Announcements Thank you attending the ACCP Cardiology PRN
Journal Club Thank you if you attended last time
I have created a PB Works Site that will house our recorded calls, handouts, and Summary/Q&A documents. I will be e-mailing the link to this in the next 1-2 weeks.
Still trying to explore option of getting CE.
If there are any suggestions, please let us know.
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 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
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 [email protected] or [email protected]
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.