Aspirin in the primary prophylaxis of venous thromboembolism in surgical patients.

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Available online at www.sciencedirect.com

ScienceDirect The Surgeon, Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland www.thesurgeon.net

Aspirin in the primary prophylaxis of venous thromboembolism in surgical patients Shaheel M. Sahebally a,*, Donagh Healy a, Stewart R. Walsh b a b

Department of Surgery, University Hospital Limerick, Ireland Department of Vascular Surgery, University College Hospital Galway, Galway, Ireland

article info

abstract

Article history:

Introduction: Venous thromboembolism (VTE) is a common complication in surgical pa-

Received 21 October 2014

tients, especially those undergoing lower limb orthopaedic procedures as well as onco-

Received in revised form

logical resectional surgery. Numerous studies have evaluated the role of acetylsalicylic acid

13 May 2015

(ASA, aspirin) in primary VTE prevention, with contradictory results reflected in divergent

Accepted 16 May 2015

guidelines. We reviewed current evidence for ASA as primary VTE prophylaxis.

Available online xxx

Methods: English language studies meeting our inclusion criteria were retrieved from PubMed, EMBASE and Cochrane databases. Six studies (3 meta-analyses and 3 randomized

Keywords:

trials) comparing ASA with placebo and 7 studies (1 meta-analysis, 5 randomized trials,

Aspirin

and 1 prospective) comparing ASA with other anticoagulants were included in the final

Acetylsalicylic acid

analysis. Retrospective studies and case reports were excluded.

Venous thromboembolism

Results: ASA is more effective than placebo in primary VTE prevention. Although there is

Pulmonary embolism

clinical equipoise when ASA is compared with other anticoagulants, studies specific to

Deep venous thrombosis

orthopaedic surgery suggest that ASA appears as effective as low molecular weight heparin

Prophylaxis

(LMWH) and may reduce bleeding risk. Extended prophylaxis up to 4 weeks post surgery reduces VTE episodes. Conclusions: ASA may be considered as a potential strategy in primary VTE prophylaxis in orthopaedic patients at high-risk of bleeding complications. Further studies comparing ASA with LMWH/oral anticoagulants in primary thromboprophylaxis following nonorthopaedic surgery are warranted. © 2015 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Introduction Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). It affects up to 5% of the population during their lifetime with an estimated

annual incidence of 0.1e0.27%.1 The overall incidence of symptomatic VTE was 6.8% in patients not receiving thromboprophylaxis in fractures of the lower extremity below the hip, compared to 2.3% in those receiving thromboprophylaxis,2 and VTE results in prolonged hospital stays.3 Approximately 1 in 5 PE patients die before the diagnosis is made, or

* Corresponding author. Department of Surgery, University Hospital Limerick, Dooradoyle, Limerick, Ireland. Tel.: þ353 61 234920; fax: þ353 61 233778. E-mail address: [email protected] (S.M. Sahebally). http://dx.doi.org/10.1016/j.surge.2015.05.001 1479-666X/© 2015 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Sahebally SM, et al., Aspirin in the primary prophylaxis of venous thromboembolism in surgical patients, The Surgeon (2015), http://dx.doi.org/10.1016/j.surge.2015.05.001

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the following day.4 Symptomatic PE with or without DVT independently predicts reduced survival up to 3 months after onset, when compared to DVT alone.4 VTE produces significant morbidity in the acute phase, when limb pain and swelling may restrict mobility in DVT cases, while dyspnoea, hypoxia, hypotension and/or cardiogenic shock restrict activity following PE.5 Long-term, VTE may cause post-phlebitic syndrome following DVT (up to 40%) or chronic thromboembolic pulmonary hypertension after PE (1e4%).6,7 VTE pathogenesis is multifactorial. Rudolph Virchow, in 1846, proposed a triad of risk factors consisting of venous stasis, vessel wall injury and hypercoagulability. However, the greatest risk factors for thrombosis remain age and cancer.8 The latter increases risk by producing tissue factor to initiate coagulation, shedding procoagulant lipid microparticles or directly impairing blood flow.9 Other well recognised associations of VTE include congestive cardiac failure, nephrotic syndrome, stroke and surgery, particularly joint replacement surgery of the lower limb.1 Given the inherent difficulty in predicting individuals' risk, it is now accepted that widespread inpatient thromboprophylaxis (with mechanical and/or pharmacological methods), preferably continued postdischarge, is the optimal method of preventing VTE.10 Whilst anticoagulants such as unfractionated heparin, coumarin, low molecular weight heparin and factor Xa inhibitors are clearly effective in VTE prophylaxis, the role of acetylsalicylic acid (ASA) or aspirin is less well established. The 2008 American College of Chest Physicians (ACCP) guidelines11 as well as the UK National Institute for Health and Clinical Excellence (NICE) surgical thromboprophylaxis guidelines (http://www.nice.org.uk/guidance/cg92/evidence/ cg92-venous-thromboembolism) argue against the use of ASA for VTE prevention. However, the 2012 ACCP guidelines recommend ASA as a favourable alternative to other anticoagulants in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA). These differences in the recommendations are explained by the perceived disagreement in relation to ASA's efficacy. Nevertheless, ASA in VTE prophylaxis is attractive because it is inexpensive, administered orally and requires no laboratory monitoring. Given the discordant opinions regarding ASA in the guidelines, this review aims to comprehensively reappraise the evidence regarding ASA as primary VTE prevention in surgical patients and compare it with placebo and other commonly used thromboprophylactic agents. The pharmacology of the most commonly used antiplatelet agent worldwide is also reviewed.

