1
|
Jourdi G, Hulot JS, Gaussem P. An update on oral antiplatelet drug interactions with proton pump inhibitors: what are the risks? Expert Opin Drug Metab Toxicol 2024:1-16. [PMID: 38980768 DOI: 10.1080/17425255.2024.2378888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/08/2024] [Indexed: 07/11/2024]
Abstract
INTRODUCTION Aspirin and anti-P2Y12 are widely prescribed in cardiovascular patients, often in combination with proton pump inhibitors (PPIs) to limit the risk of upper gastrointestinal bleedings. The potential interaction between PPIs and antiplatelet agents has been widely discussed, but doubts remain as to whether PPIs may reduce the cardiovascular protection provided by aspirin, prasugrel, ticagrelor, and clopidogrel. AREAS COVERED Many pharmacokinetic (PK) and pharmacodynamic (PD) studies have confirmed the interaction, especially between PPIs and clopidogrel, but with uncertain consequences on clinical outcomes. Therefore, we aimed to summarize the evidence for the widespread combined use of oral antiplatelet drugs and PPIs, to outline the current evidence supporting or opposing drug-drug interaction, and to discuss the clinical implications of such interactions. EXPERT OPINION A large body of evidence describes the PK/PD interaction of antiplatelet drugs with PPIs and its potential role in increasing clinical cardiovascular adverse events, but no solid clinical data have confirmed these effects. In the light of the published studies, there seems to be no restriction on the choice of PPI with aspirin, prasugrel, and/or ticagrelor. The choice of a PPI with no (or minimal) interference with the hepatic cytochrome P450 2C19 is preferred in patients receiving clopidogrel.
Collapse
Affiliation(s)
- Georges Jourdi
- Faculté de Pharmacie de Paris, Université Paris Cité, Inserm, Innovative Therapies in Haemostasis, UMR_S1140, Paris, France
- Laboratory of haematology, Lariboisière University hospital, Paris, France
| | - Jean-Sébastien Hulot
- Université Paris Cité, Inserm, Paris Cardiovascular Research center, UMR_S970, Paris, France
- Clinical investigation center (CIC1418), Hôpital Européen Georges Pompidou, Paris, France
| | - Pascale Gaussem
- Laboratory of haematology, Hôpital Européen Georges Pompidou, Paris, France
| |
Collapse
|
2
|
Das S, Samajdar SS, Mukherjee S, Sarkar S, Sen S, Pathak A, Lundborg CS, Selvarajan S, Tripathi SK, Pal J, Chatterjee N, Joshi SR. Ten clinical pharmacological interventions in routine care to ensure better treatment outcomes. INTERNATIONAL JOURNAL OF PHARMACY PRACTICE 2023:7146135. [PMID: 37105526 DOI: 10.1093/ijpp/riad032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Affiliation(s)
- Saibal Das
- Indian Council of Medical Research, Centre for Ageing and Mental Health, Kolkata, India
- Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
| | - Shambo Samrat Samajdar
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
| | - Shatavisa Mukherjee
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
| | - Sougata Sarkar
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
| | - Sumalya Sen
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
| | - Ashish Pathak
- Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, RD Gardi Medical College, Ujjain, India
| | | | - Sandhiya Selvarajan
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | | | - Jyotirmoy Pal
- Department of Medicine, RG Kar College and Hospital, Kolkata, India
| | - Nandini Chatterjee
- Department of Medicine, Institute of Postgraduate Medical Education and Research and SSKM Hospital, Kolkata, India
| | | |
Collapse
|
3
|
Xu H, Yu Q, Zhou H, Yang J, Zheng N, Xu Z, Su J. Polymorphisms in the GCK gene increase the risk of clopidogrel resistance in stable coronary artery disease (SCAD) patients. ACTA ACUST UNITED AC 2021; 26:447-452. [PMID: 34165031 DOI: 10.1080/16078454.2021.1945789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Diabetes mellitus is a major factor in clopidogrel resistance (CR), and the glucokinase (GCK) gene plays a pivotal role in glucose homeostasis. This study investigated the contribution of GCK polymorphisms to CR risk. METHODS Two hundred SCAD patients were recruited, and their platelet functions were detected by the Verify-Now P2Y12 assay. The polymorphisms of GCK were tested based on the methods of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We investigated the associations of GCK polymorphisms and CR. Multivariate logistic regression was performed to analyse the correlations between GCK polymorphisms and clinical values. RESULTS Our study found that the SNPs rs4607517 and rs6975024 were associated with CR. Additionally, patients with the G allele of rs4607517had a greater CR risk, but the C allele of rs6975024 might be a protective factor. Finally, logistic regression revealed that CC + TC (rs6975024) as well as the values of albumin were correlated with a decreased risk of CR, and higher levels of uric acid (UA) may be positively associated with CR. CONCLUSION The GCK gene polymorphisms might increase the CR risk in SCAD patients. Meanwhile, higher albumin levels and lower UA values might decrease the risk.
Collapse
Affiliation(s)
- Hongyu Xu
- Department of Geratology, Ningbo No. 1 Hospital, Ningbo, People's Republic of China
| | - Qinglin Yu
- Department of Traditional Chinese Internal Medicine, Ningbo No. 1 Hospital, Ningbo, People's Republic of China
| | - Honglin Zhou
- Department of Cardiology, Ningbo No. 1 Hospital, Ningbo, People's Republic of China
| | - Jin Yang
- Department of Cardiology, Ningbo No. 1 Hospital, Ningbo, People's Republic of China
| | - Nan Zheng
- Department of Cardiology, Ningbo No. 1 Hospital, Ningbo, People's Republic of China
| | - Zhifeng Xu
- Department of Cardiology, Zhenhai People's Hospital of Zhejiang Province, Ningbo, People's Republic of China
| | - Jia Su
- Department of Cardiology, Ningbo No. 1 Hospital, Ningbo, People's Republic of China
| |
Collapse
|
4
|
Catapano JS, Srinivasan VM, Wakim AA, Lundberg JN, Rutledge C, Cole TS, Baranoski JF, Fredrickson VL, Rahmani R, Albuquerque FC, Ducruet AF. Omeprazole-clopidogrel interaction and neurovascular complications after flow-diverter device placement. J Neurointerv Surg 2021; 14:380-383. [PMID: 34083398 DOI: 10.1136/neurintsurg-2021-017397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 05/10/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Omeprazole is a common proton pump inhibitor that interferes with the hepatic activation of clopidogrel and potentially reduces its platelet-inhibitory effect. Omeprazole has been shown to increase P2Y12 levels and adverse cardiovascular outcomes in patients treated with drug-eluting stents. However, omeprazole use among patients treated with flow-diverting stents for intracranial aneurysms has not been evaluated. METHODS All patients with placement of a flow-diverting device for treatment of an intracranial aneurysm at a tertiary institution from January 1, 2014, to December 31, 2018, were retrospectively analyzed. Inclusion criteria included documented clopidogrel administration, available P2Y12 levels, and thorough documentation of administration of other medications, including omeprazole. RESULTS A total of 138 patients met the inclusion criteria. Sixteen patients (12%) were receiving omeprazole and clopidogrel at treatment. P2Y12 reactivity was significantly greater in the omeprazole cohort (mean P2Y12 level, 250 P2Y12 reaction units (PRU)) than in the control cohort (mean P2Y12 level, 112PRU) (P<0.001). Furthermore, a greater proportion of patients had a P2Y12 level >180 PRU in the omeprazole cohort (14 of 16 [88%] vs 24 of 122 [20%]; P<0.001; OR [95% CI], 29 [6-134]). CONCLUSION Omeprazole was associated with a significant increase in the mean P2Y12 reactivity level among patients with intracranial aneurysms treated with flow-diverting devices who received clopidogrel. However, receipt of omeprazole was not associated with an increased risk of ischemic events or stent stenosis. For neuroendovascular patients who are treated with a flow diverter while receiving clopidogrel, alternative gastrointestinal medication regimens should be considered.
