There is increasing recognition that systematic post–cardiac arrest care after return of spontaneous circulation (ROSC) can improve the likelihood of patient. Number: 0073. Aetna considers external intermittent cardiac event monitors (i.e., external loop recorders) and external intermittent cardiac event monitors.

Results During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29). A series of clinical trials have examined the effects of angiotensin-converting–enzyme (ACE) inhibitors on survival after acute myocardial infarction. Large studies have shown a moderate benefit of short-term ACE inhibition started early after infarction in unselected patients.

Other studies, in which long-term treatment was started some days after infarction in selected patients with left ventricular dysfunction or clinical signs of heart failure, have shown a greater benefit. Because of the differences among various studies in relative benefit, timing and duration of treatment, and selection of patients, important questions about the role of ACE inhibition remain unanswered. Another problem is that in most studies the portion of the screened population randomly assigned to treatment has been either small or not fully described, and the mortality among enrolled patients has been lower than in epidemiologic studies of unselected patients with myocardial infarction. Thus, even though the total number of patients enrolled in previous studies is large, it is difficult to extrapolate the results of these studies to apply to the wider population of patients with myocardial infarction. The Trandolapril Cardiac Evaluation (TRACE) study was designed to determine whether patients who have left ventricular dysfunction soon after myocardial infarction benefit from long-term oral ACE inhibition.

We used a strict procedure based on screening of consecutive patients and ensured that the majority of patients with left ventricular dysfunction would be enrolled. Methods A detailed description of the study and demographic information on the screened population have been reported previously. In brief, TRACE was a double-blind, randomized, placebo-controlled study conducted at 27 centers in Denmark. The study was registered with the National Board of Health and the Danish Data Protection Agency and was approved by the regional ethics committees. An independent safety committee reviewed quarterly safety reports, as well as three preplanned interim analyses of mortality. Screening and Inclusion All participating hospitals identified all patients with myocardial infarction within their catchment areas. Consecutive patients above the age of 18 years who were hospitalized with myocardial infarction were screened between day 2 and day 6 after the onset of symptoms.

The criteria for myocardial infarction were chest pain or electrocardiographic changes suggestive of infarction or ischemia, accompanied by an increase in the level of one or more cardiac enzymes to at least twice the upper limit of the normal value at the laboratory of the participating hospital. At the time of screening, an echocardiographic examination was recorded on videotape by the investigator and sent by courier to the study office, where within 24 hours, two of us calculated the wall-motion index using a nine-segment model originally described by Heger et al.

The scale used for the wall-motion index has been described previously, and the method validated. Potentially eligible patients were those with left ventricular systolic dysfunction (wall-motion index. Dose Titration and Duration of Treatment Double-blind medication was started between day 3 and day 7 after the myocardial infarction. Patients were randomly assigned to receive 1 mg of trandolapril once daily or matching placebo on the basis of a computer-generated assignment scheme with randomization in blocks of four and stratification according to the center and the degree of left ventricular dysfunction (wall-motion index. End Points A mortality end-point committee evaluated information on all deaths before the treatment code was broken. In the case of inadequate information, the cause of death was classified as “unknown.” If sufficient information was available, death was judged to be due to cardiovascular or noncardiovascular causes.

Among deaths from cardiovascular causes, sudden death was defined as death occurring within one hour after the onset of new symptoms. The committee determined the cause of death independently of its timing. Deaths from cardiovascular causes were further specified as due to recurrent infarction or progressive heart failure.

A reinfarction end-point committee evaluated all cases of nonfatal reinfarction reported by the investigators; again, this review was performed before the treatment code was broken. A reinfarction was defined as the onset of new symptoms or typical electrocardiographic changes accompanied by elevated cardiac enzyme levels (or both) or as the development of a new Q wave accompanied by typical symptoms. The primary end point was death from any cause.

Information on survival status was available for all patients at the end of the study. Secondary end points were death from a cardiovascular cause, sudden death, progression to severe heart failure (defined as the first of the following events: hospital admission for heart failure, death due to progressive heart failure, or heart failure necessitating the administration of open-label ACE inhibition), recurrent infarction (fatal or nonfatal), and a change in the wall-motion index. Statistical Analysis The calculation of the sample size has been described previously.

Analyses of mortality were performed on an intention-to-treat basis. The final analysis of the primary end point, which took into account the interim analyses, was planned as an asymmetric, one-sided test with a significance level of 0.0225 in favor of trandolapril and 0.10 in favor of placebo. Two-sided P values are cited throughout this report. The base-line characteristics of the treatment and placebo groups were compared with the Cochran–Mantel–Haenszel test. Frequencies of adverse events were compared with the chi-square test. Differences in base-line continuous variables, as well as serial changes in the wall-motion index, were determined by an analysis of variance.

Time-to-event curves were generated with the use of Kaplan–Meier estimates. Comparisons of mortality from all causes were made with the log-rank test, with the wall-motion index and center as stratification variables. Comparisons of time-to-event distributions for secondary end points and of the time-to-discontinuation distribution were made without stratification variables. In the analyses of end points other than mortality, data were censored at the time of the first relevant event or two weeks after withdrawal. Relative risk was calculated as a hazard ratio derived from the Cox proportional-hazards regression. For the analysis of subgroups, estimates of relative risk and the associated 95 percent confidence intervals were generated with a Cox proportional-hazards model. Calculations were performed with the SAS software (SAS Institute, Cary, N.C.).

Patient Selection and Demographic Data Between May 1, 1990, and July 7, 1992, a total of 7001 consecutive episodes of myocardial infarction were evaluated in 6676 patients, with some patients undergoing screening on more than one occasion. Screening with echocardiography resulted in the identification of 2606 eligible patients with a wall-motion index less than or equal to 1.2, corresponding to an ejection fraction less than or equal to 35 percent. A total of 3920 patients were excluded because they had a wall-motion index that was higher than 1.2, and 475 were excluded because the wall-motion index could not be determined.

