CLINICAL RESEARCH: PROTEAN EFFECTS OF STATINS
Are lipid-lowering drugs also antiarrhythmic drugs?
an analysis of the antiarrhythmics versus implantable defibrillators (AVID) trial
L. Brent Mitchell, MD, FACC*,*,
Judy L. Powell, BSN ,
Anne M. Gillis, MD, FACC*,
Victoria Kehl, PhC ,
Alfred P. Hallstrom, PhD the AVID Investigators
* Foothills Hospital/University of Calgary, Calgary, Alberta, Canada
AVID Clinical Trial Center/University of Washington, Seattle, Washington, USA
Institut fuer Medizinische Statistik, Munich, Germany
Manuscript received February 15, 2002;
revised manuscript received November 24, 2002,
accepted December 26, 2002.
* Reprint requests and correspondence: Dr. L. Brent Mitchell, Division of Cardiology, Foothills Hospital, 1403-29th Street NW, Calgary, Alberta, Canada, T2N 2T9.
brent.mitchell{at}calgaryhealthregion.ca
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Abstract
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OBJECTIVES: This study sought to evaluate the antiarrhythmic effects of lipid-lowering drug therapy as assessed by ventricular tachyarrhythmia (ventricular tachycardia [VT]/ventricular fibrillation [VF]) recurrences recorded by an implantable cardioverter defibrillator (ICD) in patients with atherosclerotic heart disease (ASHD).
BACKGROUND: Randomized trials of lipid-lowering drugs suggest reduction of sudden death (SD) in patients with ASHD. Because SD is usually secondary to VT/VF, this observation suggests that lipid-lowering therapy has antiarrhythmic effects.
METHODS: The probability of VT/VF recurrence in patients with ASHD treated with an ICD in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial who did not receive lipid-lowering drug therapy (n = 279) was compared with that in patients who received early and consistent lipid-lowering therapy (n = 83). In addition, all-cause mortality and cardiac mortality of all patients in the AVID trial with ASHD who did not receive lipid-lowering therapy (n = 564) were compared with that of those who received early and consistent lipid-lowering therapy (n = 149).
RESULTS: Using multivariate analyses, lipid-lowering therapy was associated with a reduction in the relative hazard for VT/VF recurrence of 0.40 (95% confidence interval [CI] 0.15 to 0.58) (adjusted p = 0.003) in the ICD subgroup. Lipid-lowering therapy was also associated with a reduction in the relative hazard for all-cause mortality of 0.36 (95% CI 0.15 to 0.68) (adjusted p = 0.03) and a reduction in the relative hazard for cardiac mortality of 0.39 (95% CI 0.16 to 0.78) (adjusted p = 0.04) in the larger study population.
CONCLUSIONS: In patients with ASHD who have received an ICD, lipid-lowering therapy is associated with reduction in the probability of VT/VF recurrence, suggesting that part of the benefit of lipid-lowering therapy may be due to an antiarrhythmic effect.
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Abbreviations and Acronyms
| | ASHD | | atherosclerotic heart disease | | AVID | | Antiarrhythmics Versus Implantable Defibrillator trial | | CI | | confidence interval | | HMG-CoA | | 3-hydroxy-3-methylglutaryl coenzyme A | | ICD | | implantable cardioverter defibrillator | | SD | | sudden death | | VF | | ventricular fibrillation | | VT | | ventricular tachycardia |
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Epidemiological studies have demonstrated a very clear relationship between serum cholesterol levels and all-cause mortality, in general, and atherosclerotic heart disease (ASHD) mortality, in particular (1,2). The combined results of the randomized, controlled, mortality trials of lipid-lowering using 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (3–7) have demon strated a reduction in the relative risk of all-cause mortality of 0.27 (95% confidence interval [CI] 0.21 to 0.33) and a reduction in the relative risk of ASHD mortality of 0.28 (95% CI 0.20 to 0.35) in association with a reduction in total serum cholesterol levels of 20%, a reduction in serum LDL cholesterol of 23%, an elevation of HDL cholesterol of 6%, and a reduction in serum triglycerides of 13% (3–7) over a mean follow-up of 5.2 years. Two of these controlled trials (3,6) have also reported a reduction in the relative risk of sudden death (SD) with HMG-CoA reductase inhibitor therapy. Combining their results suggests a reduction in the relative risk of SD of 0.20 (95% CI 0.05 to 0.33) over a mean follow-up of 5.4 years.
