A REB-reading of cholinesterase inhibitors' effect on all-cause mortality in patients with dementia.

We propose a new reading of the results of a solid systematic review published in 2022 in Neurology by Truong et al comparing ChEI treatment to placebo or no treatment on all-cause mortality in patients with any type of dementia. Leaving ethical considerations aside, we tested if another method of interpretation of the results of the systematic review would yield different results. We applied the "rebuild the evidence base" (REB) method to the data extracted from the meta-analysis and found that the positive result of the meta-analysis (p=0.01) and the lack of heterogeneity did not weigh enough in the balance against the strictly exploratory nature of all the results of the individual RCTs included and the suspected publication bias. There was a lack of evidence of effect of ChEI treatment on over-all mortality in patients with dementia.

A critical appraisal of acute sore throat guidelines using the AGREE II instrument: a scoping review.

BACKGROUND: Conflicting international guidelines exist on the management of sore throat by antibiotics. OBJECTIVES: To assess with the Appraisal of Guidelines for Research and Evaluation II (AGREE) instrument the quality of guidelines for uncomplicated acute group A beta-haemolytic streptococcal (GABHS) sore-throat. To make a sensitivity analysis restricted to guidelines with a rigour of development score higher than 60% and to describe their recommendations on scores, tests, and antibiotic therapy, including their justification. METHODS: A guideline literature review of acute GABHS sore throat, published between January 2000 and December 2019 in primary care and secondary care. The PubMed database, the Canadian Medical Association Infobase on Clinical Practice Guidelines and the International Network Guidelines were used. The quality of guidelines was assessed using the AGREE II instrument. The guidelines were classified into 2 categories: high-quality guidelines had to rate >60% for the rigour of development score, the others were classified as low-quality guidelines. RESULTS: Significant heterogeneity between the 15 guidelines concerned the scores of the 6 assessment domains. Among them, 6 guidelines presented a score above 60% with regards to the rigor of development domain and used a systematic literature search method, citing meta-analyses of recent randomised clinical trials. Most of the 6 high-quality guidelines no longer recommended the systematic use of diagnostic scores and tests, nor antibiotic therapy to prevent acute rheumatic fever or loco-regional complications, except for high-risk patients. CONCLUSION: Major discrepancies emphasise the need for only high-quality guidelines, based on adequately assessed evidence. Restricted antibiotic prescriptions to severe cases or high-risk patients would avoid antibiotic resistance.

Does the use of antipyretics prolong illness? A systematic review of the literature and meta-analysis on the effects of antipyretics in acute upper and lower respiratory tract infections.

OBJECTIVE: Fever contributes to the inflammatory response; in some infections, antipyretics could prolong the illness. The objective of our study was to evaluate the impact of antipyretic treatments on the evolution of acute upper and lower respiratory tract infections (RTI). METHOD: A systematic literature review of randomized controlled trials (RCTs) with meta-analysis was conducted. Our primary endpoint was the time to recovery from illness. Our prespecified secondary endpoints were quality of life, duration and number of fever episodes, repeated medical visits, and adverse events. RESULTS: Out of the 1466 references found, 25 RCTs were included. There were two studies assessing mean fever clearance time, and five studies examining the duration of symptoms associated with the illness studied. No statistically significant differences were found when pooling the results of the different studies. The assessment of adverse events showed a significant difference disadvantaging non-steroidal anti-inflammatory drugs. No meta-analysis could be performed for our other secondary endpoints. The quality of the evidence is limited by the small number of studies included for our primary endpoint and by heterogeneity between the studies. CONCLUSION: Our results suggest that the use of antipyretics does not prolong or shorten illness duration in acute upper and lower RTI. The symptomatic efficacy of antipyretics must be weighed against their adverse effects, particularly when fever is well-tolerated.

Critical appraisal of international guidelines for the management of Helicobacter pylori infection in case of dyspepsia.

