Download Effect of the angiotensin-receptor

CLINICAL RESEARCH
European Heart Journal (2015) 36, 1990–1997
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*
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 Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-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,
New York Heart Association Class II – IV symptoms, and left ventricular ejection fraction ≤40% receiving guidelineand results
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 cardiovascular 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 distributed 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
heart failure remain at high risk for heart failure progression and
death.1,2 Among patients with heart failure and reduced ejection
fraction (HF-REF), therapies that improve mortality, including
angiotensin-converting enzyme (ACE) inhibitors, angiotensinreceptor blockers (ARBs), b-adrenergic-receptor blockers, and
aldosterone antagonists influence the incidence of sudden cardiac
death and death from progressive heart failure, but not the
* Corresponding author. Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
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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
1991
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 angiotensin-receptor-neprilysin inhibitor (ARNI) comprised of the neprilysin
inhibitor prodrug sacubitril and the ARB valsartan.12,13 The Prospective 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 mortality reduction associated with LCZ696, we assessed the effect of
LCZ696 compared with enalapril on the mode of death in
PARADIGM-HF.
Methods
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 written 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 cardiovascular causes or first hospitalization for heart failure. The time to death
from any cause was pre-specified as a key secondary endpoint. All occurrences 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 includes 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 independently 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 further sub-classified as sudden or due to MI, worsening heart failure,
stroke, complications of a cardiovascular procedure, pulmonary embolism, or another cardiovascular cause. Sudden death was defined as death
occurring unexpectedly in an otherwise stable patient, and was further
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, sensitivity analyses were conducted with time to cause-specific death compared using cumulative incidence rate estimates with sub-distribution
hazard ratios, 95% confidence intervals, and two-sided P-values generated 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 capacity [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 failure 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 cardiovascular causes including 558 deaths (13.3% of total patients) in
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PARADIGM-HF design
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 dying within 14 days of a clinical MI, those with autopsy evidence of recent
infarction, or those with an abrupt death associated with ECG, biomarker, or imaging evidence of acute myocardial injury. Death from worsening heart failure was defined as death in the context of clinically
worsening symptoms and/or signs of heart failure with no other apparent 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 embolism. Remaining deaths that could be classified were presumed to be
unspecified cardiovascular deaths unless a specific non-cardiovascular
cause was identified. Non-cardiovascular deaths were further classified
as due to infection, malignancy, pulmonary, gastrointestinal, renal, accidental, suicide, or other causes. Between-reviewer agreement as to the
broad category of death (cardiovascular, non-cardiovascular, or unknown) was 92.5% (k 0.78), and for the specific cause of cardiovascular
death was 74% (k 0.67).
1992
Table 1
A.S. Desai et al.
Baseline characteristics according to vital status at trial end
Characteristic
Alive at end of trial
(N 5 6853)
Died during trial
(N 5 1546)
P
...............................................................................................................................................................................
63.4 + 11.2
65.5 + 12.1
,0.001
1567 (22.9%)
265 (17.1%)
,0.001
White
Black
4560 (66.5%)
349 (5.1%)
984 (63.6%)
79 (5.1%)
Asian
1221 (17.8%)
288 (18.6%)
723 (10.6%)
122 + 15
195 (12.6%)
121 + 16
0.13
72 + 12
74 + 12
,0.001
28.3 + 5.5
1.11 + 0.29
27.7 + 5.6
1.19 + 0.32
,0.001
,0.001
Age (years)
Sex: female, n (%)
...............................................................................................................................................................................
Race or ethnic group
Other
SBP (mmHg)
Heart rate (bpm)
BMI (kg/m2)
Creatinine (mg/dL)
0.07
...............................................................................................................................................................................
LVEF (%)
Median BNP (IQR)
Median NT-pro-BNP (IQR)
4054 (59.2%)
29.6 + 6.1
234 [146, 421]
1483 [838, 2856]
982 (63.5%)
0.002
28.9 + 6.7
,0.001
379 [206, 739]
2550 [1262, 5467]
,0.001
,0.001
...............................................................................................................................................................................
NYHA class
I
,0.001
336 (4.9%)
53 (3.4%)
II
4916 (71.9%)
1003 (64.9%)
III
IV
1542 (22.5%)
46 (0.7%)
476 (30.8%)
14 (0.9%)
Hypertension
4834 (70.5%)
1106 (71.5%)
0.43
Diabetes
Atrial fibrillation
2294 (33.5%)
2480 (36.2%)
613 (39.7%)
611 (39.5%)
,0.001
0.014
Hospitalization for HF
4245 (61.9%)
1029 (66.6%)
,0.001
MI
Stroke
2914 (42.5%)
556 (8.1%)
720 (46.6%)
169 (10.9%)
0.004
,0.001
...............................................................................................................................................................................
Medical history
...............................................................................................................................................................................
Treatment at randomization
Diuretics
5436 (79.3%)
1302 (84.2%)
,0.001
Digitalis
1998 (29.2%)
541 (35.0%)
,0.001
b-Blocker
MRA
6411 (93.6%)
3832 (55.9%)
1400 (90.6%)
839 (54.3%)
,0.001
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. Noncardiovascular 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 cardiovascular 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 assignment is summarized in Table 3. The majority of cardiovascular
deaths were categorized as sudden (44.8%) or heart failure related
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Clinical features of HF
Ischaemic CMP
1993
Mode of death in PARADIGM-HF
Table 2
Baseline characteristics according to cause of death
Characteristic
Death due to HF
(N 5 331)
Sudden Death
(N 5 561)
Other CV deatha
(N 5 359)
Non-CV Death
(N 5 295)
P (all categories)
68.1 + 11.8
,0.001
...............................................................................................................................................................................
Age (years)
Sex: female, n (%)
65.9 + 12.5
63.1 + 12.0
66.6 + 11.7
56 (16.9%)
94 (16.8%)
68 (18.9%)
47 (15.9%)
211 (63.7%)
15 (4.5%)
314 (56.0%)
36 (6.4%)
237 (66.0%)
15 (4.2%)
222 (75.3%)
13 (4.4%)
0.75
...............................................................................................................................................................................
,0.001
Race or ethnic group
White
Black
Asian
Other
SBP (mmHg)
Heart rate (bpm)
BMI (kg/m2)
Creatinine (mg/dL)
57 (17.2%)
152 (27.1%)
52 (14.5%)
27 (9.2%)
48 (14.5%)
117 + 14
59 (10.5%)
121 + 15
55 (15.3%)
124 + 16
33 (11.2%)
122 + 16
,0.001
74 + 13
73 + 12
73 + 12
74 + 14
0.59
27.5 + 5.4
1.26 + 0.36
27.4 + 5.6
1.14 + 0.30
28.1 + 5.6
1.18 + 0.31
27.8 + 5.7
1.19 + 0.32
0.28
,0.001
...............................................................................................................................................................................
LVEF (%)
Median BNP (IQR)
Median NT-pro-BNP (IQR)
176 (53.2%)
368 (65.6%)
245 (68.2%)
193 (65.4%)
,0.001
27.6 + 6.9
28.9 + 6.5
29.3 + 6.7
30.0 + 6.8
,0.001
293 [172, 571]
1941 [1085, 4114]
,0.001
,0.001
459 [270, 914]
3377 [1713, 6512]
370 [201, 695]
2402 [1251, 5076]
391 [211, 752]
2542 [1159, 5832]
...............................................................................................................................................................................
NYHA class
I
0.21
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
IV
107 (32.3%)
3 (0.9%)
177 (31.6%)
7 (1.2%)
120 (33.4%)
2 (0.6%)
72 (24.4%)
2 (0.7%)
Hypertension
213 (64.4%)
389 (69.3%)
284 (79.1%)
220 (74.6%)
0.002
Diabetes
Atrial fibrillation
134 (40.5%)
147 (44.4%)
200 (35.7%)
184 (32.8%)
162 (45.1%)
151 (42.1%)
117 (39.7%)
129 (43.7%)
0.039
0.007
...............................................................................................................................................................................
