Lights and shadows of the treatment with proton pump inhibitors in patients after myocardial infarction

Proton pump inhibitors (PPIs) are currently one of the most effective and most widely used drugs in the prevention and treatment of disorders associated with excessive secretion of hydrochloric acid. Recent reports suggest that polytherapy with PPI, clopidogrel and acetylsalicylic acid in patients after percutaneous coronary intervention is associated with the possibility of adverse interactions in the form of, inter alia, acute coronary syndromes, stroke, and even death. The latest research clearly indicate that simultaneous use of proton pump inhibitors together with dual antiplatelet therapy does not increase the risk of adverse cardiovascular events.

Proton pump inhibitors are currently among the most widely used drugs in the daily practice of each doctor, especially gastroenterologist. Although the groundbreaking moment of the PPIs discovery was almost 30 years ago, their use is still hopeful but also controversial. The main worth mentioning indicators for their use are especially the treatment of gastroesophageal reflux disease, stomach ulcers and/or duodenum, Helicobacter pylori eradication, as well as prevention and treatment of lesions of the upper gastrointestinal tract mucosa following chronic use of nonsteroidal anti-inflammatory drugs [1]. The greatest problem in the choice of treatment in viewpoint of the clinician is to assess the interaction of PPIs with other drugs co-administered to the patient. In recent years there were many scientific reports on the effect of simultaneous use of proton pump inhibitors with antiplatelet agents such as aspirin, clopidogrel or prasugrel in patients after acute coronary syndrome undergoing percutaneous coronary intervention [2,3].

The first mentions regarding adverse interaction between platelet aggregation inhibitors induced by ADP and PPIs, used to reduce the risk of gastrointestinal bleeding, appeared in the journal Thrombosis and Haemostasis in 2009 [4]. The study involved 1000 patients treated with clopidogrel in combination (n=268) with pantoprazole, esomeprazole and omeprazole. It turned out that omeprazole significantly reduces the antiaggregation effect of clopidogrel, what is reflected considerably in the risk of repeated sudden cardiovascular events. Over the years there have been many scientific and clinical research, which suggested that PPI polytherapy with clopidogrel and aspirin (ASA) is associated with an increased risk of death, recurrent myocardial infarction, ischemic stroke or thrombotic coronary stent [5,6,7,8].

The relationship between PPIs and antiplatelet drugs is explained to a large extent by the pharmacokinetic properties associated with the metabolism of these drugs with the participation of cytochrome P450. All proton pump inhibitors are metabolized by CYP 2C19, but it should be emphasized that omeprazole has the greatest inhibitory effect on CYP 2C19. Pantoprazole being converted by CYP 3A4 has the lowest inhibitory effect. This translates into a multitude of adverse effects of other drugs, in which transformation enzymes of this cytochrome are involved. On the basis of PPI properties analysis, pantoprazole seems to be the safest of them [9]. In turn, clopidogrel as the only drug of platelet aggregation inhibitors induced by ADP, is a prodrug and in order to obtain full antiaggregation effect it requires changes, which also occur by CYP 2C19. Therefore, the basic mechanism explaining the interactions between these drugs is the inhibitory effect of omeprazole on clopidogrel activation processes and full antiaggregation effect [10].

The breakthrough in the approach to the combined therapy with clopidogrel and ASA together with PPI were the results of a study published in the journal The New England Journal of Medicine in 2010. (COGENT) [11]. It was the first randomized study which finished prematurely and in combination with previous clinical observations it showed that the use of DAPT in combination with PPI, especially omeprazole does not increase the risk of cardiovascular events, and protects against the adverse effect on the mucosa of gastrointestinal tract.

Randomized study conducted by researchers from the Federico II University of Naples in Italy is the latest report on the impact of PPIs on clinical outcomes in patients after percutaneous coronary intervention (PCI) treated with dual antiplatelet therapy: clopidogrel and acetylsalicylic acid [2]. The study included 1,970 patients after PCI, who were treated with combination antiplatelet therapy (DAPT – dual-antiplatelet therapy): acetylsalicylic acid (75-100 mg p.o.) and clopidogrel (75 mg/day) for 6 or 24 months. Classification criteria regarding the duration of DAPT treatment included, inter alia, myocardial infarction with ST-segment elevation, the coexistence of type 2 diabetes, the need for at least 1 intervention in the stent. From among them, 37,5% of the patients (n=738) were taking one of proton pump inhibitors (90,9% – lansoprazole, 7,6% – pantoprazole, 1,5% – omeprazole, esomeprazole, rabeprazole) in order to prevent the complications in the form of bleeding or ulceration of the gastrointestinal tract. In the final evaluation of the effectiveness and safety of the treatment the following clinical situations were considered: recurrent myocardial infarction, stroke, death and the risk of gastrointestinal bleeding by BARC scale (grades 2,3,5).

Obtained results clearly show that the use of PPIs in combination with clopidogrel and aspirin is not burdened with the risk of cardiovascular complications. The discrepancy between the results of clinical trials [2,12], compared to the observation and consideration of the pharmacodynamic properties that indicate of interaction between the described classes of drugs, is due to the presence of interfering factors. As it turned out, in the group of patients receiving PPI, significantly higher percentage of elderly people with reduced creatinine clearance, a higher frequency of episodes of ACS and higher rates of bleeding risk (CRUSADE bleeding score) were reported. Moreover, it was observed that high percentage of patients treated with combination therapy involving proton pump inhibitors were women (27,5%; compared to the group not receiving PPIs – 20,8%), who due to the presence of a statistically significant, non-modifiable risk factors are more predisposed to diseases of the cardiovascular system [13]. It is also worth mentioning that this study showed that proton pump inhibitors did not increase the risk of incidents of acute coronary syndromes, especially myocardial infarction, both during a short six month therapy, as well as extended 24 month therapy with clopidogrel.

Data from the scientific literature showed that aspirin and other antiplatelet drugs cause significantly more life-threatening gastrointestinal bleeding because of their unfavorable synergistic influence on the mucosa of the stomach and duodenum [14]. Therefore, it is recommended to use of PPIs in prevention of gastrointestinal complications. In recent years, numerous discussions and research were conducted. They showed that simultaneous use of PPIs with DAPT in patients after PCI is associated with the risk of adverse interactions from cardiovascular system. However, the latest results of randomized clinical observations clearly show that PPIs do not increase the risk of myocardial infarction or other sudden cardiac events [2,15]. Proton pump inhibitors are drugs that signed up in the history of medicine as a “milestone” in the treatment of peptic ulcer disease or GERD. In the face of these reports, it can be stated that the twenty-first century is the age of the renaissance and a new look at the use of PPIs in different fields of medicine.

Written by: Joanna Szydełko, prof. dr hab. n. med. Barbara Skrzydło-Radomańska

Medical Student’s Association, Chair and Department of Gastroenterology with Endoscopic Unit, Medical University of Lublin

Supervisor: prof. dr hab. n. med. Barbara Skrzydło-Radomańska

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