Author + information
- Received November 10, 2000
- Revision received March 22, 2001
- Accepted April 26, 2001
- Published online August 1, 2001.
- D.George Wyse, MD, PhD, FACC∗,* (, )
- Mario Talajic, MD, FACC†,
- Gail E Hafley, MS‡,
- Alfred E Buxton, MD, FACC§,
- L.Brent Mitchell, MD∥,
- Teresa K Kus, MD, PhD, FACC∥,
- Douglas L Packer, MD, FACC¶,
- William H Kou, MD, FACC#,
- Robert Lemery, MD, FACC∗∗,
- Peter Santucci, MD††,
- Denise Grimes, RN‡‡,
- Kathleen Hickey, RN§§,
- Carolyn Stevens, RN¶,
- Steven N Singh, MD, FACC∥,
- for the MUSTT Investigators
- ↵*Reprint requests and correspondence:
Dr. D. George Wyse, Division of Cardiology, University of Calgary, G009, Health Sciences Center, 3350 Hospital Drive Northwest, Calgary, AB Canada T2N 4N1
Using data from the Multicenter UnSustained Tachycardia Trial (MUSTT), we examined the factors used to select antiarrhythmic drug therapy and their impact on outcomes.
The MUSTT examined the use of programmed ventricular stimulation (PVS) to guide antiarrhythmic therapy in patients with coronary arteriosclerosis, left ventricular dysfunction and asymptomatic, unsustained ventricular tachycardia (VT). Trial outcomes may reflect factors used to select antiarrhythmic drug therapy.
We compared subgroups of patients with inducible sustained VT randomized to PVS-guided antiarrhythmic therapy (n = 351), in particular those receiving PVS-guided antiarrhythmic drug therapy (n = 142) versus no antiarrhythmic therapy (controls, n = 353).
“Effective” antiarrhythmic drug therapy (i.e., the term “effective” was used to denote therapy that resulted in noninducible VT or hemodynamically stable induced VT) was found for 142 of the 351 patients (43%), most often at the first or second PVS session (125/142, 88%). Mortality among the 142 patients did not differ from that among control patients. Of these 142 patients, the PVS end point was noninducibility in 91 patients and stable VT in 51 patients. Mortality did not differ between these two groups either, but arrhythmia was numerically more frequent in the PVS-induced stable VT group. Mortality was greatest in the few patients receiving propafenone (unadjusted p = 0.07, adjusted p = 0.14 vs. controls), but mortality with all agents did not differ from that of controls, even after adjustment.
Even when presenting the results as favorably as possible, we found no benefit with PVS-guided drug therapy in patients with clinical unsustained VT who had inducible sustained VT. These findings are unaltered by using different end points for PVS or considering the response to individual drugs.
The Multicenter UnSustained Tachycardia Trial (MUSTT) was a randomized, controlled trial of programmed ventric-
ular stimulation (PVS) for management of patients with coronary arteriosclerosis, left ventricular dysfunction and asymptomatic, unsustained ventricular tachycardia (VT) (1). The main trial was analyzed on an intention-to-treat basis. In the main trial and the registry, arrhythmic death or nonfatal cardiac arrest was reported as the primary end point and all-cause mortality as a key secondary end point (2,3). In MUSTT, antiarrhythmic drug therapy that prevented VT induction or made induced VT hemodynamically stable conferred no survival benefit over no antiarrhythmic therapy (2). This finding was unexpected (4). The main results of MUSTT may partly reflect the choice of agents and methods for PVS. We examined these factors with regard to the end points of death and ventricular arrhythmias.
The MUSTT protocol has been reported (1). In brief, we identified patients with coronary arteriosclerosis, an ejection fraction ≤0.40 and asymptomatic, nonsustained VT on electrocardiography. Major exclusions included previous syncope, sustained VT or ventricular fibrillation >48 h after acute myocardial infarction onset; nonsustained VT occurring only with reversible causes; and symptomatic, unsustained VT requiring treatment.
