Aspirin who needs it?

Transcription

1 Aspirin who needs it? Aim: To enhance knowledge, skills and understanding of the role of aspirin in primary and secondary prevention of cardiovascular disease and venous thromboembolism. Objectives: By the end of this module you should feel confident to be able to: Describe the mechanism of action of aspirin List the indications for use of aspirin Understand the two forms of thrombus and their risk factors Discuss current evidence and controversies for the role of aspirin in primary and secondary prevention of cardiovascular disease Discuss current evidence and controversies for the role of aspirin in primary and secondary prevention of venous thrombembolism Determine appropriate therapy for prevention of stroke in patients with atrial fibrillation for an individual patient Assess and interpret gastrointestinal bleeding risk for an individual patient This activity has been accredited for 1 hour of Group One CPD (1 CPD Credit) that may be converted to 2 Group Two CPD Credits upon successful completion of the corresponding assessment for inclusion on an individual pharmacist's CPD Record. Accreditation number: A1212AP0. Under the auspices of the Australian Pharmacy Council, the Australian College of Pharmacy may accredit continuing professional development for pharmacists that is eligible to be used as supporting evidence of continuing competence. The competency standards addressed by this activity include (but may not be limited to) 6.1.1, 6.1.2, 6.1.3, 6.2.1, 6.2.2, 6.2.3, 7.1.2, 7.1.3, 7.1.4, 7.2.1, 7.2.2, Author: Debbie Rigby B.Pharm, GradDipClinPharm, AdvDipNutrPharm, CGP, AACPA, ASCP, FPS Debbie Rigby is a consultant clinical pharmacist from Brisbane. Since graduation with a Bachelor of Pharmacy from the University of Queensland she has since obtained a Graduate Diploma in Clinical Pharmacy, Certification in Geriatric Pharmacy, Advanced Diploma in Nutritional Pharmacy and certification as an Asthma Educator. Debbie is the Chair of the Australian Association of Consultant Pharmacy (AACP) Board and member of the National Advisory Group of AACP, as well as a Director of the National Prescribing Service (NPS) Board. Debbie is also a Fellow of PSA and the American Society of Consultant Pharmacists (ASCP). Academic appointments include Adjunct Senior Lecturer at University of Queensland and James Cook University. She is also on the Australian & New Zealand Continence Journal Editorial Committee. Debbie has a special interest in geriatric pharmacotherapy and chronic disease self-management, regularly conducts medication review services as an accredited pharmacist and provides many presentations to pharmacists, nurses, general practitioners, allied health professionals and consumers. In 2001 Debbie was awarded the PSA Australian Pharmacist of the Year, in 2002 the PSA Qld Bowl of Hygeia and in 2008 was the inaugural recipient of the AACP Consultant Pharmacist Award. AusPharm gratefully acknowledges the financial support provided by the sponsors of our CE program, MIMS

2 Aspirin The use of aspirin in medicine dates at least as far back as Hippocrates who found analgesic effects for the extract (salicin) of white willow bark. The first aspirin tablets were made by Bayer in Aspirin inhibits platelet aggregation by irreversibly inhibiting cyclo-oxygenase, reducing the synthesis of thromboxane A 2, a potent vasoconstrictor and inducer of platelet aggregation, for the life of the platelet (7-10 days). Aspirin also has anti-inflammatory and vasodilatory effects. Aspirin reduces pain, limits the inflammatory response, reduces cardiovascular disease (CVD) but can lead to major bleeding events and gastrointestinal (GI) upset. Aspirin is an inexpensive and widely available treatment for the following indications: Acute myocardial infarction Unstable angina Prevent thrombosis during and after percutaneous coronary interventions Primary prevention of stroke and myocardial infarction in patients with risk factors Secondary prevention of stroke, myocardial infarction and transient ischaemic attack Secondary prevention of ischaemic heart disease Prevention of thromboembolism in non-valvular atrial fibrillation in low-risk patients Primary prevention of venous thromboembolism in high-risk patients Prevention of recurrence of venous thromboembolism after a first event Relief of pain, inflammation and fever The benefits of aspirin are not limited to its analgesic and antiplatelet effect. People who take low-dose aspirin every day have a 15% reduction in the risk of dying from cancer, particularly after 5 years. 1 Aspirin is associated with lower cancer incidence from 3 years onwards, regardless of patients sex or smoking habits. 1 Aspirin is also linked with up to a 46% reduction in the risk of cancer metastases. 2 Aspirin use reduces tumour progression, recurrence, or both in patients with a diagnosis of colorectal cancer. Regular aspirin use after a diagnosis of colorectal cancer was associated with a 21% reduction in overall mortality and a 29% reduction in colorectal cancer-specific mortality in a prospective study of over 1200 patients. 3 A metaanalysis of involving 17,285 persons in five trials shows a 35% reduction in the risk of fatal adenocarcinoma and a 31% reduction in the risk of adenocarcinoma with metastasis at diagnosis. 4 In the subgroup of patients with colorectal cancer, there was a 74% reduction in the risk of metastasis at presentation or subsequent follow-up among aspirin users. 4 This CPD activity focuses on the latest evidence for the role of aspirin in primary and secondary prevention of cardiovascular disease and venous thromboembolism. Thrombosis There are two distinct forms of thrombosis, venous thrombosis and arterial thrombosis. Venous thrombosis is the formation of a thrombus (blood clot) within a vein. Arterial thrombosis is the formation of a thrombus within an