Collapse
Affiliation(s)
- Joshua S Catapano
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Visish M Srinivasan
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Andre A Wakim
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Jaclyn N Lundberg
- Department of General Medicine, Creighton University School of Medicine, Phoenix Health Sciences Campus, Phoenix, Arizona, USA
| | - Caleb Rutledge
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Tyler S Cole
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Jacob F Baranoski
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Vance L Fredrickson
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Redi Rahmani
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Felipe C Albuquerque
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Andrew F Ducruet
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| |
Collapse
|
5
|
He W, Shu X, Zhu E, Deng B, Lin Y, Wu X, Zhou Z, Wang J, Nie R. Intermittent concurrent use of clopidogrel and proton pump inhibitors did not increase risk of adverse clinical outcomes in Chinese patients with coronary artery disease. BMC Cardiovasc Disord 2021; 21:75. [PMID: 33546595 PMCID: PMC7863361 DOI: 10.1186/s12872-021-01884-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 01/11/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are frequently prescribed to patients with coronary heart disease (CHD) under antiplatelet therapy to prevent gastrointestinal (GI) bleeding. However, its clinical impact is still under debate, especially in Asian population. This study was undertaken to explore the effects of concurrent use of clopidogrel and PPIs on the clinical outcomes in Chinese patients with CHD in secondary prevention. METHODS A single-center retrospective study was conducted in 638 patients with CHD on consecutive clopidogrel therapy for at least 1 year. After 18-month follow-up, adverse clinical events were collected. Cox regression was used to calculate hazard ratios (HR) and 95% confidence interval (CI) for the effect of PPI use on the outcomes. A total of 638 patients were recruited from 2014 to 2015 in this study, among whom 201 were sustained PPI users, 188 were intermittent PPI users and the remaining 249 were non-PPI users. RESULTS Compared with sustained PPI users, intermittent use of PPIs was associated with a lower risk of stroke, major adverse cardiac events (MACE) and net adverse clinical event (NACE) (stroke: adjusted HR: 0.109, 95% CI 0.014-0.878, p = 0.037; MACE: adjusted HR: 0.293, 95% CI 0.119-0.722; p = 0.008; NACE: adjusted HR: 0.357, 95% CI 0.162-0.786, p = 0.011). Subgroup analysis further revealed the benefit of intermittent PPI use was significant in male CHD patients over 60 years old, with hypertension or chronic kidney disease, and undergoing percutaneous coronary intervention during hospitalization. CONCLUSION The current findings suggest that the intermittent concurrent use of PPIs and clopidogrel is not associated with an increased risk of 18-month adverse clinical outcomes, and intermittent use of PPIs is associated with a lower rate of MACE and NACE.
Collapse
Affiliation(s)
- Wanbing He
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Xiaorong Shu
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Enyi Zhu
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Bingqing Deng
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Yongqing Lin
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Xiaoying Wu
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Zenan Zhou
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Jingfeng Wang
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China
| | - Ruqiong Nie
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, 107 Yanjiang West Rd., Guangzhou, 510120, Guangdong Province, China.
| |
Collapse
|
6
|
Drug-Drug Interactions in Acute Coronary Syndrome Patients: Systematic Review. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2019. [DOI: 10.2478/sjecr-2019-0070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Drug-drug interaction (DDI) is defined as a clinically significant change in the exposure and/or response to a drug caused by co-administration of another drug which may result in a precipitation of an adverse event or alteration of its therapeutic effects. The aim of this systematic review was to provide an overview of DDIs that were actually observed or evaluated in acute coronary syndrome (ACS) patients with particular focus on DDIs with clinical relevance. Electronic searches of the literature were conducted in the following databases: MEDLINE, EBSCO, Scopus, Google Scholar and SCIndeks. A total of 117 articles were included in the review. This review showed that ACS patients can be exposed to a variety of DDIs with diverse outcomes which include decreased efficacy of antiplatelet drugs, thrombolytics or anticoagulants, increased risk of bleeding, rhabdomyolysis, hepatotoxicity, adverse effects on cardiovascular system (e.g. QT interval prolongation, arrhythmias, excessive bradycardia, severe hypotension), serotonin syndrome and drug-induced fever. Majority of the DDIs involved antiplatelet drugs (e.g. aspirin, clopidogrel and ticagrelor). Evidence of some of the reported DDIs is inconclusive as some of the studies have shown conflicting results. There is a need for additional post-marketing and population-based studies to evaluate the true effects of disease states and other factors on the clinical outcomes of DDIs. Clinicians should be attentive to the potential for DDIs and their associated harm in order to minimize or, if possible, avoid medication-related adverse events in ACS patients.
