Author + information
- Sabina A. Murphy, MPH∗ (, )
- Christopher P. Cannon, MD,
- Michael A. Blazing, MD,
- Robert P. Giugliano, MD,
- Andrew M. Tershakovec, MD, MPH and
- Eugene Braunwald, MD
- ↵∗TIMI Study Group, Brigham and Women’s Hospital, 350 Longwood Avenue, 1st Floor, Boston, Massachusetts 02115
In response to Drs. Mascitelli and Goldstein, we previously reported in the primary publication of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) that there was no difference between ezetimibe plus simvastatin as compared with simvastatin alone with respect to cardiovascular death or all-cause mortality (1). Because the focus of the present paper is total cardiovascular events (2), we did not re-report all-cause mortality because the data were previously published, and a subject can only die once. This lack of difference was expected in IMPROVE-IT because prior trials of intensive-dose versus standard-dose statin therapy also did not show an effect on mortality (3), nor was the IMPROVE-IT trial powered to evaluate for such an effect. Despite the lack of mortality reduction, both the European and North American guidelines endorse high-potency statins for acute coronary syndrome patients based on the important reductions that these agents have on nonfatal events, including myocardial infarctions (MIs), stroke, and revascularization.
With regard to the clinical importance of the endpoints studied, the IMPROVE-IT total events study did show a 13% reduction in the total number of MIs (183 fewer events with ezetimibe plus simvastatin) and a 23% reduction in the total number of strokes (80 fewer events with ezetimibe plus simvastatin). Both MI and stroke can be devastating to a patient, often causing permanent myocardial and neurologic damage even if not fatal. The letter incorrectly stated that “most of this reduction was driven by coronary revascularization.” Although coronary revascularization was the most frequent component of the endpoint, it was not the component that provided either the largest relative (6%) or absolute reduction (162 fewer events with ezetimibe plus simvastatin). When considering the more clinically important endpoint of urgent revascularization, the relative treatment effect was larger at 21%, but the absolute number of events fewer (n = 163) than the number of MIs prevented.
Finally, it is not clear why it was implied that the nonfatal events were “delayed” rather than “prevented.” Unlike all-cause mortality, which is inevitable, nonfatal events are not guaranteed to happen in the future; therefore, common terminology reports these events as “prevented,” whereas for fatal events the term “delayed” can be used if all patients are followed until death, which is highly uncommon in cardiology trials.
Please note: Ms. Murphy has received modest personal fees from Merck & Co., Inc., and Amarin. Dr. Cannon has received grant support from Accumentrics, Arisaph, and Janssen; grant support and personal fees from Takeda; and personal fees from Bristol-Myers Squibb, CSL Behring, Essentialis, Kowa, Lipimedix, Pfizer, Regeneron, Boehringer Ingelheim, GlaxoSmithKline, Merck & Co., Inc., and Sanofi. Dr. Blazing has received grant support from Merck during the conduct of the study; and personal fees from Merck, Sanofi, Amgen, Novartis, AstraZeneca, and Pfizer. Dr. Giugliano has received grant support from Merck during the conduct of the study; grant support and personal fees from Amgen; and personal fees from Merck, Daiichi-Sankyo, Pfizer, CVS Caremark, Regeneron, and Sanofi. Dr. Tershakovec is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co, Inc., and may hold stock/stock options in the company. Dr. Braunwald has received grant support from Merck during the conduct of the study, and personal fees from Daiichi-Sankyo, Sanofi, The Medicines Company, Menarini International, Bayer, and Medscape.
- American College of Cardiology Foundation