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Original article| Volume 75, ISSUE 2, P148-154, February 2020

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Declining clinical benefit of ICD in heart failure patients: Temporal trend of mortality outcomes from randomized controlled trials

Open ArchivePublished:September 13, 2019DOI:https://doi.org/10.1016/j.jjcc.2019.06.001
Declining clinical benefit of ICD in heart failure patients: Temporal trend of mortality outcomes from randomized controlled trials
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      Highlights

      • •
        Mortality outcome temporal evolution in implantable cardioverter-defibrillator (ICD) trials was analyzed from 1990 to 2014.
      • •
        The baseline risk of sudden cardiac death significantly and progressively declined in this time frame.
      • •
        The fraction of patients unresponsive to ICD therapy significantly increased.
      • •
        These changes concurred to a reduction of ICD clinical benefit in heart failure patients.

      Abstract

      Background

      The risk of sudden cardiac death in patients with heart failure has declined over time thanks to the sequential introduction of new treatments. However, current guidelines recommendations for implantable cardioverter-defibrillator (ICD) are based on randomized controlled trials (RCTs) carried out in the past three decades and their meta-analyses. To highlight potential changes over time in ICD clinical benefit in primary prevention of sudden cardiac death, we analyzed the temporal trends of RCT risk of mortality outcomes in this time frame.

      Methods

      By searching MEDLINE and the Cochrane Library electronic databases we identified seven RCTs (6095 patients enrolled between 1990 and 2014) on ICD versus contemporary standard medical therapy for sudden cardiac death prevention, in patients with chronic heart failure of ischemic and non-ischemic origin and reduced ejection fraction. Linear regression analysis was applied to identify the association between RCT mortality outcomes and time.

      Results

      Ordered according to the start of randomization, the trials showed a statistically significant (p = 0.03) progressive decline in the baseline annualized event rate of sudden cardiac death in RCT control arms, and a significant (p = 0.04) increase in the number of patients unresponsive to ICD treatment (i.e. patients experiencing sudden cardiac death in ICD arms). These two factors synergistically contributed to a significant (p < 0.01) and progressive reduction in the clinical benefit of ICD, assessed by the number needed to treat for total mortality at 3 years.

      Conclusions

      The clinical benefit of ICD, implanted according to the current guidelines, has significantly and progressively declined over time due to the reduction in sudden cardiac death risk and to the increase of ICD unresponsive patients.

      Keywords

      Introduction

      The risk of total mortality (TM) and sudden cardiac death (SCD) in heart failure (HF) patients has significantly and progressively decreased over the past 20 years thanks to the use of new therapies [
      • Shen L.
      • Jhund P.S.
      • Petrie M.C.
      • Claggett B.L.
      • Barlera S.
      • Cleland J.G.F.
      • et al.
      Declining risk of sudden death in heart failure.
      N Engl J Med. 2017; 377: 41-51
      ]. Nevertheless, the guidelines for implantable cardioverter-defibrillator (ICD) therapy in primary prevention of SCD have remained unchanged [
      • Al-Khatib S.M.
      • Stevenson W.G.
      • Ackerman M.J.
      • Bryant W.J.
      • Callans D.J.
      • Curtis A.B.
      • et al.
      2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      J Am Coll Cardiol. 2018; 72: e91-e220
      ]. These recommend ICD therapy in patients with HF of both ischemic and non-ischemic origin, based only on left ventricular ejection fraction (EF) values and New York Heart Association (NYHA) functional class symptoms. The guidelines are based on the results of randomized controlled trials (RCTs) carried out in the past three decades, and supported by recent meta-analyses, which obtained a statistically significant result in favor of ICD therapy efficacy by pooling data from earlier and more recent studies [
      • Shun-Shin M.J.
      • Zheng S.L.
      • Cole G.D.
      • Howard J.P.
      • Whinnett Z.I.
      • Francis D.P.
      Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials.
      Eur Heart J. 2017; 38: 1738-1746
      ,
      • Al-Khatib S.M.
      • Fonarow G.C.
      • Joglar J.A.
      • Inoue L.Y.T.
      • Mark D.B.
      • Lee K.L.
      • et al.
      Primary prevention implantable cardioverter defibrillators in patients with nonischemic cardiomyopathy: a meta-analysis.
      JAMA Cardiol. 2017; 2: 685-688
      ]. To better understand the role of ICD in the modern treatment of HF and highlight potential changes over time, in this study we used a different approach with respect to meta-analyses and analyzed the temporal evolution of RCT risk of mortality outcomes in the past three decades and the implications for ICD clinical benefit in SCD primary prevention.

      Methods

      A systematic review was conducted following the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      J Clin Epidemiol. 2009; 62: e1-e34
      ].

      Eligibility criteria

      The literature search was performed to identify RCTs assessing ICD therapy versus standard medical therapy on SCD primary prevention, in patients with chronic stable HF of ischemic and non-ischemic origin and reduced ejection fraction. Studies presenting endpoints of TM and SCD were selected. A population size larger than 150 patients was requested as an additional inclusion criterion. The search was restricted to articles published in English in peer-reviewed journals. Abstracts and session presentations were excluded.

