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Proton pump inhibitor use represents an independent risk factor for myocardial infarction
Abstract
Background
There is substantial debate regarding the development of acute coronary syndrome in patients using proton pump inhibitors (PPIs) combined with clopidogrel. However, data remain limited to address the effect of PPIs alone on the subsequent risk of myocardial infarction (MI). We aimed to explore the subsequent risk of MI in PPI users who had no previous history of MI.
Methods
The records of inpatients and outpatients with PPI prescriptions were retrieved from the Taiwan National Health Insurance Research Database between 2000 and 2009. We conducted two different study designs, the first using propensity score (PS)-matching analyses and the second using case-crossover analyses. The risk of developing MI for PPI users was analyzed in the PS-matched study. The association between risk of MI and prior PPI exposure was further validated in the case-crossover study.
Results
In the PS-matched study, we included 126,367 PPI users and 126,367 PS-matched PPI non-users. After 120 days of follow-up, PPI use was associated with a 1.58-fold greater risk of MI (adjusted hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.11 to 2.25). In the case-crossover study, adjusted odds ratios of PPI for MI risk were 4.61 (95% CI = 1.76 to 12.07) for the 7-day window and 3.47 (95% CI = 1.76 to 6.83) for the 14-day window.
Conclusions
Use of PPIs may be independently associated with an increased risk of MI. However, the benefits of PPIs may greatly outweigh the risks of adverse cardiovascular effects, with number needed to harm of 4357.
... Prescription and over-the-counter medications are commonly used in the United States, particularly among older adults. 1 While most medications are associated with any number of potential adverse effects, 2 many commonly used medication classes, including non-steroidal antiinflammatory drugs (NSAIDs), [3][4][5][6] proton pump inhibitors (PPIs), [7][8][9] and bronchodilators, [10][11][12] have established cardiovascular risks. 13,14 Such risks may be especially relevant to the elderly, many of whom may have preexisting cardiovascular disease (CVD). ...
... 15,16 Numerous scientific investigations have characterized the potential cardiovascular risks of specific products, [17][18][19] and many others have quantified the association between specific therapeutic classes and CVD, including myocardial infarction (MI), stroke, and sudden cardiac death. 3,4,[7][8][9][10][11][12][20][21][22] For example, non-aspirin NSAIDs have been consistently associated with CVD, with a 15%-44% increased risk of MI and stroke among treated patients. 3,6 By contrast, evidence linking PPIs and bronchodilators to MI and sudden cardiac death is more variable. ...
... Although the cardiovascular risks of many prescription medications have been well characterized, such investigations have typically focused on a specific products or therapeutic classes, 3,4,[7][8][9][10][11][12][20][21][22] rather than quantifying the cumulative cardiovascular risk posed by the concurrent use of medications. In this large and diverse prospec- Our findings are important because of their plausibility, magnitude, and relevance to many adults who regularly use multiple prescription medications. ...
Background:
Many commonly used prescription medications have cardiovascular adverse effects, yet the cumulative risk of cardiovascular events associated with the concurrent use of these medications is unknown. We examined the association between the concurrent use of prescription medications with known risk of a major adverse cardiovascular event (MACE) ["MACE medications"] and the risk of such events among older adults.
Methods:
A multi-center, population-based study from the Atherosclerosis Risk in Communities (ARIC) study of a cohort of 3,669 community-dwelling adults aged 61 to 86 years with no history of cardiovascular disease who reported the use of at least one medication between September 2006 and August 2013 were followed up until August 2015. Exposure defined as time-varying and time-fixed use of 1, 2 or ≥3 MACE medications with non-MACE medications serving as negative control. Primary outcome was incident MACE defined as coronary artery revascularization, myocardial infarction, fatal coronary heart disease, stroke, cardiac arrest, or death.
Results:
In fully adjusted models, there was an increased risk of MACE associated with use of 1, 2, or ≥3 MACE medications (1 MACE: hazards ratio [HR], 1.21; 95% confidence interval [CI], 0.94-1.57); 2 MACE: HR 1.89, CI 1.42-2.53; ≥3 MACE: HR 2.22, CI 1.61-3.07) compared to use of non-MACE medications. These associations persisted in propensity score-matched analyses and among new users of MACE medications, never users of cardiovascular medications and subgroups of participants with increased risk of MACE. There was no association between the number of non-MACE medications used and MACE.
Conclusions and relevance:
In this community-based cohort of older adults with no prior cardiovascular disease, the use of MACE medications was independently and consistently associated with an increased risk of such events in a dose-response fashion. This article is protected by copyright. All rights reserved.
... However, several studies suggested that the unfavourable effect of PPIs on cardiovascular health was independent of antiplatelet agents [13,17]. Thereafter, evidence has linked PPIs with risk of adverse CVD outcomes in general populations [18][19][20][21]. One of the possible explanations underlying the link between PPIs and CVD risk might be the gut microbiota dysbiosis. ...
... Some studies found that the observed associations between PPIs use and risk of CVD was independent of antiplatelet agents use [13,17]. Since then, the association between PPIs use and higher risk of CVD were also demonstrated in general populations [18][19][20][21]. Retrospective nationwide studies using data from the Taiwan National Health Insurance showed that PPIs use was associated with a higher risk of ischemic stroke and MI in general populations [18,21]. ...
... Since then, the association between PPIs use and higher risk of CVD were also demonstrated in general populations [18][19][20][21]. Retrospective nationwide studies using data from the Taiwan National Health Insurance showed that PPIs use was associated with a higher risk of ischemic stroke and MI in general populations [18,21]. A Danish national cohort study using pharmacy records also observed PPIs use was associated with a higher risk of ischemic stroke and MI, and the observed association was more prominent with high-dose PPIs use [20]. ...
Background: Proton pump inhibitors (PPIs) are widely used drugs for gastric-acid-related diseases, which may have an impact on the gut microbiome. We aimed to evaluate the associations of PPIs use with risks of cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes (T2D).
Methods: We analysed the associations of PPIs use with risks of coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), stroke, and all-cause mortality in 19,229 adults with T2D using data from the UK Biobank study.
Results: During a median follow-up of 10.9-11.2 years, we documented a total of 2,971 CAD, 1,827 MI, 1,192 HF, and 738 stroke cases, along with 2,297 total deaths. PPIs use was significantly associated with higher risks of CAD (HR, 1.27; 95% CI, 1.15-1.40), MI (HR, 1.34; 95% CI, 1.18-1.52), HF (HR, 1.35; 95% CI, 1.16-1.57) and all-cause mortality (HR, 1.30; 95% CI, 1.16-1.45). No significant association was observed between PPIs use and stroke (HR, 1.11; 95% CI, 0.90-1.36). The results were consistent in the subgroup analyses stratified by factors including indications of PPIs, anti-diabetic medication use, and antiplatelet drug use. Analyses in a 1:1 propensity score-matched cohort of PPIs users versus non-users yielded consistent results.
Conclusion: Our data suggested that PPIs use was associated with higher risks of CVD events and mortality among patients with T2D. Prescription of PPIs among patients with T2D should be cautious, and monitoring of adverse cardiovascular events during PPIs therapy should be enhanced.
... In addition to these factors, long-term exposure to proton pump inhibitors (PPIs) may be an AMI risk factor [5][6][7][8][9][10][11][12]. In 2007, Lundell et al. compared the anti-reflux surgery with omeprazole maintenance therapy in chronic gastroesophageal reflux disease (GERD) and found the higher adverse heart-related events in the omeprazole group [7]. ...
... Hsiang-Jung Tseng and Chih-Ming Cheng have contributed equally to this work. Shih et al. reported that after 120 days of follow-up, PPI use was associated with a 1.58-fold higher AMI risk [10]. Shah et al. found that patients with GERD who used PPIs had a 1.16-fold higher AMI risk [9]. ...
... Our findings corroborate those of Shih et al. [10] and Shah et al. [9]. Nevertheless, our study has some strength compared with the two studies mentioned above. ...
Background:
Association of proton pump inhibitor (PPI) exposure with acute myocardial infarction (AMI) risk in the Caucasian population remains under debate. Here, we clarified whether PPI exposure might be related to an increased new-onset AMI risk in an Asian population.
Method:
Data of 27,624 patients with PPI exposure followed by new-onset AMI development were extracted from Taiwan National Health Insurance Research Database and age- and sex-matched with 27,624 controls with PPIs exposure, but without subsequent AMI and ischemic heart disease development. The amount of PPI exposure was calculated based on the cumulative defined daily dose (cDDD) during the follow-up period. Subsequent AMI risk was measured after adjustments of demographic data and indication of PPI use.
Results:
AMI risk increased with an increase in PPI exposure: with cDDD ≤ 30 as the reference, the odds ratios (95% confidence intervals) for cDDDs of > 365 was 1.56 (1.45-1.69). All five PPI categories, including pantoprazole, lansoprazole, omeprazole, esomeprazole, and rabeprazole, increased AMI risk.
Conclusions:
Our study demonstrated long-term or high-dose PPI exposure associated with increased new-onset AMI risk in patients without a history of any ischemic heart disease. The underlying mechanisms of PPI-related cardiovascular effects deserve more investigation.
... 16) Furthermore, these risks may extend from patients with coronary artery disease to the general population. [17][18][19][20][21] However, there are several studies with conflicting results that PPIs do not manifest as an independently increased risk of adverse cardiovascular events. 22,23) To help address this association, a metaanalysis of randomized controlled trials (RCTs) demonstrated that PPI monotherapy could be a risk factor for adverse cardiovascular events in patients with gastroesophageal reflux disease (GERD). ...
... The full texts of the 53 remaining studies were reviewed. Finally, 14 observational studies (13 cohort studies and 1 case-control study) [16][17][18][19][20]22,23,[26][27][28][29][30][31][32] were included in this meta-analysis. Of them, 4 studies reported stroke, 16,19,20,23) 5 studies reported MI, [16][17][18][19]26) 2 studies reported cardiovascular death, 16,18) 4 studies reported all-cause death, 16,22,27,32) and 6 studies reported MACEs. ...
... Finally, 14 observational studies (13 cohort studies and 1 case-control study) [16][17][18][19][20]22,23,[26][27][28][29][30][31][32] were included in this meta-analysis. Of them, 4 studies reported stroke, 16,19,20,23) 5 studies reported MI, [16][17][18][19]26) 2 studies reported cardiovascular death, 16,18) 4 studies reported all-cause death, 16,22,27,32) and 6 studies reported MACEs. 16,22,[28][29][30][31] With regard to the outcome of MI, we included 5 studies with 6 risk estimates because Shah, et al. provided 2 databases: the Stanford Translational Research Integrated Database Environment (STRIDE) and Practice Fusion (PF). ...
Previous studies have provided established evidence on adverse outcomes of the coadministration of proton pump inhibitors (PPIs) and clopidogrel, whereas cerebro-cardiovascular outcomes of PPI use in the absence of clopidogrel therapy remain controversial.
In this study, we aimed to assess the association between PPIs and cerebro-cardiovascular outcomes independent of clopidogrel.
Systematic searches were conducted in the Cochrane Library, PubMed, and Embase databases for all relevant studies up to August 2018. Odds ratios (ORs) with its 95% confidence intervals (CIs) were abstracted and pooled using the random-effects model.
A total of 14 observational studies (13 cohort studies and 1 case-control study) were identified. Compared with non-PPI users, PPI users experienced higher risks of stroke (OR: 1.22, 95% CI: 1.08-1.36), myocardial infarction (MI; OR: 1.23, 95% CI: 1.14-1.32), cardiovascular death (OR: 1.83, 95% CI: 1.69-1.98), and major adverse cardiovascular events (MACEs; OR: 1.22, 95% CI: 1.05-1.40) independent of clopidogrel use, but not all-cause death (OR: 1.50, 95% CI: 0.99-2.25). In the subgroup analysis, PPI alone was associated with significant risks of new-onset MI (OR: 1.23, 95% CI: 1.13-1.35) and stroke (OR: 1.17, 95% CI: 1.05-1.30) in patients without previous MI or stoke and recurrent MI (OR: 1.24, 95% CI: 1.02-1.51) and stroke (OR: 1.36, 95% CI: 1.19-1.55) risks in patients with a previous MI.
Based on current publications, PPI use seems to be associated with increased risks of stroke, MI, cardiovascular death, and MACEs independent of clopidogrel. Greater caution should be therefore exercised while considering its clinical benefits and further investigate any causal relationships.
... Eight studies were abstracts where a corresponding fulltext publication could not be identified (Taha et al. 2013;Antunes et al. 2016;Caffrey et al. 2016;Kwon et al. 2016;Bell et al. 2017;Bang and Bendtsen 2018;Gardezi et al. 2018;Sehested et al. 2018) and were, therefore, excluded from the meta-analyses. An additional seven studies reporting adjusted effect estimates (Myles et al. 2009;Maggio et al. 2013;Chen et al. 2014;Im et al. 2014;Shih et al. 2014;Lee et al. 2015;Bettinger et al. 2018) could not be included in the meta-analysis due to variations in the baseline characteristics of the study populations (COPD, percutaneous endoscopic gastrostomy, elderly, UGIB, pneumonia, and pyogenic liver disease). See Supplemental Material V for a list of the studies excluded from the meta-analyses. ...
... Assuming these patient populations have substantially different baseline event rates, it is not recommended to pool these studies (CIOMS, 2016). Individual findings of these studies that were not included in the meta-analyses suggest a higher risk of mortality with PPI use among COPD patients (Lee et al. 2015), elderly patients discharged from acute care hospitals (Maggio et al. 2013), patients with pyogenic liver disease (Bettinger et al. 2018), and PPI users in general (Shih et al. 2014). However, no significant associations were reported with PPI use and ACM among patients with pneumonia (Myles et al. 2009) ...
... The majority of studies assessing the association between concomitant PPI and clopidogrel treatment in this review were observational studies, which are inherently prone to certain biases. The main limitation reported in several of these observational studies was the potential bias from residual confounding (Daskalopoulou et al. 2008;Myles et al. 2009;Oudit et al. 2011;Kwon et al. 2013;Maggio et al. 2013;Chen et al. 2014;Mandorfer et al. 2014;Shih et al. 2014;Dultz et al. 2015;Lee et al. 2015). Indeed, the issue of unmeasured confounders is important, as many of the observational studies included in this review were based on analyses of large databases of medical records; consequently, important information on MACE risk factors such as smoking, obesity, alcohol consumption, family history of cardiovascular disease, and other variables was not available to the investigators. ...
The potential association between major adverse cardiovascular events (MACE) and concomitant treatment with proton pump inhibitors (PPIs) and clopidogrel has been debated since 2009. Recent reports, however, suggest that PPIs may increase the risk of MACE independently of clopidogrel. This review evaluates epidemiological findings relevant to the association between PPIs, taken alone or concomitantly with antiplatelets, and the risk of MACE. A systematic review and meta-analysis were conducted. Relevant studies were identified from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and then screened. Included studies were categorized into three groups: Group A: PPIs versus no PPIs; Group B: combined PPIs and clopidogrel versus clopidogrel alone; Group C: combined PPIs and other drugs versus other drugs. Pooled risk ratios (RRs) were calculated for each outcome of interest in each comparison group. Of the 1667 studies identified, 118 were included in the systematic review, of which 66 were included in the meta-analyses. Among Group A observational studies, RRs for MACE outcomes were statistically significant for some patient populations but not others. Pooled RRs from Group A RCTs were not statistically significant for any outcome. Pooled RRs for Group B observational studies were statistically significant for all-cause mortality and MI, but were diminished in magnitude when pooling was restricted to propensity score matched studies or post hoc analyses of RCTs. Group C studies did not demonstrate an association with MACE. Findings do not consistently support an association between MACE and PPIs when taken alone, or concomitantly with antiplatelets.
... Forty-seven of them were excluded due to insufficient data on study groups and another two for statistical reasons (the event rate was zero). A total of 27 studies (Rassen et al., 2009;Bhatt et al., 2010;Cai et al., 2010;Charlot et al., 2010;Evanchan et al., 2010;Gupta et al., 2010;Hudzik et al., 2010;Kreutz et al., 2010;Ray et al., 2010;Stockl et al., 2010;van Boxel et al., 2010;Hsu et al., 2011;Ren et al., 2011;Rossini et al., 2011;Simon et al., 2011;Burkard et al., 2012;Chitose et al., 2012;Goodman et al., 2012;Ng et al., 2012;Yano et al., 2012;Hokimoto et al., 2014;Shih et al., 2014;Zou et al., 2014;Weisz et al., 2015;Ayub et al., 2016;Gargiulo et al., 2016) were selected for quantitative analyses. The researchers and committee involved in the selection (5 investigators) were in total agreement on all the inclusions and exclusions. ...
... Altogether, we found data for MACE in 23 publications (O'Donoghue et al., 2009;Bhatt et al., 2010;Cai et al., 2010;Charlot et al., 2010;Gupta et al., 2010;Hudzik et al., 2010;Kreutz et al., 2010;Ray et al., 2010;van Boxel et al., 2010;Hsu et al., 2011;Ren et al., 2011;Rossini et al., 2011;Simon et al., 2011;Burkard et al., 2012;Chitose et al., 2012;Goodman et al., 2012;Ng et al., 2012;Yano et al., 2012;Hokimoto et al., 2014;Zou et al., 2014;Weisz et al., 2015;Ayub et al., 2016;Gargiulo et al., 2016), for CV death in 10 ( Rassen et al., 2009;Bhatt et al., 2010;Gupta et al., 2010;Simon et al., 2011;Burkard et al., 2012;Chitose et al., 2012;Goodman et al., 2012;Hokimoto et al., 2014;Zou et al., 2014;Weisz et al., 2015;Gargiulo et al., 2016) and for MI in 14 (Rassen et al., 2009;Bhatt et al., 2010;Evanchan et al., 2010;Hudzik et al., 2010;Stockl et al., 2010;van Boxel et al., 2010;Simon et al., 2011;Burkard et al., 2012;Chitose et al., 2012;Goodman et al., 2012;Shih et al., 2014;Zou et al., 2014;Weisz et al., 2015;Gargiulo et al., 2016). Seventeen of them were observational studies, 16 were cohorts (Rassen et al., 2009;Charlot et al., 2010;Evanchan et al., 2010;Gupta et al., 2010;Kreutz et al., 2010;Ray et al., 2010;Stockl et al., 2010;van Boxel et al., 2010;Rossini et al., 2011;Simon et al., 2011;Chitose et al., 2012;Hokimoto et al., 2014;Shih et al., 2014;Zou et al., 2014;Weisz et al., 2015;Ayub et al., 2016), and one was a case-control study (Hudzik et al., 2010). ...
... Altogether, we found data for MACE in 23 publications (O'Donoghue et al., 2009;Bhatt et al., 2010;Cai et al., 2010;Charlot et al., 2010;Gupta et al., 2010;Hudzik et al., 2010;Kreutz et al., 2010;Ray et al., 2010;van Boxel et al., 2010;Hsu et al., 2011;Ren et al., 2011;Rossini et al., 2011;Simon et al., 2011;Burkard et al., 2012;Chitose et al., 2012;Goodman et al., 2012;Ng et al., 2012;Yano et al., 2012;Hokimoto et al., 2014;Zou et al., 2014;Weisz et al., 2015;Ayub et al., 2016;Gargiulo et al., 2016), for CV death in 10 ( Rassen et al., 2009;Bhatt et al., 2010;Gupta et al., 2010;Simon et al., 2011;Burkard et al., 2012;Chitose et al., 2012;Goodman et al., 2012;Hokimoto et al., 2014;Zou et al., 2014;Weisz et al., 2015;Gargiulo et al., 2016) and for MI in 14 (Rassen et al., 2009;Bhatt et al., 2010;Evanchan et al., 2010;Hudzik et al., 2010;Stockl et al., 2010;van Boxel et al., 2010;Simon et al., 2011;Burkard et al., 2012;Chitose et al., 2012;Goodman et al., 2012;Shih et al., 2014;Zou et al., 2014;Weisz et al., 2015;Gargiulo et al., 2016). Seventeen of them were observational studies, 16 were cohorts (Rassen et al., 2009;Charlot et al., 2010;Evanchan et al., 2010;Gupta et al., 2010;Kreutz et al., 2010;Ray et al., 2010;Stockl et al., 2010;van Boxel et al., 2010;Rossini et al., 2011;Simon et al., 2011;Chitose et al., 2012;Hokimoto et al., 2014;Shih et al., 2014;Zou et al., 2014;Weisz et al., 2015;Ayub et al., 2016), and one was a case-control study (Hudzik et al., 2010). Data from 10 RCTs (O'Donoghue et al., 2009;Bhatt et al., 2010;Cai et al., 2010;Hsu et al., 2011;Ren et al., 2011;Burkard et al., 2012;Goodman et al., 2012;Ng et al., 2012;Yano et al., 2012;Gargiulo et al., 2016) were also collected. ...
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.
... [20][21][22][23][24] Furthermore, it has been suggested that the observed risk of PPI use with anti-platelet therapy may be partly due to an increase in cardiovascular risk conferred by PPIs directly. 25,26 To help address this theory, a systematic review and meta-analysis was conducted to explore the association between cardiovascular risk and PPIs independent of concomitant clopidogrel therapy. ...
... In total, 22 studies met the inclusion criteria (including three abstracts which were excluded from meta-analysis). [24][25][26][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] The most common reasons for study exclusion were noncardiovascular outcomes (encapsulated by the broad search strategy), and the use of concomitant anti-platelet therapy. The screening process and further reasons for exclusion are documented using the PRISMA flow diagram presented in Figure 1. ...
... The screening process and further reasons for exclusion are documented using the PRISMA flow diagram presented in Figure 1. 27 Data from 16 [24][25][26][36][37][38][39][40]42,[44][45][46][47][48]50,52 of the 22 studies were included in the meta-analyses, which were undertaken separately for randomised controlled trials and observational studies. ...
Background
Clopidogrel's anti‐platelet effects may be attenuated by a pharmacokinetic interaction with co‐prescribed proton pump inhibitors, which inhibit oxidative pathways that convert clopidogrel into its active metabolites. Despite this, the impact of PPIs on cardiovascular risk in the absence of clopidogrel is not well defined.
Aim
To report on a systematic review and meta‐analysis of the association between PPIs and cardiovascular risk, independent of clopidogrel.
Methods
The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov were systematically searched in October 2017. The primary outcome was association between PPI monotherapy and any adverse cardiovascular event. The secondary outcome was association between proton pump inhibitor monotherapy and acute myocardial infarction. Studies were excluded if they reported or did not adjust for concomitant anti‐platelet therapy or involved participants aged less than 18 years.
Results
A total of 22 studies were included in the systematic review. Data from 16 studies were included in the meta‐analysis (involving 447 408 participants). Of these, eight were randomised controlled trials, seven were observational studies and one was a retrospective analysis of a randomised controlled trial. An increased risk of any adverse cardiovascular event with PPI monotherapy was observed using pooled data from observational studies (risk ratio 1.25, 95% CI 1.11‐1.42, I² 81%, P < 0.001), but not from randomised controlled trials (risk ratio 0.89, 95% CI 0.34‐2.33, I² 0%, P = 0.85).
Conclusion
There is no clear evidence of an association between PPI monotherapy and increased cardiovascular risk.
... Some observational studies investigated the cardiovascular risk in different follow-up periods and reported contradictory findings on the cardiovascular effects of PPIs. [7][8][9][10][11][12][13][14][15][16][17] Among them, some studies repeated the analyses using the alternative treatment H 2 receptor antagonists (H 2 RAs) as a negative exposure control which should have shown no association with myocardial infarction (MI), but harmful associations were found. 7,10,13,17 As cardiovascular conditions including MI may present with gastrointestinallike manifestations, PPIs and H 2 RAs may be prescribed for patients who first presented with MI. ...
... 11,12 In contrast, some cohort studies suggested a cardiovascular risk of PPIs in both the short and the long term. [8][9][10]16 Contrary to our result, long-term increased risk of MI and cardiovascular mortality (2-5 years) was also found. 8 Given that a recent randomized controlled trial provided strong evidence to support long-term cardiovascular safety of PPIs, 5 the unmeasured confounding in these between-individual comparison studies, resulting from differences between PPI and non-PPI users, might explain an apparently harmful association. ...
Background
Previous studies investigating potential cardiovascular adverse events of acid-suppressing drugs are susceptible to protopathic bias and confounding. We aimed to investigate the association between short-term risk of myocardial infarction (MI) and proton pump inhibitors (PPIs) using a self-controlled case series (SCCS) with an active comparator.
Methods
We conducted a SCCS using a population-wide database from Hong Kong from 2003–2014. Adult with ≥1 outpatient oral PPI prescription or H2 receptor antagonist (H2RA) and MI during the observation period were included. We used both simple ratio and effect modifier approaches to SCCS with active comparators to obtain comparator adjusted estimates.
Results
A total of 2802 and 1889 people with MI who had exposure to PPIs and H2RA were included respectively. We observed a higher risk of MI during days 1–14 following the start of PPI prescription (Incidence rate ratio (IRR): 2.30, 95% confidence interval (CI): 1.76–3.00) versus baseline. Similarly, we observed a higher risk of MI during days 1–14 following the start of H2RA prescription (IRR: 2.46, 95%CI: 1.92–3.16) versus baseline. In the novel SCCS analyses, comparator adjusted estimates were 0.93 (95%CI: 0.57–1.30) and 0.83 (95%CI: 0.58–1.20) during days 1–14 in simple ratio and effect modifier approach, respectively.
Conclusions
We observed no difference in risk of MI associated with PPIs compared with baseline using H2RA as the active comparator. The elevated risk of MI associated with PPIs is likely due to protopathic bias. More studies are required to explore the feasibility of using active comparators in SCCS to address protopathic bias in addition to confounding.
... 4 One approach to improve the evidence is through testing of plausible biological pathways. Several cohort studies indicated that an increased risk of myocardial infarction and ischemic stroke in PPI users was independent of aspirin or clopidogrel intake, 3,5,6 which suggests an underlying mechanism that does not directly involve either platelet aggregation or change in drug absorption due to a rise in gastric pH. 3,5 As a result, potential biochemical mechanisms were put forward that could explain the effect of PPI intake on the cardiovascular system. ...
... Several cohort studies indicated that an increased risk of myocardial infarction and ischemic stroke in PPI users was independent of aspirin or clopidogrel intake, 3,5,6 which suggests an underlying mechanism that does not directly involve either platelet aggregation or change in drug absorption due to a rise in gastric pH. 3,5 As a result, potential biochemical mechanisms were put forward that could explain the effect of PPI intake on the cardiovascular system. ...
Objective:
Long-term intake of proton pump inhibitors (PPIs) might increase the risk of cardiovascular events. One suggested mechanism is that PPIs inhibit the enzyme dimethylarginine dimethylaminohydrolase (DDAH), and thereby block the degradation of endothelial asymmetrical dimethylarginine (ADMA). Excess ADMA in turn leads to impaired endothelial nitric oxide (NO) generation. So far, this mechanism has only been established in human cell cultures. This study examined that pathway in a human population. Previous studies that examined this pathway in human populations measured circulating ADMA, and found no association with PPI use and excess plasma ADMA. But in a recent study plasma ADMA was not correlated with intracellular ADMA. We therefore focused on changes in plasma citrulline as an indicator for potential DDAH inhibition.
Methods:
We analyzed the association between regular daily PPI intake and flow-mediated dilation (FMD) of the brachial artery as well as plasma concentrations of citrulline, arginine, ADMA, and symmetric dimethylarginine using inverse probability weighting to adjust for confounding and censoring. Data that had been collected between 2008 and 2012 of 1,298 participants from two independent cohorts of the population-based Study of Health in Pomerania was used.
Results:
87 participants (57.5% female) were regular daily users of PPIs. In the fully adjusted models, associations were identified for FMD and plasma citrulline concentrations. PPI users revealed a 0.99% (95% CI: -1.96 to -0.02) lower FMD and 3.03 µmol/l (95% CI: -4.96 to -1.10) lower plasma citrulline levels as compared to non-users.
Conclusion:
Our data provide evidence that long-term intake of PPIs might inhibit human DDAH activity, resulting in impaired endothelial NO production and reduced vascular function. In the long run this might explain an increased risk for cardiovascular diseases associated with long-term PPI use.
... PPİ'ler, hem yüksek oranda hem de uzun süreli gastrik asit salgısını azalttıkları ve histamin H 2 reseptör antagonistlerinden daha fazla iyileşme oranı sağladıklarından, gastrik asit ilişkili hastalıkların tedavisinde tüm dünyada yaygın olarak kullanılmaktadır. 2,4 Günümüzde oldukça yaygın görülen gastroözofageal reflü, peptik ülser ve Zollinger-Ellison sendromu tedavisinde çoğunlukla tercih edilmektedir; peptik ülser hastalarında Helicobacter pylori eradikasyonunda 3'lü tedavide anahtar rol oynamaktadır. Buna ek olarak, stres ve nonsteroidal antiinflamatuar ilaç (NSAİİ)lar ile indüklenen peptik ülserde de proflaktik olarak kullanılmaktadır. ...
... 3 Antiülser ilaçların, 2012 yılında en çok reçete edilen ilk 10 ilaç arasında yer aldığı ve dünya genelinde 26 milyar doların bu ilaçlar için harcandığı bildirilmiştir. 4 PPİ endikasyonu olan hastalıklar, kronik ilaç tedavisi gerektirmektedir. Bu ilaçlarla birlikte diğer ilaçları kullanan hastalarda, klinik olarak önemli ilaç etkileşimlerinin görülme olasılığı artmaktadır. ...
Proton pump inhibitors (PPIs) have been frequently
used worldwide for the treatment of gastric acid related disorders
long-term. It is currently preferred for gastroesophageal reflux, peptic ulcer and Zollinger-Ellison syndrome and the key to triple treat�ment of Helicobacter pylori eradication in patients with peptic ulcer.
In addition, it is used prophylactically in stress and nonsteroidal antiinflammatory drugs (NSAIDs) induced peptic ulcer. As PPIs indications require long-term treatment, the likelihood of clinically
significant drug interactions increases in patients using these drugs
in combination with other drugs. Increasing the pH in the stomach is
one of causative mechanism of the interaction of PPIs with other
drugs. Another mechanism is the drug interactions that occur when
the PPIs metabolized by the cytochrome p450 enzyme system in the
liver are taken together with drugs that are bio-transformed with the
same enzyme system. Gastric acid suppression by PPIs has a negative effect on bacterial composition in the small intestine. In addition to increased gastric pH by suppression of gastric acid by PPIs directly targeted bacteria and fungi proton pumps to affect the gastric
microenvironment. The use of extended PPIs may result in the sup�pression of normal gastric flora and an excess of pathogenic bacte�ria. In this article, th
... Our results are consistent with another study in which Shih and colleagues used a propensity score-matched analysis design to control for differences among baseline patient characteristics between study and control cohorts in order to elucidate an association between PPI use and development of MI. 19 A case-crossover study was then further performed for unmeasured confounding F I G U R E 4 Total incidence of ischemic heart disease (IHD) among the different study arms, which are non-cardiac chest pain/ proton-pump inhibitor (NCCP/PPI), non-cardiac chest pain/ nonproton-pump inhibitor (NCCP/non-PPI), non-cardiac chest pain/ histamine-2 receptor antagonist (NCCP/H2RA), non-cardiac chest pain/ non-histamine-2 receptor antagonist (NCCP/non-H2RA). Asterisk indicates a statistically significant P-value <.05 (.0093). ...
... Additionally, patients who were prescribed both PPI and H2RA were excluded from the study, as well as patients who did not complete at least 30 days of antireflux therapy prior to developing new IHD. This 30-day buffer period was determined based on prior studies that investigated the cardiovascular adverse effects of PPIs in GERD patients that showed a 7-14 day therapeutic trial was enough to see a positive effect.11,19 Patients who were younger than 18 or older than 85 were also excluded from the study. ...
Background
The growing reports regarding cardiac‐related adverse events of chronic proton‐pump inhibitors (PPI) treatment, a mainstay therapy of non‐cardiac chest pain (NCCP), have raised concerns about alteration of the natural course in NCCP patients using PPI. We aimed to determine if NCCP patients receiving PPI have a higher risk of developing ischemic heart disease (IHD) compared to those not receiving PPI therapy.
Methods
Three groups of NCCP patients were included; PPI, histamine‐2 receptor antagonist (H2RA), and no antireflux treatment. Diagnosis of NCCP had to precede diagnosis of IHD by at least 30 days, and in those receiving antireflux treatment at 30 days after starting the medication. Data analysis was corrected for 6 known confounding factors for IHD including hyperlipidemia, hypertension, obesity, smoking status, male gender, and diabetes mellitus.
Key Results
Of the patients on PPI or H2RA, 1280 and 250, respectively, developed IHD. Patients on PPI therapy displayed an increased odd of developing ischemic heart disease compared to patients never placed on therapy (OR 1.14, 95% CI 1.03‐1.25, P‐value .0093). Patients placed on H2RA therapy did not show a statistically significant change in risk compared to patients who were not placed on therapy (OR 0.90, 95% CI 0.77‐1.06, P‐value .2049). Number needed to harm in the PPI and H2RA groups was 17 and 45, respectively.
Conclusions
PPIs confer a statistically significant, but marginal effect on the risk of IHD development in NCCP patients. Thus, PPI use in NCCP only minimally alters the overall benign natural course of the disease.
... While these recent findings show that omeprazole and other PPIs may interfere with the NO biology and increase the risk of myocardial infarction and other cardiovascular diseases [15,19], it is generally believed that other drugs used to suppress gastric acid secretion, particularly the H2 receptor antagonists, are safer than PPIs because they were not associated with increased risk of myocardial infarction [15,19]. If this idea is proven valid, it is possible that patients at increased cardiovascular risk taking PPIs to suppress gastric acid secretion in the therapy of gastroesophageal diseases may benefit from the use of H2 receptor antagonists instead of PPIs. ...
... While these recent findings show that omeprazole and other PPIs may interfere with the NO biology and increase the risk of myocardial infarction and other cardiovascular diseases [15,19], it is generally believed that other drugs used to suppress gastric acid secretion, particularly the H2 receptor antagonists, are safer than PPIs because they were not associated with increased risk of myocardial infarction [15,19]. If this idea is proven valid, it is possible that patients at increased cardiovascular risk taking PPIs to suppress gastric acid secretion in the therapy of gastroesophageal diseases may benefit from the use of H2 receptor antagonists instead of PPIs. ...
... A large study reviewed records of patients with PPI prescriptions to evaluate the risk of MI in PPI users with no previous history of MI; the study included a propensity score (PS)-matched (126,367 PPI users and 126,367 PS-matched PPI non-users) and a case-crossover (n = =5430) analysis [8]. The study showed that use of PPIs is independently associated with an increased risk of MI (adjusted hazard ratio-HR 1.58). ...
... The study showed that use of PPIs is independently associated with an increased risk of MI (adjusted hazard ratio-HR 1.58). However, the authors also stated that the benefits of PPIs may greatly outweigh the risks of adverse CV effects, with a number needed to harm of 4357 [8]. ...
Proton pump inhibitors (PPIs) are among the most widely prescribed agents, either for treatment or prophylaxis of gastrointestinal (GI) disease, that are often administered for prolonged or chronic use. Patients with cardiovascular (CV) disease frequently receive PPIs for prophylaxis against GI bleeding due to common use of antithrombotic drugs. Over the last several years there is a growing number of reports associating chronic PPI use with a variety of serious CV and non-CV adverse effects. In this context, PPI use has been independently associated with an increased risk of CV morbidity (myocardial infarction, stroke, other CV events) and mortality. However, the critique remains that these data do not largely derive from randomized controlled trials. On the other hand, in certain conditions, the benefits of PPIs may outweigh the risks of adverse CV effects. As the indications for prolonged, particularly lifelong, prophylactic use of PPIs are not compelling and in the light of evidence of serious CV and other adverse effects, clinicians have to reconsider such long-term use of these drugs. Importantly, histamine 2 blockers have not been found to be associated with increased CV risk and thus may be an alternative therapeutic option in certain patients. These issues are amply discussed together with the potential mechanisms of these pleiotropic and off-target effects of PPIs, which are also depicted in an illustrative schema; data are also presented on differential effects of specific agents involved, alternative modes of therapy available, and relevant current guidelines on this issue.
... There are multiple clinical studies showing the adverse events related with prolonged use of PPI (e.g., infection, kidney injury, dementia, hypomagnesemia, fracture, and increased risk of stroke or cardiac disease) [97,103]. For example, the Taiwan Health Insurance Research Database suggested the potential of increased MI risk in chronic PPI users [103]. ...
... There are multiple clinical studies showing the adverse events related with prolonged use of PPI (e.g., infection, kidney injury, dementia, hypomagnesemia, fracture, and increased risk of stroke or cardiac disease) [97,103]. For example, the Taiwan Health Insurance Research Database suggested the potential of increased MI risk in chronic PPI users [103]. From 126,367 pairs between 2000 and 2009 (PPI users and non-users) after propensity score matching, PPI use was associated with a 1.58-fold greater risk of MI during 4-month follow-up (adjusted HR, 1.58; 95% CI, 1.11 to 2.25). ...
East Asians are the most populous race in the world and their health status is an important global issue. Compared with Caucasian populations, East Asian patients have a different benefit/risk ratio when using antithrombotic treatment. Despite this observation, treatment strategies in East Asian patients are mostly based on the American and European guidelines. Despite a lower platelet inhibitory response to clopidogrel, East Asian patients show a similar or even a lower rate of ischemic event occurrence and higher bleeding risk compared with Caucasian patients. For potent P2Y12 inhibitors (ticagrelor and prasugrel), East Asian patients have shown less favorable net clinical benefits compared with Caucasian patients, which may be related to differences in pharmacokinetic/pharmacodynamic profiles and therapeutic zone of antiplatelet effect. This updated consensus mainly focuses on state-of-the-art and current controversies in the East Asian population. In addition, when East Asian patients are administered potent P2Y12 receptor inhibitors, the strategies and ongoing trials to overcome the related hurdles are discussed.
... First, PPIs compete with P450 isoenzyme activation of clopidogrel in the liver, 36 and second, they can directly increase vascular resistance by inhibiting nitric oxide synthase activity. 37 Ex vivo studies show that PPIs, omeprazole in particular, inhibit the liver P450 isoenzyme CYP2C19 36 that is required for creation of the active metabolite of clopidogrel. In combining this ex vivo data with the numerous observational studies, the FDA then issued a black box warning for concomitant use of clodipogrel with omeprazole in 2009. ...
... AR 0.9/1000 patient-years), with a number needed to harm of 4357. 37 Another population-based study by Shah et al. employed a novel population-based datamining algorithm to look at MI association in patients diagnoses with GERD. Still considered a population based observational study, it demonstrated an OR of MI 1.16 (95% CI, 1.09-1.24) ...
Proton pump inhibitors (PPIs) are among the most prescribed classes of drugs in this day and age. These may be beneficial to treat many gastrointestinal conditions, such as gastroesophageal reflux or Barrett's esophagus as well as laryngopharyngeal reflux. However, many reports have emerged in the literature exposing the potential association of PPIs with various risks and complications such as bone fracture, infection, myocardial infarction, renal disease, and dementia. This review highlights many of these potential adverse side effects by exploring relevant publications and addressing the controversies associated with those findings. The diligent otolaryngologist should be aware of the current state of the literature and the risks associated with prescribing PPIs to insure proper counseling of their patients.
Level of Evidence
5
... The results of this study also indicated that PPI usage was an independent risk factor for CV events in PD patients. PPIs are widely used to avoid gastrorrhagia induced by anti-platelet drugs in patients who suffer from CVD. Accumulation of clinical data uncovered associations between PPI usage and adverse CV event in general population [7,27]. A large study including 396 296 patients confirmed that the risks of first-time ischemic stroke in the general population may be higher in the PPI group in comparison to the non-PPI group [28]. ...
Objectives:
A long period of inappropriate proton pump inhibitors (PPI) treatment has been proved to be associated with adverse prognosis in general population and hemodialysis patients. This study was conducted to clarify the impact of PPI usage on mortality and adverse cardiovascular (CV) events in peritoneal dialysis (PD) patients.
Methods and design:
This is a retrospective study. A total of 905 patients were enrolled from two PD centers, including 211 patients on PPI treatment and 618 patients not on PPIs. Kaplan-Meier curves were used to identify the incidence of adverse outcomes. Multivariate Cox regression models and inverse probability of treatment weighting (IPTW) were applied to analyze hazard ratios (HRs) for adverse outcomes.