Of course, the reduction in SD mortality with lipid-lowering therapy may simply reflect the well-recognized effect of this therapy on coronary atherosclerosis. Nevertheless, the reduction in sudden cardiac death mortality associated with such therapy has led to the hypothesis that lipid-lowering has direct or indirect antiarrhythmic effects against the ventricular tachyarrhythmias that are the most common cause of SD. This hypothesis was first evaluated by De Sutter et al. (8), who reported, from an observational study of 78 patients with ASHD and life-threatening ventricular tachycardia/ventricular fibrillation (VT/VF) who were treated with an implantable cardioverter defibrillator (ICD), that patients who received lipid-lowering therapy had significantly fewer episodes of recurrent VT/VF than did patients who had not received lipid-lowering therapy. The purpose of the present analysis was to further evaluate the possibility of an antiarrhythmic effect of lipid-lowering therapy in the large, well-characterized, ICD patient population of the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial.
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Methods
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The AVID trial was a prospective, multicenter, randomized clinical trial comparing two strategies for the treatment of patients who survived life-threatening, sustained VT/VF (9,10). Briefly, patients resuscitated from VF, VT with syncope, or sustained VT with a left ventricular ejection fraction of  0.40 and symptoms of hemodynamic compromise (near-syncope, dyspnea, angina) were randomized either to receive pharmacologic antiarrhythmic therapy with sotalol guided by the suppression of either spontaneous ventricular arrhythmias or VT/VF inducible by programmed ventricular stimulation or with empiric amiodarone therapy (mostly the latter), or to receive an ICD. The primary end point was all-cause mortality. The institutional review board of each participating institution approved the study. All patients gave written informed consent.
Patients who received an ICD had their device interrogated every three months for the duration of the trial and when clinically indicated after therapy delivery. The ICD interrogation record and corresponding clinical data were forwarded to an ICD therapy events committee that classified each therapy as being appropriate or inappropriate based upon historical and ICD-derived data. Relative to the VT/VF recurrence events reported here, the ICD-derived data included electrogram records for 76% of the events and was limited to mean heart rate or sequential inter-electrogram interval records for 24% of the events. For the purposes of the present analysis, appropriate ICD therapy delivery was considered to have represented a VT/VF recurrence. All patient deaths in the AVID trial were reviewed by an events committee and were classified as being cardiac or noncardiac. Cardiac deaths were further classified as being arrhythmic or nonarrhythmic. For the purposes of the present analysis, patients with an arrhythmic death were also considered to have had a VT/VF recurrence.
The prescription of lipid-lowering drug therapy in the AVID trial was left to the discretion of the primary care physician, and its use was recorded at discharge and at follow-up visits as "yes" or "no." Detailed medical therapy histories were recorded from a sample of 237 (23%) of the 1,016 AVID patients. In this sample, 26% were prescribed a lipid-lowering therapy—79% of which were HMG-CoA reductase inhibitors, 19% were fibric acid derivatives, and 3% were bile acid resins. Serum cholesterol levels were not measured. Five patterns of lipid-lowering therapy use during the AVID trial were possible: - lipid-lowering therapy not used at any time;
- lipid-lowering therapy used continuously;
- lipid-lowering therapy started early (within 6 months of follow-up) and then continued;
- lipid-lowering therapy started early (within 6 months of follow-up) and then discontinued early (within 12 months of follow-up); and
- lipid-lowering therapy started late (after 9 months of follow-up).
The combination of latency of the effects after starting lipid-lowering therapy, the persistence of effects after stopping lipid-lowering therapy, and the limited follow-up of patients in the AVID trial suggested that the present analysis include only those patients with one of the first three patterns of lipid-lowering therapy use. The present analysis was also limited to patients with ASHD (lipid-lowering therapy was rarely prescribed to patients with other forms of structural heart disease) and to patients who survived at least one month after randomization to AVID trial therapy (to allow for patient stabilization after the index VT/VF event and to allow for lipid-lowering therapy initiation).