As described in detail previously, there was an inverse relation between the wall-motion index and mortality. Among the patients with an index higher than 1.2, 40 percent had signs of congestive heart failure, and the overall mortality at one year was 12 percent. Among the 2606 patients who were eligible for the trial (i.e., those with a wall-motion index 1.2) were included: 876 in the trandolapril group, and 873 in the placebo group. There were no important differences between the base-line characteristics of the two groups ( Table 1 Base-Line Characteristics of 1749 Patients Assigned to Receive Trandolapril or Placebo. Mortality The three preplanned interim analyses of mortality were conducted in June 1991 (with a total of 673 patients), February 1992 (with a total of 1209), and August 1993 (with a total of 1745). The outcomes were sent only to the safety committee.

The criteria for stopping the study were not met, and the study continued to its planned conclusion. The mortality from all causes at one year was 24 percent. During the study period, 304 patients in the trandolapril group died (34.7 percent), as did 369 in the placebo group (42.3 percent). Mortality curves are shown in Figure 1 Cumulative Mortality from All Causes among Patients Receiving Trandolapril or Placebo.. The relative risk of death from any cause in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91; P = 0.001). The mortality curves diverged early (Kaplan–Meier estimate of mortality at one month, 8.8 percent in the trandolapril group and 11.2 percent in the placebo group) and continued to diverge throughout the follow-up period.

The effect of trandolapril on overall mortality in subgroups of patients is shown in Table 2 Relative Risk of Death from Any Cause in Subgroups of Patients Receiving Trandolapril or Placebo.. In every subgroup, treatment with trandolapril was associated with a reduction in risk. Classifications of deaths according to cause by the mortality end-point committee are shown in Table 3 Causes of Death in the Trandolapril and Placebo Groups.. There were significantly fewer deaths from cardiovascular causes in the trandolapril group than in the placebo group (226 vs. 288; P = 0.001; relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89). There were also significantly fewer sudden deaths in the trandolapril group (105 vs.

133; P = 0.03; relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98). Time-to-event curves for these secondary end points are shown in Figure 2 Event Rates for the Secondary End Points of Death from Cardiovascular Causes, Sudden Death, Reinfarction, and Severe or Resistant Heart Failure among Patients Receiving Trandolapril or Placebo.. Other Clinical End Points Progression to severe heart failure occurred in 125 patients in the trandolapril group and 171 in the placebo group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). Heart failure developed significantly earlier in the placebo group than in the trandolapril group ( ). Eighty-two patients receiving trandolapril and 103 receiving placebo died from heart failure.

There was a trend toward a reduction in recurrent fatal or nonfatal infarction among the patients receiving trandolapril, as compared with those receiving placebo ( ). There were 99 fatal or nonfatal reinfarctions in the trandolapril group and 113 in the placebo group (P = 0.29; relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13). At base line and after 3, 6, and 12 months, the mean wall-motion index was 1.03, 1.12, 1. Best Of Rafi Downloadming. 16, and 1.15, respectively, in the trandolapril group and 1.03, 1.10, 1.15, and 1.18, respectively, in the placebo group. After three months, the mean change from the base-line index was 0.09 in the trandolapril group and 0.06 in the placebo group (P = 0.03). This statistically significant difference was absent at 6 and 12 months. Follow-up and Withdrawal The follow-up period was 24 to 50 months. Apart from the patients who died, 328 (37.4 percent) were withdrawn from the trandolapril group and 310 (35.5 percent) from the placebo group.

The need for open-label ACE inhibition to treat heart failure was a more common reason for withdrawal in the placebo group (accounting for 75 patients) than in the trandolapril group (accounting for 48). Other important reasons for withdrawal were cough (in 39 patients in the trandolapril group and 13 in the placebo group), hypotension (in 18 and 7, respectively), and a reduction in kidney function (in 18 and 6, respectively).

Discussion This study has demonstrated that survival was improved among patients with left ventricular systolic dysfunction who were selected from among consecutively screened patients with myocardial infarction and treated with the ACE inhibitor trandolapril for two to four years. The improvement in survival was observed whether or not there were clinical signs of heart failure. There was an associated reduction in deaths from cardiovascular causes and sudden deaths, as well as in the development of severe heart failure. Fatal or nonfatal reinfarctions were not significantly reduced in frequency.

Unlike other large trials of treatment after myocardial infarction, the TRACE study was performed in one small country, Denmark. This approach facilitated the screening of consecutive patients and the inclusion of a large fraction of the target population with left ventricular systolic dysfunction. Consequently, patients in TRACE were older than in other studies and had a higher mortality rate. Among the patients excluded because of a wall-motion index that was greater than 1.2, the mortality rate at one year was 12 percent. This rate is lower than that among the patients in our study with a lower wall-motion index but higher than the rates reported in most studies. We attribute these differences to systematic consecutive screening and complete regional case ascertainment without an upper age limit. To date, the TRACE study is the only trial of ACE inhibition after myocardial infarction that has shown a significant reduction in sudden deaths.

We defined sudden deaths as those occurring within one hour after the onset of symptoms. It is therefore uncertain whether our result reflects the protective effect of trandolapril against severe arrhythmias, as suggested by studies in animals, or a reduction in sudden deaths from nonarrhythmic causes. The importance of the concept of sudden death as an indicator of death from arrhythmic causes in patients with heart failure has been challenged. We did not observe a reduction in recurrent infarction, as was observed in the SAVE study. Our definition of reinfarction was strict, and the overall rate of a first recurrent infarction was low. The validity of the reduction in the rate of clinical reinfarction reported in the SAVE study has been subject to criticism.

No single trial using strict, predefined criteria for reinfarction has shown that long-term ACE inhibition has a clear-cut benefit with respect to recurrent infarction. Like the SAVE study, the TRACE study included patients with left ventricular systolic dysfunction, but there are important differences between the two trials.

