Sabina A Murphy1, Christopher P Cannon2, Michael A Blazing3, Robert P Giugliano2, Jennifer A White3, Yuliya Lokhnygina3, Craig Reist3, KyungAh Im2, Erin A Bohula2, Daniel Isaza4, Jose Lopez-Sendon5, Mikael Dellborg6, Uma Kher7, Andrew M Tershakovec7, Eugene Braunwald2. 1. TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: smurphy15@partners.org. 2. TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 3. Duke Clinical Research Institute, Durham, North Carolina. 4. Fundacion Cardioinfantil, Instituto de Cardiología, Bogotá, Cundinamarca, Colombia. 5. Hospital Universitario La Paz, Cardiology Department, Madrid, Spain. 6. Sahlgrenska University Hospital/Ostra and Sahlgrenska Academy, University of Gothenburg, Gotenburg, Sweden. 7. Merck and Company, Inc., Kenilworth, New Jersey.
Abstract
BACKGROUND: Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin. OBJECTIVES: This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy. METHODS:All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis. RESULTS: Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005). CONCLUSIONS: Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878).
RCT Entities:
BACKGROUND: Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin. OBJECTIVES: This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy. METHODS: All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis. RESULTS: Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005). CONCLUSIONS:Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878).
Authors: Sabina A Murphy; Terje R Pedersen; Zbigniew A Gaciong; Richard Ceska; Marat V Ezhov; Derek L Connolly; J Wouter Jukema; Kalman Toth; Matti J Tikkanen; Kyungah Im; Stephen D Wiviott; Christopher E Kurtz; Narimon Honarpour; Robert P Giugliano; Anthony C Keech; Peter S Sever; Marc S Sabatine Journal: JAMA Cardiol Date: 2019-07-01 Impact factor: 14.676
Authors: Gerald Chi; Megan K Yee; Arzu Kalayci; Mathieu Kerneis; Fahad AlKhalfan; Roxana Mehran; Christoph Bode; Jonathan L Halperin; Freek W A Verheugt; Peter Wildgoose; Martin van Eickels; Gregory Y H Lip; Marc Cohen; Eric D Peterson; Keith A A Fox; C Michael Gibson Journal: J Thromb Thrombolysis Date: 2018-10 Impact factor: 2.300
Authors: Christopher P Cannon; Irfan Khan; Alexa C Klimchak; Matthew R Reynolds; Robert J Sanchez; William J Sasiela Journal: JAMA Cardiol Date: 2017-09-01 Impact factor: 14.676