CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Christopher P. Cannon, MD, FACC*,
Kausik K. Ray, MRCP, MD and
Eugene Braunwald, MD, FACC
* TIMI Study Group, 350 Longwood Avenue, 1st Floor, Boston, Massachusetts 02115 (Email: cpcannon{at}partners.org).
We thank Drs. Poli and Pujia for their interest in our report (1). They suggest that the more significant reduction in clinical events observed among patients with a high low-density lipoprotein cholesterol (LDL-C) versus those with a low LDL-C at baseline provides evidence that the early benefits observed at 30 days are related more to lipids than any potential pleiotropic effects. Acute coronary syndrome (ACS) patients have a high early recurrence of adverse events after ACS. The significant early benefits of intensive statin therapy observed by day 30 in the PROVE IT–TIMI-22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction-22) trial seem more striking when compared to the benefits of intensive LDL-C reduction by ileal bypass in the POSCH (Program on the Surgical Control of the Hyperlipidemias) study, which took nearly seven years to translate into clinical benefit (2). Similarly, in the early statin trials in stable coronary artery disease (CAD) the benefits of statins were observed after one to two years, suggesting that in stable patients the benefits of modest reductions in LDL-C take place over a period of years rather than days. Whereas we agree that LDL-C reduction itself is associated with reductions in C-reactive protein (CRP) and endothelial function, we have demonstrated that, independent of achieved LDL-C and other correlates, the dose of the statin regimen is a significant determinant of CRP levels (3).
Several lines of evidence also suggest that the pleiotropic effects of statins may be as relevant as the LDL-C–dependent effects with respect to clinical outcomes (4). Comparisons across other ACS trials provide further insight into the potential mechanisms of early benefit. For instance, in the A to Z trial (5), there was a greater LDL-C differential between intensive and moderate statin regimens than in the PROVE IT–TIMI-22 trial. However, unlike the PROVE IT–TIMI-22 trial, there was no difference in CRP at 30 days between treatments in the A to Z (Aggrastat-to-Zocor) study and also no early benefit was observed. Similarly, in the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) study the benefit of intensive statin therapy at four months was independent of the baseline and six-week LDL-C (6). Taken together these data suggest that mechanisms other than LDL-C reduction may contribute to early benefit. The recent meta-regression that Drs. Poli and Pujia refer to did not include ACS patients, and it is therefore unclear whether it is applicable to an ACS population during a short follow-up.
Finally, in an additional analysis among patients alive at day 30 with LDL-C data available in the PROVE IT–TIMI-22 trial, we observed that the benefits of intensive statin therapy at reducing myocardial infarction or recurrent ACS in the previous 30 days were present irrespective of whether LDL-C was above or below the median at day 30 after adjustment for age, gender, and diabetes, providing further support for the hypothesis that mechanisms beyond intensive LDL-C reduction may play a role in the early benefits observed (Fig. 1).
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Figure 1 Risk of myocardial infarction (MI) or recurrent acute coronary syndrome (ACS) within 30 days of index ACS stratified by median day-30 low-density lipoprotein (LDL) cholesterol. HR = hazard ratio.
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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]
- Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH) N Engl J Med 1990;323:946-955.[Abstract]
- Ray KK, Cannon CP, Cairns R, et al. Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial J Am Coll Cardiol 2005;46:1417-1424.[Abstract/Free Full Text]
- Ridker PM, Cannon CP, Morrow D, Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) Investigators C-Reactive protein levels and outcomes after statin therapy N Engl J Med 2005;352:20-28.[Abstract/Free Full Text]
- De Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromesphase Z of the A to Z trial. JAMA 2004:292:1307-292:1316.
- Olsson AG, Schwartz GG, Szarek M, et al. High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndromeresults from the MIRACL trial. Eur Heart J 2005;26:890-896.[Abstract/Free Full Text]
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References