In the SAVE study, left ventricular function was measured by radionuclide cardiography an average of 11 days after infarction. Patients with overt heart failure or active ischemia were specifically excluded from the SAVE study, whereas the TRACE study was designed to include the majority of patients with left ventricular systolic dysfunction. The Acute Infarction Ramipril Efficacy (AIRE) study differed from the SAVE and TRACE studies. In the AIRE study, a 27 percent reduction in mortality was observed among patients treated with ramipril who had clinical signs of heart failure after infarction. The AIRE substudy of left ventricular function indicates that in a substantial fraction of patients, left ventricular function was preserved. On the other hand, patients with left ventricular dysfunction but without signs of heart failure would have been excluded from the AIRE study. In comparison, 40 percent of the patients excluded from the TRACE study because of a wall-motion index higher than 1.2 had clinical signs of heart failure, and 24 percent of the enrolled patients did not have signs of heart failure.

Because similar degrees of reduction in mortality were observed in all three studies, it appears likely that patients with clinical signs of heart failure and preserved left ventricular systolic function will benefit from ACE inhibition. In the TRACE study, the benefit of trandolapril appeared to be similar whether or not there were clinical signs of heart failure. This finding indicates that an assessment of left ventricular function is necessary to identify all patients who will benefit from long-term ACE inhibition. Other trials have evaluated the use of short-term ACE inhibition after acute myocardial infarction in unselected patients. The Fourth International Study of Infarct Survival (ISIS-4) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) recruited very large numbers of patients. Both studies found a moderate reduction in short-term mortality among patients treated with captopril for five weeks or lisinopril for six weeks, beginning within 24 hours after infarction. It is likely that the greater benefits of ACE inhibition observed in the more selective trials are also present in the less selective trials but are diluted because of the many patients who did not have a benefit.

In the TRACE study, 24 lives were saved after one month of treating 1000 patients. Since 25 percent of consecutive patients with acute myocardial infarction were randomly assigned to treatment and on the assumption that none of the other 75 percent would have benefited from treatment, roughly six lives would have been saved if all the patients had been treated — an outcome very similar to that in the less selective trials — suggesting that the 25 percent of patients who were selected from the screened population account for the entire benefit. The populations screened for the various studies, however, may not have been similar. In conclusion, the results of our study indicate that at least two thirds of patients who have echocardiographic signs of left ventricular systolic dysfunction three to seven days after a myocardial infarction are candidates for long-term treatment with trandolapril and that such treatment improves survival and reduces cardiovascular morbidity. References • 1 Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H.

Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study (Consensus II). N Engl J Med 1992;327:678-684 • 2 ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction.

Lancet 1995;345:669-685 • 3 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto MiocardicoGISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115-1122 • 4 Chinese Cardiac Study Collaborative Group. Oral captopril versus placebo among 13 634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345:686-687 • 5 Pfeffer MA, Braunwald E, Moye LA, et al.

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992;327:669-677 • 6 The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-828 • 7 Ambrosioni E, Borghi C, Magnani B. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction.

N Engl J Med 1995;332:80-85 • 8 Emanuelsson H, Karlson BW, Herlitz J. Characteristics and prognosis of patients with acute myocardial infarction in relation to occurrence of congestive heart failure. Eur Heart J 1994;15:761-768 • 9 Stevenson R, Ranjadayalan K, Wilkinson P, Roberts R, Timmis AD. Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis. BMJ 1993;307:349-353[Erratum, BMJ 1993;307:909.] • 10 The TRACE Study Group.

The TRAndolapril Cardiac Evaluation (TRACE) study: rationale, design, and baseline characteristics of the screened population. Am J Cardiol 1994;73:44C-50C • 11 Kober L, Torp-Pedersen C.

Clinical characteristics and mortality of patients screened for entry into the Trandolapril Cardiac Evaluation (TRACE) study. Am J Cardiol 1995;76:1-5 • 12 Heger JJ, Weyman AE, Wann LS, Rogers EW, Dillon JC, Feigenbaum H. Cross-sectional echocardiographic analysis of the extent of left ventricular asynergy in acute myocardial infarction. Circulation 19-1118 • 13 Berning J, Steensgaard-Hansen F. Early estimation of risk by echocardiographic determination of wall motion index in an unselected population with acute myocardial infarction.

Am J Cardiol 1990;65:567-576 • 14 Kober L, Torp-Pedersen C, Carlsen J, Videbaek R, Egeblad H. An echocardiographic method for selecting high risk patients shortly after acute myocardial infarction, for inclusion in multi-centre studies (as used in the TRACE study). Eur Heart J 19-1620 • 15 Berning J, Rokkedal-Nielsen J, Launbjerg J, Fogh J, Mickley H, Andersen PE. Advent Aw10 Driver Apple Mobile.

Rapid estimation of left ventricular ejection fraction in acute myocardial infarction by echocardiographic wall motion analysis. Cardiology 1992;80:257-266 • 16 Cochran WG. Some methods for strengthening the common ξ 2 tests. Biometrics 1954;10:417-451 • 17 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-748 .

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Original Article Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo — The Cardiac Arrhythmia Suppression Trial Debra S. Echt, M.D., Philip R.

Liebson, M.D., L. Brent Mitchell, M.D., Robert W. Peters, M.D., Dulce Obias-Manno, R.N., Allan H. Barker, M.D., Daniel Arensberg, M.D., Andrea Baker, R.N., Lawrence Friedman, M.D., H. Leon Greene, M.D., Melissa L. Huther, David W.

Richardson, M.D., and the CAST Investigators* N Engl J Med 1991; 324:781-788 DOI: 10.1056/NEJM41201. Background and Methods. In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo. Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo).

After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.01), and 8 of noncardiac causes (3 receiving drug vs.

