Aspirin for the Prevention of Recurrent Venous Thromboembolism
|ClinicalTrials.gov Identifier: NCT00222677|
Recruitment Status : Unknown
Verified August 2011 by Cecilia Becattini, University Of Perugia.
Recruitment status was: Active, not recruiting
First Posted : September 22, 2005
Last Update Posted : August 23, 2011
|First Submitted Date ICMJE||September 13, 2005|
|First Posted Date ICMJE||September 22, 2005|
|Last Update Posted Date||August 23, 2011|
|Study Start Date ICMJE||May 2004|
|Estimated Primary Completion Date||January 2012 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||recurrence of VTE and/or VTE related death [ Time Frame: at least 24 months per patient ]|
|Original Primary Outcome Measures ICMJE
||Incidence of a combined endpoint of cardiovascular events and recurrence of VTE|
|Change History||Complete list of historical versions of study NCT00222677 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||recurrent VTE+ death; cardiovascular events, bleeding events, critical ischemia of the lower limbs, mesenteric infarction, all cause mortality and newly diagnosed cancer [ Time Frame: at least 24 months per patient ]|
|Original Secondary Outcome Measures ICMJE
||bleeding events, critical ischemia of the lower limbs, mesenteric infarction, all cause mortality and newly diagnosed cancer|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Aspirin for the Prevention of Recurrent Venous Thromboembolism|
|Official Title ICMJE||Aspirin After Six Months or One Year of Oral Anticoagulants for the Prevention of Recurrent Venous Thromboembolism in Patients With Idiopathic Venous Thromboembolism. The WARFASA Study.|
|Brief Summary||To determine whether aspirin is more effective than placebo for the prevention of recurrent symptomatic venous thromboembolism when given for at least two years after the initial 6-12 month of oral anticoagulant therapy in patients with idiopathic venous thromboembolism|
Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is a common disease with an annual incidence of 0.5-1.6 per 1000 in the general population.1-4 Standard treatment with intravenous or subcutaneous heparin or low molecular heparin relayed with oral anticoagulants is highly effective in preventing recurrent episodes of venous thromboembolism.5 However, oral anticoagulant therapy has a number of limitations including an increased risk of major bleeding and the need for laboratory monitoring to adjust dose. Because of these limitations, venous thromboembolism is usually treated with oral anticoagulants for a limited period of time. Anticoagulants are generally discontinued when the risks and inconvenience of remaining on treatment outweigh the risk of recurrent venous thromboembolism. Indeed, recent studies showed that after discontinuation of anticoagulant treatment, the risk of recurrent venous thromboembolism remains high in patients with idiopathic venous thromboembolism.
Recently, four major randomized trials have evaluated extended-duration treatment with oral anticoagulants in patients with venous thromboembolism. In each of these trials more than 90% of recurrences occurred after oral anticoagulants had been discontinued 6-9. The rate of recurrence after discontinuation of oral anticoagulants was similar in patients assigned long-term therapy compared with short-term therapy (about 15% in the 2-3 years after warfarin discontinuation) which indicates that although oral anticoagulants are highly effective to prevent recurrence, it have no impact on the natural history of idiopathic venous thromboembolism. Taken together, these data suggest that effective therapy should be continued indefinitely in patients with idiopathic venous thromboembolism if recurrence is to be avoided. Indeed, once oral anticoagulants are discontinued, there are currently no established safe and effective alternatives to prevent recurrence in patients with idiopathic venous thromboembolism. However, the long-term use of oral anticoagulants is not only inconvenient because of the need for close laboratory monitoring but also is constrained by an increased risk of major bleeding, including fatal and intracranial bleeding. In randomized trials of extended-duration oral anticoagulants (target INR 2.0-3.0) for the treatment of venous thromboembolism,6-9 the annual incidence of intracranial bleeding was 0.3%, major bleeding 3%, and the case-fatality rate of major bleeding approximately 10%. In addition, 5-15% of patients experienced minor bleeding each year. These data highlight the need to identify simple, safe, effective, and widely applicable strategies for the long-term prevention of recurrent deep vein thrombosis or pulmonary embolism in patients with idiopathic venous thromboembolism.
