Implications of the cardiac arrhythmia suppression trial for antiarrhythmic drug treatment

Implications of the Cardiac Arrhythmia Suppression Trial for Antiarrhythmic Drug Treatment J. Thomas Bigger, Jr., MD

The Cardiac Arrhythmia Suppression Trial (CAST) is a randomized, placebo-controlled, double-blind, muiticenter clinical trial involving 27 centers and more than 106 hospitals in North America and Europe to test the l-tailed hypothesis that suppresdon of ventricular arrhythmias in patients with left ventricular dysfunction after myocardial infarction will reduce arrhythmic death. Since April l&1989, the CAST is enrotling patients aged -30 years with 16 ventricular premature complexes and left ventricular ejection fraction 540%. Sustained ventricular tachycardia, class IV congestive heart failure or class IV angina pectoris are exclusion criteria. During a prerandomization period, antiarrhythmic drugs are titrated to suppress ventricular arrhythmias. If 260% suppression is achieved during open-label tiirs.tion, patients are randomized to the effective dose or to a matched placebo. If only partial suppression (1 to 79%) is achieved, patients are eligible for a substudy that randomizes them to the best dose found during open-label titration or to placebo. The only patients not randomized to treatment are those with increased arrhythmias or drug intoterance during titration. On April 18, 1989, encainide and flecainide were removed from the CAST because these drugs increased the death rate 2.5~fold. There were no imbalances in baseline risk variables between the encainide/flecainide group and the placebo group that might explain the adverse treatment effect. There was remarkable uniformity of the adverse effect across all subgroups. There were no subgroups that benefited from treatment; all were either harmed or not evaluable. Moricizine was continued in the CAST because it has a significant chance of shqwing benefit. The CAST still has the opportunity to make a major impact on the future management of asymptomatic or minimally symptomatic ventricular From the Division of Cardiology, Department of Medicine, Columbia University, New York, New York 10032. This study was supported in part by National Institutes of Health Contract HC-65048 from the National Heart, Lung, and Blood Institute, and by Grant RR-00645 from the Research Resources Administration, Bethesda, MD; and by funds from The Milstein Family Foundation, The Dover Foundation, George and Abby O’Neill, Robert Winthrop, and the Shirlee and Henry Benach Foundation, New York, New York. Address for reprints: J. Thomas Bigger, Jr., MD, Arrhythmia Control Unit, Columbia-Presbyterian Medical Center, 630 West 168th Street, New York, New York 10032.

arrhythmias after myocardial infarction by determining whether prophylaxis or treatment of symptomatic arrhythmias is the appropriate approach. Enrollment for the CAST is actively underway and physicians are encouraged to recommend participation. (Am J Cardiol1990;65:3D-1OD)

I

t is useful to publish a body of accumulated information about a drug near the time of its launch to provide a critical massof authoritative information in one readily accessibleplace. Our review of moricizine in this symposiumis complicatedby the fact that conceptsabout antiarrhythmic drugs are changing rapidly as a result of preliminary findings for encainide and flecainide in the Cardiac Arrhythmia SuppressionTrial (CAST). Before we begin the review of the important information learned about moricizine during its long development period, it will be useful to review the CAST preliminary results and their implications for clinical practice and to have some general discussionabout the impact of the preliminary CAST results on future antiarrhythmic drug use and development. On August 10, 1989, the preliminary findings of the CAST were published in The New England Journal of Medicine.’ The results were terse and factual. In the same issue of the journal, an editorial by Ruskin2 discussedthe implications of the findings. Since that time, there have been a number of meetings to discuss the CAST preliminary results. The Working Group on Arrhythmias of the European Society of Cardiology met on October 1 and 2,1989, in Sardinia. Representativesfrom the common market countries met with a group of 6 American arrhythmia expertsto discussthe implications of the CAST results. Two CAST investigators, Thomas Bigger and Raymond Woosley, were invited to provide information for the participants. The conclusionsby the Working Group on Arrhythmias about the CAST results will be published jointly in The European Journal of Cardiology and in Circulation. The Food and Drug Administration (FDA) had a sessionon October 5 to review CAST results and discuss their implications for drug development.The opinion of the Cardiovascular and Renal Drugs Advisory Board to the FDA was summarized by Pratt et a1.3The National Institutes of Health is conducting a workshop in January 1990to review the CAST findings and discusshow to use them as a platform for

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A SYMPOSIUM: ROLE OF MORICIZINE IN MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

TABLE I Determinants Average follow up Arrhythmic death Treatment effect Type I (a) error Type II (8) error Drop-out rate Drop-in rate CAST = Cardiac Arrhythmia

of Sample Size for CAST 3 years ll%per3years 30% reduction

in arrhythmic

death

0.025 l-tail hypothesis 0.15 30% (20% in first year, then 5% per year) 6% (2% per year) Suppression Trial.

