Jay W. Mason

A Clinical Trial of Immunosuppressive Therapy for Myocarditis

BACKGROUND Myocarditis is a serious disorder, and treatment options are limited. This trial was designed to determine whether immunosuppressive therapy improves left ventricular function in patients with myocarditis and to examine measures of the immune response as predictors of the severity and outcome of disease. METHODS We randomly assigned 111 patients with a histopathological diagnosis of myocarditis and a left ventricular ejection fraction of less than 0.45 to receive conventional therapy alone or combined with a 24-week regimen of immunosuppressive therapy. Immunosuppressive therapy consisted of prednisone with either cyclosporine or azathioprine. The primary outcome measure was a change in the left ventricular ejection fraction at 28 weeks. RESULTS In the group as a whole, the mean (+/- SE) left ventricular ejection fraction improved from 0.25 +/- 0.01 at base line to 0.34 +/- 0.02 at 28 weeks (P < 0.001). The mean change in the left ventricular ejection fraction at 28 weeks did not differ significantly between the group of patients who received immunosuppressive therapy (a gain of 0.10; 95 percent confidence interval, 0.07 to 0.12) and the control group (a gain of 0.07; 95 percent confidence interval, 0.03 to 0.12). A higher left ventricular ejection fraction at base line, less intensive conventional drug therapy at base line, and a shorter duration of disease, but not the treatment assignment, were positive independent predictors of the left ventricular ejection fraction at week 28. There was no significant difference in survival between the two groups (P = 0.96). The mortality rate for the entire group was 20 percent at 1 year and 56 percent at 4.3 years. Features suggesting an effective inflammatory response were associated with less severe initial disease. CONCLUSIONS Our results do not support routine treatment of myocarditis with immunosuppressive drugs. Ventricular function improved regardless of whether patients received immunosuppressive therapy, but long-term mortality was high. Patients with a vigorous inflammatory response had less severe disease.

Determinants of Survival in Patients with Ventricular Tachyarrhythmias

We analyzed data from 239 patients with sustained ventricular tachycardia or ventricular fibrillation to determine prognosis, predictors of survival, and the prognostic value of inducing arrhythmia and assessing therapy at the time of electrophysiologic study. Therapy predicted to be effective on the basis of electrophysiologic study was administered over a sustained period. There were 71 cardiac deaths, including 44 sudden deaths, during a mean (+/- S.D.) follow-up period of 14.8 +/- 13.9 months (range, one day to 67 months). At one, two, and three years, the actuarial incidence of sudden death was 17 +/- 3, 25 +/- 4, and 34 +/- 6 per cent, and that of cardiac death was 28 +/- 3, 37 +/- 4, and 50 +/- 6 per cent. Multivariate regression analyses demonstrated that the two strongest predictors of both sudden death and cardiac death were a higher New York Heart Association functional class (P less than 0.0001 for sudden death and P less than 0.0001 for cardiac death) and the failure of any therapy to be identified as potentially effective on the basis of electrophysiologic study (P = 0.0019 and P = 0.0003). The majority of deaths in patients with ventricular tachyarrhythmias were sudden, but the severity of heart failure was the strongest independent predictor of mortality. Response to therapy during electrophysiologic study was also an independent predictor of survival.

A Comparison of Seven Antiarrhythmic Drugs in Patients with Ventricular Tachyarrhythmias

BACKGROUND The relative efficacies of various antiarrhythmic drugs in the treatment of ventricular tachyarrhythmias are not well known. This study examined the effectiveness of imipramine, mexiletine, pirmenol, procainamide, propafenone, quinidine, and sotalol in patients with ventricular tachyarrhythmias who were enrolled in the Electrophysiologic Study versus Electrocardiographic Monitoring trial. METHODS Patients were randomly assigned to undergo serial testing of the efficacy of the seven antiarrhythmic drugs by one of two strategies: electrophysiologic study or Holter monitoring together with exercise testing. The seven drugs were then tested for efficacy in random order in patients who were eligible to receive them. The frequencies of predictions of drug efficacy and of adverse drug effects during the initial drug titration were tabulated for all 486 randomized subjects. Patients received long-term treatment with the first antiarrhythmic drug that was predicted to be effective on the basis of drug testing. Recurrences of arrhythmia, deaths, and adverse drug effects during long-term follow-up were recorded for the 296 patients in whom an antiarrhythmic drug was predicted to be effective. RESULTS In the electrophysiologic-study group, the percentage of patients who had predictions of drug efficacy was higher with sotalol (35 percent) than with the other drugs (16 percent, P < 0.001). There was no significant difference among the drugs in the Holter-monitoring group. The percentage of patients with adverse drug effects was lowest among those receiving sotalol. The actuarial probability of a recurrence of arrhythmia after a prediction of drug efficacy by either strategy was significantly lower for patients treated with sotalol than for patients treated with the other drugs (risk ratio, 0.43; 95 percent confidence interval, 0.29 to 0.62; P < 0.001). With sotalol, as compared with the other drugs combined, there were lower risks of death from any cause (risk ratio, 0.50; 95 percent confidence interval, 0.30 to 0.80; P = 0.004), death from cardiac causes, (0.50; P = 0.02), and death from arrhythmia (0.50; P = 0.04). The cumulative percentage of patients in whom a drug was predicted to be effective and in whom it remained effective and tolerated was higher for sotalol than for the other drugs (P < 0.001). CONCLUSIONS Sotalol was more effective than the other six antiarrhythmic drugs in preventing death and recurrences of arrhythmia. In patients similar to those in this study, if antiarrhythmic-drug therapy is to be used to prevent recurrences of ventricular tachyarrhythmias, treatment with sotalol and assessment of its potential efficacy by Holter monitoring are a reasonable initial strategy.

