ArticlesPrevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial
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Background
Previous trials of antiplatelet therapy for the prevention of venous thromboembolism have individually been inconclusive, but a meta-analysis of their results indicated reductions in the risks of deep-vein thrombosis and of pulmonary embolism in various high-risk groups. The aim of this large randomised placebo-controlled trial was to confirm or refute these apparent benefits.
Methods
During 1992–1998, 148 hospitals in Australia, New Zealand, South Africa, Sweden and the UK randomised 13 356 patients
Eligibility
Patients with a femoral-neck fracture or other fracture of the proximal femur were potentially eligible for the trial in all participating countries: Australia, New Zealand, South Africa, Sweden, and the UK (figure 1). Furthermore, in New Zealand, patients undergoing elective hip or knee arthroplasty were also eligible (figure 1). The fundamental eligibility criterion was the treating doctor's uncertainty as to the balance of benefits and risks of low-dose aspirin for the particular patient.20
Randomisation and study treatment
Eligible patients for whom informed consent was obtained (from the patient or, when appropriate, their carer) were randomised as soon as possible after admission and before planned surgery. A free telephone call to the 24 h randomisation services in Auckland, New Zealand, or Oxford, UK, allowed double-blind assignment of study treatment packs, according to a minimisation algorithm.21 Study treatment comprised a 5-week calendar-packed supply of 160 mg daily enteric-coated aspirin or matching
Follow-up for study outcomes
Follow-up was of mortality and in-hospital morbidity up to day 35, with information about vital status supplemented if possible from national registers. Follow-up for non-fatal events (in particular, deep-vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and bleeding episodes) was to continue only during the hospital stay, whereas follow-up for deaths continued during and after the hospital stay. No special investigations were required: in particular, no special screening
Masked adjudication of outcomes
Collaborators were asked whether reports of symptomatic deep-vein thrombosis had been confirmed by investigation, and only those proven by venography or other objective methods (eg, duplex ultrasonography) were included in the analyses of study outcome. Further information was sought about each report of pulmonary embolism, myocardial infarction, stroke, or death, for review by an independent endpoint adjudication committee that was unaware of the assigned study treatment. Pulmonary embolism
Statistical analysis
All analyses were done by intention to treat using Cox's proportional hazards models. The numbers of patients in whom particular events were recorded (as given in tables and figures) may not be additive since a patient could have more than one type of event. Proportional differences and corresponding hazard ratios are given with 95% CIs, absolute differences are given with one SE, and p values are two-sided. We tested for heterogeneity of risk ratios across subgroups by Cox's proportional
Patients undergoing surgery for hip fracture
Between March, 1992, and July, 1998, 13 356 patients with hip fracture were randomised (6679 assigned aspirin and 6677 assigned placebo) from 148 hospitals. Mean age was 79 years, 79% were women, 62% were known to have femoral-neck fractures (including subcapital) and the remainder had other proximal-femur fractures (eg, intertrochanteric or subtrochanteric). Aspirin or other NSAIDs had been taken within 48 h before randomisation by 9% of patients. As expected from a properly randomised trial
Hip fracture: effects on venous thromboembolism
Symptomatic deep-vein thrombosis was confirmed in 69 (1·0%) of the hip fracture patients assigned aspirin and 97 (1·5%) assigned placebo, which represents a proportional reduction with aspirin of 29% (95% CI 3–48; p=0·03: figure 2). Similar proportional effects were seen with aspirin on deep-vein thromboses confirmed venographically and on those diagnosed by other objective tests (such as duplex ultrasonography), as well as on proximal and on distal thromboses. Definite or probable pulmonary
Hip fracture: effects on other vascular events and mortality
Non-fatal myocardial infarction or fatal ischaemic heart disease was recorded in 105 (1·6%) hip-fracture patients assigned aspirion and 79 (1·2%) assigned placebo (hazard ratio 1·33 [1·00–1·78]; p=0·05; table 1). Non-fatal or fatal stroke was recorded in 54 (0·8%) patients assigned aspirion and 49 (0·7%) assigned placebo (1·10 [0·75–1·62]; p=0·6), of which five were confirmed cerebral haemorrhages (two in the aspirin group vs those in the placebo group). Vascular deaths other than those from
Hip fracture: effects on bleeding and related complications
Fatal bleeds were rare in the two treatment groups (13 [0·2%] in the aspirin group vs 15 [0·2%] in the placebo group; table 2). No case of spinal haematoma was recorded among the 4603 hip-fracture patients who also received regional anaesthesia. Haematemesis or melaena associated with transfusion occurred in only 1 (1) more patient per 1000 assigned aspirin (p=0·3), but there was a definite excess of 9 (3) per 1000 with less severe gastrointestinal bleeding (p=0·0005). For local complications,
Patients undergoing elective hip or knee arthroplasty
Between March, 1992, and March, 1996, 2648 patients undergoing elective hip arthroplasty (1332 assigned aspirin and 1316 assigned placebo) and 1440 patients undergoing knee arthroplasty (715 assigned aspirin and 725 assigned placebo) were randomised from 22 New Zealand hospitals. Mean age was 67 years, 53% were women, and 25% had received aspirion or other NSAIDs within 48 h before randomisation (table 4). After randomisation, 93% started study treatment preoperatively and 4% postoperatively,
Discussion
The results of this large randomised placebo-controlled trial demonstrate that low-dose aspirin reduces the risk of pulmonary embolism (including fatal events) and symptomatic deep-vein thrombosis, which confirms the findings of the previous meta-analysis.17, 18 Similar proportional reductions in venous thromboembolism were seen among different groups of patients in the PEP trial (including those receiving other thromboprophylaxis), as was also the case in the meta-analysis for patients
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