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Aspirin Versus Low-Molecular-Weight Heparin for Extended Venous Thromboembolism Prophylaxis After Total Hip Arthroplasty: A Randomized Trial

David R. Anderson, MD; Michael J. Dunbar, MD; Eric R. Bohm, MD; Etienne Belzile, MD; Susan R. Kahn, MD; David Zukor, MD; William Fisher, MD; Wade Gofton, MD; Peter Gross, MD; Stephane Pelet, MD; Mark Crowther, MD; Steven MacDonald, MD; Paul Kim, MD; Susan Pleasance, BScN; Nicki Davis, BSc; Pantelis Andreou, PhD; Philip Wells, MD; Michael Kovacs, MD; Marc A. Rodger, MD; Tim Ramsay, PhD; Marc Carrier, MD; and Pascal-Andre Vendittoli, MD
[+] Article and Author Information

From Dalhousie University, Halifax, Nova Scotia; University of Manitoba, Winnipeg, Manitoba; Université Laval, Québec City, Québec; McGill University and Montréal University, Montréal, Québec; University of Ottawa, Ottawa, Ontario; McMaster University, Hamilton, Ontario; and University of Western Ontario, London, Ontario, Canada.

Note: All authors had full access to the study data. Dr. Anderson takes full responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: The authors thank the members of the EPCAT study group (see the Appendix).

Financial Support: By grant MCT-82948 from the Canadian Institutes for Health Research and by Pfizer Pharmaceuticals Canada. In-kind support was provided by Bayer HealthCare. Dr. Kahn is a recipient of a National Research Scholar Award from the Fonds de la Recherche en Santé du Québec.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2191.

Reproducible Research Statement: Study protocol, statistical code, and data set: For details, contact Dr. Anderson (david.anderson@cdha.nshealth.ca).

Corresponding Author: David Anderson, MD, Department of Medicine, Capital Health, 1276 South Park Street, Room 442, Bethune Building, VG Site, Halifax, Nova Scotia B3H 2Y9, Canada; e-mail, david.anderson@cdha.nshealth.ca.

Current Author Addresses: Dr. Anderson: Department of Medicine, Capital Health, 1276 South Park Street, Room 442, Bethune Building, VG Site, Halifax, Nova Scotia B3H 2Y9, Canada.

Dr. Dunbar: Queen Elizabeth II Health Sciences Centre, Suite 4822, Halifax Infirmary, 1796 Summer Street, Halifax, Nova Scotia B3H 3A7, Canada.

Dr. Bohm: Concordia Joint Replacement Group, Suite 300–1155, Concordia Avenue, Winnipeg, Manitoba R2K 2M9, Canada.

Dr. Belzile: Centre Hospitalier Universitaire Québec, Pavillon Hotel Dieu de Québec, Service de Chirurgie Orthopedique, 11 Côte du Palais, Québec, Québec G1R 2J6, Canada.

Dr. Kahn: Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, 5790 Côte-des-Neiges, Room H-485, Montréal, Québec H3S 1Y9, Canada.

Dr. Zukor: Department of Orthopedics, SMBD Jewish General Hospital, 3755 Chemin de la Côte Ste-Catherine, Montréal, Québec H3T 1E2, Canada.

Dr. Fisher: McGill University Health Centre, 1650 Cedar Avenue, B5.158.7, Montréal, Québec, H3G 1A4, Canada.

Dr. Gofton: Ottawa Hospital Civic Campus, Suite J153, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.

Dr. Gross: TaARI, David Braley CVSRI-5th Floor, 247 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Dr. Pelet: Departement d’orthopedie, CHA-Pavillon Enfant-Jesus, 1401, 18eme Rue, Québec, Québec G1J 1Z4, Canada.

Dr. Crowther: Room L-301, St Joseph's Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. MacDonald: London Health Sciences Centre, University Hospital, 339 Windermere Road, London, Ontario N6A 5A5, Canada.

Dr. Kim: Ottawa Hospital General Campus, 501 Smyth Road, Room W1650, Box 502, Ottawa, Ontario K1H 8L6, Canada.

Ms. Pleasance: Queen Elizabeth II Health Sciences Centre, Capital Health Centre for Clinical Research, 5790 University Avenue, Room 132, Halifax, Nova Scotia B2H 1V7, Canada.

Ms. Davis: 21 Robertson Avenue, Gander, Newfoundland A1V 1Y1, Canada.

Dr. Andreou: Department of Community Health and Epidemiology, Dalhousie University, 5790 University Avenue, Room 414, Halifax, Nova Scotia B3H 1V7, Canada.

Dr. Wells: Ottawa Hospital General Campus, LM 12 Box 206, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.

Dr. Kovacs: Victoria Hospital, 800 Commissioners Road East, Room A2-401, London, Ontario N6A 4G5, Canada.

Dr. Rodger: Ottawa Hospital General Campus, 501 Smyth Road, W6120, Box 201, Ottawa, Ontario K1H 8L6, Canada.

Dr. Ramsay: Ottawa Hospital General Campus, Box 201b, 501 Smyth Road, Ottawa K1H 4E9, Canada.

Dr. Carrier: Division of Hematology and CEP, Ottawa Hospital General Campus, 501 Smyth Road, Box 201A, Ottawa, Ontario K1H 8L6, Canada.

Dr. Vendittoli: Hospital Maisonneuve-Rosemont, 5415 boul L’Assomption, Montréal, Québec H1T 2M4, Canada.

Author Contributions: Conception and design: D. Anderson, M.J. Dunbar, E.R. Bohm, E. Belzile, D. Zukor, W. Fisher, S. Pleasance, P. Wells, M. Kovacs, M.A. Rodger, P.A. Vendittoli.

Analysis and interpretation of the data: D. Anderson, M.J. Dunbar, E.R. Bohm, W. Fisher, P. Kim, N. Davis, P. Andreou, P. Wells, M. Kovacs, M. Carrier.

Drafting of the article: D. Anderson, M.J. Dunbar, E. Belzile, W. Fisher, M. Crowther, P. Kim, S. Pleasance, P. Wells, M. Kovacs, P.A. Vendittoli.

Critical revision of the article for important intellectual content: D. Anderson, E.R. Bohm, E. Belzile, S. Kahn, W. Fisher, P. Gross, S. Pelet, S. Pleasance, P. Wells, M. Kovacs, M.A. Rodger, T. Ramsay, M. Carrier, P.A. Vendittoli.

Final approval of the article: D. Anderson, M.J. Dunbar, E.R. Bohm, E. Belzile, S. Kahn, D. Zukor, W. Fisher, W. Gofton, P. Gross, S. Pelet, S. MacDonald, P. Kim, S. Pleasance, P. Andreou, P. Wells, M. Kovacs, M.A. Rodger, T. Ramsay, M. Carrier, P.A. Vendittoli.

Provision of study materials or patients: M.J. Dunbar, E.R. Bohm, E. Belzile, S. Kahn, D. Zukor, W. Fisher, W. Gofton, P. Gross, S. Pelet, M. Crowther, S. MacDonald, P. Kim, M. Kovacs.

Statistical expertise: N. Davis, P. Andreou, T. Ramsay.

Obtaining of funding: D. Anderson, E.R. Bohm, E. Belzile, S. Kahn, S. Pelet, S. Pleasance, P. Wells, M.A. Rodger, M. Carrier.

Administrative, technical, or logistic support: E.R. Bohm, S. Pelet, M. Crowther, P. Kim, S. Pleasance, N. Davis.

Collection and assembly of data: S. Kahn, D. Zukor, S. Pelet, S. MacDonald, P. Kim, N. Davis, M. Rodger, M. Carrier, P.A. Vendittoli.


Ann Intern Med. 2013;158(11):800-806. doi:10.7326/0003-4819-158-11-201306040-00004
Text Size: A A A

Chinese translation

Background: The role of aspirin in thromboprophylaxis after total hip arthroplasty (THA) is controversial.

Objective: To compare extended prophylaxis with aspirin and dalteparin for prevention of symptomatic venous thromboembolism (VTE) after THA.

Design: Multicenter randomized, controlled trial with a noninferiority design based on a minimal clinically important difference of 2.0%. Randomization was electronically generated; patients were assigned to a treatment group through a Web-based program. Patients, physicians, study coordinators, health care team members, outcome adjudicators, and data analysts were blinded to interventions. (Current Controlled Trials: ISRCTN11902170)

Setting: 12 tertiary care orthopedic referral centers in Canada.

