Clinician's Approach to Advanced Statistical Methods: Win Ratios, Restricted Mean Survival Time, Responder Analyses, and Standardized Mean Differences.

Novel statistical methods have emerged in recent medical literature, which clinicians must understand to properly appraise and integrate evidence into their practice. Some of these key concepts include win ratios, restricted mean survival time, responder analyses, and standardized mean difference. This article offers guidance to busy clinicians on the comprehension and practical applicability of the results to patients. Win ratios provide an alternative method to analyze composite outcomes by prioritizing individual components of the composite; prioritization of the outcomes should be evidence-based, pre-specified, and patient-centered. Restricted mean survival time presents a method to analyze Kaplan-Meier curves when assumptions required for Cox proportional hazards analysis are not met. As it only considers outcomes that occur within a specific timeframe, the duration of follow-up must be appropriately defined and based on prior epidemiologic and mechanistic evidence. Researchers can analyze continuous outcomes with responder analyses, in which participants are dichotomized into "responders" or "non-responders." While clinicians and patients may more easily grasp outcomes analyzed in this way, they should be aware of the loss of information and resulting imprecision, as well as potential to manipulate data presentation. When meta-analyzing continuous outcomes, point estimates can be converted to standardized mean differences to facilitate the combination of data utilizing various outcome measures. However, clinicians may find it challenging to grasp the clinical meaningfulness of a standardized mean difference, and may benefit from converting it to well-known outcomes. By providing the background knowledge of these statistical methods, along with practical applicability, benefits, and inevitable limitations, this article aims to provide clinicians with an approach to appraise the literature and apply the results in clinical practice.

Shared decision-making approach to type 2 diabetes management.

OBJECTIVE: To provide an online interactive decision aid to facilitate shared decision making in the context of medication choices for patients with type 2 diabetes mellitus (T2DM). SOURCES OF INFORMATION: The best available clinical prediction model for patients with T2DM was selected based on a review of guidelines, DynaMed, and UpToDate and a search of PubMed. A list of pharmacotherapeutic options for T2DM was compiled based on a review of guidelines, narrative reviews, and expert opinion. To determine the benefits and harms of each treatment, federated search engines were searched for meta-analyses of randomized controlled trials, supplemented by individual randomized controlled trials for outcomes not reported in meta-analyses. MAIN MESSAGE: Approximately 2.1 million Canadians have T2DM, with a resulting increased risk of death, cardiovascular disease, and microvascular outcomes. While more than a dozen medication options are available, decisions regarding these medications are challenging, as patients vary in their preferences. Shared decision making has the potential to individualize these difficult decisions, but the number of diabetes-related outcomes and available treatment options have made this historically impractical. It is within this context that the PEER Diabetes Medication Decision Aid was developed. This decision aid provides patients with personalized 10-year risk estimates for 6 clinically important diabetes-related outcomes. The tool also allows patients to focus on the outcome that matters most to them and to compare the benefits and harms of up to 12 different treatment options. This information is displayed in personalized absolute numbers, along with practical considerations such as cost. CONCLUSION: The PEER Diabetes Medication Decision Aid provides a practical tool that can enable patients with T2DM to come to autonomous and well-informed medication decisions.

Top studies of 2023 relevant to primary care: From the PEER team.

OBJECTIVE: To provide a summary of the noteworthy medical articles published in 2023 that are relevant to family physicians. SELECTING THE EVIDENCE: Articles were chosen and ranked by the PEER (Patients, Experience, Evidence, Research) team, a group of primary care health professionals focused on evidence-based medicine. The selection process involved routine surveillance of tables of contents in high-impact medical journals and continuous monitoring of EvidenceAlerts. Articles were prioritized based on their direct applicability to and potential to influence primary care practice. MAIN MESSAGE: Selected articles addressed various clinical areas of primary care. The topics included a comparison of a treat-to-target approach versus a high-intensity statins prescription for lipid management; semaglutide and its impact on cardiovascular outcomes; respiratory syncytial virus vaccine for older adults; chlorthalidone versus hydrochlorothiazide in preventing cardiovascular events; amitriptyline for irritable bowel syndrome; the role of opioids in acute back pain; safety of oral penicillin challenges in patients allergic to penicillin; spironolactone for facial acne; strategies to reverse frailty in older adults; and identifying the provider of chronic disease management. Two "up and coming" medications are also mentioned: retatrutide for weight loss and fezolinetant for vasomotor symptoms of menopause. CONCLUSION: Research published in 2023 yielded several high-quality articles with topics relevant to primary care, including cardiovascular care, irritable bowel syndrome, care of the elderly, and acne management.

P2Y12 inhibitor adherence trajectories in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prognostic implications.

AIMS: Post-acute coronary syndrome (ACS) P2Y12 inhibitor non-adherence is common and associated with greater risk of major adverse cardiovascular events (MACEs). Non-adherence can follow different trajectories from an inability to initiate, implement, or continue therapy for the intended duration. We aimed to evaluate P2Y12 inhibitor adherence trajectories among ACS patients treated with percutaneous coronary intervention (PCI), their frequency, and association with MACE. METHODS AND RESULTS: We conducted a cohort study of adults discharged alive after PCI for ACS (2012-16) using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry linked with administrative data. The primary outcome was P2Y12 inhibitor adherence trajectory in the year after PCI assessed using group-based trajectory modelling. We used logistic regression and Cox proportional-hazards regression to assess associations of trajectories with risk factors and MACE, respectively. We included 12 844 patients (mean age 62.4 years, 23.6% female). Five trajectories were identified: early consistent non-adherence (11.0%), rapid decline (7.7%), delayed initiation (6.0%), gradual decline (20.5%), and persistent adherence (54.8%). Compared with persistent adherence, rapid decline [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.01-1.49] and delayed initiation (HR 1.41, 95% CI 1.12-1.78) were associated with higher MACE in the overall cohort, whereas early consistent non-adherence was associated with higher MACE only in the subgroup receiving a drug-eluting stent (HR 2.44, 95% CI 1.60-3.71). CONCLUSION: After PCI for ACS, patients followed one of five distinct P2Y12 inhibitor adherence trajectories. Rapid decline and delayed initiation were associated with a higher risk of MACE, whereas early consistent non-adherence was only associated with higher MACE risk in patients with a drug-eluting stent.

Top studies of 2021 relevant to primary care: From the PEER team.

OBJECTIVE: To summarize 10 high-quality studies or guidelines from 2021 that have strong relevance to physicians in comprehensive family practice. SELECTING THE EVIDENCE: Routine literature surveillance of abstracts in high-impact journals and EvidenceAlerts was completed by the PEER (Patients, Experience, Evidence, Research) team, a group of health care professionals with a research interest in evidence-based medicine and primary care. Abstracts were screened, selected, and ranked by the PEER team. MAIN MESSAGE: The articles from 2021 that are most likely to impact primary care practice discuss the following topics: empagliflozin for heart failure with preserved ejection fraction; semaglutide for weight loss; stopping antidepressants in primary care; inhaled budesonide for COVID-19; acetylsalicylic acid for preeclampsia prevention; quarter-dose blood pressure medications for hypertension; aggressive blood pressure control for elderly patients; kangaroo care for low-birth-weight infants; footwear for knee osteoarthritis; and delayed antibiotics for pediatric respiratory infections. Two "honourable mention" studies are also briefly reviewed. CONCLUSION: Research from 2021 produced several high-quality studies in cardiovascular care but also addressed a variety of conditions relevant to primary care including weight loss, depression, and COVID-19.

PEER simplified chronic pain guideline: Management of chronic low back, osteoarthritic, and neuropathic pain in primary care.

OBJECTIVE: To develop a clinical practice guideline to support the management of chronic pain, including low back, osteoarthritic, and neuropathic pain in primary care. METHODS: The guideline was developed with an emphasis on best available evidence and shared decision-making principles. Ten health professionals (4 generalist family physicians, 1 pain management-focused family physician, 1 anesthesiologist, 1 physical therapist, 1 pharmacist, 1 nurse practitioner, and 1 psychologist), a patient representative, and a nonvoting pharmacist and guideline methodologist comprised the Guideline Committee. Member selection was based on profession, practice setting, and lack of financial conflicts of interest. The guideline process was iterative in identification of key questions, evidence review, and development of guideline recommendations. Three systematic reviews, including a total of 285 randomized controlled trials, were completed. Randomized controlled trials were included only if they reported a responder analysis (eg, how many patients achieved a 30% or greater reduction in pain). The committee directed an Evidence Team (composed of evidence experts) to address an additional 11 complementary questions. Key recommendations were derived through committee consensus. The guideline and shared decision-making tools underwent extensive review by clinicians and patients before publication. RECOMMENDATIONS: Physical activity is recommended as the foundation for managing osteoarthritis and chronic low back pain; evidence of benefit is unclear for neuropathic pain. Cognitive-behavioural therapy or mindfulness-based stress reduction are also suggested as options for managing chronic pain. Treatments for which there is clear, unclear, or no benefit are outlined for each condition. Treatments for which harms likely outweigh benefits for all or most conditions studied include opioids and cannabinoids. CONCLUSION: This guideline for the management of chronic pain, including osteoarthritis, low back pain, and neuropathic pain, highlights best available evidence including both benefits and harms for a number of treatment interventions. A strong recommendation for exercise as the primary treatment for chronic osteoarthritic and low back pain is made based on demonstrated long-term evidence of benefit. This information is intended to assist with, not dictate, shared decision making with patients.