future institute- or investigator-initiated research.Also, the CAST investigatorsand the sponsorsof encainideand flecainide havecontinued to analyze the CAST data base to gain a better understanding of the preliminary findings. What is the principal objective of the CAST? The CAST is a randomized,placebo-controlled,double-blind, international, multicenter clinical trial that beganenrollment in June 1987 to test the l-tailed hypothesis that suppressionof ventricular arrhythmias after myocardial infarction with long-term antiarrhythmic drug treatment will reduce arrhythmic death by 30% or more.’ Twentysevencentersand more than 100 hospitals in 3 countries, the United States, Canada and Sweden,are participating. Enrollment will continue for 3 or 4 years (from 1987 to 1991) and follow-up for 2 to 5 years (until 1994). Who is eligible for the CAST? Before April 18,1989, survivors of myocardial infarction who were aged <80 years and had 26 ventricular premature complexesper hour on a 24-hour continuous electrocardiographic recording obtained between6 days and 2 years after myocardial infarction were eligible for the CAST. For patients enrolled between6 and 90 days after infarction, a left ventricular ejection fraction 555% was required; for patients enrolled 190 days after the onset of myocardial infarction, left ventricular ejection fraction 140% was required. After April 18, 1989, the enrollment window was restricted to within 90 days and left ventricular ejection fraction criterion was reduced to 540%. What was the rationale for the two ejection fraction criteria? The purpose of 2 ejection fraction criteria was

to equalize the risk of death early and late after myocardial infarction. In the Cardiac Arrhythmia Pilot Study (CAPS), which had a 6- to 60-day enrollment window, it was found that the incidence of death or sustained arrhythmic eventswasvery low in patients with left ventricular ejection fractions 255% (i.e., the upper quartile of the ejection fraction distribution). Therefore, it was decided to exclude patients with left ventricular ejection fractions 155% in the 6- to go-day window, as having an overall risk of arrhythmic eventstoo low to achievea risk/ benefit ratio sufficient to enroll in the CAST. For patients enrolled from 90 days to 2 years after infarction, left ventricular ejection fraction ceiling was set at 40% in order to match the expectedevent rates betweenpatients enrolled early (6 to 90 days) and late (90 days to 2 years) after myocardial infarction. This strategy worked very well. The patients enrolled before and after 90 days had almost identical mortality rates. 4D

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

Who is exeknled from the CAST? Patients with sustained ventricular tachycardia are excluded from the CAST. Also, patients are excluded who, at the time of enrollment, have New York Heart Association class IV congestiveheart failure or Canadian cardiovascularclass IV angina pectoris. What is the design of the CAST? The design of the CAST is uniquely suitable for testing the l-tailed sup pressionhypothesis(seeFig. 1). The original parameters for the CAST samplesizecomputation are given in Table I. During an open-label drug treatment period, suppression of ventricular arrhythmias is sought by titrating antiarrhythmic drugs. If 180% suppressionof ventricular premature complexesis achievedduring open-labeltitration and the effective drug is well tolerated, patients are randomized in the main study to the therapy found during open-labeltitration or to a matchedplacebo.If partial suppression(1 to 79%) is achieved,patients are eligible for a substudy that randomizesthem to the best therapy found during open-labeltitration or to a matching placebo. Patients who havean increasein frequency of ventricular premature complexes, cannot tolerate any of the drugs, die, or decideto discontinue treatment are the only onesnot randomized to treatment. As of April 18, 1989, the last day encainide and flecainide were in the CAST, 76%of thosewho signeda consentform wererandomized to the main study, 6% were randomized to the substudy for those who had partial suppression,and 18%were not randomized (Fig. 1). How was open-label

drug/dose! titration

conducted?

Before April 18, 1989, 3 active drugs were used in a number of randomly assigned sequences(Fig. 2). For patients with an ejection fraction 130%, the sequence contained all 3 drugs. For patients with left ventricular ejectionfraction <30%, only 2 drugs, encainideand moricizine, were administered. Patients were randomly assignedto start therapy with encainideor moricizine first. Each drug had 2 doselevels (seeTable II), the sameas the 2 lower dosesusedin CAPS, and dosing always proceededfrom the low to the high dose. After April 18, 1989,only moricizine remained in the CAST and, based on dose-responseinformation from the Du Pont New Drug Application data base,a third dose (900 mg) was added to the titration sequence. How is randomization conducted? Before April 18, 1989,randomization wasstratified on: (1) clinical center; (2) left ventricular ejection fraction 230 or <30%; and (3) time of enrollment, 6 to 90 days or 190 days to 2 years. Randomization to blinded treatment with drug or placebobeganthe main trial or the substudyfor partially suppressedpatients. After April 18,1989, randomization was stratified only on enrolling center and ejection fraction since the enrolling window was shortened. Why were encainide and flecainide removed from CAST? The CAST protocol permits drugs to be removed

from or added to the trial. On April 17, 1989, the Data and Safety Monitoring Board held its regular semiannual meeting, reviewed mortality data complete as of March 30, 1989, and recommendedthat encainide and flecainide be removedfrom the CAST becauseit had become

