Multimorbidity matters in low and middle-income countries.

Multimorbidity is a complex challenge affecting individuals, families, caregivers, and health systems worldwide. The burden of multimorbidity is remarkable in low- and middle-income countries (LMICs) given the many existing challenges in these settings. Investigating multimorbidity in LMICs poses many challenges including the different conditions studied, and the restriction of data sources to relatively few countries, limiting comparability and representativeness. This has led to a paucity of evidence on multimorbidity prevalence and trends, disease clusters, and health outcomes, particularly longitudinal outcomes. In this paper, based on our experience of investigating multimorbidity in LMICs contexts, we discuss how the structure of the health system does not favor addressing multimorbidity, and how this is amplified by social and economic disparities and, more recently, by the COVID-19 pandemic. We argue that generating epidemiologic data around multimorbidity with similar methods and definition is essential to improve comparability, guide clinical decision-making and inform policies, research priorities, and local responses. We call for action on policy to refinance and prioritize primary care and integrated care as the center of multimorbidity.

High quality (certainty) evidence changes less often than low-quality evidence, but the magnitude of effect size does not systematically differ between studies with low versus high-quality evidence.

RATIONALE, AIMS, AND OBJECTIVES: It is generally believed that evidence from low quality of evidence generate inaccurate estimates about treatment effects more often than evidence from high (certainty) quality evidence (CoE). As a result, we would expect that (a) estimates of effects of health interventions initially based on high CoE change less frequently than the effects estimated by lower CoE (b) the estimates of magnitude of effect size differ between high and low CoE. Empirical assessment of these foundational principles of evidence-based medicine has been lacking. METHODS: We reviewed the Cochrane Database of Systematic Reviews from January 2016 through May 2021 for pairs of original and updated reviews for change in CoE assessments based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. We assessed the difference in effect sizes between the original versus updated reviews as a function of change in CoE, which we report as a ratio of odds ratio (ROR). We compared ROR generated in the studies in which CoE changed from very low/low (VL/L) to moderate/high (M/H) versus M/H to VL/L. Heterogeneity and inconsistency were assessed using the tau and I2 statistic. We also assessed the change in precision of effect estimates (by calculating the ratio of standard errors) (seR), and the absolute deviation in estimates of treatment effects (aROR). RESULTS: Four hundred and nineteen pairs of reviews were included of which 414 (207 × 2) informed the CoE appraisal and 384 (192 × 2) the assessment of effect size. We found that CoE originally appraised as VL/L had 2.1 [95% confidence interval (CI): 1.19-4.12; p = 0.0091] times higher odds to be changed in the future studies than M/H CoE. However, the effect size was not different (p = 1) when CoE changed from VL/L → M/H [ROR = 1.02 (95% CI: 0.74-1.39)] compared with M/H → VL/L (ROR = 1.02 [95% CI: 0.44-2.37]). Similar overlap in aROR between the VL/L → M/H versus M/H → VL/L subgroups was observed [median (IQR): 1.12 (1.07-1.57) vs. 1.21 (1.12-2.43)]. We observed large inconsistency across ROR estimates (I2 = 99%). There was larger imprecision in treatment effects when CoE changed from VL/L → M/H (seR = 1.46) than when it changed from M/H → VL/L (seR = 0.72). CONCLUSIONS: We found that low-quality evidence changes more often than high CoE. However, the effect size did not systematically differ between the studies with low versus high CoE. The finding that the effect size did not differ between low and high CoE indicate urgent need to refine current EBM critical appraisal methods.

Quality of clinical practice guidelines for inadequate response to first-line treatment for depression according to AGREE II checklist and comparison of recommendations: a systematic review.

OBJECTIVE: To assess similarities and differences in the recommended sequence of strategies among the most relevant clinical practice guidelines (CPGs) for the treatment of depression in adults with inadequate response to first-line treatment. DATA SOURCES: We performed a systematic review of the literature spanning January 2011 to August 2020 in Medline, Embase, Cochrane Library and 12 databases recognised as CPGs repositories. CPGs quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II). STUDY SELECTION: The eligibility criteria were CPGs that described pharmacological recommendations for treating depression for individuals aged 18 years or older in outpatient care setting. We included CPGs considered of high-quality (≥80% in domain 3 of AGREE II) or recognised as clinically relevant. DATA EXTRACTION: Two independent researchers extracted recommendations for patients who did not respond to first-line pharmacological treatment from the selected CPGs. RESULTS: We included 46 CPGs and selected 8, of which 5 were considered high quality (≥80% in domain 3 of AGREE II) and 3 were recognised as clinically relevant. Three CPGs did not define inadequate response to treatment and 3 did not establish a clear sequence of strategies. The duration of treatment needed to determine that a patient had not responded was not explicit in 3 CPGs and was discordant in 5 CPGs. Most CPGs agree in reassessing the diagnosis, assessing the presence of comorbidities, adherence to treatment, and increase dosage as first steps. All CPGs recommend psychotherapy, switching antidepressants, and considering augmentation/combining antidepressants. CONCLUSION: Relevant CPGs present shortcomings in recommendations for non-responders to first-line antidepressant treatment including absence and divergencies in definition of inadequate response and sequence of recommended strategies. Overall, most relevant CPGs recommend reassessing the diagnosis, evaluate comorbidities, adherence to treatment, increase dosage of antidepressants, and psychotherapy as first steps. PROSPERO REGISTRATION NUMBER: CRD42016043364.

