review

Does acetyl salicylic acid (ASA) have a role in the prevention of venous thromboembolism?
Ganesan Karthikeyan,1,2 John W. Eikelboom,2 Alexander G. G. Turpie2 and Jack Hirsh3
1 3

All India Institute of Medical Sciences, New Delhi, India, 2Hamilton General Hospital, McMaster University, Hamilton, ON, and Henderson Hospital Site, McMaster University, Hamilton, ON, Canada

Summary
Guidelines differ on whether acetyl salicylic acid (ASA, aspirin) should be used for prophylaxis in patients at high-risk of venous thromboembolism (VTE), principally because of differences in perceptions of its efcacy. ASA is an attractive therapeutic option because it is inexpensive, easy to administer and does not require monitoring. We critically reappraised the evidence from randomized controlled trials for the efcacy of ASA in VTE prevention. ASA is clearly efcacious in preventing VTE compared to placebo or no treatment, but appears to be less efcacious than the low molecular weight heparins in small trials. There is little data for ASA in comparison with unfractionated heparin and warfarin. A large randomized controlled trial is required to clarify the role of ASA compared to contemporary anticoagulant strategies for the prevention of VTE. Keywords: acetyl salicylic acid, aspirin, deep venous thrombosis, pulmonary thromboembolism, venous thromboembolism.

Background
The effectiveness of acetyl salicylic acid (ASA, aspirin) in the primary and secondary prevention of arterial thrombosis (Antiplatelet Trialists Collaboration (APTC) 2002, Lauer, 2002) is in keeping with the central role of platelet activation in the pathogenesis of arterial thrombosis (Davi & Patrono, 2007). Contribution of platelet activation to the development and progression of venous thrombosis is less certain and few clinical trials have tested the efcacy of ASA in the prevention of venous thromboembolism (VTE). The efcacy of anticoagulants (heparin and vitamin K antago-

Correspondence: Dr Ganesan Karthikeyan MD, DM, Department of Medicine and Population Health Research Institute, Hamilton General Hospital, 237, Barton Street East, Hamilton, ON, Canada L8L 2X2 and Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029. E-mail: karthik2010@gmail.com

nists) for the prevention of venous thrombosis was established in the 1970s and 1980s and has been reinforced by more recent clinical trials with newer anticoagulants (Clagett & Reisch, 1988; Collins et al, 1988; Nurmohamed et al, 1992; Turpie et al, 2002). Early clinical trials with aspirin for the prevention of venous thrombosis were small and methodologically awed, and the prevailing view was that the use of aspirin is not effective in preventing VTE. This notion was rst seriously challenged by data from the APTC, which reported that ASA (and other antiplatelet therapies) produced impressive reductions in deep venous thrombosis (DVT) and pulmonary embolism (PE) (Antiplatelet Trialists Collaboration, 1994). Despite the results of the APTC analysis, ASA was not recommended for the prevention of VTE, either because it was not thought to be effective or because it was considered to be much less effective than anticoagulants. Although the results of the large pulmonary embolism prevention (PEP) trial reinforced the contention that ASA is effective for VTE prevention, (Rodgers et al, 2000) opinions regarding its efcacy remain divided as reected by divergent guideline recommendations. The 2008 edition of the American College of Chest Physicians (ACCP) guidelines (Geerts et al, 2008) recommends against ASA for the prevention of VTE, likewise the UK National Institute for Health and Clinical Excellence (NICE) surgical thromboprophylaxis guidelines do not consider ASA as an option for VTE prevention (NICE, 2007) whereas the American Association of Orthopedic Surgeons (AAOS) endorse ASA for prevention of pulmonary embolism (PE) in patients undergoing hip or knee replacement (AAOS, 2007, Haas et al, 2008). The use of ASA in VTE prevention is attractive because it is inexpensive, administered orally, does not require laboratory monitoring, and is associated with low bleeding rates. These advantages would, however, not justify its use if other methods of VTE prophylaxis were clearly superior to ASA. Given the divergent views expressed in the guidelines, we set out to critically reappraise the evidence for the efcacy of ASA in VTE prevention. We restricted our review to meta-analyses of randomized trials or individual randomized controlled trials enrolling at least 200 patients that evaluated the efcacy of ASA

