Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials

Ferreira‐González, Ignacio; Permanyer-Miralda, Gaiet; Domingo‐Salvany, Antònia; Busse, Jason W.; Heels‐Ansdell, Diane; Montori, Víctor M.; Akl, Elie A.; Bryant, Dianne; Alonso‐Coello, Pablo; Alonso, Jordi; Worster, Andrew; Upadhye, Suneel; Jaeschke, Roman; Schünemann, Holger J.; Pacheco‐Huergo, Valeria; Wu, Ping; Mills, Edward J.; Guyatt, Gordon

doi:10.1136/bmj.39136.682083.ae

Cited by 371 publications

(318 citation statements)

References 13 publications

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“…Given the lack of proven clinical impact of UA and revascularization rehospitalizations, prior studies have raised concerns regarding the use of rehospitalizations both as a quality metric and as an outcome within composite end points for clinical trials 3, 4. Part of this concern stems from the knowledge that these events are, in part, determined by the actions of clinicians and patients rather than by the disease process alone and may introduce substantial bias when used as an outcome in clinical trials 13.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, outcomes such as death or myocardial infarctions, which are objective and quantifiable, are not subject to these potential biases. Further challenging the importance of these events, a recent study that asked patients and trialists to rank the importance of the components of composite end points used in cardiovascular clinical trials, rehospitalizations and revascularizations were ranked as least important by both patients and trialists 3, 5. Our study confirms that these events are likely not as clinically relevant as events such as myocardial infarctions and strokes, given that we did not find UA and revascularization events to be associated with an increased risk of mortality.…”

Section: Discussionmentioning

confidence: 99%

“…Given that rehospitalizations for unstable angina (UA) and coronary revascularization are often included as parts of composite end points in clinical trials, better defining their clinical importance in terms of mortality and recurrent events is important 3, 4. Underscoring the heterogeneity of clinical significance for different components of composite clinical end points, a recent study asking clinical trialists and patients to rank individual components of composite end points in terms of their perceived importance found that revascularizations and rehospitalizations were considered less important than the other end points, such as mortality, stroke, and myocardial infarction 3, 5. As such, a better understanding of the clinical importance of rehospitalizations for UA and revascularization could inform the design of composite end points and support the interpretation of studies using these events as part of their primary outcome.…”

Section: Introductionmentioning

confidence: 99%

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Clinical Relevance of Rehospitalizations for Unstable Angina and Unplanned Revascularization Following Acute Myocardial Infarction

Shore

Smolderen

Spertus

et al. 2016

JAHA

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BackgroundRehospitalizations following acute myocardial infarction for unplanned coronary revascularization and unstable angina (UA) are often included as parts of composite end points in clinical trials. Although clearly costly, the clinical relevance of these individual components has not been described.Methods and ResultsPatients enrolled in a prospective, 24‐center, US acute myocardial infarction registry were followed for 1 year after an acute myocardial infarction for rehospitalizations, that were independently adjudicated by experienced cardiologists. Patients who did and did not experience UA or revascularization rehospitalization were propensity matched using greedy matching. Among 3283 patients with acute myocardial infarction who were included, mean age was 59 years, 33% were female, and 70% were white. Rehospitalization rates for UA and unplanned revascularization at 1 year were 5.0% and 4.1%, respectively. After propensity matching, we included 2433 patients in the UA rehospitalization group and 2410 in the unplanned revascularization group. Using weighted proportional hazards Cox regression, there was no significant association between a rehospitalization for UA and 5‐year all‐cause mortality (9.6% versus 13.8%; adjusted hazard ratio 0.87, 95% CI 0.60–1.16). Patients rehospitalized for unplanned revascularization had a lower 5‐year mortality risk (7.0% versus 15.1%; hazard ratio 0.68, 95% CI 0.50–0.92) compared with those without such rehospitalizations. Nevertheless, patients with UA and unplanned revascularization had a substantially greater hazard of subsequent rehospitalizations compared with patients without such events (UA: hazard ratio 4.36, 95% CI 3.48–5.47; revascularization: hazard ratio 4.38, 95% CI 3.53–5.44).ConclusionsRehospitalizations for UA and unplanned revascularization in the year after an acute myocardial infarction are associated with higher risks of subsequent rehospitalizations but not with mortality.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical Relevance of Rehospitalizations for Unstable Angina and Unplanned Revascularization Following Acute Myocardial Infarction

Shore

Smolderen

Spertus

et al. 2016

JAHA

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“…Composite end points have been widely used in contemporary clinical trials for acquiring sufficient statistical power to detect the difference in outcomes between groups 1, 2. In the field of ischemic heart disease, many trials examine the impact of therapy on combined clinical outcomes, including cardiovascular death, myocardial infarction (MI), stroke, unstable angina (UA) admissions, and revascularization procedures 3, 4, 5, 6, 7.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Impact of Subsequent Acute Coronary Syndrome and Unplanned Revascularization on Long‐Term Mortality After an Index Percutaneous Coronary Intervention: A Report From a Japanese Multicenter Registry

