Once-Daily Aggrenox Reduces Headache, Improves Tolerance

SAN FRANCISCO—Initiating aspirin/ dipyridamole (Aggrenox) once daily, together with an additional dose of aspirin, can improve tolerance so that standard twice-daily dosing of aspirin/ dipyridamole for secondary stroke prevention can begin within a week, said Andre G. Douen, MD, at the 2007 International Stroke Conference.

The Second European Stroke Prevention Study (ESPS-2) and the European/ Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) established that aspirin/dipyridamole was superior to aspirin for reducing risk of a second stroke and combined vascular disease in high-risk patients who had had a stroke or transient ischemic attack (TIA). Aspirin/ dipyridamole is associated with about a 22% relative risk reduction compared with aspirin, but a significant number of patients are unable to tolerate the former, largely due to headaches, said Dr Douen, of the University of Ottawa, Ontario, Canada.

In fact, about one third of patients enrolled in ESPS-2 and ESPRIT discontinued aspirin/dipyridamole, compared with fewer than one fifth of those randomized to aspirin. Headaches and gastrointestinal symptoms, the leading causes of aspirin/dipyridamole discontinuation, accounted for 33% of the adverse events in ESPS-2 and 26% in ESPRIT.

“Within the first day or two of starting aspirin/dipyridamole, you’re going to know if you get headache,” said Dr Douen. “The headaches tend to attenuate and go away after a week. The patients may be uncomfortable with headache and don’t want to use it, particularly if they’ve had a stroke or TIA.”

Any strategy to improve initial tolerance would likely influence long-term compliance with treatment, he said. In an attempt to overcome headache and improve tolerance, he and his colleagues studied 100 patients with stroke or TIA attending an outpatient stroke prevention clinic. They were started on 1 tablet daily of aspirin/dipyridamole (25/200 mg) for 1 week, together with 81 mg/day of aspirin. Patients were then continued on the standard twice-daily dose of aspirin/dipyridamole after 1 week.

The participants were counseled on the possibility of headache with dipyridamole and told that headaches were usually transient and typically subsided within a few days.

At 1 and 2 weeks, patients in the study answered a phone questionnaire designed to elicit symptoms and adverse events, including headache, nausea, and vomiting.

Of the patients, 86 continued using aspirin/dipyridamole without complications. Therapy was discontinued or switched in 14 others because of adverse events or medical reasons. Only 6 of the 14 patients stopped for problems related to aspirin/dipyridamole, 5 of whom reported nausea plus headache. “Nausea seemed to be the more prominent reason for discontinuing,” said Dr Douen. One patient had severe headache without nausea.

Of the remaining 8 patients who discontinued therapy, 5 were switched for medical reasons, and 3 were switched to aspirin alone by the family physician.

A previous history of headache did not seem to predict the occurrence of headache with aspirin/dipyridamole therapy in this series of patients, said Dr Douen.

“To try to avoid dropouts and encourage compliance, the best way to use aspirin/dipyridamole is 1 tablet daily, and if we’re worried about stroke protection in the first week, we give an extra 81-mg dose of aspirin,” he said. “After 5 days, you can switch to twice-daily dosing, and you can either maintain the 81 mg of aspirin if you wish, or you can remove it. A lot of stroke patients also have some cardiac risk factors or prior heart disease; the cardiologists like these patients to be on 75 mg or more of aspirin per day, and they often say that there’s not enough aspirin in the aspirin/ dipyridamole formulation. Maintaining an extra dose of 81 mg of aspirin helps to cover that.”