Concomitant Use of Thrombocyte Aggregation Inhibitors and Proton Pump Inhibitors (PPIs)

Recommendations of Current Guidelines and Statements of the American (FDA) and European (EMEA) Authorities

In 2008 the German Society for Digestive and Metabolic Diseases (DGVS) prepared the S 3-Guideline ”Helicobacter pylori and gastroduodenal ulcer disease” [1] in cooperation with other scientific societies. It recommends ”complementary PPI-medication in case of concomitant thrombocyte aggregation inhibition using ASA and clopidogrel” (recommendation grade C, evidence level 2a, consensus). In the comment that follows it is stated that due to the increased risk of gastroduodenal bleeding under dual antiplatelet therapy, complementary PPI-medication is recommended even if no directly applicable studies exist.

Also in 2008 several American associations (the American College of Cardiology Foundation ACCF, the American College of Gastroenterology ACG, and the American Heart Association AHA) founded a task force and prepared a consensus-report on the gastrointestinal risks of antiplatelet therapy and the use of non-steroidal anti-inflammatory drugs (NSAID) [2]. The text of this consensus-report does not directly address the dual platelet inhibition with ASA and clopidogrel. It points out that a combination of ASA or clopidogrel and anticoagulants poses a particular risk for severe bleeding especially gastrointestinal bleeding. It states that cardiovascular benefits and gastrointestinal risks have to be individually assessed. If ASA and anticoagulants are concomitantly taken, patients should receive comedication with PPIs. PPIs are also said to be the preferred drugs for preventing and treating ASA induced gastrointestinal lesions. When studying the report closely one does find an algorithm which recommends comedication with PPI with dual platelet inhibition (not mentioned in the text). In an update that was published in December 2009, the expert committee abstains from giving an official recommendation as long as no original published results from randomized controlled studies exist [3].

Like the American consensus-report, the German S 3-guideline also takes a stand on Helicobacter pylori eradication in this context. If upper gastroduodenal bleeding occurs under ongoing ASA therapy, initiation of long-term PPI medication and the examination for H. pylori with subsequent eradication if the test was positive are recommended. General testing for H. pylori before planned ASA long-term medication is considered unnecessary by the German S 3-guideline. The American consensus-report recommends an H. pylori test before antiplatelet therapy for patients with a history of ulcers.

In January 2009 the FDA initiated a safety review (ongoing safety review), because of various publications on the reduction of platelet inhibition by clopidogrel with concomitant use of PPI-medication [4]. At the same time, the US-authority recommended that doctors continue prescribing clopidogrel. In addition, they suggested checking whether initiating or continuing PPI-treatment is necessary. At that time the FDA was not able to give a final assessment of the problem. It, therefore, did not state any stronger restrictions. The European Medicine Agency (EMEA) went further and warned about simultaneous administration of clopidogrel and PPI [5]. It stated precisely that this combination should only be used if it is absolutely necessary. In the meantime, the FDA has also included a warning about the concomitant use of cimetidine and different PPIs to the standard clopidogrel information. This concerns omeprazole and esomeprazole [6].

Given the current data that have not been considered in the existing guidelines and recommendations, the DGVS and the DGK feel it is necessary to make a joint statement on the use of clopidogrel/platelet inhibitors and PPIs.

References

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