Does co-prescribing proton-pump inhibitors affect the efficacy of clopidogrel in secondary prevention of cardiovascular events?
Date First Published:
March 10, 2026
Last Updated:
March 10, 2026
Report by:
Monika Sramkova, Polina Nikolaeva, ED Registrar, ED clinical fellow (Jersey General Hospital)
Search checked by:
Vishal Patel, ED Associate Specialist
Three-Part Question:
Does co-prescribing [proton-pump inhibitors] affect the efficacy of [clopidogrel] in secondary prevention of [cardiovascular events]?
Clinical Scenario:
A 64-year-old man presented with indigestion and reflux symptoms, on a background of a previously documented gastric ulcer on endoscopy. An upper gastrointestinal bleed was ruled out, and a diagnosis of gastritis was made. He had undergone percutaneous coronary intervention with stent placement eight months prior and was on dual antiplatelet therapy with clopidogrel and aspirin for secondary prevention of coronary artery disease.
Search Strategy:
PubMed Medline (1946 to July 2025), EMBASE (1974 to July 2025), Cochrane Database of Systematic Reviews. Search terms included: "clopidogrel”, “omeprazole", "proton pump inhibitors", "gastritis", "gastro-oesophageal reflux disease", "peptic ulcer disease ", “cardiovascular events”
Search Details:
Studies were included only if they met the following inclusion criteria:
• Adult patients (>18 years old)
• Patients were taking PPIs prior, during and/or a period after starting clopidogrel after their index event
• Period of follow up was up to a year
• Adult patients (>18 years old)
• Patients were taking PPIs prior, during and/or a period after starting clopidogrel after their index event
• Period of follow up was up to a year
Outcome:
From over 1000 articles screened on PubMed, 8 high fidelity studies were identified high grade studies including 1 meta-analyses, 2 randomised controlled trial, 4 cohort studies and 2 case-control studies.
The focus was on cardiovascular events, including acute coronary syndrome, death and ischaemic stroke.
The focus was on cardiovascular events, including acute coronary syndrome, death and ischaemic stroke.
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| A population-based study of the drug interaction between proton pump inhibitors and clopidogrel DN Juurlink, T. Homes, DT Ko, PE. Szmitko, PC Austin, JV Tu, DA Henry, A. Kopp, MM Mamdani. 2009 Canada | Case-control study with 13 636 patients all prescribed clopidogrel after an acute myocardial infarction. Median age for 77 and 52% Male. Case group: 148/734 were CYP1A2 inhibitor and Control group 299/2057 | Case-Control Study | Readmission dates with acute myocardial infarction up to maximum 90 days. | 734 cases readmitted with MI with 2057 controls. | They didn’t accommodate for cardiac risk factors such as smoking, lipoproteins and BP |
| Concurrent use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted OR 1.27, 95% CI 1.03-1.57]. | |||||
| Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. P M Ho, TM. Maddox, Li Wang, SD. Finn, RL. Jesse, E. Peterson, JS. Rumsfeld. March 4, 2009 United States of America | Retrospective, multicentre cohort study of 8205 patients (all on clopidogrel), 63.9% given PPI (unspecified). | Cohort Study | All-cause mortality or rehospitalization for ACS (MI or unstable angina) following index hospital discharge for ACS | Death or rehospitalization for ACS occurred in 20.8% patients taking clopidogrel without PPI and 29.8% of patients taking clopidogrel plus PPI. | Observational study design causing recall bias |
| Use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI AOR, 1.25; 95% CI, 1.11-1.41 | |||||
| Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome JA Rassen, NK Choudhry, J Avorn, S. Schneeweiss 23rd November 2009 American | 3 large cohort studies (patient >65 years)- total 18,565 clopidogrel patients. PPI were mixed in 21 days before admission and/or 7 days after discharge | Cohort study | Primary end point of myocardial infarction hospitalization or death up to 180 day follow up period | The propensity score–adjusted rate ratio for the primary end point of myocardial infarction or death was 1.22 (95% CI 0.99 to 1.51); and for revascularization, 0.97 (95% CI 0.79 to 1.21) | Confounders as those patients taking PPI may have more comorbidities |
| Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials ML O’Donoghue, E. Braunwalkd, EM Antman, SA. Murphy, ER. Bates, Y. Rozenman, AD. Michelson,RW. Hautvast, PN. Ver Lee, SL. Close, L. Shen, JL. Mega, MS. Sabatine, SD. Wiviott. 19th September 2009 Worldwide | PRINCIPLE-TMI 44 201 ACS patients RCT trial (99 patients had clopidogrel for elective PCI, rest tricagrelor) TRITON-TIMI 38 trial 13608 ACS patients RCT(6795 clopidogrel, rest tricagrelor). In both PPI was unspecified | Sub-analysis of two randomised control trials | Composite of cardiovascular death, myocardial infarction, or stroke.. | No association existed between PPI use and risk of the primary endpoint for patients treated with clopidogrel (adjusted hazard ratio [HR] 0·94, 95% CI 0·80–1·11) | In both studies, PPI use was at physician’s discretion. Both underpowered (Type 2 error) to show association, if a relation exist. |
| Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis JM. Siller-Matula, B. Jilma, K. Schoro, G. Christ, K. Huber 10 September 2010 Austria | Twenty-five studies met selection criteria and included 159 138 patients | Systematic Review and Meta-analyses | Combined major adverse cardiac events (MACE), myocardial infarction (MI), stent thrombosis, and death | Administration of PPIs together with clopidogrel corresponded to a 29% increased risk of combined major cardiovascular events [RR= 1.29, 95% CI = 1.15–1.45 | Mainly observational studies that have recall biases or confounders Majority were unpowered to show any clinically significant differences (type 2 error) |
| 31% increased risk of MI (RR = 1.31, 95% CI = 1.12–1.53) | |||||
| PPI use did not negatively influence the mortality (RR = 1.04, 95% CI = 0.93–1.16) | |||||
| Clopidogrel with or without Omeprazole in Coronary Artery Disease DL.Bhatt, BL. Cryer, CF. Contant, M. Cohen, A. Lanas, TJ. Scnitzer, TL. Shook, P. Lapuerta, MA. Goldsmith, L. Laine, BM. Scirica, SA. Murphy, CP. Cannon 11 November 2010 Worldwide | 3873 patients (3761 analysed in the end). Median Age 68.5, Sex 66% males, follow up 106 days PCI used was Omeprazole | Randomised Control Trial | Composite of death from cardiovascular causes, nonfatal MI or ischaemic strokes (180 days) | Adjusted cardiovascular events (54 in placebo group and 55 in omeprazole). 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P=0.96); high-risk subgroups did not show significant heterogeneity | The confidence interval around the hazard ratio for cardiovascular events is wide, the absence of interaction is not a definitive finding |
| There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. | |||||
| Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor Insights From the Platelet Inhibition and Patient Outcomes Trial. SG. Goodman, R. Clare, KS. Pieper, JC. Nicolau, RF. Storey, WJ. Cantor, KW. Mahaffey, DJ. Angiolillo, S. Husted, CP. Cannon, SK. James, J. Kilhamn, PG. Steg, RA. Harrington, L. Wallentin 18th January 2012 America | Nonrandomised trial of the Platelet Inhibition and Patient Outcomes (PLATO) trial of 18 624 patients with ACS 9291 patients received clopidogrel, rest tricagrelor Unspecified PPI | Nonrandomised trial | PPI use and 1-year cardiovascular events (death, stroke, ACS) up to 12 months | The primary end point rates were higher for individuals on a PPI (n= 6539) compared with those not on a PPI (n= 12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04 –1.38) | Use of a PPI was not randomized, thereby, the potential for unmeasured was a confounder In some cases, PPIs was discontinued during follow-up, and this wasn’t accounted for |
| Proton Pump Inhibitor and Clopidogrel Use After Percutaneous Coronary Intervention and Risk of Major Cardiovascular Events Events J Maret- Ouda, G. Santoni, S. Xie, A. Rosengren, J. Lagergren July 2021 Sweden | Swedish cohort 99836 patients had primary PCI All patients had clopidogrel after PCI (35.8% received concomitant PPI). PPI unspecified | Cohort Study | Main outcome: Myocardial infarction, Secondary Outcomes: stroke/death | Compared to non-users, PPI users had increased adjusted HRs of all study outcomes, i.e., the main outcome myocardial infarction (HR=1.23, 95% CI 1.15–1.32) and the secondary outcomes stroke (HR=1.21, 95% CI 1.05–1.40), and death due to coronary heart disease (HR=1.52, 95% CI 1.37–1.69) | Confounders such as diet and physical activity were not adjusted for |
| Follow up: 12 months | |||||
| In patients who receive clopidogrel after PCI, concomitant use of PPI seems to increase the risk of major cardiovascular event | |||||
| Effects of treatment with clopidogrel with or without proton pump inhibitor omeprazole on the risk of ischemic stroke: a nationwide cohort study CC. Chang, Y-C. Chou, J-Y. Chang, C-A. Sun 19th January 2024 Taiwan | Retrospective cohort study in Taiwan 407 patients with ACS and exposed cohort (concomitant use of clopidogrel and omeprazole) vs 814 patients with ACS (comparison cohort (single use clopidogrel) Ischaemic stroke in patients with clopidogrel + omeprazole (227/2739, HR 1.39 (CI 1.03-1.74) | Retrospective Cohort Study | Ischaemic Stroke | The incidence rate of IS was significantly higher in the exposed cohort (81.67 per 1000 person-years) than in the comparison cohort (57.45 per 1000 person-years), resulting in an adjusted HR of 1.39 (95% CI 1.03–1.74) | No data on risk factors such as smoking, BP and obesity, opening to confounders Recall bias |
| Follow up: 12 months |
Author Commentary:
Clopidogrel is a prodrug and is converted to its active form by drug metabolising enzymes, including CYP1A2 in the liver. Proton-Pump inhibitors (PPI) are also metabolised by this enzyme although to a varying degree (Omeprazole and Lansoprazole are the strongest inducers and rest are weaker varying strengths).