I

THE CARDIAC

ARRHYTHMIA

SUPPRESSION

TRIAL

Intolerant. Died, Increased arrhyihmia, or still in titration as of 4/19/89 18%

Effective drug 38%

t

Drug/dose Selection N = 2372

280% Suppression

__c_

76% Placebo 38%

1% -79% kuppression i”

-6drug

3%

Placetx

3%

FlwmI.TbdedgnofthecudiacAmhythmia Sq8pWdmT~(cA5l).n#-iadkatethepatbntlbwinthecAsT wereremovedfromthe wal, Le.,ApalS, 1989. Iptotheday-andvirtually impossibleto establishany beneficial effect from thesedrugs if they were continued to the end of study and becauseof strong evidencethat thesedrugs increasedthe death rate comparedwith placebo.The Data and Safety Monitoring Board also recommendedthat moricizine he continued in the CAST becauseit still has a significant chanceof showing benefit and that other antiarrhythmic drugs be reviewedaspossibleadditions to the CAST. The National Heart, Lung, and Blood Institute acceptedthe recommendation that same day. On April 18, 1989, a messagewas sent to eachCAST clinical center to discontinue treatment in all patients who had been assignedto en&ride, fleoainide, or their corresponding placebos. How much did oncainide and fiecainide increase the modalBy rate in CAST? The data reviewedby the Data and Safety Monitoring Board on April 17, 1989, had a cutoff date of March 30,1989. At that time, 730 patients had been randomized to encainide or flecainide and 725 to a corresponding placebo.* With an average of about 300 days of exposureto CAST treatment, there were 78

deaths (n = 70) or nonfatal cardiac arrests (n = 8) in the group treated with encainide, f&amide, or with the correspondingplacebos(event rate 5.4%). Of the 78 events, 54% were primary arrhythmic events.The primary end point for the trial, arrhythmic death or nonfatal cardiac arrest, was experiencedby 4.5% of the patients randomized to encainideor flecainide comparedwith 1.2%of the patients randomized to placebo. All of the 8 nonfatal cardiac arrests occurred in the active treatment group. Patients taking encainide or flecainide were 3.6 times as likely to experiencearrhythmic death or nonfatal cardiac arrest as thosetreated with placebo.The chanceof experiencing death of any causeor cardiac arrest was 7.7%in patients treated with encainide or flecainide compared with 3.0% for placebo, an increase in risk of 2.5. There was no difference for noncardiac deaths betweenthe placebo and active treatment groups. The mortality events up to April 18, 1989,when encainide and flecainide were removed from the CAST, are listed in Table III. At this time, the averageexposuretime was lessthan 1 year. The

CAST: Open Label Titration I LVEF 230% ENC-Lo---,

ENC-Hi -MOWLo--,

MO&Hid

FLE-Lo -----)

FLE-Hi

FLE-LO B

FLE-Hi ----)

MO&Lo-

MOR-Hi --)

EN&LO ----)

ENC-Hi

ENC-Lo -

ENC-Hi ----c

MOR-Lo-

MOR-Hi

MOR-Lo-

MOR-Hid

ENC-Lo ----t

ENC-Hi

LVEF ~30%

THE AFAERICANJOURNAL OF CARDIOLOGY FEBRUARY 20,199O

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A SYMPOSIUM: ROLE GF MGRICIZINE IN MANAGEMENT OF VENTRICULARARRNYTNMIAS TABLE II Doses of Drugs Used in CAST Dose Ow) Drug

Low

High

Encainide Flecainide Moricizine

35 TID 100 BID 200 TID

50 TID 150 BID 250 TID

placebo becausepatients with left ventricular ejection fraction <30% were not randomized to flecainide. Thus, there was remarkable uniformity of treatment effect acrossall subgroups.There wereno subgroupsthat benefited from treatment; all were either harmed or not evaluable. Whyweredtweawareofthisadverseeffectbefore?

