Clinical Endpoint Committee Research Articles

COMPARISON BETWEEN CARDIOVASCULAR TRIAL OUTCOMES AND TREATMENT EFFECTS USING CLINICAL ENDPOINT COMMITTEE ADJUDICATION VERSUS ROUTINE HEALTH DATA: A SYSTEMATIC REVIEW

Registry based randomized controlled trials (RRCTs) allow for outcome ascertainment using routine health data (RHD). While this method offers a potential solution to the rising cost and complexity of traditional RCTs, a rigorous quantitative analysis between sources of RHD has yet to be systematically performed to compare results to traditional outcome ascertainment by clinical endpoint committee (CEC) adjudication. Among cardiovascular (CV) trials, we set out to compare the incidence of CV events and estimated randomized treatment effects ascertained from RHD versus traditional clinical evaluation and adjudication.

NT-proBNP and postoperative heart failure in surgery for aortic stenosis

ObjectivePostoperative heart failure (PHF) after aortic valve replacement (AVR) for aortic stenosis (AS) may initially appear mild and transient but has serious long-term consequences. Methods to assess PHF are not...

COMPARISON BETWEEN CARDIOVASCULAR TRIAL OUTCOMES AND TREATMENT EFFECTS USING CLINICAL ENDPOINT COMMITTEE ADJUDICATION VERSUS ROUTINE HEALTH DATA: A SYSTEMATIC REVIEW

We compared the incidence of cardiovascular (CV) events and estimated randomized treatment effects ascertained from routine health data (RHD) compared with traditional clinical endpoint committee (CEC) adjudication in CV randomized clinical trials (RCTs). We searched MEDLINE (1976 to July 2018) and

Efficacy of High-Sensitivity Troponin T in Identifying Very-Low-Risk Patients With Possible Acute Coronary Syndrome

Physicians need information on how to use the first available high-sensitivity troponin (hsTnT) assay in the United States to identify patients at very low risk for 30-day adverse cardiac events (ACE). To determine whether a negative hsTnT assay at 0 and 3 hours following emergency department presentation could identify patients at less than 1% risk of a 30-day ACE. A prospective, observational study at 15 emergency departments in the United States between 2011 and 2015 that included individuals 21 years and older, presenting to the emergency department with suspected acute coronary syndrome. Of 1690 eligible individuals, 15 (no cardiac troponin T measurement) and 320 (missing a 0-hour or 3-hour sample) were excluded from the analyses. Serial hsTnT measurements (fifth-generation Roche Elecsys hsTnT assay). Serial blood samples from each patient were collected after emergency department presentation (once identified as a potential patient with acute coronary syndrome) and 3 hours, 6 to 9 hours, and 12 to 24 hours later. Adverse cardiac events were defined as myocardial infarction, urgent revascularization, or death. The upper reference level for the hsTnT assay, defined as the 99th percentile, was established as 19 ng/L in a separate healthy US cohort. Patients were considered ruled out for acute myocardial infarction if their hsTnT level at 0 hours and 3 hours was less than the upper reference level. Gold standard diagnoses were determined by a clinical end point committee. Evaluation of assay clinical performance for acute myocardial infarction rule-out was prespecified; the hypothesis regarding 30-day ACE was formulated after data collection. In 1301 healthy volunteers (50.4% women; median age, 48 years), the upper reference level was 19 ng/L. In 1600 patients with suspected acute coronary syndrome (48.4% women; median age, 55 years), a single hsTnTlevel less than 6 ng/L at baseline had a negative predictive value for AMI of 99.4%. In 974 patients (77.1%) with both 0-hour and 3-hour hsTnT levels of 19 ng/L or less, the negative predictive value for 30-day ACE was 99.3% (95% CI, 99.1-99.6). Using sex-specific cutpoints, C statistics for women (0.952) and men (0.962) were similar for acute myocardial infarction. A single hsTnT level less than 6 ng/L was associated with a markedly decreased risk of AMI, while serial levels at 19 ng/L or less identified patients at less than 1% risk of 30-day ACE.

Heart rate and the risk of adverse outcomes in patients with heart failure with preserved ejection fraction.