Patients: 778 patients who had elective unilateral THA between 2007 and 2010.

Intervention: After an initial 10 days of dalteparin prophylaxis after elective THA, patients were randomly assigned to 28 days of dalteparin (n = 400) or aspirin (n = 386).

Measurements: Symptomatic VTE confirmed by objective testing (primary efficacy outcome) and bleeding.

Results: Five of 398 patients (1.3%) randomly assigned to dalteparin and 1 of 380 (0.3%) randomly assigned to aspirin had VTE (absolute difference, 1.0 percentage point [95% CI, −0.5 to 2.5 percentage points]). Aspirin was noninferior (P < 0.001) but not superior (P = 0.22) to dalteparin. Clinically significant bleeding occurred in 5 patients (1.3%) receiving dalteparin and 2 (0.5%) receiving aspirin. The absolute between-group difference in a composite of all VTE and clinically significant bleeding events was 1.7 percentage points (CI, −0.3 to 3.8 percentage points; P = 0.091) in favor of aspirin.

Limitation: The study was halted prematurely because of difficulty with patient recruitment.

Conclusion: Extended prophylaxis for 28 days with aspirin was noninferior to and as safe as dalteparin for the prevention of VTE after THA in patients who initially received dalteparin for 10 days. Given its low cost and greater convenience, aspirin may be considered a reasonable alternative for extended thromboprophylaxis after THA.

Primary Funding Source: Canadian Institutes of Health Research.

Figures

Grahic Jump Location
Figure.

Study flow diagram.

LMWH = low-molecular-weight heparin; VTE = venous thromboembolism.

Grahic Jump Location

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Response to: Aspirin vs. LMWH for extended venous thromboembolism prophylaxis after total hip arthroplasty
Posted on June 30, 2013
Serena Granziera, Alexander T. Cohen
King's College Hospital, London, UK
Conflict of Interest: A.T. Cohen is a medical consultant, and has received consultancy and clinical trials funding from many pharmaceutical companies, including Astellas, AstraZeneca, Bayer, Boheringer-Ingelheim, BMS, Daiichi, GSK, Johnson and Johnson, Mitsubishi Pharma, Pfizer, Portola, Sanofi-Aventis, Schering Plough, and Takeda, and is an advisor to the UK Goverment All Party Working Group on Thrombosis and the UK Thromboprophylaxis Forum.

TO THE EDITOR In a multicenter randomized trial involving 786 patients undergoing elective total hip replacement in Canada during a 3-year period, Anderson et al (1) observed how following 10 days of dalteparin, 28 days of oral aspirin prophylaxis was noninferior to 28 days of dalteparin for preventing venous thromboembolism (VTE). The results of the trial are of high interest for clinicians involved in elective hip surgery, particularly as some guidelines consider aspirin to be effective, despite the single large randomized trial quoted in the guidelines showing no effect of aspirin (2) in the setting. We believe the data from the present trial cannot be considered as definitive as indicated in the conclusions. The randomization in this relatively small trial did not result in a satisfactory distribution of important risk factors. Despite the author’s assurance of the similarity of baseline characteristics of the 2 groups, we can see several important differences. The frequency of the three strongest risk factors for VTE, a history of DVT or pulmonary embolism (8 vs. 5 cases; 2.0% vs. 1.3%), active cancer in past 5 years (13 vs. 8 cases; 3.3% vs. 2.1%) and surgery in past 6 months (16 vs. 10 cases; 4.0% vs. 2.6%), were all higher in the dalteparin group. Furthermore the most important risk factor for bleeding, a history of previous major bleeding, was also higher in the dalteparin group (6 vs. 2 cases; 1.5% vs. 0.5%). With these being the principal risk factors respectively for DVT and bleeding, we believe that the results should be interpreted with great caution. It is also important to underline that the sample size is significantly smaller in comparison with trials in a similar setting (3, 4). As a result, the number of thromboembolic events in the two groups is small and chance related findings cannot be excluded. We agree with the author that the generalizability of the findings is likely to be questionable given the recent availability of novel oral anticoagulants (NOA) for VTE prophylaxis after hip replacement (4). It would now be of major interest to outline a well-designed randomized controlled trial comparing aspirin vs. a NOA.In conclusion, we believe that this article adds useful information on the use of aspirin in the orthopaedic setting, but results need to be considered in the light of the unbalanced baseline risks and the results need to be confirmed by new larger trials. Until this happens, the weak CHEST guidelines (5), based on evidence that shows little or no effect of aspirin in THR patients, should not be given more attention or credibility.

