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He C, Li Y, Jiang X, Jiang MN, Zhao XX, Ma SR, Bao D, Qiu MH, Deng J, Wang JH, Qu P, Jiang CM, Jia SB, Yang SQ, Ru LS, Feng J, Gao W, Huang YH, Tao L, Han Y, Yang K, Wang XY, Zhang WJ, Wang BM, Li Y, Yang YL, Li JX, Sheng JQ, Ma YT, Cui M, Ma SC, Wang XZ, Li ZS, Liao Z, Han YL, Stone GW. Progression of Gastrointestinal Injury During Antiplatelet Therapy After Percutaneous Coronary Intervention: A Secondary Analysis of the OPT-PEACE Randomized Clinical Trial. JAMA Netw Open 2023; 6:e2343219. [PMID: 37976067 PMCID: PMC10656648 DOI: 10.1001/jamanetworkopen.2023.43219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/04/2023] [Indexed: 11/19/2023] Open
Abstract
Importance Gastrointestinal injury progression induced by antiplatelet therapy in patients after percutaneous coronary intervention (PCI) has not been well studied. Objective To assess the association of aspirin, clopidogrel, and their combination with gastrointestinal injury progression among patients without high bleeding risk after PCI. Design, Setting, and Participants This secondary analysis assessed data from the Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by ANKON Magnetically Controlled Capsule Endoscopy (OPT-PEACE) double-masked, placebo-controlled, multicenter randomized clinical trial. The OPT-PEACE trial was conducted at 28 centers in China, and recruitment took place from July 13, 2017, to July 13, 2019. The trial included patients with stable coronary artery disease or acute coronary syndromes without ST-segment elevation after PCI. Statistical analysis was conducted from September 13, 2022, to January 23, 2023. Interventions Patients underwent magnetically controlled capsule endoscopy (MCE) at baseline and after 6 months of dual antiplatelet therapy (DAPT) with aspirin (100 mg/d) plus clopidogrel (75 mg/d). Those with no evidence of gastrointestinal ulcers or bleeding (ie, the intention-to-treat [ITT] cohort) were randomized (1:1:1) to aspirin (100 mg/d) plus matching placebo (aspirin alone), clopidogrel (75 mg/d) plus matching placebo (clopidogrel alone), or DAPT for an additional 6 months. A third MCE was performed 12 months after PCI. Main Outcomes and Measures The primary outcome was the rate of gastric injury progression as assessed with the results of the 3 MCEs (at baseline, 6 months, and 12 months) in the modified intention-to-treat (mITT) population. The key secondary outcome was the rate of small-intestinal injury progression. Gastric or small-intestinal injury progression was defined as a quantitative increase in erosions or ulcers between the second and third MCEs (at 6 and 12 months, respectively). Results This study included the 394 patients in the mITT cohort. Their mean (SD) age was 56.9 (8.7) years, and most were men (296 [75.1%]). A total of 132 patients were randomized to aspirin alone, 132 to clopidogrel alone, and 130 to DAPT. Gastric injury progression occurred in 49 aspirin users (37.1%), 64 clopidogrel users (48.5%), and 69 DAPT users (53.1%) (P = .02), reflecting a lower rate of gastric injury progression among aspirin users vs DAPT users (risk ratio [RR], 0.70 [95% CI, 0.49-0.99]; P = .009). No significant difference was observed between clopidogrel alone and DAPT (48.5% vs 53.1%; P = .46) or between aspirin alone and clopidogrel alone (37.1% vs 48.5%; P = .06). A total of 51 aspirin users (38.6%), 65 clopidogrel users (49.2%), and 71 DAPT users (54.6%) (P = .03) developed progressive small-intestinal injury, reflecting a lower rate of small-intestinal injury among aspirin users vs DAPT users (RR, 0.71 [95% CI, 0.50-0.99]; P = .01). No difference was observed between patients treated with clopidogrel vs DAPT (49.2% vs 54.6%; P = .38) or with aspirin vs clopidogrel (38.6% vs 49.2%; P = .08). Conclusions and Relevance In this secondary analysis of a randomized clinical trial, ongoing use of aspirin, clopidogrel, or their combination between 6 and 12 months after PCI was associated with progressive gastric and small-intestinal injury in a substantial proportion of patients, more so with DAPT than with monotherapy. Clopidogrel was at least as likely as aspirin to induce gastrointestinal injury progression. Future research is warranted to determine what impact the findings from MCEs would have on decision-making of antiplatelet therapy. Trial Registration ClinicalTrials.gov Identifier: NCT03198741.
