Proton Pump Inhibitors Non-users Research Articles

Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation

Cytochrome P450 inhibition by proton pump inhibitors (PPIs) may attenuate the effectiveness of clopidogrel. To examine whether PPI use modifies the association between clopidogrel use and major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) with stent implantation, using time-varying drug exposure ascertainment. We conducted this population-based cohort study in Western Denmark (population 3 million) using medical databases. We identified all 13,001 patients with coronary stent implantation between 2002 and 2005 and ascertained their reported comorbidities. During the recommended 12-month postintervention treatment period, we tracked use of clopidogrel and PPI and the rate of MACE. We used Cox regression to compute hazard ratios (HRs), controlling for potential confounders. During follow-up, one or more prescriptions were redeemed by 91% of patients for clopidogrel and by 21% of patients for PPIs. Of the patients, 15% experienced a MACE. The adjusted HR for MACE comparing clopidogrel use with non-use was 0.57 [95% confidence interval (CI): 0.44-0.74] among PPI users and 0.47 (95% CI: 0.42-0.53) among PPI non-users, yielding an interaction effect (i.e. relative rate increase) of 1.20 (95% CI: 0.91-1.58). PPI users treated from before PCI had a 25% increased rate of MACE compared to PPI non-users, independent of clopidogrel use [adjusted HR = 1.24 (95% CI: 0.97-1.58) for clopidogrel users and 1.26 (95% CI: 0.97-1.63) for clopidogrel non-users]. The use of PPIs as a class did not modify the protective effect of clopidogrel, but its use was associated with major adverse cardiovascular events itself, particularly among patients having used PPIs before percutaneous coronary intervention.

Use of oral proton pump inhibitors is not associated with harm in patients with chronic heart failure in an ambulatory setting

Proton pump inhibitors (PPIs) produce negative inotropic effects on the human myocardium at clinically relevant plasma concentrations. We conducted this study to determine whether PPI use was associated with excess mortality in patients with both ischaemic and non-ischaemic heart failure (HF). The impact of PPIs on all-cause mortality was examined using a population-based cohort of Alberta residents over the age of 65 with a diagnosis of HF, logistic regression analysis, and a nested case-control study were used to examine the association between current medication use and mortality. Compared with non-PPI users (n= 15,676, 71% of the HF cohort), PPI users (n= 6431, 29% of the HF cohort) were more likely to be women and had more co-morbidities. Mortality in the first year after diagnosis of HF was 32% (n= 5659) in PPI non-users and 26% (n= 1153) in PPI users. Logistic regression modelling showed that PPI use was associated with a relative reduction in mortality rates compared with non-use [adjusted odds ratio (aOR) = 0.87, 95% confidence interval (CI) 0.81-0.93]. Nested case-control analysis of the 5815 patients who died matched to 9934 controls, revealed that current PPI use was not associated with excess mortality (aOR 0.88, 95%CI 0.77-1.01), while use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker s (aOR 0.70, 95%CI 0.62-0.79) or beta-blockers (aOR 0.57, 95%CI 0.50-0.66), was associated with a relative reduction in mortality. The use of PPIs in patients with HF is common. Despite in vitro concerns about negative inotropic effects with PPIs, there is no association with increased risk of mortality in chronic HF patients who use PPIs in an ambulatory setting.

Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome

There is conflicting evidence regarding the potential interaction between clopidogrel and proton pump inhibitors (PPIs), with observational studies suggesting an increased risk of adverse cardiovascular (CV) outcomes and clinical trials suggesting there is no such risk. We conducted a retrospective cohort study to assess CV outcomes of 9753 patients taking dual antiplatelet therapy of aspirin plus clopidogrel with or without a PPI after hospitalization for acute coronary syndrome (ACS). Cox proportional hazards models were used to assess our primary endpoint of re-hospitalization for ACS in overall sample and a propensity score matching subsample. Among patients taking clopidogrel plus aspirin, concomitant use of PPI was not associated with the risk of re-hospitalization for ACS (adjusted hazard ratio [HR] 1.12 [95%CI 0.72-1.73]). The findings were consistent in the propensity score matching cohort (adjusted HR 0.82 [95%CI 0.43-1.54]). Compared with PPI nonusers, there is no significant association between each specific PPI users and the risk of re-hospitalization for ACS (adjusted HR; omeprazole 0.96 [95%CI 0.35-2.66], pantoprazole 1.05 [95%CI 0.38-2.92], rabeprazole 0.60 [95%CI 0.17-2.17], esomeprazole 0.31 [95%CI 0.10-0.99], and lansoprazole 0.82 [95%CI 0.32-2.07]). In conclusion, this population-based cohort study found that concomitant use of clopidogrel and PPI in patients who received dual antiplatelet therapy after ACS was not associated with risk of ACS re-hospitalization. Together, our study and findings of recently published clinical trials suggest that there was no apparent CV interaction between clopidogrel and PPI in patients who received dual antiplatelet therapy.

