Aspirin for prophylaxis of venous thromboembolism

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1 DOI /s x Asean Heart Journal Vol. 22, no. 1, (2014) ISSN: Case Study for prophylaxis of venous thromboembolism Chloe Ting 1, Leonardo P. de Carvalho 1,2 and Mark Y. Chan 1,2 1 Yong Loo-Lin School of Medicine, National University of Singapore 2 National University Heart Centre, Singapore The Author(s) This article is published with open access by Asean Federation of Cardiology ABSTRACT Objectives: Cessation of vitamin K antagonists (VKA) after a primary incidence of spontaneous venous thromboembolism (VTE) has been associated with recurrent events in about one-fifth of patients. Although long-term continuation of VKA prophylaxis has been suggested as a means to prevent recurrent VTE, concerns remain over issues of high bleeding risk, patient non-compliance as well as dosage irregularities. Antiplatelet therapy has been proposed as a safer, cheaper and more convenient alternative for long-term prophylaxis after initial treatment with VKA following VTE. Here we compare two major randomized trials that were conducted back-to-back the WARFASA trial and the ASPIRE trial to determine the role of aspirin as a long-term treatment option to reduce the incidence of recurrent VTE. Despite the encouraging results of these trials, suggesting that aspirin may have a beneficial effect on secondary prevention of VTE, it must be emphasized that both trials only started aspirin after 6-18 months of treatment with VKA, which remain a cornerstone of management for a first unprovoked VTE. In patients who previously had a first unprovoked VTE, a course of prophylactic anticoagulant therapy is considered standard of care (Table 1). However, once anticoagulant therapy has been withdrawn, about 20% of patients have reported a recurrence of VTE within the next 2 years 1. Long-term continuation of anticoagulation therapy beyond a 3-6 month period 2 has been debated extensively, as the benefits related to the prevention of recurrent VTE may be negated by complications of major hemorrhage. Although VKA, including warfarin, coumadin and phenocoumarol, have been widely employed for anticoagulation for the past 50 years, the role of antiplatelet therapy in the prevention of recurrent VTE has been less clear 3. Antiplatelet therapy, particularly aspirin at low doses, is often hypothesized to have a better safety profile than anticoagulation, making it an attractive alternative to anticoagulation in patients who are at high risk of bleeding. is the prototype salicylate drug often used for inflammation, pain relief and pyrexia. With lowdose long-term usage, its antiplatelet effect stems from the irreversible inhibition of thromboxane A2 production, preventing platelet aggregation from commencing in damaged blood vessels. is also commonly employed during acute myocardial infarctions and acute ischemic strokes, and has been shown to reduce both the morbidity and mortality of these arterial thrombotic events 4. The chief safety concern associated with aspirin use is increased bleeding, particularly gastrointestinal bleeding 5. Correspondence to Mark Y. Chan, Associate Professor Yong Loo-Lin School of Medicine, National University of Singapore 1E, Kent Ridge Road, NUHS Tower Block, Level 9, Cardiac Department, Singapore Tel: Fax: mark_chan@nuhs.edu.sg 48

2 In 2012, two randomized controlled trials tested the efficacy of aspirin in the secondary prevention of VTE in patients with a first episode. The first trial was the WARFASA (Warfarin and ) Trial 6, which was a multicenter, randomized, double-blinded study that analyzed the efficacy of aspirin in preventing recurrent VTE after the cessation of treatment was ascertained. A total of 405 patients with a previous incidence of unprovoked or spontaneous VTE were randomized in a 1:1 fashion into 2 groups the first group received low dose aspirin after 6 to 18 months of VKA treatment, and the second group received placebo. The study continued for a median duration of 24.6 months. The primary efficacy outcome included symptomatic and confirmed VTE recurrence, non-fatal or fatal pulmonary embolism (PE). The main safety outcome encompassed any major hemorrhage or non-major but clinically significant bleeding. At the end of the study, aspirin had reduced the rate of VTE recurrence by almost 40% compared to placebo, without an increased risk of major hemorrhage. However, the WARFASA trial had several limitations, the largest of which was slow enrollment. The original 2-year study was extended to 6 years, and despite proving that aspirin has a role in preventing VTE recurrence, it still remained underpowered for showing the beneficial effect of aspirin in cerebrovascular ischemic heart disease prevention. Arterial events including cerebrovascular accidents and myocardial infarction are common in those patients with previously unprovoked VTE 7 and could lead to a substantial rate of morbidity, mortality and reduced quality of life. Fortunately, a similar study, the ASPIRE ( to Prevent Recurrence of Venous Thromboembolism) Trial, was completed shortly after the WARFASA study thereby lending support to its findings. The ASPIRE study was a randomized controlled trial where a total of 822 patients were assigned to treatment with aspirin or placebo 8. Similar to the WARFASA trial, participants with a previous spontaneous VTE had to first undergo initial anticoagulant therapy before participating. The median follow up period was 37.2 months. However at the terminal stages of the trial, it was found that aspirin had no impact in reducing the VTE recurrence rate but instead, had a positive impact on the combined rate of major cerebro- and cardiovascular events (relative risk reduction of 34% as compared with placebo). A net clinical benefit was observed in which among a 1000 patients treated yearly, there would be 17 fewer episodes of VTE recurrence and 28 lesser episodes of major thrombotic events with aspirin prophylaxis. Most importantly, there was also no associated increase in bleeding risk, at the cost of 5 to 6 non-fatal hemorrhagic episodes 9. Despite having a larger sample size, the ASPIRE trial also faced similar problems of under-recruitment, thereby resulting in it being underpowered o show a significant reduction in their primary outcome of recurrent VTE. There was also a high attrition or dropout rate from the placebo group of patients, and this could also have lead to an underestimation of the potential benefit of antiplatelet therapy. As seen in the table below (Table 2), both the WARFASA and ASPIRE trials were similar in aims and outcome measures determining if antiplatelet therapy can be considered an alternative to VKA for the prevention of VTE recurrence once patients have ceased their anticoagulation therapy. But both trials remain underpowered individually, so a combination of their data in a patient-level metaanalysis delivered more conclusive answers 9. In the meta-analysis, aspirin ultimately achieved a 32% relative reduction in the recurrence rate of VTE (P = 0.007) and a 34% (P = 0.002) relative reduction in major cerebro- and cardiovascular events, including myocardial infarction and stroke. Most importantly, the benefits of aspirin were not associated with an increased bleeding risk. The meta-analysis of the WARFASA and ASPIRE studies present aspirin as a new alternative to the long-term continuation of VKA after an initial period of anticoagulation for VTE 9. Long-term indefinite anticoagulation with VKA presents numerous problems, including a high bleeding risk, strict requirement of regular INR checkups and other chronic complications associated with prolonged vitamin K antagonism, including 49

