BACKGROUND: New methods to identify patients who benefit from a primary prophylactic implantable cardioverter-defibrillator (ICD) are needed. T-wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention. METHODS AND RESULTS: In the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter-Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24-hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all-cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points <47 μV and <60 μV. The final cohort included 1734 valid T-wave alternans samples, 1211 patients with ICD, and 523 control patients with conservative treatment, with a mean follow-up time of 2.3 years. TWA ≥60 μV was a predicter for a higher all-cause death in patients with an ICD on the basis of a univariate Cox regression model (hazard ratio, 1.484 [95% CI, 1.024-2.151]; P=0.0374; concordance statistic, 0.51). In multivariable models, TWA was not prognostic of death or appropriate shocks in patients with an ICD. In addition, TWA was not prognostic of death in control patients. In a propensity score-adjusted Cox regression model, TWA was not a predictor of ICD benefit. CONCLUSIONS: T-wave alternans is poorly prognostic in patients with a primary prophylactic ICD. Although it may be prognostic of life-threatening arrhythmias and sudden cardiac death in several patient populations, it does not seem to be useful in assessing benefit from ICD therapy in primary prevention among patients with an ejection fraction of ≤35%.

Biocenter Oulu University of Oulu Oulu Finland

Department of Cardiovascular Sciences University of Leuven and University Hospitals Leuven Leuven Belgium

Department of Internal Medicine and Cardiology Masaryk University Brno Czech Republic

Department of Medical Statistics University Medical Center Göttingen Göttingen Germany

Division of Cardiology University Hospital Basel Basel Switzerland

Division of Cardiology University Medical Center Göttingen Heart Center Göttingen Germany

DZHK partner site Göttingen Göttingen Germany

Medical Physiology University Medical Center Utrecht Utrecht Netherlands

National Heart and Lung Institute Imperial College London United Kingdom

Research Unit of Internal Medicine Medical Research Center Oulu Oulu University Hospital and University of Oulu Oulu Finland

See more in PubMed

Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12):877–883. PubMed

Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, et al. Amiodarone or an implantable cardioverter‐defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–237. PubMed

Kadish A, Dyer A, Daubert JP, Quigg R, Estes NAM, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:2151–2158. PubMed

Zabel M, Willems R, Lubinski A, Bauer A, Brugada J, Conen D, Flevari P, Hasenfuß G, Svetlosak M, Huikuri HV, et al. Clinical effectiveness of primary prevention implantable cardioverter‐defibrillators: results of the EU‐CERT‐ICD controlled multicentre cohort study. Eur Heart J. 2020;41:3437–3447. PubMed PMC

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–3726. PubMed

Al‐Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2018;138:e210–e271. PubMed

Elming MB, Nielsen JC, Haarbo J, Videbæk L, Korup E, Signorovitch J, Olesen LL, Hildebrandt P, Steffensen FH, Bruun NE, et al. Age and outcomes of primary prevention implantable cardioverter‐defibrillators in patients with nonischemic systolic heart failure. Circulation. 2017;136:1772–1780. PubMed

Seegers J, Conen D, Jung K, Bergau L, Dorenkamp M, Lüthje L, Sohns C, Sossalla ST, Fischer TH, Hasenfuss G, et al. Sex difference in appropriate shocks but not mortality during long‐term follow‐up in patients with implantable cardioverter‐defibrillators. Europace. 2016;18:1194–1202. PubMed PMC

Providência R, Marijon E, Lambiase PD, Bouzeman A, Defaye P, Klug D, Amet D, Perier MC, Gras D, Algalarrondo V, et al. Primary prevention implantable cardioverter defibrillator (ICD) therapy in women‐data from a multicenter French registry. J Am Heart Assoc. 2016;5:1–10. PubMed PMC

Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbæk L, Korup E, Jensen G, Hildebrandt P, Steffensen FH, Bruun NE, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;375:1221–1230. PubMed

Kleemann T, Strauss M, Kouraki K, Lampropoulou E, Fendt A, Werner N, Zahn R. Contemporary benefit‐harm profile over two decades in primary prophylactic ICD‐therapy. Clin Cardiol. 2019;42:866–872. PubMed PMC

Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, Dargie HJ, Granger CB, Kjekshus J, Køber L, et al. Declining risk of sudden death in heart failure. N Engl J Med. 2017;377:41–51. PubMed

Sabbag A, Suleiman M, Laish‐Farkash A, Samania N, Kazatsker M, Goldenberg I, Glikson M, Beinart R. Contemporary rates of appropriate shock therapy in patients who receive implantable device therapy in a real‐world setting: from the Israeli ICD registry. Heart Rhythm. 2015;12:2426–2433. PubMed

Koller MT, Schaer B, Wolbers M, Sticherling C, Bucher HC, Osswald S. Death without prior appropriate implantable cardioverter‐defibrillator therapy: a competing risk study. Circulation. 2008;117:1918–1926. PubMed

Bergau L, Willems R, Sprenkeler DJ, Fischer TH, Flevari P, Hasenfuß G, Katsaras D, Kirova A, Lehnart SE, Lüthje L, et al. Differential multivariable risk prediction of appropriate shock versus competing mortality—a prospective cohort study to estimate benefits from ICD therapy. Int J Cardiol. 2018;272:102–107. PubMed

Koneru JN, Jones PW, Hammill EF, Wold N, Ellenbogen KA. Risk factors and temporal trends of complications associated with transvenous implantable cardiac defibrillator leads. J Am Heart Assoc. 2018;7:e602299. PubMed PMC

Dagres N, Hindricks G. Devices for management of sudden cardiac death: successes, challenges and perspectives. Int J Cardiol. 2017;237:34–37. PubMed

Verrier RL, Klingenheben T, Malik M, El‐Sherif N, Exner DV, Hohnloser SH, Ikeda T, Martínez JP, Narayan SM, Nieminen T, et al. Microvolt T‐wave alternans: physiological basis, methods of measurement, and clinical utility—consensus guideline. J Am Coll Cardiol. 2011;58:1309–1324. PubMed PMC

Nieminen T, Lehtimäki T, Viik J, Lehtinen R, Nikus K, Kööbi T, Niemelä K, Turjanmaa V, Kaiser W, Huhtala H, et al. T‐wave alternans predicts mortality in a population undergoing a clinically indicated exercise test. Eur Heart J. 2007;28:2332–2337. PubMed

Aro AL, Kenttä TV, Huikuri HV. Microvolt t‐wave alternans: where are we now? Arrhythmia Electrophysiol Rev. 2016;5:37–40. PubMed PMC

Seegers J, Bergau L, Tichelbäcker T, Malik M, Zabel M. ICD risk stratification studies—EU‐CERT‐ICD and the European perspective. J Electrocardiol. 2016;49:831–836. PubMed

Vandenberk B, Floré V, Röver C, Vos MA, Dunnink A, Leftheriotis D, Friede T, Flevari P, Zabel M, Willems R. Repeating noninvasive risk stratification improves prediction of outcome in ICD patients. Ann Noninvasive Electrocardiol. 2020;25:1–11. PubMed PMC

Bauer A, Klemm M, Rizas KD, Hamm W, von Stülpnagel L, Dommasch M, Steger A, Lubinski A, Flevari P, Harden M, et al. Prediction of mortality benefit based on periodic repolarisation dynamics in patients undergoing prophylactic implantation of a defibrillator: a prospective, controlled, multicentre cohort study. Lancet. 2019;394:1344–1351. PubMed

Therneau T, Atkinson E. Concordance. 2024:1–20.

Hohnloser SH, Ikeda T, Bloomfield DM, Dabbous OH, Cohen RJ. T‐wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation. Lancet. 2003;362:125–126. PubMed

Bloomfield DM, Steinman RC, Namerow PB, Parides M, Davidenko J, Kaufman ES, Shinn T, Curtis A, Fontaine J, Holmes D, et al. Microvolt T‐wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the multicenter automatic defibrillator implantation Trial (MADIT) II conundrum. Circulation. 2004;110:1885–1889. PubMed

Chow T, Kereiakes DJ, Onufer J, Woelfel A, Gursoy S, Peterson BJ, Brown ML, Pu W, Benditt DG. Does microvolt T‐wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post‐Myocardial Infarction Patients) trial. J Am Coll Cardiol. 2008;52:1607–1615. PubMed

Gold MR, Ip JH, Costantini O, Poole JE, McNulty S, Mark DB, Lee KL, Bardy GH. Role of microvolt T‐wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction primary results from the T‐wave alternans sudden cardiac death in heart failure trial substudy. Circulation. 2008;118:2022–2028. PubMed PMC

Costantini O, Hohnloser SH, Kirk MM, Lerman BB, Baker JH, Sethuraman B, Dettmer MM, Rosenbaum DS. The ABCD (alternans before cardioverter defibrillator) trial. Strategies using T‐wave alternans to improve efficiency of sudden cardiac death prevention. J Am Coll Cardiol. 2009;53:471–479. PubMed

Guaricci AI, De Santis D, Rabbat MG, Pontone G. Cardiac magnetic resonance imaging and primary prevention implantable cardioverter defibrillator therapy: current recommendations and future directions. J Cardiovasc Med. 2018;19:223–228. PubMed

Chugh SS, Reinier K, Uy‐Evanado A, Chugh HS, Elashoff D, Young C, Salvucci A, Jui J. Prediction of sudden cardiac death manifesting with documented ventricular fibrillation or pulseless ventricular tachycardia. JACC: Clin Electrophysiol. 2022;8:411–423. PubMed PMC

Junttila MJ, Pelli A, Kenttä TV, Friede T, Willems R, Bergau L, Malik M, Vandenberk B, Vos MA, Schmidt G, et al. Appropriate shocks and mortality in patients with versus without diabetes with prophylactic implantable cardioverter defibrillators. Diabetes Care. 2020;43:196–200. PubMed