Intolerance upon statin rechallenge: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Although statins are often discontinued when myalgia arises, a causal relationship may not always exist. How well-tolerated statins are when rechallenge is blinded and controlled is unclear. METHODS AND FINDINGS: We performed a systematic review and meta-analysis (PROSPERO CRD42023437648) to evaluate the success of statin rechallenge versus matched placebo in those who were previously statin intolerant. Our primary outcome was intolerance; our secondary outcome was the myalgia or global symptom score. Medline, Embase, CINAHL Plus, Scopus, and CENTRAL were searched from inception to May 1, 2023. Eligible trials were randomized controlled trials with parallel or crossover designs examining statin rechallenge in statin-intolerant adults. Two independent reviewers selected studies, extracted data, and assessed risk of bias (Cochrane Collaboration's risk-of-bias tool 1). Relative risk (RR) and mean difference (MD) were estimated using fixed effect Mantel-Haenszel statistics. Of 1,941 studies screened, 8 met our inclusion criteria (8 to 491 participants from Asia, Europe, North America, and Oceana). Compared to placebo, intolerance was more common in statin users [325/906 (36%) vs 233/911 (26%), RR 1.40, 95% CI, 1.23 to 1.60, I2 = 0%, 7 trials, number needed to harm 10] and there was no statistically significant difference in myalgia or global symptom score on a 100-point scale [MD 1.08, 95% CI, -1.51 to 3.67, I2 = 0%, 5 trials]. Limitations include only 1 trial asking participants about intolerable symptoms (vs inferring intolerance from discontinuation or trial withdrawal); the small number of trials; the possibility of attrition bias; and the potential for carryover effects in crossover/n-of-1 trial designs. CONCLUSIONS: Of those previously intolerant of statins who were rechallenged with a statin and compared to placebo recipients, medication intolerance was more common amongst statin recipients. However, there was no significant difference in mean myalgia or global symptom score between statin and placebo, and only one-third of those previously believed to be statin intolerant were unable to tolerate a statin on blinded rechallenge; one-quarter were intolerant of placebo.

PEER simplified lipid guideline 2023 update: Prevention and management of cardiovascular disease in primary care.

OBJECTIVE: To update the 2015 clinical practice guideline and provide a simplified approach to lipid management in the prevention of cardiovascular disease (CVD) for primary care. METHODS: Following the Institute of Medicine's Clinical Practice Guidelines We Can Trust, a multidisciplinary, pan-Canadian guideline panel was formed. This panel was represented by primary care providers, free from conflicts of interest with industry, and included the patient perspective. A separate scientific evidence team performed evidence reviews on statins, ezetimibe, proprotein convertase subtilisin-kexin type 9 inhibitors, fibrates, bile acid sequestrants, niacin, and omega-3 supplements (docosahexaenoic acid with eicosapentaenoic acid [EPA] or EPA ethyl ester alone [icosapent]), as well as on 11 supplemental questions. Recommendations were finalized by the guideline panel through use of the Grading of Recommendations Assessment, Development and Evaluation methodology. RECOMMENDATIONS: All recommendations are presented in a patient-centred manner designed with the needs of family physicians and other primary care providers in mind. Many recommendations are similar to those published in 2015. Statins remain first-line therapy for both primary and secondary CVD prevention, and the Mediterranean diet and physical activity are recommended to reduce cardiovascular risk (primary and secondary prevention). The guideline panel recommended against using lipoprotein a, apolipoprotein B, or coronary artery calcium levels when assessing cardiovascular risk, and recommended against targeting specific lipid levels. The team also reviewed new evidence pertaining to omega-3 fatty acids (including EPA ethyl ester [icosapent]) and proprotein convertase subtilisin-kexin type 9 inhibitors, and outlined when to engage in informed shared decision making with patients on interventions to lower cardiovascular risk. CONCLUSION: These updated evidence-based guidelines provide a simplified approach to lipid management for the prevention and management of CVD. These guidelines were created by and for primary health care professionals and their patients.

Lipid-lowering therapies for cardiovascular disease prevention and management in primary care: PEER umbrella systematic review of systematic reviews.

