Abstract
Proton-pump inhibitors (PPIs) are one of the most common co-prescribed medications by almost all cardiologists to their patients, especially if they are taking one or more antiplatelet agents. Use of dual antiplatelet therapy (DAPT) at least 6 months after percutaneous coronary angioplasties is based on the recommendations of the professional bodies and several DAPT-related trials. Increased GI bleeding enhances CV events, mortality and prolongs hospitalization. Decrease in ischemic events owing to DAPT comes at a price of gastrointestinal effects, including bleeding. Concerns were expressed if clopidogrel and PPI can be used concurrently as both share the same cytochrome (CYP) enzymes [P450 2C19], and the latter can affect the platelet-inhibitory effect of the former. 1 The long-term nonjudicious use of PPIs may have adverse implications caused by the suppression of dimethyl-arginine dimethyl-amino hydrolase activity. This will affect the production of nitric oxide and may precipitate cardiovascular events. 2
The results and messages from several trials and meta-analysis on this issue are conflicting and confusing.3–5 Fortunately, COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial)—a large international trial—concluded that PPIs are safe and effective strategy to reduce the risk of bleeding in patients on DAPT. 6 The 2016 American College of Cardiology and the American Heart Association guidelines endorsed the use of PPIs to patients at a higher risk of gastrointestinal bleeding; however, they recommended no routine PPIs in those with low risk for gastrointestinal bleeding. The risk factors pointed out in this document were as follows: advanced age, use of warfarin, steroids or anti-inflammatory drugs. 7 2017 European Society of Cardiology update on the use of DAPT in post-percutaneous coronary intervention (post-PCI) patients clarified on the differential need for DAPT duration following PCI in stable versus acute coronary syndrome (ACS) on the presentation and the degree of bleeding risk. In ACS, it is recommended to use DAPT for at least 12 months for most patients but can be reduced to 6 months or even 3 months depending on the risk for bleeding. For stable patients undergoing the recommended DAPT duration is 6 months for drug-eluting stents (DESs). This update also suggested the routine use of PPI to all patients on DAPT. Esomeprazole and omeprazole were mentioned to have the highest likelihood of clinically significant interactions unlike pantoprazole and Rabeprazole. 8
A meeting was held under the chairmanship of Dr. Jamshed Dalal last year to deliberate the cardiovascular compatibility of PPIs in Indian settings and bring out practical recommendation. 9
The main messages from the proceedings of meeting were as follows:
All PPIs have affinity for either CYP2C19 or CYP3A4 and have potential for drug-drug interaction. Rabeprazole has very low affinity for CYP isoenzymes and is expected to be safer. When used along with clopidogrel, Rabeprazole had least risk of major adverse cardiac event than omeprazole, esomeprazole, lansoprazole, and pantoprazole.
The review article by Desai et al in this issue of Indian Journal of Clinical Cardiology extensively dealt with the commonly used PPIs and their interactions with clopidogrel and recommended to use rabeprazole in preference to other PPIs. Their choice is based on the fact that rabeprazole is not metabolized by CYP2C19 enzyme (which has genetic polymorphism).
The newer antiplatelet agents—ticagrelor and prasugrel—are only minimally dependent on CYP2C19 for their bioactivity. Moreover, as ticagrelor is not a pro-drug, it has no interactions with PPIs. PLATO, TRITON-TIMI 38, and PRINCIPLE-TIMI 44 did not find any reduction in antiplatelet activity in patients on co-prescription of PPIs. With the emerging regimens of shortened DAPT with newer DES and switching to non-aspirin-non-clopidogrel monotherapy, we are in a better position to avoid the gastrointestinal side-effects and bleeding in the future.
