November 17th, 2014
Large Japanese Trial Casts Further Doubt on Aspirin for Primary Prevention
A large trial from Japan failed to provide any evidence to support the use of routine aspirin in high-risk elderly people to prevent a first cardiovascular event.
The Japanese Primary Prevention Project (JPPP), presented at the American Heart Association meeting in Chicago and published simultaneously in JAMA, enrolled patients between 60 and 85 years of age with hypertension, dyslipidemia, or diabetes. The open label study randomized 14,464 patients to aspirin 100 mg once daily or no aspirin in addition to conventional therapy. Patients were followed for up to 6.5 years for the primary combined endpoint of cardiovascular death, nonfatal stroke, or nonfatal MI.
The trial was designed to accrue enough primary endpoints to make the results meaningful. The independent Data Monitoring Committee discontinued the study after a smaller number than expected endpoints had occurred and it became clear the trial would not be able to reach a statistically significant result.
There was no significant difference in the primary endpoint at any point during the course of the trial (HR 0.94, CI 0.77-1.15, p=0.544). There were 56 fatal events in each arm. Nonfatal events occurred in 137 patients in the aspirin arm versus 151 in the no aspirin arm. The results were consistent across subgroups.
Compared to placebo, aspirin resulted in a significant decrease in nonfatal MI, a marginal reduction in TIA, but a significant increase in serious extracranial hemorrhages. Aspirin also was associated with a big increase in gastrointestinal side effects, including a doubling of duodenal ulcers and a tripling of GI bleeds.
The authors said that although the power of the study was diminished by its early discontinuation, it demonstrates that “the clinical importance of aspirin in the primary prevention of cardiovascular events is less than originally anticipated in this patient population.”
In an accompanying editorial, J. Michael Gaziano and Philip Greenland write that the “results are consistent with those of other primary prevention trials,” with the exception of a higher intracranial hemorrhage rate in the Asian population studied in the trial.
Gaziano and Greenland say that the decision to use aspirin “remains clear in several situations. Aspirin is indicated for patients at high short-term risk due to an acute vascular event and those undergoing certain vascular procedures; patients with any evidence of vascular disease should be given daily aspirin. On the other hand, patients at very low risk of vascular events should not take aspirin for prevention of vascular events, even at low dose.” The decision is more difficult, they write, in people who do not have overt vascular disease but who nevertheless are at very high risk for cardiovascular disease. “It remains likely that there is some level of risk of CVD events that would result in a positive trade-off of benefit and risk for the use of aspirin, but the precise level of risk is uncertain.”