Wouter Ouwerkerk1,2, Tiew-Hwa K Teng1,3,4, Jasper Tromp1,4,5, Wan Ting Tay1, John G Cleland6, Dirk J van Veldhuisen5, Kenneth Dickstein7,8, Leong L Ng9, Chim C Lang10, Stefan D Anker11, Faiez Zannad12, Chung-Lieh Hung13,14, Jitendra P S Sawhney15, Ajay Naik16, Wataru Shimizu17, Nobuhisa Hagiwara18, Gurpreet Singh Wander19, Inder Anand20, A Mark Richards21,22, Adriaan A Voors5, Carolyn S P Lam1,4,5. 1. National Heart Centre Singapore, Singapore, Singapore. 2. Department of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands. 3. School of Population and Global Health, University of Western Australia, Nedlands, Australia. 4. Duke-National University of Singapore Medical School, Singapore, Singapore. 5. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 6. National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, UK. 7. University of Bergen, Bergen, Norway. 8. Stavanger University Hospital, Stavanger, Norway. 9. Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. 10. School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK. 11. Division of Cardiology and Metabolism-Heart Failure, Cachexia & Sarcopenia; Department of Cardiology (CVK), Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine, Berlin, Germany. 12. Inserm CIC-P 1433, Université de Lorraine, CHRU de Nancy, FCRIN INI-CRCT, Nancy, France. 13. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA. 14. Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan. 15. Sir Gangaram Hospital, New Delhi, India. 16. CIMS Hospital, Ahmedabad, India. 17. Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan. 18. Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. 19. Dayanand Medical College and Hospital, Ludhiana, India. 20. Veterans Affairs Medical Center, Minneapolis, MN, USA. 21. Cardiovascular Research Institute, National University Heart Centre, Singapore, Singapore. 22. University of Otago, Dunedin, New Zealand.
Abstract
BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF. METHODS AND RESULTS: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07). CONCLUSION: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.
BACKGROUND:Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF. METHODS AND RESULTS: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07). CONCLUSION: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB.