Efficacy Of Direct Oral Anticoagulants In Patients Research Articles

Direct oral anticoagulants versus vitamin k antagonists in patients with atrial fibrillation and bioprosthesis: a systematic review and meta-analysis

Abstract Background/Introduction The large randomized clinical trials published to date have shown that direct oral anticoagulants (DOACs) are as or more effective than vitamin K antagonists (VKAs) in the prevention of thromboembolic events in atrial fibrillation (AF) and generally show a better bleeding risk profile. However, patients with bioprosthetic valves have been underrepresented in RCTs. The aim of this study was to assess the safety and efficacy of DOAC in patients with AF and bioprosthetic valves through a systematic review and meta-analysis including recent evidence from comparative cohort studies and real-world results. Methods A systematic review of the scientific literature and a subsequent meta-analysis were carried out. We included RCTs or comparative observational studies, published from January 2017 to January 2022 comparing DOACs versus vitamin K antagonists in patients with AF or atrial flutter and bioprostheses. We collected data of all-cause mortality, major bleeding, and systemic embolism. The primary outcome of interest was all-cause mortality. Secondary outcomes were systemic embolism or stroke. The primary safety outcome was major bleeding. Results Our analysis included 12 studies, 4 RCTs and 8 observational studies that enrolled a total of 30.283 patients. All-cause mortality 6 observational and 3 RCT were combined. A 9% reduction was found for all-cause mortality in patients treated with DOACs (HR,0.91; P=.0068;95%CI,0.85–0.97;I2=8%). Stroke and systemic embolism 4 RCT and 8 observational studies were combined. No evidence showing a significant effect of DOAC therapy on risk reduction for stroke and embolism was obtained (HR, 0.87; P =.29; 95%CI, 0.67–1.14; I2=45%). Major bleeding The results of the 12 studies were combined. A robustness analysis was performed, and the ENVISAGE RCT was identified as atypical. We therefore proceeded to re-run the meta-analysis without this study’s results. The overall effect size was HR, 0.79 (P = .0001; 95%CI, 0.73-0.85; I2 = 0%), with a 21.1% reduction of major bleeding with DOAC therapy compared with VKA. The present study has several limitations. It has the inherent limitations of the studies included and the combination of findings from comparative observational cohort studies and ad hoc studies from RCTs, which entails a potential source of bias. Second, individual risks for each type of bioprosthesis were not studied. Finally, the four currently marketed DOACs were included in our meta-analysis, but their efficacy and safety were not evaluated separately. Conclusions Our study found that DOAC therapy is associated with a significant reduction of all-cause mortality with no significant increase in the risk of systemic embolism or stroke. This reduction could be attributed to a decrease in major bleeding. Our results therefore suggest that DOACs could be a safer alternative than VKAs in this group of patients.

Safety and Efficacy of DOACs in Patients with Advanced and End-Stage Renal Disease.

The prevalence of chronic kidney disease (CKD) is increasing due to the aging of the population and multiplication of risk factors, such as hypertension, arteriosclerosis and obesity. Impaired renal function increases both the risk of bleeding and thrombosis. There are two groups of orally administered drugs to prevent thromboembolic events in patients with CKD who require anticoagulation: vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). Although VKAs remain the first-line treatment in patients with advanced CKD, treatment with VKAs is challenging due to difficulties in maintaining the appropriate anticoagulation level, tendency to accelerate vascular calcification and faster progression of CKD in patients treated with VKAs. On the other hand, the pleiotropic effect of DOACs, including vascular protection and anti-inflammatory properties along with comparable efficacy and safety of treatment with DOACs, compared to VKAs observed in preliminary reports encourages the use of DOACs in patients with CKD. This review summarizes the available data on the efficacy and safety of DOACs in patients with CKD and provides recommendations regarding the choice of the optimal drug and dosage depending on the CKD stage.

Secondary prophylaxis of venous thromboembolism with direct oral anticoagulants: comparison between patients with major congenital thrombophilia versus non-thrombophilic patients.

Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Congenital thrombophilia is a condition that predisposes to a higher incidence of VTE and often requires long-term anticoagulation for secondary prophylaxis. It is less clear the efficacy of DOACs in patients with major thrombophilia. The aim of our study was to evaluate the efficacy and safety of full and reduced DOACs dose for VTE secondary prophylaxis, in patients affected by major congenital thrombophilia compared to a control group of patients with idiopathic recurrent VTE without thrombophilia. We retrospectively evaluated consecutive patients who required long-term anticoagulation for recurrent VTE, treated with DOACs, and compared the outcomes between patients affected by major thrombophilia and the control group. The examined patients were 209. The median time of DOACs therapy was 20months (range 6-90). Two (2.7%) thrombotic events were observed in the subset affected by major congenital thrombophilia (n = 72) and five (3.6%) in the control group (n = 137) (p 0.73). Four (5.5%) hemorrhagic events were reported in the group with major thrombophilia; 21 (15.3%) in the other group (p 0.039). No statistically significant differences were observed in terms of efficacy and safety between DOACs at full and reduced dose. Our data suggest that DOACs may be effective and safe in the secondary VTE prophylaxis in patients affected by major congenital thrombophilia, also at reduced dose.

Direct oral anticoagulation in atrial fibrillation and heart valve surgery-a meta-analysis and systematic review.

Aims:Oral anticoagulation with direct oral anticoagulants (DOAC) could provide an alternative to vitamin K antagonists (VKA) for patients with atrial fibrillation (AF) undergoing bioprosthetic heart valve replacement or valve repair.Methods and results:The aim of this meta-analysis was to review the safety and efficacy of DOAC in patients with surgical implanted bioprosthetic heart valves or valve repairs and AF including data from six clinical trials with a total of 1,857 patients. The efficacy and safety data of DOAC and VKA were pooled to perform random-effects meta-analyses using the Mantel–Haenszel method with pooled risk ratios (RR) and 95% confidence interval (CI). A trial sequential analysis (TSA) was performed to assess statistical robustness. Death caused by cardiovascular cause or thromboembolic events were comparable (RR 0.67, 95% CI: 0.42–1.08; p = 0.10) as DOAC significantly reduced the risk for major bleeding (RR 0.55, 95% CI: 0.35–0.88; p = 0.01) and thromboembolic stroke or systemic embolism rates (RR 0.54, 95% CI: 0.32–0.90; p = 0.02). Rates for intracranial bleeding and hemorrhagic stroke (RR 0.27, 95% CI: 0.07–0.99; p = 0.05) show a trend toward fewer events in the DOAC group. Outcomes for major or minor bleeding events and all-cause mortality were comparable for DOAC and VKA.Conclusion:Cumulative data analysis reveals that DOAC may provide an effective and safe alternative to VKA in patients with AF after surgically implanted bioprosthetic heart valves or repair with AF. Within a relatively heterogeneous study population, this meta-analysis shows a risk reduction of major bleedings and thromboembolic stroke or systemic embolisms for DOAC.

Safety and Efficacy of Direct Oral Anticoagulants in Patients With Moderate to Severe Cirrhosis.

Direct oral anticoagulants (DOACs) remain mostly investigational in patients with moderate to severe hepatic cirrhosis, yet are often selected over traditional anticoagulants including warfarin and enoxaparin in this setting. To determine the safety and efficacy of DOACs in patients with moderate to severe hepatic cirrhosis as compared with traditional anticoagulation. This was a retrospective, single-center cohort study evaluating inpatients and outpatients who were prescribed a DOAC, warfarin, or enoxaparin for therapeutic anticoagulation with Child-Turcotte-Pugh (CTP) B or C status at the time that the prescription was written. Included patients were followed until first bleeding or thromboembolic event, or until discontinuation of anticoagulation therapy. Data were collected by manual chart review. The primary outcomes included both bleeding events and thromboembolic events in the DOAC population as compared with traditional anticoagulation. A total of 101 patients were included in the study, 69 treated with DOAC therapy and 32 with traditional anticoagulation. Bleeding events occurred in 36% of patients in the DOAC group and 22% of patients in the traditional group (P = 0.149). In both groups, bleeds were most commonly gastrointestinal. Thromboembolic events occurred in 4% of the DOAC population and no patients in the traditional population (P = 0.55). No fatal bleeding or thromboembolic events occurred. DOACs do not appear to be more harmful than traditional anticoagulation in patients with CTP B or C status. These results support the use of DOACs in patients with CTP B or C hepatic cirrhosis when considering safety, efficacy, and convenience.