Collapse
|
7
|
Different Clopidogrel Response Elicited by Lansoprazole or Esomeprazole in Patients Undergoing Neurointervention with Dual Antiplatelet Therapy. Clin Drug Investig 2019; 39:939-944. [PMID: 31267433 DOI: 10.1007/s40261-019-00821-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Aspirin-clopidogrel dual antiplatelet therapy and a proton-pump inhibitor are used worldwide to prevent thromboembolism and peptic ulceration in patients undergoing neurointervention. We performed VerifyNow assays (Accumetrics, San Diego, CA, USA) to retrospectively examine the relationship between the effectiveness of antiplatelet agents and different proton-pump inhibitor types. METHODS Sixty-four patients with unruptured intracranial aneurysm scheduled for neurointervention received aspirin-clopidogrel dual antiplatelet therapy plus the proton-pump inhibitor lansoprazole (n = 34) or esomeprazole (n = 30). A low response to aspirin and clopidogrel was defined in terms of aspirin reaction units > 550 and P2Y12 reaction units ≥ 230, respectively, by VerifyNow assay. The characteristics, response to antiplatelet therapy, and clinical outcomes were compared in patients treated with lansoprazole or esomeprazole. RESULTS The preoperative mean VerifyNow aspirin reaction units and P2Y12 reaction units were 466.0 ± 67.3 and 205.0 ± 67.6, respectively. The mean aspirin reaction unit value was 482.0 ± 64.1 in the lansoprazole group, and 461.5 ± 70.9 in the esomeprazole group (p = 0.77). The mean P2Y12 reaction unit was 220.0 ± 64.4 in the lansoprazole group, and 174.5 ± 65.0 in the esomeprazole group; there was a significant difference in the clopidogrel response of patient treated with lansoprazole or esomeprazole (p = 0.005). CONCLUSIONS Our VerifyNow assay results suggest that when on lansoprazole fewer patients achieved the therapeutic goal and required extra therapy before neurointervention.
Collapse
|
8
|
Kagami T, Yamade M, Suzuki T, Uotani T, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Umemura K, Miyajima H, Furuta T. Comparative Study of Effects of Vonoprazan and Esomeprazole on Antiplatelet Function of Clopidogrel or Prasugrel in Relation to CYP2C19 Genotype. Clin Pharmacol Ther 2018; 103:906-913. [PMID: 28875498 DOI: 10.1002/cpt.863] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 08/08/2017] [Accepted: 08/26/2017] [Indexed: 12/12/2022]
Abstract
Drug-drug interaction between antiacid and antiplatelet agents has not been fully elucidated. Vonoprazan, a new potassium competitive acid blocker, has been available in Japan. CYP2C19 and CYP3A4 are involved in the metabolism of clopidogrel, prasugrel, esomeprazole, and vonoprazan. Using a P2Y12 assay, we compared the effects of vonoprazan and esomeprazole on the antiplatelet functions of clopidogrel or prasugrel in 31 healthy Japanese volunteers (14 CYP2C19 homo-extensive (homo-EMs), nine hetero-extensive (hetero-EMs), and eight poor metabolizers (PMs)). Vonoprazan decreased the median inhibition of platelet aggregation (IPA) values of clopidogrel and prasugrel more potently than esomeprazole (P < 0.001 for clopidogrel and P = 0.011 for prasugrel). The same tendencies were observed when stratified by CYP2C19 genotype groups (P = 0.004 in homo-EMs, 0.033 in hetero-EMs, and 0.043 in PMs). Vonoprazan attenuated the antiplatelet function of clopidogrel more potently than esomeprazole. Esomeprazole did not affect that of prasugrel irrespective of CYP2C19 genotype.
Collapse
Affiliation(s)
- Takuma Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Suzuki
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Uotani
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuo Umemura
- Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
| |
Collapse
|
9
|
Lee H, Koo BK, Park KW, Shin ES, Lim SW, Rha SW, Bae JW, Jeon DW, Oh SK, Hur SH, Kim BS, Lee JH, Park TH, Lee NH, Kim HS. A randomized clinical trial comparing long-term clopidogrel vs aspirin monotherapy beyond dual antiplatelet therapy after drug-eluting coronary stent implantation: Design and rationale of the Harmonizing Optimal Strategy for Treatment of coronary artery stenosis-Extended Antiplatelet Monotherapy (HOST-EXAM) trial. Am Heart J 2017; 185:17-25. [PMID: 28267471 DOI: 10.1016/j.ahj.2016.12.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Accepted: 12/01/2016] [Indexed: 01/21/2023]
Abstract
Percutaneous coronary intervention (PCI) has been developed by drug-eluting stent (DES), but stent implantation has brought the issue of stent thrombosis and optimal antiplatelet therapy. Guidelines recommend at least 6- to 12 months of dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor such as clopidogrel. Beyond DAPT after PCI with DES, however, there has been still a debate for antiplatelet regimen. Therefore, we report on the upcoming HOST-EXAM trial (NCT02044250), which will evaluate the efficacy and safety of aspirin and clopidogrel monotherapies beyond DAPT after DES implantation. TRIAL DESIGN The HOST-EXAM is a prospective, randomized, open-label, multicenter, comparative effectiveness trial, to compare between clopidogrel (75 mg once daily) and aspirin (100 mg once daily) as long-term antiplatelet agents. A total of 5,530 patients with no clinical events during combined antiplatelet therapy for 12±6 months after index PCI will be screened, enrolled, and randomized to either group (1:1 ratio) receiving antiplatelet monotherapy for 2 years. The primary endpoint will be the rate of clinical events defined as a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, or major bleeding at 24 months after randomization. CONCLUSIONS The HOST-EXAM will be the first large-scale randomized controlled study to directly compare the efficacy and safety of long-term antiplatelet monotherapy beyond DAPT after DES implantation. This study will provide clinical evidence to establish optimal regimen for long-term antiplatelet therapy after DES implantation.
Collapse
Affiliation(s)
- Heesun Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Bon-Kwon Koo
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cardiovascular Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyung Woo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cardiovascular Center, Seoul National University Hospital, Seoul, Republic of Korea
| | | | - Sang Wook Lim
- CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Seung-Woon Rha
- Korea University Guro Hospital, Seoul, Republic of Korea
| | - Jang-Whan Bae
- Chungbuk National University, College of Medicine, Cheongju, Republic of Korea
| | - Dong Woon Jeon
- National Health Insurance Corporation Ilsan Hospital, Goyang, Republic of Korea
| | - Seok-Kyu Oh
- Wonkwang University Hospital, Iksan, Republic of Korea
| | - Seung-Ho Hur
- Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Bum-Su Kim
- Kangbuk Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea
| | - Jung-Hee Lee
- Yeungnam University Medical Center, Daegu, Republic of Korea
| | - Tae-Ho Park
- Dong-A University Hospital, Busan, Republic of Korea
| | - Nam Ho Lee
- Kangnam Sacred Heart Hospital, Hallym University, Seoul, Republic of Korea
| | - Hyo-Soo Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Cardiovascular Center, Seoul National University Hospital, Seoul, Republic of Korea.
| |
Collapse
|
10
|
Proton Pump Inhibitors in Cardiovascular Disease: Drug Interactions with Antiplatelet Drugs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 906:325-350. [PMID: 27628008 DOI: 10.1007/5584_2016_124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular diseases. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies suggested an interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it was reported that PPIs may also attenuate the antiplatelet effect of aspirin. This may be clinically important, because a fixed combination of aspirin and a PPI (esomeprazole) has recently been approved and because aspirin is the most widely used drug in patients with cardiovascular disease. The antiplatelet effect of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, seems less influenced by PPI co-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover, it outlines current evidence supporting or opposing drug interactions between these drugs and discusses clinical implications.
