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Sex, Race, and Age Differences in Cardiovascular Outcomes in Implantable Cardioverter–Defibrillator Randomized Controlled Trials: A Systematic Review and Meta-analysis

Open AccessPublished:September 23, 2021DOI:https://doi.org/10.1016/j.cjco.2021.09.015

      Abstract

      Background

      Data are limited regarding the use of implantable cardioverter–defibrillators (ICDs) in diverse populations. This study explores cardiovascular (CV) outcomes and mortality from ICD randomized controlled trials (RCTs), by sex, race, and age.

      Methods

      Five electronic databases (PubMed, Emcare, Embase, MEDLINE, and Cumulative Index to Nursing & Allied Health Literature CINAHL) were searched for dates from their inception to July 12, 2021, for RCTs of ICD therapy in adult patients. Data were analyzed for clinical outcomes, including all-cause or CV death, and heart failure hospitalization (HFH).

      Results

      Among 5 RCTs (mean age: 63 years; 78% male; 76% White) with moderate overall risk of bias, clinical outcomes in patients with an ICD (n = 3260) vs a control group (n = 3685) were compared. No between-group sex differences were observed for all-cause death (odds ratio [OR] 0.86, P = 0.51), CV death (OR 0.98, P = 0.96), HFH (OR 0.95, P = 0.87), or HFH and all-cause death (OR 0.83, P = 0.51) in the ICD group, in a comparison of male vs female sex. All-cause death (OR 1.20, P = 0.67) did not differ for White vs Black patients receiving ICD therapy. Outcomes data for other non-White, non-Black race groups were often unreported. Most RCTs originated in North America, had male leadership, and were evenly sponsored by industry vs peer-reviewed funding.

      Conclusions

      Outcomes data are sparse, by sex, race, and age, in current RCTs evaluating ICD therapy. Although ICD patient outcomes did not significantly differ by sex or race, improved data analyses and reporting are needed to determine the relationship between these sociocultural factors and clinical outcomes among distinct ICD patient cohorts.

      Résumé

      Contexte

      Les données sur l’utilisation des défibrillateurs cardioverteurs implantables (DCI) dans diverses populations sont limitées. Cette étude porte sur les résultats cardiovasculaires (CV) et les décès liés aux DCI qui ont été signalés dans le cadre d'essais contrôlés randomisés (ECR), en fonction du sexe, de la race et de l’âge.

      Méthodologie

      Des recherches ont été effectuées dans cinq bases de données électroniques (PubMed, EmCare, Embase, Medline et CINAHL [Cumulative Index to Nursing & Allied Health Literature]) en ciblant une période allant de la date de leur création jusqu’au 12 juillet 2021 afin de recenser les ECR menés chez des patients adultes ayant reçu un DCI. Les données ont été analysées en fonction des résultats cliniques, notamment les décès toutes causes confondues ou d’origine CV et les hospitalisations pour insuffisance cardiaque (hIC).

      Résultats

      Cinq ECR (âge moyen des patients : 63 ans; 78 % d’hommes; 76 % de race blanche) présentant globalement un risque de biais modéré ont permis de comparer les résultats cliniques obtenus chez les patients ayant reçu un DCI (n = 3 260) et ceux du groupe témoin (n = 3 685). Aucune différence intergroupe entre les sexes n’a été observée pour les décès toutes causes confondues (rapport de cotes [RC] : 0,86, p = 0,51), les décès d’origine CV (RC : 0,98, p = 0,96) et les hIC (RC : 0,95, p = 0,87), ou les hIC et les décès toutes causes confondues (RC : 0,83, p = 0,51) au sein du groupe de patients ayant reçu un DCI, dans une comparaison entre les sexes. Aucune différence entre les patients de race blanche et de race noire ayant reçu un DCI n’a été notée pour ce qui est des décès toutes causes confondues (RC : 1,20, p = 0,67). Souvent, les données sur les résultats obtenus au sein de groupes de patients de race autre que blanche ou noire n’étaient pas signalées. La plupart des ECR avaient été menés en Amérique du Nord, étaient dirigés par des hommes et commandités à parts égales par l’industrie et des organismes offrant du financement approuvé par les pairs.

      Conclusions

      Les ECR portant sur l’utilisation des DCI fournissent actuellement peu de données sur les résultats en fonction du sexe, de la race et de l’âge. Les résultats obtenus chez les patients ayant reçu un DCI ne différaient pas significativement selon le sexe ou la race. Néanmoins, des analyses de données et des rapports plus détaillés sont nécessaires pour déterminer la relation entre ces facteurs socioculturels et les résultats cliniques au sein de cohortes distinctes de patients ayant reçu un DCI.
      An implantable cardioverter–defibrillator (ICD), which functions to treat ventricular tachycardia and ventricular fibrillation by delivering shocks and/or anti-tachycardia pacing,
      • DiMarco J.P.
      Implantable cardioverter–defibrillators.
      is indicated to prevent sudden cardiac death (SCD) in patients who have not previously experienced a ventricular arrhythmia, but are at an increased risk for it (primary prevention), and patients who have experienced a serious ventricular arrhythmia (secondary prevention).
      • Glikson M.
      • Friedman P.A.
      The implantable cardioverter defibrillator.
      Several landmark randomized controlled trials (RCTs) have demonstrated the effectiveness of ICD therapy in the primary and secondary prevention of SCD. For example, the primary prevention Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) found a 60% reduction in SCD in patients who were randomized to the ICD group, compared with the incidence among those who received placebo or amiodarone therapy.
      • Chia P.-L.
      • Foo D.
      Overview of implantable cardioverter defibrillator and cardiac resynchronisation therapy in heart failure management.
      Similarly, a study focused on secondary prevention of SCD, the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, found that ICD use, compared with antiarrhythmic therapy, resulted in a 27% relative risk reduction in death.
      • Kedia R.
      • Saeed M.
      Implantable cardioverter-defibrillators: indications and unresolved issues.
      However, few ICD RCTs have reported granular data for cardiovascular (CV) outcomes by sex, race, and age, thereby obscuring the potential survival/morbidity benefits and applicability of ICD therapy in more-diverse patient cohorts with CV diseases. Moreover, data have indicated that diverse patient populations, including women, non-White races, and the elderly, are underrepresented in RCTs evaluating major CV outcomes.
      • Jin X.
      • Chandramouli C.
      • Allocco B.
      • et al.
      Women’s participation in cardiovascular clinical trials from 2010 to 2017.
      ,
      • Sardar M.R.
      • Badri M.
      • Prince C.T.
      • et al.
      Underrepresentation of women, elderly patients, and racial minorities in the randomized trials used for cardiovascular guidelines.
      Therefore, the aim of this study was to bridge this knowledge gap by evaluating independent clinical outcomes data and study characteristics, by sex, race, and/or age, among patients who received an ICD.

      Methods

      Data sources, search strategy, and study eligibility

      This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      This study was not registered in the International Prospective Register of Systematic Reviews (PROSPERO), but it has adhered to the relevant ethical guidelines. Five electronic databases (PubMed [non-MEDLINE], Emcare, Embase, MEDLINE [Ovid], and Cumulative Index to Nursing & Allied Health Literature [CINAHL]) were searched by an information specialist (M.P.) using the Population, Intervention, Comparison, Outcomes, and Study (PICOS) framework for all relevant English-language RCTs on ICD therapy in adults (age ≥ 18 years) with CV disease, from inception until July 12, 2021. Search terms included “implantable cardioverter-defibrillator” and “ICD”; terms are detailed in the search strategy (Supplemental Table S1). All RCTs and their secondary analyses that evaluated the use of ICD alone compared with a control or comparator group (eg, medical therapy or cardiac resynchronization therapy) were included. Studies were excluded for the following criteria: duplicates, non-RCTs (eg, case reports or observational studies, reviews, or meta-analyses), animal studies, non-English publications, and pediatric (age < 18 years) studies. Reference lists of key studies and reviews were also manually searched for any potentially relevant studies.

      Data collection, data extraction, and statistical analyses

      Search results were imported into Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia),

      Covidence Systematic Review Software [program]. Melbourne, Australia: Veritas Health Innovation.

      and duplicate studies were removed. Two reviewers (H.I.S. and M.K.S.) independently screened article titles and abstracts, and reviewed full-text articles for study eligibility for data extraction. Standardized data extraction included the following: study characteristics (including authorship and funding-recipient sex and race), trial funding sources, trial origin and enrollment sites, patient characteristics, the intervention and control group details, and 12-month event rates for outcomes by sex (male vs female), race (White, Black, Hispanic, East Asian, Southeast Asian, and other), and age ( ≥ 65 and < 65 years). Discrepancies at each stage were resolved by consensus, with group discussion involving another reviewer (B.M.). Six studies were excluded for the reasons outlined, or in cases in which reported data could not be appropriately synthesized (Supplemental Table S2). Details for first and corresponding (trial lead) authorship and funding recipient, including sex, and trial funding sources, were captured as reported in the published article, from the clinicaltrials.gov website, and/or from web sources, such as an institutional biography page when possible. Trial investigators’ races were determined through an online search, by evaluating their faculty/clinical profiles and last name origins, with consensus of 2 independent reviewers (H.I.S. and M.K.S.). Lack of data precluded analyses based on age and/or career status (eg, early vs late) at the time of study publication.
      Predefined clinical outcomes of interest included the following: all-cause death and heart failure hospitalization (HFH; composite and isolated); arrhythmic death; cardiac/non-arrhythmic death; CV death; and ventricular arrhythmia. The composite 3-point major CV adverse endpoint, which includes myocardial infarction, stroke, and CV death, although it was a predefined outcome of interest, could not be evaluated due to lack of reporting that was disaggregated by the demographic variables. Summary statistics for retrievable data (means or medians) were calculated, along with 12-month event rates for each outcome. These outcomes were reported as an odds ratio (OR) or risk ratio (RR), with a 95% confidence interval (CI), utilizing a random-effects model, given the limitations in reported data availability. A P value (2-sided) of < 0.05 was considered statistically significant. Data from each study were analyzed using Cochrane Review Manager (RevMan, version 5.3, The Nordic Cochrane Centre, Copenhagen, Denmark).

      Review Manager 5 [program]. 5.3 version. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014: The Cochrane Collaboration.

      As applicable, χ2 and I2 tests of heterogeneity were also generated.

