Stabilization Of Atherosclerotic Plaque By Initiation Of Darapladib Therapy Research Articles

Serum Neurofilament Light Chain in Patients With Atrial Fibrillation.

Background Atrial fibrillation (AF) is associated with stroke and MRI features of cerebral tissue damage but its impact on levels of serum neurofilament light chain (sNFL), an established biochemical marker of neuroaxonal damage, is unknown. Methods and Results In this observational study, sNFL was analyzed in 280 patients with AF and 280 controls without AF matched for age, sex, and diabetes status within the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial. None of the patients had a history of previous stroke or transient ischemic attack. Patients with a diagnosis of AF were divided into two groups based on if they were in AF rhythm at the time of blood sampling (AF ECG+, n=74), or not (AF ECG-, n=206). Multiple linear regression analysis was performed to adjust for clinical risk factors. In patients with AF, the levels of sNFL were 15% (AF ECG+) and 10% (AF ECG-) higher than in the control group after adjustment for clinical risk factors, P=0.047 and 0.04, respectively. There was no association between anticoagulation treatment and sNFL levels. Conclusions sNFL was elevated in patients with AF compared with matched controls without AF. Ongoing AF rhythm was associated with even higher levels of sNFL than in patients with a diagnosis of AF but currently not in AF rhythm. Anticoagulation treatment did not affect sNFL levels. Trial Registration ClinicalTrials.gov NCT00799903.

Body Mass Index and Association With Cardiovascular Outcomes in Patients With Stable Coronary Heart Disease - A STABILITY Substudy.

BACKGROUNDThe obesity paradox states that patients with higher body mass index (BMI) and cardiovascular disease may experience better prognosis. However, this is less clear in patients with coronary heart disease.METHODS AND RESULTSThe prospective STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial included 15 828 patients with stable coronary heart disease with 3 to 5 years’ follow‐up on optimal secondary preventive treatment. BMI was measured at baseline (n=15 785). Associations between BMI and cardiovascular outcomes were evaluated by Cox regression analyses with multivariable adjustments. Mean age was 64±9 years and 19% women. Most risk markers (diabetes, hypertension, inflammatory biomarkers, triglycerides) showed a graded association with higher BMI. The frequency of smoking, levels of high‐density lipoprotein, growth differentiation factor 15, and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) were higher at lower BMI. Low BMI (<20 kg/m2; n=244 [1.5%]) was associated with doubled risk of total death (hazard ratio [HR], 2.27; 95% CI, 1.60–3.22), cardiovascular death (HR, 2.26; 95% CI, 1.46–3.49), and heart failure (HR, 2.51; 95% CI, 1.35–4.68) compared with BMI of 25 to <30 kg/m2 (n=6752 [42.8%]) as reference. Similarly, high BMI of ≥35 kg/m2 (n=1768 [11.2%]) was associated with increased risk of the same outcomes. A BMI between 20 and <25 kg/m2 was associated with increased risk of cardiovascular death (HR, 1.26; 95% CI, 1.03–1.54) and total death (HR, 1.21; 95% CI, 1.03–1.42).CONCLUSIONSPatients with stable coronary heart disease showed a graded increase in cardiometabolic and inflammatory risk factors with increasing BMI category >25 kg/m2. All‐cause and cardiovascular mortality were lowest at BMI of 25 to 35 kg/m2. Underweight with BMI of <20 kg/m2 and very high BMI of ≥35 kg/m2 were strong risk markers for poor prognosis.REGISTRATIONURL: https://clinicaltrials.gov/; Unique identifier NCT00799903.