Collapse
|
11
|
Juurlink DN, Gomes T, Paterson JM, Hellings C, Mamdani MM. Trends in the coprescription of proton pump inhibitors with clopidogrel: an ecological analysis. CMAJ Open 2015; 3:E428-31. [PMID: 26770965 PMCID: PMC4701655 DOI: 10.9778/cmajo.20140078] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND In early 2009, 2 observational studies and a US Food and Drug Administration (FDA) advisory addressed the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. One study suggested that pantoprazole could be used safely in this setting, whereas the other study and the FDA advisory did not distinguish among PPIs. We examined trends in PPI prescribing among clopidogrel recipients in the period following these events. METHODS We conducted a population-based time series analysis of Ontario residents aged 66 years or older for whom clopidogrel was prescribed between Apr. 1, 1999, and Sept. 30, 2013. We determined the proportion of clopidogrel recipients dispensed a PPI during each quarter and the proportions who received pantoprazole or other PPIs. The outcome of interest was change in the use of pantoprazole. RESULTS In the final quarter of 2008, pantoprazole represented 23.7% of all PPI prescriptions dispensed to patients receiving clopidogrel. Following the publications and FDA advisory in early 2009, pantoprazole use increased substantially. By the end of 2009, this medication accounted for 52.5% of all PPI prescriptions issued to patients receiving clopidogrel; by the end of the study period, it accounted for 71.0% of all PPI prescriptions dispensed to such patients (p < 0. 001). We also observed a modest drop in overall PPI use among clopidogrel recipients beginning in early 2009. INTERPRETATION In 2009, the prescribing of PPIs with clopidogrel changed substantially in Ontario, with pantoprazole rapidly becoming the most commonly prescribed agent in its class. However, a modest decline in overall PPI use also occurred that may reflect suboptimal translation of emerging drug safety information to clinical practice.
Collapse
Affiliation(s)
- David N Juurlink
- Institute for Clinical Evaluative Sciences (Juurlink, Gomes, Paterson, Hellings, Mamdani); Sunnybrook Research Institute (Juurlink); Li Ka-Shing Knowledge Institute (Gomes, Mamdani), St. Michael's Hospital; Institute of Health Policy, Management, and Evaluation (Gomes), University of Toronto; Leslie Dan Faculty of Pharmacy, the University of Toronto, Toronto, Ont.; Department of Family Medicine (Paterson), McMaster University, Hamilton, Ont
| | - Tara Gomes
- Institute for Clinical Evaluative Sciences (Juurlink, Gomes, Paterson, Hellings, Mamdani); Sunnybrook Research Institute (Juurlink); Li Ka-Shing Knowledge Institute (Gomes, Mamdani), St. Michael's Hospital; Institute of Health Policy, Management, and Evaluation (Gomes), University of Toronto; Leslie Dan Faculty of Pharmacy, the University of Toronto, Toronto, Ont.; Department of Family Medicine (Paterson), McMaster University, Hamilton, Ont
| | - J Michael Paterson
- Institute for Clinical Evaluative Sciences (Juurlink, Gomes, Paterson, Hellings, Mamdani); Sunnybrook Research Institute (Juurlink); Li Ka-Shing Knowledge Institute (Gomes, Mamdani), St. Michael's Hospital; Institute of Health Policy, Management, and Evaluation (Gomes), University of Toronto; Leslie Dan Faculty of Pharmacy, the University of Toronto, Toronto, Ont.; Department of Family Medicine (Paterson), McMaster University, Hamilton, Ont
| | - Chelsea Hellings
- Institute for Clinical Evaluative Sciences (Juurlink, Gomes, Paterson, Hellings, Mamdani); Sunnybrook Research Institute (Juurlink); Li Ka-Shing Knowledge Institute (Gomes, Mamdani), St. Michael's Hospital; Institute of Health Policy, Management, and Evaluation (Gomes), University of Toronto; Leslie Dan Faculty of Pharmacy, the University of Toronto, Toronto, Ont.; Department of Family Medicine (Paterson), McMaster University, Hamilton, Ont
| | - Muhammad M Mamdani
- Institute for Clinical Evaluative Sciences (Juurlink, Gomes, Paterson, Hellings, Mamdani); Sunnybrook Research Institute (Juurlink); Li Ka-Shing Knowledge Institute (Gomes, Mamdani), St. Michael's Hospital; Institute of Health Policy, Management, and Evaluation (Gomes), University of Toronto; Leslie Dan Faculty of Pharmacy, the University of Toronto, Toronto, Ont.; Department of Family Medicine (Paterson), McMaster University, Hamilton, Ont
| |
Collapse
|
12
|
Jiang XL, Samant S, Lesko LJ, Schmidt S. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet 2015; 54:147-66. [PMID: 25559342 DOI: 10.1007/s40262-014-0230-6] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Acute coronary syndromes (ACS) remain life-threatening disorders, which are associated with high morbidity and mortality. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in the response to clopidogrel treatment, in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19, which affect the pharmacokinetics of clopidogrel. While the US Food and Drug Administration has issued a boxed warning for CYP2C19 poor metabolizers because of potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug-drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability, and how they are interrelated, is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence the pharmacokinetics and pharmacodynamics of clopidogrel and how they mechanistically contribute to inter-individual differences in the response to clopidogrel treatment.
Collapse
Affiliation(s)
- Xi-Ling Jiang
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona (Orlando), 6550 Sanger Road, Room 467, Orlando, FL, 32827, USA
| | | | | | | |
Collapse
|
13
|
Comparison of Intravenous plus Oral Pantoprazole Therapy and Oral Pantoprazole Alone for Preventing Gastrointestinal Bleeding in Acute Coronary Syndrome Patients with High Bleeding Risk. Heart Lung Circ 2015; 24:885-90. [PMID: 25837016 DOI: 10.1016/j.hlc.2015.02.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 02/17/2015] [Accepted: 02/20/2015] [Indexed: 11/24/2022]
Abstract
BACKGROUND It is unclear whether intravenous proton pump inhibition is more effective than oral administration in preventing gastrointestinal (GI) bleeding in high bleeding risk patients with acute coronary syndromes (ACS). METHODS AND RESULTS A total of 504 patients with ACS and high bleeding risk were randomly assigned into two groups. Study group (n=252) received intravenous pantoprazole for five days and subsequent oral pantoprazole for 12 months. Control group (n=252) received oral pantoprazole for 12 months. Major adverse cardiac events (death, re-infarction, re-revascularisation and stroke) and GI bleeding were registered after a follow-up of 12 months. No statistically significant differences were found in the major adverse cardiac events between the two groups after the follow-up (p >0.05). The incidence of major GI bleeding in the study group was lower than in the control group (1.2% vs. 3.9%, p=0.049). The bleeding rates in the first 30 days in the study group were also lower than in the control group (0.3% vs. 2.7%, p=0.032). CONCLUSIONS The main outcome of cardiac events did not differ between the treatment groups. Intravenous plus oral pantoprazole therapy seemed more effective than oral therapy alone in the prevention of GI bleeding in high bleeding risk patients with ACS.
