Direct oral anticoagulants for stroke prevention in patients with atrial fibrillation: meta-analysis by geographic region with a focus on European patients.

AIMS: To analyse clinical outcomes with direct oral anticoagulants in patients with atrial fibrillation according to geographic region. METHODS: We systematically searched MEDLINE, CENTRAL, websites of regulatory agencies, clinical trials registers and conference proceedings for randomized controlled trials of direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) against warfarin for prophylaxis of stroke and systemic embolic events (SEE) in patients with atrial fibrillation (AF). Two investigators independently extracted data. Relative risks of stroke and SEE as well as major bleeding depending on geographic region were estimated using a random effect meta-analysis. RESULTS: Five trials in 72 963 patients were analysed; 32 089 (44%) patients were recruited in Europe (Western Europe: 13 676; Eastern Europe: 18 413). We found significant subgroup differences for stroke/SEE depending on the geographic region (interaction P = 0.003; I(2) 88.5%), with a neutral effect of the DOAC vs. warfarin in Europe [relative risk (RR) 0.97, 95% confidence interval (CI) 0.85-1.11, I(2) 0%] and a significant reduction of stroke/SEE in other regions including North America, Latin America and Asia-Pacific/other (RR 0.72, 95% CI 0.63-0.83, I(2) 33%). There was a similar reduction in risk of major bleeding in Europe (RR 0.82, 95% CI 0.73-0.92, I(2) 0%) and in other regions (RR 0.86, 95% CI 0.72-1.02, I(2) 78%). CONCLUSION: The DOAC did not provide additional benefit in reducing the risk of stroke/SEE compared with warfarin in European patients with AF, but were generally associated with a lower bleeding tendency than warfarin regardless of geographic region.

Pharmacotherapy for stroke prevention in nonvalvular atrial fibrillation: current strategies and future directions.

INTRODUCTION: Cardioembolic stroke, associated to nonvalvular atrial fibrillation (NVAF), accounts for approximately one in every four strokes. Cardioembolic stroke has a bad prognosis and is associated with a significant rate of recurrence. AREAS COVERED: This article reviews current pharmacotherapeutic options for prevention of stroke in NVAF, paying special attention to their use in particular clinical settings (e.g. cardioversion, catheter ablation). We also aim to review new drug candidates that have entered clinical studies in this indication. EXPERT OPINION: Oral anticoagulant therapy (OAT) remains the mainstay for ischemic stroke prophylaxis in NVAF in patients at risk. Several oral (asundexian, milvexian) and parenteral (abelacimab, osocimab, xisomab, IONIS-FXIRX, fesomersen) factor XIa inhibitors are under development. These new compounds appear to be associated with a low bleeding tendency and have the potential to complement current existing alternatives for anticoagulation. However, it is also of paramount importance to implement interventions to improve adherence to available anticoagulants, which is currently suboptimal. Non-anticoagulant drugs, such as colchicine, metformin and dronedarone, also being investigated to reduce the burden of NVAF and cardioembolic stroke. Additional clinical data are needed to more clearly define the role of these drugs for stroke prevention in NVAF.

Case Fatality Rates of Recurrent Thromboembolism and Bleeding in Patients Receiving Direct Oral Anticoagulants for the Initial and Extended Treatment of Venous Thromboembolism: A Systematic Review.