Background Although high resting heart rates are associated with adverse outcomes in heart failure with reduced ejection, the reports for heart failure with preserved ejection fraction (HFpEF) are conflicting. Design A secondary analysis was conducted in order to examine the relationship between resting heart rate and adverse outcomes in 2705 patients (mean age = 68 ± 10 years; 47% men; 88% white) with HFpEF who were in sinus rhythm from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). Methods Baseline heart rate was obtained from baseline electrocardiogram data. Outcomes were adjudicated by a clinical end-point committee and included the following factors: hospitalisation, hospitalisation for heart failure, death and cardiovascular death. Results Over a median follow-up of 3.4 years (25th-75th percentiles = 2.0-4.9 years), a total of 1157 hospitalisations, 311 hospitalizations for heart failure, 369 deaths and 233 cardiovascular deaths occurred. An increased risk (per 5-beats per minute [bpm] increase) for hospitalisation (hazard ratio [HR] = 1.03, 95% confidence interval [CI] = 1.004-1.060), hospitalisation for heart failure (HR = 1.10, 95% CI = 1.05-1.15), death (HR = 1.10, 95% CI = 1.06-1.16) and cardiovascular death (HR = 1.13, 95% CI = 1.07-1.19) was observed. When the analysis was limited to those who did not report the use of β-blockers, the magnitude of the association for each outcome (per 5-bpm increase) was not materially altered (hospitalisation: HR = 1.03, 95% CI = 0.97-1.09; hospitalisation for heart failure: HR = 1.12, 95% CI = 0.98-1.27; death: HR = 1.16, 95% CI = 1.05-1.28; cardiovascular death: HR = 1.12, 95% CI = 0.99-1.27). Conclusion High resting heart rate is a risk factor for adverse outcomes in patients with HFpEF, and future studies are needed in order to determine whether reducing heart rate improves outcomes in HFpEF.

Peripheral artery disease and risk of adverse outcomes in heart failure with preserved ejection fraction.

Peripheral artery disease (PAD) in heart failure with preserved ejection fraction (HFpEF) is associated with an increased mortality risk, but the risk of individual outcomes associated with PAD in this patient group is less clear. PAD is associated with adverse outcomes in HFpEF, including hospitalization and specific cardiovascular outcomes. We examined the association between PAD and adverse outcomes in 3385 patients with HFpEF (mean age, 69 ± 9.6 years; 49% male; 89% white) from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial (TOPCAT). Baseline PAD was identified by self-reported history and medical-record review. The following outcomes were adjudicated by a clinical endpoint committee: hospitalization, hospitalization for heart failure (HF), myocardial infarction, stroke, death, and cardiovascular death. Over a median follow-up of 3.4 years (interquartile range, 2.0-4.9 years), an increased risk for hospitalization (hazard ratio [HR]: 1.36, 95% confidence interval [CI]: 1.16-1.60), myocardial infarction (HR: 1.69, 95% CI: 1.07-2.67), death (HR: 1.56, 95% CI: 1.22-1.99), and cardiovascular death (HR: 1.53, 95% CI: 1.12-2.10) was observed for those with PAD compared with those without PAD. PAD was not associated with incident stroke. The association between PAD and hospitalization for HF was limited to participants with prior history of HF hospitalization (n = 2449; HR: 1.51, 95% CI: 1.09-2.13). PAD increases the risk for adverse outcomes in HFpEF and is associated with HF rehospitalization. Practitioners should be aware of the inherent risk associated with PAD in HFpEF.

Gender Differences in the Risk of Adverse Outcomes in Patients With Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction

Atrial fibrillation (AF) is associated with an increased risk for adverse events in patients with heart failure with preserved ejection fraction (HFpEF), but it is currently unknown if gender differences in these outcomes exist. To explore this hypothesis, we examined gender differences in the associations of AF with adverse outcomes in 3,385 (mean age 69 ± 9.6years, 49% male, 89% white) patients with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial. Baseline AF cases were identified by self-reported history, medical record review, and baseline electrocardiogram data. Outcomes were adjudicated by a clinical end point committee and included the following: hospitalization, hospitalization for heart failure, stroke, death, and cardiovascular death. Cox regression was used to examine the risk of each outcome associated with AF. Over a median follow-up of 3.4years, AF was associated with an increased risk for hospitalization (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.34 to 1.66), hospitalization for heart failure (HR 1.49, 95% CI 1.23 to 1.81), stroke (HR 2.10, 95% CI 1.43 to 2.09), death (HR 1.22, 95% CI 1.02 to 1.47), and cardiovascular death (HR 1.31, 95% CI 1.04 to 1.65). The association between AF and hospitalization was stronger in women (HR 1.63, 95% CI 1.40 to 1.91) than men (HR 1.37, 95% CI 1.18 to 1.58; p-interaction= 0.032). Although significant interactions were not observed for the other outcomes, we appreciated that the risk estimates were higher for women compared with men. In conclusion, AF increases the risk for adverse cardiovascular outcomes in patients with HFpEF, and the presence of this arrhythmia in women possibly is associated with a greater risk for adverse events than men.

The Lipid-Rich Plaque Study of vulnerable plaques and vulnerable patients: Study design and rationale

It has been hypothesized that the outcome post-PCI could be improved by the detection and subsequent treatment of vulnerable patients and lipid-rich vulnerable coronary plaques (LRP). A near-infrared spectroscopy (NIRS) catheter capable of detecting LRP is being evaluated in The Lipid-Rich Plaque Study. The LRP Study is an international, multicenter, prospective cohort study conducted in patients with suspected coronary artery disease (CAD) who underwent cardiac catheterization with possible ad hoc PCI for an index event. Patient level and plaque level events were detected by follow-up in the subsequent 2 years. Enrollment began in February 2014 and was completed in March 2016; a total of 1,562 patients were enrolled. Adjudication of new coronary event occurrence and de novo culprit lesion location during the 2-year follow-up is performed by an independent clinical end-points committee (CEC) blinded to NIRS-IVUS findings. The first analysis of the results will be performed when at least 20 de novo events have occurred for which follow-up angiographic data and baseline NIRS-IVUS measurements are available. It is expected that results of the study will be announced in 2018. The LRP Study will test the hypotheses that NIRS-IVUS imaging to detect LRP in patients can identify vulnerable patients and vulnerable plaques. Identification of vulnerable patients will assist future studies of novel systemic therapies; identification of localized vulnerable plaques would enhance future studies of possible preventive measures.

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial

Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42-0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0·0197). To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes. Vericel Corporation.

Mortality in Patients with Atrial Fibrillation Randomized to Edoxaban or Warfarin: Insights from the ENGAGE AF-TIMI 48 Trial

BackgroundWhen compared with warfarin, edoxaban significantly reduced cardiovascular mortality in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. We studied the possible reasons leading to this reduction. MethodsENGAGE AF-TIMI 48 was a double-blind, double-dummy comparison of warfarin with 2 regimens of once-daily edoxaban in 21,105 patients with atrial fibrillation followed for 2.8 years (median). Causes of deaths in the intention-to-treat population were classified as cardiovascular (including fatal bleeding and ischemic stroke), malignancy, or noncardiovascular/nonmalignancy by an independent, blinded, clinical endpoint committee. Deaths also were adjudicated as directly due to bleeding (ie, fatal), or bleeding contributing to death, or neither. ResultsThere were 839 total deaths (4.35%/y) in the warfarin arm, compared with 773 (3.99%/y, P = .08) with the higher-dose edoxaban regimen, and 737 (3.80%/y, P = .006) with the lower-dose edoxaban regimen. No significant differences between treatments were observed in (1) any of the 3 most common causes of cardiovascular death (sudden cardiac, heart failure, ischemic stroke), (2) fatal malignancies, (3) other noncardiovascular death. There were 124 fatal bleeds, 65 with warfarin, significantly fewer with the higher-dose (n = 35, P = .003) and lower-dose (n = 24, P < .001) edoxaban regimens. There were 101 bleeding events with warfarin that were either fatal or that contributed to death. There were significantly fewer with the higher-dose (n = 59, P = .001) and lower-dose (n = 54, P < .001) edoxaban regimens. ConclusionsFewer total and cardiovascular deaths were observed with edoxaban as compared with warfarin in the ENGAGE AF-TIMI 48 trial, and this predominantly resulted from the significantly lower rate of major bleeding with edoxaban. Edoxaban reduces mortality both directly (less fatal bleeding) and indirectly (fewer bleeding-related complications and interruptions in therapy after nonfatal bleeding).

Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events.