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Affiliation(s)
- Chen He
- Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yi Li
- General Hospital of Northern Theater Command, Shenyang, China
| | - Xi Jiang
- Changhai Hospital, Naval Medical University, Shanghai, China
| | - Meng-Ni Jiang
- Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xian-Xian Zhao
- Changhai Hospital, Naval Medical University, Shanghai, China
| | - Shu-Ren Ma
- General Hospital of Northern Theater Command, Shenyang, China
| | - Dan Bao
- General Hospital of Northern Theater Command, Shenyang, China
| | - Miao-Han Qiu
- General Hospital of Northern Theater Command, Shenyang, China
| | - Jie Deng
- Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jin-Hai Wang
- Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Peng Qu
- Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Chun-Meng Jiang
- Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shao-Bin Jia
- General Hospital of Ningxia Medical University, Yinchuan, China
| | - Shao-Qi Yang
- General Hospital of Ningxia Medical University, Yinchuan, China
| | - Lei-Sheng Ru
- No. 980 Hospital of Joint Logistical Support Force, Shijiazhuang, China
| | - Jia Feng
- No. 980 Hospital of Joint Logistical Support Force, Shijiazhuang, China
| | - Wei Gao
- Peking University Third Hospital, Beijing, China
| | | | - Ling Tao
- Xijing Hospital of Air Force Medical University, Xi’an, China
| | - Ying Han
- Xijing Hospital of Air Force Medical University, Xi’an, China
| | - Kan Yang
- Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiao-Yan Wang
- Third Xiangya Hospital of Central South University, Changsha, China
| | - Wen-Juan Zhang
- General Hospital of Tianjin Medical University, Tianjin, China
| | - Bang-Mao Wang
- General Hospital of Tianjin Medical University, Tianjin, China
| | - Yue Li
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - You-Lin Yang
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jun-Xia Li
- Seventh Medical Center of the General Hospital of the People’s Liberation Army, Beijing, China
| | - Jian-Qiu Sheng
- Seventh Medical Center of the General Hospital of the People’s Liberation Army, Beijing, China
| | - Yi-Tong Ma
- The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Min Cui
- The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Si-Cong Ma
- General Hospital of Northern Theater Command, Shenyang, China
| | - Xiao-Zeng Wang
- General Hospital of Northern Theater Command, Shenyang, China
| | - Zhao-Shen Li
- Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhuan Liao
- Changhai Hospital, Naval Medical University, Shanghai, China
| | - Ya-Lin Han
- General Hospital of Northern Theater Command, Shenyang, China
| | - Gregg W. Stone
- Mount Sinai Heart and the Cardiovascular Research Foundation, Icahn School of Medicine at Mount Sinai, New York, New York
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Váczi S, Barna L, Laczi K, Tömösi F, Rákhely G, Penke B, Fülöp L, Bogár F, Janáky T, Deli MA, Mezei Z. Effects of sub-chronic, in vivo administration of sigma-1 receptor ligands on platelet and aortic arachidonate cascade in streptozotocin-induced diabetic rats. PLoS One 2022; 17:e0265854. [PMID: 36395179 PMCID: PMC9671357 DOI: 10.1371/journal.pone.0265854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 09/28/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Diabetes mellitus is a chronic metabolic disorder which induces endothelial dysfunction and platelet activation. Eicosanoids produced from arachidonic acid regulate cellular and vascular functions. Sigma-1 receptors (S1R) are expressed in platelets and endothelial cells and S1R expression is protective in diabetes. OBJECTIVES Our aim was to examine the influence of sub-chronic, in vivo administered S1R ligands PRE-084, (S)-L1 (a new compound) and NE-100 on the ex vivo arachidonic acid metabolism of platelets and aorta in streptozotocin-induced diabetic rats. METHODS The serum level of the S1R ligands was detected by LC-MS/MS before the ex vivo analysis. Sigma-1 receptor and cyclooxygenase gene expression in platelets were determined by RT-qPCR. The eicosanoid synthesis was examined with a radiolabelled arachidonic acid substrate and ELISA. RESULTS One month after the onset of STZ-induced diabetes, in vehicle-treated, diabetic rat platelet TxB2 and aortic 6-k-PGF1α production dropped. Sub-chronic in vivo treatment of STZ-induced diabetes in rats for one week with PRE-084 enhanced vasoconstrictor and platelet aggregator and reduced vasodilator and anti-aggregator cyclooxygenase product formation. (S)-L1 reduced the synthesis of vasodilator and anti-aggregator cyclooxygenase metabolites and promoted the recovery of physiological platelet function in diabetic rats. The S1R antagonist NE-100 produced no significant changes in platelet arachidonic acid metabolism. (S)-L1 decreased the synthesis of vasoconstrictor and platelet aggregator cyclooxygenase metabolites, whereas NE-100 increased the quantity of aortic vasodilator and anti-aggregator cyclooxygenase products and promoted the recovery of diabetic endothelial dysfunction in the aorta. The novel S1R ligand, (S)-L1 had similar effects on eicosanoid synthesis in platelets as the agonist PRE-084 and in aortas as the antagonist NE-100. CONCLUSIONS S1R ligands regulate cellular functions and local blood circulation by influencing arachidonic acid metabolism. In diabetes mellitus, the cell-specific effects of S1R ligands have a compensatory role and aid in restoring physiological balance between the platelet and vessel.
