Clinical Research Study
Rivaroxaban Versus Warfarin and Risk of Post-Thrombotic Syndrome Among Patients with Venous Thromboembolism

https://doi.org/10.1016/j.amjmed.2018.01.041Get rights and content

Abstract

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.

Introduction

Post-thrombotic syndrome is a chronic burdensome complication of venous thromboembolism.1, 2, 3, 4 The clinical presentation is diverse and ranges from lower-extremity edema to chronic debilitating pain, intractable edema, and venous ulcers in the most severe cases, occurring in approximately 5% of patients.1 These symptoms generally develop after 3 to 6 months, but may occur up to 2 years or later after venous thromboembolism.5

The pathogenesis of post-thrombotic syndrome is complex and not fully understood. Proposed mechanisms involve obstruction of venous outflow due to impaired thrombus resolution and a thrombus-induced inflammatory response with damage of venous valves and vein wall fibrosis causing reflux and venous hypertension.5 Subtherapeutic anticoagulation with warfarin has been associated with a 2- to 3-fold increased risk of post-thrombotic syndrome by a dose-response relation with time in the subtherapeutic range.6, 7 This is a concern because studies have shown that patients with venous thromboembolism treated with warfarin spend at least one third of the time on treatment outside the target international normalized ratio range of 2.0 to 3.0, with a majority as under anticoagulation.8 Recent randomized controlled trials9, 10 and observational studies11, 12, 13, 14 have shown that rivaroxaban is an effective alternative to warfarin for reducing recurrent venous thromboembolism. It is plausible that rivaroxaban is also associated with reduced incidence of post-thrombotic syndrome compared with warfarin because of its rapid onset and more predictable pharmacokinetics. The few prior studies have indicated lower rates of post-thrombotic syndrome in patients given rivaroxaban compared with warfarin.15, 16, 17

Given the considerable morbidity and costs caused by post-thrombotic syndrome, any means to reduce the occurrence may have major public health implications. We investigated rates of post-thrombotic syndrome associated with rivaroxaban versus warfarin using a nationwide Danish cohort of patients with incident venous thromboembolism who were naïve to oral anticoagulant treatment.

Section snippets

Source Population and Data Sources

The source population comprised the entire population of Denmark encompassing 5.6 million inhabitants. Almost all treatment in Denmark (hospitalization, outpatient, and emergency) is provided free of charge by a tax-funded health care system. As a result, data on diagnoses and prescription claims are compiled in longitudinal national registries allowing a true nationwide population-based study. Each resident of Denmark is assigned a unique civil registration number, which we used to retrieve

Results

We identified 38,992 patients with incident venous thromboembolism. After exclusions, the final study population comprised 19,957 oral anticoagulation–naïve patients with venous thromboembolism, of whom 45.5% had pulmonary embolism (approximately similar proportion for warfarin and rivaroxaban) (Figure 1). A total of 11,390 patients (57.1%) received warfarin, and 8567 patients (42.9%) received rivaroxaban. Baseline characteristics varied little by treatment regimen (Table 1): Patients receiving

Discussion

This nationwide cohort study of patients with incident venous thromboembolism who were naïve to oral anticoagulant treatment demonstrated lower rates of post-thrombotic syndrome among patients with rivaroxaban therapy compared with warfarin; this finding was consistent across types of venous thromboembolism, although not statistically significant. The association was not mediated solely by an effect on recurrent events because the association remained consistent in analyses conducted to assess

Conclusion

We found that treatment with rivaroxaban after incident venous thromboembolism was associated with reduced rates of post-thrombotic syndrome compared with warfarin, although our findings were not statistically significant. This association was not mediated only by an effect of rivaroxaban on rates of recurrent venous thromboembolism. Because post-thrombotic syndrome is associated with substantial disability and reduced quality of life, our findings have potentially important clinical and

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    Funding: The Obel Family Foundation partly funded this research by an unrestricted grant. The sponsor had no role the design and conduct of the study; collection, management, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.

    Conflicts of Interest: TBL has served as an investigator for Janssen Scientific Affairs, LLC, and Boehringer Ingelheim, and has been on the speaker bureaus for Bayer, BMS/Pfizer, Roche Diagnostics, Boehringer Ingelheim, and Takeda Pharma. FS has been a consultant for Bayer. PBN has received speaking fees from Boehringer Ingelheim, consulting fees from Bayer, and grant support from BMS/Pfizer. CIC has received grant funding and consulting fees from Bayer AG, Janssen Pharmaceuticals, and Boehringer Ingelheim Pharmaceuticals.

    Authorship: All authors had access to the data and played a role in writing this manuscript.

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