Patient Eligibility for Established and Novel Guideline-Directed Medical Therapies After Acute Heart Failure Hospitalization.

BACKGROUND: Acute heart failure (AHF) hospitalization presents an opportunity to optimize pharmacotherapy to improve outcomes. OBJECTIVES: This study's aim was to define eligibility for initiation of guideline-directed medical therapy and newer heart failure (HF) agents from recent clinical trials in the AHF population. METHODS: The authors analyzed patients with an AHF admission within the CAN-HF (Canadian Heart Failure) registry between January 2017 and April 2020. Heart failure with reduced ejection fraction (HFrEF) was defined as left ventricular ejection fraction (LVEF) ≤40% and heart failure with preserved ejection fraction (HFpEF) as LVEF >40%. Eligibility was assessed according to the major society guidelines or enrollment criteria from recent landmark clinical trials. RESULTS: A total of 809 patients with documented LVEF were discharged alive from hospital: 455 with HFrEF and 354 with HFpEF; of these patients, 284 had a de novo presentation and 525 had chronic HF. In HFrEF patients, eligibility for therapies was 73.6% for angiotensin receptor-neprilysin inhibitors (ARNIs), 94.9% for beta-blockers, 84.4% for mineralocorticoid receptor antagonists (MRAs), 81.1% for sodium-glucose cotransporter-2 (SGLT2) inhibitors, and 15.6% for ivabradine. Additionally, 25.9% and 30.1% met trial criteria for vericiguat and omecamtiv mecarbil, respectively. Overall, 71.6% of patients with HFrEF (75.5% de novo, 69.5% chronic HF) were eligible for foundational quadruple therapy. In the HFpEF population, 37.6% and 59.9% were eligible for ARNIs and SGLT2 inhibitors based on recent trial criteria, respectively. CONCLUSIONS: The majority of patients admitted with AHF are eligible for foundational quadruple therapy and additional novel medications across a spectrum of HF phenotypes.

The Canadian Heart Failure (CAN-HF) Registry: A Canadian Multicentre, Retrospective Study of Inpatients With Heart Failure.

Background: Despite recent advances in the management of patients with heart failure (HF), national data regarding the quality of care provided are lacking. The Canadian Heart Failure (CAN-HF) Registry was designed to obtain contemporary, real-world data describing the management of patients with HF. Methods: Quality of care in patients admitted for acute HF (AHF), in relation to guidelines and national HF quality indicators, was assessed as part of the CAN-HF Registry study. Results: A total of 943 patients admitted to the hospital with AHF were included in this analysis. Patient weight was not recorded on admission for 26% of patients, with daily weight being captured in only 61% of patients. Only 54% of inpatients received left ventricular ejection fraction assessment while hospitalized. Patient education was documented in 31% of patients prior to discharge, with 51% receiving instructions to follow up with a specialist upon discharge, and 2% being referred to a cardiac rehabilitation program. Although use of guideline-directed medical therapy increased during hospitalization, the proportions of patients receiving renin-angiotensin-aldosterone inhibition (63%), beta-blockade (80%), and mineralocorticoid receptor antagonist (40%) upon discharge indicate that potential room for improvement exists. Conclusions: The CAN-HF Registry study demonstrated a potential quality-of-care gap in the management of patients admitted with AHF.

Contexte: Malgré les progrès récents dans la prise en charge des patients souffrant d'insuffisance cardiaque (IC), on note un manque flagrant de données nationales sur la qualité des soins prodigués. Le Registre canadien sur l'insuffisance cardiaque (Canadian Heart Failure Registry ou CAN-HF) a été conçu pour colliger des données contemporaines du monde réel décrivant la prise en charge des patients atteints d'IC. Méthodologie: Dans le cadre de l'étude CAN-HF Registry, on a évalué la qualité des soins prodigués aux patients hospitalisés pour cause d'IC aiguë (ICA) par rapport aux lignes directrices et aux indicateurs nationaux de qualité applicables à l'IC. Résultats: Notre analyse a porté sur 943 patients hospitalisés pour cause d'ICA. Le poids corporel n'avait pas été noté chez 26 % des patients au moment de leur admission à l'hôpital. Les mesures quotidiennes du poids avaient été prises chez 61 % des patients seulement. L'évaluation de la fraction d'éjection ventriculaire gauche avait été effectuée chez seulement 54 % des patients hospitalisés. Selon les documents consultés, 31 % des patients avaient reçu de l'information et des instructions avant de recevoir leur congé de l'hôpital; 51 % avaient reçu la directive de consulter un spécialiste pour assurer leur suivi après leur sortie de l'hôpital et 2 % avaient été orientés vers un programme de réadaptation cardiaque. Si le traitement médical administré durant l'hospitalisation était davantage conforme aux lignes directrices, les proportions de patients ayant reçu des inhibiteurs de la rénine-angiotensine-aldostérone (63 %), des bêtabloquants (80 %) et des antagonistes des récepteurs minéralocorticoïdes (40 %) à leur sortie de l'hôpital indiquent qu'il y a encore des progrès à faire. Conclusions: L'étude CAN-HF Registry a démontré qu'il pouvait y avoir des lacunes dans la qualité des soins prodigués aux patients hospitalisés pour cause d'ICA.

