Lexington, KY - More evidence that lower doses of aspirin are just as effective in preventing cardiovascular events as higher doses has come from a new systematic review published in the May 9, 2007 issue of the Journal of the American Medical Association [1].

The authors, led by Dr Charles Campbell (University of Kentucky, Lexington), conclude: "Currently available clinical data do not support the routine, long-term use of aspirin dosages greater than 75 to 81 mg/day in the setting of cardiovascular disease prevention. Higher dosages, which may be commonly prescribed, do not better prevent events but are associated with increased risks of gastrointestinal bleeding."

Campbell commented to heartwire: "Recommendations vary, but most state that aspirin should be taken chronically at a dose anywhere between 75 mg and 325 mg daily, and some even include doses up to 1300 mg. We need to rethink this advice. We know that the risk of bleeding increases with higher doses, and this is now even more of an issue as more patients are also taking clopidogrel. But the beneficial effect of aspirin on clinical events does not appear to increase with increasing doses. So the guidelines should change to just recommend low doses—75 or 81 mg. A lot of people buy aspirin over the counter, and they need clear information about which dose to take." He added that there was much evidence that aspirin is beneficial for high-risk patients, but the evidence is less robust for lower-risk patients (ie, for primary prevention).

Coauthor Dr Steven Steinhubl (University of Kentucky) pointed out that even 75 or 81 mg is probably overdosing aspirin, as studies have shown that platelet thromboxane is completely inhibited with just 30 mg of aspirin taken chronically. "The 75- to 81-mg dose has been arrived at completely arbitrarily, as these doses are just one quarter of a 300- or 325-mg tablet," he said.

Campbell explained that the current results are consistent with those published by the Oxford Antithrombotic Trialists' Collaboration in 2002, but the analyses differed. "They compared trials using higher doses of aspirin with other trials using low doses of aspirin, but we looked at trials that included some patients taking high doses and others taking low doses. We also included a large amount of observational studies. So our findings agree with their findings, but we've added a 'real-world' spin," he said.

In the paper, Campbell et al note that approximately 36% of the adult US population—more than 50 million people—are estimated to take aspirin regularly for heart disease prevention. This translates into roughly 10 to 20 billion aspirin tablets consumed annually in the US alone. They stress that as it so widely used, maximizing benefits and minimizing risks by providing optimal dosing is of great importance. They note that clinical trials in heart disease patients have evaluated dosages as low as 30 mg/day and as high as 1500 mg/day, and the US FDA recommends dosages ranging from 50 mg/day to 1300 mg/day for treatment of the clinical manifestations of atherosclerotic disease. Because of this, there is substantial debate regarding what represents the "correct" dosage of aspirin and whether it is the same in all patients.

They therefore conducted a systematic review of the literature of prospective studies using different aspirin dosages in the setting of cardiovascular disease. A total of 2415 references were identified and manually sorted using the abstracts or full-text publications.

They report that clinical-outcomes trials directly comparing different dosages of aspirin (from 30 to 1300 mg/day) in almost 10 000 patients with various clinical manifestations of atherosclerotic disease have not shown a significant benefit of higher dosages, and in most trials the lowest event rates were seen among patients randomized to the low-dosage groups.

They also point out that several meta-analyses have also shown similar results. One meta-analysis of 11 clinical trials including 5228 patients randomized to aspirin or placebo following a transient ischemic attack or stroke found similar efficacy for aspirin dosages ranging from 50 mg/day to 1500 mg/day. And in the Antithrombotic Trialists' Collaboration, a meta-analysis of more than 60 aspirin trials also found no relationship between dose and efficacy, with the greatest risk reduction shown in trials using a 75- to 150-mg dose of aspirin. They add that retrospective analyses of several recent large-scale clinical trials (including GUSTO IIb, PURSUIT, and CURE) are also consistent with the lack of any increase in benefit with higher dosages of aspirin.

But in contrast to the efficacy data, larger doses of aspirin are associated with an increased incidence of bleeding events, primarily related to gastrointestinal tract toxicity. Campbell et al state that if the differences in major bleeding found in the aspirin-only group of the CURE trial are translated to the general US aspirin-taking population, daily treatment with 325 mg of aspirin would lead to an excess of more than 900 000 major bleeding events per year compared with a daily dose of 81 mg.

The authors point out that interpatient variability in the platelet response to aspirin has long been recognized and has prompted some to conclude that measuring aspirin responsiveness and increasing the dosage of aspirin accordingly may be of clinical benefit. But they say that the results of the small platelet studies, some of which have found nearly 50% of patients treated with low-dose aspirin to be "nonresponsive," are very difficult to reconcile with large-scale clinical trials that have not even found a trend toward a benefit of higher doses, and that large-scale clinical trials in this area are clearly needed.

Expanding on this to heartwire, Campbell said: "There is a disconnect in the aspirin-resistance story in that many small studies have shown a significant interpatient variability in platelet response to low-dose aspirin, but there is no clinical evidence that a higher dose would overcome this. There is no large trial that has suggested higher doses are any better in terms of clinical effects."

He adds that there is still much that is not known about aspirin resistance. "There is no clear definition of what aspirin resistance actually is. In some trials, aspirin resistance has been very low; in others, it has been quite high. I'm not even sure that it actually exists. And if a patient doesn't respond today, they may do so tomorrow. Aspirin resistance is just based on platelet-function tests, and these are problematic—we have many different tests but none of them are perfect; they are either complicated to perform or have issues with applicability. I'm not sure we should take any notice of these tests."

Steinhubl agrees. He commented to heartwire: "Some platelet-function studies have suggested that higher aspirin doses have more effect on the platelet in some patients, but there has never been a group that has done worse on low-dose aspirin in long-term trials. So it appears that most measures of 'aspirin resistance' are not an accurate measure of the clinical benefit of aspirin. There is thus no clinical reason to do these platelet-function tests." He added: "There is some evidence to suggest that patients with hyperactive platelets have worse outcomes, but this has nothing to do with aspirin. Inhibition of thromboxane, which is what aspirin does, explains less than 10% of the variability in platelet aggregation."

In the paper, the authors conclude: "The greatest challenge for the future is to determine the optimal method for identifying the best antiplatelet regimen for the individual patient. The ability to routinely assess a clinically relevant measure of platelet function during treatment with aspirin or any other antiplatelet therapy and its relation to clinical outcome will be central to accomplishing this."