Alexander C Fanaroff1,2, Robert Clare2, Karen S Pieper2, Kenneth W Mahaffey3, Chiara Melloni1,2, Jennifer B Green2,4, John H Alexander1,2, W Schuyler Jones1,2, Robert W Harrison1,2, Rajendra H Mehta2, Thomas J Povsic1,2, Humberto G Moreira5, Sana M Al-Khatib1,2, Matthew T Roe1,2, David F Kong1,2, Robin Mathews1,2, Pierluigi Tricoci6, Rury R Holman7, Lars Wallentin8, Claes Held8, Robert M Califf1,2,9, Karen P Alexander1,2, Renato D Lopes1,2. 1. Division of Cardiology (A.C.F., C.M., J.H.A., W.S.J., R.W.H., T.J.P., S.M.A-K., M.T.R., D.F.K., R.M., R.M.C., K.P.A., R.D.L.), Duke University School of Medicine, Durham, NC. 2. Duke Clinical Research Institute (A.C.F. R.C., K.S.P., C.M., J.B.G., J.H.A., W.S.J., R.W.H., R.H.M., T.J.P., S.M.A-K., M.T.R., D.F.K., R.M., R.M.C., K.P.A., R.D.L.), Duke University School of Medicine, Durham, NC. 3. Stanford Center for Clinical Research, Stanford University School of Medicine, CA (K.W.M.). 4. Division of Endocrinology (J.B.G.), Duke University School of Medicine, Durham, NC. 5. Heart Institute (InCor), University of São Paulo Medical School, Brazil (H.G.M.). 6. CSL Behring, King of Prussia, PA, (P.T.). 7. Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, United Kingdom (R.R.H). 8. Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Institute, Uppsala University, Sweden (L.W., C.H.). 9. Verily Life Sciences, South San Francisco, CA (R.M.C.).
Abstract
BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.
BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.
Entities:
Keywords:
cause of death; clinical trial; death; follow-up studies; quality control
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