Original Article
A Comparison of Electrophysiologically Guided Antiarrhythmic Drug Therapy with Beta-Blocker Therapy in Patients with Symptomatic, Sustained Ventricular Tachyarrhythmias
N Engl J Med 1992; 327:987-992October 1, 1992
- Abstract
- Abstract
Background.
Antiarrhythmic drug therapy guided by invasive electrophysiologic testing is now widely used in patients with symptomatic, sustained ventricular tachyarrhythmias.
Methods.
We conducted a prospective, randomized trial in 170 patients to investigate whether this approach would improve long-term outcome. Patients whose arrhythmia was inducible by programmed electrical stimulation were assigned to treatment with electrophysiologically guided drug therapy based on serial testing (61 patients) or with metoprolol (54 patients). Electrophysiologically guided therapy consisted of serial testing of antiarrhythmic agents to identify the first one that rendered the arrhythmia noninducible. The 55 patients whose arrhythmia was noninducible during the initial electrophysiologic test were also treated with metoprolol.
Results.
During a mean (±SD) follow-up period of 23±17 months, recurrent, nonfatal arrhythmia occurred in 44 patients and sudden death due to cardiac factors in 27. The incidence of symptomatic arrhythmia and sudden death combined was virtually the same in the two groups with inducible arrhythmia after two years of observation (electrophysiologically guided therapy vs. metoprolol therapy, 46 percent vs. 48 percent). The outcome was more favorable in the patients with noninducible arrhythmia at base line (75 percent had neither adverse event after two years) than in those with inducible arrhythmia who were assigned to metoprolol therapy (P = 0.009 by log-rank test). Only 6 of the 29 patients (21 percent) with inducible arrhythmia that became noninducible during drug therapy had recurrent arrhythmia or sudden death, as compared with 21 of the 32 patients (66 percent) with arrhythmia that continued to be inducible (P<0.001). A multivariate regression analysis identified continued inducibility of the arrhythmia as an independent predictor of recurrent arrhythmia or sudden death (relative risk, 7.3; 95 percent confidence interval, 2.3 to 23.2; P<0.001).
Conclusions.
As compared with metoprolol therapy, electrophysiologically guided antiarrhythmic drug therapy did not improve the overall outcome of patients with sustained ventricular tachyarrhythmias. However, effective suppression of inducible arrhythmia by antiarrhythmic drugs was associated with a better outcome than was lack of suppression. (N Engl J Med 1992;327:987–92.)
Article Activity
- Article
ON the basis of electrophysiologic studies,1 , 2 electrophysiologic drug testing has been proposed as a means to assess the efficacy of antiarrhythmic agents and guide the long-term treatment of patients who have survived sustained ventricular tachycardia or fibrillation not associated with acute myocardial infarction.3 4 5 6 7 No previous study has proved that the incidence of recurrent arrhythmia or sudden death is reduced by electrophysiologically guided drug therapy, since all were retrospective and lacked control groups. Nevertheless, this therapy is routinely used in many institutions. The Cardiac Arrhythmia Suppression Trial showed that administration of the antiarrhythmic drugs flecainide and encainide to patients with premature ventricular contractions after myocardial infarction may be harmful.8 Such an untoward effect may also occur and may easily go undetected in patients at high risk for life-threatening arrhythmias. The net effect of these and other drugs in patients with a history of sustained ventricular tachyarrhythmias — namely, suppression of one kind of tachyarrhythmia and possible promotion of another — is not known. We therefore prospectively assessed the value of electrophysiologically guided drug therapy, as compared with beta-blocker therapy administered without invasive testing.
Methods
Patients
We studied consecutive patients who had survived electrocardiographically documented, symptomatic, sustained ventricular tachycardia (defined as hemodynamically compromising tachycardia lasting more than 30 seconds); resuscitation from cardiac arrest due to documented or witnessed ventricular fibrillation; or syncope in the presence of underlying cardiac disease, with a history of either rapid palpitations before the onset of syncope or runs of ventricular premature beats (five or more) during long-term electrocardiographic recording, if complete noninvasive and invasive evaluations had ruled out other causes.
