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.     

Will warfarin soon be passé? New approaches to stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is the most common cause for thromboembolic stroke. Oral anticoagulation with warfarin is still the most effective therapy in patients with AF, who are at an increased risk for stroke. Nevertheless, warfarin therapy has several limitations; therefore, new anticoagulants like warfarin analogs, thrombin inhibitors, or factor Xa inhibitors have been developed. Some of them are currently being tested in phase III trials in patients with AF. Furthermore, the pathophysiology of prothrombotic endocardial remodeling in fibrillating atria suggests that angiotensin II increases prothrombotic expression of vascular adhesion molecules at the atrial endocardium. Thus, novel anticoagulants or hybrid therapy with a combination of anticoagulants with inhibitors of endocardial remodelling like angiotensin II receptor blockers appear to be attractive future perspective approaches.     

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...     

Pharmacotherapy for atrial fibrillation: is rhythm control achievable?

As the most common sustained cardiac arrhythmia, the health burden presented by atrial fibrillation (AF) continues to grow. One of the current dilemmas in managing AF lies in the decision of whether to pursue a rate or rhythm control strategy. Current antiarrhythmic drugs have many limitations in terms of efficacy and adverse effects, and the availability of better antiarrhythmic drugs that are effective and safe would probably improve outcomes in AF. Enthusiasm for pulmonary vein ablation procedures has been tempered by the relatively high frequency of recurrences of AF, which are often asymptomatic. Ablation also frequently converts symptomatic episodes to asymptomatic recurrences. Irrespective of whether a rate control or a rhythm control strategy is adopted in patients with persistent AF, appropriate antithrombotic therapy should be used.     

Pharmacotherapy for atrial fibrillation: is rhythm control achievable?

As the most common sustained cardiac arrhythmia, the health burden presented by atrial fibrillation (AF) continues to grow. One of the current dilemmas in managing AF lies in the decision of whether to pursue a rate or rhythm control strategy. Current antiarrhythmic drugs have many limitations in terms of efficacy and adverse effects, and the availability of better antiarrhythmic drugs that are effective and safe would probably improve outcomes in AF. Enthusiasm for pulmonary vein ablation procedures has been tempered by the relatively high frequency of recurrences of AF, which are often asymptomatic. Ablation also frequently converts symptomatic episodes to asymptomatic recurrences. Irrespective of whether a rate control or a rhythm control strategy is adopted in patients with persistent AF, appropriate antithrombotic therapy should be used.     

PALLAS: limiting indications for dronedarone treatment of atrial fibrillation?

Atrial fibrillation increases the risk of stroke. Dronedarone has been shown to reduce the composite of hospitalizations due to cardiovascular events or death, in subjects with intermittent atrial fibrillation or flutter. Recently, dronedarone has been tested in subjects with permanent atrial fibrillation in the PALLAS (permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) trial, and this clinical trial is evaluated in this paper. PALLAS was stopped early as there was an increased incidence of cardiovascular events in the dronedarone group. Dronedarone also increased the rate of hospitalizations in PALLAS. As a result of PALLAS, dronedarone has been contraindicated in permanent atrial fibrillation. The outcomes of PALLAS highlight a discontinuity between dronedarone actions in permanent and intermittent atrial fibrillation. The mechanism(s) underlying the detrimental effects of dronedarone in permanent atrial fibrillation are unknown at present and need to be investigated.     

PALLAS: limiting indications for dronedarone treatment of atrial fibrillation?

Atrial fibrillation increases the risk of stroke. Dronedarone has been shown to reduce the composite of hospitalizations due to cardiovascular events or death, in subjects with intermittent atrial fibrillation or flutter. Recently, dronedarone has been tested in subjects with permanent atrial fibrillation in the PALLAS (permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) trial, and this clinical trial is evaluated in this paper. PALLAS was stopped early as there was an increased incidence of cardiovascular events in the dronedarone group. Dronedarone also increased the rate of hospitalizations in PALLAS. As a result of PALLAS, dronedarone has been contraindicated in permanent atrial fibrillation. The outcomes of PALLAS highlight a discontinuity between dronedarone actions in permanent and intermittent atrial fibrillation. The mechanism(s) underlying the detrimental effects of dronedarone in permanent atrial fibrillation are unknown at present and need to be investigated.     

Intravenous amiodarone for conversion of atrial fibrillation: misled by meta-analysis?

