Concomitant Nonsteroidal Anti-inflammatory Drugs Research Articles

Efficacy and Safety of Tofacitinib in Ankylosing Spondylitis by Baseline C-Reactive Protein Level: Post Hoc Analysis of Phase II and Phase III Clinical Trials.

This post hoc analysis assessed the effect of baseline C-reactive protein (CRP) on the efficacy and safety of tofacitinib (TOF) use in ankylosing spondylitis (AS), as well as patient-reported outcomes (PROs). Phase II (ClinicalTrials.gov: NCT01786668) and phase III (ClinicalTrials.gov: NCT03502616) data from patients with active AS were used. Endpoints (weeks 12, 16, and 48), including 20% and 40% improvement in Assessment of SpondyloArthritis international Society (ASAS), AS Disease Activity Score with CRP low disease activity, 50% improvement in Bath AS Disease Activity Index (BASDAI50), and PROs (pain and fatigue), were stratified by baseline CRP (mg/L) as follows: < 5 (normal), ≥ 5 (elevated), < 10, and ≥ 10. Safety outcomes were evaluated between < 5 and ≥ 5 mg/L subgroups. Overall, 372 patients were included (69.6% ≥ 5mg/L; 50.8% ≥ 10 mg/L). At baseline in the < 5mg/L group, more placebo-treated than TOF-treated patients received concomitant nonsteroidal antiinflammatory drugs (NSAIDs) or sulfasalazine (SSZ). Week 12 efficacy and PRO responses were generally higher for TOF vs placebo, regardless of baseline CRP. The treatment effect (placebo-adjusted response) at week 12 was generally numerically higher in ≥ 5 mg/L and ≥ 10 mg/L vs < 5 mg/L and < 10 mg/L groups. Incidence rates for treatment-emergent adverse events (TEAEs) and "all infections" were numerically higher for TOF vs placebo in patients in the < 5 mg/L group, but similar for TOF vs placebo in patients in the ≥ 5 mg/L group. Regardless of baseline CRP, TOF was more efficacious vs placebo at week 12. The placebo-adjusted efficacy and PRO responses were generally numerically higher in patients with CRP ≥ 5 mg/L and ≥ 10 mg/L vs < 5 mg/L and < 10 mg/L. The higher concomitant NSAID/SSZ exposure may have improved efficacy responses in the baseline < 5 mg/L placebo group, and ultimately affected the TOF treatment effect. Safety was consistent with previous studies of TOF use in AS, with numerically higher incidence rates for TEAEs and "all infections" for TOF vs placebo in patients with CRP < 5 mg/L.

Real-Life Study of Patient Preference for Dupilumab or Revision Surgery for Recurrent Chronic Rhinosinusitis with Nasal Polyps.

(1) Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has a high rate of recurrence in patients, despite therapy with local corticosteroids and functional endoscopic sinus surgery. Dupilumab, a recombinant monoclonal human IgG4 antibody directed against the IL-4 receptor α that inhibits both IL-4 and IL-13 signal transduction, is available for symptomatic therapy. Patient preference between repeated surgery and injection therapy with Dupilumab is not known. (2) Methods: Patients who had experienced at least one surgical intervention for nasal polyps and were treated with Dupilumab for at least 3 months completed a retrospective patient questionnaire. (3) Results: In a cohort of 75 previously operated CRSwNP patients, 91.5% preferred therapy with Dupilumab to repeated surgery for nasal polyps. Preference for Dupilumab in the subgroups of patients with concomitant Non-steroidal Anti-inflammatory Drugs Exacerbated Respiratory Disease (N-ERD) (n = 32), patients with concomitant asthma (n = 25), and patients without concomitant disease (n = 18) was 100%, 96%, and 72%, respectively. (4) Conclusions: Patient preference for Dupilumab over repeat surgery is strongest in previously operated CRSwNP patients with concomitant asthma or N-ERD, but remains very high in patients without concomitant disease.

Patients With Chronic Spontaneous Urticaria Who Have Wheals, Angioedema, or Both, Differ Demographically, Clinically, and in Response to Treatment—Results From CURE