About 3% of patients with venous thromboembolism experience an arterial cardiovascular event (myocardial infarction, stroke, sudden otherwise unexplained death) in the 2-3 years after the first episode of venous thromboembolism10. The long-term use of oral anticoagulants could potentially prevent these adverse events. Barriers to the more widespread appropriate use of oral anticoagulants include physician concerns regarding the risk of bleeding, particularly in the elderly, as well as the need for close monitoring and regular blood tests to measure the INR. A simple, safe, effective, and widely applicable pharmacological approach is needed for the prevention of these events.
The clinical utility of aspirin in the management of venous thromboembolism is a matter of debate. The Pulmonary Embolism Prevention Study 11 demonstrated that 35 days of low-dose aspirin (160 mg daily) compared with placebo reduced the risk of symptomatic venous thromboembolism, including fatal pulmonary embolism, by about one-third (RRR 36%, 95% CI: 19-50%, p=0.0003) in patients undergoing emergency surgery for hip fracture or elective joint arthroplasty. There was no excess of fatal or intracranial bleeding. In the Heart and Estrogen/progestin Replacement Study (HERS)12 2800 postmenopausal women with coronary artery disease were randomized to hormonal replacement therapy or placebo. A secondary analysis showed that the use of aspirin was independently associated with a 50% reduction (95% CI: 20-80%) in risk of venous thromboembolism during an average of 4.1 years of follow-up. Taken together, these data suggest that aspirin reduces the risk of a first episode of venous thromboembolism by about one-quarter (i.e., 25% risk reduction).
A systematic overview including more than 8000 patients from randomized trials on antiplatelet primary thromboprophylaxis suggested that antiplatelet therapy was effective to prevent deep vein thrombosis and pulmonary embolism in high risk patients (Antiplatelet Trialists' Collaboration).13 Antiplatelet therapy was associated with a relative risk reduction [RRR] of 39%; (p=0.00001) in the incidence of venous thromboembolism in high-risk medical patients or undergoing orthopedic or general surgery. There was no excess in cerebral or fatal bleeding.
The European Stroke Prevention Study 2 (ESPS 2)14 evaluated the efficacy and safety of aspirin, dipyridamole (extended-release preparation), or aspirin and dipyridamole, versus placebo, for the secondary prevention of ischemic stroke in 6,600 patients. Prespecified secondary analyses found that aspirin resulted in a 30% reduction in venous thromboembolism.
Bleeding, particularly within the gastrointestinal tract, is the only important side effect of low-dose aspirin therapy in patients that are not already known to be aspirin intolerant (e.g., allergy). Long term, low-dose aspirin therapy (i.e., 160 mg per day), is associated with about a two-fold increase in the risk of bleeding.15-17 This increase of bleeding is small in patients without known contraindications to aspirin. Evidences from randomized trials of aspirin in asymptomatic subjects, patients with vascular risk factors, or patients with a past history of vascular disease (more than 250,000 patient-years of follow-up), showed an absolute excess of major bleeding with aspirin from 0.3 to 1.7 episodes per 1000 patient-years, equivalent to an absolute risk of 1 event for every 1000 patients treated.15 Increasing doses of aspirin, even within the range of 100-300 mg per day, were associated with an increasing risk of gastrointestinal bleeding, with the lowest risk occurring in patients receiving 100 mg daily.15;18-19
In summary, aspirin could achieve a risk reduction of 30 to 40 episodes of deep vein thrombosis or pulmonary embolism for every 1000 patients treated, at a cost of 1 bleed requiring transfusion in high-risk patients with idiopathic venous thromboembolism. Aspirin is simple to administer and does not require laboratory monitoring.
In the present study we propose to evaluate the use of low-dose aspirin for the prevention of recurrent venous thromboembolism in patients with previous idiopathic venous thromboembolism who have received initial 6-month treatment with oral anticoagulants.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Intervention ICMJE||Drug: aspirin
100 mg daily
|Study Arms||Not Provided|
|Publications *||Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. doi: 10.1056/NEJMoa1114238. Erratum in: N Engl J Med. 2012 Oct 18;367(16):1573.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Unknown status|
|Estimated Enrollment ICMJE
|Original Enrollment ICMJE
|Study Completion Date||Not Provided|
|Estimated Primary Completion Date||January 2012 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Austria, Italy|
|Removed Location Countries|
|NCT Number ICMJE||NCT00222677|
|Other Study ID Numbers ICMJE||CRU-UniPg-01-03|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Cecilia Becattini, University Of Perugia|
|Study Sponsor ICMJE||University Of Perugia|
|Collaborators ICMJE||Not Provided|
|PRS Account||University Of Perugia|
|Verification Date||August 2011|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP