darapladib and Coronary-Disease

Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Benzaldehydes; Clinical Trials as Topic; Coronary Disease; Female; Humans; Male; Middle Aged; Oximes; Phospholipase A2 Inhibitors; Risk Factors

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Aged; Alleles; Benzaldehydes; Case-Control Studies; Coronary Disease; Female; Gene Expression Regulation; Genotype; Humans; Male; Middle Aged; Molecular Targeted Therapy; Oximes; Phospholipase A2 Inhibitors; Polymorphism, Single Nucleotide; Randomized Controlled Trials as Topic; Reference Values; Reproducibility of Results; Risk Assessment; Treatment Outcome

Over the last 10 to 15 years, animal and human observational studies have identified elevated levels of both proinflammatory secretory phospholipase A2-IIA and lipoprotein-associated phospholipase A2 as potential risk factors for coronary heart disease. However, Mendelian randomization, a genetic tool to test causality of a biomarker, and phase III randomized controlled trials of inhibitors of theses enzymes (varespladib and darapladib) converged to indicate that elevated levels are unlikely to be themselves causal of coronary heart disease and that inhibition had little or no clinical utility. The concordance of findings from Mendelian randomization and clinical trials suggests that for these 2 drugs, and for other novel biomarkers in future, validation of potential therapeutic targets by genetic studies (such as Mendelian randomization) before embarking on costly phase III randomized controlled trials could increase efficiency and offset the high risk of drug development, thereby facilitating discovery of new therapeutics and mitigating against the exuberant costs of drug development.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Animals; Benzaldehydes; Biomarkers; Coronary Disease; Humans; Indoles; Keto Acids; Molecular Targeted Therapy; Oximes; Phospholipase A2 Inhibitors; Phospholipases A2, Secretory; Signal Transduction; Treatment Outcome

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

Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD).. This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD.. In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study.. During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This "ABC-CHD" model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts.. This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903).

Topics: Aged; Benzaldehydes; Biomarkers; Coronary Disease; Female; Follow-Up Studies; Global Health; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Oximes; Peptide Fragments; Phospholipase A2 Inhibitors; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Secondary Prevention; Survival Rate; Troponin T

Evaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population.. Overall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were 2.1 (interquartile range, 1.4-3.2) ng/L and 1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97;. IL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Topics: Aged; Benzaldehydes; C-Reactive Protein; Cause of Death; Coronary Disease; Female; Humans; Inflammation Mediators; Interleukin-6; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Neoplasms; Oximes; Phospholipase A2 Inhibitors; Plaque, Atherosclerotic; Proportional Hazards Models; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

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

There is limited contemporary data on achievement of risk factor goals for secondary prevention of cardiovascular (CV) disease from countries in many regions of the world. This report describes the global and regional prevalence of CV risk factors and use of preventive medications at baseline in participants in the ongoing STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial.. Detailed individual data on CV risk factors were obtained before randomization in 15,828 patients with chronic coronary heart disease (CHD) from 39 countries on five continents. Subjects had a history of myocardial infarction, prior coronary revascularization, or multi-vessel CHD without revascularization and at least one additional CV risk factor. The majority were taking a statin (97%), antiplatelet therapy (96%), beta-blocker (79%), or angiotensin converting enzyme inhibitor/angiotensin receptor blocker (77%). However, a large proportion of patients did not achieve guideline-recommended targets. For instance, in 29% low-density lipoprotein (LDL) cholesterol was >2.5 mmol/l and in 46% blood pressure was ≥140/90 mmHg or ≥130/80 mmHg in those with diabetes or renal impairment. The body mass index was >30 kg/m(2) in 36%, waist circumference ≥102 cm for men or ≥88 cm for women in 54%, and 18% were smoking. Regional differences in risk factor prevalence and target achievement were observed and were more marked for LDL cholesterol and obesity.. The prevalence of modifiable CV risk factors was generally high in the STABILITY population. Although, most patients were receiving evidence-based secondary preventive therapy many subjects from all regions did not reach recommended secondary prevention goals.