Vertebral fracture efficacy during risedronate therapy in patients using proton pump inhibitors

Recent evidence suggests that proton pump inhibitor (PPI) use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. The results of our post hoc analysis showed that, regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo. Recent evidence suggests that PPI use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. Moreover, data suggest that concomitant use of PPIs may wane the anti-fracture effect of bisphosphonates. We explored the relationship between concomitant use of PPIs and incident vertebral fractures among patients treated with risedronate or placebo. Bone mineral density (BMD) and upper gastrointestinal (UGI) adverse events (AEs) were also assessed. This study is a post hoc analysis of a subset of patients participating in three prospective, randomized, placebo-controlled clinical trials, with durations of up to 3 years, which evaluated the efficacy of risedronate in reducing fracture risk: Vertebral Efficacy with Risedronate Trial-MultiNational (VERT-MN); Vertebral Efficacy with Risedronate Trial-North America (VERT-NA); and the risedronate Hip Intervention Program (HIP). Total enrollment included 2,729 risedronate and 2,725 placebo patients. Concomitant acid-suppressing drugs were used by 8.8% of the total population (n = 482). Regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo (risk reduction: PPI users 57%, p = 0.009; PPI non-users 38%, p < 0.001). BMD increased with risedronate, independent of PPI use. PPI users were at a 2.5-fold greater risk of experiencing at least one UGI AE compared with non-users. Risedronate significantly reduced the risk of new vertebral fractures compared with placebo, regardless of PPI concomitant use.

Proton Pump Inhibitor Use, Hip Fracture, and Change in Bone Mineral Density in Postmenopausal Women

Proton pump inhibitor (PPI) medications have been inconsistently shown to be associated with osteoporotic fractures. We examined the association of PPI use with bone outcomes (fracture, bone mineral density [BMD]). This prospective analysis included 161 806 postmenopausal women 50 to 79 years old, without history of hip fracture, enrolled in the Women's Health Initiative (WHI) Observational Study and Clinical Trials with a mean (SD) follow-up of 7.8 (1.6) years. Analyses were conducted for 130 487 women with complete information. Medication information was taken directly from drug containers during in-person interviews (baseline, year 3). The main outcome measures were self-reported fractures (hip [adjudicated], clinical spine, forearm or wrist, and total fractures) and for a subsample (3 densitometry sites), 3-year change in BMD. During 1 005 126 person-years of follow-up, 1500 hip fractures, 4881 forearm or wrist fractures, 2315 clinical spine fractures, and 21 247 total fractures occurred. The multivariate-adjusted hazard ratios for current PPI use were 1.00 (95% confidence interval [CI], 0.71-1.40) for hip fracture, 1.47 (95% CI, 1.18-1.82) for clinical spine fracture, 1.26 (95% CI, 1.05-1.51) for forearm or wrist fracture, and 1.25 (95% CI, 1.15-1.36) for total fractures. The BMD measurements did not vary between PPI users and nonusers at baseline. Use of PPIs was associated with only a marginal effect on 3-year BMD change at the hip (P = .05) but not at other sites. Use of PPIs was not associated with hip fractures but was modestly associated with clinical spine, forearm or wrist, and total fractures.

Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome

Recent studies have raised concerns about the reduced efficacy of clopidogrel when used concurrently with proton pump inhibitors (PPIs), but those studies may have overestimated the risk. We studied the potential for increased risk of adverse cardiovascular events among users of clopidogrel with versus without concurrent use of PPIs in 3 large cohorts of patients > or =65 years of age, treated between 2001 and 2005. All patients had undergone percutaneous coronary intervention or had been hospitalized for acute coronary syndrome in Pennsylvania, New Jersey, or British Columbia, and subsequently had initiated treatment with clopidogrel. We recorded myocardial infarction hospitalization, death, and revascularization among PPI users and nonusers. We assessed our primary end point of myocardial infarction hospitalization or death using cohort-specific and pooled regression analyses. We entered 18 565 clopidogrel users into our analysis. On a pooled basis, 2.6% of those who also initiated a PPI versus 2.1% of PPI nonusers had a myocardial infarction hospitalization; 1.5% versus 0.9% died; and 3.4% versus 3.1% underwent revascularization. The propensity score-adjusted rate ratio for the primary end point of myocardial infarction or death was 1.22 (95% confidence interval, 0.99 to 1.51); for death, 1.20 (95% confidence interval, 0.84 to 1.70); and for revascularization, 0.97 (95% confidence interval, 0.79 to 1.21). Matched analyses generally yielded similar results. Although point estimates indicated a slightly increased risk of myocardial infarction hospitalization or death in older patients initiating both clopidogrel and a PPI, we did not observe conclusive evidence of a clopidogrel-PPI interaction of major clinical relevance. Our data suggest that if this effect exists, it is unlikely to exceed a 20% risk increase.

Uses of proton pump inhibitors and serum potassium levels

Proton pump inhibitor (PPI) may suppress adrenal cortical steroid synthesis and release, thereby leading to electrolyte disturbances. Both hyponatremia and hyperkalemia in the setting of PPI therapy have been documented in case reports. The objective of this study was to examine the association between serum potassium (K(+)) level and PPI use. A retrospective data analysis of hospitalized adults aged > or = 65 years during 2006, including PPI users (N = 257) and PPI non-users (N = 388), was conducted. Multiple linear and logistic regression analyses were used to assess the association between PPI use and serum K(+) level. PPI users [mean age (SD):79.7 (8.0) years; 70% female] had significantly higher serum K(+) levels than PPI non-users [80.2 (8.8) years; 64% female] on admission [4.13 (0.62) vs. 3.97 (0.57) mmol/L; p < 0.001]. The linear regression model revealed that > or = 2 defined daily dose (DDD) units of PPI use were a significantly positive contributor to serum K(+) levels (p = 0.021) after adjusting for age, serum creatinine levels, sex, history of diabetes, and uses of the following drugs: angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker, beta blocker, diuretics, spironolactone, K(+) supplement, non-steroidal anti-inflammatory drugs, atypical antipsychotics, and narcotics. However, multiple logistic regression model revealed that high dose PPI therapy was not associated with an increased risk for hyperkalemia occurrence (p = 0.762). Higher serum K(+) levels were observed among PPI users when compared to PPI non-users. High daily dose PPI therapy may be an independent positive predictor of serum potassium levels.

Selective Serotonin Reuptake Inhibitors Are Associated With a Modest Increase in the Risk of Upper Gastrointestinal Bleeding

The use of the common antidepressant class of serotonin-specific reuptake inhibitors (SSRIs) is associated with an increased risk of upper gastrointestinal bleeding (UGIB). Proton pump inhibitors (PPIs) have been demonstrated to reduce the risk of gastrointestinal bleeding secondary to other risk factors, most notably non-steroidal anti-inflammatory drug (NSAID) use. The role for PPIs in chronic SSRI users without other risk factors remains uncharacterized. We used the Manitoba Population Health Research Data Repository to perform a population-based matched case-control analysis. All patients admitted to the hospital with a primary diagnosis of UGIB were matched to non-bleeding controls. We used conditional regression analysis to determine the risk of UGIB associated with SSRI use, and the risk reduction associated with concomitant PPI use, both for users and non-users of NSAIDs. SSRI use was associated with a modest increase in the risk of UGIB (odds ratio (OR), 1.43; 95% confidence interval (CI), 1.09-1.89). The addition of an SSRI to NSAID therapy did not significantly increase the risk of UGIB (OR, 1.20; 95% CI, 0.78-1.92) over use of an NSAID alone. PPI co-therapy significantly reduced the risk of SSRI-related UGIB (OR, 0.39; 95% CI, 0.16-0.94). SSRI use is associated with a modestly increased risk of UGIB, which may be significantly reduced with PPI co-therapy. SSRI use is not a major risk factor for NSAID-related UGIB.

Proton pump inhibitor omeprazole use is associated with low bone mineral density in maintenance haemodialysis patients

Limited studies have shown that proton pump inhibitor (PPI) therapy may decrease bone density or insoluble calcium reabsorption through induction of hypochlorhydria. However, PPI therapy may also reduce bone resorption via inhibition of osteoclastic vacuolar proton pumps. The aim of this study was to determine whether the opposing effects of PPI therapy may cause clinically important alterations in bone mineral densitometry (BMD) parameters in maintenance haemodialysis patients. Sixty-eight maintenance haemodialysis patients were enrolled in this study. Patients were classified into two groups involving users of PPI therapy (omeprazole 20 mg/day, group 1, n = 36 patients) and non-users of acid suppression drugs (group 2, n = 32 patients). Patients had radius, hip and spine BMD assessed by dual-energy X-ray absorptiometry. The mean duration of PPI therapy with omeprazole was 27 +/- 5 months. The users of PPI therapy had lower values of bone mineral density and T-scores at the anatomical regions than non-users of acid suppression drugs. Serum calcium and phosphate levels, calcium-phosphate product and serum intact parathormone levels and the ratio of users of vitamin D therapy were similar among groups. A mutivariable adjusted odds ratio for lower bone density associated with more than 18 months of omeprazole, when all the potential confounders were considered, was 1.31 in the proximal radius, 0.982 in the femur neck, 0.939 in the trochanter and 1.192 in the lumbal spine. The present data suggest that PPI therapy should be cautiously prescribed in maintenance haemodialysis patients, especially with lower BMD values.

Clinical use of proton-pump inhibitors but not H2-blockers or antacid/alginates raises the serum levels of amidated gastrin-17, pepsinogen I and pepsinogen II in a random adult population

Objective. Proton-pump inhibitors (PPIs), H2 receptor antagonists (H2RAs) and antacids/alginates reduce intragastric acidity and may thus influence normal gastric physiology. The purpose of this study was to examine the effect of these compounds on serum levels of amidated gastrin-17 (G-17) and pepsinogens (PGI & PGII) in a large, random, adult Swedish population sample with uninfected stomach mucosa. Material and methods. The initial sample subjects (n=1000, mean age 50 years, range 20–80 years) completed a questionnaire on the use of acid inhibitory drugs 1 week and/or 3 months before study entry. All subjects (n=590) with normal gastric mucosa as delineated by serum biomarkers were included. Among them, serum levels of PGI, PGII and G-17 were compared between those who used acid inhibitory drugs and those who did not. Results. The serum levels of G-17 or pepsinogens in the subjects who reported use of H2RAs (n=18) or antacid/alginates (n=66) during the previous 3 months did not differ from those in non-users (n=471). However, the median levels of G-17 and pepsinogens were significantly (p<0.001) higher among the PPI users (n=35) than among non-users: the levels were approximately doubled. The ratio of PGI/PGII was, however, similar between PPI users and non-users, or those using antacids/alginates or H2RAs. Among subjects using PPIs, the serum levels of pepsinogens correlated positively (p<0.01) with the serum levels of G-17. Conclusions. PPIs but not antacids/alginates or H2RAs markedly increase the fasting levels of serum amidated G-17 and pepsinogens among ordinary patients in everyday clinical practice.

Hospitalizations for Upper and Lower GI Events Associated With Traditional NSAIDs and Acetaminophen Among the Elderly in Quebec, Canada

The risk of upper/lower gastrointestinal (GI) adverse events associated with the concomitant use of traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) with acetaminophen has not been assessed. Among users of these drugs, the concomitant use of proton pump inhibitors (PPIs) with tNSAIDs may reduce the risk of upper GI adverse events, but its effect on lower GI events is not clear. To compare the rates of GI hospitalization (ulceration, perforation, or bleeding in the upper or lower GI tract) among elderly patients taking tNSAIDs or the combination of a tNSAID and acetaminophen with and without a PPI versus those taking acetaminophen alone. We conducted a population-based retrospective cohort study using data obtained from the government of Quebec health insurance agency databases and the hospital discharge summary database. Patients of 65 yr of age or older who filled a prescription for acetaminophen or a tNSAID between January 1998 and December 2004 were entered in the cohort at the date of the first filled prescription from either of these medications (index date). Follow-up ended at the first date of a GI hospitalization, death, or the end of the study period. The cohort included 644,183 elderly patients. These patients received 1,778,541 prescriptions for tNSAIDs (315,222, 17.7% with a PPI), 158,711 for the combination of a tNSAID and acetaminophen (40,797, 25.7% with a PPI), 1,597,725 for acetaminophen (> 3 g/day) (504,939, 31.6% with a PPI), and 3,641,140 for acetaminophen (< or = 3 g/day) (1,031,939, 28.3% with a PPI). Using Cox regression models that adjusted for time-dependent variables (aspirin, anticoagulants, and clopidogrel) and other fixed patient baseline characteristics, we found similar risks of GI hospitalizations among time periods when patients were exposed to either a tNSAID with a PPI, acetaminophen (> 3 g/day) with a PPI, or acetaminophen (< or = 3 g/day) with a PPI. The risk of GI hospitalization among users of PPIs during exposure to the combination of acetaminophen with a tNSAID was twice as high as that of the reference category, acetaminophen (< or = 3 g/day) without a PPI (hazard ratio [HR] 2.15, 95% confidence interval [CI][1.35-3.40]). Among nonusers of PPIs, the risk of GI hospitalization was 1.20 (1.03-1.40) during exposure to acetaminophen (> 3 g/day), 1.63 (1.44-1.85) during exposure to tNSAIDs, and 2.55 (1.98-3.28) during exposure to the combination of a tNSAID and acetaminophen compared with the reference category. Among elderly patients requiring analgesic/anti-inflammatory treatment, use of the combination of a tNSAID and acetaminophen may increase the risk of GI bleeding compared with either agent alone.

Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture

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.