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Does Atorvastatin Have Anti-ischemic Effects?
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study. This article originally appeared in the December issue of Clinical Cardiology Alert. At that time it was peer reviewed by Ethan Weiss, MD, Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco. Dr. Weiss reports no financial relationship to this field of study.
Synopsis: It seems reasonable to assume that atorva-statin has some anti-ischemic properties, based on the strong correlation between subjective angina reduction and reduction in objective ischemia demonstrated on AECG monitoring. However, there was no incremental benefit to the combination of atorvastatin and amlodipine.
Source: Deanfield JE, et al. Potent anti-ischemic effects of statins in chronic stable angina: Incremental benefit beyond lipid lowering? Eur Heart J 2010;31:2650-2659.
Statins are a cornerstone of treatment for patients with coronary artery disease (CAD). Their powerful lipid-lowering and plaque stabilization effects are well known, as is their ability to reduce myocardial infarction (MI) and death. Statins have also been shown to improve endothelial function, but whether this results in less myocardial ischemia in patients with CAD remains unknown. Amlodipine has been shown to reduce episodes of transient myocardial ischemia detected by ambulatory electrocardiogram (AECG) monitoring. Thus, Deanfield and colleagues performed a randomized controlled trial to compare the anti-ischemic effects of atorvastatin and amlodipine in patients with chronic stable CAD.
Patients with chronic stable angina (≥ 2 episodes per week) were recruited from 46 centers in 13 countries. Inclusion criteria included a positive exercise test, documentation of CAD by either coronary angiography or nuclear perfusion scintigraphy, and a total cholesterol ≥ 200 mg/dL. Eligible patients underwent 48 hour AECG monitoring and could be included if they demonstrated ≥ 15 minutes of ischemia and/or ≥ 3 episodes of ischemia. Exclusion criteria were congenital heart disease, uncontrolled hypertension, systolic blood pressure < 100 mmHg, bradycardia, abnormal electrocardiogram, liver or muscle enzyme elevation, or severe dyslipidemia. After a placebo roll-in phase, patients were randomized to amlodipine (5 mg daily, increasing to 10 mg daily), atorvastatin (10 mg daily, increasing to 80 mg daily), or both. The trial continued for 26 weeks and the primary endpoint was the number of ischemic episodes on AECG monitoring at week 26. Patients also underwent exercise testing, angina diaries, and blood tests for cholesterol and c-reactive protein (CRP).
They enrolled 312 patients: 103 were randomized to amlodipine, 104 to atorvastatin, and 104 to the combination of both. Baseline characteristics were similar between groups with a mean age of 62 years and approximately 25% were diabetic. Importantly, baseline LDL, HDL, blood pressure, and antihypertensives and anti-anginal therapy were well matched. Baseline triglycerides were slightly higher in the amlodipine arm.
At 26 weeks, there was objective evidence of ischemia reduction in all groups. AECG monitoring showed an approximate 66% reduction in the number of ischemic events compared to baseline in all three groups (P < 0.001). There was no difference between groups. Subjective assessment of ischemia by angina diaries was also reduced equally across all three groups (P < 0.001 vs baseline). The number of nitroglycerin tablets used at week 26 was reduced in all groups compared to baseline (P < 0.001), but patients receiving amlodipine (alone or in combination) used significantly fewer nitroglycerin tablets than those receiving atorvastatin monotherapy (P < 0.05). During exercise testing, fewer patients developed angina in each group at 26 weeks compared to baseline, but there was no difference in time to angina or time to onset of ST segment changes in any group.
As expected there was a significant reduction in LDL cholesterol and CRP with atorvastatin (monotherapy or combination), but not with amlodipine. The reduction in ischemia correlated significantly with the reduction in CRP. There was a greater reduction in blood pressure with amlodipine, but this did not reach statistical significance in this patient cohort with well-controlled blood pressure at baseline. Adverse event rates were similar across groups with approximately 4% discontinuing the study medication in each group. The amlodipine groups had approximately an 8% rate of peripheral edema. There was one case of myalgia in each group, one case of elevated creatine kinase in each group, and no liver enzyme abnormalities. The authors conclude that atorvastatin was as potent an anti-ischemic agent as amlodipine.
Statins continue to delight us with new and unexpected salubrious effects. This study does not compare atorvastatin to placebo and, therefore, we cannot absolutely conclude that atorvastatin has anti-ischemic benefits. However, amlodipine has been shown in prior studies to have anti-ischemic effects compared to placebo and this study by Deanfield and colleagues shows a similar reduction in ischemia with atorvastatin and amlodipine. In addition, the strong correlation between subjective angina reduction and reduction in objective ischemia demonstrated on AECG monitoring strengthens their findings. Thus, it is reasonable to assume that atorvastatin has some anti-ischemic properties. This may explain, at least in part, the reduction in ischemia with medical treatment seen in the COURAGE trial.
It is interesting that there was no incremental benefit to the combination of both treatments. They appear to have different effects on inflammation, based on the CRP lowering by atorvastatin and not by amlodipine, yet similar overall effects on ischemia, suggesting different mechanisms of action. However, the lack of additional benefit would argue against this. Further studies are needed to elucidate the mechanism of the anti-ischemic effects.