SYMPOSIA

J Clin Pharmacol 1990;30:967-974 967

The Cardiac Arrhythmia SuppressionTrial: Implications for Antiarrhythmic

Drug Development

Craig M. Pratt, MD, and Lemuel Moye, MD, PhD

T he results of the Cardiac Arrhythmia Suppres-sion Trial (CAST) have had an immediate and

profound impact on contemporary cardiology.1 TheCAST promises to exert considerable influence onantiarrhythmic drug development, the future designof clinical trials of antiarrhythmic therapy, andphysicians’ attitudes toward prescribing antiar-rhythmic drugs.

SUMMARY OF THE CAST RESULTS

The CAST was designed to test the hypothesis that

suppressing ventricular premature complexes

(VPCs) in patients surviving acute myocardial in-farction could reduce the incidence of arrhythmicdeath/cardiac arrest, the primary endpoint in theCAST. Many of the design features in the CAST areoutlined in Table I. For comparison and discussion,the design features of the previously completed Car-diac Arrhythmia Pilot Study (CAPS)2 are listed inTable I. The CAST was similar to the CAPS in that itwas double-blind with a parallel placebo group. TheVPC entrance criterion was slightly reduced, leftventricular (LV) ejection fraction (EF) limits werechanged, and the entrance window from time ofacute myocardial infarction was increased to 2years. However, patients presenting later (91 days-2years) required a baseline LVEF to be �40%. Thearrhythmia suppression goals of the CAST weremore stringent than those of the CAPS. The defini-tions of ventricular tachycardia (VT) and proar-rhythmia were liberalized. Encainide, flecainide,and moricizine were chosen for the CAST in dosesthat appeared to be effective and safe in the CAPS,3the goal being to provide alternative therapies to

From the Section of Cardiology, Department of Internal Medicine,

Baylor College of Medicine and The Methodist Hospital (Dr. Craig M.

Pratt), and the University of Texas School of Public Health (Dr. Lemuel

Moye), Houston, Texas. Address for reprints: Craig M. Pratt, MD, The

Methodist Hospital, Baylor College of Medicine, 6535 Fannin MS

FlOOl, Houston, TX 77030.

achieve VPC suppression in as many patients as pos-sible. In the CAPS, flecainide increased the inci-dence of congestive heart failure3; thus, patientswith an LVEF < 30% could be randomized only tomoricizine or encainide. Encainide and flecainideachieved the CAPS suppression goals more fre-quently than moricizine3 and therefore were the ini-tial alternatives in CAST patients whose LVEF was�30%.

As shown in Table I, the CAST was similar to thepilot study, with two major exceptions. First, as op-posed to the CAPS, the CAST was a trial only ofpatients with demonstrated arrhythmia suppres-sion. In addition, the CAST differed from the pilotstudy in that there was an open-label titration phaseto identify responders.

The CAST was designed to test the hypothesis thatarrhythmia suppression would result in a reductionin arrhythmic death/cardiac arrest. The primaryendpoint was assumed to have a 3-year cumulativeincidence of 11% in the placebo group. This wasextrapolated from the overall 1-year incidence ofarrhythmic death/cardiac arrest observed in theCAPS, which was 4.5%. A sample size of 4400 pa-tients was needed to detect a 30% reduction in theincidence of arrhythmic death/cardiac arrest with atype I or a error set at a one-tail level of 0.025 with apower to detect the hypothesized difference in mor-talities between the two groups of 0.84.1

The CAST was due to be completed in enrollmentand follow-up in 1992; however, an unexpected in-creased mortality led to the discontinuation of boththe encainide and flecainide limbs. In fact, there wasa 3.64-fold increase in arrhythmic death/cardiacarrest in patients taking encainide and flecainidecompared with their respective placebo group (P<.002).1 There did not appear to be any confoundingfactors explaining the marked mortality differencebetween the encainide- and flecainide-treated pa-tients compared with the placebo group. In fact,baseline clinical and laboratory characteristics wereremarkably similar between the two groups. Therewas increased risk of taking encainide and flecain-