Therapeutic goals for atrial fibrillation (AF) include ventricular rate control, stroke prevention, conversion to normal sinus rhythm, and maintenance of normal sinus rhythm. The optimal strategy of rate versus rhythm control for acute management of patients with AF is a continuing debate. However, selected patients may require acute treatment with antiarrhythmic agents for conversion of symptomatic AF episodes to normal sinus rhythm. Recently published randomized controlled trials, qualitative systematic reviews, meta-analyses, and evidence-based international consensus guidelines have addressed the controversy regarding acute conversion of AF using antiarrhythmic therapy. Although meta-analyses often provide the highest level of evidence, the validity and application of their results are based on the quality of their methodology and accuracy of reporting. Authors of the most recent meta-analysis of amiodarone for conversion of AF state that the drug is effective and relatively rapid acting in converting AF to normal sinus rhythm in a wide range of patients, and they recommend it as a first-line drug. We feel that these conclusions are overstated and potentially misleading due to methodologic limitations of the analysis. The results of this meta-analysis and others concerning acute conversion of AF should be viewed as hypothesis generating and not the definitive answer to this question. Ultimately, well-designed, adequately powered, randomized placebo- or rate-controlled trials are needed in specific patient populations with AF to determine the absolute benefit of intravenous amiodarone for conversion of AF to normal sinus rhythm. Until more data are available, intravenous amiodarone cannot be promoted as a first-line agent for this purpose.     

Perspective: does ranolazine have potential for the treatment of atrial fibrillation?

Atrial fibrillation is the most common arrhythmia seen in clinical practice, and novel pharmacological approaches for treatment are sought. Ranolazine (Ranexa; N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy-3-[2-methoxyphenoxy]propyl)piperazin-1-yl]acetamide) is used clinically for the treatment of angina pectoris. Evidence is reviewed from both pre-clinical and clinical studies, which suggests that ranolazine also exhibits antiarrhythmic activity with growing evidence for atrio-selectivity. Further work is required in order to explore more fully the potential of ranolazine in the treatment of atrial fibrillation. In particular, investigation of ranolazine actions against atrial fibrillation in animal models that incorporate atrial fibrillation-related remodeling and data from carefully controlled trials in human atrial fibrillation would be of value.     

Do the benefits of anti-arrhythmic drugs outweigh the associated risks? A tale of treatment goals in atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and places a substantial burden on the US healthcare system. Unfortunately, there is no consensus as to whether patients should be treated with a primary rate- or rhythm-control strategy. The use of anti-arrhythmic drugs in the treatment of AF is discussed in the broader context of AF disease-management strategies with a focus on rhythm control. Outside of rhythm/ECG, AF treatment targets and cardiovascular outcomes are highlighted.     

A systematic review of pharmacist-led medicines review services in New Zealand – is there equity for Māori older adults?

BackgroundPharmacist involvement in medicines reviews for older adults can improve prescribing and reduce adverse drug reactions. Māori experience poorer health outcomes than non-Māori resulting, in part, from inequitable access to and quality of medicine-related care. Despite international data showing benefit, it is unclear whether pharmacist-led medicines review services can improve outcomes for Māori older adults.ObjectiveThis systematic review aims to describe pharmacist-led medicines review services for community-dwelling adults in New Zealand, assess effectiveness of these interventions and identify their effect on health equity for Māori and older adults.MethodsThe review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses – Equity (PRISMA-E 2012). Observational studies were included. The intervention in included studies had to involve a pharmacist, occur in the outpatient setting in New Zealand, and involve review of all medicines for an individual patient. At least one patient-related outcome had to be reported.ResultsThe search identified seven observational studies with 542 total participants. Study interventions included adherence-based reviews in community pharmacies and multi-step comprehensive clinical reviews in outpatient haemodialysis units. Medicines reviews identified up to a median of 3 drug-related problems per review. The effect of interventions on medicines adherence and knowledge was not clear. Māori may have been less likely than non-Māori to benefit from improved medicines knowledge as a result of interventions. None of the studies incorporated aspects in study design or delivery to address inequities for Māori.ConclusionFurther investigation is needed to understand whether the development of culturally safe pharmacist-led medicines review services, responsive to community identified needs, can help to achieve equity in health outcomes for Māori older adults.     

A review of the clinical use of anti-inflammatory therapies for reperfusion injury in myocardial infarction and stroke: where do we go from here?

A number of prominent studies have been conducted using anti-inflammatory therapies to reduce reperfusion injury in myocardial infarction and stroke. Unfortunately, most strategies have failed. This review summarizes in detail the human studies of anti-inflammatory therapy that have been conducted to date. The potential reasons for treatment failure will be discussed from a non-clinical perspective, as will lessons learned from these studies that might guide the design of future clinical studies in this important area.