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Previous Volume 348:781-790 February 27, 2003 Number 9 Next

Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Curfman, G. D. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article PubMed Citation

ABSTRACT

Background Exercise-induced ventricular ectopy predicts an increased risk of death in population-based cohorts. We sought to examine in a clinical cohort the prognostic importance of ventricular ectopy immediately after exercise, when reactivation of parasympathetic activity occurs. We hypothesized that ventricular ectopy after exercise (i.e., during the recovery phase) would predict an increased risk of death better than ventricular ectopy during exercise.

Methods We studied 29,244 patients (mean [±SD] age, 56±11 years; 70 percent men) who had been referred for symptom-limited exercise testing without a history of heart failure, valve disease, or arrhythmia. Frequent ventricular ectopy was defined by the presence of seven or more ventricular premature beats per minute, ventricular bigeminy or trigeminy, ventricular couplets or triplets, ventricular tachycardia, ventricular flutter, torsade de pointes, or ventricular fibrillation.

Results Frequent ventricular ectopy occurred only during exercise in 945 patients (3 percent), only during recovery in 589 (2 percent), and during both exercise and recovery in 491 (2 percent). There were 1862 deaths during a mean of 5.3 years of follow-up. Frequent ventricular ectopy during exercise predicted an increased risk of death (five-year death rate, 9 percent, vs. 5 percent among patients without frequent ventricular ectopy during exercise; hazard ratio, 1.8; 95 percent confidence interval, 1.5 to 2.1; P<0.001), but frequent ventricular ectopy during recovery was a stronger predictor (11 percent vs. 5 percent; hazard ratio, 2.4; 95 percent confidence interval, 2.0 to 2.9; P<0.001). After propensity matching for confounding variables, frequent ventricular ectopy during recovery predicted an increased risk of death (adjusted hazard ratio, 1.5; 95 percent confidence interval, 1.1 to 1.9; P=0.003), but frequent ventricular ectopy during exercise did not (adjusted hazard ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.53).

Conclusions Frequent ventricular ectopy during recovery after exercise is a better predictor of an increased risk of death than ventricular ectopy occurring only during exercise.

Recent work has established that vagal reactivation normally occurs in the early period of recovery, immediately after exercise.¹¹ In the absence of normal vagal reactivation, heart-rate recovery is attenuated, with an associated increase in mortality.^12,13,14,15 Therefore, attenuated vagal reactivation during recovery might be associated with ventricular ectopy that is not suppressed. Accordingly, we prospectively studied the hypothesis that ventricular ectopy during recovery would be a stronger predictor of an increased risk of death than ectopy that occurred during exercise.

Methods

Study Design

Consecutive patients referred for symptom-limited treadmill exercise testing at the Cleveland Clinic Foundation in Cleveland between 1990 and 1999 were eligible. Exclusion criteria included an age of less than 30 years, absence of a U.S. Social Security number, symptomatic heart failure or use of digoxin, valvular disease, end-stage renal disease, presence of a pacemaker, concurrent evaluation for an arrhythmia, a history of cardiac transplantation, atrial fibrillation, heart block, and frequent ventricular ectopy at rest, as defined below. If a patient had undergone more than one treadmill test, only the first test was considered. The resulting study group of 29,244 patients included 2743 patients whom we previously reported on in a study that focused on ventricular ectopy during exercise only and that involved only two years of follow-up.¹⁶ The local institutional review board approved research based on the prospectively obtained computerized clinical data sets from the stress laboratory. The requirement for obtaining informed consent was waived.

The methods by which clinical data are prospectively obtained in our laboratory have been described in detail.^12,13,15,17 Before treadmill testing, all patients undergo a structured interview and chart review. Data are prospectively collected regarding symptoms, risk factors, diagnoses, medicines, and prior cardiac procedures.

The exercise-testing protocols used in our laboratory have been described in detail.¹⁷ The patients undergo symptom-limited exercise testing according to standard protocols. During each stage of exercise, data on heart rate, blood pressure, electrocardiographic changes, and arrhythmias are prospectively recorded.

