Low-dose aspirin is the best evaluated secondary prevention after transitory ischaemic attack (TIA) or ischaemic stroke. Dosages over 75 mg, in particular, are of proven benefit. Below this, the effect is less well established (1). However, only about a quarter of all recurrent vascular events can be prevented with aspirin (1). Combination with clopidogrel (PLAVIX etc.) does not confer any additional benefit but increases the risk of adverse effects (a-t 2004; 35: 62 and 2006; 37: 39) (2,3). The fixed combination of aspirin plus dipyridamole (AGGRENOX) reduces the incidence of recurrent stroke in the ESPS-2* study by an additional 3% within two years compared to aspirin alone, but not the myocardial infarction rate nor mortality (a-t 2006; 37: 21-2) (4). However, the comparator dose of aspirin at 50 mg/day is inadequate. There has also been no confirmation so far of the result of ESPS-2.

Simultaneous use of aspirin and dipyridamole has now again been compared with aspirin monotherapy in a randomised controlled study (ESPRIT*) (5). 2,739 patients with an average age of 63 years, of whom one third had TIA within the previous six months and two thirds stroke with at most moderate physical disability took part in the study. They were randomised to receive either aspirin in dosages from 30 mg to 325 mg daily alone or with 200 mg dipyridamole twice daily. The investigation was unblinded. The investigators themselves decided on the dosage of aspirin and the pharmaceutical form of dipyridamole (sustained-release/non-sustained-release). The primary endpoint was a combination of vascular deaths, nonfatal strokes, myocardial infarction or severe bleeding complications. The study is part of a larger investigation which also investigates the benefit of anticoagulation compared to aspirin (5).

After an average of 3.5 years, the primary endpoint event occurred in 173 (12.7%) patients treated with the combination and in 216 (15.7%) of those treated with aspirin alone (relative risk [RR] 0.80; 95% confidence interval [CI] 0.66-0.98). All of the individual components of the endpoint, both ischaemic and bleeding complications, were numerically rarer with the combination (5).

However, doubts about the validity of the data arise: the study is open-label, which is an unnecessary flaw. Even if the endpoints are evaluated by a blinded committee, bias is possible due to the different intensity of the treatment measures and diagnostic efforts. The endpoint committee can evaluate only cases that are submitted to it.

Moreover, those treated with dipyridamole discontinued the therapy prematurely conspicuously frequently (34%), mainly because of side effects (headache), whereas only 13% of those treated with aspirin did so. After just one year, nearly a quarter of the patients had discontinued the combination. How these were treated further is not described. However, compliance allegedly does not influence the results; analysis only of those patients who continued the treatment in accordance with the protocol until the end of the study does not differ from an intention-to-treat analysis which also includes the considerable number of these who discontinued treatment. This is not comprehensible if one assumes that the combined treatment confers a specific benefit. There is even a trend towards a greater benefit for patients who discontinue treatment. This calls into question the consistency of the data. Furtherwise it remains obscure why the protective effect against ischaemic events only commences after two years, which can be deduced from the presentation of the results (Kaplan-Meier graphs). At this time, only 73% of the patients were still taking dipyridamole but 92% were taking aspirin alone. The higher incidence of major haemorrhage with aspirin alone (3.9% vs. 2.6%) is also inexplicable and has not been described hitherto.

The median aspirin dosage was 75 mg daily. This means that about half of the patients were treated with lower dosages. 44% took only 30 mg, possibly a suboptimal dosage. According to subgroup analysis, patients taking higher aspirin dosages should also benefit from taking additional dipyridamole; however, the result is uncertain because of broad confidence intervals. It remains therefore unclear whether the results are reproducible when standard aspirin dosages are used.

The results of the study cannot be applied to AGGRENOX, the fixed combination licensed in Germany. Apart from the different aspirin dosages, dipyridamole was taken by some of the study patients in a non-sustained-release form, sometimes in free combination.

The study was not supported by the pharmaceutical industry. The authors state no conflicts of interest (5). In a recently revised COCHRANE review of dipyridamole (6), however, the main author of the ESPRIT study states that he received fees from Boehringer Ingelheim, the manufacturer of AGGRENOX.

	According to the results of the ESPRIT study 30 mg to 325 mg aspirin plus 400 mg dipyridamole daily are said to protect better against vascular complications than aspirin alone in patients after mild stroke or TIA.
	The open-label design, high rate of dropouts, the inconsistency of the results and the inadequate dosing of aspirin in a significant fraction of study patients limit the validity of the study.
	Despite two large studies of the combination of aspirin with dipyridamole there is still no adequate proof that the benefit of the fixed combination AGGRENOX extends beyond that of aspirin monotherapy.

(R = randomised study, M = meta-analysis)

1

Antithrombotic Trialists' Collaboration: BMJ 2002; 324: 71-86

2

DIENER, H.-C. et al.: Lancet 2004; 364: 331-7

3

BHATT, D.L. et al.: N. Engl. J. Med. 2006; 354: 1706-17

4

DIENER, H.-C. et al.: J. Neurol. Sci. 1996; 143: 1-13

5

ESPRIT Study Group: Lancet 2006; 367: 1665-73

6

De SCHRYVER, E.L.L.M. et al.: Dipyridamole for preventing stroke and other vascular events in patients with vascular disease, The Cochrane Database of Systematic Reviews 2006, Issue 2; Stand 6. Feb. 2006

ESPS = European Stroke Prevention Study
ESPRIT = European/Australian Stroke Prevention in Reversible Ischemia Trial