1. PARADIGM-HF Journal Club Amy Yeh, PharmD Candidate APPE Internal Medicine I
Objective: Evaluate superiority of LCZ696 200 mg bid over enalapril 10 mg bid in reducing HFrEF-related
morbidity/mortality
Rationale
 Chronic HF is a progressive disease
o Hemodynamic abnormalities (high cardiac filling pressure, decreased CO and oxygen perfusion) 
compensatory RAAS/sympathetic activation to maintain organ perfusion  myocardial hypertrophy, fibrosis,
increased SVR, fluid retention
 Current therapies focus on RAAS inhibition
o ACEI/ARB reduce mortality in HFrEF and are the standard of care
 CONSENSUS
 SOLVD
o BB and AA also improve survival, but mortality remains high (5-yr rate ~ 50%)
 Natriuretic peptide (NP) system (which opposes RAAS) may be a new target for HFrEF tx
o NPs have cardiorenal protective properties
 Cause vasodilation, decrease SVR and arterial pressures, reduce arterial stiffness, enhance
endothelial function, promote diuresis
 Chemically inactivated by an endopeptidase called neprilysin
o Advanced HF is marked by NP deficiency+ increased neprilysin expression/activity
o Inhibit neprilysin  decrease NP clearance and increase conc of of active NPs  reduce remodeling,
vasoconstriction, and renal sodium retention  improve outcomes in HFrEF
 Failure with Omapatrilat (OVERTURE)  development discontinued
o Triple inhibition of ACE, aminopeptidase P, and neprilysin  dramatically increased bradykinin levels 
severe angioedema
 Reported incidence of angioedema is much lower for ARB than ACEI
o LCZ696 (ARNI)  increased efficacy without the angioedema?
Outcomes
 Primary: composite of death from CV causes or first hospitalization for HF
 Secondary: time to all-cause mortality, symptoms/physical limitations, time to new onset of AF, time to decline in
renal function (ESRD, decrease in eGFR ≥ 50% or by 30-60 mL/min/1.73 m2)
Participants
 Inclusion criteria: adults with NYHA II-IV symptoms, EF ≤ 35%, elevated BNP/NT-proBNP levels
 Exclusion criteria: symptomatic hypotension, SBP < 100, eGFR < 30 or decrease in eGFR > 25%, K > 5.2, hx of
ACEI/ARB intolerance (ex: angioedema)
 Baseline characteristics: Mean age 63.8 yrs old, primarily male (77-79%), white (66%), BMI 28, SCr 1.1, LVEF 29%,
NYHA class II (69-71%),
Study design
 Phase II, prospective, randomized, double-blind, parallel, multi-center study in 47 countries
 3 phases (screening period  single-blind enalapril 10 mg bid for 2 wks no tx for 1 day  single-blind LCZ696 bid
for 4-6 wks no tx for 1 day  double-blind study)
o 4 wks before screening, subjects took BB + ACEI/ARB (≥ 10 mg enalapril daily)
o LCZ696 initially started at 100 mg bid; titrated to 200 mg bid
o 200 mg LCZ696 contains 160 mg valsartan
o No tx days avoid overlap of ACEI/ARNI  minimize risk of angioedema
o Those who tolerated target doses were randomized (via computer) to enalapril or LCZ696
o Dose of study drug could be reduced if ADRs occurred
 8442 subjects randomized  43 excluded  8399 assigned
o Tx groups: 4187 assigned to LCZ696 200 mg bid, 4212 assigned to enalapril 10 mg bid
 Monitoring: every 2-8 wks for the first 4 months, then every 4 months after
o Not stated how medication adherence was measured
 Duration of study: 27 months (December 8, 2009 through November 23, 2012)
 Approved by ethics committee at each site; written informed consent from subjects
Statistics/Results
 Power of 80% to detect 15% relative risk reduction [required 8000 subjects for 34 months (two-sided p = 0.05)]
 ITT analysis
o Time to event data: Kaplan-Meier curve and Cox proportional hazards model (appropriate)
 95% confidence interval, two-sided p values
o Change from baseline in KCCQ clinical summary score at 8 months
 Repeated-measures ANCOVA (appropriate)

2.  Scale of 0-100 (higher number indicating fewer symptoms/physical limitations)
 Mean of physical limitation and HF symptom scores
 Death  Score of 0
o ADRs: Fisher’s Exact (appropriate)
 Primary outcome (CV-related death or HF hospitalization)
o ARNI: 914 patients (21.8%) vs. ACEI: 1117 patients (26.5%)
o HR 0.80; 95% confidence interval: 0.73-0.87; p < 0.001
 CV-related deaths
o ARNI: 558 deaths (13.3%) vs. ACEI: 693 deaths (16.5%)
o HR 0.80; 95% confidence interval: 0.71-0.89; p < 0.001
 HF-related hospitalizations
o ARNI: 537 (12.8%) vs. ACEI: 658 (15.6%)
o HR 0.79; 95% confidence interval: 0.71-0.89; p < 0.001
 All-cause mortality
o ARNI: 711 (17%) vs. ACEI: 835 (19.8%)
o HR 0.84; 95% confidence interval: 0.76-0.93; p < 0.001
 Mean change from baseline to month 8 in KCCQ clinical summary score
o ARNI: reduction of 2.99 points, vs. ACEI: reduction of 4.63 points
