Characteristics of patients receiving extended treatment after incident venous thromboembolism.

Given high recurrence risk after venous thromboembolism (VTE), guidelines recommend extended dose rivaroxaban (10 mg OD) or apixaban (2.5 mg BID) to be considered after 6 months of initial treatment. This study aimed to provide insight into clinical practice regarding the use of extended preventive treatment and to describe duration of the initial treatment. Linkage of nationwide health registers identified all in- and outpatients with VTE from April 2017 through 2018. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated adjusting for other VTE-related factors. The study included 6030 patients with VTE. Among rivaroxaban users, 2.2% (n = 113) received the extended 10-mg dose after mean 9.4 (SD 3.1) months of standard treatment. For apixaban, 4.7% (n = 40) received extended 2.5-mg dose after mean 8.0 months (SD 3.9). After adjustments, incident pulmonary embolism (HR 1.81 95% CI 1.12;2.91) and trauma/fracture (HR 1.42 95% CI 0.46;4.43) were associated with switching to extended dose, whereas patients with unprovoked VTE were less likely to receive the extended dose (HR 0.68 95% CI 0.30;1.55). Less than 3% of patients with incident VTE received extended treatment after initial standard treatment. Even though international guidelines suggest that the risk-benefit balance is in favour of extended VTE treatment, this was yet to be translated into clinical practice as of 2018. Studies using contemporary data are warranted to investigate routine clinical practice of extended treatment for VTE recurrence.

Cancer-associated venous thromboembolism and the non-vitamin K antagonist oral anticoagulants: a review of clinical outcomes and patient perspectives.

INTRODUCTION: Cancer-associated venous thromboembolism remains an important but challenging aspect in the treatment of patients with cancer. Recently, alternatives to injection of low-molecular-weight heparin (LMWH) have been introduced, the non-vitamin K antagonist oral anticoagulants (NOACs), which could potentially alleviate patients from burdensome daily injections. AREAS COVERED: This review discusses the available evidence exploring the role of NOACs in the treatment and secondary prevention of cancer-associated venous thromboembolism, from randomized trials, observational data, contemporary guideline recommendations, and patient perspectives. EXPERT OPINION: Edoxaban, rivaroxaban, and apixaban have proven attractive alternatives to LMWH for the treatment of cancer-associated venous thromboembolism. Contemporary guidelines have promptly endorsed the use of NOACs in patients with most cancer types. Nonetheless, issues remain regarding bleeding risk, interactions with medical cancer treatment, and the effectiveness and safety for extended treatment periods. There are head-to-head comparisons of the NOACs, and therefore no data favoring the use of one NOAC over the others. Patient's preferences are highly diverse and should be part of routine considerations when weighing risks and benefits associated with various available anticoagulant drugs.

Risk of recurrence and bleeding in patients with cancer-associated venous thromboembolism treated with rivaroxaban: A nationwide cohort study.

BACKGROUND: Rivaroxaban could be an attractive alternative to low molecular weight heparin for the treatment of cancer-associated venous thromboembolism (VTE) but the safety and effectiveness remain unclear. We examined risk of recurrent VTE and major bleeding associated with rivaroxaban treatment of cancer-associated VTE. METHODS: Through linkage of nationwide Danish registries, we identified all adults with cancer-associated VTE initiating treatment with rivaroxaban, 2012-2017. We estimated rates and absolute risk of the primary outcome of recurrent VTE and major bleeding; all-cause mortality was studied as a secondary outcome. RESULTS: We identified 8901 patients with cancer-associated VTE of whom 476 (5.3%) redeemed a prescription for rivaroxaban within 30 days of VTE diagnosis (mean age 71.5 years, 41% females, 57% with pulmonary embolism). Median time from cancer diagnosis to rivaroxaban prescription was 31 days (interquartile range 12-73 days). Most frequent cancers were gastrointestinal (26.1%), genitourinary (23.3%), and hematological cancer (12.6%). Few had distant metastases (7.1%). At 6 months, recurrent VTE occurred in 6.1% (15.1 events per 100 person-years) with the highest absolute risks for genitourinary cancer (8.1%), gastrointestinal cancer (7.3%), and breast cancer (6.5%). Major bleeding occurred in 1.9% (5.3 events per 100 person-years), in particular, in genitourinary cancer (4.5%) and lung cancer (4.2%). Eighty deaths (17.8%) occurred during follow up. CONCLUSION: In this clinical practice setting, rivaroxaban was rarely used for cancer-associated VTE. However, among those who received rivaroxaban, the treatment appeared safe and effective with rates comparable to previous studies of selected populations.

