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Enoxaparin bested aspirin for preventing symptomatic venous thromboembolism (VTE) after total hip or total knee arthroplasty when used without initial anticoagulation in the CRISTAL randomized trial.

These events occurred within 90 days of surgery in 3.45% of aspirin-treated patients compared with 1.82% of enoxaparin-treated patients, which didn't hit noninferiority criteria but did show significant superiority for enoxaparin (P=0.007).

That primary endpoint advantage was driven by a 1.61-percentage point lower rate of deep vein thrombosis (DVT), specifically below-the-knee cases.

No significant differences emerged between groups for above-knee DVT or pulmonary embolism, Verinder S. Sidhu, MS, of the Ingham Institute for Applied Medical Research in Liverpool, Australia, and colleagues reported in .

In interpreting the study findings, the group cautioned 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."

Given similarly low incidences of major thromboembolic events and mortality, the results are unlikely to convince clinicians who use aspirin prophylaxis to switch, noted Noel C. Chan, MD, and Mohit Bhandari, MD, PhD, both of McMaster University in Hamilton, Ontario, in an .

"Reducing nonfatal VTE is important, but any benefits with thromboprophylaxis require a trade-off with bleeding risk, costs to the health care system, and convenience to patients, all of which make aspirin particularly attractive for thromboprophylaxis," they wrote.

In the CRISTAL trial, none of the six secondary outcomes came out different for enoxaparin versus aspirin, including mortality, major bleeding, 90-day readmission or reoperation, reoperation within 6 months, and drug adherence.

A recent large from Canada reported noninferiority of aspirin to rivaroxaban (Xarelto) for VTE prophylaxis after total hip or knee arthroplasty. "However, both groups received rivaroxaban for 5 days prior to randomization to either aspirin or continued rivaroxaban," noted Sidhu's group.

CRISTAL took that one step further for 9,711 adults (median age 68, 56.8% women) undergoing total hip or knee arthroplasty for osteoarthritis who were not getting preoperative anticoagulation. The 31 participating hospitals in Australia were cluster-randomized within a national registry to give aspirin 100 mg daily or enoxaparin 40 mg daily (except for those with underweight and poor kidney function) as the sole antithrombotic prophylaxis following a standardized protocol for a specified period before crossing over to the other agent.

Both regimens started within 24 hours of surgery and were continued for 35 days after hip arthroplasty and for 14 days after knee arthroplasty. Intraoperative and postoperative intermittent pneumatic compression calf devices were also used universally, along with compression stockings and mobilization on day 0 or day 1 postoperatively.

However, an important limitation was that the study was terminated early at 62% of the planned enrollment of 15,562.

The editorialists pointed out that this "reduced the power to detect differences in clinically important VTE," and the researchers acknowledged that the study might not have been powered to detect certain significant between-group differences, specifically the numerically higher rate of pulmonary embolism in the aspirin group (1.1% vs 0.6% with enoxaparin, P=0.17).

Another issue, the editorialists wrote, was "the potential for diagnostic suspicion bias in patients taking aspirin because physicians making the decision to perform leg ultrasound or lung imaging were not masked to the assigned prophylactic treatment."

The researchers added that another potential influence on the findings was that the 15% of people taking aspirin before the trial stayed on it, such that the group randomized to enoxaparin continued aspirin in addition to enoxaparin, whereas the aspirin group didn't take additional aspirin.

They suggested that a cost-effectiveness analysis might be warranted "to better understand the clinical relevance of the trial results."

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