Proton Pump Inhibitors Co-therapy Research Articles

Reduction of Upper Gastrointestinal Bleeding Risk With Proton Pump Inhibitor Therapy in Asian Patients With Atrial Fibrillation Receiving Direct Oral Anticoagulant: A Nationwide Population-based Cohort Study

Background & AimsIn patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), upper gastrointestinal bleeding (UGIB) is a serious complication. There are limited data on the benefit of preventive proton pump inhibitor (PPI) use to reduce the risk of UGIB in DOAC users. MethodsWe included patients with AF receiving DOAC from 2015 to 2020 based on the Korean Health Insurance Review and Assessment database. The propensity score (PS) weighting method was used to compare patients with PPI use and those without PPI use. The primary outcome was hospitalization for UGIB. Weighted hazard ratios (HR) and corresponding 95% confidence intervals (CI) were evaluated using the Cox proportional hazards regression model. ResultsA total of 165,624 patients were included (mean age: 72±11 years; mean CHA2DS2-VASc score: 4.3±1.8; mean HAS-BLED score: 3.3±1.2). Among them, 99,868 and 65,756 were in the non-PPI group and PPI group, respectively. During a median follow-up of 1.5 years, the PPI group was associated with lower risks of hospitalization for UGIB and UGIB requiring RBC transfusion than non-PPI group [weighted HR (95% CI): 0.825 (0.761-0.894) and 0.798 (0.717-0.887), respectively, both p<0.001]. The benefits of PPI on the risk of hospitalization for UGIB were greater in those with older age (≥75 years), higher HAS-BLED score (≥3), prior UGIB history, and concomitant use of antiplatelet agent (all p-for-interaction<0.1). Low-dose PPI was consistently associated with a lower risk of significant UGIB [adjusted HR: 0.564 (0.504-0.631), p<0.001]. ConclusionsIn this large Asian cohort of patients with AF on DOAC, PPI co-therapy is beneficial for reducing the risk of hospitalization for UGIB, particularly in high-risk patients.

Nonvitamin K oral anticoagulants with proton pump inhibitor cotherapy ameliorated the risk of upper gastrointestinal bleeding

Proton pump inhibitors (PPIs) can reduce the risk of upper gastrointestinal bleeding (UGIB) in patients who are taking oral anticoagulants. This study aimed to identify the association between NOACs with PPI cotherapy and UGIB. This retrospective cohort analysis included patients over the age of 18 years who were using NOACs between 2013 and 2020. NOAC categories, concomitant medications, endoscopic findings, the HAS-BLED score and the Charlson Comorbidity Index score were recorded. Using Poisson regression models, the relationship between UGIB events and risk factors was analyzed. Throughout a mean follow-up of 29.5 months, 14 (5.1%) individuals experienced UGIB. The incidence of UGIB was greater in patients receiving NOACs without PPIs (2.7 [1.26–5.60] per 1000) than in those receiving NOACs with PPIs (1.3 [0.61–2.67] per 1000). Patients receiving NOACs with PPIs had a 79.2% lower incidence of UGIB than patients receiving NOAC monotherapy (RR 0.208, 95% CI 0.061–0.706; p = 0.012). Female sex and the HAS-BLED score were associated with UGIB (RR 5.043; 95% CI 1.096–23.20; p = 0.038; RR 2.024; 95% CI 1.095–3.743; p = 0.024, respectively). Patients receiving NOAC and PPI cotherapy had a lower incidence of UGIB than those receiving NOACs alone, and female sex was a risk factor for UGIB in NOAC-treated patients.

