In chronic atherosclerotic disease such as stable coronary heart disease, clopidogrel (ISCOVER, PLAVIX) is regarded as second line drug in evidence-based guidelines (1) when low-dose acetylsalicylic acid (ASA, e.g. aspirin) is not tolerated, e.g. because of a peptic ulcer. Whether switching to clopidogrel actually reduces the risk of recurrence and bleeding has not been investigated systematically up to now. An observational study in patients with peptic ulcer (with or without previous aspirin treatment) reports an unexpectedly high rate of ulcer complications (12%) on clopidogrel within a year (2).

In a recent monocentre interventional study from Hongkong 320 patients were given a proton pump inhibitor after a upper gastrointestinal bleeding while they were taking low-dose aspirin and eradication treatment if Helicobacter pylori was found. After endoscopically confirmed healing of the ulcer and successful eradication, the antithrombotic therapy was resumed and patients were randomised to take either 75 mg clopidogrel (plus placebo) or 80 mg aspirin plus 2 x 20 mg esomeprazole (NEXIUM) daily. Within a year recurrent GI-bleeding (primary endpoint) occurred in 8.6% of those taking clopidogrel and in 0.7% of patients taking aspirin plus esomeprazole (absolute risk reduction 7.9%, 95% confidence interval [CI] 3.4% to 12.4%, p = 0.001). The incidence of lower gastrointestinal haemorrhage was the same in both groups (4.6%). Other severe haemorrhages occurred only in three patients taking clopidogrel. Ischaemic events occurred in eleven patients on aspirin and nine on clopidogrel. Eight patients in the clopidogrel group and four in the aspirin group died (3).

The study questions the safety of clopidogrel in patients who have had a bleeding peptic ulcer and a negative H. pylori status and contradicts current guideline recommendations (1). These results do not justify replacing aspirin with clopidogrel according to an accompanying editorial (4). However, it remains to be clarified whether the unusually high dose of a proton pump inhibitor used in the study in addition to aspirin is necessary or whether similar results can be obtained with the daily doses of e.g. 20 mg omeprazole (e.g. ANTRA) or esomeprazole that have been investigated (5,6) and licensed for prevention of ulcers during treatment with nonsteroidal anti-inflammatory drugs.

Indirect evidence for this may be derived from another small randomised study of patients after healing of a bleeding ulcer that occurred on low-dose aspirin. After H. pylori eradication the rate of recurrent ulcer complications during one year was 1.6% on 30 mg lansoprazole daily (AGOPTON, LANZOR; roughly equivalent to 20 mg omeprazole) in addition to 100 mg aspirin. In contrast, aspirin alone showed recurrent ulcers in 14.8% (relative risk 9.6; 95% CI 1.2 to 76.1) (7).

	Recent clinical study data argue against replacing aspirin with clopidogrel (ISCOVER, PLAVIX) in patients after peptic ulcer bleeding while on low-dose acetylsalicylic acid and for continuation of prophylaxis with a low aspirin dosage (75 mg to 100 mg) in combination with a proton-pump inhibitor.
	The results apply for Helicobacter pylori-negative patients.
	The dosage of the proton-pump inhibitor required in this situation has to be clarified.

(R = randomised study)

1

ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction
http://www.acc.org/clinical/guidelines/unstable/update_index.htm

2

NG, F.H. et al.: Aliment. Pharmacol. Ther. 2003; 18: 443-9

3

CHAN, F.K.L. et al.: N. Engl. J. Med. 2005; 352: 238-44

4

CRYER, B.: N. Engl. J. Med. 2005; 352: 287-9

5

HAWKEY, C.J. et al.: N. Engl. J. Med. 1998; 338: 727-34

6

YEOMANS, N.D. et al.: N. Engl. J. Med. 1998; 338: 719-26

7

LAI, K.C. et al.: N. Engl. J. Med. 2002; 346: 2033-8