Safety of dihydroartemisinin-piperaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria among children in Africa: a systematic review and meta-analysis of randomized control trials

Background The efficacies of artemisinin based combinations have been excellent in Africa, but also comprehensive evidence regarding their safety would be important. The aim of this review was to synthesize available evidence on the safety of dihydroartemisinin-piperaquine (DHA-PQ) compared to artemether-lumefantrine (AL) for the treatment of uncomplicated Plasmodium falciparum malaria among children in Africa. Methods A systematic literature search was done to identify relevant articles from online databases PubMed/ MEDLINE, Embase, and Cochrane Center for Clinical Trial database (CENTRAL) for retrieving randomized control trials comparing safety of DHA-PQ and AL for treatment of uncomplicated P. falciparum malaria among children in Africa. The search was performed from August 2020 to 30 April 2021. Using Rev-Man software (V5.4.1), the extracted data from eligible studies were pooled as risk ratio (RR) with 95% confidence interval (CI). Results In this review, 18 studies were included, which involved 10,498 participants were included. Compared to AL, DHA-PQ was associated with a slightly higher frequency of early vomiting (RR 2.26, 95% CI 1.46 to 3.50; participants = 7796; studies = 10; I2 = 0%, high quality of evidence), cough (RR 1.06, 95% CI 1.01 to 1.11; participants = 8013; studies = 13; I2 = 0%, high quality of evidence), and diarrhoea (RR 1.16, 95% CI 1.03 to 1.31; participants = 6841; studies = 11; I2 = 8%, high quality of evidence) were more frequent in DHA-PQ treatment arm. Conclusion From this review, it can be concluded that early vomiting, diarrhoea, and cough were common were significantly more frequent in patients who were treated with the DHA-PQ than that of AL, and both drugs are well tolerated. More studies comparing AL with DHA-PQ are needed to determine the comparative safety of these drugs.

Monitoring the Comparative Safety of SGLT2i vs GLP-1 RA in Older Adults With Type 2 Diabetes by Frailty Status

Using Medicare (4/2013-12/2017), we conducted 9 sequential analyses of patients with type 2 diabetes initiating SGLT2i vs. GLP1-RA mimicking the accrual of new data every 6 months to monitor SGLT2i safety with respect to diabetic ketoacidosis (DKA) since their U.S. approval. For each analysis, we estimated cumulative HRs (95% CIs) after 1:1 propensity score matching on >70 covariates comparing treatments within frail and non-frail patients. By analysis 1, SGLT2i were associated with a higher DKA rate vs. GLP-1RA in both frail and non-frail patients, but results were highly imprecise due to few events. With the accrual of more DKA events, precision of the estimates continued to improve through analysis 9 [HR=2.95 (95% CI, 1.19-7.31)] in frail patients; [HR=1.77 (1.15, 2.75)] in non-frail patients], with sufficiently precise estimates by analysis 6 in frail patients [HR=2.80 (95% CI, 1.03, 7.61)] and by analysis 7 in non-frail patients [HR=1.62 (95% CI, 1.01, 2.57)].

Anti-vascular endothelial growth factor therapy for age-related macular degeneration: a systematic review and network meta-analysis