Patients were excluded if they were 75 years old or older, had hypokalemia that was the likely cause of the arrhythmia, had had myocardial infarction less than four weeks before the arrhythmic event, had class IV heart failure as defined by the New York Heart Association, had a noncardiac disease with a poor prognosis, had contraindications to beta-blocker therapy, had had the arrhythmia only during treatment with antiarrhythmic drugs or beta-blockers (which suggested proarrhythmia), or declined to participate in the study after they received detailed information about it.
Programmed Stimulation
The details of programmed ventricular stimulation have been described elsewhere.9 In essence, stimulation consisted of the application of single and double premature stimuli to the right ventricle, with progressively shorter intervals between the last paced beat and the premature stimulus, during ventricular pacing at a rate slightly above the normal sinus rate and at intervals of 600, 500, 400, and 330 msec. Stimulation was performed at twice the diastolic threshold, at two sites (the apex and the septum or outflow tract of the right ventricle).
An arrhythmia (the end point of stimulation) was defined as inducible in patients with sustained ventricular tachycardia if stimulation elicited sustained ventricular tachycardia (defined as tachycardia lasting more than 30 seconds or requiring termination before 30 seconds because of hemodynamic compromise) or unsustained ventricular tachycardia (more than 20 consecutive ventricular beats during up to 30 seconds of tachycardia, reproducible twice and corresponding in rate and morphology to the spontaneous arrhythmia). An arrhythmia was considered inducible in patients with cardiac arrest or syncope if stimulation produced more than 20 consecutive ventricular premature beats, sustained ventricular tachycardia, or ventricular fibrillation.
Study Protocol
Patients without inducible arrhythmia as defined by the protocol were assigned to therapy with oral metoprolol, given first at a dose of 25 mg twice a day and then increased stepwise according to subjective tolerance, blood pressure, and heart rate, up to 100 mg twice a day. Patients with inducible arrhythmia were randomly assigned without stratification (by the Department of Biometry, University of Munich) to receive either electrophysiologically guided drug therapy based on serial testing or oral metoprolol (in a dose chosen as described above) without an invasive assessment of drug efficacy. Serial testing was performed with oral doses of the following agents: propafenone (450 to 900 mg daily for at least 4 days), flecainide (200 to 400 mg daily for at least 4 days), disopyramide (450 to 900 mg daily for at least 4 days), sotalol (160 to 480 mg daily for at least 4 days), and amiodarone (1000 mg daily for at least 14 days, and then 400 mg daily or more). Oral metoprolol (started at a dose of 25 mg twice a day and progressively increased to a dose of 50 mg twice a day) was given to all patients who received propafenone, flecainide, and disopyramide. Sotalol and amiodarone were administered alone. Invasive testing was performed after the dose was titrated to the highest dose subjectively tolerated, or after the maximal dose was reached. The drugs were tested in random order, but amiodarone was always tested last. The washout time between the administration of the various antiarrhythmic drugs was one day.
A drug was not tested if the patient's arrhythmia had occurred before the study while the patient was taking an appropriate dose of that drug. Treatment was changed to another regimen without testing if the arrhythmia recurred spontaneously during oral treatment with a sufficient dose of the drug.
As soon as a drug was identified as preventing the arrhythmia from being induced, testing was terminated. Suppression of inducibility was indicated by conversion of the arrhythmia from inducible, sustained ventricular tachycardia or fibrillation to (at worst) unsustained ventricular tachycardia, with completion of the entire protocol of stimulation at the two ventricular sites; or by a reduction of 90 percent or more in the number of induced ventricular beats, if unsustained ventricular tachycardia was induced during the base-line study.
If no therapy suppressed the inducibility of the arrhythmia, various combinations of Class I antiarrhythmic agents (including agents not listed above) and Class III agents were tested, but without the addition of metoprolol. If the arrhythmia nevertheless remained inducible, additional information derived from the results of serial drug testing (ease of induction, an increase caused by drugs in the cycle length of induced sustained arrhythmia, and symptoms during induced arrhythmia) was used to select long-term antiarrhythmic drug therapy.