Methods We searched PubMed, EMBASE and Cochrane databases using the terms ‘Acetylsalicylic acid or ASA or Aspirin’ AND/OR ‘Venous Thromboembolism or VTE or Deep Venous Thrombosis or DVT, Pulmonary Embolism or PE’ AND/OR ‘Primary Prevention or Prophylaxis or Thromboprophylaxis’ in various combinations. Cross-referencing from papers recovered in the original search identified additional articles. Studies were included if they were systematic reviews or meta-analyses, randomized, blinded or non-blinded, placebo-controlled

trials, prospective observational studies, review articles, registry data or if they represented guidelines of professional bodies pertaining to ASA. All studies had to be published in English. There was no restriction regarding publication dates. Studies that did not clearly separate ASA from other anticoagulants or those that evaluated unfractionated heparin (UFH), low molecular weight heparin (LMWH), factor Xa inhibitors, warfarin but not ASA were excluded, as were studies that examined patients with multiple myeloma, travellers' thrombosis, VTE treatment or incidence of arterial thrombosis. Retrospective studies, case reports and data derived from abstracts were also excluded based on strict inclusion criteria set out before the literature search.

Pharmacology of ASA ASA acts through the arachidonic acid (AA)ethromboxane A2 (TXA2) pathway.12 AA is a normal dietary unsaturated fatty acid, the major substrate for prostaglandin synthesis. Conversion of AA to prostaglandin is catalyzed by cyclooxygenase (COX), which exists in two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most cells and regulates prostaglandin H production, which in turn generates TXA2 via thromboxane synthase. TXA2 activates new platelets, stimulates platelet aggregation and vasoconstriction, causing thrombosis and haemostasis.13 ASA irreversibly inhibits COX through acetylation of the amino acid serine,14 with a 170-fold affinity for COX-1 over COX-2. This blocks production of prostaglandin H2 and TXA2-dependent platelet activation and aggregation. Inhibition of platelet COX-1 produces the antithrombotic effects of low-dose ASA. At higher doses, ASA also inhibits COX-2 mediated prostacyclin (PGI2) synthesis in the endothelial cells, further hindering platelet aggregation and inducing vasodilation.15

ASA vs. placebo in primary VTE prophylaxis (Table 1) Data regarding the efficacy of ASA vs. placebo are conflicting. A 1994 meta-analysis of thromboprophylaxis following total hip replacement (THR), with data from 56 trials, showed no reduction in all DVT and proximal DVT with ASA compared to placebo.16 All other interventions including compression stockings, dextran, warfarin, UFH and LMWH were associated with a reduced incidence of all DVT and proximal DVT. Of note, the reported rates of ‘clinically significant bleeding’ were 0.3% in the control arm, 0.4% in those receiving ASA and 1.8e2.6% in heparin recipients. Monreal et al.17 randomised 459 patients undergoing hip replacement (n ¼ 194) or surgery for hip fracture (n ¼ 265) to ASA (200 mg TDS), placebo or triflusal (300 mg TDS), on a background of 7500 I/U of UFH twice daily. All patients underwent B-mode ultrasound on postoperative day 8 or 9 to screen for DVT and those with a negative ultrasound result, but who were still suspected to have DVT, underwent venography. PE diagnosis, however, was clinical. There was no difference in DVT (18% with ASA and 17% with placebo) or


Study type and level of evidence

Context and dose of ASA

Outcome measure

Key results

Comments

Pooled analysis of the ASA groups found that the pooled risk of DVT, proximal DVT and PE were 0.32 (95% CI: 0.14e0.5), 0.15 (95% CI: 0.1e0.2) and 0.019 (95% CI: 0.005 e0.0033) respectively. Corresponding pooled results for the control groups were 0.47 (95% CI: 0.4e0.53), 0.23 (95% CI: 0.17 e0.29), 0.024 (95% CI: 0.013e0.035). The authors concluded that no difference existed between ASA and placebo. No significant differences between ASA and placebo in rates of DVT (18 vs. 17%) and PE (5% each). However, ASA patients required more blood transfusions postoperatively (0.36 vs. 0.16 units, P < 0.05).

17 included trials evaluated therapies other than ASA. Control arms from these trials were used in the analysis.

Imperiale, 1994 (n ¼ 7976) 511 patients (from 8 trial treatment arms) received ASA and 1436 patients (from 25 trial control arms) were assigned to placebo.

Meta-analysis of RCT's Level I

Elective total hip replacement

DVT, proximal DVT and PE. Diagnostic methods for these were not specified.

