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Falling Cardiovascular Mortality inHeart Failure With Reduced EjectionFraction and Implications for Clinical Trials

Christopher J. Rush, MBCHB,* Ross T. Campbell, BSC, MBCHB,y Pardeep S. Jhund, MBCHB, PHD,yEugene C. Connolly, MBCHB,y David Preiss, MBCHB, PHD,y Roy S. Gardner, MD,z Mark C. Petrie, BSC, MBCHB,zJohn J.V. McMurray, MDy

ABSTRACT

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OBJECTIVES This study examined the trends in the relative contributions of cardiovascular and noncardiovascular

mortality to total mortality according to use of beta-blockers in clinical trials of patients with heart failure with reduced

ejection fraction (HF-REF).

BACKGROUND With the increasingly widespread use of disease-modifying therapies, particularly beta-blockers, in

HF-REF, the proportion of patients dying from cardiovascular causes is likely to be decreasing.

METHODS In a systematic review, 2 investigators independently searched online databases to identify clinical trials

including >400 patients with chronic heart failure published between 1986 and 2014 and that adjudicated cause of

death. Trials were divided into 3 groups on the basis of the proportion of patients treated with a beta-blocker (<33%

[low], 33% to 66% [medium], and >66% [high]). Percentages of total deaths adjudicated as cardiovascular or non-

cardiovascular were calculated by weighted means and weighted standard deviations. Weighted Student t tests were

used to compare results between groups.

RESULTS Sixty-six trials met the inclusion criteria with a total of 136,182 patients and 32,140 deaths. There was a

sequential increase in the percentage of noncardiovascular deaths with increasing beta-blocker use from 11.4% of all

deaths in trials with low beta-blocker use to 19.1% in those with high beta-blocker use (p < 0.001).

CONCLUSIONS In trials of patients with HF-REF, the proportion of deaths adjudicated as cardiovascular has decreased.

Cardiovascularmortality, andnotall-causemortality, shouldbeusedasanendpoint for trialsofnewtreatments forHF-REF.

(J Am Coll Cardiol HF 2015;3:603–14) © 2015 by the American College of Cardiology Foundation.

T he stepwise introduction of several drug anddevice therapies for patients with heart fail-ure with reduced ejection fraction (HF-REF)

has led to incremental improvements in survival inclinical trial cohorts (1) and there have been associ-ated reductions in mortality in individuals with HFin the general population (2,3). By their very nature,treatments for HF are likely to affect mainly cardio-vascular (CV) causes of death, particularly deathfrom worsening HF and sudden cardiac death.

m the *Hairmyres Hospital, East Kilbride, Scotland, United Kingdom; ysgow, Glasgow, Scotland, United Kingdom; and the zGolden Jubilee Nat

. Campbell is supported by a British Heart Foundation Project Grant, num

t they have no relationships relevant to the contents of this paper to disc

s work.

nuscript received January 13, 2015; revised manuscript received March 11

They should have little impact on non-CV causes ofdeath. As a result, the respective proportions ofdeaths attributed to CV and non-CV causes in pa-tients with HF has probably changed over recentyears, with implications for the design of clinicaltrials (choice of endpoints and anticipated eventrates) and expectations for future treatment effects.To test this hypothesis, we investigated trends inCV and non-CV deaths in patients with HF over thepast 3 decades.

BHF Cardiovascular Research Centre, University of

ional Hospital, Glasgow, Scotland, United Kingdom.

ber PG/13/17/30050. All other authors have reported

lose. Drs. Rush and Campbell contributed equally to

, 2015, accepted March 13, 2015.

ABBR EV I A T I ON S

AND ACRONYMS

ACEI = angiotensin-converting

enzyme inhibitor

ARB = angiotensin receptor

blocker

BB = beta blocker

CV = cardiovascular

HF = heart failure

HF-PEF = heart failure with

preserved ejection fraction

HF-REF = heart failure with

reduced ejection fraction

NYHA = New York Heart

Association

RCT = randomized controlled

trial

Rush et al. J A C C : H E A R T F A I L U R E V O L . 3 , N O . 8 , 2 0 1 5

Falling CV Mortality in CHF Trials A U G U S T 2 0 1 5 : 6 0 3 – 1 4

604

METHODS

We collected data from randomized con-trolled trials (RCTs) of patients with chronicHF-REF to examine the respective pro-portions of deaths by CV and non-CV causes.LITERATURE SEARCH STRATEGY. We searchedthe electronic databases Medline and Embasewith the terms “heart failure” or “congestiveheart failure” as title or keywords. The search,updated until October 2, 2014, was limited toRCTs of adults, with more than 400 partici-pants, published in the English language,between January 1, 1986 and October 1, 2014.Trials were eligible for inclusion in the anal-ysis if both all-cause and CV mortality wereadjudicated in the primary results paper or

subsequent analyses. We excluded trials in acute HFand those in patients after acutemyocardial infarction.Although we did include trials in patients withHF-preserved ejection fraction (HF-PEF), there weremany fewer of these than the majority in patientswith HF-REF. Bibliographies of guidelines, reviews,andmanuscripts identified through the search strategywere also hand-searched for additional eligibletrials. Published Food andDrugAdministration reportswere also searched for CV and total mortality datafrom trials identified. Abstracts and manuscriptswere independently reviewed by 2 readers (C.R. andR.T.C.), with a third reader (J.J.M.) resolving anydiscrepancies.

SEE PAGE 615

DATA EXTRACTION. Two authors (C.R. and R.T.C.)independently abstracted and tabulated data frommanuscripts identified through the search criteria.Relevant endpoints for which data were collectedweretotal mortality, CV mortality, non-CV, and cardiacmortality. Where cardiac mortality was not described,the sum of the individual components commonly usedin cardiac mortality (myocardial infarction, HF, sud-den cardiac death, arrhythmic death) was used whereavailable. The proportion of deaths classified asunknown was recorded, as was whether the trialsreported if these deaths were classified as CV.DATA SYNTHESIS AND STATISTICAL ANALYSIS. Weincluded all participants regardless of the therapybeing investigated. Eligible trials were divided into 3groups for analysis on the basis of the proportion ofpatients treated with a beta-blocker (BB) (<33% [lowuse], 33% to 66% [medium use], >66% [high use]),and also into the decade in which the primary resultpaper was published (1985 to 1994, 1995 to 2004,2005 to 2014). The mortality data for each group were

analyzed and percentages of total mortality, CV, non-CV, cardiac, and unknown deaths, were calculated asweighted means. Weighted standard deviations werecalculated as described by Bland and Kerry (4).The odds of dying from a non-CV cause over timewere tested using a grouped logistic regression model.We examined trends adjusting for angiotensin-converting enzyme inhibitor (ACEI)/angiotensin re-ceptor blocker (ARB) and mineralocorticoid receptorantagonist (MRA) use. In 40% of studies, the propor-tion of patients receiving a MRA was not reported.Therefore, we examined this association in 2 ways:excluding those trials and after imputing the meanproportion. Analyses were performed using STATAversion 12 (Stata Corp., College Station, Texas). Assensitivity analyses, we analyzed the proportion ofCV, non-CV, and cardiac deaths by BB group (<33%,33% to 66%, >66%) and time period (1986 to 1994,1995 to 2004, 2005 to 2014) in a random effects meta-analysis (using the metaprop command in STATA)(5). Heterogeneity was assessed and interpreted usingthe I2 statistic and forest plots (6–8). A p value <0.05was considered statistically significant.

RESULTS

Our search strategy identified 66 trials that included136,182 patients and reported 32,140 deaths (9–84). Ofthe patients enrolled in these trials, 77%weremale, themean age was 65 years, and approximately 90% werein New York Heart Association (NYHA) functionalclass II or III. The weighted average left ventricularejection fraction was 27%. More detailed baseline in-formation for each trial is shown in Tables 1 and 2.

The trials were divided into 3 groups for analysison the basis of the proportion of patients treatedwith a BB. The key baseline characteristics of the 3groups were, in general, similar except by definitionfor the treatments prescribed for HF (Table 3). Thetrials with greater use of BB (which were more recentstudies) also demonstrated greater use of otherdisease-modifying therapies (e.g., mineralocorticoidreceptor antagonists: used at baseline in 14.4% ofpatients in trials with <33% BB therapy vs. 44.0%of trials with >66% BB use) and devices (e.g., 1.0% ofpatients in trials with <33% BB therapy vs. 20.4% ofpatients in trials with >66% BB use had an implant-able cardioverter defibrillator). There was also agreater proportion of patients in NYHA functionalclass III/IV in the earlier trials with low BB use(49.2%/9.6% vs. 41.1%/4.1%, respectively).

MORTALITY FROM ALL CAUSES. Details of the numberand causes of death in each trial are given in Tables 4

TABLE 1 Baseline Characteristics (All Trials)

% Beta-Blocker Trial (Ref. #) Year n

Follow-Up (Months)MeanAge(yrs)

Male(%)

MeanEF(%)

NYHA FunctionalClass (%) Adjuvant Therapy

Mean/Median* I II III IVACEI/ARB

(%)MRA(%)

ICD(%)

CRT(%)

Trials with <33% beta-blocker use (n ¼ 21)

0 V-HeFT I (9) 1986 642 28 58 100 30 0 — — — 0 0 0 0

0 V-HeFT II (10) 1991 804 30 61 100 29 6 51 43 1 50 — 0 0

0 PROMISE (11) 1991 1088 6* 64 78 21 0 0 58 42 100 — 0 0

0 GESICA (12) 1994 516 13 59 81 19 0 21 48 31 90 — 0 0

0 PRAISE I (13,14) 1996 1,153 14* 65 76 21 0 0 81 19 99 — 0 0

0 PRIME II (15) 1997 1,906 12 65 80 26 0 0 100 92 — 0 0

0 DIG (16) 1997 6,800 37 64 78 28 13 54 31 2 95 — 0 0

0 V-HeFT III (17) 1997 450 18 64 100 30 0 80 20 0 97 — 0 0

0 VEST (18) 1998 3,833 9 63 76 21 0 1 85 14 90 — 0 0

1 MOXCON (19) 2003 1,934 — 64 78 26 0 42 54 4 87 7 0 0

4 CHF-STAT (20) 1995 674 45* 66 99 — 1 56 22 78 — 0 0

8 SOLVD-T (21) 1991 2,569 41 61 80 25 11 57 30 2 50 9† 0 0

10 DIAMOND-HF (22) 1999 1,518 18* 70 73 — 2 37 53 7 74 — 0 0

11 RALES (23) 1999 1,663 24 65 73 25 0 1 70 29 95 49 0 0

11 ATLAS (24,25) 1999 3,164 46* 64 80 23 0 16 77 7 100 — 0 0

16 ELITE I (26) 1997 722 11 74 67 30 0 65 33 2 100 — 0 0

16 MACH I (27) 2000 2,590 19 63 79 25 0 26 64 10 99 — 0 0

19 PRAISE 2 (28) 2013 1,654 33* 59 66 21 0 0 80 20 100 — 0 0

21 CABG Patch (29,30) 1997 900 32 64 84 27 — 73 — 54 — 48 0

22 ELITE II (31) 2000 3,152 18* 71 69 31 0 52 43 5 100 22† 0 0

24 SOLVD-P (32) 1992 4,228 37 59 89 28 67 33 0 0 50 4† 0 0

Trials with 33% to 66% beta-blocker use (n ¼ 18)

35 Val-HeFT (33) 2001 5,010 23 63 80 27 0 62 36 2 93 5 0 0

47 CONTAK-CD (34) 2003 490 6 66 84 22 0 33 58 9 88 — 100 50

50 CIBIS I (35) 1994 641 23 60 83 25 0 0 95 5 90 — 0 0

50 AUST-NZ (36) 1997 415 19 67 80 29 30 54 16 0 86 — 0 0

50 CIBIS II (37) 1999 2,647 16 61 81 28 0 0 83 17 96 — 0 0

50 MERIT-HF (38) 2000 3,991 12 64 78 28 0 41 55 4 96 8 0 0

50 BEST (39) 2001 2,708 24 60 78 23 0 0 92 8 98 4 0 0

50 SENIORS (40) 2005 2,128 21 76 63 36 3 56 39 2 89 28 0 0

51 COPERNICUS (41,42) 2001 2,289 10 63 79 20 0 0 100 97 19 0 0

54 TEN-HMS (43) 2005 418 8* 67 79 25 20 43 29 8 85 52 0 0

55 CHARM-Added (44) 2003 2,548 42* 64 79 28 0 24 73 3 100 17 0 0

55 CHARM-Alternative (45) 2003 2,028 34* 67 68 30 0 48 49 3 50 24 0 0

61 ANDROMEDA (46) 2008 627 2* 72 75 — 0 40 57 3 86 41 2 0

62 GISSI-HF Rosuvastatin (47) 2008 4,574 47* 68 77 33 0 62 35 3 93 40 7 —

64 USCP (48) 1996 1,094 7 58 77 23 0 53 44 3 95 — 0 0

65 GISSI-HF n-3 PUFA (49) 2008 6,975 47* 67 88 33 0 63 34 3 94 39 7 —

65 FUSION II (50) 2008 911 3* 65 71 25 0 0 47 53 59 37 39 24

66 COACH (51) 2008 1,023 18 71 62 34 0 50 46 4 83 — — —

Continued on the next page

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and 5. The average mortality across all trials was24% and median follow-up ranged from 2 to 56months.

CV AND NON-CV DEATH. Across all the trials, 82.3%of deaths were attributed to CV causes, 15.3% to non-CV causes, and 2.4% to an unknown cause. The pro-portion of deaths attributed to CV causes showed adownward trend with more widespread use of BB

therapy: from 87% in the trials with low BB use to80% with high BB use (Table 6).

The proportion of non-CV deaths was higher intrials with greater use of BB. This proportionincreased from 11.4% in trials with less than one-third of patients on a BB to 19.1% in trials withgreater than two-thirds of patients on BB therapy(Figure 1) (p < 0.001). This represents a relativeproportional increase of more than two-thirds in

TABLE 1 Continued

% Beta-Blocker Trial (Ref. #) Year n

Follow-Up (Months)MeanAge(yrs)

Male(%)

MeanEF(%)

NYHA FunctionalClass (%) Adjuvant Therapy

Mean/Median* I II III IVACEI/ARB

(%)MRA(%)

ICD(%)

CRT(%)

Trials with >66% beta-blocker use (n ¼ 27)

67 CARMEN (52) 2004 572 22* 62 81 7 64 29 0 66 13 — —

68 COMPANION (53) 2004 1,520 16 67 67 21 0 0 86 14 89 54 39 80

69 SCD-HeFT (54) 2005 2,521 46 60 77 25 0 70 30 0 96 20† 32 0

72 CARE-HF (55) 2005 813 29 67 73 25 0 0 94 6 95 56 0 50

72 HEAAL (56) 2009 3,834 56* 66 70 33 0 69 30 1 100 38 — —

74 A-HeFT (57,58) 2004 1,050 10 57 60 24 0 0 96 4 86 39 17 2

75 CORONA (59) 2007 5,011 33* 73 76 31 0 37 61 2 92 39 3 0

79 AF-CHF (60) 2008 1,376 37 67 82 27 0 69 31 97 45 7 0

80 INH (61) 2012 715 6 69 71 30 2 58 36 4 88 42 — —

84 HHH (62) 2009 461 12 60 85 29 0 60 40 87 — — 0

84 SADHART-CHF (63) 2010 469 3 62 60 30 0 28 48 24 79 — 19 —

85 DEFINITE (64) 2004 458 29 58 71 21 22 57 21 0 97 — 50 0

85 RED-HF (65) 2013 2,278 28* 71* 59 31* 0 35 65 89 45 — —

86 STICH (66) 2011 1,212 56* 60* 88 w27* 11 52 34 3 90 46† 17 4

87 ACCLAIM (67) 2008 2,408 10 64 80 23 0 29 67 4 94 49 26 11

87 EMPHASIS-HF (68) 2011 2,737 21* 69 78 26 0 100 0 0 93 50 13 9

90 SHIFT (69) 2010 6,505 23* 60 76 29 0 49 50 2 93 60 3 1

90 RAFT (70) 2010 1,798 40 66 83 23 0 80 20 0 97 42 99 49

92 OPT-CHF (71) 2008 405 6 65 73 27 0 0 96 4 96 35 0 0

92 IN-TIME (72) 2014 664 11 66 81 26 0 43 57 0 89 — 59 41

93 TIM-HF (73) 2011 710 26* 67 81 27 0 50 50 0 95 64 46 16

93 PARADIGM-HF (74) 2014 8,399 27* 64 78 30 5 70 24 1 100 56 15 7

95 REVERSE (75) 2008 610 12 63 79 27 18 82 0 0 97 — 83 69

95 HF-ACTION (76) 2009 2,331 30 59 72 25 0 63 36 1 94 45 40 18

97 ECHO-CRT (77) 2013 809 19 58 72 27 1 2 94 3 95 60 100 50

100 COMET (78,79) 2003 3,029 58 62 80 26 0 48 48 4 98 11 0 0

100 CIBIS III (80) 2005 1,010 15 72 68 29 0 49 51 0 100 13 0 0

*Median. †Potassium-sparing diuretic.

