Adjudication of cardiovascular events in patients with chronic obstructive pulmonary disease: SUMMIT trial

Abstract

Background: Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality.

Methods and results: A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%).

Conclusion: A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

Trial registration: ClinicalTrials.gov NCT01313676.

Keywords: Chronic obstructive pulmonary disease mortality; major adverse cardiovascular event adjudication; myocardial infarction; stroke; unstable angina.

Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: R.A.W., P.A., M.A.D., C.R.G. and D.N. are members of the SUMMIT Clinical Endpoint Committee. J.A.A., C.C. and J.C.Y. are members of the SUMMIT Steering Committee. J.A.A., C.C., A.M. and J.C.Y. are employed by the GSK. N.J.C. and M.P.A.J. are employees of Veramed Limited – a contract research organisation that receives funding from the GlaxoSmithKline plc.

Figures

Figure 1.

Adjudication flow chart for (a) adverse events and (b) deaths. The 450 events in (a) refer to the four main components of the pre-defined major adverse cardiovascular events (MACEs): fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, unstable angina (all non-fatal) and transient ischaemic attack (all non-fatal). *Sites entered adverse events using the usual process of describing the event with a ‘verbatim term’. The verbatim term was coded by a central automatic coding procedure to a Medical Dictionary for Regulatory Activities preferred term. If this Medical Dictionary for Regulatory Activities preferred term matched a pre-specified list (see Online Supplementary Appendix B, Figure S1 and Table S1), then this triggered the adjudication process.