항응고제/항혈소판제와 프로톤펌프억제제 병용의 경제성 평가에 대한 체계적 문헌고찰

Anticoagulants/antiplatelets are effective in preventing cardiovascular diseases (CVDs). However, as an adverse effect, the risk of upper gastrointestinal bleeding (UGIB) leads to additional costs due to increased treatment and decreased quality of life. Accordingly, the administration of proton pump inhibitors (PPI) is recommended to prevent UGIB. We conducted a systematic review of economic evaluations of PPI co-therapy for patients taking long-term anticoagulants/ antiplatelets to prevent CVDs to examine the cost effectiveness of PPI co-therapy. We searched literature from PubMed and EMBASE with keywords including types of economic evaluations and active ingredients of anticoagulants and antiplatelets on 13/07/2022. Two independent reviewers conducted a systematic review. As a result, six economic evaluation studies were identified. All studies compared PPI co-therapy with low-dose aspirin to prevent CVDs. We confirmed the cost-effectiveness of PPI co-therapy with the respective incremental cost-effectiveness ratio (ICER) in each base case. In the sensitivity analyses, the PPI cost and adherence influenced the ICER the most. The quality of reporting, which was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist, was 87-96%. In the present study, we found that PPI co-therapy was cost-effective and tended to improve the patient’s life years and quality-adjusted life years. These results can be used as evidence for further economic evaluation studies to verify the costeffectiveness of anticoagulants/antiplatelets and PPI co-therapy.

Protective effect of proton pump inhibitor against gastrointestinal bleeding in patients receiving oral anticoagulants: a systematic review and meta-analysis

Abstract Background The concurrent use of proton pump inhibitor (PPI) in oral anticoagulant (OAC) treated patients may be associated with a lower risk of gastrointestinal bleeding (GIB), but evidence is still conflicting according to individual OACs. Purpose We conducted a meta-analysis to estimate the risk of GIB in patients with OAC and PPI co-therapy. Methods A systematic search of PubMed, EMBASE, and Cochrane was performed for studies reporting GIB risk in OAC and PPI co-therapy. Primary outcomes were total GIB and major GIB events. We calculated pooled estimates of GIB risk by a random-effect meta-analysis and reported as odds ratios (OR) and 95% CI. Stratified analyses according to the origin of GIB, ethnic groups, individual OACs, and the presence of underlying GIB risk factors were performed. Results A total of 10 studies (1 randomized controlled study and 9 observational studies) and 1,970,931 patients who received OAC were included. OAC and PPI co-therapy were associated with a lower risk of total GIB, and major GIB; OR (95% CI) was 0.67 (0.62–0.74) for total GIB and 0.68 (0.63–0.75) for major GIB, respectively. Among total GIB, only the risk of upper GIB was lower with OAC and PPI co-therapy (OR 0.67, 95% CI 0.64–0.70). No difference in the lower risk of primary GIB outcomes of PPI co-therapy was observed between Asians and non-Asians (p-for-difference, total GIB=0.695, major GIB=0.748, respectively) and among individual OACs except for edoxaban. The protective effect of PPI on total GIB was more significant in high-risk patients, defined as those with concurrent medication of antiplatelets or non-steroidal anti-inflammatory drugs (OR 0.62, 95% CI 0.52–0.73) and presence of high bleeding risk factors such as previous GIB history, HAS-BLED score ≥3, or underlying gastrointestinal diseases. (OR 0.65, 95% CI 0.61–0.70). Conclusion In patients who receive OAC, the use of PPI co-therapy was associated with a lower risk of total GIB and major GIB irrespective of ethnic group and OAC type except for edoxaban. PPI co-therapy can be considered particularly in patients on concomitant NSAID and antiplatelet use or patients with high GIB risk factors. Funding Acknowledgement Type of funding sources: None.

Antithrombotic and proton pump inhibitor co-therapy in patients with atrial fibrillation and stable coronary disease: a post hoc analysis of the AFIRE trial

Abstract Background Among patients with atrial fibrillation (AF) and stable coronary artery disease, bleeding events increased the cardiovascular events and mortality. We aimed to evaluate the effect of proton pump inhibitor (PPI) on the risk of bleeding events in these patients. Methods In the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease), patients with non-valvular AF and coronary artery disease were recruited and randomized to receive the rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. The present sub-analysis evaluated the risks of any bleeding events. Results Among 2,225 patients, 1,357 (61.3%) were receiving a PPI at baseline. During follow-up, 384 bleeding events were occurred, and incidence of bleeding events were significantly lower in patients with PPI compared with those without PPI (p=0.03). Among combination therapy with rivaroxaban plus antiplatelet, effect of PPI for cumulative incidence of bleeding events were significantly different between groups (p=0.01), however, these differences were not shown among rivaroxaban monotherapy patients (p=0.50, Figure 1). Multivariate Cox hazard analysis showed that PPI use had significantly lower risk of bleeding events (hazard risk 0.79, 95% confidence interval 0.64–0.97, p=0.03). In addition to PPI, male, heart failure and combination therapy with rivaroxaban plus antiplatelet drug were independent predictors of bleeding events. Conclusions PPI use was significantly associated with lower risk of bleeding events among patients with AF and stable coronary artery disease. Especially, for patients at high bleeding risk, such as receiving both anticoagulant and antiplatelet drugs, PPI is useful to reduce bleeding events. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The Japan Cardiovascular Foundation through a contract with Bayer Yakuhin.