Programmed ventricular stimulation was performed as described (1), after antiarrhythmic drugs were stopped, and included ≤3 extrastimuli at two right ventricular sites after two ventricular pacing-cycle lengths. Patients with inducible, sustained monomorphic VT induced by up to three extrastimuli, or sustained polymorphic VT induced by one or two extrastimuli, were randomized equally to PVS-guided antiarrhythmic therapy or no antiarrhythmic therapy. To declare a drug therapy potentially “effective,” the entire stimulation protocol had to be completed (three extrastimuli, two cycle lengths, two sites).
Serial antiarrhythmic drug trials
Patients randomized to PVS-guided therapy underwent serial drug testing. In trial 1, there was three-way randomization between class 1A agents (quinidine, disopyramide or procainamide, chosen by investigators), propafenone or sotalol. If treatment failed to control VT induction in trial 1, investigators could choose to implant an implantable cardioverter defibrillator (ICD) or attempt another drug trial. In trial 2, patients were randomized to one of the therapies not used in trial 1 or to a combination of mexiletine and a class 1A agent. If this treatment failed, investigators could implant an ICD or attempt additional trials, which could include treatment with amiodarone or randomization to any trial 1 or 2 drug that had not previously failed. All patients whose PVS-induced VT was not controlled by antiarrhythmic drug therapy or who developed intolerable adverse drug effects were offered ICD implantation.
Programmed ventricular stimulation was repeated four to five half-lives after antiarrhythmic drug therapy was given (after ≥1 week for amiodarone). If sustained VT was induced during a trial, the patient was observed for 5 min during VT (if clinically appropriate) to assess hemodynamic stability. If the patient had no angina, syncope or severe presyncope and the systolic blood pressure was >80 mm Hg, the VT was considered to be hemodynamically stable. If <15 consecutive complexes of VT were induced by PVS, VT was considered noninducible, and long-term treatment with that antiarrhythmic drug therapy was permitted. If no regimen could be found that rendered VT noninducible, investigators could discharge patients with antiarrhythmic drug therapy that resulted in hemodynamically stable VT as defined above. Thus, “effective” antiarrhythmic drug therapy was that which resulted in noninducible VT or hemodynamically stable induced VT.
Patients were to be seen as outpatients one month after discharge and every three months thereafter. If a patient could not be seen at a center, follow-up was conducted by telephone.
Study end points
The primary end point of the present analysis was all-cause mortality. The secondary end point was a “clinically important arrhythmia event,” defined as arrhythmic death, resuscitated cardiac arrest or spontaneous, sustained VT on electrocardiography. “Cardiac arrest” was defined as sudden unconsciousness in a patient who had been stable, requiring direct-current countershock to restore blood pressure and rhythm.
This report is an as-treated analysis of antiarrhythmic drug therapy. Patients were included in the follow-up phase when effective antiarrhythmic drug therapy was found after randomization; they were removed from follow-up if an ICD was later implanted. Follow-up was limited to two years from randomization. Any member of the comparison group of patients randomized to no antiarrhythmic therapy was also removed from follow-up if an ICD was implanted.
Continuous variables are summarized by using medians (with 25th, 75th percentiles); discrete variables are represented as frequencies and percentages. All tests of significance were two-tailed. Cumulative event rates were characterized with Kaplan-Meier curves, with time from randomization to the first event as the outcome variable (5). The log-rank test was used to assess the significance of differences between treatment subgroups (5). We adjusted the log-rank p values for differences in known predictors of mortality between subgroups (age, ejection fraction and beta-adrenergic blocking agent use) (6)with the Cox proportional hazards model (7).
In all, 704 patients with randomizable induced VT consented to randomization: 353 were randomized to receive no antiarrhythmic therapy, and 351 were randomized to receive PVS-guided antiarrhythmic therapy. Of the latter 351 patients, 330 underwent ≥1 drug trial. Of the remaining 21 patients, 11 had adverse effects during drug loading; 7 withdrew consent for PVS before receiving antiarrhythmic drug therapy; 1 patient died during drug loading; 1 had a nonfatal cardiac arrest; and 1 underwent bypass surgery, after which VT was no longer inducible. This patient was discharged without antiarrhythmic therapy.
