Correspondence

The Treatment of Ventricular Tachyarrhythmias

N Engl J Med 1994; 330:286-288January 27, 1994

Article

To the Editor:

Mason and his colleagues are to be commended for undertaking the first large, randomized study to compare the roles of electrophysiologic testing and ambulatory monitoring in predicting the efficacy of antiarrhythmic drugs (Aug. 12 issue)1-3.

However, Dr. Mason's conclusion about the effect of the study findings on the approach to patients with serious ventricular arrhythmias is misleading. The first article reporting on the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) trial1 offers a direct comparison of electrophysiologic testing with Holter-guided therapy; its conclusion simply states, “There was no significant difference [between the two methods].” However, the second article,2 assessing the relative efficacy of antiarrhythmic drugs, offers a “clinical recommendation” that “treatment with sotalol and assessment of its potential efficacy by Holter monitoring are a reasonable initial strategy.” This conclusion is made despite a one-year arrhythmia-associated mortality rate of 10 percent (in a study population in which only 21 percent of the patients were survivors of cardiac arrest) and despite low overall rates of drug efficacy. Another interpretation of the data is that none of the agents evaluated (with the possible exception of sotalol) or neither method of assessing drug efficacy offers an effective approach to serious ventricular arrhythmias. Other therapeutic options (such as amiodarone or an implantable cardioverter-defibrillator) may provide more effective treatment,4,5 and their potential roles in the management of ventricular tachyarrhythmias are not discussed in either article.

Obviously, because the treatments evaluated in the study did not include either amiodarone or an implantable cardioverter-defibrillator, no conclusions can be made regarding the potential roles of these therapeutic approaches. Nevertheless, it is important for articles appearing in the Journal to address other state-of-the art treatments in their discussion sections. The lack of a discussion about important and reasonable therapeutic options and the presentation of a blanket conclusion in its absence are misleading to the reader. To make such a firm conclusion about the treatment of patients with this life-threatening problem requires a prospective study in which Holter-guided therapy with sotalol is compared with other “reasonable” therapeutic approaches. It would be a serious error if the message from the ESVEM trial was that Holter-guided therapy with sotalol was the definitive approach to the treatment of such patients.

Roger S. Damle, M.D.
University of Colorado Health Sciences Center, Denver, CO 80262

Frederick A. Ehlert, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10025

5 References

1. 1

   Mason JW. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias. N Engl J Med 1993;329:445-451
   Full Text | Web of Science | Medline

2. 2

   Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. N Engl J Med 1993;329:452-458
   Full Text | Web of Science | Medline

3. 3

   The ESVEM Investigators. The ESVEM trial: electrophysiologic study versus electrocardiographic monitoring for selection of antiarrhythmic therapy of ventricular tachyarrhythmias. Circulation 1989;79:1354-1360
   CrossRef | Web of Science | Medline

4. 4

   The CASCADE Investigators. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study). Am J Cardiol 1993;72:280-287
   CrossRef | Web of Science | Medline

5. 5

   Winkle RA, Mead RH, Ruder MA, et al. Long-term outcome with the automatic implantable cardioverter-defibrillator. J Am Coll Cardiol 1989;13:1353-1361
   CrossRef | Web of Science | Medline

To the Editor:

A review of the design of the ESVEM study arouses concern that the protocol followed for serial drug testing with programmed stimulation to evaluate the suppression of inducible ventricular tachycardia was not sufficiently aggressive. Contrary to current practice, if sustained ventricular tachycardia was provoked by a single extrastimulus, double and triple extrastimuli were not evaluated during follow-up drug testing. Likewise, if the base-line arrhythmia was initiated by two extrastimuli, three extrastimuli were not tested at follow-up. This unconventional practice may have overestimated the predictions of efficacy based on programmed stimulation, which in turn may account for the higher incidence of recurrence in the electrophysiologic-study group, as compared with the findings of earlier studies1,2.

In a preliminary assessment, we evaluated the extent to which the number of stimuli used for programmed electrical stimulation may affect the induction of sustained ventricular tachycardia during testing to determine the efficacy of antiarrhythmic-drug therapy. In 47 of 103 consecutive drug studies (46 percent) performed in 66 patients with persistent induction of ventricular tachycardia, a more aggressive stimulation protocol than that used at base line was required to initiate sustained ventricular tachycardia. Fifty-eight percent of the 66 patients required a more aggressive stimulation protocol with serial testing to demonstrate lack of drug efficacy. Furthermore, 23 percent of the patients who had ventricular tachycardia induced at base line with one or two extrastimuli required the use of three extrastimuli at follow-up testing to assess lack of drug efficacy. Thus, the failure to complete a stimulation protocol, including the use of up to three extrastimuli, at multiple basic drive trains and from two right ventricular sites to assess the efficacy of antiarrhythmic drugs may substantially overestimate responsiveness to the drugs. These findings should be considered by anyone attempting to apply the results of the ESVEM trial to clinical practice or designing future trials.