      Search strategy, study selection, and data collection

      MEDLINE and the Cochrane Library electronic databases were systematically searched to identify primary references from January 1985 to September 2018. The following search terms were used: (implantable cardioverter-defibrillator OR defibrillator OR implanted defibrillator OR ICD) AND (mortality OR sudden cardiac death OR sudden death) AND (randomized controlled trial OR randomized trial OR RCT). The database search was followed by a review of the citations from eligible studies by two independent reviewers (MD and MM). Studies were selected based on title and abstract, and read thoroughly to identify those suitable for the analysis. The two reviewers independently extracted the demographic and clinical outcome data from the selected studies. When disagreement occurred, they reviewed the papers together to reach joint conclusions. The methodological quality of the studies was assessed by applying the Cochrane Risk of Bias Tool for RCTs [
      • Higgins J.P.T.
      • Altman D.G.
      • Gøtzsche P.C.
      • Jüni P.
      • Moher D.
      • Oxman A.D.
      • et al.
      The Cochrane tool for assessing risk of bias in randomised trials.
      BMJ. 2011; 343: d5928
      ].

      Statistical analysis

      Patient characteristics were expressed as percentage, mean ± SD or median (interquartile range), as appropriate. In each study, the baseline risk of SCD and TM was expressed in terms of annualized event rate (AER) in percentage for the patients in the control arm, which was calculated by dividing the total number of SCD and TM events in the group by the total number of years of follow-up and multiplying by 100.
      The efficacy of ICD therapy was assessed in terms of the relative risk (RR) and risk difference (RD) of SCD in the ICD arm with respect to the control arm. In particular, the RR × 100% represented the relative residual risk of SCD, which is an index of ICD unresponsive SCD [
      • Anderson K.P.
      Sudden cardiac death unresponsive to implantable defibrillator therapy: an urgent target for clinicians, industry and government.
      J Interv Card Electrophysiol. 2005; 14: 71-78
      ]. For each study, the RR and RD of SCD and 95% confidence interval (CI) were calculated from raw counts of true positives, false positives, false negatives, and true negatives reported in the primary studies, and expressed as percentages. For the TM outcome, we reported the hazard ratio declared in each study. The clinical benefit of ICD therapy was assessed in terms of the number needed to treat (NNT) to avoid a TM event over a 3-year and 5-year period, when the follow-up duration allowed a reliable estimation of the index. When not reported in the text, NNT values were estimated from Kaplan–Meier curves, which were digitized by a dedicated software (DigitizeIt, Braunschweig, Germany). The association between the randomization starting year of the trials and the AER of SCD and TM in the control arm, the RR and RD of SCD in ICD patients versus controls, the NNT of TM at 3 years was assessed by weighted univariate linear regression analysis, where time was the independent variable and weights were given by the study sample size. The strength of the association was measured in terms of the R-squared (R2) statistics. Sensitivity analyses were performed to evaluate the influence of outliers and patient characteristics on overall associations. A 2-tailed p-value <0.05 indicated statistical significance. All analyses were performed using STATA 13.1 Statistics/Data analysis (StataCorp, College Station, TX, USA).

      Results

      Study selection

      The search of Medline and the Cochrane Library databases identified 1128 relevant studies after duplicate removal (Fig. 1). A total of 1113 studies were excluded after reading title and abstract, and 15 retrieved for further evaluation. Of these, five studies were excluded: two because the randomization of patients was carried out early after acute myocardial infarction (<40 days), one because the randomization was performed at the time of coronary artery bypass surgery, and two due to the small number of patients (<150). Seven RCTs were included in this analysis [
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      ,
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      ,
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      N Engl J Med. 2002; 346: 877-883
      ,
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      N Engl J Med. 2004; 350: 2151-2158
      ,
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ,
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      ,
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ], and three additional studies provided integrative data for the included trials [
      • Greenberg H.
      • Case R.B.
      • Moss A.J.
      • Brown M.W.
      • Carroll E.R.
      • Andrews M.L.
      • et al.
      Analysis of mortality events in the Multicenter Automatic Defibrillator Implantation Trial (MADIT-II).
      J Am Coll Cardiol. 2004; 43: 1459-1465
      ,
      • Saxon L.A.
      • Bristow M.R.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial.
      Circulation. 2006; 114: 2766-2772
      ,
      • Packer D.L.
      • Prutkin J.M.
      • Hellkamp A.S.
      • Mitchell L.B.
      • Bernstein R.C.
      • Wood F.
      • et al.
      Impact of implantable cardioverter-defibrillator, amiodarone, and placebo on the mode of death in stable patients with heart failure: analysis from the sudden cardiac death in heart failure trial.
      Circulation. 2009; 120: 2170-2176
      ].
      Figure thumbnail gr1
      Fig. 1Selection process for the studies included in the systematic review and quantitative analysis. The Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA)
      [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      J Clin Epidemiol. 2009; 62: e1-e34
      ]
      flow diagram depicts the number of records identified, included, and excluded, and the reasons for exclusion, through the different phases of the systematic review and quantitative analysis.