Patients with chronic spontaneous urticaria (CSU) have spontaneous wheals (W), angioedema (AE), or both, for longer than 6 weeks. Clinical differences between patients with standalone W, standalone AE, and W and AE (W+AE) remain incompletely understood. To compare W, AE, and W+AE CSU patients regarding demographics, disease characteristics, comorbidities, disease burden, and treatment response. Baseline data from 3,698 CSU patients in the ongoing, prospective, international, multicenter, observational Chronic Urticaria REgistry (CURE) were analyzed (data cut: September 2022). Across all CSU patients, 59%, 36%, and 5% had W+AE, W, and AE, respectively. The W+AE patients, compared with W and AE patients, showed the lowest male-to-female ratio (0.33), higher rates of concomitant psychiatric disease (17% vs 11% vs 6%, respectively), autoimmune disease (13% vs 7% vs 9%, respectively), and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (9% vs 5% vs 2%, respectively) and the highest disease impact. The W patients, compared with W+AE and AE patients, showed the lowest rates of concomitant hypertension (15% vs 21% vs 40%, respectively) and obesity (11% vs 16% vs 17%, respectively), the highest rate of concomitant inducible urticaria (24% vs 22% vs 6%, respectively), and shorter W duration. The AE patients, compared with W+AE and W patients, were older at disease onset, showed longer AE duration, and the best response to increased doses of H1-antihistamines (58% vs 24% vs 31%, respectively) and omalizumab (92% vs 67% vs 60%, respectively). Our findings provide a better understanding of CSU phenotypes and may guide patient care and research efforts that aim to link them to pathogenic drivers.

Chondroitin sulfate and glucosamine combination in patients with knee and hip osteoarthritis: A long-term observational study in Russia.

Oral treatment of glucosamine (GA) combined with chondroitin sulfate (CS) was reportedly effective for pain relief and function improvement in osteoarthritis patients with moderate to severe knee pain in clinical trials. While the effectiveness of GA and CS on both clinical and radiological findings has been demonstrated, only a few high-quality trials exist. Therefore, controversy regarding their effectiveness in real-world clinical practice remains. To investigate the impact of GA + CS on clinical outcomes of patients with knee and hip osteoarthritis in routine clinical practice. A multicenter prospective observational cohort study included 1102 patients of both genders with knee or hip osteoarthritis (Kellgren & Lawrence grades I-III) in 51 clinical centers in the Russian Federation from November 20, 2017, to March 20, 2020, who had started to receive oral capsules of glucosamine hydrochloride 500 mg and CS 400 mg according to the approved patient information leaflet starting from 3 capsules daily for 3 wk, followed by a reduced dosage of 2 capsules daily before study inclusion (minimal recommended treatment duration is 3-6 mo). Changes in subscale scores [Pain, Symptoms, Function, and Quality of Life (QOL)] of the Knee Injury and Osteoarthritis Outcome Score (KOOS)/Hip Disability and Osteoarthritis Outcome Score (HOOS) questionnaires during the observational period (up to 54-64 wk with a total of 4 visits). Patients' treatment satisfaction, data on the combined oral use of glucosamine hydrochloride and CS, concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), and adverse events (AEs) were also evaluated. A total of 1102 patients with knee and hip osteoarthritis were included in the study. The mean patient age was 60.4 years, most patients were women (87.8%), and their average body mass index was 29.49 kg/m2. All subscale scores (Pain, Symptoms, Function, and QOL) of the KOOS and HOOS demonstrated clinically and statistically significant improvements. In patients with knee osteoarthritis, the mean score increases from baseline to the end of Week 64 were 22.87, 20.78, 16.60, and 24.87 on Pain, Symptoms, Physical Function (KOOS-PS), and QOL subscales (P < 0.001 for all), respectively. In patients with hip osteoarthritis, the mean score increases were 22.81, 19.93, 18.77, and 22.71 on Pain, Symptoms, Physical Function (HOOS-PS), and QOL subscales (P < 0.001 for all), respectively. The number of patients using any NSAIDs decreased from 43.1% to 13.5% (P < 0.001) at the end of the observation period. Treatment-related AEs occurred in 2.8% of the patients and mainly included gastrointestinal disorders [25 AEs in 24 (2.2%) patients]. Most patients (78.1%) were satisfied with the treatment. Long-term oral GA + CS was associated with decreased pain, reduced concomitant NSAID therapy, improved joint function and QOL in patients with knee and hip osteoarthritis in routine clinical practice.

Safety and Efficacy of Prostaglandin Analogues in the Immediate Postoperative Period after Uneventful Phacoemulsification