OBJECTIVE: To assess the benefits and harms of lipid-lowering therapies used to prevent or manage cardiovascular disease including bile acid sequestrants (BAS), ezetimibe, fibrates, niacin, omega-3 supplements, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, and statins. DATA SOURCES: MEDLINE, the Cochrane Database of Systematic Reviews, and a grey literature search. STUDY SELECTION: Systematic reviews of randomized controlled trials published between January 2017 and March 2022 looking at statins, ezetimibe, PCSK9 inhibitors, fibrates, BAS, niacin, and omega-3 supplements for preventing cardiovascular outcomes were selected. Outcomes of interest included major adverse cardiovascular events (MACE), cardiovascular mortality, all-cause mortality, and adverse events. SYNTHESIS: A total of 76 systematic reviews were included. Four randomized controlled trials were also included for BAS because no efficacy systematic review was identified. Statins significantly reduced MACE (6 systematic reviews; median risk ratio [RR]=0.74; interquartile range [IQR]=0.71 to 0.76), cardiovascular mortality (7 systematic reviews; median RR=0.85, IQR=0.83 to 0.86), and all-cause mortality (8 systematic reviews; median RR=0.91, IQR=0.88 to 0.92). Major adverse cardiovascular events were also significantly reduced by ezetimibe (3 systematic reviews; median RR=0.93, IQR=0.93 to 0.94), PCSK9 inhibitors (14 systematic reviews; median RR=0.84, IQR=0.83 to 0.87), and fibrates (2 systematic reviews; mean RR=0.86), but these interventions had no effect on cardiovascular or all-cause mortality. Fibrates had no effect on any cardiovascular outcomes when added to a statin. Omega-3 combination supplements had no effect on MACE or all-cause mortality but significantly reduced cardiovascular mortality (5 systematic reviews; median RR=0.93, IQR=0.93 to 0.94). Eicosapentaenoic acid ethyl ester alone significantly reduced MACE (1 systematic review, RR=0.78) and cardiovascular mortality (2 systematic reviews; RRs of 0.82 and 0.82). In primary cardiovascular prevention, only statins showed consistent benefits on MACE (6 systematic reviews; median RR=0.75, IQR=0.73 to 0.78), cardiovascularall-cause mortality (7 systematic reviews, median RR=0.83, IQR=0.81 to 0.90), and all-cause mortality (8 systematic reviews; median RR=0.91, IQR=0.87 to 0.91). CONCLUSION: Statins have the most consistent evidence for the prevention of cardiovascular complications with a relative risk reduction of about 25% for MACE and 10% to 15% for mortality. The addition of ezetimibe, a PCSK9 inhibitor, or eicosapentaenoic acid ethyl ester to a statin provides additional MACE risk reduction but has no effect on all-cause mortality.

Lignes directrices simplifiées de PEER sur les lipides : actualisation 2023: Prévention et prise en charge des maladies cardiovasculaires en soins primaires.

OBJECTIF: Actualiser le guide de pratique clinique de 2015 et présenter une approche simplifiée de la prise en charge des lipides dans la prévention des maladies cardiovasculaires (MCV) en première ligne. MÉTHODES: Conformément aux recommandations de l'Institute of Medicine dans Clinical Practice Guidelines We Can Trust, un panel pancanadien d'experts multidisciplinaires en lignes directrices a été formé. Ce panel était représentatif des cliniciens en soins primaires, libre de tout conflit d'intérêts avec l'industrie, et il tenait compte des points de vue des patients. Une équipe distincte, responsable des données probantes scientifiques, a passé en revue l'information sur les statines, l'ézétimibe, les inhibiteurs de la proprotéine convertase subtilisine-kexine de type 9, les fibrates, les chélateurs des acides biliaires, la niacine et les suppléments d'omega-3 (acide docosahexaénoïque avec acide eicosapentaénoïque [EPA] ou ester éthylique de l'EPA seul [icosapent]), ainsi que sur la réponse à 11 questions supplémentaires. Le panel des lignes directrices a finalisé les recommandations en utilisant la méthodologie GRADE (Grading of Recommendations Assessment, Development and Evaluation). RECOMMANDATIONS: Toutes les recommandations sont présentées de manière à être centrées sur le patient et conçues en ayant à l'esprit les besoins des médecins de famille et des autres cliniciens des soins primaires. De nombreuses recommandations sont semblables à celles publiées en 2015. Les statines demeurent le traitement de première intention pour la prévention tant primaire que secondaire des MCV, et le régime méditerranéen et l'activité physique sont recommandés pour réduire le risque cardiovasculaire (en prévention primaire et secondaire). Le panel des lignes directrices a recommandé de ne pas utiliser le dosage des lipoprotéines a, des apolipoprotéines B ou le score calcique coronarien (SCC) dans l'évaluation du risque cardiovasculaire, et de ne pas cibler de seuils précis de taux lipidiques. L'équipe a aussi passé en revue de nouvelles données concernant les acides gras omega-3 (y compris l'ester éthylique d'EAP [icosapent]) et les inhibiteurs de la proprotéine convertase subtilisine-kexine de type 9, et a précisé les moments où il convient de procéder à une prise de décision partagée avec les patients sur les interventions pour diminuer le risque cardiovasculaire. CONCLUSION: Ces lignes directrices actualisées et fondées sur des données probantes présentent une approche simplifiée de la prise en charge des lipides pour la prévention et le traitement des MCV. Ce guide de pratique clinique a été conçu par et pour des professionnels de la santé en soins primaires et leurs patients.

Bedtime versus morning use of antihypertensives in frail continuing care residents (BedMed-Frail): protocol for a prospective, randomised, open-label, blinded end-point pragmatic trial.

INTRODUCTION: BedMed-Frail explores risks and benefits of switching antihypertensives from morning to bedtime in a frail population at greater risk of hypotensive adverse effects. METHODS AND ANALYSIS: Design: Prospective parallel randomised, open-label, blinded end-point trial.Participants: Hypertensive continuing care residents, in either long-term care or supportive living, who are free from glaucoma, and using ≥1 once daily antihypertensive.Setting: 16 volunteer continuing care facilities in Alberta, Canada, with eligible residents identified using electronic health claims data.Intervention: All non-opted out eligible residents are randomised centrally by the provincial health data steward to bedtime versus usual care (typically morning) administration of once daily antihypertensives. Timing changes are made (maximum one change per week) by usual care facility pharmacists.Follow-up: Via linked governmental healthcare databases tracking hospital, continuing care and community medical services.Primary outcome: Composite of all-cause death, or hospitalisation for myocardial infarction/acute-coronary syndrome, stroke, or congestive heart failure.Secondary outcomes: Each primary outcome element on its own, all-cause unplanned hospitalisation or emergency department visit, non-vertebral fracture and, as assessed roughly 135 days postrandomisation, fall in the last 30 days, deteriorated cognition, urinary incontinence, decubitus skin ulceration, inappropriate or disruptive behaviour a minimum of 4 days per week, and receipt of antipsychotic medication or physical restraints in the last 7 days.Process outcome: Proportion of blood pressure medication doses taken at bedtime (broken down monthly).Primary outcome analysis: Cox-Proportional Hazards Survival Analysis.Sample size: The trial will continue until a projected 368 primary outcome events have occurred.Current status: Enrolment is ongoing with 642 randomisations to date (75% female, mean age 88 years). ETHICS AND DISSEMINATION: BedMed-Frail has ethical approval from the University of Alberta Health Ethics Review Board (Pro00086129) and will publish results in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04054648.

Tolerability of bedtime diuretics: a prospective cohort analysis.