Background The comparative safety and efficacy between anti-vascular endothelial growth factor agents (anti-VEGFs) and between combined therapies for patients with neovascular age-related macular degeneration (nAMD) is unclear. We conducted a systematic review to examine the comparative safety and efficacy anti-VEGFs for adults with nAMD. Methods Studies were identified through MEDLINE, EMBASE, and Cochrane CENTRAL (inception to June 3, 2019), grey literature, and scanning reference lists. Two reviewers independently screened citations and full-text articles to identify randomized controlled trials (RCTs), extracted data, and appraised risk of bias. Pairwise random-effects meta-analysis and Bayesian network meta-analysis (NMA) were conducted. The primary outcomes were the proportion of patients experiencing moderate vision gain (≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart) and the proportion of patients experiencing moderate vision loss (≤ 15 letters). Results After screening 3647 citations and 485 potentially relevant full-text articles, 92 RCTs with 24,717 patients were included. NMA (34 RCTs, 8809 patients, 12 treatments) showed small differences among anti-VEGFs in improving the proportion of patients with moderate vision gain, with the largest for conbercept versus broluczumab (OR 0.15, 95% CrI: 0.05–0.56), conbercept versus ranibizumab (OR 0.17, 95% CrI: 0.05–0.59), conbercept versus aflibercept (OR 0.19, 95% CrI: 0.06–0.65), and conbercept versus bevacizumab (OR 0.2, 95% CrI: 0.06–0.69). In NMA (36 RCTs, 9081 patients, 13 treatments) for the proportion of patients with moderate vision loss, small differences were observed among anti-VEGFs, with the largest being for conbercept versus aflibercept (OR 0.24, 95% CrI: 0–4.29), conbercept versus brolucizumab (OR 0.24, 95% CrI: 0–4.71), conbercept versus bevacizumab (OR 0.26, 95% CrI: 0–4.65), and conbercept versus ranibizumab (OR 0.27, 95% CrI: 0–4.67). Conclusion The only observed differences were that ranibizumab, bevacizumab, aflibercept, and brolucizumab were statistically superior to conbercept in terms of the proportion of patients with nAMD who experienced moderate vision gain. However, this finding is based on indirect evidence through one small trial comparing conbercept with placebo. This does not account for drug-specific differences when assessing anatomic and functional treatment efficacy in variable dosing regimens. Systematic review registration PROSPERO registration number CRD42015022041.

Evaluating Diuretics in Normal Care (EVIDENCE): protocol of a cluster randomised controlled equivalence trial of prescribing policy to compare the effectiveness of thiazide-type diuretics in hypertension

Introduction Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For commonly prescribed drugs, even small differences in effectiveness or safety could have significant public health implications. However, conventional clinical trials that randomise individual subjects are costly and unwieldy. Such trials are also often criticised as having low external validity. We describe an approach to rapidly generate externally valid evidence of comparative safety and effectiveness using the example of two widely used diuretics for the management of hypertension. Methods and analysis The EVIDENCE (Evaluating Diuretics in Normal Care) study has a prospective, cluster-randomised, open-label, blinded end-point design. By randomising prescribing policy in primary care practices, the study compares the safety and effectiveness of commonly used diuretics in treating hypertension. Participating practices are randomised 1:1 to a policy of prescribing either indapamide or bendroflumethiazide when clinically indicated. Suitable patients who are not already taking the policy diuretic are switched accordingly. All patients taking the study medications are written to explaining the rationale for changing the prescribing policy and notifying them they can opt-out of any switch. The prescribing policies’ effectiveness and safety will be compared using rates of major adverse cardiovascular events (hospitalisation with myocardial infarction, heart failure or stroke or cardiovascular death), routinely collected in national healthcare administrative datasets. The study will seek to recruit 250 practices to provide a study population of approximately 50,000 individuals with a mean follow-up time of two years. A primary intention-to-treat time-to-event analysis will be used to estimate the relative effect of the two policies. Ethics and dissemination EVIDENCE has been approved by the East of Scotland Research Ethics Service (17/ES/0016, current approved protocol version 5, 26 August 2021). The results will be disseminated widely in peer reviewed journals, guideline committees, National Health Service (NHS) organisations and patient groups. Trial registration ISRCTN46635087. Registered on 11 August 2017 (pre-recruitment).

Efficacy and safety of Impella 5.0 in cardiogenic shock: an updated systematic review

Aim: The impact on safety and efficacy outcomes of Impella 5.0 in cardiogenic shock (CS) has not been systematically assessed. Materials & methods: We conducted a systematic review of the literature (PROSPERO protocol: CRD42020164680) to critically appraise available evidence on Impella 5.0 comparative safety, efficacy and effectiveness. Results: Of 244 retrieved citations, 17 original articles met the a priori defined inclusion criteria. All included studies had a retrospective study design and, overall, reported on, respectively, 52 and 67 different safety and efficacy/effectiveness outcomes. Thirty-day survival rates ranged from 40 to 94%, myocardial recovery from 18 to 93%. Conclusion: Impella 5.0 provides a full cardiac support, it is associated with a lower rate of vascular complications, it represents a valuable bridge-to-decision and allows for resolution of intercurrent clinical conditions. As available data suggest Impella 5.0 good performance in CS of various etiologies, more solid evidence will come from much-needed large-scale all-comer registries and prospective multicenter randomized trials.