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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]. Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 2, 2016 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 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 2, 2016 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 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 2, 2016 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 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 2, 2016 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). Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 2, 2016 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. Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 2, 2016 Figure 2 Kaplan– Meier survival curve for death due to worsening heart failure, by treatment. HR, hazard ratio. 1995 1996 Supplementary material 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 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. 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. 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The Effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539 – 1549. 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 unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. Circulation 2010;122:597 –602. 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 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 2, 2016 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. 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 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 apparent 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 reduced cardiovascular death primarily by reducing both death due to worsening heart failure and sudden cardiac death. A.S. Desai et al. 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