o Between-group difference of 1.64 points; 95% confidence interval: 0.63-2.65; p = 0.001
 NNT: 21 patients need to take LCZ696 200 mg po bid for 27 wks to prevent the occurrence of one primary event
 NNT: 32 patients need to take LCZ696 200 mg po bid for 27 wks to prevent the occurrence of one CV-related death
 Subgroup analysis for the primary outcome
o NYHA class I-II: LCZ696 superior to ACEI (HR ~ 0.8, p = 0.03)
o NYHA class III-IV: No significant difference between LCZ696 and ACEI (p > 0.05)
 Hypotension was significantly more prevalent in ARNI group
o Symptomatic hypotension: 14% ARNI vs. 9.2% ACEI (p < 0.001; NNH 21)
o Symptomatic hypotension + SBP < 90: 2.7% ARNI vs. 1.4% ACEI (p < 0.001; NNH 77)
o Resulting in discontinuation: 0.9% ARNI vs. 0.7% ACEI (p = 0.38)
 SCr elevation was significantly more prevalent in ACEI group
o ≥ 2.5 mg/dL: 3.3% ARNI vs. 4.5% ACEI (p = 0.007)
o ≥ 3.0 mg/dL: 1.5% ARNI vs. 2.0% ACEI (p = 0.10)
o Resulting in discontinuation: 0.7% ARNI vs. 1.4% ACEI (p = 0.002)
 Pronounced hyperkalemia was significantly more prevalent in ACEI group
o ≥ 5.5 mmol/L: 16.1% ARNI vs. 17.3% ACEI (p = 0.15)
o > 6.0 mmol/L: 4.3% ARNI vs. 5.6% ACEI (p = 0.007)
o Resulting in discontinuation: 0.3% ARNI vs. 0.4% ACEI (p = 0.56)
 Cough was significantly more prevalent in ACEI group
o 11.3% ARNI vs. 14.3% ACEI (p < 0.001)
 No significant differences in the incidence of angioedema, new-onset AF, protocol-defined decline in renal fn,
progression to ESRD
 Discontinuations due to ADRs: 10.7% ARNI vs. 12.3% ACEI (p = 0.03)
Authors’ Conclusion: LCZ696 was superior to enalapril in reducing the risk of CV-related death or HF hospitalization, the risk
of all-cause mortality, and the symptoms/physical limitations of HFrEF.
Strengths: large sample size, novel compound, appropriate use of statistics, good study design
Confounders
 Max target dose of LCZ696 was compared to moderate-dose of enalapril
o Would there still be a significant difference if enalapril 20 mg bid was used?
 LCZ696 was compared to enalapril and not valsartan
o Using valsartan 160 mg bid would determine the additive benefit of sacubitril
o ACEI  higher risk of angioedema  biased results in ADR reporting
Limitations
 Superiority of LCZ696 was not demonstrated in NYHA class III-IV HFrEF
 Skewed population: Few patients > 75, female, black, NYHA classes I and IV. Excluded Stage IV and V CRF.
 Study was stopped early  long-standing ADRs of ARNI could have been missed
o Neprilysin degrades beta-amyloid, a compound implicated in Alzheimer’s
o Neprilysin inhibition  beta-amyloid accumulation  cognitive decline??
Clinical Relevance/Recommendations
 PARADIGM-HF was a promising study. LCZ696 is not approved by the FDA or available on the market. Cost may
initially limit its use to those who can afford it. Due to the confounders/limitations of the study, I would like to see
more research on LCZ696 before recommending it as a replacement of ACEI or ARB in HFrEF tx.

3. Abbreviations
HFrEF heart failure with reduced ejection fraction
LCZ696 sacubitril (AHU377)/valsartan 160 mg
Tx treatment
CV cardiovascular
eGFR estimated glomerular filtration rate
EF ejection fraction
LVEF left ventricular ejection fraction
SBP systolic blood pressure
BNP brain-type natriuretic peptide
NT-proBNP N-terminal pro brain-type natriuretic peptide
NP natriuretic peptide
RAAS renin-angiotensin aldosterone system
ACEI angiotensin-converting enzyme inhibitor
ARB angiotensin type 1 (AT1) receptor blocker
ARNI angiotensin-receptor neprilysin inhibitor
NYHA New York Heart Association
ESRD end-stage renal disease
K potassium
hx history
ex example
mg milligram(s)
bid twice daily
BB beta blocker
wks weeks
ADRs adverse drug reactions
ITT intention-to-treat
SVR systemic vascular resistance
KCCQ Kansas City Cardiomyopathy Questionnaire
NNT number needed to treat
NNH number needed to harm
References
 McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure.
NEJM. 2014;371(11):993-1004.
 The Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results
of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). NEJM. 1987;316(23):1429-
1435.
 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection
fractions and congestive heart failure. NEJM. 1991;325(5):293-302.
 Packer MP, Califf RM, Konstam MA, et al. Comparison of Omapatrilat and enalapril in patients with chronic
heart failure (OVERTURE). Circulation. 2002;106:920-926.
 Langenickel TH, Dole WP. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the
treatment of heart failure. Drug Discovery Today. 2012;9(4):e131-e139.