Inohara

Kohsaka

Matsubara

et al. 2017

JAHA

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BackgroundWhereas composite end points are often used in clinical trials of percutaneous coronary interventions (PCI), the impact of individual components on subsequent survival is incompletely defined. We evaluated the association of subsequent acute coronary syndromes (ACS) and unplanned coronary revascularization post‐PCI with long‐term survival.Methods and ResultsFrom 2009 to 2011, the KiCS‐PCI (Keio interhospital Cardiovascular Studies) consecutively enrolled patients undergoing PCI in 14 Japanese teaching hospitals. We identified patients who experienced ACS or unplanned coronary revascularization following their index PCI and compared subsequent survival during the 2‐year follow‐up period using propensity‐matched cohorts of patients who did and did not experience these events. Cox proportional hazard models were used to assess 2‐year all‐cause mortality. Because unstable angina is less severe than acute myocardial infarction, we also generated a separate propensity‐matched cohort for UA post‐PCI. Among 3348 PCI patients (mean age, 67.5±10.7 years; 79.7% male), 214 (6.4%) experienced a subsequent ACS (168 events [78.5%] were unstable angina), and 198 (5.9%) underwent unplanned revascularization. In the propensity‐matched cohorts, patients with a subsequent ACS admission had an increased risk of mortality as compared with those without (hazard ratio, 4.73; 95% confidence interval=1.35–16.6; P=0.015), whereas those with an unplanned revascularization did not have significantly higher risk (hazard ratio, 2.97; 95% confidence interval=0.57–14.3; P=0.19). Among unstable angina events, no association with mortality was observed (hazard ratio, 1.39; 95% confidence interval=0.48–4.00; P=0.54).ConclusionsIn the KiCS‐PCI registry, the incidence of a subsequent ACS was associated with higher mortality, but this association was less apparent after unplanned coronary revascularization or unstable angina. The prognostic implications of different outcomes in a composite end point should be considered when interpreting the results of clinical trials in PCI.

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“…In particular, experts have suggested that the use of surrogate endpoints, [2][3][4][5][6] and composite endpoints, [7][8][9][10][11] and the use of disease-specific-rather than all-cause-mortality as an endpoint, 12,13 may mislead readers if the limitations of these endpoints are not adequately explained. Similar concerns have also been raised about the reporting of trial results in relative-rather than absolute-numbers, 14,15 Table 1 describes these concerns. A limited number of studies have examined the prevalence of the use of surrogate [3][4][5] and composite endpoints 7,9,16 the use of disease specific mortality as an endpoint 12,17 and the reporting of results in relative numbers 14,18,19 in clinical trials. However, data from these studies are several years old, typically reflect trials involving treatments for only a limited spectrum of diseases, and provide only limited details about factors that may be associated with these endpoints and with relative risk reporting.…”

Section: Introductionmentioning

confidence: 99%

Endpoint Selection and Relative (Versus Absolute) Risk Reporting in Published Medication Trials

Hochman

McCormick

2011

J GEN INTERN MED

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BACKGROUND:The use of surrogate and composite endpoints, disease-specific mortality as an endpoint, and relative (rather than absolute) risk reporting in clinical trials may produce results that are misleading or difficult to interpret. OBJECTIVE: To describe the prevalence of these endpoints and of relative risk reporting in medication trials. DESIGN AND MAIN MEASURES:We analyzed all randomized medication trials published in the six highest impact general medicine journals between June 1, 2008 and September 30, 2010 and determined the percentage using these endpoints and the percentage reporting results in the abstract exclusively in relative terms. KEY RESULTS: We identified 316 medication trials, of which 116 (37%) used a surrogate primary endpoint and 106 (34%) used a composite primary endpoint. Among 118 trials in which the primary endpoint involved mortality, 32 (27%) used disease-specific mortality rather than all-cause mortality. Among 157 trials with positive results, 69 (44%) reported these results in the abstract exclusively in relative terms. Trials using surrogate endpoints and diseasespecific mortality as an endpoint were more likely to be exclusively commercially funded (45% vs. 29%, difference 15% [95% CI 5%-26%], P=0.004, and 39% vs. 16%, difference 22% [95% CI 6%-37%], P=0.007, respectively). Trials using surrogate endpoints were more likely to report positive results (66% vs. 49%, difference 17% [95% CI 5%-28%], P=0.006) while those using mortality endpoints were less likely to be positive (46% vs. 62%, difference −16% [95% CI −27%-−4%], P=0.01). CONCLUSIONS: The use of surrogate and composite endpoints, endpoints involving disease-specific mortality, and relative risk reporting is common. Articles should highlight the limitations of these endpoints and should report results in absolute terms.KEY WORDS: surrogate endpoints; composite endpoints; disease-specific mortality; relative risk reduction.

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Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials

Cited by 371 publications

References 13 publications

Clinical Relevance of Rehospitalizations for Unstable Angina and Unplanned Revascularization Following Acute Myocardial Infarction

Clinical Relevance of Rehospitalizations for Unstable Angina and Unplanned Revascularization Following Acute Myocardial Infarction

Prognostic Impact of Subsequent Acute Coronary Syndrome and Unplanned Revascularization on Long‐Term Mortality After an Index Percutaneous Coronary Intervention: A Report From a Japanese Multicenter Registry

Endpoint Selection and Relative (Versus Absolute) Risk Reporting in Published Medication Trials

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