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doi:10.1111/j.1365-2141.2009.07734.x

Review for the prevention of VTE. Our search strategy for retrieving relevant randomized controlled trials is detailed in the Appendix. In deciding on the utility of ASA for the prevention of VTE, two critically important and related questions need to be answered: (i) Is ASA better than placebo? (ii) Is ASA as effective as other thromboprophylactic agents? trials. In a trial where treatment assignment is open-label, blinded adjudication of outcomes can reduce bias, particularly if the outcome is measured in all trial participants (e.g., mandatory venography). On the other hand, in VTE prevention trials, if the decision to perform an objective diagnostic test for PE or DVT is driven by the occurrence of subjective symptoms and signs, there is a strong potential for bias. DVT was sought by systematic brinogen leg scanning or venography in 53 of the 62 studies included in the APTC meta-analysis and 17 of these studies were open label. All 62 studies reported PE, 19 of which were open label (APTC, 1994). The benets of antiplatelet therapy were reported to be almost identical irrespective of whether patients and health care providers were blinded to treatment allocation (Odds reduction of 38% for the placebo-controlled studies and 39% in the whole metaanalysis) (APTC, 1994; Collins et al, 1994). Thus, despite the shortcoming that almost a third (31%) of trials were open label, the results are likely to be valid. The second methodological issue in the APTC analysis pertains to the method used for diagnosing DVT. The traditional diagnostic gold standard for evaluating the efcacy of thromboprophylaxis is ascending contrast venography adjudicated by observers blinded to treatment allocation. Other less accurate outcome measures have the potential to systematically bias treatment estimates (Rodgers & MacMahon, 1995). Most early studies assessed the efcacy of thromboprophylaxis using I125-brinogen scanning, which has much lower sensitivity and specicity than venography for deep vein thrombosis (Cruickshank et al, 1989). The APTC investigators showed that the effectiveness of antiplatelet therapy on reducing DVT outcomes was evident irrespective of whether venography or brinogen scanning was used to assess outcome (odds reduction of 49% for the venographic trials compared to 39% for the overall meta-analysis) (APTC, 1994). Furthermore, the estimates of benet of antiplatelet therapy obtained from the APTC meta-analysis might be conservative because of the tendency of brinogen scans to underestimate the magnitude of the treatment effect when active therapy is compared with no active treatment (Rodgers & MacMahon, 1995). Indeed, Rodgers and MacMahon (1995), using data from the meta-analysis showed that ASA produced smaller relative risk reductions (RRR) for the prevention of DVT compared with placebo when the outcomes were assessed using brinogen leg scanning compared with venography (RRR 33 vs. 56% respectively).

Is ASA better than placebo in preventing VTE?

The most robust evidence for the efcacy of ASA comes from the APTC meta-analysis (APTC, 1994) and the PEP trial (Rodgers et al, 2000). All other evidence is from small or nonrandomized trials and does not change the conclusions derived from these two publications.

The Antiplatelet Trialists Collaboration meta-analysis

The APTC meta-analysis of antiplatelet therapy for VTE prevention included randomized trials in which DVT was systematically sought by either contrast venography or brinogen leg scanning, and reported data on over 9000 patients at high-risk of VTE (APTC, 1994). In all the included studies, PE was suspected clinically and conrmed by objective diagnostic testing (e.g., ventilation perfusion scanning) or at necropsy. The results of the APTC meta-analysis indicated that any antiplatelet therapy (ASA, ASA plus dipyridamole, hydroxychloroquine, or ticlopidine) compared to control was associated with a 26% reduction in the risk of DVT (248 vs. 336%, P < 00001) and a 63% reduction in PE (1 vs. 27%; P < 00001). Among 1619 patients in 16 trials, ASA reduced DVT by 20% (24130%) and PE by 69% (13%) when compared with control. Antiplatelet therapy compared to control signicantly increased the need for transfusion (from 04 to 07%, P = 004) as well as wound haematomas, reoperation and infections related to bleeding (78 vs. 56%; P = 0003). The APTC meta-analysis has important strengths. It included all unconfounded randomized trials, both published and unpublished, and thus captured the totality of the evidence available prior to 1990. A consistent benet of antiplatelet therapy was evident across subsets of patients undergoing different surgical procedures and high-risk medical patients. Surgery included general, elective orthopaedic procedures and surgery for fractures. The trials involving high-risk medical patients included patients with stroke, recurrent venous thrombosis, congestive heart failure and myocardial infarction. Two methodological issues that have been the topic of much debate (Cohen et al, 1994) are relevant to the interpretation of the results of the APTC meta-analysis. The rst pertains to the lack of blinding in many of the trials included in the APTC meta-analysis. Randomized trials in which patients, care providers, and outcome adjudicators are blinded to treatment assignment, yield higher quality evidence than open-label 2

