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Keywords:

  • acetyl salicylic acid;
  • aspirin;
  • deep venous thrombosis;
  • pulmonary thromboembolism;
  • venous thromboembolism

Summary

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. Appendix

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 efficacy. 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 efficacy of ASA in VTE prevention. ASA is clearly efficacious in preventing VTE compared to placebo or no treatment, but appears to be less efficacious 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.


Background

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. Appendix

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 efficacy of ASA in the prevention of venous thromboembolism (VTE). The efficacy of anticoagulants (heparin and vitamin K antagonists) for the prevention of venous thrombosis was established in the 1970’s and 1980’s 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 flawed, and the prevailing view was that the use of aspirin is not effective in preventing VTE. This notion was first 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 efficacy remain divided as reflected 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 efficacy 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 efficacy of ASA 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?

Is ASA better than placebo in preventing VTE?

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. Appendix

The most robust evidence for the efficacy 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 non-randomized 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 fibrinogen 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 confirmed 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 (24·8 vs. 33·6%, P < 0·0001) and a 63% reduction in PE (1 vs. 2·7%; P < 0·0001). Among 1619 patients in 16 trials, ASA reduced DVT by 20% (24·1–30%) and PE by 69% (1–3%) when compared with control. Antiplatelet therapy compared to control significantly increased the need for transfusion (from 0·4 to 0·7%, P = 0·04) as well as wound haematomas, reoperation and infections related to bleeding (7·8 vs. 5·6%; P = 0·003).

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 benefit 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 first 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 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 fibrinogen 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 benefits 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 meta-analysis) (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 efficacy 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 efficacy of thromboprophylaxis using I125-fibrinogen scanning, which has much lower sensitivity and specificity 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 fibrinogen 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 benefit of antiplatelet therapy obtained from the APTC meta-analysis might be conservative because of the tendency of fibrinogen 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 fibrinogen leg scanning compared with venography (RRR 33 vs. 56% respectively).

The Pulmonary Embolism Prevention trial

The only large trial specifically designed to test the efficacy 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 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 confirmed by venography or duplex ultrasound were counted as outcomes. Likewise, all episodes of pulmonary embolism were suspected clinically and confirmed 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% confidence interval (CI) 4–45%; P = 0·02) and PE of 39% (95% CI 16–54; P < 0·005) (Collins et al, 2000). Among the subgroup of patients undergoing surgery for hip fracture, ASA reduced the risk of DVT by 29% (95% CI 3–48%; P = 0·03) and PE by 43% (95% CI 18–60; P = 0·002). This translates into a reduction of 9 VTE events for every 1000 patients treated. The benefits of ASA were partly offset by an increase of six postoperative bleeds that required transfusion for every 1000 patients treated with ASA (2·9 vs. 2·4%; P = 0·04), and an excess of haematemesis and melena, which did not require transfusion (2·7 vs. 1·8%; P = 0·0005). A consistent reduction in VTE was found in patients undergoing elective arthroplasty (HR 0·83, 95% CI 0·47–1·47; P for heterogeneity 0·4) although it was not statistically significant. The benefits 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 prespecified 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-specified 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, significantly reduces DVT and PE in high-risk patients.

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 sought systematically by screening fibrinogen 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 significantly reduce DVT (OR 0·78, 95% CI 0·36–1·67; P = 0·52) (Sandercock et al, 2008). In the nine trials that reported symptomatic PE (n = 41, 725 patients), antiplatelet therapy compared with control significantly reduced symptomatic PE (OR 0·71, 95%CI 0·52–0·95; P = 0·02). 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 efficacy of ASA compared to placebo (Monreal et al, 1995; Cesarone et al, 2002) Monreal et al (1995) conducted a prospective, randomized, double-blind study comparing ASA with placebo or triflusal (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 (0·36 vs. 0·16 units, P < 0·05) (Monreal et al, 1995).

In the other study, Cesarone et al (2002) randomized 300 high-risk individuals undertaking a long (>10 h) flight to either 400 mg of ASA daily for 3 d, a single dose of enoxaparin 1000 i/u per 10 kg 2–4 h before the flight, or no treatment. Treatment assignment was open label. DVT was systematically sought by performing compression ultrasound in all patients at the end of the flight. Adjudicators were not blinded to treatment allocation. 3·6% of patients on ASA and 4·8% of those in the control group had DVT (RRR 25%; P < 0·05).

These data indicate that ASA prevents DVT compared to placebo but may not add to efficacy when given on a background of UFH therapy. ASA added to UFH may also increase bleeding.

A secondary analysis from the Women’s Health Study reported the effects of alternate day ASA (100 mg) compared to placebo on the occurrence of VTE over a period of 10·2 years (Glynn et al, 2007). The diagnosis of VTE was based on self report, which was then confirmed by a review of the patients’ investigations. There was no difference in the rate of DVT or PE between the two groups (HR 0·95, 95% CI 0·79–1·13). 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 1·18 and 1·25 per 1000 patient-years in the ASA and placebo groups respectively).

Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. Appendix

The PEP trial data (Rodgers et al, 2000), supported by the APTC meta-analysis (APTC, 1994) provide strong evidence for the efficacy 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% (6·4 vs. 8·8%) and symptomatic PE by 50% (0·8 vs. 1·6%) (Rodgers et al, 2000). The PEP trial indicates that the benefits of ASA are accompanied by a 21% excess of bleeding requiring transfusion (absolute increase in risk 0·5%).

Table I.   Summary of the evidence supporting the efficacy of ASA compared to placebo in preventing VTE from large clinical trials and meta-analyses.
StudyType of dataType of patientsDVT (%)PE (%)
ASAPlaceboRRR (95% CI)ASAPlaceboRRR (95% CI)
  1. ASA, aspirin; DVT, deep venous thrombosis; RRR, relative risk reduction; APTC, Antiplatelet Trialists’ Collaboration; PEP trial, pulmonary embolism prevention trial; SD, standard deviation.

  2. *Event rates are for the analysis including all antiplatelet agents used in the included studies.

  3. †The APTC meta-analysis reported % odds reduction: % odds reduction for DVT was 39 (SD 5) and for PE was 64 (SD 10).

  4. ‡Event rates in patients undergoing surgery for hip fracture and the corresponding hazard ratios.

Antiplatelet Trialists’ Collaboration (1994) (n = 9446)*Meta-analysis of randomized controlled trialsOrthopaedic surgery (hip fracture, elective hip or knee arthroplasty), general surgery, high-risk medical patients24·833·626†1·02·763†
PEP trial (Rodgers et al (2000) (n = 17444)‡Randomized controlled trialOrthopaedic surgery (hip fracture, elective hip or knee arthroplasty)1·01·529 (3–48)0·71·243 (18–60)

Is ASA better than other agents for preventing VTE?

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. Appendix

There are no large randomized trials or high quality meta-analyses 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 efficacy 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 fibrinogen leg scanning (n = 80 patients), there was no significant difference between UFH and ASA in the risk of DVT (OR 1·03, 95% CI 0·31–3·40) (Berge & Sandercock, 2002). In contrast, in two double-blind studies that reported this outcome (n = 1935 patients), LMWH compared with ASA significantly reduced symptomatic DVT (OR 0·19, 95% CI 0·07–0·58). Symptomatic PE was reported in four studies (n = 11,721) and was not reduced significantly by anticoagulants (LMWH or UFH) compared with ASA (OR 0·85, 95% CI 0·55–1·32) (Berge & Sandercock, 2002).

The results of this secondary analysis indicate that LMWH is more effective than aspirin in reducing DVT in stroke patients.

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; 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 benefits of ASA relative to other agents. Therefore the estimates obtained from these analyses are unreliable.

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 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).

Table II.   Characteristics of randomized trials of ASA compared to anticoagulants for preventing VTE.
StudyPatientsASA doseAnticoagulantBlindingDVT diagnosis*
Patient and care-providerAdjudicator
  1. ASA, aspirin; DVT, deep venous thrombosis; PE, pulmonary embolism; UFH, unfractionated heparin.

  2. *PE was sought clinically in all studies except Lotke et al (1996), which used mandatory ventilation-perfusion scans.

  3. †Background pneumatic compression device in all patients.

Vinazzer et al (1980) (n = 1210)Elective general surgery500 mg thrice dailyUFH 5000 i/u twice daily, subcutaneousYesNoDoppler ultrasound
Lotke et al (1996) (n = 388)Hip or knee arthroplasty325 mg twice dailyWarfarin to maintain prothrombin time between 1·2 and 1·5 times normalNoYesMandatory venography
Graor et al (1992) (n = 243)Hip or knee arthroplasty650 mg twice dailyArdeparin 50 U/Kg twice daily or 90 U/Kg once daily, subcutaneousNoYesMandatory venography
Gent et al (1996) (n = 251)Surgery for hip fracture100 mg twice dailyDanaparoid sodium 750 U twice daily, subcutaneousYesYesMandatory venography
Cesarone et al (2002) (n = 300)High-risk subjects undertaking a long (>10 h) flight400 mg once a day for 3 d starting 12 h before flightEnoxaparin 1000 U/10 Kg, single dose subcutaneous, 2–4 h before flightNoNoCompression ultrasound
Westrich et al (2006) (n = 275)†Knee arthroplasty325 mg twice dailyEnoxaparin 30 mg twice daily, subcutaneousNoNoColour flow duplex ultrasound
Table III.   Results of randomized trials of ASA compared to anticoagulants for preventing VTE.
StudyAnticoagulantDVT (%)PE (%)
AnticoagulantASARRRPAnticoagulantASARRRP
  1. ASA, aspirin; DVT, deep venous thrombosis; PE, pulmonary embolism; UFH, unfractionated heparin; RRR, relative risk reduction.