OBJECTIVES: We sought to validate, or refute, the common belief that bedtime diuretics are poorly tolerated due to nocturia. DESIGN: Prespecified prospective cohort analysis embedded within the randomised BedMed trial, in which hypertensive participants are randomised to morning versus bedtime antihypertensive administration. SETTING: 352 community family practices across 4 Canadian provinces between March 2017 and September 2020. PARTICIPANTS: 552 hypertensive patients (65.6 years old, 57.4% female) already established on a single once-daily morning antihypertensive and randomised to switch that antihypertensive to bedtime. Of these, 203 used diuretics (27.1% thiazide alone, 70.0% thiazide/non-diuretic combinations) and 349 used non-diuretics. INTERVENTION: Switching the established antihypertensive from morning to bedtime, and comparing the experience of diuretic and non-diuretic users. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: Adherence to bedtime allocation time at 6 months (defined as the willingness to continue with bedtime use, not an assessment of missed doses). Secondary 6-month outcomes: (1) nocturia considered to be a major burden and (2) increase in overnight urinations/week. All outcomes were self-reported and additionally collected at 6 weeks. RESULTS: At 6 months: Adherence to bedtime allocation time was lower in diuretic users than non-diuretic users (77.3% vs 89.8%; difference 12.6%; 95% CI 5.8% to 19.8%; p<0.0001; NNH 8.0), and more diuretic users considered nocturia a major burden (15.6% vs 1.3%; difference 14.2%; 95% CI 8.9% to 20.6%; p<0.0001; NNH 7.0). Compared with baseline, diuretic users experienced 1.0 more overnight urinations/week (95% CI 0.0 to 1.75; p=0.01). Results did not differ between sexes. CONCLUSIONS: Switching diuretics to bedtime did promote nocturia, but only 15.6% found nocturia a major burden. At 6 months, 77.3% of diuretic users were adherent to bedtime dosing. Bedtime diuretic use is viable for many hypertensive patients, should it ever become clinically indicated. TRIAL REGISTRATION NUMBER: NCT02990663.

Who provides chronic disease management? Population-based retrospective cohort study in Alberta.

OBJECTIVE: To determine the proportions of patients who receive care from family physicians, specialists, and nurse practitioners for the management of common chronic medical conditions. DESIGN: Population-based retrospective cohort study. SETTING: Province of Alberta. PARTICIPANTS: Adults aged 19 years or older who were registered for provincial health services and each had 2 or more interactions with the same provider between January 1, 2013, and December 31, 2017, for any of 7 specified chronic medical conditions: hypertension, diabetes, chronic obstructive pulmonary disease (COPD), asthma, heart failure, ischemic heart disease, and chronic kidney disease. MAIN OUTCOME MEASURES: Numbers of patients being managed for these conditions and which provider types were involved in their care. RESULTS: Albertans receiving care for the chronic medical conditions being studied (n=970,783) had a mean (SD) age of 56.8 (16.3) years and 49.1% were female. Family physicians were the sole providers of care for 85.7% of patients with a diagnosis of hypertension, 70.9% with diabetes, 59.8% with COPD, and 65.5% with asthma. Specialists were sole providers of care for 49.1% of patients with ischemic heart disease, 42.2% with chronic kidney disease, and 35.6% with heart failure. Nurse practitioners were involved in the care of less than 1% of patients with these conditions. CONCLUSION: Family physicians were involved in the care of most patients with any of 7 chronic medical conditions included in this study and were the sole providers of care for the majority of patients with hypertension, diabetes, COPD, and asthma. Guideline working group representation and the setting of clinical trials should reflect this reality.

Risk and distribution of chronic obstructive pulmonary disease-related hospitalizations among primary care patients.

OBJECTIVE: To determine the extent of chronic obstructive pulmonary disease (COPD) hospitalization in easily identifiable high-risk subgroups within a typical primary care practice. DESIGN: Prospective cohort analysis of administrative claims data. SETTING: British Columbia. PARTICIPANTS: British Columbia residents who were 50 years or older on December 31, 2014, and received a physician diagnosis of COPD between 1996 and 2014. MAIN OUTCOME MEASURES: Rate of acute exacerbation of COPD (AECOPD) or pneumonia hospitalization in 2015, broken down by risk identifiers including previous AECOPD admission, 2 or more community respirologist consultations, nursing home residence, or none of these. RESULTS: Of the 242,509 identified COPD patients (12.9% of British Columbia residents ≥50 years), 2.8% were hospitalized for AECOPD in 2015 (0.038 AECOPD hospitalizations per patient-year). The 12.0% with prior AECOPD hospitalization accounted for 57.7% of new AECOPD hospitalizations (0.183 hospitalizations per patient-year); the 7.7% with respirologist involvement accounted for 20.4% (0.102 hospitalizations per patient-year); and the 2.2% in nursing homes accounted for 3.6% (0.061 hospitalizations per patient-year). Those with any of the 3 risk identifiers accounted for only 1.5% more COPD hospitalizations (59.2%) than those with prior AECOPD hospitalization, suggesting prior AECOPD hospitalization is the most important indication of risk. A typical primary care practice held a median of 23 (interquartile range=4 to 65) COPD patients, of whom roughly 20 (86.4%) had none of these risk identifiers. This low-risk majority had only 0.018 AECOPD hospitalizations per patient-year. CONCLUSION: Most AECOPD hospitalizations occur in patients with previous such admissions. When time and resources are limited, COPD initiatives targeting primary care practices should focus more on the 2 to 3 patients with prior AECOPD hospitalization or more symptomatic disease, and less on the low-risk majority.