BACKGROUND: Affecting between 20% and 90% of the world's population depending on the geo-socio-economic conditions, Helicobacter pylori (Hp) infection requires an adapted management because of the medico-economic stakes it generates. Also responsible for dyspepsia, the management of Hp infection differs in this context between international guidelines. OBJECTIVES: The primary outcome of the study was assessing the quality of current guidelines for HP eradication in dyspepsia. The secondary was defining the best therapeutic strategy for patients consulting with dyspepsia in the outpatient setting. METHODS: Clinical practice guidelines (CPG) published between January 2000 and May 2021 were retrieved from various databases (PubMed; Guidelines International Network; websites of scientific societies that issued the guidelines). Their quality was assessed using the AGREE II evaluation grid. To provide decision support for healthcare practitioners, particularly in primary care, a summary of the main points of interest for management was made for each guideline. RESULTS: Fourteen guidelines were included. Only four (28.6%) could be validated according to AGREE II? Most of the non-validated guidelines had low ratings in the "Rigour of development" and "Applicability" domains with means of 40% [8%-71%] and 14% [0%-25%], respectively. Three out of four validated guidelines (75%) advocated a "test and treat" strategy for dyspepsia based on the national prevalence of Hp. Gastroscopy was the 1st line examination method in case of warning signs or high risk of gastric cancer. Triple therapy (Proton pomp inhibitor, amoxicillin, and clarithromycin) was favored for Hp eradication but required a study of the sensitivity to clarithromycin in the validated guidelines. Antibiotic resistance also had an impact on treatment duration. CONCLUSIONS: Many guidelines were of poor quality, providing few decision-making tools for practical use. Conversely, those of good quality had established a management strategy addressing the current problems associated with the emergence of antibiotic-resistant strains.

[Does aspirin have a place in primary cardiovascular prevention by the polypill ? Simulation study on a realistic virtual population]. / L'aspirine a-t-elle une place dans la prévention cardiovasculaire primaire par la polypill ? Étude de simulation sur une population virtuelle réaliste.

BACKGROUND: The polypill strategy could become widely accepted in cardiovascular prevention due to reduced costs and its simplicity, which promote compliance. Aspirin is often included as a component of the polypill for primary prevention, but three powerful recent trials failed to show any favorable net benefit even in high-risk subgroups. Our objective is to estimate the net benefit associated with aspirin in primary cardiovascular prevention. METHODS: We simulated the impact of different polypill compositions combining pravastatin, ramipril, hydrochlorothiazide, with or without aspirin, on a realistic French virtual population between 35 and 65 years old. We assessed how this impact on myocardial infarction and stroke varied according to gender, diabetes, and arterial hypertension. We identified the subgroup of individuals whose specific benefit from aspirin was greater than twice the risk of serious bleeding it induced. RESULTS: The absolute benefit associated with aspirin was reduced by co-prescriptions. No subgroup of women benefited from aspirin, and the subgroup of women with a clear net benefit represented 128 women out of 529,421. Men at high risk of cardiovascular death, or with diabetes and hypertension, had a benefit from aspirin exceeding the risk of bleeding induced, but this risk represented more than half of the benefit. No subgroup analyzed did show a benefit greater than twice the risk of bleeding. The proportion of men whose expected benefit from aspirin was greater than twice the risk of bleeding represented 3% of all men. An optimal polypill strategy in primary prevention between the ages of 35 and 65, combining three drugs but not aspirin, can hope to save two out of three strokes and more than one out of two myocardial infarctions. It would prevent a major cardiovascular accident every 16 to 193 individuals treated according to the subgroups considered. CONCLUSION: Until proven otherwise, aspirin has only a limited place in individuals between 35 and 65 years without a cardiovascular history. We showed how simulating therapeutic strategies on a realistic virtual population could be used for best applying available evidence.

Project rebuild the evidence base (REB): A method to interpret randomised clinical trials and their meta-analysis to present solid benefit-risk assessments to patients.