5 receiving placebo). Almost all cardiac deaths not due to arrhythmia were attributed to acute myocardial infarction with shock (11 patients receiving drug and 3 receiving placebo) or to chronic congestive heart failure (4 receiving drug and 2 receiving placebo). There were no differences between the patients receiving active drug and those receiving placebo in the incidence of nonlethal disqualifying ventricular tachycardia, proarrhythmia, syncope, need for a permanent pacemaker, congestive heart failure, recurrent myocardial infarction, angina, or need for coronary-artery bypass grafting or angioplasty. VENTRICULAR premature depolarizations are a risk factor for sudden and nonsudden cardiac death after myocardial infarction and are often treated with antiarrhythmic drugs. Ventricular arrhythmia and left ventricular dysfunction have been found to be independent predictors of cardiac mortality, with more than 10 ventricular premature depolarizations per hour (detected by ambulatory monitoring) associated with a fourfold higher mortality rate. Previous studies have failed to demonstrate that antiarrhythmic therapy reduces the long-term risk of sudden death. The Cardiac Arrhythmia Suppression Trial (CAST), a multicenter, randomized, placebo-controlled study, was designed to test whether the suppression of asymptomatic or mildly symptomatic ventricular arrhythmias with antiarrhythmic drug therapy after myocardial infarction would reduce the rate of death due to arrhythmia.

Recruitment for the trial began in June 1987. Three antiarrhythmic agents were studied, on the basis of the results of the Cardiac Arrhythmia Pilot Study (CAPS).

That study had shown that encainide, flecainide, and moricizine suppressed arrhythmias adequately in the target population. Recruitment was planned to last three years, from June 1987 to June 1990. However, in April 1989 the Data and Safety Monitoring Board — an independent body responsible for reviewing the results of the trial on a regular basis to protect the patients — recommended that the use of encainide and necainide be discontinued because the data indicated it was unlikely that benefit could be demonstrated, and it was likely that the drugs were harmful. Encainide and flecainide were discontinued at that time, and a preliminary report of the trial was published. Moricizine is the only antiarrhythmic drug whose use is being continued in the revised CAST (CAST II). This paper details the final analysis of mortality and also reports on morbidity among patients receiving encainide or flecainide or their corresponding placebos.

Methods The study protocol has been described previously. In brief, patients were eligible for enrollment six days to two years after myocardial infarction if they had an average of six or more ventricular premature depolarizations per hour on ambulatory electrocardiographic monitoring of at least 18 hours' duration, and no runs of ventricular tachycardia of 15 or more beats at a rate of ≥120 beats per minute. Patients were required to have an ejection fraction of 0.55 or less if recruited within 90 days of the myocardial infarction, or 0.40 or less if recruited 90 days or more after the myocardial infarction. Evaluation during an initial, open-label titration period identified patients who responded to one of the drugs with at least 80 percent suppression of ventricular premature depolarizations and at least 90 percent suppression of runs of ventricular tachycardia. Initial open-label drug assignment to encainide, flecainide, or moricizine was in part dependent on the ejection fraction.

Flecainide was not given to patients with an ejection fraction below 0.30, to avoid potential aggravation of left ventricular dysfunction., Patients with an ejection fraction below 0.30 were randomly assigned to encainide or moricizine as the first or the second drug. Because its ability to suppress ventricular arrhythmias was somewhat less than that of encainide or flecainide, moricizine was used only as a second drug in patients with an ejection fraction of 0.30 or higher. Patients in whom arrhythmias were suppressed were enrolled in the main study and randomly assigned to receive either the effective drug or its corresponding placebo. Patients whose arrhythmias were only partially suppressed were enrolled in a substudy. The primary end point of the trial was death or cardiac arrest with resuscitation, either of which was due to arrhythmia. Death was defined as the spontaneous cessation of respiration and circulation (pulse) with loss of consciousness, and this end point included cardiac arrest with resuscitation, provided that both cardiopulmonary resuscitation and defibrillation were required.

Death was judged to be due to arrhythmia if it was characterized in any of the following ways: (1) witnessed and instantaneous, without new or accelerating symptoms; (2) witnessed and preceded or accompanied by symptoms attributable to myocardial ischemia in the absence of shock or Class IV congestive heart failure as categorized by the New York Heart Association; (3) witnessed and preceded by symptoms attributable to cardiac arrhythmia — e.g., syncope or near-syncope; or (4) unwitnessed but without evidence of another cause. In the presence of severe congestive heart failure, death was judged to be not due to arrhythmia if death from heart failure appeared probable within four months of the fatal episode.

The principal investigator at the study center was responsible for classifying each death and providing a summary of the circumstances surrounding it, without knowledge of the patient's assigned treatment. The classification and summary were reviewed by a member of the Events Committee. In case of disagreement between the principal investigator and the committee member, the death was classified by the entire committee. All members of the Events Committee were unaware of the patient's assigned treatment. There was agreement between the principal investigator at the center where the death occurred and the primary reviewer of the Events Committee on the classification of 86 percent of deaths. In addition to the primary end point of death or cardiac arrest due to arrhythmia, the effects of antiarrhythmic drug therapy on other events were also examined. Statistical Analysis Analysis groups were determined by assignment at randomization, according to the principle of intention to treat.

Actuarial curves were calculated with the Kaplan–Meier method. The primary and secondary end points of the active-drug and placebo treatments were compared by standard log-rank tests. Observation began on the day of randomization to blinded therapy and was censored with respect to death or cardiac arrest or with respect to April 18, 1989, the date when the use of encainide and flecainide was discontinued.

All reported P values are nominally two-sided, but caution should be used in the interpretation of findings of statistical significance because no adjustment has been made for multiple comparisons. Findings regarding nonfatal adverse events must also be interpreted cautiously, because of the large difference between groups in mortality. Mortality We report on completed data collected up to the time of termination of the use of encainide and flecainide (April 18, 1989). Of the 1498 patients assigned to treatment, 89 died or had a cardiac arrest (63 assigned to active drug and 26 assigned to placebo) ( Table 1 Cause of Death and Cardiac Arrest (with Resuscitation) in the CAST, According to Treatment Group. A significantly greater number of deaths and cardiac arrests due to arrhythmia, cardiac causes, or any cause occurred among patients receiving active drug (encainide or flecainide, whether considered separately or together) than among patients receiving placebo.

