Skip to main content
Top
Published in: Cardiovascular Drugs and Therapy 6/2022

Open Access 09-07-2021 | Coronary Heart Disease | Original Article

Proton Pump Inhibitor and Clopidogrel Use After Percutaneous Coronary Intervention and Risk of Major Cardiovascular Events

Authors: John Maret-Ouda, Giola Santoni, Shaohua Xie, Annika Rosengren, Jesper Lagergren

Published in: Cardiovascular Drugs and Therapy | Issue 6/2022

Login to get access

Abstract

Purpose

Due to shared hepatic metabolism, concomitant medication with a proton pump inhibitor (PPI) and clopidogrel might reduce the effectiveness of clopidogrel in the prevention of cardiovascular events after percutaneous coronary intervention (PCI). We aimed to examine the risk of major cardiovascular events after PCI comparing patients who used clopidogrel together with PPI with those who used clopidogrel alone.

Methods

This Swedish nationwide cohort study included patients who received clopidogrel after primary PCI in 2005–2019. Patients were followed for up to 12 months after PCI. Data were retrieved from the Swedish Prescribed Drug Registry, Patient Registry, Cancer Registry, and Cause of Death Registry. Multivariable Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular events comparing PPI users (exposed) with non-users of PPI (non-exposed). The HRs were adjusted for sex, age, comorbidity, calendar period, obesity, diabetes, anti-diabetic medication, tobacco-related diseases, hypertension, and congestive heart failure.

Results

The cohort included 99,836 patients who received clopidogrel after primary PCI. Among these, 35,772 (35.8%) received concomitant PPI. 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 coronary heart disease (HR = 1.28, 95% CI 1.24–1.33), 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). The results were similar in analyses including both primary and secondary PCIs.

Conclusions

In patients who receive clopidogrel after PCI, concomitant use of PPI seems to increase the risk of major cardiovascular events.
Appendix
Available only for authorised users
Literature
1.
go back to reference O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-425.CrossRefPubMed O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-425.CrossRefPubMed
2.
go back to reference Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–77.CrossRefPubMed Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–77.CrossRefPubMed
3.
go back to reference Demcsak A, Lantos T, Balint ER, Hartmann P, Vincze A, Bajor J, et al. PPIs are not responsible for elevating cardiovascular risk in patients on clopidogrel-A systematic review and meta-analysis. Front Physiol. 2018;9:1550.CrossRefPubMedPubMedCentral Demcsak A, Lantos T, Balint ER, Hartmann P, Vincze A, Bajor J, et al. PPIs are not responsible for elevating cardiovascular risk in patients on clopidogrel-A systematic review and meta-analysis. Front Physiol. 2018;9:1550.CrossRefPubMedPubMedCentral
4.
go back to reference Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen M, et al. Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry. Circulation. 2011;123(5):474–82.CrossRefPubMed Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen M, et al. Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry. Circulation. 2011;123(5):474–82.CrossRefPubMed
5.
go back to reference Charlot M, Ahlehoff O, Norgaard ML, Jorgensen CH, Sorensen R, Abildstrom SZ, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010;153(6):378–86.CrossRefPubMed Charlot M, Ahlehoff O, Norgaard ML, Jorgensen CH, Sorensen R, Abildstrom SZ, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010;153(6):378–86.CrossRefPubMed
6.
go back to reference Xie SH, Santoni G, Mattsson F, Ness-Jensen E, Lagergren J. Cohort profile: the Swedish Prescribed Drugs and Health Cohort (SPREDH). BMJ Open. 2019;9(1):e023155.CrossRefPubMedPubMedCentral Xie SH, Santoni G, Mattsson F, Ness-Jensen E, Lagergren J. Cohort profile: the Swedish Prescribed Drugs and Health Cohort (SPREDH). BMJ Open. 2019;9(1):e023155.CrossRefPubMedPubMedCentral
7.
go back to reference Maret-Ouda J, Tao W, Wahlin K, Lagergren J. Nordic registry-based cohort studies: Possibilities and pitfalls when combining Nordic registry data. Scand J Public Health. 2017;45(17_suppl):14–9.CrossRefPubMed Maret-Ouda J, Tao W, Wahlin K, Lagergren J. Nordic registry-based cohort studies: Possibilities and pitfalls when combining Nordic registry data. Scand J Public Health. 2017;45(17_suppl):14–9.CrossRefPubMed
9.
go back to reference Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.CrossRefPubMedPubMedCentral Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.CrossRefPubMedPubMedCentral
11.
go back to reference Barlow L, Westergren K, Holmberg L, Talback M. The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta Oncol. 2009;48(1):27–33.CrossRefPubMed Barlow L, Westergren K, Holmberg L, Talback M. The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta Oncol. 2009;48(1):27–33.CrossRefPubMed
12.
go back to reference Brusselaers N, Vall A, Mattsson F, Lagergren J. Tumour staging of oesophageal cancer in the Swedish Cancer Registry: a nationwide validation study. Acta Oncol. 2015;54(6):903–8.CrossRefPubMed Brusselaers N, Vall A, Mattsson F, Lagergren J. Tumour staging of oesophageal cancer in the Swedish Cancer Registry: a nationwide validation study. Acta Oncol. 2015;54(6):903–8.CrossRefPubMed
13.
go back to reference Brooke HL, Talback M, Hornblad J, Johansson LA, Ludvigsson JF, Druid H, et al. The Swedish cause of death register. Eur J Epidemiol. 2017;32(9):765–73.CrossRefPubMedPubMedCentral Brooke HL, Talback M, Hornblad J, Johansson LA, Ludvigsson JF, Druid H, et al. The Swedish cause of death register. Eur J Epidemiol. 2017;32(9):765–73.CrossRefPubMedPubMedCentral
14.
go back to reference Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–17.CrossRefPubMed Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–17.CrossRefPubMed
15.
go back to reference Pello Lazaro AM, Cristobal C, Franco-Pelaez JA, Tarin N, Acena A, Carda R, et al. Use of proton-pump inhibitors predicts heart failure and death in patients with coronary artery disease. PLoS One. 2017;12(1):e0169826.CrossRefPubMedPubMedCentral Pello Lazaro AM, Cristobal C, Franco-Pelaez JA, Tarin N, Acena A, Carda R, et al. Use of proton-pump inhibitors predicts heart failure and death in patients with coronary artery disease. PLoS One. 2017;12(1):e0169826.CrossRefPubMedPubMedCentral
16.
go back to reference Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008;51(3):256–60.CrossRefPubMed Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008;51(3):256–60.CrossRefPubMed
17.
go back to reference Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004;32(8):821–7.CrossRefPubMed Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004;32(8):821–7.CrossRefPubMed
18.
go back to reference Wang Y, Zhao X, Lin J, Li H, Johnston SC, Lin Y, et al. Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. JAMA. 2016;316(1):70–8.CrossRefPubMed Wang Y, Zhao X, Lin J, Li H, Johnston SC, Lin Y, et al. Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. JAMA. 2016;316(1):70–8.CrossRefPubMed
19.
go back to reference Klein MD, Lee CR, Stouffer GA. Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions. Pharmacogenomics. 2018;19(13):1039–46.CrossRefPubMed Klein MD, Lee CR, Stouffer GA. Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions. Pharmacogenomics. 2018;19(13):1039–46.CrossRefPubMed
20.
go back to reference Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, et al. 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. J Am Coll Cardiol. 2010;56(24):2051–66.CrossRefPubMed Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, et al. 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. J Am Coll Cardiol. 2010;56(24):2051–66.CrossRefPubMed
Metadata
Title
Proton Pump Inhibitor and Clopidogrel Use After Percutaneous Coronary Intervention and Risk of Major Cardiovascular Events
Authors
John Maret-Ouda
Giola Santoni
Shaohua Xie
Annika Rosengren
Jesper Lagergren
Publication date
09-07-2021
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 6/2022
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07219-6

Other articles of this Issue 6/2022

Cardiovascular Drugs and Therapy 6/2022 Go to the issue