Collapse
|
14
|
Bae JP, Candrilli SD, Fortenberry J, Meyers JL, Jakubowski JA, Drenning D. Point-of-care platelet reactivity determination with VerifyNow-P2Y12 following administration of clopidogrel or prasugrel: data from a real-world, clinical care inpatient setting. Hosp Pract (1995) 2014; 42:7-15. [PMID: 25502126 DOI: 10.3810/hp.2014.10.1139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
OBJECTIVES To describe VerifyNow-P2Y12 (VN-P2Y12, Accumetrics, San Diego, CA) results from patients treated with either clopidogrel or prasugrel who were seeking care in a hospital setting. BACKGROUND VN-P2Y12 is a point-of-care device that measures platelet reactivity to adenosine diphosphate. Past assessments of thienopyridine therapy utilizing VN-P2Y12 have largely come from clinical trial settings. There are limited data from real-world settings. METHODS Electronic medical record data from Huntsville Hospital (Huntsville, AL) for those who underwent VN-P2Y12 testing for clopidogrel or prasugrel between January 1, 2009 and October 31, 2010 were analyzed. The VN-P2Y12 data included P2Y12 reaction units (PRUs) and device-reported percentage of inhibition. Descriptive analyses were conducted with t tests, and a logistic regression model was estimated to assess the association between patient characteristics and the likelihood of platelet nonresponse. RESULTS In total, 2882 tests (2476 with clopidogrel and 406 with prasugrel) were analyzed. For clopidogrel and prasugrel, respectively, mean PRU standard deviation (SD) was 206 (90) and 107 (93; P < 0.0001) and mean % inhibition (SD) was 31% (26%) and 63% (31%; P < 0.0001). Treatment with clopidogrel alone (odds ratio [OR] = 5.25; P < 0.0001), being non-Caucasian (OR = 1.48; P = 0.0440), obese (OR = 1.49; P = 0.0010), anemic (OR = 3.29; P < 0.0001), diabetic (OR = 1.75; P < 0.0001), and having a history of myocardial infarction (OR = 1.57; P < 0.0001) were significant predictors of having PRU ≥ 235. CONCLUSION This real-world data analysis shows results that are consistent with clinical trial results, namely that compared with clopidogrel, prasugrel is associated with significantly lower PRU and greater percentage of inhibition, regardless of age, race, gender, diabetes, obesity, or proton pump inhibitor use.
Collapse
|
15
|
D'Ugo E, Rossi S, De Caterina R. Proton pump inhibitors and clopidogrel: an association to avoid? Intern Emerg Med 2014; 9:11-22. [PMID: 24030523 DOI: 10.1007/s11739-013-1000-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 09/01/2013] [Indexed: 02/08/2023]
Abstract
Dual antiplatelet therapy with aspirin and clopidogrel reduces cardiovascular events following an acute coronary syndrome or stent implantation, but the associated increased risk of gastro-intestinal bleeding often leads to the co-administration of proton pump inhibitors (PPIs). PPIs have been shown to decrease antiplatelet effects of clopidogrel ex vivo, raising concerns about the cardiovascular safety of this drug combination. Clinical trials investigating PPI-clopidogrel interactions have provided conflicting results and are all subject to methodological critiques. The much desired and much needed prospective, double-bind, randomized, placebo-controlled trials with adequate follow-up and sample size have not yet been performed. Indeed, the Clopidogrel and the Optimization of GI Events Trial, which would have had such characteristics, was stopped prematurely. As a consequence, the question of the PPI-clopidogrel interaction is still unresolved, and clinical consequences cannot be excluded. At this time such combination therapy should, therefore, be provisionally advocated only for patients at high risk of bleeding (prior upper gastro-intestinal bleeding, advanced age, concomitant use of warfarin, steroidal or non-steroidal anti-inflammatory drugs and Helicobacter pylori infection) and avoiding PPIs with strong affinity for cytochrome CYP2C19, such as omeprazole and esomeprazole.
Collapse
Affiliation(s)
- Emilia D'Ugo
- Institute of Cardiology and Center of Excellence on Aging, "G. d'Annunzio" University-Chieti, C/o Ospedale SS. Annunziata, Via dei Vestini, 66013, Chieti, Italy
| | | | | |
Collapse
|
16
|
Oprea AD, Popescu WM. ADP-Receptor Inhibitors in the Perioperative Period: The Good, the Bad, and the Ugly. J Cardiothorac Vasc Anesth 2013; 27:779-95. [DOI: 10.1053/j.jvca.2012.11.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Indexed: 02/02/2023]
|
17
|
Abstract
PURPOSE OF REVIEW To review the current evidence on the clinical significance of the drug-drug interactions between the available antiplatelet agents and proton pump inhibitors (PPIs). RECENT FINDINGS Gastrointestinal bleeding is associated with higher rates of morbidity and mortality following a myocardial infarction. PPIs are commonly used to prevent gastrointestinal bleeding. PPIs can attenuate metabolism of clopidogrel to its active metabolite by inhibiting various hepatic CYP450 enzymes, mainly CYP2C19. Concomitant use of a PPI with clopidogrel reduces clopidogrel active metabolite generation and subsequent platelet inhibition. In observational studies, the clinical significance of this drug-drug interaction is mixed. Evidence from the only randomized trial studying the clinical implications of the PPI-clopidogrel interaction did not demonstrate any difference in cardiovascular outcomes but did show a reduction in gastrointestinal bleeding with use of a PPI. SUMMARY The drug-drug interaction between antiplatelet agents and PPIs at the enzymatic level does not seem to result in worse clinical outcomes. The risk of gastrointestinal bleeding with antiplatelet therapy is substantial. Clinicians should use PPIs in selected high-risk patients to prevent gastrointestinal bleeding.