3 artery. In most cases, arterial thrombosis follows rupture of atheroma, and is therefore referred to as atherothrombosis. Regardless of whether a blood clot forms in a vein, an artery or the heart, the coagulation cascade generates fibrin, which comprises the main structural scaffolding of the thrombus. However, arterial and venous thrombi contain different proportions of fibrin and platelets. Venous thrombi are rich in fibrin, whereas arterial thrombi are high in platelets. Therefore prevention and treatment targets this underlying pathophysiology. Venous thrombosis generally is prevented with medications that interrupt the clotting cascade, while the prevention of arterial thrombi rests more heavily on the use of drugs that block platelet activation. Risk factors for venous thrombosis differ from those for arterial thrombosis, although there may be considerable overlap (Table 1). VENOUS THROMBOSIS Multiple inherited factors Pregnancy Immediate post-childbirth period Use of oral contraceptives or oestrogen therapy High dose corticosteroid therapy Immobilisation/bone fracture Knee-hip-abdominal surgery Table 1 - Risk factors for venous and arterial thrombosis ARTERIAL THROMBOSIS Smoking Hypertension Hyperlipidaemia Diabetes mellitus Cholesterol emboli Physical inactivity Abnormal blood coagulation factors Cardiovascular disease Cardiovascular disease (CVD) has been the dominant cause of death in Australia for many decades, with coronary heart disease (CHD) and stroke ranking high among leading causes of death. 5 Arterial thrombosis is the critical event in cardiovascular diseases. It occurs when a blood clot (thrombus) adheres to an artery and blocks the flow of blood. A blood clot that dislodges from the artery wall and moves throughout the circulatory system is known as a thromboembolus, which may lead to a myocardial infarction or stroke. Most cases of arterial thrombosis are caused when an artery is damaged by atherosclerosis. Primary prevention The benefit risk ratio for aspirin in patients with no prior CVD needs to be carefully weighed as these patients are at lower absolute CVD risk than patients with known CVD; and aspirin increases the risk of bleeding. Current evidence does not support the use of aspirin for people at low absolute risk of CVD. 6 A 2009 meta-analysis by the Antithrombotic Trialists (ATT) collaboration showed that aspirin in primary prevention trials results in a 12% relative risk reduction (RRR) of CVD morbidity (absolute risk reduction, 0.51% vs 0.57%), but no benefit for reducing either CVD or total mortality. 7 In gender-specific analyses of aspirin therapy for primary prevention, aspirin reduced the risk of myocardial infarction but not stroke in men, and reduced the risk of stroke but not MI in women. 8 A recent large meta-analysis of over 100,000 participants with a mean follow-up of 6 years has shown that aspirin treatment reduces total CVD events by 10% (OR 0.90; 95% CI, ; number needed to treat, 120). The results were driven primarily by a reduction in non-fatal MI (OR, 0.80; 95% CI, , number needed to treat, 162). In this meta-analysis of nine randomised placebo-controlled trials there was no significant reduction in CVD death. There was a 30% increase in the risk of non-trivial bleeding events (OR, 1.31; 95% CI, ; number needed to harm, 73). 9

4 Number needed to treat (NNT) is 120 to prevent 1 CVD event over 6 years, at cost of 1 non-trivial bleeding event for every 73 persons treated for 6 years. 6 USA guidelines do not encourage aspirin use for primary prevention of CVD in women younger than 55 years and in men younger than 45 years. 10 In women 55 to 79 years of age - use aspirin when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal haemorrhage In men 45 to 79 years of age - use aspirin when the potential benefit of a reduction in myocardial infarction outweighs the potential harm of increase in gastrointestinal haemorrhage Aspirin can be considered for primary prevention in patients at high absolute risk of CVD. In high-risk patients aspirin reduces the frequency of arterial thrombosis by one-quarter. 11 Absolute risk of CVD can be determined using the Australian absolute cardiovascular disease risk calculator, available at This risk assessment tool, using the Framingham Risk Equation, predicts risk of a cardiovascular event over the next 5 years, taking into account the patient s age and sex, smoking status, serum lipids, blood pressure and presence of diabetes. To make a full assessment of a patient s absolute cardiovascular risk, the following additional factors need to be considered: Waist circumference and body mass index Nutrition Physical activity level Alcohol intake Family history of premature cardiovascular disease Social history including cultural identity, ethnicity, socioeconomic status and mental health Urine for microalbumin and protein Familial hypercholesterolaemia Evidence of atrial fibrillation (history, examination, electrocardiogram) Aspirin use in primary-prevention patients is associated with an increased risk of major gastrointestinal bleeding and cerebral bleeding episodes. A recent population-based cohort study using data from over 4 million Italians showed that aspirin was associated with a 55% relative increase in the risk of major bleeding. 12 This means two excess bleeding events for every 1000 patients treated annually. This bleeding rate is roughly equal to the number of major CV events avoided in primary prevention for patients with a 10-year risk of 10-20%. This study further supports the recommendation that aspirin should only be considered for primary prevention in patients with a high risk of CVD (10-year risk greater than 20%), as the benefits are likely to outweigh the harms. Risk factors for GI bleeding include: Prior GI events Older age Use of anticoagulants e.g. warfarin

5 Use of corticosteroids High dose or multiple NSAIDs e.g. NSAID plus aspirin Use of SSRI antidepressants In summary, the benefit to risk ratio for aspirin therapy among patients with no prior CVD needs to be carefully weighed because aspirin increases the risk of bleeding (GI bleeding and, more rarely, haemorrhagic stroke). Secondary prevention There is high level evidence supporting the use of low-dose aspirin for reducing risks of further cardiovascular disease events in patients with CVD such as stroke, coronary heart disease or myocardial infarction (secondary prevention). In these patients, the benefits of aspirin outweigh the risks of gastrointestinal and intracranial haemorrhage. The 2009 meta-analysis by the Antithrombotic Trialists (ATT) collaboration showed a 10% relative risk reduction (RRR) in CVD mortality and total mortality with aspirin compared to placebo. 7 An approximate 20% RRR of CVD events, coronary events and stroke was also demonstrated. 7 Australian guidelines recommend all patients with coronary heart disease should take mg/day of aspirin unless contraindicated. 13 Atrial fibrillation A common cause of arterial thrombosis is atrial fibrillation (AF). Evidence-based guidelines recommend the use of oral anticoagulant or antiplatelet therapy to reduce the incidence of stroke in patients with AF, regardless of the approach used to manage the arrhythmia. Pooled results from clinical trials show that warfarin reduces the risk of stroke in these patients by 64%, while aspirin, an antiplatelet agent, reduces this risk by 19%. 14 Warfarin is also superior to dual antiplatelet therapy with aspirin and clopidogrel for the prevention of vascular events in patients with AF. 15 While warfarin is superior to aspirin for stroke prevention, it is associated with a higher rate of the most major bleeding, including intracranial haemorrhage. The CHA 2 DS 2 -VASc risk assessment tool (Table 2) provides a validated way of deciding on treatment, based on the individual patient s risk factors. 16 The use of this tool to determine the most appropriate therapy needs to be balanced by the patient s bleeding risk. HAS-BLED tool is appropriate for assessing bleeding risk in patients with AF receiving a vitamin K antagonist. 17 The HAS-BLED score assesses the 1-year risk for major bleeding associated with oral anticoagulation. Patients are regarded as high risk of bleeding with scores of 3 or more. Risk factor Score Congestive heart failure or moderate to severe LV dysfunction (e.g. LVEF 40%) 1 Hypertension 1 Age 75 years 2 Diabetes mellitus 1 Stroke/TIA/thromboembolism 2 Vascular disease 1 Age years 1 Female 1 Maximum score 9 Table 2 - CHA 2 DS 2 -VASc risk assessment tool