Monreal, 1995 (n ¼ 459) 151 patients received ASA, 154 received triflusal and 154 received placebo.

RCT Level II

Elective hip replacement or surgery for hip fracture, ASA 200 mg TDS

APTC trial, 1994 (n ¼ 9446)


Orthopaedic surgery (hip fracture, elective hip/knee arthroplasty), general surgery, high-risk medical patients

DVT and PE Mandatory B-mode U/S in all patients on postoperative day 8 e9 ± venography for DVT. Diagnosis of PE made on clinical grounds. DVT sought systematically with fibrinogen leg scanning or venography or both.

Freedman, 2000 (n ¼ 10,929) 687 patients received ASA and 947 received placebo PEP trial, 2000 (n ¼ 17444)


Elective total hip arthroplasty

Bilateral venography to detect DVT in all patients

RCT Level II

Orthopaedic surgery (hip fracture, elective hip/knee arthroplasty), ASA 160 mg OD

Symptomatic DVT confirmed with venography or duplex U/S and symptomatic PE confirmed with V/Q scans, pulmonary angiography or at necropsy.

ASA monotherapy reduced the risk of DVT by 23% and that of PE by 67%, compared to placebo.

ASA decreased the risk of total DVT compared to placebo (30.6 vs. 48.5%, P < 0.0001), but not the risk of symptomatic PE (1.28 vs. 1.51%). In the hip fracture cohort, ASA reduced the risk of DVT by 29% (95% CI: 3e48%, P ¼ 0.03) and PE by 43% (95% CI: 18e60%, P ¼ 0.002). However, ASA also increased the risk of bleeding requiring transfusion (2.9 vs. 2.4%, P ¼ 0.04).

All patients received UFH 7500 IU s/c BD, starting 2 h preoperatively.

However, only 16 trials comprising 1619 patients compared ASA monotherapy with placebo for DVT, and 21 trials comprising 4014 patients for PE.

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Extended thromboprophylaxis with ASA for 35 days.

(continued on next page)

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Table 1 e Summary of studies comparing ASA with placebo for primary VTE prophylaxis. Study details

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Study details STRATAGEM trial, 2011 (n ¼ 291)

Study type and level of evidence RCT Level II

Context and dose of ASA

Outcome measure

Key results

Comments

At-risk patients undergoing elective non-cardiac highor intermediate-risk surgery

Primary end-point: Weighted (as per Delphi consensus) composite score including death, major thrombotic events (stroke, TIA, ACS, PAI, MAI, venous thrombosis and PE) and major bleeding events (cerebral haemorrhage, intra- or retroperitoneal haemorrhage, bleeding requiring an intervention or requiring 3 units of RBC) recorded between inclusion and day 30 after surgery Secondary end-points: Weighted composite endpoint on postoperative days 7 and 180, and each element separately

10 of 11 major thrombotic events were arterial events. The remaining one was a DVT, occurring in the ASA group. There was no difference in thrombotic events between ASA and placebo (4.1 vs. 3.4%, P ¼ 0.8).

Study initially powered to recruit 1421 patients but stopped after 291 because of major recruitment difficulties Protocol used by authors was low-dose ASA/placebo started 10 days before surgery and continued until morning of surgery, and normal anti-platelet agents resumed after surgery when postoperative bleeding risk was considered acceptable. However, exact number of days when patients were on no anti-platelet agents postoperatively is unknown. Moreover, 5 of 11 major thrombotic events occurred between day 1 and 3 postoperatively

RCT: Randomized Controlled Trial, U/S: Ultrasound, DVT: Deep Vein Thrombosis, PE: Pulmonary Embolism, V/Q: Ventilation Perfusion scans, TIA: Transcient Ischaemic Attack, ACS: Acute Coronary Syndrome, PAI: Peripheral Arterial Ischaemia, MAI: Mesenteric Arterial Ischaemia, RBC: Red Blood Cell.

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Table 1 e (continued )