The patients were evaluated for proarrhythmic effects (defined as torsades de pointes; a twofold-to-fivefold increase in the number of ventricular premature beats, pairs, or salvos; or severe bradycardia) by means of 24-hour electrocardiographic monitoring before hospital discharge, during their final drug regimen. Otherwise, such monitoring did not affect the decision about drug treatment. Follow-up examinations were performed by the investigators every three months.
The study end points were the recurrence of arrhythmia (symptomatic, sustained, documented ventricular tachycardia, or ventricular fibrillation), death, or absence of symptoms during follow-up observation for 18 to 48 months. Syncope was considered a recurrence of arrhythmia in patients who had been included in the study because they had had syncope. Death was classified as sudden cardiac death if it was witnessed to occur within seconds, if ventricular tachyarrhythmias were documented as present at the time of death, or if death occurred unexpectedly although unwitnessed, without any indication of prior prolonged severe symptoms — for example, at night. In an attempt to compare levels of clinical severity, a recurrence was given a score of 1 if it was hemodynamically tolerated, 2 if it was not tolerated (as indicated by a loss of consciousness or a need for resuscitation), or 3 if sudden death occurred.
The study protocol was approved by the ethics committee of the Ludwig-Maximilians University of Munich, Germany, and informed consent was obtained from all patients.
Statistical Analysis
All analyses were performed on an intention-to-treat basis. Results are expressed as means ±SD. The study groups were compared by t-tests and chi-square tests. A P value of less than 0.05 (two-tailed) was considered to indicate statistical significance. Kaplan–Meier curves showing the probability of survival were constructed for the recurrence of symptomatic arrhythmia and sudden cardiac death, and differences between the curves were assessed with the log-rank test (calculation with BMDP statistical software:1L).10 Stepwise multivariate logistic regression11 was applied to identify other prognostic factors in the patients undergoing serial electrophysiologic testing (calculation with BMDP LR).10 The dependent variable was the recurrence of arrhythmia or sudden death. The factors tested as independent variables were age (>65 vs. ≤65 years), sex, the type of arrhythmia (ventricular tachycardia, ventricular fibrillation, or syncope), the number of clinical events (one, two to five, or more than five), the type of underlying cardiac disease, New York Heart Association functional class, the left ventricular ejection fraction (>40 percent vs. ≤40 percent), the result of 24-hour electrocardiography (more than 20 ventricular extrasystoles per hour, more than 10 couplets per 24 hours, or triplets or more numerous beats), and the result of electrophysiologic testing (suppression of inducibility vs. no suppression).
Results
Clinical and Electrophysiologic Data
One hundred seventy patients (132 men and 38 women, with a mean age of 56±13 years) were included in the study (Table 1Table 1
Clinical Characteristics of the Study Groups.*). Programmed ventricular stimulation induced the arrhythmia in 70 of 85 patients (82 percent) with ventricular tachycardia, 28 of 49 patients (57 percent) with cardiac arrest, and 17 of 36 patients (47 percent) with syncope. Of the 115 patients with inducible arrhythmia, 61 were randomly assigned to serial drug testing and 54 to metoprolol treatment without invasive testing. Table 1 shows the clinical characteristics of the two groups with inducible arrhythmia and the group with noninducible arrhythmia.In the group undergoing serial testing, a mean of 2.8 invasive drug tests were performed per patient. Inducibility of arrhythmia was suppressed in 29 of the 61 patients (48 percent): in 18 patients with sotalol, in 5 with disopyramide and metoprolol, in 2 with flecainide and metoprolol, in 1 with propafenone and metoprolol, in 1 with amiodarone, in 1 with sotalol and flecainide, and in 1 with flecainide and mexiletine. In 32 of the 61 patients (52 percent), the arrhythmia remained inducible despite testing with all the drugs. The long-term treatment of these 32 patients consisted of amiodarone in 12 patients, propafenone and metoprolol in 7, sotalol in 6, flecainide and metoprolol in 4, disopyramide and metoprolol in 2, and sotalol and mexiletine in 1. The mean daily dose of metoprolol was 79±20 mg in the 21 patients given both metoprolol and Class I agents; the dose given to the patients in whom inducible arrhythmias were suppressed did not differ from that given to the patients without such suppression. Patients with inducible arrhythmia assigned to metoprolol therapy received 148±46 mg per day, and patients with noninducible arrhythmias received 138±42 mg per day.
