European Heart Journal (2015) 36, 1990–1997 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehv186 Heart failure/cardiomyopathy

Effect of the angiotensin-receptor-neprilysin

inhibitor LCZ696 compared with enalapril
on mode of death in heart failure patients
Akshay S. Desai 1, John J.V. McMurray2, Milton Packer 3, Karl Swedberg 4,5,
Jean L. Rouleau 6, Fabian Chen 7, Jianjian Gong 7, Adel R. Rizkala 7, Abdel Brahimi 1,
Brian Claggett 1, Peter V. Finn 1, Loren Howard Hartley1, Jiankang Liu 1,
Martin Lefkowitz 7, Victor Shi 7, Michael R. Zile8, and Scott D. Solomon 1*

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1
Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA; 2British Heart Foundation Cardiovascular Research Center, University of
Glasgow, Glasgow, UK; 3Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, USA; 4Department of Molecular and Clinical Medicine, University
of Gothenburg, Gothenburg, Sweden; 5National Heart and Lung Institute, Imperial College, London, UK; 6Institut de Cardiologie, Université de Montréal, Montreal, Canada;
7
Novartis Pharmaceuticals Corporation, East Hanover, USA; and 8Medical University of South Carolina and Ralph H. Johnston Veterans Administration Medical Center,
Charleston, USA

Received 30 January 2015; revised 23 March 2015; accepted 23 April 2015; online publish-ahead-of-print 28 May 2015

See page 1952 for the editorial comment on this article (doi:10.1093/eurheartj/ehv272)

Aims The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality
compared with enalapril in patients with chronic heart failure in the prospective comparison of ARNI with an Angio-
tensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARA-
DIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of
LCZ696 on mode of death.
.....................................................................................................................................................................................
Methods PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure,
and results New York Heart Association Class II – IV symptoms, and left ventricular ejection fraction ≤40% receiving guideline-
recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded
clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death
was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72–0.89, P , 0.001). Among cardio-
vascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68 –0.94, P ¼ 0.008) and death due to worsening heart
failure (HR 0.79, 95% CI 0.64 – 0.98, P ¼ 0.034) were reduced by treatment with LCZ696 compared with enalapril.
Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and dis-
tributed evenly between treatment groups, as were non-cardiovascular deaths.
.....................................................................................................................................................................................
Conclusions LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure,
which accounted for the majority of cardiovascular deaths.
.....................................................................................................................................................................................
Clinical Trial https://clinicaltrials.gov/, NCT01035255.
Registration
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Heart failure † Clinical trial † Pharmacotherapy † Neprilysin inhibition † Angiotensin-receptor blocker † Mortality

Despite significant therapeutic advances, patients with chronic angiotensin-converting enzyme (ACE) inhibitors, angiotensin-
heart failure remain at high risk for heart failure progression and receptor blockers (ARBs), b-adrenergic-receptor blockers, and
death.1,2 Among patients with heart failure and reduced ejection aldosterone antagonists influence the incidence of sudden cardiac
fraction (HF-REF), therapies that improve mortality, including death and death from progressive heart failure, but not the

* Corresponding author. Email: ssolomon@rics.bwh.harvard.edu

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
Mode of death in PARADIGM-HF
incidence of death from myocardial infarction (MI), stroke, or
non-cardiovascular causes.3 – 11 LCZ696 is a first-in-class angioten-
sin-receptor-neprilysin inhibitor (ARNI) comprised of the neprilysin
inhibitor prodrug sacubitril and the ARB valsartan.12,13 The Pro-
spective Comparison of ARNI with an ACE-Inhibitor to Determine
Impact on Global Mortality and Morbidity in Heart Failure trial
(PARADIGM-HF) randomized patients with chronic HF-REF to
LCZ696 or enalapril, and demonstrated that treatment with
LCZ696 reduced the composite primary outcome of cardiovascular
death or heart failure hospitalization, as well as cardiovascular death
and all-cause mortality.14 To more completely understand the mor-
tality reduction associated with LCZ696, we assessed the effect of
LCZ696 compared with enalapril on the mode of death in
PARADIGM-HF.
Methods
PARADIGM-HF design
The detailed study design, methods, and principal results of the
PARADIGM-HF study have been previously reported.15 Briefly, the
study was a randomized, double-blind, and prospective comparison of
the angiotensin-receptor-neprilysin inhibitor LCZ696 with enalapril in
subjects with chronic heart failure (New York Heart Association
Classes II – IV) and left ventricular ejection fraction of 40% or less who
were treated with guideline-recommended medical therapy. Prior to
randomization, all subjects underwent a single-blind, sequential run-in
phase to ensure tolerability of both study drugs at target doses. Eligible
subjects who did not experience unacceptable side effects during the
run-in phase were randomly allocated in 1 : 1 fashion to double-blind
treatment with either enalapril 10 mg twice daily or LCZ696 200 mg
twice daily. The study was approved by the institutional review board
or ethics committee at each site, and all enrolled subjects provided writ-
ten informed consent prior to participation. As previously reported,
8399 patients were randomly assigned and prospectively included in
the intention-to-treat analysis.
Endpoints and adjudication of cause of death
The primary composite endpoint for the trial was death from cardiovas-
cular causes or first hospitalization for heart failure. The time to death
from any cause was pre-specified as a key secondary endpoint. All oc-
currences of death, heart failure hospitalization, and other predefined
clinical outcomes during the trial were adjudicated against standardized
criteria by a blinded clinical endpoints committee (CEC) at Brigham and
Women’s Hospital. The CEC was comprised of physicians trained and
experienced in endpoint adjudication and was co-chaired by two of the
co-authors (A.S.D., S.D.S.). The full roster of CEC members (which in-
cludes co-authors P.V.F., A.B., and L.H.H.) is provided in the supplement
to the original published manuscript.14 All events were reviewed inde-
pendently by two CEC members, with disagreements resolved by the
CEC chairman in regular committee meetings held periodically during
the course of the trial.
In each case, the primary cause of death was classified by the CEC as
cardiovascular or non-cardiovascular in aetiology. Deaths ascertained
from the public record or for which no more specific cause could be
identified were classified as unknown. Cardiovascular deaths were fur-
ther sub-classified as sudden or due to MI, worsening heart failure,
stroke, complications of a cardiovascular procedure, pulmonary embol-
ism, or another cardiovascular cause. Sudden death was defined as death
occurring unexpectedly in an otherwise stable patient, and was further
1991
sub-classified according to whether patients had been last seen alive
within 1 h or between 1 and 24 h. Apparent sudden deaths in patients
who were last seen .24 h prior to death were separately categorized as
presumed sudden death. Death due to MI was assigned for patients dy-
ing within 14 days of a clinical MI, those with autopsy evidence of recent
infarction, or those with an abrupt death associated with ECG, biomark-
er, or imaging evidence of acute myocardial injury. Death from worsen-
ing heart failure was defined as death in the context of clinically
worsening symptoms and/or signs of heart failure with no other appar-
ent cause, death as a consequence of a surgical procedure to treat heart
failure, or death after referral to hospice for heart failure. Death due to
stroke was assigned if deaths occurred as a sequela of a stroke defined
by clinical or imaging criteria. Death within 14 days of a cardiovascular
procedure (other than a surgical procedure to treat heart failure) was
attributed to complications of that procedure, unless another cause
was readily apparent. Pulmonary embolism death was assigned only
for deaths occurring as a direct result of a documented pulmonary em-
bolism. Remaining deaths that could be classified were presumed to be
unspecified cardiovascular deaths unless a specific non-cardiovascular
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cause was identified. Non-cardiovascular deaths were further classified
as due to infection, malignancy, pulmonary, gastrointestinal, renal, acci-
dental, suicide, or other causes. Between-reviewer agreement as to the
broad category of death (cardiovascular, non-cardiovascular, or un-
known) was 92.5% (k 0.78), and for the specific cause of cardiovascular
death was 74% (k 0.67).
Statistical analysis
We compared the incidence of death from specific causes according to
treatment assignment during the median 27-month follow-up in the
trial. Primary analyses were conducted using Kaplan – Meier survival
curves, comparing time with cause-specific death between treatment
groups via Cox proportional hazards models, with geographical region
as a stratification factor. To account for the fact that each specific cause
of death precludes the occurrence of all other causes of death, sensitiv-
ity analyses were conducted with time to cause-specific death com-
pared using cumulative incidence rate estimates with sub-distribution
hazard ratios, 95% confidence intervals, and two-sided P-values gener-
ated from proportional hazards competing risk regression models16
with region and treatment assignments as fixed effects. All statistical
analyses were conducted in STATA version 13.0 (College Station,
TX, USA).
Results
At the conclusion of PARADIGM-HF, vital status was ascertained
for all but 20 subjects. A total of 1546 patients, including 711
(17.0% of total patients) in the LCZ696 group and 835 patients
(19.8%) in the enalapril group died during the trial (hazard ratio,
HR, for death from any cause 0.84, 95% CI 0.76–0.93). Compared
with those who survived to trial end, patients who died during the
trial tended to be older and more likely male, with lower body mass
index, higher heart rate, higher creatinine, poorer functional cap-
acity [as assessed by New York Heart Association (NYHA) class],
higher natriuretic peptide levels, and greater comorbidity burden
(Table 1). The mode of death was not clearly associated with patient
characteristics at baseline, though subjects who died from heart fail-
ure tended to have higher natriuretic peptide levels, lower EF, and
more atrial fibrillation than those who died suddenly (Table 2).
Of the deaths, 1251 (80.9% of deaths) were ascribed to cardio-
vascular causes including 558 deaths (13.3% of total patients) in
1992 A.S. Desai et al.

Table 1 Baseline characteristics according to vital status at trial end

Characteristic Alive at end of trial Died during trial P

(N 5 6853) (N 5 1546)
...............................................................................................................................................................................
Age (years) 63.4 + 11.2 65.5 + 12.1 ,0.001
Sex: female, n (%) 1567 (22.9%) 265 (17.1%) ,0.001
...............................................................................................................................................................................
Race or ethnic group 0.07
White 4560 (66.5%) 984 (63.6%)
Black 349 (5.1%) 79 (5.1%)
Asian 1221 (17.8%) 288 (18.6%)
Other 723 (10.6%) 195 (12.6%)
SBP (mmHg) 122 + 15 121 + 16 0.13
Heart rate (bpm) 72 + 12 74 + 12 ,0.001
BMI (kg/m2) 28.3 + 5.5 27.7 + 5.6 ,0.001
Creatinine (mg/dL) 1.11 + 0.29 1.19 + 0.32 ,0.001
...............................................................................................................................................................................

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Clinical features of HF
Ischaemic CMP 4054 (59.2%) 982 (63.5%) 0.002
LVEF (%) 29.6 + 6.1 28.9 + 6.7 ,0.001
Median BNP (IQR) 234 [146, 421] 379 [206, 739] ,0.001
Median NT-pro-BNP (IQR) 1483 [838, 2856] 2550 [1262, 5467] ,0.001
...............................................................................................................................................................................
NYHA class ,0.001
I 336 (4.9%) 53 (3.4%)
II 4916 (71.9%) 1003 (64.9%)
III 1542 (22.5%) 476 (30.8%)
IV 46 (0.7%) 14 (0.9%)
...............................................................................................................................................................................
Medical history
Hypertension 4834 (70.5%) 1106 (71.5%) 0.43
Diabetes 2294 (33.5%) 613 (39.7%) ,0.001
Atrial fibrillation 2480 (36.2%) 611 (39.5%) 0.014
Hospitalization for HF 4245 (61.9%) 1029 (66.6%) ,0.001
MI 2914 (42.5%) 720 (46.6%) 0.004
Stroke 556 (8.1%) 169 (10.9%) ,0.001
...............................................................................................................................................................................
Treatment at randomization
Diuretics 5436 (79.3%) 1302 (84.2%) ,0.001
Digitalis 1998 (29.2%) 541 (35.0%) ,0.001
b-Blocker 6411 (93.6%) 1400 (90.6%) ,0.001
MRA 3832 (55.9%) 839 (54.3%) 0.24
ICD 1041 (15.2%) 202 (13.1%) 0.034
CRT 474 (6.9%) 100 (6.5%) 0.53

SBP, systolic blood pressure; BMI, body mass index; HF, heart failure; CMP, cardiomyopathy; NYHA, New York Heart Association; MI, myocardial infarction; ACE-I,
angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ICD, implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy; LVEF, left
ventricular ejection fraction.

the LCZ696 group and 693 (16.5%) in the enalapril group (HR for
death from cardiovascular causes with LCZ696 vs. enalapril 0.80;
95% CI 0.72 – 0.89; P , 0.001). An additional 229 deaths (14.8%
of deaths) were assigned to non-cardiovascular causes, including
120 deaths (2.8% of total patients) in the LCZ696 group and 109
deaths (2.5% of total patients) in the enalapril group. Non-
cardiovascular deaths did not differ by randomized treatment
groups (HR 1.07 for non-CV death, LCZ696 vs. enalapril, 95% CI
0.85 – 1.34, P ¼ 0.59). The remaining 66 unknown deaths (4.3% of
deaths, 0.8% of patients) could not be assigned to a clear cardiovas-
cular or non-cardiovascular cause, and were distributed similarly
between the treatment groups. Regional variations in the proportion
of cardiovascular and non-cardiovascular deaths and the mode of
cardiovascular death are summarized in Supplementary material
online, Table S1.
The incidence of cause-specific death, according to treatment as-
signment is summarized in Table 3. The majority of cardiovascular
deaths were categorized as sudden (44.8%) or heart failure related
Mode of death in PARADIGM-HF 1993

