1. ACCP Cardiology PRN Journal Club

2. 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.
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If there are any suggestions, please let us know.

3. 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:

4. Disclosures
I have no financial interest or affiliation with the manufacturer of any marketed product discussed herein

5. 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:
Yancy CW, et al. JACC. 2013; 62(16): e147-e239.

6. Background: Neprilysin Inhibition (NI)
LCZ696
Inactive Metabolite
AHU377
(sacubitril)
Natriuretic peptide system
Renin-angiotensin system
Natriuretic Peptides
Angiotensinogen (liver)
Angiotensin I
Inactive Fragments
Valsartan
Angiotensin II
1.) Vasodilation
2.) Natriuresis/diuresis
1.) Vasoconstriction
Adapted from Bonow RO, et al. Global Cardiology Science and Practice. 2014; 34: dx.doi.org/ /gcsp Fig. 1.

7. Background and Purpose
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 LCZ mg BID and ACE inhibition (enalapril 10 mg BID) in patients with HFrEF
McMurray JV, et al. N Eng J Med. 2014; 371:

8. Study Design
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)
McMurray JV, et al. N Eng J Med. 2014; 371:

9. Study Design: Run-In Period
McMurray JV, et al. N Eng J Med. 2014; 371:

10. Study Demographics 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%)
McMurray JV, et al. N Eng J Med. 2014; 371:

11. Methods 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
McMurray JV, et al. N Eng J Med. 2014; 371:

12. Outcomes Primary: Secondary:
Time to first occurrence of composite endpoint: CV death or HF hospitalization
Improvement in the Kansas City Cardiomyopathy Questionaire (KCCQ) at 8 months
All-cause mortality
Decline in renal function defined as:
1.) 50% eGFR reduction (relative to baseline
2.) > 30% reduction in eGFR (relative to baseline)
3.) Progression to ESRD
Decline in renal function
New-onset atrial fibrillation
McMurray JV, et al. N Eng J Med. 2014; 371:

13. Statistics
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
McMurray JV, et al. N Eng J Med. 2014; 371:

14. Primary composite endpoint (%) Secondary Outcomes (%)
Results
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 ( )
<0.001
2.) 1st hosp. for worsening HF
537 (12.8)
658 (15.6)
0.79 ( )
Secondary Outcomes (%)
1.) Death from any cause
711 (17.0)
835 (19.8)
0.84 ( )
2.) KCCQ Score change (8 months)
1.64 ( )
0.001
3.) Decline in renal function
94 (2.2)
108 (2.6)
0.86 ( )
0.28
4.) New Afib
84 (3.1)
83 (3.1)
0.97 ( )
0.83
McMurray JV, et al. N Eng J Med. 2014; 371:

15. Results 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%)
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%)
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
McMurray JV, et al. N Eng J Med. 2014; 371:

16. Results
McMurray JV, et al. N Eng J Med. 2014; 371:

17. Discussion
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
McMurray JV, et al. N Eng J Med. 2014; 371:

18. Author’s Conclusion
Angiotensin-receptor-neprilysin inhibition with LCZ696 proves superior to ACE inhibition alone in reducing the risk of death and re-hospitalization due to HF
McMurray JV, et al. N Eng J Med. 2014; 371:

19. Critique Strengths Weaknesses Thought-Provoking Study Design
Robust statistical power
High statistical significance
Potential degree of clinical significance
Weaknesses
Were the “sickest” patients studied?
Reproducibility to U.S. patients
Under-representation of ICD/CRT patients and those of African descent
Thought-Provoking
Reduction in atrial fibrillation
Comparative efficacy of valsartan 320 mg versus enalapril 20 mg
Previous use of ACE/ARB
Drug run-in period
Cost-prohibitive therapy
McMurray JV, et al. N Eng J Med. 2014; 371:
Yancy, Clyde W. "Commentary on PARADIGM HF Study Design." ESC 2014 Science News (31 Aug. 2014).

20. Impact on Clinical Practice
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
McMurray JV, et al. N Eng J Med. 2014; 371:
Kostis JB, et al. Am J Hypertens. 2004; 17:

21. Acknowledgements Journal Club Mentors Program Director
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)

22. 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:

23. 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 or
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.