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PE (5% in both ASA and placebo groups) between ASA and placebo, but post-operative blood transfusion requirements were increased among recipients of ASA (0.36 vs. 0.16 units, P < 0.05). In the meta-analysis by Freedman et al.18 looking at thromboprophylaxis after elective total hip arthroplasty, published in 2000 and capturing 52 trials comprising 10,929 patients, ASA decreased the risk of total (proximal and distal) DVT compared to placebo (30.6 vs. 48.5%, P < 0.0001) but not the risk of distal DVT (19.7 vs. 22.4%). In addition, ASA significantly reduced the risk of proximal DVT compared to placebo (11.4 vs. 25.8%, P < 0.0001) without a significant reduction in the risk of symptomatic PE (1.28 vs. 1.51%). There was no significant increase in total minor or major bleeding with ASA compared to placebo (1.2 vs. 3.0% and 0.73 vs. 0.56%, respectively). Two studies provide the best evidence regarding the efficacy of ASA in comparison to placebo. Firstly, the Anti Platelet Trialists' Collaboration (APTC) meta-analysis of antiplatelet therapy in VTE prevention reported data on 9623 high VTErisk patients (814 medical, 8809 surgical).19 While either venography or fibrinogen leg scanning systematically diagnosed DVT, PE was suspected clinically and confirmed by objective diagnostic assessment (e.g. ventilation-perfusion scanning) or at necropsy. DVT was reported in 640/2576 (24.8%) antiplatelet drug recipients compared with 875/2605 (33.6%) controls in 53 studies, and PE, in 47/4716 (1%) of patients allocated antiplatelet therapy compared with 129/4730 (2.7%) controls in 62 studies. This translated into 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) in favour of any antiplatelet medications (ASA, ASA plus dipyridamole, hydroxychloroquine or ticlopidine). When ASA monotherapy was compared to placebo in 16 trials comprising 1619 patients, ASA reduced DVT risk by 23% (10%) and that of PE by 67% (15%) in 21 trials comprising 4014 patients. However, the combined use of antiplatelet therapy compared to control significantly increased transfusions (0.4 vs. 0.7%, P ¼ 0.04) and wound haematomas, reoperation and bleeding-related infection (7.8 vs. 5.6%; P ¼ 0.003). It is important to emphasise that varying doses of ASA (75e1500 mg daily) were employed in the studies included in the APTC meta-analysis. The Pulmonary Embolism Prevention (PEP) Trial20 is the largest prospective randomized, double blind, placebocontrolled trial. Conducted in 5 countries, it recruited 13,556 patients undergoing surgery for hip fracture and 4088 patients undergoing elective hip arthroplasty. Patients received either ASA 160 mg per day or placebo, beginning preoperatively and continued for 35 days postoperatively. However, any other form of additional thromboprophylaxis deemed necessary was allowed, so about 30% of patients received compression stockings, 18% received UFH and about 26% received LMWH. The primary outcome was the occurrence of symptomatic VTE at 35 days. Only clinically suspected DVT and PE cases subsequently objectively confirmed with venography, duplex ultrasound, ventilation-perfusion scans, pulmonary angiography or at necropsy were recorded as outcomes. The PEP study demonstrated that ASA resulted in proportional reductions in DVT of 28% (95% CI: 4e45%, P ¼ 0.02) and PE of 39% (95% CI: 16e54%, P < 0.005). In those undergoing surgery for

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hip fracture, ASA reduced DVT risk by 29% (95% CI: 3e48%, P ¼ 0.03) and PE by 43% (95% CI: 18e60%, P ¼ 0.002). This represents an absolute reduction in VTE events of 9 for every 1000 patients treated and interestingly, there was a trend towards a greater reduction in events after the first postoperative week. This may reflect the benefit of extended thromboprophylaxis with ASA (35 days) after discharge from hospital, following cessation of other methods. However, because 44% of patients received additional chemical thromboprophylaxis with either UFH or LMWH during their hospital stay and subgroup analysis of agents was not performed, it is impossible to attribute these benefits to ASA monotherapy alone. Unfortunately treatment with ASA also resulted in an increase of six postoperative bleeds requiring transfusion for every 1000 patients treated (2.9 vs. 2.4%, P ¼ 0.04), and an excess of haematemesis and melena, which did not require transfusion (2.7 vs. 1.8%, P ¼ 0.0005). Mantz et al.21 conducted a randomized, blinded, multicenter, placebo-controlled trial (STRATAGEM trial) comparing maintenance vs. interruption of low-dose ASA (75 mg) on thrombotic (both arterial and venous events) and bleeding events in 291 high-risk patients undergoing intermediate- or high-risk non-cardiac surgery (including orthopaedic, abdominal, urologic, oncologic ENT and vascular surgery but excluding carotid endarderectomy and coronary artery bypass grafting). They substituted non-aspirin anti-platelet agents with ASA (n ¼ 145) or placebo (n ¼ 146) beginning 10 days before, and continued until the morning of surgery. There was a history of venous thromboembolic disease in 6.9% of the ASA-treated patients and 7.5% of placebo recipients. The primary end-point was a weighted (according to a Delphi consensus) composite score evaluating both bleeding and thrombotic events occurring within 30 post-operative days. There was no significant difference in the mean outcome scores between ASA and placebo [mean (SD) ¼ 0.67 (2.05) in ASA group vs. 0.65 (2.04) in placebo group, P ¼ 0.94]. Of 11 thrombotic events reported, 10 were arterial (i.e. acute coronary syndromes, peripheral and mesenteric ischaemia) while one was a DVT, occurring in the ASA group. There was no difference in the occurrence of major thrombotic events at day 30 between the ASA and the placebo group (4.1 vs. 3.4%, P ¼ 0.8). The major limitation of this study was that it was underpowered.

