Erin A Bohula1, Stephen D Wiviott2, Robert P Giugliano2, Michael A Blazing3, Jeong-Gun Park2, Sabina A Murphy2, Jennifer A White3, Francois Mach4, Frans Van de Werf5, Anthony J Dalby6, Harvey D White7, Andrew M Tershakovec8, Christopher P Cannon2, Eugene Braunwald2. 1. TIMI Study Group, Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., S.D.W., R.P.G., J.-G.P., S.A.M., C.P.C., E.B.) ebohula@partners.org. 2. TIMI Study Group, Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (E.A.B., S.D.W., R.P.G., J.-G.P., S.A.M., C.P.C., E.B.). 3. Duke Clinical Research Institute, Durham, NC (M.A.B., J.A.W.). 4. Cardiology Dvision, Geneva University Hospital, Switzerland (F.M.). 5. Departments of Cardiovascular Medicine and Cardiovascular Sciences, University of Leuven, Belgium (F.V.d.F.). 6. Milpark Hospital, Johannesburg, South Africa (A.J.D.). 7. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand (H.D.W.). 8. Merck & Co., Inc, Kenilworth, NJ (A.M.T.).
Abstract
BACKGROUND:Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. METHODS:Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. RESULTS: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; P=0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; P=0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; P=0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; P=0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; P=0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; P=0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; P=0.011) with ezetimibe added to simvastatin therapy. CONCLUSIONS: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.
RCT Entities:
BACKGROUND:Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. METHODS:Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. RESULTS: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; P=0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; P=0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; P=0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; P=0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; P=0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; P=0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; P=0.011) with ezetimibe added to simvastatin therapy. CONCLUSIONS: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.
Authors: Jesse Dawson; Yannick Béjot; Louisa M Christensen; Gian Marco De Marchis; Martin Dichgans; Guri Hagberg; Mirjam R Heldner; Haralampos Milionis; Linxin Li; Francesca Romana Pezzella; Martin Taylor Rowan; Cristina Tiu; Alastair Webb Journal: Eur Stroke J Date: 2022-06-03
Authors: Maciej Banach; Niloofar Shekoohi; Dimitri P Mikhailidis; Gregory Y H Lip; Adrian V Hernandez; Mohsen Mazidi Journal: Arch Med Sci Date: 2022-01-19 Impact factor: 3.707
Authors: Amand F Schmidt; Michael V Holmes; David Preiss; Daniel I Swerdlow; Spiros Denaxas; Ghazaleh Fatemifar; Rupert Faraway; Chris Finan; Dennis Valentine; Zammy Fairhurst-Hunter; Fernando Pires Hartwig; Bernardo Lessa Horta; Elina Hypponen; Christine Power; Max Moldovan; Erik van Iperen; Kees Hovingh; Ilja Demuth; Kristina Norman; Elisabeth Steinhagen-Thiessen; Juri Demuth; Lars Bertram; Christina M Lill; Stefan Coassin; Johann Willeit; Stefan Kiechl; Karin Willeit; Dan Mason; John Wright; Richard Morris; Goya Wanamethee; Peter Whincup; Yoav Ben-Shlomo; Stela McLachlan; Jackie F Price; Mika Kivimaki; Catherine Welch; Adelaida Sanchez-Galvez; Pedro Marques-Vidal; Andrew Nicolaides; Andrie G Panayiotou; N Charlotte Onland-Moret; Yvonne T van der Schouw; Giuseppe Matullo; Giovanni Fiorito; Simonetta Guarrera; Carlotta Sacerdote; Nicholas J Wareham; Claudia Langenberg; Robert A Scott; Jian'an Luan; Martin Bobak; Sofia Malyutina; Andrzej Pająk; Ruzena Kubinova; Abdonas Tamosiunas; Hynek Pikhart; Niels Grarup; Oluf Pedersen; Torben Hansen; Allan Linneberg; Tine Jess; Jackie Cooper; Steve E Humphries; Murray Brilliant; Terrie Kitchner; Hakon Hakonarson; David S Carrell; Catherine A McCarty; Kirchner H Lester; Eric B Larson; David R Crosslin; Mariza de Andrade; Dan M Roden; Joshua C Denny; Cara Carty; Stephen Hancock; John Attia; Elizabeth Holliday; Rodney Scott; Peter Schofield; Martin O'Donnell; Salim Yusuf; Michael Chong; Guillaume Pare; Pim van der Harst; M Abdullah Said; Ruben N Eppinga; Niek Verweij; Harold Snieder; Tim Christen; D O Mook-Kanamori; Stefan Gustafsson; Lars Lind; Erik Ingelsson; Raha Pazoki; Oscar Franco; Albert Hofman; Andre Uitterlinden; Abbas Dehghan; Alexander Teumer; Sebastian Baumeister; Marcus Dörr; Markus M Lerch; Uwe Völker; Henry Völzke; Joey Ward; Jill P Pell; Tom Meade; Ingrid E Christophersen; Anke H Maitland-van der Zee; Ekaterina V Baranova; Robin Young; Ian Ford; Archie Campbell; Sandosh Padmanabhan; Michiel L Bots; Diederick E Grobbee; Philippe Froguel; Dorothée Thuillier; Ronan Roussel; Amélie Bonnefond; Bertrand Cariou; Melissa Smart; Yanchun Bao; Meena Kumari; Anubha Mahajan; Jemma C Hopewell; Sudha Seshadri; Caroline Dale; Rui Providencia E Costa; Paul M Ridker; Daniel I Chasman; Alex P Reiner; Marylyn D Ritchie; Leslie A Lange; Alex J Cornish; Sara E Dobbins; Kari Hemminki; Ben Kinnersley; Marc Sanson; Karim Labreche; Matthias Simon; Melissa Bondy; Philip Law; Helen Speedy; James Allan; Ni Li; Molly Went; Niels Weinhold; Gareth Morgan; Pieter Sonneveld; Björn Nilsson; Hartmut Goldschmidt; Amit Sud; Andreas Engert; Markus Hansson; Harry Hemingway; Folkert W Asselbergs; Riyaz S Patel; Brendan J Keating; Naveed Sattar; Richard Houlston; Juan P Casas; Aroon D Hingorani Journal: BMC Cardiovasc Disord Date: 2019-10-29 Impact factor: 2.298