Table 2 Baseline characteristics according to cause of death

Characteristic Death due to HF Sudden Death Other CV deatha Non-CV Death P (all categories)
(N 5 331) (N 5 561) (N 5 359) (N 5 295)
...............................................................................................................................................................................
Age (years) 65.9 + 12.5 63.1 + 12.0 66.6 + 11.7 68.1 + 11.8 ,0.001
Sex: female, n (%) 56 (16.9%) 94 (16.8%) 68 (18.9%) 47 (15.9%) 0.75
...............................................................................................................................................................................
Race or ethnic group ,0.001
White 211 (63.7%) 314 (56.0%) 237 (66.0%) 222 (75.3%)
Black 15 (4.5%) 36 (6.4%) 15 (4.2%) 13 (4.4%)
Asian 57 (17.2%) 152 (27.1%) 52 (14.5%) 27 (9.2%)
Other 48 (14.5%) 59 (10.5%) 55 (15.3%) 33 (11.2%)
SBP (mmHg) 117 + 14 121 + 15 124 + 16 122 + 16 ,0.001
Heart rate (bpm) 74 + 13 73 + 12 73 + 12 74 + 14 0.59
BMI (kg/m2) 27.5 + 5.4 27.4 + 5.6 28.1 + 5.6 27.8 + 5.7 0.28
Creatinine (mg/dL) 1.26 + 0.36 1.14 + 0.30 1.18 + 0.31 1.19 + 0.32 ,0.001
...............................................................................................................................................................................

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Clinical features of HF
Ischaemic CMP 176 (53.2%) 368 (65.6%) 245 (68.2%) 193 (65.4%) ,0.001
LVEF (%) 27.6 + 6.9 28.9 + 6.5 29.3 + 6.7 30.0 + 6.8 ,0.001
Median BNP (IQR) 459 [270, 914] 370 [201, 695] 391 [211, 752] 293 [172, 571] ,0.001
Median NT-pro-BNP (IQR) 3377 [1713, 6512] 2402 [1251, 5076] 2542 [1159, 5832] 1941 [1085, 4114] ,0.001
...............................................................................................................................................................................
NYHA class 0.21
I 7 (2.1%) 23 (4.1%) 14 (3.9%) 9 (3.1%)
II 214 (64.7%) 354 (63.1%) 223 (62.1%) 212 (71.9%)
III 107 (32.3%) 177 (31.6%) 120 (33.4%) 72 (24.4%)
IV 3 (0.9%) 7 (1.2%) 2 (0.6%) 2 (0.7%)
...............................................................................................................................................................................
Medical history
Hypertension 213 (64.4%) 389 (69.3%) 284 (79.1%) 220 (74.6%) 0.002
Diabetes 134 (40.5%) 200 (35.7%) 162 (45.1%) 117 (39.7%) 0.039
Atrial fibrillation 147 (44.4%) 184 (32.8%) 151 (42.1%) 129 (43.7%) 0.007
Hospitalization for HF 237 (71.6%) 362 (64.5%) 241 (67.1%) 189 (64.1%) 0.13
MI 144 (43.5%) 276 (49.2%) 167 (46.5%) 133 (45.1%) 0.38
Stroke 44 (13.3%) 51 (9.1%) 40 (11.1%) 34 (11.5%) 0.26
...............................................................................................................................................................................
Treatment at randomization
Diuretics 297 (89.7%) 457 (81.5%) 298 (83.0%) 250 (84.7%) 0.01
Digitalis 137 (41.4%) 195 (34.8%) 118 (32.9%) 91 (30.8%) 0.031
b-Blocker 297 (89.7%) 507 (90.4%) 325 (90.5%) 271 (91.9%) 0.83
MRA 196 (59.2%) 311 (55.4%) 197 (54.9%) 135 (45.8%) 0.007
ICD 70 (21.1%) 36 (6.4%) 45 (12.5%) 51 (17.3%) ,0.001
CRT 34 (10.3%) 20 (3.6%) 18 (5.0%) 28 (9.5%) ,0.001

a
Other CV death includes all CV deaths not ascribed to pump failure or sudden death; CV, cardiovascular; SBP, systolic blood pressure; BMI, body mass index; HF, heart failure;
CMP, cardiomyopathy; NYHA, New York Heart Association; MI, myocardial infarction; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; ICD,
implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction.

(26.5%). Of those who died due to heart failure, 33.2% experienced
a hospitalization for heart failure prior to death. Among those who
died suddenly, the majority (380, 67.7%) had been last seen alive
within the hour prior, and 181 (32.3%) had been last seen alive be-
tween 1 and 24 h. The hazard for both sudden death (HR 0.80,
LCZ696 vs.. enalapril, 95% CI 0.68 – 0.94, P ¼ 0.008) and death
due to worsening heart failure (HR 0.79, LCZ696 vs. enalapril,
95% CI 0.64 – 0.98, P ¼ 0.034) was significantly reduced by
treatment with LCZ696. Kaplan – Meier curves depicting the time
to sudden death and to death from worsening heart failure by treat-
ment arm are displayed in Figure 1 and Figure 2. Inclusion of the 49
patients with presumed sudden deaths and the 66 patients with un-
known cause of death in the sudden death definition did not alter
the apparent treatment benefit of LCZ696 (HR 0.84, 95% CI
0.72 –0.97, P ¼ 0.02). Resuscitated sudden deaths, in which the pa-
tient survived, occurred in 16 patients in the LCZ696 arm compared
1994 A.S. Desai et al.