Thus, the VT/VF-free survival analyses were performed using all patients in the AVID trial with ASHD who had received an ICD and survived one month after AVID randomization, comparing subjects who had not received lipid-lowering drug therapy with those subjects who received early and consistent lipid-lowering drug therapy. Hallstrom et al. (11) recently reported the baseline factors that were predictive of VT/VF recurrence in the patients in the AVID study who received an ICD—presenting arrhythmia (VT vs. VF), history of cerebrovascular disease, lower left ventricular ejection fraction, history of supraventricular or ventricular tachyarrhythmias prior to the VT/VF, and the absence of revascularization during the baseline hospitalization. These factors were used to generate a hazard score for VT/VF recurrence in each patient who received an ICD. These individual hazard scores were adjusted for using Cox proportional hazard methods when investigating the association between lipid-lowering therapy and time to VT/VF recurrence. Total survival analyses and cardiac survival analyses were also performed using all of the patients in the AVID trial with ASHD who were randomized to receive an ICD or antiarrhythmic drug therapy and survived at least one month after AVID randomization, comparing subjects who had not received lipid-lowering drug therapy with those subjects who received early and consistent lipid-lowering drug therapy.
Statistical analysis.
Continuous data are presented as mean ± 1 SD and were compared using Student t test. Categorical data are presented as ratios (%) and were compared using the chi-square statistic. Kaplan-Meier estimates were used to display VT/VF-free survival rates within the ICD patient population and survival and cardiac survival rates for the combined ICD and antiarrhythmic drug patient populations. Cox proportional hazard methods were used to adjust for baseline differences when investigating the association between the use of lipid-lowering therapy and survival time. A two-tailed p value of <0.05 was used to exclude the null hypothesis.
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Results
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Study population.
Of the 1,016 patients randomized in the AVID study, 19 patients either died during the baseline hospitalization or were still in hospital when the AVID study was stopped. Of the remaining 997 patients, 187 patients did not have ASHD, and 18 patients died within one month of randomization. Seventy-nine of the remaining 792 patients were excluded, having received late (56 patients) or inconsistent (22 patients) lipid-lowering drug therapy or because their lipid-lowering treatment status was unknown (1 patient). Thus, the overall study group consisted of 713 patients: 564 patients (79%) who did not receive lipid-lowering drug therapy and 149 patients (21%) who did receive lipid-lowering therapy. The ICD patient study group was comprised of 362 patients who received an ICD within one month of AVID randomization (349 patients from the randomized ICD arm and 13 patients from the randomized antiarrhythmic drug treatment arm). Of the ICD patient study group, 279 patients (77%) received no lipid-lowering drug therapy, and 83 patients (23%) received continuous (66 patients) or early (17 patients) lipid-lowering drug therapy.
The patient baseline demographic and clinical characteristics for the ICD patient study group are displayed in Table 1. Patients receiving lipid-lowering drug therapy were younger than were patients not receiving lipid-lowering drug therapy. Furthermore, patients receiving lipid-lowering drugs were also more likely to have sustained VT, were less likely to have VF, and were less likely to be of minority race than were patients not receiving lipid-lowering drugs. Finally, patients receiving lipid-lowering drugs were less likely to be female.
The patient baseline demographic and clinical characteristics for the entire study group are displayed in Table 2. Patients receiving lipid-lowering drugs were younger than were those not receiving lipid-lowering drugs. Patients receiving lipid-lowering drugs were also more likely to have a history of myocardial infarction and to have a history of hypertension. Patients receiving lipid-lowering drugs were more likely to be discharged also receiving angiotensin-converting enzyme inhibitor therapy, nitrate therapy, or aspirin/antiplatelet therapy. Conversely, patients receiving lipid-lowering therapy were less likely to be discharged receiving digitalis therapy or to have received a revascularization procedure during the baseline hospitalization.
