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Inglis JM, Caughey G, Thynne T, Brotherton K, Liew D, Mangoni AA, Shakib S. Association of Drug-Disease Interactions with Mortality or Readmission in Hospitalised Middle-Aged and Older Adults: A Systematic Review and Meta-Analysis. Drugs Real World Outcomes 2024; 11:345-360. [PMID: 38852118 PMCID: PMC11365905 DOI: 10.1007/s40801-024-00432-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2024] [Indexed: 06/10/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Multimorbidity is common in hospitalised adults who are at increased risk of inappropriate prescribing including drug-disease interactions. These interactions occur when a medicine being used to treat one condition exacerbates a concurrent medical condition and may lead to adverse health outcomes. The aim of this review was to examine the association between drug-disease interactions and the risk of mortality and readmission in hospitalised middle-aged and older adults. METHODS A systematic review was conducted on drug-disease interactions in hospitalised middle-aged (45-64 years) and older adults (≥65 years). The study protocol was prospectively registered with PROSPERO (Registration Number: CRD42022341998). Drug-disease interactions were defined as a medicine being used to treat one condition with the potential to exacerbate a concurrent medical condition or that were inappropriate based on a comorbid medical condition. Both observational and interventional studies were included. The outcomes of interest were mortality and readmissions. The databases searched included MEDLINE, CINAHL, EMBASE, Web of Science, SCOPUS and the Cochrane Library from inception to 12 July, 2022. A meta-analysis was performed to pool risk estimates using the random-effects model. RESULTS A total of 563 studies were identified and four met the inclusion criteria. All were observational studies in older adults, with no studies identified in middle-aged adults. Most of the studies were at risk of bias because of an inadequate adjustment for covariates and a lack of clarity around individuals lost to follow-up. There were various definitions of drug-disease interactions within these four studies. Two studies assessed drugs that were contraindicated based on renal function, one assessed an individual drug-disease combination, and one was based on the clinical judgement of a pharmacist. There were two studies that showed an association between drug-disease interactions and the outcomes of interest. One reported that the use of diltiazem in patients with heart failure was associated with an increased risk of readmissions. The second reported that the use of medicines contraindicated according to renal function were associated with increased risk of all-cause mortality and a composite of mortality and readmission. Three of the studies (total study population = 5705) were amenable to a meta-analysis, which showed no significant association between drug-disease interactions and readmissions (odds ratio = 1.0, 95% confidence interval 0.80-1.38). CONCLUSIONS Few studies were identified examining the risk of drug-disease interactions and mortality and readmission in hospitalised adults. Most of the identified studies were at risk of bias. There is no universal accepted definition of drug-disease interactions in the literature. Further studies are needed to develop a standardised and accepted definition of these interactions to guide further research in this area.
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Affiliation(s)
- Joshua M Inglis
- Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia.
- Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA, 5000, Australia.
| | - Gillian Caughey
- Registry of Senior Australians, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Tilenka Thynne
- Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia
| | - Kate Brotherton
- Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia
| | - Danny Liew
- Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA, 5000, Australia
- Department of General Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Arduino A Mangoni
- Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia
| | - Sepehr Shakib
- Adelaide Medical School, University of Adelaide, North Terrace, Adelaide, SA, 5000, Australia
- Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA, Australia
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Narendren A, Whitehead N, Burrell LM, Yudi MB, Yeoh J, Jones N, Weinberg L, Miles LF, Lim HS, Clark DJ, Al-Fiadh A, Farouque O, Koshy AN. Management of Acute Coronary Syndromes in Older People: Comprehensive Review and Multidisciplinary Practice-Based Recommendations. J Clin Med 2024; 13:4416. [PMID: 39124683 PMCID: PMC11312870 DOI: 10.3390/jcm13154416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Managing health care for older adults aged 75 years and older can pose unique challenges stemming from age-related physiological differences and comorbidities, along with elevated risk of delirium, frailty, disability, and polypharmacy. This review is aimed at providing a comprehensive analysis of the management of acute coronary syndromes (ACS) in older patients, a demographic substantially underrepresented in major clinical trials. Because older patients often exhibit atypical ACS symptoms, a nuanced diagnostic and risk stratification approach is necessary. We aim to address diagnostic challenges for older populations and highlight the diminished sensitivity of traditional symptoms with age, and the importance of biomarkers and imaging techniques tailored for older patients. Additionally, we review the efficacy and safety of pharmacological agents for ACS management in older people, emphasizing the need for a personalized and shared decision-making approach to treatment. This review also explores revascularization strategies, considering the implications of invasive procedures in older people, and weighing the potential benefits against the heightened procedural risks, particularly with surgical revascularization techniques. We explore the perioperative management of older patients experiencing myocardial infarction in the setting of noncardiac surgeries, including preoperative risk stratification and postoperative care considerations. Furthermore, we highlight the critical role of a multidisciplinary approach involving cardiologists, geriatricians, general and internal medicine physicians, primary care physicians, and allied health, to ensure a holistic care pathway in this patient cohort.
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Affiliation(s)
- Ahthavan Narendren
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Cardiology, Northern Health, Epping, VIC 3076, Australia
| | - Natalie Whitehead
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
| | - Louise M. Burrell
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Matias B. Yudi
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
| | - Julian Yeoh
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
| | - Nicholas Jones
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Laurence Weinberg
- Department of Critical Care, The University of Melbourne, Melbourne, VIC 3010, Australia; (L.W.); (L.F.M.)
- Department of Anaesthesia, Austin Health, Heidelberg, VIC 3084, Australia
| | - Lachlan F. Miles
- Department of Critical Care, The University of Melbourne, Melbourne, VIC 3010, Australia; (L.W.); (L.F.M.)
- Department of Anaesthesia, Austin Health, Heidelberg, VIC 3084, Australia
| | - Han S. Lim
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Cardiology, Northern Health, Epping, VIC 3076, Australia
- Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - David J. Clark
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Ali Al-Fiadh
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Omar Farouque
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
| | - Anoop N. Koshy
- Department of Cardiology, Austin Health, Heidelberg, VIC 3084, Australia; (A.N.); (N.W.); (L.M.B.); (M.B.Y.); (J.Y.); (N.J.); (H.S.L.); (D.J.C.); (A.A.-F.); (O.F.)
- Department of Medicine, The University of Melbourne, Melbourne, VIC 3052, Australia
- Department of Cardiology, The Royal Melbourne Hospital, Parkville, VIC 3052, Australia
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Bou Malham C, El Khatib S, Cestac P, Andrieu S, Rouch L, Salameh P. Management of potentially inappropriate medication use among older adult's patients in primary care settings: description of an interventional prospective non-randomized study. BMC PRIMARY CARE 2024; 25:213. [PMID: 38872125 PMCID: PMC11170768 DOI: 10.1186/s12875-024-02334-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 03/07/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND The management of inappropriate medication use in older patients suffering from multimorbidity and polymedication is a major healthcare challenge. In a primary care setting, a medication review is an effective tool through which a pharmacist can collaborate with a practitioner to detect inappropriate drug use. AIM This project described the implementation of a systematic process for the management of potentially inappropriate medication use among Lebanese older adults. Its aim was to involve pharmacists in geriatric care and to suggest treatment optimization through the analysis of prescriptions using explicit and implicit criteria. METHOD This study evaluated the medications of patients over 65 years taking a minimum of five chronic medications a day in different regions of Lebanon. Descriptive statistics for all the included variables using mean and standard deviation (Mean (SD)) for continuous variables and frequency and percentage (n, (%)) for multinomial variables were then performed. RESULTS A total of 850 patients (50.7% women, 28.6% frail, 75.7 (8.01) mean age (SD)) were included in this study. The mean number of drugs per prescription was 7.10 (2.45). Roughly 88% of patients (n = 748) had at least one potentially inappropriate drug prescription: 66.4% and 64.4% of the patients had at least 1 drug with an unfavorable benefit-to-risk ratio according to Beers and EU(7)-PIM respectively. Nearly 50.4% of patients took at least one medication with no indication. The pharmacists recommended discontinuing medication for 76.5% of the cases of drug related problems. 26.6% of the overall proposed interventions were implemented. DISCUSSION The rate of potentially inappropriate drug prescribing (PIDP) (88%) was higher than the rates previously reported in Europe, US, and Canada. It was also higher than studies conducted in Lebanon where it varied from 22.4 to 80% depending on the explicit criteria used, the settings, and the medical conditions of the patients. We used both implicit and explicit criteria with five different lists to improve the detection of all types of inappropriate medication use since Lebanon obtains drugs from many different sources. Another potential source for variation is the lack of a standardized process for the assessment of outpatient medication use in the elderly. CONCLUSION The prevalence PIDP detected in the sample was higher than the percentages reported in previous literature. Systematic review of prescriptions has the capacity to identify and resolve pharmaceutical care issues thus improving geriatric care.
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Affiliation(s)
- Carmela Bou Malham
- Aging Research Team, Center for Epidemiology and Research in POPulation health (CERPOP), Université de Toulouse, Université Paul Sabatier, Inserm, Toulouse, 31000, France.
- University Paul Sabatier Toulouse III, Toulouse, 31062, France.
| | - Sarah El Khatib
- Aging Research Team, Center for Epidemiology and Research in POPulation health (CERPOP), Université de Toulouse, Université Paul Sabatier, Inserm, Toulouse, 31000, France
- University Paul Sabatier Toulouse III, Toulouse, 31062, France
| | - Philippe Cestac
- Aging Research Team, Center for Epidemiology and Research in POPulation health (CERPOP), Université de Toulouse, Université Paul Sabatier, Inserm, Toulouse, 31000, France
- University Paul Sabatier Toulouse III, Toulouse, 31062, France
- Department of Pharmacy, Toulouse University Hospitals, Purpan Hospital, Toulouse, 31059, France
| | - Sandrine Andrieu
- Aging Research Team, Center for Epidemiology and Research in POPulation health (CERPOP), Université de Toulouse, Université Paul Sabatier, Inserm, Toulouse, 31000, France
- University Paul Sabatier Toulouse III, Toulouse, 31062, France
- Department of Pharmacy, Toulouse University Hospitals, Purpan Hospital, Toulouse, 31059, France
| | - Laure Rouch
- Aging Research Team, Center for Epidemiology and Research in POPulation health (CERPOP), Université de Toulouse, Université Paul Sabatier, Inserm, Toulouse, 31000, France
- University Paul Sabatier Toulouse III, Toulouse, 31062, France
- Department of Pharmacy, Toulouse University Hospitals, Purpan Hospital, Toulouse, 31059, France
| | - Pascale Salameh
- School of Medicine, Lebanese American University, Byblos, 1401, Lebanon
- University of Nicosia Medical School, Nicosia, 1065, Cyprus
- Faculty of Pharmacy, Lebanese University, Hadath, 1100, Lebanon
- Institut National de Santé Publique, Epidémiologie Clinique et Toxicologie INSPECT-LB), Beirut, 1100, Lebanon
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Song HJ, Seo HJ, Jiang X, Jeon N, Lee YJ, Ha IH. Proton pump inhibitors associated with an increased risk of mortality in elderly: a systematic review and meta-analysis. Eur J Clin Pharmacol 2024; 80:367-382. [PMID: 38147074 DOI: 10.1007/s00228-023-03606-0] [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: 08/28/2023] [Accepted: 12/10/2023] [Indexed: 12/27/2023]
Abstract
PURPOSE The increased use of proton pump inhibitors (PPIs) in the elderly has raised concerns about potential severe adverse effects. Our systematic review investigated the mortality associated with PPI use in elderly populations. METHODS We searched MEDLINE, EMBASE, and the Cochrane Library for relevant publications until August 2022. We included randomized controlled trials (RCTs), quasi-RCTs, and observational studies on the association between proton pump inhibitors and mortality in the elderly. To estimate the pooled relative risk (RR) and 95% confidence interval (CI), the inverse-variance random effect model was used. Heterogeneity was assessed using the I2 test. Subgroup analyses were performed by follow-up period, population, and study design. RESULTS A total of 4 RCTs and 36 cohort studies were included in the meta-analysis. Four RCTs showed that there was no significant association between PPIs and the risk of death. From 23 observational studies (26 cohorts), the use of proton pump inhibitors was not significantly associated with increased mortality in the elderly (RR 1.14; 95% CI, 0.90-1.45). However, when controlling for covariates from 33 observational studies (41 cohorts), proton pump inhibitors in older adults aged 50 years or more were significantly associated with a 15% higher risk of mortality compared to nonusers (RR 1.15; 95% CI, 1.10-1.20). CONCLUSIONS Our meta-analysis of RCTs found that PPIs did not show a significant association with increased mortality risk in older adults. However, the meta-analysis of cohort studies and long-term follow-up studies showed a higher increased risk of death with PPI use in older adults. The prescription of PPIs in patients aged 50 years or older should be carefully considered.
