darapladib and Stroke

Inflammation plays an important role in origin and progression of atheromatous plaque. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered a biomarker of inflammation and a predictor of vascular events. Lp-PLA2 is an enzyme secreted by leukocytes and associated with circulating lipoproteins and macrophages in atherosclerotic plaques. Lp-PLA2 hydrolizes phospholipids of oxidized low density lipoproteins and generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions, myocardial infarction and ischemic stroke. Recently the first publications appeared about selective inhibitor of phospholipase A2 - darapladib as a novel therapeutic approach for the treatment of patients with coronary artery disease. However, first results need to be confirmed by ongoing large long-term randomized clinical trials.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Benzaldehydes; Biomarkers; Fatty Acids, Nonesterified; Humans; Inflammation; Leukocytes; Lipoproteins; Lysophosphatidylcholines; Myocardial Infarction; Oximes; Plaque, Atherosclerotic; Stroke; Therapies, Investigational

Lipoprotein-associated phospholipase A2 (Lp PLA2) is postulated to occupy a key position in the pathogenic sequence leading to formation of complex atherosclerotic lesions. This study reviews evidence supporting its role as a biomarker of vascular disease and as a possible therapeutic target.. Evidence continues to build supporting the usefulness of Lp PLA2 as a predictor of coronary events in the general population and in those with established coronary heart disease. Elevated Lp PLA2 is also associated with stroke and heart failure. The crystal structure of Lp PLA2 is now available and offers insight into the links between structure, function and atherogenic properties. Recently completed studies on the efficacy of darapladib, a specific Lp PLA2 inhibitor, show beneficial changes in plaque morphology in animal models and in humans.. Lp PLA2 is gaining acceptance as a useful biomarker of chronic inflammation and as a predictor of vascular disease. Early results with darapladib offer promise, but not definitive proof, of a potential role for Lp PLA2 inhibition in coronary heart disease prevention.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Anti-Inflammatory Agents; Benzaldehydes; Biomarkers; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Humans; Inflammation; Oximes; Prognosis; Risk Factors; Stroke; United States

Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease.. Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results.. In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]).. The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.

Topics: Angina, Unstable; Benzaldehydes; Coronary Disease; Endpoint Determination; Heart Failure; Hospitalization; Humans; Ischemic Attack, Transient; Kaplan-Meier Estimate; Myocardial Infarction; Oximes; Percutaneous Coronary Intervention; Phospholipase A2 Inhibitors; Placebos; Stroke

Topics: Aged; Benzaldehydes; Cardiovascular Diseases; Cognition; Cognitive Dysfunction; Coronary Disease; Exercise; Female; Humans; Male; Middle Aged; Oximes; Phospholipase A2 Inhibitors; Risk Factors; Stroke

Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with myocardial fibrosis and renin-angiotensin system upregulation, potentially providing prognostic information distinct from standard cardiovascular (CV) biomarkers.. To evaluate the association of FGF-23 with recurrent CV events in patients after an acute coronary syndrome (ACS).. C-terminal FGF-23 was measured in plasma samples using an established enzyme-linked immunosorbent assay system for 4947 patients within 30 days of ACS (median, 14 days) and with 1 additional CV risk factor in the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial of the lipoprotein-associated phospholipase A2 inhibitor darapladib vs placebo performed from December 1, 2009, to April 24, 2014 (median follow-up, 2.5 years). Analyses were adjusted for clinical risk factors, renal function, and established cardiorenal biomarkers. This secondary analysis was performed from September 25, 2014, to October 1, 2017.. The FGF-23 concentration at baseline.. The primary end point for this post hoc analysis was the composite of CV death or hospitalization for heart failure.. In this study, baseline FGF-23 concentrations were available for 4947 patients (median age, 64.0 years; interquartile range, 59.0-71.0 years; 1276 [25.8%] female). Patients with higher FGF-23 concentrations were older and more likely female, with a greater proportion of hypertension, diabetes, and previous myocardial infarction. After multivariable adjustment for baseline clinical characteristics and established biomarkers (high-sensitivity troponin I, brain-type natriuretic peptide, and high-sensitivity C-reactive protein), FGF-23 concentration in the top quartile was independently associated with an increased risk of CV death or heart failure hospitalization (adjusted hazard ratio [HR], 2.35; 95% CI, 1.82-3.02; P < .001) and its individual components. Elevated FGF-23 concentration was also associated with an increased risk of all-cause mortality (adjusted HR, 2.27; 95% CI, 1.73-2.97; P < .001) and CV death, myocardial infarction, or stroke (adjusted HR, 1.42; 95% CI, 1.17-1.71; P < .001). When analyses were stratified by patient sex, the association between FGF-23 and CV risk, including CV death or heart failure, appeared to be attenuated in women (adjusted HR, 1.11; 95% CI, 0.70-1.76; P = .67) compared with men (HR, 3.11; 95% CI, 2.29-4.22; P < .001; P < .001 for interaction).. In patients stabilized after ACS, elevated FGF-23 concentrations may be associated with recurrent major CV events and all-cause mortality, providing information independent of established clinical risk factors and cardiorenal biomarkers. A potential sex difference in these findings deserves further study.

Topics: Acute Coronary Syndrome; Aged; Benzaldehydes; Biomarkers; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Myocardial Infarction; Oximes; Phospholipase A2 Inhibitors; Recurrence; Stroke; Survival Rate

We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.. Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1-204.2 μmol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes.. Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Benzaldehydes; Biomarkers; Coronary Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Myocardial Infarction; Oximes; Phospholipase A2 Inhibitors; Prospective Studies; Stroke

Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2.. In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization).. During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02).. In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

Topics: Aged; Benzaldehydes; Coronary Artery Disease; Coronary Disease; Double-Blind Method; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Oximes; Phospholipase A2 Inhibitors; Stroke; Treatment Failure

Interleukin-6 (IL-6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL-6 post-ACS.. IL-6 concentration was assessed at baseline in 4939 subjects in SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS. Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS, ACS type, and randomized treatment arm. For every SD increase in IL-6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR] 1.10, 95% confidence interval [CI] 1.01-1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11-1.34). Patients in the highest IL-6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22-2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6-3.29). After further adjustment for biomarkers (high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A. In patients after ACS, IL-6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL-6 as a potential therapeutic target in patients with unstable ischemic heart disease.

Topics: Acute Coronary Syndrome; Aged; Benzaldehydes; Biomarkers; Disease Progression; Disease-Free Survival; Female; Heart Failure; Humans; Inflammation Mediators; Interleukin-6; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Oximes; Phospholipase A2 Inhibitors; Plaque, Atherosclerotic; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Treatment Outcome

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Arterial Occlusive Diseases; Benzaldehydes; China; Coronary Disease; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Oximes; Phospholipase A2 Inhibitors; Stroke