      Risk of bias and GRADE

      Two reviewers (H.I.S. and M.K.S.) independently assessed the risk of bias within the eligible studies using the Cochrane risk-of-bias tool for RCTs (RoB2)
      • Sterne J.A.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ; any discrepancy was resolved by consensus with an additional reviewer (B.M.). The risk of bias was defined as “low,” “some concerns,” or “high,” based on overall and individual assessment for the following 5 domains (Supplemental Fig. S1): bias arising from the randomization process, bias due to deviations from intended intervention, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported results. Overall quality of the evidence in included trials was also assessed independently (H.I.S. and M.K.S.) utilizing the Grading of Recommendations, Assessment, Development and Evaluations (GRADE)
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • et al.
      GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables.
      certainty scale. Individual studies were defined as “very low,” “low,” “moderate,” or “high” certainty, with the assumption of “high” certainty and then down-rated in the presence of serious concerns about study limitations. The limitations that could have led to a lowered rating included risk of bias, indirectness of evidence, heterogeneity, imprecision, and publication bias.

      Results

      Study selection and risk of bias

      The literature search yielded 6875 studies. After 2976 duplicates were removed, 3896 citations were eligible for abstract screening, of which 175 were eligible for further full-text review. Of 25 publications reporting on ICD therapy, there were 11 distinct RCTs; sex- and race-based clinical outcome data were only available from 5 of these ICD RCTs.
      • Albert C.M.
      • Quigg R.
      • Saba S.
      • et al.
      Sex differences in outcome after implantable cardioverter defibrillator implantation in nonischemic cardiomyopathy.
      • de Waard D.
      • Manlucu J.
      • Gillis A.M.
      • et al.
      Cardiac resynchronization in women: a substudy of the resynchronization-defibrillation for ambulatory heart failure trial.
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      • Russo A.M.
      • Poole J.E.
      • Mark D.B.
      • et al.
      Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial.
      • Vorobiof G.
      • Goldenberg I.
      • Moss A.J.
      • et al.
      Effectiveness of the implantable cardioverter defibrillator in Blacks versus Whites (from MADIT-II).
      (Fig. 1). The corresponding authors of the 6 remaining trials were approached for relevant data disaggregated by sex, race, and age, for potential inclusion in the study analyses. However, only one author responded, and this author no longer had access to the data. Therefore, no new data could be added. Consequently, study characteristics and results of the excluded trials were also extracted to determine if the included trials were still representative of ICD trials as a whole. Moreover, similarities between the included vs excluded study cohorts suggested adequate representation by the included studies of ICD trials in general (Supplemental Table S2). Prespecified study characteristics of the eligible ICD RCTs included study authorship and funding recipient, trial funding sources, trial origin and site locations, patient characteristics, and outcomes data in the trial intervention and control arms. Trial information, patient characteristics by sex, race, and age, and outcomes data are summarized in Table 1. Although no studies reported CV outcomes and mortality based on dichotomized age ≥ 65 or < 65 years, Køber et al.
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      reported all-cause death in those aged < 59 years, ≥ 59 to < 68 years, and ≥ 68 years.
      Figure thumbnail gr1
      Figure 1Study flow diagram: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol recommendations were used to determine study inclusion.
      Table 1Summary of included implantable cardioverter–defibrillator (ICD) randomized controlled trials
      Study characteristicVorobiof
      • Vorobiof G.
      • Goldenberg I.
      • Moss A.J.
      • et al.
      Effectiveness of the implantable cardioverter defibrillator in Blacks versus Whites (from MADIT-II).
      (2006)
      Vorobiof et al.16 reported data on MADIT-II and included 1073 White patients, 102 Black Patients, and 37 Hispanic patients, and 20 patients categorized as ‘other’. However, race characteristics were only documented for White and Black patients, so not all participants are included for those characteristics.
      Albert
      • Albert C.M.
      • Quigg R.
      • Saba S.
      • et al.
      Sex differences in outcome after implantable cardioverter defibrillator implantation in nonischemic cardiomyopathy.
      (2008)
      Russo
      • Russo A.M.
      • Poole J.E.
      • Mark D.B.
      • et al.
      Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial.
      (2008)
      Køber
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      (2016)
      De Waard
      • de Waard D.
      • Manlucu J.
      • Gillis A.M.
      • et al.
      Cardiac resynchronization in women: a substudy of the resynchronization-defibrillation for ambulatory heart failure trial.
      (2019)
      Trial nameMADIT-IIDEFINITESCD-HeFTDANISHRAFT
      Trial sites/ regionNorth America, EuropeNorth AmericaNorth America, AustraliaEuropeNorth America, Europe, Australia, Asia
      No. of trial sites76NR148534
      Eligible age, y> 21NR≥ 18NRNR
      Enrollment by sex (male vs female)1039 (84), 197 (16)326 (71), 132 (29)1933 (76.7), 588 (23.3)809 (72.5), 307 (27.5)1490 (83), 308 (17)
      Male enrollment by race (White, Black, Hispanic, other)934 (93.7) White, 63 (6.3) Black232 (71), 69 (21), 20 (6), 5 (2)1527 (79) White, 406 (21) reported as non-White raceNRNR
      Female enrollment by race (White, Black, Hispanic, other)140 (78.2), White 39 (21.8) Black77 (58%, 49 (37), 6 (5), 0 (0)406 (69) White, 182 (31) reported as non-White raceNRNR
      Mean age, y64 ± 1058.360 (median)63.5 (median)66.1 ± 9.4
      Patient populationPast MI, LVEF < 0.30LVEF < 36%, HF, or arrhythmiasNYHA class II or class II chronic, stable CHF, and LVEF ≥ 35%LVEF < 36%, arrhythmias, HF, or non-ischemic DCMNYHA class II HF, LVEF < 30%, prolonged QRS duration, sinus rhythm/AF/AFL < 60 bpm at rest, or planned ICD for indicated prevention of SCD
      Trial subgroupMINon-ischemic DCMSCD, CHFSystolic HFHF, ventricular arrhythmia
      Primary outcome(s)Death from any cause
      Indicates significance at P < 0.05.
      Death from any causeDeath from any cause
      Indicates significance at P < 0.05.
      Death from any causeDeath from any cause or HFH
      Indicates significance at P < 0.05.
      Secondary outcome(s)N/ASudden death from arrhythmia
      Indicates significance at P < 0.05.
      Arrhythmic deathSCD, CV death, cardiac arrest, sustained ventricular tachycardia, and change in quality of lifeDeath from any cause, death from any CV cause, and HFH
      Treatment armICDICDICDICDICD
      Control armConventional medical therapyStandard medical therapyAmiodarone or placeboUsual clinical careICD-CRT
      No. of patients (treatment vs control)1232 (742
      Indicates significance at P < 0.05.
      vs 490)
      458 (229
      Indicates significance at P < 0.05.
      vs 229)
      2521 (Tx1: 845, Tx2: 829
      Indicates significance at P < 0.05.
      vs 847)
      1116 (556 vs 560)1798 (904 vs 894
      Indicates significance at P < 0.05.
      )
      Overall quality of the evidence (GRADE)
      Studies were assessed for all-cause death only.
      ⊕⊕⊕⊕

