Philip Joseph1, Gholamreza Roshandel2, Peggy Gao1, Prem Pais3, Eva Lonn1, Denis Xavier4, Alvaro Avezum5, Jun Zhu6, Lisheng Liu6, Karen Sliwa7, Habib Gamra8, Shrikant I Bangdiwala1, Koon Teo1, Rafael Diaz9, Antonio Dans10, Patricio Lopez-Jaramillo11, Dorairaj Prabhakaran12, Jose Maria Castellano13, Valentin Fuster14, Anthony Rodgers15, Mark D Huffman16, Jackie Bosch1, Gilles R Dagenais17, Reza Malekzadeh18, Salim Yusuf19. 1. Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada. 2. Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran; Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran. 3. St John's Research Institute, Bangalore, India. 4. St John's Research Institute, Bangalore, India; St John's Medical College, Bangalore, India. 5. International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil. 6. Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 7. Cape Heart Institute, Department of Medicine and Cardiology, University of Cape Town, Cape Town, South Africa. 8. Fattouma Bourguiba University Hospital and University of Monastir, Monastir, Tunisia. 9. Estudios Clínicos Latino América, Instituto Cardiovascular de Rosario, Rosario, Argentina. 10. University of the Philippines, Manila, Philippines. 11. Universidad de Santander, Instituto Masira, Facultad de Ciencias de la Salud, Bucaramanga, Colombia. 12. Public Health Foundation of India, Haryana, India. 13. Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain; Centro Integral de Enfermedades Cardiovasculares, Hospital Universitario Monteprincipe, Grupo HM Hospitales, Madrid, Spain. 14. Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA. 15. The George Institute for Global Health, Sydney, NSW, Australia. 16. The George Institute for Global Health, Sydney, NSW, Australia; Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 17. Université Laval, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada. 18. Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. 19. Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, ON, Canada. Electronic address: yusufs@mcmaster.ca.
Abstract
BACKGROUND: In randomised controlled trials, fixed-dose combination treatments (or polypills) have been shown to reduce a composite of cardiovascular disease outcomes in primary prevention. However, whether or not aspirin should be included, effects on specific outcomes, and effects in key subgroups are unknown. METHODS: We did an individual participant data meta-analysis of large randomised controlled trials (each with ≥1000 participants and ≥2 years of follow-up) of a fixed-dose combination treatment strategy versus control in a primary cardiovascular disease prevention population. We included trials that evaluated a fixed-dose combination strategy of at least two blood pressure lowering agents plus a statin (with or without aspirin), compared with a control strategy (either placebo or usual care). The primary outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularisation. Additional outcomes included individual cardiovascular outcomes and death from any cause. Outcomes were also evaluated in groups stratified by the inclusion of aspirin in the fixed-dose treatment strategy, and effect sizes were estimated in prespecified subgroups based on risk factors. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to compare strategies. FINDINGS: Three large randomised trials were included in the analysis (TIPS-3, HOPE-3, and PolyIran), with a total of 18 162 participants. Mean age was 63·0 years (SD 7·1), and 9038 (49·8%) participants were female. Estimated 10-year cardiovascular disease risk for the population was 17·7% (8·7). During a median follow-up of 5 years, the primary outcome occurred in 276 (3·0%) participants in the fixed-dose combination strategy group compared with 445 (4·9%) in the control group (hazard ratio 0·62, 95% CI 0·53-0·73, p<0·0001). Reductions were also observed for the separate components of the primary outcome: myocardial infarction (0·52, 0·38-0·70), revascularisation (0·54, 0·36-0·80), stroke (0·59, 0·45-0·78), and cardiovascular death (0·65, 0·52-0·81). Significant reductions in the primary outcome and its components were observed in the analyses of fixed-dose combination strategies with and without aspirin, with greater reductions for strategies including aspirin. Treatment effects were similar at different lipid and blood pressure levels, and in the presence or absence of diabetes, smoking, or obesity. Gastrointestinal bleeding was uncommon but slightly more frequent in the fixed-dose combination strategy with aspirin group versus control (19 [0·4%] vs 11 [0·2%], p=0·15). The frequencies of haemorrhagic stroke (10 [0·2%] vs 15 [0·3%]), fatal bleeding (two [<0·1%] vs four [0·1%]), and peptic ulcer disease (32 [0·7%] vs 34 [0·8%]) were low and did not differ significantly between groups. Dizziness was more common with fixed-dose combination treatment (1060 [11·7%] vs 834 [9·2%], p<0·0001). INTERPRETATION: Fixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. These benefits are consistent irrespective of cardiometabolic risk factors. FUNDING: Population Health Research Institute.
