general medicine update minnesota acp november 7, 2008 steve hillson hennepin county medical center...
TRANSCRIPT
General Medicine Update
Minnesota ACP
November 7, 2008
Steve Hillson
Hennepin County Medical Center
University of Minnesota
Objectives
• At the end of this session you should be able to:– Describe the main results of several
important reports from the past year– Decide how you want to change your
practice in the context of these findings
Disclosure
• I have no direct financial relationships with any commercial firm having any interest in any of the reports or topics I am about to discuss.
Process• Personally reviewed title of every original research
article from 10/01/07 till 10/22/08 in:– Annals of Internal Medicine– BMJ– JAMA– Lancet– New England Journal of Medicine
• Reviewed subspecialty updates, scattered other sources
• Personally reviewed abstract of every article with “interesting” title.
Process (cont’d)
• Selected “promising” articles by initial abstract review (about 100)
• Re-reviewed all abstracts, selecting about 60 with medium or high impact potential
• Solicited abstract reviews from colleagues to select subset of greatest importance
• Critically appraised final subset for presentation
Limitations on Process
• Personal idiosyncrasies• Incomplete survey of medical literature• No claim to comprehensive context for
assessing these articles• Very simplified presentation of complex
research• Final slide set available at
– www.paralleltext.net/ppt.html
In Pursuit of the Perfect A1C
• How intensely should we be controlling type 2 diabetes?
• 3 Important Articles– ACCORD, NEJM, June 2008
• Funded by NIH, CDC, with drugs contributed by many makers
– ADVANCE, NEJM, June 2008• Funded by maker of gliclazide
– UKPDS, NEJM, October 2008• Funded initially by UK government agencies, this follow-
up funded by drug makers
Purpose
• Assess tighter vs looser glycemic control in type 2 diabetes
• Previously limited information– None showing mortality or macrovascular
benefit in type 2 DM
• But extensive promulgation of the idea that lower is better
#1 - ACCORD
• Compare target A1C <6.0 to less tight (7-7.9) for cardiovascular outcomes
• Clinical Trial, unblinded– 10,000 US/Canadian patients with DM-2,
A1C≥7.5, and CV disease or risk factor– Any standard diabetes medications– More frequent visits and medication adjustments
for intensive therapy group– Followed 3.5 years for CV death, MI, CVA
#2 - ADVANCE
• Compare target A1C (<6.5) to less tight (local guideline) for vascular outcomes
• Clinical Trial, unblinded• 11,000 patients worldwide, type 2 diabetes,
age≥55, no insulin, and pre-existing vascular disease or a risk factor
• Gliclazide, plus frequent clinic visits and other drugs as needed, OR
• Usual care, with gliclazide excluded• Followed 5 years for vascular events
#3 - UKPDS 10-year follow-up
– Compare tight glycemic control (fasting glucose 108), to less tight (fasting glucose < 270) for macro- and microvascular outcomes
– Clinical Trial, unblinded– 4000 UK patients with new DM-2, age 25-65– Received one of several drug-based strategies OR– “Usual Care” with diet alone unless FPG>270– Treated 10 years, then followed additional 10
years on community standard care, for vascular outcomes
Findings - Achieved A1C
0
1
2
3
4
5
6
7
8
ACCORD ADVANCE UKPDS*
IntensiveStandard
Findings - Primary Outcomes
0
10
20
30
40
50
60
ACCORD ADVANCE UKPDS - All UKPDS -Metformin
IntensiveStandard
*
* *
Findings - Death
0
5
10
15
20
25
30
35
ACCORD ADVANCE UKPDS All UKPDSMetformin
IntensiveStandard
*
* *
Limitations• ACCORD used a lot of rosiglitazone
• Neither ACCORD nor ADVANCE achieved target A1C on most patients
• UKPDS “usual care” isn’t
Implications
• Target A1C of 6.5 or less is at best ambiguous for macrovascular disease, possibly dangerous– May depend on drug choice– Death (NNH of 100) trumps improved
nephropathy/retinopathy (NNT of 70)
• Metformin, without a tight target A1C, is useful for survival in obese diabetics (NNT about 15 over 20 years)
• I will not seek extremely tight A1C• I will use still more metformin
Preventing the Clot
• There’s a new perioperative anticoagulant on the block - 2 studies– RECORD1, NEJM, June 2008– RECORD3, NEJM, June 2008
Purpose
• Compare rivaroxaban to enoxaparin for preventing post-op VTE– Total Hip Arthroplasty (RECORD 1)– Total Knee Arthroplasty (RECORD 3)
• Funded by makers of rivaroxaban– Orally administered, fixed dose factor Xa inhibitor– Reportedly out in January
• Related drugs– Argatroban - parenteral– Ximelagatran - oral, withdrawn due to liver toxicity– Dabigatran - oral, possibly out in 2010
Method• Clinical trials, blinded• 2500 (knee) and 4400 (hip) patients, age≥ 18
with no hepatic or renal disease• Given rivaroxaban 10 mg orally each day, OR• Enoxaparin 40 mg SC each day
– KNEE study: 10-14 total days– HIP study: 35 total days
• Followed 2-6 weeks for venographic DVT and symptomatic VTE or death
Findings - Detectable Venous Thromboembolism
02468
1012
14161820
Hip Knee Bleeding
RivaroxabanEnoxaparin
Limitations
• Symptomatic VTE was rare (about one-tenth of all VTE events)
• Industry-funded research has many opportunities to mislead
• Issue of spinal catheter management not clarified
Implications
• I’m usually a turtle, but…– I will start using perioperative rivaroxaban when it
is released• Easier for everyone• Question of pricing
– Not for frail or otherwise high-risk patients– Does not replace heparin– Watch for studies comparing it to chronic
coumadin for long term anticoagulation– Look for dabigatran
The Infected Respiratory Tract
• Two studies of antibiotics– BMJ, October 2008– JAMA, December 2007
Purpose
• Assess the value of antibiotics (and steroids) for common respiratory tract infections
• Many guidelines and some prior evidence– Largely recommend against antibiotics for
most conditions in absence of pneumonia– Acute bacterial sinusitis more equivocal
#1 - Antibiotics for common respiratory infections
• Historical cohort study• 1.1 million episodes of respiratory infection
(URI, “chest infection,” sore throat, otitis,) in UK
• Record assessed for antibiotic prescription• Followed 1 month for diagnosis-specific
complications (pneumonia, quinsy, mastoiditis)
• Funded by UK Department of Health
Findings - Complications of Respiratory Infections
0
0.51
1.52
2.53
3.54
4.5
URI SoreThroat
Otitis ChestInfection
TreatedUntreated
(Elderly Patients Only)
#2 - Antibiotics and topical steroids for maxillary sinusitis
• Clinical trial, blinded• 240 adults with < 4 weeks acute
bacterial sinusitis (purulent discharge, local pain, pus on exam), no diabetes
• Treated with amoxicillin, budesonide spray, both or neither
• Followed for clinical cure at 10 days• Funded by UK Department of Health
Findings - Resolution of Sinusitis
01020304050
60708090
100
Amoxicillin Budesonide Nothing
10 Day Cure
Limitations• The respiratory complication study was
not a trial– Many ways that treated and untreated
groups may have differed– Including getting diagnosis of complication
• The sinusitis study was small– Could have missed difference in serious
complications
Implications
• Despite limitations– Antibiotics don’t seem important for bacterial
sinusitis, otitis, sore throat, URI– BUT, may be quite useful for “Chest Infection”
• Acute bronchitis?• NNT 40 to prevent pneumonia
– I will try to use less antibiotic for sinusitis (even acute bacterial) and otitis
– I will try to distinguish “chest infection” in older patients and treat
How Do You See the Colon?