— ¼ not reported; ACCLAIM ¼ Advanced Chronic heart failure CLinical Assessment of IMmunomodulation; ACEi ¼ angiotensin-converting enzyme inhibitor; AF-CHF ¼ Atrial Fibrillation and CongestiveHeart Failure; A-HeFT ¼ African-American Heart Failure Trial; ANDROMEDA ¼ Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease; ARB ¼ angiotensin receptorblocker; ATLAS ¼ Assessment of Treatment with Lisinopril and Survival; AUST-NZ ¼ Australia/New Zealand heart failure research collaborative group; BEST ¼ Beta-blocker Evaluation of Survival Trial; CABGPatch ¼ Coronary Artery Bypass Graft Patch trial; CARE-HF ¼ CArdiac REsynchronization in Heart Failure; CARMEN ¼ Carvedilol ACE-Inhibitor Remodelling Mild CHF EvaluatioN; CHARM-Added ¼ Can-desartan in Heart failure Assessment of Reduction in Mortality and morbidity-Added; CHARM-Alternative ¼ Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity-Alternative; CHF-STAT ¼ Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure; CIBIS I, II, III ¼ Cardiac Insufficiency Bisoprolol Study I, II, III; COACH ¼ Coordinating Study Evaluating Outcomes of Advising andCounseling in Heart Failure; COMET ¼ Carvedilol Or Metoprolol European Trial; COMPANION ¼ Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial; CONTAK-CD ¼ CardiacResynchronization Therapy for the Treatment of Heart Failure in Patients With Intraventricular Conduction Delay and Malignant Ventricular Tachyarrhythmias; COPERNICUS ¼ Carvedilol ProspectiveRandomized Cumulative Survival Study; CORONA ¼ Controlled Rosuvastatin Multinational Trial in Heart Failure; CRT ¼ cardiac resynchronization therapy; DEFINITE ¼ Defibrillators in Non-Ischemic Car-diomyopathy Treatment Evaluation; DIAMOND – HF ¼ Danish Investigations of Arrhythmia and Mortality on Dofetilide; DIG ¼ Digitalis Investigation Group; ECHO-CRT ¼ Echocardiography Guided CardiacResynchronization Therapy; EF ¼ ejection fraction; ELITE I ¼ Evaluation of Losartan in the Elderly I; ELITE II ¼ Evaluation of Losartan in the Elderly II; EMPHASIS – HF ¼ Eplerenone in Mild PatientsHospitalization and Survival Study in Heart Failure; FUSION II ¼ Follow-Up Serial Infusions of Nesiritde trial; GESICA ¼ Groupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina; GISSI-HFrosuvastatin ¼ Gruppo Italiano per lo Studio della Sopravvivenza nell’Insuffi cienza cardiaca Heart Failure trial-rosuvastatin; GISSI-HF n-3 PUFA ¼ Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca Heart Failure trial-n3-PUFA; HEAAL ¼ Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan study; HF-ACTION ¼ Heart Failure: A Controlled Trial Investigating Outcomes ofExercise traiNing; HHH ¼ Home or Hospital in Heart failure; ICD ¼ implantable cardioverter defibrillator; INH ¼ Interdisciplinary Network for Heart failure study; IN-TIME ¼ INfl uence of home moniToring onmortality and morbidity in heart failure patients with IMpaired lEft ventricular function; MACH I ¼ Mortality Assessment in Congestive Heart Failure Trial; MERIT-HF ¼ Metoprolol CR/XL RandomizedIntervention Trial in congestive Heart Failure; MOXCON ¼ MOXonidine CONgestive heart failure trial; MRA ¼ mineralocorticoid receptor antagonist; NYHA ¼ New York Heart Association; OPT-CHF ¼ TheEfficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients With New York Heart Association Class III-IV Congestive Heart Failure; PARADIGM- HF ¼ Prospective Comparison of ARNI withACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial; PRAISE I ¼ Prospective Randomized Amlodipine Survival Evaluation; PRAISE II ¼ Prospective Randomized AmlodipineSurvival Evaluation II; PRIME II ¼ Prospective Randomised Study of Ibopamine on Mortality and Efficacy II; PROMISE ¼ Prospective Ransomized Milirinone Survival Evaluation; RAFT ¼ Resynchronization–defibrillation for Ambulatory heart Failure trial; RALES ¼ Randomized Aldactone Evaluation Study; RED-HF ¼ Reduction of Events by Darbepoetin Alfa in Heart Failure; REVERSE ¼ REsynchronizationreVErses Remodeling in Systolic left vEntricular dysfunction; SADHART-CHF ¼ Sertraline Against Depression and Heart Disease in Chronic Heart Failure; SCD-HeFT ¼ Sudden Cardiac Death in Heart Failure;SENIORS ¼ Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure; SHIFT ¼ Systolic Heart failure treatment with the If inhibitor ivabradine Trial;SOLVD-P ¼ Studies of Left ventricular dysfunction-prevention; SOLVD –T ¼ Studies of Left ventricular dysfunction- treatment; STICH ¼ Surgical Treatment for Ischemic Heart Failure; TEN-HMS ¼ Trans-European Network–Home-Care Management System study; TIM-HF ¼ Telemedical Interventional Monitoring in Heart Failure study; USCP ¼ US Carvedilol Heart Failure Program; Val-HeFT ¼ Valsartan HeartFailure Trial; VEST ¼ VESnarinone Trial; V-HeFT I ¼ Veterans Administration Cooperative Vasodilator-Heart Failure Trial I; V-HeFT II ¼ Veterans Administration Cooperative Vasodilator-Heart Failure Trial II;V-HeFT III ¼ Veterans Administration Cooperative Vasodilator-Heart Failure Trial III.

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non-CV deaths with greater BB use. Unsurprisingly,BB use increased most following the landmark trialsof BB therapy in HF (35–41), with a rise in non-CVmortality seen over the same period. The

proportion of non-CV deaths increased from 10%between 1985 and 1994, to 19.4% between 2005 and2014 (Figure 2A [p for trend <0.001]). We examinedthe association between BB use and non-CV deaths

TABLE 3 Baseline Characteristics According to the Proportion of

Patients Treated With a Beta-Blocker

<33% BB 33%-66% BB >66% BB

Trials 21 18 27

n 41,960 40,517 53,705

Age, yrs 63.8 � 3.5 65.3 � 3.9 64.7 � 4.5

Male % 79.2 � 7.6 78.4 � 6.6 75.2 � 5.7

Mean EF, % 25.7 � 3.2 28.4 � 5.5 27.9 � 3.1

NYHA functionalclass, %

I 10.2 � 19.9 0.7 � 3.7 1.6 � 3.6

II 31.1 � 22.6 41.1 � 24.7 53.4 � 23.4

III 49.2 � 25.6 50.1 � 20.0 41.3 � 22.8

IV 9.6 � 10.0 5.6 � 8.3 4.1 � 7.4

HF therapies, %

ACEI/ARB 84.0 � 21.3 91.1 � 11.3 94.6 � 5.1

MRA 14.4 � 14.4 22.6 � 15.2 44.0 � 15.0

ICD 1.0 � 7.0 4.2 � 12.5 20.2 � 24.8

CRT 0 1.7 � 7.7 11.3 � 19.5

Values are n or mean � SD.

BB ¼ beta-blocker; other abbreviations as in Table 2.

TABLE 2 Baseline Characteristics HF-PEF Trials

% Beta-Blocker Trial (Ref. #) Year n

Follow-Up (Months)

Mean Age(yrs)

Sex(%)

Mean EF(%)

NYHA FunctionalClass (%) Adjuvant Therapy

Mean/Median* I II III IVACEI/ARB

(%)MRA(%)

ICD(%)

CRT(%)

0 DIG-PEF (85) 2006 988 37 67 59 55 20 58 21 1 86 8† — —

54 PEP-CHF (86) 2006 850 26 75 56 65 76 24 50 10 — —

56 CHARM-Preserved (87) 2003 3023 37* 67 60 54 0 61 38 2 19 12 1 —

59 I-PRESERVE (88) 2008 4133 50 72 40 59 0 21 76 3 25 15 0.3 —

78 TOPCAT (89) 2014 3445 40 69 49 56 3 64 33 0.4 84 50 — —

*Median. †Potassium-sparing diuretic.

