disclosures cardiovascular disease 2019 update: important ......months, clinical event within 6...

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Cardiovascular Disease 2019 Update: Important Bits & Pieces from Recent Studies

William L. Baker, Pharm.D., FCCP, FACC, FAHA

Associate Professor

University of Connecticut School of Pharmacy

Department of Pharmacy Practice

[email protected]

@wbaker0621

• I have no disclosures germane to the content of this presentation.

Disclosures

• Discuss the role of SGLT-2 inhibitors in the management of heart failure

• Describe the pharmacologic options for management of heart failure with preserved ejection fraction

• Identify the role of PUFAs for managing hyperlipidemia and cardiovascular disease

• Describe the modern role of aspirin for primary and secondary cardiovascular prevention

Learning Objectives

Advances in Heart Failure with Reduced Ejection Fraction

2019 ADA Guidelines: Pharmacologic Approach to Glycemic Treatment

Metformin + Lifestyle Management

Established ASCVD

ASCVD Predominates Heart Failure

GLP-1 RA OR

SGLT2i

SGLT2i (preferred)GLP-1 RA (if SGLT2i not

tolerated)

If HbA1c above target If HbA1c above target

Add other classDPP-4i

Basal insulinTZD or SU

Avoid TZDChoose agent with CV safety (DPP-4i, basal insulin, SU)

Modified From: American Diabetes Association. Diabetes Care. 2019;42(Suppl. 1):S90-S102.

SGLT-2i & HF Hospitalization

Zelker TA, et al. Lancet. 2019;393:31-9.

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No Association Between HbA1c Reduction & Heart Failure Hospitalization

Kramer CK, et al. J Am Coll Cardiol HF. 2018;6:823-30.

SGLT2 Inhibition & Effects on Myocardial Na+/H+ Exchange

Verma S, et al. Diabetologia. 2018;61:2108-17.

• 97 pts with T2DM & established CAD (LVEF >30%)

• Randomized to empagliflozin 10 mg/d or placebo X 6 months

• 1 outcome: Change in LV mass (baseline ~60 g/m2)

• 2 outcomes: LVEDV, LVESV, LVEF

• Biomarkers (NT-proBNP, sST2, troponin I)

RCT of Empagliflozin on LV Structure/Function in T2DM & CHD: EMPA-HEART CardioLink-6 Trial

-2.6

-1

2.2

-0.1

0.04

-0.1

-3

-2

-1

0

1

2

3LV Mass

index (g/m2)p=0.01

LVESV (ml/m2)p=0.36

LVEF (%) p=0.07

Empagliflozin

Placebo

Natila A, et al. Cardiovasc Diabetol. 2017;16:130.Verma S. AHA 2018 Scientific Sessions, Nov 10-12, 2018. LBS.05 McMurray JJV, et al. N Engl J Med. 2019 Sep 19. [Epub ahead of print]

• Key inclusion criteria: Symptomatic HF; EF ≤ 40%; NT-proBNP ≥ 600 pg/mL (if hospitalized for HF within last 12 months ≥ 400 pg/mL; if atrial fibrillation/flutter ≥ 900 pg/mL)

• Key exclusion criteria: eGFR <30 mL/min; symptomatic hypotension or SBP <95 mmHg; type 1 diabetes mellitus

• Primary endpoint: Worsening HF event or cardiovascular death (worsening HF event = unplanned HF hospitalization or an urgent HF visit requiring IV therapy)

DAPA-HF: Trial Design

McMurray JJV, et al. N Engl J Med. 2019 Sep 19. [Epub ahead of print]

Characteristic Dapagliflozin (n=2373) Placebo (n=2371)

Mean age (yr) 66 67

Male (%) 76 77

NYHA class II/III/IV (%) 68/31/1 67/32/1

Mean LVEF (%) 31 31

Median NT-proNP (pg/mL) 1428 1466

Mean systolic BP (mmHg) 122 122

Ischemic etiology (%) 55 57

Mean eGFR (mL/min) 66 66

Prior diagnosis T2DM (%) 42 42

Any baseline T2DM (%) 45 45

DAPA-HF: Key Baseline Characteristics


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Treatment (%) Dapagliflozin (n=2373) Placebo (n=2371)