Prostaglandin analogues (PGAs) have been associated with the development of pseudophakic macular edema (PME) in complicated cataract cases, but evidence on their effects in uncomplicated phacoemulsification remains controversial. This two-arm, prospective, randomised study included patients with glaucoma or ocular hypertension under PGA monotherapy who were scheduled for cataract surgery. The first group continued PGA use (PGA-on), while the second discontinued PGAs for the first postoperative month and reinitiated use afterwards (PGA-off). Topical non-steroidal anti-inflammatory drugs (NSAIDs) were routinely administered to all patients during the first postoperative month. The patients were followed up for three months and the primary outcome was PME development. Secondary outcomes were corrected distance visual acuity (CDVA), central and average macular thickness (CMT and AMT), and intraocular pressure (IOP). The analysis included 22 eyes in the PGA-on group and 33 eyes in the PGA-off group. No patient developed PME. CDVA was not significantly different between the two groups (p = 0.83). CMT and AMT showed a small but statistically significant increase until the end of follow-up (p &lt; 0.001). Mean IOP values had no significant differences between the groups at each visit (p &gt; 0.05). At the end of follow-up, the IOP values were significantly lower than baseline in both groups (p &lt; 0.001). In conclusion, PGA administration with concomitant topical NSAIDs appears to be a safe practice in the early postoperative period of uncomplicated phacoemulsification.

Modulation of the Immune Response to Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination by Nonsteroidal Anti-Inflammatory Drugs.

Evidence is scarce to guide the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-related adverse effects, given the possibility of blunting the desired immune response. In this pilot study, we deeply phenotyped a small number of volunteers who did or did not take NSAIDs concomitant with SARS-CoV-2 immunizations to seek initial information on the immune response. A SARS-CoV-2 vaccine-specific receptor binding domain (RBD) IgG antibody response and efficacy in the evoked neutralization titers were evident irrespective of concomitant NSAID consumption. Given the sample size, only a large and consistent signal of immunomodulation would have been detectable, and this was not apparent. However, the information gathered may inform the design of a definitive clinical trial. Here we report a series of divergent omics signals that invites additional hypotheses testing. SIGNIFICANCE STATEMENT: The impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on the immune response elicited by repeat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunizations was profiled by immunophenotypic, proteomic, and metabolomic approaches in a clinical pilot study of small sample size. A SARS-CoV-2 vaccine-specific immune response was evident irrespective of concomitant NSAID consumption. The information gathered may inform the design of a definitive clinical trial.

Dynamic Characteristics and Predictive Profile of Glucocorticoids Withdrawal in Rheumatoid Arthritis Patients Commencing Glucocorticoids with csDMARD: A Real-World Experience.

Glucocorticoids (GC) are currently recommended as a bridging therapy in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) for the treatment of rheumatoid arthritis (RA) and should be tapered as rapidly as clinically feasible. We aimed to explore potential predictors for GC discontinuation in patients commencing GC with concomitant csDMARD. We used data from a longitudinal real-world cohort. RA patients who newly started GC concomitantly with csDMARD were included. All patients were divided into four groups, according to degree of change in disease activity at 3months from baseline (group 1: worsening or no decrease; group 2: 0-24.9% decrease; group 3: 25.0-49.9% decrease; group 4: ≥ 50.0% decrease). Cox regression was used to estimate hazard risk (HR) with 95% confidence interval (CI). In total, 124 out of 207 RA patients discontinued GC at the rheumatologist's discretion and 79.1% (91/115) of them successfully stopping GC without flare within 6months after GC withdrawal. Increasing age (HR 0.99, 95% CI 0.98-1.00, p = 0.043) and concomitant nonsteroidal anti-inflammatory drugs use at GC initiation (HR 0.47, 95% CI 0.25-0.88, p = 0.018) were independently associated with GC withdrawal failure. Moreover, the degrees of disease activity improvement at 3months significantly predicted the possibility of subsequent GC discontinuation (fully adjusted HR 1.35-1.47, p < 0.01), with 2.38-3.59 times higher in group 4 than group 1. Switching the outcome to successfully stopping GC without short-term flare yielded similar findings. The degrees of disease activity improvement at 3months independently predicted the subsequent GC withdrawal. These findings suggest the importance of dynamic treatment strategies with a closer look at disease activity during GC tapering and discontinuation.

Does coprescribing nonsteroidal anti-inflammatory drugs and oral anticoagulants increase the risk of major bleeding, stroke and systemic embolism?

To examine the risk of gastrointestinal (GI) bleeding, major bleeding, stroke and systemic embolism associated with prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) to adults receiving oral anticoagulant (OAC) therapy. We conducted a population-based cohort study in adults receiving OAC therapy using linked primary care (Clinical Practice Research Datalink GOLD) and hospital (Hospital Episodes Statistics) electronic health records. We used cause-specific Cox regression models with time-dependent NSAID treatment in a propensity score matched population to estimate the increased risk of GI bleeding, stroke, major bleeding and systemic embolism associated with NSAID use. The matched cohort contained 3177 patients with OAC therapy alone and 3177 with at least 1 concomitant NSAID prescription. Compared with OAC therapy alone, concomitant prescription of NSAIDs with OACs was associated with increased risk of GI bleeding (hazard ratio [HR] 3.01, 95% confidence interval [CI] 1.63 to 5.55), stroke (HR 2.71, 95% CI 1.48 to 4.96) and major bleeding (HR 2.77, 95% CI 1.84 to 4.19). The association with systemic embolism did not reach statistical significance (HR 3.02, 95% CI 0.82 to 11.07). Sensitivity analyses indicated that the results were robust to changes in exclusion criteria and the choice of potential confounding variables. When OACs are coprescribed with NSAIDs, the risk of adverse bleeding events increases and, simultaneously, the protective effect of OACs to prevent strokes reduces. There is a need for interventions that reduce hazardous prescribing of NSAIDs in people receiving OAC therapy.