DIG-PEF ¼ Digitalis Investigation Group Preserved Ejection Fraction; I-PRESERVE ¼ Irbesartan in patients with heart failure and preserved ejection fraction; PEP-CHF ¼ Perindopril in Elderly People withChronic Heart Failure study; TOPCAT ¼ Treatment Of Preserved Cardiac function heart failure with an Aldosterone Antagonist Trial; other abbreviations as in Table 1.

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adjusted for ACEI/ARB and MRA use (Online Table 1).After adjustment, increasing BB use was still associ-ated with higher rates of non-CV death and contrib-uted most to the model, as indicated by the highest zscore after adjusting for ACEI/ARB use and afteradjusting for MRA use imputing the mean proportionfor trials with missing data on MRA use. Similar re-sults were observed when trials that did not reportMRA use were excluded (Online Appendix). Thesame trends in the proportion of CV and non-CVdeaths by BB group and time period were observedin the sensitivity analyses using a meta-analysisapproach (Online Appendix, Online Figures 1 to 4).Because of the large number of studies in the ana-lyses, the heterogeneity between groups was statis-tically significant (p < 0.001) but examination of theplots confirmed that the proportion of CV and non-CV deaths in each subgroup was consistent.

Only 11 (17%) of the 66 trials (with 25,062 patients)published data on the subclassification of non-CVdeaths. The most common cause of death was can-cer, accounting for 46% of non-CV deaths (and 9% ofall deaths) in those trials.

CARDIAC DEATH. Forty-five trials (with 93,528 pa-tients) further described the proportion of CV deathsfrom cardiac causes (adjudicated as myocardialinfarction, HF, arrhythmia, or sudden cardiacdeath). Cardiac deaths showed a downward trendwith greater BB use (from 81% of all deaths in thegroup with low BB use to 71% in the group with highBB use), whereas there was a 45% relative propor-tional increase in noncardiac deaths (i.e., vascularand non-CV deaths) (Table 7). Again, increasing BBuse was still associated with lower rates of cardiacdeath and contributed most to the model, as indi-cated by the highest z score, after adjusting for

ACEI/ARB use and after adjusting for MRA use(imputing the mean proportion for trials withmissing data on MRA use; see Online Table 2).Between 1986 and 2014, there was a significant fallin the proportion of deaths due to cardiac causes(Figure 2B) (p for trend <0.001). Again, the sametrend in cardiac deaths by BB group and time periodwere observed using the meta-analysis approach(Online Figures 5 and 6). Similarly, because of the largesize of the trials, there was statistically significantheterogeneity (p < 0.001) that was not evident on theforest plots.

UNKNOWN CAUSE OF DEATH. Only 28 of the 66 tri-als (with 57,614 patients) reported unknown deaths.

TABLE 4 Mortality Data (All Trials)

% Beta-Blocker Trial (Ref. #) Year nAll Deaths

n (%)CV Deaths

n (% All Deaths)Cardiac Deaths

n (% All Deaths)Unknown Deathsn (% All Deaths)

CV þ Unknown Deathsn (% All Deaths)

Non-CV Deathsn (% All Deaths)

Trials with <33% beta-blocker use (n ¼ 21)

0 V-HeFT I (9) 1986 642 283 (44.1) 267* (94.3*) 267 (94.3) — 267 (94.3) 16 (5.7)

0 V-HeFT II (10) 1991 804 285 (35.4) 249* (87.4*) 249 (87.4) — 249 (87.4) 36 (12.6)

0 PROMISE (11) 1991 1,088 295 (27.1) 284 (96.3) — — 284 (96.3) 11 (3.7)

0 GESICA (12) 1994 516 193 (37.4) 170 (88.1) 167 (86.5) 18 (9.3) 188 (97.4) 5 (2.6)

0 PRAISE I (13,14) 1996 1,153 413 (35.8) 368 (89.0) 362 (87.6) — 368 (89.0) 45 (11.0)

0 PRIME II (15) 1997 1,906 425 (22.3) 386 (90.8) 357 (84.0) 7 (1.6) 393 (92.5) 32 (7.5)

0 DIG (16) 1997 6,800 2375 (34.9) 2020 (85.1) 1795 (75.6) 130 (5.5) 2150 (90.5) 225 (9.5)

0 V-HeFT III (17) 1997 450 60 (13.3) 48 (80.0) 47 (78.3) — 48 (80.0) 12 (20.0)

0 VEST (18) 1998 3,833 802 (20.9) 750* (93.5*) 750 (93.5) — 750 (93.5) 52 (6.5)

1 MOXCON (19) 2003 1,934 86 (4.4) 80 (93.0) 71 (82.6) — 80 (93.0) 6 (7.0)

4 CHF-STAT (20) 1995 674 274 (40.7) 213* (77.7*) 213 (77.7) 16 (5.8) 229 (83.6) 45 (16.4)

8 SOLVD-T (21) 1991 2,569 962 (37.4) 858 (89.2) 817 (84.9) 2 (0.2) 860 (89.4) 102 (10.6)

10 DIAMOND-HF (22) 1999 1,518 628 (41.4) 467* (74.4*) 467 (74.4) 39 (6.2) 506 (80.6) 122 (19.4)

11 RALES (23) 1999 1,663 670 (40.3) 584 (87.2) 540 (80.6) 16 (2.4) 600 (89.6) 70 (10.4)

11 ATLAS (24,25) 1999 3,164 1383 (43.7) 1224 (88.5) 1131 (81.8) 13 (0.9) 1237 (89.4) 146 (10.6)

16 MACH I (27) 2000 2,590 669 (25.8) 599 (89.5) 567 (84.8) — 599 (89.5) 70 (10.5)

16 ELITE I (26) 1997 722 49 (6.8) 36 (73.5) 26 (53.1) — 36 (73.5) 13 (26.5)

19 PRAISE II (28) 2013 1,654 540 (32.6) 454 (84.1) — — 454 (84.1) 86 (15.9)

21 CABG Patch (29,30) 1997 900 198 (22.0) 163 (82.3) 155 (78.3) 1 (0.5) 164 (82.8) 34 (17.2)

22 ELITE II (31) 2000 3,152 530 (16.8) 429 (80.9) 389 (73.4) — 429 (80.9) 101 (19.1)

24 SOLVD-P (32) 1992 4,228 647 (15.3) 563 (87.0) 509 (78.7) — 563 (87.0) 84 (13.0)

Trials with 33% to 66% beta-blocker use (n ¼ 18)