The CAST findings point out the need for large-scale BID = 2 times a day: CAST = Cardiac Arrhythmia Suppression Trial: TID = 3 times a controlled clinical trials for long-term safety assessment day. of drugs. The modest-sizedcontrolled studies performed by drug companiesbefore FDA approval usually do not values in this table represent an update to those in the have the power to detect a mortality effect, even one as article in The New England Journal of Medicine. Ten large as that found in the CAST. Also, there is no way additional deathsare recordedand someof the classifica- that the harmful effectsof encainideand flecainide could tions have changed. The overall result is, of course, un- be detected in uncontrolled clinical use becausethere is changed. no comparisongroup in this setting. For the public safety, Couldbasehedifferencesatthetimeofrandomiifor our patients, and for physicianswho treat patients we tion account for the hii mortality rate in the active must have this kind of knowledge.There is only one way treatment group than in the control group? There were to get it and that’s controlled clinical trials. Not only are no imbalancesbetweenthe group treated with encainide drug developmentprograms too small to detect adverse or flecainide and the group treated with placebo with effectson mortality, but alsopatients with recentmyocarrespectto baselinerisk variables that might confound the dial infarction often are excluded from premarketing apparent adversetreatment effect. Age, history of previ- antiarrhythmic drug trials. ous infarction, angina pectoris, congestiveheart failure, Are them subgroups of patients with vedicular arhypertension, diabetes, sustained arrhythmias, baseline rhythmiasaftermyocardialinfarcth~whomightbenefit left ventricular ejection fraction, ventricular arrhythmia from ~inide or -de treatment? First, all pafrequency, electrocardiographic intervals, therapy in hos- tients in the CAST who could be treated with antiarpital and dischargemedicationsall were closely matched rhythmic drugs were treated so that no subgroupswere in patients randomized to encainide or flecainide and excluded. The CAST protocol simulates the way antiarthose randomized to placebo. Also, almost 90% of the rhythmic drugs are used during conventional treatment patients who died or experienceda nonfatal cardiac arrest of postinfarction ventricular arrhythmias. Patients with were taking their assignedstudy medication at the time of ventricular arrhythmia and left ventricular dysfunction the event. were selectedfor treatment and thosewhosearrhythmias Did any subgroups beneftt from encainide or flecaiwere suppressedby L 1%were followed with treatment in nide treatment? The increase in death rate for patients the main study or the substudy for patients with partial treated with encainide or flecainide was observedconsis- suppression;82% of the patients who had qualifying artently in the various subgroups within the study (i.e., rhythmias and were enrolled in the study were randomthere wasno interaction betweentreatment and age,time ized and treated. The only patients who were not treated from myocardial infarction to enrollment, left ventricular and followed were thosewho died during titration, had no ejection fraction, baseline ventricular arrhythmia fre- arrhythmia suppression,or could not tolerate any study quency, baseline QRS duration, or the use of digitalis, drug and dose available in the titration strategy. It is diuretics, /3 blockers or calcium channel blockers). The unlikely that such patients could be treated in a practice relative risk of dying or experiencing a nonfatal cardiac setting. Second,there were no subgroupsthat benefited arrest was almost identical for both drugs (2.3 for encai- from treatment. Patientswith higher mortality rates,e.g., nide and 2.7 for flecainide), although the absolute mor- older patients, patients with severelydepressedleft ventality rate was lower for flecainide and its corresponding tricular function, and those with higher arrhythmia frequency or complexity were harmed as much as groups with lower mortality rates. Therefore, the CAST results TABLE III Deaths and Cardiac Arrests in 1,498 Patients are relevant to clinical practice and there are no groups Randomized to Encainide/Flecainide or to Placebo (Before that seemto havea chanceof benefit from treatment with April 18, 1989) encainide or flecainide. Type of Death

Encainide/ Flecainide (n = 755)

Placebo (n - 743)

Arrhythmic or cardiac arrest Other cardiac death Noncardiac Total (deaths and cardiac arrest)

43 16 3 62

16 5 5 26

Average expxposurcl: encninldr/flecalnlde,

60

302 days: placebo. 311 days.

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

What is the mechanism of the increased mortality In posthfarction patbts treated with encablde or flecal-

We? The mechanismof the increasedmortality in the patients treated with encainideor flecainide in the CAST is not known. Ruskin speculatedthat the deaths might be due to aggravation of ventricular arrhythmias. The higher relative risk in the encainide/flecainide group for sudden cardiac death/cardiac arrest than for total or

noncardiac death suggeststhat arrhythmic deaths were increased by treatment with these 2 drugs.’ However, severalfeaturesof the mortality findings in the CAST are different from thosepreviously describedfor proarrhythmic effects. First, the increased mortality occurred despite marked suppressionin the frequency of ventricular premature complexes and episodesof unsustained ventricular tachycardia. Second,the survival curves for patients treated with encainidelflecainide and the correspondingplacebogroup continue to separateover the 300 days of follow-up reported by CAST.’ Current concepts of proarrhythmia predict that the frequency of ventricular premature complexes and unsustained ventricular tachycardia will increasewhen patients experienceproarrhythmia.4,5Also, proarrhythmic eventsare expectedto concentrate in the first 30 to 60 days after starting treatment.6-8Current conceptsabout proarrhythmia may be incomplete and biased by what is easy to observe and recognize. Encainide or flecainide might exert their adverse effect on mortality by: (1) making sustained,reentrant ventricular arrhythmias more likely by increasing the relative infarct size, (2) depressingleft ventricular function, (3) increasing ischemia, or (4) increasing the likelihood of fatal ventricular arrhythmias during ischemia or periods of increasedsympathetic nervoussystem activity. Flecainide can causeinducible, sustainedventricular arrhythmia in dogsthat havesubacutemyocardial infarction but are not inducible without the drug,g,10Flecainide slowsconduction around infarcted tissue so that the conduction path is lengthened and sustained ventricular tachycardia is easierto induce.l i Also, flecainide does not increasethe electrical ventricular fibrillation threshold.12 Flecainide hasbeennotedto aggravateleft ventricular dysfunction, especially in patients with preexisting congestiveheart failure or in thosewith left ventricular ejection fraction <30%, or both.i3 More recently, encainide has also been implicated. 14,15Encainide and flecainide could increase mortality by aggravating left ventricular dysfunction per se.Also, thesedrugs could increasemyocardial ischemia and the likelihood of sudden cardiac death by depressingleft ventricular function and thereby increasing myocardial oxygen demand. Encainide and flecainide could increasethe likelihood of malignant ventricular arrhythmias during myocardial ischemia.Flecainide increasesthe probability of ventricular fibrillation during ischemia in dogs with previous myocardial infarction. l”sll In the samemodel, ,&adrenergic blocking drugs (class II action) and amiodarone or sotalol (class III action) were protective (i.e., the model discriminates among antiarrhythmic drugs.16-*8)The effect of encainideor flecainide treatment on the likelihood of ventricular fibrillation during increased sympathetic nervous activity in animals with previous myocardial infarction has not been explored. Recent reports of sustained ventricular tachycardia or ventricular fibrillation occurring during exercisetesting during treatment with encainide or flecainide suggestan interaction with exer-

