Late-Breaking Science Abstracts From the American Heart Association’s Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018
2018; Lippincott Williams & Wilkins; Volume: 138; Issue: 25 Linguagem: Inglês
10.1161/cir.0000000000000636
ISSN1524-4539
Tópico(s)Cardiac Arrest and Resuscitation
ResumoHomeCirculationVol. 138, No. 25Late-Breaking Science Abstracts From the American Heart Association’s Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018 Free AccessAbstractPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessAbstractPDF/EPUBLate-Breaking Science Abstracts From the American Heart Association’s Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018 Originally published17 Dec 2018https://doi.org/10.1161/CIR.0000000000000636Circulation. 2018;138:e751–e782Prevention, Health and WellnessLate-Breaking Clinical Trial: Answers to Critical Questions in Cardiovascular Prevention19539The VITamin D and OmegA-3 TriaL (VITAL): Principal Results for Vitamin D and Omega-3 Fatty Acid Supplementation in the Primary Prevention of Cardiovascular Disease and CancerJoAnn E Manson, Nancy R Cook, I-Min Lee, William Christen, Samia Mora, Heike Gibson, Christine M Albert, Shari Bassuk, David Gordon, Trisha Copeland, Denise D’Agostino, Georgina Friedenberg, Claire Ridge, Vadim Bubes, Julie E Buring; Medicine, Harvard Med Sch, Boston, MA,Supplemental vitamin D and marine omega-3 fatty acids have promise for reducing risks of cardiovascular disease (CVD) and cancer, but the evidence remains inconclusive regarding causality. The VITamin D and Omega-A 3 TriaL (VITAL) is a recently completed nationwide, randomized, double-blind, placebo-controlled clinical trial designed to fill this knowledge gap. The study population includes 25,871 U.S. adults (men aged ≥50 and women aged ≥55), without CVD or cancer at baseline, with an oversampling of African Americans (n=5,106). Participants were randomized in a 2x2 factorial design to one of four supplement groups: (1) vitamin D3 (cholecalciferol; 2000 IU daily) and marine omega-3 fatty acids (Omacor® fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], 1 g daily, ratio of EPA to DHA = 1.3:1); (2) vitamin D and omega-3 placebo; (3) vitamin D placebo and omega-3 fatty acids; or (4) both placebos. The median duration of the randomized treatment period was 5.3 (range 3.8–6.1) years. Randomization was successful, as evidenced by similar distributions of baseline demographic, clinical, and behavioral characteristics across treatment groups. Baseline blood samples were collected from willing participants (n=~17,000), with follow-up blood samples from >6000. Assays for serum 25(OH)D and plasma omega-3 (EPA+DHA) concentrations were performed on baseline and follow-up samples. The primary endpoints of VITAL are: (a) major CVD events (a composite endpoint of MI, stroke, and CVD mortality) and (b) total invasive cancer. Secondary CVD endpoints include: (a) an expanded composite of major CVD events plus coronary revascularization (i.e., coronary artery bypass grafting or percutaneous coronary intervention) and (b) the individual components of the composite CVD endpoints. Secondary cancer endpoints include site-specific cancers and total cancer mortality. In addition, all-cause and cause-specific mortality is ascertained, and monitored safety outcomes include hypercalcemia, parathyroid disorders, and kidney stones. Randomized treatment ended as scheduled at the end of December 2017. VITAL will provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation. The principal findings of VITAL, for each intervention and with a particular emphasis on CVD outcomes, will