Strategies for Transfer From Methadone to Buprenorphine for Treatment of Opioid Use Disorders and Associated Outcomes: A Systematic Review.

OBJECTIVES: To review the currently available evidence on transfer strategies from methadone to sublingual buprenorphine used in clinical trials and observational studies of medication for opioid use disorder treatment, and to consider whether any strategies yield better clinical outcomes than others. METHODS: Six medical and public health databases were searched for articles and conference abstracts. The Cochrane Central Register of Controlled Trials and the World Health Organization International Clinical Trials Registry Platform were used to identify unpublished trial results. Records were dually screened, and data were extracted and checked independently. Results were summarized qualitatively and, when possible, analyzed quantitatively. RESULTS: Eighteen studies described transfer from methadone to buprenorphine. Transfer protocols were extremely varied. Most studies reported successful rates of transfer, even among studies involving transfer from high methadone doses, although lower pretransfer methadone dose was significantly associated with higher rate of successful transfer. Precipitated withdrawal was not reported frequently. A range of innovative approaches to transfer from methadone to buprenorphine remains untested. CONCLUSIONS: Few studies have used designs that enable comparison of different approaches to transfer patients from methadone to buprenorphine. Most international clinical guidelines provide recommendations consistent with the available evidence. However, clinical guidelines should be perceived as providing "guidance" rather than "protocols," and clinicians and patients need to exercise judgment when attempting transfers.

Optimal Usage of Sacubitril/Valsartan for the Treatment of Heart Failure: The Importance of Optimizing Heart Failure Care in Canada.

BACKGROUND: Heart failure (HF) with reduced ejection fraction represents approximately 50% of the 600,000 Canadians currently living with HF and over 90,000 new cases diagnosed each year. The angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, demonstrated superior efficacy in reducing cardiovascular death and HF hospitalization over standard of care therapy. METHODS: The potential magnitude of benefit in Canada with respect to preventing or postponing deaths and reducing hospitalizations resulting from its optimal implementation in patients with HF with an ejection fraction <40% was estimated based on published sources. RESULTS: Of the potentially eligible 225,562 patients, this would amount to the prevention of 4699 cardiovascular deaths and first HF hospitalizations, 3698 thirty-day HF readmissions, and 2820 deaths due to all-cause mortality. The number of patients receiving sacubitril/valsartan nationally in 2018 was 27,267. This represents approximately 12% of the calculated eligible population for this therapy in Canada. CONCLUSIONS: The findings from this analysis suggest that a substantial number of deaths, hospitalizations, and HF readmissions could potentially be avoided by optimal usage of sacubitril/valsartan therapy in Canada. This emphasizes the importance of rapidly and appropriately implementing evidence-based medications into routine clinical practice, to achieve the best possible outcomes for our patients with HF and to reduce the high burden and cost of HF in Canada.

CONTEXTE: L'insuffisance cardiaque (IC) avec diminution de la fraction d'éjection touche actuellement environ 50 % des 600 000 Canadiens qui sont atteints d'IC, et plus de 90 000 nouveaux cas de cette affection sont diagnostiqués chaque année. L'association sacubitril-valsartan (inhibiteur de la néprilysine et antagoniste des récepteurs de l'angiotensine) a démontré une efficacité supérieure à celle du traitement de référence au chapitre de la réduction de la mortalité d'origine cardiovasculaire et des hospitalisations dues à l'IC. MÉTHODOLOGIE: L'ampleur potentielle des bienfaits du médicament au Canada en matière de prévention ou de report des décès et de réduction des hospitalisations par suite de son utilisation optimale chez les patients atteints d'IC présentant une fraction d'éjection < 40 % a été estimée sur la base de sources publiées. RÉSULTATS: Chez les 225 562 patients potentiellement admissibles au traitement, le médicament permettrait de prévenir 4 699 décès d'origine cardiovasculaire et premières hospitalisations pour cause d'IC, 3 698 réhospitalisations pour cause d'IC dans les 30 jours suivant la sortie de l'hôpital et 2 820 décès toutes causes confondues. À l'échelle nationale en 2018, 27 267 patients ont été traités par l'association sacubitril-valsartan. Cela représente environ 12 % de la population admissible au traitement selon les calculs s'appliquant au Canada. CONCLUSIONS: Les résultats de cette analyse permettent de penser que beaucoup de décès, d'hospitalisations et de réhospitalisations pour cause d'IC pourraient être évités par suite de la mise en œuvre optimale du traitement par l'association sacubitril-valsartan au Canada. Sous cet éclairage, force est de constater l'importance que revêt l'intégration rapide et appropriée des pharmacothérapies factuelles à la pratique clinique courante, dans l'optique d'une démarche visant à obtenir les meilleurs résultats possible chez nos patients atteints d'IC et à réduire le lourd fardeau de cette affection au Canada.

4ß-Hydroxycholesterol as an Endogenous Biomarker for CYP3A Activity: Literature Review and Critical Evaluation.

A number of cytochrome P450 (CYP)3A phenotyping probes have been used to characterize the drug interaction potential of new molecular entities; of these, midazolam has emerged as the gold standard. Recently, plasma 4ß-hydroxycholesterol (4ß-OHC), the metabolite of CYP3A-mediated cholesterol metabolism, has been championed as an endogenous biomarker for CYP3A, particularly during chronic conditions where CYP3A activity is altered by disease and in long-term treatment studies where midazolam administration is not optimal. Multiple studies in humans have shown that 4ß-OHC can qualitatively differentiate among weak, moderate, and potent CYP3A induction when an inducer, typically rifampin, is administered for up to 2 weeks. Conversely, longer durations of CYP3A inhibitor administration (≥1 month) appear to be necessary to differentiate among weak, moderate, and potent CYP3A inhibitors. A number of studies have reported statistically significant linear relationships between 4ß-OHC plasma concentrations (and 4ß-OHC:cholesterol ratios) and midazolam clearance. However, sufficiently powered studies assessing the ability of 4ß-OHC or 4ß-OHC:cholesterol ratios to measure CYP3A activity (ie, predictive performance) have not been conducted to date. Additional limitations associated with 4ß-OHC phenotyping include inability to detect acute changes in CYP3A activity, uncertainty with regard to its intestinal formation, ambiguity surrounding the role of CYP3A5 in its metabolism, and lack of clarity regarding the role of transporters in its disposition. As such, the data do not support the use of 4ß-OHC or 4ß-OHC:cholesterol ratios as an endogenous biomarker for CYP3A activity.

Deprescribing recommendations: An essential consideration for clinical guideline developers.

One area of focus of the Bruyère Evidence-Based Deprescribing Guidelines Symposium held in March 2018 was encouraging the routine inclusion of deprescribing recommendations in clinical guidelines. Clinical guidelines often do not accommodate frailty or patients with multiple comorbid conditions. This can give rise to complex medication regimens and risk of medication harm. Despite monitoring and stopping treatment being a key part of rational prescribing, deprescribing is often overlooked in general and in the context of guidelines. There are several challenges to increasing deprescribing recommendations in clinical guidelines. These include limited evidence on the effects of deprescribing, lack of awareness among guideline developers, potential conflicts of interest, and lack of incentives for deprescribing research. To date, medicines regulators, payers, governments, and journals have not encouraged the inclusion of deprescribing recommendations in guidelines. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system could address some of these challenges through its focus on values and preferences, distinct rating of quality of evidence and strength of recommendations, downgrading quality due to indirect evidence, and an explicit approach to conflicts of interest. Further work to adapt GRADE methods to deprescribing could be of benefit. Establishing deprescribing recommendations as a routine part of clinical guidelines is an important opportunity to improve evidence-based clinical practice, and ultimately, patient care.

CFH and ARMS2 Polymorphisms Interact with Zinc Supplements in Cognitive Impairment in the Women's Health Initiative Hormone Trial.

BACKGROUND: An interaction between genetic variants in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) and high-dose zinc supplementation on progression to advanced age-related macular degeneration (AMD) exists. Because cognitive impairment (CI) is associated with AMD, we used data from the Women's Health Initiative (WHI) to search for a zinc/genetics interaction. OBJECTIVE: To study the interaction of chronic zinc supplementation with genetic variants in CFH and ARMS2 on the development of CI. BACKGROUND: Zinc dietary supplements, CFH and ARMS2 genotypes, and serial mental status was analyzed in participants with available genetic data (n = 7,483). Cognition was assessed using the Modified Mini-Mental State Examination. The development of CI over 5 years was analyzed by genotype and zinc intake using a repeated measures logistic regression model. RESULTS: Zinc supplementation of approximately 15 mg/day was associated with decreased development of CI in women with 1 or 2 CFH and no ARMS2 risk alleles (OR = 0.46: 1 CFH risk allele; 0.20: 2 CFH risk alleles; p = 0.002). CONCLUSION: Low-dose zinc (approximately 15 mg) is associated with reduced CI in women with 2 CFH and 0 ARMS2 AMD risk alleles. This interaction is opposite in direction to that observed in AMD, where patients with 2 CFH and 0 ARMS2 risk alleles had increased progression to neovascular AMD if treated with 80 mg/day of zinc. This may be due to a zinc dose-response or to a fundamental difference in the role of zinc in the progression of early CI versus advanced AMD.

Deprescribing antipsychotics for behavioural and psychological symptoms of dementia and insomnia: Evidence-based clinical practice guideline.

OBJECTIVE: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper and stop antipsychotics; to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes. METHODS: The overall team comprised 9 clinicians (1 family physician, 1 family physician specializing in long-term care, 1 geriatric psychiatrist, 2 geriatricians, 4 pharmacists) and a methodologist; members disclosed conflicts of interest. For guideline development, a systematic process was used, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence was generated from a Cochrane systematic review of antipsychotic deprescribing trials for the behavioural and psychological symptoms of dementia, and a systematic review was conducted to assess the evidence behind the benefits of using antipsychotics for insomnia. A review of reviews of the harms of continued antipsychotic use was performed, as well as narrative syntheses of patient preferences and resource implications. This evidence and GRADE quality-of-evidence ratings were used to generate recommendations. The team refined guideline content and recommendation wording through consensus and synthesized clinical considerations to address common front-line clinician questions. The draft guideline was distributed to clinicians and stakeholders for review and revisions were made at each stage. RECOMMENDATIONS: We recommend deprescribing antipsychotics for adults with behavioural and psychological symptoms of dementia treated for at least 3 months (symptoms stabilized or no response to an adequate trial) and for adults with primary insomnia treated for any duration or secondary insomnia in which underlying comorbidities are managed. A decision-support algorithm was developed to accompany the guideline. CONCLUSION: Antipsychotics are associated with harms and can be safely tapered. Patients and caregivers might be more amenable to deprescribing if they understand the rationale (potential for harm), are involved in developing the tapering plan, and are offered behavioural advice or management. This guideline provides recommendations for making decisions about when and how to reduce the dose of or stop antipsychotics. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients and families.

Déprescription des antipsychotiques pour les symptômes comportementaux et psychologiques de la démence et l'insomnie: Guide de pratique clinique fondé sur des données probantes.

OBJECTIF: Élaborer un guide de pratique clinique fondé sur des données probantes pour aider les cliniciens à prendre des décisions quant au moment et à la façon de réduire et de cesser les antipsychotiques en toute sécurité; insister sur les données les plus probantes et solliciter les contributions des professionnels des soins primaires pour l'élaboration, la révision et l'approbation des lignes directrices. MÉTHODOLOGIE: L'équipe comptait 9 cliniciens (1 médecin de famille, 1 médecin de famille spécialisée en soins de longue durée, 1 psychiatre gériatrique, 2 gériatres, 4 pharmaciens) et une spécialiste en méthodologie; les membres ont divulgué leurs conflits d'intérêts. Un processus systématique a été utilisé pour l'élaboration du guide de pratique, y compris le protocole GRADE (Grading of Recommendations Assessment, Development and Evaluation). Les données probantes ont été tirées d'une revue systématique de Cochrane portant sur des études sur la déprescription des antipsychotiques pour les symptômes comportementaux et psychologiques de la démence. Nous avons effectué une revue systématique pour évaluer les données probantes étayant les bienfaits de l'utilisation des antipsychotiques pour traiter l'insomnie. Nous avons examiné les revues portant sur les torts associés à l'utilisation des antipsychotiques sur une base continue, et nous avons fait une synthèse narrative des préférences des patients et des répercussions sur le plan des ressources. Ces données probantes, de même que l'évaluation de la qualité des données selon GRADE, ont été utilisées pour produire les recommandations. L'équipe a peaufiné le contenu du guide de pratique et le libellé des recommandations, et elle a résumé les considérations d'ordre clinique pour répondre aux questions courantes des cliniciens de première ligne. Une ébauche du guide de pratique a été distribuée à des cliniciens et à des intervenants aux fins d'examen. Des révisions ont été apportées au texte à chaque étape. RECOMMANDATIONS: Nous recommandons la déprescription des antipsychotiques chez les adultes ayant des symptômes comportementaux et psychologiques de démence traités depuis au moins 3 mois (symptômes stabilisés ou sans réponse après un essai adéquat) et chez les adultes souffrant d'insomnie primaire, quelle que soit la durée du traitement, ou d'une insomnie secondaire lorsque les comorbidités sous-jacentes sont prises en charge. Un algorithme décisionnel accompagne le guide de pratique clinique. CONCLUSION: Les antipsychotiques sont associés à des préjudices et il est possible de procéder à un sevrage en toute sécurité. Les patients et leurs aidants peuvent être plus réceptifs à la déprescription s'ils comprennent ce qui la justifie (potentiel de préjudices), s'ils participent à l'élaboration du plan de sevrage et si on leur offre des conseils ou une prise en charge quant aux comportements. Le présent guide de pratique clinique offre des recommandations pour décider du moment et de la façon de réduire la dose d'antipsychotiques ou de les cesser complètement. Les recommandations servent à aider à prendre les décisions conjointement avec les patients et leur famille plutôt qu'à les dicter.

Deprescribing antihyperglycemic agents in older persons: Evidence-based clinical practice guideline.

OBJECTIVE: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper, stop, or switch antihyperglycemic agents in older adults. METHODS: We focused on the highest level of evidence available and sought input from primary care professionals in guideline development, review, and endorsement processes. Seven clinicians (2 family physicians, 3 pharmacists, 1 nurse practitioner, and 1 endocrinologist) and a methodologist comprised the overall team; members disclosed conflicts of interest. We used a rigorous process, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, for guideline development. We conducted a systematic review to assess evidence for the benefits and harms of deprescribing antihyperglycemic agents. We performed a review of reviews of the harms of continued antihyperglycemic medication use, and narrative syntheses of patient preferences and resource implications. We used these syntheses and GRADE quality-of-evidence ratings to generate recommendations. The team refined guideline content and recommendation wording through consensus and synthesized clinical considerations to address common front-line clinician questions. The draft guideline was distributed to clinicians and stakeholders for review and revisions were made at each stage. A decision-support algorithm was developed to accompany the guideline. RECOMMENDATIONS: We recommend deprescribing antihyperglycemic medications known to contribute to hypoglycemia in older adults at risk or in situations where antihyperglycemic medications might be causing other adverse effects, and individualizing targets and deprescribing accordingly for those who are frail, have dementia, or have a limited life expectancy. CONCLUSION: This guideline provides practical recommendations for making decisions about deprescribing antihyperglycemic agents. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients.

Déprescription des antihyperglycémiants chez les personnes âgées: Guide de pratique clinique fondé sur les données probantes.

OBJECTIF: Formuler des lignes directrices fondées sur les données probantes afin d'aider les cliniciens à décider du moment et de la façon sécuritaire de réduire la dose des antihyperglycémiants, de mettre fin au traitement ou de passer à un autre agent chez les personnes âgées. MÉTHODES: Nous nous sommes concentrés sur les données les plus probantes disponibles et avons cherché à obtenir les commentaires des professionnels de première ligne durant le processus de rédaction, de révision et d'adoption des lignes directrices. L'équipe était formée de 7 professionnels de la santé (2 médecins de famille, 3 pharmaciens, 1 infirmière praticienne et 1 endocrinologue) et d'une spécialiste de la méthodologie; les membres ont divulgué tout conflit d'intérêts. Nous avons eu recours à un processus rigoureux, y compris l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) pour formuler les lignes directrices. Nous avons effectué une revue systématique dans le but d'évaluer les données probantes indiquant les bienfaits et les torts liés à la déprescription des antihyperglycémiants. Nous avons révisé les revues des torts liés à la poursuite du traitement antihyperglycémiant, et effectué des synthèses narratives des préférences des patients et des répercussions sur les ressources. Ces synthèses et évaluations de la qualité des données selon l'approche GRADE ont servi à formuler les recommandations. L'équipe a peaufiné le texte sur le contenu et les recommandations des lignes directrices par consensus et a synthétisé les considérations cliniques afin de répondre aux questions courantes des cliniciens de première ligne. Une version préliminaire des lignes directrices a été distribuée aux cliniciens et aux intervenants aux fins d'examen, et des révisions ont été apportées au texte à chaque étape. Un algorithme d'appui décisionnel a été conçu pour accompagner les lignes directrices. RECOMMANDATIONS: Nous recommandons de déprescrire les antihyperglycémiants reconnus pour contribuer à l'hypoglycémie chez les personnes âgées à risque ou dans les situations où les antihyperglycémiants pourraient causer d'autres effets indésirables, et d'individualiser les cibles et de déprescrire en conséquence chez les personnes frêles, atteintes de démence ou dont l'espérance de vie est limitée. CONCLUSION: Les présentes lignes directrices émettent des recommandations pratiques pour décider du moment et de la façon de déprescrire les antihyperglycémiants. Elles visent à contribuer au processus de décision conjointement avec le patient et non à le dicter.

Assessment of Oral Anticoagulant Use in Residents of Long-Term Care Homes: Evidence for Contemporary Suboptimal Use.

OBJECTIVE: To describe the quality of warfarin use in residents of long-term care facilities and investigate potential predictors oral anticoagulant use. DESIGN: Retrospective chart review (August 2013 to September 2014). SETTING: Thirteen long-term care (LTC) and assisted living facilities (ALF). PARTICIPANTS: Residents from LTC or ALF settings who ( a) received warfarin or direct-acting oral anticoagulants (DOACs) and ( b) residents with a valid indication for oral anticoagulants such as atrial fibrillation, venous thromboembolism, but were not receiving these drugs. PRIMARY OUTCOME: Time in therapeutic international normalized ratio (INR) range (TTR). RESULTS: A total of 563 residents (70% female) with an average age of 85 years were identified. Participants had an average of 7.5 comorbidities and 9 medications. A total of 391 (69%) residents with indications for OACs were receiving such medications. Indications were atrial fibrillation (63%), venous or pulmonary embolism (16%), cardiac valves (0.4%); 26% did not have documented indications. Warfarin and DOACs were prescribed for 213 (38%) and 178 (32%) respectively, and 172 (31%) received no OACs The TTR ranged from 56%-75% (mean 63%). The frequency of INR determinations ranged from every 7 to 20 days, (mean 13 days) with no apparent relationship between frequency of testing and TTR. CONCLUSION: The TTR was higher (63.8%) than literature average (50%), but remains suboptimal given expected benefits of TTRs >75% versus TTRs circa 60%. Documentation of indications for OACs needs improvement, and it is possible that OACs are underused. Further work is necessary to understand how OAC use may be optimized in these facilities.

Deprescribing proton pump inhibitors: Evidence-based clinical practice guideline.

OBJECTIVE: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper or stop proton pump inhibitors (PPIs); to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes. METHODS: Five health professionals (1 family physician, 3 pharmacists, and 1 gastroenterologist) and 5 nonvoting members comprised the overall team; members disclosed conflicts of interest. The guideline process included the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, with a detailed evidence review in in-person, telephone, and online meetings. Uniquely, the guideline development process included a systematic review of PPI deprescribing trials and examination of reviews of the harm of continued PPI use. Narrative syntheses of patient preferences and resource-implication literature informed recommendations. The team refined guideline content and recommendation wording through consensus and synthesized clinical considerations to address common front-line clinician questions. The draft guideline was distributed to clinicians and then to health care professional associations for review and revisions made at each stage. A decision-support algorithm was developed in conjunction with the guideline. RECOMMENDATIONS: This guideline recommends deprescribing PPIs (reducing dose, stopping, or using "on-demand" dosing) in adults who have completed a minimum of 4 weeks of PPI treatment for heartburn or mild to moderate gastroesophageal reflux disease or esophagitis, and whose symptoms are resolved. The recommendations do not apply to those who have or have had Barrett esophagus, severe esophagitis grade C or D, or documented history of bleeding gastrointestinal ulcers. CONCLUSION: This guideline provides practical recommendations for making decisions about when and how to reduce the dose of or stop PPIs. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients.

Deprescribing versus continuation of chronic proton pump inhibitor use in adults.

BACKGROUND: Proton pump inhibitors (PPIs) are a class of medications that reduce acid secretion and are used for treating many conditions such as gastroesophageal reflux disease (GERD), dyspepsia, reflux esophagitis, peptic ulcer disease, and hypersecretory conditions (e.g. Zollinger-Ellison syndrome), and as part of the eradication therapy for Helicobacter pylori bacteria. However, approximately 25% to 70% of people are prescribed a PPI inappropriately. Chronic PPI use without reassessment contributes to polypharmacy and puts people at risk of experiencing drug interactions and adverse events (e.g. Clostridium difficile infection, pneumonia, hypomagnesaemia, and fractures). OBJECTIVES: To determine the effects (benefits and harms) associated with deprescribing long-term PPI therapy in adults, compared to chronic daily use (28 days or greater). SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10), MEDLINE, Embase, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). The last date of search was November 2016. We handsearched the reference lists of relevant studies. We screened 2357 articles (2317 identified through search strategy, 40 through other resources). Of these articles, we assessed 89 for eligibility. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-randomized trials comparing at least one deprescribing modality (e.g. stopping PPI or reducing PPI) with a control consisting of no change in continuous daily PPI use in adult chronic users. Outcomes of interest were: change in gastrointestinal (GI) symptoms, drug burden/PPI use, cost/resource use, negative and positive drug withdrawal events, and participant satisfaction. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted data and completed the risk of bias assessment. A third review author independently confirmed risk of bias assessment. We used Review Manager 5 software for data analysis. We contacted study authors if there was missing information. MAIN RESULTS: The review included six trials (n = 1758). Trial participants were aged 48 to 57 years, except for one trial that had a mean age of 73 years. All participants were from the outpatient setting and had either nonerosive reflux disease or milder grades of esophagitis (LA grade A or B). Five trials investigated on-demand deprescribing and one trial examined abrupt discontinuation. There was low quality evidence that on-demand use of PPI may increase risk of 'lack of symptom control' compared with continuous PPI use (risk ratio (RR) 1.71, 95% confidence interval (CI) 1.31 to 2.21), thereby favoring continuous PPI use (five trials, n = 1653). There was a clinically significant reduction in 'drug burden', measured as PPI pill use per week with on-demand therapy (mean difference (MD) -3.79, 95% CI -4.73 to -2.84), favoring deprescribing based on moderate quality evidence (four trials, n = 1152). There was also low quality evidence that on-demand PPI use may be associated with reduced participant satisfaction compared with continuous PPI use. None of the included studies reported cost/resource use or positive drug withdrawal effects. AUTHORS' CONCLUSIONS: In people with mild GERD, on-demand deprescribing may lead to an increase in GI symptoms (e.g. dyspepsia, regurgitation) and probably a reduction in pill burden. There was a decline in participant satisfaction, although heterogeneity was high. There were insufficient data to make a conclusion regarding long-term benefits and harms of PPI discontinuation, although two trials (one on-demand trial and one abrupt discontinuation trial) reported endoscopic findings in their intervention groups at study end.

The ACHRU-CPP versus usual care for older adults with type-2 diabetes and multiple chronic conditions and their family caregivers: study protocol for a randomized controlled trial.

BACKGROUND: Many community-based self-management programs have been developed for older adults with type-2 diabetes mellitus (T2DM), bolstered by evidence from randomized controlled trials (RCTs) that T2DM can be prevented and managed through lifestyle modifications. However, the evidence for their effectiveness is contradictory and weakened by reliance on single-group designs and/or small samples. Additionally, older adults with multiple chronic conditions (MCC) are often excluded because of recruiting and retention challenges. This paper presents a protocol for a two-armed, multisite, pragmatic, mixed-methods RCT examining the effectiveness and implementation of the Aging, Community and Health Research Unit-Community Partnership Program (ACHRU-CPP), a new 6-month interprofessional, nurse-led program to promote self-management in older adults (aged 65 years or older) with T2DM and MCC and support their caregivers (including family and friends). METHODS/DESIGN: The study will enroll 160 participants in two Canadian provinces, Ontario and Alberta. Participants will be randomly assigned to the control (usual care) or program study arm. The program will be delivered by registered nurses (RNs) and registered dietitians (RDs) from participating diabetes education centers (Ontario) or primary care networks (Alberta) and program coordinators from partnering community-based organizations. The 6-month program includes three in-home visits, monthly group sessions, monthly team meetings for providers, and nurse-led care coordination. The primary outcome is the change in physical functioning as measured by the Physical Component Summary (PCS-12) score from the short form-12v2 health survey (SF-12). Secondary client outcomes include changes in mental functioning, depressive symptoms, anxiety, and self-efficacy. Caregiver outcomes include health-related quality of life and depressive symptoms. The study includes a comparison of health care service costs for the intervention and control groups, and a subgroup analysis to determine which clients benefit the most from the program. Descriptive and qualitative data will be collected to examine implementation of the program and effects on interprofessional/team collaboration. DISCUSSION: This study will provide evidence of the effectiveness of a community-based self-management program for a complex target population. By studying both implementation and effectiveness, we hope to improve the uptake of the program within the existing community-based structures, and reduce the research-to-practice gap. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT02158741 . Registered on 3 June 2014.

Lack of Evidence to Guide Deprescribing of Antihyperglycemics: A Systematic Review.

INTRODUCTION: Individualizing glycemic targets to goals of care and time to benefit in persons with type 2 diabetes is good practice, particularly in populations at risk of hypoglycemia and adverse outcomes relating to the use of antihyperglycemics. Guidelines acknowledge the need for relaxed targets in frail older adults, but there is little guidance on how to safely deprescribe (i.e. stop, reduce or substitute) antihyperglycemics. METHODS: The purpose of this study was to synthesize evidence from all studies evaluating the effects of deprescribing versus continuing antihyperglycemics in older adults with type 2 diabetes. To this end, we searched MEDLINE, EMBASE, and Cochrane Library (July 2015) for controlled studies evaluating the effects of deprescribing antihyperglycemics in adults with type 2 diabetes. All such studies were eligible for inclusion in our study, and two independent reviewers screened titles, abstracts and full-text articles, extracted data, and evaluated risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment and a narrative summary were completed. RESULTS: We identified two controlled before-and-after studies, both of very low quality. One study found that an educational intervention decreased glyburide use while not compromising glucose control. The other reported that cessation of antihyperglycemics in elderly nursing home patients resulted in a non-significant increase in glycated hemoglobin (HbA1C). No significant change in hypoglycemia rate was found in the only study with this outcome measure. CONCLUSIONS: There is limited evidence available regarding deprescribing antihyperglycemic medications. Adequately powered, high-quality studies, particularly in the elderly and with clinically important outcomes, are required to support evidence-based decision-making. PROTOCOL REGISTRATION NUMBER: CRD42015017748.

Benefits, Potential Harms, and Optimal Use of Nutritional Supplementation for Preventing Progression of Age-Related Macular Degeneration.

OBJECTIVE: To briefly review age-related macular degeneration (AMD), the main findings from the Age Related Eye Disease Study (AREDS) report number 8 on the use of nutritional supplements for AMD, and to focus on data suggesting that supplement use should be guided using genetic testing of AMD risk genes. DATA SOURCES: A literature search (January 2001 through October 26, 2016) was conducted using MEDLINE and the following MeSH terms: Antioxidants/therapeutic use, Genotype, Macular Degeneration/drug therapy, Macular degeneration/genetics, Dietary Supplements, Proteins/genetics, and Zinc Compounds/therapeutic use. Bibliographies of publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing AREDS supplement response in patients with AMD in relation to complement factor H gene ( CFH) and age-related maculopathy susceptibility 2 gene ( ARMS2) risk alleles were evaluated. DATA SYNTHESIS: Three of the 4 studies demonstrated a treatment interaction between ARMS2 and CFH genotypes and a differential response to supplements. The fourth study documented an interaction for the CFH genotype only. Reported response interactions included attenuated response, no response, and good response, whereas a subset showed increased progression of AMD. Conversely, one study reported no interactions between CFH and ARMS2 risk alleles and response to supplements. CONCLUSIONS: The weight of the evidence supports using genetic testing to guide selection of ocular vitamin use. This approach will avoid using supplements that could speed the progression of AMD in vulnerable patients, avoid using supplements that will have little to no effect in others, and result in appropriately using supplements in those that are likely to derive meaningful benefits.

The Aging, Community and Health Research Unit-Community Partnership Program for older adults with type 2 diabetes and multiple chronic conditions: a feasibility study.

