Significance and Incidence of Concordance of Drug Efficacy Predictions by Holter Monitoring and Electrophysiological Study in the ESVEM Trial
Background Selection of antiarrhythmic therapy may be based on either suppression of spontaneous ventricular arrhythmias assessed by Holter monitoring or by suppression of inducible ventricular arrhythmias during electrophysiological study. This study examines the frequency and significance of concordance of these two approaches in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial.
Methods and Results Twenty-four-hour Holter monitoring was performed in patients randomized to the electrophysiology limb of the ESVEM study at the time of the first drug trial and at the time of an effective drug trial. Holter monitors were available in 65% (146/226) of patients at the time of the first drug trial and in 93% (100/108) of patients at the time of an electrophysiology study predicting drug efficacy. There were no clinical differences between patients who had and those who did not have a Holter monitor. At the time of the first drug trial, concordance of Holter and electrophysiological predictions of drug efficacy was observed in 46% of patients (both techniques predicted efficacy in 23%; neither predicted efficacy in 23%). Discordant results were observed in 54% (Holter suppression without electrophysiological suppression in 44%; electrophysiological suppression without Holter suppression in 10%). At the time of an electrophysiology study predicting drug efficacy, 68 of the 100 patients without inducible ventricular tachyarrhythmias also had suppression of spontaneous ventricular arrhythmias on the Holter recorded at the time of the electrophysiological study. Neither arrhythmia recurrence nor mortality was significantly different in patients with suppression of both inducible and spontaneous ventricular arrhythmias compared with those with only suppression of inducible arrhythmias. Comparison of patients with suppression of both inducible and spontaneous ventricular arrhythmias with the 188 patients in the Holter limb, in whom efficacy was predicted by Holter monitoring only, revealed no difference in outcome.
Conclusions In this population, (1) there is frequent discordance in prediction of drug efficacy and inefficacy between electrophysiological study and Holter monitoring; (2) a requirement to fulfill both Holter and electrophysiological efficacy criteria reduces the number of patients with an efficacy prediction; and (3) suppression of both spontaneous ventricular ectopy and inducible ventricular tachyarrhythmias does not identify a group with better outcome.
Antiarrhythmic agents are prescribed for the majority of patients with sustained ventricular arrhythmias, either as primary therapy or as secondary therapy in patients with implanted cardioverter/defibrillators.1 Selection of a specific antiarrhythmic agent is often arbitrary, with efficacy subsequently defined by either suppression of spontaneous ventricular ectopy assessed by Holter monitoring2 or suppression of inducible ventricular arrhythmias assessed by electrophysiological evaluation.3
Comparative predictive accuracy and correlation of these two intrinsically different methods have not been extensively studied.4 5 6 Recently, the ESVEM trial described outcomes in patients in whom drug efficacy was predicted by Holter monitoring and by electrophysiological study.7 In this trial, patients with both frequent spontaneous ventricular arrhythmias (≥10 premature ventricular contractions per hour) and inducible sustained ventricular arrhythmias were randomized to have antiarrhythmic drug efficacy defined either by Holter monitoring and exercise testing or by electrophysiological study. Patients then received a randomized series of antiarrhythmic agents until one was predicted efficacious by the assigned method. The ESVEM study demonstrated that there were no significant differences in the rate of arrhythmia recurrence or death in patients with drug efficacy defined by Holter monitoring compared with patients with drug efficacy defined by electrophysiological study.7
No direct correlation of Holter monitoring and electrophysiological evaluation in the same patient was reported in the ESVEM study. However, by design, 24-hour Holter ECG recordings were obtained in patients randomized to the electrophysiology limb at the time of the first drug trial. These Holter monitors were not used to guide therapy but rather were obtained to examine the frequency of concordant efficacy predictions by the two methods. Holter monitors were also recorded at the time of an efficacious drug trial. These Holters were used in a separate analysis to determine the clinical significance of a combined definition of drug efficacy by the two methods. We present the results of these analyses in this article.
The ESVEM trial was a prospective, multicenter study. Details of the trial design have been published.8 Briefly, patients with documented sustained ventricular arrhythmias, resuscitation from cardiac arrest, or syncope (with subsequent inducible ventricular tachycardia) who lacked exclusion criteria8 (n=1503) and who gave informed consent (n=1005) underwent baseline electrophysiological study and 48 hours of Holter monitoring. Those who had both reproducibly inducible, sustained (≥15 seconds) ventricular tachyarrhythmias and an average of ≥10 premature ventricular contractions per hour (n=486) were randomly assigned to undergo testing of drug efficacy by either serial electrophysiological studies (n=242) or Holter monitoring (n=244).