be presented for the first time.Author Disclosures: J.E. Manson: None. N.R. Cook: None. I. Lee: None. W. Christen: None. S. Mora: None. H. Gibson: None. C.M. Albert: None. S. Bassuk: None. D. Gordon: None. T. Copeland: None. D. D’Agostino: None. G. Friedenberg: None. C. Ridge: None. V. Bubes: None. J.E. Buring: Other; Modest; Dr. Buring reports that her spouse is on the Scientific Advisory Board of Pharmavite.Key Words: cardiovascular disease; vitamin D; omega-3 fatty acids19515The Primary Results of the REDUCE-IT TrialDeepak L Bhatt1, Ph. Gabriel Steg2, Michael Miller3, Eliot A Brinton4, Terry A Jacobson5, Steven B Ketchum6, Ralph T Doyle6, Rebecca A Juliano6, Lixia Jiao6, Craig Granowitz7, Jean-Claude Tardif8, Christie M Ballantyne9; 1Heart and Vascular Cntr, Brigham and Women’s Hosp, Boston, MA, 2Cardiology, Hopital Bichat, Paris, France, 3Dept of Medicine, Univ of Maryland Sch of Medicine, Baltimore, MD, 4Utah Lipid Cntr, Utah Lipid Cntr, Salt Lake City, UT, 5Lipid Clinic and Cardiovascular Risk Reduction Program, Dept of Medicine, Emory Univ Sch of Medicine, Atlanta, GA, 6Rsch and Development, Amarin Pharma Inc., Bedminster, NJ, 7Med Affairs, Amarin Pharma Inc., Bedminster, NJ, 8Montreal Heart Institute, Universite de Montreal, Montreal, Canada, 9Cntr for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Cntr, Baylor College of Medicine, Houston, TX,Introduction: Despite therapy with statins, residual cardiovascular risk remains, especially in patients with persistent hypertriglyceridemia. Icosapent ethyl is a highly purified ethyl ester of eicosapentaenoic acid that lowers triglyceride levels and also has anti-oxidative, anti-inflammatory, and other potentially anti-atherogenic properties.Methods: Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial (REDUCE-IT, NCT01492361) is a Phase 3b randomized, double-blinded, placebo-controlled trial of icosapent ethyl in patients with fasting triglycerides greater than or equal to 150 mg/dL and less than 500 mg/dL and LDL-C greater than 40 mg/dL and less than or equal to 100 mg/dL on stable statin therapy and with a prior cardiovascular event or diabetes and other cardiovascular risk factors. The primary endpoint is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina. The key secondary endpoint is the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Several other secondary, tertiary, and exploratory endpoints will be examined.Results: Over 8000 patients were randomized to icosapent ethyl versus placebo. Over 1600 adjudicated primary efficacy endpoint events have occurred. The median follow-up time in the trial is over 4.5 years. Results of the primary, key secondary, and other selected endpoints will be presented.Conclusions: The primary results of the REDUCE-IT trial will establish whether treating at-risk patients with high-dose icosapent ethyl will lower the rates of important ischemic events beyond statin therapy, and when combined with the results of other triglyceride-lowering trials, will provide insight into whether the triglyceride-lowering, anti-oxidative, anti-inflammatory, or other effects of icosapent ethyl are clinically relevant.Author Disclosures: D.L. Bhatt: Research Grant; Significant; Amarin Pharma Inc. P. Steg: Research Grant; Modest; Bayer, Merck, Sanofi, Servier. Consultant/Advisory Board; Modest; Amarin Pharma Inc., Amgen, Bayer/Janssen, Boehringer-Ingelheim, Bristol-Myers Squibb, Lilly, Merck, Novartis, Novo-Nordisk, Regeneron, Servier. Consultant/Advisory Board; Significant; AstraZeneca, Pfizer, Sanofi. M. Miller: Consultant/Advisory Board; Significant; Amarin Pharma Inc. E.A. Brinton: Other Research Support; Modest; Amarin Pharma Inc., Kowa. Speakers Bureau; Significant; Kowa. Consultant/Advisory Board; Significant; Kowa. T.A. Jacobson: Consultant/Advisory Board; Modest; Amarin Pharma Inc. S.B. Ketchum: Employment; Significant; Amarin Pharma Inc.. Ownership Interest; Significant; Amarin Pharma Inc. R.T. Doyle: Employment; Significant; Amarin Pharma Inc.. Ownership Interest; Significant; Amarin Pharma Inc. R.A. Juliano: Employment; Significant; Amarin Pharma Inc.. Ownership Interest; Significant; Amarin Pharma Inc. L. Jiao: Employment; Significant; Amarin Pharma Inc.. Ownership Interest; Significant; Amarin Pharma Inc. C. Granowitz: Employment; Significant; Amarin Pharma Inc.. Ownership Interest; Significant; Amarin Pharma Inc. J. Tardif: Research Grant; Significant; Amarin Pharma Inc.. Honoraria; Significant; Amarin Pharma Inc. C.M. Ballantyne: Research Grant; Significant; All paid to institution, not individual:, Akcea, Amarin Pharma Inc., Amgen, Esperion, Novartis, Regeneron, Sanofi-Synthelabo, NIH, AHA, ADA. Consultant/Advisory Board; Modest; Akcea, Amarin Pharma Inc., Amgen, Eli Lilly, Esperion, Matinas BioPharma Inc., Novartis, Regeneron. Consultant/Advisory Board; Significant; AstraZeneca, Merck, Sanofi-Synthelabo.17581Ezetimibe in Prevention of Cerebro- and Cardiovascular Events in Middle- to High-Risk, Elderly (75 Years Old or Over) Patients With Elevated LDL-Cholesterol: A Multicenter, Randomized, Controlled, Open-Label TrialHidenori Arai1, Jun Sasaki2, Koutaro Yokote3, Masanari Kuwabara4, Kazumasa Harada5, Takumi Imai6, Shiro Tanaka6, Yasuo Ohashi7, Hideki Ito8, Yasuyoshi Ouchi9; 1Dept of Geriatric Medicine, NCGG, Obu, Japan, 2Dept of Physical Therapy, International Univ of Health and Welfare, Fukuoka, Japan, 3Dept of Internal Medicine, Chiba Univ Graduate Sch of Medicine, Chiba, Japan, 4Dept of Cardiology, Toranomon Hosp, Tokyo, Japan, 5Dept of Cardiology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan, 6Dept of Clinical Biostatistics, Kyoto Univ Graduate Sch of Medicine, Kyoto, Japan, 7Dept of Integrated Science and Engineering for Sustainable Society, Chuo Univ, Tokyo, Japan, 8Hosp and Rsch Institute, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan, 9Hosp, Toranomon Hosp, Tokyo, JapanIntroduction: The efficacy of lipid-lowering therapy with statins for high-risk patients is well established. However, there is no evidence about its clinical benefits in Japanese elderly (> 75 years old) patients with elevated low-density lipoprotein cholesterol (LDL-C) levels who have no history of coronary artery disease.Hypothesis: We hypothesized that the onset of cerebral and cardiovascular events can be prevented by decreasing LDL-C levels with ezetimibe in these patients.Methods: Between 2009 and 2016, a prospective, multicenter, open-label, blinded end point, randomized controlled trial was conducted in these patients whose LDL-C level was > 140 mg/dL and who had one or more cardiovascular risk factors (e.g., diabetes, hypertension, smoking, how high-density lipoprotein cholesterol levels, and high triglyceride levels). The primary endpoint was a composite of sudden cardiac death, fatal myocardial infarction, nonfatal myocardial infarction, coronary revascularization, fatal stroke, and/or nonfatal stroke.Results: A total of 3,796 patients were enrolled, and 1898 patients each were randomly assigned to the ezetimibe group (ezetimibe 10 mg/day plus diet counseling) or the control group (diet counseling alone). Baseline demographic characteristics were as follows: mean age, 80.7±4.8 years; body mass index, 23.4±3.6; male, 25.7%; hypertension, 78.0%; and diabetes, 22.8%. Despite the high incidence (78.0%) of concomitant hypertension, systolic and diastolic blood pressures were well controlled (136.1±15.9 mmHg and 74.1±10.5 mmHg, respectively). Mean LDL-C, high-density lipoprotein cholesterol, and triglycerides at baseline were 161.6±19.7 mg/dL, 56.8±14.1 mg/dL, and 131.3±55.3 mg/dL, respectively. Mean LDL-C levels at 1 year after randomization were 126.1±26.2 mg/dL and 144.0±29.2 mg/dL in the ezetimibe and control groups, respectively, and the difference was statistically significant.Conclusion: The present study provides valuable evidence about the clinical relevance of lipid-lowering therapy with ezetimibe in the study population. Clinical outcomes from the present study will be presented at the meeting. (UMIN000001988)Author Disclosures: H. Arai: Honoraria; Significant; Daiichisankyo, Astellas, MSD, Sanofi, Astellas-Amgen Biopharma, Kowa Pharmaceuticals, Kowa Company. J. Sasaki: None. K. Yokote: Research Grant; Significant; Tanabe-Mitsubishi, Takeda, MSD, Pfizer. Honoraria; Modest; Pfizer, Bayer. Honoraria; Significant; Kowa, MSD, Astellas, Tanabe-Mitsubishi, Sanofi, Astellas- Amgen Biopharma, Takeda, Ono, Astra-Zeneca. M. Kuwabara: None. K. Harada: None. T. Imai: None. S. Tanaka: Employment; Significant; The Japan Agency for Medical Research and Development. Honoraria; Modest; Boehringer Ingelheim. Consultant/Advisory Board; Modest; DeNA Life Science, Satt, Public Health Research Foundation. Y. Ohashi: Research Grant; Modest; Yakult. Honoraria; Modest; Chugai, Sanofi, Daiichi-Sankyo. Ownership Interest; Significant; Statcom Ltd.. H. Ito: None. Y. Ouchi: None.Key Words: cardiocascular event; dyslipidemia; old old19490Cost-Effectiveness of Alirocumab Based on Evidence From a Large Multinational Outcome Trial: The ODYSSEY OUTCOMES Economics StudyDeepak L Bhatt1, Andrew Briggs2, Shelby D Reed3, Lieven Annemans4, Michael Szarek5, Vera A Bittner6, Rafael Diaz7, Jay M Edelberg8, Shaun G Goodman9, Corinne Hanotin10, Robert A Harrington11, J. Wouter Jukema12, Kenneth W Mahaffey13, Angèle Moryusef14, Robert Pordy15, Matthew T Roe16, Robert Sanchez17, Keiko Higuchi18, Harvey D White19, Andreas M Zeiher20, Gregory G Schwartz21, Ph G Steg22, ODYSSEY OUTCOMES Investigators; 1Cardiology, Brigham and Women’s Hosp, Boston, MA, 2Health Economics & Health Technology Assessment, Institute of Health & Wellbeing, Univ of Glasgow, Glasgow, United Kingdom, 3Duke Clinical Rsch Institute, Duke Univ Sch of Medicine, Durham, NC, 4Dept of Public Health, Ghent Univ, Ghent, Belgium, 5Public Health, SUNY Downstate Med Cntr Sch of Public Health, Brooklyn, NY, 6Sch of Medicine, Univ of Alabama at Birmingham, Birmingham, AL, 7Cardiology, Estudios Cardiológicos Latinoamérica, Rosario, Argentina, 8Cardiovascular Development, Sanofi, Bridgewater, NJ, 9Cardiology, Univ of Toronto, Toronto, Canada, 10Clinical Rsch, Sanofi, Paris, France, 11Cardiology, Stanford Univ, Stanford, CA, 12Cardiology, Leiden Univ Med Cntr, Leiden, Netherlands, 13Cardiovascular Medicine, Stanford Univ Med Cntr, Stanford, CA, 14Clinical Rsch, Sanofi, Bridgewater, NJ, 15Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, 16Duke Clinical Rsch Institute, Duke Univ Med Cntr, Durham, NC, 17Health Economics and Outcomes Rsch, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, 18Cardiovascular Global Evidence, Sanofi, Bridgewater, NJ, 19Cardiology, Auckland City Hosp, Auckland, New Zealand, 20Cardiology, J.W. Goethe Univ, Frankfurt am Main, Germany, 21Div of Cardiology, Univ of Colorado Sch of Medicine, Aurora, CO, 22Dept of Cardiology, Hôpital