Follow-up
No patient was lost to follow-up, which was carried out for 18 to 48 months or until death or a symptomatic recurrence of arrhythmia. A substantial reduction in the dosage or a change in the antiarrhythmic regimen was necessary in six patients (four patients with inducible arrhythmia, of whom two underwent serial drug testing and two received metoprolol, and two patients with noninducible arrhythmia); invasive studies were not repeated in these patients. Three patients had aortocoronary bypass operations, and one an orthotopic heart transplantation. During follow-up, 44 patients had a recurrence of arrhythmia and 27 died suddenly.
Kaplan–Meier survival probabilities were estimated for the combined end point of symptomatic recurrence of arrhythmia or sudden death (Fig. 1Figure 1
Kaplan–Meier Estimate of Survival without Recurrence of Arrhythmia or Sudden Cardiac Death (Combined End Point, Panel A) or Sudden Death Alone (Single End Point, Panel B) in 115 Patients with Sustained Ventricular Tachyarrhythmias.A). Patients with noninducible arrhythmia (all of whom received metoprolol) had significantly better survival than those with inducible arrhythmia who received metoprolol (P = 0.009 by log-rank test). On the other hand, there was no difference in outcome between the two groups with inducible arrhythmia (patients assigned to electrophysiologically guided drug therapy and patients assigned to empirical metoprolol treatment) (Fig. 1A). The result was similar when sudden cardiac death was analyzed as the only end point (Fig. 1B).Table 2Table 2
Outcomes in the Three Study Groups during the Follow-up Period. shows the number of sudden deaths or recurrences of arrhythmia, the number of sudden deaths alone, the number of recurrences of nonfatal arrhythmia, and the severity scores for recurrences in the three study groups. As compared with the patients in whom inducibility of the arrhythmia persisted, those in whom inducibility was suppressed had fewer arrhythmic events and sudden deaths combined and fewer sudden deaths alone (P<0.001 and P = 0.005, respectively, by log-rank test) (Fig. 2Figure 2
Kaplan–Meier Estimate of Survival without Recurrence of Arrhythmia or Sudden Cardiac Death (Combined End Point, Panel A) or Sudden Death Alone (Single End Point, Panel B) in 61 Patients Treated with Electrophysiologic Drug Testing.).In the stepwise selection procedure to construct a multivariate logistic model applicable to patients undergoing drug testing (data not shown), a lack of suppression of inducibility of the arrhythmia during electrophysiologic testing was selected first (nominal P<0.001). When added to the model, all other variables had P values of 0.16 or higher according to the maximum-likelihood-ratio test. The left ventricular ejection fraction remained unimportant when it was treated as a dichotomous variable with cutoff points lower or higher than 40 percent or when treated as a continuous variable. Thus, a lack of suppression of inducibility of the arrhythmia predicted the recurrence of arrhythmia or sudden death independently of other variables (relative risk, 7.3; 95 percent confidence interval, 2.3 to 23.2; P<0.001) (Fig. 2A).
Discussion
Our objective was to assess in a prospective, controlled trial the value of electrophysiologically guided antiarrhythmic drug therapy in patients with a history of sustained ventricular tachyarrhythmias. It would not have been ethical to include an untreated control group. Because beta-blockers have been shown to reduce the rate of sudden death among patients who have had a myocardial infarction12 , 13 and because recent studies also point to a beneficial effect in patients with ventricular tachyarrhythmias,14 15 16 we chose to treat our comparison group with metoprolol. In the group given the treatment of interest, patients underwent electrophysiologic testing and long-term treatment with Class I antiarrhythmic agents (propafenone, disopyramide, or flecainide) in combination with metoprolol, or treatment with Class III antiarrhythmic agents (sotalol or amiodarone).