      Study characteristics

      The seven RCTs included in the analysis showed differences in trial design, enrollment criteria, period, severity and treatment of HF, as reported in Table 1, Table 2. In three studies HF was of ischemic origin [
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      ,
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      ,
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      N Engl J Med. 2002; 346: 877-883
      ], in two of non-ischemic origin [
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      N Engl J Med. 2004; 350: 2151-2158
      ,
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ], while in the remaining two the population was mixed [
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ,
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      ]. The enrollment period was between 1990 and 2002 in six studies; only the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality) trial [
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ] enrolled patients later, starting in 2008 and terminating in 2014. The follow-up period was ≥20 months in all trials except for the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial [
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ], where the follow-up lasted 15.7 months.
      Table 1Characteristics of the seven trials included in the study, ordered according to randomization start.
      TrialRandomization period (years)Publication date (year)Trial designEnrollment criteriaRisk of bias
      MADIT
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      		1990–19961996ICD vs OMTICM; EF ≤ 35%; NYHA I–III; NSVT; VT/VF inducibility.U, U, H, U, L, L
      MUSTT
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      		1990–19961999ICD vs OMTICM; EF ≤ 40%; NYHA I–III; NSVT; VT/VF inducibility.L, L, H, U, L, L
      MADIT-II
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      N Engl J Med. 2002; 346: 877-883
      		1997–20022002ICD vs OMTICM; EF ≤ 30%; NYHA I–III.U, U, H, U, L, L
      SCD-HeFT
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      		1997–20012005ICD vs OMT vs Amiodarone
      Amiodarone and RCT-P groups were not included in our analysis.
      		ICM + NICM; EF ≤ 35%; NYHA II–III.L, L, H, U, L, L
      DEFINITE
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      N Engl J Med. 2004; 350: 2151-2158
      		1998–20022004ICD vs OMTNICM; EF ≤ 35%; NYHA I–III; NSVT or PVC.U, U, H, L, L, L
      COMPANION
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      		2000–20022004CRT-D vs CRT-P
      Amiodarone and RCT-P groups were not included in our analysis.
      vs OMT      		ICM + NICM; EF ≤ 35%; NYHA III–IV; QRS ≥ 120.U, U, H, L, L, L
      DANISH
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      		2008–20142016ICD vs OMTNICM; EF ≤ 35%; NYHA II–III; raised NT-proBNP.L, L, H, L, L, L
      CRT-D, cardiac resynchronization therapy-defibrillator; CRT-P, cardiac resynchronization therapy-pacemaker; EF, ejection fraction; ICD, implantable cardiovert-defibrillator; ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; NSVT, non-sustained ventricular tachycardia; NYHA, New York Heart Association functional classes of heart failure (I, II, II, IV); OMT, optimal medical therapy; PVC, frequent premature ventricular contractions; VT/VF, ventricular tachycardia/fibrillation. Domains for the risk of bias: randomization sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). The H, L, and U means high, low, and unclear risk of bias, respectively
      • Higgins J.P.T.
      • Altman D.G.
      • Gøtzsche P.C.
      • Jüni P.
      • Moher D.
      • Oxman A.D.
      • et al.
      The Cochrane tool for assessing risk of bias in randomised trials.
      BMJ. 2011; 343: d5928
      .
      a Amiodarone and RCT-P groups were not included in our analysis.
      Table 2Baseline clinical data of the seven trials included in the study.
      VariableMADIT
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      		MUSTT
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      		MADIT-II
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      N Engl J Med. 2002; 346: 877-883
      		SCD-HeFT
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      		DEFINITE
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      N Engl J Med. 2004; 350: 2151-2158
      		COMPANION
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      		DANISH
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      No. patients (ICD/control)95/101161/353742/490829/847229/229595/308556/560
      Age (years)6366*6460*58 [20–84]6763*
      Male (%)92908477716872
      LVEF (%)2629*2325*21 [7–35]2225 (20–30)
      Heart failure: Etiology and NYHA classes
       Etiology100% ICM100% ICM100% ICM52% ICM100% NICM57% ICM100% NICM
       Class I (%)35363602200
       Class II (%)65§39356957054
       Class III (%)–252431218545
       Class IV (%)00500151
      Therapy
       Beta-blocker (%)17447069856792
       ACE-I/ARB (%)57757096979097
       MRA (%)NRNRNR19NR5558
       CRT (%)0000010058
      Data are mean, mean [range], median (*), or median (interquartile range). §Classes II and III. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; CRT, cardiac resynchronization therapy; ICM, ischemic cardiomyopathy; LVEF, left ventricular ejection fraction; MRA, mineralcorticoid-receptor antagonist; NICM, non-ischemic cardiomyopathy; NYHA, New York Heart Association; NR, data not reported.
      The severity of HF, defined according to the distribution of patients in different NYHA classes, was low in the MADIT (Multicenter Automatic Defibrillator Implantation Trial) [
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      ], MUSTT (Multicenter Unsustained Tachycardia Trial) [
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      ], MADIT-II [
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      N Engl J Med. 2002; 346: 877-883
      ], and DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) [
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      N Engl J Med. 2004; 350: 2151-2158
      ] trials, where the 22–36% of patients were in class I. The SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) [
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      ] and DANISH [
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ] trials analyzed mild HF, whereas the COMPANION trial [
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ] examined severe HF, with all patients in class III and IV.
      The enrollment criteria determined an EF value ≤35%, except for the MUSTT and MADIT-II trials where the EF value was ≤40% and ≤30%, respectively. The earliest RCTs (MADIT and MUSTT) performed a preselection of patients, based on the presence of non-sustained ventricular tachycardia and the inducibility of ventricular tachycardia/ventricular fibrillation (VT/VF) at electrophysiological evaluation. Patient preselection was applied also in the DEFINITE trial, which required the presence of non-sustained ventricular tachycardia or frequent premature ventricular contractions for inclusion.

