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Zhang M, Wang Z, Ding C. Pharmacotherapy for osteoarthritis-related pain: current and emerging therapies. Expert Opin Pharmacother 2024; 25:1209-1227. [PMID: 38938057 DOI: 10.1080/14656566.2024.2374464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 06/26/2024] [Indexed: 06/29/2024]
Abstract
INTRODUCTION Osteoarthritis (OA) related pain has affected millions of people worldwide. However, the current pharmacological options for managing OA-related pain have not achieved a satisfactory effect. AREAS COVERED This narrative review provides an overview of the current and emerging drugs for OA-related pain. It covers the drugs' mechanism of action, safety, efficacy, and limitations. The National Library of Medicine (PubMed) database was primarily searched from 2000 to 2024. EXPERT OPINION Current treatment options are limited and suboptimal for OA pain management. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are the recognized and first-line treatment in the management of OA-related pain, and other drugs are inconsistent recommendations by guidelines. Emerging treatment options are promising for OA-related pain, including nerve growth factor (NGF) inhibitors, ion channel inhibitors, and calcitonin gene-related peptide (CGRP) antagonists. Besides, drugs repurposing from antidepressants and antiepileptic analgesics are shedding light on the management of OA-related pain. The management of OA-related pain is challenging as pain is heterogeneous and subjective. A more comprehensive strategy combined with non-pharmacological therapy needs to be considered, and tailored management options to individualized patients.
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Affiliation(s)
- Mengdi Zhang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhiqiang Wang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Changhai Ding
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Bosco E, Riester MR, Beaudoin FL, Schoenfeld AJ, Gravenstein S, Mor V, Zullo AR. Comparative safety of tramadol and other opioids following total hip and knee arthroplasty. BMC Geriatr 2024; 24:319. [PMID: 38580920 PMCID: PMC10996118 DOI: 10.1186/s12877-024-04933-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 03/29/2024] [Indexed: 04/07/2024] Open
Abstract
BACKGROUND Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA. METHODS This retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models. RESULTS The study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons. CONCLUSIONS Postoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.
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Affiliation(s)
- Elliott Bosco
- Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI, USA
- Center for Gerontology and Healthcare Research, Brown University School of Public Health, Providence, RI, USA
| | - Melissa R Riester
- Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI, USA.
- Center for Gerontology and Healthcare Research, Brown University School of Public Health, Providence, RI, USA.
- Department of Epidemiology, Brown University School of Public Health, Providence, RI, 02912, USA.
| | - Francesca L Beaudoin
- Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI, USA
- Department of Epidemiology, Brown University School of Public Health, Providence, RI, 02912, USA
- Department of Emergency Medicine, Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Andrew J Schoenfeld
- Department of Orthopaedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Stefan Gravenstein
- Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI, USA
- Center for Gerontology and Healthcare Research, Brown University School of Public Health, Providence, RI, USA
- Center of Innovation in Long-Term Services and Supports, Providence Veterans Affairs Medical Center, Providence, RI, USA
- Department of Medicine, Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Vincent Mor
- Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI, USA
- Center for Gerontology and Healthcare Research, Brown University School of Public Health, Providence, RI, USA
- Center of Innovation in Long-Term Services and Supports, Providence Veterans Affairs Medical Center, Providence, RI, USA
| | - Andrew R Zullo
- Department of Health Services, Policy, and Practice, Brown University School of Public Health, Providence, RI, USA
- Center for Gerontology and Healthcare Research, Brown University School of Public Health, Providence, RI, USA
- Department of Epidemiology, Brown University School of Public Health, Providence, RI, 02912, USA
- Center of Innovation in Long-Term Services and Supports, Providence Veterans Affairs Medical Center, Providence, RI, USA
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Nguyen TNM, Laetsch DC, Chen LJ, Holleczek B, Meid AD, Brenner H, Schöttker B. Comparison of Five Lists to Identify Potentially Inappropriate Use of Non-Steroidal Anti-Inflammatory Drugs in Older Adults. PAIN MEDICINE 2021; 22:1962-1969. [PMID: 33749754 DOI: 10.1093/pm/pnaa480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE To compare the prevalence of potentially inappropriate non-steroidal anti-inflammatory drugs (NSAIDs) among NSAIDs users defined with frequently used potentially inappropriate medication (PIM) lists and to identify the determinants of their use. DESIGN AND SETTING Cross-sectional survey among community-dwelling older adults from Germany. SUBJECTS N = 284 NSAIDs users aged 65-89 years. METHODS All currently regularly or as-needed used drugs were recorded during a home visit. Multivariate logistic regression models were applied to assess the potential determinants of potentially inappropriate NSAIDs use. RESULTS Prevalence of potentially inappropriate NSAIDs use was 54.2%, 45.4%, 29.9%, 20.4%, and 3.5% when applying the STOPP, 2019 Beers, EU(7)-PIM, FORTA, and PRISCUS list, respectively. No study participant was identified as a potentially inappropriate NSAIDs user by all five lists simultaneously. The majority (68%) were identified only by one or two lists. Merely the STOPP and Beers criteria had a moderate inter-instrument agreement. Lower pain severity, gout, peptic ulcer (PU), cardiovascular disease (CVD), and chronic kidney disease (CKD) were statistically significantly associated with potentially inappropriate NSAIDs use defined by the STOPP criteria and the latter three conditions also with the 2019 Beers criteria. CONCLUSIONS The STOPP and Beers criteria may be superior to the other lists because they more frequently identify potentially inappropriate NSAIDs use in conditions implying a high risk for NSAIDs' adverse events (i.e., PUD, CKD and CVD). We developed a harmonized, country-independent PIM list for NSAIDs with the same advantages as observed for the STOOP and 2019 Beers criteria and recommended its use.
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Affiliation(s)
- Thi Ngoc Mai Nguyen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Network Aging Research, University of Heidelberg, Heidelberg, Germany
| | - Dana Clarissa Laetsch
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Li-Ju Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Network Aging Research, University of Heidelberg, Heidelberg, Germany
| | | | - Andreas D Meid
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Network Aging Research, University of Heidelberg, Heidelberg, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Network Aging Research, University of Heidelberg, Heidelberg, Germany
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Sisay W, Andargie Y, Molla M, Norahun A. Hydromethanolic Crude Extract of the Leaf of Urtica simensis Hochst. ex. A. Rich. (Urticaceae) Acquires Appreciable Antiulcer Effect: Validation for In Vivo Antiulcer Activity. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:6591070. [PMID: 34335831 PMCID: PMC8318768 DOI: 10.1155/2021/6591070] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/04/2021] [Accepted: 07/12/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Urtica simensis has been used for the treatment of peptic ulcer disease in Ethiopian folkloric medicine by drinking its juice after boiling the semicrushed leaf. To our latest understanding, no in vivo study was available regarding its antiulcer activity. The present study was done to appraise the ulcer-protective and ulcer healing activity of hydromethanolic crude extract of leaf of U. simensis in rats. METHODS Preliminary qualitative phytochemical screening and oral acute toxicity were carried out using a standard protocol. To validate U. simensis in vivo antiulcer potential pyloric ligature, cold restraint stress and acetic acid-induced ulcer models were employed. The extracts (100, 200, and 400 mg per kg of body weight per day), standard treatment (omeprazole 20 mg/kg/day), and vehicle (distilled water 10 ml/kg/day) were given to treatment, positive, and negative controls by oral gavage, respectively. Parameters were then evaluated accordingly after the humane scarification of rats. RESULTS Any sign of toxicity was not observed in the oral acute toxicity test. The crude extracts exerted a significant (P < 0.05) inhibition of ulcer risk compared to the negative control. In the pylorus ligation-induced ulcer model, its antisecretory activity was in a dose-dependent manner. The highest gastroprotective effect (67.68%) was exhibited by the 400 mg/kg/day dose of 80% methanolic crude extract. Regarding the chronic ulcer model, treatment at a dosage of 100, 200, and 400 mg/kg/day cures ulcers by 33.54%, 58.33%, and 67.07%, respectively, as compared to the negative control groups remarkably. CONCLUSION The findings of the present study confirmed the safety and a promising in vivo ulcer healing and antiulcerogenic activity of U. simensis, thus supporting the traditional claim. In-depth investigations on the plant, however, are highly recommended.