In our trial, electrophysiologically guided drug therapy did not improve the overall outcome of patients with sustained ventricular tachyarrhythmias. Our study population had various forms of cardiac disease (65 percent had coronary artery disease, and 24 percent had dilated cardiomyopathy) and various clinical presentations of arrhythmia (sustained ventricular tachycardia in 50 percent, primary ventricular fibrillation in 29 percent, and syncope in 21 percent). However, analyses of only the patients with coronary artery disease or of only the patients without syncope gave the same results.
Our study results are applicable to patients with sustained ventricular tachycardia or primary cardiac arrest due to chronic coronary artery disease and dilated cardiomyopathy; they may not be applicable to patients with arrhythmias inducible only by more aggressive stimulation than that used in our study, to patients with rarer forms of cardiac diseases, or to patients with unsustained ventricular tachycardia.
Although electrophysiologic drug testing was not superior to empirical treatment with metoprolol, drug therapy guided in this way identified patients with a favorable prognosis (characterized by the suppression of inducibility) and those with an unfavorable prognosis (characterized by a lack of suppression). In fact, stepwise multivariate regression analysis revealed that among the 13 variables analyzed, persistence of inducibility was the only variable independently associated with a poor outcome (defined as a recurrence of arrhythmia or sudden death). The same result, with no additional predictive information from the left ventricular ejection fraction, has been obtained in a subgroup of patients with inducible arrhythmia and cardiac arrest.17 However, when all patients with a history of sustained ventricular tachyarrhythmias were included in the analysis (i.e., regardless of the results of electrophysiologic study at base line),6 , 17 , 18 left ventricular function was shown to be an equally important predictor of outcome or even the most powerful predictor. The long-term results of our prospective study in one group of patients — those receiving electrophysiologically guided drug therapy — may be compared with the results of previous retrospective studies. If important variables such as the left ventricular ejection fraction, presentation of the arrhythmia, and type of therapy are taken into account, our results appear quite similar to those of two other large studies.6 , 17
Our results in patients with inducible arrhythmias who received electrophysiologically guided therapy may have two interpretations, as follows. Electrophysiologically guided drug therapy may simply identify patients with an intrinsically good clinical outcome (suppression of inducibility) or a bad outcome (lack of suppression of inducibility), regardless of whether they receive antiarrhythmic drugs. Alternatively, drug therapy may actually improve clinical outcome in patients in whom inducibility is suppressed, or not improve or even worsen outcome in patients in whom inducibility persists. It is important to determine which explanation is correct, since that finding will have a major impact on the future clinical role of electrophysiologically guided antiarrhythmic therapy. To learn whether electrophysiologically guided drug therapy will actively change outcome, half the patients in whom a drug suppresses inducibility should be randomly assigned to therapy with that drug, and half to placebo. Such a study may not be ethical, since it would require withholding therapy predicted to be effective in patients with potentially life-threatening ventricular tachyarrhythmias. However, implantation of an automatic defibrillator as a safeguard might make it possible to answer this important question.
Supported in part by grants (Ste 257/5–3 and 257/5–4) from the Deutsche Forschungsgemeinschaft.
We are indebted to Hein J.J. Wellens, M.D. (Maastricht, the Netherlands), for his advice during the study, and to Peter Dirschedl and Wolfgang Köpcke, Ph.D. (University of Munich), for performing the statistical analysis.
Source Information
From Medical Hospital I, University of Munich, Klinikum Grosshadern, Munich (G.S., P.B., R.H., E.H.), and the Cardiological Department of the Free University of Berlin, Klinikum Steglitz, Berlin (D.A., M.O., E.-R.v.L.), both in Germany. Address reprint requests to Dr. Steinbeck at Medical Hospital I, University of Munich, Klinikum Grosshadern, P.O. Box 701260, 8000 Munich 70, Germany.
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