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Affiliation(s)
- Sándor Váczi
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary
| | - Lilla Barna
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
- Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - Krisztián Laczi
- Department of Biotechnology, University of Szeged, Szeged, Hungary
| | - Ferenc Tömösi
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Gábor Rákhely
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
- Department of Biotechnology, University of Szeged, Szeged, Hungary
| | - Botond Penke
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Lívia Fülöp
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Ferenc Bogár
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Tamás Janáky
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - Mária A. Deli
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
| | - Zsófia Mezei
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
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Váczi S, Barna L, Laczi K, Tömösi F, Rákhely G, Penke B, Fülöp L, Bogár F, Janáky T, Deli MA, Mezei Z. Effects of sub-chronic, in vivo administration of sigma non-opioid intracellular receptor 1 ligands on platelet and aortic arachidonate cascade in rats. Eur J Pharmacol 2022; 925:174983. [PMID: 35487254 DOI: 10.1016/j.ejphar.2022.174983] [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: 10/09/2021] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 12/25/2022]
Abstract
Platelets regulate cell-cell interactions and local circulation through eicosanoids from arachidonic acid. Sigma non-opioid intracellular receptor 1 (sigma-1 receptor) expressed in platelets and endothelial cells can regulate intracellular signalization. Our aim was to examine the influence of sub-chronic, in vivo-administered sigma-1 receptor ligands 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084); N-benzyl-2-[(1S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]ethan-1-amine; dihydrochloride, a new compound ((S)-L1); and N-[2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethyl]-N-propylpropan-1-amine (NE-100) on the ex vivo arachidonic acid metabolism of the platelets and aorta of male rats. The serum level of sigma-1 receptor ligands was determined by liquid chromatography-mass spectrometry. Sigma-1 receptor and cyclooxygenase gene expression in the platelets were determined by a reverse transcription-coupled quantitative polymerase chain reaction. The eicosanoid synthesis was examined using a radiolabeled arachidonic acid substrate and enzyme-linked immunosorbent assay. We confirmed the absorption of sigma-1 receptor ligands and confirmed that the ligands were not present during the ex vivo studies, so their acute effect could be excluded. We detected no changes in either sigma-1 receptor or cyclooxygenase mRNA levels in the platelets. Nevertheless, (S)-L1 and NE-100 increased the quantity of cyclooxygenases there. Both platelet and aortic eicosanoid synthesis was modified by the ligands, although in different ways. The effect of the new sigma-1 receptor ligand, (S)-L1, was similar to that of PRE-084 in most of the parameters studied but was found to be more potent. Our results suggest that sigma-1 receptor ligands may act at multiple points in arachidonic acid metabolism and play an important role in the control of the microcirculation by modulating the eicosanoid synthesis of the platelets and vessels.
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Affiliation(s)
- Sándor Váczi
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary; Doctoral School of Theoretical Medicine, University of Szeged, H-6725, Szeged, Hungary.
| | - Lilla Barna
- Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), H-6725, Szeged, Hungary; Doctoral School of Biology, University of Szeged, H-6725, Szeged, Hungary.
| | - Krisztián Laczi
- Department of Biotechnology, University of Szeged, H-6725, Szeged, Hungary.
| | - Ferenc Tömösi
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary.
| | - Gábor Rákhely
- Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), H-6725, Szeged, Hungary; Department of Biotechnology, University of Szeged, H-6725, Szeged, Hungary.
| | - Botond Penke
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary.
| | - Lívia Fülöp
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary.
| | - Ferenc Bogár
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary; MTA-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), H-6725, Szeged, Hungary.
| | - Tamás Janáky
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary.
| | - Mária A Deli
- Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network (ELKH), H-6725, Szeged, Hungary.
| | - Zsófia Mezei
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary; Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725, Szeged, Hungary.