      High (n = 5 studies)
      Values are n (%), unless otherwise indicated.
      AF, atrial fibrillation; AFL, atrial flutter; bpm, beats per minute; CHF, congestive heart failure; CRT, cardiac resynchronization therapy; CV, cardiovascular; DANISH, Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality; DCM, dilated cardiomyopathy; DEFINITE, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation Trial; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HF, heart failure; HFH, heart failure hospitalization; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MADIT-II, Multicenter Automatic Defibrillator Implantation Trial II; MI, myocardial infarction; NR, not reported; NYHA, New York Heart Association; RAFT, Resynchronization–Defibrillation for Ambulatory Heart Failure Trial; RCT, randomized controlled trial; SCD, sudden cardiac death; SCD-HeFT, Sudden Cardiac Death in Heart Failure Trial; Tx, treatment.
      Vorobiof et al.
      • Vorobiof G.
      • Goldenberg I.
      • Moss A.J.
      • et al.
      Effectiveness of the implantable cardioverter defibrillator in Blacks versus Whites (from MADIT-II).
      reported data on MADIT-II and included 1073 White patients, 102 Black Patients, and 37 Hispanic patients, and 20 patients categorized as ‘other’. However, race characteristics were only documented for White and Black patients, so not all participants are included for those characteristics.
      Indicates significance at P < 0.05.
      Studies were assessed for all-cause death only.
      Using RoB2 to assess the methodological quality, 4 studies
      • Albert C.M.
      • Quigg R.
      • Saba S.
      • et al.
      Sex differences in outcome after implantable cardioverter defibrillator implantation in nonischemic cardiomyopathy.
      ,
      • de Waard D.
      • Manlucu J.
      • Gillis A.M.
      • et al.
      Cardiac resynchronization in women: a substudy of the resynchronization-defibrillation for ambulatory heart failure trial.
      ,
      • Russo A.M.
      • Poole J.E.
      • Mark D.B.
      • et al.
      Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial.
      ,
      • Vorobiof G.
      • Goldenberg I.
      • Moss A.J.
      • et al.
      Effectiveness of the implantable cardioverter defibrillator in Blacks versus Whites (from MADIT-II).
      showed “some concerns” overall, and one study
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      showed “high” bias. Most risk of bias was related to deviations from the intended intervention, in cases in which personnel or patients could not be blinded to certain variables due to the nature of device
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      ,
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      implantations. A visual plot of the individual risk of bias domains and summary report is shown in Supplemental Fig. S1. GRADE assessment of the included studies yielded an overall “high” quality of evidence. Funnel-plot analyses for publication bias are shown for data regarding clinical outcomes by sex (Supplemental Fig. S2); inadequate data points from a limited number of studies precluded such plots for clinical outcomes by race or age. The χ2 and I2 tests highlighting limited statistical heterogeneity in clinical outcomes were also generated (Fig. 2 and Supplemental Fig. S3). Limited heterogeneity was observed in part, as data for the various clinical outcomes was from a single trial.
      Figure thumbnail gr2
      Figure 2Reported all-cause death by sex between implantable cardioverter–defibrillator (ICD) treatment arms. Shown are forest plot analyses for all-cause death by sex between ICD treatment arms. Only all-cause death was included in Forest plot analyses due to limited availability of data regarding cardiovascular outcomes. CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel method.

      Study patient demographics

      Descriptive baseline data on 7125 adult patients (n = 3260 patients with an ICD; n = 3865 in the control group) from 5 ICD RCTs are reported in Table 2. The percent composition of female sex was lower, relative to that of male sex (23% vs 78%), within the ICD group, which was comprised primarily of White patients (76%), with a mean age of 63 ± 4 years. Similar study patient characteristics were noted within the control group, which consisted of 23% of female sex and 77% White patients, also with a mean age of 63 ± 4 years. Comprehensive race data were not reported in all studies; for instance, one study reported all non-White patients as being in the “other” category, without further qualifying the “other” ethnic distribution among patients, if present.
      • Russo A.M.
      • Poole J.E.
      • Mark D.B.
      • et al.
      Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial.
      Table 2Study patient characteristics by sex, race, and age from included implantable cardioverter–defibrillator randomized controlled trials (ICD RCTs)
      CharacteristicICD arm (n = 3260)Comparator arm (n = 3018)
      Comparator arm included either standard medical therapy, usual clinical care, treatment with amiodarone, conventional medical therapy, or ICD-CRT. Comparator arm 2 was composed of a placebo arm from Russo et al.15
      Comparator arm 2 (n = 847)
      Age, y
      Mean62.9 ± 4.063.1 ± 4.3NR
      Median62.161.759.1
      Sex, % of n
       Male77.577.577.0
       Female22.522.523.0
      Race, % of n
       White75.877.1NR
       Black17.316.9NR
       Hispanic5.75.7NR
       East Asian00.4NR
       Southeast AsianNRNRNR
       Other
      “Other” includes all non-White races as reported in one study, but these were unspecified by Russo et al.15
      12.012.024.0
      NR, not reported.
      Comparator arm included either standard medical therapy, usual clinical care, treatment with amiodarone, conventional medical therapy, or ICD-CRT. Comparator arm 2 was composed of a placebo arm from Russo et al.
      • Russo A.M.
      • Poole J.E.
      • Mark D.B.
      • et al.
      Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial.
      Other” includes all non-White races as reported in one study, but these were unspecified by Russo et al.
      • Russo A.M.
      • Poole J.E.
      • Mark D.B.
      • et al.
      Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial.

      Cardiovascular outcomes and mortality, by sex, race, and age

      CV outcomes and mortality data have been reported as ORs, by sex (n = 4 studies) and race (n = 1 study), in Tables 3 and 4, between ICD treatment arms. Mortality data, by sex, are further reported as RRs in forest plots (Fig. 2), between ICD treatment arms, and between ICD and control arms (Supplemental Fig. S3). Data for age were commonly dichotomized into age groups of ≥ 65 years and < 65 years, which limited age-related data analysis. Within the ICD group, women, relative to men, had lower odds (nonsignificant difference) of CV death (OR 0.98, 95% CI 0.47-2.07, P = 0.96; nstudies = 1; nsubjects = 904), HFH (OR 0.95, 95% CI 0.51-1.78, P = 0.87; nstudies = 1; nsubjects = 904), and composite HFH and all-cause death (OR 0.83, 95% CI 0.49-1.42, P = 0.51; nstudies = 1; nsubjects = 904). All-cause death, by sex, within ICD arms was the only dataset with a sufficient number of studies for pooled analysis, which showed that the difference between men and women was also nonsignificant, with lower odds in women (OR 0.86, 95% CI 0.55-1.35, P = 0.51; nstudies = 3; nsubjects = 2289; χ2 = 0.58; degrees of freedom = 2; I2 = 0%). Although also a nonsignificant difference, one study reported that women had higher odds of non-arrhythmic CV death within its ICD group, in comparison to men (OR 1.78, 95% CI 0.29-10.92, P = 0.53; nsubjects = 229). Only all-cause death between intervention groups was evaluated for race, due to limited data points: Black adults had nonsignificant higher odds of all-cause death, relative to White adults, within ICD arms (OR 1.18, 95% CI 0.56-2.57, P = 0.66; nstudies = 1). Finally, Køber et al.
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      published the only study reporting any outcome comparison by age. The difference in all-cause death between the ICD and control groups was nonsignificant in all age groups ( < 59 years, RR 1.85, 95% CI 0.47-7.26, P = 0.38; ≥ 59 to < 68 years, RR 1.10, 95% CI 0.42-2.89, P = 0.85; and ≥ 68 years, RR 0.92, 95% CI 0.39-2.12, P = 0.84).
      Table 3Clinical outcomes by sex in implantable cardioverter–defibrillator (ICD) randomized controlled trial treatment arms
      Clinical outcome
      Number of events per total patients in group at 1 year, unless otherwise stated.
      Total, nMale sex, nFemale sex, nOdds ratio (95% CI)P
      ICD arm
      All-cause death and HFH108/90490/73218/1720.83 (0.49, 1.42)0.51
      All-cause death131/2289106/177625/5130.86 (0.55, 1.35)0.51
      HFH71/90458/73213/1720.95 (0.51, 1.78)0.87
      CV death48/90439/7329/1720.98 (0.47, 2.07)0.96
      CV death (non-arrhythmic)5/2293/1662/631.78 (0.29, 10.92)0.53
      Arrhythmic death2/2292/1660/630.52 (0.03, 10.94)0.67
      Ventricular arrhythmia133/904111/73222/1720.82 (0.50, 1.34)0.43
      Comparator arm
      All-cause death and HFH88/89480/7588/1360.53 (0.25, 1.12)0.10
      All-cause death130/2299109/180121/4980.68 (0.42, 1.10)0.12
      HFH52/89448/7584/1360.45 (0.16, 1.26)0.13
      CV death39/89434/7585/1360.81 (0.31, 2.12)0.67
      CV death (non-arrhythmic)6/2293/1603/692.38 (0.46, 12.10)0.30
      Arrhythmic death7/2295/1602/690.92 (0.17, 4.90)0.93
      Ventricular arrhythmia125/894113/75812/1360.55 (0.29, 1.03)0.06
      Comparator arm 2
      All-cause death50/84741/6559/1920.75 (0.35, 1.57)0.44
      CV, cardiovascular; HFH, heart failure hospitalization.
      Number of events per total patients in group at 1 year, unless otherwise stated.
      Table 4All-cause death by race in implantable cardioverter–defibrillator (ICD) randomized controlled trials
      Clinical outcome
      Number of events per total patients in group at one year unless otherwise stated. No race-specific data were reported in the study with the second comparator arm.


