Suspected adverse drug reaction reports with oral anticoagulants in Portugal: a pharmacovigilance study

Objective: In this pharmacovigilance study, we aimed to determine the incidence of spontaneously reported suspected adverse drug reactions (ADRs) related to oral anticoagulants: non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, rivaroxaban) and vitamin K antagonists (VKA)

Research design and methods: In this retrospective observational study, we extracted all the individual case safety reports related to oral anticoagulants recorded in the Portuguese Pharmacovigilance Database (January 2010 to April 2015). The annual incidence of suspected ADRs was estimated using drug exposure data. Disproportionality of reporting ADR was addressed through reporting odds ratio (ROR) and 99% confidence intervals.

Results: We appraised 794 suspected ADR (78% related to NOACs). The annual number of ADRs increased overtime with 9 ADRs/million Defined Daily Dose (DDD) at the end of 2014. The incidence of NOACs ADRs decreased from 2012 onwards. VKA showed a disproportion in ‘Investigation’ (ROR 0.10, 99%CI 0.05–0.22) and ‘Injury, poisoning and procedural complications’ (ROR 0.36, 99%CI 0.19–0.69) ADRs compared with NOACs. NOACs had a higher significant disproportion of ‘Nervous system disorders’ related ADRs (ROR 3.98, 99%CI 1.50–10.53).

Conclusions: Reporting of ADRs associated with oral anticoagulants (mainly NOACs), is increasing. Exploratory disproportion analyses showed an increase of reports of nervous system ADRs with NOACs, and INR-related ADRs with VKA.     

Dabigatran affects thrombin-dependent platelet aggregation after a week-long therapy

Objective. Dabigatran is a direct thrombin inhibitor. As the main adverse event is bleeding, it is relevant whether dabigatran has additional effects on platelet function. If so, it could affect the bleeding risk. We aimed to assess in vitro aggregation in patients with atrial fibrillation (AF) receiving dabigatran. Design. We evaluated 32?AF patients treated with dabigatran (study group) and 18 non-anticoagulated non-AF blood donors (control group). We assessed light transmittance platelet aggregation (LTA) with 100?nmol/L γ-thrombin in both groups. The LTA was performed at two time-points in our dabigatran group of patients. Results. The thrombin-induced platelet aggregation was significantly lower two hours after dabigatran was taken compared to baseline measurement (9%?±?6% vs. 29%?±?21%) in our study group. Moreover, we observed that the baseline value of platelet aggregation in patients on dabigatran treatment was significantly lower compared to healthy volunteers (29%?±?21% vs. 89?±?8). However, one subanalysis showed that this significant reduction in platelet aggregation at baseline was only observed in patients who received dabigatran for over a week. Conclusion. The thrombin-induced platelet aggregation is reduced in non-valvular AF patients receiving dabigatran after a week-long therapy.     

Idarucizumab for Reversal of Dabigatran-Associated Bleeding: Misnomer or Miracle?

Background

The development of novel oral anticoagulants (NOACs) has revolutionized oral anticoagulation. Rapid incorporation of NOACs into general practice has heightened the demand for directed reversal agents. Idarucizumab is a targeted reversal agent that is approved for the urgent reversal of the anticoagulant effects of dabigatran. While it is a welcome addition to reversal strategies of dabigatran, a number of clinical questions exist regarding its place in therapy.

Comparative coronary risks of apixaban,rivaroxaban and dabigatran: a meta-analysis and adjusted indirect comparison

Aims

There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran.

Methods

We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I². We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran.

Results

Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran.Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran.

Conclusions

There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events.     

Hemorrhagic Gastritis with Dabigatran in a Patient with Renal Insufficiency

Background

Dabigatran etexilate is the first oral direct thrombin inhibitor approved in the United States. Unlike warfarin, dabigatran has no known antidote. Providers should be aware of patients that may be at risk for dabigatran coagulopathies and recognize potential treatment options.

Objective

To report a case of hemorrhagic gastritis in a patient with chronic renal insufficiency recently initiated on dabigatran etexilate.

Case Summary

An 85-year-old white man with a known history of hypertension and stage III chronic kidney disease presented to the Emergency Department complaining of dark stools, shortness of breath, and abdominal pain. The patient recently started dabigatran 150 mg twice daily for new-onset atrial fibrillation. An upper gastrointestinal endoscopy identified non-specific gastritis with hemorrhage. It was determined to be probable using the Naranjo Probability Scale that gastrointestinal hemorrhaging was a result of dabigatran therapy. Fresh frozen plasma was used to reverse the dabigatran-induced coagulopathy.

Conclusion

This case highlights the challenges that providers may face when dealing with life-threatening bleeding in patients receiving dabigatran.     

Stroke in atrial fibrillation: Update on pathophysiology,new antithrombotic therapies,and evolution of procedures and devices

Atrial fibrillation (AF) is said to be an epidemic, affecting 1%–1.5% of the population in the developed world. The clinical significance of AF lies predominantly in a 5‐fold increased risk of stroke. Strokes associated with AF are usually more severe and confer increased risk of morbidity, mortality, and poor functional outcome. Despite the advent of promising experimental therapies for selected patients with acute stroke, pharmacological primary prevention remains the best approach to reducing the burden of stroke.

New antithrombotic drugs include both parenteral agents (e.g. a long‐acting factor Xa inhibitor idraparinux) and oral anticoagulants, such as oral factor Xa inhibitors and direct oral thrombin inhibitors (ximelagatran, dabigatran). Ximelagatran had shown significant potential as a possible replacement to warfarin therapy, but has been withdrawn because of potential liver toxicity. Its congener dabigatran appears to have a better safety profile and has recently entered a phase III randomized clinical trial in AF. Oral factor Xa inhibitors (rivaroxaban, apixaban, YM150) inhibit factor Xa directly, without antithrombin III mediation, and may prove to be more potent and safe.

Selective inhibitors of specific coagulation factors involved in the initiation and propagation of the coagulation cascade (factor IXa, factor VIIa, circulating tissue factor) are at an early stage of development. Additional new agents with hypothetical, although not yet proven, anticoagulation benefits include nematode anticoagulant peptide (NAPc2), protein C derivatives, and soluble thrombomodulin.

A battery of novel mechanical approaches for the prevention of cardioembolic stroke has recently been evaluated, including various models of percutaneous left atrial appendage occluders which block the connection between the left atrium and the left atrial appendage, minimally invasive surgical isolation of the left atrial appendage, and implantation of the carotid filtering devices which divert large emboli from the internal to the external carotid artery, preventing the embolic material from reaching intracranial circulation.

Despite recent advances and promising new approaches, prevention of recurrent AF may be one of the best protections against AF‐related stroke and may reduce the prevalence of stroke by almost 25%. Improved pharmacological and nonpharmacological rhythm control strategies for AF as well as primary prevention of AF with ‘upstream’ therapy and risk factor modification are likely to produce a larger effect on the reduction of stroke rates in the general population than will specific interventions.     

New anticoagulants for prevention of stroke in patients with atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using vitamin K antagonists (VKA) is currently prescribed for prevention of ischemic stroke in patients with AF. A narrow therapeutic range and frequent food and drug interactions underly the need for regular monitoring of anticoagulation intensity and impairs the utility and safety of VKA, stimulating a quest for alternative anticoagulant agents. Recently developed anticoagulants include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban, edoxaban, to name those in the most advanced stages of clinical development. This review focuses on advances in the development of novel antithrombotic agents to provide practical information to clinicians on the use of these new drugs in patients with AF.