Pharmacokinetic studies show there is 30% reduction in mean inhibition of platelet aggregation when omeprazole (for example) was given concurrently as clopidogrel.
Conclusive evidence of a clinically significant interaction of co-prescribing proton pump inhibitors (regardless of type) with clopidogrel in causing secondary cardiovascular events was not established.
Some of the studies did show slight increased risk, but this was not statistically significant.
Most studies were underpowered and retrospective in design, making them susceptible to recall bias, and several did not adequately account for important confounders such as smoking and obesity.
There was heterogeneity in the data collection and analysis as some studies looked at omeprazole only and others didn’t specify the PPI in question. Some studies looked at all-cause mortality (including strokes), whereas others only looked at cardiovascular events.
Pharmacokinetic studies show there is 30% reduction in mean inhibition of platelet aggregation when omeprazole (for example) was given concurrently as clopidogrel.
Conclusive evidence of a clinically significant interaction of co-prescribing proton pump inhibitors (regardless of type) with clopidogrel in causing secondary cardiovascular events was not established.
Some of the studies did show slight increased risk, but this was not statistically significant.
Most studies were underpowered and retrospective in design, making them susceptible to recall bias, and several did not adequately account for important confounders such as smoking and obesity.
There was heterogeneity in the data collection and analysis as some studies looked at omeprazole only and others didn’t specify the PPI in question. Some studies looked at all-cause mortality (including strokes), whereas others only looked at cardiovascular events.
Bottom Line:
As our patient was at risk of gastrointestinal bleeding (given he had previous gastric ulcers) and he had the recent acute coronary syndrome, he was prescribed nizatidine, a H2 receptor antagonist, with follow up with the gastroenterologist.
Level of Evidence:
Level 1: Recent well-done systematic review was considered or a study of high quality is available
References:
- DN Juurlink, T. Homes, DT Ko, PE. Szmitko, PC Austin, JV Tu, DA Henry, A. Kopp, MM Mamdani.. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel
- P M Ho, TM. Maddox, Li Wang, SD. Finn, RL. Jesse, E. Peterson, JS. Rumsfeld.. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome.
- JA Rassen, NK Choudhry, J Avorn, S. Schneeweiss. Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome
- ML O’Donoghue, E. Braunwalkd, EM Antman, SA. Murphy, ER. Bates, Y. Rozenman, AD. Michelson,RW. Hautvast, PN. Ver Lee, SL. Close, L. Shen, JL. Mega, MS. Sabatine, SD. Wiviott.. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials
- JM. Siller-Matula, B. Jilma, K. Schoro, G. Christ, K. Huber. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis
- DL.Bhatt, BL. Cryer, CF. Contant, M. Cohen, A. Lanas, TJ. Scnitzer, TL. Shook, P. Lapuerta, MA. Goldsmith, L. Laine, BM. Scirica, SA. Murphy, CP. Cannon. Clopidogrel with or without Omeprazole in Coronary Artery Disease
- SG. Goodman, R. Clare, KS. Pieper, JC. Nicolau, RF. Storey, WJ. Cantor, KW. Mahaffey, DJ. Angiolillo, S. Husted, CP. Cannon, SK. James, J. Kilhamn, PG. Steg, RA. Harrington, L. Wallentin. Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor Insights From the Platelet Inhibition and Patient Outcomes Trial.
- Events J Maret- Ouda, G. Santoni, S. Xie, A. Rosengren, J. Lagergren. Proton Pump Inhibitor and Clopidogrel Use After Percutaneous Coronary Intervention and Risk of Major Cardiovascular Events
- CC. Chang, Y-C. Chou, J-Y. Chang, C-A. Sun. Effects of treatment with clopidogrel with or without proton pump inhibitor omeprazole on the risk of ischemic stroke: a nationwide cohort study