Chronotropic incompetence was considered present if no more than 80 percent of heart-rate reserve was used by peak exercise in the absence of beta-blocker use.¹⁸ An abnormal heart-rate recovery was defined as failure of the heart rate to fall by more than 12 beats during the first minute after exercise^12,13; among patients undergoing stress echocardiography, the cutoff value was more than 18 beats per minute.¹⁵ Functional capacity was considered abnormal if the estimated number of metabolic equivalents was fair or poor for age and sex according to a validated scheme.¹⁷ The persons responsible for acquiring data were unaware of the hypothesis of this study or the outcome of the patients.

Information regarding ventricular ectopy was systematically recorded on the resting electrocardiogram as well as during each stage of exercise and recovery according to prespecified definitions. We prospectively defined frequent ventricular ectopy as the presence of seven or more ventricular premature beats per minute during any given stage, ventricular bigeminy, ventricular trigeminy, ventricular couplets, ventricular triplets, sustained or nonsustained ventricular tachycardia, ventricular flutter, torsade de pointes, or ventricular fibrillation. If the patient had more than one of these findings during any given stage of the exercise test, each was recorded individually. This definition of frequent ventricular ectopy was based on previous work by our group, which showed that during exercise it is associated with scintigraphically evident myocardial perfusion defects.¹⁶

We divided frequent ventricular ectopy into less severe and more severe categories based on the Lown classification.¹⁹ Patients with ventricular triplets, sustained or nonsustained ventricular tachycardia, ventricular flutter, torsade de pointes, or ventricular fibrillation were considered to have more severe ventricular ectopy.

The primary end point was death from all causes, which is an objective, clinically relevant, and unbiased end point.^20,21 The end point of death from all causes was determined with use of the Social Security Death Index.^22,23,24 The high degree of specificity of the Social Security Death Index has been documented.²³ We have shown that application of this data base to patients in the Cleveland Clinic stress laboratory results in a sensitivity of 97 percent.¹³

Statistical Analysis

The cohort was divided into four groups, according to the presence or absence of frequent ventricular ectopy during exercise or during the first three minutes of recovery. Differences between groups were tested by the Kruskal–Wallis or the chi-square test. The association of frequent ventricular ectopy with time to death was tested by the construction of Kaplan–Meier curves²⁵ and by Cox proportional-hazards modeling.²⁶ The proportional-hazards assumption was confirmed by means of a time-dependent interaction covariate and by examination of weighted Schoenfeld residuals.

Although multivariable regression modeling is used to account for base-line differences, it may lead to invalid conclusions when those base-line differences are marked or numerous.^27,28 We therefore constructed nonparsimonious logistic-regression models²⁹ in which ventricular ectopy during exercise or during recovery was a dependent variable and the variables listed in Table 1 were independent variables. For the model in which ventricular ectopy during recovery was the dependent variable, ventricular ectopy during exercise was included as an additional independent variable. Similarly, for the model in which ventricular ectopy during exercise was the dependent variable, ventricular ectopy during recovery was included as an additional independent variable. These models made possible the calculation of a propensity score,²⁷ indicating the likelihood that any individual patient would have ventricular ectopy, given all other known variables except outcome. Patients with and without ventricular ectopy were then matched on the basis of their propensity score.³⁰

View this table: [in this window] [in a new window]   Table 1. Base-Line and Exercise-Related Characteristics of the Study Patients According to the Timing of Frequent Ventricular Ectopy.

 
All analyses were performed with SAS software (version 8.2, SAS).

Results

Among 29,244 patients, 945 (3 percent) had frequent ventricular ectopy only during exercise, 589 (2 percent) had frequent ventricular ectopy only during recovery, and 491 (2 percent) had frequent ventricular ectopy during both exercise and recovery. The clinical and exercise-related characteristics of the patients according to the timing of frequent ventricular ectopy are shown in Table 1. Patients who had frequent ventricular ectopy during exercise or recovery were older and more likely to have coronary artery disease than patients who did not have frequent ventricular ectopy during exercise or recovery; there were multiple other differences as well.

Specific arrhythmias noted during exercise included frequent ventricular premature beats in 933 (3 percent), ventricular bigeminy in 386 (1 percent), ventricular trigeminy in 150 (0.5 percent), ventricular couplets in 92 (0.3 percent), ventricular triplets in 330 (1 percent), nonsustained ventricular tachycardia in 164 (0.6 percent), and sustained ventricular tachycardia in 4 (0.01 percent). Specific arrhythmias noted during recovery included frequent ventricular premature beats in 742 (3 percent), ventricular bigeminy in 315 (1 percent), ventricular trigeminy in 133 (0.5 percent), ventricular couplets in 45 (0.2 percent), ventricular triplets in 154 (0.5 percent), nonsustained ventricular tachycardia in 91 (0.3 percent), sustained ventricular tachycardia in 4 (0.01 percent), ventricular fibrillation in 2 (0.01 percent), and torsade de pointes in 1 (<0.01 percent). More severe ventricular ectopy was noted in 22 percent of patients who had ventricular ectopy only during exercise, 15 percent of those who had ventricular ectopy only during recovery, and 12 percent of those who had ventricular ectopy during both exercise and recovery (P<0.001).

During a mean follow-up of 5.3 years, there were 1862 deaths. Among patients with frequent ventricular ectopy only during exercise, there were 81 deaths; among those with frequent ectopy only during recovery, there were 68 deaths; and among those with frequent ectopy during both exercise and recovery, there were 79 deaths. Frequent ventricular ectopy during exercise predicted a higher likelihood of death (five-year death rate, 9 percent, vs. 5 percent in patients without frequent ventricular ectopy during exercise; hazard ratio, 1.8; 95 percent confidence interval, 1.5 to 2.1; P<0.001), and frequent ventricular ectopy during recovery was associated with an even higher estimated likelihood of death (five-year death rate, 11 percent vs. 5 percent; hazard ratio, 2.4; 95 percent confidence interval, 2.0 to 2.9; P<0.001). Patients with frequent ventricular ectopy during recovery had the lowest survival rates, whereas those who had frequent ventricular ectopy only during exercise had a slightly lower survival rate than those who had no ventricular ectopy (Figure 1).

View larger version (16K): [in this window] [in a new window]   Figure 1. Kaplan–Meier Analysis of the Association of Frequent Ventricular Ectopy (VE) Only during Exercise, Only during Recovery from Exercise, or during Both Exercise and Recovery, with Survival.

 
After adjustment for the variables listed in Table 1 and for frequent ventricular ectopy during exercise, frequent ventricular ectopy during recovery was a predictor of an increased risk of death (adjusted hazard ratio, 1.6; 95 percent confidence interval, 1.3 to 1.9; P<0.001). Other predictors included older age, male sex, insulin-treated diabetes mellitus, smoking, impaired functional capacity, and attenuated heart-rate recovery (P<0.001 for all comparisons). Frequent ventricular ectopy during exercise did not predict an increased risk of death in this analysis (adjusted hazard ratio, 1.2; 95 percent confidence interval, 1.0 to 1.4; P=0.09).

Propensity matching was performed to match patients with frequent ventricular ectopy during recovery to those who did not have frequent ventricular ectopy during recovery. The C statistic of the logistic-regression model used to generate the propensity score was 0.80. The base-line characteristics of the propensity-matched cohort are shown in Table 2. The two populations were well matched.

View this table: [in this window] [in a new window]   Table 2. Base-Line and Exercise-Related Characteristics According to the Presence or Absence of Frequent Ventricular Ectopy during Recovery in Propensity-Matched Groups.

 
The prognostic importance of frequent ventricular ectopy during recovery in this propensity-matched cohort is shown in Figure 2. Patients with frequent ventricular ectopy during recovery had decreased survival, particularly after three to four years of follow-up. After adjustment for the propensity score, frequent ventricular ectopy during exercise, and the other variables listed in Table 2, frequent ventricular ectopy during recovery predicted an increased risk of death (adjusted hazard ratio, 1.5; 95 percent confidence interval, 1.1 to 1.9; P=0.003).

View larger version (8K): [in this window] [in a new window]   Figure 2. Kaplan–Meier Analysis of the Association of Frequent Ventricular Ectopy (VE) during Recovery from Exercise with Survival in the Propensity-Matched Cohort. The cohort was derived by using propensity scores to match patients with ventricular ectopy during recovery to patients who did not have ventricular ectopy during recovery. Of 1080 patients who had ventricular ectopy during recovery, 1072 were matched. The characteristics of the cohort are shown in Table 2.

 
A similar analysis was performed regarding frequent ventricular ectopy during exercise. Frequent ventricular ectopy during exercise was not associated with decreased survival in this propensity-matched cohort (adjusted hazard ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.53).

The results of prespecified subgroup analyses are shown in Table 3. Frequent ventricular ectopy during recovery was predictive of an increased risk of death in all subgroups tested. No clinically significant interactions were noted.

View this table: [in this window] [in a new window]   Table 3. Association between Ventricular Ectopy during Recovery and Mortality in Prespecified Subgroups.

 
More severe ventricular ectopy during recovery from exercise, defined as ventricular triplets or worse, was noted in 128 patients (0.4 percent), whereas 952 (3 percent) had less severe ventricular ectopy. There was a gradient of mortality, in which death rates were lowest among patients without frequent ventricular ectopy (5 percent), higher among those with less severe frequent ventricular ectopy (12 percent), and highest among those with more severe frequent ventricular ectopy (15 percent). In a multivariable Cox regression model that adjusted for the variables listed in Table 1, less severe frequent ventricular ectopy during recovery was predictive of death (adjusted hazard ratio, 1.5; 95 percent confidence interval, 1.3 to 1.8; P<0.001), and more severe frequent ventricular ectopy was associated with a greater risk (adjusted hazard ratio, 2.1; 95 percent confidence interval, 1.4 to 3.3; P<0.001).

Data on left ventricular systolic function were available for 6421 patients. The ejection fraction was assessed by simultaneous echocardiography in 4007 patients (mean value, 53±6 percent) and by contrast ventriculography within three months of stress testing in 2414 patients (mean value, 53±6 percent). Impaired left ventricular systolic function, defined as an ejection fraction of 40 percent or less, was present in 751 of 5953 patients without frequent ventricular ectopy (13 percent), 39 of 212 with frequent ventricular ectopy only during exercise (18 percent), 35 of 129 with frequent ventricular ectopy only during recovery (27 percent), and 35 of 127 with frequent ventricular ectopy during both exercise and recovery (28 percent, P<0.001).

There were 485 deaths during follow-up among the patients for whom data on left ventricular systolic function were available. Frequent ventricular ectopy during recovery predicted an increased risk of death among patients with preserved left ventricular systolic function (death rate, 11 percent, vs. 6 percent among those without frequent ventricular ectopy during recovery; hazard ratio, 2.0; 95 percent confidence interval, 1.3 to 3.1; P=0.001) and among patients with depressed left ventricular systolic function (25 percent vs. 14 percent; hazard ratio, 1.8; 95 percent confidence interval, 1.1 to 3.0; P=0.02). No interaction was noted between frequent ventricular ectopy during recovery and left ventricular systolic function in the prediction of an increased risk of death (P=0.78).

In a multivariable Cox regression model that included the variables listed in Table 1 as well as frequent ventricular ectopy during recovery, frequent ventricular ectopy during exercise, and left ventricular ejection fraction, frequent ventricular ectopy during recovery was predictive of an increased risk of death (adjusted hazard ratio, 1.6; 95 percent confidence interval, 1.2 to 2.2; P=0.005), whereas frequent ventricular ectopy during exercise was not (adjusted hazard ratio, 1.1; 95 percent confidence interval, 0.7 to 1.5; P=0.73). Impaired left ventricular systolic function was an independent predictor of an increased risk of death (adjusted hazard ratio, 1.4; 95 percent confidence interval, 1.1 to 1.7; P=0.002).

Among the 4007 patients who underwent exercise echocardiography, evidence of myocardial ischemia was present in 461 (12 percent). Frequent ventricular ectopy during recovery was associated with a higher rate of echocardiographic evidence of ischemia (22 percent, vs. 11 percent in those without frequent ventricular ectopy during recovery; P<0.001). There were only 6 deaths among the 34 patients who had both echocardiographic ischemia and frequent ventricular ectopy during recovery, precluding further analyses.

Discussion

In a large cohort of patients referred for exercise stress testing, the occurrence of frequent ventricular ectopy during recovery was strongly predictive of an increased risk of death from all causes over a five-year follow-up period, whereas the occurrence of frequent ventricular ectopy only during exercise was not. This association persisted even after propensity-based adjustment for clinical and exercise characteristics known to predict an increased risk of death.

Until recently, it was thought that exercise-induced ventricular ectopy was not independently related to an increased risk of coronary heart disease, the extent of coronary artery disease, mortality from all causes, or the risk of major cardiac events.^4,8,16,31 However, one recent report showed that among over 6000 asymptomatic men ventricular ectopy during exercise was associated with a relative risk of death from cardiovascular disease of approximately 3 when the cohort was followed for 23 years.⁶

The current study clarifies these previous findings and extends them to a large cohort likely to be representative of patients seen in clinical practice. Because of the size of the study sample, we were able to examine carefully the prognostic importance of frequent ventricular ectopy during and after exercise in large numbers of subjects (more than 1000 patients in each group). The large cohort also made it possible for us to perform propensity matching,²⁷ thus allowing a more valid comparison of patients with and without frequent ventricular ectopy than would have been possible by standard regression techniques.²⁸ Finally, our observations were consistent with our a priori hypothesis that frequent ventricular ectopy during recovery would be a stronger predictor of risk than ectopy during exercise, which had been based on the recognition of recovery as a period of rapid vagal reactivation.¹¹

Because the cohort was a heterogeneous one, including patients who underwent stress testing with electrocardiography only, with echocardiography, or with nuclear perfusion scintigraphy, we did not have systematic data on left ventricular systolic function and myocardial ischemia in all patients. Nonetheless, it is noteworthy that in the subgroup of 6421 patients for whom ejection-fraction data were available, a low ejection fraction (40 percent or less) was associated with frequent ventricular ectopy during recovery. Furthermore, both ventricular ectopy during recovery and a low ejection fraction were independent predictors of death. We focused on death from all causes and could not differentiate among deaths due to arrhythmias, those due to other cardiac causes, and those due to noncardiac causes. We and others have commented on this issue before, pointing out that only death from all causes can be considered a truly unbiased and objective end point that is also clinically relevant when arrhythmia-related outcomes are studied.^20,21

How should the finding of an association between frequent ventricular ectopy during recovery from exercise and mortality from all causes be incorporated into clinical practice? Because this was a prospective, observational study, making treatment recommendations on the basis of our results is problematic. Nonetheless, it is clear that frequent ventricular ectopy during recovery is a marker of an increased risk of death. Accordingly, comprehensive risk-factor assessment and aggressive management of the risk factors identified may well be justified in patients with this finding. In addition, the association of asymptomatic left ventricular dysfunction with frequent ventricular ectopy during recovery suggests that echocardiography may be indicated, since treatment of asymptomatic left ventricular dysfunction is of clinical benefit.³²

Frequent ventricular ectopy during recovery from exercise was found to be an important, independent predictor of an increased risk of death in a large clinical cohort. Frequent ventricular ectopy that occurred only during exercise did not independently predict an increased risk. In accordance with previous findings of a strong relation between attenuated recovery of the heart rate after exercise and an elevated risk of death, these results support the central importance of vagal mediation in cardiac function. They also underscore the value of the exercise stress test as a tool for prognosis and risk stratification.

Supported in part by a grant from the National Heart, Lung, and Blood Institute (HL 66004, to Drs. Lauer and Blackstone and Ms. Pothier).

Source Information

From the Departments of General Internal Medicine (J.P.F.), Cardiovascular Medicine (C.E.P., M.S.L.), Cardiothoracic Surgery (E.H.B.), and Epidemiology and Biostatistics (E.H.B.), Cleveland Clinic Foundation, Cleveland.

Address reprint requests to Dr. Lauer at Desk F25, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, or at lauerm{at}ccf.org.

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Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Curfman, G. D. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article PubMed Citation

Related Letters:

Ventricular Ectopy after Exercise as a Predictor of Death
Shah A. P., Rubin S. A., Gammenthaler S. A., Jouven X. P., Empana J.-P., Ducimetière P., Lauer M. S., Frolkis J. P., Blackstone E. H.
Extract | Full Text | PDF  
N Engl J Med 2003; 348:2357-2359, Jun 5, 2003. Correspondence

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