Doxorubicin Cardiomyopathy: Evaluation by Phonocardiography, Endomyocardial Biopsy, and Cardiac Catheterization

Right ventricular endomyocardial biopsy, right heart catheterization, and systolic time intervals were done in 33 adult patients receiving doxorubicin (AdriamycinTM). Doxorubicin administration was associated with a dose-related increase in the degree of myocyte damage, and 27 of 29 patients biopsied at doses greater than or equal to 240 mg/m2 had doxorubicin-associated degenerative changes identified on biopsy. The pre-ejection period to left ventriculr ejection time ratio (PEP/LVET) showed a threshold phenomenon and did not begin to increase until a total dose of 400 mg/m2 had been reached. Seven patients with catheterization-proven heart failure had a significantly greater amount of myocyte damage on biopsy than dose-matched control subjects (P less than 0.01). Preveious mediastinal radiation appeared to potentiate the doxorubicin-associated degenerative process. Mediastinal radiation and age greater than or equal to 70 years appeared to be risk factors for doxorubicin-associated heart failure. Dose limitation by combined clinical, noninvasive, invasive, and morphologic criteria offered an advantage over empirical dose limitation or dose limitation by PEP/LVET alone.

A Comparison of Electrophysiologic Testing with Holter Monitoring to Predict Antiarrhythmic-Drug Efficacy for Ventricular Tachyarrhythmias

BACKGROUND Invasive electrophysiologic study and noninvasive Holter monitoring (in conjunction with exercise testing) have both been used to evaluate the efficacy of antiarrhythmic drugs in patients with sustained ventricular tachycardia and in survivors of cardiac arrest. We directly compared these two approaches to the prediction of drug efficacy. METHODS A total of 486 patients who had documented ventricular tachyarrhythmias that were inducible during electrophysiologic study and 10 or more premature ventricular complexes per hour during Holter monitoring were randomly assigned to undergo serial testing of antiarrhythmic-drug efficacy by electrophysiologic study or Holter monitoring. The patients received up to six drugs in random order until one was predicted to be effective either in suppressing inducible arrhythmia (in the electrophysiologic-study group) or in suppressing premature ventricular complexes (in the Holter-monitoring group). The patients were then followed for recurrences of arrhythmia or death. RESULTS In the electrophysiologic-study group, 108 of 242 patients (45 percent) received a prediction of efficacy, as compared with 188 of 244 patients (77 percent) in the Holter-monitoring group (P < 0.001). Over a six-year follow-up period, there were 150 recurrences of arrhythmia and 46 deaths among the 296 patients receiving drugs predicted to be effective. Thirty-four of the deaths were from arrhythmic causes, and eight were from cardiac causes. There was no significant difference between the two study groups in the actuarial probabilities of these events. The risk of a recurrence of arrhythmia was significantly lower in patients who received sotalol than in those who received other antiarrhythmic drugs, and the risk was lower in those who had not previously failed to respond to antiarrhythmic drugs than in those who had. CONCLUSIONS Although Holter monitoring led to predictions of antiarrhythmic-drug efficacy more often than did electrophysiologic study in patients with sustained ventricular tachyarrhythmias, there was no significant difference in the success of drug therapy as selected by the two methods.