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4
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Váczi S, Barna L, Harazin A, Mészáros M, Porkoláb G, Zvara Á, Ónody R, Földesi I, Veszelka S, Penke B, Fülöp L, Deli MA, Mezei Z. S1R agonist modulates rat platelet eicosanoid synthesis and aggregation. Platelets 2021; 33:709-718. [PMID: 34697991 DOI: 10.1080/09537104.2021.1981843] [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] [Indexed: 10/20/2022]
Abstract
Sigma-1 receptor (S1R) is detected in different cell types and can regulate intracellular signaling pathways. S1R plays a role in the pathomechanism of diseases and the regulation of neurotransmitters. Fluvoxamine can bind to S1R and reduce the serotonin uptake of neurons and platelets. We therefore hypothesized that platelets express S1R, which can modify platelet function. The expression of the SIGMAR1 gene in rat platelets was examined with a reverse transcription polymerase chain reaction and a quantitative polymerase chain reaction. The receptor was also visualized by immunostaining and confocal laser scanning microscopy. The effect of S1R agonist PRE-084 on the eicosanoid synthesis of isolated rat platelets and ADP- and AA-induced platelet aggregation was examined. S1R was detected in rat platelets both at gene and protein levels. Pretreatment with PRE-084 of resting platelets induced elevation of eicosanoid synthesis. The rate of elevation in thromboxane B2 and prostaglandin D2 synthesis was similar, but the production of prostaglandin E2 was higher. The concentration-response curve showed a sigmoidal form. The most effective concentration of the agonist was 2 µM. PRE-084 increased the quantity of cyclooxygenase-1 as detected by ELISA. PRE-084 also elevated the ADP- and AA-induced platelet aggregation. S1R of platelets might regulate physiological or pathological functions.
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Affiliation(s)
- Sándor Váczi
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary.,Doctoral School of Theoretical Medicine, University of Szeged, Szeged, Hungary.,Gedeon Richter Talentum Foundation Scholarship, Budapest, Hungary
| | - L Barna
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary.,Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - A Harazin
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
| | - M Mészáros
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
| | - G Porkoláb
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary.,Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - Á Zvara
- Institute of Genetics, Biological Research Centre, Szeged, Hungary
| | - R Ónody
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - I Földesi
- Department of Laboratory Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - S Veszelka
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
| | - B Penke
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - L Fülöp
- Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
| | - M A Deli
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
| | - Z Mezei
- Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary.,Department of Physiology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
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Lee SH, Ryu DR, Lee SJ, Park SC, Cho BR, Lee SK, Choi SJ, Cho HS. Small bowel ulcer bleeding due to suspected clopidogrel use in a patient with clopidogrel resistance: A case report. World J Clin Cases 2021; 9:3689-3695. [PMID: 34046471 PMCID: PMC8130066 DOI: 10.12998/wjcc.v9.i15.3689] [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] [Received: 12/21/2020] [Revised: 03/10/2021] [Accepted: 03/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Clopidogrel is a platelet aggregation inhibitor used for the management of cardiovascular disease. While antiplatelet therapy decreases cardiovascular events after successful coronary drug-eluting stenting, it increases the risk of gastrointestinal (GI) bleeding. About 20% of the patients who take clopidogrel exhibit resistance to the drug.
CASE SUMMARY We report the first case of a small bowel bleeding ulcer in an 86-year-old man with clopidogrel resistance. He had a history of taking clopidogrel due to unstable angina. There was no evidence of bleeding in the stomach, duodenum, or colon through upper and lower GI endoscopies. The abdominal computed tomography showed the extravasation of radiocontrast media at the ileum. Because of unstable vital signs, emergency surgery was performed. Multiple ulcers with inflammation were found in the ileum. The pathologic findings revealed simple inflammation. The VerifyNow P2Y12 test showed clopidogrel resistance. One year after changing to aspirin, capsule endoscopy was performed and the small bowel ulcers were improved.
CONCLUSION Small bowel ulcers and bleeding due to clopidogrel are not very common, but the prevalence is expected to increase in older age patients with risk factors despite clopidogrel resistance.
