CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Christopher P. Cannon, MD* and
Eugene Braunwald, MD
* TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115 (Email: cpcannon{at}partners.org).
We would like to thank Drs. Deshpande, Mardikar, and Deo for their important comments regarding our study (1). The term "intensive" statin therapy has recently been used to identify statin regimens that lower low-density lipoprotein cholesterol (LDL-C) by approximately 50%, as we did in the PROVE IT–TIMI-22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial: "Intensive Versus Moderate Lipid Lowering With Statins After Acute Coronary Syndromes" (2). On the active debate regarding whether the appropriate treatment should be based on the dose of the statin or the achieved LDL, we agree that there have not been trials that directly compare 2 strategies of titrating to a specific LDL-C goal. All the trials use different, largely fixed regimens of a specific statin dose (either with intensive vs. moderate, or of statin therapy vs. placebo). In PROVE IT–TIMI-22, we designed the trial very specifically to have 2 different levels of achieved LDL-C so as to be able to compare patients who reached an average of <100 mg/dl, as recommended in the National Cholesterol Education Program (NCEP) III guidelines, versus a much lower LDL-C with a more intensive regimen, with the final median LDL-C values of 95 and 62 mg/dl, respectively.
Almost a decade ago, the NCEP Guideline committee adopted a practical approach to lipid lowering—where members specified target levels for LDL-C and other lipid levels. This was believed to be a means of having physicians identify high cholesterol values in patients and adjust treatment accordingly. The evidence directly supporting this approach does not exist, as recently lamented (3), but can be inferred from all the randomized trials.
For clinical care, we take a practical view. If we have a patient with an LDL <70 mg/dl on a moderate dose of a statin, we do not feel compelled to increase the dose. However, we are currently conducting the IMPROVE IT trial to address this question, to ascertain whether an even lower LDL is even better. It compares strategies using simvastatin versus simvastatin plus ezetimibe, which are anticipated to have achieved LDL levels of 65 versus 50 mg/dl, respectively. When the trial is completed in several years, we may have evidence to support an even lower target level for LDL.
For additional targets of therapy, we agree, and published the prospective analysis relating clinical event rates to levels of achieved C-reactive protein (4). We similarly have recently found triglycerides to be an important target for therapy (5). We agree that HDL is an important target as well, and we anticipate new approaches to address this important risk factor. All these data support the call for comprehensive management of all components of dyslipidemia.
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1. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy J Am Coll Cardiol 2006;48:438-445.[Abstract/Free Full Text]2. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes N Engl J Med 2004;350:1495-1504.[Abstract/Free Full Text] 3. Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem Ann Intern Med 2006;145:520-530.[Abstract/Free Full Text] 4. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy N Engl J Med 2005;352:20-28.[Abstract/Free Full Text] 5. Miller M, Cannon CP, Ray K, Qin J, Murphy S, Braunwald E, PROVE-IT Investigators Impact of triglycerides in PROVE-IT TIMI-22: does TG <150 improve CHD risk beyond LDL <70 (abstr) Circulation 2006;114(Suppl 2):II-290.
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