Predicting Sudden Cardiac Death After Myocardial Infarction

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 14, No. 1Predicting Sudden Cardiac Death After Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBPredicting Sudden Cardiac Death After Myocardial InfarctionA Great Unsolved Challenge Ratika Parkash, MD, MSc Ciorsti MacIntyre, MD Paul DorianMD, MSc Ratika ParkashRatika Parkash Correspondence to: Ratika Parkash, MD, MSc, Queen Elizabeth II Health Sciences Center, Rm 2501-D Halifax Infirmary, 1796 Summer St, Halifax, NS B3H 3A7. Email E-mail Address: [email protected] https://orcid.org/0000-0001-7630-7795 Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia (R.P., C.M.). Search for more papers by this author , Ciorsti MacIntyreCiorsti MacIntyre Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia (R.P., C.M.). Search for more papers by this author , Paul DorianPaul Dorian https://orcid.org/0000-0002-8244-3520 St Michael’s Hospital, University of Toronto, ON, Canada (P.D.). Search for more papers by this author Originally published19 Jan 2021https://doi.org/10.1161/CIRCEP.120.009422Circulation: Arrhythmia and Electrophysiology. 2021;14:e009422This article is a commentary on the followingLong-Term Outcome of the Randomized DAPA TrialThe yearly prevalence of acute myocardial infarction (MI) in the United States is 610 000, with age- and sex-adjusted incidence of 208 cases per 100 000 person-years; 30% of these are estimated to be due to ST-segment–elevation MI.1 Thirty-day mortality rates have declined progressively over the past 2 decades, owing primarily to improved acute therapy, as well as improved secondary prevention.1 Sudden cardiac death, presumably due mostly to tachyarrhythmias, remains an important cause of death post-MI, with highest rates in the first 30 days (1.4%), and with a plateau incidence of 0.14% to 0.18%/mo thereafter.2 Predicting which patients are at the highest risk of sudden death remains challenging. The risk of sudden death post-MI is related to the interplay between scar formation and subsequent remodeling, neurohormonal abnormalities that may be due to heart failure, recurrent ischemia, impaired autonomic tone, and abnormalities in cardiac repolarization (T wave alternans).3,4 Current guideline recommendations about implantable cardioverter-defibrillator (ICD) implantation in the primary prevention of sudden death post-MI discriminate patients based primarily on a left ventricular ejection fraction (LVEF) ≤35%. However, ≈50% of those patients who die suddenly are not recommended to undergo device implantation.5,6 The search for additional variables that identify an abnormal electrical substrate, beyond the ejection fraction (EF), have ensued. So far, there has been little success in this regard, although variables in addition to LVEF have been identified, including nonsustained ventricular tachycardia, T wave alternans, and abnormal heart rate variability on ECG monitoring,3,7 and inducibility of ventricular tachycardia at electrophysiological study. None of these modalities of risk stratification have been systematically implemented in the post-MI population. The DINAMIT (Defibrillator in Acute Myocardial Infarction Trial)8 and the IRIS (Immediate Risk Stratification Improves Survival)9 randomized trials both tested prophylactic ICD versus standard care in patients early post-MI, who had risk markers in addition to a reduced EF, including low heart rate variability, high heart rate, and nonsustained ventricular tachycardia. Neither study showed a reduction in all-cause mortality with ICD therapy (Table).See Article by Haanschoten et alTable. Randomized Trials of Early ICD Use Postmyocardial InfarctionStudyPopulationICDControlOutcomeCABG-Patch10Scheduled for CABG, LVEF<36%, abnormal signal-averaged ECGN=446; 2.7% crossoverN=454; 4% crossoverMortality in control 24%, ICD group 27%, P=0.64DINAMIT8Post-MI 6–40 d, LVEF≤35%, abnormal heart rate variabilityN=332; 6% crossoverN=34218.7% in ICD group, 17% in control group, P=0.66; arrhythmic death HR 0.42 (95% CI, 0.22–0.83, P=0.009); nonarrhythmic death 1.75 (95% CI, 1.11–2.76, P=0.02)IRIS95–31 d post-MI, LVEF≤40% and one of: heart rate >90 beats per minute OR nonsustained ventricular tachycardiaN=445N=454Mortality HR 1.04 (95% CI, 0.81–1.35, P=0.78); sudden death HR 0.55 (95% CI, 0.31–1.0, P=0.049), nonsudden death HR 1.92 (95% CI, 1.29–2.84, P=0.001)DAPA11LVEF<30% within 4 d post-ST-segment–elevation MI, primary VF, Killip class ≥2, and TIMI flow <3 after percutaneous coronary interventionN=131; crossover 4.6%N=135; crossover 15.6%Mortality HR 0.58 (95% CI, 0.37–0.91, P=0.02); sudden death HR 0.45 (95% CI, 0.14–1.50, P=0.19); nonsudden cardiac death HR 0.52 (95% CI, 0.28–0.94, P=0.04)CABG indicates coronary artery bypass graft; DAPA, Defibrillator After Primary Angioplasty; DINAMIT, Defibrillator in Acute Myocardial Infarction Trial; HR, hazard ratio; ICD, implantable cardioverter-defibrillation; IRIS, Immediate Risk Stratification Improves Survival; LVEF, left ventricular ejection fraction; MI, myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction; and VF, ventricular fibrillation.In the November 2020 issue of Circulation: Arrhythmia and Electrophysiology, the DAPA trial (Defibrillator After Primary Angioplasty) enrolled 266 patients in a randomized, multicenter trial comparing ICD versus conventional medical therapy in patients who underwent