Table 3 Adjudicated causes of death and rates of death by cause according to treatment assignment, PARADIGM-HF
(N 5 8399)

LCZ Enalapril HR (95% CI)

................................................ ................................................ P-value
N % of patients % of deaths N % of patients % of deaths
LCZ vs. Enalapril
...............................................................................................................................................................................
Total deaths 711 17.0 100 835 19.8 100 0.84 (0.76, 0.93)
P ¼ 0.001
Cardiovascular death 558 13.3 78.5 693 16.5 83.0 0.80 (0.72, 0.89)
P , 0.001
Sudden death 250 6.0 35.2 311 7.4 37.2 0.80 (0.68, 0.94)
P ¼ 0.008
Last contact ,1 h 167 4.0 23.5 213 5.1 25.5 0.78 (0.64–0.95)
P ¼ 0.015
1 –24 h 83 2.0 11.7 98 2.3 11.7 0.84 (0.63–1.13)
P ¼ 0.26
Worsening heart failure 147 3.5 20.7 184 4.4 22.0 0.79 (0.64, 0.98)
P ¼ 0.034

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Other cardiovascular 161 3.8 22.6 198 4.7 23.7 0.81 (0.66–1.00)
P ¼ 0.045
Fatal MI 24 0.6 3.4 33 0.8 4.0 0.73 (0.43, 1.23)
P ¼ 0.24
Fatal stroke 30 0.7 4.2 34 0.8 4.1 0.88 (0.54, 1.44)
P ¼ 0.62
Presumed sudden death 26 0.6 3.7 23 0.5 2.8 1.12 (0.64, 1.96)
P ¼ 0.69
Presumed cardiovascular death 67 1.6 9.4 95 2.3 11.4 0.70 (0.51, 0.95)
P ¼ 0.024
Non-cardiovascular death 120 2.9 16.9 109 2.6 13.1 1.09 (0.84, 1.41)
P ¼ 0.53
Infection 36 0.9 5.1 34 0.8 4.1 1.04 (0.65, 1.67)
P ¼ 0.85
Malignancy 41 1.0 5.8 41 1.0 4.9 0.99 (0.64, 1.52)
P ¼ 0.96
Pulmonary 7 0.2 1.0 13 0.3 1.6 0.53 (0.21, 1.33)
P ¼ 0.18
GI 16 0.4 2.3 9 0.2 1.1 1.77 (0.78, 4.01)
P ¼ 0.17
Accidental 13 0.3 1.8 6 0.1 0.7 2.12 (0.81, 5.59)
P ¼ 0.13
Other 7 0.2 1.0 6 0.1 0.7 1.15 (0.39, 3.43)
P ¼ 0.80
Unknown death 33 0.8 4.6 33 0.8 3.9 0.99 (0.61, 1.61)
P ¼ 0.97

HR, hazard ratio; MI, myocardial infarction; GI, gastrointestinal.

