Cardiovascular Compatibility of Proton Pump Inhibitors: Practice Recommendations

Statement 1: There Is a Strong Association Between Cardiac and GI DisordersReview of the Literature

There is a clear link between heart disease and GI problems (Fig. 1). Most patients attribute their coronary artery disease (CAD) symptoms to “gas” and acidity, which results in delayed diagnosis and poor outcomes of CAD.

Fig. 1figure 1

Association between cardiac and GI disorders. This figure illustrates the strong association between cardiac and GI disorders. The consensus level among participants was 100%, with 62% strongly agreeing and 38% agreeing with some reservations. GI gastrointestinal

Gastroesophageal reflux disease (GERD) is associated not only with non-cardiac chest pain episodes, but also with increased incidence of ischemic events in patients with CVD and refractory chest pain [4]. In patients with CAD undergoing percutaneous coronary intervention (PCI), antithrombotic therapy is used to minimize the risk of stent thrombosis and recurrent CV events [5]. Antithrombotic therapy is associated with high risk of GI bleeding. Increased GI bleeding is associated with an increased risk of CV events and mortality, and prolonged hospitalization [6]. Polypharmacy with drugs used to manage CVD can cause upper GI symptoms. Some drugs used to treat upper GI symptoms may increase CVD risk either directly or through drug–drug interactions. Therefore, recognizing patients with both CVD and upper GI conditions is an important step in the clinical care setting [7]. PPI use for an extended period of time may suppress dimethylarginine dimethylaminohydrolase (DDAH) activity. This leads to increased asymmetrical dimethyl arginine (ADMA) levels which inhibit nitric oxide (NO) synthesis and increase the risk of CVD [8].

Statement 2: Increased GI Bleeding Increases CV Events, Mortality, and Prolonged HospitalizationReview of the Literature

Acute myocardial infarction (AMI), percutaneous coronary intervention (PCI), and anticoagulant or antiplatelet drugs are all known to cause GI bleeding in patients admitted to the cardiology department [9]. Not only does this cause prolonged hospitalization but also increases the risk of CV events and mortality (Fig. 2) [10]. Post-procedural bleeding episodes were linked to an elevated risk of in-hospital mortality in a large registry of PCI patients, with an estimated 12.1% of fatalities due to bleeding complications [11]. GI bleeding is a catastrophic condition in the setting of acute coronary syndrome (ACS). It is associated with increased rates of mortality, nonfatal MI, stent thrombosis, and prolonged hospitalization. The duration of hospitalization is twice as long in patients with GI bleeding as in those without GI bleeding [12]. GI bleeding adversely affects CAD outcomes in many ways. One of them which is not often discussed is that secondary to bleeding as a compensatory mechanism, coagulation factors become more proactive resulting in more thrombotic events [6]. According to international societal guidelines, patients with a history of upper GI bleeding should take PPIs to minimize GI bleeding. PPIs are helpful for patients who require antiplatelet medication and have associated risk factors for GI bleeding [13].

Fig. 2figure 2

Consequences of increased GI bleeding with respect to cardiovascular events, mortality, and hospitalization. The figure illustrates the association between increased GI bleeding and its consequences, including cardiovascular events, mortality, and prolonged hospitalization. The consensus level reached 100% agreement. GI gastrointestinal

Statement 3: There Is an Immense Burden of Polypharmacy and Significant DDI in Cardiac PatientsReview of Literature

Patients with CVD need to be prescribed two or more essential drugs [14]. These drugs together can cause drug interactions (Fig. 3). Cardiovascular pharmaceuticals make up 48.0% of all prescribed medications, which is quite high [15]. A study which included 466 patients showed that 26.7% of participants met the criteria of polypharmacy. Polypharmacy, while sometimes unavoidable, is not always effective or safe. It can have a high risk of negative side effects [16]. The most severe medication interactions were identified to be aspirin + clopidogrel (46.8%) and omeprazole + clopidogrel (32.4%) in the same prescription. It has been shown that combining a PPI with clopidogrel in a single prescription can result in serious medication interactions [15]. Despite these interactions, PPIs have been suggested as a way to reduce the risk of GI bleeding after dual antiplatelet therapy (DAPT). The patient's GI risk must be assessed, and PPIs with the least interaction with clopidogrel must be chosen carefully [15]. Therefore, clinicians should differentiate between appropriate and inappropriate polypharmacy and strive to reduce inappropriate polypharmacy and severe DDI [16].

