Elsevier

The Lancet

Volume 353, Issue 9171, 26 June 1999, Pages 2179-2184
The Lancet

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Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial*

https://doi.org/10.1016/S0140-6736(99)05388-XGet rights and content

Summary

Background

Endarterectomy benefits certain patients with carotid stenosis, but benefits are lessened by perioperative surgical risk. Acetylsalicylic acid lowers the risk of stroke in patients who have experienced transient ischaemic attack and stroke. We investigated appropriate doses and the role of acetylsalicylic acid in patients undergoing carotid endarterectomy.

Methods

In a randomised, double-blind, controlled trial, 2849 patients scheduled for endarterectomy were randomly assigned 81 mg (n=709), 325 mg (n=708), 650 mg (n=715), or 1300 mg (n=717) acetylsalicylic acid daily, started before surgery and continued for 3 months. We recorded occurrences of stroke, myocardial infarction, and death. We compared patients on the two higher doses of acetylsalicylic acid with patients on the two lower doses.

Findings

Surgery was cancelled in 45 patients, none were lost to follow-up by 30 days, and two were lost by 3 months. The combined rate of stroke, myocardial infarction, and death was lower in the low-dose groups than in the high-dose groups at 30 days (5·4 vs 7·0%, p=0·07) and at 3 months (6·2 vs 8·4%, p=0·03). In an efficacy analysis, which excluded patients taking 650 mg or more acetylsalicylic acid before randomisation, and patients randomised within 1 day of surgery, combined rates were 3·7% and 8·2%, respectively, at 30 days (p=0·002) and 4·2% and 10·0% at 3 months (p=0·0002).

Interpretation

The risk of stroke, myocardial infarction, and death within 30 days and 3 months of endarterectomy is lower for patients taking 81 mg or 325 mg acetylsalicylic acid daily than for those taking 650 mg or 1300 mg.

Introduction

Randomised trials have shown that patients with symptoms related to severe (>70%) carotid-artery stenosis benefit from carotid endarterectomy, 1, 2 with smaller benefits for patients who have symptoms associated with moderate (50–70%) stenosis, 3, 4 or patients with symptomless carotid stenosis.5 Publication of these results has led to an increase in the frequency of carotid endarterectomy. The number of procedures done at non-Veterans hospitals in the USA have risen from 60000 in 1991, to 130000 in 1995.6

Achievement of benefit from carotid endarterectomy is dependent on the degree of perioperative stroke and death. In trials of symptomatic patients, the rate of perioperative stroke and death was 6·7% 1, 2, 3, 4 In a systematic review of 25 studies, perioperative stroke and death was lower for symptom-free patients than for patients with symptoms (3·4 vs 5·2%).5 To match the benefit of carotid endarterectomy reported in the randomised trials, and to extend the procedure to a wider community of surgeons, measures to lower perioperative risk are needed. As well as surgical skill, perioperative medication may be of importance.

The benefit of acetylsalicylic acid in stroke prevention has long been established, 7, 8 but the optimum dose has not been found or adequately tested in randomised trials.

Patients entering the North American Symptomatic Carotid Endarterectomy Trial (NASCET)1, 3 were recommended to receive 1300 mg acetylsalicylic acid daily on randomisation, if tolerated. In 1991, the study stopping rule was reached (p<0·001) for the 659 patients who had 70–99% stenosis. Carotid endarterectomy had led to a 17% absolute decrease in risk of ipsilateral stroke at 2 years. The trial was stopped in this group and the results published,1 but randomisation continued for patients with moderate stenosis (<70%). In a secondary analysis, not planned by protocol, an association was found between perioperative stroke and death and the amount of acetylsalicylic acid taken before surgery. The risk of perioperative stroke and death was 1·8% for patients taking 650–1300 mg acetylsalicylic acid daily, compared with 6·9% for patients taking 0–325 mg daily. The wide area of collagen exposed by endarterectomy was suggested to be a sufficiently strong stimulus to platelet aggregation to require a larger dose of antiaggregant.10

Subsequent to those results, we designed the ASA and Carotid Endarterectomy (ACE) trial to test whether perioperative complication rates are affected by dose of acetylsalicylic acid. Because many patients scheduled for carotid endarterectomy have had previous strokes and transient ischaemic attacks, a group known to benefit from acetylsalicylic acid, we decided that to include a placebo control group was unethical. We therefore compared four different doses of acetylsalicylic acid.

In early 1998, at the end of the moderate-stenosis phase of NASCET, a second post-hoc analysis in patients with less than 70% stenosis showed similar results to those seen in 1991 for patients with 70–99% stenosis. The risk of stroke or death within 30 days of surgery was 8·3% in patients who were taking less than 650 mg acetylsalicylic acid daily, compared with 3·7% in patients taking 650 mg or more.3 Additionally, the long-term outlook for patients on the higher dose was better than that for patients on less than 650 mg daily. These observations confirmed the need for the ACE trial.

Section snippets

Methods

We did the study in 74 centres: 48 in the USA, 19 in Canada, four in Australia, one in Italy, one in Argentina, and one in Finland. Most centres were participants in the NASCET trial. Surgeons were eligible to participate if the rate of stroke and death in the 30 days after they performed surgery was no more than 6%. Surgical technique was at the discretion of the surgeon. At each centre there was a neurologist and a clinical-research coordinator, who together did baseline and follow-up

Results

2849 patients were randomly assigned treatment between July 8, 1994, and April 30, 1998 (figure). In 45 patients, endarterectomy was cancelled because angiography revealed a lesion judged to be inappropriate for surgery (29), medical risk was too high (eight), development or discovery of a medical contraindication (five), and because patients decided not to have surgery (three). Of the remaining 2804 patients, 1292 (46%) had had ischaemic carotid-territory symptoms in the preceding 6 months and

Discussion

Acetylsalicylic acid was established as a platelet-inhibiting drug in 1967,12, 13 and was first shown to prevent stroke in patients with transient ischaemic attack or mild stroke in 1978.9 In that trial, patients who received 1300 mg acetylsalicylic acid daily had a 30% lower relative risk of stroke and death than patients receiving no acetylsalicylic acid. The choice of acetylaslicylic-acid dose for platelet inhibition in that trial was arbitrary. The antithrombotic mode of action of

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