Results:
During follow-up, 162 deaths and 102 CV events were recorded. Kaplan-Meier curve demonstrated all-cause mortality (log-rank test p = .018) and CV events (log-rank test p = .024) were significantly higher in PPI usage group. Multivariate Cox regression models and IPTW showed that PPI usage was an indicator for all-cause mortality (HR = 1.35, 95%CI = 1.09-1.67, p = .006) and CV events (HR = 1.78, 95%CI = 1.35-2.32, p < .001).
Conclusions:
PPI usage is associated with higher all-cause mortality and CV events in PD patients. Clinicians are supposed to be more careful when using PPI and need to master the indications more rigorously in patients receiving PD treatment.
... A large retrospective study from Taiwan including more than 120,000 PPIs users matched with non-users showed a slightly higher risk of MI in inpatient and outpatients taking PPI after 120 days (HR 1.58, 95%CI: 1.11-2.25). However, authors concluded that the benefits of PPIs may outweigh the risks, with number needed to harm of 4357 [71]. ...
Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs, due to the increasing incidence of acid-related disorders but also to a large number of prescriptions with inappropriate indications. Despite PPIs being effective and well tolerated, there have been growing concerns of potential adverse effects associated with long-term use of PPIs. Indeed, pharmacovigilance agencies have issued broad-based product warnings on the association between PPIs treatment and long-term complications, including increased risk of fractures and impaired magnesium absorption. On the contrary, despite plausible underlying biological mechanisms, for most side effects the available clinical evidence is weak or contradictory, and benefits of PPIs treatments seem to outweigh potential adverse effects. This review aims to discuss the most important and ascertained side effects of long-term use of PPIs, and provides practical considerations for their clinical management.
... Another recent RCT, the PRODIGY study, showed the similar results [11]. Studies in Asian populations have found that clopidogrel combined with PPIs was not associated with cardiovascular events (such as AMI, cardiovascular death, etc.) [32,33]. The above series of clinical research conclusions were consistent with the results of this study. ...
Background
Proton pump inhibitors (PPIs) are frequently prescribed to patients with coronary heart disease (CHD) under antiplatelet therapy to prevent gastrointestinal (GI) bleeding. However, its clinical impact is still under debate, especially in Asian population. This study was undertaken to explore the effects of concurrent use of clopidogrel and PPIs on the clinical outcomes in Chinese patients with CHD in secondary prevention.
Methods
A single-center retrospective study was conducted in 638 patients with CHD on consecutive clopidogrel therapy for at least 1 year. After 18-month follow-up, adverse clinical events were collected. Cox regression was used to calculate hazard ratios (HR) and 95% confidence interval (CI) for the effect of PPI use on the outcomes. A total of 638 patients were recruited from 2014 to 2015 in this study, among whom 201 were sustained PPI users, 188 were intermittent PPI users and the remaining 249 were non-PPI users.
Results
Compared with sustained PPI users, intermittent use of PPIs was associated with a lower risk of stroke, major adverse cardiac events (MACE) and net adverse clinical event (NACE) (stroke: adjusted HR: 0.109, 95% CI 0.014–0.878, p = 0.037; MACE: adjusted HR: 0.293, 95% CI 0.119–0.722; p = 0.008; NACE: adjusted HR: 0.357, 95% CI 0.162–0.786, p = 0.011). Subgroup analysis further revealed the benefit of intermittent PPI use was significant in male CHD patients over 60 years old, with hypertension or chronic kidney disease, and undergoing percutaneous coronary intervention during hospitalization.
Conclusion
The current findings suggest that the intermittent concurrent use of PPIs and clopidogrel is not associated with an increased risk of 18-month adverse clinical outcomes, and intermittent use of PPIs is associated with a lower rate of MACE and NACE.
... Besides the established efficacy of PPIs in the treatment of acidrelated diseases, their safety has arisen serious worries (Strand et al., 2017). Several studies have reported potential adverse effects associated with PPIs consumption, including hypomagnesaemia (Choi et al., 2012;Florentin and Elisaf, 2012;Janett et al., 2015;Rafiei et al., 2015), hypocalcemia (Choi et al., 2012;Galdo, 2013;Shirazi et al., 2014), clostridium difficile infection (Bernal et al., 2019;McDonald et al., 2015;Patil and Blankenship, 2013), pneumonia (Bashar et al., 2013;Giuliano et al., 2012;Khorvash et al., 2014) and more serious cardiovascular adverse events (Cardoso et al., 2015;Charlot et al., 2010;Ghebremariam et al., 2013;Ho et al., 2009;Shah et al., 2015;Shih et al., 2014;Simon et al., 2011;Yan et al., 2016). There are still competing theories about on whether/how PPIs enhance the risk of major cardiovascular adverse events amongst individuals with a history of adverse cardiovascular syndrome. ...
Proton pump inhibitors (PPIs) are one of the highly prescribed or over-the-counter available medications among Iranians, mainly to treat conditions such as helicobacter pylori infection, gastroesophageal reflux disease or frequent heartburn. In recent years, several reports have shown potential adverse effects of PPI administration among which cardiovascular adverse events, myocardial infarction and chronic kidney disease are considered as the greatest risks. Recent addition of proton pump inhibitors to the list of medications on Beers Criteria of Potentially Inappropriate Drugs has arisen significant concerns about their safety. This review aims at providing an up-to date overview of PPIs indications and their pharmacogenomics and pharmacokinetics in Iranian population. The focus of this review is on PPIs regimens in Iranian population and then it is compared with the reported studies performed on other ethnic groups around the world. An extensive review of the literature was carried out and data under various sections were identified using a computerized literature search via Pubmed, Web of Science, Google Scholar and some local search engines. All abstracts and full text articles were examined and most relevant papers were selected for inclusion in this review. Also several expert internalists were interviewed for their clinical experiences in this field.
... Accumulating clinical data had uncovered associations between PPI use and adverse CV event in general population 27,28 . In a large study including 396296 patients con rmed that the risks of rst-time ischemic stroke in the general population may be higher in the PPI group compared to non-PPI group 29 . ...
Background: A long period of inappropriate proton pump inhibitors (PPI) treatment have been proved to be associated with adverse prognosis in general population and hemodialysis (HD) patients. This study was conducted to clarify the impact of PPI taking on mortality and adverse cardiovascular (CV) events in peritoneal dialysis (PD) patients.
Methods: This is a retrospective study. We enrolled 904 patients from two PD centers, included 211 patients on PPI treatment and 618 patients not taking PPIs. Kaplan-Meier curves were used to identify the incidence of adverse outcomes. Multivariate Cox regression models and inverse probability of treatment weighting (IPTW) were applied to analyze hazard ratios (HRs) for adverse outcomes.
Results: During follow-up, 162 deaths and 102 CV events were recorded. Kaplan-Meier curve demonstrated all-cause mortality (log-rank test P=0.018) and CV events (log-rank test P=0.024) were significantly higher in PPI usage group. Multivariate COX regression models and IPTW showed that PPI taking was an indicator for all-cause mortality (HR=1.33, 95%CI=1.07-1.65, P=0.010) and CV events (HR=1.81, 95%CI=1.38-2.38, P<0.001).
Conclusions: PPI usage associates with higher all-cause mortality and CV events in PD patients. Clinicians are supposed to be more careful when using PPI and need to master the indications more rigorously in patients receiving PD treatment.
... The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. [1][2][3][4] Several techniques have been developed to estimate PAN in its bulk form, pharmaceutical and biological matrices, including liquid chromatography with different detectors, [5][6][7][8][9][10][11][12] UV-spectrophotometry, [13][14][15] and capillary electrophoresis. 16,17 Electrochemical assays such as voltammetric methods have been widely used for drug analysis due to their sensitivity, simplicity, cheapness and rapidity. ...
The electrochemical oxidation of pantoprazole, a selective proton pump inhibitor, was studied in aqueous as well as aqueous/surfactant media at a disposable pencil graphite electrode using cyclic and adsorptive stripping voltammetric techniques. The sensitivity of the stripping voltammetric measurements was significantly improved when the cationic surfactant, cetyltrimethylammonium bromide (CTAB) was present in the neutral electrolyte solution. For analytical purposes, well resolved voltammetric peaks at +1.05 V (versus Ag/AgCl) were obtained in Britton-Robinson buffer at pH 7.0 containing 3×10-4 M CTAB using square-wave stripping mode (after 30 s accumulation at open-circuit condition). The process could be used to determine pantoprazole concentrations in the range of 2.4×10-8 - 7.1×10-7 M (9.2 - 272 µg L-1) with a detection limit of 7.0×10-9 M (2.7 µg L-1). The proposed method was applied to the determination of pantoprazole in pharmaceutical formulation and in the spiked human urine samples with acceptable recoveries.
... Our work is consistent with another population-based study from Taiwan of more than 250,000 individuals; this study revealed that PPIs but not H2 antagonists increased the risk of myocardial infarction by 50% after 4 months of continuous use. 15 In a longitudinal observational cohort study of new users of PPIs or H2 antagonists (n = 349,312) from the US Department of Veterans Affairs database, PPI use was associated with increased mortality over 5.7 years compared with H2 antagonists (HR 1.25, CI 1.23-1.28). 16 To be sure, the retrospective nature of these reports may introduce confounding factors that could affect these correlations. ...
... Our work is consistent with another population-based study from Taiwan of more than 250,000 individuals; this study revealed that PPIs but not H2 antagonists increased the risk of myocardial infarction by 50% after 4 months of continuous use. 15 In a longitudinal observational cohort study of new users of PPIs or H2 antagonists (n = 349,312) from the US Department of Veterans Affairs database, PPI use was associated with increased mortality over 5.7 years compared with H2 antagonists (HR 1.25, CI 1.23-1.28). 16 To be sure, the retrospective nature of these reports may introduce confounding factors that could affect these correlations. ...
Proton pump inhibitors (PPIs) are effective agents for the treatment of gastroesophageal reflux (GERD). However, these drugs have not been approved for long-term use. Now sold over the counter, these agents are being used chronically for GERD without medical supervision. The long-term use of PPIs may have significant adverse effects, in part mediated by their effect of accelerating vascular aging. Physicians should assist patients in tapering off their use of PPIs and replacing them with lifestyle modifications and/or other agents that have better long-term safety profiles.
... However, a Taiwanese study concluded that PPIs might be independently associated with increased risk of myocardial infarction (MI). 33 Researchers performed a propensity score matched analysis with an adjusted hazard ratio (aHR) =1.58; 95% CI: 1.11-2.25. Furthermore, the aOR was 4.61 (95% CI:1.76-12.07) ...
Objectives:
To identify the predictors of acute coronary syndrome (ACS) and to determine the relationship between usage of proton pump inhibitors (PPIs) and the occurrence of a first non-fatal ACS event among patients that attended governmental hospitals in Jeddah, Saudi Arabia.
Methods:
A matched, multi-centric case-control study was performed between January and June of 2015 in Jeddah involving 2 governmental hospitals and the main university hospital. A total of 118 cases aged ≥18 years who were recently diagnosed with ACS were selected. For each case, one control matched by age and gender was selected. Information from an interview questionnaire and from reviewing patients' medical records was recorded on a standardized data collection sheet.
Results:
Risk factors for ACS and the relationship between usage of PPIs and the occurrence of a first non-fatal ACS event were measured in 236 cases and matched controls. Current smoking (OR: 4.5; 95% CI: 1.92-10.98), excessive body weight (OR: 2.99; 95% CI: 1.38-6.45), and dyslipidemia (OR: 2.51; 95% CI: 1.07-5.84) were the predictors of ACS. Hypertension, diabetes, and moderate-to-high physical activity were associated with ACS. However, there was no statistical association between use of PPIs and occurrence of the first non-fatal ACS event (p greater than 0.05).
Conclusions:
There was no association between PPIs and the occurrence of a first non-fatal ACS event. Smoking, increased weight, and dyslipidemia are considered predictors of ACS. Furthermore, ACS is associated with self-reported diabetes, hypertension, and physical activity.
... Additionally, PPIs may increase vascular resistance directly by inhibiting endothelial nitric synthase activity. [23] Nephrotoxicity (weak evidence) Dementia (weak evidence) ...
... Additionally, PPIs may increase vascular resistance directly by inhibiting endothelial nitric synthase activity. [23] Nephrotoxicity (weak evidence) Dementia (weak evidence) ...
... [13] Limited observational studies also suggested that PPI use may increase the risk of MI in the general population, albeit confounding variables including adherence, over-the-counter use, and dosage of PPIs were not considered. [14,15] Various mechanisms have been postulated with respect to this association. [16] It is widely believed that PPIs interfere with nitric oxide synthesis by diminishing the vasoprotective effect of endothelial nitric oxide synthase. ...
Objective:
There is limited and conflicting evidence on the association between proton pump inhibitors (PPIs) and myocardial infarction (MI). This study aims to examine the occurrence of MI associated with PPI use from the Food and Drug Administration (FDA) Adverse Event Reporting System database.
Methods:
This is a cross-sectional study using data from the FDA dated from December 2013 to April 2018. Standard descriptive statistics were used to describe demographic information. Logistic regression analyses were performed to investigate the association between the independent variables and MI.
Findings:
Among the 52,443 individuals who were taking a PPI and experienced an adverse event which was registered on the FDA database, 726 (1.38%) experienced MI. Of all the PPIs, esomeprazole had the largest proportion of users experiencing MI (1.81%). Compared to other PPIs, esomeprazole was associated with a significantly higher rate of MI (odds ratio [OR] =1.53, P < 0.001), whereas lansoprazole was associated with a lower rate of MI (OR = 0.74, P = 0.03).