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Affiliation(s)
- Sang Hoon Lee
- Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea
| | - Dong Ryeol Ryu
- Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea
| | - Sung Joon Lee
- Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea
| | - Sung Chul Park
- Division of Gastroenterology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea
| | - Byung Ryul Cho
- Division of Cardiology, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea
| | - Seung Koo Lee
- Department of Anatomic Pathology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea
| | - Sang Ji Choi
- Department of Surgery, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si 24289, South Korea
| | - Hyun Seok Cho
- Department of Hospital Medicine, Kangwon National University Hospital , Chuncheon-si 24289, South Korea
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Ebi M, Inoue S, Sugiyama T, Yamamoto K, Adachi K, Yoshimine T, Yamaguchi Y, Tamura Y, Izawa S, Hijikata Y, Funaki Y, Ogasawara N, Sasaki M, Kasugai K. A Small Bowel Ulcer due to Clopidogrel with Cytomegalovirus Enteritis Diagnosed by Capsule and Double-Balloon Endoscopy. Case Rep Gastroenterol 2018; 12:303-310. [PMID: 30022920 PMCID: PMC6047549 DOI: 10.1159/000490096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 05/07/2018] [Indexed: 12/17/2022] Open
Abstract
We report the first case of small bowel ulcers due to clopidogrel in a 74-year-old man. He presented with diarrhea and melena after having been taking low-dose aspirin (LDA) and clopidogrel. There was no evidence of bleeding in the stomach, duodenum, or colon. Capsule endoscopy showed multiple ulcers and erosions in the small intestine. Double-balloon endoscopy revealed multiple ulcers throughout the ileum. Examination of the biopsy specimen showed cytomegalovirus infection. His LDA was discontinued and he was prescribed ganciclovir. However, the small bowel ulcers were aggravated. Therefore, clopidogrel was discontinued. The small bowel ulcers subsequently healed completely, forming scars.
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Affiliation(s)
- Masahide Ebi
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Satoshi Inoue
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Tomoya Sugiyama
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kazuhiro Yamamoto
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kazunori Adachi
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Takashi Yoshimine
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshiharu Yamaguchi
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yasuhiro Tamura
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Shinya Izawa
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yasutaka Hijikata
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yasushi Funaki
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Naotaka Ogasawara
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Makoto Sasaki
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kunio Kasugai
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Japan
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Kono Y, Kawano S, Okamoto Y, Obayashi Y, Baba Y, Sakae H, Abe M, Gotoda T, Inokuchi T, Kanzaki H, Iwamuro M, Kawahara Y, Okada H. Clinical outcome of patients with obscure gastrointestinal bleeding during antithrombotic drug therapy. Therap Adv Gastroenterol 2018; 11:1756283X17746930. [PMID: 29399040 PMCID: PMC5788140 DOI: 10.1177/1756283x17746930] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 11/16/2017] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The clinical outcome of patients with obscure gastrointestinal bleeding (OGIB) during antithrombotic drug therapy has not been fully investigated. METHODS Patients who underwent video capsule endoscopy (VCE) for the investigation of OGIB at Okayama University Hospital from January 2009 to March 2016 were enrolled. We evaluated the VCE findings, the patterns of OGIB, and the rate of rebleeding within 1 year in antithrombotic drug users and antithrombotic drug nonusers. RESULTS A total of 181 patients were enrolled. Among the antithrombotic drug users, the rate of VCE positivity in the patients with overt OGIB was significantly higher in comparison with patients with occult OGIB (45% versus 16%, p = 0.014), whereas there was no significant difference among the antithrombotic drug nonusers (27% versus 26%, p = 1.0). Among the antithrombotic drug users, the rate of rebleeding among the VCE-positive patients was significantly higher in comparison with the VCE-negative patients (50% versus 5.9%, p = 0.011). Moreover, among antithrombotic drug users who did not receive therapeutic intervention, the rate of rebleeding among the VCE-positive patients was significantly higher in comparison with the VCE-negative patients (75% versus 6.3%, p = 0.001). However, among the antithrombotic drug nonusers who did not receive therapeutic intervention, the rebleeding rate of the VCE-positive patients was not significantly different from that of the VCE-negative patients (20% versus 9.4%, p = 0.43). CONCLUSION Therapeutic intervention should be considered for patients with overt OGIB who are VCE positive and who use antithrombotic drugs due to the high risk of rebleeding.
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Affiliation(s)
| | - Seiji Kawano
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuki Okamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuka Obayashi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuki Baba
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroyuki Sakae
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Makoto Abe
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tatsuhiro Gotoda
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Toshihiro Inokuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiromitsu Kanzaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshiro Kawahara
- Department of Endoscopy, Okayama University Hospital, Okayama, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Yi X, Zhou Q, Wang C, Lin J, Cheng W, Chi L. Concomitant Use of Proton Pump Inhibitors and Clopidogrel Is Not Associated with Adverse Outcomes after Ischemic Stroke in Chinese Population. J Stroke Cerebrovasc Dis 2016; 25:2859-2867. [DOI: 10.1016/j.jstrokecerebrovasdis.2016.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/27/2016] [Accepted: 08/01/2016] [Indexed: 12/11/2022] Open
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Parekh PJ, Oldfield EC, Johnson DA. Current Strategies to Reduce Gastrointestinal Bleeding Risk Associated with Antiplatelet Agents. Drugs 2015; 75:1613-25. [PMID: 26330139 DOI: 10.1007/s40265-015-0455-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Antiplatelet agents remain the cornerstone in the primary and secondary therapeutic intervention for cardiovascular disease. Some patients may be subjected to a year or more of dual antiplatelet therapy to reduce the risk of subsequent cardiovascular events. Patients on antiplatelet therapy have an increased risk of gastrointestinal bleeding; however, not all patients benefit from concomitant acid suppressive therapy. This review will provide an overview of the pharmacology of antiplatelet agents and outline patient risk profiles that ought to be considered when considering prophylactic therapy to reduce gastrointestinal toxicity. In addition, we discuss the current risk-reduction strategies intended to mitigate against the potential for related gastroduodenal injury.
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Affiliation(s)
- Parth J Parekh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tulane University, New Orleans, LA, USA
| | - Edward C Oldfield
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - David A Johnson
- Division of Gastroenterology, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 23510, USA.
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10
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Mezei Z, Zamani-Forooshani O, Csabafi K, Szikszai B, Papp E, Ónodi Á, Török D, Leprán Á, Telegdy G, Szabó G. The effect of kisspeptin on the regulation of vascular tone. Can J Physiol Pharmacol 2015; 93:787-91. [DOI: 10.1139/cjpp-2015-0013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Kisspeptin has been implicated in cardiovascular control. Eicosanoids play a crucial role in the activation of platelets and the regulation of vascular tone. In the present study, we investigated the effect of kisspeptins on eicosanoid synthesis in platelets and aorta in vitro. Platelets and aorta were isolated from Wistar–Kyoto rats. After preincubation with different doses of kisspeptin, samples were incubated with [1-14C]arachidonic acid (0.172 pmol/mL) in tissue culture Medium 199. The amount of labeled eicosanoids was measured with liquid scintillation, after separation with overpressure thin-layer chromatography. Kisspeptin-13 stimulated the thromboxane synthesis. The dose–response curve was bell-shaped and the most effective concentration was 2.5 × 10−8 mol/L, inducing a 27% increase. Lipoxygenase products of platelets displayed a dose-dependent elevation up to the dose of 5 × 10−8 mol/L. In the aorta, kisspeptin-13 induced a marked elevation in the production of 6-keto-prostaglandin F1α, the stable metabolite of prostacyclin, and lipoxygenase products. Different effects of kisspeptin on cyclooxygenase and lipoxygenase products indicate that beyond intracellular Ca2+ mobilization, other signaling pathways might also contribute to its actions. Our data suggest that kisspeptin, through the alteration of eicosanoid synthesis in platelets and aorta, may play a physiologic and (or) pathologic role in the regulation of vascular tone.
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Affiliation(s)
- Zsófia Mezei
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Omid Zamani-Forooshani
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Krisztina Csabafi
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Bence Szikszai
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Eszter Papp
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Ádám Ónodi
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Dóra Török
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Ádám Leprán
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Gyula Telegdy
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
| | - Gyula Szabó
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
- Department of Pathophysiology, University of Szeged, P.O. Box 427, H-6701, Semmelweis u. 1, 6725 Szeged, Hungary
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Van Weyenberg SJB, Van Turenhout ST, Jacobs MAJM, Bouma G, Mulder CJJ. Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti-thrombotic drugs. Dig Endosc 2012; 24:247-54. [PMID: 22725110 DOI: 10.1111/j.1443-1661.2011.01228.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Little is known about the causes of overt obscure gastrointestinal bleeding (OGIB) in patients using anti-thrombotic therapy. We aimed to describe video capsule endoscopy (VCE) findings and to identify factors associated with positive findings in these patients. METHODS We carried out a retrospective study of 56 patients who underwent VCE for evaluation of previous overt OGIB during anti-thrombotic therapy. VCE studies were re-evaluated by a gastroenterologist blinded to clinical details. Clinical data included in the multivariate analysis were sex, age, indication for and type of anti-thrombotic therapy, hemodynamic instability on admission, type of blood loss, hemoglobin on admission, use of a proton pump inhibitor, NSAID use, time between bleeding episodes and VCE, and whether or not anti-thrombotic therapy was resumed before the VCE study. RESULTS A probable cause for gastrointestinal bleeding was identified in 28 (50%) of the 56 studies. Angiodysplasia was found in 19 patients. Twenty-two studies showed a possible cause in the small bowel. Multivariate logistic regression analysis showed that reinstitution of anti-thrombotic therapy before VCE was carried out was the only independent predictor of positive VCE findings (OR: 8.61, 95% CI: 1.20-60.42, P=0.032). CONCLUSIONS Small intestinal angiodysplasia was the most common cause for overt OGIB. Reinstitution of withdrawn anti-thrombotic drugs before the VCE examination was carried out was associated with positive VCE findings in multivariate analysis.