BackgroundPatients with type 2 diabetes (T2D) have a substantial increased risk for cardiovascular (CV) disease and associated mortality than those without diabetes. Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist that is approved for treatment of T2D.MethodsThis meta-analysis evaluates the CV risk in patients with T2D treated with dulaglutide in 9 randomized safety and efficacy trials. Mean (median) treatment duration was 333 (358) days. Reported CV events were independently adjudicated by a treatment-blinded clinical endpoint committee. The primary measure was a 4-component major adverse CV event (4-component MACE) composite endpoint of death due to CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina. Additional pre-specified endpoints included adjudicated coronary revascularizations, hospitalization for heart failure, and all-cause mortality. A Cox proportional hazards regression model (stratified by study) was used to estimate the hazard ratio (HR) and confidence interval (CI). Tests of treatment effects for the primary endpoint were conducted at a 2-sided alpha level of 0.0198 and a corresponding 98.02 % CI was calculated. Statistical heterogeneity between the strata (studies) was tested by including in the Cox model an interaction term between treatment and strata.ResultsThe analysis included 6010 randomized patients [dulaglutide: 3885; comparator therapy (active or placebo): 2125]; cumulative exposure to dulaglutide or comparator therapy was 3941 and 2223 patient-years, respectively. The demographic and baseline CV disease characteristics were similar across groups. Twenty-six (0.67 %) patients in the dulaglutide group versus 25 (1.18 %) in the comparator group experienced a primary 4-component MACE (HR 0.57; adjusted 98.02 % CI 0.30, 1.10). Results for the 3-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke), 6-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke, hospitalization for unstable angina or heart failure, or coronary revascularizations) and all-cause mortality were consistent with the primary analysis (HR < 1.0 for all).ConclusionsThese results suggest that dulaglutide does not increase the risk of major CV events in T2D patients. The ongoing CV outcomes study, Researching CV Events with a Weekly Incretin in Diabetes (REWIND), will further assess CV safety of dulaglutide.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0355-z) contains supplementary material, which is available to authorized users.

Experience from creating electronic systems with generic endpoint review and adjudication flows

Background An increasing number of Clinical Trial Web Portals now include systems to manage endpoint adjudication. These cover the entire process from the initial identification of potential endpoints, the creation of electronic endpoint packages, and assignment of endpoints to members of the relevant Clinical Endpoint Committee (CEC) to the final adjudication verdict being entered into the system. The number and types of users involved at each stage and the number and size of Endpoint Committees varies across trials, depending on the trial design and requirements of the Sponsor, so the challenge has been to create generic systems that can handle the variations in design.

A prediction model for sudden cardiac death in patients with heart failure and preserved ejection fraction.

Sudden cardiac death (SCD) accounts for ∼ 25% of all deaths in heart failure with preserved ejection fraction (HFpEF). However, strategies to identify HFpEF patients at a higher risk of SCD have not been developed. We studied 4128 patients with HFpEF enrolled in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. All SCDs were adjudicated by a clinical endpoint committee. Cumulative incidences of SCD were estimated counting other deaths as competing risks. Cox regression analysis was used to generate a risk model for SCD. During a mean follow-up of 4.1 years, 231 (5.6%) patients died suddenly and 650 (15.7%) died non-suddenly. A multivariable model in 3480 patients including age, gender, history of diabetes and myocardial infarction, LBBB on ECG, and the natural logarithm of NT-proBNP identified a subgroup of 837 (24%) patients with ≥10% cumulative incidence of SCD over 5 years, accounting for other deaths as competing risk (Harrell's C index 0.75). The 5-year cumulative incidences of SCD in the higher and lower risk groups were 11% and 4%, respectively. In the higher risk group, 32% of deaths were SCD compared with 26% in the entire I-PRESERVE cohort. A multivariable prediction model identified patients with HFpEF who have a ≥10% risk of SCD over 5 years, similar to the risk of SCD in the Sudden Cardiac Death in Heart Failure (SCD-Heft) trial. This model may be useful for selecting patients with HFpEF for SCD prevention trials.

Prognostic Evaluation of Catalytic Iron in Patients With Acute Coronary Syndromes

The potential of iron to generate reactive oxygen species has motivated a long-standing interest in whether excess iron is causally linked to atherosclerotic heart disease. Circulating catalytic iron ("free" iron) is that which is not bound to transferrin or ferritin and is available to generate reactive oxygen species that may have deleterious vascular effects. We hypothesized that increased levels of catalytic iron would be associated with increased cardiovascular events. We investigated the association of catalytic iron with clinical outcomes in 1701 patients with unstable angina, non-ST-segment elevation myocardial infarction (MI), or ST-segment elevation MI who were followed for a median of 10 months. All endpoints were adjudicated by a blinded Clinical End Points Committee. The median catalytic iron level was significantly higher in those who died, 0.45 µmol/L (0.37, 0.57), compared with survivors, 0.37µmol/L (0.31, 0.46; P = 0.016). Catalytic iron was associated with a stepwise increased risk of death, with the highest quartile at an almost 4-fold risk compared with baseline (hazard ratio: 3.94, P = 0.035), which persisted after adjustment for age, diabetes, prior MI, prior congestive heart failure, ST-segment deviation, creatinine clearance, B-type natriuretic peptide, smoking, and Killip class (adjusted hazard ratio: 3.97, P = 0.036). There was no association between catalytic iron and risk of MI, recurrent ischemia, heart failure, or bleeding. Increasing catalytic iron levels were associated with increased all-cause mortality. Although our findings suggest that catalytic iron is not likely to add to available tools as a routine biomarker for risk stratification of recurrent ischemic events, its association with mortality is intriguing and leaves open the question of whether cardiovascular therapeutics aimed at catalytic iron may be useful. The TIMI Study Group has received research grant support from the Muljibhai Patel Society for Research in Nephro-Urology.

Abstract 18754: Prognostic Evaluation of Catalytic Iron in Patients with Acute Coronary Syndromes: Observations from OPUS-TIMI 16

BACKGROUND: The potential of iron to generate reactive oxygen species (ROS) has motivated a long-standing interest in whether excess iron is causally linked to atherosclerotic heart disease. Catalytic iron, or “free” iron, is the circulating store of iron that is not bound to transferrin or ferritin and is available to generate ROS that may have deleterious vascular effects. METHODS: We investigated the association of catalytic iron with clinical outcomes in 1701 patients with UA, NSTEMI, or STEMI who were followed for a median of 10 months. All endpoints were adjudicated by a blinded Clinical Endpoints Committee. RESULTS: The median catalytic iron level was significantly higher in those who died, 0.45μmol/L (0.37, 0.57), compared with survivors 0.37μmol/L (0.31, 0.46), p= 0.016. Catalytic iron was associated with a step-wise increased risk of death, with the highest quartile at an almost 4-fold risk compared to baseline (HR 3.94, p=0.035), which persisted after adjustment for age, diabetes, prior MI, prior CHF, ST deviation, CrCl, BNP, and Killip class (adjHR 3.89, p=0.038, FIGURE). There was no association between catalytic iron and risk of myocardial infarction, recurrent ischemia, heart failure, or bleeding. CONCLUSION: Increasing catalytic iron levels were associated with all-cause mortality. Our findings suggest that catalytic iron is not likely to add to currently available tools as a routine clinical biomarker for risk stratification of ischemic events, but its association with mortality is intriguing and leaves open the question of whether cardiovascular therapeutics aimed at catalytic iron may have utility.

Cause-specific mortality adjudication in the UPLIFT® COPD trial: Findings and recommendations

Mortality is an important endpoint in chronic obstructive pulmonary disease (COPD) trials, although accurately determining cause of death is difficult. In the Understanding the Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, a mortality adjudication committee (MAC) provided systematic, independent and blinded assessment of cause-specific mortality of all 981 reported deaths. Here we describe this process of mortality adjudication and methodological revisions introduced to help standardise the adjudication of two areas recognised to pose particular difficulty; firstly, the classification of fatal COPD exacerbations that occur in the setting of pneumonia and secondly, the categorisation of sudden death. In addition MAC determined cause of death was compared with that reported by site investigators (SIs). MAC-assigned causes of death were: respiratory, 35%; cancer, 25%; cardiovascular, 11%; sudden cardiac death, 4.4%; sudden death, 3.4%; other, 8.8%; unknown, 12.4%. Cancer/cardiac deaths were more common in Global Initiative for Chronic Obstructive Lung Disease stage II, respiratory deaths in stages III and IV. Agreement between MAC and SI regarding cause of death was complete (50.2%), incomplete (18.5%) or none (31.3%). The SI classified deaths as cardiac three-fold more frequently than MAC (incidence rate [IR]/100 patient-years 0.797 vs. 0.257), although IR ratios for cardiac deaths for tiotropium vs. control were similar between SI and MAC. Discrepancies between MAC- and SI-adjudicated causes of death are common, especially increased reporting of cardiac deaths by the SI. Future multicentre COPD trials should plan appropriate infrastructure before study initiation to ensure collection and interpretation of fatal events data.