Conclusion:
Among the PPIs, esomeprazole appeared to have the highest risk of MI. Although the observed associations do not infer causality, this study highlighted a need for further studies to determine if a PPI, especially esomeprazole, can indeed cause MI.
... Pantoprazole is a proton pump inhibitor and an effective antagonist of gastric acid secretion for the treatment of many gastroesophageal diseases, including dyspepsia, gastroesophageal reflux disease (GERD) and peptic ulcer disease [4,5]. Beyond its role on the suppression of acid secretion, it has been reported that PPI exerts anti-inflammatory effects as well [6]. ...
To investigate the effect of pantoprazole on acute lung and kidney injury with sepsis and its possible mechanism. Rats were randomly divided into six groups, the status and lung wet/dry weight ratio were determined at various time points. Hematoxylin Eosin staining (HE) for pathological changes in the lungs and kidneys of rats with sepsis. Western blot (WB) and immunohistochemistry were used to detect the pulmonary surfactant protein A(SPA) and D(SPD). The levels of markers for kidney damage in serum and urine various time points were measured by ELISA. The apoptosis in lung and kidney tissue of rats were detected using TUNEL assay. Subsequently, the cell apoptosis of LPS-induced BEAS-2B and HK-2 cells after pantoprazole treatment were detected using flow cytometry. The levels of RHOA/ROCK signaling pathway proteins in the lung and kidney tissues and cells were detected using WB. Our results indicated that Pantoprazole could suppress the expression of inflammatory factors in the blood and alleviate pathological damage of lung and kidney tissues in rats with sepsis. Pantoprazole treatment could reduce apoptosis in lung and kidney tissues and inhibit cell apoptosis induced by LPS. In addition, pantoprazole can inhibit RHOA/ROCK signaling pathway proteins and the levels of inflammatory factors in LPS-induced BEAS-2B and HK-2 cells. Pantoprazole can improve the symptoms of acute lung and kidney injury in septic rats, which suggested that pantoprazole might be used to guide the treatment of sepsis.
... Thus, the effect of PPIs on platelet aggregation would result from their deleterious effect on endothelial function. 35 NO released by endothelial cells plays a crucial role in vascular homeostasis, acting as an endogenous vasodilator regulating local vascular tone, as an endogenous platelet inhibitor regulating platelet activity, and through its antiatherogenic action on the endothelium, maintaining the normal structure of the vessel wall. 36 NO synthesis in vessels is regulated by endothelial NO synthase, 37 which is inhibited by ADMA (asymmetric dimethylarginine), such that higher levels of ADMA reduce endothelial NO production. ...
Proton pump inhibitors are currently one of the most prescribed pharmacological classes in developed countries, given their effectiveness and safety profile, which has until now been considered favorable.
However, in recent years, several papers have been published that associate prolonged use of these drugs with a wide range of adverse effects, posing doubts about their safety. Among the adverse effects described is an increased risk of cardiovascular events. This relationship was first described in subjects after acute coronary syndrome due to the interference of proton pump inhibitors in the cytochrome P450 2C19 and the conversion of clopidogrel to its active metabolite. More recent studies have also reported this relationship with the use of antiplatelet agents that do not depend on cytochrome P450 2C19 activation. The proposed mechanism is inhibition of dimethylarginine dimethylaminohydrolase, a physiological inhibitor of asymmetric dimethylarginine, which increases plasma concentrations of the latter enzyme, leading to lower levels of nitric oxide.
By reviewing in this article the relationship between the use of proton pump inhibitors and increased risk of cardiovascular and cerebrovascular events, the authors aim to alert the medical community to the potentially harmful effects of these drugs, and recommend the setting of a moratorium on their prolonged use.
... (3) PPIs are generally considered safe; however, several studies have reported a num- ber of adverse side effects after long-term use. These include bone fracture, (4) enteric infection, (5) pneumo- nia, (6) myocardial infarction, (7) stroke, (8) dementia, (9) Abbreviations : aHR , adjusted hazard ratio ; cDDD , cumulative def ined daily dose ; CI , conf idence interval ; HBV , hepatitis B virus ; HCC , hepatocellular carcinoma ; HCV , hepatitis C virus ; HR , hazard ratio ; ICD-9-CM , International Classification of Diseases, Ninth Revision, Clinical Modif ication ; LHID , Longitudinal Health Insurance Database ; NHI , National Health Insurance ; NSAID , nonsteroidal anti- inf lammatory drug ; PPI , proton pump inhibitor ; PSM , propensity score matching . chronic kidney disease, (10) micronutrient deficien- cies, (11) and even malignancies. ...
Researchers have hypothesized that the long‐term use of proton pump inhibitors (PPIs) can increase the risk of developing cancer. However, the association between PPI use and hepatocellular carcinoma (HCC) risk is unclear. Using data from the Taiwan National Health Insurance Research Database for the period between 2003 and 2013, we identified 35,356 patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. One‐to‐one propensity score matching by gender, age, cohort entry year, comorbidity, and medication resulted in the inclusion of 7,492 pair of patients (PPI users and non‐PPI users) for analyses. We performed multivariate and stratified analysis using the Kaplan‐Meier method and Cox proportional hazards models in order to estimate the association between PPIs use and the risk of developing HCC. In the HBV cohort, 237 patients developed HCC during a median follow‐up of 53 months. However, PPI use was not associated with an increased HCC in the risk of developing HCC (adjusted hazard ratio aHR, 1.25; 95% confidence interval CI, 0.90‐1.73; p=0.18). In the HCV cohort, 211 patients developed HCC, but again, PPI use was not associated with an increase in the risk of developing HCC (aHR, 1.19; 95% CI, 0.88‐1.61; p=0.25). We observed no relationship between dose‐dependent effect of PPI use and HCC risk. Subgroup analysis also confirmed PPI use was not correlated to an increased HCC risk. Conclusions Based on a retrospective, nationwide population‐based cohort study in Taiwan, where the prescription of PPI is tightly regulated, PPI use is not associated with the risk of developing HCC among patients with chronic HBV or HCV infections. This article is protected by copyright. All rights reserved.
... Overall, 33, 7, and 3 studies were case-control, cohort, and cross-sectional studies, respectively. In the systematic review, hip fractures [26][27][28][29][30][31][32][33][34][35][36][37] were reported in 12 studies, community-acquired pneumonia [38][39][40][41][42][43][44][45] and various types of cancer [46][47][48][49][50][51][52][53] in eight studies each, kidney disease in four studies [54][55][56][57], hypomagnesemia [58][59][60][61][62] in five studies, cardiac disease [11,63,64] in three studies, vitamin B 12 deficiency [65,66] in two studies, and Alzheimer [67] in one study. The included studies were published between 2004 [65] and 2016 [67], and 21, 15, and 7 studies were conducted in Europe, North America, and Asia, respectively. ...
The association between the long-term use of proton pump inhibitors (PPIs) and the risks of various diseases remains controversial. Therefore, the primary objective of this study was to quantify the associations as presented in the literature and to also provide this information to healthcare professionals and patients about their potentially adverse effects. In July 2016, we searched through Medline (PubMed), Embase, and the Cochrane Library from inception using common keywords. We included observational studies that provided risk estimates on the long-term use of PPIs and their adverse effects. Overall, 43 studies were included in the systematic review, of which 28 studies were also included in the random effect meta-analysis. Odds of community-acquired pneumonia, hip fracture, and colorectal cancer were 67% [odds ratio (OR)=1.67; 95% confidence interval (CI): 1.04-2.67], 42% (OR=1.42; 95% CI: 1.33-1.53), and 55% (OR=1.55; 95% CI: 0.88-2.73) higher in patients with long-term PPIs use compared with patients who did not use PPIs. Although the use of PPIs provides short-term health benefits, their prolonged use is associated with minor and also potentially major adverse health outcomes. Hence, we strongly recommend that the prescription of PPIs should be done with caution to improve the medication's efficacy and patients' safety.
... Proton pump inhibitors (PPI) are a worldwide used drug class for the treatment of gastric reflux. Recent epidemiological studies have raised concern about the increased cardiovascular risk of long-term PPI use [1,2]. One of the hypothesized pathophysiological mechanism is that PPI inhibit the degradation of plasma asymmetric dimethylarginine (ADMA) through inhibition of the dimethylarginine dimethylaminohydrolases, which largely metabolize ADMA [3]. ...
Background:
Proton pump inhibitors (PPIs) are widely used drugs for gastric-acid-related diseases, which may have an impact on the gut microbiome. We aimed to evaluate the associations of PPI use with risks of cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes (T2D).
Methods:
We analysed the associations of PPI use with risks of coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), stroke, and all-cause mortality in 19,229 adults with T2D using data from the UK Biobank study.
Results:
During a median follow-up of 10.9-11.2 years, we documented a total of 2,971 CAD, 1,827 MI, 1,192 HF, and 738 stroke cases, along with 2,297 total deaths. PPI use was significantly associated with higher risks of CAD (HR, 1.27; 95% CI, 1.15-1.40), MI (HR, 1.34; 95% CI, 1.18-1.52), HF (HR, 1.35; 95% CI, 1.16-1.57) and all-cause mortality (HR, 1.30; 95% CI, 1.16-1.45). No significant association was observed between PPI use and stroke (HR, 1.11; 95% CI, 0.90-1.36). The results were consistent in the subgroup analyses stratified by factors including indications of PPI, anti-diabetic medication use, and antiplatelet drug use. Analyses in a 1:1 propensity score-matched cohort of PPI users versus non-users yielded similar results.
Interpretation:
Our data suggested that PPI use was associated with higher risks of CVD events and mortality among patients with T2D. The benefits and risks of PPI use should be carefully balanced among patients with T2D, and monitoring of adverse CVD events during PPI therapy should be enhanced.
Background and Aims
Observational research has indicated that proton pump inhibitors (PPIs) might increase the long-term risk of cardiovascular events. This study evaluated the evidence from observational studies for an effect of PPI monotherapy on the risk of incident cardiovascular events and cardiovascular mortality.
Methods
The databases MEDLINE, EMBASE, and Scopus were systematically searched up to September 2021. The primary outcome was first cardiovascular event, i.e. first myocardial infarction or first ischaemic stroke. The secondary outcome was cardiovascular mortality. Studies were included following a detailed risk of bias assessment with the ROBINS-I tool. Sensitivity and bias analyses adjusted for potential publication bias, immortal time bias, and unmeasured confounding.
Results
We included ten studies with 75,371 first cardiovascular events, as well as seven studies on cardiovascular mortality with 50,329 cardiovascular deaths in total. The pooled hazard ratios (HRs) for PPI use and cardiovascular events were 1.05 with a 95% confidence interval of (0.96; 1.15) before and 0.99 (0.93; 1.04) after adjusting for observational study design bias. The pooled HRs for PPI use and cardiovascular mortality were 1.27 (1.11; 1.44) before and 1.06 (0.96; 1.16) after adjusting for publication bias and observational study design bias.
Conclusion
It is questionable, whether PPI monotherapy constitutes a cardiovascular risk factor.
In this work, cerium oxide nanoparticles (CeO2NPs) were prepared by naturally available Aloe-Vera (AV) gel as fuel via gel-combustion technique (GCT). Obtained CeO2NPs were blended with graphite powder to produce cerium oxide fabricated carbon paste electrode (CeO2/CPE) and used for the detection of pantoprazole (PPZ). Surface features of CeO2NPs were premeditated by X-ray diffraction analysis (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), Brunauer–Emmett–Teller (BET) measurement, and transmission electron microscopy (TEM). The modified CeO2/CPE gives notable current enhancement compared to the bare carbon paste electrode (BCPE) during electrochemical oxidation of pantoprazole (PPZ) in 0.1 M PBS of pH 7. The behaviour of PPZ was studied in presence of epinephrine (EPN) at modified CeO2/CPE. The influence of modifiers, effect of pH, scan rate, and concentration of PPZ has been studied by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. The effect of PPZ concentration has been studied by DPV technique in the range of 2–5.5 µM, with a detection limit of 0.371 µM L⁻¹. The modified sensor was also used for the real sample analysis of drug present in a pharmaceutical sample. Stability, sensitivity, and limit of detection for the analysis of PPZ indicated the potentiality of modified CeO2/CPE.
Background and aims:
Proton pump inhibitors (PPIs) are among the most widely prescribed agents. Whereas PPIs are widely regarded as harmlesss, long-term use of PPIs (LTUPPI) can have the potential to increase the risk of developing cardiovascular (CV) disease (CVD). Pulse wave velocity (PWV) is a good indicator of arterial stiffness. There are several studies showing a relationship between LTUPPI and CVD. However, the association with LTUPPI and PWV or arterial stiffness has not been reported.
Patients and methods:
Patients (n=64) with LTUPPI and controls (n=91) were included. PWV, glucose, creatinine, total cholesterol, triglyceride, low-density lipoprotein cholesterol, cholesterol, high-density lipoprotein cholesterol, and magnesium levels were measured.
Main results:
In the LTUPPI group, PWV was greater than in controls (9.08±2.04 vs 7.77±1.52 m/s, respectively, p=0.01); 34.4% of patients and 8.8% of controls had PWV levels <10 m/s (p=0.000). Multiple logistic regression analysis showed that age (p<0.001) and LTUPPI (p=0.024) were predictors of elevated PWV.
Conclusions:
PWV values are increased in patients with LTUPPI compared with controls independently of conventional CV risk factors. Measurement of PWV and other arterial stiffness parameters in cases with LTUPPI may be useful to predict possible CVD. Studies with greater numbers are needed to confirm these findings.
Objective:
Our goal was to compile the most recent and accurate data on the side effects of proton pump inhibitors (PPI). We also compared the efficacy of PPI to the efficacy of different surgical options for acid reflux control.