35 Val-HeFT (33,81) 2001 5,010 979 (19.5) 855 (87.3) 763 (77.9) — 855 (87.3) 124 (12.7)

47 CONTAK-CD (34) 2003 490 109 (22.2) 60* (55.0*) 60 (55.0) 28 (25.7) 88 (80.7) 21 (19.3)

50 CIBIS I (35) 1994 641 120 (18.7) 99 (82.5) 86 (71.7) 14 (11.7) 113 (94.2) 7 (5.8)

50 AUST-NZ (36) 1997 415 46 (11.1) 38 (82.6) 38 (82.6) — 38 (82.6) 8 (17.4)

50 CIBIS II (37) 1999 2,647 384 (14.5) 280 (72.9) 229 (59.6) 72 (18.8) 352 (91.7) 32 (8.3)

50 MERIT-HF (38) 2000 3,991 362 (9.1) 331 (91.4) 299 (82.6) — 331 (91.4) 31 (8.6)

50 BEST (39) 2001 2,708 860 (31.8) 731 (85.0) 670 (77.9) 36 (4.2) 767 (89.2) 93 (10.8)

50 SENIORS (40) 2005 2,128 361 (17.0) 268 (74.2) — 47 (13.0) 315 (87.3) 46 (12.7)

51 COPERNICUS (41,42) 2001 2,289 323 (14.2) 282 (87.3) 262 (81.1) 18 (5.6) 300 (92.9) 23 (7.1)

54 TEN-HMS (43) 2005 418 75 (17.9) 70* (93.3*) 70 (93.3) — 70 (93.3) 5 (6.7)

55 CHARM-Added (44) 2003 2,548 789 (31.0) 649 (82.3) 565 (71.6) — 649 (82.3) 140 (17.7)

55 CHARM-Alternative (45) 2003 2,028 561 (27.7) 471 (84.0) 401 (71.5) — 471 (84.0) 90 (16.0)

61 ANDROMEDA (46) 2008 627 37 (5.9) 25 (67.6) 22 (59.5) 8 (21.6) 33 (89.2) 4 (10.8)

62 GISSI-HF Rosuvastatin (47) 2008 4,574 1301 (28.4) 966 (74.3) 839 (64.5) 49 (3.8) 1015 (78.0) 286 (22.2)

64 USCP (48) 1996 1,094 53 (4.8) 51 (96.2) 48 (90.6) — 51 (96.2) 2 (3.8)

65 GISSI-HF n-3 PUFA (49) 2008 6,975 1969 (28.2) 1477 (75.0) 1274 (64.7) 74 (3.8) 1551 (78.8) 418 (21.2)

65 FUSION II (50) 2008 911 85 (9.3) 74 (87.1) — — 74 (87.1) 11 (12.9)

66 COACH (51) 2008 1,023 272 (26.6) 219 (80.5) — 15 (5.5) 234 (86.0) 38 (14.0)

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These accounted for 5.7% of all deaths in these trials(Table 8). In 10 trials, unknown deaths were catego-rized as CV deaths by default. In combination, deathsfrom CV causes and unknown deaths fell between1986 and 2014 (p for trend <0.001).

HF-PEF. There were too few HF-PEF trials to do atrend analysis, but the baseline demographics andproportions of CV and non-CV deaths from these tri-als are displayed for comparison purposes (Tables 2and 5) (85–89). The proportion of deaths attribute

to non-CV causes was much higher in HF-PEF thanHF-REF.

DISCUSSION

This analysis of more than 60 trials published be-tween 1986 and 2014, and including more than136,000 patients, shows that the relative proportionof deaths attributed to non-CV has increased bymore than two-thirds in the more recent trials withgreater use of BB (and other disease-modifying

TABLE 4 Continued

% Beta-Blocker Trial (Ref. #) Year nAll Deaths

n (%)CV Deaths

n (% All Deaths)Cardiac Deathsn (% All Deaths)

Unknown Deathsn (% All Deaths)

CV þ Unknown Deathsn (% All Deaths)

Non-CV Deathsn (% All Deaths)

Trials with >66% beta-blocker use (n ¼ 27)