Diabetes status modifies the long-term effect of lipoprotein-associated phospholipase A2 on major coronary events

Aims/hypothesisLipoprotein-associated phospholipase A2 (Lp-PLA2) activity has an independent prognostic association with major coronary events (MCE). However, no study has investigated whether type 2 diabetes status modifies the effect of Lp-PLA2 activity or inhibition on the risk of MCE. We investigate the interaction between diabetes status and Lp-PLA2 activity with risk of MCE. Subsequently, we test the resulting hypothesis that diabetes status will play a role in modifying the efficacy of an Lp-PLA2 inhibitor.MethodsA retrospective cohort study design was utilised in two study populations. Discovery analyses were performed in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort based in Scotland, UK. Participants were categorised by type 2 diabetes control status: poorly controlled (HbA1c ≥ 48 mmol/mol or ≥6.5%) and well-controlled (HbA1c < 48 mmol/mol or <6.5%) diabetes (n = 7420). In a secondary analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial of Lp-PLA2 inhibitor (darapladib) efficacy, 15,828 participants were stratified post hoc by type 2 diabetes diagnosis status (diabetes or no diabetes) at time of recruitment. Lp-PLA2 activity was then divided into population-specific quartiles. MCE were determined from linked medical records in GoDARTS and trial records in STABILITY. First, the interaction between diabetes control status and Lp-PLA2 activity on the outcome of MCE was explored in GoDARTS. The effect was replicated in the placebo arm of STABILITY. The effect of Lp-PLA2 on MCE was then examined in models stratified by diabetes status. This helped determine participants at higher risk. Finally, the effect of Lp-PLA2 inhibition was assessed in STABILITY in the higher risk group. Cox proportional hazards models adjusted for confounders were used to assess associations.ResultsIn GoDARTS, a significant interaction between increased Lp-PLA2 activity (continuous and quartile divided) and diabetes control status was observed in the prediction of MCE (p < 0.0001). These effects were replicated in the placebo arm of STABILITY (p < 0.0001). In GoDARTS, stratified analyses showed that, among individuals with poorly controlled diabetes, the hazards of MCE for those with high (Q4) Lp-PLA2 activity was 1.19 compared with individuals with lower (Q1–3) Lp-PLA2 activity (95% CI 1.11, 1.38; p < 0.0001) and 1.35 (95% CI 1.16, 1.57; p < 0.0001) when compared with those with the lowest activity (Q1). Those in the higher risk group were identified as individuals with the highest Lp-PLA2 activity (Q4) and poorly controlled diabetes or diabetes. Based on these observations in untreated populations, we hypothesised that the Lp-PLA2 inhibitor would have more benefit in this higher risk group. In this risk group, Lp-PLA2 inhibitor use was associated with a 33% reduction in MCE compared with placebo (HR 0.67 [95% CI 0.50, 0.90]; p = 0.008). In contrast, Lp-PLA2 inhibitor showed no efficacy in individuals with low activity, regardless of diabetes status, or among those with no baseline diabetes and high Lp-PLA2 activity.Conclusions/interpretationThese results support the hypothesis that diabetes status modifies the association between Lp-PLA2 activity and MCE. These results suggest that cardiovascular morbidity and mortality associated with Lp-PLA2 activity is especially important in patients with type 2 diabetes, particularly those with worse glycaemic control. Further investigation of the effects of Lp-PLA2 inhibition in diabetes appears warranted.Data availabilitySTABILITY trial data are available from clinicaltrials.gov repository through the GlaxoSmithKline clinical study register https://clinicaltrials.gov/ct2/show/NCT00799903. GoDARTS datasets generated during and/or analysed during the current study are available following request to the GoDARTS Access Managements Group https://godarts.org/scientific-community/.Graphical abstract

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.

Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. ClinicalTrials.gov NCT00799903.

Risk markers of incident atrial fibrillation in patients with coronary heart disease

In patients with coronary heart disease (CHD), atrial fibrillation (AF) is associated with increased morbidity and mortality. We investigated the associations between clinical risk factors and biomarkers with incident AF in patients with CHD. Around 13,153 patients with optimally treated CHD included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial with plasma samples obtained at randomization. Mean follow-up time was 3.5 years. The association between clinical risk factors and biomarkers with incident AF was estimated with Cox-regression models. Validation was performed in 1,894 patients with non-ST-elevation acute coronary syndrome included in the FRISC-II trial. The median (min-max) age was 64 years (range 26-92) and 2,514 (19.1%) were women. A total of 541 patients, annual incidence rate of 1.2%, developed AF during follow-up. In multivariable models, older age, higher levels of NT-proBNP, higher body mass index (BMI), male sex, geographic regions, low physical activity, and heart failure were independently associated with increased risk of incident AF with hazard ratios ranging from 1.04 to 1.79 (P ≤ .05). NT-proBNP improved the C-index from 0.70 to 0.71. In the validation cohort, age, BMI, and NT-proBNP were associated with increased risk of incident AF with similar hazard ratios. In patients with optimally treated CHD, the incidence of new AF was 1.2% per year. Age, NT-proBNP as a marker of impaired cardiac function, and BMI were the strongest factors, independently and consistently associated with incident AF. Male sex and low physical activity may also contribute to the risk of AF in patients with CHD.

Cardiovascular and Lifestyle Risk Factors and Cognitive Function in Patients With Stable Coronary Heart Disease.

BackgroundVascular risk factors have been associated with differences in cognitive performance in epidemiological studies, but evidence in patients with coronary heart disease is more limited.Methods and ResultsThe Montreal Cognitive Assessment score obtained 3.2±0.37 years after randomization to darapladib, a reversible inhibitor of lipoprotein phospholipase A2 or placebo was evaluated for 10 634 patients with coronary heart disease from 38 countries in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial. The Montreal Cognitive Assessment scores for darapladib and placebo groups were similar (mean±SD, 25.3±3.84 versus 25.4±3.73, respectively; P=0.27) and the adjusted odds ratio (OR) for mild cognitive impairment (Montreal Cognitive Assessment score <26) was 1.00 (95% CI, 0.93–1.09). Mild cognitive impairment was more likely with increasing age (OR, 1.33 [1.27–1.41], +5 years after 65). For other baseline clinical characteristics, the strongest independent predictors of cognitive impairment were education (≤8 years versus college/university, OR, 2.95 [2.60–3.35]; >8 years/trade school versus college/university, OR, 1.38 [1.25–1.52] and geographic grouping). Cardiovascular risk factors independently associated with cognitive impairment were history of stroke (OR, 1.43 [1.20–1.71]); <2.5 hours of moderate or vigorous intensity exercise/week (OR, 1.19 [1.04–1.37]); high‐density lipoprotein cholesterol <1.16 mmol/L (OR, 1.19 [1.04–1.37]); diabetes mellitus requiring treatment (OR, yes versus no: 1.15 [1.05–1.26]); and history of hypertension (OR, 1.12 [1.02–1.23]).ConclusionsIn patients with stable coronary heart disease, cognitive performance was associated with modifiable cardiovascular risk factors, educational level, and global region, but was not influenced by darapladib.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Lp-PLA2, scavenger receptor class B type I gene (SCARB1) rs10846744 variant, and cardiovascular disease.

BackgroundWe previously reported association of SCARB1 SNP rs10846744 with common carotid IMT (cIMT) and cardiovascular disease (CVD) events. Since rs10846744 has been reported in association with Lp-PLA2 mass and activity, we hypothesized that inflammatory pathways might mediate the association of rs10846744 with atherosclerosis.MethodsWe first examined association of rs10846744 in CVD in multiple large-scale consortium-based genome-wide association studies. We further examined 27 parameters of interest, including Lp-PLA2 mass and activity, inflammatory markers, and plasma phospholipid fatty acids, and fatty acid ratios in participants from the Multi-Ethnic Study of Atherosclerosis (MESA), as potential mediators in the pathway linking rs10846744 with cIMT and incident CVD. Finally, we examined the association of rs10846744 with Lp-PLA2 activity, cardiovascular outcomes, and interaction with the Lp-PLA2 inhibitor, darapladib, in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies.ResultsSCARB1 rs10846744 was associated with coronary artery disease events in CARDIoGRAMplusC4D (odds ratio 1.05; 95% CI [1.02, 1.07]; P = 1.4x10-4). In combined analysis across race/ethnic groups in MESA, rs10846744 was associated with Lp-PLA2 mass (P = 0.04) and activity (P = 0.001), homocysteine (P = 0.03), LDL particle number (P = 0.01), docosahexaenoic acid [DHA] (P = 0.01), docosapentaenoic acid [DPA] (P = 0.04), DPA/ eicosapentaenoic acid [EPA] ratio (P = 0.002), and DHA/EPA ratio (P = 0.008). Lp-PLA2 activity was identified as a mediator of rs10846744 with cIMT in a basic model (P = 8x10-5), but not after adjustment for CVD risk factors. There was no interaction or modifier effect of the Lp-PLA2 inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52.SummarySCARB1 rs10846744 is significantly associated with Lp-PLA2 activity, atherosclerosis, and CVD events, but Lp-PLA2 activity is not a mediator in the association of rs10846744 with cIMT in MESA.