BACKGROUND: In patients with venous thromboembolism (VTE), the study of the case fatality rate (CFR) of VTE recurrences and bleeding complications may be of help to balance the risks and benefits of anticoagulant therapy. OBJECTIVE: To investigate the CFR with the direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, and edoxaban) in patients with VTE. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials testing the DOACs versus standard initial treatment of VTE (parenteral anticoagulant for ≥5 days plus vitamin K antagonists [VKAs] for ≥3 months) and DOACs versus placebo or VKA for extended treatment. Two investigators independently extracted the data. A random effects meta-analysis was conducted using StatsDirect software. RESULTS: Overall, 10 trials in 35 029 patients were included. During initial treatment, the rate of recurrent VTE per 100 patient-years (%/yr) and CFR (%) was similar in patients receiving DOACs or standard therapy (4.1%/yr vs 4.4%/yr; P = .21 and 16% vs 13%; P = .61, respectively). However, major bleeding (1.8%/yr vs 3.1%/yr; P = .003), fatal bleeding (0.1%/yr vs 0.3%/yr; P = .02), and CFR (6% vs 10%; P = .18) were lower with DOACs than with standard therapy. During extended treatment, both all-cause mortality and recurrent VTE per 100 patient-years were lower with DOACs than with placebo (0.6%/yr vs 1.1%/yr; P = .01 and 1.9%/yr vs 10.9%/yr; P < .0001, respectively), but there were no statistical differences between treatments on CFR of VTE recurrences (P = .17). No fatal bleeding events were reported during extended treatment. CONCLUSION: The use of DOACs was associated with fewer major and fatal bleedings and corresponding CFR than standard initial treatment of VTE, and fewer recurrent VTEs and mortality than placebo during extended therapy, although the CFR of recurrent VTE was not reduced.

Direct oral anticoagulants in the treatment of venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review.

Pulmonary embolism (PE) is a relatively common cardiovascular emergency. PE and deep vein thrombosis (DVT) are considered expressions of the same disease, termed as venous thromboembolism (VTE). In the present review, we describe and meta-analyze the efficacy and safety data available with the direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) in clinical trials testing these new compounds in the acute/long-term and extended therapy of VTE, providing subgroup analyses in patients with index PE. We analyzed ten studies in 35,019 randomized patients. A total of 14,364 patients (41%) had index PE. In the acute/long-term treatment of VTE, the DOAC showed comparable efficacy in preventing recurrent VTE to standard treatment in patients with index PE (risk ratio [RR]: 0.88; 95% confidence interval [CI]: 0.70-1.11) and index DVT (RR: 0.93; 95% CI: 0.75-1.16) (P for subgroup differences =0.76). VTE recurrence depending on PE anatomical extension and presence/absence of right ventricular dysfunction was only reported in two trials, with results being consistent with those obtained in the overall study populations. In the single trial comparing extended therapy of VTE with DOAC versus warfarin, the point estimate for recurrent VTE tended to disfavor the DOAC in patients with index PE (RR: 2.05; 95% CI: 0.83-5.03) and in patients with index DVT (RR: 1.11; 95% CI: 0.49-2.50) (P for subgroup differences =0.32). In trials that compared DOAC versus placebo for extended therapy, the reduction in recurrent VTE was consistent in patients with PE (RR: 0.15; 95% CI: 0.01-1.82) and in patients with DVT (RR: 0.25; 95% CI: 0.10-0.61) (P for subgroup differences =0.71). The DOAC were associated with a consistently lower risk of clinically relevant bleeding (CRB) than standard treatment of acute VTE and higher risk of CRB than placebo for extended therapy of VTE regardless of index event. In summary, the DOAC were as effective as, and safer than, standard treatment of (hemodynamically stable) PE. Their efficacy in preventing recurrent VTE seemed consistent regardless of anatomical extension of PE (extensive, intermediate, or limit) or presence/absence of right ventricular dysfunction although the data are limited. For extended therapy, the DOAC were more effective than placebo in preventing recurrent VTE but were associated with an increase in CRB regardless of index event.

Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis.

INTRODUCTION: Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality. MATERIALS AND METHODS: We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software). RESULTS: Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, -0.6%; 95% confidence interval -1.0% to -0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis. CONCLUSIONS: The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients.

Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups.

