1950 to week 2 October 2010) and EMBASE (Ovid) (1980 to Week 42 2010). Additional searches were done on CAB Health (1972 to December 1999), CVRCT registry (2000), CCT (2000) and SIGLE (1980 to 2000). Dissertation abstracts and reference lists of articles were checked and researchers were contacted. Selection criteria: Randomised studies with no more than 20% loss to follow-up, lasting at least three months and involving healthy adults comparing dietary advice with no advice or minimal advice. Trials involving children, trials to reduce weight or those involving supplementation were excluded. Data collection and analysis: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Main results: Forty-four trials with 52 intervention arms (comparisons) comparing dietary advice with no advice were included in the review; 18,175 participants or clusters were randomised. Twenty-nine of the 44 included trials were conducted in the USA. Dietary advice reduced total serum cholesterol by 0.15 mmol/L (95% CI 0.06 to 0.23) and LDL cholesterol by 0.16 mmol/L (95% CI 0.08 to 0.24) after 3 to 24 months. Mean HDL cholesterol levels and triglyceride levels were unchanged. Dietary advice reduced blood pressure by 2.61 mm Hg systolic (95% CI 1.31 to 3.91) and 1.45 mm Hg diastolic (95% CI 0.68 to 2.22) and 24-hour urinary sodium excretion by 40.9 mmol (95% CI 25.3 to 56.5) after 3 to 36 months but there was heterogeneity between trials for the latter outcome. Three trials reported plasma antioxidants, where small increases were seen in lutein and β-cryptoxanthin, but there was heterogeneity in the trial effects. Self-reported dietary intake may be subject to reporting bias, and there was significant heterogeneity in all the following analyses. Compared to no advice, dietary advice increased fruit and vegetable intake by 1.18 servings/day (95% CI 0.65 to 1.71). Dietary fibre intake increased with advice by 6.5 g/day (95% CI 2.2 to 10.82), while total dietary fat as a percentage of total energy intake fell by 4.48% (95% CI 2.47 to 6.48) with dietary advice, and saturated fat intake fell by 2.39% (95% CI 1.4 to 3.37). Two trials analysed incident cardiovascular disease (CVD) events (TOHP I/II). Follow-up was 77% complete at 10 to 15 years after the end of the intervention period and estimates of event rates lacked precision but suggested that sodium restriction advice probably led to a reduction in cardiovascular events (combined fatal plus non-fatal events) plus revascularisation (TOHP I hazards ratio (HR) 0.59, 95% CI 0.33 to 1.08; TOHP II HR 0.81, 95% CI 0.59 to 1.12). Authors' conclusions: Dietary advice appears to be effective in bringing about modest beneficial changes in diet and cardiovascular risk factors over approximately 12 months, but longer-term effects are not known.

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Appendix

Risk Calculator URL:

• http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

o This equation was developed by the Risk Assessment Work Group

Table 1: High- Moderate- and Low-Intensity Statin Therapy High-Intensity Statin

Therapy Moderate-Intensity Statin

Therapy Low-Intensity Statin Therapy

Lowers LDL~ ≥50%

Lowers LDL ~ 30% to <50%

Lowers LDL ~ <30%

Atorvastatin 40 - 80 Atorvastatin 10 - 20 Rosuvastatin 20 - 40 Rosuvastatin 5 - 10 Simvastatin 20 - 40 Simvastatin 10 Pravastatin 40 - 80 Pravastatin 10 - 20 Lovastatin 40 Lovastatin 20 Fluvastatin 40 bid Fluvastatin 20 - 40 Pitavastatin 2 - 4 Pitavastatin 1 % reduction used as an indicator of adherence to therapy, but is not itself a treatment goal

Table 2: Secondary Causes of Hyperlipidemia Cause Elevated LDL-C Elevated TGs

Diet Saturated or trans fats, weight gain, anorexia

Weight gain, VLCD, High intake of CHO, Excessive ETOH

Drugs Diuretics, glucocorticoids, amiodarone

Estrogens, Glucocorticoids, Bile acid sequestrants, Protease inhibitors, ralixifene, beta-blockers, thiazides

Diseases Biliary Obstr, Nephrotic syndrome

CRF

Disorders and altered states of metabolism

Hypothyroidism, obesity, pregnancy

DM (poorly controlled), hypothyroid, obesity, pregnancy

Reference: Circulation 2013 Nov 12. [Epub ahead of print]

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Figure 1: ACC/AHA Blood Cholesterol Guideline:

Major Recommendations for statin therapy for ASCVD prevention

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Recommendation Grades

Grade A recommendation = strong recommendation (high certainty that net benefit is substantial) Grade B recommendation = moderate recommendation (moderate certainty that net benefit is moderate to substantial, high certainty that the net benefit is moderate) Grade C recommendation = weak recommendation (moderate certainty that net benefit is small) Grade D recommendation = recommend against Grade E recommendation expert opinion (net benefits are unclear, due to no evidence, insufficient evident) but the working group recommends Grade N recommendation – No recommendation for or against; working group thought no recommendation should be made

Recommendations Grades - abbreviated Grade A recommendation = strong Grade B recommendation = moderate Grade C recommendation = weak Grade D recommendation = recommend against Grade E recommendation = expert opinion Grade N recommendation = No recommendation

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Sports Medicine

John Hickner, MD, MSc

Objectives

1. Review current evidence for the effectiveness or lack of effectiveness of a variety of injection therapies for tendonopathies

2. Review evidence for effective treatments for lateral epicondylitis

3. Review current evidence for the comparative effectiveness of platelet rich plasma injections for knee osteoarthritis

4. Discuss studies published in the past 2 years that provide important evidence about several sports medicine topics important for family medicine practitioners Are plasma rich platelet (PRP) injections and prolotherapy (dextrose injections) effective for tendonitis/tendonosis? Doctors have been injecting a variety of chemicals and solutions into tendons and joints for many years. Do any of these injections really work, and compared to what? Prolotherapy (dextrose injection) shows some promise but the evidence is not strong. The following studies illustrate the shaky evidence base for using platelet rich plasma injections for tendonopathies. Smaller uncontrolled trials show some promise, but larger, controlled trials do not provide strong evidence of effectiveness. PRP appears more effective than hyaluronic acid for symptoms of knee osteoarthritis, according to a meta-analysis. #1: Dextrose injection effective for Osgood-Schlatter disease Clinical question: Can injection with hyperosmolar dextrose decrease sports-related symptoms in young athletes with Osgood-Schlatter disease? Study design: Randomized controlled trial (double-blinded) Setting: Outpatient (any) Synopsis: These researchers enrolled 51 boys aged 10 years to 17 years and 4 girls aged 9 years to 15 years identified through a screening of teams of jumping or kicking sports in a city in Argentina. All the patients had a diagnosis of OSD, characterized as pain during sport activity, pain over the tibial tuberosity during a single leg squat, and the lack of patellofemoral crepitus and patellar tenderness. Before enrollment, all the athletes underwent 2 months of stretching and strengthening. If the pain during activity remained, the children were randomized (concealed allocation unknown) into 1 of 3 groups. One group received usual care (continued strengthening and stretching). Children in the other 2 groups received an injection with either lidocaine 1% or lidocaine 1% mixed with dextrose 12.5%. After identifying the tender point, 1/2 mL lidocaine or lidocaine/dextrose solution was administered via a 27-gauge needle to a depth of less than 1.25 cm. Three to 4 injections at 1-cm intervals were administered over and above the tibial tuberosity, with additional injections administered 5 minutes later, either medial or lateral, until all pain was relieved (hence the lidocaine in both groups). This procedure was repeated monthly for 2 more months, regardless of the degree of pain at these times. One month after the third injection, the majority of children in both injection groups had full return to their sports (100% and 91%) as compared with 60% of children treated with usual care (P < .05 for both comparisons). At 1 year, 32 of 38 (84%) dextrose-treated knees were pain-free as compared with 6 of 13 lidocaine-treated knees and 2 of 14 usual care knees (P < .05 for both comparisons). Bottom line: An injection of a solution of 12.5% dextrose and 1% lidocaine is an effective treatment of Osgood-Schlatter disease (OSD) symptoms in young athletes. The mechanism of action is not clear, but it likely involves local healing prompted by the increased availability of glucose rather than the scarring-down that occurs with prolotherapy using higher concentrations. Topol GA, Podesta LA, Reeves KD, Raya MF, Fullerton BD, Yeh HW. Hyperosmolar dextrose injection for recalcitrant Osgood-Schlatter disease. Pediatrics 2011;128(5):e1121-e1128. #2: Preliminary results: prolotherapy may be effective for chronic lateral epicondylosis OBJECTIVE: Chronic lateral epicondylosis is common, debilitating, and often refractory. Prolotherapy (PrT) is an injection therapy for tendinopathy. The efficacy of two PrT solutions for chronic lateral epicondylosis was evaluated. DESIGN: This study is a three-arm randomized controlled trial. Twenty-six adults (32 elbows) with chronic lateral epicondylosis for 3 mos or longer were randomized to ultrasound-guided PrT with dextrose solution, ultrasound-guided PrT with dextrose-morrhuate sodium solution, or watchful waiting ("wait and see").The primary outcome was the Patient-Rated Tennis Elbow Evaluation (100 points) at 4, 8, and 16 wks (all groups) and at 32 wks (PrT groups). The secondary outcomes included pain-free grip strength and magnetic resonance imaging severity score.

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RESULTS: The participants receiving PrT with dextrose and PrT with dextrose-morrhuate reported improved Patient-Rated Tennis Elbow Evaluation composite and subscale scores at 4, 8, and/or 16 wks compared with those in the wait-and-see group (P < 0.05). At 16 wks, compared with baseline, the PrT with dextrose and PrT with dextrose-morrhuate groups reported improved composite Patient-Rated Tennis Elbow Evaluation scores by a mean (SE) of 18.7 (9.6; 41.1%) and 17.5 (11.6; 53.5%) points, respectively. The grip strength of the participants receiving PrT with dextrose exceeded that of the PrT with extrose-morrhuate and the wait and see at 8 and 16 wks (P < 0.05). There were no differences in magnetic resonance imaging scores. Satisfaction was high; there were no adverse events. CONCLUSIONS: PrT resulted in safe, significant improvement of elbow pain and function compared with baseline status and follow-up data and the wait-and-see control group. This pilot study suggests the need for a definitive trial. Rabago D(1), Lee KS, Ryan M, Chourasia AO, Sesto ME, Zgierska A, Kijowski R, Grettie J, Wilson J, Miller D. Hypertonic dextrose and morrhuate sodium injections (prolotherapy) for lateral epicondylosis (tennis elbow): results of a single-blind, pilot-level, randomized controlled trial. Am J Phys Med Rehabil. 2013 Jul;92(7):587-96. doi: 10.1097/PHM.0b013e31827d695f. PMID: 23291605 #3: PRP better than prolotherapy for plantar fasciitis OBJECTIVE: To determine the efficacy of autologous platelet-rich plasma (PRP) compared with dextrose prolotherapy (DP) in patients with chronic recalcitrant plantar fasciitis (PF) DESIGN: A single-blinded, randomized, controlled study. SETTING: hospital. PARTICIPANTS: Twenty-one patients with a clinical diagnosis of chronic PF confirmed by diagnostic ultrasound (plantar fascia thickness >4 mm) were randomly assigned to the PRP group (n = 10) or the DP group (n = 11). INTERVENTIONS: Each patient received 2 injections into the plantar fascia through a peppering technique under ultrasound guidance at an interval of 2 weeks, either with 2 mL of autologous PRP or 2 mL of 15% dextrose/lidocaine solution. MAIN OUTCOME MEASUREMENTS: The outcome measures included the pain, disability, and activity limitation subscales, measured by means of the Foot Functional Index. Data were collected before the first injection, at 2 weeks (before the second injection), and at the 2- and 6-month follow-ups. RESULTS: All patients completed the follow-ups, with the exception of 1 patient in the PRP group. The mean Foot Functional Index total and subcategory score improvements were greater in the PRP group compared with the DP group (improvement with PRP vs DP, total: 30.4% vs 15.1%, pain: 29.7% vs 17.1%, disability: 26.6% vs 14.5%, activity limitation: 28.0% vs 12.4%). However, no statistically significant difference was noted at any follow-up. In the pain and disability subcategories, both groups showed significant improvements at the lastre-evaluation. The PRP group also showed significant improvements in the disability and activity limitation subscales at the second re-evaluation. CONCLUSIONS: Each treatment seems to be effective for chronic recalcitrant PF, expanding the treatment options for patients in whom conservative care has failed. PRP treatment also may lead to a better initial improvement in function compared with DP treatment. Kim E, Lee JH. Autologous platelet-rich plasma versus dextrose prolotherapy for the treatment ofchronic recalcitrant plantar fasciitis. PM R. 2014 Feb;6(2):152-8. doi: 10.1016/j.pmrj.2013.07.003. Epub 2013 Jul 19. PMID: 23876935 #4: Platelet rich plasma found effective for treatment resistant rotator cuff tendinopathy in a case series OBJECTIVE: Assess platelet rich plasma (PRP) injection for rotator cuff tendinopathy (RCT). DESIGN: Prospective open label study with 1-year follow-up. METHODS: Participants recruited from an outpatient sports medicine clinic had clinically and magnetic resonance image (MRI)-demonstrated RCT refractory to physical therapy and corticosteroid injection. They received one ultrasound-guided injection of 3.0 mL of 1% xylocaine followed by 3.5 mL of PRP at the lesion and surrounding tendon. Primary outcome: 0-10 visual analog scale (VAS; baseline, 8, 12, and 52 weeks). Secondary outcomes: functional shoulder tests assessing rotator cuff strength and endurance (at baseline and 8 and 12 weeks), MRI severity (1-5 points [at baseline and 4 and 8 weeks]), and patient satisfaction (52 weeks). RESULTS: Eighteen participants with 19 assessed shoulders reported VAS pain score improvement from 7.5 ± 0.3 points to 0.5 ± 0.3 points by week 12 and 0.4 ± 0.2 (P = .0001) points at week 52. Functional outcomes significantly improved; the largest effect was seen in the external rotation test: 33.5 ± 5.7 seconds to 62.6 ± 7.2 seconds at week 12 (P = .0001). MRI appearance improved by 1 to 3 points in 16 of 18 assessed shoulders. Seventeen participants were "completely satisfied" (12) or "satisfied" (5). One participant was "unsatisfied." CONCLUSIONS: A single ultrasound-guided, intralesional injection of PRP resulted in safe, significant, sustained improvement of pain, function, and MRI outcomes in participants with refractory RCT. Randomized multidisciplinary effectiveness trials that add ultrasound and validated clinical outcome measures are needed to further assess PRP for RCT. Scarpone M, Rabago D, Snell E, Demeo P, Ruppert K, Pritchard P, Arbogast G, Wilson JJ, Balzano JF. Effectiveness of Platelet-rich Plasma Injection for Rotator Cuff Tendinopathy: A Prospective Open-label Study. Glob Adv Health Med. 2013 Mar;2(2):26-31. doi: 10.7453/gahmj.2012.054. PMID: 24416661 #5: PRP is not effective for chronic lateral epicondylar tendinopathy BACKGROUND: Chronic lateral epicondylar tendinopathy is frequent in athletes, and platelet-rich plasma (PRP) is being used increasingly in its treatment. OBJECTIVE: To systematically review the literature on the efficacy of PRP injections for chronic lateral epicondylar tendinopathy. METHODS: The databases of PubMed, EMBASE, CINAHL, Medline OvidSP, Scopus, Google Scholar, Web of Science and Cochrane Library were searched in October 2013. Inclusion criteria were a clinical diagnosis of chronic lateral epicondylar tendinopathy, a