ASA vs. other anticoagulants in primary VTE prophylaxis (Table 2) Freedman et al.,18 in their meta-analysis evaluating thromboprophylaxis after elective total hip arthroplasty, which included over 10,000 patients, showed that the risk of distal DVT was significantly higher with ASA than pneumatic compression (19.7 vs. 7.7%, P ¼ 0.0001) or LMWH (19.7 vs. 9.6%, P ¼ 0.0005). However, the risk of proximal DVT was not significantly different between ASA and warfarin (11.4 vs. 6.3%, P ¼ 0.7955) or between ASA and LMWH (11.4 vs. 7.7%, P ¼ 0.8862). There were no comparisons between ASA and other anticoagulants for PE (Table 3). Similarly, Westrich et al.,22 in a meta-analysis capturing just over 6000 patients undergoing total knee arthroplasty


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Study details

Anticoagulant used

Context, dose of ASA

Method used for DVT and PE diagnosis

Key results

Comments

No statistically significant differences in the rates of DVT (3.9 vs. 2.4%) or PE (0.3% each) between ASA and UFH. No differences in the rates of DVT (56.6% for ASA and 53.4% for warfarin) or PE (9.6% for ASA and 8.2% for warfarin). VTE rate significantly higher in ASA vs. danaparoid group (44.3 vs. 27.8%, RRR of 37% with danaparoid, P ¼ 0.028). No significant differences in bleeding complications however (6.4 vs. 1.6%, P ¼ 0.10). LMWH was significantly better than ASA in preventing DVT (29 vs. 53%, P < 0.0001). With regards to asymptomatic PE, warfarin was significantly better than ASA (8.2 vs. 11.7%, P < 0.05). As for symptomatic PE, there were no differences observed between groups. No significant difference in overall DVT rates between ASA and LMWH groups (17.8 vs. 14.1%, P ¼ 0.27). ASA patients had significantly more postoperative blood loss (901 vs. 793 mL, P ¼ 0.03). Increased rate of VTE in ASA vs. LMWH/warfarin (7.9 vs. 1.2%, P ¼ 0.001). No significant differences in major bleeding, death or minor bleeding between groups.

Patients received 500 mg ASA intravenously for the first 3 days postoperatively and then orally subsequently.

Vinazzer, 1980 RCT (n ¼ 1210)

S/c UFH 5000 I/U BD

Elective general surgery, 500 mg ASA TDS

Mandatory Doppler US for DVT and clinical suspicion for PE.

Lotke, 1996 RCT (n ¼ 388)

Warfarin (to maintain prothrombin time between 1.2 and 1.5 times normal)

Hip or knee arthroplasty, 325 mg ASA BD

Mandatory venography for DVT and mandatory ventilation perfusion (V/Q) scans for PE.

Gent, 1996 RCT (n ¼ 251)

S/c danaparoid sodium 750 U BD

Hip fracture, 100 mg ASA BD

Westrich, 2000 Meta-analysis (n ¼ 6001) 3214 patients were on ASA

LMWH (unspecified) Warfarin (5 or 10 mg started on the evening before surgery, or on the night of surgery, with PT kept between 1.3 and 1.5 times normal).

Total knee arthroplasty, 325 e650 mg ASA OD

Periodic fibrinogen leg scanning ± venography during hospital stay or standard venography at day 14 for DVT, while V/Q scans or pulmonary angiogram in patients symptomatic for PE. Venography for DVT, and V/ Q scans or pulmonary angiogram for PE.

Westrich, 2006 RCT (n ¼ 275)

S/c enoxaparin 30 mg BD

Knee arthroplasty, 325 mg ASA BD

Woller, 2012 Prospective study (n ¼ 696)

Warfarin (with INR maintained between 1.8 and 2.5) or enoxaparin 30 mg s/c BD

Elective hip and knee arthroplasty, ASA 600 mg once PR in PACU, followed by 325 mg BD

Mandatory colour flow duplex US between postoperative days 3 and 5, and then again at 4e6 weeks postoperatively for DVT. PE was suspected clinically and confirmed by CT. 90-day follow-up thrombosis questionnaire was administered followed by CTPA, compression U/S, pulmonary angiogram or V/ Q scans in suspected patients

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Table 2 e Summary of studies comparing ASA with other anticoagulants for primary VTE prophylaxis.

Background pneumatic compression device in all patients and open-label study. Only 1 PE was observed (ASA group).

2007 AAOS guidelines (with PE risk stratification) compared with 2008 ACCP guidelines. Background pneumatic compression device in all patients.

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Study compared extended prophylaxis with ASA vs. dalteparin postoperatively after all patients received dalteparin initially for 10 days postoperatively

Table 3 e Evidence summarizing the superiority/ inferiority of ASA vs. other anticoagulants in primary VTE prevention. ASA comparison with other anticoagulants in terms of VTE rates

LMWH significantly better than ASA Danaparoid significantly better than ASA LMWH similar to ASA ASA significantly better than warfarin

UFH: Unfractionated Heparin, LMWH: Low Molecular Weight Heparin, VTE: Venous ThromboEmbolism.

