Adverse Effects of Proton Pump Inhibitor Use in Patients with Cardiovascular Disease: Pharmacovigilance Attention Needed!!

Despite an apparent excellent safety profile throughout their first two decades of use, the nearly universal popularity of PPIs has prompted several concerns about both their short- and long-term effects. This led to the US Food and Drug Administration (FDA) ultimately issuing a warning in 2009 for potential adverse cardiovascular outcomes when PPIs are co-administered with antiplatelet agents, such as clopidogrel, due to their mutual dependence on CYP2C19-mediated metabolism.[2]

This article aims to shed light on the interaction of PPIs with anti-platelet agents and examine the applicability of PPIs in cardiovascular diseases with the available scientific literature.

Rationale for Adopting Gastroprotective Strategies in Cardiovascular Disease Patients[2,3]

Cardiovascular disease (CVD) accounts for almost 18 million deaths annually and is the leading cause of mortality globally. Many clinical therapies are available to clinicians in which anti-platelet agents are widely prescribed that reduce cardiovascular events in acute coronary syndromes (ACS) patients and those undergoing percutaneous coronary intervention (PCI). One of the most common drugs is clopidogrel, typically used with aspirin as dual antiplatelet therapy (DAPT).

DAPT significantly reduces the risk of stroke, myocardial infarction (MI), and death in ACS patients; however, the risk of primary gastrointestinal (GI) bleeding also increases.

Pressing Concern Related to Concomitant Administration of PPIs and DAPT[2]

Studies have mentioned the drug interactions between clopidogrel and PPIs as hepatic metabolism of clopidogrel, and several of the PPIs are dependent on the cytochrome-P450 (CYP450) enzymes CYP2C19 and CYP3A4. Clopidogrel is a prodrug that requires conversion to its active form by the enzyme CYP2C19 in the liver. PPIs can inhibit the activity of CYP2C19.

The 2009 drug interaction warning by the US FDA (United States Food and Drug Administration) was largely based on initial pharmacokinetic and pharmacodynamic studies that reported impaired platelet inhibition following concomitant administration of DAPT and PPIs.

Clinical significance-

• Many non-randomized observational studies have found increased risks of subsequent Myocardial Infarction (MI)/ACS and major adverse cardiovascular events (MACE) in coronary patients receiving clopidogrel and PPIs.
• Several case-control studies have also found PPI use is associated to be a significant predictor of early stent thrombosis.

Clinical Evidence Substantiating the Antagonism of PPIs Towards Clopidogrel

Several meta-analyses and studies suggest that there may be an interaction between clopidogrel, an anti-platelet agent, and proton pump inhibitors (PPIs), which are commonly used to treat acid-related disorders such as gastroesophageal reflux disease (GERD).

