Circulation Editors' Picks

Introduction: Proton pump inhibitors (PPIs) are used by an estimated 29 million Americans. PPIs increase the levels of asymmetrical dimethylarginine, a known risk factor for cardiovascular disease (CVD). Data from a select population of patients with CVD suggest that PPI use is associated with an increased risk of stroke, heart failure, and coronary heart disease. The impact of PPI use on incident CVD is largely unknown in the general population. Hypothesis: We hypothesized that PPI users have a higher risk of incident total CVD, coronary heart disease, stroke, and heart failure compared to nonusers. To demonstrate specificity of association, we additionally hypothesized that there is not an association between use of H 2 -blockers - another commonly used class of medications with similar indications as PPIs - and CVD. Methods: We used the Rochester Epidemiology Project’s medical records-linkage system to identify all residents of Olmsted County, MN on our baseline date of January 1, 2004 (N=140217). We excluded persons who did not grant permission for their records to be used for research, were <18 years old, had a history of CVD, had missing data for any variable included in our model, or had evidence of PPI use within the previous year.We followed our final cohort (N=58175) for up to 12 years. The administrative censoring date for CVD was 1/20/2014, for coronary heart disease was 8/3/2016, for stroke was 9/9/2016, and for heart failure was 1/20/2014. Time-varying PPI ever-use was ascertained using 1) natural language processing to capture unstructured text from the electronic health record, and 2) outpatient prescriptions. An incident CVD event was defined as the first occurrence of 1) validated heart failure, 2) validated coronary heart disease, or 3) stroke, defined using diagnostic codes only. As a secondary analysis, we calculated the association between time-varying H 2 -blocker ever-use and CVD among persons not using H 2 -blockers at baseline. Results: After adjustment for age, sex, race, education, hypertension, hyperlipidemia, diabetes, and body-mass-index, PPI use was associated with an approximately 50% higher risk of CVD (hazard ratio [95% CI]: 1.51 [1.37-1.67]; 2187 CVD events), stroke (hazard ratio [95% CI]: 1.49 [1.35-1.65]; 1928 stroke events), and heart failure (hazard ratio [95% CI]: 1.56 [1.23-1.97]; 353 heart failure events) compared to nonusers. Users of PPIs had a 35% greater risk of coronary heart disease than nonusers (95% CI: 1.13-1.61; 626 coronary heart disease events). Use of H 2 -blockers was also associated with a higher risk of CVD (adjusted hazard ratio [95% CI]: 1.23 [1.08-1.41]; 2331 CVD events). Conclusions: PPI use is associated with a higher risk of CVD, coronary heart disease, stroke and heart failure. Use of a drug with no known cardiac toxicity - H 2 -blockers - was also associated with a greater risk of CVD, warranting further study.

Effects of Proton Pump Inhibitors in Cirrhotic Patients: What Do We Really Know?

Inhibitory Effects of Ticagrelor Compared With Clopidogrel on Platelet Function in Patients With Acute Coronary Syndromes: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET Substudy

Concomitant use of antiplatelet agents and proton-pump inhibitors (PPIs) has been recommended in patients with a history of gastrointestinal (GI) hemorrhage. However, recent studies have reported that PPIs may alter clopidogrel's pharmacokinetics and potentially lead to an increased risk of recurrent adverse cardiovascular (CV) events. Using Taiwan's 2000-2006 National Health Insurance database, this population-based retrospective cohort study assessed CV and GI events in patients who had a prior history of GI bleeding and had been prescribed ongoing antiplatelet therapy after acute coronary syndrome (ACS) discharge. We identified 3,580 ACS patients and categorized them into (1) those taking clopidogrel alone, (2) those taking clopidogrel plus PPIs, and (3) those taking aspirin plus PPIs. Cox proportional hazards models were used to assess the association between the use of antiplatelet therapies and CV/GI events. The clopidogrel only group and the clopidogrel plus PPI group were found to be at lower risk for GI events than the aspirin plus PPI group [adjusted hazard ratio (HR) 0.23 (95% confidence interval; CI 0.14-0.36) and HR 0.70 (0.52-0.96), respectively]. However, while the clopidogrel only group had a lower risk of CV events than the aspirin plus PPI group [HR 0.57 (0.38-0.84)], the clopidogrel plus PPI group had a significantly higher CV risk than the aspirin plus PPI group [HR 1.59 (1.18-2.13)]. Our findings suggest that although the use of clopidogrel plus PPIs provides GI benefits, with this treatment, there is an increased CV risk among patients with a history of GI bleeding.

BackgroundChronic Proton Pump Inhibitor (PPI) use after anti-reflux surgery (ARS) remains common. Which patient factors contribute to chronic PPI use after surgery is unclear. The primary aim was to provide a long-term outcome of ARS by evaluating PPI use in the years after surgery and identify determinants of chronic PPI use after surgery.MethodsPatients aged ≥ 18 years who underwent ARS between 2011 and 2020 in a single referral center were eligible. Patient data were retrospectively assessed by medical record review. PPI data were acquired from primary care pharmacies. Chronic PPI use was defined as ≥ 180 Defined Daily Doses (DDD) per year. Patient characteristics predisposing chronic PPI use were identified. Statistical analysis included descriptive statistics and multivariable logistic regressions and a Kaplan-Meier curve.ResultsOnly 45 out of 364 eligible patients (12%) had complete data for analysis. Chronic PPI use was present in 79.5% before surgery compared to 29.5% at 1 and 2 years and 32.0% for 5 years after surgery. A median difference in PPI use of -257 DDD was found for the year after surgery compared to the year before surgery. Male gender was associated with chronic PPI use after surgery but no other determinants were found.ConclusionApproximately a third of the patients use PPIs up to 5 years after surgery. Although ARS is recommended when PPI treatment fails or to avert lifelong PPI use, quality of life and PPI use may not correlate linearly. Adequate patient selection and expectation management before surgery is paramount.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12876-025-04247-6.

<i>Circulation:</i> Clinical Summaries

2633 Background: Emerging data suggest that concomitant medications (CM) influence response to ICI. CM impact the host microbiome which may mitigate tumor-immune responsiveness. PPI use in patients treated with ICI has been associated with worse survival. Few data exist regarding the effects of PPI use in terms of prior chemotherapy or in risk for immune related adverse events (irAE) (e.g., colitis). Methods: This retrospective study of patients with advanced cancer treated with ICI between 2011 and 2019 was conducted at The Ohio State University. Patients who received ICI as either single agent or combination were included. Clinical data was abstracted from chart review, including CM, toxicity, and survival. Overall survival (OS) was evaluated to date of death or last contact. Associations between OS and proton pump inhibitor (PPI) use were studied using log-rank tests and Cox regression analyses overall and by the groups of whether prior chemotherapy was administered and timing from chemotherapy to ICI. The associations between PPI and incidence of irAE (overall and colitis) were assessed by chi-square tests. Results: We identified 1,091 patients treated with ICI, of whom 415 (38%) received PPI at time of ICI. Most common cancers were NSCLC and melanoma; most common therapy was PD1/L1 (Table). PPI use was associated with shorter OS in patients treated as first line therapy (HR = 1.46, 95% CI = [1.11, 1.91], p=0.006) and in second line and beyond (HR = 1.30, 95% CI = [1.10, 1.53], p=0.002). PPI use was associated with shorter OS in patients treated with ICI for those without prior chemotherapy (HR = 1.47, 95% CI = [1.17, 1.86], p=0.001). When evaluated by timing from chemotherapy to ICI, PPI use was associated with shorter OS only in patients where last chemotherapy was &gt; 1 year from ICI (HR = 1.99, 95% CI [1.15, 3.45], p=0.014) but not for patients with chemotherapy within 1 year of ICI (HR = 1.01, 95% CI = [0.79, 1.29], p=0.960). The use of PPI was not associated with incidence of irAE (p=0.317) or colitis in particular (p=0.781). Conclusions: PPI use was associated with shorter survival in patients treated with ICI across a broad variety of cancers and in first line of therapy or beyond. In patients with recent chemotherapy (&lt;1 year), PPI use was not associated with survival, which may be due to disruption of the microbiome by chemotherapy. Further study is needed to determine the impact of CM (e.g, PPI), on outcomes of patients treated with ICI.[Table: see text]

Cardiovascular disease (CVD) in women has been historically understudied. For many years, heart disease had been thought to be primarily a “man’s disease.” Consequently, women have been significantly under-represented in longitudinal studies of disease history and in clinical trials. High-quality data from women at the extremes of age, with multiple co-morbidities, and from racial and ethnic minorities have been particularly rare. In order to increase awareness of cardiovascular prevention among women, in 1999 the American Heart Association (AHA) published its first women-specific clinical recommendations for the prevention of CVD.1 In 2004, the AHA and multiple other collaborating organizations subsequently sponsored “Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women,” which underwent updates in 2007 and 2011. As a result of these and other related initiatives, the rate of public awareness of CVD as the leading cause of death among US women has increased from 30% in 1997 to 54% in 2009.2 CVD-associated death among US women has declined significantly over this time period.3,4 Yet substantial work still needs to be done to improve women’s cardiovascular health. CVD remains the number one killer among women.4 As the obesity epidemic continues, we are actually finding increases in coronary heart disease (CHD) death among young women 35 to 54 years of age.2 Morbidity and mortality from stroke and hypertension remain high.4 In addition, substantial outcomes disparities continue for women from racial and ethnic minorities.4 We have therefore dedicated our topic summaries in this issue of Circulation: Cardiovascular Quality and Outcomes to CVD in women. We have included only those studies where authors provided a convincing a priori reason to study a particular disease process or clinical intervention in women and reported primary endpoints that were sex-specific. We have included articles on the representation of women …

The few prospective studies examining the relation between proton pump inhibitor (PPI) use and risk of vertebral fracture (VF) suggest a higher risk, but the magnitude of the association has been inconsistent. Moreover, no prospective studies have examined the association between substantially longer duration of PPI use and VF risk. Our objective was to determine the association between PPI use, H2RA use, and incident clinical VF in women. We conducted a prospective study in 55,545 women participating in the Nurses' Health Study. PPI and H2RA use was assessed by questionnaire every 4years. Self-reports of VF were confirmed by medical record. Our analysis included 547 incident VF cases (2002-2014). The multivariate adjusted relative risk (MVRR) of VF for women taking PPIs was 1.29 (95% CI 1.04-1.59) compared with non-users. Longer duration of PPI use was associated with higher VF risk (MVRR 1.16 [0.90-1.49] for < 4years; 1.27 [0.93-1.73] for 4-7.9years; 1.64 [1.02-2.64] for ≥ 8years; ptrend = 0.01). The MVRR of VF for women taking H2RAs was 1.22 (0.90-1.67) compared with non-users. Longer duration of H2RA use was not associated with VF risk (MVRR 1.16 [0.88-1.53] for < 4years; 0.98 [0.60-1.59] for ≥ 4years; ptrend = 0.72). PPI use is independently associated with a modestly higher risk of VF and the risk increases with longer duration of use. There was no statistically significant association between H2RA use and VF risk. Our findings add to the growing evidence suggesting caution with PPI use, particularly with longer duration of use.

Proton pump inhibitor (PPI) use may alter the gut microbiome and increase the risk of cholangitis. However, the association of PPI use with the risk of incident cholangitis has not been evaluated. To evaluate whether PPI use was associated with a higher risk of cholangitis. This cohort study included a nationwide representative sample of the Korean general population followed up for 10years (1 January 2003 to 31 December 2013). PPI use was identified from treatment claims and considered as a time-varying variable. Incident cholangitis was identified from hospitalisation and out-patient visit claims. During 4212003 person-years of follow-up, 58,863 participants had at least one PPI prescription and 1834 participants developed cholangitis. The age-, sex-, residential area- and income-adjusted hazard ratio (HR) for incident cholangitis comparing PPI use with non-use was 6.06 (95% CI, 4.64-7.91). The association was essentially unchanged in fully adjusted models (HR 5.75; 95% CI, 4.39-7.54). The risk was highest during PPI treatment and decreased gradually after PPI discontinuation (Ptrend <.001). In this large cohort, PPI use was associated with an increased risk of cholangitis. Physicians prescribing PPIs should consider cholangitis as a potential complication of PPI use.

An association between proton pump inhibitor (PPI) use and an increased risk of acute kidney injury (AKI) has been confirmed. This study aimed to evaluate the effects of PPI use on the risk of AKI in patients with cancer who were administered immune checkpoint inhibitors (ICIs), a class of drugs used in cancer treatment, and in those who were not. We used a database provided by the Health, Clinic, and Education Information Evaluation Institute, which included demographic data, diagnoses, prescriptions, and laboratory results. We conducted a nested case-control study of 38,930 patients with cancer who were new PPI or ICI users and had no history of AKI before cohort entry. The odds ratio (OR) for AKI was estimated using conditional logistic regression models. During a mean follow-up of 8.3 months, 5,870 cases of AKI were identified (incidence rate, 21.9/100 person-years). Compared to never or past PPI use without ICI use, the adjusted ORs of AKI for current PPI use without ICI use, past or never PPI use with prior ICI use, current PPI use with prior ICI use were 1.82 (95% CI, 1.67 to 2.00), 1.47 (95% CI, 1.17 to 1.86), or 2.13 (95% CI, 1.42 to 3.20), respectively. The risk of AKI in patients treated with both PPIs and ICIs was not higher than the additional or multiplication of the risks in those who were treated with PPIs or ICIs alone. This study reinforces the association between PPIs and ICIs use and the increased risk of AKI. Although the interaction between the two drug classes was not detected, these findings highlight the need for careful monitoring and evaluation of kidney function in patients treated with PPIs and ICIs.

Introduction: Gastric polyps (GPs) are mucosal growths with unclear etiology, though Helicobacter pylori infection and proton pump inhibitor (PPI) use are known risk factors. Their prevalence ranges from 0.6% to 6%, varying by ethnicity, geography, and clinical setting. Often asymptomatic, GPs can present with anemia, bleeding, or epigastric pain. Hyperplastic and fundic gland polyps are the most common subtypes. Despite their clinical relevance, data from Middle Eastern populations remain limited. This study aims to assess the prevalence and potential risk factors of GPs in a Middle Eastern cohort. Methods: We conducted a retrospective analysis of patients who underwent esophagogastroduodenoscopy (EGD) for any indication at a tertiary hospital in the Middle East between 2017 and 2022. Institutional Review Board (IRB) approval was obtained. Two cohorts were identified: patients with GPs (cohort 1) and those without (cohort 2). Collected data included demographics, H. pylori status, PPI use, endoscopic findings, and histopathological results. Patients with missing data from EGD or clinical records were excluded. Statistical analysis was performed using Statistical Package for the Social Sciences. Results: GPs were identified in 312 (4.9%) out of 6,389 EGDs. Among patients with GPs, the mean age was 61.7 years, and 65.7% were women. Epigastric pain was the most frequently reported symptom (47.6%), while gastritis was the most common endoscopic finding (60.9%). PPI use was observed in 76% of patients with GPs compared to 31.48% in the comparison cohort. H. pylori was detected in 57.4% of patients with GPs versus 47.14% in the comparison cohort. Hyperplastic polyps (59.3%) and fundic gland polyps (36.5%) were the most common subtypes. Gastric polyps were associated with female sex (P < 0.001), older age (P < 0.001), and PPI use (P < 0.001). Subtype analysis showed fundic gland polyps were associated with female sex (P = 0.008) and PPI use (P = 0.011), while hyperplastic polyps were associated with PPI use (P < 0.001) and iron deficiency anemia (P = 0.011). Conclusion: In this study, gastric polyps were identified in 4.9% of patients, with hyperplastic and fundic gland polyps as the most common subtypes. PPI use was associated with GPs and their subtypes, while no association was found with H. pylori, in contrast to the existing literature. These findings contribute to understanding GP patterns and emphasize the need for further research on risk factors and management in Middle Eastern populations.

The dynamics of patients’ attendance at outpatient clinics after acute coronary syndrome: The data of LISS-3 registry

To investigate whether there is an increased risk of cardiac events with a combined therapy of clopidogrel and proton pump inhibitors (PPIs) after percutaneous coronary intervention (PCI). In the BAsel Stent Kosten Effektivitäts Trial (BASKET), all patients undergoing PCI received 6 months of clopidogrel and were analysed for the use of PPI therapy. Endpoints were major adverse cardiac events (MACE), myocardial infarction (MI), death and target vessel revascularization (TVR) after 36 months. Of 801 patients with available discharge medication data, 109 (14%) received PPIs. Patients who received PPIs were older (66.5 ± 10.5 vs. 63.3 ± 11.3 years, P = 0.006), more likely to be woman (80% vs. 69%, P = 0.009) and have a history of diabetes (29.6% vs. 17.3%, P = 0.002) or gastrointestinal ulcer disease (8.3% vs. 3.3%, P = 0.015) and more often received nonsteroidal anti-inflammatory drugs (7.3% vs. 2.2%, P = 0.003) and corticosteroids (11% vs. 3.6%, P = 0.001) but not aspirin (91.7% vs. 97%, P = 0.008) compared with those who did not receive PPIs. Patients who received PPI therapy had higher rates of MACE (30.3% vs. 20.8%, P = 0.027) and MI (14.7% vs. 7.4%, P = 0.01) but similar rates of death (9.2% vs. 7.4%, P = 0.51) and TVR (20.2% vs. 15.3%, P = 0.2) compared with those who did not. By multivariate analysis, diabetes (hazard ratio 1.83, 95% confidence interval 1.07-3.15) and PPI use (hazard ratio 1.88, 95% confidence interval 1.05-3.37) were the only independent risk factors for MI. In a real-world PCI population, the combination of PPIs and clopidogrel was associated with a doubling of MI rates after 3 years. Even after correction for confounding factors, concomitant PPI use remained an independent predictor of outcome emphasizing the clinical importance of this drug-drug interaction.

PurposePreeclampsia is a leading cause of maternal morbidity and mortality. Calcium-based antacids and proton pump inhibitors (PPIs) are commonly used during pregnancy to treat symptoms of gastroesophageal reflux disease. Both have been hypothesized to reduce the risk of preeclampsia. We determined associations of calcium-based antacid and PPI use during pregnancy with late-onset preeclampsia (≥34 weeks of gestation), taking into account dosage and timing of use.Patients and MethodsWe included 9058 pregnant women participating in the PRIDE Study (2012–2019) or The Dutch Pregnancy Drug Register (2014–2019), two prospective cohorts in The Netherlands. Data were collected through web-based questionnaires and obstetric records. We estimated risk ratios (RRs) for late-onset preeclampsia for any use and trajectories of calcium-based antacid and PPI use before gestational day 238, and hazard ratios (HRs) for time-varying exposures after gestational day 237.ResultsLate-onset preeclampsia was diagnosed in 2.6% of pregnancies. Any use of calcium-based antacids (RR 1.2 [95% CI 0.9–1.6]) or PPIs (RR 1.4 [95% CI 0.8–2.4]) before gestational day 238 was not associated with late-onset preeclampsia. Use of low-dose calcium-based antacids in gestational weeks 0–16 (<1 g/day; RR 1.8 [95% CI 1.1–2.9]) and any use of PPIs in gestational weeks 17–33 (RR 1.6 [95% CI 1.0–2.8]) seemed to increase risks of late-onset preeclampsia. We did not observe associations between late-onset preeclampsia and use of calcium-based antacids (HR 1.0 [95% CI 0.6–1.5]) and PPIs (HR 1.4 [95% CI 0.7–2.9]) after gestational day 237.ConclusionIn this prospective cohort study, use of calcium-based antacids and PPIs during pregnancy was not found to reduce the risk of late-onset preeclampsia.