Reduced fixed dose tocilizumab 400 mg IV compared to weight-based dosing in critically ill patients with COVID-19: A before-after cohort study.

Background: Interleukin-6 inhibitors reduce mortality in severe COVID-19. British Columbia began using tocilizumab 8 mg/kg (maximum 800 mg) in January 2021 in critically ill patients with COVID-19, but due to drug shortages, decreased dosing to 400 mg IV fixed dose in April 2021. The aims of this study were twofold: to compare physiological responses and clinical outcomes of these two strategies, and examine the cost-effectiveness of treating all patients with 400 mg versus half the patients with 8 mg/kg and the other half without tocilizumab. Methods: This was a single-centre, before-after cohort study of critically ill COVID-19 patients treated with tocilizumab, and a control cohort treated with dexamethasone only. Physiological responses and clinical outcomes were compared between patients receiving both doses of tocilizumab and those receiving dexamethasone only. We built a decision tree model to examine cost-effectiveness. Findings: 152 patients were included; 40 received tocilizumab 8 mg/kg, 59 received 400 mg and 53 received dexamethasone only. Median CRP fell from 103 mg/L to 5.2 mg/L, 96 mg/L to 6.8 mg/L and from 81.3 mg/L to 48 mg/L in the 8 mg/kg, 400 mg tocilizumab, and dexamethasone only groups, respectively. 28-day mortality was 5% (n=2) vs 8% (n=5) vs 13% (n=7), with no significant difference in all pair-wise comparison. At an assumed willingness-to-pay threshold of $50,000 Canadian per life-year, utilizing 400 mg for all patients rather than 8 mg/kg for half the patients is cost-effective in 51.6% of 10,000 Monte Carlo simulations. Interpretation: Both doses of tocilizumab demonstrated comparable reduction of inflammation with similar 28-day mortality. Without consideration of equity, the net monetary benefits of providing 400 mg tocilizumab to all patients are comparable to 8 mg/kg to half the patients. In the context of ongoing drug shortages, fixed-dose 400 mg tocilizumab may be a practical, feasible and economical option. Funding: This work was supported by a gift donation from Hsu & Taylor Family to the VGH Foundation, and the Yale Bernard G. Forget Scholarship.

Reassessment of venous thromboembolism and bleeding risk in medical patients receiving VTE prophylaxis.

RATIONALE, AIMS, AND OBJECTIVES: The majority of hospitalized nonsurgical medical patients receive pharmacological prophylaxis for venous thromboembolism (VTE), and reassessment of changes in thrombosis and bleeding risk factors during hospital admission may represent an opportunity to discontinue unnecessary or unsafe therapy. The use of validated, clinically derived risk assessment models (RAMs) represents a shift towards an individualized, patient-centred approach to VTE prophylaxis. We are interested in using these tools to assess whether risk categories for VTE and bleeding change during admission and to assess whether such changes result in discontinuation of prophylaxis. Our primary objective was to determine whether VTE and bleed risk categories changed during the course of admission to warrant discontinuation of VTE prophylaxis, using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE and Bleed RAMs, respectively. Secondary objectives were to determine the number of patients whose risk categorizations for VTE and bleeding warranted discontinuation of VTE prophylaxis and to survey whether prophylaxis was continued or discontinued. METHODS: A retrospective review was undertaken for a cross-sectional, randomly selected sample of patients who received VTE prophylaxis while admitted to medical wards in a collection of regional hospitals. RESULTS: Of the 351 medical records reviewed, only eight patients (2.3%) changed their VTE risk category and six (1.7%) changed their bleed risk category to warrant discontinuation of VTE prophylaxis. Ninety patients (26%) were at high risk of VTE and low risk of bleed throughout admission, warranting continued VTE prophylaxis. The majority of patients remained at low risk of VTE throughout admission but remained on VTE prophylaxis until discharge. CONCLUSIONS: Risk categories for VTE and bleeding for medical patients did not appreciably change throughout hospital admission. Use of VTE RAMs at admission and prior to initiation of therapy should reduce unnecessary prophylaxis in the majority of medical patients who are at low risk of VTE.

Is There a Reason for the Proton Pump Inhibitor? An Assessment of Prescribing for Residential Care Patients in British Columbia.

BACKGROUND: The use of proton pump inhibitors (PPIs) may cause significant harm to patients in the residential care setting, as these patients are often frail with multiple morbidities. The extent of non-evidence-based use of PPIs in residential care sites of the Fraser Health Authority in British Columbia is unknown. OBJECTIVE: To determine the proportion of non-evidence-based use of PPI therapy for residential care patients of the Fraser Health Authority. METHODS: This retrospective cross-sectional study was conducted in 6 Fraser Health residential care facilities in British Columbia between April 1, 2015, and March 31, 2016. Two definitions of "evidence-based indications" were used. The first definition encompassed broad evidence-based indications for PPI use, specifically gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), gastritis, esophagitis, Barrett esophagus, and gastrointestinal protection from concurrent oral steroids, oral nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. The second definition involved common evidence-based indications for PPI use, specifically GERD or PUD. Descriptive statistics were used to evaluate the primary outcome: the proportion of PPI orders without a documented broad or common evidence-based indication for PPI treatment. RESULTS: A total of 331 residential care patients and 407 PPI orders were assessed. The proportion of PPI orders without a documented broad evidence-based indication was 16.2% (66/407). The proportion of PPI orders without a documented common evidence-based indication was 43.7% (178/407). The most frequently documented reason for a PPI order was GERD (214/407 or 52.6%). PPI orders for patients with GERD and gastrointestinal bleeding had the longest duration of therapy during residential care admission, averaging 205.1 and 218.1 days, respectively. CONCLUSION: About 1 in 6 PPI orders for Fraser Health residential care patients did not have a documented broad evidence-based indication, and about 2 in 5 PPI orders did not have a documented common evidence-based indication. These results indicate a need to assess the appropriateness of therapy for every patient with an active PPI order in residential care facilities.

CONTEXTE: L'emploi d'inhibiteurs de la pompe à protons (IPP) peut causer des torts importants aux patients qui résident en centre d'hébergement et de soins de longue durée, car souvent ces personnes sont fragiles et souffrent de multiples maladies. On ignore quelle est la proportion d'utilisation d'IPP ne reposant pas sur des données probantes dans les centres d'hébergement et de soins de longue durée de la Fraser Health Authority en Colombie-Britannique. OBJECTIF: Déterminer la proportion d'utilisation de traitement par IPP ne reposant pas sur des données probantes chez les patients en centre d'hébergement et de soins de longue durée de la Fraser Health Authority. MÉTHODES: Cette étude rétrospective transversale a été menée dans six centres d'hébergement et de soins de longue durée de la Fraser Health en Colombie-Britannique, entre le 1er avril 2015 et le 31 mars 2016. Deux définitions du terme « indications fondées sur des données probantes ¼ ont été utilisées. La première définition englobait des indications larges fondées sur des données probantes appuyant l'utilisation d'IPP, plus particulièrement : pour traiter le reflux gastro-œsophagien, l'ulcère gastroduodénal, la gastrite, l'œsophagite et l'œsophage de Barrett ainsi que pour fournir une protection gastrique contre les effets indésirables de la prise de médicaments anti-inflammatoires oraux stéroïdiens ou non stéroïdiens, d'antiplaquettaires et d'anticoagulants. La seconde définition comprenait les indications usuelles fondées sur des données probantes pour appuyer l'utilisation d'IPP, plus précisément : le reflux gastro-œsophagien ou l'ulcère gastroduodénal. Des statistiques descriptives ont été employées pour analyser le principal paramètre d'évaluation : la proportion d'ordonnances d'IPP pour lesquelles aucune indication, large ou usuelle, fondée sur des données probantes n'a été consignée. RÉSULTATS: Au total, les dossiers de 331 résidents de centres d'hébergement et de soins de longue durée et 407 ordonnances d'IPP ont été évalués. La proportion d'ordonnances d'IPP pour lesquelles aucune indication large fondée sur des données probantes n'a été consignée était de 16,2 % (66/407). La proportion d'ordonnances d'IPP pour lesquelles aucune indication usuelle fondée sur des données probantes n'a été consignée était de 43,7 % (178/407). La raison la plus souvent consignée pour l'émission d'une ordonnance d'IPP était le reflux gastro-œsophagien (214/407 ou 52,6 %). Les ordonnances d'IPP destinées aux patients souffrant de reflux gastro-œsophagien ou d'hémorragie gastro-intestinale étaient celles pour lesquelles la durée du traitement était la plus longue au cours du séjour en centre d'hébergement et de soins de longue durée, soit respectivement de 205,1 et 218,1 jours en moyenne. CONCLUSION: Environ 1 ordonnance d'IPP sur 6 pour les patients de centres d'hébergement et de soins de longue durée de la Fraser Health ne reposait pas sur une indication large consignée et fondée sur des données probantes et environ 2 ordonnances d'IPP sur 5 ne s'appuyaient pas sur une indication usuelle consignée et fondée sur des données probantes. Les résultats révèlent la nécessité d'évaluer la pertinence des traitements par IPP pour chaque patient ayant une ordonnance active d'IPP dans les centres d'hébergement et de soins de longue durée.

5α-Reductase Inhibitors for Treatment of Benign Prostatic Hyperplasia: A Systematic Review and Meta-Analysis.

BACKGROUND: Finasteride and dutasteride are competitive inhibitors of 5α-reductase enzymes and are commonly used to treat symptomatic benign prostatic hyperplasia (BPH). OBJECTIVE: To compare the efficacy and safety of finasteride and dutasteride in terms of clinically important outcomes. DATA SOURCES: A literature search was performed using the search terms "prostatic hyperplasia", "prostatic hypertrophy", "dutasteride", "finasteride", "quality of life", "adverse drug reaction", and "mortality". The Embase, PubMed, Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and Latin American and Caribbean Health Sciences Literature databases were searched from inception to December 2015. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials, quasi-randomized trials, and systematic reviews comparing finasteride with dutasteride, either as monotherapy or in combination with α-blockers, for treatment of men with BPH were included. The outcomes of interest included need for prostate-related surgery, episodes of acute urinary retention, withdrawals due to adverse events, number of patients experiencing serious adverse events, mortality, and sexual dysfunction. DATA SYNTHESIS: Four studies involving a total of 1879 patients were included in the analysis. There were no significant differences in any of the clinically important outcomes examined: for prostate-related surgery, odds ratio (OR) 2.01 (95% confidence interval [CI] 0.18-22.24); for episodes of acute urinary retention, OR 1.47 (95% CI 0.68-3.19); for number of withdrawals due to adverse events, OR 1.10 (95% CI 0.68-1.75); for total number of patients experiencing adverse events, OR 0.94 (95% CI 0.78-1.14); for number of patients experiencing serious adverse events, OR 1.31 (95% CI 0.87-1.97); and for sexual dysfunction, OR 0.83 (95% CI 0.64-1.08). CONCLUSION: There is insufficient evidence to suggest that either finasteride or dutasteride offers an advantage in efficacy or safety over the other, in terms of clinically important outcomes.

CONTEXTE: Le finastéride et le dutastéride sont des inhibiteurs compétitifs de l'enzyme 5 alpha-réductase. Ils sont fréquemment employés comme traitement symptomatique de l'hyperplasie bénigne de la prostate (HBP). OBJECTIF: Comparer l'efficacité et l'innocuité du finastéride et du dutastéride en ce qui concerne les résultats thérapeutiques cliniquement importants. SOURCES DES DONNÉES: Une recherche documentaire a été effectuée à l'aide des termes « hyperplasie de la prostate ¼, « hypertrophie de la prostate ¼, « dutastéride ¼, « finastéride ¼, « qualité de vie ¼, « réaction indésirable aux médicaments ¼ et « mortalité ¼. Les bases de données Embase, PubMed, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature et Latin American and Caribbean Health Sciences Literature ainsi que le Registre central Cochrane des essais comparatifs ont été interrogées pour la période allant de leur création à décembre 2015. SÉLECTION DES ÉTUDES ET EXTRACTION DES DONNÉES: Les essais comparatifs à répartition aléatoire, les essais quasi-aléatoires et les analyses systématiques qui comparent le finastéride et le dutastéride, en monothérapie ou en association avec des α-bloquants, pour le traitement de la HBP chez l'homme, ont été retenus. Parmi les résultats d'intérêt, on comptait : la nécessité de recourir à une chirurgie de la prostate, les épisodes de rétention urinaire aiguë, les retraits de l'étude pour cause d'événements indésirables, le nombre total de patients ayant subi des événements indésirables graves, la mortalité et le dysfonctionnement sexuel. SYNTHÈSE DES DONNÉES: Quatre études comptant au total 1879 patients ont été retenues pour l'analyse. Aucune différence significative n'a été relevée en ce qui touche les résultats thérapeutiques cliniquement importants : la nécessité de recourir à une chirurgie de la prostate (risque relatif approché [RRA] de 2,01, intervalle de confiance [IC] à 95 % de 0,18 à 22,24), les épisodes de rétention urinaire aiguë (RRA de 1,47, IC à 95 % de 0,68 à 3,19), le nombre de retraits de l'étude pour cause d'événements indésirables (RRA de 1,10, IC à 95 % de 0,68 à 1,75), le nombre total de patients ayant subi des événements indésirables (RRA de 0,94, IC à 95 % de 0,78 à 1,14); le nombre de patients ayant subi des événements indésirables graves (RRA de 1,31, IC à 95 % de 0,87 à 1,97) et le dysfonctionnement sexuel (RRA de 0,83, IC à 95 % de 0,64 à 1,08). CONCLUSION: Il n'y a pas suffisamment de données probantes pour croire que le finastéride ou le dutastéride offrent, l'un par rapport à l'autre, un avantage quant à l'efficacité ou à l'innocuité, en ce qui concerne les résultats thérapeutiques cliniquement importants.

Eplerenone for hypertension.

BACKGROUND: Eplerenone is an aldosterone receptor blocker that is chemically derived from spironolactone. In Canada, it is indicated for use as adjunctive therapy to reduce mortality for heart failure patients with New York Heart Association (NYHA) class II systolic chronic heart failure and left ventricular systolic dysfunction. It is also used as adjunctive therapy for patients with heart failure following myocardial infarction. Additionally, it is indicated for the treatment of mild and moderate essential hypertension for patients who cannot be treated adequately with other agents. It is important to determine the clinical impact of all antihypertensive medications, including aldosterone antagonists, to support their continued use in essential hypertension. No previous systematic reviews have evaluated the effect of eplerenone on cardiovascular morbidity, mortality, and magnitude of blood pressure lowering in patients with hypertension. OBJECTIVES: To assess the effects of eplerenone monotherapy versus placebo for primary hypertension in adults. Outcomes of interest were all-cause mortality, cardiovascular events (fatal or non-fatal myocardial infarction), cerebrovascular events (fatal or non fatal strokes), adverse events or withdrawals due to adverse events, and systolic and diastolic blood pressure. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers up to 3 March 2016. We handsearched references from retrieved studies to identify any studies missed in the initial search. We also searched for unpublished data by contacting the corresponding authors of the included studies and pharmaceutical companies involved in conducting studies on eplerenone monotherapy in primary hypertension. The search had no language restrictions. SELECTION CRITERIA: We selected randomized placebo-controlled trials studying adult patients with primary hypertension. We excluded studies in people with secondary or gestational hypertension and studies where participants were receiving multiple antihypertensives. DATA COLLECTION AND ANALYSIS: Three review authors independently reviewed the search results for studies meeting our criteria. Three review authors independently extracted data and assessed trial quality using a standardized data extraction form. A fourth independent review author resolved discrepancies or disagreements. We performed data extraction and synthesis using a standardized format on Covidence. We conducted data analysis using Review Manager 5. MAIN RESULTS: A total of 1437 adult patients participated in the five randomized parallel group studies, with treatment durations ranging from 8 to 16 weeks. The daily doses of eplerenone ranged from 25 mg to 400 mg daily. Meta-analysis of these studies showed a reduction in systolic blood pressure of 9.21 mmHg (95% CI -11.08 to -7.34; I2 = 58%) and a reduction of diastolic pressure of 4.18 mmHg (95% CI -5.03 to -3.33; I2 = 0%) (moderate quality evidence).There may be a dose response effect for eplerenone in the reduction in systolic blood pressure at doses of 400 mg/day. However, this finding is uncertain, as it is based on a single included study with low quality evidence. Overall there does not appear to be a clinically important dose response in lowering systolic or diastolic blood pressure at eplerenone doses of 50 mg to 400 mg daily. There did not appear to be any differences in the number of patients who withdrew due to adverse events or the number of patients with at least one adverse event in the eplerenone group compared to placebo. However, only three of the five included studies reported adverse events. Most of the included studies were of moderate quality, as we judged multiple domains as being at unclear risk in the 'Risk of bias' assessment. AUTHORS' CONCLUSIONS: Eplerenone 50 to 200 mg/day lowers blood pressure in people with primary hypertension by 9.21 mmHg systolic and 4.18 mmHg diastolic compared to placebo, with no difference of effect between doses of 50 mg/day to 200 mg/day. A dose of 25 mg/day did not produce a statistically significant reduction in systolic or diastolic blood pressure and there is insufficient evidence for doses above 200 mg/day. There is currently no available evidence to determine the effect of eplerenone on clinically meaningful outcomes such as mortality or morbidity in hypertensive patients. The evidence available on side effects is insufficient and of low quality, which makes it impossible to draw conclusions about potential harm associated with eplerenone treatment in hypertensive patients.