Adverse events of exercise therapy in randomised controlled trials: a systematic review and meta-analysis

The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.

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

Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin. Ranolazine is a second-line anti-anginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance. To assess the effects of ranolazine on cardiovascular and non-cardiovascular mortality, all-cause mortality, quality of life, acute myocardial infarction incidence, angina episodes frequency and adverse events incidence in stable angina patients, used either as monotherapy or as add-on therapy, and compared to placebo or any other anti-anginal agent. We searched CENTRAL, MEDLINE, Embase and the Conference Proceedings Citation Index - Science in February 2016, as well as regional databases and trials registers. We also screened reference lists. Randomised controlled trials (RCTs) which directly compared the effects of ranolazine versus placebo or other anti-anginals in people with stable angina pectoris were eligible for inclusion. Two authors independently selected studies, extracted data and assessed risk of bias. Estimates of treatment effects were calculated using risk ratios (RR), mean differences (MD) and standardised mean differences (SMD) with 95% confidence intervals (CI) using a fixed-effect model. Where we found statistically significant heterogeneity (Chi² P < 0.10), we used a random-effects model for pooling estimates. Meta-analysis was not performed where we found considerable heterogeneity (I² ≥ 75%). We used GRADE criteria to assess evidence quality and the GRADE profiler (GRADEpro GDT) to import data from Review Manager 5.3 to create 'Summary of findings' tables. We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear.For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence).For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence). We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.

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...

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

Clinical effects of antivirals for hepatitis C: context is critical

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.

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.

Rotavirus is a common cause of diarrhoea, diarrhoea-related hospital admissions, and diarrhoea-related deaths worldwide. Rotavirus vaccines prequalified by the World Health Organization (WHO) include Rotarix (GlaxoSmithKline), RotaTeq (Merck), and, more recently, Rotasiil (Serum Institute of India Ltd.), and Rotavac (Bharat Biotech Ltd.).

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

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.

The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease. The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE, and full text searches were combined. Only randomized clinical trials studying patients with alcoholic liver disease were included. Interventions encompassed anabolic-androgenic steroids at any dose or duration versus placebos or no intervention. The statistical package (RevMan and MetaView) provided by The Cochrane Collaboration was used. Five randomized clinical trials (including mainly men with alcoholic hepatitis and/or cirrhosis) were identified. Only one trial was assessed as adequate regarding all methodological quality components. Anabolic-androgenic steroids versus placebos or no intervention demonstrated no significant effects on mortality (relative risk [RR] = 0.96, 95% CI = 0.72-1.28), liver-related mortality (RR = 0.83, 95% CI = 0.60-1.15), complications to the liver disease (RR = 1.25, 95% CI = 0.74-2.10), liver histology, and a number of other outcome measures. Anabolic-androgenic steroids were not associated with a significantly increased risk of nonserious adverse events, but with the seldom occurrence of serious adverse events (RR = 4.54,95% CI = 0.57-36.30). This systematic review could not demonstrate any significant beneficial effects of anabolic-androgenic steroids on any clinically important outcomes of patients with alcoholic liver disease.

Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD). To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine. This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine. Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d). The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression. In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome. In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.

Antibiotics for induction and maintenance of remission in Crohn's disease.