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Affiliation(s)
- Woretaw Sisay
- Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Yared Andargie
- Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Mulugeta Molla
- Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Alefe Norahun
- Department of Pharmacy, Teda Health Science College, Gondar, Ethiopia
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Sisay Zewdu W, Jemere Aragaw T. Evaluation of the Anti-Ulcer Activity of Hydromethanolic Crude Extract and Solvent Fractions of the Root of Rumex nepalensis in Rats. J Exp Pharmacol 2020; 12:325-337. [PMID: 33061674 PMCID: PMC7520116 DOI: 10.2147/jep.s258586] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022] Open
Abstract
Background Rumex nepalensis(RN) Spreng has been used to treat ulcer disease in Ethiopian folk medicine. This study aimed to determine the anti-ulcer activity of hydroalcoholic root crude extract and solvent fractions of R. nepalensis in rats. Methods The effect of R. nepalensis crude hydromethanolic extract and solvent fractions at doses (100, 200, 400 mg/kg/day) and repeated dosing (200 mg/kg/day for 10 and 20 days) was examined on ulcers in rats in pyloric ligation-, cold restraint stress-, and acetic acid-induced ulcer models. Cimetidine (100 mg/kg/day) and/or Omeprazole (20 mg/kg/day) were used as standard drugs and served as a positive control. Data were analyzed by one-way ANOVA post hoc followed by a Tukey HSD test with SPSS software version 24.0, and P≤ 0.05 was considered as statistically significant. Results In the pylorus ligation-induced ulcer model, pretreatment with the crude extract significantly reduced the degree of gastric secretions, pH, total acidity, and ulcerations in a dose-dependent manner. Gastroprotection offered by the R. nepalensis 400 mg/kg test extract was comparable to that of the standard. Among fractions, the ethyl acetate fraction at 400 mg/kg had the highest protection of ulcer but the chloroform fraction was ineffective. In the cold restraint stress-induced ulcer model, R. nepalensis at 200 and 400 mg/kg reduced the lesion index significantly (P<0.01). With relevant chronic ulcer model treatment, a dose of R. nepalensis at 200 and 400 mg/kg healed ulcers significantly with a curative ratio of 53.22% and 54.59%, respectively. Conclusion From this study, it is concluded that hydromethanolic crude extract and solvent fractions of R. nepalensis root showed promising anti-ulcer activity. This upholds its folkloric use. Thus, it is considered as a possible source to develop a new anti-ulcer agent.
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Affiliation(s)
- Woretaw Sisay Zewdu
- Department of Pharmacy, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia
| | - Tezera Jemere Aragaw
- Department of Pharmacology, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Zeng C, Wei J, Persson MSM, Sarmanova A, Doherty M, Xie D, Wang Y, Li X, Li J, Long H, Lei G, Zhang W. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med 2018; 52:642-650. [PMID: 29436380 PMCID: PMC5931249 DOI: 10.1136/bjsports-2017-098043] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVES To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA). METHODS PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies. RESULTS 43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=-0.30, 95% CI -0.40 to -0.20) and improving function (SMD=-0.35, 95% CI -0.45 to -0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=-0.81, 95% CI -1.12 to -0.52) and piroxicam was most effective for functional improvement (SMD=-1.04, 95% CI -1.60 to -0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs. CONCLUSIONS Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study.
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Affiliation(s)
- Chao Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jie Wei
- Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Health Management Center, Xiangya Hospital, Central South University, Changsha, China
| | - Monica S M Persson
- Academic Rheumatology, Clinical Sciences Building, University of Nottingham, City Hospital, Nottingham, UK
- Arthritis Research UK Pain Centre, Nottingham, UK
| | - Aliya Sarmanova
- Academic Rheumatology, Clinical Sciences Building, University of Nottingham, City Hospital, Nottingham, UK
- Arthritis Research UK Pain Centre, Nottingham, UK
| | - Michael Doherty
- Academic Rheumatology, Clinical Sciences Building, University of Nottingham, City Hospital, Nottingham, UK
- Arthritis Research UK Pain Centre, Nottingham, UK
| | - Dongxing Xie
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - YiLun Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoxiao Li
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, Hunan, China
| | - Jiatian Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Huizhong Long
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guanghua Lei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, Hunan, China
- National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Center for Clinical Technology and Research of Joint Surgery, Hunan, China
| | - Weiya Zhang
- Academic Rheumatology, Clinical Sciences Building, University of Nottingham, City Hospital, Nottingham, UK
- Arthritis Research UK Pain Centre, Nottingham, UK
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Raza H, Abbas Q, Hassan M, Eo SH, Ashraf Z, Kim D, Phull AR, Kim SJ, Kang SK, Seo SY. Isolation, characterization, and in silico, in vitro and in vivo antiulcer studies of isoimperatorin crystallized from Ostericum koreanum. PHARMACEUTICAL BIOLOGY 2017; 55:218-226. [PMID: 27927061 PMCID: PMC6130598 DOI: 10.1080/13880209.2016.1257641] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 08/03/2016] [Accepted: 11/02/2016] [Indexed: 06/01/2023]
Abstract
CONTEXT Ostericum koreanum (Maxim.) Kitagawa (Apiaceae) roots are traditionally used as an analgesic and antiulcer agent. However, the antiulcer potential of isoimperatorin isolated from O. koreanum has not yet been explored. AIM To evaluate the antiulcer activity of isoimperatorin isolated from the roots of O. koreanum. MATERIALS AND METHODS Isoimperatorin was isolated as cubic crystals by repeated column chromatography of the ethyl acetate fraction and structure was verified with 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS-FAB). The crystals obtained were analyzed with the single crystal X-ray method. The MTT assay was used to determine its cytotoxicity against chondrocytes at different concentrations (0.0-737.74 μM, 24 h). The in vivo antiulcer activity of isoimperatorin (40 mg/kg) was determined against ethanol-, indomethacin- and pyloric ligation-induced ulcers in Sprague-Dawley rats. Furthermore, the effect of isoimperatorin (0.0-737.74 μM, 24 h) on the expression of type II collagen in chondrocytes was determined using western blot method. The in vitro urease inhibitory activity of isoimperatorin (0-80 μM) and molecular docking was also performed against urease. RESULTS AND DISCUSSION Isoimperatorin demonstrated significant inhibitory activity (IC50 36.43 μM) against urease as compared to the standard drug thiourea (IC50 33.57 μM) without cytotoxic effects. It provided 70.9%, 67.65% and 54.25% protection in ulcer models induced by ethanol, indomethacin and pyloric ligation, respectively. Isoimperatorin showed the highest expression level of type II collagen at 368.87 μM. The docking results confirmed strong binding affinity with the target protein. CONCLUSION Isoimperatorin may be used to develop antiulcer drugs with decreased side effects.
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Affiliation(s)
- Hussain Raza
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
| | - Qamar Abbas
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
| | - Mubashir Hassan
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
| | - Seong-Hui Eo
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
| | - Zaman Ashraf
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
| | - Daeyoung Kim
- Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea
| | - Abdul Rehman Phull
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
| | - Song Ja Kim
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
| | - Sung Kwon Kang
- Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea
| | - Sung-Yum Seo
- Department of Biological Sciences College of Natural Sciences, Kongju National University, Gongju, Chungnam, Republic of Korea
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Bakhriansyah M, Souverein PC, de Boer A, Klungel OH. Gastrointestinal toxicity among patients taking selective COX-2 inhibitors or conventional NSAIDs, alone or combined with proton pump inhibitors: a case-control study. Pharmacoepidemiol Drug Saf 2017; 26:1141-1148. [PMID: 28370857 PMCID: PMC5655916 DOI: 10.1002/pds.4183] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 01/12/2017] [Accepted: 01/22/2017] [Indexed: 02/02/2023]
Abstract
PURPOSE To assess the risk of gastrointestinal perforation, ulcers, or bleeding (PUB) associated with the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) with proton pump inhibitors (PPIs) and selective COX-2 inhibitors, with or without PPIs compared with conventional NSAIDs. METHODS A case-control study was performed within conventional NSAIDs and/or selective COX-2 inhibitors users identified from the Dutch PHARMO Record Linkage System in the period 1998-2012. Cases were patients aged ≥18 years with a first hospital admission for PUB. For each case, up to four controls were matched for age and sex at the date a case was hospitalized (index date). Logistic regression analysis was used to calculate odds ratios (ORs). RESULTS At the index date, 2634 cases and 5074 controls were current users of conventional NSAIDs or selective COX-2 inhibitors. Compared with conventional NSAIDs, selective COX-2 inhibitors with PPIs had the lowest risk of PUB (adjusted OR 0.51, 95% confidence interval [CI]: 0.35-0.73) followed by selective COX-2 inhibitors (adjusted OR 0.66, 95%CI: 0.48-0.89) and conventional NSAIDs with PPIs (adjusted OR 0.79, 95%CI: 0.68-0.92). Compared with conventional NSAIDs, the risk of PUB was lower for those aged ≥75 years taking conventional NSAIDs with PPIs compared with younger patients (adjusted interaction OR 0.79, 95%CI: 0.64-0.99). However, those aged ≥75 years taking selective COX-2 inhibitors, the risk was higher compared with younger patients (adjusted interaction OR 1.22, 95%CI: 1.01-1.47). CONCLUSIONS Selective COX-2 inhibitors with PPIs, selective COX-2 inhibitors, and conventional NSAIDs with PPIs were associated with lower risks of PUB compared with conventional NSAIDs. These effects were modified by age. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.