cisevariables, e.g.,heart rate, ischemia,or increasedsympathetic nervoussystemactivity, that can provokemalignant ventricular arrhythmias.14J5Jg~20 Our working hypothesisto explain the increasedmortality in the CAST encainide/flecainide groups is an adverse interaction between these drugs and myocardial ischemia that promotesventricular fibrillation. Some of the encainidelflecainide associateddeathsmay be due to ventricular tachycardia promoted by drug-induced conduction slowing. It appearsunlikely that the latter mechanism accounts for many of the drug-associateddeaths. Otherwise, there should have been a higher relative risk of nonfatal, sustainedventricular tachycardia in the encainidelflecainide treated groups. Do the CAST results apply to other drugs with class I antiarrhythmic action? May et a12i and Furberg re-

viewed clinical trials of antiarrhythmic drug therapy after myocardial infarction when 100or more patients were studied, patients were randomizedto treatment or control groups, and all-causemortality was reported. No overall trend suggestingbenefit was found in 8 long-term postinfarction antiarrhythmic drug trials, 6 of which studied antiarrhythmic drugs with class IB action (i.e., phenytoin, tocainide or mexiletine) and 2 others that studied aprindine. Three of the studieshad almost identical mortality rates in the control and active treatment groups, 3 studiesshoweda mortality rate that was 32 to 58%higher in the group treated with antiarrhythmic drugs, and the 2 aprindine studies, which only enrolled patients who had ventricular arrhythmias and attempted to suppressventricular arrhythmias by dose ranging, showed a 40 and 23% lower mortality rate in the aprindine-treated patients.21,22The results of these 8 small studies fail to suggest any benefit of treatment with antiarrhythmic drugs in unselectedpatients after myocardial infarction. Hine et a123performed a meta-analysis of these studies and found a statistically significant increasein mortality rate. The overall oddsratio for patients dying with active treatment vs placebo was 1.38 (95% confidence interval 1.09to 1.74). Theseworkers concludedthat treatment of unselectedpatients at moderate risk of sudden cardiac death after myocardial infarction with drugs that have class I antiarrhythmic action is unwarranted. Recently, Coplen et a124conducted a meta-analysisof 6 trials that evaluated the safety and efficacy of quinidine for maintaining sinus rhythm after cardioversionfor chronic atria1 fibrillation. Although the probability of sustaining sinus rhythm for a year was doubled in the quinidine-treated group (50 vs 25%), the probability of dying was quadrupled in the quinidine-treated group (2.7 vs 0.6%). Although only about 16%of the 800 patients evaluatedhad coronary heart disease,88% had structural heart disease of some kind. Thus, there are discouraging results for antiarrhythmic drugs with class IA, IB and IC action. The only encouraging results are for aprindine and moricizine, 2 drugs with class I action but with other special features. By virtue of usein the CAPS and CAST, moricizine has the largest body of controlled safety information of any drug with classI action for useagainstventric-

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A SYMPOSWM: ROLE OF MORICIZINE IN MANAGEMENT OF VENTRICULAR ARRWYlllMIAS

ular arrhythmias after myocardial infarction. With what is currently known, it would not be prudent to treat asymptomatic or minimally symptomatic ventricular arrhythmias after myocardial infarction with any conventional drugs with class I antiarrhythmic action. What about dnyrr with other classes of antiarrhyth-

a&on? Drugs with classII antiarrhythmic action (/3 blockade) have been shown to reduce arrhythmias after myocardial infarction and to decreasemortality.25 The effect on mortality is larger in patients who havearrhythmias or left ventricular dysfunction beforetreatment, and arrhythmic or sudden death is reduced more strikingly than total mortality. The effect of drugs with class III antiarrhythmic action (those that prolong cardiac action potentials) on patients with postinfarction ventricular arrhythmias and mortality is not known. Several clinical trials are underway to determine whether amiodarone will improve survival after myocardial infarction. Drugs with class IV antiarrhythmic action (those that block calcium channels) have no significant effect on spontaneousventricular arrhythmias after myocardial infarction26 and no effect on mortality.27 mic

