Routine combination of dual antiplatelet therapy with proton pump inhibitors - are we not throwing the baby out with the bath water?
Abstract
Antithrombotic therapy involves an increased risk of bleeding, with gastrointestinal bleeding being particularly feared. Thus, antiplatelet therapy is often administered concurrently with proton pump inhibitors (PPIs) that reduce the risk of bleeding.
Papers dealing with platelet functions as well as meta-analyses of clinical studies suggest a lower effect of antiplatelet therapy when clopidogrel, acetylsalicylic acid (ASA), or dual therapy are comedicated with PPIs. In terms of clopidogrel therapy, there is a relative consensus among papers testing platelet aggregability in treatments using in vitro methods that concurrent administration of PPIs reduces clopidogrel bioactivation and the proportion of constantly active platelets increases during treatment.
The clinical significance of these papers remains unresolved. Meta-analyses of mostly observational or post-hoc evaluation studies reveal a significant increase in severe atherothrombotic events with concurrent administration of dual antiplatelet therapy and PPIs.
However, the only prospective controlled study failed to confirm this finding. Unfortunately, due to a number of restrictions of the study (small statistical power, a special dosage form for the administration of clopidogrel with omeprazole, or an enterosolvent form of ASA), the conclusion on insignificance of the interaction cannot be generally accepted.
From a legal perspective, the warning of regulatory bodies against the combination of clopidogrel and PPIs is still valid. Negative interaction of PPIs with acetylsalicylic acid is far less taken into consideration.
Both a markedly reduced ASA availability with an increase in gastric pH due to PPIs and ASA deacetylation by intestinal esterases significantly limit the supply of effective acetylsalicylic acid in the circulation, particularly in the portal one. The significance of reduced antiplatelet effect of ASA following the administration of PPIs is also indicated by the results of retrospective analyses of secondary preventive studies in patients treated not with clopidogrel, but with ASA only.
An increased rate of severe vascular events by more than 40% in patients treated with ASA will have to be confirmed in prospective studies. The unclear situation concerning the significance of the drug interaction between PPIs and dual antiplatelet therapy should lead to restraint in a widespread, routine use of this comedication in patients after acute coronary events or coronary interventions.