The Pulmonary Embolism Prevention trial

The only large trial specically designed to test the efcacy and safety of ASA for VTE prevention is the PEP study (Rodgers et al, 2000). The PEP trial was a double blind randomized trial that included more than 13 000 patients undergoing surgery for hip fracture and about 4000 patients undergoing elective joint replacement surgery. Patients were randomized to receive either 160 mg per d of ASA or placebo, beginning
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Review preoperatively and continued for 35 d. About 18% of the randomized patients received treatment with unfractionated heparin (UFH) and about 26% received low molecular weight heparins (LMWH). The primary outcome was the occurrence of symptomatic VTE at 35 d. In contrast to earlier studies of VTE prophylaxis, ascertainment of outcomes in the PEP trial did not involve mandatory screening for DVT; only clinically suspected DVTs that were objectively conrmed by venography or duplex ultrasound were counted as outcomes. Likewise, all episodes of pulmonary embolism were suspected clinically and conrmed by objective testing using ventilation perfusion scanning, pulmonary angiography, or at necropsy. Outcomes were adjudicated by a committee that was masked to treatment assignment. The results of the PEP study demonstrated that ASA produced proportional reductions in DVT of 28% (95% condence interval (CI) 445%; P = 002) and PE of 39% (95% CI 1654; P < 0005) (Collins et al, 2000). Among the subgroup of patients undergoing surgery for hip fracture, ASA reduced the risk of DVT by 29% (95% CI 348%; P = 003) and PE by 43% (95% CI 1860; P = 0002). This translates into a reduction of 9 VTE events for every 1000 patients treated. The benets of ASA were partly offset by an increase of six postoperative bleeds that required transfusion for every 1000 patients treated with ASA (29 vs. 24%; P = 004), and an excess of haematemesis and melena, which did not require transfusion (27 vs. 18%; P = 00005). A consistent reduction in VTE was found in patients undergoing elective arthroplasty (HR 083, 95% CI 047147; P for heterogeneity 04) although it was not statistically signicant. The benets of ASA were evident irrespective of whether patients received concomitant LMWH therapy. The authors of the PEP study have been criticized appropriately for de-emphasizing their prespecied primary endpoints of any vascular death, and major non-fatal vascular events (PE, myocardial infarction or stroke) (MacMahon et al, 1994; Cohen & Quinlan, 2000). The PEP investigators apparently made the decision to focus on secondary outcomes (DVT, PE and any VTE) in preference to their pre-specied primary endpoint after the results were known to them. This oversight weakens the conclusions as these are derived from what are essentially post-hoc analyses (Collins et al, 2000). Nevertheless, criticism notwithstanding, data from the PEP trial, supported by the results of the APTC meta-analysis, provide convincing evidence that ASA, compared to placebo, signicantly reduces DVT and PE in high-risk patients. sought systematically by screening brinogen scans in only 2 of the 12 studies (n = 133 patients). Ticlopidine was used in one of these trials and a combination of ASA and dipyridamole in the other. Compared with placebo, antiplatelet therapy did not signicantly reduce DVT (OR 078, 95% CI 036167; P = 052) (Sandercock et al, 2008). In the nine trials that reported symptomatic PE (n = 41, 725 patients), antiplatelet therapy compared with control signicantly reduced symptomatic PE (OR 071, 95%CI 052095; P = 002). Three of the nine trials were open label but outcome assessment was blinded in two of these trials. The effect of antiplatelet therapy on PE was similar in the double-blind and open-label trials (Sandercock et al, 2008). These results are consistent with those reported in the APTC meta-analysis (APTC, 1994) and the PEP trial (Rodgers et al, 2000). Evidence from other systematic reviews. Other systematic reviews of trials comparing ASA with placebo for prevention of VTE have been published (Imperiale & Speroff, 1994; Freedman et al, 2000). The evidence from these reviews is however, of much lower quality than the evidence from the APTC meta-analysis, because the authors pooled the data from treatment and control arms across studies and performed indirect comparisons without performing a meta-analysis of the included studies. Evidence from other randomized trials. Two trials enrolling at least 200 patients reported on the efcacy of ASA compared to placebo (Monreal et al, 1995; Cesarone et al, 2002) Monreal et al (1995) conducted a prospective, randomized, doubleblind study comparing ASA with placebo or triusal (in a three-arm design), on a background of UFH therapy in 459 patients undergoing hip replacement or surgery for hip fracture. All patients received 7500 i/u of UFH twice daily and the dose of ASA used was 200 mg thrice daily. Mandatory B-mode ultrasound was used to screen for DVT. Patients who had a negative ultrasound study, but were suspected to have DVT on clinical grounds, underwent venography. The diagnosis of PE was clinically driven. There was no difference in the rates of DVT (18% with ASA and 17% with placebo) or PE (5% in both ASA and placebo groups) with ASA, but there was a small increase in the requirement for blood transfusions in the postoperative period among those who received ASA (036 vs. 016 units, P < 005) (Monreal et al, 1995). In the other study, Cesarone et al (2002) randomized 300 high-risk individuals undertaking a long (>10 h) ight to either 400 mg of ASA daily for 3 d, a single dose of enoxaparin 1000 i/u per 10 kg 24 h before the ight, or no treatment. Treatment assignment was open label. DVT was systematically sought by performing compression ultrasound in all patients at the end of the ight. Adjudicators were not blinded to treatment allocation. 36% of patients on ASA and 48% of those in the control group had DVT (RRR 25%; P < 005). 3

Other evidence
Meta-analysis of antiplatelet trials in stroke. Sandercock et al (2008) examined the effectiveness of antiplatelet therapy (including ASA, ticlopidine and dipyridamole) for the prevention of VTE in a meta-analysis 12 stroke trials involving 43 041 patients. Ninety-four percent of the patients in this meta-analysis received ASA. DVT was
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Review These data indicate that ASA prevents DVT compared to placebo but may not add to efcacy when given on a background of UFH therapy. ASA added to UFH may also increase bleeding. A secondary analysis from the Womens Health Study reported the effects of alternate day ASA (100 mg) compared to placebo on the occurrence of VTE over a period of 102 years (Glynn et al, 2007). The diagnosis of VTE was based on self report, which was then conrmed by a review of the patients investigations. There was no difference in the rate of DVT or PE between the two groups (HR 095, 95% CI 079 113). These data provide no support for the effectiveness of ASA for prevention of VTE, but the patients were very low risk ambulatory women (the incidence of any VTE was 118 and 125 per 1000 patient-years in the ASA and placebo groups respectively).

Is ASA better than other agents for preventing VTE?

There are no large randomized trials or high quality metaanalyses that address this question.

Meta-analysis of antiplatelet trials in stroke

A meta-analysis of trials of antiplatelet therapy in stroke included four trials involving 16 558 patients that compared the efcacy and safety of anticoagulants (UFH or LMWH) with ASA for the prevention of VTE (Berge & Sandercock, 2002). In the one study that systematically sought DVT using brinogen leg scanning (n = 80 patients), there was no signicant difference between UFH and ASA in the risk of DVT (OR 103, 95% CI 031340) (Berge & Sandercock, 2002). In contrast, in two double-blind studies that reported this outcome (n = 1935 patients), LMWH compared with ASA signicantly reduced symptomatic DVT (OR 019, 95% CI 007058). Symptomatic PE was reported in four studies (n = 11,721) and was not reduced signicantly by anticoagulants (LMWH or UFH) compared with ASA (OR 085, 95% CI 055132) (Berge & Sandercock, 2002). The results of this secondary analysis indicate that LMWH is more effective than aspirin in reducing DVT in stroke patients.

