Diagnostic expansion in clinical trials: myocardial infarction, stroke, cancer recurrence, and metastases may not be the hard endpoints you thought they were

Nishikawa, Go; Prasad, Vinay

doi:10.1136/bmj.k3783

Cited by 7 publications

(4 citation statements)

References 21 publications

(22 reference statements)

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“…Postoperative complications may be underdiagnosed and/or under-reported. More importantly, the impact of such complications on patient recovery and survival is not always obvious when simply coded as dichotomous outcomes [54]. Some major complications, especially mortality, are rare, and so the ability to detect poor care or worse outcomes in a clinical trial is dependent on a large sample size.…”

Section: Discussionmentioning

confidence: 99%

Days at Home after Surgery: An Integrated and Efficient Outcome Measure for Clinical Trials and Quality Assurance

et al. 2019

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Background Surgical audit, sometimes including public reporting, is an important foundation of high quality health care. We aimed to assess the validity of a novel outcome metric, days at home up to 30 days after surgery , as a surgical outcome measure in clinical trials and quality assurance. Methods This was a multicentre, registry-based cohort study. We used prospectively collected hospital and national healthcare registry data obtained from patients aged 18 years or older undergoing a broad range of surgeries in Sweden over a 10-year period. The association between days at home up to 30 days after surgery and patient (older age, poorer physical status, comorbidity) and surgical (elective or non-elective, complexity, duration) risk factors, process of care outcomes (re-admissions, discharge destination), clinical outcomes (major complications, 30-day mortality) and death up to 1 year after surgery were measured. Findings From January, 2005, to December, 2014, we obtained demographic and perioperative data on 636,885 patients from 21 Swedish hospitals. Mortality at 30 days and one year was 1.8% and 7.3%, respectively. The median (IQR) days at home up to 30 days after surgery was 27 (23–29), being significantly lower among high-risk patients, those recovering from more complex surgical procedures, and suffering serious postoperative complications (all p < 0.0001). Patients with 8 days or less at home up to 30 days after surgery had a nearly 7-fold higher risk of death up to 1 year postoperatively when compared with those with 29 or 30 days at home (adjusted HR 6.78 [95% CI: 6.44–7.13]). Interpretation Days at home up to 30 days after surgery is a valid, easy to measure patient-centred outcome metric. It is highly sensitive to changes in surgical risk and impact of complications, and has prognostic importance; it is therefore a valuable endpoint for perioperative clinical trials and quality assurance. Funding Swedish National Research Council Medicine and Stockholm County Council ALF-project grant (LE), and the Australian National Health and Medical Research Council (PM).

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Section: Discussionmentioning

confidence: 99%

Days at Home after Surgery: An Integrated and Efficient Outcome Measure for Clinical Trials and Quality Assurance

et al. 2019

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“…Nonfatal MI was subsequently incorporated as an end point in landmark studies of acute coronary syndromes and ultimately in almost all studies of treatment or prevention of coronary artery disease based on the assumption that nonfatal MI was a surrogate for mortality and that preventing nonfatal MI would reduce mortality—a belief that endures . However, the use of nonfatal MI as a surrogate for mortality has been questioned for not meeting accepted standards for surrogacy …”

Section: Introductionmentioning

confidence: 99%

Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality in Treatment or Prevention of Coronary Artery Disease