Comparison of the Kaplan-Meier estimates of VT/VF-free survival for patients who received an ICD within one month of randomization showed improved VT/VF-free survival for those patients on lipid-lowering drug therapy. However, the difference did not reach statistical significance (p = 0.19). After adjustment for baseline inequities in the hazard score for VT/VF recurrence, there was a statistically significant association between time to VT/VF recurrence and use of lipid-lowering drug therapy (adjusted p = 0.003) (Fig. 1). The reduction in relative hazard for VT/VF recurrence associated with lipid-lowering drug therapy was 0.40 (95% CI 0.15 to 0.58). The proportion of VT/VF recurrences that were attributed to VF was comparable in the group of patients that received lipid-lowering therapy (17%) and in the group of patients that did not receive lipid-lowering therapy (16%).
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Figure 1 Kaplan-Meier survival curves for the outcome of freedom from ventricular tachyarrhythmia recurrence in patients with an implantable cardioverter defibrillator as a function of whether lipid-lowering drug therapy was not used (dashed line, no LL Rx) or was used early and consistently (solid line, LL Rx). VT/VF = ventricular tachycardia/ventricular fibrillation.
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Kaplan-Meier estimates of survival for the total study group are shown in Figure 2. The univariate association between survival and the use of lipid-lowering drugs was statistically significant (p = 0.02). Similar patterns of survival as a function of use of lipid-lowering drug therapy were seen in each of the randomized AVID treatment arms, but the differences in the smaller subgroups did not reach statistical significance (p = 0.15 in the ICD arm, p = 0.05 in the antiarrhythmic drug arm). Adjustment for inequities in baseline determinants of survival (treatment arm, left ventricular ejection fraction, VT vs. VF index arrhythmia, history of renal disease, history of cerebrovascular disease, history of revascularization, history of any arrhythmia) in the total study group did not alter these results (adjusted p = 0.03). The reduction in relative hazard for all-cause mortality associated with lipid-lowering drug therapy was 0.36 (95% CI 0.15 to 0.68).
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Figure 2 Kaplan-Meier survival curves for the outcome of freedom from all-cause mortality as a function of whether lipid-lowering drug therapy was not used (dashed line, no LL Rx) or was used early and consistently (solid line, LL Rx).
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Kaplan-Meier estimates of cardiac-death free survival for the total study group are shown in Figure 3. The univariate association between survival and the use of lipid-lowering drugs was statistically significant (p = 0.02). Similar patterns of survival as a function of use of lipid-lowering drug therapy were seen in each of the randomized AVID treatment arms, but the differences in the smaller subgroups did not reach statistical significance (p = 0.13 in the ICD arm, p = 0.11 in the antiarrhythmic drug arm). Adjustment for inequities in baseline determinants of survival in the total study group did not alter these results (adjusted p = 0.04). The reduction in relative hazard for cardiac death associated with lipid-lowering drug therapy was 0.39 (95% CI 0.16 to 0.78).
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Figure 3 Kaplan-Meier survival curves for the outcome of freedom from cardiac mortality as a function of whether lipid-lowering drug therapy was not used (dashed line, no LL Rx) or was used early and consistently (solid line, LL Rx).
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Discussion
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This study of patients with ASHD being treated for life-threatening VT/VF with an ICD finds a strong association between the use of lipid-lowering drug therapy and freedom from VT/VF recurrence. The use of lipid-lowering drug therapy was associated with a 40% reduction in the relative hazard for VT/VF recurrence. Similarly, lipid-lowering drug therapy was also associated with a 36% reduction in the relative hazard for death and a 39% reduction in the relative hazard for cardiac death in patients with ASHD treated for life-threatening VT/VF with either antiarrhythmic drug therapy or ICD therapy.
Relative to the prevention of death or cardiac death, the present results support the previous literature in the general population of patients with or at risk to develop atherosclerotic coronary artery disease (3–6). Nevertheless, it is noteworthy that magnitude of the survival benefit associated with lipid-lowering therapy in patients with a demonstrated propensity to life-threatening VT/VF is higher than that generally reported from mortality trials in patients without a demonstrated propensity to life-threatening VT/VF (3–6). Furthermore, this benefit is expressed early in follow-up. These observations support the possibility that direct or indirect antiarrhythmic effects of lipid-lowering therapy contribute to a greater and earlier benefit in patients with life-threatening VT/VF.