Summary of evidence for efcacy of ASA versus placebo or control for prevention of VTE
The PEP trial data (Rodgers et al, 2000), supported by the APTC meta-analysis (APTC, 1994) provide strong evidence for the efcacy of ASA compared to placebo or no treatment for the prevention of VTE in high-risk medical and surgical patients (Table I). In the updated meta-analysis that includes the PEP study, ASA was reported to reduce the risk of symptomatic and asymptomatic DVT by 27% (64 vs. 88%) and symptomatic PE by 50% (08 vs. 16%) (Rodgers et al, 2000). The PEP trial indicates that the benets of ASA are accompanied by a 21% excess of bleeding requiring transfusion (absolute increase in risk 05%).

Evidence from other systematic reviews

Several systematic reviews have reported on studies that compared ASA with other active agents for the prevention of VTE (Imperiale & Speroff, 1994; Freedman et al, 2000;

Table I. Summary of the evidence supporting the efcacy of ASA compared to placebo in preventing VTE from large clinical trials and meta-analyses. DVT (%) Study Antiplatelet Trialists Collaboration (1994) (n = 9446)* Type of data Meta-analysis of randomized controlled trials Type of patients Orthopaedic surgery (hip fracture, elective hip or knee arthroplasty), general surgery, high-risk medical patients Orthopaedic surgery (hip fracture, elective hip or knee arthroplasty) ASA 248 Placebo 336 RRR (95% CI) 26 PE (%) ASA 10 Placebo 27 RRR (95% CI) 63

PEP trial (Rodgers et al (2000) (n = 17444)

Randomized controlled trial

10

15

29 (348)

07

12

43 (1860)

ASA, aspirin; DVT, deep venous thrombosis; RRR, relative risk reduction; APTC, Antiplatelet Trialists Collaboration; PEP trial, pulmonary embolism prevention trial; SD, standard deviation. *Event rates are for the analysis including all antiplatelet agents used in the included studies. The APTC meta-analysis reported % odds reduction: % odds reduction for DVT was 39 (SD 5) and for PE was 64 (SD 10). Event rates in patients undergoing surgery for hip fracture and the corresponding hazard ratios.

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Review Westrich et al, 2000). In these reviews, the control and treatment arms of various trials were pooled and indirect comparisons were performed to estimate the benets of ASA relative to other agents. Therefore the estimates obtained from these analyses are unreliable. open label, but outcome adjudicators were blinded to treatment allocation in two of these studies. Most of these trials were too small to reliably detect clinically important differences between two active treatments and, with the exception of two studies, did not provide any information on the occurrence of symptomatic PE (Table II). Only one study meeting our inclusion criteria directly compared ASA with warfarin. This was an open label trial with blinded outcome adjudication in 388 patients undergoing hip or knee replacement (Lotke et al, 1996). DVT was systematically sought by mandatory venography and PE was

Evidence from randomized trials

Six trials comparing ASA with an anticoagulant and which included at least 200 patients have been reported (Tables II and III). Treatment assignment in four of these studies was

Table II. Characteristics of randomized trials of ASA compared to anticoagulants for preventing VTE. Blinding Patient and care-provider Yes No Adjudicator DVT diagnosis* No Yes Doppler ultrasound Mandatory venography Mandatory venography Mandatory venography Compression ultrasound

Study Vinazzer et al (1980) (n = 1210) Lotke et al (1996) (n = 388) Graor et al (1992) (n = 243) Gent et al (1996) (n = 251) Cesarone et al (2002) (n = 300)

Patients Elective general surgery Hip or knee arthroplasty Hip or knee arthroplasty Surgery for hip fracture High-risk subjects undertaking a long (>10 h) ight Knee arthroplasty

ASA dose 500 mg thrice daily 325 mg twice daily

Anticoagulant UFH 5000 i/u twice daily, subcutaneous Warfarin to maintain prothrombin time between 12 and 15 times normal Ardeparin 50 U/Kg twice daily or 90 U/Kg once daily, subcutaneous Danaparoid sodium 750 U twice daily, subcutaneous Enoxaparin 1000 U/10 Kg, single dose subcutaneous, 24 h before ight

650 mg twice daily

No

Yes

100 mg twice daily 400 mg once a day f or 3 d starting 12 h before ight

Yes No

Yes No

Westrich et al (2006) (n = 275)

325 mg twice daily

Enoxaparin 30 mg twice daily, subcutaneous

No

No

Colour ow duplex ultrasound

ASA, aspirin; DVT, deep venous thrombosis; PE, pulmonary embolism; UFH, unfractionated heparin. *PE was sought clinically in all studies except Lotke et al (1996), which used mandatory ventilation-perfusion scans. Background pneumatic compression device in all patients.

Table III. Results of randomized trials of ASA compared to anticoagulants for preventing VTE. DVT (%) Study Vinazzer et al (1980) (n = 1210) Lotke et al (1996) (n = 388)* Graor et al (1992) (n = 243) Gent et al (1996) (n = 251) Cesarone et al (2002) (n = 300) Westrich et al (2006) (n = 275) Anticoagulant UFH Warfarin Ardeparin Danaparoid Enoxaparin Enoxaparin Anticoagulant 24 534 13 (20) 278 0 126 ASA 39 566 44 443 36 14 RRR 38 6 69 (55) 373 10 P NS NS <0001 (0003) 0028 <005 NS PE (%) Anticoagulant 09 82 ASA 03 96 RRR 15 P NS NS

ASA, aspirin; DVT, deep venous thrombosis; PE, pulmonary embolism; UFH, unfractionated heparin; RRR, relative risk reduction. *The gures listed under PE are rates of high-probability ventilation-perfusion scans. Event rates with twice daily dose of ardeparin; event rates for the once daily dose are in parentheses. Combined event rates for DVT and PE.

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Review
Table IV. Estimated event rates in patients undergoing elective arthroplasty and surgery for hip fracture. Elective hip or knee arthroplasty 08 (0709) 14 22 54 72 Surgery for hip fracture 08 (0412) 32 40 54 94 Table V. Sample size estimation for a large pragmatic trial comparing ASA with an anticoagulant in patients at high risk of VTE. Total number of patients required*

Outcome Symptomatic VTE* Vascular death Composite of symptomatic VTE and vascular death Non-fatal vascular events (myocardial infarction, stroke) Composite of symptomatic VTE, non-fatal vascular events and vascular death Major bleeding*

Primary outcome (%) Event rate in ASA arm 20 30 40 60 80 Event rate in anticoagulant arm 14 21 28 42 56

80% power 14 572 9630 7160 4688 3454

90% power 19 506 12 892 9584 6276 4622

13 (0917)

24 (2127)

*Sample size calculations for detecting a 30% reduction in events at a 2-sided a level of 005.

All gures are percentages (95% condence intervals are provided for pooled estimates). *Event rates on anticoagulants; data pooled from the phase III randomized trials of enoxaparin, fondaparinux, rivaroxaban and dabigatran. Event rates in patients undergoing non-cardiac surgery; data from the Perioperative Ischemic Evaluation (POISE) study. Data from the Pulmonary embolism prevention (PEP) trial.

systematically sought by mandatory ventilation perfusion scans. In this study, the rates of venographically detected thrombi with ASA (325 mg twice daily) and warfarin (prothrombin time 1215 times normal) were similar (566 vs. 534%) (Lotke et al, 1996). Moreover, there were no differences in the rates of high-probability ventilation perfusion scans between the two treatments (ASA 96 vs. 82% warfarin). One study that directly compared ASA with UFH met our inclusion criteria (Vinazzer et al, 1980). In this double blind study, femoral DVT was systematically sought by performing Doppler ultrasound in all patients. PE was diagnosed clinically and necropsy was performed in all patients who died. ASA was given at a dose of 500 mg thrice daily, intravenously for the rst 3 d and orally subsequently. UFH was given at a dose of 5000 i/u twice daily. All treatments were given until patients were completely mobilized. No statistically signicant difference was observed in the rates of DVT (ASA 39 vs. UFH 24%) or PE (ASA and UFH, both 03%). The risk of bleeding that required discontinuation of study drug was identical in both groups (07%). Four studies compared ASA with LMWH Graor et al (1992) randomized 243 patients undergoing hip or knee arthroplasty to receive either ASA 650 mg twice daily or ardeparin 90 antiXa U/kg once or 50 anti-Xa U/kg twice daily. Patients underwent mandatory venography at day 6 after surgery. Treatment assignment was open label but outcome assessment was by radiologists blinded to treatment assignment. Both doses of ardeparin were signicantly better than ASA in reducing the occurrence of DVT. DVT occurred in 44% of patients receiving ASA, 20% of those who received once daily ardeparin (RRR with ardeparin 55%, 95% CI 2474%; P = 0003) and 13% of those who received the twice daily 6