et al. 2021

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IMPORTANCEAlthough nonfatal myocardial infarction (MI) is associated with an increased risk of mortality, evidence validating nonfatal MI as a surrogate end point for all-cause or cardiovascular (CV) mortality is lacking.OBJECTIVE To examine whether nonfatal MI may be a surrogate for all-cause or CV mortality in patients with or at risk for coronary artery disease.DATA SOURCES In this meta-analysis, PubMed was searched from inception until December 31, 2020, for randomized clinical trials of interventions to treat or prevent coronary artery disease reporting mortality and nonfatal MI published in 3 leading journals.STUDY SELECTION Randomized clinical trials including at least 1000 patients with 24 months of follow-up. DATA EXTRACTION AND SYNTHESISTrial-level correlations between nonfatal MI and all-cause or CV mortality were assessed for surrogacy using the coefficient of determination (R 2 ). The criterion for surrogacy was set at 0.8. Subgroup analyses based on study subject (primary prevention, secondary prevention, mixed primary and secondary prevention, and revascularization), era of trial (before 2000, 2000-2009, and 2010 and after), and follow-up duration (2.0-3.9, 4.0-5.9, and Ն6.0 years) were performed. MAIN OUTCOMES AND MEASURES All-cause or CV mortality and nonfatal MI.RESULTS A total of 144 articles randomizing 1 211 897 patients met the criteria for inclusion. Nonfatal MI did not meet the threshold for surrogacy for all-cause (R 2 = 0.02; 95% CI, 0.00-0.08) or CV (R 2 = 0.11; 95% CI, 0.02-0.27) mortality. Nonfatal MI was not a surrogate for all-cause mortality in primary (R 2 = 0.01; 95% CI, 0.001-0.26), secondary (R 2 = 0.03; 95% CI, 0.00-0.20), mixed primary and secondary prevention (R 2 = 0.001; 95% CI, 0.00-0.08), or revascularization trials (R 2 = 0.21; 95% CI, 0.002-0.50). For trials enrolling patients before 2000 (R 2 = 0.22; 95% CI, 0.08-0.36), between 2000 and 2009 (R 2 = 0.02; 95% CI, 0.00-0.17), and from 2010 and after (R 2 = 0.01; 95% CI, 0.00-0.09), nonfatal MI was not a surrogate for all-cause mortality. Nonfatal MI was not a surrogate for all-cause mortality in randomized clinical trials with 2.0 to 3.9 (R 2 = 0.004; 95% CI, 0.00-0.08), 4.0 to 5.9

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“…This has led some to question whether data based on acute MI diagnostic criteria from just a decade or more ago are applicable to today's diagnosis of acute MI. 15 Appropriate acute MI characterization and classification has profound implications for (1) evaluating the incidence of MI over time, (2) MI risk prediction, (3) targeted use of therapies (eg, precision medicine), and (4) translational research from risk factor discovery to targeted drug development.…”

Section: A Call To Actionmentioning

confidence: 99%

Myocardial Infarction as a Clinical End Point in Research

DeFilippis

Nasir

Blaha³

2019

Circulation Research

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R eflecting the greater understanding of the many diverse causes of myocardial injury, international consensus definition of myocardial injury now includes nonischemic causes of myocardial injury and several etiologically distinct subtypes of myocardial infarction (MI). It is time that all ongoing prospective cohorts and clinical trials systematically differentiate and report on all the etiologically distinct types of myocardial injury. Such reporting will undoubtedly advance the fundamental understanding of the epidemiology of myocardial injury events, including differing risk factor associations, allowing better prediction, prevention, and pharmacotherapies for all identified subtypes of myocardial injury eventsincluding all subtypes of MI.

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Diagnostic expansion in clinical trials: myocardial infarction, stroke, cancer recurrence, and metastases may not be the hard endpoints you thought they were

Abstract: What qualifies as disease in clinical trials may be getting so broad that outcomes are becoming less meaningful and harder to interpret, argue Go Nishikawa and Vinay Prasad

Cited by 7 publications

References 21 publications

Days at Home after Surgery: An Integrated and Efficient Outcome Measure for Clinical Trials and Quality Assurance

Days at Home after Surgery: An Integrated and Efficient Outcome Measure for Clinical Trials and Quality Assurance

Assessment of Nonfatal Myocardial Infarction as a Surrogate for All-Cause and Cardiovascular Mortality in Treatment or Prevention of Coronary Artery Disease

Myocardial Infarction as a Clinical End Point in Research

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