The relative risk of death or cardiac arrest due to arrhythmia was 2.64 (95 percent confidence interval, 1.60 to 4.36), and that of death or cardiac arrest due to all causes was 2.38 (95 percent confidence interval, 1.59 to 3.57); the actuarial curves are shown in Figure 1 Actuarial Probabilities of Freedom from Death or Cardiac Arrest Due to Arrhythmia in 1498 Patients Receiving Encainide or Flecainide or Corresponding Placebo. The number of patients at risk of an event is shown along the bottom of the figure. And Figure 2 Actuarial Probabilities of Freedom from Death or Cardiac Arrest Due to Any Cause in 1498 Patients Receiving Encainide or Flecainide or Corresponding Placebo. The number at risk is shown along the bottom.. The relative risk of death or cardiac arrest due to arrhythmia in patients receiving active drug was similar in the subgroup with ejection fractions of less than 0.30 (1.97) and the subgroup with ejection fractions of 0.30 or more (3.38).

More cardiac deaths and cardiac arrests not due to arrhythmia also occurred in the active-drug groups than in their corresponding placebo groups. Twenty-two of these deaths ( Table 2 Causes of Cardiac Death and Cardiac Arrest Not Due to Arrhythmia. ) were attributed to acute myocardial infarction resulting in cardiogenic shock in 14 patients, to congestive heart failure in 6 patients, and to postoperative coronary-artery bypass grafting in 2 patients. There were eight noncardiac deaths. Of 81 patients with cardiac death or cardiac arrest, 28 had a witnessed arrest not preceded by symptoms (asymptomatic), 35 had a witnessed symptomatic arrest, and 18 had an unwitnessed arrest. All asymptomatic witnessed arrests, 14 of the 35 witnessed symptomatic arrests, and 17 of the 18 unwitnessed arrests were classified as due to arrhythmia.

Of the 42 witnessed deaths or arrests due to arrhythmia, 33 were instantaneous or preceded by symptoms lasting less than 5 minutes, 4 were preceded by symptoms lasting 5 to 60 minutes, and 5 were preceded by symptoms lasting more than 60 minutes. Thus, although the elapsed time from the onset of symptoms to death was not a criterion for death due to arrhythmia, the majority of patients classified as having a witnessed death due to arrhythmia had symptoms for less than one hour. Eight patients classified as having a cardiac death or cardiac arrest had been successfully resuscitated from cardiac arrest ( ). Two of the eight cardiac arrests were secondary to congestive heart failure and were not classified as due to arrhythmia.

In 62 of the 89 patients who died the cardiac rhythm was documented electrocardiographically during or after the onset of the lethal event. Thirty-eight of the 59 patients in whom death was attributed to arrhythmia underwent monitoring (60 percent in the active-drug group and 75 percent in the placebo group) ( Table 3 First Monitored Rhythm in Patients with Death or Arrest Due to Arrhythmia.

In 66 percent of the patients who died of arrhythmia during monitoring, the first arrhythmia detected was ventricular tachycardia or fibrillation. The numbers of patients with ventricular fibrillation detected in the active-drug and placebo groups were the same despite the difference between these groups in mortality due to arrhythmia. There was a trend for more of the patients receiving active drug to have ventricular tachycardia or ventricular tachycardia degenerating into ventricular fibrillation on monitoring. More deaths due to arrhythmia in which asystole was the documented rhythm occurred in the active-treatment groups. There were also more patients receiving active drug in whom no monitoring was performed or for whom the monitored rhythm was unknown.

Overall, the mean time from the onset of an event to monitoring was similar — 12.4±11.7 minutes in the active-drug groups and 12.1±8.3 minutes in the placebo groups. However, it was notable that the mean time from event to monitoring was shortest when the times in the patients with ventricular tachycardia were combined with those in the patients with ventricular tachycardia degenerating into ventricular fibrillation (6.4 minutes), longer in those with ventricular fibrillation (11.6 minutes), and longest in those with asystole (16.2 minutes). In five patients monitored before and during the event, the rhythm was identified as idioventricular or severe bradycardia; in none of these patients was death attributed to arrhythmia. Compliance and Concomitant Drug Therapy During the average 10-month follow-up period, compliance of more than 90 percent was achieved in 70 percent of all patients. The rates of tablet compliance were similar in the active-drug and placebo groups. Table 6 Concurrent Use of Nonstudy Drugs at the Time of the Patient's Last Visit. Shows the concomitant drug therapy in each treatment group, as assessed at the last clinic visit for which information was available.

There was no significant difference (active drug vs. Placebo) in either the encainide or flecainide group in the concomitant use of cardioactive medications. A notable finding was the relatively low incidence of use of betablockers (25 to 30 percent) in each treatment group.

In contrast, approximately 50 percent of all patients were receiving a calcium-channel—blocking agent. The concomitant drug therapy in the patients with death or cardiac arrest due to arrhythmia differed from the therapy in the other patients, in that fewer of the patients in this subgroup were receiving aspirin and more were receiving digitalis, diuretics, or nitrates. Potential Mechanisms Responsible for Mortality In the CAST study, treatment with encainide or flecainide was associated with a poorer outcome, whether the end point was death due to arrhythmia, death due to any cardiac cause, or death due to any cause. There were no confounding factors identified that could explain the marked difference in mortality rates between the active-drug and placebo groups. Base-line clinical and laboratory characteristics were similar in patients receiving active drug and those receiving placebo. The use of other medications at base line and during follow-up was also similar. The adverse outcome in patients treated with encainide or flecainide was attributed primarily to unforeseen death or cardiac arrest due to arrhythmia caused by the study drugs.

