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Network Meta-Analysis

Drug Efficacy in the Treatment of Antipsychotic-Induced Akathisia: A Systematic Review and Network Meta-Analysis

Author/s: 
Gerolymos, C, Barazer, R, Yon, D.K., Loundou, A, Boyer, L, Fond, G

Importance: Antipsychotic-induced akathisia (AIA) occurs in 14% to 35% of patients treated with antipsychotics and is associated with increased suicide and decreased adherence in patients with schizophrenia. However, no comprehensive review and network meta-analysis has been conducted to compare the efficacy of treatments for AIA.

Objective: To compare the efficacy associated with AIA treatments.

Data sources: Three databases (MEDLINE, Web of Science, and Google Scholar) were systematically searched by multiple researchers for double-blind randomized clinical trials (RCTs) comparing active drugs for the treatment of AIA with placebo or another treatment between May 30 and June 18, 2023.

Study selection: Selected studies were RCTs that compared adjunctive drugs for AIA vs placebo or adjunctive treatment in patients treated with antipsychotics fulfilling the criteria for akathisia, RCTs with sample size of 10 patients or more, only trials in which no additional drugs were administered during the study, and RCTs that used a validated akathisia score. Trials with missing data for the main outcome (akathisia score at the end points) were excluded.

Data extraction and synthesis: Data extraction and synthesis were performed, estimating standardized mean differences (SMDs) through pairwise and network meta-analysis with a random-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.

Main outcomes and measures: The primary outcome was the severity of akathisia measured by a validated scale at the last available end point.

Results: Fifteen trials involving 492 participants compared 10 treatments with placebo. Mirtazapine (15 mg/d for ≥5 days; SMD, -1.20; 95% CI, -1.83 to -0.58), biperiden (6 mg/d for ≥14 days; SMD, -1.01; 95% CI, -1.69 to -0.34), vitamin B6 (600-1200 mg/d for ≥5 days; SMD, -0.92; 95% CI, -1.57 to -0.26), trazodone (50 mg/d for ≥5 days; SMD, -0.84; 95% CI, -1.54 to -0.14), mianserin (15 mg/d for ≥5 days; SMD, -0.81; 95% CI, -1.44 to -0.19), and propranolol (20 mg/d for ≥6 days; SMD, -0.78; 95% CI, -1.35 to -0.22) were associated with greater efficacy than placebo, with low to moderate heterogeneity (I2 = 34.6%; 95% CI, 0.0%-71.1%). Cyproheptadine, clonazepam, zolmitriptan, and valproate did not yield significant effects. Eight trials were rated as having low risk of bias; 2, moderate risk; and 5, high risk. Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found.

Conclusions and relevance: In this systematic review and network meta-analysis, mirtazapine, biperiden, and vitamin B6 were associated with the greatest efficacy for AIA, with vitamin B6 having the best efficacy and tolerance profile. Trazodone, mianserin, and propranolol appeared as effective alternatives with slightly less favorable efficacy and tolerance profiles. These findings should assist prescribers in selecting an appropriate medication for treating AIA.

Keywords 
Antipsychotic Agents akathisia biperiden trazodone cyproheptadine gallopamil propranolol vitamin B 6

Shorter Dual Antiplatelet Therapy for Older Adults After Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis

Author/s: 
Dae Yong Park, Jiun-Ruey Hu, Yasser Jamil, Michelle D Kelsey, W Schuyler Jones, Jennifer Frampton, Ajar Kochar, Wilbert S Aronow, Abdulla A Damluji, Michael G Nanna

Importance: The optimal duration of dual antiplatelet therapy (DAPT) for older adults after percutaneous coronary intervention (PCI) is uncertain because they are simultaneously at higher risk for both ischemic and bleeding events.

Objective: To investigate the association of abbreviated DAPT with adverse clinical events among older adults after PCI.

Data sources: The Cochrane Library, Google Scholar, Embase, MEDLINE, PubMed, Scopus, and Web of Science were searched from inception to August 9, 2023.

Study selection: Randomized clinical trials comparing any 2 of 1, 3, 6, and 12 months of DAPT were included if they reported results for adults aged 65 years or older or 75 years or older.

Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was used to abstract data and assess data quality. Risk ratios for each duration of DAPT were calculated with alternation of the reference group.

Main outcomes and measures: The primary outcome of interest was net adverse clinical events (NACE). Secondary outcomes were major adverse cardiovascular events (MACE) and bleeding.

Results: In 14 randomized clinical trials comprising 19 102 older adults, no differences were observed in the risks of NACE or MACE for 1, 3, 6, and 12 months of DAPT. However, 3 months of DAPT was associated with a lower risk of bleeding compared with 6 months of DAPT (relative risk [RR], 0.50 [95% CI, 0.29-0.84]) and 12 months of DAPT (RR, 0.57 [95% CI, 0.45-0.71]) among older adults. One month of DAPT was also associated with a lower risk of bleeding compared with 6 months of DAPT (RR, 0.68 [95% CI, 0.54-0.86]).

Conclusions and relevance: In this systematic review and meta-analysis of different durations of DAPT for older adults after PCI, an abbreviated DAPT duration was associated with a lower risk of bleeding without any concomitant increase in the risk of MACE or NACE despite the concern for higher-risk coronary anatomy and comorbidities among older adults. This study, which represents the first network meta-analysis of this shortened treatment for older adults, suggests that clinicians may consider abbreviating DAPT for older adults.

Keywords 
Cardiology elderly patients heart health dual antiplatelet therapy

Management of de Quervain Tenosynovitis: A Systematic Review and Network Meta-Analysis

Author/s: 
Dimitris Challoumas, Rohan Ramasubbu, Elliot Rooney, Emily Seymour-Jackson, Amit Putti, Neal L. Millar

Importance: There is a plethora of treatment options for patients with de Quervain tenosynovitis (DQT), but there are limited data on their effectiveness and no definitive management guidelines.

Objective: To assess and compare the effectiveness associated with available treatment options for DQT to guide musculoskeletal practitioners and inform guidelines.

Data sources: Medline, Embase, PubMed, Cochrane Central, Scopus, OpenGrey.eu, and WorldCat.org were searched for published studies, and the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, The European Union Clinical Trials Register, and the ISRCTN registry were searched for unpublished and ongoing studies from inception to August 2022.

Study selection: All randomized clinical trials assessing the effectiveness of any intervention for the management of DQT.

Data extraction and synthesis: This study was prospectively registered on PROSPERO and conducted and reported per Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions (PRISMA-NMA) and PRISMA in Exercise, Rehabilitation, Sport Medicine and Sports Science (PERSIST) guidance. The Cochrane Risk of Bias tool and the Grading of Recommendations, Assessment, Development, and Evaluations tool were used for risk of bias and certainty of evidence assessment for each outcome.

Main outcomes and measures: Pairwise and network meta-analyses were performed for patient-reported pain using a visual analogue scale (VAS) and for function using the quick disabilities of the arm, shoulder, and hand (Q-DASH) scale. Mean differences (MD) with their 95% CIs were calculated for the pairwise meta-analyses.

Results: A total of 30 studies with 1663 patients (mean [SD] age, 46 [7] years; 80% female) were included, of which 19 studies were included in quantitative analyses. From the pairwise meta-analyses, based on evidence of moderate certainty, adding thumb spica immobilization for 3 to 4 weeks to a corticosteroid injection (CSI) was associated with statistically but not clinically significant functional benefits in the short-term (MD, 10.5 [95% CI, 6.8-14.1] points) and mid-term (MD, 9.4 [95% CI, 7.0-11.9] points). In the network meta-analysis, interventions that included ultrasonography-guided CSI ranked at the top for pain. CSI with thumb spica immobilization had the highest probability of being the most effective intervention for short- and mid-term function.

Conclusions and relevance: This network meta-analysis found that adding a short period of thumb spica immobilization to CSI was associated with statistically but not clinically significant short- and mid-term benefits. These findings suggest that administration of CSI followed by 3 to 4 weeks immobilization should be considered as a first-line treatment for patients with DQT.

