CORRESPONDENCE: LETTER TO THE EDITOR
Pleiotropic Effects of Statins and Early Benefit in the PROVE IT–TIMI-22 Study
Andrea Poli, MD* and
Arturo Pujia, MD
* University of Milan, Pharmacological Sciences, via Balzaretti, 9, viale Tunisia, 38, Milan, Italy (Email: poli.nfi{at}tin.it).
Ray et al. (1) discuss the early and late benefits of 80 mg/day of atorvastatin in the acute coronary syndrome patients of the PROVE IT–TIMI-22 (Pravastatin or Atorvastatin Evaluation and Infection Trial–Thrombolysis In Myocardial Infarction-22), and they conclude that the early benefit observed in this trial is likely due to the pleiotropic effects of the statin used.
Conversely, the difference in the triple end-point incidence they observe after 30 days, as can be seen in Table 1 of their study, is limited to patients with plasma low density lipoprotein (LDL) cholesterol levels  125 mg/dl at randomization (hazard ratio [HR] 0.31; 95% confidence interval [CI] 0.15 to 0.64; p < 0.002), whereas it is completely absent in patients with LDL cholesterol <125 mg/dl at randomization (HR 0.92; 95% CI 0.63 to 1.36; p = 0.7). It is intriguing that a purported nonlipidic effect of a statin is observed only in patients with elevated LDL cholesterol. Pleiotropic effects should, conceptually, exert their protective properties at any lipid level.
Attribution of the early protective action observed in the PROVE IT–TIMI-22 trial to the pleiotropic effects of the statin used should be, in our opinion, more cautious. In actuality, a clear demonstration of the clinical relevance of these effects is still lacking. A recent meta-regression of published clinical trials testing different hypolipidemic treatments concludes that cholesterol reduction is likely to be the major (or unique) determinant of coronary heart disease and stroke events reduction (2).
Indeed, LDL reduction obtained by a single LDL apheresis markedly reduces C-reactive protein and ameliorates the endothelial function of coronary arteries (3), suggesting that LDL reduction, by itself, can rapidly translate into a variety of biochemical or clinical benefits. Perhaps we should abandon the concept of "pleiotropic effects of statins" in favor of that of "pleiotropic effects of cholesterol reduction."
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References
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- Ray KK, Cannon CP, McCabe CH, et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromesresults from the PROVE-IT–TIMI-22 trial. J Am Coll Cardiol 2005;46:1405-1410.[Abstract/Free Full Text]
- Robinson JG, Smith B, Maheshwari N, Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis J Am Coll Cardiol 2005;46:1855-1862.[Abstract/Free Full Text]
- Igarashi K, Tsuji M, Nishimura M, Horimoto M. Improvement of endothelium-dependent coronary vasodilation after a single LDL apheresis in patients with hypercholesterolemia J Clin Apheresis 2004;19:11-16.[CrossRef][ISI][Medline]
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