Diuretic 93 94

RAAS Inhibitor 94 93

ACE Inhibitor 56 56

ARB 28 27

Sacubitril/valsartan 11 11

Beta-blocker 96 96

MRA 71 71

ICD 26 26

CRT 8 7

DAPA-HF: Baseline Treatment


DAPA-HF: Primary Outcome (CV Death/HF Event)


NNT =21

DAPA-HF: CV Death & All-Cause Mortality


Cardiovascular Death All-Cause Mortality

DAPA-HF: No Diabetes/Diabetes Subgroup


DapagliflozinN=2,373

PlaceboN=2,371

HR (95%CI)

All patients 386/2373 502/2371 0.74 (0.65, 0.85)

Type 2 diabetes at baseline

Yes 215/1075 271/1064 0.75 (0.63, 0.90)

No 171/1298 231/1307 0.73 (0.60, 0.88)

0.00 0.50 1.00 1.50

Favors Dapagliflozin Favors Placebo

Adverse Event (%) Dapagliflozin (n=2368) Placebo (n=2368) P-value

Volume depletion 7.5 6.8 0.40

Renal ADEs 6.5 7.2 0.36

Volume depletion 1.2 1.7 0.23

Fracture 2.1 2.1 1.00

Amputation 0.5 0.5 1.00

Major hypoglycemia 0.2 0.2 -

Diabetic ketoacidosis 0.1 0.0 -

ADE Leading to DC 4.7 4.9 0.79

Any Serious ADE 38 42 <0.01

DAPA-HF: Safety/Adverse Events


Relative Risk 2 Year Mortality

None -- 35.0%

ARNI ↓ 28% 25.2%

Beta-blocker ↓ 35% 16.4%

Aldosterone Antagonist ↓ 30% 11.5%

SGLT2 Inhibitor ↓ 17% 9.5%

Cumulative Impact of Evidence-Based HFrEFMedical Therapies on All-Cause Mortality

Fonarow GC, et al. Am Heart J. 2011;161:1024-30.Fonarow GC, et al. Lancet. 2008;372:1195-6.

• Cumulative risk reduction in mortality if all evidence-based medical therapies are used:

• Relative risk reduction = 72.9%• Absolute risk reduction = 25.5%• NNT = 3.9

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• Which of the following would be the most appropriate candidate to begin an SGLT-2?

A. A 57-year-old woman with type 2 diabetes, ischemic cardiomyopathy (EF 30%) due to an MI, atrial fibrillation

B. A 47-year-old man with type 2 diabetes uncontrolled on metformin

C. A 65-year-old woman without diabetes and with HFrEF controlled on an ARNI, beta-blocker, aldosterone antagonist and diuretic

D. An SGLT-2 inhibitor could reasonable be initiated in each of the above people

Self-Assessment Question

Advances in Heart Failure with Preserved Ejection Fraction

Yusuf S, et al. Lancet. 2003;362:777. Cleland JGF, et al. Eur Heart J. 2006;27:2338.Massie BM, et al. NEJM. 2008;359:2456.; Ahmed A, et al. Circulation. 2006;114:397

DIG Trial Substudy

• No mortality or HF hospbenefit

I-PRESERVE• No mortality or

HF hospbenefit

CHARM-Preserved

• Slight benefit after adjustment for BL differences

PEP-HF• No mortality• Maybe lower

HF hosp• High study

crossover rate

TOPCAT: Spironolactone in HFpEF

Pitt B, et al. N Engl J Med. 2014;370:1383.Pfeffer MA, et al. Circulation. 2015;131:34.

Primary Endpoint* Regional Outcome Variation

* Composite of CV death, aborted cardiac arrest, or HF hospitalization

HFpEF & HFrEF: Similar HF Hospitalization & Mortality Rates

Wikstrom et al. ESC 2011 Gothenburg, Sweden, 21–24 May 2011. Solomon SD, et al. N Engl J Med. 2019;381:1609-20.