67 CARMEN (52) 2004 572 42 (7.3) 36 (85.7) — — 36 (85.7) 6 (14.3)

68 COMPANION (53, 82) 2004 1,520 313 (20.6) 251 (80.2) 243 (77.6) 16 (5.1) 267 (85.3) 46 (14.7)

69 SCD-HeFT (54,83) 2005 2,521 666 (26.4) 484 (72.7) 451 (67.7) 60 (9.0) 544 (81.7) 122 (18.3)

72 CARE-HF (55) 2005 813 202 (24.8) 143 (70.8) — 25 (12.4) 168 (83.2) 34 (16.8)

72 HEAAL (56) 2009 3,834 1300 (33.8) 926 (71.2) — — 926 (71.2) 374 (28.8)

74 A-HeFT (57,58) 2004 1,050 86 (8.20) 71 (82.6) 63 (73.3) 7 (8.1) 78 (90.7) 8 (9.3)

75 CORONA (59) 2007 5,011 1487 (29.7) 1174 (79.0) 1051 (70.7) 16 (1.1) 1190 (80.0) 297 (20.0)

79 AF-CHF (60) 2008 1,376 445 (32.3) 357 (80.2) 313 (70.3) — 357 (80.2) 88 (19.8)

80 INH (61) 2012 715 84 (11.7) 57 (67.9) — — 57 (67.9) 27 (32.1)

84 HHH (62) 2009 461 33 (7.2) 30* (90.9*) 30 (90.9) — 30 (90.9) 3 (9.1)

84 SADHART-CHF (63) 2010 469 33 (7.0) 26 (78.8) — — 26 (78.8) 7 (21.2)

85 DEFINITE (64) 2004 458 68 (14.8) 43 (63.2) 38 (55.9) 4 (5.9) 47 (69.1) 21 (30.9)

85 RED-HF (65) 2013 2,278 932 (40.9) 764 (82.0) — — 764 (82.0) 168 (18.0)

86 STICH (66) 2011 1,212 462 (38.1) 369 (79.9) — — 369 (79.9) 93 (20.1)

87 ACCLAIM (67) 2008 2,408 245 (10.2) 202 (82.4) — — 202 (82.4) 43 (17.6)

87 EMPHASIS-HF (68) 2011 2,737 384 (14.0) 332 (86.5) — — 332 (86.5) 52 (13.5)

90 SHIFT (69) 2010 6,505 1055 (16.2) 940 (89.1) — — 940 (89.1) 115 (10.9)

90 RAFT (70) 2010 1,798 422 (23.5) 292 (69.2) — — 292 (69.2) 130 (30.8)

92 IN-TIME (72) 2014 664 37 (5.6) 29 (78.4) — — 29 (78.4) 8 (21.6)

92 OPT-CHF (71) 2008 405 16 (4.0) 12 (75.0) — — 12 (75.0) 4 (25.0)

93 TIM-HF (73) 2011 710 109 (15.4) 86 (78.9) — — 86 (78.9) 23 (21.1)

93 PARADIGM HF (74) 2014 8,399 1546 (18.4) 1251 (80.9) — — 1251 (80.9) 295 (19.1)

95 REVERSE (75) 2008 610 12 (2.0) 6 (50.0) 6 (50.0) 2 (16.7) 8 (66.7) 4 (33.3)

95 HF-ACTION (76) 2009 2,331 387 (16.6) 274 (70.8) — — 274 (70.8) 113 (29.2)

97 ECHO-CRT (77) 2013 809 71 (8.8) 48 (67.6) 45 (63.4) 6 (8.5) 54 (76.1) 17 (23.9)

100 COMET (78,79) 2003 3,029 1112 (36.7) 972 (87.4) 845 (76.0) — 972 (87.4) 140 (12.6)

100 CIBIS III (80,84) 2005 1,010 138 (13.7) 107 (77.5) 96 (69.6) 4 (2.9) 111 (80.4) 27 (19.6)

*CV deaths not reported; figures represent cardiac deaths.

CV ¼ cardiovascular; other abbreviations as in Table 1.

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therapies) when compared with older trials with lowBB use. Although the greater use of BB probablyaccounts for much of this change, more compre-hensive use of ACEI (or ARBs), devices (includingcardiac resynchronization therapy and implantablecardioverter defibrillators) and, particularly, MRAs

TABLE 5 Mortality Data HF-PEF Studies

% Beta-Blocker Trial (Ref. #) Year nAll Deaths

n (%) n

0 DIG-PEF (85) 2006 988 231 (23.3)

50 SENIORS-PEF (40) 2009 353 92 (26.0)

54 PEP-CHF (86) 2006 850 109 (12.8)

56 CHARM-Preserved (87) 2003 3,023 481 (16.0)

59 I-PRESERVE (88) 2008 4,133 881 (21.3)

78 TOPCAT (89) 2014 3,445 526 (15.3)

Abbreviations as in Tables 1 to 4.

is also important. It seems unlikely that changingpatient characteristics could have accounted for thechanges observed because age, sex, ejection frac-tion, and NYHA functional class distribution did notdiffer substantially across the 3 groups of trials. It isalso unlikely that the changing proportion of CV and

CV Deaths(% All Deaths)

Cardiac Deathsn (% All Deaths)

Unknown Deathsn (% All Deaths)

CV þ Unknown Deathsn (% All Deaths)

Non-CV Deathsn (% All Deaths)

162 (70.1) — 14 (6.1) 176 (76.1) 55 (23.8)

63 (68.5) — — 63 (68.5) 29 (31.5)

78 (71.6) — — 78 (71.6) 31 (28.4)

340 (70.7) 257 (53.4) — 340 (70.7) 141 (29.3

532 (60.4) 401 (45.5) 81 (9.2) 613 (69.6) 268 (30.4)

336 (63.9) — — 336 (63.9) 190 (36.1)

TABLE 6 Cardiovascular and Noncardiovascular Deaths According to the

Proportion of Patients Treated With a Beta-Blocker at Baseline

Overall <33% BB 33%-66% BB >66% BB

Trials 66 21 18 27

Patients 136,182 41,960 40,517 53,705

Deaths 32,140 11,767 8,686 11,687

CV deaths* 82.3 � 7.4 87.0 � 5.0 81.2 � 7.6 79.5 � 7.2

Non-CV deaths* 15.3 � 6.4 11.4 � 4.6 14.3 � 5.6 19.1 � 6.2

Unknown deaths* 2.4 � 4.4 1.6 � 2.4 4.5 � 6.0 1.5 � 3.3

Values are n or mean % � SD. *As a proportion of all deaths.

BB ¼ beta-blocker; CV ¼ cardiovascular.

FIGURE 1 Proporti

According to BB Use

Proportion of deaths

percentage of all de

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non-CV deaths could be accounted for by changingdefinitions of cause of death or adjudication practicebecause, as far as we can tell from the trial reports,classification of a death as non-CV consistentlyrequired identification of a definite non-CV cause.Last, the way in which deaths from an “unknown”cause were handled between trials should not haveinfluenced our findings because whether thesedeaths were reported separately or classified as“cardiovascular” by default, the number and pro-portion of such cases was tiny. The reduction in theproportion of deaths from CV causes was mirrored(and even exceeded) by the downward trend in the

on of Deaths That Are Noncardiovascular Deaths

from noncardiovascular causes, expressed as a weighted mean

aths, according to percentage of beta-blocker (BB) use.

proportion of deaths from a cardiac (as opposed tovascular) cause. This is presumably because disease-modifying drugs and effective devices probablyhave less effect on non-heart failure related CVmortality (e.g., stroke, aortic aneurysm rupture, andso on).

We did not analyze trends in subtypes of cardiacdeath because not all trials reported how these wereadjudicated and in those that did provide definitions,there were differences between trials in how deathfrom HF (or pump failure) and sudden death weredefined.