After randomization to a specific method of defining drug efficacy, patients received, in random order, up to six of seven antiarrhythmic agents (imipramine, mexiletine, pirmenol, procainamide, propafenone, quinidine, or sotalol) at levels defined by protocol.8 Serial electrophysiological or noninvasive drug efficacy assessments were performed until a drug was predicted effective or until all available study drugs were tested. In patients randomized to drug assessment by electrophysiological study, 24-hour Holter monitors were obtained at the time of the first drug trial. In addition, 24-hour Holter monitoring was also performed after electrophysiological study had defined a drug as being efficacious and before hospital discharge. These Holter monitors were not analyzed before discharge.
Data obtained at the time of the first drug trial were used to determine the frequency of concordance and to determine clinical predictors of concordance or discordance between the two drug assessment techniques. Data obtained at the time of an effective drug trial were used to assess differences in outcome between patients who met both electrophysiological and Holter criteria of drug efficacy, those who met only electrophysiological criteria (ie, without concomitant suppression of spontaneous arrhythmias), and patients in whom drug efficacy was predicted by Holter monitoring alone.
Holter monitoring consisted of continuous two-channel recordings in which a minimum of 20 analyzable hours was required except at baseline, when a minimum of 40 hours was required. All Holter tapes were analyzed by a centralized tape analysis system (Personal Computers for Medicine) at the University of Utah. Analysis reproducibility was assessed by rescanning 9% of all tapes from December 1989 until trial completion. Reproducibility (mean percent difference in premature ventricular contraction counts between two scans of the same tape) was within 1.4%. Count accuracy was assessed by hand-counting full disclosure printouts of another 2% of tapes. Accuracy of total premature ventricular contraction counts (mean difference between scanned and hand counts) averaged 1.0±2.1% (mean±SEM).
Definition of Drug Efficacy
Holter monitor criteria for drug efficacy in ESVEM were defined8 as ≥70% reduction in premature ventricular contractions, ≥80% reduction in ventricular pairs, ≥90% reduction in ventricular tachycardia (3 to 15 beats), and elimination of ventricular tachycardia >15 beats. In addition, the absence of ventricular tachycardia ≥5 beats was required during exercise testing. The same criteria were used for the present study. Drug efficacy for patients randomized to the electrophysiology study limb required failure to induce ventricular tachycardia >15 beats with at least two ventricular extrastimuli at the right ventricular apex at multiple cycle lengths.8 In patients in whom a second pacing site or third extrastimulus was required for induction of a sustained arrhythmia during the baseline study, the same protocol was used for drug assessments.
Patients were seen 1, 3, and 6 months after discharge and then twice annually. Follow-up consisted of symptom assessment, physical examination, drug plasma concentration determination, and a 24-hour Holter monitor. End points defining drug failure were sudden death, cardiac arrest, documented ventricular tachycardia >15 beats, unmonitored syncope without other explanation, or torsade de pointes.
Clinical characteristics of patients were compared by a two-tailed Fisher’s exact test or a χ2 statistic (for categorical data) and a standard t test or nonparametric test (for continuous data). Concordance between Holter monitoring and electrophysiological techniques was assessed with McNemar’s test.9 The influence of clinical characteristics on concordance was evaluated by logistic regression analysis.10 Multivariate models were constructed by backward elimination stepwise procedures, starting with all univariate predictors significant at P<.25. Cumulative estimates of arrhythmia recurrence and mortality end points (all-cause, cardiac, and arrhythmic death) were summarized by Kaplan-Meier actuarial methods,11 and actuarial outcomes were compared by a log-rank test or multivariate Cox proportional-hazards regression models12 after adjustment for covariates8 (presenting arrhythmia, frequency of premature ventricular contractions, symptom-activity scale class of Goldman et al,13 enrolling center, underlying cardiac disease, failure of previous antiarrhythmic drug therapy, and treatment with sotalol). The data were analyzed with SAS software.14 A value of P<.05 was considered statistically significant.
Concordance of Holter and Electrophysiological Evaluations: First Drug Study
Of the 242 patients assigned to have drug efficacy defined by serial electrophysiological studies, 226 underwent at least one restudy on drug. The other 16 patients did not undergo electrophysiological study because of either premature drug failure before assessment for all drugs taken (6 patients), patient withdrawal after premature drug failure on one or more drugs (8 patients), or withdrawal before drug administration (2 patients). Holter monitors were available in 65% (146/226) of these patients at the time of the first electrophysiological drug assessment. No Holter recording was available for analysis in 80 patients either because of technical difficulties (4 patients) or because continuing ineffective therapy while monitoring would interfere with clinical care (76 patients). There were no clinical differences between patients who did and did not have a Holter monitor.
Of 146 patients in whom Holter monitoring data were available, 48 (33%) met electrophysiological criteria for drug efficacy, and 97 (66%) met Holter efficacy criteria on the initial drug trial (P<.001; Fig 1⇓). The Holter monitoring and electrophysiological techniques were concordant in 46% of patients, half with concordant predictions of drug efficacy and half with concordant predictions of drug inefficacy. Seventy-five patients (54%) had discordant electrophysiological and Holter results, 64 of whom were suppressed by Holter but not by electrophysiological criteria. Fifteen of the 49 patients (31%) who did not have suppression of spontaneous ventricular ectopy met electrophysiological criteria for drug efficacy. The sensitivity of Holter monitor suppression in predicting electrophysiological suppression was 0.69, but the specificity of Holter nonsuppression in predicting electrophysiological inducibility was only 0.35.
Patients with concordant drug efficacy (positive concordance), patients with concordant drug inefficacy (negative concordance), and those with discordant electrophysiological and Holter results were similar in most baseline clinical characteristics (Table 1⇓), but multivariate analysis did identify predictors of the two types of concordance (positive and negative). Since the importance of the predictors varied for positive and negative concordance, individual regression models were used instead of one model with a polytomous outcome. Sotalol therapy was the only clinical characteristic possibly associated with positive concordance (odds ratio, 2.37; 95% CI, 0.98 to 5.72). Cause of disease other than coronary artery disease (odds ratio, 3.07; 95% CI, 1.05 to 9.02) and left ventricular ejection fraction <25% (odds ratio, 2.73; 95% CI, 1.06 to 7.01) were significant predictors of concordant drug inefficacy.
Because the Holter monitor criteria for declaring drug efficacy in the ESVEM trial may have been less stringent than criteria used in other published series,15 we retrospectively analyzed the frequency of concordance using two additional Holter criteria of drug efficacy: (1) ≥70% suppression of premature ventricular contractions, ≥80% suppression of pairs, and elimination of ventricular tachycardia ≥3 beats in duration and (2) ≥80% suppression of premature ventricular contractions, ≥90% suppression of pairs, and elimination of ventricular tachycardia ≥3 beats in duration. Efficacy by Holter monitor was achieved in 66% with the original criteria, in 61% with the first revised criteria, and in 54% with the second revised criteria. Similar proportions of concordance (46%, 43%, and 46%, respectively) were observed for the original and the two additional Holter criteria, with sensitivity of Holter monitor efficacy in predicting electrophysiological efficacy decreasing but specificity in predicting electrophysiological inducibility increasing with the more stringent criteria (Fig 1⇑).
Twenty-nine patients who underwent repeated electrophysiological evaluations without definition of an effective antiarrhythmic agent had a 24-hour Holter recorded at the time of the last available (and ineffective) antiarrhythmic agent. Of these 29 patients, Holter monitoring predicted drug efficacy in 15 patients (52%).
Significance of Concordant Holter and Electrophysiological Evaluations: Effective Drug Study
Holter monitors were available for analysis in 100 of 108 patients (93%) at the time of an electrophysiological study that predicted drug efficacy. Forty-six of these 100 patients met efficacy criteria on the first drug exposure, as described above. Two patients who met electrophysiological efficacy criteria at the time of first drug exposure had the drug discontinued because of side effects after discharge and were not included in this outcome analysis on this drug. The outcome of patients who met electrophysiological efficacy criteria was not influenced by whether electrophysiological efficacy was met on the first or subsequent drug trials (P=.790). Therefore, for the remainder of the analysis, these patients were pooled.