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Affiliation(s)
- Stijn J B Van Weyenberg
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.
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12
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Tsai TJ, Lai KH, Hsu PI, Lin CK, Chan HH, Yu HC, Wang HM, Lin KH, Wang KM, Chang SN, Liu CP, Hsiao SH, Huang HR, Lin CH, Tsay FW. Upper gastrointestinal lesions in patients receiving clopidogrel anti-platelet therapy. J Formos Med Assoc 2012; 111:705-10. [PMID: 23265750 DOI: 10.1016/j.jfma.2011.11.028] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 08/29/2011] [Accepted: 11/30/2011] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND/PURPOSE Clopidogrel is associated with a high incidence of upper gastrointestinal bleeding in high-risk patients. However, the characteristic upper gastrointestinal lesions in symptomatic clopidogrel users remain unclear. The aims of this study were to investigate the characteristics of endoscopic findings in clopidogrel users undergoing endoscopy for upper gastrointestinal symptoms and to compare the clinical characteristics and upper gastrointestinal lesions between symptomatic clopidogrel and aspirin users. METHODS This observational study included 215 consecutive patients receiving clopidogrel (n=106) or low-dose aspirin (n=109) therapy who underwent endoscopy for dyspeptic symptoms. The upper gastrointestinal lesions were carefully assessed, and a complete medical history was obtained by a standard questionnaire. RESULTS The frequencies of hemorrhagic spots, erosions and peptic ulcers in the symptomatic clopidogrel users were 25%, 39% and 39%, respectively. Among the peptic ulcer patients on clopidogrel therapy, the distributions of ulcers were 78%, 5% and 17% in the stomach, duodenum and both, respectively. Compared with the aspirin group, the clopidogrel group was older and had higher frequencies of past ulcer history and past gastrointestinal bleeding history in their clinical characteristics. By contrast, the clopidogrel users had a lower prevalence of active Helicobacter pylori infection than aspirin users (17% vs. 35%, respectively, p=0.007). Regarding to the endoscopic findings, the clopidogrel users had higher frequencies of hemorrhagic spots (25% vs. 10%) and peptic ulcer (39% vs. 24%) than aspirin users (p=0.004 and 0.027, respectively). CONCLUSION Most peptic ulcers in clopidogrel users are located in the stomach. The frequencies of hemorrhagic spots and peptic ulcers in symptomatic clopidogrel users are higher than those in symptomatic aspirin users.
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Affiliation(s)
- Tzung-Jiun Tsai
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
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13
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Abstract
Patients taking antiplatelet agents for the prevention of cardiovascular diseases who develop gastrointestinal bleeding represent a serious challenge in clinical practice. The initial step in reducing gastrointestinal risk of antiplatelet therapy is to assess whether the patient has a continued need for antiplatelet therapy. The next step is to eliminate the risk factors that may place the patient at increased gastrointestinal risk. In the management of bleeding ulcer patients with high-risk stigmata of recent hemorrhage, resuming antiplatelet agents at 3-5 days after the last dosing is a reasonable strategy. However, patients with low-risk stigmata can keep taking antiplatelet agents immediately following endoscopy. In the management of aspirin-related uncomplicated peptic ulcers in patients requiring antiplatelet therapies, continuing aspirin plus a powerful proton pump inhibitor is the choice of treatment. Patients who require antiplatelet agents for the prevention of cardiovascular diseases should be tested and treated for Helicobacter pylori infection before starting antiplatelet therapy. Additionally, those with high risks for upper gastrointestinal bleeding should receive co-therapy with a gastroprotective drug, preferably a proton pump inhibitor at standard dose. H2-receptor antagonist can significantly reduce upper gastrointestinal bleeding risk in patients taking low-dose aspirin but it is ineffective in the prevention of upper gastrointestinal bleeding in clopidogrel users. Although several retrospective studies reported that patients prescribed clopidogrel who also took proton pump inhibitors had significant increases in cardiovascular events, the current evidence from a prospective randomized trial does not justify a conclusion that proton pump inhibitors are associated with cardiovascular events among clopidogrel users.