Bichat, Paris, FranceIntroduction: Phase 3 trials have shown that PCSK9 inhibitors reduce ischemic cardiovascular (CV) events in patients with atherosclerotic CV disease, with a well-tolerated safety profile. However, the substantial cost of these drugs makes it imperative to estimate their cost-effectiveness in clinical practice. ODYSSEY OUTCOMES was a 18,924-patient international randomized clinical trial that demonstrated reduced major adverse cardiovascular events (MACE) with the PCSK9 inhibitor alirocumab compared with placebo in patients 1–12 months post-ACS and elevated low-density lipoprotein cholesterol (LDL-C) levels despite use of high-intensity statins. In this presentation, we will report on the projected cost-effectiveness of alirocumab using patient-level data from the ODYSSEY OUTCOMES trial. In contrast to prior cost-effectiveness analyses of PCSK9 inhibitors, this one is based on trial-level LDL-C values and longer-term outcome data.Methods: Data were collected prospectively on all doses of study medication, hospitalizations, and health-related quality of life (HRQOL) via the EQ-5D. We will estimate the direct medical costs for all outcome variables of interest using published sources. Age-based survival analysis will be applied to the empirical trial data to estimate long-term survival and quality-adjusted life-years (QALYs) for patients randomized to alirocumab or placebo. A sensitivity analysis will be conducted in those with a baseline LDL-C ≥100 mg/dL (a pre-specified subgroup), in whom absolute clinical benefit was most marked.Results: Over a mean follow-up period of 2.8 years, the number of CV events will be calculated. The cost-effectiveness of alirocumab compared with placebo based on estimated increases in lifetime costs and gains in QALYs will be presented.Conclusions: The ODYSSEY OUTCOMES trial demonstrated decreases in CV events. The presentation will provide empirically-based estimates of the long-term cost-effectiveness of alirocumab in patients post-ACS and with elevated LDL-C levels despite intensive statin therapy.Author Disclosures: D.L. Bhatt: Research Grant; Significant; Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Sanofi Aventis, Eisai, Roche, Pfizer, Ethicon, Medtronic, Forest Laboratories, Lilly, Ironwood, Ischemix. Consultant/Advisory Board; Significant; Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis. A. Briggs: Consultant/Advisory Board; Significant; Amgen, Sanofi. S.D. Reed: Research Grant; Significant; Abbott Vascular, AstraZeneca, Alexion, Janssen Scientific Affairs, LLC, Lundbeck, TESARO, Merck. Consultant/Advisory Board; Modest; PHAR, LLC, AstraZeneca. Consultant/Advisory Board; Significant; Minomic International Ltd, Madeleine Pharmaceuticals, Regeneron Pharmaceuticals, Inc. Other; Significant; PhRMA Foundation. L. Annemans: Speakers Bureau; Modest; Sanofi, Amgen, AstraZeneca. Consultant/Advisory Board; Modest; Sanofi, Amgen, AstraZeneca. M. Szarek: Consultant/Advisory Board; Modest; CiVi, Resverlogix, Baxter, Regeneron Pharmaceuticals Inc. Consultant/Advisory Board; Significant; Sanofi. V.A. Bittner: Research Grant; Modest; Amgen, DalCor, Esperion. Research Grant; Significant; Sanofi, AstraZeneca, Bayer Healthcare. Honoraria; Modest; American College of Cardiology, American Heart Association, National Lipid Association. Consultant/Advisory Board; Significant; Sanofi. R. Diaz: None. J.M. Edelberg: Employment; Significant; Sanofi. S.G. Goodman: Research Grant; Modest; Daiichi-Sankyo, Luitpold Pharmaceuticals, Merck, Novartis, Servier, Regeneron. Research Grant; Significant; Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Pfizer, Tenax