Do the CAST rerults

apply to other populations

as

well? The overall mortality effect of encainideand flecainide was about the sameearly and late after infarction so that their adverseeffect is not restricted to the healing period after myocardial infarction. However, previous infarction may be necessaryfor the adverse effect of encainide and flecainide to expressitself. If so, the findings in the CAST do not necessarilyapply to other groups of patients with heart disease.The European view is that the CAST results should not be extrapolated beyond the population actually studied in the CAST.28 The American view is that the closer a patient is to those studied in the CAST, the greater the concern when considering the useof classI antiarrhythmic drugs. The risk/benefit ratio should be consideredcarefully in patients with structural heart diseaseand ventricular arrhythmias. Most physicians in the United States and in Europe believe that patients with supraventricular arrhythmias who do not have structural heart diseaseare sufficiently different from those in the CAST to have a lower level of concern even though encainide and flecainide have not been proved safe in these patients. On October 6, the Cardiovascular and Renal Drugs Advisory Board to the FDA recommendedapproval of flecainide for this use.

tween left ventricular dysfunction and ventricular arrhythmias with increased mortality rates. What will be the publii

health impact of the CAST?

Recentsurveyssuggestthat about half of the patients like those recruited for the CAST were treated with antiarrhythmic drugs with classI action.3s,36 Until the preliminary CAST results were available, the fastest growing segment of the antiarrhythmic drug market was the drugs with classIC action. When the results of the CAST have been adequately communicated to practitioners, a marked reduction in the use of drugs with classI antiarrhythmic action should be seenin patients with postinfarction ventricular arrhythmias and a correspondingincreasein the useof /3blockers.If this prediction is correct, we can expect the changesin medical practice as a result of the CAST to saveseveralthousand lives per year. The CAST results will stimulate a thorough reexamination of the safety standards for all drugs. We are likely to see guidelines for drug developmentthat give more emphasis to the assessmentof mortality as an end point. If so, the cost of drug developmentwill go up and new modelsfor safety assessmentand new cost-sharingarrangementsare likely to emerge.In the future, we will demand stronger safety standards for drugs and we will have to find new ways to conduct or to fund safety assessmentin order to make more stringent safety assessmentfeasible. Why was the mortality rate so low In the placebo group in the main trial? The possiblereasonsfor the low

mortality rate were given in the CAST article appearing in the The New England Journal of Medicine on August 10, 1989. New conventional treatments, e.g., thrombolysis and angioplasty, might lower the mortality rate substantially. This factor should affect the number of eligible patients more than the mortality rate of those who are eligible. The sickest patients were not enrolled. This is probably not the case (read later). The follow-up was short, i.e., an average of 10 months. Nonsudden deaths predominate early, suddendeaths occur proportionately more frequently later. 32This accountsfor some,but certainly not all, of the low mortality in the placebogroup. A positive responseto an antiarrhythmic drug selectslowrisk patients. In considering all patients who signed a CAST consentform, the l-year total mortality rate was about 8% which is only slightly lessthan the anticipated rate. This figure subtractsthe deathsattributable to drug. This is a minimum figure becausethe mortality statushas Has the problem of sudden cardiac death after myonot beendetermined for about 40%of the group that was eardial infarction gone away? The most recent data not randomized either to the main study or to the subavailable indicate that changesin conventional treatment study for patients whose arrhythmia was partially suphave not changedthe significance of ventricular arrhyth- pressed.These figures suggestthat the main reason for mias after myocardial infarction.29 Ventricular arrhyth- the low mortality rate in the placebo group in the main mias still double the risk of dying within 2 years of myo- trial is that patients who started titration but were not cardial infarction after adjusting for left ventricular dys- randomized had a much higher mortality than thosewho function and other variables.30-34 It would be reasonable tolerated the drugs well, were suppressed,and were ranto expect widespread efforts to achieve reperfusion of domized. Patients whose ventricular arrhythmias were ischemic myocardium early in the course of myocardial suppressedduring open-label titration had a lower morinfarction to decreasethe prevalence of left ventricular tality rate than thosewhoseventricular arrhythmias were dysfunction and ventricular arrhythmias. However, it is not suppressedeven though treatment was withdrawn unlikely that these measureswill alter the relation be- after titration. Thus, suppressionof ventricular arrhyth-