Adverse Events in Patients with Cancer Treated with Direct Oral Anticoagulants and Cancer Therapy

IntroductionFour direct oral anticoagulants (DOAC) have been approved for the treatment of venous thromboembolism VTE and prevention of stroke in patients with non-valvular atrial fibrillation (NVAF) in the USA: rivaroxaban, apixaban, edoxaban and dabigatran. Data regarding efficacy and safety of DOAC in the cancer population however are currently limited to very small cohorts in the large randomized trials for treatment of VTE in which many cancer patients did not meet eligibility requirements, or to retrospective studies and quality improvement initiatives. Despite major consensus guidelines recommending low molecular weight heparin (LMWH) as the preferred treatment for cancer-associated VTE, DOAC are commonly prescribed for cancer patients in both community and academic settings. Data on the safety and efficacy of DOAC in patients getting active cancer treatment are lacking. We aimed to characterize the use of DOAC in patients managed at an academic comprehensive cancer center, to examine the incidence of thrombotic and bleeding events among patients receiving active cancer therapy during the study period.MethodsFollowing IRB approval, a retrospective chart review was performed in patients treated at an academic comprehensive cancer center. Patients >18 years old who had a prescription written for a DOAC between June 2015 and December 2016 were identified. Patients were included if they were receiving DOAC for NVAF, acute VTE, and secondary prevention and had active cancer. Patients were assessed for baseline demographics, indications for anticoagulation, DOAC management strategies, arterial and venous thrombotic events and bleeding complications during treatment with DOAC. Descriptive statistics were used to analyze study outcomes.ResultsOf the 721 patients screened, 392 were patients with cancer of which 241 s were actively being treated with chemotherapy while on DOAC. The other 151 patients were not actively receiving treatment. VTE was the most common indication for DOAC use in 75% of cancer patients (n=297), followed by NVAF in20% (n=78). There were 15 patients with history of both NVAF and VTE, and 2 patients with TIA. Apixaban was used in 48% of patients; rivaroxaban in 47%; dabigatran in 4%, and edoxaban < 1%.Of the 392 evaluated cancer patients, 15 (3.83%) experienced thrombotic events with 11/15 new or recurrent VTE, 3/15 stroke, and 1/15 myocardial infarction while on DOAC. The VTE rate was strikingly higher in those patients receiving active cancer treatment at 4.15% compared to 0.66% in those not getting treatment. The rate of major bleeding and clinically overt bleeding was not different between the 2 groups and was approximately 4.5%. (table 1)ConclusionWe found in our retrospective analysis of DOAC use in cancer patients, that patients getting active cancer treatment had higher rates of primarily venous and arterial thrombotic events while treated with DOAC compared to those patients not getting active cancer treatment. The rate of VTE at 4.14% compares favorably with published rates for VTE recurrence for LMWH and VKA in randomized controlled trials and is roughly 7 times higher than the rate in our patients with cancer treated with DOAC but not getting active cancer treatment. Despite differences in rates of thrombotic events, the bleeding rates were the same, and also comparable to published rates, confirming the known increased risk of bleeding in cancer patients. While our results are promising, dedicated randomized controlled trials comparing DOAC to LMWH are required to truly determine the efficacy and safety of DOAC in cancer patients simultaneously receiving cancer treatment. [Display omitted] DisclosuresConnors:BMS: Consultancy, Other: Scientific Advisory Board; Pfizer/BMS -Alliance: Other: Independent review committe; Unum Therapeutics: Other: Data Safety Monitoring Board; boehringer Ingelheim: Other: Scientific Advisory Board.

Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation and Weighing ≥ 120 Kilograms versus 60-120 Kilograms.

Direct oral anticoagulants (DOACs) have become favorable choices for anticoagulation due to their fixed-dose schedule, limited need for monitoring, and non-inferiority or superiority to warfarin. DOACs are currently not recommended in patients with a body weight ≥120 kg or body mass index ≥40 kg/m2 due to limited data regarding safety and efficacy. The aim of this study was to compare the safety and efficacy of DOACs in patients with nonvalvular atrial fibrillation (NVAF) and weighing ≥120 kg with those weighing <120 kg. A single-center, retrospective study was conducted in patients weighing ≥120 kg who received either apixaban, dabigatran, or rivaroxaban for stroke risk reduction in NVAF, and matched to patients who weighed <120kg. The primary outcome was the incidence of stroke, deep vein thrombosis, pulmonary embolism, or myocardial infarction, while the safety outcome was the incidence of major or clinically relevant non-major bleeding based on the International Society on Thrombosis and Haemostasis (ISTH) definitions. A total of 318 patients weighing ≥120 kg with NVAF and meeting the inclusion criteria were evaluated and matched with 318 patients weighing <120 kg. The primary outcome occurred in 2.5% of patients in the ≥120 kg group and in 3.1% of patients in the <120 kg group (p=0.632). The safety outcome occurred in 5.3% and 6.6% of patients in these respective groups (p=0.503). Apixaban, dabigatran, or rivaroxaban may be well-tolerated and effective anticoagulant options in patients with NVAF weighing ≥120 kg.

Safety and efficacy of direct oral anticoagulants under long-term immunosuppressive therapy after liver, kidney and pancreas transplantation.

The safety of direct oral anticoagulants (DOACs) in patients after solid organ transplantation (SOT) is not well defined. This study aimed at describing the safety and efficacy of DOACs in patients after SOT. Patients after kidney and/or liver transplantation under maintenance immunosuppression treated with rivaroxaban (n=26), apixaban (n=20) and edoxaban (n=1) were included. Clinical data were collected retrospectively and using a questionnaire. DOAC plasma levels and thrombin generation (TG) were measured in patients after SOT and compared with nontransplanted controls receiving DOACs. DOACs were administered for 84.6 patient-years. Mean immunosuppressive trough levels after DOAC initiation increased from baseline by 18.8±29.6% compared to 3.0±16.5% in matched controls (P=0.004), without significant differences in dose adjustments. No transplant rejection or significant change in liver or renal function was observed. There was one major bleeding after the observation period but no thromboembolic complication. DOAC plasma levels reached the expected range in all patients. The intrinsic hemostatic activity in transplanted patients was higher compared to nontransplant controls. Treatment with DOACs after SOT is safe and effective. Immunosuppressive trough levels should be monitored after DOAC initiation, particularly in the early phase after SOT. These data should be confirmed in a prospective study.

Direct Oral Anticoagulants in Select Patients With Hypercoagulable Disorders.

To summarize the literature assessing the safety and efficacy of direct oral anticoagulants (DOACs) for the acute treatment and secondary prevention of venous thromboembolism (VTE) in select patients with hypercoagulable disorders. An electronic PubMed literature search was conducted from January 2010 to July 2020 using the following keywords: DOAC, rivaroxaban, apixaban, dabigatran, edoxaban, thrombophilia, cancer, antiphospholipid syndrome, protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden, prothrombin G20210A gene mutation, congenital thrombophilia, hypercoagulable, hereditary thrombophilia, acquired thrombophilia. Articles were included if they reported clinical outcomes associated with cancer-associated VTE, antiphospholipid syndrome (APS), and other hereditary thrombophilias. The safety and efficacy of using a DOAC is highly dependent on the type of hypercoagulable disease state. Current trials support the use of edoxaban, rivaroxaban, and apixaban for the treatment of cancer-associated thrombosis (CAT), with apixaban being preferred because of lower bleeding rates compared with standard of care. The use of DOACs, especially rivaroxaban, have been associated with worse outcomes in patients with APS, whereas data on DOAC use in hereditary thrombophilia remains scarce and limited to low-risk patients. This review evaluates the literature assessing the safety and efficacy of DOACs in patients with various hypercoagulable disorders. The current body of evidence supports the use of select DOACs for the treatment of CAT. In contrast, DOAC use in patients with APS and hereditary thrombophilia should be avoided at this time.

Outcomes of Direct Oral Anticoagulants in Patients With Mitral Stenosis

BackgroundPatients with mitral stenosis and atrial fibrillation (AF) require anticoagulation for stroke prevention. Thus far, all studies on direct oral anticoagulants (DOACs) have excluded patients with moderate to severe mitral stenosis. ObjectivesThe aim of this study was to validate the efficacy of DOACs in patients with mitral stenosis. MethodsThe study population was enrolled from the Health Insurance Review and Assessment Service (HIRA) database in the Republic of Korea, and it included patients who were diagnosed with mitral stenosis and AF and either were prescribed DOACs for off-label use or received conventional treatment with warfarin. The primary efficacy endpoint was ischemic strokes or systemic embolisms, and the safety outcome was intracranial hemorrhage. ResultsA total of 2,230 patients (mean age 69.7 ± 10.5 years; 682 [30.6%] males) were included in the present study. Thromboembolic events occurred at a rate of 2.22%/year in the DOAC group, and 4.19%/year in the warfarin group (adjusted hazard ratio for DOAC: 0.28; 95% confidence interval: 0.18 to 0.45). Intracranial hemorrhage occurred in 0.49% of the DOAC group and 0.93% of the warfarin group (adjusted hazard ratio for DOAC: 0.53; 95% confidence interval: 0.22 to 1.26). ConclusionsIn patients with AF accompanied with mitral stenosis, DOAC use is promising and hypothesis generating in preventing thromboembolism. Our results need to be replicated in a randomized trial.

Anticoagulation prescribing patterns in patients with cancer.

Cancer is a known hypercoagulable state that leads to an increased risk of venous thromboembolism (VTE). Low molecular weight heparin remains the preferred anticoagulant for VTE in patients with cancer over vitamin K antagonist. However, the preferred anticoagulant in prevention of stroke and systemic embolism in atrial fibrillation (AF) in patients with cancer has yet to be determined. The direct oral anticoagulants (DOACs) are increasingly being utilized; however their role in cancer has only recently been investigated. The objective of this retrospective cohort was to describe real-world anticoagulation prescribing patterns in cancer patients at a large academic medical center between January 1, 2013 and October 31, 2016. We sought to assess the safety, tolerability, and efficacy of DOACs in patients with cancer for either VTE and/or AF. Patient demographic, clinical characteristics, as well as bleeding and thrombotic events were collected. There were 214 patients in our analysis, of which 71 patients (33%) received a DOAC [apixaban (n = 22), dabigatran (n = 17), and rivaroxaban (n = 32)]. There were fewer bleeding events and/or discontinuations in the DOAC group compared to enoxaparin (13 vs. 27, p = 0.022). There was no difference in major or minor bleeds or thromboembolic events in comparing DOAC to enoxaparin or DOAC to warfarin. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs compared to warfarin or enoxaparin in patients with cancer. DOACs may represent an alternative to warfarin or enoxaparin in patients with cancer for VTE and/or stroke reduction in AF.

Use of direct oral anticoagulants in patients on immunomodulatory agents.

Immunomodulatory agents (IMiDs) are used to treat multiple hematologic malignancies. Their use is also associated with increased risk of venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) have been increasingly utilized but due to their relative novelty, their role in malignancy has only been recently investigated. The objective of this study was to assess the safety and efficacy of DOACs in patients receiving IMiDs. This was a retrospective study of patients at our institution treated with an IMiD and concomitant warfarin or DOAC between January 1, 2010 and December 31, 2015. Information on demographic and clinical characteristics was collected. Separate encounters were collected for each specific combination of IMiD and anticoagulant. Bleeding and thrombotic events were recorded. There were four bleeding events in the DOAC group; all were non-major. There were six bleeding events in the warfarin group, two of which were major (gastrointestinal bleeding (GIB) and subarachnoid hemorrhage (SAH)) and four of which were non-major. Of the two major bleeds in this group, neither event occurred with concomitant antiplatelet therapy. There was one thrombotic event in the DOAC group, which was a myocardial infarction, suspected to be related to carfilzomib. There were no thrombotic events in the warfarin group. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs as compared to warfarin in patients on IMiDs. DOACs may represent an attractive alternative to warfarin for VTE prophylaxis in patients on IMiDs but prospective studies in this population are warranted.