Should dabigatran replace warfarin for stroke prevention in AF?

Dabigatran etexilate (Pradaxa - Boehringer Ingelheim) is an oral anticoagulant that has been licensed in the EU since 2008 for thromboprophylaxis in adults following a hip or knee joint replacement. The marketing authorisation for the drug in the EU has recently been extended to include the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF). In theory, dabigatran could offer an advantage to patients who need anticoagulation because, unlike warfarin, its dose does not need to be individually adjusted and its effects do not require regular monitoring through blood sampling. Here we review the evidence for dabigatran in this new indication and consider its place in the management of patients with AF.     

Is vaccine therapy the future in cancer prevention?

One vaccine designed to prevent cancer by preventing a precursor infection is already in common use, and at least one more is in the latter stages of clinical development. These vaccines are part of a new era of cancer immunoprophylaxis. Several further vaccines are in preclinical and clinical development, targeted at preventing cancer precursor infections, and these should add to our ability to prevent this common human disorder. However, vaccines to prevent cancers not triggered by infection are a more remote prospect, for a variety of reasons.     

Is vaccine therapy the future in cancer prevention?

One vaccine designed to prevent cancer by preventing a precursor infection is already in common use, and at least one more is in the latter stages of clinical development. These vaccines are part of a new era of cancer immunoprophylaxis. Several further vaccines are in preclinical and clinical development, targeted at preventing cancer precursor infections, and these should add to our ability to prevent this common human disorder. However, vaccines to prevent cancers not triggered by infection are a more remote prospect, for a variety of reasons.     

What plays a role in the choice of inhaler device for asthma therapy?

Inhalation is the preferred route of delivery for anti-asthma drugs. However, in reality inhalers are often prescribed on an empirical basis rather than on evidence-based awareness. Asthma management guidelines also guide inhaler choice, but they offer non-specific advice regarding inhaler choice, are very long and complicated and not conducive to rapid assimilation by a busy GP. In addition, device selection criteria differ according to who you are asking (i.e. the inhalation technologist, the physician or the patient). The ideal inhaler should be small and have a guided sequence of inhalation, leading patients in a logical sequence of events through the inhalation manoeuvre. It should be breath-activated, releasing medication only when all prerequisites for successful inhalation are met. Most importantly, there should be flow-independent deposition of drug in the lungs and feedback on the successfully performed inhalation manoeuvre to reassure the patient that the drug has been successfully released from the inhaler. The ideal inhaler should also have a low intrinsic airflow resistance, making it suitable for use by patients who have a low inspiratory airflow (e.g. children and elderly patients). In order to check for compliance, the ideal inhaler should have an accurate dose counter which is linked to correct inhalation rather than simply to dose release, and patients should be able to use an identical inhaler device to deliver each of their different medications. Finally, from an environmental and cost-effectiveness point of view, the ideal inhaler should be refillable. Among the currently available dry powder inhalers the Novolizer device fulfils several characteristics of an ideal inhaler for the treatment of asthma and chronic obstructive pulmonary disease (COPD).     

Decision-making around antithrombotics for stroke prevention in atrial fibrillation: the health professionals’ views

International Journal of Clinical Pharmacy - Background For stroke prevention in patients with atrial fibrillation (AF), the decision-making around antithrombotic therapy has been complicated by...     

Dabigatran or warfarin for the prevention of stroke in atrial fibrillation? A closer look at the RE-LY trial

INTRODUCTION: In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, dabigatran 150 mg was shown to be superior to warfarin for the prevention of stroke or systemic embolism. However, there are some concerns with the RE-LY trial, such as its open-label design, potential unblinding of "blinded" adjudicators, the use of concomitant warfarin-aspirin (ASA), the disparity between baseline use of nonselective NSAIDs; the high unequal rate of drop-outs; unaccounted drop-ins; high rates of major bleeds in warfarin-treated patients, despite being a low risk population; and rates of major bleeds that do not match historic warfarin trials. Furthermore, although dabigatran offers potential advantages versus warfarin, there are disadvantages that must be taken into consideration before a patient is switched from the latter to the former. This review will summarize the flaws of the RE-LY trial as well as the clinically important advantages and disadvantages of dabigatran and warfarin. AREAS COVERED: This review examines the differences between dabigatran and warfarin in terms of side effects, drug-drug interactions, drug-food interactions, and potential reasons for using one anticoagulant rather than the other. The main focus of this review is a discussion of the design, procedures and results of the RE-LY trial. EXPERT OPINION: There seem to be major flaws with the RE-LY trial. A double-blinded trial should be performed testing dabigatran against warfarin to verify the results of the RE-LY trial.     

Candesartan for the prevention and treatment of stroke – results of the SCOPE and ACCESS trials

Stroke is a leading cause of death and disability. The SCOPE clinical trial assessed the effects of the angiotensin Type 1 (AT₁)-receptor antagonist, candesartan, on major cardiovascular events in elderly hypertensive patients. A first major cardiovascular event (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) occurred to a lesser extent in the candesartan group (242 of 2477) than the placebo group (268 of 2460) and this difference represented a reduction in stroke rather than cardiac events. The ACCESS trial was designed to assess the safety of a modest blood pressure reduction with the AT₁-receptor antagonist, candesartan, in the early treatment of stroke. What ACCESS actually showed was that, in the absence of blood pressure lowering, candesartan treatment for 7 days, started within 24 h of motor deficit associated with stoke, reduced the cumulative 12-month mortality rate (7.2 and 2.9% for placebo and candesartan, respectively) and vascular events (18.7 and 9.8% for placebo and candesartan, respectively). In conclusion, candesartan is safe to use in the prevention and treatment of acute stroke, and may provide therapeutic benefits.     

