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 follow-up, 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.
Subject(s)
Cardiovascular Diseases/mortality , Cause of Death/trends , Clinical Trials as Topic/methods , Endpoint Determination , Metabolic Syndrome/mortality , Research Design , Aged , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/therapy , Comorbidity , Female , Health Status , Humans , Male , Metabolic Syndrome/diagnosis , Metabolic Syndrome/therapy , Middle Aged , Residence Characteristics , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
Previous studies have shown that both sympathetic hyperactivity and enhanced inflammatory responses are associated with poor outcomes in patients with acute coronary syndrome (ACS). Whether there is a correlation between these two characteristics remains unclear. Thirty-four patients with uncomplicated ACS were evaluated; their mean age was 51.7±7.0 years, 79.4% were male, and 94.1% had myocardial infarction (MI). On the fourth day of hospitalization, they underwent muscle sympathetic nerve activity (MSNA) analysis (microneurography), as well as ultrasensitive C-reactive protein (usCRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity measurements. These evaluations were repeated at 1, 3, and 6 months after hospitalization. Both MSNA and inflammatory biomarkers were elevated during the acute phase of ACS and then decreased over time. At hospitalization, the median usCRP level was 17.75 (IQR 8.57; 40.15) mg/l, the median IL-6 level was 6.65 (IQR 4.45; 8.20), the mean Lp-PLA2 activity level was 185.8 ±52.2 nmol/min per ml, and mean MSNA was 64.2±19.3 bursts/100 heart beats. All of these variables decreased significantly over 6 months compared with the in-hospital levels. MSNA was independently associated with the peak level of creatine kinase isoenzyme MB (CKMB) in the acute phase (P=0.027) and with left ventricular ejection fraction (LVEF) at 6 months (P=0.026). Despite the increased levels of inflammatory biomarkers and sympathetic hyperactivity in the initial phase of ACS, no significant correlations between them were observed in any of the analyzed phases. Our data suggest that although both sympathetic hyperactivity and inflammation are concomitantly present during the early phase of ACS, these characteristics manifest via distinct pathological pathways.
Subject(s)
Acute Coronary Syndrome/physiopathology , Biomarkers/blood , Inflammation Mediators/blood , Inflammation/physiopathology , Sympathetic Nervous System/physiopathology , 1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , Acute Coronary Syndrome/blood , Adult , C-Reactive Protein/metabolism , Creatine Kinase, MB Form/blood , Female , Humans , Inflammation/blood , Interleukin-6/blood , Linear Models , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/physiopathologyABSTRACT
BACKGROUND: Gln27Glu (rs1042714) polymorphism of the ß2-adrenergic receptor (ADRB2) has been association with cardiovascular functionality in healthy subjects. However, it is unknown whether the presence of the ADRB2 Gln27Glu polymorphism influences neurovascular responses during exercise in patients with acute coronary syndromes (ACS). We tested the hypothesis that patients with ACS homozygous for the Gln allele would have increased muscle sympathetic nerve activity (MSNA) responses and decreased forearm vascular conductance (FVC) responses during exercise compared with patients carrying the Glu allele (Gln27Glu and Glu27Glu). In addition, exercise training would restore these responses in Gln27Gln patients. METHODS AND RESULTS: Thirty-days after an ischemic event, 61 patients with ACS without ventricular dysfunction were divided into 2 groups: (1) Gln27Gln (n = 35, 53±1years) and (2) Gln27Glu+Glu27Glu (n = 26, 52±2years). MSNA was directly measured using the microneurography technique, blood pressure (BP) was measured with an automatic oscillometric device, and blood flow was measured using venous occlusion plethysmography. MSNA, mean BP, and FVC were evaluated at rest and during a 3-min handgrip exercise. The MSNA (P = 0.02) and mean BP (P = 0.04) responses during exercise were higher in the Gln27Gln patients compared with that in the Gln27Glu+Glu27Glu patients. No differences were found in FVC. Two months of exercise training significantly decreased the MSNA levels at baseline (P = 0.001) and in their response during exercise (P = 0.02) in Gln27Gln patients, but caused no changes in Gln27Glu+Glu27Glu patients. Exercise training increased FVC responses in Gln27Glu+Glu27Glu patients (P = 0.03), but not in Gln27Gln patients. CONCLUSION: The exaggerated MSNA and mean BP responses during exercise suggest an increased cardiovascular risk in patients with ACS and Gln27Gln polymorphism. Exercise training emerges as an important strategy for restoring this reflex control. Gln27Glu polymorphism of ADRB2 influences exercise-induced vascular adaptation in patients with ACS.