Medical history
Hospitalization for HF
237 (71.6%)
362 (64.5%)
241 (67.1%)
189 (64.1%)
0.13
MI
Stroke
144 (43.5%)
44 (13.3%)
276 (49.2%)
51 (9.1%)
167 (46.5%)
40 (11.1%)
133 (45.1%)
34 (11.5%)
0.38
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
MRA
297 (89.7%)
196 (59.2%)
507 (90.4%)
311 (55.4%)
325 (90.5%)
197 (54.9%)
271 (91.9%)
135 (45.8%)
0.83
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 between 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 treatment arm are displayed in Figure 1 and Figure 2. Inclusion of the 49
patients with presumed sudden deaths and the 66 patients with unknown 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 patient survived, occurred in 16 patients in the LCZ696 arm compared
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Clinical features of HF
Ischaemic CMP
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
................................................
N
% of patients
% of deaths
Enalapril
................................................
N
% of patients
% of deaths
HR (95% CI)
P-value
LCZ vs. Enalapril
...............................................................................................................................................................................
Total deaths
711
17.0
Cardiovascular death
558
13.3
Sudden death
250
19.8
78.5
693
16.5
83.0
6.0
35.2
311
7.4
37.2
167
4.0
23.5
213
5.1
25.5
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
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
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
GI
16
0.4
2.3
9
0.2
1.1
Accidental
13
0.3
1.8
6
0.1
0.7
7
0.2
1.0
6
0.1
0.7
33
0.8
4.6
33
0.8
3.9
0.53 (0.21, 1.33)
P ¼ 0.18
1.77 (0.78, 4.01)
P ¼ 0.17
2.12 (0.81, 5.59)
P ¼ 0.13
1.15 (0.39, 3.43)
P ¼ 0.80
0.99 (0.61, 1.61)
P ¼ 0.97
1 –24 h
Non-cardiovascular death
Other
Unknown death
100
0.84 (0.76, 0.93)
P ¼ 0.001
0.80 (0.72, 0.89)
P , 0.001
0.80 (0.68, 0.94)
P ¼ 0.008
0.78 (0.64–0.95)
P ¼ 0.015
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 enalapril (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 accounting 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 cardiovascular procedures. Malignancy and infection accounted for over half of
the non-cardiovascular deaths, which did not differ between treatment groups (Table 3).
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835
Last contact ,1 h
100
Mode of death in PARADIGM-HF
Figure 1 Kaplan – Meier survival curve for sudden death, 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 reductions in the incidence of both sudden death and death due to progressive 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 aggregate, 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 consistent with other contemporary trials that enrolled patients with chronic
HF-REF. While sudden death and death from heart failure commonly
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 proportion 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 EVEREST,11 COMPANION,18 and CARE-HF,19 have typically shown larger
proportions of death due to progressive heart failure and fewer sudden 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); however, 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
seen in heart failure hospitalization, the other component of the primary 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 already known to reduce sudden death and death from worsening
heart failure (aldosterone antagonists, b-blockers, and ICDs).
The precise mechanism by which LCZ696 influences cardiovascular 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 endogenous vasoactive peptides, inhibition of this pathway may be an important 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 include haemodynamic improvements as a consequence of neprilysin
inhibition, including natriuretic peptide-mediated reduction in ventricular 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 neprilysin inhibition; anti-atherosclerotic or anti-thrombotic effects of
enhanced natriuretic peptide expression with improvements in regional 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.
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Figure 2 Kaplan– Meier survival curve for death due to worsening heart failure, by treatment. HR, hazard ratio.
1995
1996
Supplementary material
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11.
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14.
Supplementary material is available at European Heart Journal online.
Funding
15.
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 consulted 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, CardioMEMS, 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.
16.
17.
18.
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This analysis should be viewed in the context of its limitations. Attribution of cause of death in a clinical trial is based on historical information, 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 regions, and in both treatment groups. Attributing causes to death
in clinical trials is especially challenging in cases of suspected sudden
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minority of cases in PARADIGM-HF, but were taken into account
when provided to the adjudication committee. The definitions
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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 reduced cardiovascular death primarily by reducing both death due to
worsening heart failure and sudden cardiac death.
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