      Quality assessment

      The quality of the seven RCTs was evaluated by the Cochrane Risk of Bias Tool for RCTs, as reported in Table 1. Since ICD implantation is a surgical procedure, blinding was not effective, and, consequently, the risk of bias for blinding of participants and personnel was high in all the studies. However, the risk of bias for the other domains was low or unclear in all the studies, resulting in an overall judgment of low risk of bias for the MUSTT, SCD-HeFT, DEFINITE, COMPANION, and DANISH trials, and unclear for the MADIT and MADIT-II trials.

      Evolution of heart failure treatment

      As reported in Table 2, the pharmacological treatment of HF showed a progressive improvement from earlier to more recent studies, which involved an increase in the use of beta-blockers (17% and 44% in the MADIT and MUSTT trials, respectively, versus 92% in the DANISH trial), as well as in the use of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin-receptor blockers (ARBs), and mineralcorticoid-receptor antagonists (MRAs). Cardiac resynchronization therapy was present only in the COMPANION trial (100% of patients, all having a QRS ≥ 120 ms) and in the DANISH trial (56% of patients).

      Evolution of RCT outcomes

      The temporal evolution of RCT mortality outcomes over the analyzed 3-decade period is shown in Fig. 2, Fig. 3. The baseline risk for SCD, assessed by the annualized event rate (AER) of SCD in the control arms of the RCTs, showed a progressive reduction over time (Fig. 2A), decreasing from 5.7–7.8% in the MADIT and MUSTT trials (start of randomization 1990) to 2.5–3.0% in the DEFINITE and SCD-HeFT trials (start of randomization 1997–1998) to 1.5% in the DANISH trial (start of randomization 2008). Linear regression analysis testified a significant (p = 0.03) decrease over time with a reduction in AER of −0.3% per calendar year. Sensitivity analysis performed excluding the two trials on non-ischemic patients (DEFINITE and DANISH trials) showed a progressive decrease of AER of −0.36% per calendar year, although this did not reach statistical significance (R2 = 0.44, p = 0.22).
      Figure thumbnail gr2
      Fig. 2Temporal evolution of the baseline risk of sudden cardiac death (SCD, A) and total mortality (TM, B) in the seven trials, ordered according to the start of randomization. SCD and TM baseline risks are expressed in terms of annualized event rates (AER) of SCD and TM, respectively, in the control arm of the trials. In each panel, study outcomes are reported as blue circles, where circle size is proportional to sample dimension, and the linear regression fit is indicated by the red lines. Linear regression showed the baseline risk of SCD to undergo a significant (p = 0.03) decrease over time (regression line: y = −0.30x + 599.61), while for TM the decrease was non-significant (p = 0.18). The reduction of the baseline risk of TM became significant (regression line: y = −0.55x + 1109.15, p = 0.02) after removal of the COMPANION trial
      [
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ]
      . R2, R-squared of the linear regression.
      Figure thumbnail gr3
      Fig. 3Temporal evolution of implantable cardioverter-defibrillator (ICD) therapy efficacy in the seven trials, ordered according to the start of randomization. In each panel, study outcomes are reported as blue circles, where circle size is proportional to sample dimension, and the linear regression fit is indicated by the red lines. (A) The relative risk (RR) of sudden cardiac death (SCD) in ICD versus control patients, expressed as percentage and indicative of ICD unresponsive patients, showed a significant (p = 0.04) increase over time (regression line: y = +1.4x − 2831.3). (B) The number needed to treat (NNT) for total mortality (TM) at 3 years, indicative of ICD clinical benefit, showed a significant (p < 0.01) increase over time (regression line: y = +2.4x − 4699.9). In panel (B), the COMPANION trial
      [
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ]
      was excluded from NNT analysis due to its short follow-up. R2, R-squared of the linear regression.
      Similarly, the baseline risk (AER) for TM (Fig. 2B) showed a reduction over time from 17.2% in the MADIT to 4.2% in the DANISH trial, although the relationship did not reach statistical significance (p = 0.18). Sensitivity analysis showed that this was due to the COMPANION trial, which displayed an outlying value of 19.1%, probably related to the exclusive enrollment of patients with severe HF (class III and IV). After removal of the trial, the baseline risk of TM showed a significant (p = 0.02) reduction over time, with a decrease of −0.55% per calendar year.