Background:
Proton pump inhibitors are the primary therapy for chronic control of gastroesophageal reflux disease (GERD), but newer studies demonstrate deleterious side effects. Collating this information and contrasting it with surgical therapy for GERD provides evidence for possible practice changes in treatment.
Methods:
A literature search utilizing PubMed was performed evaluating for PPI and anti-reflux surgery (ARS), focusing on articles that reflected information regarding the usage and efficacy of symptom control of both PPI and ARS. Search terms included "ARS, fundoplication, MSA, acute interstitial nephritis, acute kidney injury, chronic kidney disease, meta-analysis, PPI, H2 blocker, cardiovascular risk, and gut dysbiosis." We evaluated 271 articles by title, abstract, and data for relevance and included 70.
Results:
Long-term control of GERD with PPI may have a greater than expected side effect profile than initially thought. Surgical options may provide greater symptom control than PPI without the side effects of long-term medical therapy.
Conclusions:
Anti-reflux control can be safely achieved with either PPI or surgical options; however, the long-term side effects noted in the review such as increased risk of cardiovascular events, renal disease, and gut dysbiosis may suggest surgical anti-reflux control as a better long-term option.
Background
It is unknown whether gastroesophageal reflux disease (GERD) is a risk factor or consequence of idiopathic pulmonary fibrosis (IPF). This study aimed to determine whether patients with IPF were more likely to have GERD compared with age- and sex-matched controls who either had 1) interstitial lung disease (ILD) other than IPF or 2) no diagnosed lung disease (population control).
Methods
We used the medical records-linkage system of the Rochester Epidemiology Project (REP) to identify patients with IPF who resided in Olmsted County, Minnesota, from January 1, 1997, through June 30, 2017. IPF cases were each matched with patients from 2 control groups (non-IPF ILD controls and population controls). We used conditional logistic regression to model associations between GERD diagnosis and IPF case status. P values were adjusted for multiple comparisons by using the Bonferroni adjustment (P values <.025 were considered statistically significant).
Results
One hundred thirteen IPF cases were identified and matched to 226 population controls and 226 controls with non-IPF ILD. After multivariable adjustment, the odds of having GERD were 1.78 times higher (95% CI, 1.09-2.91; P=.02) in IPF cases compared with population controls. After multivariable adjustment, the odds of having GERD were 0.46 times lower (95% CI, 0.23-0.94; P=.03) in IPF cases compared with non-IPF ILD controls.
Conclusion
GERD may be an important contributor to the development of lung fibrosis. Thus, it should be investigated and addressed adequately when detected in patients with IPF and patients with non-IPF ILD.
Goals:
The goal of this study was to evaluate whether proton pump inhibitor (PPI) use is cross-sectionally associated with hypomagnesemia and whether hypomagnesemia mediates the prospective association between PPIs and cardiovascular disease (CVD) risk.
Background:
Use of PPIs has been associated with hypomagnesemia, primarily in case reports or within insurance databases. Both PPI use and low serum magnesium (Mg) have been associated with modestly higher CVD risk. Yet, the interrelation between PPI use and Mg in relation to CVD risk is unclear.
Study:
The 4436 Atherosclerosis Risk in Communities participants without prevalent CVD at visit 5 (baseline, 2011-2013) were included. Multivariable relative risk regression was used for cross-sectional analyses between PPI and hypomagnesemia prevalence (≤0.75 mmol/L). Incident CVD (defined by atrial fibrillation, coronary heart disease, CVD mortality, heart failure, stroke) was identified through 2017. Multivariable Cox regression was used to examine the PPI-CVD association.
Results:
Participants were mean±SD aged 75±5 years; 63% were women, 23% Black, and 24% were PPI users. PPI users had 1.24-fold (95% confidence interval: 1.08-1.44) higher prevalence of hypomagnesemia than nonusers. Over a median 5 years of follow-up, 684 incident CVD events occurred. PPI users had higher CVD risk [hazard ratio (95% confidence interval) 1.31 (1.10-1.57)] than nonusers. The effect estimate was largely unchanged when hypomagnesemia was added to the model as a potential mediator.
Conclusions:
In this elderly community-based study, PPI users had a higher prevalence of hypomagnesemia than in nonusers. PPI users also had higher CVD risk than nonusers; however, it appears unlikely that hypomagnesemia explains associations of PPIs with CVD risk.
Proton pump inhibitors (PPIs) are popular and widely used “gastroprotectives”. More than 10% of our population is treated. In addition to classical indications such as gastroduodenal peptic disease or gastroesophageal reflux disease, they are indicated for the reduction of hemorrhagic complications in the digestive tract during antithrombotic treatment. The effect of PPIs on reducing upper gastrointestinal bleeding in antithrombotic treatment (rivaroxaban, acetylsalicylic acid or a combination) was called into question by a recently published randomised mega-study - COMPASS pantoprazole. Treatment of PPIs is accompanied by a number of significant drug interactions, in particular a severe reduction in the bioactivation of clopidogrel and a reduction in the absorption of acetylsalicylic acid or dabigatran. As a result, the effect of these antithrombotics is reduced. A number of observational studies - in the indication of PPIs in the treatment of gastroduodenal or gastrooesophageal disease or when used in the treatment of PPIs in antithrombotic treatment - found a greater incidence of major vascular events and an increase in mortality. So are PPIs effective in protecting gastrointestinal bleeding and are they safe?
Proton pump inhibitors (PPIs) continue to be the medication of choice for treatment of acid-related disease, with few if any overt side effects seen with daily use. They are often prescribed empirically, often in high doses and with many patients being treated with multiple PPIs without an objective diagnosis. Therefore, they are believed to be overprescribed and used without indication. In this article we discuss the appropriate clinical indications for PPIs, review in detail the major associated adverse events, and put in perspective key issues in balancing benefits and risk of this exceptional (and safe) class of drug.
Proton‐pump inhibitors (PPIs) have been reported to increase the risk of acute and chronic renal disease. However, the data is unclear in patients with acute kidney injury (AKI) requiring dialysis (AKI‐D) who are often candidates for PPI. To investigate this important issue, we identified 26,052 patients from Taiwan’s National Health Insurance Research Database weaning dialysis from AKI‐D. During a mean follow‐up period of 3.52 years, the PPI users had a higher incidence of end‐stage renal disease (ESRD) than the PPI non‐users (P<.001). After propensity score matching and treating mortality as a competing risk factor, the PPIs users had a higher risk in ESRD (sHR 1.40; 95% CI 1.31‐1.50) and major adverse cardiac events (MACE, sHR1.53; 95 %CI 1.37‐1.71) compared to the PPI non‐users with AKI‐D survivors. In conclusion, the use of PPIs was associated with a higher risk of ESRD and MACE, compared to the PPI non‐users in AKI‐D patients.
Rationale
The overuse of antibiotics has been an important clinical issue, and antibiotic exposure is linked to alterations in gut microbiota, which has been related to risks of various chronic diseases such as cardiovascular disease and cancer. Also, duration of antibiotic exposure may be a risk factor of premature death.
Objective
We investigated associations of life-stage and duration of antibiotic use during adulthood with risks of all-cause and cause-specific mortality.
Methods and Results
This prospective cohort study included 37 516 women aged ≥60 years who were free of cardiovascular disease or cancer from the Nurses’ Health Study. Participants reported a total amount of time they used antibiotics (none, <15 days, 15 days to <2 months, or ≥2 months) in the middle- (age, 40–59) and late adulthood (age, 60 or older). We estimated hazard ratios for all-cause mortality and deaths from cardiovascular disease or cancer over 10 years according to duration of antibiotic use. During 355 918 person-years of follow-up, we documented 4536 deaths from any cause (including 728 cardiovascular deaths and 1206 cancer deaths). As compared with women who did not use antibiotics, those who used them for ≥2 months in late adulthood had increased risks of all-cause mortality (hazard ratio, 1.16 [95% CI, 1.01–1.33]) and cardiovascular mortality (hazard ratio, 1.49 [95% CI, 1.04–2.13]), but not cancer mortality (hazard ratio, 0.85 [95% CI, 0.65–1.12]) after adjustment for chronic metabolic diseases, antibiotic use during middle adulthood, indication for use, demographic factors, and lifestyle/dietary factors. The association was more evident among women who also used antibiotics in middle-adulthood than among those who did not use during this life-stage.
Conclusions
Long-term use of antibiotics in late adulthood may be a risk factor for all-cause and cardiovascular mortality. The unfavorable effect of antibiotic exposure for subsequent risks of deaths due to chronic diseases needs to be considered.
Background:
Use of proton pump inhibitors (PPIs) is suggested to be associated with adverse cardiovascular (CV) events via endothelial dysfunction. Studies show that PPIs are associated with increased risk of myocardial infarction (MI) among patients with preexisting CV disease. However, little is known about their risk among people without known CV disease.
Methods:
We conducted a nested case-control study in the UK Clinical Practice Research Datalink (CPRD) GOLD to evaluate the association between PPI use and risk of MI in patients without known CV disease. From among PPIs users aged 25 to 65 between 1988 and 2017, we identified 32793 MI cases and 127291 controls matched 4:1 on age, sex, general practice setting, and calendar time. Using logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for MI comparing PPI users to non-users, adjusting for body mass index, smoking, alcohol abuse, drug abuse, type 2 diabetes, hyperlipidemia, hypertension, and peripheral artery disease. We repeated this analysis in users of histamine 2 receptor antagonists (H2RA), a drug with a similar indication, to assess protopathic bias.
Results:
The risk of MI was elevated in new users of PPIs with one to five prescriptions (adjusted OR 2.8 95%CI 2.6-3.0), but not in any other exposure category. The results among H2RA users were similar across all exposure categories, suggesting that protopathic bias likely explains the results.
Conclusions:
Our study results were not consistent with the hypothesis that PPI use increases MI risk among people without known heart disease.
Objectives/Hypothesis
To describe the trends in proton pump inhibitor (PPI) prescription rates and durations and compare them to those of H2‐receptor antagonists (H2RAs) between 2013 and 2016 in otolaryngology, gastroenterology, and family practice, following the increasing publications on PPI adverse effects and inappropriate prescribing.
Study Design
Retrospective review of publicly available Medicare Part D prescribing data.
Methods
PPI and H2RA prescription and beneficiary data were obtained through the Centers for Medicare and Medicaid Services website. For prescription rates, 30‐day fill counts were analyzed nationally and regionally per 10,000 Medicare members. Days supply per beneficiary was examined to show average prescription durations. Results were compared between otolaryngology, gastroenterology, and family practice. Medication‐related economic burden per year was calculated based on reported drug cost.
Results
From 2013 to 2016, PPI 30‐day fill counts remained stable, whereas H2RA prescription rates increased by up to 62% per 10,000 Medicare beneficiaries. The South consistently prescribed two to three times as much antireflux medication as the lowest prescribing region over time and across all three specialties. The days supply per beneficiary remained stable and ranged from an average of 128 to 203 days depending on the specialty. Antireflux medication‐related healthcare cost decreased steadily.
Conclusions
Despite numerous publications describing a multitude of adverse events and inappropriate prescribing patterns of PPIs in the past decade, prescription rates and durations per beneficiary have remained stable in the fields of otolaryngology, gastroenterology, and family practice. Additionally, H2RA prescriptions have increased from 2013 to 2016.
Level of Evidence
NA Laryngoscope, 2019
Background and aims:
A potential increased risk of cardiovascular events has been suggested for proton pump inhibitors (PPIs), the most commonly prescribed drugs for the management of upper gastrointestinal disorders. We aimed to estimate the risk of hospitalization for cardio/cerebrovascular (CV) events in a cohort of incident PPI users.
Methods:
A nested case-control study was carried out using regional healthcare utilization databases. For each case (hospitalization for non-haemorrhagic CV event), up-to-five controls randomly selected from the cohort were matched by gender, age at cohort entry, and index date. Exposure was estimated as recency of therapy (current, recent and past users) and number of days covered. Adjusted conditional logistic regression was used to estimate the association between exposure and outcome.
Results:
Among new PPI users, we identified 17,832 cases and 89,160 controls (males 64.9%; mean age 58.9 years). Cases showed a significantly higher prevalence of use of drugs for diabetes, hypertension and hypercholesterolemia than controls. Risk of CV events was significantly higher for current (OR 1.61; 95%CI 1.55-1.68) and recent users (OR 1.15; 95%CI 1.06-1.26) compared to past users. Analogous results were found stratifying for cardiovascular (ORcurrent 1.71; 95%CI 1.63-1.81) and cerebrovascular events (ORcurrent 1.43; 95%CI 1.34-1.54). The increased risk was confirmed in subgroups by antithrombotic, statin use, or exposure duration. The same analysis for H2-antagonists use showed no significant results.
Conclusions:
In primary care setting, PPI use was independently associated with increased risk of first-time cardiovascular event, consistent with the evidence that PPIs adversely impact vascular function, underlying the need to promote appropriate prescribing of these drugs.
Background and aims: Proton pump inhibitors (PPIs) are effective antagonists of gastric acid secretion used to treat a number of gastro-esophageal disorders. The present study investigated the effect of Pantoprazole on vascular relaxation in-vitro and ex-vivo and its effect on blood coagulation in an animal model. Main methods: Isolated mouse arterial rings were pre-contracted in-vitro with phenylephrine and concentration–response curves to the acetylcholine relaxing effect were constructed in the presence of escalating concentrations of pantoprazole. In another set of experiments, male albino mice weighing ∼25 g were administered a daily dose of pantoprazole (0.4 mg by oral gavage) for four consecutive weeks; a vehicle control group was run in parallel. At the end of the treatment period, thoracic aorta was isolated for the assessment of vascular function ex-vivo. Blood samples were also collected to evaluate the effect of chronic pantoprazole therapy on coagulation parameters, namely, prothrombin time (PT) and activated partial thromboplastin time (aPTT). Key findings: Vascular responsiveness to acetylcholine demonstrated a reduced relaxation of the arterial ring from baseline in the presence of different concentrations of pantoprazole (1 μM: 54.69 ± 1.42%, 10 μM: 34.64 ± 0.90% and 100 μM: 31.50 ± 0.67% vs. control 74.39 ± 1.426%, p
Recent evidence suggests that proton pump inhibitors (PPIs) might be linked with adverse cardiac events, but a causal relationship is unproven.