Collapse
|
18
|
Lin CF, Shen LJ, Wu FLL, Bai CH, Gau CS. Cardiovascular outcomes associated with concomitant use of clopidogrel and proton pump inhibitors in patients with acute coronary syndrome in Taiwan. Br J Clin Pharmacol 2013; 74:824-34. [PMID: 22364155 DOI: 10.1111/j.1365-2125.2012.04250.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Conflicting results have been reported regarding the increased risk of adverse outcomes in the concomitant use of clopidogrel and proton pump inhibitors (PPIs) compared with the use of clopidogrel alone. WHAT THIS STUDY ADDS Our study indicated no statistically significant increase in the risk of rehospitalization for acute coronary syndrome due to concurrent use of clopidogrel and PPIs in an Asian population with higher prevalence of CYP2C19 intermediate and poor metabolizers. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for acute coronary syndrome. AIMS Our study aimed to examine the impact of concomitant use of proton pump inhibitors (PPIs) with clopidogrel on the cardiovascular outcomes of patients with acute coronary syndrome (ACS). Furthermore, we sought to quantify the effects of five individual PPIs when used concomitantly with clopidogrel. METHODS We conducted a retrospective cohort study of patients who were newly hospitalized for ACS between 1 January 2006 and 31 December 2007 retrieved from the Taiwan National Health Insurance Research Database (NHIRD) and who were prescribed clopidogrel (n= 37 099) during the follow-up period. A propensity score technique was used to establish a matched cohort in 1:1 ratio (n= 5173 for each group). The primary clinical outcome was rehospitalization for ACS, while secondary outcomes were rehospitalization for percutaneous transluminal coronary angioplasty (PTCA) with stent, PTCA without stent and revascularization (PTCA or coronary artery bypass graft surgery) after the discharge date for the index ACS event. RESULTS The adjusted hazard ratio of rehospitalization for ACS was 1.052 (95% confidence interval, 0.971-1.139; P= 0.214) in the propensity score matched cohort. Among all PPIs, only omeprazole was found to be statistically significantly associated with an increased risk of rehospitalization for ACS (adjusted hazard ratio, 1.226; 95% confidence interval, 1.066-1.410; P= 0.004). Concomitant use of esomeprazole, pantoprazole, rabeprazole and lansoprazole did not increase the risk. CONCLUSIONS Our study indicated no statistically significant increase in the risk of rehospitalization for ACS due to concurrent use of clopidogrel and PPIs overall. Among individual PPIs, only omeprazole was found to be statistically significantly associated with increased risk of rehospitalization for ACS.
Collapse
Affiliation(s)
- Chen-Fang Lin
- School of Pharmacy Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road, Taipei, Taiwan
| | | | | | | | | |
Collapse
|
19
|
Chen J, Chen SY, Lian JJ, Zeng XQ, Luo TC. Pharmacodynamic impacts of proton pump inhibitors on the efficacy of clopidogrel in vivo--a systematic review. Clin Cardiol 2013; 36:184-9. [PMID: 23450832 DOI: 10.1002/clc.22094] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Revised: 12/20/2012] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND There is considerable debate about whether concomitant use of proton pump inhibitors (PPIs) should be recommended for patients who are prescribed clopidogrel after acute coronary syndrome. Most pharmacokinetic and pharmacodynamic studies in vivo were conducted using small sample sizes and were single centered, resulting in conflicting data. HYPOTHESIS PPIs may attenuate the antiplatelet effect of clopidogrel in vivo and lead to an increased risk of cardiovascular events. METHODS PubMed, the Cochrane Library, Embase, Web of Science, and China Biology Medicine Disc were searched. Randomized controlled trials that compared pharmacodynamic impacts of a PPI on the efficacy of clopidogrel in vivo were included. Two independent reviewers evaluated study quality and extracted data for meta-analysis. RESULTS We identified 8 eligible studies. Compared to clopidogrel treatment alone, patients who received both a PPI and clopidogrel had less of a decrease in the platelet reactivity index (weighted mean difference [WMD]: 8.18; 95% confidence interval [CI]: 6.81-9.56; P<0.00001), less adenosine 5'-diphosphate-induced platelet aggregation inhibition (WMD: 7.28; 95% CI: 2.44-12.11; P=0.003), higher P2Y12 reaction units (WMD: 40.58; 95% CI: 19.31-61.86; P=0.0002), and higher risks of clopidogrel resistance (odds ratio [OR]: 2.49; 95% CI: 1.49-4.14; P=0.0005). There were no significant differences, however, for the incidences of major adverse cardiovascular events between the 2 groups (OR: 1.07; 95% CI: 0.44-2.59; P=0.88), and treatment with a PPI and clopidogrel significantly reduced the risk of adverse gastrointestinal events (OR: 0.16; 95% CI: 0.04-0.62; P=0.008). CONCLUSIONS Concomitant use of a PPI with clopidogrel attenuated the antiplatelet effect of clopidogrel, but may be clinically unimportant because there were no clinical differences in the risk for major adverse cardiovascular events.
Collapse
Affiliation(s)
- Jie Chen
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | | | | | | |
Collapse
|
20
|
Wu HL, Zhang ZY, Duan ZT, Yuan FC, Gao X, Wang JS, Huang WB. Mosapride protects against clopidogrel-induced gastric mucosal epithelium cell damage via the p38 MAPK signaling pathway. Shijie Huaren Xiaohua Zazhi 2012; 20:3632-3637. [DOI: 10.11569/wcjd.v20.i36.3632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether mosapride has a protective effect against clopidogrel-induced gastric mucosal epithelium cells (GES-1) damage and to explore the underlying mechanisms.
METHODS: GES-1 cells were cultured in vitro and divided into control group, clopidogrel group (treated with clopidogrel at a concentration of IC50, 0.36 mmol/L) and clopidogrel plus mosapride groups (treated with clopidogrel and 0.4, 0.5, or 0.6 µmol/L of mosapride). MTT assay and flow cytometry were used to detect the proliferation and apoptosis of cells of each group. The expression of phosphorylated P38 (p-P38), occludin and ZO-1 proteins in GES-1 cells was detected by Western blot.
RESULTS: Compared to the control group, p-P38 expression was significantly up-regulated in the clopidogrel group (P < 0.05). The expression of p-P38 in the clopidogrel plus mosapride groups was significantly lower than that in the clopidogrel group (all P < 0.05). With the decrease in p-P38 expression, the expression of occludin and ZO-1 were gradually increased.
CONCLUSION: Mosapride exerts a protective effect against clopidogrel-induced GES-1 cell damage probably by inhibiting p38/MAPK phosphorylation and up-regulating the expression of tight junction proteins occludin and ZO-1.
Collapse
|
21
|
Abstract
Proton pump inhibitors (PPI) and antiplatelet agents, especially aspirin and clopidogrel, are among the most prescribed medications worldwide. Their co-administration is justified by the increased risk of gastrointestinal bleeding related to the antiplatelet therapy. The issue of the interaction between PPI and clopidogrel has been raised with the emergence of the concept of "high on-clopidogrel platelet reactivity" (or "clopidogrel resistance") together with the discovery of the role of CYP2C19 isoform in the pharmacokinetics of those two medications. Indeed, CYP2C19 is involved in the conversion of the clopidogrel pro-drug into its active metabolite and is involved in the metabolisation of PPI into inactive metabolites, acting as substrates/inhibitors of CYP2C19. Despite their heterogeneity, most pharmacodynamic studies have shown a decreased clopidogrel antiplatelet effect when associated to PPI, especially those with the highest CYP2C19 inhibiting activity (omeprazole, lansoprazole, rabeprazole). On the other hand, clinical studies are inconclusive. Retrospective studies have shown an increased risk of major cardiovascular events or mortality when clopidogrel and PPI are associated in comparison with clopidogrel alone, particularly in the patients with the higher cardiovascular risk. However, the two prospective randomized studies published so far did not find any interaction and confirmed the benefit of PPI on the gastrointestinal bleeding. As a conclusion, as the clinical studies are not conclusive, the French health authorities have recently removed the alert about this interaction. PPI and clopidogrel can thus be co-prescribed.