Protective effect of proton-pump inhibitor against gastrointestinal bleeding in patients receiving oral anticoagulants: A systematic review and meta-analysis.

The evidence of a protective effect of proton-pump inhibitor (PPI) in oral anticoagulant (OAC)-treated patients against gastrointestinal bleeding (GIB) is still lacking. We conducted a meta-analysis to estimate the risk of GIB in patients with OAC and PPI cotherapy. A systematic search of PubMed, EMBASE, Cochrane and Scopus databases was performed for studies reporting GIB risk in OAC and PPI cotherapy. Primary outcomes were total GIB and major GIB events. Pooled estimates of GIB risk were calculated by a random-effect meta-analysis and reported as odds ratios and 95% confidence interval. A total of 10 studies and 1 970 931 patients were included. OAC and PPI cotherapy were associated with a lower odds of total and major GIB; odds ratio (95% confidence interval) was 0.67 (0.62-0.74) for total and 0.68 (0.63-0.75) for major GIB, respectively. No differences in the GIB of PPI cotherapy were observed between Asians and non-Asians (P-for-difference, total GIB = .70, major GIB = .75, respectively). For all kinds of OAC except for edoxaban, PPI cotreatment was related to lower odds of GIB by 24-44%. The protective effect of PPI on total GIB was more significant in concurrent antiplatelets or nonsteroidal anti-inflammatory drug users and those with high bleeding risks: patients with previous GIB history, HAS-BLED ≥3 or underlying gastrointestinal diseases. In patients who receive OAC, PPI cotherapy is associated with a lower total and major GIB irrespective of ethnic group and OAC type, except for edoxaban. PPI cotherapy can be considered particularly in patients with high risk of GIB.

Rebamipide as a Potential Alternative Gastroprotective Agent to Proton Pump Inhibitor in Elderly Chronic Nonsteroidal Anti-Inflammatory Drug Users without Risk Factors.

PurposeThe use of proton pump inhibitors (PPI) is recommended to prevent nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) complications. The incidence of several adverse effects during the long-term use of PPI prompts the search for other alternatives. Limited studies have evaluated the efficacy of rebamipide, a widely used mucoprotective drug, as a gastroprotective agent (GPA) compared to PPI, focusing on the elderly chronic NSAID users, nor with GI risk stratification. We aimed to determine the population who would get benefit from the use of rebamipide as an alternative to PPI to prevent traditional nonsteroidal anti-inflammatory drug (tNSAID)-associated GI complications.Patients and MethodsWe identified 41,889 and 35,708 elderly chronic tNSAID users with PPI and rebamipide co-therapy, respectively, from the national claims database. Outcome was defined as hospitalization or emergency department visits due to serious GI complications. Propensity score-matched cohorts were constructed and compared within risk strata.ResultsIn high and moderate risk groups with two risk factors, rebamipide showed a higher risk of serious GI complication compared to PPI (aHR 2.63, 95% CI 1.24–5.59 and aHR 2.42, 95% CI 1.21–4.83, respectively). However, in elderly patients without risk factors, there was no significant difference in the risk of serious GI complications between PPI and rebamipide (aHR 0.69, 95% CI 0.27–1.76).ConclusionThis study suggested that rebamipide can be considered as an alternative to PPI in elderly chronic tNSAID users without risk factors. However, elderly patients with other risk factors should use PPI rather than rebamipide. Therefore, the presence of GI risk factors needs to be evaluated in elderly chronic tNSAID users to prescribe the most suitable GPA in clinical practice.

Risk of upper gastrointestinal bleeding in patients on oral anticoagulant and proton pump inhibitor co-therapy.