primary percutaneous coronary intervention and had one of the following: reduced LVEF (<30%) within 4 days after ST-segment–elevation MI, primary ventricular fibrillation, Killip class ≥2, and TIMI (Thrombolysis In Myocardial Infarction) flow <3 after percutaneous coronary intervention.11 The supplementary data demonstrate that the majority of patients were enrolled with the low EF criterion (66.5%) as the only criterion; TIMI flow <3 was the next most common inclusion (20.3%), primary ventricular fibrillation occurred in 1.5%, and Killip class ≥2 in 1.9%. The remainder of the patients had more than one criterion, the majority of whom had low EF as one of those criteria. The ICD was implanted a median of 50 days (interquartile range, 41–60) post-MI, without a further assessment of the EF at that time. The primary end point was all-cause mortality at 3 years. The trial began recruitment in 2004 and was stopped prematurely in December 2013, after 38% of the sample size was enrolled, due to slow recruitment. The analysis included an intention-to-treat analysis, a per-protocol analysis, and an on-treatment analysis. Follow-up was extended on the entire cohort, with the exception of 26 patients (9.8%) enrolled in Poland where follow-up was curtailed to a median of 26 (interquartile range, 15–34) months. Crossover occurred in 10.1% overall, with 21 patients (15.6%) in the control group receiving an ICD. The authors did present a per-protocol analysis and on-treatment analysis, but the interpretation of these analyses is significantly encumbered by the small sample size and the nonrandomized and open-label nature of this outcome. The main finding from the intention-to-treat analysis was a 42% relative risk reduction in total mortality in the ICD group (hazard ratio, 0.58 [95% CI, 0.37–0.91], P=0.02). The rate of sudden death at 3 years in the control arm was 3.6% (n=5), and 0.8% (n=1) in the ICD arm, which was not statistically significant. Cardiac death occurred in 11% in the ICD arm, compared with 22% in the control arm; nonsudden cardiac death was the main driver for the difference in total mortality. There was no difference in noncardiac death.There are several issues with this study that affect the interpretation of the results and must be highlighted. There were overall, at 9 years, 21 nonsudden deaths in the ICD arm, and 43 nonsudden deaths in the control arm. These observations strongly suggest that the treatment and follow-up and management of the ICD and the control patients were dissimilar. The main concern in this and other similar open-label trials is that the use of optimal medical therapy was left to the treating physician. Patients with ICDs may be seen more frequently as they have an ICD and may be more likely to have medications adjusted, compared with patients who do not have a device. This is of particular importance given that the rate of cardiac but nonsudden death accounted for the major difference in mortality between the 2 groups. The curtailed enrollment resulted in an underpowered study that leaves interpretation of results tenuous, despite the extended follow-up. A similar phenomenon was seen in the VEST trial (Vest Prevention of Early Sudden Death) where cardiac death, rather than sudden death, accounted for the mortality difference and could not be otherwise explained.12 It is possible that the presence of a device changes how patients pay attention to symptoms leading them to seek medical care. These observations require further investigation to further understand the mechanism behind the associated reduction in mortality.The sudden death risk of patients with primary ventricular fibrillation and heart failure during index admission may be lower than those with LVEF<30% as the only criterion. The authors did address this with a sensitivity analysis that demonstrated no effect on the results. The treatment of concomitant coronary disease was also left to the discretion of the treating physician, and this could also introduce bias into the randomized groups. There may have been changes to medical therapy, such as the use of sacubitril-valsartan and the increasing use of aldosterone antagonists that would have affected risk and outcomes as the trial went on.13,14 There were significant improvements in the LVEF when measured at 18 months, but 34.1% of those in the control group met traditional criteria for ICD implantation, hence resulting in a significant cross over rate in the control group. Importantly, many of the cardiac deaths in the control group occurred before the 2-year follow-up echocardiogram could be performed. It is possible that these deaths occurred predominantly in patients with very poor left ventricular function. The medication changes that may have occurred during the course of the follow-up are not reported, nor is additional revascularization which was left to physician discretion. From a methodologic standpoint, the slow enrollment rate, high crossover rate, and the termination of follow-up of 26 patients in one enrolling country are important considerations affecting generalizability of the study, as well as introducing bias in the results.Given all of the challenges with this trial, it is difficult to ascertain what led to the significant mortality benefit, particularly where the mechanism of mortality benefit, if present, would be expected to be due to the effect on sudden death, rather than nonsudden