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• Key inclusion criteria: Symptomatic HF (NYHA class II-IV); EF ≥ 45%; NT-proBNP ≥ 600 pg/mL (if hospitalized for HF within last 12 months ≥ 400 pg/mL; if atrial fibrillation/flutter ≥ 900 pg/mL); receiving diuretic therapy

• Key exclusion criteria: LVEF <40%, ACS/CV Surgery within 3 months, clinical event within 6 months, history of angioedema, eGFR < 30 mL/min/1.73 m2, serum potassium > 5.2 mEq/L

• Primary endpoint: Total (first and recurrent) hospitalizations for heart failure and death from CV causes

PARAGON-HF: Trial Design

Solomon SD, et al. N Engl J Med. 2019;381:1609-20.

Characteristic (%) Sacubitril-Valsartan (n=2407) Valsartan (n=2389)

Diuretic 95.3 95.9

ACE-I or ARB 86.2 86.4

Beta-blocker 79.9 79.5

MRA 24.6 27.1

PARAGON-HF: Baseline Treatment


• Age = 72.2 ± 8.4 years

• Female sex = ~ 52%

• Black race = ~ 2%

• Ischemic cause = ~36%

• Hypertension = ~ 95%

• Diabetes = ~43%

• Atrial fibrillation = ~32%

• Hosp for HF = ~48%

PARAGON-HF: Primary Outcome (CV Death/HF Event)


RR 0.87 (0.75-1.01)p = 0.06

PARAGON-HF: Individual Components

HF Hospitalizations

CV Death


RR 0.85 (0.72-1.00)p = 0.056

HR 0.95 (0.79-1.16)p = 0.62

PARAGON-HF: Secondary Endpoints


How Should We Most Optimally Manage HFpEFPatients?

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• Which of the following is the most appropriate interpretation of the topline findings from the PARAGON-HF Trial?

A. The trial was negative, throw the baby away with the bath water

B. Sacubitril-valsartan did not significantly lower the rate of CV death or HF hospitalization in HFpEF

C. Please, please for the love of everything holy stop conducting HFpEFtrials until we have a better understanding of what HFpEF is

D. All of the above


PUFA for Treating Hyperlipidemia and Cardiovascular Disease

Triglycerides a Causal Risk Factor?

Libby P. Eur Heart J. 2015;36:774-6.

Impact of EPA Along the Atherosclerosis Pathway

Nelson JR, et al. Postgrad Med. 2017;129:822-7.

Key Triglyceride-Lowering Trials Over the Last 2 Decades

Patel PN, et al. Curr Opin Cardiol. 2019;34:721-7.

Omega-3 Fatty Acids: Rx Products

ProductEPA (mg)

Per capsule

DHA (mg)Per

capsuleDosing

Take with food?

% △ TG % △ LDL-C

Omega-3 acid ethyl esters (Lovaza®)#

465 3754g QD

or2g BID

With our without

↓ 30-50 ↑ 0-45*

Icosapent ethyl (Vascepa®) 1000 -- 2g BID Yes ↓ 30-60 ↓ 0-5*

Omega-3carboxylic acids (Epanova®)

850 150 2-4g QD With our without

↓ 20-30 ↑ 0-26*

*When used as monotherapy#Lovaza® generic available as of 2014

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Low-Dose (<2g/d) Omega-3 Mixtures Show No Significant Cardiovascular Benefit

Aung T, et al. JAMA Cardiol. 2018;3:225-34.

JELIS: CV Risk Reduction with EPA in Japanese Hypercholesterolemic Patients

Yokoyama M, et al. Lancet. 2007;369:1090-8.

EPA and DHA Have Differing Effects on Cellular Membranes

Scherratt SCR & Mason RP. Chem Phys Lipids. 2018;212:73-9. Bhatt DL, et al. N Engl J Med. 2018;380:11-22.

REDUCE-IT: Primary Outcome (CV Death/HF Event)

Bhatt DL, et al. N Engl J Med. 2018;380:11-22.