In the 100 patients who met electrophysiological criteria of drug efficacy, 68% also met Holter criteria for drug efficacy on the Holter obtained before discharge. Patients who met electrophysiological but not Holter criteria for drug efficacy were more likely to have presented with ventricular fibrillation or sudden death (38%) than were patients with suppression of both inducible and spontaneous arrhythmias (12% of whom presented with ventricular fibrillation or sudden death; P=.006). No other clinical characteristic or the antiarrhythmic agent being evaluated affected the incidence of concordant drug efficacy definitions by both electrophysiological and Holter criteria (Table 2⇓) by univariate analysis, although multivariate analysis identified both presenting arrhythmia and cause of disease to be significant predictors of suppression of both inducible and spontaneous ventricular arrhythmias (P=.001). The odds of suppression of both inducible and spontaneous ventricular arrhythmias for patients without ventricular fibrillation or sudden death compared with those with this presenting arrhythmia were 5.03 (95% CI, 1.73 to 14.59), and the odds ratio for patients with coronary artery disease compared with those without it was 3.14 (95% CI, 1.12 to 8.82). An antiarrhythmic drug was predicted to be effective in 45% of patients (108/242) randomized to undergo electrophysiological evaluation.7 If suppression of both inducible and spontaneous arrhythmias was required for a definition of drug efficacy, the proportion of patients for whom drug efficacy was predicted would decrease to 30%.
There was no significant difference (P=.664) in arrhythmia recurrence for patients who met both electrophysiological and Holter criteria for drug efficacy (n=68) compared with those who met electrophysiological but not Holter criteria (n=32) (Fig 2⇓). There was no significant difference in the type of end point or arrhythmia recurrence (ie, sudden death, cardiac arrest, sustained ventricular tachycardia requiring therapy, nonsustained tachycardia >15 beats, unwitnessed syncope) in patients who met both criteria compared with those who met electrophysiological but not Holter criteria. Arrhythmia-free survival for patients with suppression of both inducible and spontaneous ventricular arrhythmias was 71%, 35%, and 28% at 1, 3, and 5 years, respectively. In patients rendered noninducible but without suppression of spontaneous ventricular ectopy, arrhythmia-free survival at 1, 3, and 5 years was 68%, 40%, and 34%, respectively. Using more stringent criteria for Holter suppression did not influence the similar outcomes in the two groups. In addition, comparison of patients in the electrophysiological limb who fulfilled both electrophysiological and Holter criteria for drug efficacy with patients in the Holter limb in whom efficacy was guided by Holter monitoring alone (n=188) revealed no outcome differences (P=.867) (Fig 3⇓).
There were no significant differences in the three mortality end points (all-cause, P=.105; cardiac, P=.127; arrhythmic, P=.221) in patients who met both electrophysiological and Holter criteria for drug efficacy compared with those who met electrophysiological but not Holter criteria. Survival for patients with suppression of both inducible and spontaneous ventricular arrhythmias was 88%, 68%, and 59% at 1, 3, and 5 years. In patients who met electrophysiological but not Holter criteria, survival at 1, 3, and 5 years was 96%, 83%, and 71%, respectively. Additionally, there were no significant differences in mortality (all-cause, P=.143; cardiac, P=.247; arrhythmic, P=.323) among electrophysiological study limb patients who met both electrophysiological and Holter criteria for drug efficacy compared with patients in the Holter monitor limb who met efficacy criteria. Survival for the patients in the Holter limb was 89%, 79%, and 67% at 1, 3, and 5 years, respectively.
For 39 patients in whom sotalol was predicted efficacious by electrophysiological study and in whom a Holter tape was available, there was no significant difference in arrhythmia recurrence (P=.723), all-cause mortality (P=.156), cardiac mortality (P=.192), or arrhythmic death (P=.245) between patients who met (n=29) compared with those who did not meet (n=10) Holter criteria for drug efficacy.
We observed a significant discordance between electrophysiological and noninvasive assessments of drug efficacy in the ESVEM trial but, most importantly, did not find that suppression of both spontaneous ventricular ectopy and inducible ventricular tachyarrhythmias predicted a better outcome than suppression of either spontaneous or inducible ventricular arrhythmias alone. Discordance between Holter monitor and electrophysiological results has been reported previously for class Ia,16 17 Ib,18 and III5 19 20 antiarrhythmic agents. In the previous studies, as in the present study, discordance was due primarily to suppression of spontaneous arrhythmias without a prediction of efficacy by electrophysiological study. This observation was interpreted to result from a combination of nonspecificity (excessive “strictness”) of programmed stimulation and insensitivity (excessive “leniency”) of Holter monitoring.16 However, the comparable outcomes in patients with concordant and discordant results observed in the present study and the similar outcomes in patients with therapy guided by either Holter monitoring or electrophysiology studies7 are not consistent with this interpretation.