Association of Antisecretory Drugs with Upper Gastrointestinal Bleeding in Patients Using Oral Anticoagulants: A Systematic Review and Meta-Analysis

BackgroundThe role of antisecretory drugs for the prevention of upper gastrointestinal bleeding in patients using anticoagulants is unclear. We investigated this question in a systematic review and meta-analysis. MethodsWe searched Embase, PubMed, Web of Science, Scopus, the Cochrane Library, and clinicaltrials.gov thru April 2021 for controlled randomized trials and observational studies evaluating the association of proton pump inhibitors (PPIs) or H2-receptor antagonists with overt upper gastrointestinal bleeding in patients using anticoagulants. Independent duplicate review, data extraction, and risk of bias assessment were performed. Observational studies were included only if they provided results controlled for at least 2 variables. Meta-analyses were performed using random effects models. ResultsSix observational studies and 1 randomized trial were included. All but 1 study had low risk of bias. None of the studies excluded patients with concomitant aspirin or nonsteroidal anti-inflammatory drug use. For PPIs, the pooled relative risk of upper gastrointestinal bleeding was 0.67 (95% confidence interval 0.61, 0.74) with low statistical heterogeneity (I2 = 15%). Individual studies showed greater treatment effect in patients with higher risk for upper gastrointestinal bleeding (eg, nonsteroidal anti-inflammatory drug or aspirin use, elevated bleeding risk score). A single observational study evaluating the association of H2-receptor antagonists with upper gastrointestinal bleeding found a relative risk of 0.69 (95% confidence interval 0.24-2.02). ConclusionsEvidence drawn mostly from observational studies with low risk of bias demonstrate that PPIs reduce upper gastrointestinal bleeding in patients prescribed oral anticoagulants. The benefit appears to be most clearcut and substantial in patients with elevated risk of upper gastrointestinal bleeding.

Impact of Preventive Strategies on Gastrointestinal Complications in Elderly Patients on Concomitant Use of Oral Anticoagulants and Nonsteroidal Anti-Inflammatory Drugs: A Nationwide Cohort Study.

Despite growing evidence showing an increased risk of concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and anticoagulants, few studies have investigated whether proton pump inhibitors can prevent gastrointestinal (GI) complications in patients receiving both NSAIDs and anticoagulants. We aimed to evaluate the risk of serious GI complications and the impact of GI preventive strategies on the concomitant use of NSAIDs and anticoagulants. Our nationwide cohort study using Korea's claims data included elderly patients (aged ≥65 years) who started anticoagulants and NSAIDs from 2016 to 2017. The outcome was serious GI complications defined as hospitalization or emergency department visits with GI bleeding or perforation. A Cox regression analysis was performed using time-dependent variables and propensity score matching. In total, 92,379 patients were identified. Compared with non-prophylaxis, proton pump inhibitors and selective cyclooxygenase-2 inhibitors were associated with a 64% [adjusted hazard ratio, 0.36 (95% confidence interval 0.25-0.53)] and 74% [adjusted hazard ratio, 0.26 (95% confidence interval 0.19-0.36)] lower risk of serious GI complications, respectively. Cyclooxygenase-2 inhibitor use was not different from the use of non-selective NSAIDs with proton pump inhibitors for the prevention of serious GI complications. H2-receptor antagonists did not reduce the risk of serious GI complications compared with non-prophylaxis during concomitant non-selective NSAID and anticoagulant therapy. Proton pump inhibitors or cyclooxygenase-2 inhibitors used as GI preventive strategies did not completely eliminate but lowered the risk of serious GI complications among elderly patients receiving both NSAIDs and anticoagulants.

Time until onset of acute kidney injury by combination therapy with "Triple Whammy" drugs obtained from Japanese Adverse Drug Event Report database.