Collapse
Affiliation(s)
- J Szymezak
- Laboratoire d'hématologie, hôpital Robert-Debré, CHU de Reims, France
| | | |
Collapse
|
22
|
Zhu LL, Xu LC, Chen Y, Zhou Q, Zeng S. Poor awareness of preventing aspirin-induced gastrointestinal injury with combined protective medications. World J Gastroenterol 2012; 18:3167-72. [PMID: 22791953 PMCID: PMC3386331 DOI: 10.3748/wjg.v18.i24.3167] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Revised: 05/02/2012] [Accepted: 05/05/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate prescribing pattern in low-dose aspirin users and physician awareness of preventing aspirin-induced gastrointestinal (GI) injury with combined protective medications.
METHODS: A retrospective drug utilization study was conducted in the 2nd Affiliated Hospital, School of Medicine, Zhejiang University. The hospital has 2300 beds and 2.5 million outpatient visits annually. Data mining was performed on all aspirin prescriptions for outpatients and emergency patients admitted in 2011. Concomitant use of proton-pump inhibitors (PPIs), histamine 2-receptor antagonists (H2RA) and mucoprotective drugs (MPs) were analyzed. A defined daily dose (DDD) methodology was applied to each MP. A further investigation was performed in aspirin users on combination use of GI injurious medicines [non-steoid anti-inflammatory drugs (NSAIDs), corticosteroids and clopidogrel and warfarin] or intestinal protective drugs (misoprostol, rebamipide, teprenone and gefarnate). Data of major bleeding episodes were derived from medical records and adverse drug reaction monitoring records. The annual incidence of major GI bleeding due to low-dose aspirin was estimated for outpatients.
RESULTS: Prescriptions for aspirin users receiving PPIs, H2RA and MPs (n = 1039) accounted for only 3.46% of total aspirin prescriptions (n = 30 015). The ratios of coadministration of aspirin/PPI, aspirin/H2RA, aspirin/MP and aspirin/PPI/MP to the total aspirin prescriptions were 2.82%, 0.12%, 0.40% and 0.12%, respectively. No statistically significant difference was observed in age between patients not receiving any GI protective medications and patients receiving PPIs, H2RA or MPs. The combined medication of aspirin and PPI was used more frequently than that of aspirin and MPs (2.82% vs 0.40%, P < 0.05) and aspirin/H2RA (2.82% vs 0.12%, P < 0.05). The values of DDDs of MPs in descending order were as follows: gefarnate, hydrotalcite > teprenone > sucralfate oral suspension > L-glutamine and sodium gualenate granules > rebamipide > sucralfate chewable tablets. The ratio of MP plus aspirin prescriptions to the total MP prescriptions was as follows: rebamipide (0.47%), teprenone (0.91%), L-glutamine and sodium gualenate granules (0.92%), gefarnate (0.31%), hydrotalcite (1.00%) and sucralfate oral suspension (0.13%). Percentages of prescriptions containing aspirin and intestinal protective drugs among the total aspirin prescriptions were: rebamipide (0.010%), PPI/rebamipide (0.027%), teprenone (0.11%), PPI/teprenone (0.037%), gefarnate (0.017%), and PPI/gefarnate (0.013%). No prescriptions were found containing coadministration of aspirin and other NSAIDs. Among the 3196 prescriptions containing aspirin/clopidogrel, 3088 (96.6%) prescriptions did not contain any GI protective medicines. Of the 389 prescriptions containing aspirin/corticosteroids, 236 (60.7%) contained no GI protective medicines. None of the prescriptions using aspirin/warfarin (n = 22) contained GI protective medicines. Thirty-five patients were admitted to this hospital in 2011 because of acute hemorrhage of upper digestive tract induced by low-dose aspirin. The annual incidence rates of major GI bleeding were estimated at 0.25% for outpatients taking aspirin and 0.5% for outpatients taking aspirin/warfarin, respectively.
CONCLUSION: The prescribing pattern of low-dose aspirin revealed a poor awareness of preventing GI injury with combined protective medications. Actions should be taken to address this issue.
Collapse
|
23
|
Drepper MD, Spahr L, Frossard JL. Clopidogrel and proton pump inhibitors - where do we stand in 2012? World J Gastroenterol 2012; 18:2161-71. [PMID: 22611308 PMCID: PMC3351765 DOI: 10.3748/wjg.v18.i18.2161] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2011] [Revised: 02/20/2012] [Accepted: 02/26/2012] [Indexed: 02/06/2023] Open
Abstract
Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events. Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines. Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19 (CYP2C19) and proton pump inhibitors (PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well. Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole, but not for pantoprazole. Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events, when under clopidogrel and PPI treatment at the same time. These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI (especially omeprazole) in the same year. In contrast, more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel. Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality, with high and moderate quality studies not reporting any association, rising concern about unmeasured confounders biasing the low quality studies. Thus, no definite evidence exists for an effect on mortality. Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding, combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.
Collapse
|
24
|
Kwok CS, Loke YK. Effects of proton pump inhibitors on platelet function in patients receiving clopidogrel: a systematic review. Drug Saf 2012; 35:127-39. [PMID: 22204719 DOI: 10.2165/11594900-000000000-00000] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND There is considerable debate regarding the negative impact of concomitant proton pump inhibitor (PPI) therapy on the antiplatelet efficacy of clopidogrel. AIM The aim of this study was to perform a systematic review of studies that have evaluated the platelet function of patients receiving clopidogrel alone compared with those receiving both clopidogrel and PPIs. METHODS We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register in February 2011 for randomized and non-randomized studies that reported platelet function results in patients taking clopidogrel, with or without PPIs. RESULTS Our review included 19 studies (13 trials and 6 observational studies) involving 4693 patients. There was considerable heterogeneity in the study designs, patient characteristics, laboratory tests of platelet function, and drug exposure (dose and duration of PPI and clopidogrel). There was some evidence against omeprazole, with five of nine studies demonstrating a significant interaction with clopidogrel. The available platelet function data on esomeprazole (six studies) or pantoprazole (six studies) did not demonstrate a significant interaction. Of the six studies that statistically analysed platelet function data with omeprazole compared with pantoprazole, three showed a significantly greater interaction between omeprazole and clopidogrel, whereas three studies with limited sample sizes were unable to find a significant difference in the effects of omeprazole and pantoprazole. CONCLUSION Platelet function studies do not demonstrate a clear or consistent interaction between clopidogrel and PPIs. These studies are difficult to interpret given the lack of information on drug exposure (dose and duration), variation in laboratory methodology and lack of genetic information. Consequently, platelet function data are of uncertain clinical relevance in determining the risk of an adverse cardiovascular interaction between PPIs and clopidogrel. Clinicians should continue to clinically assess the gastrointestinal risk of the patients and make their prescribing decision for PPIs based on any anticipated benefits in reducing risk of peptic ulcers and gastrointestinal haemorrhage.