BackgroundProton pump inhibitors (PPIs) are known to reduce the risk of upper gastrointestinal bleeding in patients on oral anticoagulants, and patients are increasingly on oral anticoagulants and PPI co-therapy. However, evidence is lacking on the safety and effectiveness of oral anticoagulants when co-administered with PPIs.MethodsAmong patients initiating oral anticoagulants (warfarin and non-vitamin K antagonist oral anticoagulants [NOACs], i.e. rivaroxaban, dabigatran, apixaban, and edoxaban) during 2013–2017, those concomitantly prescribed PPIs were identified (n = 19,851). The primary endpoint was hospitalization for major upper gastrointestinal bleeding, and secondary endpoints were death and ischemic stroke.ResultsDuring a mean 1.4 years of follow-up, the primary endpoint occurred in 512 (2.58%) patients. Overall, NOACs were associated with lower upper gastrointestinal bleeding risk after adjustment for age, sex, comorbidities and concomitant medications (adjusted hazard ratio 0.78, 95% confidence interval 0.65–0.94), compared to warfarin. There was no significant difference in upper gastrointestinal bleeding risk among the individual NOACs. This trend of reduced risk for upper gastrointestinal bleeding in NOACs compared to warfarin was consistent for both regular and reduced doses, throughout bleeding risk groups, and other subgroup analyses. NOACs were also associated with lower risk of death compared to warfarin. The risk for ischemic stroke was not significantly different among the oral anticoagulants in patients with atrial fibrillation.ConclusionIn patients on oral anticoagulant and PPI co-therapy, NOACs were associated with lower risk of upper gastrointestinal bleeding and mortality compared to warfarin, while there was no difference among the oral anticoagulants for stroke prevention. In patients on PPI therapy, NOACs may preferred over warfarin for decreasing risk of upper gastrointestinal bleeding and mortality.

Proton Pump Inhibitor Co-Therapy in Patients with Atrial Fibrillation Treated with Oral Anticoagulants and a Prior History of Upper Gastrointestinal Tract Bleeding.

The risk of gastrointestinal bleeding (GIB) can be mitigated by proton pump inhibitor (PPI) co-therapy in patients with atrial fibrillation (AF) treated with anticoagulants. We aimed to evaluate the effect of PPIs on the risk of GIB in Asian patients with AF, treated with oral anticoagulants (OACs), and with a prior history of upper GIB. Using a nationwide claims database, OAC-naïve patients with AF and a history of upper GIB before initiating OAC treatment between January 2010 and April 2018 were included. Patients were categorized into 10 groups according to the index OAC (warfarin, rivaroxaban, dabigatran, apixaban, and edoxaban) and whether or not they received PPI co-therapy, and were followed up for incidence of major GIB. Among a total of 42,048 patients, 40% were prescribed PPIs as co-therapy with OACs. Over a median 0.6years (interquartile ranges 0.2-1.7years) of follow-up, rivaroxaban use without PPIs showed the highest crude incidence of major GIB (2.62 per 100 person-years), followed by the use of warfarin without a PPI (2.20 per 100 person-years). Compared to the patients without PPI use, PPI co-therapy was associated with a significantly lower risk of major GIB, by 40% and 36%, in the rivaroxaban and warfarin groups, respectively. In dabigatran, apixaban, and edoxaban users, PPI co-therapy did not show a significant reduction in the risk of major GIB. Among patients with AF receiving anticoagulant treatment and with a prior history of upper GIB, PPI co-therapy was associated with a significant reduction in the risk of major GIB in patients treated with rivaroxaban and warfarin.

Proton Pump Inhibitor (PPI) co-therapy and gastrointestinal bleeding with antithrombotic drugs: a step forward but not enough

Nonvariceal gastrointestinal (GI) bleeding is common and one of the most frequent medical events which determine hospitalizations worldwide. Death rates (5-12%) in patients with GI bleeding are resistant to decrease despite the new advances in diagnosis and therapy, which is probably linked to a higher proportion of elderly patients with significant comorbidities who suffer from this complication [1]. However, the number of hospitalizations due to GI bleeding is decreasing over time in many countries with a sharp reduction of upper GI bleeding events, which is not compensated by the observed increase in the number of hospitalizations due to lower GI bleeding events [2].

Proton Pump Inhibitor Utilization in Veteran Patients on Combined Antithrombotic Therapy and Validation of Simplified Bleeding Risk Score.