Acute kidney injury (AKI) associated with “Triple Whammy” drug therapy consisting of renin-angiotensin system inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported. There have been no reports investigating “Triple Whammy” drug therapy and the time to AKI onset using adverse drug events report databases. The aim of this study was to determine the relationship between the time to AKI onset and treatment with “Triple Whammy” drug therapy. We analyzed AKI cases registered in the Japanese Adverse Drug Event Report database. The data were analyzed using the Kaplan–Meier approach, generalized Wilcoxon tests, and Weibull distribution. AKI was reported in 18,415 cases, of which 7,466 cases used Triple Whammy drugs. All combinations of Triple Whammy drugs were associated with significantly higher odds ratios for reporting AKI. In Weibull analysis, AKI onset was early for most combination patterns of Triple Whammy drugs. The Kaplan–Meier approach showed that the treatment duration to AKI onset was much shorter in cases using NSAIDs; median onsets, 8 days for triple combination, 7 days for NSAIDs added to renin-angiotensin system inhibitors, 9 days for NSAIDs added to diuretics, 6 days for diuretics added to NSAIDs, and 9 days for NSAIDs alone. AKI associated with Triple Whammy drugs is likely to occur in the early stages of treatment, especially with concomitant NSAIDs. Patients should be monitored for the occurrence of AKI within the first 2 weeks.

Risk of Bleeding Associated With Nonsteroidal Anti-inflammatory Drug Use in Patients Exposed to Antithrombotic Therapy: A Case-Crossover Study.

Concomitant nonsteroidal anti-inflammatory drug (NSAIDs) and antithrombotic drug use is associated with an increased risk of bleeding, mainly gastrointestinal. The goal of this study was to quantify the transient increase in the risk of hospitalization for bleeding associated with NSAID use in patients treated with antiplatelet agents or anticoagulants. We performed a unidirectional case-crossover study using the EGB (Échantillon généraliste de bénéficiaires), a permanent random sample of the French nationwide health database. Patients receiving antithrombotic therapy and hospitalized for bleeding between 2009 and 2017 were included. We compared their NSAID exposure during a 15-day hazard window immediately before hospital admission to 3 earlier 15-day control windows. The risk of hospitalization for bleeding associated with the recent use of NSAIDs was estimated using conditional logistic regression to estimate odds ratios (ORs). During the study period, 33 patients treated with anticoagulants and 253 treated with antiplatelet agents received NSAIDs and were included in the case-crossover analysis. We found an increased risk of hospitalization for gastrointestinal bleeding after exposure to NSAIDs, with an adjusted OR of 3.59 (95%CI, 1.58-8.17) in patients receiving anticoagulant therapy and 1.44 (95%CI, 1.07-1.94) in patients receiving antiplatelet therapy. The risk of nongastrointestinal bleeding was also increased after exposure to NSAIDs with an adjusted OR of 2.72 (95%CI, 1.23-6.04) in patients exposed to anticoagulant therapy. The risk of gastrointestinal and nongastrointestinal bleeding increases after NSAID use in patients treated with anticoagulants, while the risk of gastrointestinal bleeding increases, but to a lesser extent in those treated with antiplatelets.

Association Between Biologics Use and Risk of Serious Infection in Patients With Psoriasis

Biologics and targeted therapies, such as apremilast, are efficient treatments to manage moderate to severe psoriasis. More information about the risk of serious infection is needed for the newest treatment options in a real-world setting. To assess the risk of serious infection among biologics and apremilast used to treat psoriasis, with etanercept as the comparator. This nationwide cohort study from France involved data from the National Health Data System covering approximately 99% of the French population. All adults with psoriasis, defined as receiving at least 2 prescriptions of a topical vitamin D derivative within a 2-year period, registered in the database between January 1, 2008, and May 31, 2019, were eligible. The study population included those who were new users of biologic agents or apremilast (ie, without any prescriptions of a biologic or apremilast during the previous year). Patients with HIV infection or a history of cancer, transplant, or serious infection were excluded. End of follow-up was January 31, 2020. The primary end point was a serious infection in a time-to-event analysis using propensity score-weighted Cox proportional hazards regression models, estimating weighted hazard ratios (wHRs) and 95% CIs. A total of 44 239 new users of biologic treatment were identified (mean [SD] age, 48.4 [13.8] years; 22 866 [51.7%] men; median follow-up, 12 months [interquartile range, 7-24 months]). A total of 29 618 (66.9%) were prescribed a tumor necrosis factor inhibitor first, 6658 (15.0%) an interleukin (IL) 12/23 inhibitor, 4093 (9.3%) an IL-17 inhibitor, 526 (1.2%) an IL-23 inhibitor, and 3344 (7.6%) apremilast. The total number of serious infections was 1656, and the overall crude incidence rate was 25.0 (95% CI, 23.8-26.2) per 1000 person-years. The most frequent serious infections were gastrointestinal infections (645 patients [38.9%]). After adjusting for time-dependent covariables, risk of serious infections was higher for new users of adalimumab (wHR, 1.22; 95% CI, 1.07-1.38) or infliximab (wHR, 1.79; 95% CI 1.49-2.16) vs etanercept, whereas ustekinumab was associated with a lower risk of having a serious infection (wHR, 0.79; 95% CI, 0.67-0.94). Risk of serious infections was not increased for new users of IL-17 and the IL-23 inhibitor guselkumab or apremilast vs etanercept. Risk of serious infections was increased with concomitant nonsteroidal anti-inflammatory drugs or systemic corticosteroids. In this cohort study of individuals with moderate to severe psoriasis, risk of serious infections was increased in new users of infliximab and adalimumab vs etanercept, whereas ustekinumab users had lower risk of having a serious infection but not new users of IL-17 and IL-23 inhibitors or apremilast. Other observational studies are needed to confirm results for the most recent drugs.