We applied the self-matched case series method to two studies using population-based health care data from Ontario, Canada between 1996 and 2008. The first included subjects aged 66 years or older hospitalized for acute myocardial infarction within 12 weeks following initiation of PPI, while the second included subjects hospitalized for heart failure. In both studies we designated the primary risk interval as the initial 4 weeks of therapy and the control interval as the final 4 weeks. To test the specificity of our findings we examined use of histamine H2 receptor antagonists and benzodiazepines, drugs with no plausible causal link to adverse cardiac events.
During the 13-year study period, we identified 5550 hospital admissions for acute myocardial infarction and 6003 admissions for heart failure within 12 weeks of commencing PPI therapy. In the main analyses, we found that initiation of a PPI was associated with a higher risk of acute myocardial infarction (odds ratio 1.8; 95% confidence interval 1.7 to 1.9) and heart failure (odds ratio 1.8; 95% confidence interval 1.7 to 1.9). However, secondary analyses revealed similar risk estimates histamine H2 receptor antagonists and benzodiazepines, drugs with no known or suspected association with adverse cardiac events.
PPIs are associated with a short-term risk of adverse cardiac events, but similar associations are seen with other drugs exhibiting no known cardiac toxicity. Collectively these observations suggest that the association between PPIs and adverse cardiac events does not represent reflect cause-and-effect.
To examine the relation between the type of stress ulcer prophylaxis administered and the risk of postoperative pneumonia in patients undergoing coronary artery bypass grafting.
Retrospective cohort study.
Premier Research Database.
21 214 patients undergoing coronary artery bypass graft surgery between 2004 and 2010; 9830 (46.3%) started proton pump inhibitors and 11 384 (53.7%) started H2 receptor antagonists in the immediate postoperative period.
Occurrence of postoperative pneumonia, assessed using appropriate diagnostic codes.
Overall, 492 (5.0%) of the 9830 patients receiving a proton pump inhibitor and 487 (4.3%) of the 11 384 patients receiving an H2 receptor antagonist developed postoperative pneumonia during the index hospital admission. After propensity score adjustment, an elevated risk of pneumonia associated with treatment with proton pump inhibitors compared with H2 receptor antagonists remained (relative risk 1.19, 95% confidence interval 1.03 to 1.38). In the instrumental variable analysis, use of a proton pump inhibitor (compared with an H2 receptor antagonist) was associated with an increased risk of pneumonia of 8.2 (95% confidence interval 0.5 to 15.9) cases per 1000 patients.
Patients treated with proton pump inhibitors for stress ulcer had a small increase in the risk of postoperative pneumonia compared with patients treated with H2 receptor antagonists; this risk remained after confounding was accounted for using multiple analytic approaches.
Objective:
The association between selective serotonin receptor inhibitors (SSRIs) and risk of upper gastrointestinal bleeding remains controversial. Previous studies have generally evaluated the issue for approximately 3 months, even though the SSRI-mediated inhibition of platelet serotonin concentrations occurs within 7-14 days. The authors explored the risk of upper gastrointestinal bleeding after short-term SSRI exposure by a case-crossover design.
Method:
The records of psychiatric inpatients with upper gastrointestinal bleeding were retrieved from the Taiwan National Health Insurance Database (1998-2009). Rates of antidepressant use were compared for case and control periods with time windows of 7, 14, and 28 days. The adjusted self-matched odds ratios from a conditional logistic regression model were used to determine the association between SSRI use and upper gastrointestinal bleeding.
Results:
A total of 5,377 patients with upper gastrointestinal bleeding were enrolled. The adjusted odds ratio for the risk of upper gastrointestinal bleeding after SSRI exposure was 1.67 (95% CI=1.23-2.26) for the 7-day window, 1.84 (95% CI=1.42-2.40) for the 14-day window, and 1.67 (95% CI=1.34-2.08) for the 28-day window. SSRIs with high and intermediate, but not low, affinity for serotonin transporter were associated with upper gastrointestinal bleeding. An elevated risk of upper gastrointestinal bleeding after SSRI exposure was seen in male but not female patients.
Conclusions:
Short-term SSRI use (7-28 days) is significantly associated with upper gastrointestinal bleeding. Gender differences may exist in the relationship between SSRI use and upper gastrointestinal bleeding. Physicians should carefully monitor signs of upper gastrointestinal bleeding even after short-term exposure to SSRIs, as is done with nonsteroidal anti-inflammatory drugs and aspirin.
Objectives:
To examine the incidence of Campylobacter and Salmonella infection in patients prescribed proton pump inhibitors (PPIs) compared with controls.
Methods:
Retrospective cohort study using anonymous general practitioner (GP) data. Anonymised individual-level records from the Secure Anonymised Information Linkage (SAIL) system between 1990 and 2010 in Wales were selected. Data were available from 1,913,925 individuals including 358,938 prescribed a PPI. The main outcome measures examined included incidence of Campylobacter or Salmonella infection following a prescription for PPI.
Results:
The rate of Campylobacter and Salmonella infections was already at 3.1-6.9 times that of non-PPI patients even before PPI prescription. The PPI group had an increased hazard rate of infection (after prescription for PPI) of 1.46 for Campylobacter and 1.2 for Salmonella, compared with baseline. However, the non-PPI patients also had an increased hazard ratio with time. In fact, the ratio of events in the PPI group compared with the non-PPI group using the prior event rate ratio was 1.17 (95% CI 0.74-1.61) for Campylobacter and 1.00 (0.5-1.5) for Salmonella.
Conclusions:
People who go on to be prescribed PPIs have a greater underlying risk of gastrointestinal (GI) infection beforehand and they have a higher prevalence of risk factors before PPI prescription. The rate of diagnosis of infection is increasing with time regardless of PPI use, and there is no evidence that PPI is associated with an increase in diagnosed GI infection. It is likely that factors associated with the demographic profile of the patient are the main contributors to increased rate of GI infection for patients prescribed PPIs.
Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6 mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012 mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028 mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy.Kidney International advance online publication, 16 January 2013; doi:10.1038/ki.2012.452.
Gastroesophageal reflux disease (GERD) is a chronic, relapsing disease with symptoms that have negative effects on daily life. Two treatment options are long-term medication or surgery.
To evaluate optimized esomeprazole therapy vs standardized laparoscopic antireflux surgery (LARS) in patients with GERD.
The LOTUS trial, a 5-year exploratory randomized, open, parallel-group trial conducted in academic hospitals in 11 European countries between October 2001 and April 2009 among 554 patients with well-established chronic GERD who initially responded to acid suppression. A total of 372 patients (esomeprazole, n = 192; LARS, n = 180) completed 5-year follow-up. Interventions Two hundred sixty-six patients were randomly assigned to receive esomeprazole, 20 to 40 mg/d, allowing for dose adjustments; 288 were randomly assigned to undergo LARS, of whom 248 actually underwent the operation.
Time to treatment failure (for LARS, defined as need for acid suppressive therapy; for esomeprazole, inadequate symptom control after dose adjustment), expressed as estimated remission rates and analyzed using the Kaplan-Meier method.
Estimated remission rates at 5 years were 92% (95% confidence interval [CI], 89%-96%) in the esomeprazole group and 85% (95% CI, 81%-90%) in the LARS group (log-rank P = .048). The difference between groups was no longer statistically significant following best-case scenario modeling of the effects of study dropout. The prevalence and severity of symptoms at 5 years in the esomeprazole and LARS groups, respectively, were 16% and 8% for heartburn (P = .14), 13% and 2% for acid regurgitation (P < .001), 5% and 11% for dysphagia (P < .001), 28% and 40% for bloating (P < .001), and 40% and 57% for flatulence (P < .001). Mortality during the study was low (4 deaths in the esomeprazole group and 1 death in the LARS group) and not attributed to treatment, and the percentages of patients reporting serious adverse events were similar in the esomeprazole group (24.1%) and in the LARS group (28.6%).
This multicenter clinical trial demonstrated that with contemporary antireflux therapy for GERD, either by drug-induced acid suppression with esomeprazole or by LARS, most patients achieve and remain in remission at 5 years.
clinicaltrials.gov Identifier: NCT00251927.
Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.
We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing.
We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole.
Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).
Controversy remains on whether the dual use of clopidogrel and proton-pump inhibitors (PPIs) affects clinical efficacy of clopidogrel.
To examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel compared with that of PPIs alone in adults hospitalized for myocardial infarction.
A nationwide cohort study based on linked administrative registry data.
All hospitals in Denmark.
All patients discharged after first-time myocardial infarction from 2000 to 2006.
The primary outcome was a composite of rehospitalization for myocardial infarction or stroke or cardiovascular death. Patients were examined at several assembly time points, including 7, 14, 21, and 30 days after myocardial infarction. Follow-up was 1 year.
Of 56 406 included patients, 9137 (16.2%) were re-hospitalized for myocardial infarction or stroke or experienced cardiovascular death. Of the 24 702 patients (43.8%) who received clopidogrel, 6753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for myocardial infarction or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% CI, 1.17 to 1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21 to 1.37). No statistically significant interaction occurred between a PPI and clopidogrel (P = 0.72).
Unmeasured and residual confounding, time-varying measurement errors of exposure, and biases from survival effects were possible.
Proton-pump inhibitors seem to be associated with increased risk for adverse cardiovascular outcomes after discharge, regardless of clopidogrel use for myocardial infarction. Dual PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events over that observed for patients prescribed a PPI alone.
Prior mechanistic studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel, yet the clinical significance of these findings is not clear.
To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS).
Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006. Vital status information was available for all patients through September 30, 2006.
All-cause mortality or rehospitalization for ACS.
Of 8205 patients taking clopidogrel after discharge, 63.9% (n = 5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n = 2961) were not prescribed PPI. Death or rehospitalization for ACS occurred in 20.8% (n = 615) of patients taking clopidogrel without PPI and 29.8% (n = 1561) of patients taking clopidogrel plus PPI. In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n = 5244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or rehospitalization for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). In analyses of secondary outcomes, patients taking clopidogrel plus PPI had a higher risk of hospitalizations for recurrent ACS compared with patients taking clopidogrel without PPI (14.6% vs 6.9%; AOR, 1.86 [95% CI, 1.57-2.20]) and revascularization procedures (15.5% vs 11.9%; AOR, 1.49 [95% CI, 1.30-1.71]), but not for all-cause mortality (19.9% vs 16.6%; AOR, 0.91 [95% CI, 0.80-1.05]). The association between use of clopidogrel plus PPI and increased risk of adverse outcomes also was consistent using a nested case-control study design (AOR, 1.32; 95% CI, 1.14-1.54). In addition, use of PPI without clopidogrel was not associated with death or rehospitalization for ACS among patients not taking clopidogrel after hospital discharge (n = 6450) (AOR, 0.98; 95% CI, 0.85-1.13).
Concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS.
Most proton pump inhibitors inhibit the bioactivation of clopidogrel to its active metabolite. The clinical significance of this drug interaction is unknown.
We conducted a population-based nested case-control study among patients aged 66 years or older who commenced clopidogrel between Apr. 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute myocardial infarction. The cases in our study were those readmitted with acute myocardial infarction within 90 days after discharge. We performed a secondary analysis considering events within 1 year. Event-free controls (at a ratio of 3:1) were matched to cases on age, percutaneous coronary intervention and a validated risk score. We categorized exposure to proton pump inhibitors before the index date as current (within 30 days), previous (31-90 days) or remote (91-180 days).
Among 13 636 patients prescribed clopidogrel following acute myocardial infarction, we identified 734 cases readmitted with myocardial infarction and 2057 controls. After extensive multivariable adjustment, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03-1.57). We found no association with more distant exposure to proton pump inhibitors or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70-1.47).
Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopidogrel and an increased risk of reinfarction.
Objective.
—To review the management of gastroesophageal reflux disease (GERD) in adults with esophageal complications (esophagitis, stricture, adenocarcinoma, or Barrett metaplasia) or extraesophageal complications (otolaryngological manifestations and asthma).
To review the management of gastroesophageal reflux disease (GERD) in adults with esophageal complications (esophagitis, stricture, adenocarcinoma, or Barrett metaplasia) or extraesophageal complications (otolaryngological manifestations and asthma).
Peer-reviewed publications located via MEDLINE or cross-citation.
Emphasis was placed on new developments in diagnosis and therapeutics. Thus, fewer than 10% of identified citations are discussed.
Controlled therapeutic trials were emphasized. The validity of pathophysiological observations and uncontrolled trials were critiqued by the author.
Esophagitis is typically a chronic, recurring disorder treated with long-term antisecretory therapy, titrated to disease severity. Laparoscopic [correction of Laparascopic] antireflux surgery is an alternative strategy, but neither long-term efficacy data nor an appropriate controlled trial comparing it with proton pump inhibitor therapy exists. The main risk of esophagitis is adenocarcinoma arising from Barrett metaplasia, the incidence of which is increasing. Strong evidence suggests that both reflux-induced asthma and otolaryngological complications (subglottic stenosis, laryngitis, pharyngitis, or cancer) can occur without esophagitis. While the otolaryngological manifestations usually respond to antisecretory medications, reflux-induced asthma responds convincingly only to antireflux surgery.