Anderson, 2013 (EPCAT study) RCT (n ¼ 778)

S/c dalteparin 5000 U OD

Elective total hip arthroplasty, ASA 81 mg OD

Suspected VTE was confirmed with objective testing (no specific mention of diagnostic tests employed)

ASA was noninferior (P < 0.001) but not superior to LMWH (P ¼ 0.22) for VTE prevention. The absolute betweengroup difference in a composite of all VTE and clinically significant bleeding events was 1.7 percentage points (95% CI: 0.3 to 3.8 percentage points; P ¼ 0.091) in favour of ASA.

ASA significantly better than UFH ASA similar to warfarin ASA significantly better than LMWH Warfarin significantly better than ASA

Evidence

0 1 (Lotke, RCT) 0 1 (Westrich meta analysis, for asymptomatic PE) 1 (Woller, prospective) 1 (Westrich meta analysis, for DVT) 1 (Woller, prospective) 1 (Gent, RCT) 1 (Westrich, RCT) 1 (Anderson, RCT) 0

showed LMWH significantly outperformed ASA in preventing DVT (29 vs. 53%, P < 0.0001). The end-point DVT was poorly defined however. With regards to asymptomatic PE, the rates were significantly reduced with warfarin compared to ASA (8.2 vs. 11.7%, P < 0.05). The generalizability of these findings is however, questioned. The authors pooled the data from the treatment and control arms and performed indirect comparisons rather than a true meta-analysis. We identified 5 randomized trials comparing ASA with other anticoagulants, namely ASA with LMWH (n ¼ 2), ASA with warfarin (n ¼ 1), ASA with UFH (n ¼ 1) and ASA with danaparoid (n ¼ 1). Vinazzer et al.,23 in their double blind study, randomized general surgery patients to either 500 mg of ASA TDS (intravenously for the first three days postoperatively and orally subsequently) or 5000 I/U of UFH BD until patients were completely ambulatory. Doppler U/S for DVT was mandatory while PE was suspected clinically and necropsy performed in all deaths. They found no statistically significant differences in the rates of DVT (3.9 vs. 2.4%) or PE (0.3% each) between ASA and UFH. In addition, the risk of bleeding requiring study medication withdrawal was similar for both groups (0.7%). In 388 patients undergoing total hip or knee arthroplasty randomized to either 325 mg ASA BD or warfarin, and undergoing mandatory venography and ventilation perfusion scans, Lotke et al.24 showed no differences in DVT (56.6% for ASA and 53.4% for warfarin) or PE (9.6% for ASA and 8.2% for warfarin) between the two groups. There were no differences regarding haemorrhagic complications. Gent et al.25 randomized 251 consecutive patients undergoing surgery for hip fracture to either ASA 100 mg BD or 750 I/ U of subcutaneous danaparoid sodium BD, starting 12e24 h postoperatively and continued for 14 days or until discharge. All patients underwent fibrinogen leg scanning and impedance plethysmography, followed by venography if one of the former two tests was positive, or standard venography at day


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14 if both tests were negative. PE in symptomatic patients was diagnosed on the basis of a high probability perfusion ventilation lung scan, a positive angiogram, or a clinically significant embolism detected at autopsy. The incidence of VTE was 44.3% in ASA recipients and 27.8% in those on danaparoid sodium. This translated into a 37% relative risk reduction with danaparoid compared to ASA (95% CI: 3.7e59.7%, P ¼ 0.028). Bleeding complications were not statistically significantly different between ASA and danaparoid (6.4 vs. 1.6%, P ¼ 0.10), although the trend was worse with ASA. In the study by Westrich et al.,26 275 patients undergoing total knee arthroplasty treated with spinal anaesthesia and receiving mechanical prophylaxis with pneumatic compression, received either ASA 325 mg BD or enoxaparin, starting 48 h postoperatively, initially at 30 mg subcutaneously BD until hospital discharge then 40 mg OD for 3 weeks thereafter. DVT was diagnosed by colour flow duplex ultrasound performed in all patients between days 3 and 5 after surgery, and then again 4e6 weeks after surgery. PE was suspected clinically and confirmed by spiral computed tomography. Of all 275 patients enrolled, 264 were included in the final analysis. There were no statistically significant differences in the overall rates of DVT between the ASA and LMWH groups (17.8 vs. 14.1%, P ¼ 0.27). Mean postoperative blood loss (mean or median) was higher in those who received ASA (901 vs. 793 mL, P ¼ 0.03). This study lacked a prior power calculation and may have been underpowered to detect a significant difference between the 2 treatment arms. In the prospective study carried out by Woller et al., the 2008 ACCP guidelines and the 2007 American Academy of Orthopaedic Surgeons (AAOS) recommendations for VTE prophylaxis were applied to 696 consecutive patients undergoing joint arthroplasty (265 total hip arthroplasties and 431 total knee arthroplasties) such that patients deemed as standard risk for PE (n ¼ 152) by the AAOS received ASA 600 mg PR once in the postanaesthesia care unit followed by 325 mg BD for 4 weeks, while those at heightened risk (n ¼ 129) received warfarin starting the night before surgery and continued for 4 weeks to maintain an international normalized ratio of 1.8e2.5. The comparator group (n ¼ 415) followed the ACCP guidelines and received warfarin (n ¼ 408) on the night before surgery or enoxaparin (n ¼ 7) 30 mg BD begun 6e12 h postoperatively and continued for 4 weeks. In addition all patients received mechanical prophylaxis in the form of pneumatic calf compression. The major outcomes of the study (symptomatic PE, DVT, major bleeding and death) were adjudicated by a panel of 3 physicians who were blinded to the VTE prevention policy. To identify VTE, patients were firstly administered a 90-day follow-up thrombosis questionnaire before their electronic medical record was cross-examined for CTPA, whole-leg compression ultrasound. pulmonary angiogram or ventilation perfusion scanning during the study period. When patients who were treated with warfarin/enoxaparin in accordance with the ACCP guidelines (n ¼ 415, no risk stratification) were compared with the ASA treated patients (n ¼ 152, deemed to be of standard PE risk) according to the ACCS guidelines, ASA-treated patients had higher rates of both symptomatic PE (4.6% vs. 0.7%, P ¼ 0.03) and symptomatic DVT (4.6% vs. 0.7%, P ¼ 0.03). The odds of symptomatic VTE in the ASA-treated patients were 7 times that of the

