Abstract
Background
Headache is a common adverse event in patients treated with dipyridamole (DP) for secondary stroke prevention. The headache resembles migraine, possibly indicating that vessel walls and endothelium of cerebral vessels are still intact and able to dilate.
Purpose
We hypothesized that patients who develop headache on DP will have a lower risk of recurrent stroke compared to patients without headache.
Methods
We analysed data from PROFESS (N=20,332) comparing aspirin plus DP with clopidogrel. Prospective data on headache as an adverse event within 7 days of start of medication or reason for discontinuation of study drug and recurrent stroke incidence were collected. We compared the relative risk of recurrent stroke in patients who did and did not get headache and who did or did not discontinue study medication due to headache. Analyses were repeated in the smaller ESPS 2 study (N=6,602) investigating aspirin, aspirin plus DP, DP or placebo in secondary stroke prevention.
Results
In PROFESS 3067 patients taking aspirin plus DP complained of headache in the first 7 days while 6988 did not. In the aspirin plus DP group, the recurrent stroke risk after 2.5 years was 8.2% in patients with and 9.4% in patients without headache resulting in a RR of 0.90 (95% CI 0.81-1.01, p= 0.07). In the clopidogrel treated group there was no difference in stroke risk between patients with and without headache RR = 1.00 (95% CI 0.82-1.23). In PROFESS, 518 patients taking aspirin plus DP discontinued treatment due to headache in the first 90 days. Their risk of recurrent stroke was 5.0%. In patients who did not discontinue aspirin plus DP due to headache in the first 90 days, the recurrent stroke risk was 9.2% resulting in a RR of 0.53 (95% CI 0.36-0.79, p=0.001). In the clopidogrel treated patients the RR was 0.89(95% CI 0.36-2.20); 7.9% of 63 clopidogrel patients who discontinued due to headache within 90 days of randomization had stroke vs. 8.9% in all other patients. In ESPS 2, 129 patients taking aspirin plus DP discontinued treatment due to headache in the first 90 days. Their rate of recurrent stroke was 6.2%. In patients who did not discontinue aspirin plus DP due to headache in the first 90 days, the recurrent stroke rate was 9.8% resulting in a RR of 0.63 (95% CI 0.31-1.26, p=0.18).
Conclusions
In PROFESS patients who developed headache on aspirin plus DP for secondary stroke prevention had a reduced risk of stroke recurrence in comparison with those who did not or were treated with clopidogrel. These results are directionally supported by similar but non-significant findings on treatment discontinuation of aspirin plus DP in ESPS 2. Headache in clopidogrel treated patients did not demonstrate any protective effects, suggesting specificity. These results suggest that DP-induced headache may be a marker for more reactive vessel walls in cerebral arteries.