• Hulot et al. conducted a meta-analysis that included 23 studies consisting of 48,674 patients. The endpoints assessed were MACE, mortality, or stent thrombosis. The study concluded that PPI users (42% [n = 19,614]) displayed increased risk for MACE (21.8% vs 16.7%; OR: 1.41; 95% CI: 1.34 to 1.48; p < 0.001) and mortality (12.7% vs 7.4%; OR: 1.18; 95% CI: 1.07 to 1.30; p < 0.001) compared with nonusers suggesting a potential antagonistic role of PPIs with clopidogrel.[4]
• Siller-Matula et al. conducted a meta-analysis to analyse the negative effect of PPIs in patients treated with clopidogrel. The meta-analysis included 25 studies with 1,59,138 patients. The outcomes evaluated were combined major adverse cardiac events (MACE), myocardial infarction (MI), stent thrombosis, and death. The study concluded that administration of PPIs together with clopidogrel corresponded to a 29% increased risk of combined MACE [risk ratio (RR) = 1.29, 95% confidence intervals (CI) = 1.15-1.45] and a 31% increased risk of MI (RR = 1.31, 95% CI = 1.12-1.53) suggesting concomitant administration of PPI-clopidogrel can increase the risk of cardiovascular events.[5]
• Chen et al. conducted a study to find a possible interaction between PPIs and clopidogrel. The study included comparative concomitant use of clopidogrel with PPIs versus clopidogrel without PPIs. Clinical endpoints set were cardiovascular death, readmission for myocardial infarction/readmission for acute coronary syndrome, and non-fatal stroke. The study concluded that in observational studies, the risk ratio of the clinical endpoints for clopidogrel with PPI compared to clopidogrel without PPI was 1.40 (P < 0.001) in the random-effects model and 1.49 (P < 0.001) in the fixed-effects model suggesting PPIs can increase the risk of cardiovascular diseases.[6]
• Huang et al. conducted a meta-analysis that included 32 studies and comprised 159,998 patients. The clinical endpoints were adverse cardiovascular outcomes. The study concluded that concomitant use of PPIs and clopidogrel is associated with an increased risk of major cardiovascular events (MACE) (HR 1.40, 95% CI 1.19-1.64; OR 1.27, 95% CI 1.13-1.42) and acute coronary syndrome (HR 1.42, 95% CI 1.14-1.77; OR 1.42, 95% CI 1.08-1.87). The study also found a positive correlation between pantoprazole and increased MACE (HR 1.52, 95% CI 1.18-1.94), suggesting that concomitant use of PPIs and clopidogrel in patients with coronary artery disease is associated with an increased risk of MACE or acute coronary syndrome.[7]
• Stockl et al. conducted a retrospective propensity matching study among post-MI patients or coronary stent placement for one year to evaluate adverse clinical outcomes in patients using clopidogrel plus a PPI compared with clopidogrel alone. The study included 1033 patients, each in both PPI and non-PPI groups. The study concluded that patients who received clopidogrel plus a PPI had a 93% higher risk of rehospitalization for MI (adjusted hazard ratio, 1.93; 95% confidence interval, 1.05-3.54; P = 0.03) and a 64% higher risk of rehospitalization for MI or coronary stent placement (1.64; 1.16-2.32; P = 0.005) than patients receiving clopidogrel alone. Increased risk of rehospitalization for MI or coronary stent placement was also observed for the subgroup of patients receiving clopidogrel plus pantoprazole (adjusted hazard ratio, 1.91; 95% confidence interval, 1.19-3.06; P = 0.008), suggesting a positive correlation between PPIs and cardiovascular events.[8]

Clinical Evidence Substantiating the Antagonism of PPIs Towards Anticoagulants

A retrospective review analysed if the concomitant use of warfarin increases the incidence of GI bleeding relative to warfarin alone. The review analysed the medical records of 626 patients taking warfarin for at least two weeks. The result showed that patients on PPI and warfarin simultaneously are more likely to be associated with increased incidences of GI bleeding. The incidence of GI bleeding was higher among concomitant PPI users (14.5%) than non/PPI users (7.1%) (p=0.003). This indicates that concomitant use of warfarin and PPI appears to be associated with an increased incidence of GI bleeding. [9]

Using Ranitidine in Addition to Antiplatelet Treatment: Supporting Clinical Evidence

Ranitidine vs PPI over the effect of Clopidogrel: A prospective, double-blinded, double-dummy study compared the antiplatelet effect of clopidogrel before and after adding omeprazole or ranitidine. The study enrolled 41 patients in the omeprazole and 44 in the ranitidine group. Inhibition of platelet aggregability (IPA) measured after one week of clopidogrel 75 mg daily showed a significant decrease after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p = 0.025), with no statistically significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p = 0.310). The repeated IPA tests after one additional week showed a statistical significance (32.7± 30.8 vs 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p=0.04). The study suggested that ranitidine did not influence platelet aggregability response to clopidogrel, unlike omeprazole. [10]

Ranitidine Prevents GI Bleeding in Post-PCI DAPT-treated Patients: Another study explored the efficacy and safety of ranitidine in preventing upper gastrointestinal haemorrhage from dual antiplatelet drugs after PCI and provided the basis for clinical treatment after PCI. The study included 121 coronary heart disease (CHD) patients (60 each in the ranitidine and control group). The patients in the ranitidine group received treatment for 12 weeks. Follow-up at 6 months showed no gastrointestinal bleeding in the ranitidine group, while six cases of gastrointestinal bleeding were reported in the control group. The results suggest that ranitidine can prevent dual antiplatelet drug-induced gastrointestinal bleeding complications in patients with CHD after PCI. [11]

Scientific Society Consensus for Prudent Use of PPIs with Antiplatelet Therapy

The expert consensus document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridine developed by the American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the American Heart Association (AHA) recommended PPI-only for patients with a high risk of upper gastrointestinal bleeding and patients with history of upper gastrointestinal bleeding for reducing the gastrointestinal risks of antiplatelet therapy and NSAIDs. [12]

The most recent European Society of Cardiology 2023 Guidelines for the management of acute coronary syndrome published in the last week of August 2023, suggest that proton pump inhibitor in combination with DAPT is recommended in patients at high risk of gastrointestinal bleeding. [Grade IA] [13]

Strategies to Avoid the Effects of PPIs – Antiplatelet Agents’ Interaction[14]

PPIs are extensively used in modern clinical settings because of their potency and application in a wide spectrum of gastrointestinal disorders. Despite its several advantages, PPIs can cause harm to patients in the form of adverse effects and drug interactions. Interaction with anti-platelet medications is a significant interaction leading to many cardiovascular repercussions. Hence, different strategies should be adopted to avoid this, and PPIs should be deprescribed without their indications. Different gastroprotective drugs, such as H2 receptor antagonists, could be considered in appropriate patients. Available data suggest that H2RAs may be a reasonable alternative in patients at lower risk for GI bleeding and in those who do not require PPI for refractory gastroesophageal reflux disease[12].

References

1. Strand, D. S., Kim, D., & Peura, D. A. (2017). 25 years of proton pump inhibitors: a comprehensive review. Gut and Liver, 11(1), 27–37.

2. Scott, S. A., Owusu Obeng, A., & Hulot, J. S. (2014). Antiplatelet drug interactions with proton pump inhibitors. Expert Opinion on Drug Metabolism & Toxicology, 10(2), 175–189.

3. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

4. Hulot, J. S., Collet, J. P., Silvain, J., Pena, A., Bellemain-Appaix, A., Barthélémy, O., Cayla, G., Beygui, F., & Montalescot, G. (2010). Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. Journal of the American College of Cardiology, 56(2), 134–143.

5. Siller-Matula, J. M., Jilma, B., Schrör, K., Christ, G., & Huber, K. (2010). Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. Journal of Thrombosis and Haemostasis: JTH, 8(12), 2624–2641.

6. Chen, M., Wei, J. F., Xu, Y. N., Liu, X. J., & Huang, D. J. (2012). A meta-analysis of impact of proton pump inhibitors on antiplatelet effect of clopidogrel. Cardiovascular Therapeutics, 30(5), e227–e233.

7. Huang, B., Huang, Y., Li, Y., Yao, H., Jing, X., Huang, H., & Li, J. (2012). Adverse cardiovascular effects of concomitant use of proton pump inhibitors and clopidogrel in patients with coronary artery disease: a systematic review and meta-analysis. Archives of Medical Research, 43(3), 212–224.

8. Stockl KM, Le L, Zakharyan A, et al. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med. 2010;170(8):704–710.

9. Tang J, Sharma U, Desai S, Molnar J, Perlmuter L, Feller A, Shah P. A Study of Proton Pump Inhibitors and Other Risk Factors in Warfarin-Associated Gastrointestinal Bleeding. Cureus. 2021 Jan 11;13(1):e12624. doi: 10.7759/cureus.12624.

10. Furtado RHM, Giugliano RP, Strunz CMC, Filho CC, Ramires JAF, Filho RK, Neto PAL, Pereira AC, Rocha TR, Freire BT, D'Amico EA, Nicolau JC. Drug Interaction Between Clopidogrel and Ranitidine or Omeprazole in Stable Coronary Artery Disease: A Double-Blind, Double Dummy, Randomized Study. Am J Cardiovasc Drugs. 2016 Aug;16(4):275-284. doi: 10.1007/s40256-016-0172-5.

11. Chen Z, Hong L, Wang H, et al Influence of ranitidine on gastrointestinal haemorrhage and thrombosis induced by dual antiplatelet therapy after percutaneous coronary interventionHeart 2011;97:A143-A144.

12. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, Scheiman J, Sperling LS, Tomaselli GF. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010;122:2619–2633.

13. Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, Claeys MJ, Dan GA, Dweck MR, Galbraith M, Gilard M, Hinterbuchner L, Jankowska EA, Jüni P, Kimura T, Kunadian V, Leosdottir M, Lorusso R, Pedretti RFE, Rigopoulos AG, Rubini Gimenez M, Thiele H, Vranckx P, Wassmann S, Wenger NK, Ibanez B; ESC Scientific Document Group. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023 Aug 25:ehad191. doi: 10.1093/eurheartj/ehad191.

14. Moukarbel, G. V., & Bhatt, D. L. (2012). Antiplatelet therapy and proton pump inhibition: clinician update. Circulation, 125(2), 375–380.