However, it was surprising that there was not a correspondingly higher incidence of nonlethal events involving arrhythmia, such as disqualifying ventricular tachycardia, proarrhythmia, syncope, or need for a permanent pacemaker, in the patients receiving active drug. The adverse outcome in the patients receiving encainide or flecainide could have reflected proarrhythmic properties of the two agents., They slow myocardial conduction velocity profoundly, an effect that might facilitate reentry.

These agents do not often suppress the induction of sustained ventricular arrhythmias by programmed stimulation,, they raise the energy requirement for ventricular defibrillation in experimental models,, and their use has been associated with an incessant ventricular tachycardia resistant to cardioversion., In other studies, potentially lethal ventricular tachycardia developed in 11 percent of encainide-treated patients and 16 percent of flecainide-treated patients. However, the rates of proarrhythmia detected by ambulatory monitoring in both the CAPS and the CAST were extremely low. During drug titration in the CAPS, proarrhythmia developed in 2 percent of patients receiving encainide or flecainide, as compared with 3 percent of patients receiving placebo. In the CAST, after randomization only one patient met the criteria for proarrhythmia, and that patient was receiving placebo. Evidence of proarrhythmia may not have been identified because Holier monitoring was not performed in most patients during follow-up, and exercise testing and electrophysiologic testing were not performed.

Incessant ventricular tachycardia was not observed. Although asystole was often the first rhythm recorded in patients at the time of death or cardiac arrest due to arrhythmia, this appeared to be a consequence of the prolonged interval between symptoms and electrocardiographic monitoring rather than of depression of sinus-node function by the drugs.

Although it is possible that active metabolites of encainide that are eliminated slowly may accumulate and facilitate proarrhythmic effects, 1 flecainide is not known to form active metabolites. Thus, the lethal events attributed to arrhythmia in the present trial may not fit our preexisting definitions or understanding of proarrhythmia.

Death due to cardiac causes other than arrhythmia was also more common in the patients receiving active drug than in those receiving placebo. The majority of cardiac deaths not due to arrhythmia were attributed to acute myocardial ischemia or recurrent infarction with subsequent cardiogenic shock. There was not a correspondingly higher incidence of angina, nonlethal recurrent acute myocardial infarction, coronary-artery angioplasty, or coronary-artery bypass grafting procedures.

However, the total number of deaths and nonlethal ischemic events (angina and nonfatal myo->cardial infarction) was nearly identical in the activedrug and placebo groups. One may speculate that ischemic events occurred equally in these two groups but were more likely to be fatal in the group receiving active drug. Thus, acute myocardial ischemia may have facilitated the occurrence of fatal arrhythmias, or the negative inotropic effects of flecainide and encainide may have resulted in severe hypoperfusion or increased myocardial oxygen demands during acute ischemia. Attributing the excess of deaths to both ischemia and proarrhythmia possibly suggests that these mechanisms are interrelated. Clinical Implications The CAST study has demonstrated that the use of encainide or flecainide to treat asymptomatic or mildly symptomatic ventricular arrhythmias in patients with left ventricular dysfunction after myocardial infarction carries a risk of excess mortality. This study emphasizes the need for placebo-controlled clinical trials of antiarrhythmic drugs with end points of related mortality. It also demonstrates the necessity for a data- and safety-monitoring board to establish guidelines for monitoring and discontinuing a study to protect patients.

The lack of benefit of the two Class IC agents used in this study suggests that, despite their increased risk, asymptomatic or mildly symptomatic patients with ventricular premature depolarizations or nonsustained ventricular tachycardia after a myocardial infarction may not benefit from therapy beyond the general use of beta-adrenergic-blocking agents. Although no conclusion can be drawn from the present trial except in regard to the agents and the drug classification studied, it must be noted that trials of other drugs also have not shown a beneficial effect on mortality. CAST II will provide information on the efficacy of moricizine in preventing death due to arrhythmia after myocardial infarction. We are indebted to Ms. Julie Macpherson and Mrs. Linda Hawkins for superb assistance in the preparation of the manuscript. Appendix The investigators of the CAST are as follows: University of Alabama at Birmingham, Birmingham, Ala.: William J.

(principal investigator), Andrew E. Epstein, M.D., Joaquin G. Arciniegas, M.D., Sharon M. Dailey, M.D., G. Neal Kay, M.D., Randall E.

Little, M.D., William A.H. MacLean, M.D., Silvio E.

Papapietro, M.D., Vance J. Plumb, M.D., Sigmund Silber, M.D., Andrea R. Baker, R.N., Melanie Cox, Carolynn Thomas, R.N., Donna Von Hagel, R.N., and Annie E. Walton, R.N.; Baylor College of Medicine, Houston: Craig M. (principal investigator), John Mahmarian, M.D., Terry Eaton, R.N., and Gail Morris, R.N.; Beth Israel Medical Center, New York: Thomas Killip, M.D. (principal investigator), Andrew Van Tosh, M.D. (principal investigator), Susan R.

Hecht, M.D., George A. Gabor, M.D., Warren A. Kossowsky, M.D., Martin Dolgin, M.D., John E. Madias, M.D., Orest B. Bartoszyk, M.D., Ann Grayeski, R.N., B.S.N., Melissa Flon, R.N., B.S., Ann M. Kelly, R.N., B.S.N., and Mary Louise Conte, R.N., B.S.N.; Brown University Affiliated Hospitals Center, Providence, R.I.: Robert J.

(principal investigator), Lawrence Gorkin, Ph.D., Abdul Hakim Khan, M.D., Kenneth Korr, M.D., Andrew Ross, M.D., Kathy Alberti, R.N., B.S., Emily Connolly, R.N., Pat Rubbert, R.N., B.S., and Tina Cameron, R.N.; University of Calgary and Cooperating Hospitals, Calgary, Alta.: D. George Wyse, M.D., Ph.D. (principal investigator), Henry J. Duff, M.D., L. Brent Mitchell, M.D., Anne M.