N-acetylcysteine for non-paracetamol (acetaminophen)-related acute liver failure.

BACKGROUND: Acute liver failure is a rare and serious disease. Acute liver failure may be paracetamol-induced or non-paracetamol-induced. Acute liver failure not caused by paracetamol (acetaminophen) has a poor prognosis with limited treatment options. N-acetylcysteine has been successful in treating paracetamol-induced acute liver failure and reduces the risk of needing to undergo liver transplantation. Recent randomised clinical trials have explored whether the benefit can be extrapolated to treat non-paracetamol-related acute liver failure. The American Association for the Study of Liver Diseases (AASLD) 2011 guideline suggested that N-acetylcysteine could improve spontaneous survival when given during early encephalopathy stages for patients with non-paracetamol-related acute liver failure. OBJECTIVES: To assess the benefits and harms of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, in people with non-paracetamol-related acute liver failure. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (searched 25 June 2020), Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 6) in The Cochrane Library, MEDLINE Ovid (1946 to 25 June 2020), Embase Ovid (1974 to 25 June 2020), Latin American and Caribbean Health Science Information database (LILACS) (1982 to 25 June 2020), Science Citation Index Expanded (1900 to 25 June 2020), and Conference Proceedings Citation Index - Science (1990 to 25 June 2020). SELECTION CRITERIA: We included randomised clinical trials that compared N-acetylcysteine at any dose or route with placebo or no intervention in participants with non-paracetamol-induced acute liver failure. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as described in the Cochrane Handbook for Systematic Reviews of Interventions. We conducted meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CIs). We quantified statistical heterogeneity by calculating I2. We assessed bias using the Cochrane risk of bias tool and determined the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included two randomised clinical trials: one with 183 adults and one with 174 children (birth through age 17 years). We classified both trials at overall high risk of bias. One unregistered study in adults is awaiting classification while we are awaiting responses from study authors for details on trial methodology (e.g. randomisation processes). We did not meta-analyse all-cause mortality because of significant clinical heterogeneity in the two trials. For all-cause mortality at 21 days between adults receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (N-acetylcysteine 24/81 (29.6%) versus placebo 31/92 (33.7%); RR 0.88, 95% CI 0.57 to 1.37; low certainty evidence). The certainty of the evidence was low due to risk of bias and imprecision. Similarly, for all-cause mortality at one year between children receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (25/92 (27.2%) versus 17/92 (18.5%); RR 1.47, 95% CI 0.85 to 2.53; low certainty evidence). We downgraded the certainty of evidence due to very serious imprecision.  We did not meta-analyse serious adverse events and liver transplantation at one year due to incomplete reporting and clinical heterogeneity. For liver transplantation at 21 days in the trial with adults, there was inconclusive evidence of effect (RR 0.72, 95% CI 0.49 to 1.06; low certainty evidence). We downgraded the certainty of the evidence due to serious risk of bias and imprecision. For liver transplantation at one year in the trial with children, there was inconclusive evidence of effect (RR 1.23, 95% CI 0.84 to 1.81; low certainty of evidence). We downgraded the certainty of the evidence due to very serious imprecision.   There was inconclusive evidence of effect on serious adverse events in the trial with children (RR 1.25, 95% CI 0.35 to 4.51; low certainty evidence). We downgraded the certainty of the evidence due to very serious imprecision.  We did not meta-analyse non-serious adverse events due to clinical heterogeneity. There was inconclusive evidence of effect on non-serious adverse events in adults (RR 1.07, 95% CI 0.79 to 1.45; 173 participants; low certainty of evidence) and children (RR 1.19, 95% CI 0.62 to 2.16; 184 participants; low certainty of evidence). None of the trials reported outcomes of proportion of participants with resolution of encephalopathy and coagulopathy or health-related quality of life. The National Institute of Health in the United States funded both trials through grants. One of the trials received additional funding from two hospital foundations' grants. Pharmaceutical companies provided the study drug and matching placebo, but they did not have input into study design nor involvement in analysis. AUTHORS' CONCLUSIONS: The available evidence is inconclusive regarding the effect of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, on mortality or transplant rate in non-paracetamol-induced acute liver failure. Current evidence does not support the guideline suggestion to use N-acetylcysteine in adults with non-paracetamol-related acute liver failure, nor the rising use observed in clinical practice. The uncertainty based on current scanty evidence warrants additional randomised clinical trials with non-paracetamol-related acute liver failure evaluating N-acetylcysteine versus placebo, as well as investigations to identify predictors of response and the optimal N-acetylcysteine dose and duration.

Switching to Clopidogrel in Patients With Acute Coronary Syndrome Managed With Percutaneous Coronary Intervention Initially Treated With Prasugrel or Ticagrelor: Systematic Review and Meta-analysis.

Objective: To evaluate the effects of switching from ticagrelor or prasugrel to clopidogrel in acute coronary syndrome (ACS) patients managed with percutaneous coronary intervention on major adverse cardiovascular events (MACEs) and bleeding. Data Sources: We searched MEDLINE, EMBASE, CENTRAL, bibliographies of relevant articles, and clinicaltrials.gov for eligible articles published from inception to January 27, 2019. Study Selection and Data Extraction: We included randomized controlled trials (RCTs) and cohort and case-control studies that reported on ≥1 outcome of interest. Primary outcomes were MACE and major bleeding, and the secondary outcome was any bleeding. Data Synthesis: From 483 articles, we included 7 relevant studies (2 RCTs, 5 cohort studies) at high/unclear risk of bias. Random-effects meta-analysis revealed inconclusive effects on MACE (hazard ratio [HR] = 1.00, 95% CI = 0.59-1.68; I2 = 82%), major bleeding (HR = 0.51; 0.19-1.35; I2 = 91%), and any bleeding (HR = 0.64; 0.38-1.07; I2 = 85%). Similar nonsignificant results were obtained in secondary analyses evaluating risk ratios. Relevance to Patient Care and Clinical Practice: Ticagrelor and prasugrel, are now considered preferred therapy over clopidogrel in patients with ACS. Switching from these potent P2Y12 inhibitors to clopidogrel is commonly performed to reduce bleeding risk, other adverse effects, or costs. Current best-available evidence is inconclusive regarding the effects of switching to clopidogrel on the risk of MACE and bleeding. Overall, studies were underpowered to detect clinically important differences. Conclusions: Until adequately powered trials demonstrate an advantage to switching to clopidogrel from prasugrel or ticagrelor, clinicians may consider this approach as clinically indicated on an individual, case-by-case basis.

Les meilleures études de 2021 adéquates pour les soins de première ligne: De l'équipe du groupe PEER.

OBJECTIF: Résumer 10 études ou lignes directrices de grande qualité publiées en 2021 qui présentent un intérêt marqué pour les médecins qui ont une pratique familiale complète. SÉLECTION DES DONNÉES PROBANTES: L'équipe PEER (Patients, Experience, Evidence, Research), un groupe de professionnels de la santé dont la recherche s'intéresse à la médecine fondée sur les données probantes et à la médecine de première ligne, a systématiquement surveillé les résumés publiés dans les revues savantes importantes et dans EvidenceAlerts. L'équipe PEER a passé au crible, sélectionné et placé les résumés en ordre d'importance. MESSAGE PRINCIPAL: Les articles publiés en 2021 qui influeront le plus probablement sur la pratique de première ligne traitent des sujets suivants : empagliflozine contre l'insuffisance cardiaque avec fraction d'éjection préservée; sémaglutide pour perdre du poids; arrêter les antidépresseurs en première ligne; budésonide par inhalation contre la COVID-19; acide acétylsalicylique en prévention de la prééclampsie; quart de dose d'antihypertenseurs contre l'hypertension; contrôle énergique de la tension artérielle chez les patients âgés; méthode kangourou pour les nouveau-nés de faible poids; chaussures pour la gonarthrose; et report de l'antibiothérapie pour les infections respiratoires pédiatriques. On jette également un coup d'œil rapide à deux « mentions honorables ¼. CONCLUSION: En 2021, la recherche a produit plusieurs études de grande qualité dans le domaine des soins cardiovasculaires, mais elle a également porté sur une gamme d'affections présentant un intérêt pour les soins de première ligne, dont la perte pondérale, la dépression et la COVID-19.

Lignes directrices simplifiées de PEER sur la douleur chronique: Gestion de la douleur chronique lombaire, arthrosique et neuropathique en première ligne.

OBJECTIF: Formuler des lignes directrices de pratique clinique pour soutenir la prise en charge de la douleur chronique, y compris la douleur lombaire, arthrosique et neuropathique, dans les soins primaires. MÉTHODES: Ces lignes directrices ont été élaborées en mettant l'accent sur les meilleures données probantes disponibles et sur les principes de décision partagée. Dix professionnels de la santé (4 omnipraticiens, 1 médecin de famille spécialisée en gestion de la douleur, 1 anesthésiste, 1 physiothérapeute, 1 pharmacienne, 1 infirmière praticienne et 1 psychologue), 1 représentant des patients, et 1 pharmacienne et spécialiste de la méthodologie des lignes directrices sans droit de vote composaient le comité des lignes directrices. Les membres ont été sélectionnés en fonction de leur profession, de leur milieu de pratique, et de l'absence d'un conflit d'intérêts de nature financière. Les lignes directrices sont le fruit d'un processus itératif incluant la détermination des questions clés, l'examen des données probantes et la formulation des recommandations des lignes directrices. Trois revues systématiques, totalisant 285 études avec répartition aléatoire et contrôlées ont été réalisées. Ces études n'étaient incluses que si elles avaient rapporté une analyse des répondants (p. ex. combien de patients ont obtenu un soulagement d'au moins 30% de la douleur). Le comité a confié à une équipe d'examen des données (composée de spécialistes des données probantes) la tâche de répondre à 11 autres questions complémentaires. Les principales recommandations découlent d'un consensus au sein du comité. Des cliniciens et des patients ont minutieusement examiné les lignes directrices et les outils de décision partagée avant leur publication. RECOMMANDATIONS: L'activité physique est recommandée comme fondement de la gestion de la douleur arthrosique et lombaire chronique; les données probantes étayant un bienfait ne sont pas concluantes dans le cas de la douleur neuropathique. La thérapie cognitivo-comportementale ou la réduction du stress basée sur la pleine conscience sont également suggérées comme des options pour gérer la douleur chronique. Les traitements pour lesquels le bienfait est clair, non concluant ou absent sont décrits sous chaque affection. Les traitements dont les préjudices surpassent probablement les bienfaits pour toutes les affections étudiées, ou la plupart d'entre elles, sont les opioïdes et les cannabinoïdes. CONCLUSION: Ces lignes directrices sur la gestion de la douleur chronique, y compris la douleur arthrosique, lombaire et neuropathique, met en lumière les meilleures données probantes disponibles, y compris les bienfaits et préjudices pour un certain nombre d'interventions thérapeutiques. Une forte recommandation en faveur de l'exercice comme principal traitement de la douleur arthrosique et lombaire chronique repose sur des données probantes ayant démontré un bienfait depuis longtemps. Cette information vise à contribuer au processus de décision partagée avec le patient et non à le dicter.

Familial hypercholesterolemia: Review of diagnosis, screening, and treatment.

OBJECTIVE: To summarize the pathophysiology, epidemiology, screening, diagnosis, and treatment of familial hypercholesterolemia (FH). QUALITY OF EVIDENCE: A PubMed search was conducted (inception to July 2014) for articles on pathophysiology, screening, diagnosis, and management of FH, supplemented with hand searches of bibliographies of guidelines and reviews. A supporting level of evidence for each recommendation was categorized as level I (randomized controlled trial or systematic review of randomized controlled trials), level II (observational study), or level III (expert opinion). The best available evidence is mostly level II or III. MAIN MESSAGE: Familial hypercholesterolemia affects 1 in 500 Canadians. Risk of a coronary event is high in these patients and is underestimated by risk calculators (eg, Framingham). Clinicians should screen patients according to guidelines and suspect FH in any patient with a premature cardiovascular event, physical stigmata of hypercholesterolemia, or an elevated plasma lipid level. Physicians should diagnose FH using either the Simon Broome or Dutch Lipid Network criteria. Management of heterozygous FH includes reducing low-density lipoprotein levels by 50% or more from baseline with high-dose statins and other lipid-lowering agents. Clinicians should refer any patient with homozygous FH to a specialized centre. CONCLUSION: Familial hypercholesterolemia represents an important cause of premature cardiovascular disease in Canadians. Early identification and aggressive treatment of individuals with FH reduces cardiovascular morbidity and mortality.