Inflammatory Biomarkers Interleukin-6 and C-Reactive Protein and Outcomes in Stable Coronary Heart Disease: Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial.

BackgroundEvaluation 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.Methods and ResultsOverall, 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; P<0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53–3.04; P<0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14–2.04; P<0.05); all‐cause mortality (HR, 2.11; 95% CI, 1.62–2.76; P<0.0001); and risk of hospitalization for heart failure (HR, 2.28; 95% CI, 1.34–3.89; P<0.001). Cancer death was doubled in the highest IL‐6 quartile group (HR, 2.34; 95% CI, 1.20–4.53; P<0.05). High‐sensitivity C‐reactive protein was associated with both cardiovascular and non‐cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments.Conclusions 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.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Physical Activity and Mortality in Patients With Stable Coronary Heart Disease

BackgroundRecommendations for physical activity in patients with stable coronary heart disease (CHD) are based on modest evidence. ObjectivesThe authors analyzed the association between self-reported exercise and mortality in patients with stable CHD. MethodsA total of 15,486 patients from 39 countries with stable CHD who participated in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) study completed questions at baseline on hours spent each week taking mild, moderate, and vigorous exercise. Associations between the volume of habitual exercise in metabolic equivalents of task hours/week and adverse outcomes during a median follow-up of 3.7 years were evaluated. ResultsA graded decrease in mortality occurred with increased habitual exercise that was steeper at lower compared with higher exercise levels. Doubling exercise volume was associated with lower all-cause mortality (unadjusted hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.79 to 0.85; adjusting for covariates, HR: 0.90; 95% CI: 0.87 to 0.93). These associations were similar for cardiovascular mortality (unadjusted HR: 0.83; 95% CI: 0.80 to 0.87; adjusted HR: 0.92; 95% CI: 0.88 to 0.96), but myocardial infarction and stroke were not associated with exercise volume after adjusting for covariates. The association between decrease in mortality and greater physical activity was stronger in the subgroup of patients at higher risk estimated by the ABC-CHD (Age, Biomarkers, Clinical–Coronary Heart Disease) risk score (p for interaction = 0.0007). ConclusionsIn patients with stable CHD, more physical activity was associated with lower mortality. The largest benefits occurred between sedentary patient groups and between those with the highest mortality risk.

Sex Differences in Clinical Characteristics, Psychosocial Factors, and Outcomes Among Patients With Stable Coronary Heart Disease: Insights from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial.

BackgroundGreater understanding of differences between men and women with coronary heart disease is needed.Methods and ResultsIn this post hoc analysis of the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, we described psychosocial factors, treatments, and outcomes of men versus women with stable coronary heart disease and explored the association of sex with psychosocial characteristics and cardiovascular risk. Cox proportional hazards models were used to assess the relationship between sex and outcomes. Interactions among sex, psychosocial factors, and the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were tested. Of 15 828 patients, 2967 (19%) were women. Among women, 21.2% felt often or always stressed at home (versus 9.8% of men), and 19.2% felt often or always sad or depressed (versus 10.1% of men; all P<0.0001). The median duration of follow‐up was 3.7 years (25th–75th percentiles: 3.5–3.8 years). Use of evidence‐based medications for coronary heart disease at baseline and 24 months was similar between sexes, as were event rates for all outcomes analyzed. In the multivariable model including psychosocial measures, female sex was associated with lower cardiovascular risk. There was a statistically significant interaction (P=0.03) such that the lower risk in women varied by depressive symptom frequency, whereby women who were more depressed had a risk similar to men.ConclusionsFemale sex was independently associated with better long‐term clinical outcomes, although this was modified by frequency of depressive symptoms. This suggests that emotional state may be an important target for improving outcomes in patients with coronary heart disease, specifically in women.Clinical Trial RegistrationSTABILITY ClinicalTrials.gov number (NCT00799903).

Self-Reported Health and Outcomes in Patients With Stable Coronary Heart Disease.

BackgroundThe major determinants and prognostic importance of self‐reported health in patients with stable coronary heart disease are uncertain.Methods and ResultsThe STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial randomized 15 828 patients with stable coronary heart disease to treatment with darapladib or placebo. At baseline, 98% of participants completed a questionnaire that included the question, “Overall, how do you feel your general health is now?” Possible responses were excellent, very good, good, average, and poor. Adjudicated major adverse cardiac events, which included cardiovascular death, myocardial infarction, and stroke, were evaluated by Cox regression during 3.7 years of follow‐up for participants who reported excellent or very good health (n=2304), good health (n=6863), and average or poor health (n=6361), before and after adjusting for 38 covariates. Self‐reported health was most strongly associated with geographic region, depressive symptoms, and low physical activity (P<0.0001 for all). Poor/average compared with very good/excellent self‐reported health was independently associated with major adverse cardiac events (hazard ratio [HR]: 2.30 [95% confidence interval (CI), 1.92–2.76]; adjusted HR: 1.83 [95% CI, 1.51–2.22]), cardiovascular mortality (HR: 4.36 [95% CI, 3.09–6.16]; adjusted HR: 2.15 [95% CI, 1.45–3.19]), and myocardial infarction (HR: 1.87 [95% CI, 1.46–2.39]; adjusted HR: 1.68 [95% CI, 1.25–2.27]; P<0.0002 for all).ConclusionsSelf‐reported health is strongly associated with geographical region, mood, and physical activity. In a global coronary heart disease population, self‐reported health was independently associated with major cardiovascular events and mortality beyond what is measurable by established risk indicators.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00799903.

Abstract 13938: Relationships Between ‘Mediterranean’ and ‘Western’ Dietary Patterns and Biomarkers Associated With Increased Cardiovascular Risk in Patients With Stable Coronary Heart Disease in the Global STABILITY Trial

Introduction: In the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial greater adherence to a Mediterranean dietary pattern (MD) was associated with major cardiovascular (CV) events (MACE) but there was no association between a ‘Western Diet Score’ (WDS) and MACE. The lowest mortality and MACE was in patients with a MD score (MDS) ≥15. Hypothesis: Low adherence to a MD may be associated with higher plasma levels of biomarkers known to predict adverse CV events. Methods: At baseline, 15,482 (97.8%) trial participants completed a lifestyle questionnaire. MDS was calculated for increasing consumption of whole grains, fruits, vegetables, legumes, fish, and alcohol, and for less meat. WDS was calculated for increasing consumption of refined grains, sweets and desserts, sugared drinks, and deep-fried foods. In 15,287 of these participants hs C-reactive protein (hs-CRP), hs troponin T (hs-TnT), N-terminal B type natriuretic peptide (NT-proBNP), interleukin-6 (IL-6), cystatin-C, growth differentiation factor-15 (GDF-15) and lipoprotein-associated phospho-lipase A 2 (Lp-PLA 2 ) were measured from stored plasma samples taken at baseline. The ratios of the geometric mean level of each biomarker by diet group are reported adjusted for age, gender, darapladib treatment, geographic region, markers of disease severity, and CV risk factors including body mass index, diabetes, hypertension, and low and high-density lipoprotein cholesterol. Results: Lower MDS (13-14/ ≥15 and ≤12/ ≥15 respectively) was associated with higher hs-CRP 1.12 (95%CI 1.05; 1.19), 1.18 (1.11; 1.25), cystatin-C 1.01 (1.00; 1.02), 1.03 (1.01; 1.04), GDF-15 1.05 (1.02; 1.07), 1.06 (1.04; 1.09) and LpPLA2 1.02 (1.01; 1.04), 1.04 (1.02; 1.06) after adjusting for all co-variables (p&lt;0.01 for all). IL-6, hs-TnT and NT-proBNP were not independently associated with MDS. WDS was not independently associated with higher plasma levels of any biomarkers. Conclusions: MD may be associated with lower CV risk in part by effects on inflammatory activity and pathways of cellular function independent of plasma lipids. Greater consumption of food in the WDS was not associated with adverse CV events or with biomarkers known to be associated with risk.

