Potential Cardiovascular Risks of Proton Pump Inhibitors in the General Population

Zhu, Wenzhen; Hong, Kui

doi:10.1536/ihj.16-208

Cited by 15 publications

(10 citation statements)

References 42 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, like in the case of other drugs, PPIs are not as safe as it has been thought and more recently, concerns have been raised about their potential association with pneumonia[ 65 - 67 ], bone fractures[ 68 - 70 ], interstitial nephritis and acute kidney injury[ 71 ]. More recently, reports of other potential PPIs adverse events such as risk for chronic kidney disease[ 72 , 73 ], dementia[ 74 ], spontaneous bacterial peritonitis[ 75 , 76 ], acute myocardial infarction[ 77 , 78 ], micronutrient deficiency (magnesium, calcium, iron)[ 79 , 80 ] were published, although the quality of evidence for these is consistently low to very low[ 81 ].…”

Section: Introductionmentioning

confidence: 99%

Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis

Trifan

Stanciu

Gîrleanu

et al. 2017

WJG

220

138

View full text Add to dashboard Cite

AIMTo perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI).METHODSWe conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran’s Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS).RESULTSFifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002).CONCLUSIONThis meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.

show abstract

Section: Introductionmentioning

confidence: 99%

Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis

Trifan

Stanciu

Gîrleanu

et al. 2017

WJG

220

138

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

confidence: 99%

Real-World Relationship Between Proton Pump Inhibitors and Cerebro-Cardiovascular Outcomes Independent of Clopidogrel

Liu

Chen

et al. 2019

Int. Heart J.

Self Cite

View full text Add to dashboard Cite

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 (

show abstract

“…Furthermore, we could not rule out the possibility that the cardiovascular risk may be additionally increased by mechanisms other than the attenuated effectiveness of clopidogrel due to CYP2C19 inhibition by concomitant PPI. A recent study suggested that PPIs may increase cardiovascular risk by inhibiting dimethylarginine dimethylaminohydrolase activity, leading to increased superoxide anion generation, reduced nitric oxide generation, and impaired vascular homeostasis . In contrast, previous studies showed no association between PPI use and adverse events among patients not receiving clopidogrel, indicating the need for further studies …”

Section: Discussionmentioning

confidence: 95%

Effectiveness and Safety of Clopidogrel Co‐administered With Statins and Proton Pump Inhibitors: A Korean National Health Insurance Database Study

Kim

Song

Lee

et al. 2019

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction −0.14, 95% CI −0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.Antiplatelet therapy is the cornerstone of treatment in patients with acute coronary syndrome (ACS), especially following percutaneous coronary intervention (PCI) with stenting. According to several large randomized clinical trials (RCTs), clopidogrel, the most widely used antiplatelet agent administered with aspirin, is beneficial in reducing ischemic complications. 1-4 However, in clinical settings in which factors affecting the response to clopidogrel are not well controlled, the recurrence of ischemic complications is observed in a considerable number of patients despite clopidogrel therapy. This observation is considered attributable to a Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Proton pump inhibitors (PPIs) and cytochrome P450 (CYP) 3A4-metabolized statins affect clopidogrel conversion into an active metabolite, although clinical implications are disputed. The joint effects of administering PPIs and CYP3A4-metabolized statins with clopidogrel have been rarely studied. WHAT QUESTION DID THIS STUDY ADDRESS? We assessed the potential for additional risks associated with simultaneously administering PPI and CYP3A4-metabolized statins in combination with clopidogrel, in addition to the independent effects of PPI and CYP3A4-metabolized statins on clopidogrel. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? PPI co administration with clopidogrel and statin was associated with increased risks for major thrombotic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention with stenting but CYP3A4-metabolized statin did not synergistically exacerbate PPI-associated risks. HOW MIGHT THIS CHANGE CLINICAL PHARMA COLOGY OR TRANSLATIONAL SCIENCE? The results suggest that PPI co administration should be avoided in patients with ACS recei...

show abstract

Potential Cardiovascular Risks of Proton Pump Inhibitors in the General Population

Cited by 15 publications

References 42 publications

Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis

Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis

Real-World Relationship Between Proton Pump Inhibitors and Cerebro-Cardiovascular Outcomes Independent of Clopidogrel

Effectiveness and Safety of Clopidogrel Co‐administered With Statins and Proton Pump Inhibitors: A Korean National Health Insurance Database Study

Contact Info

Product

Resources

About