Although esophagitis and GERD symptoms predictably respond to antisecretory medicines, the risk of adenocarcinoma from Barrett metaplasia dictates that if heartburn is refractory to treatment, chronic (>5 years), or accompanied by dysphagia, odynophagia, or bleeding, it should be evaluated by endoscopy. Thereafter, patients with Barrett metaplasia require surveillance endoscopy to control the cancer risk. Reflux-induced asthma remains a vexing problem in the absence of either medical therapy or proven efficacy of a reliable mechanism of prospectively identifying affected patients.
Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps.
To determine the association between PPI therapy and risk of hip fracture.
A nested case-control study was conducted using the General Practice Research Database (1987-2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed.
The risk of hip fractures associated with PPI use.
There were 13,556 hip fracture cases and 135,386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons).
Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.
The objective of this study was to develop a prospectively applicable method for classifying comorbid conditions which might alter the risk of mortality for use in longitudinal studies. A weighted index that takes into account the number and the seriousness of comorbid disease was developed in a cohort of 559 medical patients. The 1-yr mortality rates for the different scores were: "0", 12% (181); "1-2", 26% (225); "3-4", 52% (71); and "greater than or equal to 5", 85% (82). The index was tested for its ability to predict risk of death from comorbid disease in the second cohort of 685 patients during a 10-yr follow-up. The percent of patients who died of comorbid disease for the different scores were: "0", 8% (588); "1", 25% (54); "2", 48% (25); "greater than or equal to 3", 59% (18). With each increased level of the comorbidity index, there were stepwise increases in the cumulative mortality attributable to comorbid disease (log rank chi 2 = 165; p less than 0.0001). In this longer follow-up, age was also a predictor of mortality (p less than 0.001). The new index performed similarly to a previous system devised by Kaplan and Feinstein. The method of classifying comorbidity provides a simple, readily applicable and valid method of estimating risk of death from comorbid disease for use in longitudinal studies. Further work in larger populations is still required to refine the approach because the number of patients with any given condition in this study was relatively small.
Background:
Controversy remains on whether the dual use of clopidogrel and proton-pump inhibitors (PPIs) affects clinical efficacy of clopidogrel.
Objective:
To examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel compared with that of PPIs alone in adults hospitalized for myocardial infarction.
Design:
A nationwide cohort study based on linked administrative registry data.
Setting:
All hospitals in Denmark.
Patients:
All patients discharged after first-time myocardial infarction from 2000 to 2006.
Measurements:
The primary outcome was a composite of rehospitalization for myocardial infarction or stroke or cardiovascular death. Patients were examined at several assembly time points, including 7, 14, 21, and 30 days after myocardial infarction. Follow-up was 1 year.
Results:
Of 56 406 included patients, 9137 (16.2%) were re-hospitalized for myocardial infarction or stroke or experienced cardiovascular death. Of the 24 702 patients (43.8%) who received clopidogrel, 6753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for myocardial infarction or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% CI, 1.17 to 1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21 to 1.37). No statistically significant interaction occurred between a PPI and clopidogrel (P = 0.72).
Limitations:
Unmeasured and residual confounding, time-varying measurement errors of exposure, and biases from survival effects were possible.
Conclusion:
Proton-pump inhibitors seem to be associated with increased risk for adverse cardiovascular outcomes after discharge, regardless of clopidogrel use for myocardial infarction. Dual PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events over that observed for patients prescribed a PPI alone.
Acid-suppressant drugs are commonly prescribed for elderly patients, a population in which vitamin B12 deficiency is a common disorder. The purpose of this study was to examine the possible association between use of prescription histamine H-2 receptor antagonists (H2RA) or proton pump inhibitors (PPI) and vitamin B12 deficiency in older adults.Study design and settingThis was a case–control study in a University-based geriatric primary care setting. Among patients aged 65 years or older with documented serum vitamin B12 studies between 1990 and 1997, 53 vitamin B12-deficient cases were compared with 212 controls for past or current use of prescription H2RA/PPI according to information in subjects' medical records.ResultsControlling for age, gender, multivitamin use, and Helicobacter pylori infection, chronic (⩾12 months) current use of H2RA/PPI was associated with a significantly increased risk of vitamin B12 deficiency (OR 4.45; 95% CI 1.47–13.34). No association was found between past or short-term current use of H2RA/PPI and vitamin B12 deficiency.Conclusion
These findings support an association between chronic use of H2RA/PPI by older adults and development of vitamin B12 deficiency. Additional studies are needed to confirm these findings.
We thank the authors for their positive comments and amplifying remarks in response to our article in Circulation .1 We agree with the authors that the proton pump inhibitors (PPIs) may adversely influence cardiovascular physiology in multiple ways. We found that PPIs reduce the enzymatic activity of dimethylarginine dimethylaminohydrolase. In this way, PPIs increase plasma levels of asymmetrical dimethylarginine (ADMA).1 Because it inhibits the generation of vascular nitric oxide (NO), ADMA would be expected to increase platelet interaction with the vessel wall. Chyrchel and colleagues correctly point out that our findings may explain why PPIs attenuate the benefit of clopidogrel, as well as other P2Y12 antiplatelet agents not dependent on CYP2C19 for their activity.
We thank Montenegro and Lundberg for pointing out that NO may be generated in the stomach by the reduction of ingested nitrite, an effect that depends on low gastric pH. Dietary nitrate and nitrite …
Proton pump inhibitors (PPIs) are gastric acid suppressing agents widely prescribed for the treatment of gastro-esophageal reflux disease (GERD). Recently, several studies in patients with acute coronary syndrome (ACS) have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events (MACE). The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed.
Plasma ADMA is an endogenous inhibitor of nitric oxide synthase (NOS). Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely due to its attenuation of the vasoprotective effects of endothelial NOS. We find that PPIs elevate plasma asymmetric dimethylarginine (ADMA) level and reduce nitric oxide (NO) levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to, and inhibit dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA.
We present a plausible biological mechanism to explain the association of PPIs with increased MACE in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with use of the PPIs in the general population.
Objectives:
This study sought to determine whether known genetic, drug, dietary, compliance, and lifestyle factors affecting clopidogrel absorption and metabolism fully account for the variability in clopidogrel pharmacokinetics and pharmacodynamics.
Background:
Platelet inhibition by clopidogrel is highly variable. Patients with reduced inhibition have increased risk for major adverse cardiovascular events. Identification of factors contributing to clopidogrel's variable response is needed to improve platelet inhibition and reduce risk for cardiovascular events.
Methods:
Healthy subjects (n = 160; ages 20 to 53 years; homozygous CYP2C19 extensive metabolizer genotype; no nicotine for 6 weeks, prescription drugs for 4 weeks, over-the-counter drugs for 2 weeks, and no caffeine or alcohol for 72 h; confined; restricted diet) received clopidogrel 75 mg/day for 9 days, at which time clopidogrel pharmacokinetic and pharmacodynamic endpoints were measured.
Results:
At steady-state, clopidogrel active metabolite (clopidogrel(AM)) pharmacokinetics varied widely between subjects (coefficients of variation [CVs] 33.8% and 40.2% for clopidogrel(AM) area under the time-concentration curve and peak plasma concentration, respectively). On-treatment vasodilator stimulated phosphoprotein P2Y(12) platelet reactivity index (PRI), maximal platelet aggregation (MPA) to adenosine phosphate, and VerifyNow P2Y12 platelet response units (PRU) also varied widely (CVs 32% to 53%). All identified factors together accounted for only 18% of intersubject variation in pharmacokinetic parameters and 32% to 64% of intersubject variation in PRI, MPA, and PRU. High on-treatment platelet reactivity was present in 45% of subjects.
Conclusions:
Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite rigorous exclusion or control of known disease, polymorphisms (CYP2C19, CYP3A5, ABCB1, PON1), noncompliance, co-medications, diet, smoking, alcohol, demographics, and pre-treatment platelet hyperreactivity. Thus, as yet unidentified factors contribute to high on-treatment platelet reactivity with its known increased risk of major adverse cardiovascular events. (A Study of the Effects of Multiple Doses of Dexiansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants: NCT00942175).
Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death.
We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score-matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).
During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.
During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.).
OBJECTIVES: Conflicting data exist on whether discontinuation of proton pump inhibitors (PPIs) is associated with rebound secretion of gastric acid. METHODS: A total of 48 healthy Helicobacter pylori-negative volunteers (24 females) were randomized in a double-blinded manner to treatment with either pantoprazole 40 mg or placebo once daily for 28 days. Dyspeptic symptoms were registered daily using the Glasgow dyspepsia score (GDS) 2 weeks before, during, and 6 weeks after treatment. Plasma levels of gastrin and serum levels of chromogranin-A levels were measured before, during, and after treatment. RESULTS: During the 2 weeks before treatment, the placebo group had a mean GDS of 0.20 + or - 0.7 compared with the pantoprazole group score of 0.54 + or - 1.3 (NS). No significant differences between the symptom severity scores of the two groups were shown during the treatment period. During the first week after discontinuation of treatment, the pantoprazole group had a mean symptom score of 5.7 + or - 11.7 vs. 0.74 + or - 2.6 in the placebo group (P<0.01). A total of 11 out of 25 (44%) subjects in the pantoprazole group developed dyspepsia compared with 2 out of 23 (9%) in the placebo group (P<0.01). During the second week of follow-up, the pantoprazole group had a mean symptom score of 1.6 + or - 3.4 compared with 0 + or - 0 in the placebo group (P<0.05). There were no significant differences in the mean symptom score for the pantoprazole group (1.1 + or - 0.6) compared with the placebo group (0.4 + or - 0.3) during the third week of follow-up. Symptom scores during the first week after treatment correlated with basal (P<0.01) and meal-stimulated (P<0.01) gastrin levels at the end of treatment. CONCLUSIONS: A 4-week course of pantoprazole seems to induce dyspeptic symptoms in previously asymptomatic healthy H. pylori-negative subjects. The correlation between symptom score and gastrin levels suggests that these symptoms are due to acid rebound hypersecretion and seem to be related to the degree of acid inhibition.
The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear.
We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49).
The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events.
http://www.clinicaltrials.gov. Unique identifier: NCT00391872.
In the evaluation of a hypertension treatment program, the end-point surveillance included incidence of acute myocardial infarction and acute stroke identified from hospital in-patient registers and the national mortality register. To ascertain the validity, in-patient records containing the ICD-codes 410-411 and 430-438 were validated. First event of acute myocardial infarction and acute stroke suggested in the in-patient register could be confirmed in 96% and 94%, respectively. In-patient diagnoses of suspected acute myocardial infarction or other acute or subacute ischemic heart diseases, transient ischemic attack and unspecified heart diseases, transient ischemic attack and unspecified cerebrovascular disease revealed high proportions of what in fact turned out to be definite events (11%, 24% and 53% respectively). It is concluded that disease ascertainment for this cohort study claims validation of register data with hospital records.
The incidence of acute cardiovascular and cerebrovascular events in patients treated for complicated or uncomplicated peptic ulcer disease (PUD) has not been ascertained completely.
All patients with in-hospital treatment due to PUD between 1987 and 2007, who did not have any past history of acute or chronic cardiovascular or cerebrovascular disease, were identified through the Swedish Patient Register. Standardized incidence ratios were calculated to compare the subsequent incidence of acute myocardial infarction (AMI), ischemic, or hemorrhagic stroke after hospital admission in six different subgroups of PUD relative to the general population. To partly account for the impact of smoking, the incidence of lung cancer in those treated for PUD was compared with that of the general population.
A total of 84 156 patients with no past history of acute or chronic cardiovascular or cerebrovascular disease were discharged from hospital due to PUD. The risk of AMI, ischemic, or hemorrhagic stroke was increased from 2-fold to 4-fold within the first 60 days of hospitalization due to PUD compared with the general population. This risk remained 30-70% higher among all subgroups of PUD compared with the general population throughout the entire follow-up period.
Patients treated in hospital for PUD have a higher risk of AMI and stroke compared with the general population. Careful surveillance of these patients seems to be indicated, particularly during the first 60 days after discharge.
Only limited studies have evaluated the risk of non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and coxibs for lower gastrointestinal (GI) adverse outcomes. The objective of this study was to evaluate risks of lower GI adverse events associated with use of celecoxib, oral and parenteral nsNSAIDs.
Retrospective case-crossover study.
Records of all patients aged ≥20 years hospitalised for lower GI adverse events (bleeding from small or large intestine, perforation, and complicated diverticular disease) in 2006 were retrieved using ICD-9-CM diagnosis codes from inpatient claims from the Taiwan National Health Insurance database.
Case periods were defined for each patient as 1-30 days prior to hospital admission date and control period as 91-120 days prior to hospital admission date. The pharmacy prescription database was searched for NSAID use during case and control periods.
We calculated adjusted self-matched ORs and 95% CIs with a conditional logistic regression model to determine the associations between NSAID use and lower GI adverse outcomes.
A total of 1297 patients hospitalised for lower GI adverse events were included. Celecoxib was associated with an adjusted OR of 2.33 (95% CI 0.97 to 5.59); the association became statistically significant (OR: 3.26, 95% CI 1.07 to 9.91) when a different control period (31-60 days) was applied. Both oral and parenteral nsNSAIDs significantly increased risk for lower GI adverse events (OR: 2.26, 95% CI 1.78 to 2.85 and OR: 5.64, 95% CI 3.24 to 9.82, respectively).
Oral and parenteral NSAIDs were associated with significantly increased risk for lower GI adverse events. Celecoxib also increased risk to a comparable extent, despite risk estimates being affected slightly by the control period chosen for comparison. The association of NSAIDs with specific lower GI adverse events and long-term complications requires further investigation.