Clinical experience with apixaban in atrial fibrillation: implications of AVERROES

Raffaele De CaterinaInstitute of Cardiology and Center of Excellence on Aging, G d'Annunzio University, Chieti, G Monasterio Foundation, Pisa, ItalyAbstract: Atrial fibrillation is an extremely common arrhythmia, which substantially increases the risk of stroke and thromboembolism. Prevention of stroke and thromboembolism is therefore an important part of the management of atrial fibrillation. Guidelines until now have recommended that patients with atrial fibrillation receive some form of antithrombotic therapy, ie, a vitamin K antagonist or aspirin, with a preference for anticoagulants in most cases. However, current treatments are suboptimal, and despite the recommendations, many patients do not receive adequate thromboprophylaxis, because they are considered, for various reasons, "unsuitable" to receive a vitamin K antagonist. In this patient population, apixaban, a new oral anticoagulant inhibiting activated coagulation factor X, administered in fixed doses and without anticoagulation monitoring, has undergone testing against aspirin in the recently published AVERROES trial. This paper addresses the strengths and limitations of this trial and the practical relevance of the new clinical information it provides.Keywords: atrial fibrillation, apixaban, thromboprophylaxi

Antiatherogenic effects of n-3 fatty acids - evidence and mechanisms

N-3 (omega-3) (polyunsaturated) fatty acids are thought to display a variety of beneficial effects for human health. Clues to the occurrence of cardiovascular protective effects have been, however, the spur for the first biomedical interest in these compounds, and are the best documented. Historically, the epidemiologic association between dietary consumption of n-3 fatty acids and cardiovascular protection was first suggested by Bang and Dyerberg, who identified the high consumption of fish, and therefore, of fish oil-derived n-3 fatty acids, as the likely explanation for the strikingly low rate of coronary heart disease events reported in the Inuit population. Since their initial reports, research has proceeded in parallel to provide further evidence for their cardioprotection and to understand underlying mechanisms. Decreased atherogenesis is currently thought to be a part of the cardiovascular protection by n-3 fatty acids. This article summarizes the evidence for such a claim and the mechanisms putatively involved

Cell-Based Gene Therapies and Stem Cells for Regeneration of Ischemic Tissues

Coronary (CAD) and peripheral (PAD) artery disease are major causes of morbidity and mortality, requiring bypass surgery or angioplasty in approximately one million patients/year in the world (MERIT-HF Study Group, 1999). While collateral vessel formation as an alternative pathway for blood supply occurs in some of these patients, many do not form vascular networks adequate to compensate for the loss of the original blood supply (Hirsch et al., 2006). These patients might therefore benefit from stem cell transplantation therapies that would accelerate natural processes of postnatal collateral vessel formation, an approach referred to as therapeutic angiogenesis. On the other hand, recent seminal reports have indicated that the adult heart is self-healing and self-renewing. Specifically, these studies have demonstrated that there is a pool of resident cardiac stem cells (CSCs) that are clonogenic and multipotent and are capable of differentiating into new blood vessels or into new myocytes, and of cardiac progenitor cells (CPCs) (Marban, 2007). This suggests the possibility of using a therapeutic angiogenesis approach to complement other treatments (e.g., stem cell therapy) that facilitate myocardial repair. Such combined modalities may facilitate myocardial regeneration by inducing endogenous cardiac cells to migrate, differentiate, and proliferate in situ, replacing lost endothelial cells and cardiomyocytes (Urbaneket al., 2005). However, despite recent progress in applying the approaches of regenerative medicine to the treatment of such diseases, valid strategies aimed at repairing the infarcted heart and, in general, at treating end-organ ischemia continue to be elusive. Major obstacles are the difficulty in isolating and delivering stem cells that are specifically effective in myocardial repair, and in stimulating recruitment of endogenous stem cells to the ischemic tissue. To address these issues, there has been increasing focus on novel biotechnologies or pharmacological strategies to enhance the implantation of exogenous stem cells or to boost endogenous regeneration of myocardial tissue. By employing three fundamental “tools”, namely stem cells, biomaterials and growth factors (GFs) (Lavik & Langer, 2004; Mikos et al., 2006), such tissue engineering strategies may enhance the efficacy of stem cell therapy in several ways: by mobilizing endogenous stem/progenitor cells in vivo; by promoting cell proliferation and differentiation; and by augmenting cell engraftment and survival in the injured myocardium. In general, because of the short half-lives of GFs in the body and the necessity to deliver them to specific target sites, GF injections themselves do not always produce the anticipated therapeutic effect. At present, GF delivery in regenerative medicine basically relies upon two strategies: 1) delivery of the GF genes; 2) direct delivery of GFs by incorporating them into a vehicle. In the gene delivery approach, delivery of the GF gene may result in higher and more constant levels of protein produced, since the gene - rather than a degradable protein - is being delivered (Haastert & Grothe, 2007). Two major problems are associated however with this approach: 1) the complexity of cloning and integrating the gene into the target cells; 2) safety and efficiency of transduction. At present, there are insufficient well-controlled long-term studies in the preclinical area to make any conclusive statements about the clinical suitability/efficacy of gene delivery in humans. If resolved, cell-mediated synthesis of GFs should be associated with more efficient targeting of receptors and, consequently, a more robust and predictable approach in ischemic tissue regeneration