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968 #{149}J Clin Pharmacol 1990;30:967-974

TABLE I

Comparison of Selected Design Features of CAPS and CAST

Design FeaturesCAPS CAST

Parallel placebo group + +Double blind + +

VPC/hr �10 �6LVEF limits LVEF � 20% LVEF � 55% (6-90 days)

LVEF � 40% (19 days-2 yrs)

Time from Ml 6-60 days 6-90 days (LVEF < 55%)91 days-2 yrs (LVEF <40%)

Age cut-off (yr) <75 <80Open-label drug titration 0 +Antiarrhythmic drugs Encainide, flecainide, moricizine, Encainide, flecainide, * moricizine, placebo

imipramine, placeboBeta blocker therapy Encouraged EncouragedVPC suppression goalt 70% VPC reduction 80% VPC reductionVT suppression goalt 90% VT reduction if �10 runs 90% VT reduction if �5 runs

100% VT reduction if �10 runs 100% VT reduction if �5 runsDefinition of nonsustained VT 3-9 consecutive VPC � 100/mm 3-15 consecutive VPC � 120/mmVT proarrhythmia definition >50 runs/day if <5 runs >50 runs/day if <5 runs

>10 X increase if �5 runs >10 X increase if �5 runsNew VT, length � 10 consecutive VPCs New VT, length � 15 consecutive VPCs

Flecainide considered only for patients with LVEF> 30%. LVEF = left ventricular ejection fraction; Ml = myocardial infarction; VPC = yen-

t Holter on antiarrhythmic drug compared with baseline Holter; CAPS Car- tricular premature contraction; VT = ventricular tachycardia.diac Arrhythmia Pilot Study; CAST Cardiac Arrhythmia Suppression Trial;

ide in all subgroups analyzed. This consistency ofthe excessive risk of encainide and flecainide in allsubgroups was a remarkable feature of the CASTresults.1

LESSONS FROM THE CARDIACARRHYTHMIA PILOT STUDY (CAPS)

Some of the key design features of the CAPS are

presented in Table I. The CAPS was designed to col-lect information that would be useful in planning anational mortality trial to reduce arrhythmic death.The CAPS itself was not designed to be a mortalitytrial. However, it is fair to ponder the question ofwhy the CAPS, a 502-patient pilot study, could notdetect the magnitude of the 3.64-fold increase in ar-rhythmic death/cardiac arrest in the encainide/fle-cainide groups ultimately detected in the CAST.3The CAPS evaluated four groups of 100 patients as-signed to one of four antiarrhythmic drugs and a100-patient, parallel placebo group. The results ofthe CAPS supported the feasibility of performing afull-scale clinical trial designed to test the VPC sup-pression hypothesis. The cumulative incidence ofarrhythmic death/cardiac arrest in the CAPS was

4.5% in 1 year.3 This figure was used to estimate the

CAST sample size.There was no statistically significant difference

between the arrhythmic death/cardiac arrest mor-tality of any of the CAPS antiarrhythmic drugs (fle-cainide, encainide, imipramine, moricizine) com-pared with placebo over the 1 year of the trial. Thetotal mortality in the placebo group was 7%. Ap-proximately one-half of the entire CAPS mortalitywas due to arrhythmic death/cardiac arrest. Onecan calculate the power of the CAPS to detect signif-icant increases or decreases in arrhythmic deathmortality on active antiarrhythmic therapy com-pared with placebo (Table II). Even if one combinedthe observations made from two of the treatmentlimbs (e.g., N = 200 for encainide and flecainide), theCAPS had <5% power to detect a 3.64-fold increasein arrhythmic death/cardiac arrest rate if one as-sumes that the arrhythmic death rate in the placebogroup was 3.5%. The power of a study is its ability todetect the treatment effect of interest through thebackground variability created by the different reac-tions of individual patients. Table II documents thatCAPS had little ability to detect an adverse treat-ment effect (even a 3.64-fold increase in arrhythmic