Evidence-based medicine is the cornerstone of shared-decision making in healthcare today. The public deserves clear, transparent and trust-worthy information on drug efficacy. Yet today, many drugs are prescribed and used without solid evidence of efficacy. Clinical trials and randomised clinical trials (RCTs) are the best method to evaluate drug efficacy and side effects. In a shared medical decision-making approach, general practitioners need drug assessment based on patient-important outcomes. The aim of project rebuild the evidence base (REB) is to bridge the gap between the data needed in clinical practice and the data available from clinical research. The drugs will be assessed on clinical patient important outcomes and for a population. Using the Cochrane tools, we propose to analyse for each population and outcome: 1) a meta-analysis based on RCTs with a low risk of bias overall; 2) an evaluation of results of confirmatory RCTs; 3) a statistical analysis of heterrogeneity between RCTs and 4) an analysis of publication bias. Depending on the results of these analyses, the evidence will be categorized in 4 different levels: firm evidence, evidence (to be confirmed), signal or absence of evidence. Project REB proposes a method for reading and interpreting RCTs and their meta-analysis to produce quality data for general practitioners to focus on risk-benefit assessment in the interest of patients. If this data does not exist, it could enable clinical research to better its aim.

SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits.

AIMS/HYPOTHESIS: Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes. METHODS: We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane 'Risk of bias' assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i. RESULTS: A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from 'genital mycotic infection' to 'genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events'. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection. CONCLUSIONS/INTERPRETATION: Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation. TRIAL REGISTRATION: OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Impact of a phone call with a medical student/general practitioner team on morbidity of chronic patients during the first French COVID-19 lockdown (COVIQuest): a cluster randomised trial.

OBJECTIVES: The first COVID-19 lockdown led to a significantly reduced access to healthcare, which may have increased decompensations in frail patients with chronic diseases, especially older patients living with a chronic cardiovascular disease (CVD) or a mental health disorder (MHD). The objective of COVIQuest was to evaluate whether a general practitioner (GP)-initiated phone call to patients with CVD and MHD during the COVID-19 lockdown could reduce the number of hospitalisation(s) over a 1-month period. DESIGN: This is a cluster randomised controlled trial. Clusters were GPs from eight French regions. PARTICIPANTS: Patients ≥70 years old with chronic CVD (COVIQuest_CV subtrial) or ≥18 years old with MHD (COVIQuest_MH subtrial). INTERVENTIONS: A standardised GP-initiated phone call aiming to evaluate patients' need for urgent healthcare, with a control group benefiting from usual care (ie, the contact with the GP was by the patient's initiative). MAIN OUTCOME MEASURES: Hospital admission within 1 month after the phone call. RESULTS: In the COVIQuest_CV subtrial, 131 GPs and 1834 patients were included in the intervention group and 136 GPs and 1510 patients were allocated to the control group. Overall, 65 (3.54%) patients were hospitalised in the intervention group vs 69 (4.57%) in the control group (OR 0.82, 95% CI 0.56 to 1.20; risk difference -0.77, 95% CI -2.28 to 0.74). In the COVIQuest_MH subtrial, 136 GPs and 832 patients were included in the intervention group and 131 GPs and 548 patients were allocated to the control group. Overall, 27 (3.25%) patients were hospitalised in the intervention group vs 12 (2.19%) in the control group (OR 1.52, 95% CI 0.82 to 2.81; risk difference 1.38, 95% CI 0.06 to 2.70). CONCLUSION: A GP-initiated phone call may have been associated with more hospitalisations within 1 month for patients with MHD, but results lack robustness and significance depending on the statistical approach used. TRIAL REGISTRATION NUMBER: NCT04359875.

How do they add up? The interaction between the placebo and treatment effect: A systematic review.

AIM: The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. METHODS: We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance. RESULTS: Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). CONCLUSION: Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo-sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity.