      All-cause death
      White race, nBlack race, nOdds ratio (95% CI)P
      ICD arm59/6467/651.18 (0.56, 2.47)0.66
      Comparator arm43/4274/371.08 (0.37, 3.20)0.89
      CI, confidence interval.
      Number of events per total patients in group at one year unless otherwise stated. No race-specific data were reported in the study with the second comparator arm.

      Study characteristics of trial leads and sites

      Table 5 reports study details for trial leads, sites, and authorship of included studies. Most trials originated in North America and enrolled subjects from 4 sites in North America, 3 sites in Europe, 2 sites in Australia, and 1 site in Asia. These studies were evenly supported by industry partners and peer-reviewed grant support; this funding support was given predominantly to White men from North America (80%). The corresponding and first authors were both male in 2 studies (40%), and both female in 3 studies (60%); they were White in 4 studies (80%) and Asian in 1 study (20%). Important to note is that the data for this analysis were provided mainly from secondary-analysis publications, which more often had female vs male lead authors. By contrast, the primary RCT analyses were more often published by male lead authors.
      Table 5Study details for trial leads, sites, and authorship of included implantable cardioverter–defibrillator randomized controlled trials
      ParameterFrequencyParameterFrequency
      Trial originTrial enrollment sites
       North America4 (80) North America4 (40)
       Europe1 (20) Europe3 (30)
       Australia0 Australia2 (20)
       Asia0 Asia1 (10)
       Africa0 Africa0
       South America0 South America0
      First author by sexCorresponding author by sex
       Male2 (40) Male2 (40)
       Female3 (60) Female3 (60)
      First author by raceCorresponding author by race
       White4 (80) White4 (80)
       Black0 Black0
       Hispanic1 (20) Hispanic0
       Asian0 Asian1 (20)
       Southeast Asian0 Southeast Asian0
       Other0 Other0
      First author by siteCorresponding author by site
       North America4 (80) North America4 (80)
       Europe1 (20) Europe1 (20)
       Australia0 Australia0
       Asia0 Asia0
       Africa0 Africa0
       South America0 South America0
      Funding recipient by sex
      Funding recipient/s were those acknowledged from the article, when possible, or was considered to be the corresponding study lead as listed at clinicaltrials.gov, if not otherwise stated.
      Funding sponsor by trial
      One study, Tang et al.,17 reported funding from both sources.
       Male5 (100) Industry3 (50)
       Female0 Peer-reviewed3 (50)
      Funding recipient by race
      Funding recipient/s were those acknowledged from the article, when possible, or was considered to be the corresponding study lead as listed at clinicaltrials.gov, if not otherwise stated.
      Funding recipient by site
      Funding recipient/s were those acknowledged from the article, when possible, or was considered to be the corresponding study lead as listed at clinicaltrials.gov, if not otherwise stated.
       White4 (80) North America4 (80)
       Black0 Europe1 (20)
       Hispanic0 Australia0
       Asian1 (20) Asia0
       Southeast Asian0 Africa0
       Other0 South America0
      Values are n (%).
      Funding recipient/s were those acknowledged from the article, when possible, or was considered to be the corresponding study lead as listed at clinicaltrials.gov, if not otherwise stated.
      One study, Tang et al.,
      • Tang A.S.
      • Wells G.A.
      • Talajic M.
      • et al.
      Cardiac-resynchronization therapy for mild-to-moderate heart failure.
      reported funding from both sources.

      Discussion

      This study sought to investigate CV outcomes and mortality, by sex, race, and age, among patients implanted with an ICD. Only 45% (5 of 11 studies) reported data on age, sex, and race. Among these 5 ICD RCTs that met the study inclusion criteria, no sex- or race-specific differences in pooled CV outcomes were observed in patients implanted with an ICD, in terms of all-cause death, CV death, and HFH. Additionally, data on these CV outcomes and mortality were not reported based on the prespecified age cutoff of 65 years, and thus could not be pooled for evaluation. Interesting to note is that the majority of trials originate and are carried out largely in North America, followed by Europe.
      The primary RCTs had predominantly White male leadership, supported evenly by industry and peer-reviewed funding. Many of the secondary-analysis publications that provided data for the current analysis had female lead authors, in contrast to the primary-analysis publications, which had mainly male lead authors. Expanding on the origins and sites of trials, as well as the diversity of funding recipients and trial leadership, may improve recruitment diversity via enhanced patient–physician concordance. Higher patient–physician concordance may be associated with greater levels of trust, which in turn has the potential to enhance the generalizability of study outcomes to a more-diverse group of patients, owing to the increased enrollment.
      • Street R.L.
      • O’Malley K.J.
      • Cooper L.A.
      • et al.
      Understanding concordance in patient-physician relationships: personal and ethnic dimensions of shared identity.
      As well, patient–physician concordance (eg, patients identifying with physicians in terms of personal beliefs, values, and/or communication style) may be associated with improved health outcomes, trusting relationships that lead to greater shared decision-making and intent to adhere to recommendations, and overall satisfaction with care.
      • Blanchard J.
      • Nayar S.
      • Lurie N.
      Patient–provider and patient–staff racial concordance and perceptions of mistreatment in the health care setting.
      • Greenwood B.N.
      • Carnahan S.
      • Huang L.
      Patient-physician gender concordance and increased mortality among female heart attack patients.
      • Traylor A.H.
      • Schmittdiel J.A.
      • Uratsu C.S.
      • et al.
      Adherence to cardiovascular disease medications: does patient-provider race/ethnicity and language concordance matter?.
      Future prospective studies with more granular analyses and reporting are warranted to evaluate the relationship between diverse sociocultural variables and clinical outcomes among patients requiring ICD therapy.