BACKGROUND: Few studies have examined the effectiveness of community-based self-management interventions in older adults with type 2 diabetes mellitus (T2DM) and multiple chronic conditions (MCC). The objectives of this study were to examine the feasibility of implementation in practice (primary) and the feasibility of study methods and potential effectiveness (secondary) of the Aging, Community and Health-Community Partnership Program, a new 6-month interprofessional, nurse-led program to promote diabetes self-management in older adults (>65 years) with T2DM and MCC. METHODS: This study used a prospective one-group pre-test/post-test design. Participants were recruited from a specialized diabetes clinic. They received a median of three in-home/clinic visits by certified diabetes educators (CDEs) and attended a median of three group wellness sessions provided by the CDEs in partnership with a community-based seniors' association. The primary outcome was the feasibility of the program (acceptability, fidelity, implementation barriers/facilitators). Secondary outcomes included the feasibility of the study methods (recruitment/retention rates and procedures, eligibility criteria, data collection and analysis methods) and potential effectiveness of the program based on 6-month changes in self-reported outcomes including self-management behavior (diet, exercise, self-monitoring), health status (quality of life, mental health), and costs of service use. Analysis of feasibility outcomes was primarily based on descriptive statistics. The potential effectiveness of the program was explored using different tests, with the results expressed using descriptive statistics and effect estimates (95 % confidence intervals). RESULTS: In total, 45 (88 %) of 51 eligible persons consented to participate. Of these, 37 (82 %) completed the 6-month follow-up. Participants and providers viewed the program as acceptable and feasible. Participants had a higher SF-12 physical component summary score at 6 months compared with baseline (mean score difference 3.0, 95 % CI 0.2-5.8). Median costs for diabetes care increased over 6 months (reflecting inclusion of program costs), while other service costs either decreased or remained unchanged. CONCLUSIONS: This study offers preliminary evidence that the program was feasible to deliver and acceptable to participants and providers. Initial results suggest that the program may improve physical functioning. A randomized controlled trial is feasible, with some adaptations to the program and study methods that were identified from this feasibility study. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01880476.

Atypical antipsychotics for insomnia: a systematic review.

BACKGROUND: Observational evidence suggests that atypical antipsychotics such as quetiapine are increasingly being used to manage insomnia. This is concerning given the uncertain efficacy and potential adverse effects associated with these medications. OBJECTIVES: The objectives of this study are to evaluate the benefits and adverse effects of atypical antipsychotics used specifically for insomnia. METHODS: The methods used in this study are systematic review and narrative synthesis. DATA SOURCES: The data were collected from PubMed; EMBASE; Cochrane Library; PsycINFO; grey literature; and the manufacturers of risperidone, quetiapine and olanzapine. PARTICIPANTS AND INTERVENTIONS: Adult patients ≥18 years of age using atypical antipsychotics specifically for primary or co-morbid insomnia for ≥ 1 week were compared to those receiving active intervention or placebo. APPRAISAL AND SYNTHESIS METHODS: Two independent reviewers screened titles, abstracts and full-text articles; extracted data; and conducted risk-of-bias analysis. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was completed. RESULTS: One double-blind randomized controlled trial (n = 13) met the eligibility criteria. Statistically significant differences were not observed from baseline between quetiapine and placebo after 2 weeks for primary insomnia in terms of total sleep time (mean difference (MD) 52.68 min, 95% CI -27.27 to 132.6), reduction in sleep latency (MD 72.44 min, 95% CI -2.65 to 147.5) or improved sleep satisfaction measured with a visual analogue scale out of 100 (MD 6.16, 95% CI -12.32 to 24.64), despite a trend towards improved sleep parameters. The study was rated as very low quality. CONCLUSIONS AND IMPLICATIONS: Very low quality evidence suggests that quetiapine does not significantly improve sleep parameters compared with placebo in primary insomnia, despite a trend towards clinical improvements. Atypical antipsychotics should be avoided in the first-line treatment of primary insomnia until further evidence is available.

Methodology for Developing Deprescribing Guidelines: Using Evidence and GRADE to Guide Recommendations for Deprescribing.

BACKGROUND: Class specific deprescribing guidelines could help clinicians taper and stop medications no longer needed or which may be causing more harm than benefit. We set out to develop methodology to create such guidelines using evidence-based methods for guideline development, evidence synthesis and recommendation rating. METHODS AND FINDINGS: Using a comprehensive checklist for a successful guideline enterprise, we conducted a national modified Delphi consensus process to identify priorities for deprescribing guidelines, then conducted scoping exercises to identify feasible topics, and sequentially developed three deprescribing guidelines. We selected guideline development team members for clinical expertise; a GRADE member worked with staff to ensure guideline development processes were followed. We conducted or used systematic searches and reviews of deprescribing trials of selected drug classes, reviews or systematic reviews of drug class effectiveness, reviews of reviews of drug class harm and narrative syntheses of contextual questions to inform recommendations and guideline development. Our 8 step process for guideline development included defining scope and purpose, developing a logic model to guide the process and generate key clinical questions, setting criteria for admissible evidence and conducting systematic reviews, synthesizing evidence considering additional contextual information and performing quality estimates, formulating recommendations and providing strength estimations, adding clinical considerations, conducting clinical and stakeholder review and finally updating content pre-publication. Innovative aspects of the guideline development process included synthesizing evidence for outcomes of tapering or stopping medication, and incorporating evidence for medication harm into the recommendation strength rating. Through the development of three deprescribing guidelines (for proton pump inhibitors, benzodiazepine receptor agonists and antipsychotics) and associated decision-support algorithms, we were able to gradually hone the methodology; each guideline will be published separately. CONCLUSION: Our methodology demonstrates the importance of searching for short and long-term outcomes, showing the benefits of deprescribing and studying patient preferences. This publication will support development of future deprescribing guidelines.