ACCP Cardiology PRN Journal Club

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Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure

(PARADIGM-HF)

Prepared By: Robert K. Tunney, PharmD, BCPS

PGY2 Cardiology Resident, Vanderbilt University Medical Center, Nashville, TN

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Disclosures I have no financial interest or affiliation with the

manufacturer of any marketed product discussed herein

Background Heart Failure (HF)

Constellation of symptoms 5.1 million Americans (and rising) with HF ~20% lifetime risk for the development of HF in

patients > 40 years old

Lack of consistency in mortality benefit with angiotensin-receptor blockers (ARBs) CHARM (2004) and Val-HeFT (2001) 2013 ACC/AHA Guidelines: ARBs recommended in

patients intolerant to ACE-I therapy (IA)

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Yancy CW, et al. JACC. 2013; 62(16): e147-e239.

Background: Neprilysin Inhibition (NI)

Adapted from Bonow RO, et al. Global Cardiology Science and Practice. 2014; 34: dx.doi.org/10.5339/gcsp.2014.34. Fig. 1.

Natriuretic peptide system

Renin-angiotensin system

N a t r i u r e t i c P e p t i d e s

Inactive Fragment

s

LCZ696

Inactive Metabolit

e

AHU377(sacubitri

l)

Angiotensinogen (liver)

Angiotensin I

Angiotensin IIValsartan

1.) Vasodilation2.) Natriuresis/diuresis

1.) Vasoconstriction

Background and Purpose

McMurray JV, et al. N Eng J Med. 2014; 371: 993-

1004.

OCTAVE trial (2004): Neprilysin (omapatrilat) and ACE-I combination intolerance secondary to angioedema LCZ696: sacubitril + valsartan (fixed molecular

complex)

Purpose Assess the relative superiority of morbidity

and mortality benefits between LCZ696 200 mg BID and ACE inhibition (enalapril 10 mg BID) in patients with HFrEF

Study Design

McMurray JV, et al. N Eng J Med. 2014; 371: 993-

1004.

Randomized, double-blind, parallel group, active-control trial of 8,442 patients in 47 different countries

Screening Period (Visit 1)

Single-blind run-in Period 5-

10 weeks (Visits 2-4)

Double-blind, randomized treatment period: 22

months (Visit 5)

Study Design: Run-In Period

McMurray JV, et al. N Eng J Med. 2014; 371: 993-

1004.

Study Demographics

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Characteristic LCZ696 (n = 4187) Enalapril (n = 4212)

Region

• North America 310 (7.4%) 292 (6.9%)

NYHA Functional Class

• I 180 (4.3%) 209 (5.0%)

• II 2998 (71.6%) 2921 (69.3%)

• III 969 (23.1%) 1049 (24.9%)

• IV 33 (0.8%) 27 (0.6%)

Medical History

• Implantable cardioverter-defibrillator

623 (14.9%) 620 (14.7%)

• Cardiac resynchronization therapy (CRT)

292 (7.0%) 282 (6.7%)

Methods

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Inclusion Criteria Exclusion Criteria

• CHF (NYHA Class II-IV) • Hypotension (SBP < 100 mmHg at screening or < 95 mmHg at randomization)

• Male or female aged >18 yrs • Known history of angioedema

• LVEF < 40% (within the past six months prior to randomization) – changed to < 35% in 12/10

• Patients in acute decompensated HF

• BNP > 150 pg/mL or NT-proBNP > 600 pg/mL at visit 1

• Estimated eGFR < 30 mL/min/1.73 m2 (MDRD)

• Stable dose of an ACE-I or ARB for 4 weeks prior to visit 1

• Serum potassium > 5.2 mmol/L (visit 1) or > 5.4 mmol/L at visit 3 or 5

• Stable dose of beta-blocker for 4 weeks prior to visit 1 (unless contraindicated)

• CVA, ACS, ventricular arrhythmia, or cardiac resynchronization device within the previous 3 months

Outcomes

McMurray JV, et al. N Eng J Med. 2014; 371: 993-

1004.

Primary:

Secondary:

Time to first occurrence of composite endpoint: CV death or HF hospitalization

All-cause mortality

Decline in renal function

Improvement in the Kansas City Cardiomyopathy Questionaire (KCCQ) at 8 months

New-onset atrial fibrillation

Statistics

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Primary efficacy variable Cox proportional hazards model (alpha = 0.05, two tail)

Kaplan-Meier curves to summarize primary composite endpoint

Sample Size 7,980 patients 34 months 1,229 CV-related deaths Assumed 7% annual CV death rate Est rate of primary end point = 14.5% (CHARM-Added

Trial)

Three planned interim efficacy analyses (33%, 50%, and 67% event accrual)