Collapse
Affiliation(s)
- Chun Shing Kwok
- School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK
| | | |
Collapse
|
25
|
Abstract
Proton pump inhibitors and clopidogrel are commonly prescribed medications, both alone and in combination. In January of 2009 the US Food and Drug Administration and the European Medicines Agency issued warnings with regard to the concomitant use of clopidogrel and proton pump inhibitors. Later that year, these warnings were limited to the proton pump inhibitor omeprazole. These warnings were largely based on in-vitro studies and observational analyses suggesting decreased efficacy of clopidogrel in the presence of proton pump inhibitors. Recent literature has suggested there may not be a clinically meaningful interaction.
Collapse
Affiliation(s)
- Robert W Harrison
- Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27715, USA.
| | | |
Collapse
|
26
|
Schiff M, Peura D. HZT-501 (DUEXIS(®); ibuprofen 800 mg/famotidine 26.6 mg) gastrointestinal protection in the treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Expert Rev Gastroenterol Hepatol 2012; 6:25-35. [PMID: 22149579 DOI: 10.1586/egh.11.88] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Arthritis affects nearly 50 million people in the USA and, with the aging of the population, the prevalence is expected to rise. While NSAIDs are very effective in relieving pain associated with osteoarthritis (OA) and rheumatoid arthritis (RA), they are associated with side effects, including gastrointestinal (GI) toxicity, which may manifest as dyspepsia, ulcers and/or bleeding. A number of approaches have been employed in an effort to either completely avoid or reduce the risk of GI toxicities associated with NSAID use. Two new products combining an NSAID with a gastroprotective agent have recently been approved and other agents are in the pipeline. Patient adherence to prescribed gastroprotective therapy is known to be poor, often resulting in an increased risk of GI events in patients taking NSAIDs. These newer combination products may fulfill an important need for many patients who need to receive NSAIDs for the pain of OA and RA, but who are also at risk of upper GI events. This article reviews preclinical and clinical results for a new fixed-dose combination of ibuprofen and famotidine, DUEXIS(®) (HZT-501), which has recently been approved in the USA for the relief of signs and symptoms of RA and OA and to decrease the risk of developing upper GI ulcers.
Collapse
Affiliation(s)
- Michael Schiff
- Division of Rheumatology, University of Colorado School of Medicine, Denver, CO, USA.
| | | |
Collapse
|
27
|
Magro L, Moretti U, Leone R. Epidemiology and characteristics of adverse drug reactions caused by drug-drug interactions. Expert Opin Drug Saf 2011; 11:83-94. [PMID: 22022824 DOI: 10.1517/14740338.2012.631910] [Citation(s) in RCA: 166] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Drug-drug interactions (DDIs) arise in numerous different ways, involving pharmacokinetic or pharmacodynamic mechanisms. Adverse drug reactions are a possible consequence of DDIs and health operators are often unaware of the clinical risks of certain drug combinations. Many papers on drug interactions have been published in recent years, but most of them focused on potential DDIs while few studies have been conducted on actual interactions. AREAS COVERED This paper reviews the epidemiology of actual DDIs in outpatients as well as in hospital settings and in spontaneous reporting databases. The incidence of actual DDIs is consistently lower than that of potential DDIs. However, the absolute number of patients involved is high, representing a significant proportion of adverse drug reactions. The importance of risk factors such as age, polypharmacy and genetic polymorphisms is also evaluated. The relevance and efficacy of tools for recognizing and preventing DDIs are discussed. EXPERT OPINION Potential DDIs far outnumber actual drug interactions. The potential for an adverse interaction to occur is often theoretical, and clinically important adverse effects occur only in the presence of specific risk factors. Several studies have shown the efficacy of computers in early detection of DDIs. However, a correct risk-benefit evaluation by the prescribing physician, together with a careful clinical, physiological and biochemical monitoring of patients, is essential. Future directions of drug interaction research include the increasing importance of pharmacogenetics in preventing DDIs and the evaluation of interactions with biological drugs.
Collapse
Affiliation(s)
- Lara Magro
- University of Verona, Faculty of Medicine, Department of Public Health and Community Medicine, Section of Pharmacology, p.le L.A. Scuro 10, 37134 Verona, Italy
| | | | | |
Collapse
|
28
|
Hulot JS, Collet JP, Montalescot G. Thienopyridine-Associated Drug-Drug Interactions: Pharmacologic Mechanisms and Clinical Relevance. Curr Cardiol Rep 2011; 13:451-8. [DOI: 10.1007/s11886-011-0206-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
|
29
|
Hsiao FY, Mullins CD, Wen YW, Huang WF, Chen PF, Tsai YW. Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome. Pharmacoepidemiol Drug Saf 2011; 20:1043-9. [DOI: 10.1002/pds.2202] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 05/04/2011] [Accepted: 06/07/2011] [Indexed: 12/15/2022]
Affiliation(s)
- Fei-Yuan Hsiao
- Graduate Institute of Clinical Pharmacy, College of Medicine; National Taiwan University; Taipei Taiwan
| | - C. Daniel Mullins
- Pharmaceutical Health Services Research Department; University of Maryland School of Pharmacy; Baltimore MD USA
| | - Yu-Wen Wen
- Clinical Informatics and Medical Statistics Research Center; Chang Gung University; Tao-Yuan Taiwan
| | - Weng-Foung Huang
- Institute of Health and Welfare Policy; National Yang-Ming University; Taipei Taiwan
| | - Pei-Fen Chen
- Institute of Population Health Sciences; National Health Research Institutes; Miaoli Taiwan
| | - Yi-Wen Tsai
- Institute of Health and Welfare Policy; National Yang-Ming University; Taipei Taiwan
| |
Collapse
|
30
|
PPI therapy: Clopidrogel-PPI drug interaction may not be a class effect. Nat Rev Gastroenterol Hepatol 2011; 8:302. [PMID: 21643032 DOI: 10.1038/nrgastro.2011.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
|