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Affiliation(s)
- Hyun Jin Song
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
- College of Pharmacy, University of Florida, Gainesville, FL, USA.
| | - Hyun-Ju Seo
- College of Nursing, Chungnam National University, Daejeon, South Korea
| | - Xinyi Jiang
- College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Nakyung Jeon
- College of Pharmacy, Pusan National University, Busan, South Korea
| | - Yoon Jae Lee
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, South Korea
| | - In-Hyuk Ha
- Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, South Korea
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Lee YK, Lim HS, Choi YI, Choe EJ, Kim S, You SC, Lee KJ, Kim Y, Park DH, Shin WG, Seo SI. Impact of Concomitant Use of Proton Pump Inhibitors and Clopidogrel on Recurrent Stroke and Myocardial Infarction. Pharmaceuticals (Basel) 2023; 16:1213. [PMID: 37765021 PMCID: PMC10535402 DOI: 10.3390/ph16091213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/10/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND/AIMS Conflicting results have been reported regarding the interaction between proton pump inhibitors (PPIs) and clopidogrel. We investigated whether concomitant PPI use influenced the risk of recurrence in patients with stroke and myocardial infarction (MI). METHODS This study used two databases for two different designs, the Korean National Health Insurance Service (NHIS) database for a self-controlled case series design, and the national sample cohort of the NHIS data base converted to the Observational Medical Outcomes Partnership-Common Data Model version for a cohort study based on large-scale propensity score matching. RESULTS In the PPI co-prescription group, recurrent hospitalization with stroke occurred in 17.6% of the 8201 patients with history of stroke, and recurrent MI occurred in 17.1% of the 1216 patients with history of MI within1 year. According to the self-controlled case series, the overall relative risk (RR) of recurrent stroke was 2.09 (95% confidence interval (CI); 1.83-2.38); the RR showed an increasing trend parallel to the time from the beginning of PPI co-prescription. In the cohort study, there was a higher incidence of recurrent stroke in the PPI co-prescription group (Hazard ratio (HR): 1.34, 95% CI: 1.01-1.76, p = 0.04). The overall RR of recurrent MI was 1.47 (95% CI; 1.02-2.11) in the self-controlled case series; however, there was no statistically significant difference in recurrent MI in the cohort study (HR:1.42, 95% CI:0.79-2.49, p = 0.23). The impact of individual PPIs on stroke and MI showed different patterns. CONCLUSIONS A PPI co-prescription >4 weeks with clopidogrel was associated with hospitalization of recurrent stroke within 1 year of initial diagnosis; however, its association with recurrent MI remains inconclusive. The influence of individual PPIs should be clarified in the future.
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Affiliation(s)
- Yong Kang Lee
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang 10444, Republic of Korea; (Y.K.L.); (Y.I.C.); (E.J.C.)
| | - Hyun Sun Lim
- Department of Research and Analysis, National Health Insurance Service Ilsan Hospital, Goyang 10444, Republic of Korea;
| | - Youn I Choi
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang 10444, Republic of Korea; (Y.K.L.); (Y.I.C.); (E.J.C.)
| | - Eun Ju Choe
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang 10444, Republic of Korea; (Y.K.L.); (Y.I.C.); (E.J.C.)
| | - Seonji Kim
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (S.K.); (S.C.Y.)
- Institute for Innovation in Digital Healthcare, Yonsei University, Seoul 03722, Republic of Korea
| | - Seng Chan You
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (S.K.); (S.C.Y.)
- Institute for Innovation in Digital Healthcare, Yonsei University, Seoul 03722, Republic of Korea
| | - Kyung Joo Lee
- Department of Medical Informatics & Statistics, Kangdong Sacred Heart Hospital, Seoul 05355, Republic of Korea;
| | - Yerim Kim
- Department of Neurology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 24252, Republic of Korea;
| | - Da Hee Park
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Republic of Korea; (D.H.P.); (W.G.S.)
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 05355, Republic of Korea
| | - Woon Geon Shin
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Republic of Korea; (D.H.P.); (W.G.S.)
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 05355, Republic of Korea
| | - Seung In Seo
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Republic of Korea; (D.H.P.); (W.G.S.)
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 05355, Republic of Korea
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Wyss R, Plasek JM, Zhou L, Bessette LG, Schneeweiss S, Rassen JA, Tsacogianis T, Lin KJ. Scalable Feature Engineering from Electronic Free Text Notes to Supplement Confounding Adjustment of Claims-Based Pharmacoepidemiologic Studies. Clin Pharmacol Ther 2023; 113:832-838. [PMID: 36528788 PMCID: PMC10913938 DOI: 10.1002/cpt.2826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
Abstract
Natural language processing (NLP) tools turn free-text notes (FTNs) from electronic health records (EHRs) into data features that can supplement confounding adjustment in pharmacoepidemiologic studies. However, current applications are difficult to scale. We used unsupervised NLP to generate high-dimensional feature spaces from FTNs to improve prediction of drug exposure and outcomes compared with claims-based analyses. We linked Medicare claims with EHR data to generate three cohort studies comparing different classes of medications on the risk of various clinical outcomes. We used "bag-of-words" to generate features for the top 20,000 most prevalent terms from FTNs. We compared machine learning (ML) prediction algorithms using different sets of candidate predictors: Set1 (39 researcher-specified variables), Set2 (Set1 + ML-selected claims codes), and Set3 (Set1 + ML-selected NLP-generated features), vs. Set4 (Set1 + 2 + 3). When modeling treatment choice, we observed a consistent pattern across the examples: ML models utilizing Set4 performed best followed by Set2, Set3, then Set1. When modeling the outcome risk, there was little to no improvement beyond models based on Set1. Supplementing claims data with NLP-generated features from free text notes improved prediction of prescribing choices but had little or no improvement on clinical risk prediction. These findings have implications for strategies to improve confounding using EHR data in pharmacoepidemiologic studies.
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Affiliation(s)
- Richard Wyss
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Joseph M. Plasek
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Li Zhou
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Lily G. Bessette
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Sebastian Schneeweiss
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | | | - Theodore Tsacogianis
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Kueiyu Joshua Lin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School
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Lin KJ, Singer DE, Bykov K, Bessette LG, Mastrorilli JM, Cervone A, Kim DH. Comparative Effectiveness and Safety of Oral Anticoagulants by Dementia Status in Older Patients With Atrial Fibrillation. JAMA Netw Open 2023; 6:e234086. [PMID: 36976562 PMCID: PMC10051113 DOI: 10.1001/jamanetworkopen.2023.4086] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/04/2023] [Indexed: 03/29/2023] Open
Abstract
Importance The development of an optimal stroke prevention strategy, including the use of oral anticoagulant (OAC) therapy, is particularly important for patients with atrial fibrillation (AF) who are living with dementia, a condition that increases the risk of adverse outcomes. However, data on the role of dementia in the safety and effectiveness of OACs are limited. Objective To assess the comparative safety and effectiveness of specific OACs by dementia status among older patients with AF. Design, Setting, and Participants This retrospective comparative effectiveness study used 1:1 propensity score matching among 1 160 462 patients 65 years or older with AF. Data were obtained from the Optum Clinformatics Data Mart (January 1, 2013, to June 30, 2021), IBM MarketScan Research Database (January 1, 2013, to December 31, 2020), and Medicare claims databases maintained by the Centers for Medicare & Medicaid Services (inpatient, outpatient, and pharmacy; January 1, 2013, to December 31, 2017). Data analysis was performed from September 1, 2021, to May 24, 2022. Exposures Apixaban, dabigatran, rivaroxaban, or warfarin. Main Outcomes and Measures Composite end point of ischemic stroke or major bleeding events over the 6-month period after OAC initiation, pooled across databases using random-effects meta-analyses. Results Among 1 160 462 patients with AF, the mean (SD) age was 77.4 (7.2) years; 50.2% were male, 80.5% were White, and 7.9% had dementia. Three comparative new-user cohorts were established: warfarin vs apixaban (501 990 patients; mean [SD] age, 78.1 [7.4] years; 50.2% female), dabigatran vs apixaban (126 718 patients; mean [SD] age, 76.5 [7.1] years; 52.0% male), and rivaroxaban vs apixaban (531 754 patients; mean [SD] age, 76.9 [7.2] years; 50.2% male). Among patients with dementia, compared with apixaban users, a higher rate of the composite end point was observed in warfarin users (95.7 events per 1000 person-years [PYs] vs 64.2 events per 1000 PYs; adjusted hazard ratio [aHR], 1.5; 95% CI, 1.3-1.7), dabigatran users (84.5 events per 1000 PYs vs 54.9 events per 1000 PYs; aHR, 1.5; 95% CI, 1.2-2.0), and rivaroxaban users (87.4 events per 1000 PYs vs 68.5 events per 1000 PYs; aHR, 1.3; 95% CI, 1.1-1.5). In all 3 comparisons, the magnitude of the benefits associated with apixaban was similar regardless of dementia diagnosis on the HR scale but differed substantially on the rate difference (RD) scale. The adjusted RD of the composite outcome per 1000 PYs for warfarin vs apixaban users was 29.8 (95% CI, 18.4-41.1) events in patients with dementia vs 16.0 (95% CI, 13.6-18.4) events in patients without dementia. The corresponding adjusted RD estimates of the composite outcome were 29.6 (95% CI, 11.6-47.6) events per 1000 PYs in patients with dementia vs 5.8 (95% CI, 1.1-10.4) events per 1000 PYs in patients without dementia for dabigatran vs apixaban users and 20.5 (95% CI, 9.9-31.1) events per 1000 PYs in patients with dementia vs 15.9 (95% CI, 11.4-20.3) events per 1000 PYs in patients without dementia for rivaroxaban vs apixaban users. The pattern was more distinct for major bleeding than for ischemic stroke. Conclusions and Relevance In this comparative effectiveness study, apixaban was associated with lower rates of major bleeding and ischemic stroke compared with other OACs. The increased absolute risks associated with other OACs compared with apixaban were greater among patients with dementia than those without dementia, particularly for major bleeding. These findings support the use of apixaban for anticoagulation therapy in patients living with dementia who have AF.
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Affiliation(s)
- Kueiyu Joshua Lin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston
| | - Daniel E. Singer
- Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston
| | - Katsiaryna Bykov
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Lily G. Bessette
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Julianna M. Mastrorilli
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Alexander Cervone
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Dae Hyun Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts
- Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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8
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Kumamaru H, Jalbert JJ, Nguyen LL, Williams LA, Miyata H, Setoguchi S. Utility of automated data-adaptive propensity score method for confounding by indication in comparative effectiveness study in real world Medicare and registry data. PLoS One 2022; 17:e0272975. [PMID: 35969535 PMCID: PMC9377588 DOI: 10.1371/journal.pone.0272975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 07/31/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Confounding by indication is a serious threat to comparative studies using real world data. We assessed the utility of automated data-adaptive analytic approach for confounding adjustment when both claims and clinical registry data are available. METHODS We used a comparative study example of carotid artery stenting (CAS) vs. carotid endarterectomy (CEA) in 2005-2008 when CAS was only indicated for patients with high surgical risk. We included Medicare beneficiaries linked to the Society for Vascular Surgery's Vascular Registry >65 years old undergoing CAS/CEA. We compared hazard ratios (HRs) for death while adjusting for confounding by combining various 1) Propensity score (PS) modeling strategies (investigator-specified [IS-PS] vs. automated data-adaptive [ada-PS]); 2) data sources (claims-only, registry-only and claims-plus-registry); and 3) PS adjustment approaches (matching vs. quintiles-adjustment with/without trimming). An HR of 1.0 was used as a benchmark effect estimate based on CREST trial. RESULTS The cohort included 1,999 CAS and 3,255 CEA patients (mean age 76). CAS patients were more likely symptomatic and at high surgical risk, and experienced higher mortality (crude HR = 1.82 for CAS vs. CEA). HRs from PS-quintile adjustment without trimming were 1.48 and 1.52 for claims-only IS-PS and ada-PS, 1.51 and 1.42 for registry-only IS-PS and ada-PS, and 1.34 and 1.23 for claims-plus-registry IS-PS and ada-PS, respectively. Estimates from other PS adjustment approaches showed similar patterns. CONCLUSIONS In a comparative effectiveness study of CAS vs. CEA with strong confounding by indication, ada-PS performed better than IS-PS in general, but both claims and registry data were needed to adequately control for bias.
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Affiliation(s)
- Hiraku Kumamaru
- Department of Healthcare Quality Assessment, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Jessica J. Jalbert
- Health Economics and Outcomes Research, Regeneron Pharmaceuticals, Inc, Tarrytown, New York, United States of America
| | - Louis L. Nguyen
- Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Lauren A. Williams
- Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, United States of America
| | - Hiroaki Miyata
- Department of Healthcare Quality Assessment, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Soko Setoguchi
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America
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9
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Guo H, Ye Z, Huang R. Clinical Outcomes of Concomitant Use of Proton Pump Inhibitors and Dual Antiplatelet Therapy: A Systematic Review and Meta-Analysis. Front Pharmacol 2021; 12:694698. [PMID: 34408652 PMCID: PMC8366318 DOI: 10.3389/fphar.2021.694698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/23/2021] [Indexed: 11/27/2022] Open
Abstract
Background: The safety and efficacy associated with the use of proton pump inhibitors (PPIs) by patients with coronary artery disease receiving dual antiplatelet therapy (DAPT) remain unclear. Methods: The evaluated outcomes included combined major adverse cardiovascular events (MACEs), myocardial infarction (MI), all-cause mortality, and gastrointestinal (GI) bleeding. A random effects meta-analysis, stratified by study design, was performed and heterogeneity was assessed using the I2 statistic. Results: In total, 6 randomized controlled trials (RCTs) (6930 patients) and 16 observational studies (183,546 patients) were included. Analysis of RCTs showed that there were no significant differences in the incidences of MACEs (risk ratio [RR] = 0.89 [95% confidence interval (CI) = 0.75-1.05]), MI (RR = 0.93 [95% CI = 0.76-1.15]), and all-cause mortality (RR = 0.79 [95% CI = 0.50-1.23]) in the PPI groups vs. the non-PPI groups. Pooled data from observational studies revealed an inconsistent association between the use of each PPI subtype and the increased risks of MACEs during clopidogrel treatment. There was no increased risk of MACEs or all-cause mortality associated with the use of PPIs (as a class) and other P2Y12 inhibitors. Both the RCTs and observational studies revealed that the use of PPIs significantly reduced the risks of GI bleeding. Conclusion: The use of PPIs was associated with a reduced risk of GI bleeding in patients treated with DAPT after percutaneous coronary intervention or acute coronary syndrome. There was no clear evidence of an association between the use of PPIs and adverse cardiovascular events. Clinical Trial Registration: identifier [CRD42020190315].
