Low-Molecular-Weight Heparin Is Superior to Aspirin in the Prevention of Thromboembolic Disease: Or Is It?*

A recent study published in the Journal of the American Medical Association (JAMA), “Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty. The CRISTAL Randomized Trial,” has again raised controversy concerning the optimal modality for venous thromboembolism (VTE) prophylaxis1. The authors should be congratulated on completing this prospective, randomized, crossover, and registry-nested trial. This massive undertaking involved enrolling a large number of patients from 31 centers in Australia. The authors of the study reported that the incidence of symptomatic VTE was significantly higher in patients receiving aspirin (3.45%) compared with enoxaparin (1.82%). As the authors stated, the use of aspirin for VTE prophylaxis has increased in the U.S. over the past decade, with 95% of members of the American Association of Hip and Knee Surgeons (AAHKS) using aspirin as the main modality for patients undergoing total joint arthroplasty (TJA)2. The experiences in the U.S. and other parts of the world, as well as in numerous recent randomized studies, have shown that aspirin, at a dosage of 81 or 325 mg, twice per day, is an effective and safe modality for VTE prophylaxis in patients undergoing TJA3. The use of aspirin for VTE prophylaxis has been shown to lead to reductions in mortality4-6, periprosthetic joint infection7, stiffness8,9, readmission10, reoperation11, and wound-related complications12-14 while also providing numerous other benefits3. These attributes, together with patient convenience and low expense, have contributed to the increased popularity of aspirin in the U.S. and other parts of the world. Other randomized controlled studies and meta-analyses that have compared aspirin with more potent anticoagulants have not demonstrated significant decreases in VTE rates with more potent anticoagulation15-20. The findings of the recent JAMA study are unlikely to impact the popularity of aspirin as the main modality for VTE prophylaxis as the published work suffers from some methodological shortcomings that need to be considered: The study involved the use of an unorthodox dosage and duration of aspirin (100 mg once per day, started within 24 hours, and continued for only 14 days after total knee arthroplasty)1. A majority of surgeons in the U.S. and other parts of the world utilize higher cumulative doses of aspirin, start the medication on the day of surgery, and continue it beyond 2 weeks. Even the Pulmonary Embolism Prevention (PEP) trial, in which many Australian patients were enrolled, used a dosage of 160 mg of aspirin per day and continued it for 35 days17. A relatively large proportion of patients (15%) in the enoxaparin group were allowed to continue antiplatelet medications, including aspirin, resulting in “dual” VTE prophylaxis for the enoxaparin group, whereas patients in the aspirin cohort received aspirin only1. Among patients who developed VTE, there was a markedly higher proportion of patients who had a history of prior VTE in the aspirin cohort (8.3%) compared with the enoxaparin group (2.6%)1. Although aspirin may be a suitable agent for patients who have a history of VTE, there is no contention that these patients have a higher risk for subsequent VTE3. The main difference in the incidence of symptomatic VTE in this study was related to the rate of distal deep venous thrombosis (DVT), with the difference in the rate of above-knee DVT and pulmonary embolus being non-significant between the groups. The authors elegantly articulated that “Below-knee DVT represents a less clinically important form of VTE compared with above-knee DVT or pulmonary embolism, and the clinical importance of these findings remains uncertain.”1 The early cessation of enrollment (only 62% of the intended target were enrolled) exposed the study to type-II error in the examination of outcome parameters, including pulmonary embolus and mortality. It is also important to note that hospital- and registry-nested cluster randomization is a potential source of bias and contamination21. For example, any differences in rehabilitation protocols between institutions could have contributed to this bias as crossover was not complete. As noted by the authors, more diagnostic tests for VTE may have been ordered for patients receiving aspirin (data not collected) as hospitals were not blinded to the allocated treatment1. The fact that the hospitals were not blinded to treatment enrollment is important as almost 40% more patients were enrolled in the aspirin group as compared with the enoxaparin group. The study failed to report on some other important parameters such as the rate of wound-related complications, which has been shown to be higher with low-molecular-weight heparin13. Patients who had wound-related complications may have needed additional interventions, short of readmission or reoperation. There are immense challenges associated with the conduct of randomized prospective studies, and the authors should be congratulated for their incredible accomplishment. We hope that the authors will receive our perspectives and interpretation of their findings as constructive, which is very much our intention. VTE following elective TJA is fortunately an uncommon event, and a complex interaction between patient, surgical, rehabilitative, and other factors may contribute to its pathogenesis. Selection of VTE prophylaxis requires careful assessment of benefits and risks, including cost-effectiveness. Consequently, we agree with the conclusions of the authors that “a cost-effectiveness analysis is needed to better understand the clinical relevance of the (published) trial results.” In the meantime, we will continue to use aspirin as the main VTE prophylaxis in the majority of patients undergoing TJA.