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Affiliation(s)
- Mohammad Bakhriansyah
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, The Netherlands.,Department of Pharmacology, Medical Faculty, Lambung Mangkurat University, Banjarmasin, Indonesia
| | - Patrick C Souverein
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, The Netherlands
| | - Anthonius de Boer
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, The Netherlands
| | - Olaf H Klungel
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, The Netherlands
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Ray WA, Chung CP, Murray KT, Smalley WE, Daugherty JR, Dupont WD, Stein CM. Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding. Gastroenterology 2016; 151:1105-1112.e10. [PMID: 27639805 PMCID: PMC5124401 DOI: 10.1053/j.gastro.2016.08.054] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/29/2016] [Accepted: 08/31/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Proton pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. METHODS This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow-up. The study end points were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. RESULTS Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94-1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84-1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39-0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations. CONCLUSIONS In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper gastrointestinal bleeding; the greatest reduction occurred in patients also taking antiplatelet drugs or NSAIDs.
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Affiliation(s)
- Wayne A Ray
- Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee.
| | - Cecilia P Chung
- Department of Medicine, Division of Rheumatology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee; Veterans' Administration Tennessee Valley Health Care System, Nashville, Tennessee
| | - Katherine T Murray
- Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Medicine, Division of Cardiology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Walter E Smalley
- Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee; Veterans' Administration Tennessee Valley Health Care System, Nashville, Tennessee; Department of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - James R Daugherty
- Department of Health Policy, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - C Michael Stein
- Department of Medicine, Division of Rheumatology, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee
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Malek N, Starowicz K. Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems-A Novel Treatment Option for Chronic Pain Management. Front Pharmacol 2016; 7:257. [PMID: 27582708 PMCID: PMC4987369 DOI: 10.3389/fphar.2016.00257] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 08/02/2016] [Indexed: 12/17/2022] Open
Abstract
Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time, and is often resistant to medical treatment. Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments. The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects. Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target. A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain. Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme. Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors) that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins. The plasticity of the endocannabinoid system (ECS) and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated. Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively. Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.
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Affiliation(s)
- Natalia Malek
- Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences Krakow, Poland
| | - Katarzyna Starowicz
- Laboratory of Pain Pathophysiology, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences Krakow, Poland
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Abstract
Gastroenterologists care for users of nonsteroidal anti-inflammatory drugs (NSAIDs) when the vast population exposed to the medication class experiences a relatively uncommon serious gastrointestinal (GI) side effect. As serious adverse cardiovascular (CV) effects of these drugs have also been recognized, there remains continued confusion about the best treatment for patients who benefit from NSAID therapy and are at risk for GI and CV adverse events. Recognition of those patients at risk and strategies to reduce the adverse side effects of NSAIDs continues to provide an opportunity to improve patient outcomes. This review discusses the injury induced by these agents throughout the GI tract as well as strategies to prevent acute injury and reduce the development of serious adverse events. NSAID medication selection as well as GI cotherapy should balance individual patients' GI and CV risks.
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Schjerning Olsen AM, Lindhardsen J, Gislason GH, McGettigan P, Hlatky MA, Fosbøl E, Køber L, Torp-Pedersen C, Lamberts M. Impact of proton pump inhibitor treatment on gastrointestinal bleeding associated with non-steroidal anti-inflammatory drug use among post-myocardial infarction patients taking antithrombotics: nationwide study. BMJ 2015; 351:h5096. [PMID: 26481405 PMCID: PMC4609736 DOI: 10.1136/bmj.h5096] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
STUDY QUESTION What is the effect of proton pump inhibitors (PPIs) on the risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with non-steroidal anti-inflammatory drugs (NSAIDs)? METHODS This was a nationwide cohort study based on linked administrative registry data from all hospitals in Denmark between 1997 and 2011. The study included patients aged 30 years and over admitted with a first myocardial infarction who survived at least 30 days after discharge. The association between PPIs and risk of gastrointestinal bleeding according to NSAID plus antithrombotic therapy was estimated using adjusted time dependent Cox regression models. STUDY ANSWER AND LIMITATIONS The use of PPIs was independently associated with decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDs. Of 82,955 post-myocardial infarction patients (mean age 67.4 years, 64% (n=53,070) men), all of whom were taking single or dual antithrombotic therapy, 42.5% (n=35,233) filled at least one prescription for NSAIDs and 45.5% (n=37,771) received PPIs. Over a mean follow-up of 5.1 years, 3229 gastrointestinal bleeds occurred. The crude incidence rates of bleeding (events/100 person years) on NSAID plus antithrombotic therapy were 1.8 for patients taking PPIs and 2.1 for those not taking PPIs. The adjusted risk of bleeding was lower with PPI use (hazard ratio 0.72, 95% confidence interval 0.54 to 0.95) regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. The main limitation of the study is its observational non-randomised design. The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well. The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding. WHAT THIS STUDY ADDS In post-myocardial infarction patients, bleeding complications have been associated with both antithrombotic and NSAID treatment. Concurrent use of PPIs was independently associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and NSAID, regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. FUNDING, COMPETING INTERESTS, DATA SHARING AMSO has received a grant from the Danish Council of Independent Research (grant 12-132760). GHG is supported by an unrestricted research scholarship from the Novo Nordisk Foundation.
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Affiliation(s)
- Anne-Marie Schjerning Olsen
- Department of Cardiology, Copenhagen University Hospital Herlev and Gentofte, 2900 Hellerup, Denmark William Harvey Research Institute (WHRI) at Barts and the London School of Medicine and Dentistry, London, UK
| | - Jesper Lindhardsen
- Department of Cardiology, Copenhagen University Hospital Herlev and Gentofte, 2900 Hellerup, Denmark
| | - Gunnar H Gislason
- Department of Cardiology, Copenhagen University Hospital Herlev and Gentofte, 2900 Hellerup, Denmark Danish Heart Foundation, Copenhagen, Denmark National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
| | - Patricia McGettigan
- William Harvey Research Institute (WHRI) at Barts and the London School of Medicine and Dentistry, London, UK
| | - Mark A Hlatky
- Stanford University School of Medicine, Stanford, CA, USA
| | - Emil Fosbøl
- Department of Cardiology, Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Lars Køber
- Department of Cardiology, Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | - Morten Lamberts
- Department of Cardiology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
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Liu D, Guo M, Hu Y, Liu T, Yan J, Luo Y, Yun M, Yang M, Zhang J, Guo L. Effect of sanhuangwuji powder, anti-rheumatic drugs, and ginger-partitioned acupoint stimulation on the treatment of rheumatoid arthritis with peptic ulcer: a randomized controlled study. J TRADIT CHIN MED 2015; 35:273-80. [PMID: 26237830 DOI: 10.1016/s0254-6272(15)30097-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To observe the efficacy and safety of oral sanhuangwuji powder, anti-rheumatic drugs (ARDs), and ginger-partitioned acupoint stimulation at zusanli (ST 36) on the treatment of rheumatoid arthritis (RA) complicated by peptic ulcer. METHODS This prospective randomized controlled study included 180 eligible inpatients and outpatients randomly assigned to an ARD treatment (n.= 60), ginger-partitioned stimulation (n = 60), or combination treatment (n = 60). Patients assigned to the ARD group were given oral celecoxib, methotrexate, and esomeprazole. Patients assigned to the ginger-partitioned stimulation group were given ginger-partitioned acupoint stimulation at zusanli (ST 36) in addition to the ARDs. Patients in the combination treatment group were given oral sanhuangwuji powder, ginger-partitioned acupoint stimulation at susanli (ST 36), and ARDs. All patients were followed up for 2 months to evaluate clinical effects and safety. The study was registered in the World Health Organization database at the General Hospital of Chengdu Military Area Command Chinese People's Liberation Army (ChiCTR-TCC12002824). RESULTS The combination treatment group had significantly greater improvements in RA symptoms, laboratory outcomes, and gastrointestinal symptom scores, compared with the other groups (P < 0.05). The peptic ulcer healing rate in the combination treatment group was significantly greater than that in the ARD treatment group (χ2= 16.875, P < 0.05) and the ginger-partitioned stimulation group (χ2= 6.171, P < 0.05). CONCLUSION Combination treatment with ginger-partitioned acupoint stimulation at zusanli (ST 36), oral sanhuangwuji powder, and ARDs had a better clinical effect for RA with complicated peptic ulcer, compared with ARD treatmentalone or in combination with ginger-partitioned acupoint stimulation.
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Bello AE, Kent JD, Grahn AY, Rice P, Holt RJ. Risk of Upper Gastrointestinal Ulcers in Patients With Osteoarthritis Receiving Single-Tablet Ibuprofen/Famotidine Versus Ibuprofen Alone: Pooled Efficacy and Safety Analyses of Two Randomized, Double-Blind, Comparison Trials. Postgrad Med 2015; 126:82-91. [DOI: 10.3810/pgm.2014.07.2786] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Boyapati R, Ong SY, Ye B, Kruavit A, Lee N, Vaughan R, Nandurkar S, Gibson P, Garg M. One fifth of hospitalizations for peptic ulcer-related bleeding are potentially preventable. World J Gastroenterol 2014; 20:10504-10511. [PMID: 25132768 PMCID: PMC4130859 DOI: 10.3748/wjg.v20.i30.10504] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Revised: 02/28/2014] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To calculate the proportion of potentially preventable hospitalizations due to peptic ulcer disease (PUD), erosive gastritis (EG) or duodenitis (ED).