Accuracy of the Ventricular Tachycardia-Induction Study for Predicting Long-Term Efficacy and Inefficacy of Antiarrhythmic Drugs

We evaluated the prophylactic effect of antiarrhythmic agents against induction of ventricular tachycardia by extrastimulation in 51 patients with recurrent ventricular tachycardia. These patients subsequently underwent 58 long-term trials with tested agents. In 39 trials an agent predicted to be effective by electrophysiologic study was administered, and in 19 a drug predicted to be ineffective was used. There were no clinical differences between the two treatment groups. During a mean follow-up period of 8.2 months, arrhythmias recurred significantly less frequently in the group treated with drugs predicted to be effective than in the other group (P < 0.001); at six months 80 per cent of the patients in the former group were successfully treated, as compared with 33 per cent in the latter group. At 18 months the corresponding figures were 68 per cent and 11 per cent. We conclude that the arrhythmia-induction technique accurately predicts the clinical effectiveness of drugs used in the long-term treatment of recurrent ventricular tachycardia.

Early Anthracycline Cardiotoxicity

Eight patients in whom cardiac dysfunction developed within four weeks of receiving their first or second course of daunorubicin or doxorubicin are described. Four patients presented with pericarditis; three of these four had evidence of myocardial dysfunction. Histopathologic analysis of these patients was consistent with an acute myocyte damage and secondary inflammatory process. An additional group of four patients presented with symptoms and signs of heart failure. These patients were either elderly or had evidence of previous cardiac disease. One of these patients suffered a myocardial infarction 24 hours after receiving 60 mg/m2 of daunorubicin; earlier doses in the same course had been associated with evidence of myocardial ischemia. We conclude that anthracycline antibiotics may manifest clinically significant cardiotoxicity at total cumulative doses much less than have been associated with chronic cardiomyopathy.

Treatment of acute inflammatory myocarditis assisted by endomyocardial biopsy

Abstract Right ventricular endomyocardial biopsy was performed to make a diagnosis of inflammatory myocarditis in 10 patients with congestive heart failure. All 10 patients were treated with immunosuppressive agents (either prednisone alone or prednisone in combination with azathioprine) and were followed up prospectively. Each patient had serial invasive and noninvasive assessments of cardiac performance, and 9 of 10 had one or more follow-up endomyocardial biopsies. The course of four patients who showed dramatic improvement in association with immunosuppressive therapy is described in detail. In addition to these four patients, one other had definite improvement and four subjects had stabilization of previously progressive heart failure; the condition of one patient worsened, and he died despite immunosuppression. In the seven patients who had cell inflammation, six underwent a second biopsy after a period of immunosuppressive therapy, and in each case, the inflammatory infiltrate had been eliminated. In two of these patients, signs and symptoms of myocarditis recurred after discontinuation of therapy, and myocardial biopsy confirmed the recrudescence of cell inflammation. Reinstitution of therapy improved symptoms and histologic findings. It is concluded that endomyocardial biopsy can be used to diagnose inflammatory myocarditis and to monitor the histologic results of therapy. Our findings constitute circumstantial evidence that immunosuppressive therapy is effective in eliminating myocardial cell inflammation and thereby improving myocardial performance.

Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias.

Ninety-six patients with recurrent, drug-refractory tachyarrhythmias were treated with amiodarone for 8.0 +/- 7.5 months (range 1 day to 27 months): 77 for recurrent ventricular tachycardia or ventricular fibrillation (VT/VF), two for complex ventricular ectopy, and 17 for supraventricular tachyarrhythmias. The actuarial incidence of successful amiodarone therapy was 52 +/- 7% at 12 months and 28 +/- 9% at 24 months for patients with VT/VF. Neither patient with complex ventricular ectopy was successfully treated. Among the patients with supraventricular tachyarrhythmias, 64.7% were successfully treated for 7.7 +/- 7.6 months (range 1 to 22 months). Amiodarone toxicity occurred in 66 of 91 patients (72.5%) treated for more than 1 week. Fourteen patients had therapy-limiting toxicity. Of these 14, six had pulmonary toxicity, four had arrhythmia exacerbation, one had hepatitis, one had renal toxicity, one had rash, and one had erythema nodosum. The actuarial incidence of therapy-limiting side effects was 27 +/- 7% at 15 months. We conclude that amiodarone is useful in the treatment of refractory tachyarrhythmias but that the rate of efficacy in VT/VF is lower and the incidence of significant toxicity is higher than has been generally appreciated.

Techniques for Right and Left Ventricular Endomyocardial Biopsy

Right ventricular endomyocardial biopsy using percutaneous right internal jugular approach proved a safe and easily performed technique in more than 1,300 procedures. Adequate tissue was obtained in more than 98 percent of patients and morbidity rate was remarkably low. Other approaches to the right ventricle may be used, but retrograde left ventricular endomyocardial biopsy appears to be the safest and most reliable alternative to transjugular right ventricular biopsy. The safety and success of the techniques for right and left heart biopsy described depend on meticulous attention to methodologic detail.