Low-Dose Methotrexate and Serious Adverse Events Among Older Adults With Chronic Kidney Disease

Case reports and pharmacokinetic studies have suggested that concomitant use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with increased risk of methotrexate toxicity. This study aimed to investigate the risk of serious adverse events associated with concomitant use of low-dose methotrexate and NSAIDs, compared with use of methotrexate alone, among patients with rheumatoid arthritis. The study was conducted as a register-based cohort study in Denmark, 2004 to 2015, including episodes of concomitant use of methotrexate and NSAIDs (n=21536) and control episodes of use of methotrexate alone (n=21725). The primary outcome was the composite end point any serious adverse event, including liver toxicity, acute renal failure, and cytopenia. Secondary outcomes were the individual outcome components. Analyses were conducted using proportional-hazards regression, with adjustment using inverse-probability-of-treatment weighting based on propensity scores. During follow-up, 110 cases of the primary outcome occurred during concomitant use of methotrexate and NSAIDs (unadjusted incidence rate 12.1 per 1000 person-years) and 129 during control episodes (11.0 per 1000 person-years). Concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of any serious adverse event (weighted hazard ratio 1.40; 95% CI, 1.07-1.82). In secondary analyses, concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of acute renal failure and cytopenia. Concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, expanding on the evidence base for current regulatory recommendations that advocate caution when low-dose methotrexate and NSAID are coprescribed.

Antihypertensive prescribing and risk of adverse events in a female medicaid population

A meta-analysis was performed to compare the risk of serious adverse events associated with the use of all formulations of isradipine, when used as monotherapy in hypertension, to active drug or placebo controls. Eligible studies totalled 65 published and unpublished randomised controlled trials involving 9903 subjects and 10,675 treatment exposures: 4492 to isradipine, 1473 to isradipine sustained release, 2768 to other active drugs, and 1942 to placebo. Mortality, cardiovascular outcomes, other serious incident illnesses, such as cancer, and withdrawals were sought. Seventy-five per cent of the isradipine exposures were to standard-release formulations and 25% were to sustained-release formulations. Overall, isradipine therapy shows no difference in risk of major adverse events or withdrawals compared to other active controls or placebo (odds ratios [OR] 0.9; 95% CI 0.7-1.46 and 0.5; 95% CI 0.2-1.3). These major adverse events included angina, fatal and non-fatal myocardial infarction, stroke and overall mortality. Isradipine sustained release could be compared only to placebo, based on available data, and shows a lower risk of withdrawals (OR 0.5; 95% CI 0.3-0.9), and a similar trend was observed for major adverse events, (OR 0.8; 95% CI 0.3-2.5). Published and unpublished randomised controlled trials were analysed in separate meta-analyses and later combined when this sensitivity analysis of risk showed no differences between the groups. In conclusion, we find no evidence for increased risk of serious adverse events in patients receiving isradipine as monotherapy for hypertension.

Objective To compare the survival and risk of serious adverse events in older patients with stages II-IIIA non-small cell lung cancer treated with or without postoperative platinum based chemotherapy.Design Observational...

There is currently no consensus on the optimal treatment for Dupuytren contracture. Prior meta-analyses have been limited by suboptimal data synthesis methodologies. The authors conducted an updated evidence review comparing the effectiveness and safety of percutaneous needle fasciotomy (PNF), collagenase clostridium histolyticum (CCH), and limited fasciectomy (LF) using the Grading of Recommendations Assessment, Development and Evaluation approach. CENTRAL, MEDLINE, and Embase were searched for randomized controlled trials comparing outcomes following PNF, CCH, and LF for Dupuytren contracture treatment. Outcomes of interest included residual contracture, recurrence rate, hand function, pain, global satisfaction, and adverse events. Time points included 3 months, 1 year, and 2 to 3 years. Seventeen publications (1010 patients) were included. High- to moderate-certainty evidence showed no clinically important difference in long-term contracture reduction (PNF versus LF: mean difference [MD], 7.6 degrees; 95% CI, 1.8 to 13.4 degrees. CCH versus LF: MD, 4.8 degrees; 95% CI, -1.3 to 10.9 degrees). Moderate-certainty evidence indicated that LF provides the lowest risk of long-term recurrence (PNF versus LF: relative risk [RR], 12.3; 95% CI, 1.6 to 92.4. CCH versus LF: RR, 9.5; 95% CI, 1.2 to 73.4), LF has a higher risk of serious adverse events than PNF (RR, 0.5; 95% CI, 0.3 to 0.9), and CCH has a higher risk of overall adverse events than PNF (RR, 4.8; 95% CI, 2.9 to 7.0). CCH, PNF, and LF are equally effective in long-term contracture reduction. However, LF yields more durable results at a higher risk of rare but serious adverse events. Current evidence suggests the use of PNF over CCH. However, ultimate treatment decisions should be tailored to individual patient preferences. Therapeutic, II.