Team approach to polypharmacy evaluation and reduction: feasibility randomized trial of a structured clinical pathway to reduce polypharmacy.

BACKGROUND: Polypharmacy is associated with poorer health outcomes in older adults. Other than the associated multimorbidity, factors contributing to this association could include medication adverse effects and interactions, difficulties in managing complicated medication regimes, and reduced medication adherence. It is unknown how reversible these negative associations may be if polypharmacy is reduced. The purpose of this study was to determine the feasibility of implementing an operationalized clinical pathway aimed to reduce polypharmacy in primary care and to pilot measurement tools suitable for assessing change in health outcomes in a larger randomized controlled trial (RCT). METHODS: We randomized consenting patients ≥ 70 years old on ≥ 5 long-term medications into intervention or control groups. We collected baseline demographic information and research outcome measures at baseline and 6 months. We assessed four categories of feasibility outcomes: process, resource, management, and scientific. The intervention group received TAPER (team approach to polypharmacy evaluation and reduction), a clinical pathway for reducing polypharmacy using "pause and monitor" drug holiday approach. TAPER integrates patients' goals, priorities, and preferences with an evidence-based "machine screen" to identify potentially problematic medications and support a tapering and monitoring process, all supported by a web-based system, TaperMD. Patients met with a clinical pharmacist and then with their family physician to finalize a plan for optimization of medications using TaperMD. The control group received usual care and were offered TAPER after follow-up at 6 months. RESULTS: All 9 criteria for feasibility were met across the 4 feasibility outcome domains. Of 85 patients screened for eligibility, 39 eligible patients were recruited and randomized; two were excluded post hoc for not meeting the age requirement. Withdrawals (2) and losses to follow-up (3) were small and evenly distributed between arms. Areas for intervention and research process improvement were identified. In general, outcome measures performed well and appeared suitable for assessing change in a larger RCT. CONCLUSIONS: Results from this feasibility study indicate that TAPER as a clinical pathway is feasible to implement in a primary care team setting and in an RCT research framework. Outcome trends suggest effectiveness. A large-scale RCT will be conducted to investigate the effectiveness of TAPER on reducing polypharmacy and improving health outcomes. TRIAL REGISTRATION: clinicaltrials.gov NCT02562352 , Registered September 29, 2015.

Public reporting of clinical trial findings as an ethical responsibility to participants: a qualitative study.

OBJECTIVE: To understand how the experiences and views of trial participants, trial investigators and others connected to clinical trial research relate to whether researchers have a duty to participants to publicly report research findings. DESIGN: Qualitative interview study. SETTING: Semistructured interviews held in person or by telephone between March 2019 and April 2021 with participants in the Canadian provinces of Alberta, British Columbia and Ontario. PARTICIPANTS: 34 participants, including 10 clinical trial participants, 17 clinical trial investigators, 1 clinical research coordinator, 3 research administrators and 3 research ethics board members. ANALYSIS: We conducted a thematic analysis, including qualitative coding of interview transcripts and identification of key themes. MAIN OUTCOME MEASURES: Key themes identified through qualitative coding of interview data. RESULTS: Most clinical trial participants felt that reporting clinical trial results is important. Accounts of trial participants suggest their contributions are part of a reciprocal relationship involving the expectation that research will advance medical knowledge. Similarly, comments from trial investigators suggest that reporting trial results is part of reciprocity with trial participants and is a necessary part of honouring informed consent. Accounts of trial investigators suggest that when drug trials are not reported, this may undermine informed consent in subsequent trials by withholding information on harms or efficacy relevant to informed decisions on whether to conduct or enroll in future trials of similar drugs. CONCLUSION: The views of trial participants, trial investigators and others connected to clinical trial research in Canada suggest that researchers have an obligation to participants to publicly report clinical trial results and that reporting results is necessary for honouring informed consent.