Gillis, M.D., J. Wayne Warnica, M.D., Robert S. Sheldon, M.D., Ph.D., N. Robert Lesoway, M.D., Joyce Kellen, R.N., B.N., Charlotte Hale, R.N., and Karen Hillier, R.N.; Case Western Reserve University, Cleveland: Albert L. (principal investigator), Richard W. Henthorn, M.D., Mark D.

Carlson, M.D., Joel B. Holland, M.D., Dale Adler, M.D., Robert C. Bahler, M.D., Frank X. Pamelia, M.D., Carol Buchter, M.D., Pammela Redmon, R.N., B.S., Melinda A.

Vargas, R.N., B.S.N., and Christopher E. Kobus, R.N., B.S.N.; Columbia University Affiliated Hospitals, New York: J. Thomas Bigger, M.D. (principal investigator), Jonathan S.

Steinberg, M.D., Judith S. Hochman, M.D., Robert Case, M.D., Henry M. Greenberg, M.D., Edward M. Dwyer, Jr., M.D., John J. Gregory, M.D., Stephen T. Rothbart, M.D., Annmarie Squatrito, R.N., Madeline Kelly, R.N., Jeanne M. Campion, R.N., Deborah Tormey, R.N., Robin Anthony, R.N., Elizabeth Callaghan, R.N., Maureen Chapnick, R.N., Barbara Ripley, L.P.N., R.N., and Cheryl Fontana, R.N.; Emory University School of Medicine, Atlanta: Robert C.

Schlant, M.D. (principal investigator), Daniel Arensberg, M.D., John D. Cantwell, M.D., J.

Arturo Corso, M.D., John W. Hurst, Jr., M.D., Lawrence M. Lesser, M.D., Douglas C. Morris, M.D., Corrine F. Quinn, M.D., Stanley W.

Sherman, M.D., Barry D. Silverman, M.D., Mark E. Silverman, M.D., Shirley K. Ballou, M.S., Velma D. Jeffries, R.N., Joy Lee Crowe, R.N., and Janice M.

Parrott, R.N.; George Washington University Medical Center, Washington, D.C.: Richard J. (principal investigator), George A. Besch, M.D., David Brill, M.D., Robert Di-Bianco, M.D., Dennis Donohue, M.D., Gregory Fisher, M.D., Cleveland Francis, M.D., Dennis Friedman, M.D., Daniel Goldberg, M.D., Samuel Goldberg, M.D., Gregorio Koss, M.D., Louis Larca, M.D., Roger Leonard, M.D., Keith Lindgren, M.D., James Ronan, M.D., Arnold Rosenblatt, M.D., Douglas Rosing, M.D., Allan Ross, M.D., Alberto Rotsztain, M.D., Harry Schwartz, M.D., Fayez Shawl, M.D., Thomas Sinderson, M.D., Roger Stevenson, M.D., Bruce Tinker, M.D., Jacob Varghese, M.D., Mark Weinstein, M.D. John Yackee, M.D., Kay Cross, R.N., Joan Daly, R.N., and Mary Beth Swisher, R.N.; Gothenburg University, Gothenburg, Sweden: Lars Wilhelmsen, M.D. (principal investigator), Robert Bergstrand, M.D. (principal investigator), Bengt-Olof Fredlund, M.D., Christer Gottfridsson, M.D., Axel Sigurdsson, M.D., Sverker Jern, M.D., Ramon Sivertsson, M.D., Karl Swedberg, M.D., Gunnel Schlyter, R.N., Svisse Haegelind, R.N., Gunnel Hedelin, R.N., and Margareta Leijon, R.N.; Hahnemann University, Philadelphia: Joel Morganroth, M.D. (principal investigator), Joseph Carver, M.D., Leonard Horowitz, M.D., Steven Kutalek, M.D., Louis Papa, D.O., James Sandberg, M.D., Mark Victor, M.D., Sharon Cesare, R.N., Brenda Krein, R.N., Chris Vrabel, R.N., Donna Trigone, R.N., Karen Talarico, R.N., Karen Nuschke, R.N., Susan Luhmann, R.N., and Donna Palazzo; Henry Ford Hospital, Detroit: Sidney Goldstein, M.D.

(principal investigator), A. David Goldberg, M.D., Howard Frumin, M.D., Douglas Westveer, M.D., Michael DeButlier, M.D., John Schairer, D.O., Robert Stomel, D.O., Diane M. Frank, R.N., B.S.N., Regina Jarandilla, R.N., B.S.N., Debbie Davey, R.N., Karen Stemmer, R.N., B.S.N., Chris Thom, R.N., and Elaine Martin, R.N.; University of Kentucky, Lexington: Anthony N. DeMaria, M.D. (principal investigator), Chien-Suu Kuo, M.D., James M. Kammerling, M.D., Chris Dunn, R.N., Debra M. Powers, R.N., and Jody Corum, R.N.; University of Maryland, Baltimore: Robert Peters, M.D.

(principal investigator), Frederick Sutton, M.D., Stephen Gottlieb, M.D., Lisa Martin, M.D., Laurie Todd, R.N., B.S.N., and Cynthia Cusack, R.N., B.S.N.; University of Massachusetts, Worcester: Joseph S. (principal investigator), Joel M.

(principal investigator), S.K. Steven Huang, M.D., Mary Ryan, R.N., and Carol Shustak, R.N.; University of Minnesota, Minneapolis: M. (principal investigator), D.M. Salerno, M.D., Ph.D., B.

Anderson, M.D., W. Hession, M.D., M. Manoles, M.D., J.M. Haugland, M.D., C. Gornick, M.D., M. Tolins, M.D., D. Berman, M.D., G.

Granrud, M.D., J. McBride, M.D., D.

Dunbar, M.D., D. Benditt, M.D., S. Riendl, M.D., A. Ettinger, R.N., S. Tait Peterson, R.N., R.

