Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Circulating oxidized low-density lipoprotein and common carotid artery intima-media thickness in a random sample of middle-aged men.

Circulating oxidized low-density lipoprotein (oxLDL) has been suggested to play an important role in atherosclerosis development. According to previous observations, oxLDL correlates with clinically manifest coronary and carotid artery disease. We investigated the association between the oxLDL concentration measured directly in plasma and common carotid artery intima-media thickness (IMT) in a population-based, case-control study in middle-aged men from Southern Finland. oxLDL was determined in 214 men by a commercially available sandwich ELISA test (Mercodia). Carotid artery IMT was measured at 12 standardized segments by B-mode ultrasonography (at the near and far wall of the left and right common carotid arteries, bifurcations and internal carotid arteries), and the overall mean maximum IMT (MMaxIMT) was calculated. The MMaxIMT of the carotid arteries was significantly associated with circulating oxLDL (r(s) = 0.16, p = 0.018). In a stepwise multiple regression model with MMaxIMT as dependent variable and systolic blood pressure, smoking, oxLDL, HDL cholesterol and apolipoprotein B as covariates, systolic blood pressure (beta = 0.22, p < 0.001), oxLDL (beta = 0.15, p = 0.022) and smoking (beta = 0.17, p = 0.014) showed an independent association with IMT (R(2) = 0.10, p < 0.001). Our results show that oxLDL measured directly from plasma is independently associated with subclinical carotid artery atherosclerosis in middle-aged men.

Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S.

BACKGROUND: Patients with low HDL cholesterol (HDL-C) and elevated triglyceride had an increased risk for coronary heart disease (CHD) events and received the greatest benefit with fibrate therapy in substudy analyses of the Helsinki Heart Study and the Bezafibrate Infarction Prevention Study. METHODS AND RESULTS: In this post hoc analysis of the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol (LDL-C) and CHD, subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy. Patients in the lowest HDL-C (<1.00 mmol/L [39 mg/dL]) and highest triglyceride (>1.80 mmol/L [159 mg/dL]) quartiles (lipid triad; n=458) had increased proportions of other features of the metabolic syndrome (increased body mass index, hypertension, diabetes), men, prior myocardial infarction, prior revascularization, and beta-blocker use than patients in the highest HDL-C (>1.34 mmol/L [52 mg/dL]) and lowest triglyceride (<1.11 mmol/L [98 mg/dL]) quartiles (isolated LDL-C elevation; n=545). The major coronary event rate was highest in lipid triad patients on placebo (35.9%), and this subgroup had the greatest event reduction (relative risk 0.48, 95% CI 0.33 to 0.69); a significant treatment-by-subgroup interaction (P=0.03) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup. CONCLUSIONS: Patients with elevated LDL-C, low HDL-C, and elevated triglycerides were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome, had increased risk for CHD events on placebo, and received greater benefit with simvastatin therapy.

Apolipoprotein E polymorphism and carotid artery intima-media thickness in a random sample of middle-aged men.

Genetic polymorphism of apolipoprotein E (apoE) is an important factor in the development of coronary artery disease but the results concerning apoE genotype and carotid artery atherosclerosis remain controversial. We investigated a random sample of 189 Finnish middle aged men (mean age 54 years, range 50-59) to assess the role of apoE in the process of carotid atherosclerosis. Intima-media thickness (IMT) of the carotid artery wall was measured at three standardised segments (common carotid artery, bifurcation and internal carotid artery) by B-mode ultrasonography. Overall mean IMT value was also calculated. The carriers of E3/2 (n=20) genotype had significantly lower (P<0.01) total cholesterol and LDL cholesterol concentrations than carriers of E3/3 genotype (n=109) or the E4 allele (n=60). ApoE polymorphism was associated with common carotid artery IMT (P=0.034) when adjusted for age and body-mass index (model 1). The carriers of E3/2 had on average 9% (95% CI 0.8-16%, P=0.028) lower common carotid IMT values than the carriers of E3/3. After further adjustment with LDL and HDL cholesterol, systolic blood pressure, lipoprotein (a), apolipoprotein B and pack-years of smoking (model 2) the association was not statistically significant. The overall mean IMT varied significantly with apoE genotype (P=0.03 for model 1 and P=0.07 for model 2), and it was also lowest in the carriers of E3/2 genotype. This suggests that apoE E3/2 genotype is a protective factor in the development of carotid artery atherosclerosis in randomly selected middle-aged men. The favourable effect might be mediated at least partly by the lowering effect of E3/2 genotype on serum cholesterol.

Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin.

The long-term safety profile of simvastatin, established over 10 years of clinical use, is excellent. The principal adverse effect of all inhibitors of hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infrequent. Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhibitory activity derived from simvastatin. Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopathy. Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of myopathy. Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed. In megatrials with simvastatin, the overall incidence of myopathy was 0.025%. The proportion of patients developing myopathy who were taking a calcium channel blocker with simvastatin (1 of 3) was similar to the proportion of patients taking a calcium channel blocker overall. Among marketed-use adverse event reports, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports was observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. Potent CYP3A4 inhibitors, especially cyclosporine, significantly increase the risk. There is no evidence that weaker CYP3A4 inhibitors such as calcium channel blockers increase the risk.