LEXINGTON, Ky. -- For secondary prevention of cardiovascular disease, a single 81 mg aspirin seems to be the superior approach.
LEXINGTON, Ky., May 9 -- For secondary prevention of cardiovascular disease, a single 81 mg aspirin seems to be the superior approach.
Compared with 81 mg dosing, a 325 mg a day dose of aspirin was no more effective and the higher dose increased the risk of bleeding, according to a systematic review of the literature.
That's particularly true for gastrointestinal bleeding, reported Charles L. Campbell, M.D., of the University of Kentucky here, and colleagues.
The FDA recommends daily dosages ranging from 50 mg to 1,300 mg to treat the clinical manifestations of atherosclerotic disease. Thus, there is substantial controversy regarding the "correct" dose and whether it is the same for all patients, the researchers noted in the May 9 issue of the Journal of the American Medical Association.
Pharmacodynamic data, they said, demonstrate that long-term aspirin dosages as low as 30 mg/d are adequate to fully inhibit platelet thromboxane production.
In the U.S., it's estimated that 36% of the adult population takes aspirin daily to prevent cardiovascular disease. Among those who already have heart disease, the percentage increases to more than 80%, the researchers said. Most of the time (60%), the daily dose prescribed is 81 mg.
To evaluate efficacy and safety of various dosages, the researchers did a systematic review of the English-language literature using MEDLINE and EMBASE (through February 2007), plus pertinent original data and review articles.
The review comprised 11 studies, including eight randomized controlled trials and three retrospective observational studies (GUSTO/PURSUIT and the aspirin-only arms of the BRAVO and CURE trials). The data represent the 12-month period ending in September 2006.
Cardiovascular disease in the patients in these trials included an array of disorders, ranging from TIA and minor stroke to acute MI, stroke, or treatment following cardiovascular intervention.
According to the evidence, predominantly from secondary-prevention observational studies, dosages greater than 75 to 81 mg/d did not enhance efficacy, but they were associated with an increased rate of bleeding, primarily in the gastrointestinal tract, the researchers reported.
Retrospective analyses of several recent large-scale clinical trials found a consistent lack of any increased benefit with higher dosages of aspirin (75 mg/day versus 325 mg/day). At a mean follow-up of 366 days in the BRAVO trial studying recent MI and stroke, there were no differences for all-cause mortality, MI, stroke, or urgent revascularization, with a trend favoring lower doses, the researchers found.
As an example of increased bleeding risk, data from the BRAVO and CURE (studying acute coronary syndrome) trials also showed an increased risk of bleeding with higher doses of aspirin, even when they were no greater than 325 mg.
In a Dutch TIA study, a trend toward less bleeding was noted in patients who took 30 mg a day (2.6%) than in those on 283-mg (3.2%).
Although most data indicated that an increase in the aspirin dose was linked to an increased risk of gastrointestinal bleeding, the clinical importance of these findings when associated with contemporary doses of 75 to 325 mg still remains poorly defined, the researchers said.
Nevertheless, they added, if the differences in major bleeding found in the aspirin-only arm of the CURE trial reflect the overall U.S. population who take daily aspirin, then 325-mg dosing would lead to an excess of more than 900,000 major bleeding events a year compared with an 81 mg dose, the researchers said.
Both the beneficial and harmful effects of aspirin are believed to be primarily the result of inhibition of prostanoid biosynthesis, in particular that of thromboxane A2 and prostaglandins. It has been postulated that aspirin's anti-inflammatory properties may explain at least part of its mechanism of benefit in cardiovascular disease, the researchers said.
However, they added, with aspirin's much greater selectivity for COX-1 and the central role of COX-2 in inflammation, usages that achieve measurable anti-inflammatory activity-up to several grams a day-are much higher than those proven clinically effective in the prevention of athero-thrombotic events.
Although the studies seem to show that the clinical benefit of aspirin is not increased with doses greater than 75 mg to 81 mg and that the potential for harm may increase, it remains unclear how to apply these data to individual patients, Dr. Campbell said.
Not only has it been hypothesized that specific groups of patients, such as those with diabetes, may require higher doses of aspirin, but several studies using measures of platelet responsiveness to aspirin have found a wide range of responses among individuals.
However, these studies have been small and are difficult to reconcile with the results of large-scale clinical trials that have not found a trend toward a benefit of higher doses.
Differences in pharmacokinetics related to gender may also affect aspirin dosing and efficacy, the researchers said. There are emerging data that suggest that the efficacy of aspirin may be gender dependent. Large-scale clinical trials are clearly needed, they said.
The results of this study suggest that following the rapid, acute inhibition of platelet COX-1 with 160 to 325 mg of aspirin, every effort should be made to minimize the long-term dosage, the researchers said. Currently, the clinical data support a 75-mg or 81-mg daily dose.
"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," the researchers concluded.