Concomitant use of anticoagulant and antiplatelet agents can increase the risk of gastrointestinal bleed (GIB). Use of proton pump inhibitors (PPIs) has been proposed to decrease the risk of GIB in patients on combined antithrombotic therapy (CAT). To describe the current utilization of PPIs in veteran patients on CAT and associated clinical predictors of GIB. This retrospective study included patients on CAT receiving PPIs, with at least one of the CAT agents initiated between January 1, 2018 and October 30, 2018. Data were extracted from the computerized patient record system. Primary end point included estimating proportion of patients on CAT receiving PPI co-therapy, describing patient characteristics, and identifying clinical predictors of GIB. Secondary outcomes included reporting GIB events and all-cause mortality. Additional outcome was to validate the five-factor risk score (FFRS) for GIB in patients on CAT and compare its overall predictive performance to HAS-BLED score. This study reports an overall rate of PPI co-therapy in patients on CAT of 40.9% (484/1181), with only 22.3% of patients on CAT receiving PPI for GIB prophylaxis. There was no difference in the mean follow up duration of PPI users and PPI co-therapy (264.01 vs 271.92days; p=0.3761). Current alcohol use (p=0.005), current smokers (p=0.022), chronic kidney disease (p=0.004), peptic ulcer disease (p<0.001), and non-steroidal anti-inflammatory drug use (p=0.048) were significant predictors of GIB in multivariate analyses of our study cohort. We further provide exploratory validation that use of a simplified FFRS to predict GIB showed a trend towards better overall predictive performance as compared to HAS-BLED score (C-statistic: 0.738; 95% CI 0.684-0.787 for FFRS vs C-statistic: 0.596; 95% CI 0.538-0.653 for HAS-BLED; p=0.0094). This study reports lower rate of PPI co-therapy in veteran patients on CAT per currently available guidance. Further we explore utilization of simplified FFRS model to predict GIB in patients on CAT with long-term PPI co-therapy.

PPIs and Beyond: A Framework for Managing Anticoagulation-Related Gastrointestinal Bleeding in the Era of COVID-19.

Coronavirus disease of 2019 (COVID-19) can be associated with high morbidity and mortality; patients with severe clinical manifestations may develop significant coagulopathy as well as unexpected thromboembolic complications. In response, centers are increasingly treating selected patients with intermediate-dose prophylactic or even therapeutic dose anticoagulation in order to prevent potentially catastrophic thrombotic complications. With this changing practice, the authors suspect that inpatient gastrointestinal consult teams across the country will be frequently managing COVID-19 patients with gastrointestinal bleeding (GIB). In order to reduce potentially avoidable hospital readmissions for GIB while improving patient outcomes, it is imperative to appropriately risk-stratify patients prior to initiation of anticoagulation. In this review, we discuss how to appropriately identify high-risk patients for GIB and how to mitigate GIB risk with proton-pump inhibitor co-therapy, medication reconciliation, and Helicobacter pylori testing and treating in this complex and morbid population.

628 Proton Pump Inhibitors or Histamine-2 Receptor Antagonist Co-Therapy Decrease the Risk of Upper Gastrointestinal Bleeding in Patients on Direct Oral Anticoagulation: A Systematic Review and Meta-Analysis

INTRODUCTION: Direct oral anticoagulation (DOAC) has gained more universal acceptance for use in patients with venous thrombosis or atrial fibrillation because of its safety profile and the elimination of drug monitoring. However, upper gastrointestinal bleeding (UGIB) is a major complication, especially in those with higher bleeding risk. Recent studies have reported a decreased risk of UGIB in patients using DOAC with proton pump inhibitors (PPI) or histamine-2 receptor (H2RA) but the results are controversial. We aimed to assess the effect of PPI or H2RA co-therapy with DOAC on the risk of UGIB by a systematic review and meta-analysis. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2019. Included studies were cohort (prospective or retrospective) studies that investigated the incidence of UGIB comparing between DOAC with and without PPI or H2RA co-therapy. Upper gastrointestinal bleeding is defined as melena or hematemesis that required hospitalization. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate pooled risk ratio (RR) and 95% confidence intervals. RESULTS: Six studies from 2015 to 2018 were included in this meta-analysis and reported a total of 469,593 patients using DOAC. Mean age was more than 70 years. Proton pump inhibitors co-therapy and histamine-2 receptor antagonist co-therapy significantly decreased the incidence of UGIB in DOAC users (pooled RR 0.58 (0.45-0.74), P &lt; 0.001, I2 = 0.0% and 0.63 (0.42-0.96), P = 0.033, I2 = 0.0% respectively) (Figure1 and 2). Three studies reported PPI plus H2RA co-therapy with DOAC decreased the incidence of UGIB but it is not statistically significance (pooled RR 0.71 (0.18-2.74), P = 0.616, I2 = 88.5%) (Figure 3). CONCLUSION: Our study demonstrated statistically significant benefit of the combination either PPI or H2RA co-therapy with DOAC to lower the incidence of UGIB. However, the combination of PPI and H2RA did not decrease the risk of bleeding. Randomized controlled trials studies are needed to further evaluate this association.

Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding

Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment. To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk. Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015. Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy. Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10 000 person-years of anticoagulant treatment, incidence rate ratios (IRRs). There were 1 643 123 patients with 1 713 183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651 427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870 330 person-years [74.9%]). During 754 389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n = 7119) was 115 per 10 000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n = 1278) was 144 per 10 000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n = 279; 73 per 10 000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n = 629; 120 per 10 000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n = 4933; 113 per 10 000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, -47.5 [95% CI,-60.6 to -34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, -40.5 [95% CI, -50.0 to -31.0]). When anticoagulant treatment with PPI cotherapy (264 447 person-years; 76 per 10 000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n = 2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, -24 [95% CI, -38 to -11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, -61.1 [95% CI, -74.8 to -47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, -35.5 [95% CI, -48.6 to -22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, -39.3 [95% CI, -44.5 to -34.2]). Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding

Proton pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow-up. The study end points were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94-1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84-1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39-0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations. In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper gastrointestinal bleeding; the greatest reduction occurred in patients also taking antiplatelet drugs or NSAIDs.

The cost-effectiveness of celecoxib versus non-steroidal anti-inflammatory drugs plus proton-pump inhibitors in the treatment of osteoarthritis in Saudi Arabia.

BackgroundCyclooxygenase (COX)-2 inhibitors including celecoxib are as effective as non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) in the treatment of osteoarthritis (OA) and have less gastrointestinal toxicity. Although they are associated with higher treatment costs, COX-2 inhibitors may simultaneously reduce costs associated with adverse events, hence, their overall economic benefit should be assessed.ObjectiveTo evaluate the incremental cost effectiveness ratio (ICER) of celecoxib versus ns-NSAIDs, with/without proton-pump inhibitor (PPI) co-therapy, for managing OA in Saudi Arabian subjects aged ≥65 years.MethodsThe National Institute for Health and Care Excellence health economic model from the UK, updated with relative risks of adverse events using CONDOR trial data, was adapted. Patients received celecoxib or ns-NSAIDs, with/without omeprazole. The effectiveness measure was quality-adjusted life years (QALYs) gained per patient. The analysis was conducted from the patient’s perspective. Frequencies of resource use for adverse events were based on data collected in July 2012 from seven private hospitals in Jeddah, Saudi Arabia. Probabilistic sensitivity analysis was performed to construct cost-effectiveness acceptability curves (CEACs).ResultsOver a 6-month treatment duration, QALYs gained per patient were higher with celecoxib (0.37) and celecoxib plus PPI (0.40) versus comparators. Ibuprofen plus PPI showed the lowest expected cost per patient (US$ 1,314.50 versus US$ 1,422.80 with celecoxib plus PPI and US$ 1,543.50 with celecoxib). Celecoxib plus PPI was the most cost-effective option with an ICER of US$ 1,805.00, followed by celecoxib (ICER, US$ 7,633.33) versus ibuprofen plus PPI. Over 2- and 5-year treatment durations, celecoxib plus PPI, and celecoxib, showed higher QALYs gained/patient and lower ICERs versus comparators. These ICERs are <1 gross domestic product/capita in Saudi Arabia in 2013 (US$ 25,961).CEACs over 6 months’ treatment showed a significantly higher likelihood that celecoxib plus PPI and celecoxib alone would be more cost effective versus comparators once the willingness to pay is over US$ 2,000.00.ConclusionAfter considering new adverse event risks, celecoxib with/without PPI co-therapy was deemed very cost effective for medium- and long-term use in Saudi Arabian OA patients aged ≥65 years.