Understanding the Value of Real-World Evidence: Focus on Stroke Prevention in Atrial Fibrillation with Rivaroxaban.

Real-world data are a well-recognized component within the drug lifecycle, and such data are generated from a range of sources and study designs, including claims databases, electronic health records, non-interventional studies (NIS) and registries. While this information can be of vital clinical importance, there may be challenges in understanding the relevance of the differing study designs, endpoints and populations. Here, we summarize the value of real-world evidence and considerations pertinent to their use in clinical research. Owing to the variety of analyses being conducted using real-world data, it is important for researchers and clinicians to have a clear understanding of the nature and origin of those data, and to ensure they are valid, reliable and robust in terms of extrapolating meaningful findings. There are crucial questions to address when evaluating real-world studies, and we introduce a checklist to meet these objectives. In addition to advice for appraising data quality and study designs, several updates will be covered from real-world studies of rivaroxaban for stroke prevention in patients with atrial fibrillation (AF): the nationwide Danish cohort study, U.S. Department of Defense Military Health System database, retrospective claim database study REAFFIRM and a pooled analysis from the global NIS XArelto on preveNtion of sTroke and non-central nervoUS system systemic embolism in patients with non-valvular atrial fibrillation (XANTUS). Real-world studies consistently show that rivaroxaban is an effective treatment option with acceptable safety when used for stroke prevention in a large number of patients with AF across the globe.

Rivaroxaban Versus Warfarin and Risk of Post-Thrombotic Syndrome Among Patients with Venous Thromboembolism.

BACKGROUND: The effectiveness of rivaroxaban to reduce post-thrombotic syndrome in patients with venous thromboembolism is largely unknown. We compared rates of post-thrombotic syndrome in patients given rivaroxaban versus warfarin in a cohort of patients with incident venous thromboembolism receiving routine clinical care. METHODS: We linked Danish nationwide registries to identify all patients with incident venous thromboembolism who were new users of rivaroxaban or warfarin and compared rates of post-thrombotic syndrome using an inverse probability of treatment-weighting approach to account for baseline confounding. RESULTS: We identified 19,957 oral anticoagulation-naive patients with incident venous thromboembolism treated with warfarin or rivaroxaban (mean age, 64 years; 48% were female, 45.5% had pulmonary embolism). The propensity-weighted rate of post-thrombotic syndrome at 3 years follow-up was 0.53 incidents per 100 person-years with rivaroxaban versus 0.55 per 100 person-years with warfarin, yielding a hazard rate of 0.88 (95% confidence interval, 0.66-1.17). This association remained consistent across types of venous thromboembolism (deep venous thrombosis vs pulmonary embolism, and provoked vs unprovoked venous thromboembolism) and when censoring patients with recurrent venous thromboembolism. CONCLUSIONS: In this clinical practice setting, rivaroxaban was associated with lower but statistically nonsignificant rates of post-thrombotic syndrome, which did not appear to be mediated only by an effect on recurrent venous thromboembolism.

Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin Among Patients With Atrial Fibrillation With a Single Stroke Risk Factor: A Nationwide Cohort Study.

Importance: The randomized clinical trials comparing nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin largely focused on recruiting high-risk patients with atrial fibrillation with more than 2 stroke risk factors, with only the trials testing dabigatran or apixaban including few patients with 1 stroke risk factor. Despite this, regulatory approvals of all NOACs have been based on stroke prevention for patients with atrial fibrillation with 1 or more stroke risk factors. Objective: To compare the effectiveness and safety study of standard-dose NOACs (dabigatran at 150 mg twice daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg twice daily) and warfarin in patients with atrial fibrillation with 1 low-risk, nonsex-related stroke risk factor. Design, Setting, and Participants: This nationwide observational cohort study used data from Danish registries to determine the inverse probability of treatment-weighted comparative effectiveness and safety of standard-dose NOACs (dabigatran at 150 mg twice daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg twice daily) compared with treatment with warfarin among 14 020 patients with atrial fibrillation with 1 low-risk, nonsex- related stroke risk factor. Main Outcomes and Measures: Rates of ischemic stroke/systemic embolism, death, and bleeding. Results: Of 14 020 participants, 5151 (36.7%) were women, and the median age for participants was 66.5 years. For the principal effectiveness end point of ischemic stroke/systemic embolism, no significant differences of the NOACs compared with treatment with warfarin across strata were evident. For the end point of "any bleeding," this was significantly lower for treatment with apixaban (hazard ratio [HR], 0.35; 95% CI, 0.17-0.72) and dabigatran (HR, 0.48; 95% CI, 0.30-0.77) compared with warfarin in the main analysis, and was not significantly different for treatment with rivaroxaban vs warfarin (HR, 0.84; 95% CI, 0.49-1.44). There was broad consistency across most subgroups in the sensitivity analyses and whether 1- or 2.5-year follow-up periods were analyzed. However, falsification end points generally did not falsify, indicating the possible presence of residual confounding across these comparisons, presumably related to selective prescribing and unobserved covariates. Conclusions and Relevance: In this Danish cohort study of patients with atrial fibrillation and a single stroke risk factor, there was no difference between NOACs compared with treatment with warfarin in terms of the risk of having an ischemic stroke/systemic embolism. For "any bleeding," this was lower for treatment with apixaban and dabigatran compared with warfarin. These data do not allow for a definitive statement of the comparative effectiveness or safety of NOACs because of the possible residual confounding that was unmasked with falsification outcomes.