Keywords 
de Quervain tenosynovitis DQT pain management Visual Analog Scale VAS Q-DASH corticosteroid injection CSI ultrasonography tendonitis

Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction

Author/s: 
Kuno, T, Ueyama, H, Fujisaki, T, Briasouli, A, Takagi, H, Briasoulis, A

Clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in heart failure with preserved ejection fraction (HFpEF) have suggested neutral results and treatment is focused on associated symptoms and comorbidities. MEDLINE and EMBASE were searched through October 2019 for randomized controlled studies investigating the effects of different RAAS antagonists in patients with HFpEF. The main outcomes were all-cause mortality, trial defined cardiovascular mortality, and heart failure (HF) hospitalizations. To compare different RAAS antagonists, a random-effects restricted-maximum-likelihood network meta-analysis based on a frequentist framework for indirect and mixed comparisons was used. We used p scores to rank best treatments per outcome. Our search identified 5 eligible clinical trials (PEP-CHF, perindopril; CHARM-preserved, candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone; PARAGON-HF, sacubitril-valsartan and valsartan) enrolling a total 10,523 on RAAS antagonists and 6,259 controls. We did not identify any statistical difference in all-cause and cardiovascular mortality among RAAS antagonists and placebo. The combination of sacubitril-valsartan was associated with significantly decreased HF hospitalization risk compared with controls (odds ratio 0.73, 95% confidence interval 0.61 to 0.87) and angiotensin II receptor blockers (odds ratio 0.80, 95% confidence interval 0.71 to 0.91), without heterogeneity among studies (I2 = 0). Angiotensin receptor neprilysin inhibitor (ARNI) ranked better than other RAAS antagonists for HF hospitalizations (p value 0.9). In conclusion, RAAS antagonists do not affect mortality but the combination of sacubitril-valsartan is associated with lower HF hospitalizations in HFpEF patients.

Keywords 
RAAS Anatgonists heart failure

Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis

Author/s: 
Gregori, D., Giacovelli, G., Minto, C., Barbetta, B., Gualtieri, F., Azzolina, D., Vaghi, P.

IMPORTANCE:

Even though osteoarthritis is a chronic and progressive disease, pharmacological agents are mainly studied over short-term periods, resulting in unclear recommendations for long-term disease management.

OBJECTIVE:

To search, review, and analyze long-term (≥12 months) outcomes (symptoms, joint structure) from randomized clinical trials (RCTs) of medications for knee osteoarthritis.

DATA SOURCES AND STUDY SELECTION:

The databases of MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until June 30, 2018 (MEDLINE alerts through August 31, 2018) for RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer.

DATA EXTRACTION AND SYNTHESIS:

Data at baseline and at the longest available treatment and follow-up of 12 months' duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta-analysis was performed.

MAIN OUTCOMES AND MEASURES:

The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value.

RESULTS:

Forty-seven RCTs (22 037 patients; mean age range, mostly 55-70 years; and a higher mean proportion of women than men, around 70%) included the following medication categories: analgesics; antioxidants; bone-acting agents such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs in osteoarthritis such as glucosamine and chondroitin sulfate; and putative disease-modifying agents such as cindunistat and sprifermin. Thirty-one interventions were studied for pain, 13 for physical function, and 16 for joint structure. Trial duration ranged from 1 to 4 years. Associations with decreases in pain were found for the nonsteroidal anti-inflammatory drug celecoxib (SMD, -0.18 [95% CrI, -0.35 to -0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, -0.29 [95% CrI, -0.49 to -0.09]), but there was large uncertainty for all estimates vs placebo. The association with pain improvement remained significant only for glucosamine sulfate when data were analyzed using the mean difference on a scale from 0 to 100 and when trials at high risk of bias were excluded. Associations with improvement in joint space narrowing were found for glucosamine sulfate (SMD, -0.42 [95% CrI, -0.65 to -0.19]), chondroitin sulfate (SMD, -0.20 [95% CrI, -0.31 to -0.07]), and strontium ranelate (SMD, -0.20 [95% CrI, -0.36 to -0.05]).

CONCLUSIONS AND RELEVANCE:

In this systematic review and network meta-analysis of studies of patients with knee osteoarthritis and at least 12 months of follow-up, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo. Larger RCTs are needed to resolve the uncertainty around efficacy of medications for knee osteoarthritis.

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