Of the 142 patients (43%) for whom effective antiarrhythmic drug therapy was identified (91 noninducible, 51 stable VT), 88% had such therapy determined by one or two PVS trials (Table 1). The maximum number of trials in any patient was four (only six such patients). The proportion whose effective antiarrhythmic therapy was due to noninducibility was low (19% of first trials) and fell after trial 1, whereas the proportion whose effective antiarrhythmic therapy was assigned by hemodynamically stable VT increased in later trials. Outcomes of stable VT were not recorded if patients became noninducible at a later trial; therefore, patients who actually had stable induced VT may be underreported for earlier trials.
Of the 330 patients randomized to PVS-guided therapy and having PVS at least once while taking an antiarrhythmic drug, 88% had monomorphic VT induced at baseline; the remainder had polymorphic VT induced. Effective antiarrhythmic drug therapy was found for 41% of those with monomorphic VT at baseline and for 55% of those with polymorphic VT at baseline (p = 0.10).
Of the agents assigned by randomization in trial 1, propafenone was least likely to produce effective therapy (10% in trial 1, 11% overall), compared with class 1A agents (31% in trial 1, 29% overall) or sotalol (33% in trial 1, 35% overall) (Table 2). However, these three groups of agents were equally likely to produce stable VT (6%, 8% and 6%, respectively). Amiodarone seemed to be quite efficacious in the few cases when it was used in trial 1, but this largely reflected the production of stable VT (15 of 51 trials or 29% overall). Drug combinations rarely rendered the VT noninducible (five of 44 trials, 11%) but were equally likely to produce stable VT (seven of 44 trials, 16%).
Survival did not differ between the 142 patients discharged with effective antiarrhythmic drug therapy and those randomized to no antiarrhythmic therapy (Fig. 1A). Of patients discharged with effective antiarrhythmic drug therapy, 50% of deaths were attributable to arrhythmic causes, compared with 53% in patients discharged without antiarrhythmic therapy. Survival did not differ even when noninducible patients and those with stable induced VT were analyzed separately (Fig. 1B). Among patients discharged with noninducible VT, 52% of deaths were attributed to arrhythmic causes, compared with 46% in patients with stable VT. Mortality in those patients receiving effective therapy, likewise, did not differ by monomorphic or polymorphic VT induced at baseline (p = 0.76, data not shown). Clinically important ventricular arrhythmias occurred more often in patients receiving effective antiarrhythmic drug therapy (Fig. 2A), particularly in those with stable inducible VT (Fig. 2B). The proportion of arrhythmic events that resulted in arrhythmic death was 63% in patients discharged without antiarrhythmic therapy, compared with 51% in patients discharged with effective antiarrhythmic drug therapy. In patients discharged with noninducible VT, the proportion of arrhythmic events that resulted in arrhythmic death was 57%, compared with 43% in patients discharged with stable inducible VT. The differences in overall survival between groups were not statistically significant. There was no difference in clinically important ventricular arrhythmias by monomorphic or polymorphic VT induced at baseline (p = 0.75, data not shown). We also found no significant difference in either outcome when we defined noninducibility as <5 beats (n = 53) or 5 to 14 beats (n = 38) of induced VT (data not shown).
Mortality did not differ whether effective antiarrhythmic drug therapy was found in trial 1 versus trial 2 or later trials (Fig. 3). With respect to clinically important ventricular arrhythmias, outcomes tended to be better when therapy was determined at trial 2 or later trials (not shown), but these differences were not statistically significant.
Figure 4shows overall survival for patients randomized to no antiarrhythmic therapy and patients receiving effective antiarrhythmic therapy by class of drug used. Twelve patients had effective antiarrhythmic therapy identified with combinations of antiarrhythmic drugs (“Other” in Table 2). Because these patients were receiving a class 1A agent with mexiletine, we included their data with those of patients given class 1A agents in Figure 4(Table 3). Numerically, survival was best with sotalol and worst with propafenone. The results using clinically important arrhythmic events (not shown) as an end point are similar to those for mortality depicted in Figure 4.
There were some important differences in baseline characteristics for the subgroups depicted in Figure 4(Table 3). Patients randomized to no antiarrhythmic drug therapy were slightly younger than those receiving effective therapy, significantly so for amiodarone. Ejection fractions were higher in those treated with sotalol. Beta-blocker use was highest in those randomized to no antiarrhythmic drug therapy. All subgroups receiving antiarrhythmic drug therapy had significantly fewer patients who were being treated with beta-blocker therapy, most notably the subgroup given amiodarone. Patients taking sotalol less often received digitalis or nitrates.
The primary analysis of MUSTT suggested that PVS-selected antiarrhythmic drug therapy confers no benefit (1). We have extended this observation to include clinically important ventricular arrhythmias, with evaluation of the effects of various antiarrhythmic drugs and definitions of “effective” antiarrhythmic drug therapy. Importantly, we found that regardless of the agent(s) or definitions used, a PVS-guided approach does not appear to select antiarrhythmic drug therapy that provides a tangible benefit to this group of patients.
The proportion of patients tested for whom effective antiarrhythmic drug therapy was determined in MUSTT is similar to that seen in studies of sustained ventricular tachyarrhythmias (8,9). These studies often included more drug trials, the end point of which was noninducibility. Few patients in MUSTT had >2 PVS-guided antiarrhythmic drug trials. The proportion tested whose VT became noninducible declined after trial 1, as has been reported in patients with sustained ventricular tachyarrhythmias (10). The MUSTT investigation is the first large trial to evaluate hemodynamically stable VT as a prospective PVS end point. About 30% of the patients for whom effective therapy was determined had such therapy identified by this end point. With respect to total mortality, hemodynamically stable VT did not differ from noninducibility as an end point of PVS. Observational studies have shown similar findings, most notably with amiodarone (11). As noted in the study of Waller et al. (11), however, clinically important ventricular arrhythmia was more likely when hemodynamically stable VT was used as the PVS end point. The overall results of MUSTT might have quantitatively differed if noninducibility alone had been used as the PVS end point. Because most patients had only one or two drug trials, however, more patients in the PVS-guided arm would have been likely to receive an ICD.
The most appropriate definition of “noninducibility” remains controversial. The definition used by MUSTT investigators (1)and others (8)was ≤14 beats of VT, whereas some have used ≤4 beats (9). However, a randomized trial of these two measures strongly suggests that long-term outcomes are better when ≤4 beats is used as the PVS end point (12). We found no significant difference between ≤4 and 5 to 14 beats of noninducible VT. A more stringent definition of “noninducibility” in MUSTT might have yielded a different overall result but would have been likely to result in implantation of more ICDs. Whether the number of trials played a role in the overall results is difficult to explore, because most patients had only one or two trials. The analysis chosen (first trial vs. second or further trials) showed no difference. An observational study of this point (10)suggests that the predictive value of the first few trials is about the same; but after the third trial, long-term arrhythmias are more frequent despite documented noninducibility. This observational study is difficult to compare with ours, because of differences in the number of drug trials, in the agents used, and in the end points of PVS.
The final factor regarding drug selection in MUSTT was the agent used. Class 1A agents were used most often, alone or with mexiletine, followed by sotalol and amiodarone. Very few patients achieved effective therapy with propafenone. The strongest trend was that mortality and clinically important ventricular arrhythmias were more likely in the few patients who achieved effective therapy with propafenone. This potentially harmful effect of propafenone is comparable to that seen in the Cardiac Arrest Study Hamburg (CASH) (13). Patients taking the other agents fared no differently from those randomized to no antiarrhythmic therapy.
