In April of this year the champagne corks were popping at Boehringer Ingelheim. In a press communiqué (1) widely distributed by the company, it had been announced that the aspirin/dipyridamole combination AGGRENOX had been given the "highest degree of recommendation" for secondary prophylaxis of stroke. Background: In updating their guidelines, the German Neurological Society and the German Stroke Association under the chairmanship of Hans-Christoph Diener (cf. a-t 2006; 37: 21-2) raised the recommendation to use AGGRENOX for stroke patients with a high risk of recurrence (> 4%/year) from grade B to grade A (the highest degree of recommendation) (2).

This is based on the findings of the ESPRIT* study (3), in which a free combination of acetylsalicylic acid (ASA; aspirin etc.) and dipyridamole was tested against ASA alone in patients who had had transitory ischaemic attacks or stroke. The advantages stated seem to be poorly validated, however, owing to the open design of the study and other weaknesses such as the high drop-out rate in the ASA/dipyridamole group and less than optimal effective dosing of ASA (a-t 2006; 37: 55-6). There is still no direct comparison of AGGRENOX with ASA in the demonstrably effective standard dose of 75 to 100 mg.

The results of the ESPRIT study have been adopted without criticism by Diener's guidelines group. Furthermore the recommendation is explicitly for the fixed combination of 25 mg ASA plus 200 mg of slow-release dipyridamole (the single preparation on the German market called AGGRENOX), though this precise combination was not investigated in any selective way in the ESPRIT study, where the choice was left to the study doctors to use aspirin doses between 30 and 325 mg and slow-release or immediate release dipyridamole, as they wished.

Moreover specifically recommending this substance for patients with a high risk of recurrence (over 4%/year) cannot be justified. It cannot be deduced directly from either the earlier ESPS*-2 study (4) or the ESPRIT study that high risk groups particularly benefit from the combination: they do not include corresponding analyses of subgroups. Basis of the risk classification is a non validated score (Essen risk score) that was created from data from the CAPRIE study (5). This score was subsequently used for the AGGRENOX studies. Presenting such questionable "data" as the basis for a guideline recommendation in 2007 is a major deviation from scientific quality and standards.

	Despite guideline recommendations, no advantage of the acetylsalicylic acid (ASA)/dipyridamole combination, AGGRENOX, over an appropriate ASA monotherapy (at least 75 mg/day) for secondary prophylaxis of stroke has been adequately confirmed.
	Upgrading the fixed combination AGGRENOX to the highest degree of recommendation for "high-risk patients" reflects industrial collusion rather than any reasonable use of the existing scientific evidence.

(R = randomised study)

1

Boehringer Ingelheim: Press communiqué of April 2007

2

DIENER, H.C. et al.: Akt. Neurol. 2007; 34: 8-12

3

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

4

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

5

DIENER, H.C. et al.: Expert Opin. Pharmacother. 2005; 6: 755-64

*

ESPRIT = European and Australian Stroke Prevention in Reversible Ischemia Trial
ESPS-2 = European Secondary Prevention Study
CAPRIE = Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events