CARDIAC ARRHYTHMIA SUPPRESSION TRIAL

SYMPOSIA 969

TABLE II

Power of CAPS to Detect Changes in ArrhythmicDeath Mortality (Assuming 4.5% Arrhythmia

Death Rate)

Ratio of Treatmentto Placebo Mortality

Power to DetectDifference

Placebo Better Than Drug

5.002.501.671.25

5.9%3.2%1.7%0.9%

Drug Better Than Placebo

0.800.600.400.200.100.05

0.9%1.7%3.2%5.9%8.1%9.5%

See text for explanation. Calculation assumptions: 3.5%; arrhythmic deathrate, a error = 0.013; sample size = 200. drop-in -0.02; drop-out -0.20.

death mortality) with any statistical certainty. Aspilot study, CAPS could not be expected to detecteven large mortality differences between such smallgroups with statistical certainty, given the low inci-dence of arrhythmic deaths.

DO THE CAST RESULTS DEFY TRADITIONALCONCEPTS OF PROARRHYTHMIA?

One of the most striking observations made in theCAST was that patients receiving encainide and fle-cainide had an increased arrhythmic death/cardiacarrest event rate in every month of the trial.1Whereas the traditional prevailing wisdom was thatantiarrhythmic drugs most often produce a proar-rhythmic effect within the first days of therapy,46the CAST results clearly documented an increasedproarrhythmic death rate for all 10 months of thetrial. Thus, the traditional view of proarrhythmiarequires a conceptual re-evaluation. In this respect,the increase in arrhythmic deaths defied the pre-vailing wisdom regarding proarrhythmia. This tem-poral assumption was based on many publications,including retrospective analysis of torsade(s) depointes VT4 and database observations of various an-tiarrhythmic drugs,5-7 as well as the electrophysio-logic study of antiarrhythmic drugs.6 Based on elec-trophysiologic data, Minardo et al concluded that

the mean time for development of drug-associatedsustained VT or ventricular fibrillation was 3 days.6

The discovery of a 3.64-fold increase in arrhyth-mic death/cardiac arrest in the encainide and fle-cainide groups of the CAST is all the more strikingconsidering that patients randomized in the CASThad already undergone the usual surveillance forproarrhythmia. They had been given encainide orflecainide for an average of 2 weeks during an open-label titration phase. They were only entered intothe randomized CAST trial if they demonstrated tol-erance of the antiarrhythmic drug given during theopen-label phase and had �80% VPC suppressioncompared with their baseline Holter recording.Thus, the excessive number of arrhythmic deathsamong patients given encainide and flecainide in theCAST occurred despite meticulous use of the stan-dard clinical methods of screening for proarrhyth-mia before randomization. The observation of anexcessive arrhythmic death mortality in patients al-ready proven to tolerate these drugs and to be “sup-

pressors” is especially troublesome and further dis-pels the previous concepts of proarrhythmia.

SUGGESTED MECHANISMS OF ENCAINIDE/FLECAINIDE PROARRHYTHMIA IN THE CAST

It has been suggested that the mechanism by whichantiarrhythmic drugs can induce life-threateningventricular arrhythmias is their electrophysiologicproperties of slowing conduction in diseased areas ofthe myocardium.8 This potentially enhances thepossibility of a re-entrant sustained VT. Rinken-berger and associates have postulated that antiar-rhythmic drugs may facilitate the initiation of sus-tained VT by significantly prolonging activationwhile minimally changing refractoriness.8 These ef-fects may be accentuated during myocardial isch-emia. Animal studies support this concept. In a ca-nine model with previous myocardial infarction,Nattel and colleagues noted that dogs pretreatedwith aprinidine had a greatly increased incidence ofsustained VT during a repeat acute ischemic episodecompared with dogs with no pretreatment.9 In thismodel, pretreatment with an antiarrhythmic drugbefore coronary occlusion was “proarrhythmic.” Pa-tients randomized in the CAST did not have a sys-tematic evaluation of ischemia, making retrospec-tive assessment of that variable difficult. However,perhaps patients in the CAST, as demonstrated inthe animal model, had a decreased fibrillationthreshold during acute ischemia that was enhancedby the presence of either flecainide or encainide.

