Br HeartJ_ 1995;74:631-635 631 Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I Br Heart J: first published as 10.1136/hrt.74.6.631 on 1 December 1995. Downloaded from Henry M Greenberg, Edward M Dwyer Jr., Judith S Hochman, Jonathan S Steinberg, Debra S Echt, Robert W Peters Abstract (Br Heart _J 1995;74:631-635) Objective-To determine whether an interaction between encainide or fle- cainide and intercurrent ischaemia could Keywords: antiarrhythmic drugs, ischaemia, CAST I, account for the observed increase in car- encainide/flecainide diac and sudden deaths in the study group in the Cardiac Arrhythmia Suppression Although ventricular tachycardia/ventricular Trial (CAST) I. fibrillation is a dominant mechanism of car- Design-CAST I was a randomised, dou- diac death in patients who have had a recent ble blind, placebo controlled study in myocardial infarction (< 1 year), and although which patients received the drug which the density of ventricular ectopy following suppressed at least 6 premature ventricu- shortly upon an acute infarction predicts sub- lar contractions per minute by 80% or sequent cardiac mortality, efforts to reduce episodes of non-sustained ventricular mortality by suppressing ventricular ectopy tachycardia by 90%. Arrhythmic sudden have failed.'-3 In the Cardiac Arrhythmia death or aborted sudden death were the Suppression Trial (CAST I)'2 the active drug study end points. Measured secondary groups had a higher cardiac and sudden death end points included recurrent myocardial mortality than the placebo group. infarction, new or increasing angina pec- In an earlier analysis mortality and morbidity toris, congestive heart failure, and syn- in CAST I Echt et al presented data suggesting cope. The CAST I database was analysed that the increase in mortality for the patients to determine which of three end points assigned to active drugs was associated with an occurred first-cardiac death or cardiac increase in angina pectoris and non-fatal rein- arrest, angina pectoris, or non-fatal farction in the placebo group.2 Because these recurrent infarction. They were regarded end points were not mutually exclusive, no as mutually exclusive end points. The conclusion could be drawn relating these two http://heart.bmj.com/ triad of cardiac or sudden arrhythmic observations, although Echt et al speculated death plus congestive heart failure and that an interaction might exist. Akiyama et al, syncope was similarly analysed. also in an analysis of CAST I data, showed Division of Cardiology, Results-It was assumed that recurrent that the 1 year mortality in patients with a St Luke's/Roosevelt non-fatal infarction and new or increas- non-Q wave myocardial infarction assigned to Hospital and Columbia ing angina pectoris were ischaemic in ori- the treatment group was markedly increased, University, New York, gin. The sum ofthese non-fatal ischaemic with a relative risk of nearly four times that of New York, USA on September 28, 2021 by guest. Protected copyright. H M Greenberg end points and sudden death were nearly the placebo group.4 Because of the enhanced J S Hochman identical in the placebo group (N = 129) ischaemic potential in the non-Q wave J S Steinberg and the treatment group (N = 131). The myocardial infarction, Akiyama et al postu- Division of Cardiology, one year event rate in each group was lated an ischaemia-drug interaction causing an University Hospital, and New Jersey 21%. However, the treatment group had a increased mortality in the treatment group. Medical School, much greater fatality rate (55 v 17; These two observations as well as the earlier Newark, New Jersey, P < 0.0001) than the placebo group. The suggestions made by the Task Force of the USA E M Dwyer same relation was found when the data Working Group on Arrhythmias of the were examined on the basis of drug expo- of led us to Division of Cardiology, European Society Cardiology,5 Vanderbilt University, sure rather than intention to treat. The evaluate the possibility that an interaction Memphis, Tennessee, temporal and circadian events were simi- between encainide/flecainide treatment and USA lar in each group and were consistent with ischaemia accounted for the excess mortality D S Echt an ischaemic pattern. No such patterns of the treatment group in CAST I. Division of Cardiology, Baltimore Department emerged from analysis of the presumed of Veterans Affairs non-ischaemic end points of congestive Hospital and heart failure and syncope. University of data that the and methods Maryland, Baltimore, Conclusions-These suggest Patients Maryland,USA interaction between active ischaemia and The CAST protocol has been described in R W Peters treatment with encainide or flecainide detail previously.'2 In brief, patients with at Correspondence to: may have been responsible for the least six premature ventricular depolarisations Dr H M Greenberg, Division of Cardiology, St Luke's increased mortality seen in the treatment per hour without ventricular tachycardia last- Roosevelt Hospital, 1000 group in CAST I. This conversion of a ing more than 15 beats at a rate of > 120 per 10th Avenue, New York NY 10019, USA. non-fatal to a fatal event emphasises the minute were eligible for enrolment after docu- Accepted for publication need for future antiarrhythmic drugs to mented myocardial infarction. Based on the 12 June 1995 be screened in ischaemic models. results of open label titration which demon- 632 Greenberg, Dwyer, Hochman, Steinberg, Echt, Peters strated a predefined, high-level suppression of the significance of differences between the ventricular ectopy (80% ofpremature ventricu- curves. lar contractions and 90% of runs of non-sus- tained ventricular tachycardia) patients were Br Heart J: first published as 10.1136/hrt.74.6.631 on 1 December 1995. Downloaded from randomly assigned to drug treatment or Results placebo. Holter electrocardiograms were We created two sets of data. One set used the obtained at 4 months and scheduled for 12 intention-to-treat data and the other the expo- months after the index myocardial infarction. sure-to-drug data censored three days after the The primary end point of the trial was start of individualised treatment. Figure lA-C arrhythmic death or cardiac arrest with resus- shows the intention to treat data. In each fig- citation, where these were presumed to be due ure the placebo and treatment groups are to ventricular arrhythmia. The site principal compared. When cardiac death and non-fatal, investigator classified each death and provided ischaemic end points of new/worsening angina a summary of the circumstances surrounding or non-fatal reinfarction were mutually exclu- the death. An events committee reviewed each sive end points, the estimated one year event death and differences were resolved by con- rate was 21% in both treatment and placebo sensus.6 There was an initial 86% concurrence groups (fig IA). Mortality was higher in between the events committee and the site the encainide/flecainide treatment group investigator. (P < 0-001) whereas non-fatal ischaemic end- In addition to the primary end point, all car- points were more frequent in the placebo diac deaths and secondary end points were group (P < 0 006) (figure 1B & C). The bar prospectively defined and tabulated.2 The sec- graph shows numerical data for the intention ondary end points included new or worsened to treat groups (fig 2). Increased mortality in angina pectoris; recurrent non-fatal myocar- the treatment group is balanced by the dial infarction; syncope, defined as unex- increased non-fatal ischaemic end points in pected, transient loss of consciousness not the placebo group. explained by physical trauma; and new or When patients were censored three days worsened congestive heart failure. Angina pec- after individualised treatment started, the toris was regarded as new if it was not present results were no different from the intention to at baseline and as worsened if the patient treat data. The censored data curves are deteriorated by at least one Canadian almost identical to the intention to treat curves Cardiovascular Society functional class. (not shown). One reason for the similarity of Congestive failure was regarded as new if the the two analyses may be that 34 of the 120 findings were not present at baseline and wors- patients in whom encainide/flecainide treat- ened if the patient's symptoms worsened by at ment (28%) was stopped were given another least one New York Heart Association func- primary antiarrhythmic drug. Nineteen of tional class. these 34 patients were given open label We analysed the CAST I database to deter- encainide or flecainide. http://heart.bmj.com/ mine which of three end points occurred first, We assumed that non-fatal syncope and either cardiac death or cardiac arrest, or congestive heart failure were non-ischaemic angina pectoris, or non-fatal recurrent infarc- clinical end points. The estimated survival to tion. These were regarded as mutually exclu- these end points combined with the mortality sive end points. For this study patients were end point showed a higher mortality for the censored when they reached the first end treatment group, reflecting that group's higher point. Death which followed quickly upon a mortality. However, unlike the presumed reinfarction or change in the angina pattern ischaemic end points (when the data were cen- on September 28, 2021 by guest. Protected copyright. was regarded as a fatal end point; by definition sored for cardiac death), there was no differ- a patient who did not survive an admission to ence between the placebo and drug groups. hospital for angina pectoris or recurrent There was no evidence of an interaction myocardial infarction was considered to have between drug assignment and these non- reached a fatal end point. We performed a ischaemic end points.