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Affiliation(s)
- Ping-I Hsu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.
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Gurbel PA, Tantry US, Kereiakes DJ. Interaction between clopidogrel and proton-pump inhibitors and management strategies in patients with cardiovascular diseases. DRUG HEALTHCARE AND PATIENT SAFETY 2010; 2:233-40. [PMID: 21701635 PMCID: PMC3108705 DOI: 10.2147/dhps.s7297] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Indexed: 01/09/2023]
Abstract
Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in ‘high risk’ and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided.
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Affiliation(s)
- Paul A Gurbel
- Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, MD, USA
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15
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Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363:1909-17. [PMID: 20925534 DOI: 10.1056/nejmoa1007964] [Citation(s) in RCA: 823] [Impact Index Per Article: 54.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 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 two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).
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Affiliation(s)
- Deepak L Bhatt
- Veterans AffairsBoston Healthcare System, Brigham and Women's Hospital, Boston, MA 02132, USA.
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Triantafyllou K, Vlachogiannakos J, Ladas SD. Gastrointestinal and liver side effects of drugs in elderly patients. Best Pract Res Clin Gastroenterol 2010; 24:203-15. [PMID: 20227033 DOI: 10.1016/j.bpg.2010.02.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Revised: 02/07/2010] [Accepted: 02/08/2010] [Indexed: 01/31/2023]
Abstract
It is expected that the percentage of people >60 years of age will be 22% worldwide by the year 2050. Multi-morbidity and poly-pharmacy are common in individuals during old age, while adverse drug reactions are at least twice as common in the elderly compared to younger adults. Publications related to drug side effects are rather rare in this age group since most clinical trials exclude patients >75-80 years of age. Gastrointestinal adverse drug reactions studied in the elderly include non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulant-induced gastrointestinal tract mucosal injuries. Malabsorption, diarrhoea and constipation are common side effects of laxatives, antibiotics, anticholinergics and calcium channel blockers. Drug (amoxycilin/clavulanic acid, isoniazide, nitrofurantoin, diclifenac and methotrexate)-induced hepatotoxicity in the elderly is four times more common than in younger adults and may simulate almost all known liver disorders. Further clinical studies are needed to investigate gastrointestinal and hepatic side effects of drugs in elderly patients.
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Affiliation(s)
- Konstantinos Triantafyllou
- Hepatogastroenterology Unit, 2nd Department of Internal Medicine - Propaedeutic, Attikon University General Hospital, Medical School, Athens University, Chaidari, Greece
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Gaglia MA, Torguson R, Hanna N, Gonzalez MA, Collins SD, Syed AI, Ben-Dor I, Maluenda G, Delhaye C, Wakabayashi K, Xue Z, Suddath WO, Kent KM, Satler LF, Pichard AD, Waksman R. Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes. Am J Cardiol 2010; 105:833-8. [PMID: 20211327 DOI: 10.1016/j.amjcard.2009.10.063] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Revised: 10/28/2009] [Accepted: 10/28/2009] [Indexed: 02/08/2023]
Abstract
Recent evidence has shown that clopidogrel and proton pump inhibitors (PPIs) are metabolized by the same pathway and that patients taking both drugs have greater levels of platelet reactivity and more adverse outcomes than patients taking only clopidogrel. We sought to examine the effect of a PPI at discharge from the hospital after percutaneous coronary intervention with drug-eluting stents on the incidence of major adverse cardiac events (MACE) at 1 year. We compared 502 patients who were not prescribed a PPI at discharge and 318 patients who were prescribed a PPI. All patients were taking clopidogrel. We followed patients for 1 year with regard to MACE, including death, Q-wave myocardial infarction, target vessel revascularization, and stent thrombosis. We performed multivariate Cox regression to adjust for confounding variables, including compliance with clopidogrel, to assess the effect of a PPI at discharge on the 1-year outcomes. The baseline characteristics of patients discharged with a PPI were similar to those of patients discharged without a PPI. Univariate survival analysis of the outcomes showed a greater rate of MACE (13.8% vs 8.0%, p = 0.008) and overall mortality (4.7% vs 1.8%, p = 0.02) in the PPI group. After multivariate analysis, the adjusted MACE hazard ratio for PPI at discharge was 1.8 (95% confidence interval 1.1 to 2.7, p = 0.01). In conclusion, in patients undergoing percutaneous coronary intervention with drug-eluting stents and receiving clopidogrel, the prescription of a PPI at discharge was associated with a greater rate of MACE at 1 year.
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Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2009. [DOI: 10.1002/pds.1846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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