Relative to the prevention of VT/VF recurrences, the present results also support De Sutter et al.’s report (8) that lipid-lowering therapy decreases the probability of VT/VF recurrences in patients treated with an ICD. That study compared the VT/VF recurrence rates of 27 patients with ASHD who had received an ICD after experiencing a life-threatening VT/VF who were also receiving lipid-lowering therapy with those of 51 similar patients who were not also receiving lipid-lowering therapy. As in the present analysis, the delivery of an appropriate ICD therapy was considered to represent a VT/VF recurrence. De Sutter et al. (8) reported that six of the 27 patients (22%) who received lipid-lowering therapy and 29 of the 51 patients (57%) who did not receive lipid-lowering therapy received an appropriate ICD shock (p = 0.004) over a mean follow-up period of 16.1 ± 10.5 months. This difference suggested a relative risk reduction of 0.61 (95% CI 0.34 to 0.77) associated with lipid-lowering therapy. Although this difference persisted in a multivariate analysis, that analysis was limited in terms of covariates given its small sample size. The results of the present analysis refine the point estimate of the apparent association between lipid-lowering therapy and VT/VF recurrences after correction for a wider range of baseline differences in VT/VF recurrence risk factors, and indicate a more conservative reduction in the relative risk of VT/VF recurrence of approximately 43% by 16.1 months.
There are a number of potential mechanisms by which lipid-lowering drug therapy could reduce VT/VF recurrences in this study population. Lipid-lowering therapy has been demonstrated to prevent progression and, in some patients, to promote regression of atherosclerotic plaques (12). Experimental data suggest that lipid-lowering therapy modifies the lipid content of high-risk plaques, thereby stabilizing them and preventing plaque rupture (13). Lipid-lowering therapy, especially with HMG-CoA reductase inhibitors, also improves coronary artery endothelial function (14). Improvement in coronary artery endothelial function would reduce the probability of plaque rupture, thereby preventing the ischemia-induced electrophysiologic effects that predispose to VT/VF (15). Furthermore, the antioxidant effects of some lipid-lowering drugs could inhibit ischemia-induced development of the oxygen free radicals that lead to sarcoplasmic injury and intracellular calcium overload, which may be important contributors to the development of VT/VF (16). Finally, therapy with an HMG-CoA reductase inhibitor has also been reported to beneficially affect disordered autonomic control of cardiovascular function (17).
These potential indirect antiarrhythmic effects of lipid-lowering therapy notwithstanding, such therapy may also have more direct antiarrhythmic effects. Lipid-lowering drug therapy modulates the fatty acid composition and physiochemical properties of the sarcolemma, with resultant alterations in transmembrane ion channel properties (18–20). Changes in these properties affect ventricular conduction and excitability (21,22). Thus, it is possible that lipid-lowering drug therapy has direct effects on cardiac ion channel function contributing to the prevention of the development of VT/VF during acute ischemia or in the setting of ventricular dysfunction (23).
Study limitations.
The major limitation of the present study is the nonrandom allocation of patients to those who did and to those who did not receive lipid-lowering therapy. Instead, such therapy was prescribed or not prescribed according to the perception of need by each patient’s attending physician(s). Accordingly, the populations of patients who did and who did not receive lipid-lowering therapy differ in ways that may also impact prognosis. After adjustment for these baseline differences in multivariate analysis, patients in the AVID study who received lipid-lowering therapy had a lower incidence of VT/VF recurrences, cardiac death, and all-cause mortality. Nevertheless, these data, particularly the newer observation of a decreased incidence of VT/VF recurrences, must be considered to be hypothesis-generating until confirmed in a randomized, controlled clinical trial.
Conclusions.
The use of lipid-lowering drug therapy in patients with ASHD who are being treated for life-threatening VT/VF is associated with a substantial reduction in both all-cause mortality and cardiac death. Furthermore, lipid-lowering drug therapy in this setting is also associated with a substantial reduction in the probability of VT/VF recurrences.
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Footnotes
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This work was supported by contract NO1-HC-25117 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland.
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