Aspirin and the Primary Prevention of Cardiovascular Diseases. An Approach Based on Individualized, Integrated Estimation of Risk

While the use of aspirin in the secondary prevention of cardiovascular (CVD) is well established, aspirin in primary prevention is not systematically recommended because the absolute CV event reduction is similar to the absolute excess in major bleedings. Recently, emerging evidence suggests the possibility that the assumption of aspirin, may also be effective in the prevention of cancer. By adding to the CV prevention benefits the potential beneficial effect of aspirin in reducing the incidence of mortality and cancer could tip the balance between risks and benefits of aspirin therapy in the primary prevention in favour of the latter and broaden the indication for treatment with in populations at average risk. While prospective and randomized study are currently investigating the effect of aspirin in prevention of both cancer and CVD, clinical efforts at the individual level to promote the use of aspirin in global (or total) primary prevention could be already based on a balanced evaluation of the benefit/risk ratio

Do we need P2Y12 inhibitor pretreatment in non-ST elevation acute coronary syndrome?

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Erratum to "Do we need P2Y12 inhibitor pretreatment in non-ST elevation acute coronary syndrome?"

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Is there equivalence between PCI and CABG surgery in long-term survival of patients with diabetes? Importance of interpretation biases and biological plausibility.

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Pharmacological modulation of vascular inflammation in atherothrombosis

Vascular inflammation, especially at the level of endothelial cells, has been shown to play a pivotal role in the inception, progression, and clinical complications of atherosclerosis. The common denominators for the activation of inflammatory genes appear to be a small subset of transcription factors-among which include nuclear factor-κB, activator protein-1 (AP-1), and GATA-that function as the central hub of vascular inflammation. Strategies directed to inhibit both the secondary mediators and the primary triggers (atherosclerosis risk factors) appear viable to inhibit atherosclerosis. However, attempts have now been made to address the central hub of vascular inflammation. "Old" drugs, such as dipyridamole, can also now be revisited for properties related to inhibition of vascular inflammation, probably by acting on the common hub of inflammation

Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease

Abstract Background Valvular heart disease (VHD) and atrial fibrillation (AF) often coexist. Phase III trials comparing non–vitamin K antagonist oral anticoagulants (NOACs) with warfarin excluded patients with moderate/severe mitral stenosis or mechanical heart valves, but variably included patients with other VHD and valve surgeries. Objectives This study aimed to determine relative safety and efficacy of NOACs in patients with VHD. Methods We performed a meta-analysis of the 4 phase III AF trials of the currently available NOACs versus warfarin in patients with coexisting VHD to assess pooled estimates of relative risk (RR) and 95% confidence intervals (CIs) for stroke/systemic embolic events (SSEE), major bleeding, intracranial hemorrhage (ICH), and all-cause death. Results Compared with warfarin, the rate of SSEE in patients treated with higher-dose NOACs was lower and consistent among 13,585 patients with (RR: 0.70; 95% CI: 0.58 to 0.86) or 58,098 without VHD (RR: 0.84; 95% CI: 0.75 to 0.95; interaction p = 0.13). Major bleeding in patients on higher-dose NOACs versus warfarin was similar and consistent among patients with (RR: 0.93; 95% CI: 0.68 to 1.27) or without VHD (RR: 0.85; 95% CI: 0.70 to 1.02; interaction p = 0.63 for VHD/no-VHD difference). Intracranial hemorrhage was lower with higher-dose NOACs than with warfarin irrespective of VHD (RR: 0.47; 95% CI: 0.24 to 0.93, and 0.49; 95% CI: 0.41 to 059, respectively; interaction p = 0.91). No protective effect of higher-dose NOACs in preventing all-cause death seemed to be present in patients with VHD versus without VHD (RR:1.01; 95% CI: 0.90 to 1.14 vs. RR: 0.88; 95% CI: 0.82 to 0.94, respectively; interaction p = 0.03). Conclusions High-dose NOACs provide overall efficacy and safety similar in AF patients with or without VHD