regimen (RRR with ardeparin 69%, 95% CI 4483%; P < 0001). In the second study, 251 patients undergoing surgery for hip fracture were randomly allocated to either 100 mg ASA twice daily or 750 U of danaparoid sodium twice daily for 14 d (Gent et al, 1996). Patients, care-givers and event adjudicators were all blinded to treatment assignment. Surveillance for DVT was performed using periodic brinogen leg scanning or impedance plethysmography during hospital stay, and any positive results were conrmed by venography. Patients with negative leg scan or plethysmography results underwent venography on day 14. Any DVT or PE occurred in 443% of patients receiving ASA and in 278% of those on danaparoid (RRR with danaparoid 37%, 95% CI 37597%; P = 0028). There was a non-signicant increase in bleeding in the ASA group (64 vs. 16%; P = 010). In the study by Cesarone et al (2002) (described earlier and in Table III), 36% of patients on ASA had a DVT compared to none receiving enoxaparin (Cesarone et al, 2002). Finally, Westrich et al (2006) randomized 275 patients undergoing knee arthroplasty to either ASA 325 mg twice daily or enoxaparin 30 mg subcutaneously twice daily. All patients received mechanical prophylaxis with a pneumatic calf compression device. DVT was diagnosed by colour ow duplex ultrasound performed in all patients between days 3 and 5 after surgery. Neither treatment assignment nor event ascertainment was blinded. PE was suspected clinically and conrmed by spiral computed tomography. DVT occurred in 14% of those on ASA and 126% of those on enoxaparin (RRR with enoxaparin 10%; P = 034). In summary, there is insufcient data to comment on the efcacy of ASA compared with warfarin or UFH. LMWHs appear to be better than ASA for preventing VTE.

Conclusions
There is convincing evidence that ASA compared with placebo is effective in preventing VTE, particularly PE, in high-risk
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Review hospitalized patients. There are insufcient data to comment on the efcacy of ASA compared with warfarin or UFH. LMWHs appear to be better than ASA for preventing VTE, although the data are not denitive. How then can the disagreements on the appropriateness of using aspirin as a sole prophylactic agent, in patients undergoing major orthopaedic surgery, be resolved? The obvious answer is, by performing an appropriately designed clinical trial comparing ASA with an approved anticoagulant. How should such a trial be designed, and would it be feasible? We suggest that the trial should be performed in patients undergoing hip or knee surgery using outcome measures that reect the clinically important complications of major surgery that might be prevented by the use of antithrombotic thromboprophylaxis. Recent evidence suggests that, in addition to symptomatic and fatal VTE, patients undergoing major surgery are at risk of developing other non-fatal and fatal vascular complications (myocardial infarction, stroke) which are potentially preventable by antithrombotic therapy (Devereaux et al, 2008). Therefore, it would be appropriate also to measure and report these non-VTE vascular events, either separately or in combination with VTE as a single composite outcome. Estimated event rates for a composite of symptomatic VTE and death, and for a composite of symptomatic VTE, death, myocardial infarction and stroke are shown in Table IV. Estimated sample sizes, to detect a 30% difference in efcacy between ASA and an anticoagulant are given in Table V.
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Appendix Search strategy

Using the OvidSP search engine, we searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Cochrane Clinical Trials register for randomized trials of ASA in the prevention of VTE. We used the following search terms in combination: (Aspirin or ASA or Acetyl salicylic acid).mp1, (Venous thromboembolism or VTE or Deep venous thrombosis or DVT or Pulmonary embolism or pulmonary thromboembolism or PE).mp, and (randomized controlled trial.pt2. or randomized.mp). We also hand searched the reference lists of retrieved articles. We included randomized trials which enrolled at least 200 patients. For trials comparing ASA with placebo or no treatment, we restricted inclusion to studies published in or after 1990 (the cut-off date used by the APTC meta-analysis).

mp, multiple posting (term appears in title, abstract or MeSH heading). 2 pt, publication type. 8
2009 Blackwell Publishing Ltd, British Journal of Haematology