Is it possible to apply secondary stroke prevention guidelines to very old populations?

The aging population is an undeniable reality which must be faced by all health systems all over the world. Among people over 80 years old, increase in stroke incidence, high mortality rates and adverse outcomes are problems of major public concern. Lack of evidence-based data to guide rational decision making on vascular risk factors management to avoid recurrence in elderly stroke patients increases the areas of uncertainty, and sometimes favors medical inertia at the time of taking care of this growing elderly population.     

Antiplatelet therapy in children: why so different from adults'?

Antiplatelet agents are administered in the treatment of a large number of adult diseases: coronary heart disease, ischemic stroke, peripheral arterial disease, arrhythmias with their thromboembolic complications, primary and secondary prevention. In childhood however, the situation is substantially different. The lack of large interventional trials on the use of antiplatelet drugs in children, has led to greater uncertainty, and a less extensive use of these drugs, limited to fewer indications. The purpose of this article was to review the studies conducted to date on the use of antiplatelet agents in children. A concerted effort has been made to identify which are the shared therapeutic indications of this class of compounds, the recommended dose, the contraindications and the possible side effects. In brief, an attempt has been made to ascertain the interesting potential of these drugs which are so often neglected in children.     

Finding the right route for insulin delivery – an overview of implantable pump therapy

Introduction: Implantable pump therapy adopting the intraperitoneal route of insulin delivery has been available for the past three decades. The key rationale for implantable pump therapy is the restoration of the portal-peripheral insulin gradient of the normal physiology. Uptake in clinical practice is limited to specialized centers and selected patient populations.

Areas covered: Implantable pump therapy is discussed, including technical aspects, rationale for its use, and glycemic and non-glycemic effects. Target populations, summaries of clinical studies and issues related to implantable pump therapy are highlighted. Limitations of implantable pump therapy and its future outlook in clinical practice are presented.

Expert opinion: Although intraperitoneal insulin delivery appears closer to the normal physiology, technical, pharmacological, and costs barriers prevent a wider adoption. Evidence from clinical studies remains scarce and inconclusive. As a consequence, the use of implantable pump therapy will be confined to a small population unless considerable technological progress is made and well-conducted studies can demonstrate glycemic and/or non-glycemic benefits justifying wider application.     

Chemokine blockers--therapeutics in the making?

Chemokines are a family of small chemoattractant cytokines that have an important role in controlling leukocyte migration. The finding that some chemokines and their receptors are upregulated in both acute and chronic inflammatory diseases, and that they are key players in the development of AIDS, has provided the pharmaceutical industry with new targets for therapeutic intervention in these diseases. Although the chemokine system shows apparent redundancy in vitro, target validation is possible largely through expression studies in human disease tissues and the use of transgenic and knockout mice as disease models. Several approaches are being developed to block the effects of chemokines, including small-molecule antagonists of chemokine receptors, modified chemokines and antibodies directed against chemokine receptors. Here, we describe the rationale behind these different approaches, the pitfalls that have been encountered and future perspectives.     

Hormone therapy for the prevention of bone loss in menopausal women with osteopenia: is it a viable option?

Osteopenia is a state of low bone mass, the appropriate clinical management of which is not always clear. The use of hormone therapy for postmenopausal bone loss has become controversial given recent data regarding the risks of therapy. Fragility fractures are common, and result in substantial morbidity and mortality. Although the fracture rate is higher among osteoporotic women, the substantially larger population of osteopenic women accounts for a higher absolute number of fractures. Osteopenia is defined solely according to the statistical properties of the distribution of bone mineral density (BMD) values, which limits its usefulness in clinical care. BMD, although inversely related to fracture risk, should not be used as the sole criterion for fracture risk. Limited data suggest that benefits of treatment seen in women with documented osteoporosis may not extend to osteopenic women. Although estrogen prevents postmenopausal bone loss, preservation of BMD does not necessarily translate into reduced fracture risk. In making decisions about whether to treat a woman with osteopenia, it is critical to estimate how treatments will affect the individual's risk of fracture. Treatment decisions should be based on whether the net benefits of treatment outweigh the anticipated risks, which will depend on the age of the patient and her risk profile. In our opinion, there is insufficient evidence to support treatment for women with a BMD in the osteopenic range in the absence of fragility fracture. For osteopenic women with higher risk, the availability of other treatments with a more favourable risk-benefit profile eliminates the role of hormone therapy for fracture prevention.     

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

Introduction: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk.

Areas covered: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence.

Expert opinion: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.     

Pharmaceutical perspectives for the delivery of TNF-α in cancer therapy

TNF-?? is an endogenous signaling protein which controls physiological activities and participates in immune response. It is known to interact with TNF receptors (TNFR), of which have two kinds leading to totally different effects. Binding of TNF-?? to TNFR1 can induce either cell proliferation or cell death, i.e., necroptosis, depending on the kinds of protein to which it binds during the signaling cascade. On the contrary, binding of TNF-?? to TNFR2 induces only cell death process. TNF-?? can also cause antiviral effect by inducing interferon, and can inhibit tumor growth. Moreover, TNF-?? helps action of immune cells and it leads to increasement of tumor cell lysis. TNF-?? also makes tumor vessels more permeable and induces coagulation and thrombosis in the tumor vessels, which ultimately contribute to antitumor effect. However, TNF-?? also has several toxic effects, which include the change in redox status of antioxidant factors, induction of excess inflammation response, and action as pro-inflammatory cytokine of itself. These toxicities need to be considered when developing TNF-?? as an anticancer agent. In this review, pharmaceutical approaches to optimize and utilize its antitumor activity of TNF-?? as well as to decrease its adverse effect are discussed.