6 Risk category CHA 2 DS 2 -VASc score Recommended antithrombotic therapy One major risk factor or 2 Oral anticoagulant 2 clinically relevant non-major risk factors One clinically relevant non-major risk factor 1 Either oral anticoagulant or aspirin mg daily Preferred: oral anticoagulant No risk factors 0 Either aspirin mg daily or no antithrombotic therapy Preferred: no antithrombotic therapy Table 3 - Recommendations for thromboprophylaxis in patients with AF 18 Risk category Score Hypertension 1 Abnormal liver/renal function 1 Stroke history 1 Bleeding predisposition 1 Labile INRs 1 Elderly (age > 65 years) 1 Drugs / alcohol usage 1 Table 4 - HAS-BLED bleeding risk assessment tool Venous thrombosis Venous thromboembolism affects about 1 to 2 per 1000 people in the general population each year. 19 Venous thrombosis is the process of clot (thrombus) formation within veins. Although this can occur in any venous system, the predominant clinical events occur in the vessels of the leg, giving rise to deep vein thrombosis (DVT), or in the lungs, resulting in a pulmonary embolus (PE). The incidence is greater in older people. Other risk factors include recent surgery (especially orthopaedic), cancer, and thrombophilia. Effective primary prevention in high-risk patients and long-term secondary prevention is managed with anticoagulant and antiplatelet therapy. Aspirin is used to prevent venous thrombosis in high-risk surgical patients. Oral anticoagulants (e.g. warfarin, dabigatran, rivaroxaban) have superior efficacy but are associated with a substantially increased risk of bleeding. Warfarin with its need for regular monitoring and numerous drug interactions may be inconvenient for some patients. Aspirin does not accumulate in patients with renal insufficiency, in contrast to dabigatran and rivaroxaban. Primary prevention There is mixed evidence on the role of aspirin in primary prevention of venous thromboembolism. In a systematic review, the Antiplatelet Trialists Collaboration (ATC) suggested that aspirin could reduce the risk of venous thromboembolism in patients at high risk, with a relative risk reduction of 39%. 11 An earlier metaanalysis performed by the ATC showed aspirin reduced the incidence of DVT by 20% and PE by 69% in patients at high risk for thromboembolic events. 20 However, most recent data showed no effect of aspirin in the prevention of venous thromboembolism among healthy women. 21

7 Recurrent VTE Patients who have had a first episode of unprovoked venous thromboembolism are at high risk for recurrence after anticoagulant therapy is discontinued. The risk is as high as 20 events per 100 patient-years after initial treatment for 3 to 12 months with warfarin, dabigatran or rivaroxaban. 22 This rate is even higher if anticoagulants are prescribed for less than 3 months. The long-term risk of recurrence 6 to 9 months after stopping anticoagulant treatment is about 5 events per 100 patient-years. 22 Long-term treatment with warfarin is very effective in preventing a recurrence of venous thromboembolism while treatment continues. Warfarin reduces the risk of recurrent venous thromboembolism by 60% to 90%. 23 This benefit needs to be balanced by the risk of major bleeding with warfarin (~ 2% per patient-year). 24 Patients with low-to-moderate risk for bleeding are expected to derive the greatest overall benefit from extending warfarin therapy. 23 However, warfarin has not been shown to improve survival, is associated with a substantially increased risk of bleeding, and is inconvenient for patients. Consequently, many patients who have had a first episode of unprovoked venous thromboembolism discontinue anticoagulant therapy after 3 to 6 months despite recommendations to prolong therapy. Aspirin is an alternative, although substantially less effective, to extended oral anticoagulant treatment for the long-term secondary prevention of venous thromboembolism. It remains important that effective anticoagulant is provided for at least 3 months, to avoid the high risk of early recurrence. Two large trials, the Warfarin and Aspirin (WARFASA) study 25 and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE), 26 have recently evaluated aspirin compared with placebo in patients with unprovoked venous thromboembolism. These patients had completed initial treatment with heparin, followed by warfarin. The WARFASA study showed a 42% reduction in the rate of recurrence of VTE with aspirin as compared with placebo (6.6% vs 11.2% per year). 25 Although aspirin as compared with placebo did not significantly reduce the rate of recurrence of VTE in the ASPIRE study (rate of recurrence 4.8% vs 6.5% per year), due to lack of power, it did significantly reduce the rate of major vascular events, with improved net clinical benefit. The ASPIRE study suggests that for every 1000 patients treated for one year, aspirin can be expected to be associated with 17 fewer episodes of recurrent venous thromboembolism and 28 fewer major thrombotic events, at the cost of 5 non-fatal bleeding episodes. 26 When data from these two studies are pooled, there was a one-third reduction in the rate of recurrence of venous thromboembolism. The studies also showed a reduced rate (34% RRR) of major vascular events (VTE plus stroke, myocardial infarction and cardiovascular death). These benefits were achieved with a low risk of major bleeding (~0.3% per patient-year). These studies show that aspirin is a reasonable option for long-term dual prevention of recurrent venous thromboembolism and arterial cardiovascular events.