It is also established that both of these agents have

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970 #{149}J Clin Pharmacol 1990;30:967.-974

a significant negative inotropic effect.31#{176} We havepublished data on a variety of antiarrhythmic drugsdemonstrating that patients with a reduced LVEF

are more likely not to suppress on the antiarrhyth-mic drugs and that the incidence of both life-threat-ening proarrhythmia and heart failure is signifi-cantly increased, especially in patients with anLVEF � 30%.h1 Thus, since the CAST included manypatients with LV dysfunction, the proarrhythmic ef-fects of encainide and flecainide were potentiallyenhanced.31011

LIMITATIONS IN THE ANALYSIS OFA PHARMACEUTICAL DATABASE

It is common practice to analyze the entire experien-tial database5712 of a new antiarrhythmic drug toestimate its proarrhythmic and negative inotropic

potential when filing a New Drug Application (NDA)with the Food and Drug Administration (FDA). It is

therefore somewhat troubling why the analysis ofthe databases of encainide (N = 1755) and flecainide

(N = 1330) did not detect, or at least raise suspicionof, the high incidence of proarrhythmic death in pa-tients presenting with potentially lethal ventriculararrhythmias.5-12 By the classification system com-

monly used, the CAST population would be in thepotentially lethal category.57 Yet, the CAST encain-ide/flecainide population had a 4.4% arrhythmic

death mortality after a mean of 10 months of ther-apy, higher even than the estimated incidence oflethal proarrhythmia for patients presenting withlethal ventricular arrhythmias in the flecainide andencainide database studies. In the analysis of drugdatabases, it has been conventional to define theproarrhythmic effects of antiarrhythmic drugs as ar-rhythmic events occurring within days or weeks ofthe initiation of therapy.57-12 Arrhythmic death oc-curring months or years after the initiation of antiar-rhythmic therapy has usually been considered bythe clinical investigators and/or the sponsor as rep-resenting either “inefficacy” or “natural disease pro-gression.” The antiarrhythmic drug databases of en-cainide and flecainide were reviewed along suchlines,512 the proarrhythmic potential of these twodrugs in the potentially lethal category was not ap-preciated despite the large numeric experience withboth drugs. The combined size of these databases(>3000) exceeded the size of the CAST encainide/flecainide treatment group by fourfold. Also, themean observation in the flecainide database was 292days, nearly identical to the CAST (300 days); yet a0.2% incidence of proarrhythmic death for flecain-ide was reported in the potentially lethal category.5

In our view, the primary reason for this large mor-tality discrepancy is that the CAST population rep-resented a group of patients not included in phar-maceutical drug trials. In fact, patients with recentacute myocardial infarction are almost always ex-

cluded from pharmaceutical studies for reasons thatseem logical. One might speculate that the uniqueproarrhythmia discovered in the CAST is in fact due

to the sporadic recurring episodes of acute ischemiathat would not occur in most patient populations butoccur in a population such as the CAST. A secondand equally important major difference between theCAST study and the database approach to the deter-mination of the proarrhythmic death rate was theinclusion of a parallel placebo group in the CAST. Asa rule, parallel placebo groups are only included inpharmaceutical trials containing patients with be-nign ventricular arrhythmia. They are virtuallynever used in evaluating patients with lethal ven-tricular arrhythmias. The CAST study design, by in-

cluding a parallel placebo group, allowed the dem-onstration of the unusual temporal profile of thisunique lethal proarrhythmia and led to its detection.It is likely that many of the arrhythmic deaths thatoccurred in the CAST after months of treatmentwith either encainide or flecainide would have beenattributed to lack of efficacy or changes in clinicalstatus had it not been for the presence of a parallelplacebo group.

DATABASE PROARRHYTHMIA ESTIMATES:WHAT DO THEY MEAN?

Since estimation of the proarrhythmic potential ofan antiarrhythmic drug using a database approachlacks a parallel placebo group, the interpretation orcomparison of these results with those of patientsreceiving other antiarrhythmic drugs or with theexpected (untreated) arrhythmic death rate due tonatural history is difficult and elusive. It is probablyreasonable to state that the expected arrhythmicdeath rate (untreated) in patients with a benign ven-tricular arrhythmia should be 0%. What are the ex-pected arrhythmic death rates for patients with po-tentially lethal ventricular arrhythmias and forthose with lethal ventricular arrhythmias? It is ex-tremely difficult to analyze the literature to answerthese questions. If we are not clear what the ex-pected sudden death rate is in untreated patients,what yardstick do we use when evaluating theiroutcome on antiarrhythmic therapy? One couldmake a compelling argument that it is impossible toanswer this question, let alone compare the efficacyor safety of the approved antiarrhythmic drugs with

L VEF = left ventricular ejection fraction; Ml = myocardial infarction; VT= ventricular tachycardia; VPCs = ventricular premature complexes.

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SYMPOSIA 971

that of an investigational antiarrhythmic drug,based on a review of the published literature. Thevariables confounding such an assessment or com-parison are contained in Table III.

We live in an imperfect world and must do thebest we can with imperfect data. Therefore, it is stillnecessary to estimate the proarrhythmic rates of an-

tiarrhythmic drugs for benign, potentially lethal,and lethal ventricular presenting arrhythmias in auniform manner. In this sense, the strength of ana-lyzing the entire antiarrhythmic drug database ispreferable to the alternative of analyzing reportsfrom individual clinical centers where sample sizesare small, thereby enhancing the potential for inac-curate and inconsistent arrhythmic death rate esti-mates.

In a typical NDA, the experiential database with anew antiarrhythmic agent usually contains at least1000 patients. Of these, there might be 100-200 pa-tients with benign ventricular arrhythmias, 400-600with potentially lethal ventricular arrhythmias, andperhaps 200 to 400 patients with lethal ventriculararrhythmias. It is difficult to determine the “natu-ral” annual arrhythmic death rate in either the po-tentially lethal or lethal ventricular arrhythmia cat-egory. Each category is hardly uniform, containing

various proportions of patients with a wide spectrum

TABLE III

Confounding Variables When Assessing orComparing Efficacy/Safety of Antiarrhythmic

Drugs Using the Published Literature

1. Assorted patient populations (asymptomatic VPCs,

post-MI, cardiomyopathy, congestive heart failure)2. Patients with new-onset arrhythmia versus patients

previously refractory to therapy3. Various presenting arrhythmias, varying definitions of

sustained VT4. Lack of baseline quantitative LVEF in some trials/patients5. Different suppression endpoints6. Different evaluation modalities (Holter, programmed

electrical stimulation)7. Various durations of Holter recording, different

electrophysiologic stimulation protocols8. Different drug doses, dosing intervals9. Different durations of study to assess outcome (from

acute drug testing to chronic oral therapy)10. Different drug sequences (first choice or last resort?)11. Lack of mortality endpoints12. Lack of parallel placebo group

of arrhythmic death risk. Also, there is the inherentmisclassification introduced by investigator bias in

the assignment of which deaths represent lethalproarrhythmia. Interpretation of which deaths rep-resent lethal proarrhythmia may differ greatly be-tween investigators; thus, the combined estimatewould be difficult to interpret.

A second and equally important issue in the accu-racy of the proarrhythmic death rate is the precisionof the estimator. When analyzing such lethalproarrhythmic death rates, a reasonable questionmight be: What are the widths of the confidenceintervals for different observed proarrhythmic deathrates during antiarrhythmic therapy? That suchconfidence interval widths are sample-size depen-dent is illustrated in Table IV, where the confidenceintervals for a range of events rates are expressed forsample sizes of 100-2000 patients. Let us assumethat the proarrhythmic death rate attributed to anew drug in patients with lethal arrhythmias is 2%.If this database is unusually large, containing 1000patients in the lethal category, the observation of a2% proarrhythmic death rate will have a theoretic

range of actual proarrhythmic deaths between1.1%-2.9%. That is, it is unlikely that the actuallethal proarrhythmia rate will exceed 2.9%. How-ever, if the sample size is smaller in any category,the upper bounds of the actual as compared with theobserved event rate increases dramatically so that atruly unacceptable proarrhythmic death rate couldbe masked. That is, if one assumes that the sameobserved arrhythmic death rate of 2% and a smaller

sample size of 200, the upper bounds of actual lethalproarrhythmia would further increase to nearly 4%(Table IV), double the observed rate.

From a regulatory standpoint, database informa-tion on the estimated incidence of lethal proar-rhythmias derived from sample sizes of a fewhundred patients with potentially lethal arrhyth-mias could dramatically miscalculate (underesti-mate or overestimate) the actual prevalence of ar-rhythmic deaths, potentially masking an unaccept-

able lethal proarrhythmic effect. This observationamplifies the wisdom of the FDA guidelines require-ment of a “large experiential database.” The CASThighlights the need to reassess the sample sizerequirements for each category of presenting ar-rhythmia.

Without the benefit of a parallel placebo group,the database approach to estimating the proarrhyth-mic potential of a new antiarrhythmic drug also hasa second serious defect: misinterpretation of causal-ity by the local study physician. Individual investi-gators may incorrectly infer that an arrhythmic

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972 #{149}J Clin Pharmacol 1990;30:967-974

TABLE IV

Confidence Intervals for a Range of Event Rates and Sample Size

Observed Event Rate(%)

Sample Size

N = 100 N = 200 N = 500 N = 1000 N = 2000

0.51.52.02.53.03.5

4.04.55.05.56.0

.000_.019* .000-015 .000-011

.000-.039 .000-.032 .0O4-.026

.000-.047 .001-.039 .008-032

.000-056 .003-.047 .011-039

.000-063 .006-.054 .015-045

.000-.071 .010-.060 019-.051

.002-.078 .013-067 .023-057

.004-086 .016-.074 .027-063

.007-.093 .020-.080 .031-069

.060-. 100 .023-.087 .035-079

.013-. 107 .027-093 .039-081

.001-009

.007-023

.011-029

.015-035

.019-.041

.024-046

.028-053

.032-058

.036-064

.041-069

.045-075

.002-.008

.010-020

.014-026

.018-.032

.023-.037

.027-043

.031-.049

.037-054

.040-060

.045-.065

.050-070

* Lower and upper bound s of the confidence limits; all computations are two-tailed, beta error 0.05.

death was a result of either lack of efficacy or thechanging clinical status of that patient rather than alethal proarrhythmic effect. The results of the CASTstrongly support the concept that proarrhythmicdeaths can occur over long periods and in fact arenot limited to the initial days or weeks of treatment,at least in patients such as those studied in theCAST. The degree to which this observation can beextrapolated to other patient populations is un-known. Thus, as observed with use of encainide andflecainide, a “large experiential database” does notguarantee an accurate interpretation of the rate oflethal proarrhythmia. A large sample size is neces-sary but not always sufficient to describe accuratelythe actual lethal proarrhythmia rate.

Thus, there two major but independent interpre-tive problems. The former can be knowledgeablymanaged by attention to confidence intervals for anygiven observed event rate and sample size and anaccurate estimate of the expected arrhythmic deathrate in that specific population. The latter, misclas-sifying lethal proarrhythmic events, has an un-known magnitude in any database and no statisticalsolution. A straightforward but harsh “worse casescenario” approach would be to include all observedsudden deaths during the first year of drug exposureas being considered lethal proarrhythmic events andthen calculate event rates and confidence limits ac-cordingly. This is clearly unreasonable. The idealsolution to the latter problem is the inclusion of aparallel placebo group. Identical problems exist fordatabase assessment of the negative inotropic effectof a new compound.

REGULATORY CONSIDERATIONSAS A RESULT OF THE CAST

As a direct result of the CAST, it is clear that theguidelines for the development of a new antiar-rhythmic drug require intensive re-evaluation.When basic investigations are completed and clini-

cal trials begin, there are five essential elements to aviable antiarrhythmic drug development program.13

Each of these elements will require careful reassess-ment of what should be considered feasible and ade-quate. First, the antiarrhythmic properties of a newagent must be defined, including attention to dose-response relationships in clinical trials involving pa-tients with non-life-threatening stable VPCs. Theresults of the CAST offer no assurance that VPCsuppression in that population has any patient ben-efit. In fact, they suggest that it may be dangerous.Therefore, the number of trials, the type of patients,the sample size required, and the goals of such trialsrequire careful re-evaluation.

It is also a basic component of a new antiarrhyth-mic drug development program to describe the de-gree to which the drug can prevent inducibility ofsustained monomorphic VT during programmedelectrical stimulation (PES). Careful considerationwill have to be given to whether there should be acomparative trial with an approved drug, and if so,with what agent. Is the goal that the new agentshould achieve comparability of preventing induc-ible sustained VT with the approved antiarrhythmicdrug? If so, with what sample size and with whatacceptable beta error would one conclude compara-

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SYMPOSIA 973

bility? Does the electrophysiologic assessment of

proarrhythmias accurately reflect the long-termtoxic potential of antiarrhythmic drugs? If selectedby PES, are all arrhythmic deaths after 3 or 6 monthsof therapy really “lack of efficacy?” What guaranteeis there that PES assessment accurately character-izes and detects all of the long-term lethal proar-rhythmic potential of an antiarrhythmic drug?

A complete NDA usually contains additional trialswith the new agent involving patients presentingwith lethal arrhythmias that are not controlled

(open-label). If these trials do not have a placebo-control group, what is an acceptable rate of proar-rhythmic death? Of death due to congestive heartfailure? What sample size will be required so thatthe confidence intervals of the observed proar-rhythmic death rates and heart failure death ratesare, with some confidence, not excessive? The FDAguidelines have called for a “large” experiential da-tabase. In this review, we have pointed out the widerange of confidence intervals of observed arrhyth-mic death rates when sample sizes in an individual

arrhythmia category are limited to a few hundredpatients with no parallel placebo group. A muchmore accurate reflection of these lethal toxic effectsis possible with a parallel placebo group. Techno-logic advances with defibrillator pacemakers may

make such an approach feasible and ethical in thelethal arrhythmia category, using the frequency ofdefibrillations as a surrogate endpoint of arrhythmicdeath mortality.

Should the experiential database include patientswith recent acute myocardial infarction? Shouldapprovability of a new antiarrhythmic drug be lim-ited to the specific patient populations studied, andthis clearly stated in the labeling? How far could

positive results be extrapolated? The results of theCAST point out the importance of these questions.Both will require careful deliberation on the part ofthe FDA. Finally, the FDA guidelines for the devel-opment of a new antiarrhythmic agent require care-ful descriptions of proarrhythmic and negative mo-tropic effects. The CAST provides an excellent ex-ample of the improved accuracy (not to mentionsurprising results) of measuring this potential whena parallel placebo group is feasible and is used. TheCAST should greatly reinforce the legitimate andethical bases of the judicial use of parallel placebogroups.