METHODS: Retrospective cohort study using ICD-10 codes to identify all patients with upper gastrointestinal hemorrhage secondary to endoscopically proven PUD, EG or ED during the period from March 2007 to October 2010 in three major metropolitan hospitals in Melbourne, Australia. Patients were divided into “high risk” (those who would benefit from gastroprotection) and “not high risk” groups as defined by established guidelines. Mean Rockall score, transfusion requirement, length of stay, rebleeding rates, need for surgery and in-hospital mortality was compared between “high risk” and “not high risk” groups. Within the “high risk” group, those on gastroprotection and those with no gastroprotection were also compared.
RESULTS: Five hundred and seven patients were included for analysis of which 174 were classified as high risk. Median values of complete Rockall Score (5 vs 4, P = 0.002) and length of stay (5 d vs 4 d, P = 0.04) were higher in the high risk group but in-hospital mortality was lower (0.6% vs 3.9%, P = 0.03). 130 out of the 174 patients in the high risk group were not taking recommended gastroprotective therapy prior to hospitalization. Past history of PUD (OR = 3.7, P = 0.006) and clopidogrel use (OR = 3.2, P = 0.007) significantly predicted prescription of gastroprotective therapy. Using proton pump inhibitor protection rates of 50%-85% from published studies, an estimation of 13% to 22% of the total number of the hospitalizations due to PUD or EG/ED related bleeding may have been preventable.
CONCLUSION: Up to one fifth of all hospitalizations for bleeding secondary to PUD or EG/ED are potentially preventable.
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Leacy FP, Stuart EA. On the joint use of propensity and prognostic scores in estimation of the average treatment effect on the treated: a simulation study. Stat Med 2013; 33:3488-508. [PMID: 24151187 DOI: 10.1002/sim.6030] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 10/04/2013] [Accepted: 10/07/2013] [Indexed: 11/11/2022]
Abstract
Propensity and prognostic score methods seek to improve the quality of causal inference in non-randomized or observational studies by replicating the conditions found in a controlled experiment, at least with respect to observed characteristics. Propensity scores model receipt of the treatment of interest; prognostic scores model the potential outcome under a single treatment condition. While the popularity of propensity score methods continues to grow, prognostic score methods and methods combining propensity and prognostic scores have thus far received little attention. To this end, we performed a simulation study that compared subclassification and full matching on a single estimated propensity or prognostic score with three approaches combining the estimated propensity and prognostic scores: full matching on a Mahalanobis distance combining the estimated propensity and prognostic scores (FULL-MAHAL); full matching on the estimated prognostic propensity score within propensity score calipers (FULL-PGPPTY); and subclassification on an estimated propensity and prognostic score grid with 5 × 5 subclasses (SUBCLASS(5*5)). We considered settings in which one, both, or neither score model was misspecified. The data generating mechanisms varied in the degree of linearity and additivity in the true treatment assignment and outcome models. FULL-MAHAL and FULL-PGPPTY exhibited strong to superior performance in root mean square error terms across all simulation settings and scenarios. Methods combining propensity and prognostic scores were no less robust to model misspecification than single-score methods even when both score models were incorrectly specified. Our findings support the joint use of propensity and prognostic scores in estimation of the average treatment effect on the treated.
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Affiliation(s)
- Finbarr P Leacy
- MRC Biostatistics Unit, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge CB2 0SR, U.K
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The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage. Arthritis Res Ther 2013; 15 Suppl 3:S5. [PMID: 24267413 PMCID: PMC3891010 DOI: 10.1186/ar4177] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks.
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Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gastroenterol 2013. [PMID: 23208017 DOI: 10.1007/s00535-012-0717-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND There are conflicting and inconsistent data regarding the gastrointestinal (GI) protective effect of cyclooxygenase-2 (COX-2) inhibitors and of non-steroidal anti-inflammatory drugs (NSAIDs) plus proton-pump inhibitors (PPI). AIM To compare the adverse GI effects between COX-2 inhibitors and NSAIDs plus PPI. METHODS We performed a systematic review of randomized trials comparing GI adverse effects between COX-2 inhibitors and NSAID plus PPI. Trials were identified in MEDLINE, EMBASE, and the Cochrane Library. Primary outcomes were major GI complications including hemorrhage, perforation, and obstruction. RESULTS A total of nine trials involving 7,616 participants from 2002 to 2011 were included. All trials were randomized, double blinded, and placebo-controlled with moderate to high quality. COX-2 inhibitors were found to have significantly reduced the risk of major GI events, including perforation, obstruction, and bleeding (relative risk or RR 0.38, 95 % confidence interval or CI 0.25-0.56, p < 0.001); however, the benefit was significant only for patients who were at high risk for NSAID-related GI complications and long-term users. Additionally, the risk of diarrhea (RR 0.56, 95 % CI 0.35-0.9, p 0.02) and withdrawal (RR 0.77, 95 % CI 0.62-0.94, p 0.01) was significantly lower in use of COX-2 inhibitors, while the rate of dyspepsia was higher (RR 1.58, 95 % CI 1.26-1.98, p < 0.001). CONCLUSIONS COX-2 inhibitors significantly reduced the risk of perforation, obstruction, bleeding, diarrhea, and withdrawal due to GI adverse events, while the risk of dyspepsia was lower with NSAIDs plus PPI.
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Castellsague J, Riera-Guardia N, Calingaert B, Varas-Lorenzo C, Fourrier-Reglat A, Nicotra F, Sturkenboom M, Perez-Gutthann S. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2013; 35:1127-46. [PMID: 23137151 DOI: 10.2165/11633470-000000000-00000] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community's Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. OBJECTIVE The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. METHODS We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. RESULTS A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4-5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. CONCLUSIONS We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.
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20
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Castellsague J, Riera-Guardia N, Calingaert B, Varas-Lorenzo C, Fourrier-Reglat A, Nicotra F, Sturkenboom M, Perez-Gutthann S. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2013. [PMID: 23137151 PMCID: PMC3714137 DOI: 10.1007/bf03261999] [Citation(s) in RCA: 217] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.
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Kuan R, Holt RJ, Johnson KE, Kent JD, Peura DA, Malone D. Budget Impact Modeling for a Single-Tablet Formulation of Ibuprofen and Famotidine for Prevention of Upper Gastrointestinal Ulcers in Patients With Osteoarthritis and/or Rheumatoid Arthritis. Clin Ther 2013; 35:321-32. [DOI: 10.1016/j.clinthera.2013.02.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 02/07/2013] [Accepted: 02/09/2013] [Indexed: 01/16/2023]
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Tadrous M, Gagne JJ, Stürmer T, Cadarette SM. Disease risk score as a confounder summary method: systematic review and recommendations. Pharmacoepidemiol Drug Saf 2013; 22:122-9. [PMID: 23172692 PMCID: PMC3691557 DOI: 10.1002/pds.3377] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 10/20/2012] [Accepted: 10/23/2012] [Indexed: 01/16/2023]
Abstract
PURPOSE To systematically examine trends and applications of the disease risk score (DRS) as a confounder summary method. METHODS We completed a systematic search of MEDLINE and Web of Science® to identify all English language articles that applied DRS methods. We tabulated the number of publications by year and type (empirical application, methodological contribution, or review paper) and summarized methods used in empirical applications overall and by publication year (<2000, ≥2000). RESULTS Of 714 unique articles identified, 97 examined DRS methods and 86 were empirical applications. We observed a bimodal distribution in the number of publications over time, with a peak 1979-1980, and resurgence since 2000. The majority of applications with methodological detail derived DRS using logistic regression (47%), used DRS as a categorical variable in regression (93%), and applied DRS in a non-experimental cohort (47%) or case-control (42%) study. Few studies examined effect modification by outcome risk (23%). CONCLUSION Use of DRS methods has increased yet remains low. Comparative effectiveness research may benefit from more DRS applications, particularly to examine effect modification by outcome risk. Standardized terminology may facilitate identification, application, and comprehension of DRS methods. More research is needed to support the application of DRS methods, particularly in case-control studies.
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Affiliation(s)
- Mina Tadrous
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto
ON
| | - Joshua J. Gagne
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of
Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA
| | - Til Stürmer
- Department of Epidemiology, UNC Gillings School of Global Public
Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Castellsague J, Pisa F, Rosolen V, Drigo D, Riera-Guardia N, Giangreco M, Clagnan E, Tosolini F, Zanier L, Barbone F, Perez-Gutthann S. Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti-inflammatory drugs in Friuli Venezia Giulia, Italy. Pharmacoepidemiol Drug Saf 2012; 22:365-75. [PMID: 23229866 DOI: 10.1002/pds.3385] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 09/21/2012] [Accepted: 10/29/2012] [Indexed: 11/11/2022]
Abstract
PURPOSE Information on the risk of upper gastrointestinal complications (UGIC) in users of nimesulide, the most used nonsteroidal anti-inflammatory drug (NSAID) in Italy, is scarce. In the context of the European regulatory review on nimesulide, we estimated and compared the risk associated with nimesulide and other individual NSAIDs with the risk in nonusers. METHODS We used 2001-2008 data from regional health databases in Friuli Venezia Giulia (FVG), Italy, to conduct a cohort and nested case-control study of users of NSAIDs. Cases were identified by specific and nonspecific hospital discharge diagnoses in primary and secondary position and validated through hospital records. Ten controls per case were selected using density-based sampling from the cohort. Conditional logistic regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS The cohort included 588,827 NSAIDs users and 3031 UGIC cases. Nonspecific codes contributed to 23% of cases and secondary codes to 5%. Among current users, IR per 1000 person-years decreased from 4.45 cases in 2001 to 2.21 cases in 2008. The RR (95%CI) for current use of NSAIDs was 3.28 (2.86, 3.76). RR was <2 for rofecoxib, celecoxib, and nimesulide; 2 to <5 for naproxen, ibuprofen, diclofenac, etoricoxib, and meloxicam; and ≥ 5 for ketoprofen, piroxicam, and ketorolac. CONCLUSIONS IRs of UGIC in FVG decreased about 50% between 2001 and 2008. Nimesulide was in the low-medium range of RR. A complete ascertainment of UGIC cases in databases may require validation of nonspecific codes, secondary codes, and additional codes such as peritonitis and acute posthemorrhagic anemia.
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Valkhoff VE, van Soest EM, Mazzaglia G, Molokhia M, Schade R, Trifiro G, Goldstein JL, Hernandez-Diaz S, Kuipers EJ, Sturkenboom MCJM. Adherence to gastroprotection during cyclooxygenase 2 inhibitor treatment and the risk of upper gastrointestinal tract events: a population-based study. ACTA ACUST UNITED AC 2012; 64:2792-802. [PMID: 22508379 DOI: 10.1002/art.34433] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Guidelines recommend coprescription of gastroprotective agents (GPAs) in patients receiving cyclooxygenase 2 inhibitors (coxibs) who are at high risk of upper gastrointestinal (UGI) tract complications (i.e., patients with a previous complicated ulcer or with multiple risk factors). Suboptimal GPA adherence has been shown to diminish the gastroprotective effect during use of nonselective nonsteroidal antiinflammatory drugs, but little is known about the effect of GPA adherence during coxib treatment. We undertook this study to determine the association between GPA adherence and UGI tract events among patients receiving coxibs. METHODS Using primary care data from 3 databases, we conducted a case-control study in a cohort of patients age ≥50 years who were newly starting treatment with coxibs and concomitantly taking GPAs. Patients who had a UGI tract event (bleeding or symptomatic ulcer) were matched to event-free controls for age, sex, database, and calendar date. Coxib treatment intervals were defined as consecutive coxib prescriptions with intervening gaps not exceeding the duration of the previous coxib prescription. Adherence to GPAs was calculated as the proportion of days of coxib treatment covered by a GPA prescription. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using conditional logistic regression analysis. RESULTS The coxib plus GPA-treated cohort consisted of 14,416 coxib-treated patients who received GPAs for at least 1 day, yielding 16,442 coxib treatment intervals in which a GPA was coprescribed. Most patients were treated with coxibs for <30 days. Seventy-four patients had a UGI tract event during or shortly after a coxib treatment interval in which a GPA was coprescribed, with an incidence rate of 11.9 (95% CI 9.4-14.8) per 1,000 years of coxib treatment. The risk of UGI tract events was 1.97 (95% CI 0.84-4.60) for patients with <20% adherence to GPAs compared to patients with >80% adherence to GPAs. For every 10% decrease in GPA adherence, the risk of UGI tract events increased by 9% (OR 1.09 [95% CI 1.00-1.18]). CONCLUSION Decreasing GPA adherence among coxib-treated patients is associated with an increased risk of UGI tract events.
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Affiliation(s)
- Vera E Valkhoff
- Erasmus University Medical Centre, Rotterdam, The Netherlands.
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Evaluation of the anti-ulcerogenic activity of the antidepressants duloxetine, amitriptyline, fluoxetine and mirtazapine in different models of experimental gastric ulcer in rats. Eur J Pharmacol 2012; 691:46-51. [DOI: 10.1016/j.ejphar.2012.06.041] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 06/26/2012] [Accepted: 06/29/2012] [Indexed: 11/18/2022]
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KuKanich B, Bidgood T, Knesl O. Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs. Vet Anaesth Analg 2012; 39:69-90. [PMID: 22151877 DOI: 10.1111/j.1467-2995.2011.00675.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVES To discuss the clinical pharmacology of currently licensed veterinary NSAIDs and to review gastrointestinal and renal adverse effects as well as drug-drug interactions that have been reported with these drugs. To review the use of NSAIDs in the peri-operative setting and their use in patients with osteoarthritis. To further review the reported effects of NSAIDs on canine articular cartilage and liver as well as the clinical relevance of a washout period. DATABASES USED PubMed, CAB abstracts and Google Scholar using dog, dogs, nonsteroidal anti-inflammatory drugs and NSAID(s) as keywords. CONCLUSIONS A good understanding of the mechanisms by which NSAIDs elicit their analgesic effect is essential in order to minimize adverse effects and drug-drug interactions. Cyclooxygenase (COX) is present in at least two active isoforms in the body and is the primary pharmacologic target of NSAIDs. Inhibition of COX is associated with the analgesic effects of NSAIDs. COX is present in the gastrointestinal tract and kidneys, along with other areas of the body, and is also the likely reason for many adverse effects including gastrointestinal and renal adverse effects. The newer veterinary approved NSAIDs have a lower frequency of gastrointestinal adverse effects in dogs compared to drugs such as aspirin, ketoprofen and flunixin, which may be due to differential effects on the COX isoforms. There are currently no published reports demonstrating that the newer NSAIDs are associated with fewer renal or hepatic adverse effects in dogs. NSAIDs remain the cornerstone of oral therapy for osteoarthritis unless contraindicated by intolerance, concurrent therapies or underlying medical conditions. NSAIDs are also effective and frequently used for the management of post-operative pain.
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Affiliation(s)
- Butch KuKanich
- Kansas State University College of Veterinary Medicine, Manhattan, KS, USA
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Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int 2011; 32:1491-502. [PMID: 22193214 PMCID: PMC3364420 DOI: 10.1007/s00296-011-2263-6] [Citation(s) in RCA: 262] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 12/08/2011] [Indexed: 12/16/2022]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) represent a diverse class of drugs and are among the most commonly used analgesics for arthritic pain worldwide, though long-term use is associated with a spectrum of adverse effects. The introduction of cyclooxygenase-2-selective NSAIDs early in the last decade offered an alternative to traditional NSAIDs with similar efficacy and improved gastrointestinal tolerability; however, emerging concerns about cardiovascular safety resulted in the withdrawal of two agents (rofecoxib and valdecoxib) in the mid-2000s and, subsequently, in an overall reduction in NSAID use. It is now understood that all NSAIDs are associated with some varying degree of gastrointestinal and cardiovascular risk. Guidelines still recommend their use, but little is known of how patients use these agents. While strategies and guidelines aimed at reducing NSAID-associated complications exist, there is a need for evidence-based algorithms combining cardiovascular and gastrointestinal factors that can be used to aid treatment decisions at an individual patient level.
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Affiliation(s)
- Philip G Conaghan
- Section of Musculoskeletal Disease, Department of Musculoskeletal Medicine, Leeds Institute of Molecular Medicine, University of Leeds, 2nd Floor Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK.
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Al-Saeed A. Gastrointestinal and Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs. Oman Med J 2011; 26:385-91. [PMID: 22253945 PMCID: PMC3251190 DOI: 10.5001/omj.2011.101] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Accepted: 10/15/2011] [Indexed: 12/22/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) confer a gastrointestinal (GI) side effect profile and concerns regarding adverse cardiovascular effects have emerged associated with considerable morbidity and mortality. NSAIDs are highly effective in treating pain and inflammation, but it is well recognized that these agents are associated with substantial gastrointestinal toxicity. Cyclo-oxygenase-2 inhibitors may also reduce the risk for gastrointestinal events, although they may increase cardiovascular adverse events. The selection of an appropriate analgesic or anti-inflammatory agent with or without gastroprotective therapy should be individualized.
