Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

SERUM MARKERS OF APOPTOSIS AND CONVENTIONAL RISK FACTORS IN PATIENTS WITH MYOCARDIAL INFARCTION AND HEALTHY RESIDENTS OF ARKHANGELSK REGION: TRENDS, CAUSES, AND CONSEQUENCES

Aim. To improve the risk stratification in young patients with myocardial infarction (MI), using the data on the Fas-mediated apoptosis activity in early and late post-infarction periods.Material and methods. The study included 28 young MI patients (mean age 42,5±5,6 years), 56 elderly MI patients (mean age 63,0±7,8 years), and 66 healthy volunteers. The following parameters were assessed 2 weeks and 7 months (5,7–10,9 months) after MI: conventional risk factors of coronary heart disease (CHD), lipid profile, electrocardiography, echocardiography, and coronary angiography parameters, the levels of apoptosis biomarkers (sFas, sFasL), Cys C, and BNP-32 (immunoenzymatic method).Results. The mean concentration of sFasL varied by gender, reaching 65,09±36,95 pg/ml in women vs. 77,27±27,48 pg/ml in men (р=0,008). The levels of sFasL were higher in young MI patients (80,18±40,54 pg/ ml), compared to healthy volunteers (58,38±25,79 pg/ml; р=0,012), while there was no marked variation in the levels of sFas. Smoking was associated with higher sFas levels. The concentration of sFasL was associated with the levels of blood lipids, fibrinogen, and body mass index. Patients with arterial hypertension had a higher concentration of sFasL (81,80±37,98 pg/ml) than their non-hypertensive peers (55,30±11,96 pg/ml; р=0,029). The sFas/sFasL ratio was linked to the number of metabolic syndrome (MS) components. Among young MI patients, the levels of sFasL, measured 2 weeks after MI, could be used for the prediction of a new coronary event in the next 6–8 months (sensitivity 75% and specificity 90%).Conclusion. The concentration of sFasL was higher in young MI patients than in healthy individuals. The levels of sFasL were inversely associated with the number of MS components and also demonstrated predictive value for the assessment of the 6–8-month risk of recurrent angina in young MI patients

THE INFLUENCE OF GLYCEMIA ON SHORT-TERM PROGNOSIS IN MYOCARDIAL INFARCTION WITHOUT ANAMNESIS OF 2ND TYPE DIABETES

Aim. To estimate the impact of glycemia recorded during myocardial infarction (MI) in-patient care on short-term prognosis of patients without 2nd type diabetes mellitus (2DM).Material and methods. Totally 296 patients were prospectively investigated. According to glucose levels patients were divided into three groups: 1st with ≤4,0 mM/l (7,4%); 2nd with 4,01–7,79 mM/l (69,9%); 3rd with ≥7,8 mM/l (22,6%). The rate of glucose metabolism disorders and complications during in-hospital care were studied.Results. In 2/3 of patients with glycemia ≥7,8 mM/l at hospitalization, later the changes of glucose metabolism were found by glucosetolerance test: prediabetes (36,9%), 2DM (32,3%). In the patients of 3rd group significantly higher was the rate of 3-vessel disease (41,8%) anf MI complications: congestive left-ventricular failure — 52,2% vs 27,3% in the 1st group and 34,1% in the second (p=0,017), cardiogenic shock — 26,9% vs 4,5% and 6,8% (p<0,001), conduction disorders — 27,3% vs 9,1% and 11,7% (p=0,006), in-hospital mortality — 13,8% vs 4,5% and 4,4% (p=0,025). The risk of death in subjects with glycemia ≥7,8 mM/l was 3,48 (95% CI: 1,41–8,60) times higher than in normoglycemic (p=0,007). The glycemia was independently linked with complications of MI during in-hospital period: OR = 1,128; 95% CI: 1,005–1,266 (p=0,042), — as also with the age, severity of myocardial damage and systolic pressure at admittance.Conclusion. There was higher prevalence of MI complications and 3 times higher risk of death in patients without 2DM, but having ≥7,8 mM/l glucose (22,6% of patients) at admittance. The glycemia parameter was an independent predictor for unfavorable prognosis of MI without previous 2DM diagnosis and should be used as part of secondary prevention care

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk