Abelacimab vs Rivaroxaban in Older Individuals With Atrial Fibrillation

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks

Utilization of Anticoagulation and Antiplatelet Therapies in Patients with Atrial Fibrillation and Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Factor XI as a target for preventing venous thromboembolism

Received June 2, 2009; accepted November 16, 2009. Percutaneous coronary intervention (PCI) is the most commonly performed invasive therapeutic cardiac procedure and plays an important role in the treatment of ischemic heart disease. Since the first description of coronary angioplasty in a human by Gruntzig,1 the technique, equipment, and associated pharmacotherapy have undergone substantial evolution, leading to significant improvements in periprocedural complications.2 In particular, procedural anticoagulant therapy has been the focus of numerous clinical trials, and several options are now available and supported by practice guidelines; each agent has both advantages and disadvantages, and procedural pharmacotherapy continues to be a focus of drug development. The purpose of this review is to summarize the goals of anticoagulant therapy during PCI, the pharmacokinetics and pharmacodynamics of available agents, and the clinical data surrounding each agent and to identify new agents in development. The goals of pharmacotherapy during PCI are 2-fold: (1) to mitigate the sequelae of iatrogenic plaque rupture from balloon angioplasty or stenting and (2) to reduce the risk of thrombus formation on intravascular PCI equipment. Central to these thrombotic events is thrombin (factor IIa). Iatrogenic damage to the endothelium during PCI leads to increased expression of tissue factor, activation of the coagulation cascade, and formation of activated factor Xa. This ultimately leads to the generation of thrombin, conversion of fibrinogen to fibrin, and thrombus formation.3 In addition to its effects on fibrin, thrombin also directly activates platelets, enhances platelet aggregation, and is proinflammatory.4 Because of its multiple actions in promoting thrombosis, the focus of most anticoagulant agents is thrombin inhibition. Available agents for use include unfractionated heparin (UFH), low-molecular-weight heparins (LMWH, of which enoxaparin has the largest body of clinical data), the synthetic pentasaccharides (of which fondaparinux has the largest body of clinical data), and the …

Vitamin K antagonists (VKAs) such as warfarin are the only oral anticoagulants currently available for clinical use. Warfarin has numerous limitations, including slow onset and offset of action, a narrow therapeutic window, and a metabolism that is affected by diet, drugs, and genetic polymorphisms.1 Because of its unpredictable dose response, warfarin requires careful coagulation monitoring to ensure that a therapeutic anticoagulant effect is achieved.2 Variable dose requirements, concern about the risk of bleeding, and the need for frequent coagulation monitoring have prompted the development of new oral anticoagulants to replace warfarin. With a predictable anticoagulant response and little potential for food or drug interactions, these new agents have been designed to be administered in fixed doses without coagulation monitoring. Consequently, these drugs have the potential to simplify long-term anticoagulant therapy. Article p 180 The features of the new oral anticoagulants in the most advanced stages of clinical development are listed in the Table and are compared with those of warfarin. Unlike warfarin, which reduces the functional levels of factors II (prothrombin), VII, IX, and X, these novel agents are directed against the active site of factor Xa or thrombin, the enzymes responsible for thrombin generation and fibrin formation, respectively (see the Figure). Rivaroxaban and apixaban target factor Xa, whereas dabigatran etexilate inhibits thrombin. View this table: Comparison of Warfarin to New Oral Anticoagulants in Advanced Stages of Clinical Development Targets of new oral anticoagulant drugs. Oral factor Xa inhibitors (rivaroxaban, apixaban) bind directly to factor Xa and prevent thrombin generation. Dabigatran etexilate, an orally active direct thrombin inhibitor, undergoes metabolic activation to dabigatran, which binds to the active site of thrombin (factor IIa) and blocks its capacity to convert fibrinogen to fibrin, to activate platelets, and to amplify its own generation by activating factors V, VIII, and XI. By blocking the …

<i>Circulation</i> Editors’ Picks

Considerations when choosing an appropriate bleeding risk assessment tool for patients with atrial fibrillation

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks

Scientific and Standardization Committee Communication: Guidance document on the periprocedural management of patients on chronic oral anticoagulant therapy: Recommendations for standardized reporting of procedural/surgical bleed risk and patient‐specific thromboembolic risk