Vibration of effect in more than 16 000 pooled analyses of individual participant data from 12 randomised controlled trials comparing canagliflozin and placebo for type 2 diabetes mellitus: multiverse analysis.

Objective: To evaluate the impact of conducting all possible pooled analyses across different combinations of randomised controlled trials and endpoints. Design: Multiverse analysis, consisting of numerous pooled analyses of individual participant data. Setting: Individual patient data from 12 randomised controlled trials comparing canagliflozin treatment with placebo, shared on the Yale University Open Data Access project (https://yoda.yale.edu/) platform, up to 16 April 2021. Participants: 15 094 people with type 2 diabetes mellitus. Main outcome measures: Pooled analyses estimated changes in serum glycated haemoglobin (HbA1c), major adverse cardiovascular events, and serious adverse events at weeks 12, 18, 26, and 52. The distribution of effect estimates was calculated for all possible combinations, and the direction and magnitude of the first and 99th centiles of effect estimates were compared. Results: Across 16 332 distinct pooled analyses comparing canagliflozin with placebo for changes in HbA1c, standardised effect estimates were in favour of canagliflozin treatment at both the first centile (-0.75%) and 99th centile (-0.48%); 15 994 (97.93%) analyses showed significant results (P<0.05) in favour of canagliflozin. For major adverse cardiovascular events, estimated hazard ratios were 0.20 at the first centile and 0.90 at the 99th centile; 2705 of 8144 analyses (33.21%) were significant, all of which were in favour of canagliflozin treatment. For serious adverse events, estimated hazard ratios were 0.59 at the first centile and 1.14 at the 99th centile; 5793 of 16 332 (35.47%) analyses were significant, with 5754 in favour of canagliflozin and 39 in favour of placebo. Conclusion: Results from pooled analyses can be subject to vibration of effects and should be critically appraised, especially regarding the risk for selection and availability bias in individual participant data retrieved.

Development of a patient decision aid for COVID-19 vaccination with the Comirnaty vaccine.

BACKGROUND: SARS-CoV-2 has been responsible for a pandemic since the beginning of 2020. Vaccine arrival brings a concrete solution to fight the virus. However, vaccine hesitancy is high. In France, the first available vaccine was Comirnaty from Pfizer-BioNTech. Shared decision-making, based on tools such as patient decision aids (PtDAs), can help patients make an informed choice about vaccination with Comirnaty. OBJECTIVE: The French College of Teachers in General Practice (CNGE) aimed to create a PtDA for people who have to decide whether they will receive the Comirnaty vaccine. METHODS: Development of the PtDA was performed according to the International Patient Decision Aids Standards (IPDAS). The initial design was based on a literature review and semistructured interviews with 17 patients to explore and clarify patients' expectations. A first draft of the PtDA was then alpha tested by a patient expert group and a physician expert group. The PtDA was finally beta tested in 14 prevaccine consultations. A steering group was consulted throughout the work. Patient support, community groups and the French National Authority for Health (HAS) were involved in the development process. RESULTS: A literature review identified one randomized trial on Comirnaty efficacy and safety. The first part of the PtDA allows patients to identify their own risk factors. The second part of the PtDA provides information on vaccination: benefits and risks, unknown data, and technical explanations about the mRNA vaccine. CONCLUSIONS: We developed a PtDA to be used in primary care settings for shared decision-making regarding vaccination with Comirnaty.

Reappraisal of the efficacy of intensive glycaemic control on microvascular complications in patients with type 2 diabetes: A meta-analysis of randomised control-trials.