BACKGROUND: In randomised controlled trials, fixed-dose combination treatments (or polypills) have been shown to reduce a composite of cardiovascular disease outcomes in primary prevention. However, whether or not aspirin should be included, effects on specific outcomes, and effects in key subgroups are unknown. METHODS: We did an individual participant data meta-analysis of large randomised controlled trials (each with ≥1000 participants and ≥2 years of follow-up) of a fixed-dose combination treatment strategy versus control in a primary cardiovascular disease prevention population. We included trials that evaluated a fixed-dose combination strategy of at least two blood pressure lowering agents plus a statin (with or without aspirin), compared with a control strategy (either placebo or usual care). The primary outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularisation. Additional outcomes included individual cardiovascular outcomes and death from any cause. Outcomes were also evaluated in groups stratified by the inclusion of aspirin in the fixed-dose treatment strategy, and effect sizes were estimated in prespecified subgroups based on risk factors. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to compare strategies. FINDINGS: Three large randomised trials were included in the analysis (TIPS-3, HOPE-3, and PolyIran), with a total of 18 162 participants. Mean age was 63·0 years (SD 7·1), and 9038 (49·8%) participants were female. Estimated 10-year cardiovascular disease risk for the population was 17·7% (8·7). During a median follow-up of 5 years, the primary outcome occurred in 276 (3·0%) participants in the fixed-dose combination strategy group compared with 445 (4·9%) in the control group (hazard ratio 0·62, 95% CI 0·53-0·73, p<0·0001). Reductions were also observed for the separate components of the primary outcome: myocardial infarction (0·52, 0·38-0·70), revascularisation (0·54, 0·36-0·80), stroke (0·59, 0·45-0·78), and cardiovascular death (0·65, 0·52-0·81). Significant reductions in the primary outcome and its components were observed in the analyses of fixed-dose combination strategies with and without aspirin, with greater reductions for strategies including aspirin. Treatment effects were similar at different lipid and blood pressure levels, and in the presence or absence of diabetes, smoking, or obesity. Gastrointestinal bleeding was uncommon but slightly more frequent in the fixed-dose combination strategy with aspirin group versus control (19 [0·4%] vs 11 [0·2%], p=0·15). The frequencies of haemorrhagic stroke (10 [0·2%] vs 15 [0·3%]), fatal bleeding (two [<0·1%] vs four [0·1%]), and peptic ulcer disease (32 [0·7%] vs 34 [0·8%]) were low and did not differ significantly between groups. Dizziness was more common with fixed-dose combination treatment (1060 [11·7%] vs 834 [9·2%], p<0·0001). INTERPRETATION: Fixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. These benefits are consistent irrespective of cardiometabolic risk factors. FUNDING: Population Health Research Institute.
Authors: David Flood; Pascal Geldsetzer; Kokou Agoudavi; Krishna K Aryal; Luisa Campos Caldeira Brant; Garry Brian; Maria Dorobantu; Farshad Farzadfar; Oana Gheorghe-Fronea; Mongal Singh Gurung; David Guwatudde; Corine Houehanou; Jutta M Adelin Jorgensen; Dimple Kondal; Demetre Labadarios; Maja E Marcus; Mary Mayige; Mana Moghimi; Bolormaa Norov; Gastón Perman; Sarah Quesnel-Crooks; Mohammad-Mahdi Rashidi; Sahar Saeedi Moghaddam; Jacqueline A Seiglie; Silver K Bahendeka; Eric Steinbrook; Michaela Theilmann; Lisa J Ware; Sebastian Vollmer; Rifat Atun; Justine I Davies; Mohammed K Ali; Peter Rohloff; Jennifer Manne-Goehler Journal: Diabetes Care Date: 2022-09-01 Impact factor: 17.152
Authors: Maja E Marcus; Jennifer Manne-Goehler; Michaela Theilmann; Farshad Farzadfar; Sahar Saeedi Moghaddam; Mohammad Keykhaei; Amirali Hajebi; Scott Tschida; Julia M Lemp; Krishna K Aryal; Matthew Dunn; Corine Houehanou; Silver Bahendeka; Peter Rohloff; Rifat Atun; Till W Bärnighausen; Pascal Geldsetzer; Manuel Ramirez-Zea; Vineet Chopra; Michele Heisler; Justine I Davies; Mark D Huffman; Sebastian Vollmer; David Flood Journal: Lancet Glob Health Date: 2022-03 Impact factor: 26.763