Articles www.thelancet.com Published online February 23, 2015 http://dx.doi.org/10.1016/S0140-6736(14)61903-6 1 Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE) Jeff S Healey, Stefan H Hohnloser, Michael Glikson, Jorg Neuzner, Phillipe Mabo, Xavier Vinolas, Josef Kautzner, Gilles O’Hara, Lieselot VanErven, Fredrik Gadler, Janice Pogue, Ursula Appl, Jim Gilkerson, Thierry Pochet, Kenneth M Stein, Bela Merkely, Susan Chrolavicius, Brandi Meeks, Csaba Foldesi, Bernard Thibault, Stuart J Connolly, on behalf of the Shockless IMPLant Evaluation [SIMPLE] investigators Summary Background Defibrillation testing by induction and termination of ventricular fibrillation is widely done at the time of implantation of implantable cardioverter defibrillators (ICDs). We aimed to compare the efficacy and safety of ICD implantation without defibrillation testing versus the standard of ICD implantation with defibrillation testing. Methods In this single-blind, randomised, multicentre, non-inferiority trial (Shockless IMPLant Evaluation [SIMPLE]), we recruited patients aged older than 18 years receiving their first ICD for standard indications at 85 hospitals in 18 countries worldwide. Exclusion criteria included pregnancy, awaiting transplantation, particpation in another randomised trial, unavailability for follow-up, or if it was expected that the ICD would have to be implanted on the right-hand side of the chest. Patients undergoing initial implantation of a Boston Scientific ICD were randomly assigned (1:1) using a computer-generated sequence to have either defibrillation testing (testing group) or not (no- testing group). We used random block sizes to conceal treatment allocation from the patients, and randomisation was stratified by clinical centre. Our primary efficacy analysis tested the intention-to-treat population for non-inferiority of no-testing versus testing by use of a composite outcome of arrhythmic death or failed appropriate shock (ie, a shock that did not terminate a spontaneous episode of ventricular tachycardia or fibrillation). The non-inferiority margin was a hazard ratio (HR) of 1·5 calculated from a proportional hazards model with no-testing versus testing as the only covariate; if the upper bound of the 95% CI was less than 1·5, we concluded that ICD insertion without testing was non-inferior to ICD with testing. We examined safety with two, 30 day, adverse event outcome clusters. The trial is registered with ClinicalTrials.gov, number NCT00800384. Findings Between Jan 13, 2009, and April 4, 2011, of 2500 eligible patients, 1253 were randomly assigned to defibrillation testing and 1247 to no-testing, and followed up for a mean of 3·1 years (SD 1·0). The primary outcome of arrhythmic death or failed appropriate shock occurred in fewer patients (90 [7% per year]) in the no-testing group than patients who did receive it (104 [8% per year]; HR 0·86, 95% CI 0·65–1·14; p non-inferiority <0·0001). The first safety composite outcome occurred in 69 (5·6%) of 1236 patients with no-testing and in 81 (6·5%) of 1242 patients with defibrillation testing, p=0·33. The second, pre-specified safety composite outcome, which included only events most likely to be directly caused by testing, occurred in 3·2% of patients with no-testing and in 4·5% with defibrillation testing, p=0·08. Heart failure needing intravenous treatment with inotropes or diuretics was the most common adverse event (in 20 [2%] of 1236 patients in the no-testing group vs 28 [2%] of 1242 patients in the testing group, p=0·25). Interpretation Routine defibrillation testing at the time of ICD implantation is generally well tolerated, but does not improve shock efficacy or reduce arrhythmic death. Funding Boston Scientific and the Heart and Stroke Foundation (Ontario Provincial office). Introduction The implantable cardioverter defibrillator (ICD) prevents arrhythmic death, both in primary and secondary prevention. 1,2 More than 150 000 ICDs are implanted in the USA every year and twice that number worldwide. 3 In the 1980s, when ICD therapy was introduced, it was deemed necessary to establish that the ICD would recognise and terminate ventricular fibrillation with the electrical lead or patch system used, with the opportunity to immediately modify that configuration if it was not successful. 4 Thus, defibrillation testing of ICDs became widespread in clinical practice and is included as a recommendation in product labels. 5–7 Defibrillation testing was done at the time of implantation in every randomised trial investigating the efficacy of ICD therapy; 1,2,8,9 however, such testing has never been shown to independently improve ICD shock efficacy or to reduce mortality. 10,11 In the past two decades, ICD technology has improved substantially 11 and when formally measured, defibrillation thresholds are usually 10–20 J less than the maximum ICD output. 5,6,12,13 The first ICD shock for clinical ventricular arrhythmias is successful about 90% of the time, 5,14 and subsequent shocks rarely fail to terminate the arrhythmia. 5,14 Published Online February 23, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)61903-6 See Online/Comment http://dx.doi.org/10.1016/ S0140-6736(15)60242-2 Population Health Research Institute, McMaster University, Hamilton, ON, Canada (J S Healey MD, J Pogue PhD, S Chrolavicius BA, B Meeks MEng, Prof S J Connolly MD); JW Goethe University, Frankfurt, Germany (S H Hohnloser MD); Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel (Prof M Glikson MD); Klinikum Kassel, Kassel, Germany (J Neuzner MD); Centre Hospitalier Universitaire, Rennes, France (Prof P Mabo MD); Hospital de Santa Creu i Sant Pau, Barcelona, Spain (X Vinolas); Institute for Clinical and Experimental Medicine, Prague, Czech Republic (Prof J Kautzner); Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Canada (G O’Hara MD); Leiden University Medical Center, Leiden, the Netherlands (L VanErven MD); Karolinska Institute, Stockholm, Sweden (F Gadler MD); Boston Scientific, Minneapolis MN, USA, and Brussels, Belgium (U Appl BSBME, J Gilkerson DVM, T Pochet PhD, K M Stein MD); Semmelweis University, Heart and Vascular Centre, Budapest, Hungary (Prof B Merkely MD); Gottsegen National Institute of Cardiology, Budapest, Hungary (C Foldesi MD); and Montreal Heart Institute, Montreal, QC, Canada (B Thibault MD) Correspondence to: Dr Jeff S Healey, DBCVSRI Building, General Site, Hamilton Health Sciences, Hamilton ON, L88L 2X2, Canada Jeff.Healey@phri.ca