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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.

SUBMITTER: Wise RA

PROVIDER: S-EPMC7416329 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Wise Robert A RA Anderson Julie A JA Amarenco Pierre P Cowans Nicholas J NJ Crim Courtney C Denvir Martin A MA Gomez Camilo R CR Jones Matthew Pa MP Morris Andrea A Niewoehner Dennis D Yates Julie C JC

Clinical trials (London, England) 20200522 4

<h4>Background</h4>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 a ...[more]

PMID: 32441114

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Project description:Background The association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. Methods and Results This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time-dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time-to-first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations. CVAESI risk was compared between the period before and during/after exacerbation. CVAESI risk increased significantly during a moderate (hazard ratio [HR], 2.63 [95% CI, 2.08-3.32]) or severe (HR, 21.84 [95% CI, 17.71-26.93]) exacerbation and remained elevated for 30 days following an exacerbation (moderate: HR, 1.63 [95% CI, 1.28-2.08]; severe: HR, 1.75 [95% CI, 0.99-3.11; nonsignificant]) and decreased over time, returning to baseline by 90 days. Risk of CVAESI resulting in hospitalization or death also increased during an exacerbation (moderate: HR, 2.46 [95% CI, 1.53-3.97]; severe: HR, 41.29 [95% CI, 30.43-56.03]) and decreased in a similar time-dependent pattern. Results were consistent regardless of exacerbation history, cardiovascular risk at screening, or study treatment. Conclusions Overall risk of cardiovascular events was higher during and in the 30 days following chronic obstructive pulmonary disease exacerbations, even among those with low cardiovascular risk, highlighting the need for exacerbation prevention and vigilance for cardiovascular events following exacerbations. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02164513; Unique identifier: NCT02164513.

Project description:Cardiovascular diseases (CVDs) are the most common comorbidities in the chronic obstructive pulmonary disease (COPD), which increase the risk of hospitalization, length of stay, and death in COPD patients. This study aimed to identify the predictors for CVDs in COPD patients and construct a prediction model based on these predictors. In total, 1022 COPD patients in National Health and Nutrition Examination Surveys (NHANES) were involved in the cross-sectional study. All subjects were randomly divided into the training set (n = 709) and testing set (n = 313). The differences before and after the manipulation of the missing data were compared via sensitivity analysis. Univariate and multivariable analyses were employed to screen the predictors of CVDs in COPD patients. The performance of the prediction model was evaluated via the area under the curve (AUC), accuracy, sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and calibration. Subgroup analysis was performed in patients using different COPD diagnosis methods and patients smoking or not smoking in the testing set. We found that male, older age, a smoking history, overweight, a history of blood transfusion, a history of heart disease in close relatives, higher levels of white blood cell (WBC), and monocyte (MONO) were associated with the increased risk of CVDs in COPD patients. Higher levels of platelets (PLT) and lymphocyte (LYM) were associated with reduced risk of CVDs in COPD patients. A prediction model for the risk of CVDs in COPD patients was established based on predictors including gender, age, a smoking history, BMI, a history of blood transfusion, a history of heart disease in close relatives, WBC, MONO, PLT, and LYM. The AUC value of the prediction model was 0.75 (95% CI: 0.71-0.79) in the training set and 0.79 (95%CI: 0.73-0.85) in the testing set. The prediction model established showed good predictive performance in predicting CVDs in COPD patients.

Project description:ImportanceThere is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD).ObjectiveTo determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors.Design, setting, and participantsMulticenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017.InterventionsPatients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years.Main outcomes and measuresThe primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization.ResultsAmong 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]).Conclusions and relevanceAmong patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year.Trial registrationClinicalTrials.gov Identifier: NCT01966107.

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

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

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