warfarin/enoxaparin patients (P ¼ 0.001). Most events (16/18) occurred in patients undergoing total knee arthroplasty. There were no significant differences in major bleeding and death between ASA recipients and warfarin/LMWH recipients (0.7 vs. 0.2%, P ¼ 0.464 and 0 vs. 1.5%, P ¼ 0.350, respectively), nor were there differences in minor bleeding (1.3 vs. 3.9%, P ¼ 0.177) or unanticipated return to theatre (2 vs. 1.7%, P ¼ 0.732). Finally, in 778 patients who received an initial 10-day course of prophylactic dalteparin following total hip arthroplasty and subsequently randomized to 28 days of either 5000 I/U of dalteparin subcutaneously OD or 81 mg of ASA OD, Anderson et al.27 showed that the rates of VTE in the 90-day follow-up period was 1.3% in the dalteparin group compared to 0.3% in those assigned ASA (95% CI: 0.5 to 2.5). ASA was found to be non-inferior (P < 0.001) but not superior (P ¼ 0.22) to dalteparin for VTE prophylaxis. In addition there were no significant differences in haemorrhagic complications between the 2 regimens, although the trend favoured ASA. When combined, both VTE and clinically significant bleeding events favoured ASA over dalteparin (P ¼ 0.091).

Discussion While ASA has a well-proven role in the primary and secondary prevention of arterial thrombosis,28,29 its role in primary VTE prophylaxis has been the subject of uncertainty. This can be partly explained by the perceived mechanistic differences between arterial (predominantly composed of platelets, i.e. white clot) and venous (predominantly composed of fibrin and erythrocytes, i.e. red clot) thrombi. However, it is now generally accepted that platelets and fibrin are found in both arterial and venous clots, and platelet activation and accumulation have been demonstrated within venous thrombi.30 Furthermore, there is evidence that patients with symptomatic arterial occlusive disease are at increased risk of incident VTE,31,32 and that patients with clinical manifestations of VTE, especially if unprovoked, are at increased risk of incident atherothrombotic events,33e35 hence the rationale for the use of ASA in VTE prevention. The evidence presented in the current review seems to suggest that ASA is more effective than placebo in primary VTE prevention. The most robust evidence demonstrating superiority of ASA over placebo comes from the APTC meta-analysis and the PEP trial. However, methodological flaws have been highlighted in both studies, in particular, the use of fibrinogen leg scanning over the gold standard venography to diagnose DVT in some of the studies included in the APTC metaanalysis, and the permission to use any additional form of thromboprophylaxis in addition to the agent being studied (i.e. ASA) in the PEP randomized trial. Despite these criticisms however, the results of these 2 studies are likely to be valid. On the other hand, when it comes to deciding between ASA and other anticoagulants for VTE prophylaxis, there appears to be clinical equipoise in the literature, resulting from substantial heterogeneity among studies due to varying regimens of medications as well as evolving care pathways (such as increasing use of regional anaesthesia and prompt ambulation), especially in orthopaedic surgery.