ObjectiveTo evaluate the relative risk (RR) of serious and non-serious adverse events in patients treated with exercise therapy compared with those in a non-exercising control group.DesignSystematic review and meta-analysis.Data sourcesPrimary...

ObjectiveTo evaluate the prognostic impact of collateral circulation on outcomes of direct thrombectomy (DT) versus bridging thrombectomy (BT) for acute ischemic stroke (AIS) patients with anterior circulation large vessel occlusion (LVO).MethodThis retrospective study included 460 AIS patients with anterior circulation LVO who underwent either DT (n = 220) or BT (n = 240). Collateral status was assessed using multiphase computed tomographic angiography. The primary outcome was functional prognosis at 3 months, measured by the modified Rankin Scale (mRS). Prognostic factors for good prognosis (90-day mRS ≤ 2) and adverse events were identified through multivariate logistic regression and receiver operating characteristic (ROC) analyses.ResultsThe BT group had significantly higher rates of intracerebral hemorrhage and hemorrhagic transformation compared to the DT group (p < 0.05). Good collateral circulation was independently associated with good prognosis and lower risk of serious adverse events (p < 0.001). Lower NIHSS scores, shorter OTR, absence of atrial fibrillation, and lower serum BNP levels were also significantly associated with favorable outcomes in AIS patients (all p < 0.01). Elevated serum BNP levels increased the risk of serious adverse events in both DT and BT groups (p < 0.001). ROC analysis showed that a combined model including NIHSS, BNP, collateral circulation, onset-to-reperfusion time, and atrial fibrillation achieved high predictive performance for good prognosis (AUC = 0.907, 95% CI: 0.881–0.934, p < 0.001).ConclusionCollateral circulation is a strong predictor of both functional recovery and risk of adverse events in AIS patients undergoing thrombectomy, regardless of treatment strategy. While serum BNP may offer additional prognostic value, its moderate performance and overlap with cardiovascular conditions suggest that it should be interpreted cautiously. Pre-intervention collateral assessment remains a valuable tool for guiding individualized treatment decisions.

Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP–IPV) vaccine

Risk of Serious Adverse Events, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Idelalisib

Background: Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia.Methods: PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach.Results: Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included (n = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; p < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; p < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: −54.95 to −18.30; p < 0.001) and ferritin (MD −56.24; 95% CI: −77.37 to −35.11; p < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; p < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke.Conclusion: Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.

BackgroundWhether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown.MethodsIn this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks.ResultsA total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, −4.1 percentage points; 95% confidence interval [CI], −8.6 to 0.5; P=0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of −9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of −11.0 percentage points (95% CI, −18.4 to −3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management.ConclusionsAlthough the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.)

Clinical and service delivery outcomes following medication abortion provided with or without pretreatment ultrasound or pelvic examination: An updated comparative analysis

Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk. This was a retrospective cohort study using 2013-2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs. The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03-1.33) and galantamine (aHR 1.51; 95% CI 1.24-1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06-1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17-2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses. The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care.

Finerenone—A New Frontier in Renin-Angiotensin-Aldosterone System Inhibition in Diabetic Kidney Disease

Background Alirocumab and evolocumab, as protein convertase subtilisin kexin type 9 (PCSK9) inhibitors, have been reported to reduce cardiovascular risk. This meta-analysis is aimed at updating the safety data of PCSK9 inhibitors. Methods We assessed the relative risk for all treatment-related adverse events, serious adverse events, diabetes-related adverse events, and neurocognitive and neurologic adverse events with PCSK9 inhibitors compared to controls (placebo or ezetimibe). In addition, we conducted a meta-analysis to quantitatively integrate and estimate the adverse event rates in long-term studies. Results There were no significant differences between PCSK9 inhibitors and controls in the relative risk analysis. In a subgroup analysis of each PCSK9 inhibitor, alirocumab treatment significantly reduced the risk of serious adverse events compared to control treatment (risk ratio (RR) = 0.937; 95% confidence interval (CI), 0.896–0.980), but no significant difference was observed with evolocumab treatment (RR = 1.003; 95% CI, 0.963–1.054). Moreover, alirocumab treatment afforded a significant reduction in the risk of diabetes-related adverse events compared to control treatment (RR = 0.9137; 95% CI, 0.845–0.987). The overall incidence (event rate) of long-term adverse events was 75.1% (95% CI, 71.2%–78.7%), and the incidence of serious long-term event rate was 16.2% (95% CI, 11.6%–22.3%). Conclusions We suggest that alirocumab and evolocumab are generally safe and well tolerated and that their addition to background lipid-lowering therapy is not associated with an increased risk of adverse events or toxicity.