Risk of Intracranial Hemorrhage With Concomitant Use of Antidepressants and Nonsteroidal Anti-inflammatory Drugs: A Nested Case-Control Study.

Whereas previous studies found that concomitant antidepressant and nonsteroidal anti-inflammatory drug (NSAIDs) use may increase the risk of gastrointestinal bleeding, either drug alone increases the risk of intracranial hemorrhage (ICH). To assess the risk for ICH in patients on concomitant treatment with antidepressants and NSAIDs. This was a nested case-control study using national insurance claims data in Taiwan between 2005 and 2013. Drug exposure was measured and compared during 3 time windows: 1 to 30, 31 to 60, and 61 to 90 days before the index date, which is the date of the ICH event. Both traditional and newer-generation antidepressants were considered in this study. Patients exposed to both antidepressants and NSAIDs 1 to 30 days before the index date presented a 50% increased odds of developing ICH (OR: 1.53; 95% CI: 1.31-1.80) compared with patients receiving antidepressants alone. Specifically, the concomitant use of nonselective NSAIDs and antidepressants increased these odds compared with antidepressants alone (OR: 1.56; 95% CI: 1.31-1.84), but using a selective cyclooxygenase-2 inhibitor with antidepressant did not alter ICH risk. Regarding antidepressant class, newer-generation antidepressants generally increase the odds of developing ICH by 60% when used concomitantly with NSAIDs. Our results suggested that the concomitant use of antidepressants and NSAIDs was associated with an increased odds of developing ICH. NSAIDs, especially nonselective NSAIDs, and serotonergic antidepressants played an important role in this risk. Given the prevalent use of these 2 classes of drugs, this potential drug interaction deserves more attention.

Risk of Major Adverse Cardiovascular Events Associated with Concomitant Use of Antidepressants and Non-steroidal Anti-inflammatory Drugs: A Retrospective Cohort Study.

Both antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to affect platelet aggregation, blood pressure and heart rate. Despite the high prevalence of the combined use of antidepressants and NSAIDs, there is limited evidence on the potential risk of major adverse cardiovascular events (MACE) associated with their use. The objective of this study was to assess the association between concomitant antidepressant and NSAID use and MACE. We conducted a retrospective cohort study using South Korea's nationwide healthcare database. The study cohort was defined as those with new prescriptions for antidepressants and NSAIDs between 2004 and 2015. Exposure was assessed as time varying into four discrete periods: non-use, antidepressant use, NSAID use and concomitant use. Our primary outcome was MACE, a composite of haemorrhagic and thromboembolic events; secondary outcomes were the individual events of MACE. A multivariable Cox proportional hazards model was used to estimate hazards ratios with 95% confidence intervals. We also performed subgroup analyses by class of antidepressant/type of NSAIDs, age and sex. From 240,982 patients, 235,080, 4393 and 1509 patients were users of NSAIDs, antidepressants or both drugs at cohort entry, respectively. The cohort generated 2.1 million person-years of follow-up with 22,453 events of MACE (incidence rate 1.07 per 100 person-years). Compared with non-use, concomitant use (hazard ratio 1.13, 95% confidence interval 1.01-1.26) and NSAID-only use (1.05, 1.001-1.10) were positively associated with MACE, while antidepressant-only use showed a negative association (0.91, 0.83-0.99). Concomitant use increased the individual risk of haemorrhagic stroke (1.46, 1.06-2.00), ischaemic stroke (1.22, 1.07-1.38) and heart failure (1.19, 1.02-1.38), but showed a protective effect on cardiovascular deaths (0.36, 0.21-0.62). Of the six possible combinations of antidepressants and NSAIDs by their classes, only concomitant use of tricyclic antidepressants and non-selective NSAIDs was positively associated with MACE (1.26, 1.09-1.47). The risk of MACE remained elevated with concomitant use among those aged ≥ 45years (1.14, 1.01-1.29) and male patients (1.19, 1.01-1.42). Concomitant use of antidepressants and NSAIDs moderately elevated the risk of MACE, of which the observed risk appears to be driven by the concomitant use of tricyclic antidepressants and non-selective NSAIDs. Thus, healthcare providers should take precaution when co-prescribing these drugs, weighing the potential benefits and risks associated with their use.

Cardiovascular and Bleeding Risks Associated With Nonsteroidal Anti-Inflammatory Drugs After Myocardial Infarction

BackgroundLimited data are available regarding the risk for adverse clinical events with concomitant nonsteroidal anti-inflammatory drug (NSAID) treatment after myocardial infarction (MI). ObjectivesThe aim of this study was to investigate the risk for cardiovascular and bleeding events according to groups of antithrombotic medications and subtypes of NSAIDs in patients with MI. MethodsThis was a nationwide cohort study to enroll a study population from the Health Insurance Review and Assessment Service database in Korea between 2009 and 2013. Patients were divided into groups on the basis of the prescribed antithrombotic medications. The primary and secondary outcomes were thromboembolic cardiovascular and clinically relevant bleeding events. The risk for adverse clinical events was assessed by ongoing NSAID treatment and subtypes of NSAIDs. ResultsIn total, 108,232 patients (mean age 64.2 ± 12.8 years, 72.1% men, mean follow-up duration 2.3 ± 1.8 years) with first diagnosed MI were enrolled. Concomitant NSAID treatment significantly increased the risk for cardiovascular events (hazard ratio [HR]: 6.96; 95% confidence interval [CI]: 6.24 to 6.77; p < 0.001) and bleeding events (HR: 4.08; 95% CI: 3.51 to 4.73; p < 0.001) compared with no NSAID treatment. Among NSAID subtypes, the risk for cardiovascular and bleeding events was lowest with the use of celecoxib (HR: 4.65; 95% CI: 3.17 to 6.82; p < 0.001, and 3.44; 95% CI: 2.20 to 5.39; p < 0.001, respectively) and meloxicam (HR: 3.03; 95% CI: 1.68 to 5.47; p < 0.001, and 2.80; 95% CI: 1.40 to 5.60; p < 0.001, respectively). ConclusionsConcomitant NSAID treatment significantly increased the risk for cardiovascular and bleeding events after MI. Although NSAID treatment should be avoided after MI, celecoxib and meloxicam could be considered as alternative options in cases in which NSAID use is unavoidable.

Risk of Bleeding with Exposure to Warfarin and Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review and Meta-Analysis.

Warfarin use can trigger the occurrence of bleeding independently or as a result of a drug-drug interaction when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs). This article examines the risk of bleeding in individuals exposed to concomitant warfarin and NSAID compared with those taking warfarin alone (Prospero Registry ID 145237). PubMed, EMBASE, Scopus, and Web of Science were searched. The primary outcome of interest was gastrointestinal bleeding and general bleeding. Summary effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran's Q and I 2. Risk of bias was also assessed using the Agency for Healthcare Research and Quality bias assessment tool. A total of 651 studies were identified, of which 11 studies met inclusion criteria for meta-analysis. The odds ratio (OR) for gastrointestinal bleeding when exposed to warfarin and an NSAID was 1.98 (95% confidence interval [CI]: 1.55-2.53). The risk of gastrointestinal bleeding was also significantly elevated with exposure to a COX-2 inhibitor and warfarin relative to warfarin alone (OR = 1.90, 95% CI: 1.46-2.46). There was an increased risk of general bleeding with the combination of warfarin with NSAIDs (OR = 1.58, 95% CI: 1.18-2.12) or COX-2 inhibitors (OR = 1.54, 95% CI: 0.86-2.78) compared with warfarin alone. Risk of bleeding is significantly increased among persons taking warfarin and a NSAID or COX-2 inhibitor together as compared with taking warfarin alone. It is important to caution patients about taking these medications in combination.

Better outcomes for patients with gout.