Comparable outcomes in patients whose therapy is guided by Holter monitoring or electrophysiological study could occur if each technique identifies an effective agent but a different therapeutic effect. It has been suggested20 21 22 that the spontaneous occurrence of a sustained ventricular arrhythmia requires both an anatomic substrate (ie, reentry circuit) and a trigger to initiate tachycardia (eg, spontaneous ventricular ectopy). Suppression of ventricular ectopy by an antiarrhythmic drug (identified by Holter monitoring) may decrease the occurrence of sustained ventricular arrhythmias by decreasing the frequency of the trigger. Suppression of inducible ventricular arrhythmias at the time of electrophysiological study, on the other hand, may identify effects of an antiarrhythmic drug on the reentry circuit. On the basis of this thesis, it has been suggested22 that patients in whom an antiarrhythmic agent had beneficial effects on both substrate and trigger would do better than patients with only electrophysiological suppression. The observation that patients who met both electrophysiological and Holter criteria for drug efficacy were similar in terms of arrhythmia recurrence and survival compared with patients with only electrophysiological suppression does not support this hypothesis. Our data suggest that electrophysiological and noninvasive approaches are not complementary in the selection of effective antiarrhythmic therapy.
Implications of the Present Analysis for the ESVEM Study
The ESVEM trial has received significant attention because of the important implications this study has for clinical practice. It has been suggested21 that the results of this trial were misleading, in part because the outcome of patients whose therapy was defined by electrophysiological study in the ESVEM study was not as good as previously reported for some electrophysiologically guided trials. One potential explanation for this difference is that in the previous trials, drug efficacy was evaluated electrophysiologically only after formal or informal assessment of the effect of the antiarrhythmic agent on spontaneous arrhythmias. For example, many electrophysiologists would not restudy a patient on antiarrhythmic therapy if telemetry revealed frequent ventricular ectopy or nonsustained ventricular tachycardia. If this practice is widespread, many patients with efficacy predicted by electrophysiological study reported in previous trials may in reality be both electrophysiologically and noninvasively suppressed. Since patients in the ESVEM study whose therapy was defined by electrophysiological restudy were not “prescreened,” their outcome could conceivably be worse than “electrophysiologically guided” patients in the literature. However, patients who fulfilled both Holter and electrophysiological criteria of drug efficacy in the present study would then be expected to have a better outcome than patients without Holter monitor suppression, and this was not observed.
In light of these observations, the similar outcomes of patients with therapy guided by either invasive or noninvasive techniques may have at least two other alternative explanations: (1) additive effects of the two techniques are too small to be detected in our sample size (this analysis had a power of 0.84 at a two-tailed significance level of .05 to detect a difference of 50% in the actuarial probability of arrhythmia recurrence between patients who were electrophysiologically suppressed with Holter suppression versus those without Holter suppression and a power of 0.79 to detect a 25% difference between patients who were electrophysiologically suppressed with Holter suppression versus patients randomized to the Holter limb who met efficacy criteria for suppression of spontaneous ectopy) or do not occur, or (2) neither technique identifies an effective therapy.21
The risk of arrhythmia recurrence in the ESVEM trial was significantly lower in patients who received sotalol than in those who received other antiarrhythmic agents.23 The recurrence benefit of sotalol was apparent regardless of the method used to determine drug efficacy. In the present analysis, the outcomes of patients treated with sotalol (ie, who met electrophysiological criteria of drug efficacy) were similar regardless of whether or not there was suppression of spontaneous ventricular arrhythmias. Thus, it does not appear that the lower arrhythmia recurrence seen in patients receiving sotalol is related to achievement of greater concordance of electrophysiological and Holter suppression.
This study has several potential limitations. Not all patients underwent monitoring at the time of the first or the effective electrophysiological study. At the time of the first electrophysiological evaluation, 80 patients did not receive a 24-hour Holter. In the majority, electrophysiological evaluation was ineffective and Holter recordings were not obtained because it was thought to be inappropriate to continue ineffective therapy during the recording of this additional Holter monitor. Although these omissions might change the exact incidence of concordance, we do not believe this to be a serious limitation, since the patients who did undergo monitoring were not distinguishable clinically from those who did not.
These results are specific to the patient population in the ESVEM study (ie, patients with both frequent premature ventricular contractions and inducible ventricular arrhythmias) and to the methods and suppression criteria used. The extent to which these results can be generalized to other patient populations or methods is unknown, although the use of more stringent Holter criteria does not appear to influence the results.