with 28 patients in the enalapril arm (HR 0.57, 95% CI 0.31 – 1.04,
P ¼ 0.07). When combining both resuscitated and non-resuscitated
sudden death events, we observed a 22% reduction in the risk of
sudden death in those treated with LCZ696 compared with enala-
pril (HR 0.78, 95% CI 0.66, 0.92, P ¼ 0.002). The magnitude of the
treatment effect on sudden death did not differ amongst patients
with (36 of 561 sudden deaths) and without (525 of 561 sudden
deaths) an implantable defibrillator (HR in those with an ICD 0.49
(95% CI 0.25 – 0.98); HR in those without an ICD 0.82 (95% CI
0.69 – 0.98, interaction P ¼ 0.17). Further sensitivity analyses using
competing risks methods to examine the cumulative incidence of
sudden death and death due to worsening heart failure produced
nearly identical results to those already described (Supplementary
material online, Figures S1 and S2).
Fatal MI was infrequent, occurring in ,1% of patients, and ac-
counting for 3.7% of all deaths; the observed difference between
treatment arms was similar to that seen in HF death and sudden
death, but was not statistically significant. Fatal strokes occurred in
,1% of patients, accounted for 4.1% of all deaths, and did not differ
between treatment arms. Very few deaths were ascribed to other
cardiovascular causes such as pulmonary embolism or cardiovascu-
lar procedures. Malignancy and infection accounted for over half of
the non-cardiovascular deaths, which did not differ between treat-
ment groups (Table 3).
Mode of death in PARADIGM-HF
Figure 1 Kaplan – Meier survival curve for sudden death, by
treatment. HR, hazard ratio.
Figure 2 Kaplan– Meier survival curve for death due to worsen-
ing heart failure, by treatment. HR, hazard ratio.
Discussion
Over 80% of deaths in PARADIGM-HF had a cardiovascular cause.
The 20% reduction in cardiovascular deaths with LCZ696 relative to
enalapril seen during the trial was attributable primarily to reduc-
tions in the incidence of both sudden death and death due to pro-
gressive heart failure. There was no discernible impact of LCZ696
relative to enalapril on the incidence of non-cardiovascular death.
Cardiovascular deaths related to MI and stroke were infrequent
and equally distributed between the two treatment arms. In aggre-
gate, these data suggest that the mortality benefits of LCZ696 in
heart failure patients are related primarily to modification of the
risk for sudden death and death due to worsening heart failure.
The distribution of cause of death in PARADIGM-HF was consist-
ent with other contemporary trials that enrolled patients with chronic
HF-REF. While sudden death and death from heart failure commonly
1995
comprise the majority of cardiovascular deaths in heart failure trials,17
the proportion of deaths contributed by each varies according to the
symptomatic severity of the population enrolled.10 The greater pro-
portion of sudden death in our predominantly NYHA II–III population
is consistent with other chronic heart failure trials enrolling patients
with mild-to-moderate symptoms, including the CHARM reduced
EF trials,3 V-HEFT II,9 and MERIT-HF.10 Trials enrolling patients with
more advanced disease including CONSENSUS,7 RALES,6 EVER-
EST,11 COMPANION,18 and CARE-HF,19 have typically shown larger
proportions of death due to progressive heart failure and fewer sud-
den deaths. As in most heart failure trials, we observed low rates of
death due to clinically apparent MI and stroke (despite enrolment of
nearly 60% with known CAD and ischaemic cardiomyopathy); how-
ever, these rates may underestimate the true prevalence since some
sudden deaths may have been due to MI.20,21
The incremental 20% reduction in cardiovascular death during
LCZ696 treatment relative to enalapril was similar to the reduction
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seen in heart failure hospitalization, the other component of the pri-
mary composite endpoint in PARADIGM-HF. This result stands in
contrast to the results of many pivotal placebo-controlled studies
of renin–angiotensin system antagonists in heart failure (SOLVD-T8,
CHARM-Alternative,22 and EMPHASIS-HF23) and studies of more
intensive renin – angiotensin system inhibition (ATLAS24 and
HEAAL25) in which a more pronounced reduction was noted in
hospitalizations for worsening heart failure than cardiovascular
death. The impact of LCZ696 on cardiovascular death was apparent
despite an effective dose of an active comparator, enalapril, and
widespread use of the other contemporary medical therapies al-
ready known to reduce sudden death and death from worsening
heart failure (aldosterone antagonists, b-blockers, and ICDs).
The precise mechanism by which LCZ696 influences cardiovas-
cular mortality is uncertain, and requires further study. Since
ARBs and ACE-inhibitors have comparable effects on outcomes in
heart failure patients, the observed benefit is likely to be related to
the incremental benefits of neprilysin inhibition in heart failure. Since
neprilysin is important in the degradation of a number of endogen-
ous vasoactive peptides, inhibition of this pathway may be an im-
portant counter to the detrimental effects of renin – angiotensin
system and sympathetic nervous system activation in heart failure
patients. Plausible, but unproven, mechanisms of benefit might in-
clude haemodynamic improvements as a consequence of neprilysin
inhibition, including natriuretic peptide-mediated reduction in ven-
tricular wall stress or improvements in ventricular function leading
to a reduction in the occurrence of electromechanical dissociation;
modification of the substrate for fatal ventricular arrhythmias
through reductions in myocardial fibrosis, reduction in ventricular
hypertrophy, or attenuation of progressive ventricular remodelling;
sympatholytic or vagotonic effects of hormones potentiated by ne-
prilysin inhibition; anti-atherosclerotic or anti-thrombotic effects of
enhanced natriuretic peptide expression with improvements in re-
gional myocardial perfusion; or novel anti-arrhythmic properties
of the drug that have yet to be defined. Of note, circulating levels
of the cardiac biomarkers N-terminal-pro-BNP and troponin in
PARADIGM-HF were lower during treatment with LCZ696 than
during treatment with enalapril (data not shown), suggesting that
LCZ696 may favourably impact the haemodynamic profile and
attenuate cardiac injury in heart failure patients over time.
1996
Understanding the precise mechanism of benefit of LCZ696 in heart
failure may provide important insights into the pathophysiology of
heart failure and should be a priority for future study.
This analysis should be viewed in the context of its limitations. At-
tribution of cause of death in a clinical trial is based on historical in-
formation, which is dependent on the quality of the source
documentation available and presumes that such documentation
can provide mechanistic insights. Nevertheless, the use of a blinded,
independent clinical events committee provided consistency
throughout the endpoint review process, and assured that deaths
would be ascribed similarly in patients from different sites and re-
gions, and in both treatment groups. Attributing causes to death
in clinical trials is especially challenging in cases of suspected sudden
cardiac death, and this classification does not necessarily imply a
common pathophysiology. However, in PARADIGM-HF, attribution
of sudden death did require the death to be an unexpected death in
an apparently stable patient; patients last seen .24 h prior to death
we characterized separately as presumed sudden deaths and abrupt
deaths in the context of worsening heart failure or clinically appar-
ent MI were not classified as sudden. Autopsies were available in the
minority of cases in PARADIGM-HF, but were taken into account
when provided to the adjudication committee. The definitions
used were nearly identical to the proposed universal cardiovascular
clinical trial definitions being currently reviewed by the United
States Food and Drug Administration.26
In summary, we found that treatment with LCZ696 compared
with enalapril in chronic heart failure patients in PARADIGM-HF re-
duced cardiovascular death primarily by reducing both death due to
worsening heart failure and sudden cardiac death.
Supplementary material
Supplementary material is available at European Heart Journal online.
Funding
The PARADIGM-HF Study was funded by Novartis AG.
Conflict of interest: F.C., J.G., A.R.R., M.L., and V.S. are employees of
Novartis Pharmaceuticals Corporation. All other authors have con-
sulted for or received research support from Novartis, sponsor of the
PARADIGM-HF trial. In addition, A.S.D. consulted for Novartis, Relypsa,
and St. Jude Medical; M.P. has consulted for Novartis, Actelion, Sanofi,
Cardiokinetix, BioControl, Janssen, Amgen, AMAG, Daiichi, Cardio-
MEMS, and Cardiorentis; J.J.V.M.’s employer, University of Glasgow,
was paid by Novartis for his time spent as co-chairman of the
PARADIGM-HF trial.
References
1. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme
inhibitors on mortality and morbidity in patients with heart failure. Collaborative
group on ace inhibitor trials. JAMA 1995;273:1450 – 1456.
2. Cubbon RM, Gale CP, Kearney LC, Schechter CB, Brooksby WP, Nolan J, Fox KA,
Rajwani A, Baig W, Groves D, Barlow P, Fisher AC, Batin PD, Kahn MB, Zaman AG,
Shah AM, Byrne JA, Lindsay SJ, Sapsford RJ, Wheatcroft SB, Witte KK, Kearney MT.
Changing characteristics and mode of death associated with chronic heart failure
caused by left ventricular systolic dysfunction: A study across therapeutic eras. Cir-
culation 2011;4:396 –403.
3. Solomon SD, Wang D, Finn P, Skali H, Zornoff L, McMurray JJ, Swedberg K, Yusuf S,
Granger CB, Michelson EL, Pocock S, Pfeffer MA. Effect of candesartan on cause-
specific mortality in heart failure patients: The candesartan in heart failure
A.S. Desai et al.
assessment of reduction in mortality and morbidity (charm) program. Circulation
2004;110:2180 –2183.
4. Remme WJ, Cleland JG, Erhardt L, Spark P, Torp-Pedersen C, Metra M, Komajda M,
Moullet C, Lukas MA, Poole-Wilson P, Di Lenarda A, Swedberg K. Effect of carve-
dilol and metoprolol on the mode of death in patients with heart failure. Eur J Heart
Fail 2007;9:1128 –1135.
5. Cleland JG, Erhardt L, Murray G, Hall AS, Ball SG. Effect of ramipril on morbidity
and mode of death among survivors of acute myocardial infarction with clinical evi-
dence of heart failure. A report from the AIRE study investigators. Eur Heart J 1997;
18:41 –51.
6. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J.
The effect of spironolactone on morbidity and mortality in patients with severe
heart failure. Randomized Aldactone Evaluation study investigators. N Engl J Med
1999;341:709 –717.
7. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe
congestive heart failure. N Engl J Med 1987;316:1429 –1435.
8. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced
left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;
325:293 –302.
9. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R,
Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J,
Hughes V, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of ena-
lapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on February 19, 2016
heart failure. N Engl J Med 1991;325:303 –310.
10. Metoprolol CR/XL randomized intervention trial in congestive heart failure
(MERIT-HF) MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart
failure. Lancet 1999;353:2001 –2007.
11. O’Connor CM, Miller AB, Blair JE, Konstam MA, Wedge P, Bahit MC, Carson P,
Haass M, Hauptman PJ, Metra M, Oren RM, Patten R, Piña I, Roth S,
Sackner-Bernstein JD, Traver B, Cook T, Gheorghiade M. Causes of death and re-
hospitalization in patients hospitalized with worsening heart failure and reduced
left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism
in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Efficacy of
Vasopressin Antagonism in heart Failure Outcome Study with Tolvaptan (EVER-
EST) investigators. Am Heart J 2010;159:841 –849.
12. Vardeny O, Tacheny T, Solomon SD. First-in-class angiotensin receptor neprilysin
inhibitor in heart failure. Clin Pharmacol Ther 2013;94:445 – 448.
13. Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S,
Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP. Pharmacokinetics and
pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin
inhibitor (ARNi). J Clin Pharmacol 2010; 50:401 –414.
14. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL,
Shi VC, Solomon SD, Swedberg K, Zile MR. PARADIGM-HF Investigators and
Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N
Engl J Med 2014;371:993–1004.
15. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau J,
Shi VC, Solomon SD, Swedberg K, Zile MR. PARADIGM-HF Committees and In-
vestigators. Dual angiotensin receptor and neprilysin inhibition as an alternative to
angiotensin-converting enzyme inhibition in patients with chronic systolic heart
failure: rationale for and design of the Prospective comparison of ARNI with
ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial
(PARADIGM-HF). Eur J Heart Fail 2013;15:1062 –1073.
16. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a compet-
ing risk. J Am Stat Assoc 1999;94:496 –509.
17. O’Connor CM, Carson PE, Miller AB, Pressler ML, Belkin RN, Neuberg GW,
Frid DJ, Cropp AB, Anderson S, Wertheimer JH, DeMets DL. Effect of amlodipine
on mode of death among patients with advanced heart failure in the PRAISE trial.
Prospective Randomized Amlodipine Survival Evaluation. Am J Cardiol 1998;82:
881 –887.
18. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P,
DiCarlo L, DeMets D, White B, DeVries DW, Feldman AM; for the Comparison
of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) In-
vestigators. Cardiac-resynchronization therapy with or without an implantable de-
fibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140 –2150.
19. Cleland JGF, Daubert J-C, Erdmann E, Freemantle N, Gras D, Kappenberger L,
Tavazzi L, for the Cardiac Resynchronization—Heart Failure (CARE-HF) Study In-
vestigators. The Effect of cardiac resynchronization on morbidity and mortality in
heart failure. N Engl J Med 2005;352:1539 – 1549.
20. Pouleur AC, Barkoudah E, Uno H, Skali H, Finn PV, Zelenkofske SL, Belenkov YN,
Mareev V, Velazquez EJ, Rouleau JL, Maggioni AP, Køber L, Califf RM, McMurray JJ,
Pfeffer MA, Solomon SD; VALIANT Investigators. Pathogenesis of sudden unex-
pected death in a clinical trial of patients with myocardial infarction and left ven-
tricular dysfunction, heart failure, or both. Circulation 2010;122:597 –602.
21. Uretsky BF, Thygesen K, Armstrong PW, Cleland JG, Horowitz JD, Massie BM,
Packer M, Poole-Wilson PA, Ryden L. Acute coronary findings at autopsy in heart
Mode of death in PARADIGM-HF
failure patients with sudden death: results from the assessment of treatment with
lisinopril and survival (ATLAS) trial. Circulation 2000;102:611 –616.
22. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J,
Pfeffer MA, Swedberg K; CHARM Investigators and Committees. Effects of candesar-
tan in patients with chronic heart failure and reduced left-ventricular systolic function
intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative
trial. Lancet 2003;362:772–776.
23. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J,
Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic
heart failure and mild symptoms. N Engl J Med 2011;364:11–21.
24. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM,
Ryden L, Thygesen K, Uretsky BF. Comparative effects of low and high doses of
the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and
1997
mortality in chronic heart failure. ATLAS study group. Circulation 1999;100:
2312 –2318.
25. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA,
Riegger GA, Malbecq W, Smith RD, Guptha S, Poole-Wilson PA. Effects of high-
dose versus low-dose losartan on clinical outcomes in patients with heart failure
(HEAAL study): a randomised, double-blind trial. Lancet 2009;374:1840 –1848.
26. Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Stockbridge NL,
Targum SL, Temple R; on behalf of the Standardized Data Collection for Cardio-
vascular Trials Initiative. Standardized definitions for cardiovascular and stroke end
point events in clinical trials. Draft definitions for CDISC, July 3, 2014. http://www.
cdisc.org/system/files/all/reference_material/application/pdf/Draft%
20Definitions%20for%20CDISC%20July%203,%202014.pdf (18 December
2014).
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on February 19, 2016