      In all the analyzed trials, a fraction of patients who received ICD therapy was unresponsive to it and experienced SCD. The temporal evolution of the relative risk of SCD for ICD versus control arms (Fig. 3A), indicative of the fraction of ICD unresponsive patients, showed a progressive augment over time, increasing from 24.5% in the MADIT to 37.7% in the MADIT II to 52.5% in the DANISH trial. Consistently, linear regression analysis showed a statistically significant (p = 0.04) increase of the RR with an increment of 1.4% per calendar year. Sensitivity analysis confirmed the significant increase of the RR for SCD over time (R2 = 0.90, p = 0.01) when excluding the two trials with non-ischemic patients. Similarly to the RR, the risk difference of SCD for ICD patients with respect to controls showed a progressive increase, from negative values of −9.7% and −18.0% in the MADIT and MUSTT trials to −3.9% in the DANISH trial (R2 = 0.53, p = 0.06), which indicated a progressive decrease of the efficacy of ICD therapy.
      The clinical benefit of ICD in SCD primary prevention in the different trials was evaluated by the number needed to treat (NNT) for TM at 3-year follow-up. As shown in Fig. 3B, NNT values showed a progressive increase over time, passing from 4–5 in the MADIT and MUSTT trials, to 11 in the MADIT-II trial, to 20 in the SCD-HeFT trial and to 45 in the DANISH trial. Overall, linear regression analysis pointed out a statistically significant (p < 0.01) increase in the NNT with an increment of 2 per calendar year, indicating a progressive deterioration of ICD clinical benefit over time. As reported in Table 3, only five [
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      ,
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      ,
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      N Engl J Med. 2002; 346: 877-883
      ,
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ,
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      ] of the seven trials demonstrated the clinical efficacy of ICD therapy in preventing TM outcome, reporting a statistically significant hazard ratio. These trials had a NNT value for TM at 3 years ranging between 4 and 20. NNT values at 5 years could be reliably calculated only in three studies [
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      ,
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      ,
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ] and displayed an increase from 4 in the MUSTT to 21 in the DANISH trial.
      Table 3Outcome data of the seven trials included in the study.
      TrialsFollow-up (months)Total mortalitySudden cardiac death
      AER in control patients (%)HR (95% CI), p-value ICD vs controlNNT at 3 yearsNNT at 5 yearsAER in control patients (%)RR (95% CI) ICD vs control (%)RD (95% CI) ICD vs control (%)
      Ischemic cardiomyopathy
       MADIT
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      		2717.20.46 (0.26–0.82), p < 0.014–5.724.5 (7.2; 83.4)−9.7 (−17.1; −2.3)
       MUSTT
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      		39*13.80.49 (0.35–0.69), p < 0.001547.829.2 (16.5; 51.8)−18.0 (−24.1; −11.9)
       MADIT-II
      • Moss A.J.
      • Zareba W.
      • Hall W.J.
      • Klein H.
      • Wilber D.J.
      • Cannom D.S.
      • et al.
      Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
      N Engl J Med. 2002; 346: 877-883
      		2011.90.69 (0.51–0.93), p < 0.0511–6.037.7 (24.1; 59.2)−6.2 (−9.2; −3.2)
      Mixed ischemic and non-ischemic cardiomyopathy
       SCD-HeFT
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      		45.5*7.60.77 (0.62–0.96), p < 0.0120143.039.8 (27.6; 57.5)−6.8 (−9.3; −4.2)
       COMPANION
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      		15.719.10.64 (0.48–0.86), p < 0.005NA–4.548.9 (25.6; 93.5)−3.0 (−5.9; −0.0)
      Non-ischemic cardiomyopathy
       DEFINITE
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      N Engl J Med. 2004; 350: 2151-2158
      		29 ± 147.20.65 (0.40–1.06), p = 0.0816–2.521.4 (6.2; 73.6)−4.8 (−8.2; −1.4)
       DANISH
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      		67.7*4.20.87 (0.68–1.12), p = 0.2845211.552.5 (32.5; 84.9)−3.9 (−6.7; −1.1)
      Data are mean, mean ± standard deviation, or median (*). AER, annualized event rate; CI, confidence interval; HR, hazard ratio; ICD, implantable cardioverter-defibrillator; RD, risk difference; RR, relative risk; NA, data not available due to short follow-up; NNT, number needed to treat.