A prospective study using a combined Holter and electrophysiological definition of drug efficacy could yield results different from those observed in the present study because many patients in the ESVEM study suppressed by only one technique would have received different therapy in a trial requiring both Holter and electrophysiological suppression. The outcome of these patients on different therapy is not known. Different results might also be expected if Holter recording were used as the primary method of determining drug efficacy (with electrophysiological evaluation at the time of the first or effective Holter trial), although this parallel protocol was not performed.
Approximately one half of the patients analyzed at the time of an effective drug trial were also included in the analysis of concordance at the time of the first drug trial (ie, first and effective trials were the same). However, since the primary analyses were different for the first drug exposure and the effective drug exposure, we do not believe this overlap to be an important limitation. Although predictors of concordance at the time of the first and the effective drug exposures may be statistically correlated, the lack of differences in outcomes between patients who met electrophysiological efficacy criteria with and without Holter suppression makes this correlation clinically unimportant. Moreover, a single analysis of predictors of concordance using the pooled population yields identical results.
We conclude that (1) there is a frequent discordance in the results of drug efficacy testing by electrophysiological study compared with Holter monitoring; (2) a requirement for both Holter and electrophysiological suppression reduces the number of patients who achieve an efficacy prediction; and (3) suppression of both spontaneous and inducible ventricular arrhythmias does not provide predictive or prognostic benefit over suppression of either alone. Therefore, this approach cannot be recommended at the present time.
The enrollment centers and study investigators participating in the ESVEM trial are listed below. For each center, the first person listed was the principal investigator.
University of Arizona, Tucson: F.I. Marcus, A. Caruso, H.L. Faitelson, T.E. Raya, Z. Garcia, K. Gear, and M.K. Pierce; Baylor College of Medicine, Houston, Tex: C.M. Pratt, A. Boahene, A. Pacifico, C. Wyndham, and M. Francis; University of British Columbia, Vancouver: C.R. Kerr, J.A. Yeung, and S. Vorderbrugge; University of California, San Francisco: J.C. Griffin, M. Lesh, M.M. Scheinman, M. Wong, and M. Wong; University of Colorado, Denver: M.J. Reiter, D. Mann, T. Heyborne, and C. Kenny; Columbia University, New York: J.T. Bigger, Jr, J. Coromilas, F.D. Livelli, Jr, J. Reiffel, J.S. Steinberg, J. Campion, and A.M. Squatrito; University of Massachusetts, Worcester: S.K. Huang, R. Mittleman, P. Collett-Willey, and K. Rofino; Newark Beth Israel Medical Center, Newark, NJ: S. Saksena, R.B. Krol, and L. Duque; University of New Mexico, Albuquerque: R.C. Klein, C. Machell, L. Widman, C. Acosta-Miller, and G. Lomeli; Northwestern University, Chicago, Ill: R. Kehoe, T.A. Zheutlin, T. Mattioni, and C. Dunnington; University of Oklahoma, Oklahoma City: R. Lazzara, K. Beckman, K. Friday, W.M. Jackman, T. Deaton, K. Drennan, J. Foster, and S. Harris; Oregon Health Sciences University, Portland: J.H. McAnulty, J. Kron, B.D. Halperin, K. Sinner, and K. Martin; University of Pennsylvania–Presbyterian Medical Center, Philadelphia: L.N. Horowitz, C.D. Gottlieb, and C. Vrabel; University of Utah, Salt Lake City: J.W. Mason, J.L. Anderson, K.P. Anderson, R.A. Freedman, L. Karagounis, D.A. Rawling, M. Hutson, D. Mannis, and M. Roskelley.
Principal Investigator: J.W. Mason, University of Utah.
Trial Coordinating Center: University of Utah.
Data Coordinating Center (University of Arizona): T. Moon, E. Hahn, V. Hartz, A. Rico, and N. Jenrow.
Safety Monitoring Committee: R. Bressler (chair), H.L. Greene, M. Lebowitz, T. Moon, and E. Morkin.
End Points Committee: W.D. Weaver (chair), T. Bump, F. Morady, and B. Olshansky.
This study was supported in part by a grant (RO-1-HL34071) from the National Heart, Lung, and Blood Institute; a grant (M01-RR00064) from the National Center for Research Resources; and by Bristol-Myers Squibb Co, Knoll Pharmaceutical Co, Boehringer-Ingelheim, Parke-Davis, and Ciba-Geigy.
↵1 A complete list of investigators appears in the “Appendix.”
- Received September 13, 1994.
- Accepted November 26, 1994.
- Copyright © 1995 by American Heart Association
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