Topics: Aged; Benzaldehydes; Biomarkers; Blood Glucose; Blood Pressure; Cardiovascular Agents; Coronary Disease; Double-Blind Method; Female; Guideline Adherence; Humans; Hypolipidemic Agents; Lipids; Male; Middle Aged; Oximes; Phospholipase A2 Inhibitors; Practice Guidelines as Topic; Practice Patterns, Physicians'; Prevalence; Prospective Studies; Risk Factors; Secondary Prevention; Time Factors; Treatment Outcome

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies.. STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo.. The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years.. STABILITY will assess whether direct inhibition of Lp-PLA(2) with darapladib added to the standard of care confers clinical benefit to patients with CHD.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Administration, Oral; Aged; Atherosclerosis; Benzaldehydes; Biomarkers; Blood Pressure Monitoring, Ambulatory; Coronary Disease; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Oximes; Tablets, Enteric-Coated; Treatment Outcome

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture.. This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA(2) inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers.. =0.37). In contrast, Lp-PLA(2) activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5+/-17.9 mm(3); P=0.009), whereas darapladib halted this increase (-0.5+/-13.9 mm(3); P=0.71), resulting in a significant treatment difference of -5.2 mm(3) (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95).. Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA(2) inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA(2) inhibition may represent a novel therapeutic approach.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Anti-Inflammatory Agents; Benzaldehydes; Cardiovascular Agents; Coronary Disease; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Necrosis; Oximes; Treatment Outcome

Topics: Benzaldehydes; Biomarkers; C-Reactive Protein; Coronary Disease; Humans; Inflammation; Interleukin-6; Oximes; Plaque, Atherosclerotic

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

Despite the known benefits of regular exercise, the reasons why many coronary heart disease (CHD) patients engage in little physical activity are not well understood. This study identifies factors associated with low activity levels in individuals with chronic CHD participating in the STABILITY study, a global clinical outcomes trial evaluating the lipoprotein phospholipaseA2 inhibitor darapladib.. Prior to randomization, 15 486 (97.8%) participants from 39 countries completed a lifestyle questionnaire. Total physical activity was estimated from individual subject self-reports of hours spend each week on mild, moderate, and vigorous exercise, corresponding approximately to 2, 4, and 8 METS, respectively. Multivariate logistic regression evaluated clinical and demographic variables for the lowest compared with higher overall exercise levels, and for individuals who decreased rather than maintained or increased activity since diagnosis of CHD. The least active 5280 subjects (34%) reported exercise of ≤ 24 MET.h/week. A total of 7191 subjects (46%) reported less exercise compared with before diagnosis of CHD. The majority of participants were either 'not limited' or 'limited a little' walking 100 m (84%), climbing one flight of stairs (82%), or walking 1 km/1/2; mile (68%), and <10% were limited 'a lot' by dyspnoea or angina. Variables independently associated with both low physical activity and decreasing exercise after diagnosis of CHD included more co-morbid conditions, poorer general health, fewer years of education, race, and country (P < 0.001 for all).. In this international study, low physical activity was only partly explained by cardiovascular symptoms. Potentially modifiable societal and health system factors are important determinants of physical inactivity in patients with chronic CHD.

Topics: Age Factors; Aged, 80 and over; Benzaldehydes; Coronary Disease; Exercise; Female; Health Status; Humans; Male; Multicenter Studies as Topic; Oximes; Phospholipase A2 Inhibitors; Randomized Controlled Trials as Topic; Sedentary Behavior; Sex Factors

Topics: Atherosclerosis; Benzaldehydes; Cardiovascular Diseases; Clinical Trials as Topic; Coronary Disease; Humans; Meta-Analysis as Topic; Oximes; Phospholipase A2 Inhibitors

Topics: Atorvastatin; Benzaldehydes; Cholesterol, LDL; Clinical Trials, Phase II as Topic; Coronary Artery Disease; Coronary Disease; Enzyme Inhibitors; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oximes; Phospholipases A2, Secretory; Pyrroles

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Anti-Inflammatory Agents; Benzaldehydes; Cardiovascular Agents; Coronary Disease; Enzyme Inhibitors; Humans; Oximes