We believe that our findings are important fora number of reasons. First, they suggest that all-causemortality is becoming an increasingly insensitiveendpoint for the evaluation of new treatments in HFbecause, even in patients with REF, 1 in 5 deathsprobably cannot be modified by therapies targetingCV pathophysiological processes related to HF. Thispoint may be even more important in older patients(who are often underrepresented in clinical trials), inwhich non-CV deaths are proportionately more com-mon than in younger patients. Our findings supportthe move towards the use of “disease-specific” end-points in trials in HF.

Another and related reason that the present find-ings are important is that they show that the residualmodifiable risk in patients with HF is decreasing(although still large). This observation indicates thatthe size of trials in HF will have to increase in thefuture, particularly if all-cause mortality (or amortality-morbidity composite including death fromany cause), as opposed to CV mortality, is the primarymeasure of the effect of treatment.

Of course, the most important implication of ourfindings is that, if the benefits of treatments shown intrials are translated into the general population, wemight anticipate that patients with heart failure willnot only live longer but will also be less likely to diefrom heart failure (or another CV cause), as wasalmost invariably the case in the past.

Many fewer outcome trials have been conductedin HF-PEF. In this type of HF, non-CV death consti-tutes a much larger proportion of overall deaths,compared with HF-REF, and this proportion may alsobe increasing with time and other changes (e.g., inbackground therapy), although the number of trialswas too small to do a meaningful trend test. Themuch higher proportion of non-CV deaths in HF-PEFdoes question the assumption that deaths where thecause is unknown should be automatically attributedto a CV reason. Indeed, it may be wise to adoptstrategies to augment risk of CV death in trials ofnew therapies in heart failure; for example, by

FIGURE 2 Trends Over Time in Proportion of All Deaths Attributed to

Noncardiovascular and Cardiac Causes

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requiring an elevated natriuretic peptide level forinclusion.

Unfortunately, little information is published aboutnon-CV causes of death in patients with HF, but fromwhat is available it seems that cancer and infectionsare the 2 most common fatal events. Of note, deathsfrom renal failure were rarely reported in the HF trialsstudied, but could conceivably become more commonin the future as the risk of CV death continues to fall.Whether these, and other deaths from non-CV condi-tions, are preventable or modifiable and how HF in-fluences the therapeutic options available (e.g., use ofcertain types of chemotherapy) deserved moreconsideration in the light of the growing importanceof these non-CV events.

STUDY LIMITATIONS. Our study has a number ofstrengths and weaknesses. In terms of strengths, wewere able to identify more than 60 trials includingmore than 136,000 patients and reporting more than32,000 deaths. Deaths were systematically identifiedand the cause adjudicated in a more objective,thorough, and standardized way than is possible inmost administrative datasets, registries, and evenepidemiological studies. However, there were alsolimitations. First, we did not have access to indi-vidual patient data, limiting the analyses we couldperform. Also, ours was an analysis of clinical trialsthat always enroll selected patients who tend to beyounger and have less comorbidity than “real-world”patients. We do not know whether the trends iden-tified in trials will apply to patients with heart failuremore generally (90,91). We had too few trials in HF-PEF to do a formal trend analysis. As mentionedpreviously, varying and uncertain definitions ofdeath from HF and sudden death made comparisonof these modes of death impossible across trials andover time.

(A) Proportion of deaths from noncardiovascular causes, expressed as a weighted mean

percentage of all deaths, grouped by decade of trial publication. (B) Proportion of deaths

from cardiac causes, expressed as a weighted mean percentage of all deaths, grouped by

decade of trial publication.TABLE 7 Cardiac and Noncardiac Deaths According to the

Proportion of Patients Treated With a Beta-Blocker at Baseline

Overall <33% BB 33%-66% BB >66% BB

Trials 45 19 15 11

Patients 93,528 39,218 36,455 17,855

Deaths 23,331 10,932 7,968 4,431

Cardiacdeaths, %*

75.6 � 8.9 80.9 � 7.1 72.2 � 8.8 70.9 � 6.6

Noncardiacdeaths, %*†

21.4 � 7.4 17.4 � 6.7 23.7 � 7.0 25.3 � 5.8

Unknowndeaths, %*

3.0 � 4.6 1.7 � 2.4 4.1 � 6.0 3.8 � 4.2

Values are n or mean% � SD. *As a proportion of all deaths. †Noncardiac deaths ¼vascular and noncardiovascular.

BB ¼ beta-blocker.

TABLE 8 Unknown Cause of Death According to the Proportion of Patients Treated With

a Beta-Blocker at Baseline

Overall <33% BB 33%-66% BB >66% BB

Trials 28 9 10 9

Patients 57,614 19,710 24,102 13,802

Deaths 15,887 7,108 5,736 3,043

CV deaths, %* 79.4 � 7.4 85.8 � 4.3 76.7 � 6.0 75.2 � 7.1

Non-CV deaths, %* 14.9 � 6.0 10.9 � 3.5 15.7 � 6.0 19.3 � 5.0

Unknown deaths, %* 5.7 � 5.1 3.4 � 2.5 7.6 � 6.1 5.6 � 4.4

Values are n or mean % � SD. *As a proportion of all deaths.

BB ¼ beta-blocker; CV ¼ cardiovascular.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: The

increasing use of disease-modifying therapies,

including beta-blockers, has led to a decline in car-

diovascular deaths in HF-REF. As a result, among

patients with HF-REF, the proportion of all deaths

from noncardiovascular causes has increased steadily

over the past 25 years.

TRANSLATIONAL OUTLOOK: All-cause mortality

is probably increasingly insensitive to the effect of

new treatments for HF-REF and cardiovascular mor-

tality should be the preferred endpoint in future

clinical trials.

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CONCLUSIONS

In recent trials in HF-REF, the proportion of deathsfrom CV causes has decreased and there has been acorresponding increase in the proportion of non-CVdeaths. This suggests that all-cause mortality isnow a less sensitive endpoint for detecting the ef-fect of new treatments for HF-REF and CV mortal-ity should be preferred for this purpose in clinicaltrials.

REPRINT REQUESTS AND CORRESPONDENCE: Prof.John J. V. McMurray, Institute of Cardiovascular andMedical Sciences, BHF Glasgow CardiovascularResearch Centre, University of Glasgow, GlasgowG12 8TA, United Kingdom. E-mail: john.mcmurray@glasgow.ac.uk.

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KEY WORDS beta-blocker, cause of death,heart failure, heart failure with reducedejection fraction, mode of death

APPENDIX For supplemental tables and figures,please see the online version of this article.