Umbrella review of 42 systematic reviews with meta-analyses: the safety of proton pump inhibitors.

BACKGROUND: Proton pump inhibitors (PPIs) are widely used to treat and prevent acid-related disorders. Despite high efficacy, PPI safety has been increasingly scrutinised. However, no comprehensive review summarising investigations of various adverse events is available. AIMS: To perform an umbrella review to comprehensively assess associations between adverse events and PPI use. METHODS: In accordance with PRISMA, an umbrella review of systematic reviews with meta-analyses was conducted. PubMed and EMBASE were searched from 2015 to July 2019. AMSTAR 2 and GRADE were used to assess quality and certainty of evidence. Author-reported quality assessments were also reviewed. RESULTS: Forty-two systematic reviews with meta-analyses, supported predominantly by observational evidence, were included. The most comprehensive studies reported statistically significant associations with PPI use for several outcomes, including: fractures (eg, hip; RR = 1.20; 95% CI = 1.14-1.28; n = 2 103 800), kidney disease (eg, acute kidney injury; RR = 1.61; 95% CI = 1.16-2.22; n = 2 396 640), infections (eg, Clostridioides difficile; OR = 1.99; 95% CI = 1.73-2.30; n = 356 683), gastric cancer (OR = 2.50; 95% CI = 1.74-3.85; n = 943 070) and gastrointestinal events (eg, fundic gland polyps; OR = 2.46; 95% CI = 1.42-4.27; n = 40 218). No associations with non-gastric cancers, or neurological disease were concluded, with conflicting evidence for cardiovascular outcomes. Certainty based on GRADE was very low for most outcomes. CONCLUSIONS: This review identified several published associations between PPIs and adverse outcomes, however, further investigation is needed to understand their clinical significance and the likelihood of causal relationship. If higher quality evidence is generated substantiating the potential risks, it may be necessary for clinicians to consider alternative treatment strategies, especially when PPI efficacy is suboptimal.

Risk of recurrence among patients with HR-positive, HER2-negative, early breast cancer receiving adjuvant endocrine therapy: A systematic review and meta-analysis.

BACKGROUND: A systematic review and meta-analysis was conducted to assess breast cancer (BC) outcomes among patients with early-stage hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) BC, receiving adjuvant endocrine therapy. METHODS: Randomized controlled trials (RCTs) and real-world evidence (RWE) studies were identified using Ovid MEDLINE®, Embase, and Evidence-Based Medicine Reviews. Clinical and methodological similarities including alignment of outcome definitions with standardized definitions for efficacy endpoints criteria were assessed to evaluate feasibility of conducting a meta-analysis. Where feasible, 5-year probabilities of BC recurrence or death were estimated using a Bayesian hierarchical arm-based model. RESULTS: Of 21 included studies, 8 RCTs and 4 RWE studies reported outcome data of interest. There was heterogeneity in outcome reporting, as well as variation in recurrence risk amongst studies with aligned reporting. Of the 12 studies, 10 were considered for inclusion in a meta-analysis of BC recurrence or death. Only a subgroup analysis of node-positive patients (3 studies; n = 7307) was deemed feasible. The 5-year probability of BC recurrence or death was 17.2% (95% credible interval: 14.6%-20.3%). CONCLUSION: Although studies reporting recurrence outcomes were limited, there remains a high risk of BC recurrence, especially among node-positive patients. Approximately 1 in 6 women with node-positive HR+/HER2- early-stage BC receiving endocrine therapy experience recurrence or death within 5-years of initiating treatment, suggesting a need for novel treatments for this population.

The impact of clinical heterogeneity on conducting network meta-analyses in transthyretin amyloidosis with polyneuropathy.

Objective: The comparative safety and efficacy of tafamidis, patisiran and inotersen treatments for transthyretin amyloidosis with polyneuropathy (ATTR-PN) has not been evaluated in clinical trials. In the absence of head-to-head evidence, indirect treatment comparisons such as network meta-analyses (NMAs) can be performed to evaluate relative effects of treatments. This study aims to assess the feasibility of conducting an NMA of available therapies for ATTR-PN patients.Methods: Pivotal trials for three approved ATTR-PN treatments, tafamidis (Fx-005), patisiran (APOLLO) and inotersen (NEURO-TTR), were compared in terms of study design, baseline population characteristics, outcome definitions and baseline risk. These assessments of heterogeneity informed the decision to perform Bayesian NMAs.Results: Despite similar study designs, clear differences in eligibility criteria between trials were accompanied by imbalances in baseline population characteristics considered to be plausible effect modifiers, such as disease stage and previous treatment. Of the outcomes assessed, only quality of life and adverse events were similarly reported in all trials. Neuropathy outcomes were not evaluated consistently between trials.Conclusions: An NMA of ATTR-PN treatments was not feasible, given the observed cross-trial heterogeneity. This decision highlights the importance of careful consideration for clinical heterogeneity that may threaten the validity of indirect comparisons.