September 8, 2023

Mitigating Risks: Pharmacovigilance Urgently Required for Cardiovascular Patients on Proton Pump Inhibitors

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Since the Introduction of Proton Pump Inhibitors (PPIs)

Rationale for Adopting Gastroprotective Strategies in Cardiovascular Disease Patients

Cardiovascular disease (CVD) is the leading cause of mortality globally. Anti-platelet agents, such as clopidogrel, are widely prescribed to reduce cardiovascular events in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI).

Clopidogrel is 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 increases with DAPT.

Pressing Concern Related to Concomitant Administration of PPIs and DAPT

PPIs and clopidogrel have been found to interact due to their dependence on the cytochrome-P450 (CYP450) enzymes CYP2C19 and CYP3A4.

PPIs can inhibit the activity of CYP2C19, affecting the metabolism of clopidogrel.
Studies have reported impaired platelet inhibition when PPIs are taken with DAPT.
Non-randomized observational studies suggest increased risks of subsequent MI/ACS and major adverse cardiovascular events (MACE) in patients receiving clopidogrel and PPIs.

Clinical Evidence Substantiating the Antagonism of PPIs Towards Clopidogrel

Several meta-analyses and studies have suggested a potential antagonistic role of PPIs with clopidogrel:

Hulot et al. (meta-analysis) – PPI users displayed increased risk for MACE and mortality compared with nonusers.
Siller-Matula et al. (meta-analysis) – Administration of PPIs with clopidogrel corresponded to an increased risk of combined MACE and MI.
Chen et al. (study) – Observational studies showed a higher risk of clinical endpoints in patients using clopidogrel with PPIs compared to clopidogrel alone.
Huang et al. (meta-analysis) – Concomitant use of PPIs and clopidogrel is associated with an increased risk of major cardiovascular events and acute coronary syndrome.
Stockl et al. (retrospective study) – Patients receiving clopidogrel plus a PPI had a higher risk of rehospitalization for MI or coronary stent placement compared to patients receiving clopidogrel alone.

Clinical Evidence Substantiating the Antagonism of PPIs Towards Anticoagulants

A retrospective review analyzed the concomitant use of warfarin and PPIs, showing an increased incidence of GI bleeding in patients using both.

Using Ranitidine in Addition to Antiplatelet Treatment: Supporting Clinical Evidence

Ranitidine has shown potential in reducing the antagonistic effects of PPIs when used with antiplatelet therapy:

Ranitidine vs PPI over the effect of Clopidogrel (study) – Ranitidine did not influence platelet aggregability response to clopidogrel, unlike omeprazole.
Ranitidine Prevents GI Bleeding in Post-PCI DAPT-treated Patients (study) – Ranitidine can prevent dual antiplatelet drug-induced gastrointestinal bleeding complications.

Scientific Society Consensus for Prudent Use of PPIs with Antiplatelet Therapy

The American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the American Heart Association (AHA) recommend PPIs for patients at high risk of upper GI bleeding and those with a history of upper GI bleeding.