| 1. |
- Fanaroff, Alexander C., et al.
(författare)
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Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials : A Pooled Analysis of 9259 Deaths in 9 Trials
- 2019
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 139:7, s. 863-873
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient-and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term followup, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.
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| 2. |
- Lopes, Renato D., et al.
(författare)
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Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer : The Primary Results of the PRONOUNCE Randomized Trial
- 2021
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Ingår i: Circulation. - 1524-4539. ; 144:16, s. 1295-1307
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial. METHODS: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months. RESULTS: Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; P=0.53). CONCLUSIONS: PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.
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| 3. |
- Melloni, Chiara, et al.
(författare)
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Efficacy and Safety of Apixaban Versus Warfarin in Patients with Atrial Fibrillation and a History of Cancer : Insights from the ARISTOTLE Trial.
- 2017
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Ingår i: American Journal of Medicine. - : Elsevier BV. - 0002-9343 .- 1555-7162. ; 130:12, s. 1440-1448.e1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.METHODS: The association between cancer and clinical outcomes was assessed using Cox regression models. At baseline, 1236 patients (6.8%) had a history of cancer; 12.7% had active cancer, and 87.3% had remote cancer.RESULTS: There were no significant associations between history of cancer and stroke/systemic embolism, major bleeding, or death. The effect of apixaban versus warfarin for the prevention of stroke/systemic embolism was consistent among patients with a history of cancer (event/100 patient-years = 1.4 vs 1.2; hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.53-2.26) and no cancer (1.3 vs 1.6; HR, 0.77; 95% CI, 0.64-0.93) (P interaction = .37). The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, myocardial infarction, and death in active cancer (HR, 0.30; 95% CI, 0.11-0.83) versus without cancer (HR, 0.86; 95% CI, 0.78-0.95), but not in remote cancer (HR, 1.46; 95% CI, 1.01-2.10) (interaction P = .0028).CONCLUSIONS: Cancer was not associated with a higher risk of stroke. The superior efficacy and safety of apixaban versus warfarin were consistent in patients with and without cancer. Our positive findings regarding apixaban use in patients with atrial fibrillation and cancer are exploratory and promising, but warrant further evaluation.
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| 4. |
- Melloni, Chiara, et al.
(författare)
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Safety and efficacy of adjusted-dose eptifibatide in patients with acute coronary syndromes and reduced renal function
- 2011
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 162:5, s. 884-892
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Tidskriftsartikel (refereegranskat)abstract
- Background Dose adjustment of renally excreted antithrombotic drugs is recommended for patients with reduced renal function. We examined the influence of dose modification on bleeding and efficacy. Methods Based on initial study drug infusion rate, Early GP IIb/IIIa Inhibition in non-ST-segment elevation acute coronary syndromes (EARLY ACS) patients were categorized into groups: standard dose (2 mu g/kg/min; estimated creatinine clearance [eCrCl] >= 50 ml/min), adjusted dose (1 mu g/kg/min; eCrCl <50 ml/min, per protocol), excess dose (2 mu g/kg/min; eCrCl <50 ml/min). We explored relationships among initial dosing, randomized treatment assignment, and bleeding and ischemic end points (96-h composite of death, myocardial infarction [MI], recurrent ischemia requiring urgent revascularization or thrombotic bailout, and 30-d death or MI). Results Of 8,708 patients with eCrCl and dosing data, 19% had eCrCl <50 ml/min. Of these, 13% received adjusted dose eptifibatide and 6% received an excess dose. Across all dosing groups, no significant reductions were found in ischemic end points between early versus delayed provisional eptifibatide (OR 1.14, 95% CI 0.80-1.65; OR 1.13, 95% CI 0.81-1.56, respectively, for 96-h and 30-d composite end points). Bleeding risk was not significantly increased in the early versus delayed provisional treatment group in either the adjusted (OR 1.50, 95% CI 0.95-2.39) or excess dose group (OR 1.67, 95% CI 0.85-3.39). There were no significant interactions between dose group and treatment strategy on bleeding or efficacy. Conclusion Similar to observations in practice, despite guidelines recommendations and protocol guidance, 34% of EARLY ACS patients with reduced renal function failed to receive an appropriately adjusted study drug infusion. Use of an appropriately adjusted eptifibatide infusion was not associated with expected reductions in bleeding among patients with renal insufficiency.
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| 5. |
- Ungar, Leo, et al.
(författare)
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Stroke Outcomes With Vorapaxar Versus Placebo in Patients With Acute Coronary Syndromes : Insights From the TRACER Trial
- 2018
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Ingår i: Journal of the American Heart Association. - 2047-9980 .- 2047-9980. ; 7:24
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundVorapaxar, a protease‐activated receptor‐1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage.Methods and ResultsTRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow‐up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan‐Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22–6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58–1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71–1.24]).ConclusionsStroke occurred in <2% of patients. Vorapaxar‐assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.
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| 6. |
- Zimerman, Andre, et al.
(författare)
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Pooled analysis of adverse event collection from 4 acute coronary syndrome trials
- 2016
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 174, s. 60-67
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.Methods: Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.Results: In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.Conclusions: Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.
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