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Affiliation(s)
| | | | - Rongchong Huang
- Cardiac Center/Division of Cardiovascular Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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10
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Yang SC, Wu CK, Tai WC, Liang CM, Yao CC, Wu KL, Hsu CN, Chuah SK. Risks of adverse events for users of proton-pump inhibitors plus aspirin or clopidogrel in patients with aspirin-related ulcer bleeding. J Gastroenterol Hepatol 2021; 36:1828-1835. [PMID: 33247982 DOI: 10.1111/jgh.15360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/22/2020] [Accepted: 11/21/2020] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIM Clopidogrel is widely prescribed for patients with of aspirin-related upper gastrointestinal bleeding (UGIB) history. This study aimed to compare the risk of a major adverse cardiovascular event (MACE), UGIB, and mortality between aspirin and clopidogrel in patients at risk of bleeding. METHODS We analyzed adult patients at high risk of UGIB following aspirin-related bleeding for secondary MACE prevention between 2000 and 2012. Secondary prevention was for those patients who had ever been hospitalized for cardiovascular disease and reused aspirin or changed to clopidogrel after discharge. Study endpoints were recurrence of MACE, UGIB, and death in 90 days of follow-up. The associations between study outcomes and the use of clopidogrel (vs aspirin) were analyzed. RESULTS Among 947 eligible patients, 653 reused aspirin (in combination with a proton-pump inhibitor), and 294 were treated with clopidogrel (in combination with a proton-pump inhibitor) after discharge for UGIB. Compared with aspirin treatment, clopidogrel showed an increased risk of MACE (adjusted hazard ratio [aHR] 1.65; 95% confidence interval [CI] 0.87-3.12) and UGIB (aHR 1.25; 95% CI 0.66-2.36), but without statistical significance in 90 days' follow-up. Clopidogrel use was associated with greater than four times the risk of any cause of mortality (aHR 4.84; 95% CI 1.59-14.75), but the significance did not hold in propensity score-matched cohort analysis (P = 0.06). CONCLUSIONS A nonsignificant difference between clopidogrel and aspirin for short-term MACE prevention as well as UGIB recurrence was found in the present study. Further research to assess 90-day mortality would assist clinical decision making.
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Affiliation(s)
- Shih-Cheng Yang
- Division of Hepato-gastroenterology; Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepato-gastroenterology; Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Wei-Chen Tai
- Division of Hepato-gastroenterology; Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,College of Medicine, Chang Gung University, Kaohsiung, Taiwan
| | - Chih-Ming Liang
- Division of Hepato-gastroenterology; Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Chien Yao
- Division of Hepato-gastroenterology; Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Keng-Liang Wu
- Division of Hepato-gastroenterology; Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,College of Medicine, Chang Gung University, Kaohsiung, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Seng-Kee Chuah
- Division of Hepato-gastroenterology; Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,College of Medicine, Chang Gung University, Kaohsiung, Taiwan
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11
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Catapano JS, Srinivasan VM, Wakim AA, Lundberg JN, Rutledge C, Cole TS, Baranoski JF, Fredrickson VL, Rahmani R, Albuquerque FC, Ducruet AF. Omeprazole-clopidogrel interaction and neurovascular complications after flow-diverter device placement. J Neurointerv Surg 2021; 14:380-383. [PMID: 34083398 DOI: 10.1136/neurintsurg-2021-017397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 05/10/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Omeprazole is a common proton pump inhibitor that interferes with the hepatic activation of clopidogrel and potentially reduces its platelet-inhibitory effect. Omeprazole has been shown to increase P2Y12 levels and adverse cardiovascular outcomes in patients treated with drug-eluting stents. However, omeprazole use among patients treated with flow-diverting stents for intracranial aneurysms has not been evaluated. METHODS All patients with placement of a flow-diverting device for treatment of an intracranial aneurysm at a tertiary institution from January 1, 2014, to December 31, 2018, were retrospectively analyzed. Inclusion criteria included documented clopidogrel administration, available P2Y12 levels, and thorough documentation of administration of other medications, including omeprazole. RESULTS A total of 138 patients met the inclusion criteria. Sixteen patients (12%) were receiving omeprazole and clopidogrel at treatment. P2Y12 reactivity was significantly greater in the omeprazole cohort (mean P2Y12 level, 250 P2Y12 reaction units (PRU)) than in the control cohort (mean P2Y12 level, 112PRU) (P<0.001). Furthermore, a greater proportion of patients had a P2Y12 level >180 PRU in the omeprazole cohort (14 of 16 [88%] vs 24 of 122 [20%]; P<0.001; OR [95% CI], 29 [6-134]). CONCLUSION Omeprazole was associated with a significant increase in the mean P2Y12 reactivity level among patients with intracranial aneurysms treated with flow-diverting devices who received clopidogrel. However, receipt of omeprazole was not associated with an increased risk of ischemic events or stent stenosis. For neuroendovascular patients who are treated with a flow diverter while receiving clopidogrel, alternative gastrointestinal medication regimens should be considered.
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Affiliation(s)
- Joshua S Catapano
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Visish M Srinivasan
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Andre A Wakim
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Jaclyn N Lundberg
- Department of General Medicine, Creighton University School of Medicine, Phoenix Health Sciences Campus, Phoenix, Arizona, USA
| | - Caleb Rutledge
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Tyler S Cole
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Jacob F Baranoski
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Vance L Fredrickson
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Redi Rahmani
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Felipe C Albuquerque
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Andrew F Ducruet
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
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12
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Farhat N, Birkett N, Haddad N, Fortin Y, Momoli F, Wen SW, Wielgosz A, McNair DS, Mattison DR, Krewski D. Risk of Adverse Cardiovascular Events Following a Myocardial Infarction in Patients Receiving Combined Clopidogrel and Proton Pump Inhibitor Treatment: A Nested Case-Control Study. Drugs Real World Outcomes 2020; 7:191-203. [PMID: 32617885 PMCID: PMC7392938 DOI: 10.1007/s40801-020-00204-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Background The clinical implications of potential interactions between proton pump inhibitors (PPIs) and clopidogrel have been debated for over a decade. Objective We assessed the association between combined clopidogrel–PPI treatment and the risk of recurrent myocardial infarction (MI) and three secondary outcomes. Patients and Methods A nested case–control study was conducted within Cerner Corporation’s Health Facts® database. A retrospective cohort of patients who experienced a first MI and started clopidogrel treatment was created. Within this cohort, patients experiencing a second MI (cases) were matched with up to five controls. Logistic regression was used to estimate adjusted odds ratios (aORs). Findings were compared with those obtained from models with three negative control exposure drugs: H2 receptor antagonists, prasugrel, and ticagrelor. Results In total, 2890 recurrent MI cases were identified within 12 months following entry into the cohort of clopidogrel users (N = 52,006). aOR for PPI use versus non-use among clopidogrel users was 1.08 [95% confidence interval (CI) 0.95–1.23]. Similar ORs were obtained for secondary endpoints. A positive association between combined use of clopidogrel/PPIs and increased risk of MI was seen in the group aged 80–89 years (aOR 1.26; 95% CI 1.05–1.51). No associations with MI were observed for (1) H2 receptor antagonist use versus non-use among clopidogrel users or (2) PPI use versus non-use among prasugrel users or among ticagrelor users. Conclusions Overall, our findings do not support a significant adverse clinical impact of concomitant clopidogrel/PPI use by patients with MI. Nonetheless, investigation of the possible association seen in those aged 80–89 years may be warranted. Electronic supplementary material The online version of this article (10.1007/s40801-020-00204-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nawal Farhat
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada. .,McLaughlin Centre for Population Health Risk Assessment, Ottawa, ON, Canada.
| | - Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.,McLaughlin Centre for Population Health Risk Assessment, Ottawa, ON, Canada
| | - Nisrine Haddad
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.,McLaughlin Centre for Population Health Risk Assessment, Ottawa, ON, Canada
| | - Yannick Fortin
- McLaughlin Centre for Population Health Risk Assessment, Ottawa, ON, Canada
| | - Franco Momoli
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.,Risk Sciences International, Ottawa, ON, Canada
| | - Shi Wu Wen
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.,Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,OMNI Research Group, Department of Obstetrics and Gynecology, University of Ottawa Faculty of Medicine, Ottawa, ON, Canada
| | | | | | - Donald R Mattison
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.,McLaughlin Centre for Population Health Risk Assessment, Ottawa, ON, Canada.,Risk Sciences International, Ottawa, ON, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.,McLaughlin Centre for Population Health Risk Assessment, Ottawa, ON, Canada.,Risk Sciences International, Ottawa, ON, Canada
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13
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Drug-Drug Interactions in Acute Coronary Syndrome Patients: Systematic Review. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2019. [DOI: 10.2478/sjecr-2019-0070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Drug-drug interaction (DDI) is defined as a clinically significant change in the exposure and/or response to a drug caused by co-administration of another drug which may result in a precipitation of an adverse event or alteration of its therapeutic effects. The aim of this systematic review was to provide an overview of DDIs that were actually observed or evaluated in acute coronary syndrome (ACS) patients with particular focus on DDIs with clinical relevance. Electronic searches of the literature were conducted in the following databases: MEDLINE, EBSCO, Scopus, Google Scholar and SCIndeks. A total of 117 articles were included in the review. This review showed that ACS patients can be exposed to a variety of DDIs with diverse outcomes which include decreased efficacy of antiplatelet drugs, thrombolytics or anticoagulants, increased risk of bleeding, rhabdomyolysis, hepatotoxicity, adverse effects on cardiovascular system (e.g. QT interval prolongation, arrhythmias, excessive bradycardia, severe hypotension), serotonin syndrome and drug-induced fever. Majority of the DDIs involved antiplatelet drugs (e.g. aspirin, clopidogrel and ticagrelor). Evidence of some of the reported DDIs is inconclusive as some of the studies have shown conflicting results. There is a need for additional post-marketing and population-based studies to evaluate the true effects of disease states and other factors on the clinical outcomes of DDIs. Clinicians should be attentive to the potential for DDIs and their associated harm in order to minimize or, if possible, avoid medication-related adverse events in ACS patients.
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14
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Dawwas GK, Dietrich E, Winchester DE, Winterstein AG, Segal R, Park H. Comparative Effectiveness and Safety of Ticagrelor versus Prasugrel in Patients with Acute Coronary Syndrome: A Retrospective Cohort Analysis. Pharmacotherapy 2019; 39:912-920. [DOI: 10.1002/phar.2311] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Ghadeer K. Dawwas
- Department of Biostatistics, Epidemiology and Informatics Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
| | - Erich Dietrich
- Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Gainesville Florida
| | - David E. Winchester
- Division of Cardiovascular Medicine College of Medicine University of Florida Gainesville Florida
| | - Almut G. Winterstein
- Department of Pharmaceutical Outcomes and Policy College of Pharmacy University of Florida Gainesville Florida
| | - Richard Segal
- Department of Pharmaceutical Outcomes and Policy College of Pharmacy University of Florida Gainesville Florida
| | - Haesuk Park
- Department of Pharmaceutical Outcomes and Policy College of Pharmacy University of Florida Gainesville Florida
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15
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Farhat N, Fortin Y, Haddad N, Birkett N, Mattison DR, Momoli F, Wu Wen S, Krewski D. Systematic review and meta-analysis of adverse cardiovascular events associated with proton pump inhibitors used alone or in combination with antiplatelet agents. Crit Rev Toxicol 2019; 49:215-261. [DOI: 10.1080/10408444.2019.1583167] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Nawal Farhat
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Yannick Fortin
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Nisrine Haddad
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Donald R. Mattison
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
| | - Franco Momoli
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Shi Wu Wen
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
- Ottawa Hospital Research Institute, Ottawa, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
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16
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Schneeweiss S, Rassen JA, Brown JS, Rothman KJ, Happe L, Arlett P, Dal Pan G, Goettsch W, Murk W, Wang SV. Graphical Depiction of Longitudinal Study Designs in Health Care Databases. Ann Intern Med 2019; 170:398-406. [PMID: 30856654 DOI: 10.7326/m18-3079] [Citation(s) in RCA: 166] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Pharmacoepidemiologic and pharmacoeconomic analysis of health care databases has become a vital source of evidence to support health care decision making and efficient management of health care organizations. However, decision makers often consider studies done in nonrandomized health care databases more difficult to review than randomized trials because many design choices need to be considered. This is perceived as an important barrier to decision making about the effectiveness and safety of medical products. Design flaws in longitudinal database studies are avoidable but can be unintentionally obscured in the convoluted prose of methods sections, which often lack specificity. We propose a simple framework of graphical representation that visualizes study design implementations in a comprehensive, unambiguous, and intuitive way; contains a level of detail that enables reproduction of key study design variables; and uses standardized structure and terminology to simplify review and communication to a broad audience of decision makers. Visualization of design details will make database studies more reproducible, quicker to review, and easier to communicate to a broad audience of decision makers.