Gout is increasing in prevalence despite effective pharmacotherapies. Barriers to effective management are largely educational deficiencies. Sufferers, usually men, need to understand more about gout, especially that maintaining serum urate below 0.36mmol/L will eliminate recurrent attacks. Also, of great importance is appreciating that sub-optimal adherence to urate-lowering therapy (ULT) will result in a return of attacks. Prescribers also need to understand that acute attacks are likely to occur in the first few months of urate-lowering therapy (ULT), but these can be mitigated by commencing with a dose of ULT reflective of renal function and escalating the dose slowly, every 2-5weeks until target serum urate is achieved. Prophylaxis against acute attacks over the initial 6months period of ULT can be enhanced further with concomitant colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs).Gout is largely managed in primary care. Rates of adherence to ULT are 50% or less, worse than most other chronic illnesses. Efforts at educating primary care physicians to, firstly, manage gout effectively and, secondly, to educate their gout patients sufficiently have not been successful. Allied health practitioners, such as nurses, working with prescribers in primary care settings and given the mandate to educate and manage patients with gout, have been spectacularly effective. However, this approach is resource intensive. 'Personalised' eHealth interventions show promise as an alternative strategy, notably in improving adherence to ULT.Numerous applications for smart phones (apps) are now available to assist people with chronic health conditions. Their design needs to accommodate the barriers and enablers perceived by patients to maintaining adherence to prescribed therapies. Personalised feedback of serum urate may represent an important enabler of adherence to ULT in the case of gout.Harnessing mobile apps to support patients managing their chronic illnesses represents an important opportunity to enhance health outcomes. Rigorous, patient-centred and driven development is critical. These tools also require careful evaluation for effectiveness.

Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding: validation of endoscopy guidelines.

It remains unclear whether type of antiplatelet (AP) therapy, AP combination therapy, and AP continuing or switching strategy affect the risk of post-polypectomy bleeding (PPB). In this study, we sought to elucidate this risk. We analyzed 1050 patients who underwent colonoscopic polypectomy: 525 AP users and 525 controls matched for age, sex, comorbidities, concomitant non-steroidal anti-inflammatory drugs use, and polyp characteristics who did not receive antithrombotics. PPB risk was evaluated by AP number, type, and continuing or switching strategies during the peri-endoscopic period. In multivariate analysis, bleeding risk increased significantly as the number of AP agents used increased (monotherapy, adjusted odds ratio [aOR], 3.7; dual antiplatelet therapy (DAPT), 4.6; triple antiplatelet therapy (TAPT), 11.1) compared with controls. With monotherapy, significantly increased PPB risk was found for aspirin (aOR 4.3), thienopyridine (aOR 6.3), and cilostazol (aOR 5.9), but not for eicosapentaenoic acid or other APs (beraprost, limaprost, sarpogrelate, dilazep, or dipyridamole). With DAPT, significantly increased PPB risk was found for combination aspirin plus cilostazol, but not aspirin plus other APs. Bleeding rates for continuing monotherapy were 4.3% for aspirin and 0% for thienopyridine, cilostazol, and other APs, respectively. Analysis of this large polypectomy dataset showed that the use of low-dose aspirin, thienopyridine, or cilostazol and a combination of these is associated with increased PPB risk. Although PPB risk was high with DAPT or TAPT, PPB rate in any antiplatelet monotherapy even with a continuing strategy was low at < 5%.

Concomitant Use of NSAIDs or SSRIs with NOACs Requires Monitoring for Bleeding.

PurposeNon-vitamin K antagonist oral anticoagulants (NOACs) are widely used in patients with atrial fibrillation (AF) because of their effectiveness in preventing stroke and their better safety, compared with warfarin. However, there are concerns for an increased risk of bleeding associated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) or selective serotonin reuptake inhibitors (SSRIs) with NOACs. In this study, we aimed to evaluate the risk of bleeding events in individuals taking concomitant NSAIDs or SSRIs with NOACs after being diagnosed with AF.Materials and MethodsA nested case-control analysis to assess the safety of NSAIDs and SSRIs among NOAC users with AF was performed using data from Korean National Health Insurance Service from January 2012 to December 2017. Among patients who were newly prescribed NOACs, 1233 cases hospitalized for bleeding events were selected, and 24660 controls were determined.ResultsThe risk of bleeding events was higher in patients receiving concomitant NSAIDs [adjusted odds ratio (aOR) 1.41; 95% confidence interval (CI) 1.24–1.61] or SSRIs (aOR 1.92; 95% CI 1.52–2.42) with NOACs, compared to no use of either drug, respectively. The risk of upper gastrointestinal bleeding was higher in patients receiving concomitant NSAIDs or SSRIs without proton pump inhibitors (PPIs) (NSAIDs: aOR 2.47; 95% CI 1.26–4.83, SSRI: aOR 10.8; 95% CI 2.41–2.48) compared to no use.ConclusionWhen NSAIDs or SSRIs are required for NOAC users with AF, physicians need to monitor bleeding events and consider the use of PPIs, especially for combined use of both drugs or when initiating NOACs treatment.