8 Trial Outcomes Statistical significance WARFASA 42% reduction in rate of recurrence of HR 0.58, 95% CI ; p = 0.02 venous thromboembolism Non-significant 33% reduction in rate of HR 0.67, 95% CI ; p = 0.06 major vascular events ASPIRE Non-significant 26% reduction in rate of HR 0.74, 95% CI ; p = 0.09 recurrence of venous thromboembolism 34% reduction in rate of major vascular HR 0.66, 95% CI ; p = 0.01 events WARFASA + 32% reduction in rate of recurrence of HR 0.68, 95% CI ; p = ASPIRE venous thromboembolism 34% reduction in rate of major vascular events HR 0.66, 95% CI ; p = Table 5 - Comparison of trial outcomes

9 MCQs Questions based on this article: Select ONE alternative that best represents the correct answer to each of the following multiple choice questions (only one answer per question is correct) 1. Which of the following best describes the mechanism of action of aspirin? a. Inhibits platelet aggregation by irreversibly inhibiting cyclo-oxygenase b. Potent vasoconstrictor c. Increases production of thromboxane A 2 d. Thins the blood 2. Which of the following outcomes is most improved with aspirin as primary prevention of cardiovascular disease and cancer? a. Nonfatal MI b. Fatal MI c. Stroke mortality d. Overall mortality 3. Which of the following statements regarding the use of aspirin in primary prevention of cardiovascular disease reflects gender-specific analyses of trial data? a. Use aspirin when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal haemorrhage in men 55 to 79 years of age b. Use aspirin when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal haemorrhage in women 55 to 79 years of age c. Use aspirin when the potential benefit of a reduction in myocardial infarction outweighs the potential harm of increase in gastrointestinal haemorrhage in women 55 to 79 years of age d. Use aspirin when the potential benefit of a reduction in myocardial infarction outweighs the potential harm of increase in gastrointestinal haemorrhage in men 55 to 79 years of age 4. Using the CHA 2 DS 2 -VASc risk assessment tool, what is the most appropriate therapy for a 56 year old male with atrial fibrillation, no previous history of cerebrovascular disease, diabetes, heart disease or hypertension? a. No therapy indicated b. Aspirin 100mg daily c. Warfarin (dose titrated to INR 2-3) d. Dabigatran etexilate 150mg twice daily 5. Compared to placebo, which of the following statements best describes the role of aspirin from pooled results of the WARFASA and ASPIRE trials? a. Aspirin significantly reduces the risk of recurrence of VTE, but not major vascular events b. Aspirin significantly reduces the major vascular events, but not the risk of recurrence of VTE c. Aspirin significantly reduces the composite of VTE, stroke, MI and cardiovascular death d. Aspirin does not significantly reduce the composite of VTE, stroke, MI and cardiovascular death

10 References: 1 Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. The Lancet 2012;379: Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. The Lancet Oncology 2012;13: Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA 2009;302: Rothwell PM, Wilson M, Price JF, Belch JFF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379: Australian Institute of Health and Welfare Cardiovascular disease mortality: trends at different ages. Cardiovascular series no. 31. Cat. no.47. Canberra: AIHW. 6 Mora S. Aspirin therapy in primary prevention. Arch Intern Med 2012;172: Baigent C, Blackwell L, Collins R, et al; Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373: Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006;295: Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes. Meta-analysis of randomized controlled trials. Arch Intern Med 2012;172(3): US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;150: Antithrombotic Trialists Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324: De Barardis G, Lucisano G, D Ettorre A, et al. Association of aspirin use with major bleeding in patients with and without diabetes. JAMA 2012;307: National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Reducing risk in heart disease: an expert guide to clinical practice for secondary prevention of coronary heart disease. Melbourne: National Heart Foundation of Australia, Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146: Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367: Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor based approach: the euro heart survey on atrial fibrillation. Chest 2010;137: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138: Camm AJ. Managing anticoagulation for atrial fibrillation: current issues and future strategies. J Intern Med 2012; doi: /joim Ho WK, Hankey GJ, Lee CH, Eikelboom JW. Venous thromboembolism: diagnosis and management of deep venous thrombosis. Med J Aust 2005;182: Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. III. Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994;308: Glynn RJ, Ridker PM, Goldhaber SZ, Buring JE. Effect of low-dose aspirin on the occurrence of venous thromboembolism: a randomized trial. Ann Intern Med 2007;147: Kearon C. A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism. J Thromb Haemost 2012;10: Becker RC. Aspirin and the prevention of venous thromboembolism. New Engl J Med 2012;366: Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for with venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139: Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366: Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med DOI: /NEJMoa