Therapeutics. Honoraria; Modest; Bristol-Myers Squibb, Eli Lilly, Fenix Group International, Ferring Pharmaceuticals, Merck, Novartis, Pfizer, Servier, Regeneron. Honoraria; Significant; Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim. Consultant/Advisory Board; Modest; AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, Servier, Tenax Therapeutics. Consultant/Advisory Board; Significant; Sanofi, Amgen, Bayer. C. Hanotin: Employment; Significant; Sanofi. R.A. Harrington: Ownership Interest; Modest; SignalPath (software), inui Health (consumer health). Consultant/Advisory Board; Modest; Element Science, MyoKardia. Research Grant; Significant; Apple, CSL Behring, sanofi aventis, Astra Zeneca, Portola, Janssen, BMS, Novartis, The Medicines Company. Consultant/Advisory Board; Significant; WebMD. J. Jukema: Research Grant; Modest; Netherlands Heart Foundation, Interuniversity Cardiology Institute of the Netherlands, Interuniversity Cardiology Institute of the Netherlands, the European Community Framework KP7 Program. Other Research Support; Modest; Amgen, Astellas, AstraZeneca, Daiichi Sankyo, Lilly, Merck-Schering-Plough, Pfizer, Roche, Sanofi-Aventis. K.W. Mahaffey: Research Grant; Significant; Afferent, Amgen, Apple Inc., AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson and Johnson, Lupitold, Medtronic, Merck, Novartis, Sanofi, St. Jude, Tenax. Honoraria; Modest; Ablynx, Baim Institute, Cardiometabolic Health Congress, Elsevier, Medergy, Medscape, Merck, Mitsubishi, Myokardia, Novartis, Oculeve, Springer publishing, Theravance, UCSF, WebMD. Honoraria; Significant; AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Glaxo Smith Kline, Johnson and Johnson, Portola, Radiometer. Expert Witness; Modest; Bioprint Fitness. A. Moryusef: Employment; Significant; Sanofi. R. Pordy: Employment; Significant; Regeneron Pharmaceuticals, Inc. M.T. Roe: Research Grant; Significant; American College of Cardiology, American Heart Association, Familial Hypercholesterolemia Foundation, Ferring Pharmaceuticals, Myokardia, Patient Centered Outcomes Research Institute, Sanofi-Aventis. Consultant/Advisory Board; Modest; Amgen, Ardea Biosciences, AstraZeneca. Consultant/Advisory Board; Significant; Eli Lilly, Merck. Other; Modest; Flatiron, Janssen Pharmaceuticals, Novartis, Novo Nordisk, Regeneron Pharmaceuticals, Roche-Genentech. R. Sanchez: Employment; Significant; Regeneron Pharmaceuticals, Inc. K. Higuchi: Employment; Significant; Sanofi. H.D. White: Research Grant; Modest; Sanofi-Aventis, Dalcor Pharma, NIH, Eisai, Omthera Pharmaceuticals. Other; Modest; SAHMRI, ESC, AHA, Sanofi/Regeneron. A.M. Zeiher: None. G.G. Schwartz: Research Grant; Modest; Resverlogix. Research Grant; Significant; Sanofi, Roche. P.G. Steg: Research Grant; Significant; Merck, Sanofi, Servier. Consultant/Advisory Board; Significant; Amarin, Amgen, Bayer, GSK, Regeneron Pharmaceuticals, Inc, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Lilly, Merck, Novartis, Janssen. Other; Significant; AstraZeneca, Sanofi, Servier.Prevention, Health and WellnessLate-Breaking Clinical Trial: Novel Approaches to CV Prevention19485The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 TrialStephen D Wiviott1, Itamar Raz2, Marc P Bonaca1, Ofri Mosenzon2, Eri T Kato3, Avivit Cahn4, Michael G Silverman5, Thomas A Zelniker1, Deepak L Bhatt1, Lawrence A Leiter6, Darren K McGuire7, John P Wilding8, Ingrid A Gause-Nilsson9, Anna Maria Langkilde9, Peter A Johansson9, Marc S Sabatine1; 1Cardiovascular Div, Brigham and Womens Hosp, Boston, MA, 2Dept of Endocrinology and Metabolism, Hadassah Hebrew Univ Hosp, Jerusalem, Israel, 3Dept of Cardiovascular Medicine, Kyoto Univ Graduate Sch of Medicine, Kyoto, Japan, 4Dept of Endocrinology and Metabolism, Hadassah Hebrew Univ, Jerusalem, Israel, 5Cardiovascular Div, Mass General Hosp, Boston, MA, 6Cardiology and Diabetes, St Michael’s Hosp, Univ of Toronto, Toronto, Canada, 7Cardiovascular Div, Univ of Texas Southwestern Med Cntr, Dallas, TX, 8Obesity and Endocrinology, Univ of Liverpool, Liverpool, United Kingdom, 9Metabolic, AstraZeneca, 431 53 Mölndal, SwedenBackground: Dapagliflozin is a selective sodium-glucose co-transporter-2 inhibitor (SGLT-2i) that reduces blood glucose, weight and blood pressure by promoting glycosuria via inhibiting urinary glucose reabsorption. Previous SGLT-2i trials have demonstrated statistically significant reductions in the combined primary outcome of CV death, MI and stroke (MACE), primarily in patients with known atherosclerotic CVD, and have demonstrated reductions in hospitalization for heart failure (HHF).Methods: DECLARE - TIMI 58 [NCT01730534] is a phase 3b randomized, double-blind, placebo-controlled trial to evaluate the CV safety and efficacy of dapagliflozin in patients with type 2 diabetes mellitus (T2DM) and either CVD or multiple risk factors (MRF) for CVD. Patients were randomized 1:1 to dapagliflozin 10 mg or matching placebo. The primary safety outcome is MACE. The dual primary efficacy outcomes are MACE and the composite of HHF or CV death. This event-driven trial was planned to randomize approximately 17,000 subjects and continue until at least 1390 adjudicated MACE events occurred. This event number provides >99% power for the safety outcome to reject the hypothesis that the upper bound of the confidence interval is >=1.3. There will also be approximately 80% power to detect a 15% relative risk reduction in MACE and 80% power for a 20% reduction in the composite of HHF or CV death, each at two-sided alpha levels of 0.0231. If one of the efficacy endpoints is significant, the alpha will be recycled, allowing testing of the other endpoint at a two-sided alpha of 0.0462, providing at least 85% and 87% power, respectively.Results: DECLARE - TIMI 58 randomized 17,160 patients (6974 w/ CVD and 10,186 w/ MRF). The trial has met its planned number of endpoints and database lock is anticipated in September, 2018. At the AHA we plan to present the primary efficacy and safety results.Conclusion: DECLARE - TIMI 58 is testing the hypotheses that dapagliflozin is safe and will reduce the occurrence of important CV events. DECLARE - TIMI 58 is the largest trial with an SGLT-2i to address these questions in a broad population of patients with T2DM and includes participants both with established CVD and those without CVD, but with multiple CV risk factors.Download figureDownload PowerPointAuthor Disclosures: S.D. Wiviott: Employment; Significant; Spouse is employee of Merck. Research Grant; Significant; AstraZeneca, Bristol Myers Squibb, Eisai, Merck, Eli Lilly, Daiichi Sankyo, Sanofi-Aventis, Amgen, Janssen, Arena. Consultant/Advisory Board; Modest; AstraZeneca, Bristol Myers Squibb, Eisai, Merck, Aegerion, Angelmed, Xoma, ICON Clinical, Boston Clinical Research Institute, Eli Lilly, Daiichi Sankyo, Boehringer-Ingelheim, Amgen, Allergan, Janssen, St Jude Medical, Lexicon. Other; Modest; Merck Research Laboratory. I. Raz: Speakers Bureau; Modest; AstraZeneca/BristolMyers Squibb, Boehringer Ingelheim, Eli Lilly and Company, Johnson & Johnson, Merck Sharp and Dhome Limited, Novartis Pharma AG, Novo Nordisk, Inc, Sanofi, Teva. Ownership Interest; Significant; Stock/Shareholder Glucome