• Two studies of CT Colonography– NEJM, October 2007
• Funding not reported,investigators receive money from makers of the colonography processing software
– NEJM, September 2008• Funded by National Cancer Institute and
American College of Radiology
Purpose• Determine whether a relatively non-invasive colonic
imaging technique can approach the ability of colonoscopy to detect pre- and early malignancies
• Colonoscopy never proven to reduce colon cancer mortality, but almost certainly does (FOBT does)
• Colonoscopy is expensive, inconvenient, and not completely safe– 1-3/1,000 have serious consequences, usually
associated with biopsies
• CT Colonography uses similar prep, insufflation, plus fluid tagging
#1 - CT Colonography for advanced neoplasia
– Cohort study, sort of– 6300 adults with no bowel disorder
• Half had enrolled in a CT colonography screening program (why?), with colonoscopy follow-up for selected findings
• Half were getting ordinary colonoscopic screening
– Assessed number and pathology of lesions found
– No follow-up
#2 - Accuracy of CT colonography
• “Test of a Test”• 2600 adults over 50, asymptomatic,
referred for ordinary colonoscopic screening– First received CT colonography– Follwed by immediate colonoscopy
• Assessed concordance for important polyps
Findings - Cohort Study
0
0.5
1
1.5
2
2.5
3
3.5
Advanced Adenomas Cancers
CTScope
*
Findings - Sensitivity Study
• CT detected– 90% of advanced lesions ≥ 1 cm– 65% of advanced lesions ≥ 5 mm
• CT incorrectly called abnormalities in 14% of subjects
Limitations
• First study had no direct comparison of CT to scope in the same patient– Why the excess of cancers in colonography?
• In both studies, CT found extracolonic stuff in majority of patients– Mostly trivial, often requiring further assessment
• In practice, unlikely to get immediate colonoscopy after positive CT– Requires repeat preps, other inconvenience
Implications
• CT Colonography still not ready for prime time– Difficult prep– Lots of follow-up colonoscopies– Lots of irrelevant findings
• I won’t be doing it• Fecal Occult Blood for my patients who
don’t want colonoscopy
After the Fall
• Prevention after a hip fracture
• NEJM, November 2007
• KW Lyles et al.
Purpose
• Determine whether annual infusion of zoledronic acid reduces subsequent fracture after hip fracture repair
• Inconclusive prior evidence about bisphsphonates following hip fracture
• Funded by the maker of zoledronic acid
Method
• Clinical Trial, blinded• 2100 adults with recent “minimal trauma” hip
fracture, previously ambulatory, no kidney disease, and refusing oral bisphosphonate
• Received Calcium and Vitamin D, plus– 5 mg IV zoledronic acid or placebo infusion
annually
• Followed 2 years for new clinical fractures and survival
Findings
0
2
4
6
8
10
12
14
Hip Fx Vertebral Fx Any Fx Death
Zoledronic AcidPlacebo
Limitations
• Mortality benefit unexpected and unexplained
• Industry-funded research has many opportunities for misleading reports
Implications
• Bisphoshonates reduce subsequent fractures and possibly mortality following hip fracture repair– NNT for another hip fx = 70 over 2 years– NNT for death = 27 (!)
• If oral bisphosphonates aren’t an option, zoledronic acid can be given IV yearly– Alendronate $100/month– Zoledronic acid $1200/year
Is the Blockade Working?
• Perioperative beta blockers
• The Lancet, May 2008
• The POISE study group– Funded by governments of Canada,
Australia and Spain, with some support from maker of the study drug
Purpose
• Reassess perioperative beta-blockade for preventing cardiac complications after non-cardiac surgery
• Several prior studies indicate improved post-operative cardiac outcomes with beta-blockade
• “Standard of care” for higher risk patients for at least 5 years– Some doubts due to study limitations and some
conflicting results
Method
• Clinical trial, blinded• 8300 adults worldwide, age ≥ 45, either existing
major vascular disease or at least 3 risk factors– Age>70, TIA, DM, CRF (2.0), CHF history, emergent
or high-risk surgery
• Received metoprolol, starting 4 hours pre-op, or placebo– Held for P<45 or SBP < 100
• Followed 1 month for major vascular outcomes and death
Findings
0
1
2
3
4
5
6
7
CompositeEndoint
MI Stroke Death
MetoprololPlacebo
Limitations
• Beta-blocker started immediately pre-op
• Drug held only for “consistent” severe bradycardia or hypotension
• Excluded patients whose physicians had planned to beta-block
Implications
• Perioperative beta-blockade, at least as done in this study, may be dangerous
• I’m limiting my use– Only beta-block if otherwise indicated– Only with plenty of advance time for slow up-
titration (a month!)– Not in higher stroke risk setting
• (Sad sigh…)
All you need is…Salt?
• Saline or bicarbonate for preventing contrast nephropathy
• JAMA, September 2008
• SS Brar et al.
