Abstract In the ENSURE-AF study (NCT 02072434), edoxaban was compared to enoxaparin–warfarin in 2199 patients undergoing electrical cardioversion of non-valvular atrial fibrillation (AF). In this ...multicenter PROBE trial, we analyzed patients randomized to enoxaparin–warfarin. We determined time to achieve therapeutic range (TtTR), time in therapeutic range (TiTR), their clinical determinants, relation to SAMe-TT2 R2 score, and impact on primary endpoints (composite of stroke, systemic embolic event SEE, myocardial infarction MI, and cardiovascular death CVD and composite of major + clinically relevant non-major CRNM bleeding). Among 1104 patients randomized to enoxaparin––warfarin, 27% were oral anticoagulant naïve. Mean age was 64.2±11 years and mean CHA2 DS2 -VASc score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching INR 2.0–3.0 was 71%. In 695 patients with INR <2.0 prior to first dose and who reached ≥2.0, 436 had a SAMe-TT2 R2 score ≤2 and 259 a score of >2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (CrCl) P =0.02. TtTR was marginally related to stroke/SEE/MI/CVD ( P =0.06; OR=0.23, 95% CI 0.02–1.17) but not to any bleeding. Independent predictors of TiTR were prior VKA experience ( P <0.01) and low HAS-BLED score ( P =0.02). TiTR was related to any bleeding ( P =0.02; OR=0.39, 95% CI 0.16–0.88), but not stroke/SE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2 R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events.
Summary Background Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, ...however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18–80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov , number NCT01524289. Findings Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% 95% CI −39·5 to −32·5 compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% –1·2 to 8·6, with a difference in percentage change between anacetrapib and placebo of −39·7% (95% CI −45·7 to −33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 2% of 203 vs none 0% of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 6% of 203 vs five 5% of 102). Interpretation In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. Funding Merck & Co, Inc
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