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Affiliation(s)
- Sebastian Schneeweiss
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.S., S.V.W.)
| | | | - Jeffrey S Brown
- Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Massachusetts (J.S.B.)
| | | | - Laura Happe
- Journal of Managed Care and Specialty Pharmacy, Alexandria, Virginia (L.H.)
| | - Peter Arlett
- European Medicines Agency, London, United Kingdom (P.A.)
| | - Gerald Dal Pan
- U.S. Food and Drug Administration, Silver Spring, Maryland (G.D.)
| | - Wim Goettsch
- The National Health Care Institute, Diemen, and Utrecht University, Utrecht, the Netherlands (W.G.)
| | | | - Shirley V Wang
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.S., S.V.W.)
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17
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Gopalakrishnan C, Gagne JJ, Sarpatwari A, Dejene SZ, Dutcher SK, Levin R, Franklin JM, Schneeweiss S, Desai RJ. Evaluation of Socioeconomic Status Indicators for Confounding Adjustment in Observational Studies of Medication Use. Clin Pharmacol Ther 2019; 105:1513-1521. [PMID: 30659590 DOI: 10.1002/cpt.1348] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/07/2018] [Indexed: 11/12/2022]
Abstract
Methodologic research evaluating confounding due to socioeconomic status (SES) in observational studies of medications is limited. We identified 7,109 patients who initiated brand or generic atorvastatin from Medicare claims (2011-2013) linked to electronic medical records and census data. We created a propensity score (PS) containing only claims-based covariates and augmented it with additional claims-based proxies for SES, ZIP code, and block group level SES. Cox models with PS fine-stratification and weighting were used to compare rates of a cardiovascular end point and emergency department visits. Adjustment with only claims-based variables substantially improved balance on all SES variables compared with the unadjusted. Although inclusion of SES in PS models further improved balance on SES variables compared with models with claims-based covariates only, it did not materially change point estimates for either outcome. Inclusion of claims-based proxies may mitigate confounding by SES when aggregate-level SES information is unavailable.
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Affiliation(s)
- Chandrasekar Gopalakrishnan
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joshua J Gagne
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ameet Sarpatwari
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sara Z Dejene
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sarah K Dutcher
- Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Raisa Levin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jessica M Franklin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sebastian Schneeweiss
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Rishi J Desai
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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18
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Kim MS, Song HJ, Lee J, Yang BR, Choi NK, Park BJ. Effectiveness and Safety of Clopidogrel Co-administered With Statins and Proton Pump Inhibitors: A Korean National Health Insurance Database Study. Clin Pharmacol Ther 2019; 106:182-194. [PMID: 30648733 DOI: 10.1002/cpt.1361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 12/16/2018] [Indexed: 12/16/2022]
Abstract
Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007-2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4-metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction -0.14, 95% CI -0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.
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Affiliation(s)
- Mi-Sook Kim
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.,Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea
| | - Hong Ji Song
- Department of Family Medicine, Health Promotion Center, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Joongyub Lee
- Department of Prevention and Management, Inha University Hospital, Incheon, Korea
| | - Bo Ram Yang
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea
| | - Nam-Kyong Choi
- Department of Health Convergence, College of Science & Industry Convergence, Ewha Womans University, Seoul, Korea
| | - Byung-Joo Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
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19
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Demcsák A, Lantos T, Bálint ER, Hartmann P, Vincze Á, Bajor J, Czopf L, Alizadeh H, Gyöngyi Z, Márta K, Mikó A, Szakács Z, Pécsi D, Hegyi P, Szabó IL. PPIs Are Not Responsible for Elevating Cardiovascular Risk in Patients on Clopidogrel-A Systematic Review and Meta-Analysis. Front Physiol 2018; 9:1550. [PMID: 30510515 PMCID: PMC6252380 DOI: 10.3389/fphys.2018.01550] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 10/16/2018] [Indexed: 12/29/2022] Open
Abstract
Background: Clopidogrel and proton pump inhibitors (PPIs) are metabolized by cytochrome P450 enzymes. Contradictory results have been reported on possible complications of simultaneous PPI and clopidogrel use. Our aim was to investigate the clinical relevance of this debate with a systematic review and meta-analysis. Methods: The PubMed, Embase, and Cochrane Central Register of Controlled Trials electronic databases were searched for human studies [randomized controlled trials (RCTs) and observational studies] using the PICO format (P: patients on clopidogrel; I: patients treated with PPI; C: patients without PPI treatment; O: cardiovascular risk). We screened eligible studies from 2009 to 2016. After study exclusions, we extracted data from 27 articles for three outcomes: major adverse cardiac event (MACE), myocardial infarction (MI) and cardiovascular (CV) death. The meta-analysis was registered on PROSPERO (CRD42017054316). Results: Data were extracted on 156,823 patients from the 27 trials included (MACE: 23, CV death: 10, MI: 14). The risks of MACE (RR = 1.22, 95% CI = 1.06-1.396, p = 0.004) and MI (RR = 1.43, 95% CI = 1.24-1.66, p < 0.001) were significantly higher in the PPI plus clopidogrel group. However, subgroup analysis demonstrated that this significance disappeared in RCTs (RR = 0.99, 95% CI = 0.76-1.28, p = 0.93) in the MACE outcome group. There was no effect of combined PPI and clopidogrel therapy on CV death outcome (RR = 1.21, 95% CI = 0.97-1.50, p = 0.09). Conclusion: Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs. Based on our results, no restrictions should be applied whenever PPIs and clopidogrel are administered simultaneously.
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Affiliation(s)
- Alexandra Demcsák
- Department of Pediatrics and Pediatric Health Centre, University of Szeged, Szeged, Hungary
| | - Tamás Lantos
- Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary
| | - Emese Réka Bálint
- First Department of Internal Medicine, University of Szeged, Szeged, Hungary
| | - Petra Hartmann
- Institute of Surgical Research, University of Szeged, Szeged, Hungary
| | - Áron Vincze
- Division of Gastroenterology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary
| | - Judit Bajor
- Division of Gastroenterology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary
| | - László Czopf
- Division of Cardiology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary
| | - Hussain Alizadeh
- Division of Hematology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary
| | - Zoltán Gyöngyi
- Department of Public Health Medicine, University of Pécs Medical School, Pécs, Hungary
| | - Katalin Márta
- Institute for Translational Medicine, University of Pécs Medical School, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Alexandra Mikó
- Division of Gastroenterology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary
- Institute for Translational Medicine, University of Pécs Medical School, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, University of Pécs Medical School, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Dániel Pécsi
- Institute for Translational Medicine, University of Pécs Medical School, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Division of Gastroenterology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary
- Institute for Translational Medicine, University of Pécs Medical School, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary
| | - Imre László Szabó
- Division of Gastroenterology, First Department of Internal Medicine, University of Pécs Medical School, Pécs, Hungary
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20
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Pharmacogenetic and clinical predictors of response to clopidogrel plus aspirin after acute coronary syndrome in Egyptians. Pharmacogenet Genomics 2018; 28:207-213. [PMID: 30188374 PMCID: PMC9903350 DOI: 10.1097/fpc.0000000000000349] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVES Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the risk for recurrent cardiovascular events after acute coronary syndrome (ACS). However, there is significant variation in response to DAPT that may be influenced by both genetic and nongenetic factors. This study aimed to assess the effect of genetic polymorphisms in PON-1, PEAR-1, P2Y12, CES1, and CYP2C19, along with clinical, demographic, and social factors, on variation in response to DAPT in Egyptians. PARTICIPANTS AND METHODS This study included 230 Egyptians treated with clopidogrel 75 mg/day and aspirin 81 mg/day for at least 12 months following their first ACS. Simple and multivariable logistic regression analyses were carried out to identify factors associated with major adverse cardiovascular events (MACE), defined as the occurrence of recurrent ACS, ischemic stroke, stent-related revascularization, or death, in clopidogrel-treated participants. RESULTS Using multivariable logistic regression analysis, the CYP2C19*2 polymorphism was the only genetic predictor of MACE [odds ratio (OR): 2.23, 95% confidence interval (CI): 1.15-4.33, P=0.01]. In addition, proton pump inhibitor use (OR: 4.77, 95% CI: 1.47-15.54, P=0.009) and diabetes (OR: 1.83, 95% CI: 1.03-3.26, P=0.03) were associated with higher cardiovascular risk, whereas statin use was associated with lower risk (OR: 0.43, 95% CI: 0.25-0.76, P=0.003). The contribution of these four genetic and nongenetic factors explained 19% of the variability in risk for MACE in Egyptians treated with DAPT. CONCLUSION These results highlight that CYP2C19*2, along with diabetes, and use of proton pump inhibitor and statin are important factors jointly associated with variability in clinical response to DAPT following ACS in Egyptians.
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21
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Trends in cardiovascular and bleeding outcomes in acute coronary syndrome patients treated with or without proton-pump inhibitors during the introduction of novel P2Y12 inhibitors: a five-year experience from a single-centre observational registry. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2018; 5:127-138. [DOI: 10.1093/ehjcvp/pvy030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/17/2018] [Accepted: 08/01/2018] [Indexed: 01/24/2023]
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22
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Schneeweiss S. Automated data-adaptive analytics for electronic healthcare data to study causal treatment effects. Clin Epidemiol 2018; 10:771-788. [PMID: 30013400 PMCID: PMC6039060 DOI: 10.2147/clep.s166545] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Decision makers in health care increasingly rely on nonrandomized database analyses to assess the effectiveness, safety, and value of medical products. Health care data scientists use data-adaptive approaches that automatically optimize confounding control to study causal treatment effects. This article summarizes relevant experiences and extensions. METHODS The literature was reviewed on the uses of high-dimensional propensity score (HDPS) and related approaches for health care database analyses, including methodological articles on their performance and improvement. Articles were grouped into applications, comparative performance studies, and statistical simulation experiments. RESULTS The HDPS algorithm has been referenced frequently with a variety of clinical applications and data sources from around the world. The appeal of HDPS for database research rests in 1) its superior performance in situations of unobserved confounding through proxy adjustment, 2) its predictable efficiency in extracting confounding information from a given data source, 3) its ability to automate estimation of causal treatment effects to the extent achievable in a given data source, and 4) its independence of data source and coding system. Extensions of the HDPS approach have focused on improving variable selection when exposure is sparse, using free text information and time-varying confounding adjustment. CONCLUSION Semiautomated and optimized confounding adjustment in health care database analyses has proven successful across a wide range of settings. Machine-learning extensions further automate its use in estimating causal treatment effects across a range of data scenarios.
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Affiliation(s)
- Sebastian Schneeweiss
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital,
- Harvard Medical School, Boston, MA, USA,
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23
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Updating the Evidence of the Interaction Between Clopidogrel and CYP2C19-Inhibiting Selective Serotonin Reuptake Inhibitors: A Cohort Study and Meta-Analysis. Drug Saf 2018. [PMID: 28623527 DOI: 10.1007/s40264-017-0556-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION We previously found that patients who initiate clopidogrel while treated with a cytochrome P450 (CYP) 2C19-inhibiting selective serotonin reuptake inhibitor (SSRI) have a higher risk of subsequent ischemic events than patients treated with other SSRIs. It is not known whether initiating an inhibiting SSRI while treated with clopidogrel will also increase risk of ischemic events. OBJECTIVE The aim of this study was to assess clinical outcomes following initiation of a CYP2C19-inhibiting SSRI versus initiation of other SSRIs among patients treated with clopidogrel and to update existing evidence on the clinical impact of clopidogrel-SSRI interaction. METHODS Using five US databases (1998-2013), we conducted a cohort study of clopidogrel initiators who encountered treatment with SSRI during their clopidogrel therapy. Patients were matched by propensity score (PS) and followed for as long as they were exposed to both clopidogrel and index SSRI group. Outcomes were a composite ischemic event (myocardial infarction, ischemic stroke, or a revascularization procedure, whichever came first) and a composite major bleeding event (gastrointestinal bleed or hemorrhagic stroke, whichever came first). Results were combined via random-effects meta-analysis with previous evidence from subjects initiating clopidogrel while on SSRI therapy. RESULTS The PS-matched cohort comprised 2346 clopidogrel users starting CYP2C19-inhibiting SSRI therapy and 16,115 starting other SSRIs (mean age 61 years; 59% female). Compared with those treated with a non-inhibiting SSRI, the hazard ratio (HR) for patients treated with a CYP2C19-inhibiting SSRI was 1.07 (95% confidence interval [CI] 0.82-1.40) for the ischemic outcome and 1.00 (95% CI 0.42-2.36) for bleeding. The pooled estimates were 1.11 (95% CI 1.01-1.22) for ischemic events and 0.80 (95% CI 0.55-1.18) for bleeding. CONCLUSIONS We observed similar estimates of association between the two studies. The updated evidence still indicates a small decrease in clopidogrel effectiveness associated with concomitant exposure to clopidogrel and CYP2C19-inhibiting SSRIs.