      Discussion

      This is the first study analyzing the temporal evolution of ICD efficacy in RCTs (seven trials and 6095 patients) over a 3-decade period, from 1990 to 2014, in primary prevention of SCD. When ordered according to the respective year of randomization start, RCT outcome data showed a progressive decline in the baseline risk of SCD and TM, and a progressive increase in the percentage of patients unresponsive to ICD treatment, which synergistically led to a progressive reduction in ICD clinical benefit. These temporal patterns could not be pointed out by a pooled analysis of the studies, as provided by previous meta-analyses [
      • Shun-Shin M.J.
      • Zheng S.L.
      • Cole G.D.
      • Howard J.P.
      • Whinnett Z.I.
      • Francis D.P.
      Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials.
      Eur Heart J. 2017; 38: 1738-1746
      ,
      • Al-Khatib S.M.
      • Fonarow G.C.
      • Joglar J.A.
      • Inoue L.Y.T.
      • Mark D.B.
      • Lee K.L.
      • et al.
      Primary prevention implantable cardioverter defibrillators in patients with nonischemic cardiomyopathy: a meta-analysis.
      JAMA Cardiol. 2017; 2: 685-688
      ].

      Reduction of SCD and TM baseline risk

      The decline in the baseline risk of SCD and TM over time observed in RCT control arms (Fig. 1) can be explained in the light of the progressive and tremendous improvement that occurred in HF treatment in the analyzed period. Increasingly extensive use of beta-blockers, ACE-Is, ARBs, and MRAs, associated with cardiac resynchronization therapy in selected cases, reduced both cardiac death [
      • Rush C.J.
      • Campbell R.T.
      • Jhund P.S.
      • Connolly E.C.
      • Preiss D.
      • Gardner R.S.
      • et al.
      Falling cardiovascular mortality in heart failure with reduced ejection fraction and implications for clinical trials.
      JACC Heart Fail. 2015; 3: 603-614
      ] and SCD [
      • Shen L.
      • Jhund P.S.
      • Petrie M.C.
      • Claggett B.L.
      • Barlera S.
      • Cleland J.G.F.
      • et al.
      Declining risk of sudden death in heart failure.
      N Engl J Med. 2017; 377: 41-51
      ] in patients with HF and low EF. The patterns observed in our analysis are in agreement with the recent study by Shen et al. on HF patients [
      • Shen L.
      • Jhund P.S.
      • Petrie M.C.
      • Claggett B.L.
      • Barlera S.
      • Cleland J.G.F.
      • et al.
      Declining risk of sudden death in heart failure.
      N Engl J Med. 2017; 377: 41-51
      ]. By analyzing data from 40,195 HF patients with depressed EF, enrolled from 1995 to 2014 in 12 clinical trials with a mixed population of ischemic and non-ischemic origin, the study pointed out a progressive and significant (p = 0.03) decline in the risk of SCD throughout the analyzed period, with an overall decrease of 44%.
      Although the reduction in SCD risk may be mainly related to the progressive improvement in HF treatment, other factors may modulate SCD risk. Patients with ischemic HF may be more prone to SCD than non-ischemic patients. In the aforementioned study by Shen et al. [
      • Shen L.
      • Jhund P.S.
      • Petrie M.C.
      • Claggett B.L.
      • Barlera S.
      • Cleland J.G.F.
      • et al.
      Declining risk of sudden death in heart failure.
      N Engl J Med. 2017; 377: 41-51
      ], a positive association was observed between the risk of SCD and the ischemic cause of HF, and adjustment for this and other baseline variables attenuated the observed temporal trend. Similarly, in our study, sensitivity analysis showed an attenuated association of SCD baseline risk with time, when the two studies with exclusively non-ischemic patients were removed. On the other hand, the significant decrease of the relative risk for SCD in ICD versus control patients was confirmed despite the exclusion of non-ischemic patients, suggesting that the increase in ICD unresponsive patients over time was not affected by HF etiology.

      Increase in patients unresponsive to ICD

      Since the first RCTs a percentage of patients experiencing SCD was observed also in ICD implanted arm [
      • Anderson K.P.
      Sudden cardiac death unresponsive to implantable defibrillator therapy: an urgent target for clinicians, industry and government.
      J Interv Card Electrophysiol. 2005; 14: 71-78
      ]. In the present study, we observed that the percentage of patients unresponsive to ICD therapy progressively increased over time, as shown in Fig. 3A, reaching a maximum RR of SCD of 52.5% in the recent DANISH trial. This result may be explained in the light of different factors. First, the definition of SCD provided by the World Health Organization (WHO) criteria [
      Sudden cardiac death, Report of a WHO Scientific Group.
      World Health Organ Tech Rep Ser. 1985; 726: 5-25
      ] is elusive and can contain different definitions within, thus hindering a precise assessment of this mortality outcome. Second, the introduction of novel therapies for HF may have produced alterations in arrhythmia properties, leading to changes in ICD effectiveness. Specifically, before 2000 VT/VF were thought to be the most common cause of out-of-hospital cardiac arrest, accounting for approximately the 75% of cases [
      • Bayés de Luna A.
      • Coumel P.
      • Leclercq J.F.
      Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases.
      Am Heart J. 1989; 117: 151-159
      ]. Conversely, more recent studies have suggested a declining incidence of VT/VF as cause of SCD, and an increasing incidence of pulseless electrical activity (both primary and post-shock) [
      • Myerburg R.J.
      • Halperin H.
      • Egan D.A.
      • Boineau R.
      • Chugh S.S.
      • Gillis A.M.
      • et al.
      Pulseless electric activity: definition, causes, mechanisms, management, and research priorities for the next decade: report from a National Heart, Lung, and Blood Institute workshop.
      Circulation. 2013; 128: 2532-2541
      ], likely due to the increasing use of aggressive pharmacological management of HF. In addition, in a recent large surveillance study reviewing 20,440 deaths, nearly half of the presumed SCDs were found to be not of arrhythmic origin [
      • Tseng Z.H.
      • Olgin J.E.
      • Vittinghoff E.
      • Ursell P.C.
      • Kim A.S.
      • Sporer K.
      • et al.
      Prospective countywide surveillance and autopsy characterization of sudden cardiac death: POST SCD Study.
      Circulation. 2018; 137: 2689-2700
      ]. The decline in the number of VT/VF-related SCDs and the fact that ICD can treat only episodes of ventricular arrhythmias, and not other types of SCD, may thus explain the progressive increase in the number of patients unresponsive to ICD therapy observed in our study in HF of both ischemic and non-ischemic origin.

      Clinical considerations

      The observed association of a progressively reduced baseline risk of SCD and TM, and a progressively augmented percentage of patients unresponsive to ICD synergistically determined a progressive reduction in the clinical benefit of ICD in SCD primary prevention. Indeed, as reported in Fig. 3B, the NNT for TM at 3 years progressively increased. Among the RCTs displaying a statistically significant hazard ratio (Table 3), the highest NNT (and therefore with the lowest clinical benefit) was reported in the SCD-HeFT trial with a value of 20. This value can thus be assumed as an upper threshold of clinical efficacy, with NNT values above the threshold indicating a reduction in the clinical benefit of ICD in comparison with RCTs included in the ICD guidelines. Assuming a percentage of unresponsive patients consistent with modern HF therapy (RR = 52.5% from the DANISH trial) and a null effect of ICD on deaths of non-sudden origin, a baseline AER for SCD greater than 3.5% would be required to obtain a 3-year NNT smaller than the upper threshold of 20. However, as recently reviewed by Shen et al. [
      • Shen L.
      • Jhund P.S.
      • Petrie M.C.
      • Claggett B.L.
      • Barlera S.
      • Cleland J.G.F.
      • et al.
      Declining risk of sudden death in heart failure.
      N Engl J Med. 2017; 377: 41-51
      ], the current annual incidence of SCD reported in the three most recent trials on HF patients with impaired left ventricular function, treated with modern optimal medical therapy, ranged between 2.5 and 3.0% [
      • Tavazzi L.
      • Maggioni A.P.
      • Marchioli R.
      • Barlera S.
      • Franzosi M.G.
      • Latini R.
      • et al.
      Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.
      Lancet. 2008; 372: 1231-1239
      ,
      • Zannad F.
      • McMurray J.J.V.
      • Krum H.
      • van Veldhuisen D.J.
      • Swedberg K.
      • Shi H.
      • et al.
      Eplerenone in patients with systolic heart failure and mild symptoms.
      N Engl J Med. 2011; 364: 11-21
      ,
      • McMurray J.J.V.
      • Packer M.
      • Desai A.S.
      • Gong J.
      • Lefkowitz M.P.
      • Rizkala A.R.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      N Engl J Med. 2014; 371: 993-1004
      ]. These incidence values correspond to estimated 3-year NNT values ranging between 24 and 30, which suggest a reduced clinical benefit of ICD in the modern therapy of HF when current patient selection criteria are applied (i.e. left ventricular EF value and NYHA functional class). It is worth noting that our results pertained only to primary prevention, since studies on secondary prevention are sparse and dated [
      • Connolly S.J.
      • Hallstrom A.P.
      • Cappato R.
      • Schron E.B.
      • Kuck K.H.
      • Zipes D.P.
      • et al.
      Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs implantable defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study.
      Eur Heart J. 2000; 21: 2071-2078
      ], precluding the assessment of time evolution in the latter setting. As well, consistently with the available follow-up data, clinical benefit was estimated at 3 years, whereas ICD benefit should be assessed at 5-year follow-up, which is the expected life span of the device. In the three studies where longer follow-ups were available [
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      ,
      • Bardy G.H.
      • Lee K.L.
      • Mark D.B.
      • Poole J.E.
      • Packer D.L.
      • Boineau R.
      • et al.
      Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
      N Engl J Med. 2005; 352: 225-237
      ,
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ], however, the 5-year NNT values suggested a progressive increase over time. Despite these restrictions, the observed reduction in ICD clinical benefit suggests the necessity of identifying additional risk markers for SCD, other than or to be associated with EF, in order to improve the selection of patient subsets at higher risk for SCD [
      • Disertori M.
      • Masè M.
      • Rigoni M.
      • Nollo G.
      • Arbustini E.
      • Ravelli F.
      Implantable cardioverter-defibrillator in dilated cardiomyopathy after the DANISH-trial lesson. A poly-parametric risk evaluation is needed to improve the selection of patients.
      Front Physiol. 2017; 8: 873
      ,
      • Dagres N.
      • Hindricks G.
      Devices for management of sudden cardiac death: successes, challenges and perspectives.
      Int J Cardiol. 2017; 237: 34-37
      ,
      • Disertori M.
      • Rigoni M.
      • Pace N.
      • Casolo G.
      • Masé M.
      • Gonzini L.
      • et al.
      Myocardial fibrosis assessment by LGE is a powerful predictor of ventricular tachyarrhythmias in ischemic and nonischemic LV dysfunction: a meta-analysis.
      JACC Cardiovasc Imaging. 2016; 9: 1046-1055
      ,
      • Disertori M.
      • Masè M.
      • Rigoni M.
      • Nollo G.
      • Ravelli F.
      Ventricular tachycardia-inducibility predicts arrhythmic events in post-myocardial infarction patients with low ejection fraction. A systematic review and meta-analysis.
      Int J Cardiol Heart Vasc. 2018; 20: 7-13
      ,
      • Disertori M.
      • Masé M.
      • Rigoni M.
      • Nollo G.
      • Ravelli F.
      Heart rate turbulence is a powerful predictor of cardiac death and ventricular arrhythmias in postmyocardial infarction and heart failure patients: a systematic review and meta-analysis.
      Circ Arrhythm Electrophysiol. 2016; 9 (pii: e004610)
      ]. In particular, SCD risk markers should be specific for ventricular tachyarrhythmias treatable by ICD, with respect to other forms of SCD. Promising markers for risk stratification of SCD of arrhythmic origin are represented by the assessment of ventricular fibrosis by late gadolinium enhancement cardiac magnetic resonance [
      • Disertori M.
      • Rigoni M.
      • Pace N.
      • Casolo G.
      • Masé M.
      • Gonzini L.
      • et al.
      Myocardial fibrosis assessment by LGE is a powerful predictor of ventricular tachyarrhythmias in ischemic and nonischemic LV dysfunction: a meta-analysis.
      JACC Cardiovasc Imaging. 2016; 9: 1046-1055
      ], and the evaluation of sustained VT inducibility during an electrophysiological study [
      • Disertori M.
      • Masè M.
      • Rigoni M.
      • Nollo G.
      • Ravelli F.
      Ventricular tachycardia-inducibility predicts arrhythmic events in post-myocardial infarction patients with low ejection fraction. A systematic review and meta-analysis.
      Int J Cardiol Heart Vasc. 2018; 20: 7-13
      ]. Unfortunately, only one ongoing RCT is evaluating the efficacy of these risk stratification markers in patients with ischemic cardiomyopathy and depressed EF, but it will not be completed before 2023 [
      • Zaman S.
      • Taylor A.J.
      • Stiles M.
      • Chow C.
      • Kovoor P.
      Programmed ventricular stimulation to risk stratify for early cardioverter-defibrillator implantation to prevent tachyarrhythmias following acute myocardial infarction (PROTECT-ICD): trial protocol, background and significance.
      Heart Lung Circ. 2016; 25: 1055-1062
      ]. In the meanwhile, to improve the appropriateness of ICD therapy, guidelines may be updated considering the evidence provided by subgroup analyses of RCTs, and by non-randomized studies and their meta-analyses [
      • Disertori M.
      • Masè M.
      • Rigoni M.
      • Nollo G.
      • Arbustini E.
      • Ravelli F.
      Implantable cardioverter-defibrillator in dilated cardiomyopathy after the DANISH-trial lesson. A poly-parametric risk evaluation is needed to improve the selection of patients.
      Front Physiol. 2017; 8: 873
      ], which may help the appropriate development and validation of poly-parametric prognostic models to identify high-risk patients.

