Effect of Intensive Lipid Lowering, With or Without Antioxidant Vitamins, Compared With Moderate Lipid Lowering on Myocardial Ischemia in Patients With Stable Coronary Artery Disease

Abstract

Background-Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia. Methods and Results-In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with Ն1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to Ͻ80 mg/dL (nϭ96), intensive atorvastatin to reduce LDL to Ͻ80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (nϭ101), or diet and low-dose lovastatin, if needed, to reduce LDL to Ͻ130 mg/dL (nϭ103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from Ϸ153 mg/dL at baseline in the 2 atorvastatin groups to Ϸ83 mg/dL at 12 months (each PϽ0.0001) and from 147 to 120 mg/dL in the control group (PϽ0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each PϽ0.001; Pϭ0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each PϽ0.001; Pϭ0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes. Conclusions-Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of Ͻ120 mg/dL. (Circulation. 2005;111:1747-1755.)

Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease

“…The reductions in ischemia from baseline in SAGE confirm the results from the Vascular Basis for the Treatment of Myocardial Ischemia study, which likewise revealed significant reductions in ischemia as measured by 48-hour ambulatory ECG in stable CAD patients randomized to an intensive (atorvastatin) or a moderate (lovastatin) statin regimen. 10 In SAGE, the change in total duration of myocardial ischemia was already evident at 3 months with no further improvement at month 12 and may indicate that reduction in coronary tone preceded changes in plaque composition, which are responsible for most cardiac events. In the Vascular Basis for the Treatment of Myocardial Ischemia study, it was hypothesized that there was a threshold effect of LDL-C lowering below which there is no incremental improvement in endothelial dysfunction and episodic coronary vasoconstriction, the mechanisms that contribute to the development of ischemia, and that the on-treatment LDL-C values in both groups in the Vascular Basis for the Treatment of Myocardial Ischemia study were beneath this threshold.…”

“…7 In patients with stable CAD, too, statin therapy was associated with reductions in ambulatory ischemia, as compared with placebo in a randomized pilot study 8 and in a nonrandomized database study. 9 The recent Vascular Basis for the Treatment of Myocardial Ischemia Study 10 further demonstrated that both intensive and more moderate lipid-lowering regimens reduced the duration of ischemia from baseline as measured by ambulatory ECG in patients with stable CAD. However, the mean age of the participants in these studies ranged from 56 to 67 years, participants were predominantly male, and none of the studies addressed the unique group of older patients with stable CAD-a population that is at highest risk of cardiac events and mortality.…”

The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials

“…[15][16][17][18][19][20][21] We excluded 2 potentially eligible trials that compared different intensities of statin therapy: 1 trial enrolled only patients with familial hypercholesterolemia 22 and 1 enrolled a wide variety of patients of whom the majority (54%) did not have coronary artery disease. included in our review.…”

“…included in our review. [15][16][17][18][19][20][21] Of these trials, 2 enrolled patients after acute coronary syndromes and 5 enrolled patients with chronic coronary artery disease. The demographic characteristics of study participants were similar across the included trials.…”

“…Baseline LDL cholesterol ranged between 2.74 mmol/L in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) trial to 3.9 mmol/L in the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid-Lowering Therapy) trial, TNT (Treating to New Targets) trial (before the run-in period, 2.6 mmol/L before randomization) and the Vascular Basis trial. Three trials were designed with continuous outcomes as their primary outcome: the Vascular Basis and the SAGE (Study Assessing Goals in the Elderly) trials reported the number of ischemic episodes 20,21 and the REVERSAL trial reported percent change in atheroma volume. 19 Four trials used clinical primary composite outcomes, but the individual components differed (Table 1).…”