Background: Combining antiplatelet (APT) with anticoagulant therapy increases the risk of bleeding. In AZALEA-TIMI 71, the novel factor XI inhibitor abelacimab reduced the risk of bleeding compared with rivaroxaban in patients with atrial fibrillation (AF). In this analysis, we investigated whether the safety of abelacimab vs rivaroxaban was modified by antiplatelet therapy. Methods: AZALEA-TIMI 71 randomized 1,287 patients with AF to abelacimab (90 or 150 mg subcutaneously monthly) or rivaroxaban (20 mg orally daily), with stratification by planned use of concomitant APT. The primary outcome, major or clinically relevant non-major (CRNM) bleeding, was compared using Cox proportional hazards adjusted for age, sex, and BMI, with an interaction term for randomized treatment and APT use. Results: Of 1,287 patients, 318 (25%) were on APT at baseline (16% aspirin only, 8% P2Y 12 only, 2% DAPT) and were younger (median age 72 vs 75 years) and had a higher prevalence of CAD (74% vs 40%), prior MI (36% vs 16%) and PAD (15% vs 11%) than those not on APT (p&lt;0.05 for each). The rate of major or CRNM bleeding tended to be higher in those on APT than those not taking APT in the rivaroxaban group (10.6% vs. 7.7%), but not in the abelacimab group (Fig). Both abelacimab doses significantly reduced major or CRNM bleeding compared with rivaroxaban regardless of APT use [60-66% in patients not on ATP and 70-74% in patients on ATP] (Fig). Given the higher rates of bleeding in patients on both rivaroxaban and APT, the corresponding absolute risk reductions with abelacimab tended to be greater in patients on APT (7.1-8.1%) compared to those not on APT (4.6-5.0%) (Fig). Conclusion: Inhibition of FXI with abelacimab results in substantial reductions in bleeding compared with rivaroxaban regardless of concomitant APT use. These data support the potential advantage of FXI inhibitors in patients who require concomitant APT.

Personalized prophylactic anticoagulation decision analysis in patients with membranous nephropathy

Acute coronary syndromes

When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH

Thirty days only double antiplatelet therapy after drug-eluting stenting: could a 'short-term' treatment be advantageous?

BACKGROUND: Patients with atrial fibrillation (AF) who receive both antiplatelet (AP) and anticoagulant therapy are at markedly higher risk of bleeding. The ENGAGE AF-TIMI 48 trial showed that both the high- (HD) and low-dose (LD) regimens of the once-daily factor Xa inhibitor edoxaban (Edox) were as effective as well-managed warfarin (Warf) (median TTR 68.4%) in preventing stroke or systemic embolism (SEE) with significant reductions in major bleeding and cardiovascular mortality. In this study, we assessed the relative efficacy and safety of Edox as compared with Warf in patients with and without concomitant use of AP therapy. METHODS: This was a randomized, double-blind, double-dummy trial comparing HD (60 mg daily, reduced to 30mg in patients with anticipated increased drug exposure) and LD (30 mg daily, reduced to 15mg) Edox with Warf. Dual AP therapy was prohibited while receiving study drug. Cox proportional hazards models were performed stratified by AP use at 3 months with treatment as a covariate. RESULTS: Of the 21,105 patients, 4,912 (23%) were receiving AP therapy at 3 months (92% aspirin). Patients who received concomitant AP therapy had higher rates of major bleeding compared to patients who did not (Fig). Both Edox regimens had similar relative efficacy in preventing stroke or SEE compared with Warf regardless of concomitant AP use (P int &gt;0.10 for both) with consistent reductions in major bleeding (HD Edox vs. Warf: P int =0.91; LD Edox vs. Warf: P int =0.59). In patients randomized to LD Edox, AP therapy was associated with a further reduction in the net clinical outcome of death, stroke, SEE, or major bleeding (P int =0.02) compared with Warf. CONCLUSIONS: Regardless of concomitant AP therapy, both doses of Edox significantly reduced bleeding compared to well-managed Warf. The safety profile of Edox may be particularly attractive in patients with AF who receive a combination of AP and anticoagulant therapy because of higher absolute risk of bleeding.