      Sex differences in CV outcomes and mortality post-ICD implantation

      We reported no sex differences in CV outcomes and mortality following 1-year post-ICD implantation in male vs female patients. Notably, although we included 4 studies that had ICD outcomes reported by sex, women tended to be underrepresented (only 23%). Albert et al.
      • Albert C.M.
      • Quigg R.
      • Saba S.
      • et al.
      Sex differences in outcome after implantable cardioverter defibrillator implantation in nonischemic cardiomyopathy.
      did not report any sex differences following ICD therapy, but they acknowledged that their study was inadequately powered. Similarly, Russo et al.,
      • Russo A.M.
      • Poole J.E.
      • Mark D.B.
      • et al.
      Primary prevention with defibrillator therapy in women: results from the Sudden Cardiac Death in Heart Failure Trial.
      included in our analysis, suggested that men may exhibit a greater reduction in mortality risk than women; however, the smaller sample size of women may explain the treatment differences observed. Previous work on sex-based differences in outcomes following ICD implantation also reported that men, but not women, demonstrated a reduction in mortality.
      • Narasimha D.
      • Curtis A.B.
      Sex differences in utilisation and response to implantable device therapy.
      Therefore, future research also must be adequately powered to detect sex differences for clinical outcomes following ICD therapy.

      Race differences in CV outcomes and mortality post-ICD implantation

      We reported no significant race differences in CV outcomes and mortality following 1-year post-ICD implantation; yet, RCTs in our analysis included primarily White participants and/or were inadequately powered to evaluate race-based differences following ICD therapy. As an example, a substudy of the Multicenter Automatic Defibrillatory Implantation Trial (MADIT-II) reported that ICD therapy was associated with a reduction in all-cause death, CV death, and SCD in White but not Black participants; however, Black participants were greatly underrepresented in the trial (8% of enrollees).
      • Vorobiof G.
      • Goldenberg I.
      • Moss A.J.
      • et al.
      Effectiveness of the implantable cardioverter defibrillator in Blacks versus Whites (from MADIT-II).
      As with sex, enhanced reporting of race-related data is imminently required, along with targeted recruitment efforts to better understand how ICD therapy impacts clinical outcomes in ethnically diverse patient groups. Resource allocation and ongoing access to clinical care, based on the regional interplay of different races and the universality of healthcare insurance coverage, also may be critical influencers of the ultimate effectiveness of ICD therapy among these diverse populations.

      Age differences in CV outcomes and mortality post-ICD implantation

      We were unable to report on age-related CV outcomes and mortality differences following 1-year post-ICD implantation, as these data were not reported based on the prespecified age cutoff of ≥ 65 or < 65 years, in any of the 5 RCTs included in this review. One study highlighted a sign of mortality benefit of ICD therapy in those aged ≥ 68 years. Additional studies are warranted to understand whether this effect is “real,” given the clinical implications of resource allocation, the risks vs benefits of ICD therapy, and the ongoing device care needs that may result in multiple device generator or lead revisions in a patient who is much younger than age 65 years at the time of initial ICD implantation. Furthermore, although population-level analyses provide some insight as to the ICD therapy risk–benefit balance, it may not translate directly to an individual patient. The healthcare team should understand that although individual risk–benefit may depend in part on age, for instance, there are other covariables, such as comorbidities and frailty, that can influence individual patient survival and relative risk of arrhythmic vs non-arrhythmic death with ICD therapy.