Background. New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation in non-valvular atrial fibrillation (NVAF). Methods. MEDLINE and CENTRAL, regulatory agencies websites, clinical trials registers and conference proceedings were searched to identify randomised controlled trials of NOAC versus warfarin in NVAF. Two investigators reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes. Relative risks (RR) and 95% confidence intervals (CI) were estimated using a random effect meta-analysis. Results. Three clinical trials in 50,578 patients were included. The risk of non-hemorrhagic stroke and systemic embolic events (SEE) was similar with the NOAC and warfarin (RR = 0.93; 95% CI = 0.83-1.04), while the risk of intracranial bleeding (ICB) with the NOAC was lower than with warfarin (RR = 0.46; 95% CI = 0.33-0.65). We found differences in the effect size on all strokes and SEE depending on geographic region as well as on non-hemorrhagic stroke, SEE, bleeding and mortality depending on time in therapeutic range. Conclusion. The NOAC seem no more effective than warfarin for prevention of nonhemorrhagic stroke and SEE in the overall NVAF population, but are generally associated with a lower risk of ICB than warfarin.

Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients.

Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in patients with cancer. Low molecular weight heparins are the preferred option for anticoagulation in cancer patients according to current clinical practice guidelines. Fondaparinux may also have a place in prevention of VTE in hospitalized cancer patients with additional risk factors and for initial treatment of VTE. Although low molecular weight heparins and fondaparinux are effective and safe, they require daily subcutaneous administration, which may be problematic for many patients, particularly if long-term treatment is needed. Studying anticoagulant therapy in oncology patients is challenging because this patient group has an increased risk of VTE and bleeding during anticoagulant therapy compared with the population without cancer. Risk factors for increased VTE and bleeding risk in these patients include concomitant treatments (surgery, chemotherapy, placement of central venous catheters, radiotherapy, hormonal therapy, angiogenesis inhibitors, antiplatelet drugs), supportive therapies (ie, steroids, blood transfusion, white blood cell growth factors, and erythropoiesis-stimulating agents), and tumor-related factors (local vessel damage and invasion, abnormalities in platelet function, and number). New anticoagulants in development for prophylaxis and treatment of VTE include parenteral compounds for once-daily administration (ie, semuloparin) or once-weekly dosing (ie, idraparinux and idrabiotaparinux), as well as orally active compounds (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). In the present review, we discuss the pharmacology of the new anticoagulants, the results of clinical trials testing these new compounds in VTE, with special emphasis on studies that included cancer patients, and their potential advantages and drawbacks compared with existing therapies.

Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons.

OBJECTIVE: To analyse clinical outcomes with new oral anticoagulants for prophylaxis against venous thromboembolism after total hip or knee replacement. DESIGN: Systematic review, meta-analysis, and indirect treatment comparisons. DATA SOURCES: Medline and CENTRAL (up to April 2011), clinical trials registers, conference proceedings, and websites of regulatory agencies. STUDY SELECTION: Randomised controlled trials of rivaroxaban, dabigatran, or apixaban compared with enoxaparin for prophylaxis against venous thromboembolism after total hip or knee replacement. Two investigators independently extracted data. Relative risks of symptomatic venous thromboembolism, clinically relevant bleeding, deaths, and a net clinical endpoint (composite of symptomatic venous thromboembolism, major bleeding, and death) were estimated using a random effect meta-analysis. RevMan and ITC software were used for direct and indirect comparisons, respectively. RESULTS: 16 trials in 38,747 patients were included. Compared with enoxaparin, the risk of symptomatic venous thromboembolism was lower with rivaroxaban (relative risk 0.48, 95% confidence interval 0.31 to 0.75) and similar with dabigatran (0.71, 0.23 to 2.12) and apixaban (0.82, 0.41 to 1.64). Compared with enoxaparin, the relative risk of clinically relevant bleeding was higher with rivaroxaban (1.25, 1.05 to 1.49), similar with dabigatran (1.12, 0.94 to 1.35), and lower with apixaban (0.82, 0.69 to 0.98). The treatments did not differ on the net clinical endpoint in direct or indirect comparisons. CONCLUSIONS: A higher efficacy of new anticoagulants was generally associated with a higher bleeding tendency. The new anticoagulants did not differ significantly for efficacy and safety.