Wouter Ouwerkerk1, Aeilko H Zwinderman2, Leong L Ng3, Biniyam Demissei4, Hans L Hillege4, Faiez Zannad5, Dirk J van Veldhuisen4, Nilesh J Samani3, Piotr Ponikowski6, Marco Metra7, Jozine M Ter Maaten4, Chim C Lang8, Pim van der Harst4, Gerasimos Filippatos9, Kenneth Dickstein10, John G Cleland11, Stefan D Anker12, Adriaan A Voors4. 1. Department of Clinical Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: w.ouwerkerk@amc.uva.nl. 2. Department of Clinical Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 3. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom. 4. Department of Cardiology, University of Groningen, Groningen, the Netherlands. 5. Inserm CIC 1433, Université de Lorraine, CHU de Nancy, Nancy, France. 6. Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland; Cardiology Department, Military Hospital, Wroclaw, Poland. 7. Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 8. School of Medicine Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom. 9. Department of Cardiology, Heart Failure Unit, Athens University Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece. 10. Department of Cardiology, University of Stavanger, Stavanger, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway. 11. National Heart and Lung Institute, Royal Brompton and Harefield Hospitals, Imperial College, London, United Kingdom. 12. Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center, Göttingen, Göttingen, Germany.
Abstract
BACKGROUND: Heart failure guidelines recommend up-titration of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) to doses used in randomized clinical trials, but these recommended doses are often not reached. Up-titration may, however, not be necessary in all patients. OBJECTIVES: This study sought to establish the role of blood biomarkers to determine which patients should or should not be up-titrated. METHODS: Clinical outcomes of 2,516 patients with worsening heart failure from the BIOSTAT-CHF (BIOlogy Study to Tailored Treatment in Chronic Heart Failure) were compared between 3 theoretical treatment scenarios: scenario A, in which all patients are up-titrated to >50% of recommended doses; scenario B, in which patients are up-titrated according to a biomarker-based treatment selection model; and scenario C, in which no patient is up-titrated to >50% of recommended doses. The study conducted multivariable Cox regression using 161 biomarkers and their interaction with treatment, weighted for treatment-indication bias to estimate the expected number of deaths or heart failure hospitalizations at 24 months for all 3 scenarios. RESULTS: Estimated death or hospitalization rates in 1,802 patients with available (bio)markers were 16%, 16%, and 26%, respectively, in the ACE inhibitor/ARB up-titration scenarios A, B, and C. Similar rates for beta-blocker and MRA up-titration scenarios A, B, and C were 23%, 19%, and 24%, and 12%, 11%, and 24%, respectively. If up-titration was successful in all patients, an estimated 9.8, 1.3, and 12.3 events per 100 treated patients could be prevented at 24 months by ACE inhibitor/ARB, beta-blocker, and MRA therapy, respectively. Similar numbers were 9.9, 4.7, and 13.1 if up-titration treatment decision was based on a biomarker-based treatment selection model. CONCLUSIONS: Up-titrating patients with heart failure based on biomarker values might have resulted in fewer deaths or hospitalizations compared with a hypothetical scenario in which all patients were successfully up-titrated.
BACKGROUND:Heart failure guidelines recommend up-titration of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) to doses used in randomized clinical trials, but these recommended doses are often not reached. Up-titration may, however, not be necessary in all patients. OBJECTIVES: This study sought to establish the role of blood biomarkers to determine which patients should or should not be up-titrated. METHODS: Clinical outcomes of 2,516 patients with worsening heart failure from the BIOSTAT-CHF (BIOlogy Study to Tailored Treatment in Chronic Heart Failure) were compared between 3 theoretical treatment scenarios: scenario A, in which all patients are up-titrated to >50% of recommended doses; scenario B, in which patients are up-titrated according to a biomarker-based treatment selection model; and scenario C, in which no patient is up-titrated to >50% of recommended doses. The study conducted multivariable Cox regression using 161 biomarkers and their interaction with treatment, weighted for treatment-indication bias to estimate the expected number of deaths or heart failure hospitalizations at 24 months for all 3 scenarios. RESULTS: Estimated death or hospitalization rates in 1,802 patients with available (bio)markers were 16%, 16%, and 26%, respectively, in the ACE inhibitor/ARB up-titration scenarios A, B, and C. Similar rates for beta-blocker and MRA up-titration scenarios A, B, and C were 23%, 19%, and 24%, and 12%, 11%, and 24%, respectively. If up-titration was successful in all patients, an estimated 9.8, 1.3, and 12.3 events per 100 treated patients could be prevented at 24 months by ACE inhibitor/ARB, beta-blocker, and MRA therapy, respectively. Similar numbers were 9.9, 4.7, and 13.1 if up-titration treatment decision was based on a biomarker-based treatment selection model. CONCLUSIONS: Up-titrating patients with heart failure based on biomarker values might have resulted in fewer deaths or hospitalizations compared with a hypothetical scenario in which all patients were successfully up-titrated.
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