cardiac death. DAPA provides some interesting insight into the sudden death risk in this population with severe ischemic heart disease but does not provide enough evidence to change current guidelines. Some of the patients included in the DAPA trial would have qualified for primary prevention ICD based on guidelines in place during the study timeframe if a repeat echocardiogram was performed at 40 days, thus clouding some of the benefit that may have been seen in the trial.15 Importantly, understanding that the classification of death is challenging, 8 patients were reported to have sudden death out of 135 control patients, over 9 years. This is equivalent to a crude annual sudden death rate of one percent or less.Other much larger studies have examined the use of early ICD therapy in patients with coronary artery disease. A summary of these trials is provided in the Table. Overall, none of these demonstrated a benefit in all-cause mortality, with the exception of VEST, as discussed above. The VEST trial is plagued by similar issues as the DAPA study; the IRIS, DINAMIT, and Coronary Artery Bypass Graft Patch trials all demonstrated negative results, despite a significant reduction in arrhythmic death in the ICD arm.8–10 A secondary analysis of the DINAMIT study indicated that an increase in nonsudden death risk completely offset any benefit from ICD therapy, and that ICD therapy, when it did occur, resulted in postponement of an inevitable result of death due to heart failure, recurrent ischemia, or other causes.16 The high-risk features that were meant to enrich the populations of these trials identified both those at higher sudden death risk but also those at higher risk of nonsudden cardiac death. The observations about the increased mortality risk in those who receive ICD and appropriate shocks, as well as the observation about risk of heart failure and ICD shocks, suggesting that factors which increase sudden death risk also increase risk from heart failure death.17,18 Uncoupling these risks to identify those who would benefit most from ICD therapy remains a great unsolved challenge.The search for suitable clinical criteria for risk stratification ensues. The REFINE study (Risk Estimation Following Infraction, Noninvasive Evaluation) identified patients with LVEF<40% in the initial 48 hours post-MI, or a persistently reduced EF<50% beyond the 48 hours and measured T wave alternans, phenylephrine-induced baroreflex sensitivity testing and measures of heart rate variability and turbulence.3 Testing 10 to 14 weeks post-MI proved to be optimal in prediction of sudden death; the presence abnormal T wave alternans, abnormal heart rate variability, and EF<50% was associated with a >6-fold risk of cardiac death or resuscitated cardiac arrest (over the absence of these risk markers), resulting in improved identification of patients at risk for sudden arrhythmic events. The PREDETERMINE group evaluated risk factors associated with sudden death in a prospective registry of post-MI patients and reported that >70% of individuals experiencing sudden death have an LVEF of >35%.19 The greatest potential benefit conferred by an ICD is likely to be in those with fewer competing risks of death, particularly those with age<60 years, where the risk of nonsudden death compared with sudden death is >7 fold lower than in those above 69 years. The REFINE-ICD study is a randomized clinical trial enrolling patients beyond 2 months post-MI, with LVEF 36% to 50% and who screen positive for abnormal heart rate turbulence and T wave alternans on a Holter to determine the benefit of ICD therapy (URL: https://www.clinicaltrials.gov. Unique identifier: NCT00673842). The results of this trial will help to unravel some of the challenges faced to identify those who will benefit from life-saving device therapy to prevent sudden death. The DAPA trial should not alter our current guidelines, which we recognize as imperfect but reflect interpretation of existing data in this area; we hope to derive improved risk stratification techniques as future data becomes available.Sources of FundingNone.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 4.Correspondence to: Ratika Parkash, MD, MSc, Queen Elizabeth II Health Sciences Center, Rm 2501-D Halifax Infirmary, 1796 Summer St, Halifax, NS B3H 3A7. Email ratika.[email protected]caReferences1. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction.N Engl J Med. 2010; 362:2155–2165. doi: 10.1056/NEJMoa0908610CrossrefMedlineGoogle Scholar2. 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Chatterjee NA, Moorthy MV, Pester J, Schaecter A, Panicker GK, Narula D, Lee DC, Goldberger JJ, Kadish A, Cook NR, et al.; PRE-DETERMINE Study Group. Sudden death in patients with coronary heart disease without severe systolic dysfunction.JAMA Cardiol. 2018; 3:591–600. doi: 10.1001/jamacardio.2018.1049CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesLong-Term Outcome of the Randomized DAPA TrialJan Paul Ottervanger, et al. Circulation: Arrhythmia and Electrophysiology. 2020;13 January 2021Vol 14, Issue 1Article InformationMetrics Download: 224 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.120.009422PMID: 33464943 Originally publishedJanuary 19, 2021 Keywordsdeathheart failuremyocardial infarctionEditorialsdefibrillatorsincidencePDF download SubjectsCatheter Ablation and Implantable Cardioverter-DefibrillatorSudden Cardiac Death