BACKGROUND: Unfractionated and low-molecular-weight (LMW) heparins are popular and successful agents for preventing pulmonary embolism (PE) and deep vein thrombosis (DVT) after major surgery, but they are usually stopped at hospital discharge. The use of an antiplatelet agent such as low-dose aspirin might provide additional benefits. A meta-analysis of data from 8000 patients indicated several weeks of such therapy reduced the frequency of PE and DVT by 40% to 60%. The Pulmonary Embolism Prevention (PEP) trial of low-dose aspirin was a large randomized control trial (RCT) designed to confirm or refute these findings.
POPULATION STUDIED: This was a multicountry trial (Australia, New Zealand, South Africa, Sweden, and the United Kingdom) of patients with proximal femur fractures or undergoing hip or knee arthroplasty. Patients with a clear indication for aspirin (such as a recent myocardial infarction) or clear contraindication (such as an active peptic ulcer) were not eligible. Concurrent use of other thromboprophylactic agents and previous use of nonsteroidal anti-inflammatory drugs (NSAIDs) were allowed.
STUDY DESIGN AND VALIDITY: The PEP study was a double-blind placebo-controlled trial in which eligible patients who gave consent were randomly assigned to receive either 160 mg enteric-coated aspirin or placebo daily for 5 weeks, starting before surgery. The authors described the methods used to prevent researchers from knowing to which group the patient would be assigned (ie, concealed allocation). Patients were advised to avoid other NSAIDs during this time. A diagnosis of DVT required confirmation by venography or ultrasound; PEs were classified as definite or probable by an independent committee on the basis of a combination of clinical findings, angiogram, ventilation-perfusion scan, or venographic evidence of DVT. Follow-up assessed in-hospital morbidity and mortality and out-of-hospital mortality for the month following surgery. Analysis was by intention to treat. This was a large well-conducted trial involving at least 150 hospitals, with complete follow-up of 99.4% of enrollees. Randomization resulted in equal distribution on the basis of age and sex; no data on race or ethnicity were presented. The concurrent use of heparin agents was equally distributed between the intervention and control groups. Diagnosis of DVT, PE, MI, and cerebrovascular accident was made by a committee unaware of the subjects' group assignment.
OUTCOMES MEASURED: Follow-up was for cause of death through day 35 and for nonfatal events during the hospitalization (mean duration=16 days).
RESULTS: Approximately 13,000 patients with hip fracture were randomized, with 92% initiating treatment preoperatively or immediately postoperatively and 80% taking the assigned medication for the entire 35-day follow-up. Approximately 45% of the participants were receiving a form of heparin (similar numbers in both groups). Symptomatic DVT was confirmed in 1.03% of those assigned aspirin and 1.45% of those assigned placebo (P=.03; number needed to treat [NNT]=238). Definite or probable PE was confirmed in 0.69% of patients taking aspirin and 1.21% of those taking placebo (P=.002; NNT=192). For fatal PE, the NNT was 270 (P=.002). The overall mortality was identical in both groups. Aspirin had statistically significant benefits on total thromboembolic events in those patients taking unfractionated heparin or no heparin but not in those who received LMW heparin. Nonfatal and fatal cardiac ischemic events occurred more frequently in the aspirin group (1.57% vs 1.18%, P=.05). A total of 256 patients would need to receive aspirin for one additional event to occur (number needed to harm [NNH]=256). Fatal bleeding episodes were approximately equal in both groups; however, 2.95% of the patients assigned to aspirin required transfusion versus 2.35% of patients assigned to placebo (P=.04; NNH=167). The number of patients in the arthroplasty section of the trial was smaller (n=4000), and none of the comparisons between the intervention and placebo groups showed statistically significant results.
This well-designed RCT, mainly of patients with hip fractures, shows the incidence of thromboembolic events to be quite low in the first 5 weeks after injury. The addition of low-dose aspirin to these patients' treatment significantly reduced the incidence of DVT and PE, but large numbers need to be treated to realize any benefit (NNT=approximately 200 for nonfatal events and 270 for fatal events), and there was no effect on overall mortality. The aspirin group also had significantly more bleeding complications requiring transfusions and a higher incidence of fatal and nonfatal ischemic heart disease events. Despite aspirin's low cost and ease of use, the benefits of its perioperative use for 35 days in patients with new hip fractures are small, and the rate of complications from its use almost balance its benefits. The increased use of other thromboprophylactic treatments (various forms of heparin and pressure stockings) probably made it difficult for aspirin to produce a marked additional effect that would lower an already low rate of adverse events.