Fig. 3figure 3

Polypharmacy and DDI burden in cardiac patients. The figure highlights a significant consensus level (100%) regarding the burden of polypharmacy and DDI in cardiac patients, with 62% strongly agreeing and 38% agreeing with some reservations. DDI drug–drug interaction

Statement 4: The Most Prescribed Single Drug in Cardiac Patients Is Aspirin and the Fixed-Dose Combination Is Aspirin + ClopidogrelReview of the Literature

Antiplatelet agents (67.7%) dominate the cardiology outpatient department (OPD) prescribing trend and are projected to overtake anti-cholesterol medications as the top seller. The most prescribed single drug was aspirin (59.9%) [17] (Fig. 4). Aspirin and clopidogrel were the most widely recommended antiplatelet drugs for the treatment of CVD [18].

Fig. 4figure 4

Aspirin and aspirin + clopidogrel—common medications in cardiac patients. The figure summarizes the common medications used in cardiac patient care, including aspirin as the single drug and the combination of aspirin + clopidogrel. The consensus level was 100%, with 87% strongly agreeing and 13% agreeing with some reservations

The combination of aspirin and clopidogrel is essential in the treatment of CVD because the drugs minimize the risk of additional clot formation and help to improve survival rates [18]. Platelet activation is inhibited by aspirin and clopidogrel through complementary but distinct mechanisms. Both these antiplatelet drugs have a substantial protective impact against unfavorable vascular events, but the combination of the two agents has an even stronger antiplatelet effect, resulting in superior antithrombotic protection in CVD and peripheral arterial disease (PAD) [19].

Statement 5: PPIs Are Recommended for Gastroprotection in Patients with CAD Receiving Antithrombotic TherapyReview of the Literature

DAPT with aspirin and a P2Y12 inhibitor improves CV outcomes in patients with acute coronary syndrome (ACS) and is recommended by guidelines for one year following initial hospitalization [20]. Clopidogrel has been linked to an elevated risk of upper GI bleeding and ulcers. To reduce the risk of GI hemorrhage, PPIs are recommended. In CAD, PPIs have been demonstrated to minimize dyspepsia caused by DAPT and to achieve a clinically significant reduction in GI bleeding [20]. According to a systematic assessment of 18 randomized controlled trials (RCTs) involving over 10,000 patients, PPIs reduced peptic ulcer bleeding by almost 80.0% when compared to controls [21]. Mistry et al. reported that gastroprotection in the form of PPIs is required for patients on DAPT and/or with a history of GI bleeding [22]. A meta-analysis conducted by Almufleh et al. reported that PPIs are superior to H2 receptor antagonists (H2RAs) for gastroprotection in patients on DAPT [23]. These data suggest that PPI therapy has a definite gastroprotective role in patients with CVD (Fig. 5) who are prescribed antiplatelets, but the usage should be in accordance with the recommended dose and treatment period [24].

Fig. 5figure 5

PPI recommendations for gastroprotection in patients with CAD. The figure highlights the recommendations for PPIs in providing gastroprotection for patients with CAD, with a consensus level of 100%, including 87% strongly agreeing and 13% agreeing with some reservations. CAD coronary artery disease, PPI proton pump inhibitor

Statement 6: PPIs Affect the Efficacy of DAPT in Cardiac PatientsReview of the Literature

Clopidogrel has been used as an antiplatelet drug in most studies for DAPT. Concurrent use of clopidogrel and PPIs may reduce the overall efficacy of clopidogrel (Fig. 6) due to the DDIs between some PPIs and clopidogrel, metabolized via the same CYP450 liver enzymes [25]. In 2009, the Food and Drug Administration (FDA) issued a warning about concomitant use of clopidogrel and certain PPIs, as the antiplatelet action of clopidogrel may be limited by PPIs like omeprazole and esomeprazole [26]. Yamane et al. reported that omeprazole lowered clopidogrel's antiplatelet action more than rabeprazole [26]. Among individual PPIs, only omeprazole was significantly linked with an increased risk of hospitalization for ACS [27]. The results of a meta-analysis exploring the risk of major adverse cardiovascular events (MACE) following combined use of clopidogrel and PPIs in patients with CAD showed that the increased risk of MACE was similarly high with omeprazole, esomeprazole, lansoprazole, and pantoprazole but not with rabeprazole [28]. A study by Parri et al. showed that pantoprazole increased the adenosine diphosphate-induced maximal aggregation (ADP-MA) in patients with ST-elevation myocardial infarction (STEMI) treated with DAPT. It significantly interferes with the antiplatelet effects of clopidogrel. Therefore, pantoprazole is not a safer choice for patients on DAPT [29]. The available evidence suggests that there is an increased risk of MACE in patients with concomitant use of clopidogrel and PPIs, but it is different for different PPIs [30]. In the last few years, newer antiplatelet agents (ticagrelor/prasugrel) have been used as alternatives to clopidogrel after coronary intervention. There are no known drug interactions with prasugrel and ticagrelor that would significantly hinder their antiplatelet effects [31].

Fig. 6figure 6

Influence of PPIs on DAPT effectiveness in cardiac patients. The figure highlights how PPIs influence the effectiveness of DAPT in cardiac patients, with a consensus level of 100%, agreeing with some reservations. PPI proton pump inhibitor, DAPT dual antiplatelet therapy

Statement 7: PPIs and Antiplatelet Drugs Share a Common Cytochrome P450 Metabolic PathwayReview of the Literature

Most drugs undergo oxidation by one or more CYP isoenzymes, which is the most important metabolic pathway. The activity of CYP isoenzymes may also be required for the conversion of a prodrug into a clinically useful active metabolite [32]. Several PPIs and antiplatelet agents are metabolized by the hepatic cytochrome P450 enzymes (mainly CYP 2C19 and 3A4) (Fig. 7) implying the possibility of DDIs. Clopidogrel is a prodrug and is converted into active form through cytochrome-P450 enzymes dependent metabolism, however, PPIs have the potential to compete for the active site of CYP2C19, the enzyme responsible for converting clopidogrel into its active form. Clopidogrel's antiplatelet activity is thought to be inhibited by competitive inhibition, putting patients taking both these drugs at a higher risk of CV events than clopidogrel-treated individuals who do not take PPIs [33]. All PPIs except for rabeprazole are extensively metabolized by and competitively inhibit CYP2C19 and CYP3A4 (Fig. 8). Omeprazole, pantoprazole, and lansoprazole appear to be the strongest inhibitors of these enzymes, whereas the inhibitory potency of rabeprazole was lower than that of the other PPIs [34]. Ticagrelor and prasugrel are metabolized predominantly by CYP enzymes other than CYP2C19 [35, 36]. Clopidogrel is hydrolyzed by esterases to an inactive carboxylic acid metabolite, and the remaining drug is oxidized to active thiol metabolite in a two-step process by hepatic P450 cytochromes (CYP3A4/5 and CYP2C19 have a greater role). Multiple pharmacodynamic drug interactions can influence active thiol metabolite levels [32].

Fig. 7figure 7

PPIs and antiplatelet drugs share a common cytochrome P450 metabolic pathway. This figure highlights the common cytochrome P450 metabolic pathway shared by PPIs and antiplatelet drugs, with a consensus level of 100%, including 38% strongly agreeing and 62% agreeing with some reservations. PPI proton pump inhibitor

Fig. 8figure 8

Copyright © 2012 Sugimoto et al. This is an open access article, licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)

Major metabolic pathways for the PPIs and the CYP 450 enzymes involved. The contribution of each isoenzyme is represented by the thickness of the arrow (thick arrows indicate the dominant pathway; thin arrows indicate the non-dominant pathway). PPI proton pump inhibitor. Note: Adapted from Sugimoto et al. Proton pump inhibitor therapy before and after endoscopic submucosal dissection: A review. Diagn Ther Endosc. 2012; 791873. https://doi.org/10.1155/2012/791873.

Statement 8: Not All PPIs Are Metabolized Predominantly by the CYP450 PathwayReview of the Literature

PPIs are largely eliminated in the liver by the CYP2C19 enzyme, with CYP3A4 playing a smaller role. The extent to which PPIs are metabolized by CYP2C19 varies, resulting in variations in their pharmacokinetic and pharmacodynamic properties, which has an impact on their efficacy (Fig. 9). CYP2C19 is responsible for more than 80.0% of the metabolism of omeprazole, lansoprazole, and pantoprazole [37].

Fig. 9figure 9

Not all PPIs are metabolized predominantly by the CYP450 pathway. The figure illustrates that not all PPIs are predominantly metabolized by the CYP450 pathway. The consensus level among participants was 100%, with 25% strongly agreeing and 75% agreeing with some reservations. PPI proton pump inhibitor

Rabeprazole undergoes extensive hepatic metabolism, predominantly nonenzymatic reduction to thioether and to a lesser extent via CYP2C19 and CYP3A4. As a result, rabeprazole may be less affected by CYP2C19 genetic variation or medication interactions than other PPIs. Rabeprazole has a much smaller difference in area under the curve (AUC) between the two groups (extensive metabolizers [EM]; poor metabolizers [PM]) compared to other PPIs. The acid suppression effect of PPIs is dependent on the plasma levels of the parent compound, and the AUC of PPIs is related to the degree of acid inhibition. As a result, it stands to reason that changes in CYP2C19 metabolic activity, which are influenced by genetic variability, would alter PPI efficacy [37]. Differences in hepatic metabolism caused by the CYP2C19 genetic polymorphism may contribute to inter-patient heterogeneity in PPI plasma levels, acid suppression, and clinical effectiveness [38]. Omeprazole alters the absorption, metabolism, and/or excretion of a wide range of drugs, including bismuth, caffeine, carbamazepine, diazepam, digoxin, mephenytoin, methotrexate, nifedipine, phenytoin, and warfarin. Ketoconazole inhibits the metabolism of omeprazole to omeprazole sulfone in both CYP2C19 poor and extensive metabolizers. Drug interaction studies with rabeprazole reveal no such significant drug interactions with drugs like theophylline, phenytoin, warfarin, or diazepam [38].

Statement 9: A PPI with Minimal DDI Is Recommended, Especially in Patients Requiring Clopidogrel or PolypharmacyReview of the Literature

Clopidogrel, a widely used P2Y12 inhibitor, is associated with an increased risk of upper GI bleeding and ulcer, and to mitigate this risk of GI hemorrhage, PPIs are recommended for providing gastroprotection by maintaining the intragastric milieu. Considering the pharmacological interaction between clopidogrel and some PPIs on the basis of mutual CYP450-dependent metabolism, PPIs may inhibit the conversion of clopidogrel to its active metabolite and thereby diminish its clinical efficacy. This has led to growing debate about polypharmacy, arguing that it is sometimes inevitable but not always efficacious [20].

Both clopidogrel and PPIs are extensively metabolized by the CYP2C19 isoenzyme; therefore, PPIs with high affinity towards CYP2C19 should be avoided to minimize the interaction between this combination (PPI and clopidogrel) or with other drugs in the prescription that are metabolized by the same pathway, and PPIs with the lowest affinity towards CYP2C19 is recommended (Fig. 10). Of note, numerous studies have demonstrated that PPI-induced risk reduction in GI bleeding clearly outweighs the risk of adverse CV events; therefore, in patients at high risk of GI bleeding, PPIs with less CYP2C19-inhibiting potential are recommended [39].

Fig. 10figure 10

PPIs with minimal DDI should be preferred. The figure shows that a PPI with minimal DDI should be preferred, especially in patients requiring clopidogrel or polypharmacy. The consensus level among participants was 100%, with 100% strongly agreeing. PPI proton pump inhibitor, DDI drug–drug interaction

Statement 10: Rabeprazole Does Not Interact with Clopidogrel to the Same Extent as Other PPIsReview of the Literature

The efficacy, availability, and lower side effect profile of PPIs make them suitable candidates to be prescribed along with clopidogrel to alleviate the risk of GI bleeding in the susceptible population. Of note, different PPIs are associated with different CV risks.

As noted by Sarnaik et al. [40], the increasing order of interaction strength of different PPIs, from lowest to highest affinity towards CYP2C19, is as follows: rabeprazole, pantoprazole, lansoprazole, esomeprazole, and omeprazole (Fig. 11).

Fig. 11figure 11

Rabeprazole does not interact with clopidogrel to the same extent as other PPIs. The figure illustrates that rabeprazole does not interact with clopidogrel to the same extent as other PPIs. The consensus level among participants was 100%, with 100% strongly agreeing. PPIs proton pump inhibitors

Further, the results of a recent meta-analysis exploring the risk of MACE following the combined use of clopidogrel and PPIs in patients with CAD showed that the risk of MACE in the rabeprazole group was negligible as compared to other PPIs [28].

Statement 11: Rabeprazole Prevents Recurrence of Peptic Ulcers in Patients on Low-Dose Aspirin TreatmentReview of the Literature

A study conducted by Sugimoto et al. [41] concluded that rabeprazole remarkably inhibits acid secretion regardless of CYP2C19 genotypes and reduces the incidence of aspirin-related mucosal injury.

Further, these results were substantiated by Uotani et al. [42], who reported that rabeprazole provides protection against low-dose aspirin (LDA)-induced mucosal injury, and that too without interfering with clopidogrel's action (Fig. 12).

Fig. 12figure 12

Rabeprazole prevents recurrence of peptic ulcers in patients on low-dose aspirin treatment. The figure illustrates that rabeprazole prevents recurrence of peptic ulcers in patients on low-dose aspirin treatment. The consensus level among participants was 100%, with 75% strongly agreeing and 25% agreeing with some reservations

Later on, a study was planned to assess the long-term (76 weeks) efficacy and safety profile of rabeprazole in preventing peptic ulcer recurrence in patients on LDA therapy. In this study, 151 subjects in the rabeprazole 10-mg group and 150 subjects in the rabeprazole 5-mg group (5/10 mg is the standard dose in Japan, whereas the approved dosage of rabeprazole in India is 10/20 mg) were analyzed. The results of the study revealed that the cumulative peptic ulcer recurrence rates were as low as 2.2% in the 10-mg group and 3.7% in the 5-mg group, and no bleeding ulcers or clinically significant CV events were reported; also, both doses of rabeprazole were well tolerated [

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