REFERENCES:

1) Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, Fisher W, Gofton W, Gross P, Pelet S, Crowther M, MacDonald S, Kim P, Pleasance S, Davis N, Andreou P, Wells P, Kovacs M, Rodger MA, Ramsay T, Carrier M, Vendittoli P-A. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty. Ann Intern Med 2013;158:800-806.

2) Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295-302.

3) Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Arch Intern Med. 2000; 160:2208-15.

4) Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-755) Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann HJ, American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel, et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence.Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl.):7S-47S

The Authors Respond
Posted on July 19, 2013
David R. Anderson, Michael Dunbar, Susan R. Kahn
Departments of Medicine and Surgery, Dalhousie University, Halifax, Nova Scotia and Department of Medicine, McGill University
Conflict of Interest: Study was funded by Canadian Institutes of Health Research, Pfizer Pharmaceuticals (Canada) and in kind support from Bayer Pharmaceuticals.

We thank Drs. Granziera and Cohen for their comments about our recent EPCAT study that provides further evidence about the benefit of aspirin for the prevention of venous thromboembolism following total hip arthroplasty (1). As these authors point out, in this trial, patients randomized to either low molecular weight heparin or aspirin had very low rates of major risk factors for venous thromboembolism and bleeding. Over 90% of the participants had none of the major risk factors cited for thromboembolism and over 98% of the patients had no previous history of major bleeding. These risk factors were similarly distributed in the two groups of patients.

 Furthermore, we reviewed our database, which demonstrated that none of the patients with previous venous thromboembolism, active cancer in the previous five years, or surgery in the past six months developed pulmonary embolism or deep vein thrombosis in follow up. Likewise none of the patients with a previous history of major bleeding developed a clinically important bleeding complication in follow up. Therefore, it is unlikely the potential concern of group imbalance raised by Drs. Granziera and Cohen can account for the results of our study.We agree with Drs. Granziera and Cohen that further study is needed to determine the relative benefits of aspirin compared with the new oral anticoagulants agents for the prevention of venous thromboembolism following joint arthroplasty.

Our group is currently performing the EPCAT II study which, following a five day post-operative course of rivaroxaban, patients are randomized to receive either aspirin or continued rivaroxaban for the prevention of pulmonary embolism or deep vein thrombosis following total hip or knee arthroplasty (NCT01720108). We expect this study will give us more definitive evidence about whether the results of our recent trial can be generalized to the more expensive new oral anticoagulant agents (2).

REFERENCES:

1) Anderson DR, Dunbar MJ, Bohm ER, Belzile E, Kahn SR, Zukor D, et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty. Ann Intern Med 2013;158:800-806.

2) Gomez-Outes A, Teieira-Fernandez AI, Suarez-Gea ML, Vaargas-Castrillon E. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. Br Med J 2012;344:e3675.

Claim of non-inferiority
Posted on August 22, 2013
Glenn Dexter O. Pebanco, Du Thuy Huy (Fiona) Tran, and Marisel Segarra-Newnham
West Palm Beach Veterans Affairs Medical Center, West Palm Beach, FL
Conflict of Interest: None Declared