Piper, R.N., and R. Slivken, R.N.; Montreal Heart Institute, Montreal: Denis Roy, M.D. (principal investigator), Pierre Theroux, M.D., Robert Lemery, M.D., Doris Morissette, R.N., Louise Girard, and Suzanne Ranger; Oregon Health Sciences University, Portland: John H. McAnulty, M.D.

(principal investigator), Steven E. Reinhart, M.D., Gordon Maurice, M.D., Edward S.

Murphy, M.D., Joel E. Cutler, M.D., Jack Kron, M.D., Christy Marchant, R.N., Janie Boxer, R.N., Laurie Princehouse, and the Cardiologists at Southwest Washington Hospitals, Tuality Hospital, Good Samaritan Hospital, Portland Veterans Affairs Hospital, and Providence Medical Center; University of Ottawa Heart Institute, Ottawa, Ont.: Donald Beanlands, M.D. (principal investigator), Richard Davies, M.D., Martin Green, M.D., William Williams, M.D., Michael J. Baird, M.D., Linda Warriner, R.N., B.Sc.N., Janet Borthwick, R.N., Liliane Marois, R.N., and Kirsten Woodend, R.N., B.Sc.N.; University of Rochester, Rochester, N.Y.: Toshio Akiyama, M.D.

(principal investigator), William B. Hood, M.D., Paul N. Serge Barold, M.D., Robert Easleyjr., M.D., Richard Kunis, M.D., Gerald Ryan, M.D., John Gillespie, M.D., Laura L. Butler, B.S., Phyllis A. Gehring, R.N., B.S.N., Marcia L. Keller, R.N., B.S.N., Michael Roache, P.A., and Polly Stanley; Rush–Presbyterian–St.

Luke's Medical Center, Chicago: Pablo Denes, M.D. (principal investigator, 1986 to 1988) James A. Schoenberger, M.D. (principal investigator, 1989 to present), Philip R. Liebson, M.D., Philip E. Hill, M.D., A. Tom Petropoulos, M.D., Joanne Kocourek, R.N., and Cathleen Daly, R.N.; Salt Lake Clinic Research Foundation, Salt Lake City: Allan H.

(principal investigator), Jeffrey L. Anderson, M.D., Robert E. Fowles, M.D., Thomas B. Keith, M.D., C. Basil Williams, M.D., Fidela Moreno, M.D., Ellen N. Doran, Barbara Fowler, Kaye Summers, R.N., and Carla White, L.P.N.; St.

Louis University Medical Center, St. Louis: Jerome D. (principal investigator), Harold L. Kennedy, M.D., M.P.H., William P. Hamilton, M.D., Thomas A. Buckingham, M.D., Sondra M.

Seiler, E.A., and Sally S. Anderson, R.N., B.S.N.; State University of New York Health Science Center at Brooklyn, Brooklyn: Nabil El-Sherif, M.D. (principal investigator), Shantha N.

Ursell, M.D., Soad Bekheit-Saad, M.D., Arnold M. Einhorn, M.D., Mary Lynn Brezsnyak, R.N., Ann V. Porter, R.N., and Patricia M. Rosa, R.N.; Vanderbilt University, Nashville: Raymond L. Woosley, M.D., Ph.D. (principal investigator, 1986 to 1988), Dan M.

(principal investigator, 1988 to present), W. Barton Campbell, M.D., Debra S. Echt, M.D., John T. Judi Diekhoff Spell, R.N., M.S.N., Susan T. Bonhotal, R.N., M.S.N., Leslie L. Jared, R.N., M.S.N., and Tina Ingle Thomas, R.N.; Medical College of Virginia, Virginia Commonwealth University, Richmond: David W.

Richardson, M.D. (principal investigator), Donald W. Romhilt, M.D. (principal investigator), Kenneth A. Ellenbogen, M.D., Robert A.

Bauernfeind, M.D., Barbara B. Bane, Jeanne K. Sanders, R.N., M.S.N., and Sherry F. Shrader, R.N., B.S.N.; Washington Hospital Center, Washington, D.C.: Edward V. (principal investigator), Susan O'Donoghue, M.D., Cynthia M. Tracy, M.D., Nayab Ali, M.D., Patrick Bowen, M.D., Andrew I.

Cohen, M.D., Kenneth M. Brooks, M.D., Andrew J. Keller, M.D., William Oetgen, M.D., Lawrence T. Weston, M.D., Sue Barrett, R.N., Maria R. Johnson, R.N., Diane E. Law, R.N., and Dulce Obias-Manno, R.N.; Drug Distribution Center, Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, N.M.: Clair M.

Haakenson, R.Ph., M.S., Mike R. Sather, R.Ph., M.S., and Loretta A.

Malone; Coordinating Center, University of Washington, Seattle: Alfred P. Hallstrom, Ph.D. (principal investigator), Mary Jo Gillespie, M.S., H. Leon Greene, M.D., Yudianto Pawitan, Ph.D., Ruth McBride, Robert Ledingham, M.S., Robin Reynolds-Haertle, M.S., Melissa Huther, and Margit Scholz; Program Office, Clinical Trials Branch, Division of Epidemiology and Clinical Applications, National Heart, Lung and Blood Institute, Bethesda, Md.: Lawrence M.

Friedman, M.D., Eleanor Schron, R.N., M.S., Joel Verter, Ph.D., and Cheryl Jennings; and Data and Safety Monitoring Board: Oregon Health Sciences University, Portland —J. David Bristow, M.D. (chairman and principal investigator); University of Wisconsin, Madison — David L. DeMets, Ph.D.; Indiana University School of Medicine, Krannert Institute of Cardiology, Indianapolis — Charles Fisch, M.D.; University of Colorado Medical School, Denver — Alan S. Nies, M.D.; Harvard Medical School, Boston — Jeremy Ruskin, M.D.; Duke University Medical Center, Durham, N.C.

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