Ltd, Stock/Shareholder Insuline Medical, Stock/Shareholder Orgenesis, Stock/Shareholder DarioHealth, Stock/Shareholder CamerEyes. Consultant/Advisory Board; Modest; AstraZeneca, Boehringer Ingelheim, Concenter BioPharma/Silkim Ltd, Eli Lilly and Company, Merck Sharp& Dhome, Novo Nordisk, Inc, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Ltd, Panaxia, AstraZeneca/Bristol Myers Squibb, Diabetes medical Center, FuturRx, Ltd, Insuline Medical, Medical EarlySign Ltd, CamerEyes, Exscopia, Dermal Biomics Inc. M.P. Bonaca: Research Grant; Significant; AstraZeneca, MedImmune, Merck. Consultant/Advisory Board; Modest; AstraZeneca, Aralez, Merck, Bayer. O. Mosenzon: Research Grant; Significant; AstraZeneca, Bristol Myers Squibb, Novo Nordisk. Speakers Bureau; Modest; AstraZeneca, Bristol Myers Squibb, Novo Nordisk, Eli Lilly, Sanofi, Novartis, Merck Sharp and Dhome, Boehringer Ingelheim. Consultant/Advisory Board; Modest; Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dhome, Boehringer ingelheim, Janssen, Novartis, AstraZeneca. E.T. Kato: Honoraria; Modest; Daiichi Sankyo, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Mitsubishi Tanabe Pharma. A. Cahn: Research Grant; Significant; AstraZeneca. Speakers Bureau; Modest; AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dhome, Boehringer Ingelheim. Ownership Interest; Significant; Stock/shareholder Glucome Ltd. Consultant/Advisory Board; Modest; Novo Nordisk, Eli Lilly, Sanofi, Boehringer ingelheim, AstraZeneca. M.G. Silverman: None. T.A. Zelniker: Research Grant; Significant; Funded by Deutsche Forschungsgemeinschaft (ZE 1109/1-1). D.L. Bhatt: Research Grant; Significant; Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company. Honoraria; Modest; American College of Cardiology, Baim Institute for clinical ResearchBelvoir Publications, Belvoir Publications, Duke Clinical Research Institute, HMP Global, Journal ofthe American College of Cardiology, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD. Consultant/Advisory Board; Modest; Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences. Other; Modest; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft, Chair: American Heart AssociationQuality Oversight Committee, Data Monitoring Committees: Baim Institute for Clinical Research, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute, NCDR-ACTION Registry Steering Committee Chair, VA CART Research and Publications Committee chair, Royalties: Elsevier, Site Co-Investigator:Biotronik, Boston Scientific, St Jude Medical, Svelte, Trustee: American College of Cardiology, Unfunded research: FlowCo, Merck, PLx Pharma, Takeda. L.A. Leiter: Research Grant; Significant; AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novo Nordisk, Sanofi, Servier. Consultant/Advisory Board; Modest; AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novo Nordisk, Sanofi, Servier. D.K. McGuire: Honoraria; Modest; AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline, Esperion. Consultant/Advisory Board; Modest; AstraZeneca, Sanofi Aventis, Lilly (US), Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk. J.P. Wilding: Research Grant; Significant; Takeda, Novo Nordisk, Astra Zeneca. Honoraria; Modest; AstraZeneca, Astellas, Biologix, Boehringer Ingelheim, Janssen, Lilly, Napp, Novo Nordisk, Mundipharma, Orexigen, Sanofi. Consultant/Advisory Board; Modest; AstraZeneca, Boehringer Ingelheim, Janssen, Napp, Lilly, Orexigen, Wilmington Healthcare. I.A. Gause-Nilsson: Employment; Significant; Employee of AstraZeneca. Ownership Interest; Significant; Shareholder of AstraZeneca. A. Langkilde: Employment; Signif
Referência(s)