      Limitations

      The main limitation of our study is related to the heterogeneity of the analyzed studies, which showed differences in trial design, enrollment criteria, severity and treatment of HF (Table 1, Table 2). However, it is worth noting that the analyzed studies were used to draw up the current ICD guidelines [
      • Al-Khatib S.M.
      • Stevenson W.G.
      • Ackerman M.J.
      • Bryant W.J.
      • Callans D.J.
      • Curtis A.B.
      • et al.
      2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      J Am Coll Cardiol. 2018; 72: e91-e220
      ], and heterogeneity did not preclude their pooled analysis in recent meta-analyses [
      • Shun-Shin M.J.
      • Zheng S.L.
      • Cole G.D.
      • Howard J.P.
      • Whinnett Z.I.
      • Francis D.P.
      Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials.
      Eur Heart J. 2017; 38: 1738-1746
      ,
      • Al-Khatib S.M.
      • Fonarow G.C.
      • Joglar J.A.
      • Inoue L.Y.T.
      • Mark D.B.
      • Lee K.L.
      • et al.
      Primary prevention implantable cardioverter defibrillators in patients with nonischemic cardiomyopathy: a meta-analysis.
      JAMA Cardiol. 2017; 2: 685-688
      ]. We analyzed together the outcomes data of RCTs in patients with HF of ischemic and non-ischemic origin, since the low number of available RCTs and the presence of two studies with mixed populations precluded a separate analysis of the temporal trends. Nevertheless, a specific sensitivity analysis, which excluded the studies with exclusively non-ischemic patients, confirmed the overall trends. As an additional limitation, in three studies [
      • Moss A.J.
      • Hall W.J.
      • Cannom D.S.
      • Daubert J.P.
      • Higgins S.L.
      • Klein H.
      • et al.
      Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators.
      N Engl J Med. 1996; 335: 1933-1940
      ,
      • Buxton A.E.
      • Lee K.L.
      • Fisher J.D.
      • Josephson M.E.
      • Prystowsky E.N.
      • Hafley G.
      A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
      N Engl J Med. 1999; 341: 1882-1890
      ,
      • Kadish A.
      • Dyer A.
      • Daubert J.P.
      • Quigg R.
      • Estes N.A.M.
      • Anderson K.P.
      • et al.
      Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy.
      N Engl J Med. 2004; 350: 2151-2158
      ] there was a preselection of patients with VT/VF risk markers (presence of non-sustained VT or frequent premature ventricular contractions, or the inducibility of ventricular tachyarrhythmias), which may have increased the rate of SCD in the control arm and reduced the number of patients unresponsive to ICD. Likewise, in two studies a fraction of HF patients were treated with cardiac resynchronization therapy [
      • Bristow M.R.
      • Saxon L.A.
      • Boehmer J.
      • Krueger S.
      • Kass D.A.
      • De Marco T.
      • et al.
      Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.
      N Engl J Med. 2004; 350: 2140-2150
      ,
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ]. However, as shown in one of the two studies [
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • Haarbo J.
      • Videbæk L.
      • Korup E.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      N Engl J Med. 2016; 375: 1221-1230
      ], no significant differences in mortality outcomes were present between patients with and without cardiac resynchronization therapy.

      Conclusions

      The results of our study on the temporal evolution of RCT outcomes in the last three decades pointed out a progressive reduction in the baseline risk of SCD and TM, and a progressive increase in the percentage of patients unresponsive to ICD treatment, which synergistically contributed to the reduction in the clinical benefit of ICD, implanted according to guideline recommendations, in SCD primary prevention. These results corroborate the perceived need of an improvement in patient selection criteria to ICD therapy in the modern treatment of HF patients.

      Funding

      This work was partially funded by the Autonomous Province of Trento (the Healthcare Research and Innovation Program at Fondazione Bruno Kessler).

      Conflict of interest

      The authors declare that there is no conflict of interest.

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      Article info

      Publication history

      Published online: September 13, 2019
      Accepted: June 14, 2019
      Received in revised form: May 23, 2019
      Received: March 27, 2019

      Identification

      DOI: https://doi.org/10.1016/j.jjcc.2019.06.001

      Copyright

      © 2019 Japanese College of Cardiology. Published by Elsevier Ltd.

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