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Like surgery, cancer is a risk factor for VTE,36 and not surprisingly, VTE is the leading cause of mortality in the first 30 postoperative days following cancer surgery.37 Hypercoagulability underlies neoplasia and this is mediated by increased circulating levels of vascular endothelial growth factor (VEGF), tissue factor and cancer procoagulant.38,39 In addition, concomitant oncologic therapeutic modalities (such as chemotherapy and radiotherapy) increase the risk of VTE.40,41 Because it is now recognised that substantial VTE events occur following hospital discharge, current guidelines from the National Comprehensive Cancer Network, the American Society of Clinical Oncology and the American College of Chest Physicians endorse extended thromboprophylaxis for up to 4 weeks in high-risk patients undergoing major abdominopelvic oncological resections.10,42,43 A recent randomized controlled trial demonstrated that prolonged antithrombotic prophylaxis for up to 4 weeks following laparoscopic surgery for colorectal cancer was safe and significantly reduced VTE rates compared to 1-week only prophylaxis.44 Therefore, the ideal agent should be inexpensive, easy to administer at home, as well as effective. One study45 that evaluated the cost-effectiveness of prolonged antithrombotic prophylaxis for up to 4 weeks after major abdominopelvic oncologic procedures showed that while low dose unfractionated heparin (LDUH) administered three times daily was the most cost effective strategy, once-daily ASA was a viable alternative, saving $123 per patient without VTE compared to no prophylaxis, only $31 less than LDUH. LMWH once daily was the least cost-effective method. Moreover, when compliance, bleeding rates and the risk of heparininduced thrombocytopenia were factored in, ASA became the most cost-effective agent. Jameson and colleagues46 reported the annual cost of extended prophylaxis with LMWH in joint arthroplasty patients across the United Kingdom and Wales to be around £13 million, compared to approximately £110,000 for ASA. An observational study47 comprising over 17,000 hip arthroplasty patients concluded that significant postoperative surgical site infections might result from increased use of perioperative LMWH for VTE prophylaxis. Unfortunately the risk associated with the use of ASA only was not documented. Given the enormous costs, bleeding and infective complications associated with LMWH, ASA appears to be associated with a better cost-benefit and risk-benefit ratio. Moreover, one randomized double-blinded controlled trial48 has recently shown a reduction by about 40% of recurrent VTE with ASA compared to placebo, in patients having completed initial treatment with oral anticoagulants for a first episode of unprovoked VTE, with no apparent increase in the risk of major haemorrhage. While this risk reduction is lower than that afforded by newer oral anticoagulants49,50 (around 80% with agents such as dabigatran and rivaroxaban), ASA is associated with less bleeding complications.13 We wish to highlight that the aim of our review was to compare ASA with other pharmacological methods of VTE prophylaxis and that therefore we did not evaluate the effects of mechanical thromboprophylaxis. A large 2013 meta-analysis51 addressed this issue and made several important conclusions: intermittent pneumatic compression (IPC) was more effective that no compression; IPC seemed to be as effective as pharmacological prophylaxis but with reduced bleeding risk;

9

adding pharmacological prophylaxis to IPC further reduced the risk of DVT. Therefore, we advise that mechanical thromboprophylaxis, ideally with IPC, should be routinely administered to those at VTE risk unless contraindications exist. In conclusion, ASA is better than placebo in both primary and secondary VTE prevention but there is less certainty when ASA is compared with other anticoagulants. Three studies in orthopaedic surgery26,27,52 suggest that ASA is as effective as LMWH, but additional studies in a range of other settings are needed to justify any changes in practice. Further adequately powered trials with well-defined end points are needed to explore the protection afforded by extended primary thromboprophylaxis with ASA following hospital discharge in surgical oncology and orthopaedic patients, as well as its safety (prolonged ASA use may result in gastrointestinal or renal complications) and efficacy profile in comparison to the newer oral anticoagulants in secondary prevention of provoked VTE episodes.

Author contribution SMS: literature search, data analysis, manuscript writing, proofreading. DA: literature search, data analysis, manuscript editing, proofreading. SRW: critical appraisal, final authorization of article for submission.

Sources of financial support None.

Conflicts of interest None.

references

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Prophylaxis against venous thromboembolism in surgical patients.

Primary venous thromboembolism prophylaxis in patients with solid tumors.

Aspirin prophylaxis of venous thromboembolism after total hip replacement.

Venous thromboembolism prophylaxis in critically ill patients.

Prophylaxis of venous thromboembolism.

The Prophylaxis of Venous Thromboembolism.

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Prophylaxis against venous thromboembolism.

Prophylaxis against venous thromboembolism.

Dosing of enoxaparin for venous thromboembolism prophylaxis in obese patients.

PROPHYLAXIS OF VENOUS THROMBOEMBOLISM IN ORTHOPAEDIC SURGERY.

Prophylaxis against venous thromboembolism in patients with cancer.

Prophylaxis against venous thromboembolism in patients with cancer.

Medical rota changes and venous thromboembolism prophylaxis in orthopaedic patients.

Prophylaxis against venous thromboembolism in patients with cancer.

Prophylaxis against venous thromboembolism in ambulatory patients with cancer.

Primary venous thromboembolism prophylaxis in patients with solid tumors: a meta-analysis.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

Deep venous thrombosis and venous thromboembolism prophylaxis.

Direct Costs of Aspirin versus Warfarin for Venous Thromboembolism Prophylaxis after Total Knee or Hip Arthroplasty.

Primary prophylaxis for venous thromboembolism in people undergoing major amputation of the lower extremity.

An overview of venous thromboembolism prophylaxis.

Should patients with chronic liver disease receive venous thromboembolism prophylaxis?

Cost-effective prophylaxis against venous thromboembolism after total joint arthroplasty: warfarin versus aspirin.