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mias may be identifying a patient characteristic as much sicians for support by encouraging their patients with as identifying an effective drug.37The CAST protocol postinfarction ventricular arrhythmias to participate. mimics clinical practice closely, and everybodywho could be treated was treated. During titration, the sickestpeo- REFERENCES ple died, did not have suppressionor had increasesin 1. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Increased arrhythmia, or had pulmonary edemaor someother ad: mortality due to encainide or flecainide in a randomized trial of arrhythmia after myocardial infarction. N Engl J Med 1989;321:406-412. verse effect that prompted their doctor to discontinue suppression 2. Ruskin JN. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J treatment. These sameeventswould causetreatment to Med 1989:321:386-387. 3. Pratt CM, Brater CD, Harrell FE Jr, Kowey PR, L&r CV, Lowenthal DT, be discontinued in conventional clinical practice. Why wasn’t the CAST stopped altogether; what is happening now? First, the Data, Safety and Monitoring

Board, the only group who has seenthe moricizne data, recommended in the strongest terms that moricizine should be continued in the CAST eventhough encainide and flecainide should be removed. Evidently, there were striking differences between moricizine and the other drugs. Moricizine is worthy of further testing and it seems unlikely that moricizine will be harmful. But considerthe difference in the future of clinical practice and of drug development by industry with 2 different possible outcomes.If results show that when moricizine suppresses arrhythmias it improves survival, it will be used to treat asymptomatic ventricular arrhythmias after myocardial infarction. The market for antiarrhythmic drugs will expand substantially. Such a finding alsowill encouragethe drug industry to search for other chemical entities with class I antiarrhythmic action that not only improve survival but also have other advantages, e.g., once-a-day dosingand lessnoncardiac adverseeffects.If resultsshow that when moricizine suppressesarrhythmias it has no effect on survival, the drug will be used only to treat symptomatic ventricular arrhythmias, a much smaller market. However, moricizine can be usedwith confidence that no harm is being causedwhile controlling symptoms. This outcome will provide much less incentive for the American drug industry to develop new drugs to treat ventricular arrhythmias. The importance of substantial suppressionvs mere treatment of the arrhythmia can be assessed by comparing the active treatment groups in the main study and in the substudy for patients who have partial suppression.Also, comparing the placebo groups in the main study with the substudy for patients with partial suppressionwill establish the prognostic significance of suppressionduring titration. With the information available, it seemsthat patients whosearrhythmias can be suppressedduring titration with antiarrhythmic drugs have a better survival experience than patients whose arrhythmias are not suppressedeven when drug treatment is discontinued after titration. These findings indicate that suppressibility is an important prognostic indicator. There are many important questionsleft that can be answeredby the CAST. The protocol has beenchanged: encainide and flecainide were removed, the qualifying ejection fraction was reduced to 40?&, the enrolling window was shortened to 6 to 90 days, and a third doseof moricizine, 900 mg/day, was added. These measures should lead to a higher risk group being enrolled and safer treatment. The CAST is enrolling actively and asksphy-

Messerli FH, Packer M, Pritchett ELC, Ruskin JN. Clinical and regulatory implications of the Cardiac Arrhythmia Suppression Trial (CAST). Am J Cardial 1990; in press. 4. Velebit V. Podrid P, Low B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by arrhythmic drugs. Circulation 1982; 65:886-894. 5. Bigger JT Jr, Sahar DI. Clinical types of proarrhythmic response to antiarrhythmic drugs. Am J Cardiol 1987:59:2E-9E. 6. Minardo JD, Heger JJ, Miles WM, Zipes DP, Prystowsky EN. Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med 1988:319:257-262. 7. Stanton MS, Prystowsky EN, Fineberg NS, Miles WM. Zipes DP, Heger JJ. Arrhythmogenic effects of antiarrhythmic drugs: a study of 506 patients treated for ventricular tachycardia or fibrillation. JACC /989;14:209-215. 8. Morganroth J, Borland M, Chao G. Application of a frequency definition of ventricular proarrhythmia. Am .I Cardiol 1987;59:97-99. 9. Zimmerman JM, Bigger JT, Coromilas J. Flecainide acetate is arrhythmogenie in a canine model of sustained ventricular tachycardia (abstr). JACC /985;5:391. 10. Kou WH, Nelson SD, Lynch JJ, Montgomery DC, DiCarlo L, Lucchesi BR. Effect of flecainide acetate on prevention of electrical induction of ventricular tachycardia and Occurrence of ischemic ventricular fibrillation during the early postmyocardial infarction period: evaluation in a conscious canine model of sudden death. JACC 1987,9:359-365. 11. Coromilas J, Saltman AE, Waldecker B, Dillon SM. Wit AL. Effect of class IC antiarrhythmic drugs on anisotropic reentry in canine infarcts (abstr). Circulation 1988:78:Il:ll-460. 12. Lynch JJ, DiCarlo LA, Montgomery DG, Lucchesi BR. Effects of flecainide acetate on ventricular tachyarrhythmia and fibrillation in dogs with recent myocardial infarction. Pharmacology 1987;35:181-193. 13. de Pa& AAV, Horowitz LN, Morganroth J, Senior S, Spielman SR, Greenspan AM, Kay HR. Influence of left ventricular dysfunction on flecainide therapy. JACC 1987;9:163-168. 14. Slater W, Lampert S, Podrid PJ, Low B. Clinical predictors of arrhythmia worsening by antiarrhythmic drugs. Am J Cardial 1988;61:349-353. 15. Tardjman T, Podrid PJ, Raeder E, Low B. Safety and efficacy of encainide for malignant ventricular arrhythmias. Am J Cardiol 1986;58:87C-95C. 16. Patterson E, Lucchesi BR. Antifibrillatory actions of nadolol. J F’harmacol Exp Ther 1982:223:144-l 52. 17. Patterson E, Lynch JJ, Lucchesi BR. Ant&rhythmic and antitibrillatory actions of the beta-adrenergic receptor antagonist, dl-sot&l. J Pharmacol Exp Ther 1984:230:519-526. 18. Patterson E, Eller BT, Abrams CD, Vasiliades J, Lucchesi BR. Ventricular fibrillation in a conscious canine preparation of sudden coronary death: prevention by short- and long-term amiodarone administration. Circulation 1983;68:857864. 19. Falk RH. Flecainide-induced ventricular tachycardia and fibrillation in patients treated for atrial fibrillation. Ann Intern Med /989;111:107-1 Il. 20. Anastasiou-Nana MI, Anderson JL, Stewart JR, Crevey BJ, Yanowitz FG, Lutz JR, Johnson TA. Occurrence of exercise-induced and spontaneous wide complex tachycardia during therapy with flecainide for complex ventricular arrhythmias: a probable proarrhythmic effect. Am Heart J 1987:113:/071-1077. 21. May GS, Eberlein KA, Furberg CD, Passamani ER, DeMets DL. Secondary prevention after myocardial infarction: a review of long-term trials. Prog CardioLWSCDis 1982:24:331-352. 22. Furberg CD. Effect of ant&rhythmic drugs on mortality after myocardial infarction. Am J Cardiol /983;52:32C-36C. 23. Hine L, Laird N, Hewitt P, Chalmers T. Meta-analysis of empiric chronic antiarrhythmic therapy after myocardial infarction. JAMA /989;262:3037-3040. 24. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Prevention of recurrent atrial fibrillation by quinidine. A me&analysis of randomized trials (abstr). Circulation 1989:80:lI:II-633. 25. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiouasc Dis 1985:27:335-371. 26. Bigger JT Jr, Coromilas J, Rolnitzky LM. Fleiss JL, Kleiger RE, and The Multicenter Diltiazem Post-Infarction Trial Investigators. Effect of diltiazem on cardiac rate and rhythm after myocardial infarction. Am J Cordial 1990;65:in press.

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27. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview of the result from the randomized trials. Br Med J 1989; in press. 28. Editorial. Flecainide and CAST. Lmcet 1989;2:481-482. 33. Coromilas J, Bigger JT Jr, Kleiger RE, Rolnitzky LM, Fleiss JL, and the MDPIT Research Group. Relations among left ventricular dysfunction, ventricular arrhythmias, and mortality after myocardial infarction. Circulation 1989; 8O:mppl II:II-48. 30. Ruberman W. Weinblatt E. Goldbera JD. Frank CW. Shapiro S. Ventricular premature beats &d mortalit; after myo&diaI infar&ion: N Engl J Med 1977~?97.750-757 31. Moss AJ, Davis HT. DeCamilla J, Bayer LW. Ventricular ectopic beats and their relation to sudden and nonsudden cardiac death after myocardial infarction. Circulation 1979$0:998-1003. 33. Bigger JT Jr, Fleiss JL, Kleiger R, Miller JP, Rolnitzky LM and the Multicenter Post-Infarction Research Group. The relationship among ventricular arrhythmias, left ventricular dysfunction and mortality in the 2 years after myocardial infarction. Circulation 1984,69:250-258.

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33. Mukherji J, Rude RE, Poole KE, Gustafson N, Thomas LJ Jr, Strauss HW, Jaffe AS, Muller JE, Roberts R, Raabe DS Jr, Croft CH, Passamani E, Braunwald E, WilIerson JT, and the MILIS Study Group. Risk factors for sudden death after acute myocardial infarction: two-year follow-up. Am J Cardiol1984;54:3136. 34. Nicod P, Gilpin E, Dittrich H, Henning H, Ross J Jr. Prognostic significance of complex ventricular arrhythmia for cardiac death during the first year after myocardial infarction. J Electrophysiol 1987:1:93-102. 35. Vlay S. How the university cardiologist treats ventricular premature beats: a nationwide survey of 65 university medical centers. Am Heart J 1985;110:904909. 36. Morganroth J, Bigger JT, Anderson JL. Treatment of ventricular arrhythmias by United States cardiologists: a survey before the Cardiac Arrhythmia Suppression Trial (CAST) results were available. Am J Cordiol 1990,65:4048. 37. Graboys TB, Lown B, Podrid PJ, DeSilva R. Long term survival of patients with ventricular arrhythmia treated with antiarrhythmic drugs. Am J Curdiol 1982;50:437-443.