Dr. Anderson and colleagues compared aspirin to low-molecular-weight heparin – dalteparin – for extended venous thromboembolism prophylaxis after total hip arthroplasty (EPCAT) in a multicenter randomized, controlled trial with non-inferiority design. The authors concluded that aspirin is non-inferior to dalteparin for VTE prophylaxis after THA based on a non-inferiority margin of 2% (1). However there are several statistical shortcomings that show this conclusion is erroneous. Firstly, this study specified a sample size of 1100 patients to achieve 95% power. Unfortunately the study was terminated prematurely due to the availability of another novel anticoagulant for the same indication, affecting enrollment. The investigators only randomized 786 patients, 314 patients short of the projected required number of study subjects (1). This would greatly increase the potential for a type 2 error of concluding that aspirin is non-inferior to dalteparin when in reality it is not (2). Secondly, the study pre-specified non-inferiority margin was 2% (1). Based on the definition from CONSORT statement on non-inferiority study design, if confidence interval (CI) crosses the non-inferiority margin to the right, the result is deemed inconclusive (3). The primary efficacy outcome from EPCAT, defined as combined pulmonary embolism or symptomatic proximal DVT, showed an absolute difference of 1% (CI -0.5 – 2.5). Although the absolute difference is less than 2%, the CI includes the 2% pre-specified non-inferiority margin (1). Therefore the result should have been reported as inconclusive. In addition, the investigators only performed an intention-to-treat analysis and not a per-protocol analysis which may have led falsely claiming non-inferiority (Type I error) (3). Lastly, the authors conducted a composite analysis of net clinical benefit that combined VTE and clinically relevant major and nonmajor bleeding complications. The absolute difference was 1.7% (CI -0.3 to 3.8%; P = 0.091) (1). The authors concluded that there is a trend favoring aspirin. However this statement is irrelevant as this analysis is not meant to show "trend", only if there is a statistically significant difference.In conclusion, based on the above comments the result of this study is inconclusive and one cannot claim that aspirin is non-inferior to dalteparin. It is best described as an intriguing result that should help to spark more research in this area.

(1) Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty. Ann Intern Med 2013;158:800-806.

(2) Demuth, JE. Preparing for the first meeting with a statistician. Am J Health-Syst Pharm 2008;65:2358-66.

(3) Piaggio G, Elbourne DR, Altman DG, et al. Reporting of noninferiority and equilance randomized trials: an extension of the CONSORT statement. JAMA 2006;295:1152-60.

Author's Response
Posted on September 12, 2013
David Anderson, MD, Pantelis Andreou, MD
Dalhousie University
Conflict of Interest: None Declared
Dr. Pebanco and colleagues raise four concerns about the EPCAT study which demonstrated the non-inferiority of expended prophylaxis with aspirin compared to low molecular weight heparin for the prevention of venous thromboembolism following total hip arthroplasty (1). First, the study was prematurely terminated because of difficulties with patient recruitment following the availability and widespread use of novel oral anticoagulants for this indication in Canada. Given that we did not achieve our target sample size, we acknowledged in our discussion the potential that the result observed in our study was a chance finding (1). Second, Pebanco and colleagues have incorrectly interpreted the CONSORT statement (2) on the demonstration of non-inferiority with respect to our study results. As they point out, the EPCAT study was designed based upon a minimal clinically important difference (non-inferiority margin) of 2% favoring low molecular weight heparin for the primary outcome measure of symptomatic pulmonary embolism and proximal deep vein thrombosis. In the study results we observed an absolute difference in the primary outcome of 1% favoring aspirin (95% confidence interval 2.5 to -0.5 %). Since the lower bound of this 95% confidence interval did not cross minus 2.0%, the prespecified non-inferiority margin, our results clearly demonstrated the non-inferiority of aspirin compared to low-molecular-weight heparin as per the CONSORT statement (2). Third, our primary analysis was intention-to-treat and included all randomized patients. In the EPCAT study, 93% of patients indicated they took all their doses of study medication. We have performed per-protocol efficacy analyses for patients who took at least one dose of study medication or for patients who were fully compliant with study medication and demonstrated findings fully comparable with the intention-to-treat analysis. Fourth, as we reported in our paper our composite analysis of the endpoints symptomatic pulmonary embolism, proximal deep vein thrombosis and clinically relevant bleeding demonstrated a non-significant trend favoring aspirin. We did not report or imply this difference was statistically significant. The EPCAT study provides further data about the benefit of aspirin for the prevention of venous thromboembolism following total hip arthroplasty. We too look forward to further research in this important field.

(1) Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty. Ann Intern Med 2013;158:800-806.
(2) Piaggio G, Elbourne DR, Altman DG, et al. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 2006;295:1152-60.


Dr. David Anderson, Department of Medicine, Dalhousie University and Capital Health, Halifax, Nova Scotia

Dr. Pantelis Andreou, Department of Community Health and Epidemiology, Dalhousie University and Capital Health, Halifax, Nova Scotia
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