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randomised controlled trial, an intervention with a PRP injection and the outcome measures described in terms of pain and/or function. One author screened the search results and two authors independently assessed the study quality using the Physiotherapy Evidence Database (PEDro) score. A study was considered to be of high quality if its PEDro score was ≥6. A best evidence synthesis was used to identify the level of evidence. RESULTS: 6 studies were included, of which four were considered to be of high quality. Three high-quality studies (75%) and two low-quality studies showed no significant benefit at the final follow-up measurement or predefined primary outcome score when compared with a control group. One high-quality study (25%) showed a beneficial effect of a PRP injection when compared with a corticosteroid injection (corticosteroid injections are harmful in tendinopathy). Based on the best evidence synthesis, there is strong evidence that PRP injections are not efficacious in chronic lateral epicondylar tendinopathy. CONCLUSIONS: There is strong evidence that PRP injections are not efficacious in the management of chronic lateral elbow tendinopathy. de Vos RJ(1), Windt J, Weir A. Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review. Br J Sports Med. 2014 Feb 21. doi: 10.1136/bjsports-2013-093281. #6: Treatment of lateral epicondylitis: meta-analysis OBJECTIVES: To evaluate the current evidence for the efficacy of corticosteroid injection and non-electrotherapeutic physiotherapy compared with control for treating lateral epicondylitis. DESIGN: Systematic review. PARTICIPANTS: We searched five databases in September 2012 for randomized controlled studies with a minimum quality rating. Of the 640 studies retrieved, 11 were included, representing 1161 patients of both sexes and all ages. INTERVENTIONS: Corticosteroid injection and non-electrotherapeutic physiotherapy. OUTCOME MEASURES: Relative risk (RR) or standardised mean difference (SMD) for overall improvement, pain and grip strength at 4-12, 26 and 52 weeks of follow-up. RESULTS: Corticosteroid injection gave a short-term reduction in pain versus no intervention or non-steroidal anti-inflammatory drugs (SMD -1.43, 95% CI -1.64 to -1.23). At intermediate follow-up, we found an increase in pain (SMD 0.32, 95% CI 0.13 to 0.51), reduction in grip strength (SMD -0.48, 95% CI -0.73 to -0.24) and negative effect on the overall improvement effect (RR 0.66 (0.53 to 0.81)). For corticosteroid injection versus lidocaine injection, the evidence was conflicting. At long-term follow-up, there was no difference on overall improvement and grip strength, with conflicting evidence for pain. Manipulation and exercise versus no intervention showed beneficial effect at short-term follow-up (overall improvement RR 2.75, 95% CI 1.30 to 5.82), but no significant difference at intermediate or long-term follow-up. We found moderate evidence for short-term and long-term effects of eccentric exercise and stretching versus no intervention. For exercise versus no intervention and eccentric or concentric exercise and stretching versus stretching alone, we found moderate evidence of no short-term effect. CONCLUSIONS: Corticosteroid injections have a short-term beneficial effect on lateral epicondylitis, but a negative effect in the intermediate term. Evidence on the long-term effect is conflicting. Manipulation and exercise and exercise and stretching have a short-term effect, with the latter also having a long-term effect. Olaussen M, Holmedal O, Lindbaek M, Brage S, Solvang H.Treating lateral epicondylitis with corticosteroid injections or non-electrotherapeutical physiotherapy: a systematic review. BMJ Open. 2013 Oct 29;3(10):e003564. doi: 10.1136/bmjopen-2013-003564. PMID: 24171937 #7: Insufficient evidence for choosing an injection therapy for lateral epicondylitis BACKGROUND: Injection therapy with glucocorticoids has been used since the 1950s as a treatment strategy for lateral epicondylitis (tennis elbow). Lately, several novel injection therapies have become available. PURPOSE: To assess the comparative effectiveness and safety of injection therapies in patients with lateral epicondylitis. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Randomized controlled trials comparing different injection therapies for lateral epicondylitis were included provided they contained data for change in pain intensity (primary outcome). Trials were assessed using the Cochrane risk of bias tool. Network (random effects) meta-analysis was applied to combine direct and indirect evidence within and across trial data using the final end point reported in the trials, and results for the arm-based network analyses are reported as standardized mean differences (SMDs). RESULTS: Seventeen trials (1381 participants; 3 [18%] at low risk of bias) assessing injection with 8 different treatments-glucocorticoid (10 trials), botulinum toxin (4 trials), autologous blood (3 trials), platelet-rich plasma (2 trials), and polidocanol, glycosaminoglycan, prolotherapy, and hyaluronic acid (1 trial each)-were included. Pooled results (SMD [95% confidence interval]) showed that beyond 8 weeks, glucocorticoid injection was no more effective than placebo (-0.04 [-0.45 to 0.35]), but only 1 trial (which did not include a placebo arm) was at low risk of bias. Although botulinum toxin showed marginal benefit (-0.50 [-0.91 to -0.08]), it caused temporary paresis of finger extension, and all trials were at high risk of bias. Both autologous blood (-1.43 [-2.15 to -0.71]) and platelet-rich plasma (-1.13 [-1.77 to -0.49]) were also statistically superior to placebo, but only 1 trial was at low risk of bias. Prolotherapy (-2.71 [-4.60 to -0.82]) and hyaluronic acid (-5.58 [-6.35 to -4.82]) were both more efficacious than placebo, whereas polidocanol (0.39 [-0.42 to 1.20]) and glycosaminoglycan (-0.32 [-1.02 to 0.38]) showed no effect compared with placebo.The criteria for low risk of bias were only met by the prolotherapy and polidocanol trials. CONCLUSION: This systematic review and network meta-analysis of randomized controlled trials found a paucity of evidence from unbiased trials on which to base treatment recommendations regarding injection therapies for lateral epicondylitis. Krogh TP, Bartels EM, Ellingsen T, Stengaard-Pedersen K, Buchbinder R, Fredberg U, Bliddal H, Christensen R. Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials. Am J Sports Med. 2013 Jun;41(6):1435-46. doi:10.1177/0363546512458237 PMID: 22972856

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#8: Systematic review of treatments for patellar tendinopathy PURPOSE: Patellar tendinopathy is a common, painful, overuse disorder. Although many different treatment methods have been described, there is no consensus regarding the optimal treatment for this condition. The purpose of this study was to systematically review, summarize, and compare treatments for patellar tendinopathy from published randomized controlled trials. METHODS: Database searches were performed for randomized prospective controlled trials comparing treatment methods for patellar tendinopathy. The thirteen articles considered relevant were scrutinized according to quality assessment guidelines and levels of evidence. RESULTS: Strong evidence was found for the use of eccentric training to treat patellar tendinopathy. Moderate evidence was found for conservative treatment (heavy slow resistance training) as an alternative to eccentric training. Moderate evidence suggests that low-intensity pulsed ultrasound treatment did not influence treatment outcomes. Limited evidence was found for surgery, sclerosing injections, and shockwave therapy. CONCLUSION: Physical training, and particularly eccentric training, appears to be the treatment of choice for patients suffering from patellar tendinopathy. However, type of exercise, frequency, load, and dosage must also be analyzed. Other treatment methods, such as surgical treatment, sclerosing injections, and shockwave therapy, must be investigated further before recommendations can be made regarding their use. Ultrasound can likely be excluded as a treatment for patellar tendinopathy. There is a persistent lack of well-designed studies with sufficiently long-term follow-up and number of patients to draw strong conclusions regarding therapy. LEVEL OF EVIDENCE: II. Larsson ME(1), Käll I, Nilsson-Helander K. Treatment of patellar tendinopathy--a systematic review of randomized controlled trials. Knee Surg Sports Traumatol Arthrosc. 2012 Aug;20(8):1632-46. doi: 10.1007/s00167-011-1825-1. Epub 2011 Dec 21.PMID: 22186923 #9: Meta-analysis: efficacy of injection therapies for non-insertional Achilles tendinosis unproven BACKGROUND: Although there has been a recent increase in interest regarding injectable therapy for noninsertional Achilles tendinosis, there are currently no clear treatment guidelines for managing patients with this condition. The objective of this study was (1) to conduct a systematic review of clinical outcomes following injectable therapy of noninsertional Achilles tendinosis, (2) to identify patient-specific factors that are prognostic of treatment outcomes, (3) to provide treatment recommendations based on the best available literature, and (4) to identify knowledge deficits that require further investigation. METHODS: We searched MEDLINE (1948 to March week 1 2012) and EMBASE (1980 to 2012 week 9) for clinical studies evaluating the efficacy of injectable therapies for noninsertional Achilles tendinosis. Specifically, we included randomized controlled trials and cohort studies with a comparative control group. Data abstraction was performed by 2 independent reviewers. The Oxford Level of Evidence Guidelines and GRADE recommendations were used to rate the quality of evidence and to make treatment recommendations. RESULTS: Nine studies fit the inclusion criteria for our review, constituting 312 Achilles tendons at final follow-up. The interventions of interest included platelet-rich plasma (n = 54), autologous blood injection (n = 40), sclerosing agents (n = 72), protease inhibitors (n = 26), hemodialysate (n = 60), corticosteroids (n = 52), and prolotherapy (n = 20). Only 1 study met the criteria for a high-quality randomized controlled trial. All of the studies were designated as having a low quality of evidence. While some studies showed statistically significant effects of the treatment modalities, often studies revealed that certain injectables were no better than a placebo. CONCLUSIONS: The literature surrounding injectable treatments for noninsertional Achilles tendinosis has variable results with conflicting methodologies and inconclusive evidence concerning indications for treatment and the mechanism of their effects on chronically degenerated tendons. Prospective, randomized studies are necessary in the future to guide Achilles tendinosis treatment recommendations using injectable therapies. LEVEL OF EVIDENCE: Level II, systematic review. Gross CE(1), Hsu AR, Chahal J, Holmes GB Jr. Injectable treatments for noninsertional achilles tendinosis: a systematic review. Foot Ankle Int. 2013 May;34(5):619-28. doi: 10.1177/1071100713475353. Epub 2013 Feb 4. PMID: 23637232 #10: PRP injections somewhat more effective than normal saline and hyaluronic acid injections for knee osteoarthritis but more adverse events: a meta-analysis PURPOSE: The purpose of this systematic review was to synthesize the available Level I and Level II literature on platelet-rich plasma (PRP) as a therapeutic intervention in the management of symptomatic knee osteoarthritis (OA). METHODS: A systematic review of Medline, Embase, Cochrane Central Register of Controlled Trials, PubMed, and www.clinicaltrials.gov was performed to identify all randomized controlled trials and prospective cohort studies that evaluated the clinical efficacy of PRP versus a control injection for knee OA. A random-effects model was used to evaluate the therapeutic effect of PRP at 24 weeks by use of validated outcome measures (Western Ontario and McMaster Universities Arthritis Index, visual analog scale for pain, International Knee Documentation Committee Subjective Knee Evaluation Form, and overall patient satisfaction). RESULTS: Six Level I and II studies satisfied our inclusion criteria (4 randomized controlled trials and 2 prospective nonrandomized studies). A total of 577 patients were included, with 264 patients (45.8%) in the treatment group (PRP) and 313 patients (54.2%) in the control group (hyaluronic acid [HA] or normal saline solution [NS]). The mean age of patients receiving PRP was 56.1 years (51.5% male patients) compared with 57.1 years (49.5% male patients) for the group receiving HA or NS. Pooled results using the Western Ontario and McMaster Universities Arthritis Index scale (4 studies) showed that PRP was significantly better than HA or NS injections (mean difference, -18.0 [95% confidence interval, -28.8 to -8.3]; P < .001). Similarly, the International Knee Documentation Committee scores (3 studies) favored PRP as a treatment modality (mean difference, 7.9 [95% confidence interval, 3.7 to 12.1]; P < .001). There was no difference in the pooled results for visual analog scale score or overall patient satisfaction. Adverse events occurred more frequently in patients treated with PRP than in those treated with HA/placebo (8.4% v 3.8%, P = .002).

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CONCLUSIONS: As compared with HA or NS injection, multiple sequential intra-articular PRP injections may have beneficial effects in the treatment of adult patients with mild to moderate knee OA at approximately 6 months. There appears to be an increased incidence of nonspecific adverse events among patients treated with PRP. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies. Khoshbin A, Leroux T, Wasserstein D, Marks P, Theodoropoulos J, Ogilvie-Harris D, Gandhi R, Takhar K, Lum G, Chahal J.The efficacy of platelet-rich plasma in the treatment of symptomatic knee osteoarthritis: a systematic review with quantitative synthesis. Arthroscopy. 2013 Dec;29(12):2037-48. doi: 10.1016/j.arthro.2013.09.006. PMID: 24286802 #11: Meta-analysis finds no proven benefits to platelet-rich therapies BACKGROUND: Platelet-rich therapies are being used increasingly in the treatment of musculoskeletal soft tissue injuries such as ligament, muscle and tendon tears and tendinopathies. These therapies can be used as the principal treatment or as an augmentation procedure (application after surgical repair or reconstruction). Platelet-rich therapies are produced by centrifuging a quantity of the patient's own blood and extracting the active, platelet-rich, fraction. The platelet-rich fraction is applied to the injured tissue; for example, by injection. Platelets have the ability to produce several growth factors, so these therapies should enhance tissue healing. There is a need to assess whether this translates into clinical benefit. OBJECTIVES: To assess the effects (benefits and harms) of platelet-rich therapies for treating musculoskeletal soft tissue injuries. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (25 March 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013 Issue 2), MEDLINE (1946 to March 2013), EMBASE (1980 to 2013 Week 12) and LILACS (1982 to March 2012). We also searched trial registers (to Week 2 2013) and conference abstracts (2005 to March 2012). No language or publication restrictions were applied. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared platelet-rich therapy with either placebo, autologous whole blood, dry needling or no platelet-rich therapy for people with acute or chronic musculoskeletal soft tissue injuries. Primary outcomes were functional status, pain and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed each study's risk of bias. Disagreement was resolved by discussion or by arbitration by a third author. We contacted trial authors for clarification of methods or missing data. Treatment effects were assessed using risk ratios for dichotomous data and mean differences (MD) or standardised mean differences (SMD) for continuous data, together with 95% confidence intervals. Where appropriate, data were pooled using the fixed-effect model for RR and MD, and the random-effects model for SMD. The quality of the evidence for each outcome was assessed using GRADE criteria. MAIN RESULTS: We included data from 19 small single centre trials (17 randomised and two quasi-randomised; 1088 participants) that compared platelet-rich therapy with placebo, autologous whole blood, dry needling or no platelet-rich therapy.These trials covered eight clinical conditions: rotator cuff tears (arthroscopic repair) (six trials); shoulder impingement syndrome surgery (one trial); elbow epicondylitis (three trials); anterior cruciate ligament (ACL) reconstruction (four trials), ACL reconstruction (donor graft site application) (two trials), patellar tendinopathy (one trial), Achilles tendinopathy (one trial) and acute Achilles rupture surgical repair (one trial). We also grouped trials into 'tendinopathies' where platelet-rich therapy (PRT) injections were the main treatment (five trials), and surgical augmentation procedures where PRT was applied during surgery (14 trials). Trial participants were mainly male, except in trials including rotator cuff tears, and elbow and Achilles tendinopathies. Three trials were judged as being at low risk of bias; the other 16 were at high or unclear risk of bias relating to selection, detection, attrition or selective reporting, or combinations of these. The methods of preparing platelet-rich plasma (PRP) varied and lacked standardisation and quantification of the PRP applied to the patient. We were able to pool data for our primary outcomes (function, pain, adverse events) for a maximum of 11 trials and 45% of participants. The evidence for all primary outcomes was judged as being of very low quality. Data assessing function in the short term (up to three months) were pooled from five trials that assessed PRT in three clinical conditions and used four different measures. These showed no significant difference between PRT and control (SMD 0.24; 95% confidence interval (CI) -0.07 to 0.56; P value 0.13; I² = 35%; 273 participants; positive values favour PRT). Medium-term function data (at six months) were pooled from six trials that assessed PRT in five clinical conditions and used six different measures. These also showed no difference between groups (SMD 0.06; 95% CI -0.39 to 0.51; P value 0.79; I² = 64%; 262 participants). Long-term function data (at one year) were pooled from 10 trials that assessed PRT in five clinical conditions and used six different measures. These also showed no difference between groups (SMD 0.25, 95% CI -0.07 to 0.57; P value 0.12; I² = 66%; 484 participants). Although the 95% confidence intervals indicate the possibility of a slightly poorer outcome in the PRT group up to a moderate difference in favour of PRT at short- and long-term follow-up, these do not translate into clinically relevant differences. Data pooled from four trials that assessed PRT in three clinical conditions showed a small reduction in short-term pain in favour of PRT on a 10-point scale (MD -0.95, 95% CI -1.41 to -0.48; I² = 0%; 175 participants). The clinical significance of this result is marginal. Four trials reported adverse events; another seven trials reported an absence of adverse events. There was no difference between treatment groups in the numbers of participants with adverse effects (7/241 versus 5/245; RR 1.31, 95% CI 0.48 to 3.59; I² = 0%; 486 participants).In terms of individual conditions, we pooled heterogeneous data for long-term function from six trials of PRT application during rotator cuff tear surgery. This showed no statistically or clinically significant differences between the two groups (324 participants). Pooled data for short-term function for three elbow epicondylitis trials (179 participants) showed a statistically significant difference in favour of PRT, but the clinical significance of this finding is uncertain. The available evidence is insufficient to indicate whether the effects of PRT will differ importantly in individual clinical conditions. AUTHORS' CONCLUSIONS: Overall, and for the individual clinical conditions, there is currently insufficient evidence to support the use of PRT for treating musculoskeletal soft tissue injuries. Researchers contemplating RCTs should consider the coverage of currently ongoing trials when assessing the need for future RCTs on specific conditions. There is need for standardisation of PRP preparation methods. Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Platelet-rich therapies for musculoskeletal soft tissue injuries. Cochrane Database Syst Rev. 2013 Dec 23;12:CD010071. doi:10.1002/14651858.CD010071.pub2. PMID: 24363098

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Following are a potpourri of recent studies with results important for family medicine practitioners #12: Early surgical treatment of ACL tears appears more effective in children and adolescents compare to late surgical repair BACKGROUND: Debate regarding the optimal initial treatment for anterior cruciate ligament (ACL) injuries in children and adolescents has not resulted in a clear consensus for initial nonoperative treatment or operative reconstruction. PURPOSE: The purpose of this meta-analysis was to systematically analyze aggregated data from the literature to determine if a benefit exists for either nonoperative or early operative treatment for ACL injuries in the pediatric patient. The hypothesis was that combined results would favor early operative reconstruction with respect to posttreatment episodes of instability/pathological laxity, symptomatic meniscal tears, clinical outcome scores, and return to activity. STUDY DESIGN: Meta-analysis. METHODS: A literature selection process included the extraction of data on the following clinical variables: symptomatic meniscal tears, return to activities, clinical outcome scores, return to the operating room, and posttreatment instability/pathological laxity. A symptomatic meniscal tear was defined as occurring after the initial presentation, limiting activity, and requiring further treatment. Instability/pathological laxity was defined for the sake of this study as having an episode of giving way, a grade ≥2 Lachman/pivot-shift test result, or a side-to-side difference of >4 mm as measured by the KT-1000 arthrometer. All studies were evaluated using a formal study quality analysis. Meta-analysis wasconducted for aggregated data in each category. RESULTS: Six studies (217patients) comparing operative to nonoperative treatment and 5 studies (353 patients) comparing early to delayed reconstruction were identified. Three studies reported posttreatment instability/pathological laxity; 13.6% of patients after operative treatment experienced instability/pathological laxity compared with 75% of patients after nonoperative treatment (P < .01). Two studies reported symptomatic meniscal tears; patients were over 12 times more likely to have a medial meniscal tear after nonoperative treatment than after operative treatment (35.4% vs 3.9%, respectively; P = .02). A significant difference in scores between groups was noted in 1 of 2 studies reporting International Knee Documentation Committee (IKDC) scores (P = .002) and in 1 of 2 studies reporting Tegner scores (P = .007). Two studies reported return to activity; none of the patients in the nonoperative groups returned to their previous level of play compared with 85.7% of patients in the operative groups (P < .01). Study quality analysis revealed that the majority of the studies were inconsistent in reporting outcomes. CONCLUSION: Meta-analysis revealed multiple trends that favor early surgical stabilization over nonoperative or delayed treatment. Patients after nonoperative and delayed treatment experienced more instability/pathological laxity and inability to return to previous activity levels than did patients treated with early surgical stabilization. Ramski DE(1), Kanj WW, Franklin CC, Baldwin KD, Ganley TJ.Anterior Cruciate Ligament Tears in Children and Adolescents: A Meta-analysis of Nonoperative Versus Operative Treatment. Am J Sports Med. 2013 Dec 4. PMID: 24305648 #13: Exercise to prevent sports injuries: Is it effective? BACKGROUND: Physical activity is important in both prevention and treatment of many common diseases, but sports injuries can pose serious problems. OBJECTIVE: To determine whether physical activity exercises can reduce sports injuries and perform stratified analyses of strength training, stretching, proprioception and combinations of these, and provide separate acute and overuse injury estimates. MATERIAL AND METHODS: PubMed, EMBASE, Web of Science and SPORTDiscus were searched and yielded 3462 results. Two independent authors selected relevant randomised, controlled trials and quality assessments were conducted by all authors of this paper using the Cochrane collaboration domain-based quality assessment tool. Twelve studies that neglected to account for clustering effects were adjusted. Quantitative analyses were performed in STATA V.12 and sensitivity analysed by intention-to-treat. Heterogeneity (I(2)) and publication bias (Harbord's small-study effects) were formally tested. RESULTS: 25 trials, including 26 610 participants with 3464 injuries, were analysed. The overall effect estimate on injury prevention was heterogeneous. Stratified exposure analyses proved no beneficial effect for stretching (RR 0.963 (0.846-1.095)), whereas studies with multiple exposures (RR 0.655 (0.520-0.826)), proprioception training (RR 0.550 (0.347-0.869)), and strength training (RR 0.315 (0.207-0.480)) showed a tendency towards increasing effect. Both acute injuries (RR 0.647 (0.502-0.836)) and overuse injuries (RR 0.527 (0.373-0.746)) could be reduced by physical activity programmes. Intention-to-treat sensitivity analyses consistently revealed even more robust effect estimates. CONCLUSIONS: Despite a few outlying studies, consistently favourable estimates were obtained for all injury prevention measures except for stretching. Strength training reduced sports injuries to less than 1/3 and overuse injuries could be almost halved. Lauersen JB, Bertelsen DM, Andersen LB.The effectiveness of exercise interventions to prevent sports injuries: asystematic review and meta-analysis of randomised controlled trials. Br J Sports Med. 2013 Oct 7. doi: 10.1136/bjsports-2013-092538. [Epub ahead of print] PMID: 24100287 #14: Concussion in young women soccer players IMPORTANCE. Despite recent increased awareness about sports concussions, little research has evaluated concussions among middle-school athletes. OBJECTIVES To evaluate the frequency and duration of concussions in female youth soccer players and to determine if concussions result in stopping play and seeking medical care. DESIGN, SETTING, AND PARTICIPANTS. Prospective cohort study from March 2008 through May 2012 among 4 soccer clubs from the Puget Sound region of Washington State, involving 351 elite female soccer players, aged 11 to 14 years, from 33 randomly selected youth soccer teams. Of the players contacted, 83.1% participated and 92.4% completed the study.

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MAIN OUTCOMES AND MEASURES. Concussion cumulative incidence, incidence rate, and description of the number, type, and duration of symptoms. We inquired weekly about concussion symptoms and, if present, the symptom type and duration, the event resulting in symptom onset, and whether the player sought medical attention or played while symptomatic. RESULTS. Among the 351 soccer players, there were 59 concussions with 43,742 athletic exposure hours. Cumulative concussion incidence was 13.0% per season, and the incidence rate was 1.2 per 1000 athletic exposure hours (95% CI, 0.9-1.6). Symptoms lasted a median of 4.0 days (mean, 9.4 days). Heading the ball accounted for 30.5% of concussions. Players with the following symptoms had a longer recover time than players without these symptoms: light sensitivity (16.0 vs 3.0 days, P = .001), emotional lability (15.0 vs 3.5 days, P = .002), noise sensitivity (12.0 vs 3.0 days, P = .004), memory loss (9.0 vs 4.0 days, P = .04), nausea (9.0 vs 3.0 days, P = .02), and concentration problems (7.0 vs 2.0 days, P = .02). Most players (58.6%) continued to play with symptoms, with almost half (44.1%) seeking medical attention. CONCLUSIONS AND RELEVANCE. Concussion rates in young female soccer players are greater than those reported in older age groups, and most of those concussed report playing with symptoms. Heading the ball is a frequent precipitating event. Awareness of recommendations to not play and seek medical attention is lacking for this age group. O'Kane JW(1), Spieker A(2), Levy MR(2), Neradilek M(3), Polissar NL(3), Schiff MA(2). Concussion Among Female Middle-School Soccer Players. JAMA Pediatr. 2014 Jan 20. doi: 10.1001/jamapediatrics.2013.4518. PMID: 24446018 #15: 75% of asymptomatic volunteers have hip abnormalities on MRI Clinical question: How common are hip abnormalities found on magnetic resonance imaging of asymptomatic adults? Study design: Cross-sectional Setting: Population-based Synopsis: The authors recruited 45 healthy volunteers from a rural skiing community by word of mouth. To be eligible, the volunteers had to be without contraindication to MRI and free of hip problems: no history of pain, injury, or surgery. The volunteers' average age was 38 years (range = 18 to 66); 28 were men, 17 were women. Most of the patients were quite active: 99% engaged in leisure-time activity and only 10% were obese. Fellowship-trained musculoskeletal radiologists reviewed the MRIs. The researchers peppered the stack of their images with images of 19 symptomatic patients of similar age in an attempt to mask the radiologists. Additionally, each radiologist was given a checklist of potential findings. If 2 of the radiologists noted one of the findings, the researchers deemed the abnormality to be present. Approximately 75% of the volunteers had at least one abnormality. Approximately two thirds had a labral tear and one tenth had a fracture of the acetabular rim. Bottom line: In this population of active skiers, approximately 75% of asymptomatic volunteers had at least one hip abnormality on magnetic resonance imaging (MRI). Register B, Pennock AT, Ho CP, Strickland CD, Lawand A, Philippon MJ. Prevalence of abnormal hip findings in asymptomatic participants: a prospective, blinded study. Am J Sports Med 2012;40(12):2720-2724. Bottom Lines 1. Prolotherapy may be effective for treatment of certain tendinopathies, but the evidence is not strong. 2. Platelet rich plasma injections, despite growing popularity, are an unproven treatment for tendinopathies, but there is evidence they can relieve symptoms of knee osteoarthritis 3. There is some evidence that both prolotherapy and PRP injections may relieve symptoms of chronic plantar fasciitis. A good, placebo-controlled trial is needed. 4. We need better, larger and more conclusive studies regarding injection therapies for tendonopathies. 5. Certain types of exercises help prevent sports injuries. 6. Concussion injuries in young female soccer players are more common that one might expect. 7. No surprise: many active people with no hip pain have hip joint MRI abnormalities, just like every other joint that has been studied.

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Cardiovascular Update - Gary Ferenchick, MD

Objectives

1. Review key recommendations from the AHA guideline on stress testing in symptomatic patients without known ischemic heart disease (IHD).

2. Review recent studies and key AHA guideline recommendations on the management of patients with SIHD (medical vs. intervention)

3. Review JNC VIII

In December of 2012 multiple national organizations including the American Heart Association (AHA) published an extensive guideline on the diagnosis and management of patients with stable ischemic heart disease (SIHD). (1) All unstable patients require urgent evaluation and are not included in this guideline.

What are some ways to perform risk assessment for patients presenting with chest pain in primary care?

For purposes of this session we will focus on the recommendations for diagnostic stress testing. One of the stated aims of the guideline is to “…promote the sensible application of appropriate testing rather than the routine use of the most expensive or complex tests, whether warranted or not”.

One of the first steps in determining if further stress testing is warranted is to determine the patient’s probability of obstructive IHD. Table 1 and 2 at the end of this chapter provide a method to determine if the probability of IHD is sufficient to recommend further testing. In general when the probability of disease is < 5% further stress testing is not warranted, as the likelihood of a false positive test is > than that of a true positive test. Additionally, in a patient with a very high likelihood of IHD has a negative stress test, there is a “substantial” chance it is falsely negative. Further testing is warranted in those with an intermediate probability of obstructive IHD (variably defined 10 – 90%, 20 – 70%) etc. Also Abstract 1 uses another clinical prediction rule to determine if a patient’s chest pain is from obstructive IHD:

• Women 65 years or older or men 55 years or older • Pain worse during exercise • Pain not reproducible by palpation • Patient assumes pain is of cardiac origin • Patient has known coronary artery or cerebrovascular disease

#1: Clinical prediction rule accurate for primary care chest pain Clinical question: Can a combination of clinical findings rule in or rule out coronary artery disease in patients with chest pain presenting to their primary care physician? Study design: Cross-sectional Setting: Outpatient (primary care) Synopsis: This study identified 1199 patients with nontraumatic chest pain who presented to 1 of 74 German primary care physicians. They were evaluated using a standardized history and physical examination. Patients were contacted 6 weeks and 6 months later to determine their disposition, and a panel reviewed all of the clinical data available at the end of 6 months (including imaging and cardiovascular studies) to determine the final diagnosis. A limitation of the study is verification bias: All patients did not undergo the same reference standard (a stress thallium test, for example). The researchers argue that serious coronary artery disease would manifest itself within 6 months, and they are probably correct. They developed a simple clinical prediction rule consisting of 5 items: women 65 years or older or men 55 years or older; pain worse during exercise; pain not reproducible by palpation; patient assumes pain is of cardiac origin; and patient has known coronary artery or cerebrovascular disease. This rule was then successfully validated in a separate group of 672 Swiss primary care patients. Among those with 0 or 1 of these clinical factors, only 3 of 542 in the combined cohort had coronary artery disease. Sixty three percent of the patients with 4 or 5 factors had coronary artery disease, and those with 2 or 3 factors had a 12% likelihood of coronary disease. Bottom line: Patients with less than 2 of 5 key clinical predictors have an extremely low likelihood of coronary artery disease, while those with 4 or 5 predictors have a very high risk and require emergent evaluation and treatment.

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BÃ¶sner S, Haasenritter J, Becker A, et al. Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule. CMAJ 2010;182(12):1295-1300.

If the pretest probability is not very low (< 10%) or very high (> 80%), then diagnostic stress testing is likely warranted

1. Obtain a diagnostic study (stress test or imaging Table 3 and 4) 2. Determine if high risk features are present or not (Table 5) 3. If present consider invasive imaging / revascularization as indicated 4. If NOT present proceed to medical management

What is the relative benefit of medical therapy vs. interventional rx in SIHD?

The AHA guideline reinforces the critical role of medical therapy in managing both symptoms and survival in most patients with low or intermediate risk (annual mortality < 3%) with SIHD, and that in many the benefits of revascularization do no outweigh the benefits of medical therapy in SIHD. However they do note that, “An ingrained preference for action (ie, revascularization) over perceived inaction (ie, medical therapy alone) likely influences the decision making of both patients and physicians”. AHA guideline directed medical therapy recommendations are in appendix 2 and 3.

#2: No benefit to stenting for stable CAD Clinical question: Does stent implantation plus medical therapy improve cardiac outcomes and mortality more than medical therapy alone in patients with stable coronary artery disease? Study design: Meta-analysis (randomized controlled trials) Setting: Various (meta-analysis) Synopsis: These investigators searched MEDLINE, as well as bibliographies from retrieved articles, to find randomized controlled trials that compared percutaneous coronary intervention (PCI) plus medical therapy with medical therapy alone for patients with stable CAD. Trials in which stent implantation was less than 50% of the PCI procedures were excluded from this review. Two of the authors independently extracted data and assessed study quality using the Jadad scale. The weighted mean follow-up of the included studies (n = 7229) was 4.3 years. Of the 8 studies, 3 enrolled patients who were stable following recent MI with persistent occlusion of the infarct-related artery and 5 enrolled patients with stable angina or ischemia on stress testing. At least 75% of patients in all the studies were men, and the majority received aspirin, beta-blockers, ACE inhibitors, and statins. For the outcomes of death, nonfatal MI, unplanned revascularization, or recurrent angina, there were no significant differences detected between the 2 groups. No publication bias was noted. Bottom line: For patients with stable coronary artery disease (CAD), coronary stent implantation in combination with medical therapy does not decrease mortality or prevent recurrent myocardial infarction (MI) or angina more than medical therapy alone. This finding supports the recommendation that the first-line therapy for patients with stable CAD should be medical optimization. Stergiopoulos K, Brown DL. Stenting vs Medical Therapy for Stable Coronary Artery Disease: A Minefield for Meta-analyses?-Reply. Arch Intern Med. 2012 Jul 9;172(13):1044-5. doi: 10.1001/archinternmed.2012.2215. PubMed PMID: 23753062.

See appendix: Guideline directed medical therapy (GDMT) to prevent death and MI in patients with SIDH

Miscellaneous Cardiovascular Abstracts

#3: ACP guidelines on treatment of anemia in patients with heart disease

Clinical question: How should anemia and iron deficiency be treated in adults with heart disease? Study design: Practice guideline Setting: Various (meta-analysis) Synopsis: The American College of Physicians developed this guideline based on a systematic review of the literature that evaluated the benefits and harms of anemia treatment in adults with heart disease. The authors searched multiple databases including MEDLINE and the Cochrane Library, to identify trials that studied the effects of blood transfusions, ESAs, and iron in patients with anemia and congestive heart failure or coronary heart disease. Observational transfusion studies were also included. Two reviewers independently assessed studies for inclusion, extracted data, and assessed study quality. Data was combined for meta-analysis when possible. Although it was low-quality evidence, liberal transfusion strategies as compared with restrictive strategies in treating anemia showed no effect on mortality for patients with heart disease. Moderate-strength to high-strength evidence from the ESA studies also showed no benefit, but did show a potential for harm, including an increased risk of venous thromboembolism. Finally, although few studies evaluated intravenous iron therapy, one good-quality study showed that it increased short-term exercise tolerance and quality of life in

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patients with heart failure. Based on these findings, the American College of Physicians guideline committee makes the following recommendations: (1) Use a restrictive red blood cell transfusion strategy with a hemoglobin threshold of 7 g/dL to 8 g/dL in hospitalized patients with coronary heart disease; and (2) avoid ESAs in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. Because of lack of evidence regarding long-term outcomes and possible harms, as well as limited overall data, there was no recommendation made regarding the use of intravenous iron. Bottom line: For hospitalized patients with anemia and coronary heart disease, the American College of Physicians recommends a restrictive transfusion strategy and a trigger hemoglobin of 7 g/dL to 8 g/dL. Furthermore, erythropoiesis-stimulating agents (ESAs) should be avoided in patients with coronary heart disease or congestive heart failure and mild to moderate anemia. Evidence regarding intravenous iron for this patient population is inconclusive. Reference: Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment of anemia in patients with heart disease. Ann Intern Med 2013;159(11):746-757. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2013;159(11):770- #4: Influenza vaccine lowers the risk of major CV events in adults Clinical question: Does the influenza vaccine lower the risk of major adverse cardiovascular events in adults with coronary disease? Study design: Meta-analysis (randomized controlled trials) Setting: Various (meta-analysis) Synopsis: These investigators searched multiple sources including MEDLINE, EMBASE, the Cochrane Register, reference lists of eligible articles, clinicaltrials.gov, and conference abstracts without language restrictions for all published and unpublished randomized clinical trials comparing influenza vaccination with placebo or standard care. Two investigators independently reviewed potential studies for inclusion and methodologic quality using standard scoring tools. Disagreements were resolved by consensus. Six randomized controlled trials met inclusion criteria for the final meta-analysis. These trials (n = 6735) compared influenza vaccine with placebo or control for a mean duration of 7.9 months. The primary outcome measured was a composite of major adverse cardiovascular events, including cardiovascular death or hospitalization for myocardial infarction, unstable angina, stroke, heart failure, or urgent coronary bypass surgery. In the analysis of the 6 included trials, significantly fewer vaccinated patients developed a major adverse cardiovascular event compared with placebo or control patients (2.9% vs 4.7%, respectively; NNT = 58 95% CI, 38-124). The benefit of vaccination was strongest in the subset of patients with a history of recent acute coronary syndrome within the previous 6 months (10.25% with vaccine vs 23.1% with placebo or control; NNT = 8; 6-13). There was, however, no significant difference in all-cause mortality between the vaccinated and placebo or control patient groups. Formal statistical analyses found no evidence of significant heterogeneity among the trials or publication bias. Bottom line: This meta-analysis found that the influenza vaccine is associated with a significantly lower risk of major adverse cardiovascular events in adults with coronary disease. The benefit of influenza vaccination is strongest in adults with a history of recent acute coronary syndrome within the previous 6 months (number needed to treat [NNT] = 8). Reference: Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients. A meta-analysis. JAMA 2013;310(16):1711-1720.

#5: Multivitamins do not work (? For anything?)

BACKGROUND: Whether high-dose multivitamins are effective for secondary prevention of atherosclerotic disease is unknown. OBJECTIVE: To assess whether oral multivitamins reduce cardiovascular events and are safe. DESIGN: Double-blind, placebo-controlled, 2 x 2 factorial, multicenter, randomized trial. (ClinicalTrials.gov: NCT00044213) SETTING: 134 U.S. and Canadian academic and clinical sites. PATIENTS: 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier and had serum creatinine levels of 176.8 mol/L (2.0 mg/dL) or less. Intervention: Patients were randomly assigned to an oral, 28-component, high-dose multivitamin and multimineral mixture or placebo. MEASUREMENTS: The primary end point was time to total death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. RESULTS: The median age was 65 years, and 18% of patients were women. The qualifying MI occurred a median of 4.6 years (interquartile range [IQR], 1.6 to 9.2 years) before enrollment. Median follow-up was 55 months (IQR, 26 to 60 months). Patients received vitamins for a median of 31 months (IQR, 13 to 59 months) in the vitamin group and 35 months (IQR, 13 to 60 months) in the placebo group (P = 0.65). Totals of 645 (76%) and 646 (76%) patients in the vitamin and placebo groups, respectively, completed at least 1 year of oral therapy (P = 0.98), and 400 (47%) and 426 (50%) patients, respectively, completed at least 3 years (P = 0.23). Totals of 394 (46%) and 390 (46%) patients in the vitamin and placebo groups, respectively, discontinued the vitamin regimen (P = 0.67), and 17% of patients withdrew from the study. The primary end point occurred in 230 (27%) patients in the vitamin group and 253 (30%) in the placebo group (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]; P = 0.21). No evidence suggested harm from vitamin therapy in any category of adverse events. LIMITATION: There was considerable nonadherence and withdrawal, limiting the ability to draw firm conclusions (particularly about safety). CONCLUSION: High-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate. REFERENCE: Lamas GA, Boineau R, Goertz C, et al. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. Ann Intern Med. 2013 Dec 17;159(12):797-805.

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JNC 8 Overview for the Primary Care Physician

In December of 2013; the “JNC 8” was published online in JAMA (Feb 2014 in the print edition). The review has several important changes in how we manage hypertension (as compared to JNC 7) and has the following issues as a backdrop; JNC 8 nuances ……

• Applies to those aged 18 years or older with hypertension • JNC 8 not redefined high BP, the 140/90 definition from JNC 7 “remains reasonable”. • This means “prehypertensive” or “nonhypertensive” people are not included in this review; (e.g. these

recommendations do not apply to those without hypertension). • JNC 8 only used data from RCT’s (JNC 7 used a range of study designs including observational

studies, systematic reviews, or meta-analyses) • JNC 8 is “not a comprehensive guideline and is limited in scope”; and it did not address adherence and

medication costs JNC 8 recommends similar treatment goals for all hypertensive populations (JNC 7 had goals defined by co-morbid conditions)

• JNC 8 limits pharmacotherapy recommendations to 4 drug classes (initial Rx and add on therapy) • No official sponsorship exists for JNC 8 and it is not a NHLBI “sanctioned report” (previous sponsor

JNC 7 was NHLBI) • Of the 11 overall recommendations, 6 have Strength of Recommendation rating of “E” (expert opinion);

and 2 have a SOR of “A” (Strong Recommendation based upon high certainty that the evidence demonstrates that the net benefit is substantial) and 2 have a SOR rating of “B” (Moderate Recommendation based upon a moderate of high certainty that the evidence for net benefit is moderate); and one SOR of “C”

Recommendations and their supporting evidence are listed below; the recommendations are listed verbatim (the emphases are mine); the discussions are synopses of JNC 8’s considerations.

Recommendation 1

• In the general population aged 60 years or older, initiate pharmacologic treatment to lower BP at systolic blood pressure (SBP) of 150 mm Hg or higher or diastolic blood pressure (DBP) of 90 mm Hg or higher and treat to a goal SBP lower than 150 mm Hg and goal DBP lower than 90 mm Hg. (SOR = A)

• In the general population aged 60 years or older, if pharmacologic treatment for high BP results in lower achieved SBP (for example, <140 mm Hg) and treatment is not associated with adverse effects on health or quality of life, treatment does not need to be adjusted.(SOR = E)

o Treating persons > 60 with hypertension to a BP goal of less than 150/90 mm Hg and a diastolic goal of less than 90 mm Hg, reduces the risk of stroke, heart failure, and coronary heart disease (CHD).

o Setting a goal SBP of lower than 140 mm Hg in patients > 60 provides no additional benefit when compared with a SBP of 140 to 160 or 140 to 149.

o In this patient group, it is not necessary to adjust medication to allow BP to increase if treatment results in SBP lower than 140 mm Hg and is not associated with adverse effects on health or quality of life.

Recommendation 2

• In the general population younger than 60 years, initiate pharmacologic treatment to lower BP at DBP of 90 mm Hg or higher and treat to a goal DBP of lower than 90 mm Hg. (SOR = A, for ages 30 - 59 years, SOR = E for ages 18 - 29 years)

o JNC 8 found no evidence for an incremental benefit in treating patients to a goal of either < 80 or < 85 mm compared with 90 mm Hg or lower.

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Recommendation 3

• In the general population younger than 60 years, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher and treat to a goal SBP of lower than 140 mm Hg. (SOR = E)

o JNC 8 found no good evidence from quality RCTs to support a specific SBP target for those < 60 years; as such the expert opinion of the panel is to treat at a SBP threshold of > 140 mm Hg with a SBP treatment goal of < 140 mm Hg.

Recommendation 4

• In the population aged 18 years or older with CKD, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher or DBP of 90 mm Hg or higher and treat to goal SBP of lower than 140 mm Hg and goal DBP lower than 90 mm Hg. (SOR = E)

o JNC 8 focuses this recommendation to patients 18 – 70 years old with an estimated or measured GFR < 60; and in people of any age with albuminuria (defined as > 30 mg of albumin/g of creatinine at any level of GFR).

� Note this is a change from JNC 7; JNC 8 states that “None of the trials showed that treatment to a lower BP goal (for example, <130/80 mm Hg) significantly lowered kidney or cardiovascular disease end points compared with a goal of lower than 140/90 mm Hg.”

� Additionally the estimating equations for GFR (e.g. Cockcroft or MDRD equations) have not been validated in older (> 70 years old) adults.

Recommendation 5

• In the population aged 18 years or older with diabetes, initiate pharmacologic treatment to lower BP at SBP of 140 mm Hg or higher or DBP of 90 mm Hg or higher and treat to a goal SBP of lower than 140 mm Hg and goal DBP lower than 90 mm Hg.(SOR = E)

o JNC 8 concluded that no RCTs addressed whether treatment to a SBP goal of < 140 improves health outcomes in adults with diabetes and hypertension compared with a higher goal (e.g. <150 mm Hg). Therefore, the use of a consistent BP goal in the general population younger than 60 years (regardless of the presence of diabetes or not) and in adults with diabetes of any age may facilitate guideline implementation.

� JNC 8 addressed the previous goal in diabetics of a SBP of >< 130; they concluded that this goal is “not supported by any RCT” data.

o They specifically referenced the ACCORD-BP, in which a SBP treatment goal of lower than 120 mm Hg demonstrated no differences in a composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, nor any secondary outcomes except for a small reduction (0.21%) in stroke when compared with a SBP goal < 140.

o Additionally JNC 8 recommends the same DBP treatment goal (<90 mm Hg) in adults with diabetes and hypertension as in the general population. JNC 8 did not find sufficient evidence to support the recommendation of treating the DBP to < 80.

Recommendation 6

• In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). (SOR = B)

o JNC 8 concluded that each of these 4 drug classes yield comparable beneficial effects on overall mortality and cardiovascular, cerebrovascular, and kidney outcomes.

� However in heart failure, initial treatment with a thiazide diuretic was more effective than a CCB or ACEI, and an ACEI was more effective than a CCB in improving heart failure outcomes.

� For the initial treatment of hypertension, JNC 8 does not recommend:

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• Beta-blocker use for the initial treatment of hypertension; in one study β-blocker use was associated with a higher rate of cardiovascular death, myocardial infarction, or stroke compared to use of an ARB.

• α-Blocker use which resulted in worse cerebrovascular, heart failure, and combined cardiovascular outcomes than initial treatment with a diuretic in one study.

• Additionally quality RCTs are lacking which compare the following drug classes to the 4 recommended classes, (therefore, these drug classes are not recommended as first-line therapy):

o dual α1- + β-blocking agents (e.g., carvedilol), o vasodilating β-blockers (e.g., nebivolol), o central α2-adrenergic agonists (e.g., clonidine), o direct vasodilators (e.g., hydralazine), o aldosterone receptor antagonists (eg, spironolactone), o adrenergic neuronal depleting agents (reserpine), o loop diuretics (e.g., furosemide).

Recommendation 7

• In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB. (SOR = B for the general black population; SOR = C for black patients with diabetes)

o In the ALLHAT study, thiazides were shown to have a greater effect than ACEI in black patients in improving cerebrovascular, heart failure, and combined cardiovascular outcomes (including diabetic and nondiabetic participants); additionally initial therapy with CCBs among black patients in the ALLHAT study was associated with a 51% relative risk reduction for stroke when compared to ACEI.

Recommendation 8

• In the population aged 18 years or older with CKD and hypertension, initial (or add-on) antihypertensive treatment should include an ACEI or ARB to improve kidney outcomes. This applies to all CKD patients with hypertension regardless of race or diabetes status.

o All patients > 18 with CKD (with and without proteinuria), have evidence of improved kidney outcomes with ACEI or ARB use. JNC 8 stated that this recommendation is based primarily on renal outcomes, as there is less evidence favoring ACEI or ARB for cardiovascular outcomes in patients with CKD.

o JNC 8 noted “the potential conflict between this recommendation to use an ACEI or ARB in those with CKD and hypertension and the recommendation to use a diuretic or CCB (recommendation 7) in black persons: what if the person is black and has CKD?”

� JNC 8 relied on expert opinion to provide guidance on this: • “In black patients with CKD and proteinuria, an ACEI or ARB is recommended as

initial therapy because of the higher likelihood of progression to ESRD. • “In black patients with CKD but without proteinuria, the choice for initial therapy is

less clear and includes a thiazide-type diuretic, CCB, ACEI, or ARB. If an ACEI or ARB is not used as the initial drug, then an ACEI or ARB can be added as a second-line drug if necessary to achieve goal BP.”

o JNC 8 concluded that no evidence exists to support ACEI or ARB treatment in those older than 75 years.

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Recommendation 9

The following is verbatim from JNC 8 but the bullets are mine

• The main objective of hypertension treatment is to attain and maintain goal BP. • If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a

second drug from one of the classes in recommendation 6 (thiazide-type diuretic, CCB, ACEI, or ARB). • The clinician should continue to assess BP and adjust the treatment regimen until goal BP is reached. • If goal BP cannot be reached with 2 drugs, add and titrate a third drug from the list provided. • Do not use an ACEI and an ARB together in the same patient. • If goal BP cannot be reached using the drugs in recommendation 6 because of a contraindication or the

need to use more than 3 drugs to reach goal BP, antihypertensive drugs from other classes can be used.

• Referral to a hypertension specialist may be indicated for patients in whom goal BP cannot be attained using the above strategy or for the management of complicated patients for whom additional clinical consultation is needed.

Bottom Lines

1. The AHA (among others) have recently published a guideline in part to “…promote the sensible application of appropriate testing rather than the routine use of the most expensive or complex tests, whether warranted or not”. (See the Tables)

2. Medical therapy for SIHD works, and several studies have validated this approach compared to intervention (PCI or CABG) in a variety of patient populations

3. JNC VIII has simplified hypertension management and will alter many previously assumed standard practices, including

a. Treat hypertensive persons aged > 60 to a BP goal < 150/<90 mm Hg; and hypertensive persons 30 through 59 years of age to BP goal of < 140/<90.

b. Use the same treatment thresholds for diabetic and non-diabetic patients < 60 with CKD. c. Use ACEI or ARBs, calcium channel blockers, or thiazide diuretics in nonblack hypertensive

patients, including those with diabetes d. In the black hypertensive patients, including those with diabetes, use a calcium channel blocker or

thiazide diuretic as initial therapy. e. Use initial or add-on antihypertensive therapy with an ACEI or ARB in patients with CKD, with the

goal of improving kidney outcomes.

References

2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507-20.

Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease. Circulation. 2012 Dec 18;126(25):e354-471. Epub 2012 Nov 19.

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Appendices:

Table 1. Clinical Classification of Chest Pain

Typical Angina (definite) Substernal with characteristic quality and duration Provoked by exertion or emotional stress Relieved by rest or NTG

Atypical Angina (probable) 2 of 3 criteria

Nonanginal chest pain 0 or 1 criteria

Table 2: Pretest probability of CAD in symptomatic patients (low risk – high risk)

Age, y Nonanginal chest pain Atypical angina Typical angina

Men Women Men Women Men Women

35 3 – 35 1 - 19 8 – 59 2 – 39 30 – 88 10 – 78

45 9 – 47 2 - 22 21 – 70 5 – 43 51 – 92 20 – 79

55 23 – 59 4 – 21 45 – 79 10 – 47 80 – 95 38 – 82

65 49 - 69 9 – 29 71 - 86 20 - 51 93 - 97 56 - 84

Normal resting EKG’s

If Q waves or ST-T wave changes present on resting ECG, probability of IHD ↑ in each category

% with significant CAD

Low risk = NO DM, smoking, hyperlipidemia

High risk = DM, smoking, hyperlipidemia Circulation. 2012 Dec 18;126(25):e354-471

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Table 3: Stress Testing Able to Exercise

Pre-test Probability of IHD

ECG Interpretable

COR LOE

Low Intermediate High Yes No

Exercise ECG X X I A

Exercise ECG X X IIa C

Exercise with nuclear MPI or ECHO

X X X I B

Exercise with nuclear MPI or ECHO

X X X IIa B

Pharmacological stress CMR

X X X IIa B

CCTA X X X IIb B

Exercise ECHO X X IIB C

Pharmacological stress with nuclear MPI, ECHO or CMR

X X X X III: No Benefit

C

Exercise stress with nuclear MPI

X X III: No benefit

C

Cells with gray X = the patient has these characteristics (e.g. in the line Exercise ECG, Do an exercise ECG if the patient has an intermediate pre-test probability of IHD AND an interpretable resting ECG)

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Table 4: Stress Testing: Unable to Exercise

Pre-test Probability of IHD

ECG Interpretable

COR LOE

Low Intermed High Yes No

Pharmacological stress with nuclear MPI or ECHO

X X X X I B

Pharmacological stress ECHO

X X X IIa C

CCTA X X X X IIa B

Pharmacological stress CMR

X X X X IIa B

Exercise ECG X X X X III: No benefit

C

Cells with gray X = the patient has these characteristics

CCTA = cardiac computed tomography angiography; CMR = cardiac magnetic resonance imaging; COR = class of recommendation, LOE = level of evidence; MPI = myocardial perfusion imaging

Able to exercise means capable of moderately working in the house, yard or recreational and most activities of daily living AND no disabling co-morbidities Intermediate probability = between 10 – 90 % Resting ECG changes that limit the accurate interpretation of exercise induced changes: ST segment abnormalities, LVH, LBBB (probably RBBB for the anterior leads), paced rhythm

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Table 5: High Risk Features on Stress Testing

Accurate risk assessment is essential in determining optimal treatment strategies

High risk features on an EST include:

o ST depression at a reduced work load o ST depression persisting into recovery o Exertional angina o Low exercise capacity o Failure to increase SBP > 120 mm Hg o Sustained decrease of SBP by 10 mm HG from resting values o Complex arrhythmia during stress or recovery o Delayed heart rate recovery < 10 beats per minute decrease in the first minute after

exercise

Table 6: Coronary angiography: AHA Recommends Against

Indications COR LOE

NOT recommended to further assess risk in patients with SIHD who have an EF > 50% and low-risk criteria on non-invasive testing

III B

NOT recommended to assess risk in patients who are at low risk according to clinical criteria and who have not undergone non-invasive testing

III C

1. Diagnostic approach in patients suspected of having IHD

Functional (or “stress”) testing for initial diagnosis of IHD looking for inducible ischemia using either exercise or pharmacological stress to ↑ myocardial oxygen demand (exercise or dobutamine) OR affect coronary blood flow (e.g. adenosine) Pharmacological stress:

• Dobutamine increases heart rate and inotropy • Vasodilators (adenosine, dipyridamole or regadenoson) increases blood flow in normal arteries

while decreasing perfusion to stenotic arteries Standard Exercise Stress Test

• Pre-requisites include: ability to exercise AND an interpretable resting EKG (normal or < 5 mm ST-T wave abnormalities)

o Diagnostic endpoint is > 1 mm ST segment depression (horizontal or down-sloping) at peak exercise

� ST segment elevation is infrequent, but is high risk and consistent with ACS o Test sensitivity is ~ 61% and specificity is ~ 75%

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o Non-EKG factors increase the accuracy of the test � Exercise duration � Angina � Ventricular arrhythmias � Heart rate recovery � Drop in SBP with exercise

Exercise AND Pharmacological (Dobutamine) Stress ECHO

• Diagnostic endpoint is new or worsening wall motion abnormalities and changes in global LV function during or after stress

o Test sensitivity and specificity is ~ 80 - 85% % for exercise and 80 - 90% for pharmacological testing

Exercise AND Pharmacological Stress MPI and myocardial perfusion PET

• Diagnostic endpoint of nuclear MPI is reduced myocardial perfusion after exercise • Non-perfusion related high risk markers include: abnormal ECG, wall-motion abnormalities

induced by stress, reduced post stress EF (> 5%), transient LV dilation, increased lung or RV uptake

• Abnormal coronary flow reserve with PET • The sensitivity and specificity is ~ 85% and 80% for exercise and 90% and 85% for

pharmacological nuclear MPI Anatomic approach testing assessing for coronary stenosis Coronary CT Angiography (CCTA)

• Images are ~ 95% sensitive and ~ 85% specific for detecting stenotic CAD • Negative predictive value for obstructive CAD is high • Can also detect non-obstructive plaque • Note: not every stenotic lesion leads to ischemia and ischemia can be present in the absence

of significant stenosis • If ischemia on EST is the outcome, then the PPV of CCTA stenosis is ~ 40% • Coronary calcification can preclude accurate assessment of lesion severity or cause a false

positive test Coronary artery calcium (CAC) Scoring

• Sensitivity is 85% and specificity is 75% for obstructive CAD, the presence of any calcium has a sensitivity of 98% and specificity of 40% for obstructive CAD

• Perfusion defects or high grade coronary stenosis can be present in up to 39% of patients with a calcium score of zero

• Obstructive disease in the absence of CAC (coronary artery calcium)

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2. Guideline directed medical therapy (GDMT) to prevent death and MI in patients with stable ischemic heart disease (SIDH)

Lipid Management Class I recommendations

• Life style modifications (exercise: 30 – 60 minutes 5 days a week moderate intensity; weight management; BMI goal 18.5 – 24.9; saturated fat < 7% and trans fat < 1% total calories and cholesterol < 200 mg /day) AND moderate to high dose of a statin.

Class IIa recommendations • Lowering LDL cholesterol with bile acid sequestrants, niacin or both is reasonable

Blood Pressure Management Class I recommendations

• Lifestyle (same as above PLUS moderate alcohol: < 1 drink/day for women and 2 drinks/day for men; sodium reduction, increased fresh fruits and vegetables) AND antihypertensive therapy if BP > 140/90 (ACE and/or BB, with other drugs such as thiazide, or CCB) to achieve a BP < 140/90

Antiplatelet Agents Class I recommendations

o ASA 75-162 mg daily in absence of contraindications (relative decrease of 37 – 53% in CV outcomes)

o ASA 75 – 162 mg daily is equally effective as 325 mg, with a lower risk of bleeding o ASA < 75 mg daily less proven benefit

o Clopidogrel reasonable alternative if ASA contraindicated Class IIb recommendations

o Daily dual anti-platelet therapy (DAPT) with ASA 75 – 162 mg AND clopidogrel 75 mg might be reasonable in certain high-risk patients with SIHD (e.g. post PCI and recent NSTEMI)

Beta-blocker (BB) therapy Class I recommendations

o BB should be started and continued for 3 years in all patients with normal LVF after MI or ACS o BB (carvedilol, metoprolol succinate or bisoprolol) should be used all patients with reduced

LVF (< 40%) with heart failure or prior MI Class II recommendations

o BB may be used as chronic therapy for patients with CAD or other vascular disease ACE or ARB’s Class I recommendations

• ACE inhibitors should be prescribed in all patient’s with SIHD PLUS hypertension, DM, EF < 40%, or CKD

• Use ARBs in all patient’s with SIHD PLUS hypertension, DM, EF < 40%, or CKD and intolerant of ACE inhibitors

Class II recommendations

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• ACE or ARBs inhibitor use is reasonable in patients with SIHD and other vascular disease

3. Medical therapy for relief of symptoms in patients with SIDH

Beta-blocker (BB) therapy Class I

o BB should be prescribed as initial therapy for symptoms relief in patients with SIHD o Calcium channel blockers (CCB) or long acting nitrates should be prescribed when BB are

contraindicated or cause unacceptable ADE (B) o CCB OR long-acting nitrates IN ADDITION TO BB should be used if initial treatment with BB is

unsuccessful (B) o Use sublingual nitroglycerin (pill or spray) for immediate relief of angina (B)

Class IIa o Long-acting CCB (verapamil or diltiazem) instead of a BB is reasonable (B) o Ranolazine can be useful as a substitute for BB (B) o Ranolzaine can be useful in combination with BB if if initial treatment with BB is unsuccessful

(A)

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Editor's Choice

#1: Testing to reassure doesn't reassure Clinical Question: Do negative test results reassure patients? Study Design: Systematic review Funding: Government Setting: Various (meta-analysis) Synopsis: These authors searched several databases, including the Cochrane Library, to find randomized controlled trials comparing the effectiveness of diagnostic testing with no testing for symptomatic patients with a low probability of serious disease based on clinical features. They included articles written in any language but excluded unpublished research. Two authors independently selected studies for inclusion. They identified 14 studies of 3828 patients. Most of the studies evaluated the effectiveness of endoscopy and radiology for dyspepsia; other studies included imaging for back pain, electrocardiogram and blood tests for chest pain, event recording for palpitations, and MRI for chronic headache. Three studies showed no overall effect of diagnostic testing on illness worry and 2 showed no effect on nonspecific anxiety. Eleven studies showed no overall long-term effect on the persistence of symptoms (ie, "therapeutic testing"). There was significant heterogeneity among some of the studies. Excluding outlying studies, a meta-analysis showed a small reduction in primary care visits (odds ratio = 0.77; 95% CI, .62-.96). This effect translates into 1 less visit for every 16 patients with dyspepsia and 1 less visit for every 26 patients with back pain who undergoes diagnostic testing. Bottom Line: Diagnostic testing does not reassure patients with low probability of serious disease. It also does not decrease their chronic symptoms. It may, however, decrease their likelihood of returning to the office. (LOE = 1a-) Rolfe A, Burton C. Reassurance after diagnostic testing with a low probability of serious disease. Systematic review and meta-analysis. JAMA Intern Med 2013;173(6)407-416. #2: Coke is it -- for phytobezoars Clinical Question: Is Coca-Cola effective in dissolving gastric phytobezoars? Study Design: Decision analysis Funding: Self-funded or unfunded Setting: Outpatient (specialty) Synopsis: When I was young (I'm old enough to remember the "Coke is it!" ad campaign), it was common knowledge that the soft drink Coca-Cola could be used to remove rust from objects. It turns out that the high acidity that removes rust may also help lyse phytobezoars. The authors of this review searched 3 databases and identified 24 publications including 46 patients with phytobezoars treated with Coca-Cola. The cola was administered orally in doses of 500 mL up to 3000 mL over 24 hours or, in a few cases, via lavage. A total of 91.3% of the patients responded to the Coca-Cola administration with complete resolution: either after a single treatment (50%) or combined with endoscopic removal. Four patients underwent surgical removal. Bottom Line: Okay, so phytobezoars don't come up that often in practice. Neither, though, does the opportunity to prescribe Coca-Cola. In this systematic review of the effectiveness of Coca-Cola as dissolution therapy, 24 case reports of a total of 46 patients found a 50% rate of complete resolution after a single treatment. One report found Diet Coke (Coca-Cola Light) also to be effective. No word yet on the effectiveness of Dr Pepper. (LOE = 4) Ladas SD, Kamberoglou D, Karamanolis G, Vlachogiannakos J, Zouboulis-Vafiadis I. Systematic review: Coca-Cola can effectively dissolve gastric phytobezoars as a first-line treatment. Aliment Pharmacol Ther 2013;37(2):169-173. #3: Increased mortality associated with oophorectomy Clinical Question: Is bilateral oophorectomy for benign indications at the time of hysterectomy associated with different mortality risks than hysterectomy with ovarian conservation? Study Design: Cohort (prospective) Funding: Government Setting: Population-based Synopsis: This paper reports an analysis of the Nurses' Health Study cohort to evaluate mortality risk associated with bilateral oophorectomy as opposed to ovarian conservation at the time of hysterectomy. The cohort began in 1976 and included 121,700 women. This analysis included 16,914 women who underwent hysterectomy with bilateral oophorectomy and 13,203 who had ovarian conservation. The cohort is relatively homogeneous with regard to race (94% white) and socioeconomic status. Life-table analysis was performed using Cox proportional hazards models with censoring at oophorectomy subsequent to hysterectomy, death, or the end of follow-up in June 2008. Three subcohorts were modeled separately according to age at hysterectomy: younger than 50 years, 50 to 59 years, and 60 years or older. Multiple analyses were conducted based on estrogen use and cardiovascular risk. All-cause mortality was higher among women who had oophorectomy (hazard ratio [HR] = 1.13; 95% CI, 1.06-1.21), despite reduced risk for ovarian cancer mortality (HR = 0.06; 0.02-0.17). Significant associations with increased mortality after oophorectomy were identified for coronary heart disease, lung cancer, colorectal cancers, and total cancers. Analysis based on age at hysterectomy did not demonstrate any age at which oophorectomy conferred a survival benefit. For women younger than 50 years at the time of hysterectomy with oophorectomy there was increased all-cause mortality among women who never used estrogen therapy (HR = 1.41; 12.04-1.91; number needed to treat to harm = 8), but not among women who were past users or current users of estrogen. An analysis of the subgroup of women with at least 15 years of follow-up subsequent to their hysterectomy also showed oophorectomy was significantly associated with death from all causes (HR = 1.09; 1.01-1.17). The subgroup of women at high risk for ovarian and breast cancers on the basis of their family history (mother or sister) did not identify a different pattern, but the total number was too small for meaningful analysis. Bottom Line: Bilateral oophorectomy at the time of hysterectomy for any indication other than gynecological cancer is associated with increased all-cause mortality as compared with ovarian conservation, despite the fact that deaths due to ovarian cancer decreased. No

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subgroup of women was identified in which oophorectomy conferred mortality benefit. The number of women included in this study who were at high risk for ovarian cancer or breast cancer on the basis of family history was too small to evaluate. (LOE = 2b) Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses' Health Study. Obstet Gynecol 2013;121(4):709-716. #4: Clarithromycin associated with cardiovascular events Clinical Question: Is clarithromycin associated with the development of cardiovascular events? Study Design: Cohort (retrospective) Funding: Self-funded or unfunded Setting: Inpatient (any location) Synopsis: This study collected data on 1343 patients admitted for treatment of COPD in 12 United Kingdom hospitals and on 1631 patients admitted for treatment of pneumonia. The patients were prospectively identified upon admission and were followed up over the course of the next year. Overall, 268 cardiovascular events occurred in the COPD group and 171 cardiovascular events occurred in the pneumonia group. After adjusting for factors such as age, sex, history of cardiovascular disease, and other co-morbidities, clarithromycin use was associated with an increased risk of cardiovascular mortality among COPD patients (adjusted hazard ratio [AHR] = 1.52; 95% CI, 1.0 - 2.26), but was not associated with an increased risk in pneumonia patients. Cardiovascular events were not higher during the time of treatment, but were higher in the subsequent year. All-cause mortality rates were not different for patients receiving clarithromycin. Clarithromycin was associated with a slightly increased risk of cardiovascular events (AHR = 1.50 - 1.68 in both groups of patients). Acute coronary syndrome rates were higher with clarithromycin in COPD patients but not the pneumonia patients. This increase was not seen with other antibiotic treatment. These results echo results from randomized controlled trials that evaluated the effect of macrolide antibiotics on cardiovascular events (Cardiology 2008;111:280-7). The underlying mechanism is not known. Bottom Line: The use of clarithromycin (Biaxin) to treat patients hospitalized with chronic obstructive pulmonary disease (COPD) or pneumonia is associated with an increased likelihood of experiencing a cardiovascular event and an increased risk of cardiovascular mortality in patients with COPD. Overall mortality rates are not affected. The increase does not occur during the course of treatment, leaving investigators scratching their heads regarding a mechanism. (LOE = 2b) Schembri S, Williamson PA, Short PM, et al. Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies. BMJ 2013;346:f11235. #5: Low-dose penicillin prevents recurrent cellulitis Clinical Question: Does penicillin in a low dose prevent recurrent cullulitis of the leg? Study Design: Randomized controlled trial (double-blinded) Funding: Foundation Allocation: Concealed Setting: Inpatient (any location) with outpatient follow-up Synopsis: Patients with at least 2 episodes of leg cellulitis within the past 3 years were eligible for the study. Their mean age was 58 years, 60% were women, their mean body mass index (BMI) was 35 kg/m2, and 25% had venous insufficiency. The average number of previous episodes of cellulitis was 3.75. Patients were randomized to receive penicillin 250 mg twice daily or placebo, and groups were balanced at the start of the study. Although 274 patients were initially randomized, 26 withdrew consent, were lost to follow-up, or died. Patients were followed up for at least 18 months and up to 3 years. At the end of the follow-up period, the median time to the first recurrent episode of cellulitis was 626 days for those receiving penicillin and 532 days for those receiving placebo. The probability of any recurrence was lower in those receiving penicillin (22% vs 37%; P = .01; number needed to treat = 6). Adverse events were slightly less common in the penicillin group and were mild. Patients with a higher BMI, those with edema, and those with more previous episodes were less likely to respond. Bottom Line: For patients with at least 2 previous episodes of cellulitis in the previous 3 years, low-dose penicillin can prevent recurrence (number needed to treat = 6). (LOE = 1b) Thomas KS, Crook AM, Nunn AJ, et al, for the U.K. Dermatology Clinical Trials Network's PATCH I Trial Team. Penicillin to prevent recurrent leg cellulitis. N Engl J Med 2013;368(18):1695-1703. #6: Continued warfarin better than bridging therapy for pacemaker or defibrillator surgery (BRUISE CONTROL) Clinical Question: For patients who are currently taking warfarin and undergoing the insertion of a pacemaker or defibrillator, should warfarin be continued or should they be bridged with heparin? Study Design: Randomized controlled trial (single-blinded) Funding: Government Allocation: Concealed Setting: Inpatient (any location) with outpatient follow-up Synopsis: There have been very few clinical trials to guide decisions about anticoagulation management during surgical procedures. This is one of the first to rigorously address this issue. The researchers identified 681 patients with at least a 5% annual risk of thromboembolism who were taking warfarin and who were scheduled to have a pacemaker or defibrillator implanted. Their mean age was 71 years, 73% were male, and most had atrial fibrillation or flutter as the indication for anticoagulation. The patients were randomized, with appropriate concealment of allocation, to either continue their usual management with warfarin or to receive bridging heparin. Patients in the bridging group received their final dose of warfarin at least 5 days before the procedure, and received full-dose low-molecular-weight or unfractionated heparin from that point until 24 hours before the procedure (for the low-molecular-weight

59

heparin) or 4 hours before the procedure (for the unfractionated heparin). The heparin was restarted 24 hours after the procedure. Once the therapeutic international normalized ratio (INR) was achieved, the warfarin was restarted and the heparin discontinued. The patients were not masked, but the members of the care team evaluating the patient for hematoma were masked to group assignment. Groups were balanced at the beginning of the study, analysis was by intention to treat, and follow-up was excellent. The primary outcome was a device-pocket hematoma that necessitated further surgery, a longer hospitalization, or interruption of anticoagulation. The study was termined prematurely because this outcome occurred in 3.5% of patients in the continued warfarin group and 16.0% in the heparin bridging group (relative risk = 0.19; 95% CI, 0.1 - 0.36; absolute risk increase = 12.5%; number needed to treat to harm = 8). Two patients in the continued warfarin group had embolic events, but both had unintentionally subtherapeutic INR values of 1.0 and 1.2. Bottom Line: This is the best and largest single trial comparing continued warfarin with a bridging strategy. Patients with an annual risk of thromboembolic events of 5% or more undergoing pacemaker or defibrillator surgery who continued to use warfarin had fewer device-pocket hematomas than patients who received bridging therapy with heparin. This result is consistent with the results of previous observational studies (Circulation 2012;138:840-7) that found bridging actually worsens outcomes. One theory is that the surgeons doing the implantation in an anticoagulated patient were better able to identify potential bleeding complications intraoperatively: what the authors call an "anticoagulant stress test." It's refreshing that the simpler, less expensive, and far less complex strategy is also the better one. (LOE = 1b) Birnie DH, Healey JS, Wells GA, et al, for the BRUISE CONTROL Investigators. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013;368(22):2084-2093. #7: NSAIDs and COX-2 agents pose vascular risk to adults Clinical Question: How common are adverse vascular and gastrointestinal events among nonsteroidal anti-inflammatory drugs? Study Design: Meta-analysis (randomized controlled trials) Funding: Government Setting: Outpatient (any) Synopsis: These authors (who have an impressive list of ties to industry) searched multiple databases to find published and unpublished randomized trials of at least 4 weeks' duration that compared a nonsteroidal anti-inflammatory drug (NSAID) against placebo, open controls, or another NSAID. In addition to analyzing the studies using standard meta-analytic approaches, the researchers also tried to obtain patient-level data. They evaluated the rate of major vascular events (defined as nonfatal myocardial infarction, nonfatal stroke, or death from a vascular cause), major coronary events (nonfatal myocardial infarction or death from coronary disease), stroke, hospitalization, and upper gastrointestinal complications (bleeding, perforation, or obstruction). Two authors independently assessed studies for inclusion and extracted study characteristics and data. The authors don't describe how discrepancies were resolved or whether they formally assessed study quality. Ultimately, they included 280 placebo-controlled trials (with more than 124,000 patients) and 470 trials comparing NSAIDs to NSAIDs (nearly 230,000 patients). Most of the trials lasted less than 1 year. The included trials provided approximately 90% of the available data to the researchers. Compared with placebo, patients taking a coxib expereinced more major vascular events (1.2% per year) than patients taking placebo (0.8% per year; number needed to treat to harm [NNTH] = 250 per year), more admissions for heart failure (0.7% vs 0.3% per year; NNTH = 250), deaths from all causes (1.7% vs 1.4% per year; NNTH = 417), and upper gastrointestinal (GI) complications (0.4% vs 0.2% per year; NNTH = 527). In studies comparing a coxib with diclofenac, the patients taking coxibs had lower annual rates of major vascular events (0.8% vs 1.1%; number needed to treat [NNT] = 358); heart failure admissions (0.9% vs 1.7%; NNT = 117); and upper GI complications (0.7% vs 1.2%; NNT = 193). Compared with ibuprofen, patients taking coxibs were less likely to be admitted for heart failure (0.4% vs 1.6% per year; NNT = 82) and upper GI complications (0.2% vs 0.6% per year; NNT = 257). Finally, in studies comparing coxibs and naproxen, patients taking coxibs had lower annual rates of heart failure admissions (0.8% vs 1.8%; NNT = 98) and upper GI complications (0.3% vs 0.5%; NNT = 477). Bottom Line: Diclofenac, ibuprofen, and COX-2 inhibitors (coxibs) cause more vascular complications than placebo. (LOE = 1a) Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013, early online publication May 30, 2013. http://dx.doi.org/10.1016/S0140-6736(13)60900-9 #8: ACG guidelines for celiac disease Clinical Question: What are the current recommendations regarding the diagnosis and treatment of celiac disease? Study Design: Practice guideline Funding: Foundation Setting: Various (guideline) Synopsis: Gluten-free diets are the new craze, yet the prevalence of CD is only approximately 1% in the general population. Nevertheless, it is the most common cause of chronic malabsorption. This guideline took an evidence-based approach to reviewing the literature and making recommendations for practice. Typical signs and symptoms include weight loss associated with chronic diarrhea, steatorrhea, abdominal pain (especially after meals), and bloating. If CD is suspected, the best initial test is for IgA anti-tTG antibodies. First-degree relatives of persons with confirmed CD who have any of the above symptoms should also be tested. Because IgA deficiency is present in approximately 2% to 3% of CD patients, it is reasonable to simultaneously order an IgA level. Patients with IgA deficiency should have an IgG-based test such as IgG-deamidated gliadin peptides; CD is ruled out in those with negative tTG and normal IgA results. It is not necessary to order multiple tests as a panel -- just get the tTG results initially. The diagnosis should be confirmed by duodenal biopsy. All tests should be performed while the patient is eating a gluten-containing diet. For those patients who refuse to eat gluten because they "know" it is the problem, HLA-DQ2/DQ8 testing can exclude CD. At least, it will exclude it to their physician's satisfaction. Treatment is, of course, with a gluten-free diet for life. Pure oats can be consumed, although sometimes glutens contaminate oat-containing products. On initial diagnosis, consider testing for iron, folic acid, vitamin D, and vitamin B12 deficiencies, especially if clinically suspected.

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Bottom Line: The measurement of IgA anti-tissue transglutaminase (tTG) antibodies is the best test for celiac disease (CD). Be aware of IgA deficiency if the test result is negative, but clinical suspicion is high. Confirm the diagnosis with a biopsy. The treatment for CD is a gluten-free diet for life. (LOE = 1a) Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108(5):656-676. #9: Skip the strict salt and fluid restriction for hospitalized heart failure patients Clinical Question: Does fluid and sodium restriction increase weight loss and improve clinical stability in hospitalized patients with acute decompensated heart failure? Study Design: Randomized controlled trial (double-blinded) Funding: Foundation Allocation: Concealed Setting: Inpatient (any location) Synopsis: Many patients hospitalized for acute decompensated systolic heart failure are placed on fluid and sodium restriction, but it is unclear whether this practice is beneficial. In this small study, investigators randomized these patients to a fluid-restricted and sodium-restricted diet or a standard hospital diet. Patients in the intervention group (n = 38) had a fluid restriction of 800 mL per day and a sodium restriction of 800 mg per day until discharge or hospital day 7, whichever came first. Patients in the control group (n = 37) received liberal fluids and sodium (at least 2.5 L per day and 3 g to 5 g per day, respectively). Baseline characteristics were similar in the 2 groups. The majority of the patients were white men, the mean ejection fraction in the entire group was 26%, and almost all patients were classified as New York Heart Association class III or IV. Three days after randomization, there were no significant differences detected in weight loss, clinical stability as assessed by the clinical congestion score, rates of intravenous diuretic or vasodilator use, mean diuretic doses required, or time to transition from intravenous to oral diuretic therapy. Patients in both groups lost approximately 4.5 kg of body weight during this time. The restricted group had significantly greater perceived thirst than the control group. At 30-day follow-up, patients in the restricted group were actually noted to be slightly more congested, with a clinical congestion score 2.4 points higher than the control group, but there was no difference in 30-day readmission rates between the groups. Given the small sample size, this study was likely underpowered to detect such a difference if it exists. Bottom Line: This study suggests that a low-sodium and fluid-restricted diet, as compared with a nonrestricted diet, for patients hospitalized with acute decompensated heart failure does not expedite weight loss or decrease congestion. Patients placed on such diets are, as expected, significantly thirstier than their standard-diet counterparts (and may complain more about the bad hospital food). (LOE = 1b) Aliti GB, Rabelo ER, Clausell N, Rohde LE, Biolo A, Beck-da-Silva L. Aggressive fluid and sodium restriction in acute decompensated heart failure. JAMA Intern Med 2013;173(12):1058-1064. #10: Antibiotic prophylaxis effective after urinary catheterization Clinical Question: Should hospitalized patients receive antibiotic prophylaxis at the time of urinary catheter removal? Study Design: Meta-analysis (other) Funding: Self-funded or unfunded Setting: Inpatient (any location) Synopsis: To develop this meta-analysis the authors searched several databases (including the Cochrane Library), conference abstracts, and reference lists of identified studies to find studies in any language that evaluated the effect of prophylaxis following removal of a short-term (14 days or less) urinary catheter. Two researchers independently selected studies for inclusion and evaluated study quality. They identified 6 randomized controlled studies and 1 nonrandomized controlled intervention study with a total of 1520 patients, most of whom had surgery. Prophylaxis consisted of 1 to 3 doses of a typical "urinary antibiotic before or at the time of catheter removal." Prophylaxis decreased the likelihood of infection within the subsequent 4 days to 42 days from 10.5% to 4.7%, translating into 1 less infection for every 17 patients who received prophylaxis (number needed to treat = 17, 95% CI, 12-30). There was little heterogeneity among the studies but some indication of publication bias risk. In addition, 2 of the larger studies, comprising 66% of the patients, had significant risk of bias, making the results of this analysis less trustworthy. Removing the nonrandomized study did little to affect the estimate of benefit. Bottom Line: One to three doses of antibiotic at the time of a urinary catheter removal following short-term placement in hospitalized patients reduces by half the likelihood of a subsequent urinary tract infection (number needed to treat = 17). The antibiotics studied include ciprofloxacin, co-trimoxazole, nitrofurantoin, and cefotaxime. (LOE = 1a-) Marschall J, Carpenter CR, Fowler S, Trautner BW, for the CDC Prevention Epicenters Program. Antibiotic prophylaxis for urinary tract infections after removal of urinary catheter: meta-analysis. BMJ 2013;346:f3147. #11: No association seen between standard-dose NSAIDs and progression of moderate CKD Clinical Question: Should patients with chronic kidney disease entirely avoid nonsteroidal anti-inflammatory drugs? Study Design: Systematic review Funding: Foundation Setting: Various (meta-analysis) Synopsis: Although patients with CKD are advised to avoid NSAIDs, the strength of evidence for this advice is uncertain. The authors of this systematic review carefully searched the literature and identified 5 cohort studies, 1 cross-sectional study, and 1 case-control study that addressed this question. The number of participants ranged from 801 to more than 1.5 million, with mean ages of participants between 45 years and 76 years. Progression of CKD was defined as an estimated glomerular filtration rate (eGFR) decrease of more than 15 mL per minute per 1.73 m2. Among patients with stage 2-3 CKD (eGFR between 30 mL/min and 90 mL/min), use of standard dose NSAIDs was not associated with an increased risk of progression of CKD. There was a modest association between high-dose NSAIDs and progression (relative risk = 1.26; 95% CI, 1.06 - 1.50). No association was seen with moderate dose NSAIDs (odds ratio = 0.96; 0.86 - 1.07), although the definition of moderate versus high-dose was not clearly stated by the authors. The 3 cohort studies that informed this conclusion included more than 55,000 patients.

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Bottom Line: Low or moderate doses of nonsteroidal anti-inflammatory drugs (NSAIDs) appear to be safe for patients with moderate chronic kidney disease (CKD; estimated glomerular filtration rate = 30 mL/min to 90 mL/min). High-dose NSAIDs should be avoided. Given the limitations of this evidence -- which was based on data from 7 observational studies rather than from randomized controlled trials -- caution is still prudent, and the lowest possible dose and duration should be advised. On the other hand, for patients with severe osteoarthritis, careful use of NSAIDs may be worth the small risk of progression of their CKD. (LOE = 2a) Nderitu P, Doos L, Jones PW, Davies SJ, Kadam UT. Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review. Fam Pract 2013;30(3):247-255. #12: Patients with claudication: start with supervised exercise Clinical Question: Are patients with claudication better off if they go straight to endovascular revascularization than if they start with supervised exercise? Study Design: Randomized controlled trial (nonblinded) Funding: Unknown/not stated Allocation: Concealed Setting: Outpatient (specialty) Synopsis: In this randomized trial with 7 years of follow-up, patients with stable claudication and radiographically confirmed iliac and femoropopliteal disease were randomized to participate in a supervised exercise program (n = 75) or to receive endovascular repair (n = 76). The supervised exercise program consisted of 24 weeks of 30 minutes on a treadmill twice a week. Additionally, the patients were asked to walk for at least 30 minutes 3 other times a week. After the 24-week period, the patients were asked to walk for at least 1 hour every day. The endovascular repairs, performed by experienced interventional radiologists, consisted of balloon angioplasty plus optional stents followed by strong encouragement to walk regularly. (Oh, and how about smoking cessation? The authors don't say a thing.) Using intention-to-treat analysis, the investigators evaluated several disease-oriented measures and a few patient-oriented outcomes: maximum walking distance, maximum pain-free walking distance, ankle-brachial indices, and several quality of life measures. Additionally, they followed up with the patients to see what happened (eg, death or subsequent interventions). Curiously, the authors don't tell us about the patients' age, gender distribution, comorbid states, and so forth. However, the clinical factors for both groups were comparable at baseline. After 7 years of follow-up, 17 patients initially assigned to exercise died compared with 15 initially assigned to endovascular repair. Additionally, approximately half of the exercise group either went on to have endovascular repair or vascular surgery, while approximately one quarter of the endovascular patients had additional repairs or surgery. Two patients in the exercise group underwent minor amputations and none had major amputations compared with 0 and 3, respectively, in the endovascular repair group. As for the other outcome measures? No meaningful differences after 7 years. But the authors couldn't leave well enough alone: They went on to compare the total number of invasive interventions. Guess what? If you include the primary procedure and subsequent procedures, the endovascular group had more procedures. I don't know what this means. Bottom Line: Among patients with intermittent claudication, the long-term functional outcomes are similar in patients initially treated with exercise and in those who go straight to endovascular repair. Although approximately 50% of the exercise patients will go on to additional interventions compared with 25% of endovascular repair patients, many patients would probably prefer starting with the conservative route. Not addressed by these researchers is the importance of convincing your patients to quit smoking, regardless of which treatment choice they make! (LOE = 2b) Fakhry F, Rouwet EV, den Hoed PT, Hunink MG, Spronk S. Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial. Br J Surg 2013;100(9):1164-1171 . #13: Steroid injection for carpal tunnel symptoms delays need for surgery Clinical Question: Does a corticosteroid injection for carpal tunnel syndrome improve symptoms and decrease the need for surgery? Study Design: Randomized controlled trial (double-blinded) Funding: Foundation Allocation: Concealed Setting: Outpatient (specialty) Synopsis: These researchers enrolled 111 patients referred by primary care physicians for further evaluation and treatment of carpal tunnel syndrome. Wrist splinting had not been effective for eligible patients. The patients were enrolled, using concealed allocation, to receive a single injection of placebo or methylprednisolone 40 mg or 80 mg. At 10 weeks, average symptom improvement was significantly better with both doses of steroid than with placebo. After one year, though, there was no difference in scores. By one year, almost all patients receiving placebo had undergone surgery (92%) as compared with 73% of those given the high-dose steroid and 81% of those given the lower dose (patients made the decision whether to undergo surgery). Steroid treatment delayed the time until surgery was deemed necessary in both steroid groups. Bottom Line: Injection of methylprednisolone will delay or decrease the need for surgery as compared with placebo in patients with carpal tunnel syndrome, though after one year, 3 of 4 treated patients will still request surgery. (LOE = 1b) Reference: Atroshi I, Flondell M, Hofer M, Ranstam J. Methylprednisolone injections for carpal tunnel syndrome. A randomized, placebo-controlled study. Ann Intern Med 2013;159(5):309-317. #14: Guideline: When to screen for and treat chronic kidney disease Clinical Question: How should patients be screened, treated, and monitored for chronic kidney disease? Study Design: Practice guideline Funding: Self-funded or unfunded Setting: Various (guideline) Synopsis: This guideline from the American College of Physicians, based on a systematic review of the evidence, was sponsored by the Agency for Healthcare Research and Quality. It addresses several important questions in the care of patients with CKD, basing recommendations on the strength of evidence and a weighing of risks and burdens. Like a lot of guidelines, though, the authors do not explicitly explain how they weighed those risks and burdens. The guidelines are straightforward: (1) Do not screen asymptomatic adults

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without risk factors for CKD. There are too many false positive results if screening for albuminuria or calculating glomerular filtration rate on the basis of urine creatinine (weak recommendation, low-quality evidence). (2) Treat patients with CKD and hypertension with an ACEI or ARB -- but not both -- to decrease bad renal outcomes (strong recommendation). (3) Stop checking for proteinuria (macro or micro) in patients treated with and ACEI or ARB. You're already treating its cause (weak recommendation, low-quality evidence). (4) Treat high cholesterol in patients with CKD to lower their risk of cardiovascular outcomes (strong recommendation, moderate-quality evidence). Interestingly, and in contrast with some other organizations, the American College of Physicians does not give a recommendation regarding screening for CKD in patients with diabetes, hypertension, or cardiovascular disease (insufficient evidence). Bottom Line: The ACP recommends against routine screening in adults without risk factors for chronic kidney disease (CKD). They cite insufficient evidence to support or refute screening in patients with diabetes, hypertension, or cardiovascular disease. Once a patient is being treated with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB), there is no need to continue checking for proteinuria. Qaseem A, Hopkins RH, Sweet DE, Starkey, Shekelle P. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: a clinical practice guideline from the clinical guidelines committee of the American College of Physicians. Ann Intern Med 2013 doi: 10.7326/0003-4819-159-12-201312170-00726. #15: Natural history of actinic keratosis progression, regression, and recurrence Clinical Question: In patients with actinic keratosis, what are the average progression, regression, and recurrence rates of these skin lesions? Study Design: Systematic review Funding: Foundation Setting: Outpatient (specialty) Synopsis: In this systematic review of 24 articles, the authors describe the natural history of AKs: progression to squamous cell carcinoma, regression to healthy skin, or recurrence of the lesions. Because the studies were quite different regarding inclusion criteria, design (both observational and randomized controlled trials), definitions, and follow-up, the authors decided that statistically combining studies was inappropriate. Therefore, they only report the ranges for similar studies and do not perform a meta-analysis. For example, the risk of progression ranged from 0% to 0.53% per lesion for patients both with and without a history of nonmelanoma skin cancer. The authors estimate regression rates of 15% to 63% per lesion, and rates of recurrence range from 15% to 53%. Data describing changes in total AK counts over time vary widely, largely due to underlying differences with regard to sunscreen use or sun avoidance among the patients. In studies where patients were explicitly told to use sunscreen or to avoid the sun, a greater trend toward reduction in total AK count was found, ranging from 53 to +20%. This study has several limitations that affect its clinical estimates. Many of the articles did not fully report sunscreen use or the impact of age upon lesion behavior. High drop-out rates in some studies, as well as highly variable follow-up rates, also affect the quality of estimates. Several studies did not include information with regard to the treatment performed, especially in situations where squamous cell carcinoma was suspected, and most studies only followed patients for up to 12 months. And, finally, relying on clinical assessments of AK changes or total count can be challenging, particularly in patients with sun-damaged skin. Bottom Line: Single actinic keratoses (AKs) progress to squamous cell carcinoma at a rate of 0% to 0.53% per year, whereas regression rates of single AKs ranged from 15% to 63% per year. AK recurrence rates range from 15% to 53%. (LOE = 1b-) Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol 2013;169(3):502-518. #16: 5-FU is most effective therapy for actinic keratosis Clinical Question: What is the best treatment for actinic keratosis? Study Design: Meta-analysis (randomized controlled trials) Funding: Unknown/not stated Setting: Various (meta-analysis) Synopsis: A network meta-analysis is a relatively new approach to synthesizing the medical literature. A traditional meta-analysis combines results from similar trials (for example, 5-FU versus placebo for the treatment of actinic keratosis); a network meta-analysis instead allows us to compare interventions indirectly. For example, if both 5-FU and imiquimod were compared with placebo in several studies, we can determine the relative efficacy of the 2 drugs compared with each other. The authors built on a recent Cochrane review, and identified a total of 32 studies comparing treatments to each other and/or to placebo. The outcome used was "participant complete clearance," which is a good patient-oriented outcome (although the exact definition varied somewhat between studies). The authors concluded that 5-FU 5% is the best treatment, followed by imiquimod, 5-aminolaevulinic acid-photodynamic therapy, ingenol mebutate, and methyl aminolaevulinate-photodynamic therapy, which were all similarly effective. Cryotherapy was less effective than all of these, diclofenac/hyaluronic acid was even less effective, and placebo was least effective of all (not surprisingly). All studies had a follow-up of one year or less, a limitation. Bottom Line: This network meta-analysis found that 5-fluorouracil (5-FU) is the most effective treatment for actinic keratosis, based on the outcome of participant complete clearance. The authors caution that the final choice of therapy should take into account other factors, such as tolerability (which might favor imiquimod) or cost (which would favor cryotherapy). (LOE = 1a-) Gupta AK, Paquet M. Network meta-analysis of the outcome 'participant complete clearance' in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol 2013;169(2):250-259. #17: Respiratory tract symptoms in children last longer than expected Clinical Question: For common respiratory tract infections in children, what is the best guidance we can give parents regarding the time to symptom resolution? Study Design: Meta-analysis (other) Funding: Government Setting: Outpatient (primary care)

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Synopsis: To determine the duration of symptoms in children seeking treatment for earache, sore throat, cough, and common cold, these authors identified 23 randomized trials and 25 observational studies by searching 3 databases, including DARE. They only included studies published in English and conducted in high-income countries. They excluded studies of children with chronic infection or medical conditions associated with a high risk of serious infections. Two authors reviewed articles for inclusion and also assessed the quality of the included studies. Most studies had a low risk of bias, but the researchers were often unable to combine data because of differences in outcomes. Earache was reported to resolve in 50% of children within 3 days and in 90% by 7 to 8 days. Fever lasted an average of 3 days. For children with sore throat, approximately one third will still have pain at day 3 and 72% will have fever for at least 2 days. Cough resolved in 50% of children at 10 days, but it took 25 days for 90% of children to be cough free.Similarly, 50% of children with bronchiolitis will improve by day 13. For nonspecific respiratory tract infections (ie, the common cold), 50% of children will improve by 10 days. Bottom Line: No one has come up with a quick-fix-acillin for children with respiratory tract infections, which last longer than we expect and certainly longer than we want. The time for half the children with earache to be pain free is 3 days, but the time for 9 of 10 children to be pain free is 7 to 8 days. Sore throat symptoms will linger for at least 3 days in one third of children and 72% will have fever for at least 2 days. Cough will resolve in 50% of children within 10 days, but for the rest it will be another 2 weeks. For half the children, general symptoms of a common cold will last for at least 10 days(.L OE = 1a-) Thompson M, Vodicka TA, Blair PS, et al, for the TARGET Programme Team. Duration of symptoms of respiratory tract infections in children: systematic review. BMJ 2013;347:f2027. #18: Surgery does not improve outcomes for partial medial meniscectomy Clinical Question: For selected patients with a degenerative medial meniscus tear, does arthroscopic surgery improve outcomes? Allocation: (Concealed) Design: Randomized controlled trial (double-blinded); LOE: 1b Setting: Outpatient (specialty) Synopsis: Previous controlled trials showed no benefit to doing arthroscopic knee surgery for osteoarthritis as the sole indication. Although orthopedic surgeons are doing less arthroscopy for this indication (prodded by reimbursement changes), they have greatly increased the number of procedures for partial meniscectomy, perhaps to compensate. These Finnish researchers identified patients aged 35 years to 65 years with at least 3 months of knee pain thought to be caused by a tear of the medial meniscus. Symptoms included medial joint line tenderness (94%), pain with compression of the medial joint line (75%), catching or locking (47%), and a positive McMurray test result (22%). Patients with an obvious traumatic cause or worse than minor osteoarthritis on radiographs were excluded, although 50% had minor arthritic changes on radiographs and more than one third had the onset of symptoms after exercise, hard work, suddenly, or after twisting. All patients underwent arthroscopy, and during the procedure patients were randomized to receive partial meniscectomy or sham surgery. Of 160 patients who underwent arthroscopy, 14 were excluded because they did not have an isolated partial medial meniscus tear, and the remaining 146 were randomized and followed up for up to 12 months. The study was adequately powered to determine a minimal clinically important difference on the validated pain and function scales used as the primary outcomes. Patients and outcome assessors (but not surgeons) were masked to treatment assignment. They asked patients whether they thought they had received a sham procedure, and there was no difference in groups. There was initially a somewhat greater improvement in the intervention arm, but by 6 months there was little difference, and at 12 months the results were indistinguishable. There was also no difference in secondary outcomes, such as the need for further knee surgery or serious adverse events. Bottom line: In patients with no osteoarthritis or mild osteoarthritis and a nontraumatic partial medial meniscus tear, partial meniscectomy does not improve outcomes at 1 year. I wish this study had come out 12 years ago, when I had this exact surgery for this exact indication. Sihvonen R, Paavola M, Malmivaara A, et al, for the Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med 2013;369(26):2515-2524. #19: Nontraumatic supraspinatus tears: PT = PT + surgery at 1 year Clinical Question: In adults with nontraumatic supraspinatus tears, is physical therapy alone as effective as physical therapy plus surgery after 1 year? Allocation: (Concealed) Design: Randomized controlled trial (nonblinded); LOE: 2b Setting: Outpatient (specialty) Synopsis: This group of surgeons randomly assigned 180 adults older than 55 years with isolated nontraumatic supraspinatus tears to 1 of 3 treatment groups: physical therapy (PT); PT plus acromioplasty; or PT plus acromioplasty plus rotator cuff repair. Although they used intention-to-treat analysis to evaluate the main outcome, the authors don't report if any study personnel (other than the radiologists) were aware of the treatment allocation. The research staff determined the multidimensional Constant score for each patient at baseline and then 3, 6, and 12 months after intervention. The authors report that a difference of 10 points on the Constant score is the minimal clinically important difference. Thirteen patients didn't complete the study. At 3 months, the group receiving triple therapy had lower Constant scores than the other groups, but by 6 months the scores were comparable. At the end of the study, 87% of patients treated with PT were satisfied compared with 95% and 96% in the other treatment groups. The study was designed to have enough power to detect modest differences in the Constant score. This is one of many studies showing long-term outcomes of various orthopedic interventions are comparable (eg, steroid injections for shoulder pain vs conservative treatment). (HB) Bottom line: In this study, the long-term outcomes of adults with nontraumatic supraspinatus tears who are treated conservatively are similar to those of patients treated with two different surgical approaches. Kukkonen J, Joukainen A, Lehtinen J, et al. Treatment of non-traumatic rotator cuff tears: A randomised controlled trial with one-year clnnical results. Bone Joint J 2014;96(1):75-81.

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