Cost-Effectiveness of Proton Pump Inhibitor Co-Therapy in Patients Taking Aspirin for Secondary Prevention of Ischemic Stroke

Low-dose aspirin (ASA) is effective for secondary prevention of ischemic stroke but can increase the risks of hemorrhagic stroke, upper gastrointestinal bleeding (UGIB), and dyspepsia. Prophylactic administration of proton pump inhibitors (PPIs) reduces the risks of these digestive symptoms. We investigated the cost effectiveness of adding a PPI to ASA therapy for ischemic stroke patients in Japan. A Markov state-transition model was developed to compare the cost effectiveness of ASA monotherapy with ASA plus PPI co-therapy in patients with histories of upper gastrointestinal ulcers and ischemic stroke. The model takes into account ASA adherence rate and adverse effects due to ASA, including hemorrhagic stroke and UGIB. The analysis was performed from the perspective of healthcare payers in 2013. In the base case, total life-years by PPI co-therapy and monotherapy were 16.005 and 15.932, respectively. The difference in duration of no therapy (no ASA or PPI) between the therapies was 558.5 days, which would prevent 30.3 recurrences of ischemic stroke per 1000 person-years. The incremental cost-effectiveness ratio of PPI co-therapy relative to monotherapy was ¥1,191,665 (US$11,458) per life-year gained. In a one-way sensitivity analysis, PPI co-therapy was consistently cost effective at a willingness to pay of ¥5,000,000 (US$48,077) per life-year gained. In a probabilistic sensitivity analysis, the probability that PPI co-therapy was cost effective was 89.74% at the willingness to pay. Co-therapy with ASA plus PPI appears to be cost-effective compared with ASA monotherapy. The addition of PPI also appeared to prolong the duration of ASA therapy, thereby reducing the risk of ischemic stroke.

Prevention and Treatment of NSAID Gastropathy.

Nonsteroidal anti-inflammatory drug (NSAID) treatment will be necessary as part of our therapeutic armamentarium for many years to come. Therefore, safe prescription is mandatory in order to prevent adverse events. In the last two decades, new strategies and new drugs have been developed to reduce NSAID-associated upper gastrointestinal (GI) adverse events. Although the implementation of guidelines into clinical practice takes time, several studies have shown a recent and profound decrease in hospitalizations due to upper GI complications, which has been linked to widespread use of proton pump inhibitors (PPIs), better NSAID prescription, and decreased prevalence of Helicobacter pylori infection. This is encouraging.Safe NSAID prescription should be straightforward since the most relevant aspects are clinical in nature. Before issuing any prescription, three key questions should be considered:1) Is NSAID treatment necessary for this patient?2) What cardiovascular (CV) and GI risk factors does this patient have?3) What is the most suitable NSAID for this patient?GI and CV risk are easy to estimate, and we know that these risks are not the same for all NSAIDs. Selective cyclooxygenase (COX)-2 inhibitors, like celecoxib at usual doses, carry the lowest GI risk and are the best option in patients with moderate/high GI risk without high CV risk. Gastroprotective therapy (PPI as the drug of choice) should be considered if a non-selective NSAID is prescribed. For those at the highest risk, a combination of PPI plus a coxib is the best option. Also, eradication of H. pylori infection in patients with previous peptic ulcer or in NSAID-naïve users must be considered. Naproxen is the best option in patients with high CV risk and low/moderate GI risk.Patients taking aspirin represent a real challenge for treatment, since interaction with frequently prescribed NSAIDs (e.g. ibuprofen/naproxen) may alter its antiplatelet effect, representing a potential clinical problem. Switching treatment (e.g. taking aspirin before NSAID dosing) may not be an alternative since interaction may persist, especially when taking enteric-coated aspirin. Changing NSAID treatment to diclofenac/celecoxib/etoricoxib may also not be an option in patients with high or previous CV event history. Under these circumstances, careful prescription should be considered at the individual patient level.When dyspepsia develops in an NSAID user, PPI co-therapy plus reduction of the NSAID dose or a change in the type of NSAID are valid alternatives, but clinical experience shows that, for some patients, stopping NSAID therapy may be the only option. After a bleeding episode, most patients can be managed with alternative therapy to NSAIDs, but if needed, a coxib plus a PPI and H. pylori eradication is a safe alternative.

The Cost-effectiveness of Celecoxib versus Non-steroidal Anti-inflammatory Drugs plus Proton-pump Inhibitors for Treating Osteoarthritis in Algeria

Background: Cyclooxygenase-2 inhibitors such as celecoxib are as effective as non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) in the treatment of osteoarthritis (OA), have fewer gastrointestinal side effects, but are more expensive. Objective: To evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib versus ns-NSAIDs, with/without proton-pump inhibitor (PPI) co-therapy, for treating OA in Algeria. Methods: The National Institute for Health and Clinical Excellence (NICE) health economic model from UK, updated with relative risks of adverse events using CONDOR trial data, was adapted for costeffectiveness analysis in OA patients aged ≥65 years. Patients could initiate treatment with celecoxib or ns-NSAIDs with/without omeprazole. Conditional probabilities were obtained from published clinical trials; effectiveness measure was quality-adjusted life years (QALYs) gained/patient. The analysis was conducted from a healthcare payer’s perspective. The average daily treatment costs and frequencies of resource use for adverse events were based on data collected in August 2011 from a private clinic located in Cheraga, Algiers, Algeria. Probabilistic sensitivity analysis (PSA) was performed to construct cost-effectiveness acceptability curves (CEACs). Results: QALYs gained/patient over a 6-month horizon were higher with celecoxib (0.368) and celecoxib+PPI (0.40) versus comparators. The lowest expected cost/patient was associated with ibuprofen (US$134.76 versus US$175.67 with celecoxib+PPI, and US$177.57 with celecoxib). Celecoxib+PPI was the most cost-effective drug treatment, with an ICER of US$584.43, versus ibuprofen. Treatment with celecoxib alone showed an ICER of US$1,530.56 versus diclofenac+PPI. These ICERs are &amp;lt;1 gross domestic product per capita in Algeria (US$7,500). Over 1-year, 3-year and 5-year horizons, celecoxib with/without PPI co-therapy showed higher QALYs/patient versus comparators, and decreasing ICERs. The ICER of celecoxib+PPI was lower than that of comparators over all time horizons. These findings were confirmed with CEACs generated via PSA. Conclusion: Using data from a single private clinic in Cheraga, Algiers, Algeria, and after considering new adverse event risks, we showed that celecoxib with/without PPI co therapy is more cost-effective than ns-NSAID+PPI for treating OA patients aged ≥65 years. Celecoxib+PPI remains dominant over a 5-year horizon, making it the most cost-effective treatment option for medium- and long-term use.

Gastroprotective Strategies in Chronic NSAID Users: A Cost-Effectiveness Analysis Comparing Single-Tablet Formulations with Individual Components

ObjectivesTo evaluate the cost-effectiveness of competing gastroprotective strategies, including single-tablet formulations, in the prevention of gastrointestinal (GI) complications in patients with chronic arthritis taking nonsteroidal anti-inflammatory drugs (NSAIDs). MethodsWe performed a cost-utility analysis to compare eight gastroprotective strategies including NSAIDs, cyclooxygenase-2 inhibitors, proton pump inhibitors (PPIs), histamine-2 receptor antagonists, misoprostol, and single-tablet formulations. We derived estimates for outcomes and costs from medical literature. The primary outcome was incremental cost per quality-adjusted life-year gained. We performed sensitivity analyses to assess the effect of GI complications, compliance rates, and drug costs. ResultsFor average-risk patients, NSAID + PPI cotherapy was most cost-effective. The NSAID/PPI single-tablet formulation became cost-effective only when its price decreased from €0.78 to €0.56 per tablet, or when PPI compliance fell below 51% in the NSAID + PPI strategy. All other strategies were more costly and less effective. The model was highly sensitive to the GI complication risk, costs of PPI and NSAID/PPI single-tablet formulation, and compliance to PPI. In patients with a threefold higher risk of GI complications, both NSAID + PPI cotherapy and single-tablet formulation were cost-effective. ConclusionsNSAID + PPI cotherapy is the most cost-effective strategy in all patients with chronic arthritis irrespective of their risk for GI complications. For patients with increased GI risk, the NSAID/PPI single-tablet formulation is also cost-effective.