REDUCE-IT: Primary Outcome (CV Death/HF Event)


HR 0.75 (95% CI 0.68-0.83)RRR = 24.8%NNT = 21 (95% CI 15-33)p = 0.00000001

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REDUCE-IT: Additional Outcomes


REDUCE-IT: Endpoints by Baseline TG Tertiles


• A 51-year-old man presents with diabetes, HTN, hypertriglyceridemia, and history of acute pancreatitis. Current medications include lisinopril, chlorthalidone, amlodipine, rosuvastatin 20 mg/d, metformin, and insulin glargine. His A1c=6.9%, TC 157 mg/dL, LDL-C 38 mg/dL, TG 1054 mg/dL? In addition to nonpharmacologic recommendations, which treatment option is best for his TG?

A. Add icosapent ethyl 2 g twice/day

B. Add niacin ER 500 mg/night

C. Add omega-3 acid ethyl esters 1 g/d

D. Increase rosuvastatin to 40 mg/d


In Whom Should We Be Using Aspirin for Primary Cardioprotection?

Reminder: Aspirin Mechanism of Action

Patrono C & Baigent C. Nature Rev Cardiol. 2019;16:675-86.

Antithrombotic Trialists’ (ATT) Collaboration: 2009

Antithrombotic Trialists’ Collaboration. Lancet. 2009;373:1849-60.

Serious Vascular Events6 fewer per 10,000/year

Major GI Bleeding3 more per 10,000/year

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ASCEND Study Group. N Engl J Med. 2019;379:1529-39.McNeil JJ, et al. N Engl J Med. 2018;379:1509-18.Gaziano JM, et al. Lancet. 2018;392:1036-46.

Primary Efficacy Findings of ASA Primary Prevention RCTs

ARRIVE

ASCEND Study Group. N Engl J Med. 2019;379:1529-39.McNeil JJ, et al. N Engl J Med. 2018;379:1509-18.Gaziano JM, et al. Lancet. 2018;392:1036-46.

ASPREE ASCEND

↑ major hemorrhageHR 1.38 (1.18-1.62); p<0.001

↑ GI bleeding eventsHR 2.11 (1.36-3.28); p=0.00007

↑ major bleedingHR 1.29 (1.09-1.52); p=0.003

Updated Meta-Analysis of Aspiring Use for Primary Prevention (Including Recent RCTs)

Zheng SL & Roddick AJ. JAMA. 2019;321:277-87.

NNT = 241

NNH = 210

• Aspirin ↑ risk of GI bleeding ~50% vs. no aspirin

• Patients >70 years old have sharp ↑ in GI bleed risk

• Enteric-coated aspirin does not confer protection from GI bleeding

What is the Role of Gastroprotectant Drugs?

Scally B, et al. Lancet Gastroenterol Hepatol. 2018;3:231-41.

Recommendations for Aspirin Use

COR LOE Recommendations

IIb A

1. Low‐dose aspirin (75‐100 mg orally daily) might beconsidered for the primary prevention of ASCVDamong select adults 40 to 70 years of age who are athigher ASCVD risk but not at increased bleeding risk.

III:

HarmB‐R

2. Low‐dose aspirin (75‐100 mg orally daily) should notbe administered on a routine basis for the primaryprevention of ASCVD among adults >70 years of age.

III:

HarmC‐LD

3. Low‐dose aspirin (75‐100 mg orally daily) should notbe administered for the primary prevention of ASCVDamong adults of any age who are at increased risk ofbleeding.

2019 ACC/AHA Primary Prevention Guidelines

Arnett DK, et al. Circulation. 2019;140:e563-95.

A Small Proportion of the Population Have High CVD Risk & Low Major Bleed Risk

Antithrombotic Trialists’ Collaboration. Lancet. 2009;373:1849-60. Patrono C & Baigent C. Nature Rev Cardiol. 2019;16:675-86.

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• A 51-year-old woman with type 2 diabetes approaches you at the pharmacy counter and asks whether she should take an aspirin daily. She has a family history of premature CVD but is otherwise heathy. Which would be the best advice to give her?

A. ASA may be indicated because of the her greater risk of early-onset coronary artery disease

B. ASA is not indicated for her as the bleed risk outweighs the potential benefit

C. ASA is indicated because of the patient’s apparent low bleed risk

D. ASA is not indicated because of the greater risk of ischemic stroke compared with the potential benefit


Thank You For Your Attention

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disclosures cardiovascular disease 2019 update: important ......months, clinical event within 6...

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