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Intensive Lipid-Lowering Therapy and Atherosclerosis



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Am Fam Physician. 2004 Oct 15;70(8):1580-1583.

The optimal low-density lipoprotein cholesterol (LDL) threshold and approach to lipid lowering is not known. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, Nissen and colleagues compared the effects of a moderate statin regimen and an intensive lipid-lowering statin regimen on atherosclerotic disease burden as measured by intravascular ultrasonography. Patients who were 30 to 75 years of age, who required coronary angiography for a clinical indication, and who demonstrated at least one obstruction with angiographic luminal diameter narrowing of 20 percent or more were enrolled.

Baseline LDL cholesterol levels were between 125 and 210 mg per dL (3.24 and 5.43 mmol per L) after a four- to 10-week washout period. After a two-week run-in period, patients were randomized to receive 40 mg of pravastatin daily in the moderate regimen or 80 mg of atorvastatin daily in the intensive regimen. Patients underwent base-line angiography and ultrasound examination of the longest and least angulated target vessel, which was required to have at least a 50 percent narrowing. Patients had clinical examinations every three months and repeat cardiac catheterization and intravascular ultrasonography after 18 months.

A total of 2,163 patients were screened. Of these, a total of 502 patients had evaluable intravascular ultrasound results at baseline and 18-month follow-up (249 of those receiving pravastatin and 253 of those receiving atorvastatin). The mean LDL cholesterol level was 79 mg per dL (2.04 mmol per L) in the atorvastatin group and 110 mg per dL (2.85 mmol per L) in the pravastatin group. The reduction in C-reactive protein level was 36.4 percent in the atorvastatin group and 5.2 percent in the pravastatin group.

The progression rate of atheroma volume as measured by percent change was significantly lower in the atorvastatin group than in the pravastatin group, with the former group showing no progression and the latter showing positive progression. The results were unchanged in 22 subgroups, varying according to age, previous statin use, baseline cholesterol levels, or comorbidities, which could influence response. Patient-oriented outcomes could not be evaluated because the number of clinical events during the trial was too small for analysis.

Overall, patients receiving atorvastatin showed significantly reduced coronary atherosclerotic progression compared with those receiving pravastatin. Results favoring intensive lipid lowering were consistent for the primary end point, three specified secondary end points, and 22 prospectively defined subgroups.

These findings suggest that a more intensive lipid-lowering regimen may achieve greater benefits and that these benefits are associated with LDL cholesterol levels well below current guidelines. Each 10 percent reduction in LDL cholesterol level corresponded with a 1 percent reduction in atheroma volume at the study’s end. Of note, the lipid-lowering effect may not be the only mechanism mediating these cardiovascular benefits, because patients in the atorvastatin group also had significantly lower C-reactive protein levels than those in the pravastatin group. Efficacy and safety appeared to be similar in both groups. Clinical outcome studies are necessary before implementing these findings in practice.

Nissen SE, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis. A randomized controlled trial. JAMA. March 3, 2004;291:1071–80.

editor’s note: The study by Nissen and colleagues appeared at the same time as a clinical outcomes study of the same medications published in the New England Journal of Medicine.1 In that study, hospitalized patients with acute coronary syndromes were randomized to receive 40 mg of pravastatin or 80 mg of atorvastatin. Outcomes were death from any cause and further vascular events. After two years, the hazard ratio in the atorvastatin group was reduced by 16 percent. As in the ultrasound study, both drugs were similarly well tolerated, with equivalent dropout rates in both groups. Thus, the combined disease-oriented and patient-oriented evidence is compelling that patients with demonstrated cardiovascular disease do better with intensive lipid-lowering therapy. However, the absolute reductions are not large. Lifestyle measures are likely to have greater impact.—c.w.

 

REFERENCE

1. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.


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