3 avascular necrosis of the hip and spine and possible detrimental neurocognitive effects. Several important considerations, however, must be borne in mind before initiating aspirin in patients with VTE. First, the proven efficacy of VKA in preventing VTE recurrence dictates that systemic anticoagulation with a VKA, or a new oral anticoagulant (NOAC), should be the treatment of choice in patients presenting acutely with VTE 10. should only be considered an alternative to long-term anticoagulation after an initial period of secondary prevention with a VKA antagonist or a NOAC. Second, the remarkable efficacy and safety of the NOACs in VTE prevention make the role of aspirin in VTE prevention less clear. Large pivotal trials have established that NOACs have similar efficacy to VKA in VTE prevention but at a lower risk of bleeding. Low cost is an advantage of aspirin but the availability of NOACs as a highly attractive alternative to VKA treatment weakens the position of aspirin in the treatment continuum of VTE 11 (Table 1). In conclusion, findings from the WARFASA and ASPIRE studies support that the role of aspirin as an alternative to VKA in long-term VTE prophylaxis, after an initial period of anticoagulation with a VKA. It must be emphasized that systemic anticoagulation with a VKA or NOAC for 6 to 18 months remains first-line treatment in the management of acute VTE. A key question that remains unanswered is the appropriate timing of switching a patient s treatment from VKA to aspirin. Among patients intolerant of continued anticoagulation with a VKA, aspirin can be safely used as a long-term prophylactic agent with modest efficacy against an episode of recurrent VTE. More studies are needed to better understand the efficacy-safety profile of aspirin as compared with the NOACs. Table 1 Recommended Long-Term Anticoagulation Therapy for Patients with Thromboembolic Episode(s). 11 First Episode Related to a Major Reversible Event Oral Warfarin should be administered as first line therapy. The standard of care requires Warfarin to overlap with initial anticoagulation therapy for a minimum of 5 days until INR range is > 2.0 for at least 24 hours, and then targeted to an INR of 2.0 to 3.0. Anticoagulation should cease after 3 months. Unprovoked / Recurrent Episode At least 6 months of anticoagulation should be administered, with the consideration of indefinite period of anticoagulation with frequent reassessment of risks and benefits of continued anticoagulation Persistent Risk Factors (E.g. Malignancy) Low molecular weight heparin is advised for at least 3 to 6 months, or as long as the malignancy or treatment is ongoing. 50

4 Table 2 Study Methods Population No. of Subjects WARFASA Multicenter, investigatorinitiated, doubleblinded randomized controlled trial Patients with previous unprovoked VTE Group = 205 Group = 197 Prior Anticoagulant Treatment At least 6 to 18 months Intervention VTE events Pulmonary Embolism Group = 28 group = 43 CI) = 0.58 ( ) 0.02 Group = 11 Group = 14 CI) = 0.70 ( ) 0.37 Major Bleeding Group = 4 Group = 4 CI) = 0.98 ( ) 0.97 All-Cause Mortality Group = 6 Group = 5 CI) = 1.04 ( ) 0.95 ASPIRE Investigatorinitiated Randomized placebocontrolled trial Patients with previous unprovoked VTE Group = 411 Group = 411 At least 6 to 18 months Group = 57 Group = 73 CI) = 0.74 ( ) 0.09 group = 18 Group = 88 CI) = 0.57 ( ) 0.06 Group = 14 = 8 CI) = 1.73 ( ) 0.22 Group = 16 Group = 18 *P-value not determined Open Access: This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. REFERENCES 1. Kearon C. Long-Term Management of Patients After Venous Thromboembolism. 2004; 110 (9 suppl 1): I-10-I-18. Available from: content/110/9_suppl_1/i-10.full [Accessed 3 Apr 2014]. 2. Jaff, Michael R, M Sean Mcmurtry, Stephen L Archer, Mary Cushman, Neil Goldenberg, Samuel Z Goldhaber, J Stephen Jenkins, Jeffrey A Kline, Andrew D Michaels, Patricia Thistlethwaite and Others. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension A Scientific Statement From the American Heart Association. Circulation, (2011): Print. 3. Quintero-Gonz\ Alez, JA. [Fifty years of clinical use of warfarin]. Investigacion clinica, (2010): Print. 4. S, Ercock P, Counsell C, Tseng M, Cecconi E. Oral antiplatelet therapy for acute ischaemic stroke. status and date: New search for studies and content updated (no change to conclusions), published in. 2014; (3). 5. S-Orensen H, Mellemkj-Aer L, Blot W, Nielsen G, Steffensen F, Mclaughlin J, Olsen J. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. The American journal of gastroenterology. 2000; 95 (9): Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, V, Elli M, Others. for preventing the recurrence of venous thromboembolism. New England Journal of Medicine. 2012; 366 (21): Becattini C, Agnelli G, Pr, Oni P, Silingardi M, Salvi R, Taliani M, Poggio R, Imberti D, Ageno W, Pogliani E, Others. A prospective study on cardiovascular events after acute pulmonary embolism.european heart journal. 2005; 26 (1): Brighton T, Eikelboom J, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Others. Low-dose aspirin for preventing recurrent 51

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