Aspirin for Preventing the Recurrence of Venous Thromboembolism

Division of Internal and Cardiovascular Medicine and Stroke Unit, Department of Internal Medicine, University of Perugia, Perugia, Italy.
New England Journal of Medicine (Impact Factor: 55.87). 05/2012; 366(21):1959-67. DOI: 10.1056/NEJMoa1114238
Source: PubMed


About 20% of patients with unprovoked venous thromboembolism have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy. Extending anticoagulation prevents recurrences but is associated with increased bleeding. The benefit of aspirin for the prevention of recurrent venous thromboembolism is unknown.
In this multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked venous thromboembolism who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment. The primary efficacy outcome was recurrence of venous thromboembolism, and major bleeding was the primary safety outcome.
Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 taking placebo had a recurrence (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups.
Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. (Funded by the University of Perugia and others; WARFASA number, NCT00222677.).

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    • "Study Treatment regimens Duration, months N (included) Patients characteristics Efficacy outcome Safety outcome Male Age, mean (SD) RE-MEDY [28] Dabigatran 150 mg Warfarin 18–36 2856 61% 55.4 ± 15.0 53.9 ± 15.3 Recurrent VTE 1.8% dabigatran, 1.3% warfarin Major bleeding: 0.9% dabigatran, 1.8% warfarin WARFASA [16] Aspirin 100 mg daily Placebo ≥ 24 402 63% 62 ± 15 Recurrent VTE 13.7% aspirin, 21.8% placebo Major bleeding: 0.5% aspirin, 0.5% placebo ASPIRE [15] Aspirin 100 mg daily Placebo 4 yrs (actual 27) 822 54% Median 54 Recurrent VTE 13.9% aspirin, 17.8% placebo Major bleeding: 1.1% aspirin, 1.5% placebo AMPLIFY-Ext, [29] Apixaban 5 mg and 2.5 mg Placebo 12 2486 58% 56 ± 15 Recurrent VTE 1.7% apixaban, 8.8% placebo Major bleeding 0.2% apixaban, 0.5% placebo RE-SONATE [28] Dabigatran 150 mg Placebo 6 1343 55% 56.1 ± 15.5 55.5 ± 15.1 Recurrent VTE 0.4% dabigatran, 5.5% placebo Major bleeding: 0.3% dabigatran, 0.0% placebo EINSTEIN-Ext [12] Rivaroxaban 20 mg Placebo 6–12 1196 58% 58 ± 16 Recurrent VTE 1.3% rivaroxaban, 7% placebo Major bleeding 0.7% rivaroxaban, 0.0% placebo Agnelli, 2001 [31] Observation* VKA 37.8 134 54.5% 66.8 ± 6.7 Recurrent VTE 15.7% in the extended VKA arm Major bleeding 3% in the extended VKA arm Agnelli, 2003 [30] Observation* VKA 34.9 165 39.4% 62.9 ± 16.3 Recurrent VTE 9.1% in the extended VKA arm Major bleeding 1.8% in the extended VKA arm Schulman, 1997 [32] Observation* VKA 48 116 59% 64 ± 12.5 Recurrent VTE 2.6% in the extended VKA arm Major bleeding 8.6% in the extended VKA arm Schulman, 2003 [33] Ximelagatran* Placebo 18 611 51% 58 ± 15 Recurrent VTE 11.6% in the extended placebo arm Major bleeding 18.2% in the extended placebo arm Kearon, 1999 [34] Placebo VKA 24 162 53% 58 ± 16 Recurrent VTE 1.3% in the extended VKA arm Major bleeding 3.8% in the extended VKA arm Ridker, 2003 [35] Placebo Low intensity VKA* 6.5 253 47.1% 54.25 Recurrent VTE 14.6% in the extended placebo arm Major bleeding 0 "
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    ABSTRACT: The duration of anticoagulation after venous thromboembolic events (VTE) is based on the balance between the risk of recurrent VTE and bleeding. The purpose of this study was to estimate the frequency and case-fatality rate of major bleeding and recurrent VTE during secondary prevention of VTE. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched through September 2014. Two reviewers independently screened citations to identify trials that enrolled patients for secondary prevention of VTE with direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs), aspirin or placebo. Two reviewers independently extracted data onto standardized forms. Twelve RCTs that enrolled 10,542 patients were included. The rate of major bleeding was 1.6 per 100 patient-years (95% CI, 1.2-2.1), and 0.58 per 100 patient-years (95% CI, 0.24-1.1) on VKAs and DOACs, respectively, with an incidence rate ratio of 0.35 (95% CI, 0.17-0.68, p=0.0023). The case-fatality rates for DOACs and VKAs were not significantly different at 0% (95% CI, 0.0-15.4) and 6.8% (95% CI, 1.4-18.6), respectively. The rate of recurrent VTE was not different between DOACs and VKA, IRR 0.88 (95% CI, 0.15-4.8, p=0.88). Case-fatality rates for recurrent VTE for DOAC and VKAs were 10.8% (95% CI, 4.4-20.9) and 5.6% (95% CI, 1.2-15.4), respectively. Only DOACs showed a significant reduction in the composite outcome of fatal recurrent VTE and fatal bleeding when compared to placebo, IRR 0.40 (95% CI, 0.14-1.0, p=0.03). Case-fatality rates for major bleeding and recurrent VTE for DOACs appear to be similar to those for VKA and the composite of fatal events is lower for DOACs than placebo. Overall, given the favorable safety profile and comparable efficacy of DOAC therapy, the threshold to continue anticoagulation with DOACs after unprovoked VTE should be low if the baseline risk of anticoagulation-related bleeding is not high. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Dec 2014 · Thrombosis Research
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    • "We tried to adjust carefully to possible confounding factors. Acetylsalicylic acid was recently shown to be useful in preventing VTE recurrences [37] [38]. In our cohort the variable " antiplatelet drug " , which was low-dose acetylsalicylic acid in 99.1% of the cases, was unevenly distributed between patients with and without statins (51.2 vs. 10.0%). "
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    ABSTRACT: Introduction Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study. Materials and Methods Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE. Results Patients (n = 1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n = 96) and atorvastatin (n = 48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p = 0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Gray’s test: p = 0.04) Conclusion This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials.
    Full-text · Article · Sep 2014 · Thrombosis Research
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    • "Nevertheless, it appears that venous thrombosis and arterial thrombosis are not completely separate entities. Becattini et al. demonstrated a 40% decrease in DVT recurrence rate by initiating antiplatelet therapy after cessation of warfarin therapy for DVT [20]. "
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    Full-text · Article · Aug 2014
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