OBJECTIVE: To re-assess the effect of tight glycaemic control on diabetic microvascular complications. METHOD: Meta-analysis and trial sequential analyses of randomised trials included in Hemmingsen et al that specifically assessed glycaemic control with a specific HbA1c level targeted in the intervention group, and compared intensive glycaemic control versus standard glycaemic control. RESULTS: Seven clinical trials that randomised 28,614 participants with type 2 diabetes (15,269 to intensive control and 13,345 to conventional control), including 3 sub-studies, were included. Strict control of blood glucose levels is associated with a reduction of retinopathy progression (RR=0.77, 95% CI: 0.66-0.89, I2=33%), incidence or progression of macular oedema (RR=0.66, 95% CI: 0.40-0.99, I2=0%), number of photocoagulations (RR=0.84, 95% CI: 0.73-0.97, I2=0%), risk of microalbuminuria (RR=0.76, 95% CI: 0.64-0.9, I2=76%) and risk of "macroalbuminuria or proteinuria" (RR=0.68, 95% CI: 0.55-0.85, I2=36%). CONCLUSION: This meta-analysis has shown that a tight control of blood glucose levels is associated with a decrease of specific microvascular complication of diabetes: photocoagulation, progression of diabetic retinopathy, incidence or progression of macular oedema, risk of microalbuminuria and risk of macroalbuminuria or proteinuria. Regarding all the other outcomes (vision loss, surgery of cataract, proliferative or non-proliferative retinopathy, death related to kidney disease, development of kidney disease, doubling of serum creatinine, neuropathy), no significant result was found.

Benefits and adverse effects of sacubitril/valsartan in patients with chronic heart failure: A systematic review and meta-analysis.

This review aims to assess the benefits and adverse effects of sacubitril/valsartan in heart failure, with a focus on important patient outcomes. A systematic review was conducted of double-blind randomized controlled trials (RCTs) comparing sacubitril/valsartan versus a reference drug, in heart failure patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction, published in French or English. Searches were undertaken of Medline, Cochrane Central, and Embase. The primary outcomes were all-cause mortality and adverse events. From 2 082 articles analyzed, 5 were included. For all-cause mortality, the absolute numbers for HFrEF (2 RCTs, 4627 patients) were 16% on sacubitril/valsartan and 18% on enalapril, with a risk ratio (RR) of 0.85 [CI = 0.78, 0.93], and 13% vs 14% in with HFpEF (2 RCTs, 5097 patients), with no statistical difference. Under the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the evidence for HFrEF patients was of moderate quality. For HFrEF patients, an increased risk of symptomatic hypotension and angioedema (low quality of evidence) was shown. There was no statistical difference for the risk of hyperkalemia or worsening renal function. There was a protective RR (0.50 [0.34, 0.75]) for worsening renal function for patients with HFpEF, with a high quality of evidence despite similar absolute numbers (1.4% vs. 2.8%). To keep in mind for shared decision-making, sacubitril/valsartan reduces all-cause mortality in HFrEF patients but for HFpEF further data are needed. Take into consideration the small number of studies to date to assess the risks.

An open science pathway for drug marketing authorization-Registered drug approval.

Florian Naudet and co-authors propose a pathway involving registered criteria for evaluation and approval of new drugs.

National institutions should improve the information made available to patients about cervical smears.

OBJECTIVE: To assess the quality of the content of leaflets tools and websites of national institutions in United Kingdom and France informing patients about cervical smears. METHODS: We collected and analyzed the data and information on these two websites and leaflets made for patients. We screened those tools with the UP TO DATE SCIENTIFIC EVIDENCE IPDAS grid. RESULTS: None of the tools specify the level of evidence of the studies on which cervix cancer screening is based. The risk of complication due to cancer is poor. The effectiveness of screening in absolute value is not available. The risks and side-effects due to cervical smears are specified without the frequency. CONCLUSION: Information is truncated and pushes readers towards taking part in screening. This is not in accordance with the quality criteria of shared decision making. PRACTICE IMPLICATIONS: Patients should take part in the creation of decision making tools, so that the information is the most suited to their representations and understanding. This is why the documents made available by institutions should be based on recognized scientific sources. Responsible of health programs should be independent and separated from those responsible of information tool creation.