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Affiliation(s)
- Abdulwahed Al-Saeed
- Section of Gastroenterology, Department of Medicine Dammam Medical Complex Hospital PO Box 18196, Al-Qatif 31911, Saudi Arabia
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Abstract
Cyclooxygenase-2 (COX-2) selective inhibitors were developed as gastrointestinal (GI) safer alternatives to nonselective NSAIDs--providing equivalent analgesic and anti-inflammatory efficacy. Their GI sparing is impaired by concomitant aspirin use, and concerns regarding adverse cardiovascular effects have emerged. Risk factors for NSAID-related complications include a history of ulcer disease or bleeding, concomitant corticosteroid or anticoagulant therapy, use of high-dose or multiple NSAIDs (including low-dose aspirin), advanced age, and certain chronic diseases. If an NSAID must be used in a patient at risk, the lowest-risk NSAID should be used with, in many cases, cotherapy to reduce the risk for ulcers. COX-2 drugs have been associated with a significantly higher risk of vascular events than placebo or naproxen. This increase may be shared by nonselective NSAIDs and appears to be medication- and dose-dependent. Prostaglandin depletion is a central mechanism for NSAID ulcer development, and replacement therapy with misoprostol reduces NSAID toxicity; however, it is rarely used due to side effects. The acid suppression provided by traditional doses of histamine 2-receptor antagonists (H(2)RAs) does not prevent most NSAID-related gastric ulcers. Despite a single study demonstrating that H(2)RAs at double the dose may be effective, studies comparing such high doses with misoprostol or proton pump inhibitors (PPIs) for preventing NSAID ulcers are not available. PPIs are effective at single daily doses, do not demonstrate tachyphylaxis, and are superior to H(2)RAs and misoprostol in reducing ulcers and NSAID-associated dyspepsia. NSAID choice should be predicated by an assessment of an individual's cardiovascular and GI risk. For those with competing cardiovascular and GI risks, the tradeoffs between reducing adverse GI events (COX-2 inhibitor instead of a nonselective NSAID) must be explicitly weighed against concerns about cardiovascular side effects (naproxen instead of other agents). Considering cost is appropriate because it may not be feasible to recommend the "safest" regimen in every circumstance. The cost effectiveness of risk-reducing therapies is intimately tied to the patient's underlying risk. For those at highest GI risk, using a PPI and a low-dose COX-2 inhibitor seems appropriate for those without high cardiovascular risk. For patients whose cardiovascular risk parallels or exceeds GI concerns, naproxen with a PPI is recommended when non-NSAID approaches fail.
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Affiliation(s)
- James M Scheiman
- James M. Scheiman, MD Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
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Lin KJ, Hernández-Díaz S, García Rodríguez LA. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology 2011; 141:71-9. [PMID: 21458456 DOI: 10.1053/j.gastro.2011.03.049] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Revised: 03/04/2011] [Accepted: 03/18/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS We investigated the effect of different prevention strategies against upper gastrointestinal bleeding (UGIB) in the general population and in patients on antithrombotic or anti-inflammatory treatments. METHODS We performed a population-based, nested, case-control study using The Health Improvement Network UK primary care database. From 2000 to 2007, we identified 2049 cases of UGIB and 20,000 controls. The relative risk (RR) of UGIB associated with various gastroprotective agents was estimated by comparing current use (defined as use within 30 days of the index date) with nonuse in the previous year, using multivariate logistic regression. RESULTS The adjusted RR of UGIB associated with current use of proton pump inhibitors (PPIs) for more than 1 month was 0.58 (95% confidence interval [CI], 0.42-0.79) among patients who received low-dose acetylsalicylic acid (ASA), 0.18 (95% CI, 0.04-0.79) for clopidogrel, 0.17 (95% CI, 0.04-0.76) for dual antiplatelet therapy, 0.48 (95% CI, 0.22-1.04) for warfarin, and 0.51 (95% CI, 0.34-0.78) for nonsteroidal anti-inflammatory drugs. The corresponding estimates for therapy with histamine-2-receptor antagonists (H2RAs) were more unstable, but tended to be of a smaller magnitude. In the general population, PPI use was associated with a reduced risk of UGIB compared with nonuse (RR, 0.80; 95% CI, 0.68-0.94); no such reduction was observed for H2RAs or nitrates. CONCLUSIONS PPI use was associated with a lower risk of UGIB in the general population and in patients on antithrombotic or anti-inflammatory therapy compared with nonuse of PPIs. The reduction in risks of UGIB was smaller in H2RA than in PPI users.
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Affiliation(s)
- Kueiyu Joshua Lin
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
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Cunningham A, Stein CM, Chung CP, Daugherty JR, Smalley WE, Ray WA. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf 2011; 20:560-6. [PMID: 21387461 PMCID: PMC3365595 DOI: 10.1002/pds.2109] [Citation(s) in RCA: 294] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2010] [Revised: 12/21/2010] [Accepted: 12/28/2010] [Indexed: 12/28/2022]
Abstract
PURPOSE Bleeding complications are a serious adverse effect of medications that prevent abnormal blood clotting. To facilitate epidemiologic investigations of bleeding complications, we developed and validated an automated database case definition for bleeding-related hospitalizations. METHODS The case definition utilized information from an in-progress retrospective cohort study of warfarin-related bleeding in Tennessee Medicaid enrollees 30 years of age or older. It identified inpatient stays during the study period of January 1990 to December 2005 with diagnoses and/or procedures that indicated a current episode of bleeding. The definition was validated by medical record review for a sample of 236 hospitalizations. RESULTS We reviewed 186 hospitalizations that had medical records with sufficient information for adjudication. Of these, 165 (89%, 95%CI: 83-92%) were clinically confirmed bleeding-related hospitalizations. An additional 19 hospitalizations (10%, 7-15%) were adjudicated as possibly bleeding-related. Of the 165 clinically confirmed bleeding-related hospitalizations, the automated database and clinical definitions had concordant anatomical sites (gastrointestinal, cerebral, genitourinary, other) for 163 (99%, 96-100%). For those hospitalizations with sufficient information to distinguish between upper/lower gastrointestinal bleeding, the concordance was 89% (76-96%) for upper gastrointestinal sites and 91% (77-97%) for lower gastrointestinal sites. CONCLUSION A case definition for bleeding-related hospitalizations suitable for automated databases had a positive predictive value of between 89% and 99% and could distinguish specific bleeding sites.
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Affiliation(s)
- Andrew Cunningham
- Division of Clinical Pharmacology, Department of Medicine, Nashville, TN, USA
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Lin KJ, García Rodríguez LA, Hernández-Díaz S. Systematic review of peptic ulcer disease incidence rates: do studies without validation provide reliable estimates? Pharmacoepidemiol Drug Saf 2011; 20:718-28. [PMID: 21626606 DOI: 10.1002/pds.2153] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Revised: 03/22/2011] [Accepted: 03/22/2011] [Indexed: 12/14/2022]
Abstract
PURPOSE Incidence rate (IR) estimates for peptic ulcer disease (PUD) vary widely among studies. We conducted a systematic review to quantify and examine the discrepancies. METHODS Of 4780 articles identified from PubMed and EMBASE databases, 31 published in the last three decades that had reported IRs of PUD in the general population were included. Random effects meta-analysis and meta-regression were performed to calculate pooled estimates and to identify sources of heterogeneity. RESULTS The pooled IR estimate per 1000 person-years was 0.90 (95% confidence interval: 0.78-1.04) for uncomplicated PUD, 0.57 (0.49-0.65) for peptic ulcer bleeding, 0.10 (0.08-0.13) for gastrointestinal perforations, and 3.18 (2.05-4.92) for nonspecific PUD. Within specific outcomes definitions, IR estimates were significantly lower in studies with restriction to hospitalized cases, case validation, and case ascertainment directly from hospital or clinical sources versus computerized health care databases. Younger age, female sex, and later calendar time were also associated with lower PUD incidence. CONCLUSIONS We found that the IR of uncomplicated PUD was in the order of one case per 1000 person-years in the general population, and that the IR of peptic ulcer complications was around 0.7 cases per 1000 person-years. Comparisons of IR estimates among studies need to take into account disease definition and other study characteristics, particularly whether outcome validation was performed in computerized claims. The use of claims to identify PUD cases might overestimate the IR by around 45%.
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Affiliation(s)
- Kueiyu Joshua Lin
- Department of Epidemiology, Harvard School of Public Health, Boston, USA
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Goldstein JL, Hochberg MC, Fort JG, Zhang Y, Hwang C, Sostek M. Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone. Aliment Pharmacol Ther 2010; 32:401-13. [PMID: 20497139 DOI: 10.1111/j.1365-2036.2010.04378.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Gastroprotective co-therapy may reduce the risk of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers, but adherence is suboptimal. AIM To compare the incidence of gastric ulcers with PN 400 [enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg], or EC naproxen. METHODS Two randomized, double-blind, multicentre studies (PN400-301, PN400-302). Patients [stratified by low-dose aspirin (< or =325 mg) use] aged > or =50 years or 18-49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. RESULTS The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low-dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non-users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). CONCLUSIONS PN 400 significantly reduces the incidence of gastric ulcers, regardless of low-dose aspirin use, in at-risk patients, and is associated with improved UGI tolerability relative to EC naproxen (ClinicalTrials.gov, NCT00527782).
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Affiliation(s)
- J L Goldstein
- Department of Medicine, University of Illinois at Chicago, 60612, USA.
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Chan FKL, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376:173-9. [PMID: 20638563 DOI: 10.1016/s0140-6736(10)60673-3] [Citation(s) in RCA: 225] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs (NSAIDs) and non-selective NSAIDs plus a proton-pump inhibitor (PPI) have similar upper gastrointestinal outcomes, but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs. We aimed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole. METHODS We undertook a 6-month, double-blind, randomised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories. Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration. We used a computer-generated randomisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day. Patients and investigators were masked to treatment allocation. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events adjudicated by an independent committee. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00141102. FINDINGS 4484 patients were randomly allocated to treatment (2238 celecoxib; 2246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. 20 (0.9%) patients receiving celecoxib and 81 (3.8%) receiving diclofenac plus omeprazole met criteria for the primary endpoint (hazard ratio 4.3, 95% CI 2.6-7.0; p<0.0001). 114 (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (p=0.0006). INTERPRETATION Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI. These findings should encourage review of approaches to reduce risk of NSAID treatment. FUNDING Pfizer Inc.
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Affiliation(s)
- Francis K L Chan
- Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.
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Chung CP, Murray KT, Stein CM, Hall K, Ray WA. A computer case definition for sudden cardiac death. Pharmacoepidemiol Drug Saf 2010; 19:563-72. [PMID: 20029823 PMCID: PMC3181496 DOI: 10.1002/pds.1888] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
PURPOSE To facilitate studies of medications and sudden cardiac death, we developed and validated a computer case definition for these deaths. The study of community dwelling Tennessee Medicaid enrollees 30-74 years of age utilized a linked database with Medicaid inpatient/outpatient files, state death certificate files, and a state 'all-payers' hospital discharge file. METHODS The computerized case definition was developed from a retrospective cohort study of sudden cardiac deaths occurring between 1990 and 1993. Medical records for 926 potential cases had been adjudicated for this study to determine if they met the clinical definition for sudden cardiac death occurring in the community and were likely to be due to ventricular tachyarrhythmias. The computerized case definition included deaths with (1) no evidence of a terminal hospital admission/nursing home stay in any of the data sources; (2) an underlying cause of death code consistent with sudden cardiac death; and (3) no terminal procedures inconsistent with unresuscitated cardiac arrest. This definition was validated in an independent sample of 174 adjudicated deaths occurring between 1994 and 2005. RESULTS The positive predictive value of the computer case definition was 86.0% in the development sample and 86.8% in the validation sample. The positive predictive value did not vary materially for deaths coded according to the ICO-9 (1994-1998, positive predictive value = 85.1%) or ICD-10 (1999-2005, 87.4%) systems. CONCLUSION A computerized Medicaid database, linked with death certificate files and a state hospital discharge database, can be used for a computer case definition of sudden cardiac death.
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Affiliation(s)
- Cecilia P Chung
- Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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Abstract
BACKGROUND Preventive strategies are advocated in patients at risk of upper-gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs (NSAIDs). AIM To examine time-trends in preventive strategies. METHODS In a study population comprising 50 126 NSAID users > or =50 years from the Integrated Primary Care Information database, we considered two preventive strategies: co-prescription of gastroprotective agents and prescription of a cyclooxygenase-2-selective inhibitor. In patients with > or =1 risk factor (history of upper-gastrointestinal bleeding/ulceration, age >65 years, use of anticoagulants, aspirin, or corticosteroids), correct prescription was defined as the presence of a preventive strategy and under-prescription as the absence of one. In patients with no risk factors, correct prescription was defined as the lack of a preventive strategy, and over-prescription as the presence of one. RESULTS Correct prescription rose from 6.9% in 1996 to 39.4% in 2006 (P < 0.01) in high-risk NSAID users. Under-prescription fell from 93.1% to 59.9% (P < 0.01). In the complete cohort, over-prescription rose from 2.9% to 12.3% (P < 0.01). CONCLUSIONS Under-prescription of preventive strategies has steadily decreased between 1996 and 2006; however, 60% of NSAID users at increased risk of NSAID complications still do not receive adequate protection.
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Bianco MA, Rotondano G, Buri L, Tessari F, Cipolletta L. Gastro-protective strategies in primary care in Italy: the "Gas.Pro." survey. Dig Liver Dis 2010; 42:359-64. [PMID: 20005189 DOI: 10.1016/j.dld.2009.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2009] [Revised: 10/21/2009] [Accepted: 11/15/2009] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Risk of gastrointestinal injury is relevant among users of anti-inflammatory or cardio-protective drugs. Adequate gastro-protection is warranted in high-risk patients. AIM To assess the perceptions and practices of Italian primary care physicians regarding gastro-protective strategies. METHODS Nationwide cross-sectional observational study. A 14-question survey questionnaire was administered to 112 primary care physicians throughout Italy. Data collection covered consecutive outpatient candidates for the prescription of a potentially GI harmful medication, observed in the physicians' office over a 3-week period. RESULTS Cohort included 3943 cases (2489 naïve and 1463 chronic NSAID/ASA users). Mean age and prevalence of cardiovascular comorbidity were significantly higher in the latter subgroup. Non-selective NSAIDs and low-dose aspirin were the most commonly prescribed drugs. Combined NSAIDS/ASA plus steroids/anticoagulant/antiplatelets were recorded in 161 cases. Helicobacter pylori status was known in only 38% of naïve and 33.2% of chronic users, being negative in 85.3% and 89.5%, respectively. When positive, H. pylori was eradicated by almost all physicians (97.9%), but in case of unknown H. pylori status, the presence of infection was investigated in only 8.6% and 14.9% of patients in the two subgroups. Gastro-protection was endorsed in 80.7% of patients, mostly PPIs (91%). In patients aged over 70, pantoprazole and lansoprazole were the preferred gastro-protective agents. CONCLUSIONS There is a significant over-use of gastro-protection in the primary care setting in Italy and the role H. pylori is largely overlooked. Educational efforts should be directed to a more targeted gastro-protection only for at-risk patients as well as improved adherence to recommendations for testing and treating H. pylori infection.
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Affiliation(s)
- Maria A Bianco
- U.O.C. di Gastroenterologia - Ospedale Maresca, Torre del Greco, Viale degli Aranci 2, 80131 Naples, Italy.
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Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty JR, Kaltenbach LA, Stein CM. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med 2010. [PMID: 20231564 DOI: 10.1059/0003-4819-152-6-201003160-00003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear. OBJECTIVE To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease. DESIGN Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease. SETTING Tennessee Medicaid program. PATIENTS 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. MEASUREMENTS Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death). RESULTS Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization. LIMITATIONS Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. CONCLUSION In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.
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Affiliation(s)
- Wayne A Ray
- Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
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Scheiman JM, Hindley CE. Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and cardiovascular adverse events. Clin Ther 2010; 32:667-77. [DOI: 10.1016/j.clinthera.2010.04.009] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2010] [Indexed: 01/30/2023]
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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; 24:203-215. [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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Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty JR, Kaltenbach LA, Stein CM. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med 2010; 152:337-45. [PMID: 20231564 PMCID: PMC3176584 DOI: 10.7326/0003-4819-152-6-201003160-00003] [Citation(s) in RCA: 163] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear. OBJECTIVE To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease. DESIGN Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease. SETTING Tennessee Medicaid program. PATIENTS 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. MEASUREMENTS Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death). RESULTS Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization. LIMITATIONS Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. CONCLUSION In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.
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Affiliation(s)
- Wayne A Ray
- Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
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Co-prescription of gastro-protectants in hospitalized patients: an analysis of what we do and what we think we do. J Clin Gastroenterol 2010; 44:e51-6. [PMID: 19609216 DOI: 10.1097/mcg.0b013e3181a9f43b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) reduce the risk of upper gastrointestinal hemorrhage (UGIH) associated with the use of many medications. GOALS To examine how clinicians perceive such risk and whether PPI co-prescribing is based on an accurate assessment. STUDY METHODS Clinicians in a single teaching hospital were asked to estimate risk of UGIH and comment on PPI co-prescription in hypothetical patients. Records of 160 hospital in-patients (median age; 74 y) were then reviewed to examine PPI prescribing and risk factors for UGIH. RESULTS In general, clinicians estimated UGIH risk accurately and reported low thresholds for PPI co-prescription. Prescribing records showed regular PPI use increased between admission and discharge of patients from 61/160 (38%) to 93/160 (58%). Ten percent had a prior history of peptic ulcer disease. Proton pump inhibitor prescription was significantly associated with the use of aspirin and clopidogrel. Half of the patients with multiple risk factors for UGIH on admission and almost a third at discharge were not co-prescribed a PPI. CONCLUSIONS Clinicians generally estimate correctly the risk of UGIH and report a low threshold for prescribing gastro-protection. Despite this, prescribing practice does not consistently take account of relative risk of UGIH. Targeted PPI co-prescribing on the basis of risk factors would lead to more rational PPI use.