Purpose
• Reassess whether bicarbonate infusion reduces contrast nephropathy
• Prior evidence that contrast nephropathy is common, around 25% of high-risk patients
• A few prior reports showed reduced nephropathy with pre-procedure bicarbonate hydration
• Funded by Kaiser Permanente
Method
• Clinical Trial, unblinded• 350 adults having non-emergent cardiac
catheterization, with GFR ≤ 60 and at least 1 of:– DM, CHF, HBP, Age > 75– Received either Sodium Bicarbonate, 150 meq in
1 liter D5, OR Normal Saline.• 3 ml/kg/hour for 1 hour pre-procedure, then 1.5
ml/kg/hour during and 4 hours after
– Followed 4 days for 25% fall in GFR
Findings
0
2
4
6
8
10
12
14
16
25% Fall in GFR 0.5 Cr Rise
BicarbonateSaline
Limitations
• Relatively small study
• Only coronary angiography patients
• Relatively good baseline GFR
Implications
• Bicarbonate might not be necessary for renal protection from contrast dye– Saline hydration probably acceptable
substitute
• However– Bicarbonate is not hard or apparently
dangerous to use– Should certainly use some form of
hydration
Staying Off the Sauce
• Baclofen to maintain alcohol abstinence
• The Lancet, December 2007
Purpose
• Assess whether baclofen can help achieve and maintain alcohol abstinence in cirrhotic alcoholics
• Growing interest in several drugs to help prevent alcohol craving and relapse– Naltrexone, acamprosate, topiramate
• Limited information, particularly in cirrhotic patients
• Funded by Italian government
Method
• Clinical Trial, blinded• 84 adults, age 18-75, with alcoholic cirrhosis,
at least 14 (women) to 21 (men) weekly drinks, and no other major system disease
• Admitted, given baclofen 5-10 mg tid, for 12 weeks, or placebo– Also frequent visits with counseling
• Followed 4 months for self- and family-reported abstinence – Dropouts assumed to be relapsed
Findings - Abstinence from Alcohol
0
10
20
30
40
50
60
70
80
Total Abstinence
BaclofenPlacebo
Limitations
• Small study
• Many dropouts, assumed relapsed– But similar results if assumed abstinent
• Duration only 3 months
• Used in context of additional support for abstinence
Implications
• I will try using it– High gain, low risk (NNT 2.5)– Avoid in renal dysfunction, epilepsy– Attempt to provide broader treatment
context
• But I’m not pushing this
Also Noted
• N-3 Polyunsaturated fatty acid supplementation may reduce 3-year mortality in CHF, NNT=60.– Lancet, 10/4/2008
• Telling smokers their “lung age,” derived from FEV1, may improve quit rates, NNT=14– BMJ, 3/6/2008
• Arthroscopic debridement and lavage does not help the osteoarthritic knee more than medicine and PT– NEJM, 9/11/2008
More “Also Noted”• In new type 2 (Irish) DM on oral treatment, home
glucose monitoring did not improve A1C but did worsen depression and anxiety– BMJ, 4/17/2008
• Low-dose risperidone may improve response in depression refractory to monotherapy, NNT=7 (Industry funded)– AnnIntMed 11/6/2007
• The US Preventive Services Task Force still does not recommend prostate cancer screening, and recommends against it after age 75– AnnIntMed, 8/5/2008
And Last -
• Coffee might decrease cardiovascular and overall mortality
• At 6 cups per day, over 25 years:– Men were 20% less likely to die– Women were 17% less likely to die– Independent of caffeine
• WARNING: Brought to you by the Nurses’ Health Study– Remember HRT?
• AnnIntMed, 6/17/2008
Summary
• Reconsider the A1C goal, use more metformin
• Oral thrombin inhibitors for perioperative DVT prophylaxis look promising
• Avoid antibiotics for most non-pneumonia respiratory infections; “chest infection” in the elderly may be an exception
• CT Colonography is pretty good, not yet ready• Bisphosphonates may be important after hip
fracture
Summary, cont’d
• Perioperative beta-blockade looks more risky than helpful
• Saline may be as good as bicarbonate for IV dye renal protection
• Baclofen may help alcohol abstinence in cirrhotics
• Coffee?
Remember:
• Before acting on anything you heard here, you may wish to study the original research, and discuss with colleagues or domain experts