Beneficial Effects of a Statin vs. an ACE Inhibitor on Coronary Atherosclerosis

Abstract & Commentary

Synopsis: Patients with coronary atherosclerosis and normal lipids should be treated with statins.

Source: Teo KK, et al. Circulation 2000;102:1748-1754.

Simvastatin/enalapril coronary atherosclerosis Trial (SCAT) tested the hypothesis that an ACE inhibitor would contribute to the proven benefits of a statin on coronary atherosclerosis. This four-center Canadian trial initiated in the early 1990s is a study of 394 patients who had quantitative coronary angiograms (QCA) at baseline and at study conclusion. The average follow-up was four years (range, 3-5 yrs). Patients had coronary atherosclerosis as documented by coronary angiography as well as preserved left ventricular function. The qualifying lipid levels included a total cholesterol of 146-236 mg/dL and HDL cholesterol less than 42 mg/dL; the patients had essentially normal lipids with baseline mean of 198 for total cholesterol; 125 for LDL cholesterol, and 38 for HDL. Patients were placed on a NCEP-ATP Step I or Step II diet. All medications were allowed other than lipid-lowering drugs and ACE inhibitors. Study end points were standard quantitative coronary angiographic measures as well as prespecified clinical events, including all major CAD end points. Angiographic end points were average per patient change in mean and minimum diameters and maximum percent stenosis in analyzed segments. Qualifiers had to have coronary disease in greater than three major coronary segments. Progression/regression was defined by appropriate criteria, with an absolute mean or minimum diameter change of greater than 0.4 mm or a 15% in baseline diameter in one or more sections. Patients were randomly assigned to simvastatin, enalapril, the combination, or double-placebo. Target doses were 40 mg of simvastatin and 20 mg/d of enalapril; average daily doses achieved were 29 ± 15 mg for simvastatin, 7 ± 3 mg b.i.d. for enalapril. Compliance was very high. The primary end point was positive for the statin and neutral for enapril. Thus, the average per-patient mean absolute diameter, minimum absolute diameter, and maximum percent diameter stenosis was favorably affected by simvastatin vs. placebo, with slowing of disease progression. Angiographic changes and change in lipid levels were correlated for simvastatin, which also produced more regression in stable patients without angiographic change compared to placebo for all QCA end points. There were no differences in any angiographic end point for the enalapril patients compared to placebo; furthermore, the combination of simvastatin and enalapril did not differ from simvastatin alone. Clinical end points were positive only for revascularization, which was reduced by greater than 50% (P = 0.02) by simvastatin. Enalapril (alone or with simvastatin), but not simvastatin alone, compared to placebo resulted in a decrease in a combined end point of death, MI, and stroke (7% vs 13%; P = 0.04). The drugs were well tolerated; there were no significant laboratory abnormalities. Teo and colleagues concluded that "long-term lipid lowering therapy…resulted in significant slowing of CAD progression in normocholesterolemic patients…related to changes in lipid levels during treatment...long-term ACE inhibition with enalapril had a neutral effect." Clinical end points were uncommon, but less with the ACE inhibitor; revascularization end points were less with the statin. The benefits with simvastatin were believed to be due to plaque shrinkage and stabilization of plaque. Teo et al could not explain why the hypothesis that the ACE inhibitor would have an additional benefit was not supported; they stress that there may be favorable vascular mechanisms with enalapril that might not be detected by the QCA techniques. This study differs from most other CAD regression trials in that the baseline lipid levels were relatively normal. They concluded that patients with coronary atherosclerosis and normal lipids should be treated with simvastatin.

Comment by Jonathan Abrams, MD

This study supplies more evidence that sustained LDL cholesterol lowering alone with a statin in patients with CAD inparts benefit. While not powered as a randomized clinical trial that would be able to detect clinical event reduction, there was a clear-cut decrease in need for revascularization in the lipid-lowering group. The unique feature of SCAT compared to prior regression trials using a statin is that the baseline lipid levels were unremarkable. The previously published Harvard Atherosclerosis Reversibility Project (HARP) trial was negative and included normal cholesterol level patients. However, that was a small study. These data are consistent with the earlier Multicenter Anti-Atheroma Study (MAAS) trial, which showed benefit from lovastatin at four years. The ACE inhibitor results in subjects with unremarkable lipids are not surprising, in that there is little evidence from animal models that coronary atherosclerosis can be attenuated with ACE inhibition. Nevertheless, the enalapril clinical results, while modest in this small trial, do resonate with the recently published HOPE trial, with reduction of composite clinical end points in those patients taking enalapril, although individual end points of death, MI, and stroke were not significantly reduced. Simvastatin treatment did not affect this combined end point.

Both lipid lowering as well as ACE inhibition appear to be beneficial, particularly the statin. ACE inhibitors have a more poorly explained effect on clinical events, which cannot be readily explained by coronary angiographic end points or studies of vascular function. While some endothelial function trials, including Trendelenburg (TREND), have been positive for ACE inhibitors, the aggregate data are not particularly robust. Many mechanisms have been hypothesized to explain long-term vascular benefits with ACE inhibitors. The robust reduction of a wide variety of cardiovascular end points in the HOPE trial in more than 9000 high-risk patients treated with ramipril, is similar to the reduction of clinical events in SCAT. It is likely that with both a statin and an ACE inhibitor, major benefits accrue only after a period of years, and not months. The data from SCAT clearly support the use of a statin and probably an ACE inhibitor as well in individuals who may not qualify for conventional lipid-lowering therapy or for an ACE inhibitor, using conventional clinical criteria.