Although the use of beta-blockers in MUSTT was at least as common as in contemporary antiarrhythmic trials (14,15), their level of use remained disappointing. Despite the extensive literature showing a salutary benefit of these drugs in patients with coronary disease (16), only slightly over 50% of patients randomized to no antiarrhythmic therapy received beta-blockers. Even fewer patients receiving PVS-guided antiarrhythmic drug therapy received these agents. Certainly, this is understandable in the case of sotalol, a fairly potent beta-blocker itself. Many physicians avoid beta-blockers in patients taking amiodarone; but the beta-blocking properties of amiodarone are quite weak, and recent evidence (17)suggests that a beta-blocker and amiodarone combination may be particularly efficacious for antiarrhythmic therapy.
A potential bias exists in that the subgroups in the present analyses were not formed by randomization. Indeed, patients treated with sotalol had better ventricular systolic function, which may explain their lesser use of digitalis and nitrates. Thus, other than noting that propafenone seldom produced PVS-guided effective therapy and may be harmful, little can be said about individual drugs.
When PVS-guided effective antiarrhythmic drug therapy was found and used, survival was no better than it was without antiarrhythmic therapy. The MUSTT data cannot be generalized to other groups, but, with these findings, the overall utility of PVS-guided antiarrhythmic drug therapy must be questioned. Implantable cardioverter defibrillator therapy has substantial benefit in drug-resistant patients and should be considered early. We cannot comment on the individual drug therapies most likely to be beneficial based on these data, and antiarrhythmic drug therapy currently is a secondary alternative for most patients. Propafenone rarely produces effective therapy in this population.
These results clearly illustrate the substantial loss of power and increased uncertainty that occurs in subgroup analyses (18). Uncertainty is particularly evident regarding the implication that propafenone may be harmful; only 13 patients received this drug. That the subgroups were not randomized introduces further uncertainty in interpreting these results. Investigators were instructed to seek noninducibility as the preferable end point for PVS but could accept stable VT when noninducibility was not achievable. The degree to which investigators adhered to this directive probably varied and may have influenced the results. Also, patients were excluded from analysis if they received an ICD, and the majority were removed from follow-up data after experiencing a cardiac arrest or sustained VT. Some ICDs were implanted for syncope without a documented tachyarrhythmia (11/39 [28%] vs. 1/26 [4%], no therapy vs. PVS-guided therapy). The remainder received ICDs for various reasons (7/39 [18%] vs. 16/26 [62%], no therapy vs. PVS-guided therapy). The high proportion of ICD use in PVS-guided therapy in the latter instance is entirely accounted for by the adverse effects of antiarrhythmic drugs. The pattern of usage of ICDs contributes to the present findings.
The authors thank Eric N. Prystowsky, MD, and Kerry L. Lee, PhD, for their careful review and helpful suggestions and Rebecca Teaff, MA, and Patricia French, BS, who assisted with preparation of the manuscript.
☆ Supported by C.R. Bard, Inc.; Berlex Laboratories, Inc.; Boehringer-Ingelheim Pharmaceuticals, Inc.; Merck & Co, Inc.; Guidant Corporation; Knoll Pharmaceutical Co.; Medtronic, Inc.; Searle Pharmaceutical; Ventritex; Wyeth-Ayerst Laboratories and grants U01HL45700 and U01HL45726 from the National Heart, Lung, and Blood Institute.
- implantable cardioverter defibrillator
- Multicenter UnSustained Tachycardia Trial
- programmed ventricular stimulation
- ventricular tachycardia
- Received November 10, 2000.
- Revision received March 22, 2001.
- Accepted April 26, 2001.
- American College of Cardiology
- Welch P.J,
- Page R.L,
- Hamdan M.H
- Cox D.R
- Kavanagh K.M,
- Wyse D.G,
- Duff H.J,
- Gillis A.M,
- Sheldon R.S,
- Mitchell L.B
- Waller T.J,
- Kay H.R,
- Spielman S.R,
- Kutalek S.P,
- Greenspan A.M,
- Horowitz L.N
- Mitchell L.B,
- Sheldon R.S,
- Gillis A.M,
- et al.
- Exner D.V,
- Reiffel J.A,
- Epstein A.E,
- et al.
- Boutitie F,
- Boissel J.P,
- Connolly S.J,
- et al.