STABILITY and SOLID-TIMI 52: Lipoprotein associated phospholipase A2 (Lp-PLA2) as a biomarker or risk factor for cardiovascular diseases.

Lipoprotein associated phospholipase A2 (Lp-PLA2) - an enzyme with several pro-inflammatory properties - has been hypothesized to be involved in the pathogenesis of atherosclerosis and plaque vulnerability. Lp-PLA2 activity has been demonstrated to be an independent predictor of coronary heart disease (CHD) and ischemic stroke. However, it has been recently reported that carriers of loss of function variants in PLA2G7 gene (encoding Lp-PLA2) had no lower CHD risk than non-carriers. The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY), and the Stabilization of Plaque Using Darapladib - Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies are two phase III, randomized, placebo-controlled, clinical trials that were conducted to evaluate the clinical efficacy and safety of the Lp-PLA2 inhibitor (darapladib), against a background of optimal medical therapy, in patients with stable CHD and acute coronary syndrome, respectively. In both studies, darapladib failed to reduce the risk of major coronary events as compared to placebo. In addition, darapladib was associated with significantly higher rates of drug discontinuation, and adverse side effects such as diahrrea and malodorous feces, urine, and skin, as compared to placebo. These data suggest that Lp-PLA2 may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular (CV) diseases. It also challenges the notion that inhibition of Lp-PLA2 is a worthwhile approach in patients with CHD. Alternate therapies that target inflammation are awaited to reduce residual risk in patients with CV diseases.

Abstract 18682: Inflammatory Biomarkers for Prognostication of Outcomes in Stable Coronary Artery Disease - Experiences From the STABILITY Trial

Introduction: Prognostication of outcome in patients with stable coronary artery disease (CAD) is currently based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction and possibly cardiac biomarkers. Hypothesis: We assessed the incremental prognostic value of biomarkers of inflammation in the Stabilization of Atherosclerotic Plaque By Initiation of Darapladib Therapy (STABILITY) trial. Methods: In STABILITY, 15,828 patients with chronic CAD on optimal medical treatment were randomized to treatment with darapladib or placebo. Serum levels of hs-C-reactive protein (CRP) and Interleukin (IL)-6 were measured at randomization in 14,373 and 4733 patients, respectively. Centrally adjudicated outcome events were accumulated during a median of 3.7 years follow-up. The associations between levels of the biomarkers and outcomes were evaluated by multivariable Cox regression. Results: The impact of biomarker levels at baseline in relation to the composite endpoint, MACE (major adverse cardiovascular event), of cardiovascular (CV) death, myocardial infarction (MI) and stroke, and its individual components are presented in the Table. Both hs-CRP and IL-6 provided strong prognostic information in addition to clinical predictors for outcomes of MACE, CV death and MI, but not for stroke. Conclusions: In conclusion, the cardiac biomarkers hs-CRP and IL-6, provided important complementary prognostic information on the risk of CV mortality and MI, but not for stroke in patients with stable CAD on optimal medical treatment.

Secondary prevention and risk factor target achievement in a global, high-risk population with established coronary heart disease: baseline results from the STABILITY study

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.