      Clinical implications and future considerations

      Our study findings suggest that diverse populations, including women, non-Whites, and elderly patients, need to be included and reported on in larger RCTs focused on clinical outcomes in patients with CV disease who require ICD therapy. There is persistent underrepresentation and/or underreporting of study data by sex, race, and age. As an example, recent clinical trials with CV outcomes (conducted between 2010 and 2017) reported that 38% of participants were female, an improved representation in stroke and heart failure trials.
      • Jin X.
      • Chandramouli C.
      • Allocco B.
      • et al.
      Women’s participation in cardiovascular clinical trials from 2010 to 2017.
      However, there is also evidence for low female enrollment in CV device trials, as described by Gong et al.,
      • Gong I.Y.
      • Tan N.S.
      • Ali S.H.
      • et al.
      Temporal trends of women enrollment in major cardiovascular randomized clinical trials.
      who reported only 29% female enrollment in device trials. Nguyen et al.
      • Nguyen Q.D.
      • Peters E.
      • Wassef A.
      • et al.
      Evolution of age and female representation in the most-cited randomized controlled trials of cardiology of the last 20 years.
      evaluated age and female representation in the most-cited RCTs in cardiology from 1996-2015 and reported similar trends. Although the mean age and percentage of women increased significantly over this time, this increase was not enough to close the enrollment gap of older adults and women.
      Further, Barra et al.
      • Barra S.
      • Providência R.
      • Boveda S.
      • et al.
      Do Women Benefit Equally As Men from the Primary Prevention Implantable Cardioverter-Defibrillator?.
      highlight in their analysis that women may benefit from ICD therapies differently than do men; for example, ICD therapy may not be associated with improved survival in female trial patients, compared with optimal medical therapy. Meanwhile, Conen et al.
      • Conen D.
      • Arendacká B.
      • Röver C.
      • et al.
      Gender differences in appropriate shocks and mortality among patients with primary prophylactic implantable cardioverter-defibrillators: systematic review and meta-analysis.
      reported that although women had a lower risk of death than men, they experienced more inappropriate shock therapy. Notably, 3 of the 5 trials included in this study were conducted prior to this report,
      • Jin X.
      • Chandramouli C.
      • Allocco B.
      • et al.
      Women’s participation in cardiovascular clinical trials from 2010 to 2017.
      but the more recent ICD trials (published in 2016
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.
      and 2019
      • de Waard D.
      • Manlucu J.
      • Gillis A.M.
      • et al.
      Cardiac resynchronization in women: a substudy of the resynchronization-defibrillation for ambulatory heart failure trial.
      ) included in our analysis had less than 30% of participants who were female. Therefore, this study serves as a call-to-action to improve representation of a diverse patient group in CV-outcome RCTs, particularly as it may inadvertently impact patient outcomes.

      Covidence Systematic Review Software [program]. Melbourne, Australia: Veritas Health Innovation.

      Our findings suggest that major ICD RCTs focusing on clinical outcomes were primarily led by investigators who were male and/or White, as primary recipients of industry or peer-reviewed funding. Although secondary-analysis publications among these studies include more women, few authorships involved non-Whites. Similarly, non-White minorities continue to be underrepresented in CV-outcome RCTs. Ultimately, the scientific community needs to overcome critical barriers to RCT enrollment to improve data reporting on diverse groups of patients with CV disease.
      • Clark L.T.
      • Watkins L.
      • Piña I.L.
      • et al.
      Increasing diversity in clinical trials: overcoming critical barriers.
      ,
      • Ortega R.F.
      • Yancy C.W.
      • Mehran R.
      • et al.
      Overcoming lack of diversity in cardiovascular clinical trials: a new challenge and strategies for success.
      In particular, RCT investigators should prioritize a number of goals,
      • Ortega R.F.
      • Yancy C.W.
      • Mehran R.
      • et al.
      Overcoming lack of diversity in cardiovascular clinical trials: a new challenge and strategies for success.
      including the recruitment and training of diverse coordinator and investigator research teams, and sex, race and age equity in clinical trial recruitment. Furthermore, economic incentives from government and industry commitments may enable trial design to be more inclusive of a diversity of patients in clinical CV trials.
      • Køber L.
      • Thune J.J.
      • Nielsen J.C.
      • et al.
      Defibrillator implantation in patients with nonischemic systolic heart failure.

      Limitations

      A few limitations of this study need to be considered. Only 5 ICD RCTs reported event rates for CV outcomes and mortality, to allow for summative analysis, limiting the overall generalizability of the results. The current authors were unable to retrieve data for the 6 excluded studies, for inclusion into the analyses; yet, study demographics are similar between the included vs excluded studies. Furthermore, 1-year estimates were extracted in some studies that reported on event numbers over longer-term follow-up periods; thus, the results of those studies may be reflected less accurately. Additionally, not all of the studies reported full patient demographics or clinical outcomes based on sex, race, or age-based categories. As a result, baseline characteristics may not be comprehensive, and a more robust meta-analysis for all CV outcomes and mortality, and a more comprehensive statistical heterogeneity, could not be achieved, due to such data-reporting inconsistencies.
      A systematic approach was used, including a formal search strategy and consensus between 2 coauthors (H.I.S. and M.K.S.), to retrieve trial investigators' race. Investigator race data were not solicited, and therefore, discrepancies may exist. Lastly, this study analyzed data from only ICD RCTs and not population-based registries or studies. Subsequent research could investigate the interactions of sex, race, and age in their impact on ICD efficacy, and compare data from ICD RCTs with population-based data such as that from registries.

      Conclusions

      Our study findings suggest no significant sex- or race-based differences in CV outcomes and mortality, utilizing cases in which some such data were reported; age-related differences could not be surmised due to lack of reported data. However, future RCTs with explicit data reporting with analyses by sex, race, and age are warranted to determine the association between these sociocultural factors and CV outcomes and mortality among patients who receive an ICD. As well, the diversification of trial leadership, trial origin, and trial sites should be considered as a means to enhance patient–physician concordance to make progress toward improving recruitment of diverse patient populations.

      Acknowledgements

      The authors thank Dr Katherine Allan for her input on this article.

      Funding Sources

      The authors have no funding sources to declare.

      Disclosures

      The authors have no conflicts of interest to disclose.

      Supplementary Material

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