80% power to detect a relative reduction of 15%

in CV-related deaths within the treatment group

Results

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Study Outcome LCZ696 (n = 4187)

Enalapril (n = 4212)

Hazard Ratio (HR)

P-Value

Primary composite endpoint (%)

1.) Death from CV causes

558 (13.3) 693 (16.5) 0.80 (0.71-0.89)

<0.001

2.) 1st hosp. for worsening HF

537 (12.8) 658 (15.6) 0.79 (0.71-0.89)

<0.001

Secondary Outcomes (%)

1.) Death from any cause

711 (17.0) 835 (19.8) 0.84 (0.76-0.93)

<0.001

2.) KCCQ Score change (8 months)

-2.99 +0.36 -4.63 +0.36 1.64 (0.63-2.65)

0.001

3.) Decline in renal function

94 (2.2) 108 (2.6) 0.86 (0.65-1.13)

0.28

4.) New Afib 84 (3.1) 83 (3.1) 0.97 (0.72-1.31)

0.83

Results

McMurray JV, et al. N Eng J Med. 2014; 371: 993-

1004.

Adverse Events LCZ696 (n = 4187)

Enalapril (n = 4212)

P-Value

Hypotension

1.) Symptomatic 588 (14%) 388 (9.2) < 0.001

2.) Symptomatic (SBP < 90 mmHg)

112 (2.7%) 59 (1.4%) < 0.001

Elevated SCr

1.) > 2.5 mg/dL 139 (3.3%) 188 (4.5%) 0.007

2.) > 3.0 mg/dL 63 (1.5%) 83 (2.0%) 0.10

Cough 474 (11.3%) 601 (14.3%) < 0.001

Angioedema

1.) No treatment/antihistamine

only

10 (0.2%) 5 (0.1%) 0.19

2.) Hospitalization (no airway compromise)

3 (0.1%) 1 (<0.1%) 0.31

Results

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Discussion

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Inhibition of both angiotensin II receptors and neprilysin was more effective in reducing morbidity and mortality relative to the control therapy

Mean enalapril dose utilized = 18.9 mg daily CONSENSUS (1987): 18.4 mg – 20 mg BID target

dose SOLVD (1991): 16.6 mg – 10 mg BID target dose

LCZ696 resulted in greater incidence of hypotension but was not associated with significant increases in serious angioedema

Author’s Conclusion

McMurray JV, et al. N Eng J Med. 2014; 371: 993-

1004.

Angiotensin-receptor-neprilysin inhibition with LCZ696 proves superior to ACE inhibition alone in reducing the risk of death and re-hospitalization due to HF

Critique

McMurray JV, et al. N Eng J Med. 2014; 371: 993-

1004.

Strengths

Study Design

Robust statistical powerHigh statistical significancePotential degree of clinical significance

Weaknesses

Were the “sickest” patients studied?Reproducibility to U.S. patientsUnder-representation of ICD/CRT patients and those of African descent

Thought-Provoking

Reduction in atrial fibrillationComparative efficacy of valsartan 320 mg versus enalapril 20 mgPrevious use of ACE/ARB

Drug run-in period

Cost-prohibitive therapy

Yancy, Clyde W. "Commentary on PARADIGM HF Study Design." ESC 2014 Science News (31 Aug. 2014).

Impact on Clinical Practice

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Kostis JB, et al. Am J Hypertens. 2004; 17: 103-111.

Potential exists for a profound impact on HF pharmacotherapy

Considerations for utilization in specific patients:

Patients with past history of angioedema are excluded

Lack of reproducible safety data in patients of African descent (OCTAVE)

Insurance status

Previous use and tolerance of an ACE-I/ARB

Acknowledgements Journal Club Mentors

1.) Elizabeth McNeely, PharmD, BCPS TriStar Centennial Medical Center, Nashville, TN

2.) Herb Patterson, PharmD, FCCP UNC Eshelman School of Pharmacy, Chapel Hill, NC

Program Director Daniel Johnson, PharmD, BCPS(AQ-Cardiology)

Vanderbilt University Medical Center, Nashville, TN

ACC PRN Journal Club Coordinator Craig Beavers; PharmD, BCPS (AQ-Cardiology)

TriStar Centennial Medical Center, Nashville, TN

Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure

(PARADIGM-HF)

Prepared By: Robert K. Tunney, PharmD, BCPS

PGY2 Cardiology Resident, Vanderbilt University Medical Center, Nashville, TN

McMurray JV, et al. N Eng J Med. 2014; 371: 993-1004.

Thank you for attending! If you would like to have your resident

present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail.com or craig.beaverspharmd@gmail.com

Our next Journal Club will be in early January with the date to be determined. Nicole Gasbarro from University of Chicago-Illinois

will be presenting DAPT trial.