Toward Precision Medicine: Circadian Rhythm of Blood Pressure and Chronotherapy for Hypertension - 2021 NHLBI Workshop Report.

Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

Factors relating to nonpublication and publication bias in clinical trials in Canada: A qualitative interview study.

AIMS: This study aims to understand factors contributing to nonpublication and publication bias in clinical trials in Canada. METHODS: Qualitative interviews were conducted between March 2019 and April 2021 with 34 participants from the Canadian provinces of Alberta, British Columbia and Ontario, including 17 clinical trial investigators, 1 clinical research coordinator, 3 research administrators, 3 research ethics board members and 10 clinical trial participants. We conducted a thematic analysis involving coding of interview transcripts and memo-writing to identify key themes. RESULTS: Several factors contribute to nonpublication and publication bias in clinical trial research. A core theme was that reporting practices are shaped by incentives within the research system taht favour publication of positive over negative trials. Investigators are discouraged from reporting by experiences or perceptions of difficulty in publishing negative findings but rewarded for publishing positive findings in various ways. Trial investigators more strongly associated positive clinical trials than negative trials with opportunities for industry and nonindustry funding and with academic promotion, bonuses and recognition. Research institutions and ethics boards tended to lack well-resourced, proactive policies and practices to ensure trial findings are reported in registries or journals. CONCLUSION: Clinical trial reporting practices in Canada are shaped by incentives favouring reporting of positive over negative trials, such as funding opportunities and academic promotion, bonuses and recognition. Research institutions could help change incentives by adopting performance metrics that emphasize full reporting of results in journals or registries.

Overestimation of benefit when clinical trials stop early: a simulation study.

BACKGROUND: Stopping trials early because of a favourable interim analysis can exaggerate benefit. This study simulated trials typical of those stopping early for benefit in the real world and estimated the degree to which early stopping likely overestimates benefit. METHODS: From 1 million simulated trials, we selected those trials that exceeded interim stopping criteria, and compared apparent benefit when stopped with the true benefit used to generate the data. Each simulation randomly assigned period of observation, number of subjects, and control event rate using normal distributions centred on the same parameters in a template trial typical of real-world "truncated" (i.e. stopped for benefit) trials. The intervention's true relative risk reduction (RRR) was also randomized, and assumed 1% of drugs have a warfarin-like effect (60% RRR), 5% a statin-like effect (35% RRR), 39% an ASA-like effect (15% RRR), 50% no effect (0% RRR), and that 5% would cause harm (modelled as a 20% relative risk increase). Trials had a single interim analysis and a z-value for stopping of 2.782 (O'Brien-Fleming threshold). We also modelled (1) a large truncated trial based on the SPRINT blood pressure trial (using SPRINT's parameters and stopping criteria) and (2) the same typical truncated trials if they instead went to completion as planned with no interim analysis. RESULTS: For typical truncated trials, the true RRR was roughly 2/3 the observed RRR at the time of stopping. RRR was overestimated by an absolute 14.9% (median, IQR 6.4-24.6) in typical truncated trials, by 5.3% (IQR -0.1 to 11.4) in the same trials if instead carried to completion, and by 2.3% (IQR 0.98-1.09) in large SPRINT-like trials. For all models, to keep the absolute RRR overestimate below 5%, 250 events were required. CONCLUSION: Simulated trials typical of those stopping early for benefit overestimate the true relative risk reduction by roughly 50% (i.e. the true RRR was 2/3 of the observed value). Overestimation was much smaller, and likely unimportant, when simulating large SPRINT-like trials stopping early. Whether trials were large or small, stopped early or not, a minimum 250 events were needed to avoid overestimating relative risk reduction by an absolute 5% or more.

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.

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.

Bedtime versus morning use of antihypertensives for cardiovascular risk reduction (BedMed): protocol for a prospective, randomised, open-label, blinded end-point pragmatic trial.

INTRODUCTION: Sleep-time blood pressure correlates more strongly with adverse cardiovascular events than does daytime blood pressure. The BedMed trial evaluates whether bedtime antihypertensive administration, as compared with conventional morning use, reduces major adverse cardiovascular events. METHODS AND ANALYSIS: DesignProspective randomised, open-label, blinded end-point trial.ParticipantsHypertensive primary care patients using blood pressure lowering medication and free from glaucoma.SettingCommunity primary care providers in 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario) are mailing invitations to their eligible patients. Social media campaigns (Google, Facebook) are additionally running in the same provinces.InterventionConsenting participants are allocated via central randomisation to bedtime vs morning use of all antihypertensives.Follow-up(1) Telephone or email questionnaire at 1 week, 6 weeks, 6 months and every 6 months thereafter, and (2) accessing linked governmental healthcare databases tracking hospital and community medical services.Primary outcomeComposite of all-cause death, or hospitalisation for myocardial infarction/acute-coronary syndrome, stroke or congestive heart failure.Secondary outcomesEach primary outcome element on its own, all-cause hospitalisation or emergency department visit, long-term care admission, non-vertebral fracture, new glaucoma diagnosis, 18-month cognitive decline from baseline (via Short Blessed Test).Select other outcomesSelf-reported nocturia burden at 6 weeks and 6 months (no, minor or major burden), 1-year self-reported overall health score (EQ-5D-5L), self-reported falls, total cost of care (acute and community over study duration) and mean sleep-time systolic blood pressure after 6 months (via 24-hour monitor in a subset of 302 sequential participants).Primary outcome analysisCox proportional hazards survival analysis.Sample sizeThe trial will continue until a projected 254 primary outcome events have occurred.Current statusEnrolment ongoing (3227 randomised to date). ETHICS AND DISSEMINATION: BedMed has ethics approval from six research ethics review boards and will publish results in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02990663.

Concerns regarding tablet splitting: a systematic review.

BACKGROUND: Tablet splitting can provide dose flexibility and cost savings; however, pharmaceutical representatives typically discourage the practice. AIM: To identify and summarise all published concerns related to tablet splitting and to present the experimental evidence that investigates those concerns. DESIGN & SETTING: Systematic review and qualitative synthesis of tablet-splitting concerns and evidence. METHOD: Medline and EMBASE databases were searched over all years of publication for articles in English discussing the splitting of tablets. Eligible articles included original research, narrative reviews, systematic reviews, and expert opinion. RESULTS: After removing duplicates, 1837 potentially relevant articles underwent dual review, whereupon 1612 articles were excluded based on title and abstract. After examination of 225 full texts, 138 articles were included (one systematic review, four narrative reviews, 101 original research articles, and 32 opinion articles). The described concerns included difficulty breaking tablets, loss of mass, weight variability, chemical instability, overly rapid dosing if sustained-release medications are split, non-compliance, and patient confusion resulting in medication errors. No substantive evidence was found to support concerns regarding loss of mass, weight variability, chemical instability, or non-compliance. Evidence does support some older adults struggling to split tablets without tablet splitters, and the inappropriateness of splitting sustained-release preparations, given the potential for alteration of the rate of drug release for some products. CONCLUSION: With the exception of sustained-release tablets, which should not be split, and excepting those older people who may struggle to split tablets based on physical limitations, there is little evidence to support tablet-splitting concerns.

Content of physical activity documentation in Canadian family physicians' electronic medical records.

The purpose of this study was to examine the content of physical activity inputs in Canadian family physician electronic medical records. Of 1 225 948 patients aged 18-64 years, a sample of 1535 patients' charts were reviewed. A minority (n = 148; 9.6%) of patients had at least 1 mention of physical activity at any time. Insufficient information existed to determine physical activity domain (21.6%), purpose (50.0%), or meeting of guidelines (98.1%). Novelty: This study examines the physical activity content of what Canadian family physicians document in their electronic medical records.