Blood pressure and prognosis in patients with incident heart failure: the Diet, Cancer and Health (DCH) cohort study.

BACKGROUND: Our objective was to test the hypothesis that elevated blood pressure (BP) is associated with increased risk of stroke, bleeding and death in patients with incident heart failure (HF). METHODS: We conducted a prospective cohort study among subjects who were participants in the Diet, Cancer and Health study, born in Denmark, aged 50-64 years at recruitment. We assessed stroke (ischemic stroke or systemic embolic events), major bleeding, death and the composite endpoint according to degree of BP control in patients with incident HF. BP was assessed prior to HF at cohort entry. RESULTS: Of the whole cohort of 55,748 subjects, n = 2159 (35 % female) had incident HF, of which 12 % had treatment for hypertension. Median follow-up after incident HF was 3.5 years. High systolic (SBP), diastolic (DBP) and pulse (PP) pressures were associated with an increased risk of stroke, major bleeding and the composite endpoint. For death and stroke/death, the relation appeared U-shaped for SBP and DBP. When comparing the highest quartile group (Q4) to first quartile group (Q1), SBP (Q4: SBP >163 mmHg) was associated with significantly higher adjusted hazard rate ratio (HR) for stroke (HR 1.46, 95 % CI 1.00-2.14) and major bleeding (HR 1.68, 95 % CI 1.12-2.53). For DBP (Q4: DBP >94 mmHg), adjusted HR was significantly higher for major bleeding (HR 1.63, 95 % CI 1.13-2.38). The highest quartile of pulse pressure (Q4: PP >74 mmHg) was associated with non-significantly higher risk of stroke (HR 1.40, 95 % CI 0.94-2.06). CONCLUSION: We have shown for the first time that amongst a population with incident HF, higher baseline systolic, diastolic and pulse pressure levels were associated with a higher rate of adverse events. Our data support the importance for optimised BP control, as part of the holistic management of HF patients.

Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis.

OBJECTIVE: To investigate the relative effect of warfarin versus non-vitamin K oral anticoagulants (NOACs) in thrombotic and bleeding outcomes in subgroups of atrial fibrillation (AF) patients with varying degrees of renal dysfunction. METHODS: Systemic review and meta-regression analyses on NOACs versus warfarin, supplemented with indirect comparisons were conducted. The eligibility criteria for inclusion were randomised controlled trials comparing NOACs against warfarin for stroke prevention in AF patients. Outcomes of interest were stroke or systemic embolism (SE) and major bleeding. RESULTS: Five studies comprising 72,845 AF patients randomised to either a NOAC or warfarin were included in the meta-regression analysis. A shift in strata from no renal impairment to renal impairment resulted in a non-significant impact on bleeding and stroke/SE, indicating similar safety and efficacy, despite renal function status. Apixaban was associated with less major bleeding compared to dabigatran and rivaroxaban but not edoxaban in patients with moderate renal impairment. For efficacy outcomes, only dabigatran 150 mg was statistically significantly favoured compared to edoxaban 30 mg. For efficacy outcomes in mild renal impairment, both dabigatran 150 mg and rivaroxaban 10 mg (J-ROCKET) were statistically significantly favoured against edoxaban 30 mg. CONCLUSION: Non-vitamin K oral anticoagulants had similar efficacy and safety compared to warfarin across different levels of renal function. Indirect comparisons suggest that apixaban and edoxaban were associated with a better safety profile in patients with moderate renal impairment. However, caution is warranted when interpreting indirect comparisons of drugs investigated in different trials. Prescribers should fit the most appropriate NOAC to the AF patient characteristics (and vice versa) to individualise effective stroke prevention.

Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation. An indirect comparison analysis.