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24
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Choi YJ, Kim N, Jang IJ, Cho JY, Nam RH, Park JH, Jo HJ, Yoon H, Shin CM, Park YS, Lee DH, Jung HC. Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea. Gut Liver 2018; 11:504-511. [PMID: 28395507 PMCID: PMC5491085 DOI: 10.5009/gnl16352] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Revised: 09/16/2016] [Accepted: 11/07/2016] [Indexed: 01/09/2023] Open
Abstract
Background/Aims Concerns that proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel could hamper the appropriate prescription of PPIs. We evaluated the influence of pantoprazole on the antiplatelet effect of clopidogrel compared with ranitidine, which is regarded as safe, after stratification of the population according to the presence of a cytochrome (CYP) 2C19 polymorphism in Korea. Methods Forty patients who underwent dual antiplatelet therapy were randomized to receive pantoprazole (n=20) or ranitidine (n=20). Platelet aggregation was evaluated by impedance aggregometry at baseline (D0) and 8 days after acid-lowering treatments (D9). CYP2C19 was genotyped by polymerase chain reaction restriction fragment length polymorphism. Results After co-treatment, the percentage of clopidogrel low-response was 11.1% (2/18) in the pantoprazole group and 10.5% (2/19) in the ranitidine group (p=0.954). The impedance values with adenosine diphosphate stimulus after acid-lowering treatments did not significantly differ between the two groups. In a multiple regression analysis, only ST-elevation myocardial infarction was marginally associated with a reduced antiplatelet effect (odds ratio, 12.07; 95% confidence interval, 0.84 to 173.78). However, pantoprazole use did not affect the antiplatelet effect after correction for the CYP2C19 polymorphism. Conclusions This study showed that pantoprazole does not increase platelet aggregation in patients receiving dual antiplatelet therapy (ClinicalTrials.gov number: NCT02733640).
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Affiliation(s)
- Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Joo-Youn Cho
- Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Jin Jo
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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25
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Farhan S, Jarai R, Wojta J, Tentzeris I, Siller-Matula J, Huber K. Platelet function variability and non-genetic causes. Thromb Haemost 2017; 105 Suppl 1:S60-6. [DOI: 10.1160/ths11-01-0025] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Accepted: 03/25/2011] [Indexed: 12/16/2022]
Abstract
SummaryDual antiplatelet therapy (DAPT) has been established for the treatment of coronary artery disease, especially in and after acute coronary syndromes, and after coronary interventions. Data suggest that a significant percentage of individuals treated with clopidogrel do not receive the expected therapeutic benefit because of a decreased responsiveness of their platelets, which is caused by several extrinsic and intrinsic mechanisms. The clinical consequence of clopidogrel non-responsiveness is severe cardiovascular complications. Besides genetic variability in response to antiplatelet therapy, non-genetic causes such as drug interactions (proton-pump inhibitors, statins, calcium-channel blockers, coumarine derivates, antibiotics, antimycotics) and co-morbidities (diabetes mellitus, renal failure, obesity) are responsible for this phenomenon. Large clinical trials with standardised laboratory methods and hard clinical endpoints are needed to identify these interactions with clopidogrel and predictors for its non-responsiveness.
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26
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Lucenteforte E, Lombardi N, Vetrano DL, La Carpia D, Mitrova Z, Kirchmayer U, Corrao G, Lapi F, Mugelli A, Vannacci A. Inappropriate pharmacological treatment in older adults affected by cardiovascular disease and other chronic comorbidities: a systematic literature review to identify potentially inappropriate prescription indicators. Clin Interv Aging 2017; 12:1761-1778. [PMID: 29089750 PMCID: PMC5656349 DOI: 10.2147/cia.s137403] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Avoiding medications in which the risks outweigh the benefits in the elderly patient is a challenge for physicians, and different criteria to identify inappropriate prescription (IP) exist to aid prescribers. Definition of IP indicators in the Italian geriatric population affected by cardiovascular disease and chronic comorbidities could be extremely useful for prescribers and could offer advantages from a public health perspective. The purpose of the present study was to identify IP indicators by means of a systematic literature review coupled with consensus criteria. A systematic search of PubMed, EMBASE, and CENTRAL databases was conducted, with the search structured around four themes and combining each with the Boolean operator “and”. The first regarded “prescriptions”, the second “adverse events”, the third “cardiovascular conditions”, and the last was planned to identify studies on “older people”. Two investigators independently reviewed titles, abstracts, full texts, and selected articles addressing IP in the elderly affected by cardiovascular condition using the following inclusion criteria: studies on people aged ≥65 years; studies on patients with no restriction on age but with data on subjects aged ≥65 years; and observational effectiveness studies. The database searches produced 5,742 citations. After removing duplicates, titles and abstracts of 3,880 records were reviewed, and 374 full texts were retrieved that met inclusion criteria. Thus, 49 studies reporting 32 potential IP indicators were included in the study. IP indicators regarded mainly drug–drug interactions, cardio- and cerebrovascular risk, bleeding risk, and gastrointestinal risk; among them, only 19 included at least one study that showed significant results, triggering a potential warning for a specific drug or class of drugs in a specific context. This systematic review demonstrates that both cardiovascular and non-cardiovascular drugs increase the risk of adverse drug reactions in older adults with cardiovascular diseases.
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Affiliation(s)
- Ersilia Lucenteforte
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Niccolò Lombardi
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | | | | | | | | | - Giovanni Corrao
- Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | | | - Alessandro Mugelli
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Alfredo Vannacci
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
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27
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Yoshihisa A, Takiguchi M, Kanno Y, Sato A, Yokokawa T, Miura S, Abe S, Misaka T, Sato T, Suzuki S, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Suzuki H, Saitoh SI, Takeishi Y. Associations of Acid Suppressive Therapy With Cardiac Mortality in Heart Failure Patients. J Am Heart Assoc 2017; 6:JAHA.116.005110. [PMID: 28512114 PMCID: PMC5524076 DOI: 10.1161/jaha.116.005110] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background It has been recently reported that histamine H2 receptor antagonists (H2RAs) are associated with impairment of ventricular remodeling and incident heart failure. In addition, favorable pleiotropic effects and adverse effects of proton pump inhibitors (PPIs) on cardiovascular disease have also been reported. We examined the associations of acid suppressive therapy using H2RAs or PPIs with cardiac mortality in patients with heart failure. Methods and Results In total, 1191 consecutive heart failure patients were divided into 3 groups: a non–acid suppressive therapy group (n=363), an H2RA group (n=164), and a PPI group (n=664). In the follow‐up period (mean 995 days), 169 cardiac deaths occurred. In the Kaplan–Meier analysis, cardiac mortality was significantly lower in the PPI group than in the H2RA and non–acid suppressive therapy groups (11.0% versus 21.3% and 16.8%, respectively; log‐rank P=0.004). In the multivariable Cox proportional hazards analysis, use of PPIs, but not H2RAs, was found to be an independent predictor of cardiac mortality (PPIs: hazard ratio 0.488, P=0.002; H2RAs: hazard ratio 0.855, P=0.579). The propensity‐matched 1:1 cohort was assessed based on propensity score (H2RAs, n=164; PPIs, n=164). Cardiac mortality was significantly lower in the PPI group than in the H2RA group in the postmatched cohort (log‐rank P=0.025). In the Cox proportional hazards analysis, the use of PPIs was a predictor of cardiac mortality in the postmatched cohort (hazard ratio 0.528, P=0.028). Conclusions PPIs may be associated with better outcome in patients with heart failure.
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Affiliation(s)
- Akiomi Yoshihisa
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Mai Takiguchi
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yuki Kanno
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Akihiko Sato
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Tetsuro Yokokawa
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Shunsuke Miura
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Satoshi Abe
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Tomofumi Misaka
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Takamasa Sato
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Satoshi Suzuki
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Masayoshi Oikawa
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Atsushi Kobayashi
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Takayoshi Yamaki
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Hiroyuki Kunii
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Kazuhiko Nakazato
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Hitoshi Suzuki
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Shu-Ichi Saitoh
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yasuchika Takeishi
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
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Sun S, Cui Z, Zhou M, Li R, Li H, Zhang S, Ba Y, Cheng G. Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: a meta-analysis. Neurogastroenterol Motil 2017; 29. [PMID: 27577963 DOI: 10.1111/nmo.12926] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 07/21/2016] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND PURPOSE Proton pump inhibitors (PPIs) are commonly used as potent gastric acid secretion antagonists for gastro-esophageal disorders and their overall safety in patients with gastro-esophageal reflux disease (GERD) is considered to be good and they are well-tolerated. However, recent studies have suggested that PPIs may be a potential independent risk factor for cardiovascular adverse events. The aim of our meta-analysis was to examine the association between PPI monotherapy and cardiovascular events in patients with GERD. METHODS A literature search involved examination of relevant databases up to July 2015 including PubMed, Cochrane Library, EMBASE, and ClinicalTrial.gov, as well as selected randomized controlled trials (RCTs) reporting cardiovascular events with PPI exposure in GERD patients. In addition, the pooled risk ratio (RR) and heterogeneity were assessed based on a fixed effects model of the meta-analysis and the I2 statistic, respectively. KEY RESULTS Seventeen RCTs covering 7540 patients were selected. The pooled data suggested that the use of PPIs was associated with a 70% increased cardiovascular risk (RR=1.70, 95% CI: [1.13-2.56], P=.01, I2 =0%). Furthermore, higher risks of adverse cardiovascular events in the omeprazole subgroup (RR=3.17, 95% CI: [1.43-7.03], P=.004, I2 =25%) and long-term treatment subgroup (RR=2.33, 95% CI: [1.33-4.08], P=.003, I2 =0%) were found. CONCLUSION & INFERENCES PPI monotherapy can be a risk factor for cardiovascular adverse events. Omeprazole could significantly increase the risk of cardiovascular events and, so, should be used carefully.
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Affiliation(s)
- S Sun
- Shenyang Pharmaceutical University, Shenyang, China
| | - Z Cui
- Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
| | - M Zhou
- Shenyang Pharmaceutical University, Shenyang, China
| | - R Li
- Shenyang Pharmaceutical University, Shenyang, China
| | - H Li
- Shenyang Pharmaceutical University, Shenyang, China
| | - S Zhang
- Shenyang Pharmaceutical University, Shenyang, China
| | - Y Ba
- Shenyang Pharmaceutical University, Shenyang, China
| | - G Cheng
- Shenyang Pharmaceutical University, Shenyang, China
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Pello Lázaro AM, Cristóbal C, Franco-Peláez JA, Tarín N, Aceña Á, Carda R, Huelmos A, Martín-Mariscal ML, Fuentes-Antras J, Martínez-Millá J, Alonso J, Lorenzo Ó, Egido J, López-Bescós L, Tuñón J. Use of Proton-Pump Inhibitors Predicts Heart Failure and Death in Patients with Coronary Artery Disease. PLoS One 2017; 12:e0169826. [PMID: 28103324 PMCID: PMC5245803 DOI: 10.1371/journal.pone.0169826] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 12/22/2016] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Proton-pump inhibitors (PPIs) seem to increase the incidence of cardiovascular events in patients with coronary artery disease (CAD), mainly in those using clopidogrel. We analysed the impact of PPIs on the prognosis of patients with stable CAD. METHODS We followed 706 patients with CAD. Primary outcome was the combination of secondary outcomes. Secondary outcomes were 1) acute ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and 2) heart failure (HF) or death. RESULTS Patients on PPIs were older [62.0 (53.0-73.0) vs. 58.0 (50.0-70.0) years; p = 0.003] and had a more frequent history of stroke (4.9% vs. 1.1%; p = 0.004) than those from the non-PPI group, and presented no differences in any other clinical variable, including cardiovascular risk factors, ejection fraction, and therapy with aspirin and clopidogrel. Follow-up was 2.2±0.99 years. Seventy-eight patients met the primary outcome, 53 developed acute ischaemic events, and 33 HF or death. PPI use was an independent predictor of the primary outcome [hazard ratio (HR) = 2.281 (1.244-4.183); p = 0.008], along with hypertension, body-mass index, glomerular filtration rate, atrial fibrillation, and nitrate use. PPI use was also an independent predictor of HF/death [HR = 5.713 (1.628-20.043); p = 0.007], but not of acute ischaemic events. A propensity score showed similar results. CONCLUSIONS In patients with CAD, PPI use is independently associated with an increased incidence of HF and death but not with a high rate of acute ischaemic events. Further studies are needed to confirm these findings.
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Affiliation(s)
| | - Carmen Cristóbal
- Department of Cardiology, Hospital de Fuenlabrada, Madrid, Spain
- Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | | | - Nieves Tarín
- Department of Cardiology, Hospital Universitario de Móstoles, Madrid, Spain
| | - Álvaro Aceña
- Department of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Rocío Carda
- Department of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Ana Huelmos
- Department of Cardiology, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | | | | | | | - Joaquín Alonso
- Rey Juan Carlos University, Alcorcón, Madrid, Spain
- Department of Cardiology, Hospital de Getafe, Madrid, Spain
| | - Óscar Lorenzo
- Autónoma University, Madrid, Spain
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Jesús Egido
- Autónoma University, Madrid, Spain
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- CIBERDEM, Madrid, Spain
| | | | - José Tuñón
- Department of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- Autónoma University, Madrid, Spain
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
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Bundhun PK, Teeluck AR, Bhurtu A, Huang WQ. Is the concomitant use of clopidogrel and Proton Pump Inhibitors still associated with increased adverse cardiovascular outcomes following coronary angioplasty?: a systematic review and meta-analysis of recently published studies (2012 - 2016). BMC Cardiovasc Disord 2017; 17:3. [PMID: 28056809 PMCID: PMC5221663 DOI: 10.1186/s12872-016-0453-6] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 12/22/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Controversies were previously observed with the concomitant use of clopidogrel and Proton Pump Inhibitors (PPIs), especially omeprazole, following coronary angioplasty. Even though several studies showed no interaction between clopidogrel and PPIs, questions have been raised about the decrease in antiplatelet effects of clopidogrel with PPIs. A previously published meta-analysis showed concomitant use of clopidogrel and PPIs to be associated with higher adverse cardiovascular outcomes. However, data which were used were extracted from studies published before the year 2012. Whether these controversies still exist in this new era is not clear. Therefore, we aim to show if the concomitant use of clopidogrel and PPIs is still associated with higher adverse outcomes following Percutaneous Coronary Intervention (PCI) using data obtained from recently published studies (2012 to 2016). METHODS Electronic databases were searched for recent publications (2012-2016) comparing (clopidogrel plus PPIs) versus clopidogrel alone following PCI. Adverse cardiovascular outcomes were considered as the clinical endpoints. Odds Ratios (OR) with 95% Confidence Intervals (CI) were used as the statistical parameters and the pooled analyses were performed with RevMan 5.3 software. RESULTS Eleven studies with a total number of 84,729 patients (29,235 patients from the PPIs group versus 55,494 patients from the non-PPIs group) were included. Results of this analysis showed that short term mortality and Target Vessel Revascularization (TVR) significantly favored the non-PPIs group with OR: 1.55; 95% CI: 1.43-1.68, P < 0.00001 and OR: 1.26; 95% CI: 1.06-1.49, P = 0.009 respectively. Long-term Major Adverse Cardiac Events (MACEs), Myocardial Infarction (MI), Stent Thrombosis (ST) and TVR significantly favored patients who did not use PPIs with OR: 1.37; 95% CI: 1.23-1.53, P < 0.00001, OR: 1.41; 95% CI: 1.26-1.57, P < 0.00001 and OR: 1.38; 95% CI: 1.13-1.70, P = 0.002 and OR: 1.28; 95% CI: 1.01-1.61, P = 0.04 respectively. However, the result for long term mortality was not statistically significant. CONCLUSION The combined use of clopidogrel with PPIs is still associated with significantly higher adverse cardiovascular events such as MACEs, ST and MI following PCI supporting results of the previously published meta-analysis. However, long-term mortality is not statistically significant warranting further analysis with randomized patients.
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Affiliation(s)
- Pravesh Kumar Bundhun
- Institute of Cardiovascular Diseases, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
| | | | - Akash Bhurtu
- Guangxi Medical University, Nanning, Guangxi, 530027, People's Republic of China
| | - Wei-Qiang Huang
- Institute of Cardiovascular Diseases, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
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31
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Hemingway H, Feder GS, Fitzpatrick NK, Denaxas S, Shah AD, Timmis AD. Using nationwide ‘big data’ from linked electronic health records to help improve outcomes in cardiovascular diseases: 33 studies using methods from epidemiology, informatics, economics and social science in the ClinicAl disease research using LInked Bespoke studies and Electronic health Records (CALIBER) programme. PROGRAMME GRANTS FOR APPLIED RESEARCH 2017. [DOI: 10.3310/pgfar05040] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BackgroundElectronic health records (EHRs), when linked across primary and secondary care and curated for research use, have the potential to improve our understanding of care quality and outcomes.ObjectiveTo evaluate new opportunities arising from linked EHRs for improving quality of care and outcomes for patients at risk of or with coronary disease across the patient journey.DesignEpidemiological cohort, health informatics, health economics and ethnographic approaches were used.Setting230 NHS hospitals and 226 general practices in England and Wales.ParticipantsUp to 2 million initially healthy adults, 100,000 people with stable coronary artery disease (SCAD) and up to 300,000 patients with acute coronary syndrome.Main outcome measuresQuality of care, fatal and non-fatal cardiovascular disease (CVD) events.Data platform and methodsWe created a novel research platform [ClinicAl disease research using LInked Bespoke studies and Electronic health Records (CALIBER)] based on linkage of four major sources of EHR data in primary care and national registries. We carried out 33 complementary studies within the CALIBER framework. We developed a web-based clinical decision support system (CDSS) in hospital chest pain clinics. We established a novel consented prognostic clinical cohort of SCAD patients.ResultsCALIBER was successfully established as a valid research platform based on linked EHR data in nearly 2 million adults with > 600 EHR phenotypes implemented on the web portal (seehttps://caliberresearch.org/portal). Despite national guidance, key opportunities for investigation and treatment were missed across the patient journey, resulting in a worse prognosis for patients in the UK compared with patients in health systems in other countries. Our novel, contemporary, high-resolution studies showed heterogeneous associations for CVD risk factors across CVDs. The CDSS did not alter the decision-making behaviour of clinicians in chest pain clinics. Prognostic models using real-world data validly discriminated risk of death and events, and were used in cost-effectiveness decision models.ConclusionsEmerging ‘big data’ opportunities arising from the linkage of records at different stages of a patient’s journey are vital to the generation of actionable insights into the diagnosis, risk stratification and cost-effective treatment of people at risk of, or with, CVD.Future workThe vast majority of NHS data remain inaccessible to research and this hampers efforts to improve efficiency and quality of care and to drive innovation. We propose three priority directions for further research. First, there is an urgent need to ‘unlock’ more detailed data within hospitals for the scale of the UK’s 65 million population. Second, there is a need for scaled approaches to using EHRs to design and carry out trials, and interpret the implementation of trial results. Third, large-scale, disease agnostic genetic and biological collections linked to such EHRs are required in order to deliver precision medicine and to innovate discovery.Study registrationCALIBER studies are registered as follows: study 2 – NCT01569139, study 4 – NCT02176174 and NCT01164371, study 5 – NCT01163513, studies 6 and 7 – NCT01804439, study 8 – NCT02285322, and studies 26–29 – NCT01162187. Optimising the Management of Angina is registered as Current Controlled Trials ISRCTN54381840.FundingThe National Institute for Health Research (NIHR) Programme Grants for Applied Research programme (RP-PG-0407-10314) (all 33 studies) and additional funding from the Wellcome Trust (study 1), Medical Research Council Partnership grant (study 3), Servier (study 16), NIHR Research Methods Fellowship funding (study 19) and NIHR Research for Patient Benefit (study 33).
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Affiliation(s)
- Harry Hemingway
- Institute of Health Informatics, University College London, London, UK
- Farr Institute of Health Informatics Research, University College London, London, UK
| | - Gene S Feder
- Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol, UK
| | - Natalie K Fitzpatrick
- Institute of Health Informatics, University College London, London, UK
- Farr Institute of Health Informatics Research, University College London, London, UK
| | - Spiros Denaxas
- Institute of Health Informatics, University College London, London, UK
- Farr Institute of Health Informatics Research, University College London, London, UK
| | - Anoop D Shah
- Institute of Health Informatics, University College London, London, UK
- Farr Institute of Health Informatics Research, University College London, London, UK
| | - Adam D Timmis
- Farr Institute of Health Informatics Research, University College London, London, UK
- Barts Health NHS Trust, London, UK
- Farr Institute of Health Informatics Research, Queen Mary University of London, London, UK
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32
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Lee J, Mark RG, Celi LA, Danziger J. Proton Pump Inhibitors Are Not Associated With Acute Kidney Injury in Critical Illness. J Clin Pharmacol 2016; 56:1500-1506. [PMID: 27492273 DOI: 10.1002/jcph.805] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/02/2016] [Accepted: 08/03/2016] [Indexed: 12/30/2022]
Abstract
Recent epidemiologic data linking proton pump inhibitor (PPI) use to acute and chronic kidney dysfunction is yet to be validated in other populations, and mechanisms have not been explored. Using a large, well phenotyped inception cohort of 15 063 critically ill patients, we examined the risk of acute kidney injury (AKI), as defined by the Kidney Disease Improving Global Outcomes criteria guidelines, according to prior use of a PPI, histamine-2 receptor antagonist (H2 RA), or neither. A total of 3725 (24.7%) patients reported PPI use prior to admission, while 905 (6.0%) patients reported H2 RA use. AKI occurred in 747 (20.0%) and 163 (18.0%) of PPI and H2 RA users respectively, compared to 1712 (16.2%) of those not taking acid suppressive medications. In unadjusted analysis, PPI and H2 RA users had a 28% (95%CI 1.17-1.41, P < .001) and 10% (95%CI 0.91-1.30, P = .31) higher risk of AKI compared to those taking neither class of medication. However, in sequential models that included adjustment for demographics, cardiovascular comorbidities, indications for PPI use, and severity of illness, the effect of PPI on the risk of AKI was attenuated, and in the adjusted analysis, PPI was not associated with AKI (OR 1.02; 95%CI 0.91-1.13, P = .73). The presence of sterile pyuria and hypomagnesemia did not modify the association between PPI use and AKI. In summary, after adjustment for demographics, illness severity, and the indication for PPI use, PPI use prior to admission is not associated with critical illness AKI.
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Affiliation(s)
- Joon Lee
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.,School of Public Health and Health Systems, University of Waterloo, Waterloo, Ontario, Canada
| | - Roger G Mark
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA
| | - Leo Anthony Celi
- Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.,Beth Israel Deaconess Medical Center, Department of Medicine, Boston, MA, USA
| | - John Danziger
- Beth Israel Deaconess Medical Center, Department of Medicine, Boston, MA, USA
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33
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Rodrigues MCS, Oliveira CD. Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: an integrative review. Rev Lat Am Enfermagem 2016; 24:e2800. [PMID: 27598380 PMCID: PMC5016009 DOI: 10.1590/1518-8345.1316.2800] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 04/13/2016] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. METHODS an integrative review of studies published from January 2008 to December 2013, according to inclusion and exclusion criteria, in MEDLINE and EMBASE electronic databases were performed. RESULTS forty-seven full-text studies including 14,624,492 older adults (≥ 60 years) were analyzed: 24 (51.1%) concerning ADR, 14 (29.8%) DDI, and 9 studies (19.1%) investigating both DDI and ADR. We found a variety of methodological designs. The reviewed studies reinforced that polypharmacy is a multifactorial process, and predictors and inappropriate prescribing are associated with negative health outcomes, as increasing the frequency and types of ADRs and DDIs involving different drug classes, moreover, some studies show the most successful interventions to optimize prescribing. CONCLUSIONS DDI and ADR among older adults continue to be a significant issue in the worldwide. The findings from the studies included in this integrative review, added to the previous reviews, can contribute to the improvement of advanced practices in geriatric nursing, to promote the safety of older patients in polypharmacy. However, more research is needed to elucidate gaps. OBJETIVO identificar e sintetizar estudos que examinam as interações medicamentosas (IM) e reações adversas a medicamentos (RAM) em idosos polimedicados. MÉTODOS revisão integrativa de estudos publicados de janeiro de 2008 a dezembro de 2013, de acordo com critérios de inclusão e exclusão, nas bases de dados eletrônicas MEDLINE e EMBASE. RESULTADOS foram analisados 47 estudos de texto completo, incluindo 14,624,492 idosos (≥ 60 anos): 24 (51,1%) sobre RAM, 14 (29,8%) sobre IM e 9 estudos (19,1%) que investigaram tanto IM como RAM. Encontramos uma variedade de desenhos metodológicos. Os estudos revisados reforçaram que a polifarmácia é um processo multifatorial, e os preditores e a prescrição inadequada estão associados a resultados negativos de saúde, como aumento da frequência e tipos de RAM e IM envolvendo diferentes classes de drogas, além disso, alguns estudos mostram as intervenções mais bem-sucedidas para otimizar a prescrição. CONCLUSÕES IM e RAM entre idosos continuam a ser um problema significativo no mundo todo. Os resultados dos estudos incluídos nesta revisão integrativa, adicionado às revisões anteriores, podem contribuir para a melhoria das práticas avançadas de enfermagem geriátrica, para promover a segurança dos pacientes idosos em polifarmácia. No entanto, são necessárias mais pesquisas para elucidar lacunas. OBJETIVO identificar y resumir los estudios que analizan tanto las interacciones medicamentosas (IM) como las reacciones adversas a medicamentos (RAM) en los adultos mayores polimedicados. MÉTODOS revisión integradora de estudios publicados entre enero de 2008 a diciembre de 2013, siguiendo criterios de inclusión y exclusión, en las bases de datos electrónicas MEDLINE y EMBASE. RESULTADOS cuarenta y siete estudios de texto completo incluidos fueron analizados incluyendo 14,624,492 adultos mayores (≥ 60 años), de ellos 24 (51,1%) en relación con RAM, 14 (29,9%) con IM y 9 estudios (19,1%) que investigaron tanto IM como RAM. Encontramos una gran variedad de diseños metodológicos. Los estudios revisados reforzaron el concepto que la polifarmacia es un proceso multifactorial, y los predictores y la prescripción inadecuada se asocian con resultados negativos para la salud tales como el aumento de la frecuencia y tipos de RAM y IM implicando diferentes clases de fármacos, además que algunos estudios muestran cuales son las intervenciones más exitosas para optimizar la prescripción. CONCLUSIONES IM y RAM siguen siendo un problema importante en el mundo entero entre los adultos mayores. Los resultados de los estudios incluidos en esta revisión integradora, sumado a las revisiones previas, pueden contribuir a la mejora de las prácticas avanzadas de enfermería geriátrica, para promover la seguridad de los pacientes de mayor edad en la polifarmacia. Sin embargo, se necesita más investigación para esclarecer los vacíos de conocimiento.
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Affiliation(s)
- Maria Cristina Soares Rodrigues
- PhD, Associate Professor, Departamento de Enfermagem, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasília, DF, Brazil. Scholarship holder from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil
| | - Cesar de Oliveira
- Researcher, Departament Epidemiology and Public Health, University College London, London, United Kingdom
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Niu Q, Wang Z, Zhang Y, Wang J, Zhang P, Wang C, Yin X, Hou Y. Combination Use of Clopidogrel and Proton Pump Inhibitors Increases Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease: A Meta-Analysis. J Cardiovasc Pharmacol Ther 2016; 22:142-152. [PMID: 27512080 DOI: 10.1177/1074248416663647] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Published data indicated that combination use of clopidogrel and proton pump inhibitors (PPIs) may increase the incidence of major adverse cardiovascular events (MACEs). This has been a highly controversial topic for years. DESIGN The present study was performed to evaluate whether combination therapy of clopidogrel and PPIs is associated with increased risk of MACEs than with clopidogrel alone in patients with coronary artery disease. METHODS A systematic search of MEDLINE, EMBASE, and the Cochrane Library was conducted for studies recording the occurrence of MACEs in patients with exposure to concomitant use of clopidogrel and PPIs up to February 2015. Odds ratios (ORs) were combined using a random-effects model. RESULTS Patients receiving combination therapy with PPIs and clopidogrel were at significantly increased risk of MACEs (OR: 1.42; 95% confidence interval [CI]: 1.30-1.55). Adding a PPI to clopidogrel treatment was associated with a higher rate of MACE occurrence in rapid metabolizers (RMs, *1/*1) of CYP2C19 (OR: 1.42; 95% CI: 1.12-1.81), but there was no obviously increased rate (OR: 1.43; 95% CI: 0.89-2.28) in decreased metabolizers (with 1 or 2 loss-of-function allele). The increased risk of MACEs was similar in 4 classes of PPIs (omeprazole, lansoprazole, esomeprazole, and pantoprazole), but rabeprazole (OR: 1.03; 95% CI: 0.55-1.95) wasn't. CONCLUSION The combination use of clopidogrel and certain types of PPIs (omeprazole, lansoprazole, esomeprazole, pantoprazole) increases the risk of MACE in patients with coronary artery disease. Only in the RMs of CYP2C19, PPIs were associated with significantly increased MACE in patients coadministered with clopidogrel.
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Affiliation(s)
- Qiang Niu
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China.,2 Department of Clinical Medicine (Seven-Year), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China
| | - Zhongsu Wang
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China
| | - Yong Zhang
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China
| | - Jiangrong Wang
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China
| | - Pei Zhang
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China
| | - Cong Wang
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China
| | - Xiangcui Yin
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China
| | - Yinglong Hou
- 1 Department of Cardiology, Qianfoshan Hospital of Shandong University, Jinan, Shandong, China
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35
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Ford NF. The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway. J Clin Pharmacol 2016; 56:1474-1483. [DOI: 10.1002/jcph.769] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/06/2016] [Accepted: 05/06/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Neville F. Ford
- Woodfield Clinical Consulting LLC; Green Valley AZ USA
- Rutgers-RWJ Medical School; New Brunswick NJ USA
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36
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Suzuki Y, Suzuki H, Umetsu R, Uranishi H, Abe J, Nishibata Y, Sekiya Y, Miyamura N, Hara H, Tsuchiya T, Kinosada Y, Nakamura M. Analysis of the Interaction between Clopidogrel, Aspirin, and Proton Pump Inhibitors Using the FDA Adverse Event Reporting System Database. Biol Pharm Bull 2016; 38:680-6. [PMID: 25947914 DOI: 10.1248/bpb.b14-00191] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Clopidogrel is an antiplatelet agent widely used in combination with aspirin to limit the occurrence of cardiovascular (embolic/thrombotic) events. Consensus guidelines recommend proton pump inhibitors (PPIs) as a gastrointestinal (GI) prophylactic measure for all patients receiving dual antiplatelet therapy with clopidogrel and aspirin. The objective of this study was to analyze the effect of the simultaneous use of clopidogrel, aspirin, and PPIs on hemorrhagic and embolic/thrombotic events using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Reports of hemorrhagic and embolic/thrombotic events between 2004 and 2013 were analyzed with a reporting odds ratio (ROR) algorithm and logistic regression methods. The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify such events. Regarding hemorrhagic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 4.40 (95% confidence interval [CI], 4.02-4.81) and 3.40 (95% CI, 2.84-4.06), respectively. For embolic/thrombotic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 2.37 (95% CI, 2.16-2.59) and 2.38 (95% CI, 2.00-2.84), respectively. Among patients included in the FAERS database, the concurrent use of aspirin and clopidogrel with PPIs reduced the adjusted ROR of GI hemorrhagic events. PPIs had little influence on the adjusted ROR of embolic/thrombotic events. These results support the use of PPIs as a preventive measure against GI hemorrhagic events for patients receiving clopidogrel and aspirin.
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Affiliation(s)
- Yukiya Suzuki
- Laboratory of Drug Informatics, Gifu Pharmaceutical University; 1–25–4 Daigaku-Nishi, Gifu 501–1196 2. Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University 1–25–4 Daigaku-Nishi, Gifu 501–1196, Japan
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Lee JK, Wu CK, Juang JM, Tsai CT, Hwang JJ, Lin JL, Chiang FT. Non-Carriers of Reduced-Function CYP2C19 Alleles are Most Susceptible to Impairment of the Anti-Platelet Effect of Clopidogrel by Proton-Pump Inhibitors: A Pilot Study. ACTA CARDIOLOGICA SINICA 2016; 32:215-22. [PMID: 27122952 DOI: 10.6515/acs20160201a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND The phenomenon of CYP2C19 polymorphism affects the metabolism of both clopidogrel and proton-pump inhibitors (PPI). However, concomitant use of both drugs may reduce the desired therapeutic effects. In this study, we evaluated whether individuals with different numbers of reduced-function CYP2C19 alleles were equally affected and whether PPIs with different dependencies on CYP2C19 metabolism were equally involved. METHODS Thirty healthy volunteers were recruited to a six-week regimen of clopidogrel. Three PPIs with different metabolic dependencies on CYP2C19 were included and separately administered in this order. Each PPI was given for a week, followed by a one-week washout period before the intervention of the next PPI. The anti-platelet effect was examined by Thromboelastography Platelet Mapping(TM) (TEG®) and vasodilator-stimulated phosphoprotein (VASP) assays. RESULTS Both TEG® and VASP tests showed the same general qualitative trend, but TEG® detected a statistically significant fluctuation of platelet aggregation in response to different drug interventions. The TEG® results also demonstrated that non-carriers experienced the most significant impairment of anti-platelet effect of clopidogrel after concomitant use of PPIs. This impairment was closely related to the metabolic dependence on CYP2C19 of PPI. CONCLUSIONS Our study indicated that non-carriers of reduced-function CYP2C19 alleles are most susceptible to impairment of the anti-platelet effect of clopidogrel after concomitant PPI use. Individual subjects are not equally affected, and PPIs are not equally involved. However, large-scale randomized clinical trials are needed to evaluate the clinical outcome. KEY WORDS Clopidogrel • CYP2C19 polymorphism • Platelet aggregation • Proton pump inhibitors • TEG • VASP.
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Affiliation(s)
- Jen-Kuang Lee
- Division of Cardiology, Department of Internal Medicine; ; Department of Laboratory Medicine, National Taiwan University College of Medicine and Hospital; ; Graduate Institute of Biomedical Electronics and Bioinformatics, College of Electrical Engineering and Computer Science, National Taiwan University, Taipei, Taiwan
| | - Cho-Kai Wu
- Division of Cardiology, Department of Internal Medicine
| | | | - Chia-Ti Tsai
- Division of Cardiology, Department of Internal Medicine
| | | | - Jiuun-Lee Lin
- Division of Cardiology, Department of Internal Medicine
| | - Fu-Tien Chiang
- Division of Cardiology, Department of Internal Medicine; ; Department of Laboratory Medicine, National Taiwan University College of Medicine and Hospital
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Cytochrome allelic variants and clopidogrel metabolism in cardiovascular diseases therapy. Mol Biol Rep 2016; 43:473-84. [DOI: 10.1007/s11033-016-3983-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 04/04/2016] [Indexed: 01/18/2023]
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Proton Pump Inhibitors in Cardiovascular Disease: Drug Interactions with Antiplatelet Drugs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 906:325-350. [PMID: 27628008 DOI: 10.1007/5584_2016_124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular diseases. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies suggested an interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it was reported that PPIs may also attenuate the antiplatelet effect of aspirin. This may be clinically important, because a fixed combination of aspirin and a PPI (esomeprazole) has recently been approved and because aspirin is the most widely used drug in patients with cardiovascular disease. The antiplatelet effect of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, seems less influenced by PPI co-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover, it outlines current evidence supporting or opposing drug interactions between these drugs and discusses clinical implications.
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Weisz G, Smilowitz NR, Kirtane AJ, Rinaldi MJ, Parvataneni R, Xu K, Stuckey TD, Maehara A, Witzenbichler B, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Brodie BR, Mazzaferri EL, Mehran R, Stone GW. Proton Pump Inhibitors, Platelet Reactivity, and Cardiovascular Outcomes After Drug-Eluting Stents in Clopidogrel-Treated Patients. Circ Cardiovasc Interv 2015; 8:CIRCINTERVENTIONS.114.001952. [DOI: 10.1161/circinterventions.114.001952] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Giora Weisz
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Nathaniel R. Smilowitz
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Ajay J. Kirtane
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Michael J. Rinaldi
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Rupa Parvataneni
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Ke Xu
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Thomas D. Stuckey
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Akiko Maehara
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Bernhard Witzenbichler
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Franz-Josef Neumann
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - D. Christopher Metzger
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Timothy D. Henry
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - David A. Cox
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Peter L. Duffy
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Bruce R. Brodie
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Ernest L. Mazzaferri
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Roxana Mehran
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
| | - Gregg W. Stone
- From the Shaare Zedek Medical Center, Jerusalem, Israel (G.W.); NYU Langone Medical Center, New York, NY (N.R.S.); NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY (G.W., A.J.K., A.M., G.W.S.); Cardiovascular Research Foundation, New York, NY (G.W., A.J.K., R.P., K.X., A.M., R.M., G.W.S.); Sanger Heart and Vascular Institute/Carolinas HealthCare System, Charlotte, NC (M.J.R.); LeBauer Cardiovascular Research Foundation/Cone Health, Greensboro, NC (T.D.S., B.R.B.)
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Parekh PJ, Oldfield EC, Johnson DA. Current Strategies to Reduce Gastrointestinal Bleeding Risk Associated with Antiplatelet Agents. Drugs 2015; 75:1613-1625. [PMID: 26330139 DOI: 10.1007/s40265-015-0455-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Antiplatelet agents remain the cornerstone in the primary and secondary therapeutic intervention for cardiovascular disease. Some patients may be subjected to a year or more of dual antiplatelet therapy to reduce the risk of subsequent cardiovascular events. Patients on antiplatelet therapy have an increased risk of gastrointestinal bleeding; however, not all patients benefit from concomitant acid suppressive therapy. This review will provide an overview of the pharmacology of antiplatelet agents and outline patient risk profiles that ought to be considered when considering prophylactic therapy to reduce gastrointestinal toxicity. In addition, we discuss the current risk-reduction strategies intended to mitigate against the potential for related gastroduodenal injury.
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Affiliation(s)
- Parth J Parekh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tulane University, New Orleans, LA, USA
| | - Edward C Oldfield
- Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - David A Johnson
- Division of Gastroenterology, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 23510, USA.
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Bazelier MT, Eriksson I, de Vries F, Schmidt MK, Raitanen J, Haukka J, Starup-Linde J, De Bruin ML, Andersen M. Data management and data analysis techniques in pharmacoepidemiological studies using a pre-planned multi-database approach: a systematic literature review. Pharmacoepidemiol Drug Saf 2015; 24:897-905. [PMID: 26175179 PMCID: PMC5034829 DOI: 10.1002/pds.3828] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 05/29/2015] [Accepted: 06/08/2015] [Indexed: 12/28/2022]
Abstract
PURPOSE To identify pharmacoepidemiological multi-database studies and to describe data management and data analysis techniques used for combining data. METHODS Systematic literature searches were conducted in PubMed and Embase complemented by a manual literature search. We included pharmacoepidemiological multi-database studies published from 2007 onwards that combined data for a pre-planned common analysis or quantitative synthesis. Information was retrieved about study characteristics, methods used for individual-level analyses and meta-analyses, data management and motivations for performing the study. RESULTS We found 3083 articles by the systematic searches and an additional 176 by the manual search. After full-text screening of 75 articles, 22 were selected for final inclusion. The number of databases used per study ranged from 2 to 17 (median = 4.0). Most studies used a cohort design (82%) instead of a case-control design (18%). Logistic regression was most often used for individual-level analyses (41%), followed by Cox regression (23%) and Poisson regression (14%). As meta-analysis method, a majority of the studies combined individual patient data (73%). Six studies performed an aggregate meta-analysis (27%), while a semi-aggregate approach was applied in three studies (14%). Information on central programming or heterogeneity assessment was missing in approximately half of the publications. Most studies were motivated by improving power (86%). CONCLUSIONS Pharmacoepidemiological multi-database studies are a well-powered strategy to address safety issues and have increased in popularity. To be able to correctly interpret the results of these studies, it is important to systematically report on database management and analysis techniques, including central programming and heterogeneity testing.
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Affiliation(s)
- Marloes T Bazelier
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Netherlands
| | - Irene Eriksson
- Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden
| | - Frank de Vries
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Netherlands.,Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Marjanka K Schmidt
- Division of Molecular Pathology, Netherlands Cancer Institute, Netherlands
| | - Jani Raitanen
- School of Health Sciences, University of Tampere, Finland.,UKK Institute for Health Promotion, Tampere, Finland
| | | | - Jakob Starup-Linde
- Aalborg University, Aalborg, Denmark.,Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Marie L De Bruin
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Netherlands
| | - Morten Andersen
- Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden
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Simon N, Finzi J, Cayla G, Montalescot G, Collet JP, Hulot JS. Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients. Eur J Clin Pharmacol 2015; 71:1059-66. [PMID: 26071277 DOI: 10.1007/s00228-015-1882-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 06/02/2015] [Indexed: 12/15/2022]
Abstract
PURPOSE Proton-pump Inhibitors use and CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses and increased cardiovascular events. METHODS Post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 41) or homozygous (*2/*2, n = 7) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel loading dose. A PK/PD model was defined using the variation of the P2Y12 reaction unit relative to baseline. RESULTS Carriage of CYP2C19*2 allele and the use of omeprazole/esomeprazole were associated with the inter-individual variability in the active metabolite clearance. The relationship between inhibition of platelet aggregation (IPA, %) and the active metabolite AUC (h*μg/L) was described by a sigmoid function (Emax 56 ± 5%; EAUC50 15.9 ± 0.8 h*μg/L) with a gamma exponent (7.04 ± 2.26). CONCLUSION This on/off shape explains that a small variation of exposure may have a clinical relevance.
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Affiliation(s)
- Nicolas Simon
- Aix-Marseille Université, INSERM, UMR912 (SESSTIM), 13003, Marseille, France,
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Bouziana SD, Tziomalos K. Clinical relevance of clopidogrel-proton pump inhibitors interaction. World J Gastrointest Pharmacol Ther 2015; 6:17-21. [PMID: 25949846 PMCID: PMC4419089 DOI: 10.4292/wjgpt.v6.i2.17] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/24/2015] [Accepted: 04/16/2015] [Indexed: 02/06/2023] Open
Abstract
Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal (GI) bleeding, the elderly, and patients with a history of prior GI bleeding, with Helicobacter pylori infection or those who are also treated with aspirin, anticoagulants, corticosteroids or nonsteroidal anti-inflammatory drugs are at high risk for GI complications when treated with clopidogrel. Accordingly, proton pump inhibitors are frequently administered in combination with clopidogrel to reduce the risk for GI bleeding. Nevertheless, pharmacodynamic studies suggest that omeprazole might attenuate the antiplatelet effect of clopidogrel. However, in observational studies, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Moreover, in the only randomized, double-blind study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for GI events and similar risk for cardiovascular events than patients treated with clopidogrel and placebo. However, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination. Other proton pump inhibitors do not appear to interact with clopidogrel. Nevertheless, given the limitations of existing observational and interventional studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient's bleeding and cardiovascular risk.
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Melloni C, Washam JB, Jones WS, Halim SA, Hasselblad V, Mayer SB, Heidenfelder BL, Dolor RJ. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review. Circ Cardiovasc Qual Outcomes 2015; 8:47-55. [PMID: 25587094 DOI: 10.1161/circoutcomes.114.001177] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Discordant results have been reported on the effects of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. We conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the postdischarge treatment of unstable angina/non-ST-segment-elevation myocardial infarction patients. METHODS AND RESULTS We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, from 1995 to 2012. Reviewers screened and extracted data, assessed applicability and quality, and graded the strength of evidence. We performed meta-analyses of direct comparisons when outcomes and follow-up periods were comparable. Thirty-five studies were eligible. Five (4 randomized controlled trials and 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class when compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic end points, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from randomized controlled trials evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole. CONCLUSIONS Large, well-conducted observational studies of PPIs and randomized controlled trials of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in patients with unstable angina/non-ST-segment-elevation myocardial infarction treated with DAPT are warranted.
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Affiliation(s)
- Chiara Melloni
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.).
| | - Jeffrey B Washam
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.)
| | - W Schuyler Jones
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.)
| | - Sharif A Halim
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.)
| | - Victor Hasselblad
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.)
| | - Stephanie B Mayer
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.)
| | - Brooke L Heidenfelder
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.)
| | - Rowena J Dolor
- From the Duke Clinical Research Institute, Duke University Medical Center (C.M., W.S.J., S.A.H., V.H., B.L.H., R.J.D.); Duke Heart Center (J.B.W.), Duke University Medical Center, Durham, NC; and Division of Endocrinology and Metabolism, Department of Medicine, Virginia Commonwealth University, Richmond (S.B.M.)
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Kim JJ, Kim N. [Does dual antiplatelet therapy increase the risk of peptic ulcer disease?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2014; 64:67-69. [PMID: 25318124 DOI: 10.4166/kjg.2014.64.2.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
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Andersson T, Nagy P, Niazi M, Nylander S, Galbraith H, Ranjan S, Wallentin L. Effect of esomeprazole with/without acetylsalicylic acid, omeprazole and lansoprazole on pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. Am J Cardiovasc Drugs 2014; 14:217-27. [PMID: 24677117 DOI: 10.1007/s40256-014-0073-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The effect of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of clopidogrel was assessed in two healthy volunteer crossover studies. SUBJECTS AND METHODS Study 1: subjects received clopidogrel alone (300-mg loading dose, then 75 mg/day for 28 days) and two of three PPIs (omeprazole 80 mg, esomeprazole 40 mg or lansoprazole 60 mg) plus clopidogrel for 29 days in three treatment periods (randomized treatment sequence assignment). Study 2: subjects received clopidogrel alone (75 mg/day for 9 days) and clopidogrel alone for 4 days followed by clopidogrel plus fixed-combination esomeprazole 20 mg/low-dose acetylsalicylic acid (ASA) 81 mg for 5 days in two treatment periods (randomized treatment sequence assignment). Pharmacokinetic effects were estimated by measuring active metabolite of clopidogrel, and pharmacodynamic effects by inhibition of adenosine diphosphate (ADP)-induced platelet aggregation. RESULTS There was a relative decrease of up to 50 % in exposure to the active metabolite of clopidogrel with the different PPIs (study 1), and close to 40 % with esomeprazole/low-dose ASA (study 2), compared with clopidogrel alone. There was an absolute decrease of up to 17 % in inhibition of ADP-induced platelet aggregation with co-administration of different PPIs, compared with clopidogrel alone; however, no differences in platelet inhibition were observed during co-administration with the esomeprazole/low-dose ASA fixed-dose combination. CONCLUSION Omeprazole, esomeprazole and lansoprazole decreased systemic exposure to the active metabolite of clopidogrel in healthy volunteers, leading to modest decreases in its antiplatelet effect. However, no apparent differences in platelet inhibition were observed when esomeprazole was co-administered with low-dose ASA as a fixed-dose combination.
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Wang Q, Ljung R, Lagergren J, Lu Y. Prognosis of concomitant users of clopidogrel and proton-pump inhibitors in a high-risk population for upper gastrointestinal bleeding. BMC Pharmacol Toxicol 2014; 15:22. [PMID: 24731755 PMCID: PMC4002561 DOI: 10.1186/2050-6511-15-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 03/25/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND It is unclear whether concomitant use of clopidogrel and proton-pump inhibitors (PPIs) increases the risk of recurrence of cardiovascular disease or death in patients at high risk of upper gastrointestinal (GI) bleeding. METHODS Based on the Swedish Patient Register, a cohort of cardiovascular disease (including acute myocardial infarction, stroke and angina, from 2006 to 2008) was selected from a population with any diagnosis of upper GI bleeding. Data on drug prescription was retrieved from the Prescribed Drug Register. Patients entered into the cohort after their first discharge for cardiovascular disease and were followed up to death, recurrence of cardiovascular disease, or 90 days. A Cox regression model was conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to evaluate the risks among users of different drug prescriptions. RESULTS Patients who were current users of only PPIs (HR 2.02, 95% CI 1.19-3.44), only clopidogrel (HR 1.14, 95% CI 0.53-2.45) and nonusers of both (HR 2.36, 95% CI 1.39-4.00) were at a higher risk of death compared with patients with a concomitant use. Results were similar among 1779 patients who had any history of upper GI bleeding (HR 2.05, 95% CI 1.18-3.54; HR 1.25, 95% CI 0.57-2.72; HR 2.30, 95% CI 1.33-3.98, respectively). CONCLUSION Among patients at high risk of upper GI bleeding, those with a concomitant use of PPIs and clopidogrel were at a decreased risk of mortality, and possibly also a decreased risk of recurrence of cardiovascular disease.
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Affiliation(s)
- Qing Wang
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - Rickard Ljung
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Division of Cancer Studies, King’s College London, London, United Kingdom
| | - Yunxia Lu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
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Amariles P, Holguín H, Angulo NY, Betancourth PM, Ceballos M. [Effect of drug interaction between clopidogrel and omeprazole in hospital readmision of patients by a recurrent acute coronary syndrome: a case-control study]. Aten Primaria 2014; 46:426-32. [PMID: 24581893 PMCID: PMC6985604 DOI: 10.1016/j.aprim.2013.11.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/11/2013] [Accepted: 11/11/2013] [Indexed: 11/20/2022] Open
Abstract
Objetivo Evaluar el efecto de la interacción clopidogrel-omeprazol en el reingreso hospitalario de pacientes por recidiva de síndrome coronario agudo (SCA) Diseño Estudio de casos y controles Emplazamiento IPS Universitaria Clínica León XIII, Medellín, Colombia. Participantes Se seleccionaron a partir de una población prevalente, entre 2009-2010, pacientes con uso de clopidogrel de forma ambulatoria (menor a un año y superior a 30 días), y la estancia hospitalaria por un SCA o la presencia de un SCA previo. Medidas principales Un paciente-caso se definió como aquel que presentó una recidiva de SCA y un paciente-control se definió como aquel que no presentó recidiva de SCA. Ambos grupos utilizaron ambulatoriamente clopidogrel debido al SCA previo. Como factor de riesgo se definió la utilización conjunta de omeprazol y clopidogrel ambulatoriamente. Resultados Durante el estudio se formuló clopidogrel a 1.680 pacientes. En este grupo se identificaron 50 casos readmitidos con SCA y 76 controles. No se encontró asociación estadísticamente significativa entre el uso de clopidogrel-omeprazol y un mayor riesgo de reingreso hospitalario por SCA (OR: 1,05; IC 95%: 0,516-2,152; p = 0,8851). Conclusiones En este pequeño grupo de pacientes con SCA previo, la utilización simultánea de clopidogrel con omeprazol no aumenta el riesgo de un reingreso hospitalario por recurrencia de este tipo de evento coronario.
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Affiliation(s)
- Pedro Amariles
- Grupo de Investigación, Promoción y Prevención Farmacéutica, Facultad de Química Farmacéutica, Universidad de Antioquia, Medellín, Antioquia, Colombia.
| | - Héctor Holguín
- Grupo de Investigación, Promoción y Prevención Farmacéutica, Facultad de Química Farmacéutica, Universidad de Antioquia, Medellín, Antioquia, Colombia
| | - Nancy Yaneth Angulo
- IPS Universitaria León XIII, Facultad de Medicina, Universidad de Antioquia, Medellín, Antioquia, Colombia
| | | | - Mauricio Ceballos
- Grupo de Investigación, Promoción y Prevención Farmacéutica, Facultad de Química Farmacéutica, Universidad de Antioquia, Medellín, Antioquia, Colombia
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