Stephen L. Winters, M.D.
Morristown Memorial Hospital, Morristown, NJ 07962-1956

Donald Rubinstein, M.D.
St. Michael's Medical Center, Newark, NJ 07102

J. Anthony Gomes, M.D.
Mount Sinai School of Medicine, New York, NY 10029

2 References

1. 1

   Waller TJ, Kay HR, Spielman SR, Kutalek SP, Greenspan AM, Horowitz LN. Reduction in sudden death and total mortality by antiarrhythmic therapy evaluated by electrophysiologic drug testing: criteria of efficacy in patients with sustained ventricular tachyarrhythmia. J Am Coll Cardiol 1987;10:83-89
   CrossRef | Web of Science | Medline

2. 2

   Wilber DJ, Garan H, Finkelstein D, et al. Out-of-hospital cardiac arrest: use of electrophysiologic testing in the prediction of long-term outcome. N Engl J Med 1988;318:19-24
   Full Text | Web of Science | Medline

Author/Editor Response

Dr. Mason replies:

To the Editor: My colleagues and I agree with Damle and Ehlert that it would be appropriate to test prospectively our recommendation of the initial use of sotalol guided by Holter monitoring. We do not agree with their other points.

It would not have been appropriate for us to compare ESVEM therapies with other therapies that we did not evaluate and that had not been studied in controlled trials. We were not writing a review article or an opinion paper.

We suggested that “if antiarrhythmic-drug therapy is to be used,” Holter-guided therapy with sotalol is a “reasonable initial strategy.” This was not offered as a “blanket conclusion” or “the definitive approach” and should not mislead the reader.

Damle and Ehlert are incorrect to suggest that mortality in the ESVEM trial was higher than expected with amiodarone or the implanted defibrillator. In another trial1 we estimated that a higher cumulative proportion of patients in the amiodarone-treated group died suddenly by four years (about 23 percent) than in the overall ESVEM population (20 percent) or the ESVEM cardiac-arrest subgroup (21 percent). In the study by Lehmann and colleagues2 involving 876 patients with implanted defibrillators, the actuarial one-year mortality from all causes was 12 percent -- exactly the same as that which we reported for 296 patients receiving drugs predicted to be effective by electrophysiologic study or Holter monitoring -- and the four-year mortality was higher than in our study population (31 percent vs. 28 percent). Nevertheless, the relative efficacy of these approaches has not been determined objectively.

Our clinical recommendation was carefully worded so as not to exclude a preference for the use of amiodarone or an implantable defibrillator. Two purposes of large, randomized clinical trials like ours are to compare treatments objectively and dispel clinical bias. Clinicians should await the results of several ongoing trials that compare defibrillators with drugs before deciding which approach is best.

Winters and colleagues misunderstand the stimulation protocol used in the ESVEM trial. We did use double extrastimuli at three rates of ventricular pacing for the assessment of drug efficacy in all subjects in whom a single extrastimulus induced tachyarrhythmia at base line. They refer to our stimulation protocol as “unconventional” and to the use of aggressive stimulation protocols as “current practice.” There is no standard stimulation protocol, nor is there an objective data base that describes current practice.

Winters and colleagues report that the use of more aggressive stimulation yields fewer predictions of efficacy. This has been known for more than a decade3. They equate this more difficult yardstick with greater predictive accuracy; that is, they assume that a drug that prevents initiation of ventricular tachyarrhythmia by more aggressive stimulation is more likely to prevent the recurrence of spontaneous arrhythmia. In fact, the only published comparison of the use of two extrastimuli with the use of three extrastimuli to assess drug efficacy in patients requiring only one or two extrastimuli for the induction of arrhythmia at base line showed a slightly better outcome in the group tested less aggressively with two extrastimuli3. An analysis of subgroups in the ESVEM trial, to be reported soon, supports this finding. The only sure result of a more aggressive stimulation protocol is not more effective drug therapy but, rather, a much lower yield of drug-efficacy predictions. In recent years, the routine use in some laboratories of three or more extrastimuli to test drug efficacy has led to greater reliance on implantable defibrillators. Does more aggressive stimulation, leading to more aggressive therapy, have a greater value for public health?

Jay W. Mason, M.D., M.D.,
University of Utah, Salt Lake City, UT 84132

for the ESVEM Investigators

3 References

1. 1

   The CASCADE Investigators. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE study). Am J Cardiol 1993;72:280-287
   CrossRef | Web of Science | Medline

2. 2

   Lehmann MH, Thomas A, Jackson K, et al. Long-term outcome with implantable cardioverter defibrillator (ICD) therapy in a multicenter investigator-edited database. Circulation 1990;82:Suppl III:III-166 abstract.
   CrossRef

3. 3

   Swerdlow CD, Blum J, Winkle RA, Griffin JC, Ross DL, Mason JW. Decreased incidence of antiarrhythmic drug efficacy at electrophysiologic study associated with the use of a third extrastimulus. Am Heart J 1982;104:1004-1011
   CrossRef | Web of Science | Medline