  2. *The figures listed under PE are rates of high-probability ventilation-perfusion scans.

  3. †Event rates with twice daily dose of ardeparin; event rates for the once daily dose are in parentheses.

  4. ‡Combined event rates for DVT and PE.

Vinazzer et al (1980) (n = 1210)UFH2·43·938NS0·90·3NS
Lotke et al (1996) (n = 388)*Warfarin53·456·66NS8·29·615NS
Graor et al (1992) (n = 243)†Ardeparin13 (20)4469 (55)<0·001 (0·003)
Gent et al (1996) (n = 251)‡Danaparoid27·844·337·30·028
Cesarone et al (2002) (n = 300)Enoxaparin03·6<0·05
Westrich et al (2006) (n = 275)Enoxaparin12·61410NS

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 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 1·2–1·5 times normal) were similar (56·6 vs. 53·4%) (Lotke et al, 1996). Moreover, there were no differences in the rates of high-probability ventilation perfusion scans between the two treatments (ASA 9·6 vs. 8·2% 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 first 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 significant difference was observed in the rates of DVT (ASA 3·9 vs. UFH 2·4%) or PE (ASA and UFH, both 0·3%). The risk of bleeding that required discontinuation of study drug was identical in both groups (0·7%).

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 anti-Xa 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 significantly 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 24–74%; P = 0·003) and 13% of those who received the twice daily regimen (RRR with ardeparin 69%, 95% CI 44–83%; P < 0·001).

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 fibrinogen leg scanning or impedance plethysmography during hospital stay, and any positive results were confirmed by venography. Patients with negative leg scan or plethysmography results underwent venography on day 14. Any DVT or PE occurred in 44·3% of patients receiving ASA and in 27·8% of those on danaparoid (RRR with danaparoid 37%, 95% CI 3·7–59·7%; P = 0·028). There was a non-significant increase in bleeding in the ASA group (6·4 vs. 1·6%; P = 0·10).

In the study by Cesarone et al (2002) (described earlier and in Table III), 3·6% 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 flow 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 confirmed by spiral computed tomography. DVT occurred in 14% of those on ASA and 12·6% of those on enoxaparin (RRR with enoxaparin 10%; P = 0·34).

In summary, there is insufficient data to comment on the efficacy of ASA compared with warfarin or UFH. LMWHs appear to be better than ASA for preventing VTE.

Conclusions

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. Appendix

There is convincing evidence that ASA compared with placebo is effective in preventing VTE, particularly PE, in high-risk hospitalized patients. There are insufficient data to comment on the efficacy of ASA compared with warfarin or UFH. LMWHs appear to be better than ASA for preventing VTE, although the data are not definitive. 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 reflect 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 efficacy between ASA and an anticoagulant are given in Table V.

Table IV.   Estimated event rates in patients undergoing elective arthroplasty and surgery for hip fracture.
OutcomeElective hip or knee arthroplastySurgery for hip fracture
  1. All figures are percentages (95% confidence intervals are provided for pooled estimates).

  2. *Event rates on anticoagulants; data pooled from the phase III randomized trials of enoxaparin, fondaparinux, rivaroxaban and dabigatran.

  3. †Event rates in patients undergoing non-cardiac surgery; data from the Perioperative Ischemic Evaluation (POISE) study.

  4. ‡Data from the Pulmonary embolism prevention (PEP) trial.

Symptomatic VTE*0·8 (0·7–0·9)0·8 (0·4–1·2)
Vascular death1·4†3·2‡
Composite of symptomatic VTE and vascular death2·24·0
Non-fatal vascular events (myocardial infarction, stroke)†5·45·4
Composite of symptomatic VTE, non-fatal vascular events and vascular death7·29·4
Major bleeding*1·3 (0·9–1·7)2·4 (2·1–2·7)
Table V.   Sample size estimation for a large pragmatic trial comparing ASA with an anticoagulant in patients at high risk of VTE.
Primary outcome (%)Total number of patients required*
Event rate in ASA armEvent rate in anticoagulant arm 80% power 90% power
  1. *Sample size calculations for detecting a 30% reduction in events at a 2-sided α level of 0·05.

2·01·414 57219 506
3·02·1963012 892
4·02·871609584
6·04·246886276
8·05·634544622
Footnotes
  • 1

    mp, multiple posting (term appears in title, abstract or MeSH heading).

  • 2

    pt, publication type.

References

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. Appendix
  • American Academy of Orthopaedic Surgeons (2007) Clinical Guideline on Prevention of Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty. http://www.aaos.org/Research/guidelines/PE_guideline.pdf (accessed on 10 November 2008).
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Appendix

  1. Top of page
  2. Summary
  3. Background
  4. Is ASA better than placebo in preventing VTE?
  5. Summary of evidence for efficacy of ASA versus placebo or control for prevention of VTE
  6. Is ASA better than other agents for preventing VTE?
  7. Conclusions
  8. References
  9. 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).