• Research Review
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Title: Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease

Authors: Andrews TC, Raby K, Barry J, Naimi C, Allred E, Ganz P, Selwyn P

Reference: Circulation 1997 (January); 95(2): 324-328

Reviewer: Edmund Bermudez

Problem addressed: Aggressive lowering of serum LDL cholesterol has been shown to reduce the incidence of adverse cardiac events. Hyperlipidemia is associated with endothelial dysfunction, which leads to unopposed constriction at coronary stenoses. This constriction plays a role in triggering myocardial ischemia, which is known to be a sign of increased cardiac risk.

Purpose of study: To determine the effect of cholesterol lowering on myocardial ischemia as measured by ST-segment depression on ambulatory ECG monitoring in patients with coronary artery disease

Location of study: Boston, MA, USA

Study design: Single-blind, placebo-controlled, randomized prospective parallel design comparing the effects of cholesterol lowering by diet with cholesterol lowering by diet plus lovastatin.  Ninety-six ambulatory patients with known CAD and measured serum cholesterol screened with ambulatory ECG monitoring. Of forty patients, twenty were randomized to diet and placebo after complete history and physical exam, fasting bloodwork for serum lipids and ambulatory ECG. Twenty were randomized to diet and lovastatin after complete history and physical exam, fasting bloodwork for lipids and ambulatory ECG.

Methods: Lovastatin was initiated at a minimum of 20mg/d and increased to a maximum of 40mg/d if a 20% reduction of LDL cholesterol was not achieved by 6 weeks. Compliance was monitored with pill counts during follow-up visits at 6 weeks, 3months and 6 months. Serum cholesterol and LDL, HDL cholesterol were determined at the end of the study at the time of repeat ambulatory ECG monitoring. One of the forty patients did not have HDL, LDL measurements at the end of the study secondary to logistical difficulty. Before repeat monitoring, patients were reinterviewed and examined to establish that no intercurrent adverse cardiac events had occurred. Monitoring was carried out on the identical medical regimen that patients were receiving at study entry. Two patients had been placed on beta-blocker therapy during the study, and this was tapered over 48 hours prior to repeat AECG. All patients completed the study. One patient receiving lovastatin stopped the medication for two weeks secondary to dyspepsia and resumed it uneventfully.

Results: Patient characteristics in the placebo and treatment groups showed that patients randomized to diet plus lovastatin were more likely to have a history of prior myocardial infarction but otherwise the groups had similar characteristics. Patients randomized to diet plus lovastatin had more significant total serum cholesterol and LDL cholesterol lowering. Diet plus lovastatin lowered mean LDL(mg/dl) from entry at 161 to 115 versus 171 to 143 in the placebo group (p=.0002). Mean total cholesterol(mg/dl) was reduced from 238 to 192 in the treatment group versus 250 to 232 in the placebo group (p=.0008). The median baseline number of ST-segment depression episodes was the same in the two groups. None of the patients reported angina during the two monitoring sessions in this study. A total of 13 of 20 patients randomized to diet plus lovastatin had total resolution of ST-segment depression, whereas only two of 20 patients randomized to diet plus placebo had resolution. In addition, only three of 20 in the treatment group had unchanged or increased numbers of ST-segment depression episodes at follow-up, compared with 11 of 20 in the placebo group. The median total duration of ischemic ST-segment depression for 48 hours at entry was 52 minutes in the placebo group and 45 minutes in the treatment group. At end study, total duration of ischemic ST-segment depression per 48 hours was unchanged at 52 minutes in the placebo group, significantly different from the treatment group, which showed a reduced duration to zero minutes (p=.001). No intercurrent adverse cardiac events occurred during the six month follow-up.

Conclusion: This study has shown that lowering of total and LDL cholesterol especially with lovastatin can result in resolution of myocardial ischemia recorded as episodes of ST-segment depression on ambulatory ECG monitoring. Episodes of ST-segment depression on AECG have been shown to be a reliable measure of transient myocardial ischemia and also been shown to predict cardiac risk and outcomes in patients with coronary artery disease. Recent trials have supported the hypothesis that the elimination of ischemia detected by AECG by medical therapy or revascularization will lead to a decrease in adverse coronary events. Moreover, large-scale clinical trials using HMG-CoA reductase inhibitors, or statins, to lower cholesterol have shown that there is a significant reduction in coronary death and myocardial infarction in patients with coronary disease and/or hypercholesterolemia. These outcome trials all showed effects at or after two years. This investigation shows that directly lowering cholesterol with diet and lovastatin can beneficially change active myocardial ischemia in a relatively short time frame. This is in agreement with previous studies of cholesterol lowering that have also shown a rapid improvement in regional perfusion abnormalities that were provoked in a laboratory setting and measured by radionuclide imaging.

Discussion: Several points are noted in review of this investigation. First, the study group is small, involving only forty patients albeit with very complete and thorough follow-up. Secondly, ambulatory ECG monitoring was chosen for the modality of choice for measuring ischemic burden. The clinical usefulness of this as a practical measure of ischemia has been questioned. More commonly, excercise tolerance testing has been utilized as a measure of ischemic burden. The relationship of cholesterol lowering , excercise capacity and ischemic burden may be a useful elucidation. Thirdly, the decrement in ischemic episodes in the treatment group may not entirely be from cholesterol reduction, but may be from direct effects of the HMG-CoA reductase inhibitor. It has been suggested that these medications are implicated not only in effectively reducing lipid levels, but may play a role in plaque stabilization and endothelial dysfunction. Lastly, the cost of these medications may be prohibitive to their dissemination and widespread use in third world countries.