Evaluation of the initial response in clinical trial efforts for COVID-19 in Brazil. / Avaliação da resposta inicial de desenvolvimento de ensaios clínicos para COVID-19 no Brasil.

OBJECTIVE: To describe the methodological characteristics and good research practices of COVID-19 interventional studies developed in Brazil in the first months of the pandemic. METHODS: We reviewed the bulletin of the National Research Ethics Committee - Coronavirus Special Edition (Comissão Nacional de Ética em Pesquisa - CONEP-COVID) (May 28, 2020) and the databases of the International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos - ReBEC) to identify interventional studies registered in Brazil that assessed drug type, biological therapy, or vaccines. We described their methodological characteristics and calculated their power for different effect magnitudes. RESULTS: A total of 62 studies were included, 55 retrieved from the CONEP website, and 7 from registry databases. The most tested pharmacological interventions in these studies were: chloroquine/hydroxychloroquine, azithromycin, convalescent plasma, tocilizumab, sarilumab, eculizumab, vaccine, corticosteroids, anticoagulants, n-acetylcysteine, nitazoxanide, ivermectin, and lopinavir/ritonavir. Out of 22 protocols published on registry databases until May 2020, 18 (82%) were randomized clinical trials, and 13 (59%) had an appropriate control group. However, 9 (41%) of them were masked, and only 5 (24%) included patients diagnosed with a specific laboratory test (for example, reverse transcription polymerase chain reaction - RT-PCR). Most of these studies had power > 80% only to identify large effect sizes. In the prospective follow-up, 60% of the studies available at CONEP until May 2020 had not been published on any registry platform (ICTRP/ReBEC/ClinicalTrials) by July 21, 2020. CONCLUSION: The interventions evaluated during the Brazilian research response reflect those of international initiatives, but with a different distribution and a large number of studies assessing hydroxychloroquine/chloroquine. Limitations in methodological design and sample planning represent challenges that could affect the research outreach.

OBJETIVO: Descrever as características metodológicas e de boas práticas em pesquisa dos estudos de intervenção para COVID-19 desenvolvidos no Brasil nos primeiros meses da pandemia. MÉTODOS: Revisamos o boletim da Comissão Nacional de Ética em Pesquisa - edição especial Coronavírus (CONEP-COVID) (28 de maio de 2020) e as bases International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov e Registro Brasileiro de Ensaios Clínicos (ReBEC) para identificar estudos registrados no Brasil que avaliassem intervenções de tipo de medicamento, terapia biológica ou vacinas. Descrevemos as características metodológicas e calculamos o poder para diferentes magnitudes de efeito. RESULTADOS: Foram incluídos 62 estudos, 55 identificados no site da CONEP e mais sete nas bases de registro. As intervenções medicamentosas mais frequentemente testadas nesses estudos foram: cloroquina/hidroxicloroquina, azitromicina, plasma convalescente, tocilizumabe, sarilumabe, eculizumabe, vacina, corticoides, anticoagulantes, n-acetilcisteína, nitazoxanida, ivermectina e lopinavir/ritonavir. De 22 protocolos publicados até maio de 2020 nas bases de registro, 18 (82%) eram ensaios clínicos randomizados e 13 (59%) tinham grupo controle adequado. Entretanto, nove (41%) eram mascarados e somente cinco (24%) incluíam pacientes diagnosticados com teste de laboratório específico (por exemplo, transcrição reversa seguida de reação em cadeia da polimerase - RT-PCR). A maioria desses trabalhos teria poder > 80% apenas para identificar grandes tamanhos de efeito. Em seguimento prospectivo, observamos que 60% dos estudos disponíveis na CONEP até maio de 2020 não estavam em nenhuma das plataformas de registro (ICTRP/ReBEC/ClinicalTrials) até o dia 21 de julho de 2020. CONCLUSÃO: As intervenções avaliadas durante a resposta brasileira em pesquisa refletem iniciativas internacionais, porém com distribuição diferente, tendo número elevado de estudos que avaliam hidroxicloroquina/cloroquina. Limitações no delineamento metodológico e planejamento amostral representam desafios que podem afetar o alcance dos trabalhos.