Lipid-lowering therapy associated with reductions in ventricular tachyarrhythmias

July 01, 2003

Calgary, AB - In patients with ischemic heart disease who have received an ICD, the use of lipid-lowering medications is associated with a reduced recurrence of ventricular tachyarrhythmias, according to a new analysis[1].

The results are part of a substudy involving patients receiving lipid-lowering therapy in the Antiarrhythmics vs Implantable Defibrillator (AVID) trial and are published in the July 2, 2003 issue of the Journal of the American College of Cardiology. In the analysis, investigators compared the recurrences of ventricular tachycardia/ventricular fibrillation (VT/VF) in ICD patients receiving lipid-lowering medications with ICD patients not receiving lipid-lowering drug therapy.

According to lead investigator Dr Brent Mitchell (University of Calgary/Foothills Hospital, AB), the lipid-lowering medications were associated with a 40% relative risk reduction in VT/VF recurrence in ICD patients with ischemic heart disease, suggesting the cholesterol-lowering drugs may have antiarrhythmic benefits.

"We have essentially an expert witness in the ICD," Mitchell told heartwire . "As the results indicate, these are dramatic reductions in the risk of ventricular tachyarrhythmias."

The original AVID trial, published in 1997 in the New England Journal of Medicine, found that ICDs were better than amiodarone or sotalol drug therapy in reducing all-cause mortality in survivors of VF or hemodynamically compromising VT.

Are lipid-lowering medications antiarrhythmic?

The analysis conducted by Mitchell et al consisted of 713 patients: 564 patients (79%) who did not receive lipid-lowering drug therapy and 149 patients (21%) who did.

The ICD subgroup within the analysis was composed of 362 patients, of whom 279 (77%) received no lipid-lowering medications and 83 (23%) received early or continuous lipid-lowering therapy. Early lipid-lowering therapy use was defined as therapy that started within six months of follow-up and then continued throughout the primary AVID study.

The prescription of lipid-lowering therapy was left to the discretion of the primary care physician, and investigators made no attempt to classify the type of lipid-lowering medications patients were taking. However, an earlier sample of 237 patients in the original AVID trial indicates that a majority (79%) were prescribed HMG-CoA reductase inhibitors. Others were prescribed fibric acid derivatives and bile acid resins.

To act as an "external check," investigators compared all-cause mortality and cardiac mortality in the overall study group, said Mitchell. Relative to all-cause and cardiac mortality, the results support the literature in the general population of patients either with or at risk of developing CAD, he said.

Reduction in the recurrence of VT/VF in the ICD subgroup (n=362)

End point Relative risk reduction 95% CI Adjusted p
Ventricular tachycardia/ ventricular fibrillation (VT/VF) 0.40 0.15 to 0.58 0.003

Reduction in all-cause and cardiac mortality in the overall study group (n=713)

End point Relative risk reduction 95% CI Adjusted p
All-cause mortality 0.36 0.15 to 0.68 0.03
Cardiac mortality 0.39 0.16 to 0.78 0.04

In the discussion section of the paper, the authors note the mortality and cardiac mortality benefits associated with lipid-lowering medications in patients at risk for VT/VF is greater than in previously reported mortality trials involving patients without a propensity to ventricular tachyarrhythmias.

"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," write the authors.

Reductions in sudden death with lipid-lowering therapy provided the rationale for the analysis, said Mitchell, as did results from an earlier observational study. That study, led by Dr Johan De Sutter (University Hospital, Ghent, Belgium) and previously reported by heartwire , reported that 22% of ICD patients on lipid-lowering drugs (n=27) had a recurrence of ventricular arrhythmias compared with 57% of ICD patients not prescribed lipid-lowering medications (n=51).

While Mitchell said the AVID substudy was not designed to assess the mechanism of action by which lipid-lowering therapies help reduce the risk of ventricular tachyarrhythmias, he speculates that changes in cardiac ion channel function may contribute to the prevention of the development of VT/VF. The antiarrhythmic effects might also be attributed to mechanisms of action involved in plaque structure and stability of patients with coronary artery disease, he said.

According to Mitchell, the major limitation of the study is the nonrandom allocation of patients to those who did and to those who did not receive lipid-lowering therapy. The results should be considered "hypothesis-generating" until confirmed in a randomized, controlled clinical trial, he said.

"The next step will involve testing patients without ischemic heart disease to see if the antiarrhythmic benefits can be extended to ICD populations without coronary artery disease," Mitchell told heartwire .

Promising results

In an editorial accompanying the study[2], Dr Kelley P Anderson (University of Wisconsin Medical School, Madison, WI) writes that the findings by Mitchell et al that lipid-lowering therapy has antiarrhythmic activity would make the drug therapy "distinctive if not unique" among other available treatments."

"An effective, safe, well-tolerated antiarrhythmic therapy could have substantial clinical impact," writes Anderson. "ICDs can prevent sudden cardiac death but patients with recurrent ventricular tachyarrhythmias can experience debilitating symptoms due to syncope, pain, and anxiety."

He points out that plausible mechanisms for lipid-lowering drug therapy to reduce ventricular tachyarrhythmia would enhance the "credibility of the statistical association" reported by the investigators.

Anderson adds that identifying the mechanism would be able to indicate whether lipid-lowering medications could benefit patients without ischemic heart disease or patients with supraventricular arrhythmias.

While the study raises the intriguing possibility that lipid-lowering therapy inhibits ventricular tachyarrhythmias, Anderson writes, the results must be considered preliminary. Future studies, such as the Cholesterol Lowering and Arrhythmias Recurrences After Internal Defibrillator Implantation (CLARIDI), will evaluate the effects of statin vs placebo in patients with ICD, ischemic heart disease, and normal or borderline cholesterol levels, he adds.

Anderson concludes by writing that the recent study "raised the level of awareness of this important potential benefit of lipid-lowering therapy but also has provided important reassurance that [it] is safe in this population of patients with severely depressed myocardial function and numerous comorbid conditions."

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