PPIs Are Not Responsible for Elevating Cardiovascular Risk in Patients on Clopidogrel—A Systematic Review and Meta-Analysis

Demcsák, Alexandra; Lantos, Tamás; Bálint, Emese Réka; Hartmann, Petra; Vincze, Áron; Bajor, Judit; Czopf, László; Alizadeh, Hussain; Gyöngyi, Zoltán; Korbonits, M; Mikó, Alexandra; Szakács, Zsolt; Pécsi, Dániel; Szabó, Imre

doi:10.3389/fphys.2018.01550

Cited by 23 publications

(15 citation statements)

References 54 publications

(207 reference statements)

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“…Residual confounding may explain the wide‐ranging associations with PPI use observed both in the literature, where PPIs have been associated with over a dozen conditions, and in this study with cause‐specific mortality from a number of causes 1–9,38–40 . Notably, noninterventional research on the interaction between clopidogrel and PPIs similarly suffered from hard to account for confounding, and ultimately randomised trials suggested the harmful associations detected in many studies were not causal 13,41 …”

Section: Discussionmentioning

confidence: 68%

“…[1][2][3][4][5][6][7][8][9][38][39][40] Notably, noninterventional research on the interaction between clopidogrel and PPIs similarly suffered from hard to account for confounding, and ultimately randomised trials suggested the harmful associations detected in many studies were not causal. 13,41 Our study has several strengths. It is the largest study to date to examine the association of PPI prescription with all-cause and causespecific mortality.…”

Section: Discussionmentioning

confidence: 99%

“…7,[10][11][12] Previous safety concerns about PPIs have highlighted important limitations of statistical techniques used to account for differences between PPI users and nonusers in noninterventional studies; several studies identified a harmful association between combined clopidogrel and PPI use, whilst randomised controlled trials (RCTs) found no clinically relevant interaction. 13 Given that PPIs are globally one of the most frequently used classes of drugs, it is vital that we are able to reliably evaluate their potential risks and benefits when making treatment decisions.…”

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confidence: 99%

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Proton pump inhibitors and risk of all‐cause and cause‐specific mortality: A cohort study

Brown

Tazare

Williamson

et al. 2021

Brit J Clinical Pharma

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To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality.Methods: We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models.Results: PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted haz-

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Proton pump inhibitors and risk of all‐cause and cause‐specific mortality: A cohort study

Brown

Tazare

Williamson

et al. 2021

Brit J Clinical Pharma

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“…Existing studies on the association between cardiovascular disorders and PPIs are conflicting. Several studies showed that PPIs were associated with an augmented risk of cardiovascular events (28-30), while others found no this association and supported the cardiovascular safety profile of PPIs (31)(32)(33).…”

Section: Discussionmentioning

confidence: 95%

Updated Insights on Cardiac and Vascular Risks of Proton Pump Inhibitors: A Real-World Pharmacovigilance Study

Zhai

et al. 2022

Front. Cardiovasc. Med.

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BackgroundProton pump inhibitors (PPIs) are among the most widely prescribed medications in clinical practice. However, there are also concerns about the potential risks of long-term PPI use. The present study aimed to examine the safety of PPIs and summarize their potential cardiac and vascular risks in a real-world setting.MethodsThis pharmacovigilance study extracted records between January 2015 and December 2019 from the FDA Adverse Event Reporting System (FAERS) database. The association of seven PPI medications with cardiac and vascular events (CVEs) were evaluated. Two established pharmacovigilance methods, reporting odds ratio (ROR) and information components (IC) based statistical shrinkage, were used to measure disproportionality.ResultsIn total 62,140 CVE records associated with PPI use were investigated. Women showed a higher proportion (54.37%) of PPI-associated CVEs. The median time from PPI initiation to CVE onset was 97 [interquartile range (IQR): 8–491] days, with the shortest median time of 42 days (IQR: 2–277 days) for esomeprazole, and the longest time of 389 days (IQR: 0–525 days) for dexlansoprazole. Although PPIs were not associated with elevated CVE risks compared those of the whole database (IC025/ROR025 = −0.39/0.74), various signals emerged. Despite some similarities exist between the PPIs, their cardiac and vascular safety profiles varied significantly. Pantoprazole showed the broadest spectrum of signals, from thrombotic thrombocytopenic purpura (IC025/ROR025 = 0.01/1.08) to renal haemangioma (IC025/ROR025 = 3.14/9.58). Esomeprazole showed the second-broadest spectrum of toxicities, ranging from duodenal ulcer hemorrhage (IC025/ROR025 = 0.07/1.28) to hypertensive nephropathy (IC025/ROR025 = 4.09/18.72). Vascular signals were more dominant than cardiac signals, suggesting that vascular function was more heavily affected. Hypertensive nephropathy, renal haemangioma, renal artery stenosis, and renal infarct had strong signals across most PPI regimens and merited further attention.ConclusionsPPIs may inflict various CVEs, particularly those involving the vascular system, on the users. Given the wide range of onset times and different toxicity profiles for various PPI medications, they should be prescribed with caution.

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“…Although most previous studies mainly focused on the effects of PPIs on CV outcomes in patients receiving clopidogrel (Kwok and Loke, 2010;Siller-Matula et al, 2010;Chen et al, 2012;Gerson et al, 2012;Kwok et al, 2013;Melloni et al, 2015;Sherwood et al, 2015;Serbin et al, 2016;Bundhun et al, 2017;Niu et al, 2017;Demcsák et al, 2018;Khan et al, 2018), the current study is the first comprehensive systematic review to examine the efficacy and safety profile of PPIs combined with DAPT in patients after PCI or ACS and is, to the best of our knowledge, the only study to evaluate the safety of PPIs with the concomitant use of other P2Y 12 inhibitors. This review of 22 studies with 6,930 patients from RCTs to 183,546 patients from observational studies showed that the use of PPIs probably reduced the risk of GI bleeding and UGI bleeding relative to no PPI use.…”

Section: Discussionmentioning

confidence: 99%

Clinical Outcomes of Concomitant Use of Proton Pump Inhibitors and Dual Antiplatelet Therapy: A Systematic Review and Meta-Analysis

Guo

Huang

2021

Front. Pharmacol.

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Background: The safety and efficacy associated with the use of proton pump inhibitors (PPIs) by patients with coronary artery disease receiving dual antiplatelet therapy (DAPT) remain unclear.Methods: The evaluated outcomes included combined major adverse cardiovascular events (MACEs), myocardial infarction (MI), all-cause mortality, and gastrointestinal (GI) bleeding. A random effects meta-analysis, stratified by study design, was performed and heterogeneity was assessed using the I2 statistic.Results: In total, 6 randomized controlled trials (RCTs) (6930 patients) and 16 observational studies (183,546 patients) were included. Analysis of RCTs showed that there were no significant differences in the incidences of MACEs (risk ratio [RR] = 0.89 [95% confidence interval (CI) = 0.75–1.05]), MI (RR = 0.93 [95% CI = 0.76–1.15]), and all-cause mortality (RR = 0.79 [95% CI = 0.50–1.23]) in the PPI groups vs. the non-PPI groups. Pooled data from observational studies revealed an inconsistent association between the use of each PPI subtype and the increased risks of MACEs during clopidogrel treatment. There was no increased risk of MACEs or all-cause mortality associated with the use of PPIs (as a class) and other P2Y12 inhibitors. Both the RCTs and observational studies revealed that the use of PPIs significantly reduced the risks of GI bleeding.Conclusion: The use of PPIs was associated with a reduced risk of GI bleeding in patients treated with DAPT after percutaneous coronary intervention or acute coronary syndrome. There was no clear evidence of an association between the use of PPIs and adverse cardiovascular events.Clinical Trial Registration: identifier [CRD42020190315]

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PPIs Are Not Responsible for Elevating Cardiovascular Risk in Patients on Clopidogrel—A Systematic Review and Meta-Analysis

Cited by 23 publications

References 54 publications

Proton pump inhibitors and risk of all‐cause and cause‐specific mortality: A cohort study

Proton pump inhibitors and risk of all‐cause and cause‐specific mortality: A cohort study

Updated Insights on Cardiac and Vascular Risks of Proton Pump Inhibitors: A Real-World Pharmacovigilance Study

Clinical Outcomes of Concomitant Use of Proton Pump Inhibitors and Dual Antiplatelet Therapy: A Systematic Review and Meta-Analysis

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