Metabolic control, anticoagulation, and gender aspects

A previous review paper published in this journal, entitled ‘Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion’, by Zannad and co-workers1 has received massive interest. In this issue of the journal, we publish three comments on that paper. Professor Torp-Pedersen from Denmark and co-workers report data from 8192 obese patients with diabetes. The patients were randomized to sibutramine or placebo plus diet and exercise after a preliminary 6 weeks in which all patients received sibutramine. Sibutramine is a neurotransmitter reuptake inhibitor that reduces the reuptake of serotonin, norepinephrine, and dopamine, and enhances satiety. The effect of sibutramine on cardiovascular outcomes in overweight and obese subjects has previously been reported.2 Subjects with pre-existing cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of non-fatal myocardial infarction and non-fatal stroke but not of cardiovascular death or death from any cause.2 The authors of the present paper concluded that weight loss induced by sibutramine, diet, and exercise attenuated falls in blood glucose levels and HbA1c compared with similar weight loss with placebo, diet, and exercise. In another study from Denmark, Professor Gislason and co-workers investigated the association between thiazolidinediones (TZDs) vs. other antidiabetic drugs and risk of atrial fibrillation (AF) in diabetic patients. The study was performed since diabetes mellitus significantly increases the risk of AF. TZD is an insulin sensitizer that also has anti-inflammatory effects. The Danish nationwide registries were used to study 108 624 patients with diabetes and without prior AF who were treated with metformin or sulphonylurea as first-line drugs. The incidence of AF was significantly lower with TZD as the second-line antidiabetic treatment compared with other second-line antidiabetic drugs (P < 0.001). The authors concluded that use of a TZD to treat diabetes was associated with reduced risk of developing AF compared with other antidiabetic drugs as second-line treatment. In a multicentre study, John Camm, Dan Atar, and co-workers report data from a cardioversion registry, particularly focusing on anticoagulation (AC) strategies in different European countries. A total of 1101 patients were registered. The usage of non-vitamin K antagonist oral anticoagulants (NOACs) vs. vitamin K antagonists (VKAs) was 31.5% vs. 68.5%, respectively. There were differences in use of AC between the countries: Spain used most VKAs (89%), while France used least VKAs (39%, P < 0.001). The authors concluded that NOAC use is increasing and there is a significant decrease in VKA use. The results are in line with the new ESC Guidelines on AF.3 Previously, the journal has published a paper reporting the prescriptions for AF in England in 1998–2014.4 Dr S. Sørensen and co-workers from Gentofte University Hospital describe adherence with NOACs and VKAs in patients with non-valvular atrial fibrillation (NVAF). In this registry study, 46 675 patients with NVAF claimed a prescription of oral anticoagulation (OAC): 57.3% used a VKA, 29.8% dabigatran, 8.5% rivaroxaban, and 4.4% apixaban. Good adherence was defined as PDC (proportion of days covered) >80%. During the first 180 days, PDC >80% was highest among users of rivaroxaban. Compared with rivaroxaban, the odds ratio was 0.79 with apixaban, 0.72 with dabigatran, and 0.76 with VKAs. Likewise the rivaroxaban group had the largest proportion of patients with no refill gaps during the first year, while the VKA group had the lowest. Refill gaps after 89 days occurred in 11.5% of VKA recipients, with substantially lower rates for patients treated with an NOAC. Switch between OACs was highest in users of dabigatran (21.0%) and lowest in users of apixaban (8.6%). The authors concluded that among NVAF patients treated with an OAC, 42.7% received an NOAC. PDC >80% and periods without refill gaps were highest among users of rivaroxaban. Refill gaps occurred most often with VKA, and switch was most common with dabigatran use. Professor Kirchhof and co-workers from Birmingham in the UK present a viewpoint about triple antithrombotic therapy in patients with AF undergoing percutaneous coronary intervention (PCI). This is an everyday clinical issue since ∼5–10% of patients undergoing PCI also have AF. Patients with AF have an additional requirement for AC, as dual antiplatelet therapy alone is insufficient to reduce the risk of stroke in patients with AF adequately. However, it is now well established that combining ACs with dual antiplatelet therapy also causes a significant increase in the risk of bleeding. Hence, there is great interest in discovering the optimal blend of antiplatelet therapy and OAC in this situation, aiming to reduce the risk of stent thrombosis, recurrent myocardial infarction, and stroke, whilst also minimizing the risk of bleeding. The review summarizes the currently available evidence on this topic and highlights the key questions that remain to be answered including ongoing clinical trials in the field. The topic is hot, and the journal has previously published papers regarding different aspects of antiplatelet treatment.4–11 In a review paper from the ESC Working Group on Cardiovascular Pharmacotherapy, Professor Tamargo from Spain and co-workers discuss gender-specific differences in cardiovascular medicine. The exact influences of gender on the effect of cardiovascular drugs remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics, so it is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-based drugs, thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than men, and remain under-represented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardiovascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these gender-related differences is fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strategies both in men and in women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovascular drugs and provides recommendations to close the gaps in our understanding of gender-specific differences in drug efficacy and safety. The authors concluded that the most effective strategy to minimize the higher incidence of adverse drug reactions in women is the development and implementation of gender-specific pharmacological guidelines.