EXTRAPOLATION OF THE CAST TOOTHER ANTIARRHYTHMIC DRUGS

The results of the CAST have also led to a re-evalua-tion of the current labeling of antiarrhythmic drugs.

It was inevitable that the extrapolation of the CASTto other patient populations and other antiarrhyth-mic agents would occur. As a direct result of theCAST, a special meeting of the Cardiovascular and

Renal Drugs Advisory Board to the FDA was heldOctober 5, 1989, to discuss the implications of the

CAST.13 In that meeting, the committee consideredissues relating to the labeling of currently marketedantiarrhythmic drugs. Information comparable tothe CAST data for flecainide and encainide is notavailable for the other antiarrhythmic drugs. There-fore, the consensus was that a conservative ap-proach be taken. The committee voted to recom-mend restrictive labeling of class IC agents identicalto encainide and flecainide if and when they areapproved and marketed. This would apply to drugssuch as indecainide and propafanone. The discus-sion regarding the electrophysiologic class IA andlB agents required extrapolation based on incom-plete data. It was a consensus of opinion that noantiarrhythmic agent (IA, IB, 1C) should have a la-beling indication to treat asymptomatic non-life-threatening ventricular arrhythmia. The committeedid not reach a consensus regarding a labeling indi-cation for symptomatic non-life-threatening VPCsfor either electrophysiologic class 1A or lB agents.However, the committee concluded that inadequatedata existed to support a recommendation that la-beling be added stating that treatment of either

symptomatic or asymptomatic arrhythmias with theelectrophysiologic class IA or lB agents is contrain-dicated.13

CONCLUSIONS

It is clear that the results of the CAST have led to anintense re-evaluation of the clinical use of antiar-rhythmic drugs for ventricular arrhythmias. Thus,the results of the CAST have far-reaching implica-tions for the development of new antiarrhythmicagents in this country. The unexpected excessivemortality caused by encainide and flecainide in theCAST magnifies the need for developing new antiar-rhythmic drugs that will be beneficial for patients.Currently, VPC suppression has not been shown toimprove prognosis in the potentially lethal riskgroup. In fact, published experience emphasizes anincreased risk of antiarrhythmic therapy in this pa-tient population that is not counterbalanced by anydemonstrated patient benefit.1-11

It is important to emphasize that the CAST is con-tinuing to enroll patients, addressing the benefits ofVPC suppression with moricizine.7 Moricizine hasthus far been judged safe by the Data and SafetyMonitoring Board of the CAST. The results of the

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974

moricizine limb (compared with placebo) will be

critically important in determining whether the in-

creased risk associated with using encainide andflecainide in this population can be generalized to

other electrophysiologic classes, since moricizinehas many electrophysiologic properties of the classesIA and lB.

In the interim, the CAST results will continue tohave a profound effect on the design of future clini-

cal trials, will promote the development of innova-

tive laboratory models to investigate arrhythmicdeath, and will affect clinicians’ attitudes toward

antiarrhythmic therapy. The public health implica-tions are enormous, given the millions of new anti-arrhythmic drug prescriptions written each year.14 If

anything, efforts to solve this dilemma should accel-erate, since excess of more than a quarter of a mil-lion Americans still die annually of arrhythmic

death.

REFERENCES

1. The Cardiac Arrhythmia Suppression Trial (CAST) Investiga-

tors: Preliminary report: Effect of encainide and flecainide on

mortality in a randomized trial of arrhythmia suppression after

myocardial infarction. N EngI J Med 1989;321:406-412.

2. The CAPS Investigators: The Cardiac Arrhythmia Pilot Study.

Am J Cardiol 1986:57:91-95.

3. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators: Ef-

fects of encainide, flecainide, imipramine, and moricizine on ven-

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