Dose Titration to Reduce Dipyridamole-Related Headache

Abstract

Background: Combination of low-dose aspirin and modified-release dipyridamole (ASA+MR-DP) provides a significantly increased benefit in stroke prevention over aspirin alone. However, headaches were reported in more patients receiving dipyridamole-containing agents than in those receiving placebo. We undertook a randomized, double-blind, placebo-controlled trial to evaluate which dosing regimens of ASA+MR-DP have better tolerance. Methods: This trial randomized 146 patients with a history of ischemic cerebrovascular disease into three groups: placebo (days 1–28), reduced dose (placebo on days 1–4, ASA+MR-DP once daily before bed during days 5–14, and b.i.d. on days 15–28), and regular dose (placebo on days 1–4, and ASA+MR-DP b.i.d. on days 5–28). Using Chinese diary card, headache was assessed as mean cumulated headache (Σ frequency × intensity/occurrence days × study days) over the study period, and was graded 0–4 according to Cancer Therapy Evaluation Program, Common Toxicity Criteria, Version 2.0. Results: Intent-to-treat patients after randomization was 46 in placebo group, 45, reduced dose, and 49, regular dose. Among commonly reported adverse effects, headache of any grade occurred significantly more in the regular dose group (38.8%), as compared to the other two groups (p < 0.05). Mean cumulated headache was higher (p < 0.05) in the regular dose group than in the reduced group during days 5–14. Of 27 patients who dropped out, 15 (55.6%) were due to headache, which was substantially more in regular dose (8, 53.3%), though the difference was statistically insignificant. Conclusions: Initial reduced dose treatment with ASA+MR-DP may cause fewer headaches than regular dosing, and seems better tolerated by those susceptible to phosphodiesterase inhibitor-induced headache.

Update to the AHA/ASA Recommendations for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack

“…Upward tapering of the dipyridamole dose may be helpful, 5,6 although this therapy requires further study. Adherence to medication use is an important factor to consider and is affected by costs, side effects, and frequency of dosing.…”

Dipyridamole-Associated Headache in Stroke Patients – Interindividual Differences?

“…However, only few patients stopped medication due to headache. Regarding the results of other titration studies [8,9,10], we believe the daily use of the combination of 25 mg ASA + 200 mg ER-DP b.i.d. with an initial titration approach of a couple of days to be safe and tolerable for the prevention of ischemic stroke and more effective than aspirin alone [3, 4, 17].…”

“…Consequently, the prevalence of headache in stroke patients on DP treatment might be decreased by a dose titration of DP during the initial treatment days, thereby also increasing the compliance of this treatment. Such studies on dose titration to reduce DP-related headache have been performed and showed significantly fewer cases with headache [8, 9] or a less cumulative number of days with headache with an initially reduced dose of DP [10]. Still, in those studies, 1 out of 10 patients stopped medication due to headache [8, 10].…”

Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack 2008

“…Dipyridamole may cause headache; the incidence of this may be reduced by increasing the dose gradually [323, 324]. …”