How the latest evidence from clinical research informs patient care

How the latest evidence from clinical research informs patient care

Cardiogenic shock and heart failure post–percutaneous coronary intervention in ST-elevation myocardial infarction: Observations from “Assessment of Pexelizumab in Acute Myocardial Infarction”

Mortality after ST-elevation myocardial infarction (STEMI) has reduced with reperfusion by primary percutaneous coronary intervention (PCI), which may have impacted on the adverse outcomes of cardiogenic shock (CS) and congestive heart failure (CHF). In the APEX-AMI trial, 5,745 patients with STEMI and planned primary PCI were randomly assigned pexelizumab or matching placebo. Post-randomization CS or CHF was adjudicated by a clinical endpoints committee. Treatment assignment to pexelizumab did not influence either endpoint or mortality rates. Cardiogenic shock developed in 196 patients (3.4%) at a median of 6.0 hours (interquartile range 3.9-28.3) post-randomization, and mortality at 90 days was 54.6%. Congestive heart failure occurred in 254 of patients (4.4%) at a median of 2.6 days (IQR 1.0-16.6), and mortality through 90 days was 10.2%; mortality among those with neither endpoint was 2.1%. Patients with CS or CHF were older, were more often female, and had more hypertension and diabetes, but smoked less compared with non-CS/CHF patients (all P < .05). Independent mortality predictors among those with CS or CHF were hyperlipidemia and a history of angina (interaction P = .011 and .008, respectively); procedural predictors among survivors to PCI were pre-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 0-1 and post-PCI TIMI flow <3 (P = .013 and <.0001, respectively). Survival after CS remains poor despite aggressive reperfusion. Both CS and CHF remain the major causes of death among STEMI patients undergoing primary PCI. Future studies should examine treatments that aim to reduce mortality in these highest risk patients.

Clinical Trials: Minimising source data queries to streamline endpoint adjudication in a large multi-national trial

BackgroundThe UK Clinical Trial Regulations and Good Clinical Practice guidelines specify that the study sponsor must ensure clinical trial data are accurately reported, recorded and verified to ensure patient safety and scientific integrity. The methods that are utilised to assess data quality and the results of any reviews undertaken are rarely reported in the literature. We have recently undertaken a quality review of trial data submitted to a Clinical Endpoint Committee for adjudication. The purpose of the review was to identify areas that could be improved for future clinical trials. The results are reported in this paper.MethodsThroughout the course of the study, all data queries were logged. Following study close out, queries were coded and categorised. A descriptive and comparative analysis was conducted to determine the frequency of occurrence for each category by country of origin.ResultsFrom 1595 endpoint packages reviewed, 782 queries were generated. No source data queries were generated for countries with ≤ 25 recruited subjects, but both low recruiting and high recruiting countries had a high number of queries relating to subject identifiers.ConclusionsThe implementation of some simple measures could help improve data quality and lead to significant savings.

Coronary artery ectasia: prevalence, clinical and angiographic characteristics using multislice computed tomography coronary angiography

A Clinical Endpoint Committee (CEC) is a panel of unbiased, third-party experts charged with centrally reviewing and classifying suspected endpoints, ascertaining whether they meet protocol definitions and providing standardized endpoint outcomes for the purposes of statistical analysis. CECs review and adjudicate endpoint-specific data, applying complex medical definitions to determine these outcomes. The use of CECs to adjudicate suspected endpoints has increased considerably over the past 10 years. CEC-adjudicated endpoint outcomes can figure prominently in a number of key clinical trial decision-making processes: power calculations, periodic safety reviews by Data Safety Monitoring Boards (DSMB), sample size reestimation and other interim analyses, next stage progress for adaptive design trials, study completion for event-driven trials and overall results for efficacy and safety analyses. Information reviewed by the CEC for each endpoint is primarily based on source documentation from the patient chart, lab reports, radiology reports, consultation notes, medical imaging data, data from external devices and autopsy reports. It is through review of this kind of descriptive chart documentation that CEC adjudicators are able to independently and critically assess the circumstances surrounding the suspected endpoint, so that they can produce a medically precise adjudicated outcome. Use of online adjudication technology enables implementation of an end-to-end, transparent endpoint workflow, which creates significant cost efficiencies and measurably reduces cycle times by offering a collaborative workspace for all relevant stakeholders to contribute to the endpoint process, by partially automating the process steps with a flexible electronic workflow and by integrating all components of the endpoint management and adjudication work flows into a single, seamless system, which is imbedded within an EDC platform.