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Etiology and Treatment of Childhood Peptic Ulcer Disease in Taiwan: A Single Center 9-Year Experience. J Formos Med Assoc 2010; 109:75-81. [PMID: 20123589 DOI: 10.1016/s0929-6646(10)60024-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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Pilotto A, Sancarlo D, Addante F, Scarcelli C, Franceschi M. Non-steroidal anti-inflammatory drug use in the elderly. Surg Oncol 2009; 19:167-72. [PMID: 20022240 DOI: 10.1016/j.suronc.2009.11.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammation and pain of various origins is well established. Prescribing these drugs, however, remains a challenge because a great variety of gastrointestinal and cardiovascular safety issues need to be considered, particularly in older patients. Recent recommendations suggest that the prescription of non-selective NSAIDs and/or selective cyclo-oxygenase-2 inhibitors (coxibs) may be appropriate in patients with low gastrointestinal risk (no prior gastrointestinal events, no concomitant treatments with other damaging drugs). Gastroprotection is appropriate in patients with gastrointestinal risk factors and in older patients. In patients at high risk for gastrointestinal and cardiovascular events, however, NSAID or coxib prescriptions are contraindicated. Multidimensional impairment is a crucial point in evaluating the clinical outcome of older patients; thus, a comprehensive geriatric assessment is useful in predicting adverse outcomes, including morbidity and mortality.
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Affiliation(s)
- Alberto Pilotto
- Department of Medical Sciences, Geriatric Unit and Research Laboratory Gerontology & Geriatrics, I.R.C.C.S. Casa Sollievo della Sofferenza, Viale Cappuccini 1, I-71013 San Giovanni Rotondo (FG), Italy.
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Abstract
PURPOSE OF REVIEW This article reviews selected publications related to nonsteroid anti-inflammatory drug (NSAID)-induced gastroduodenal toxicity in recent years. RECENT FINDINGS This article provides a comprehensive review of the latest evidence on the epidemiology of NSAID-induced gastroduodenal injury, recommendations on optimal gastroprotective regimens among patients in need of NSAID, risk stratification approach by considering gastrointestinal and cardiovascular risks, and negative interaction between proton pump inhibitors (PPIs) and clopidogrel. SUMMARY Current evidence indicates that a PPI and a cyclooxygenase (COX)-2-selective NSAID provides the best gastric protection. In light of potential cardiovascular hazard of NSAIDs, physicians should select an NSAID according to individual patients' cardiovascular risk (i.e., naproxen vs. a nonnaproxen NSAID). The choice of gastroprotective therapy depends on the number and nature of gastrointestinal risk factors. PPI co-therapy is recommended in patients with high gastrointestinal risk on aspirin. Whether there is any clinically important interaction between PPIs and clopidogrel remains uncertain.
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Abstract
Peptic ulcer disease had a tremendous effect on morbidity and mortality until the last decades of the 20th century, when epidemiological trends started to point to an impressive fall in its incidence. Two important developments are associated with the decrease in rates of peptic ulcer disease: the discovery of effective and potent acid suppressants, and of Helicobacter pylori. With the discovery of H pylori infection, the causes, pathogenesis, and treatment of peptic ulcer disease have been rewritten. We focus on this revolution of understanding and management of peptic ulcer disease over the past 25 years. Despite substantial advances, this disease remains an important clinical problem, largely because of the increasingly widespread use of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin. We discuss the role of these agents in the causes of ulcer disease and therapeutic and preventive strategies for drug-induced ulcers. The rare but increasingly problematic H pylori-negative NSAID-negative ulcer is also examined.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
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Laine L, Connors L, Griffin MR, Curtis SP, Kaur A, Cannon CP. Prescription rates of protective co-therapy for NSAID users at high GI risk and results of attempts to improve adherence to guidelines. Aliment Pharmacol Ther 2009; 30:767-74. [PMID: 19594486 DOI: 10.1111/j.1365-2036.2009.04090.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Protective co-therapy is recommended in NSAID users with GI risk factors, but adherence is poor. AIM To assess the proportion of NSAID users receiving co-therapy and strategies to improve adherence. METHODS Arthritis patients > or =50 years of age received etoricoxib or diclofenac in a double-blind randomized trial. Reminders that high-risk patients (age > or = 65; previous ulcer/haemorrhage; corticosteroid, anticoagulant, aspirin use) should receive co-therapy were given at study initiation. Free PPI was provided. An intervention midway through the study included a written reminder and required written response regarding co-therapy. RESULTS 16,244/23,504 (69%) patients had GI risk factors. Pre-intervention, co-therapy was most common with previous ulcer/haemorrhage [706/1107 (64%)] and 3-4 risk factors [331/519 (64%)]. In the 10,026 patients enrolled pre-intervention and remaining in the study > or =6 months after, co-therapy in high-risk patients increased from 2958/6843 (43%) to 4177/6843 (61%) (difference = 18%; 95% CI 16%,19%). The increase was greater outside the US (22%; 19%,24%) than in the US (15%; 13%,17%). CONCLUSIONS Less than 50% of NSAID users with GI risk factors are given protective co-therapy--even if prescribers are given reminders and cost is not an issue. Direct communication requiring written response significantly increased adherence to guidelines, but achieving higher levels of adherence will require additional strategies.
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Affiliation(s)
- L Laine
- Division of Gastrointestinal & Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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A patient with osteoarthritis and cardiovascular disease presenting with bilateral hip pain: a case report. CASES JOURNAL 2009; 2:8823. [PMID: 19918403 PMCID: PMC2769473 DOI: 10.4076/1757-1626-2-8823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Accepted: 08/11/2009] [Indexed: 11/30/2022]
Abstract
Introduction The pharmacological management of osteoarthritis normally begins with the administration of acetaminophen or a nonselective nonsteroidal anti-inflammatory drug. However, acetaminophen may not be efficacious in all patients, and nonsteroidal anti-inflammatory drugs may be associated with gastrointestinal and cardiovascular adverse effects. Case presentation A 79-year-old Caucasian man with bilateral hip pain was diagnosed with osteoarthritis of the hip. His past medical history included three prior myocardial infarctions, the most recent one occurring 2 years ago. He is taking aspirin 81 mg once daily. Despite no history of ulcer disease or bleeding, he has been reluctant to take nonsteroidal anti-inflammatory drugs, and because of his cardiac history there is a contraindication to cyclooxygenase-2-specific inhibitors. He was started on naproxen 220 mg twice daily, with the proton pump inhibitor omeprazole 20 mg once daily. Upon follow-up at 4 weeks, his hip pain had decreased from a rating of 7 (on a ten-point scale) to 5 on his left side and from 5 to 2 on his right side. The patient began a course of physical therapy in conjunction with a regimen of naproxen 440 mg in the morning and 220 mg at night, plus the omeprazole and acetaminophen 650 mg twice daily. He reported no gastrointestinal effects. Conclusion The addition of a proton pump inhibitor to nonsteroidal anti-inflammatory drug therapy can reduce the risk of peptic ulcer bleeding by ≥80%, making the incidence of gastropathy the same as with cyclooxygenase-2-specific inhibitors. The fact that naproxen is not associated with an increased risk of acute myocardial infarction made it an appropriate choice for this patient.
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van der Linden MW, Gaugris S, Kuipers EJ, van Herk-Sukel MPP, van den Bemt BJF, Sen SS, Herings RMC. COX-2 inhibitors: complex association with lower risk of hospitalization for gastrointestinal events compared to traditional NSAIDs plus proton pump inhibitors. Pharmacoepidemiol Drug Saf 2009; 18:880-90. [DOI: 10.1002/pds.1782] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Arora G, Singh G, Triadafilopoulos G. Proton pump inhibitors for gastroduodenal damage related to nonsteroidal anti-inflammatory drugs or aspirin: twelve important questions for clinical practice. Clin Gastroenterol Hepatol 2009; 7:725-35. [PMID: 19306941 DOI: 10.1016/j.cgh.2009.03.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Revised: 03/06/2009] [Accepted: 03/11/2009] [Indexed: 02/07/2023]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are among the most commonly used medications worldwide. Their use is associated with significant gastroduodenal adverse effects, including dyspepsia, bleeding, ulcer formation, and perforation. Given their long-term use by millions of patients, there is a substantial impact at the population level of these complications. In this evidence-based review, we have endeavored to answer 12 commonly encountered questions in clinical practice that deal with the following: extent of the problem of NSAID/aspirin-induced gastroduodenal damage and its impact on public health; role of proton pump inhibitors (PPIs) in the primary prevention, healing, and secondary prevention of NSAID/aspirin-induced gastroduodenal ulceration as assessed by using endoscopic end points; role of PPIs in the prevention of adverse clinical outcomes related to NSAID/aspirin use; whether PPIs are effective in NSAID-induced dyspepsia; comparison of PPI co-therapy with selective cyclooxygenase-2 inhibitors for risk reduction of adverse clinical outcomes; role of PPIs in preventing rebleeding from aspirin +/- clopidogrel therapy in high-risk patients; identifying high-risk patients who can benefit from PPI co-therapy; the role of other gastroprotective agents for prevention of NSAID/aspirin-induced gastroduodenal damage; and the cost-effectiveness of and limitations to the use of PPIs for prevention of gastroduodenal damage related to the use of NSAIDs or aspirin. We then summarized our recommendations on the use of PPIs for the clinical management of patients using NSAIDs or aspirin.
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Affiliation(s)
- Gaurav Arora
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California 94305-5187, USA
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