The Effect of a Slower than Standard Dose Escalation Scheme for Dipyridamole on Headaches in Secondary Prevention Therapy of Strokes: A Randomized, Open-Label Trial (DOSE)

Abstract

Background: Combination therapy with acetylsalicylic acid and dipyridamole is first-line treatment in secondary prevention of strokes. Approximately 40% of patients report headache as a side effect of dipyridamole. Dose escalation of dipyridamole reduces this side effect. In practice, different dose escalation schemes are used. In theory, slower dose escalation than a standard scheme reduces headaches even more. This study aimed to find the best dose escalation scheme for prevention of headaches as a side effect of dipyridamole in the secondary prevention of strokes. Methods: In this randomized, open-label, 4-week trial, 114 patients who had an ischemic stroke or transient ischemic attack were randomized to receive either a standard or slow dose escalation scheme of dipyridamole. Participants were asked to report the four most common side effects of dipyridamole in a study diary on study days 1, 3, 5, 7, 14, 21 and 28. They were asked to score headache intensity on a visual analog scale (VAS). Participants were unaware that the trial was focused on headaches. Primary end point was to determine if a slow dose escalation scheme reduces the percentage of patients with headaches. Secondary objective was to determine the number of patients who discontinued treatment with dipyridamole because of headaches. Results: Overall 37 patients (38%) of the final population reported headache, 19 (39%) in the standard dose escalation group and 18 (37%) in the slow dose escalation group (p = 1.0). In the standard dose escalation group patients scored headaches (VAS >4) on an average of 3.3 days and patients in the slow dose escalation group on 3.6 days (p = 0.82). Mean VAS scores on study days 1, 3, 5, 7, 14 and 21 ranged from 1.4 to 3.7 in both groups. These scores did not differ significantly. However, on day 28 patients scored a significantly lower mean VAS score in the standard dose escalation group than in the slow dose escalation group (2.5 vs. 4.8; p = 0.05). In the standard dose escalation group 6 patients (11%) discontinued treatment because of side effects of dipyridamole and 3 patients (6%) in the slow dose escalation group (p = 0.49, Fisher's exact test). Conclusion: We showed that slower than standard dose escalation of dipyridamole in combination therapy with acetylsalicylic acid does not reduce headaches as a side effect. The use of such schemes should be discontinued in clinical practice. Slow dose escalation might, however, reduce the number of patients who discontinue treatment, but further research is needed to confirm this.

High-throughput screening for modulators of ACVR1 transcription: discovery of potential therapeutics for fibrodysplasia ossificans progressiva

“…Dipy is a commercially available drug that was introduced on the market more than 50 years ago as a coronary vasodilator ( Kadatz, 1959 ). At present, it is widely used as an antithrombotic and vasodilator agent both as monotherapy and in combination with aspirin to prevent secondary stroke or transient ischemic attack ( Gresele et al, 2011 ; Balakumar et al, 2014 ; de Vos-Koppelaar et al, 2014 ). At the pharmacological level, Dipy acts by different mechanisms.…”

“…At the pharmacological level, Dipy acts by different mechanisms. By inhibiting the activity of phosphodiesterases 5 and 3 (PDE5 and PDE3), it increases the intracellular level of cyclic adenosine monophosphate (cAMP), which is a potent inhibitor of platelet activation, and of cyclic guanine monophosphate (cGMP), which has a vasodilator effect on smooth muscle, thus potentiating the platelet inhibitory actions of prostacyclin (PGI2) ( Gresele et al, 2011 ; de Vos-Koppelaar et al, 2014 ; Kim and Liao, 2008 ; Yip and Benavente, 2011 ). Moreover, Dipy inhibits the re-uptake of adenosine by blocking the equilibrative nucleoside transporters (ENTs), thus increasing plasma levels of this nucleoside, which also plays a role in inhibiting platelet aggregation ( Kim and Liao, 2008 ; Visser et al, 2005 ; Dresse et al, 1982 ; German et al, 1989 ), regulation of vascular tone, vasodilation, immunity and inflammation ( Kim and Liao, 2008 ).…”

Stroke Genetics: A Review and Update

“…However, such a study is now ongoing - the Genetics of Ischemic Stroke Functional Outcome Study (GISCOME) and results are expected within the coming year. 71 …”

Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke: The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial

“…There were no previous data available on initiation of both drugs together, therefore for dual administration, we integrated the dose escalation usually used for each drug. Slow dose escalation of dipyridamole and aspirin did not reduce headache, in comparison with standard dose escalation, although may have improved adherence [30]. Since the doses for licenced indications are somewhat arbitrary and wide ranging, it is reasonable to think that half dose would have some effect on the target mechanisms, and can be tested a priori in larger trials.…”