Large Phase 3 clinical trials for stroke prevention in atrial fibrillation (AF) have compared non-vitamin K antagonist oral anticoagulants (NOACs) against warfarin, with the edoxaban trial only recently reported. In the absence of head to head trials directly comparing these NOACs against each other, we compared the efficacy and safety of edoxaban to other agents by an indirect comparison analysis. We performed an indirect comparison analysis of edoxaban (2 dose strategies) against apixaban (1 dose), dabigatran etexilate (2 doses) and rivaroxaban (1 dose), for their relative efficacy and safety against each other. For high-dose edoxaban vs apixaban, there were no significant differences in efficacy endpoints, mortality, myocardial infarction and major bleeding. Apixaban was associated with less major or clinically relevant non-major bleeding (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.70-0.90) and gastrointestinal bleeding (HR 0.72; 95% CI 0.53-0.99). For dabigatran 110 mg twice daily, there were no significant differences in the main efficacy or safety endpoints. Dabigatran 150 mg bid was associated with lower stroke/systemic embolism (SE) (HR 0.75; 95% CI 0.56-0.99), stroke (HR 0.73; 95% CI 0.55-0.96) and haemorrhagic stroke (HR 0.48; 95% CI 0.23-0.99). There were no significant differences between high-dose edoxaban vs rivaroxaban for efficacy endpoints or mortality, but rivaroxaban had more major and/or clinically relevant non-major bleeding. When compared to low-dose edoxaban, apixaban was associated with lower stroke/SE (HR 0.70; 95% CI 0.55-0.89), stroke (HR 0.70; 95% CI 0.55-0.92) and ischaemic stroke (HR 0.65; 95% CI 0.50-0.89), but more major bleeding (HR 1.47; 95% CI 1.20-1.80). For dabigatran 110 mg bid, there were no significant differences in the efficacy endpoints, but dabigatran 110 mg bid had higher major (and gastrointestinal) bleeding. Dabigatran 150 mg bid and rivaroxaban were associated with lower stroke/SE and ischaemic stroke, but higher bleeding rates. In the present analysis, we have provided for the first time, comparisons of efficacy and safety of edoxaban against other NOACs. Notwithstanding the significant limitations of an indirect comparison analysis, some differential effects are evident with the NOACs for stroke prevention, allowing us to allow the prescriber a 'choice' to be able to fit the drug to the patient clinical profile (and vice versa).

Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation.

OBJECTIVES: This study sought to perform an indirect comparison analysis of dabigatran etexilate (2 doses), rivaroxaban, and apixaban for their relative efficacy and safety against each other. BACKGROUND: Data for warfarin compared against the new oral anticoagulants (OACs) in large phase III clinical trials of stroke prevention in atrial fibrillation (AF) are now available for the oral direct thrombin inhibitor, dabigatran etexilate, in 2 doses (150 mg twice daily [BID], 110 mg BID), and the oral Factor Xa inhibitors, rivaroxaban and apixaban. A "head-to-head" direct comparison of drugs is the standard method for comparing different treatments, but in the absence of such head-to-head direct comparisons, another alternative to assess the relative effect of different treatment interventions would be to perform indirect comparisons, using a common comparator. Nonetheless, any inter-trial comparison is always fraught with major difficulties, and an indirect comparison analysis has many limitations, especially with the inter-trial population differences and thus, should not be overinterpreted. METHODS: Indirect comparison analysis was performed using data from the published trials. RESULTS: There was a significantly lower risk of stroke and systemic embolism (by 26%) for dabigatran (150 mg BID) compared with rivaroxaban, as well as hemorrhagic stroke and nondisabling stroke. There were no significant differences for apixaban versus dabigatran (both doses) or rivaroxaban; or rivaroxaban versus dabigatran 110 mg BID in preventing stroke and systemic embolism. For ischemic stroke, there were no significant differences between the new OACs. Major bleeding was significantly lower with apixaban compared with dabigatran 150 mg BID (by 26%) and rivaroxaban (by 34%), but not significantly different from dabigatran 110 mg BID. There were no significant differences between apixaban and dabigatran 110 mg BID in safety endpoints. Apixaban also had lower major or clinically relevant bleeding (by 34%) compared with rivaroxaban. When compared with rivaroxaban, dabigatran 110 mg BID was associated with less major bleeding (by 23%) and intracranial bleeding (by 54%). There were no significant differences in myocardial infarction events between the dabigatran (both doses) and apixaban. CONCLUSIONS: Notwithstanding the limitations of an indirect comparison study, we found no profound significant differences in efficacy between apixaban and dabigatran etexilate (both doses) or rivaroxaban. Dabigatran 150 mg BID was superior to rivaroxaban for some efficacy endpoints, whereas major bleeding was significantly lower with dabigatran 110 mg BID or apixaban. Only a head-to-head direct comparison of the different new OACs would fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF.