Real-world persistence of erenumab for preventive treatment of chronic and episodic migraine: Retrospective real-world study.

OBJECTIVE: To describe the real-world treatment persistence (defined as the continuation of medication for the prescribed treatment duration), demographics and clinical characteristics, and treatment patterns for patients prescribed erenumab for migraine prevention in Canada. BACKGROUND: The effectiveness of prophylactic migraine treatments is often undermined by poor treatment persistence. In clinical trials, erenumab has demonstrated efficacy and tolerability as a preventive treatment, but less is known about the longer term treatment persistence with erenumab. METHODS: This is a real-world retrospective cohort study where a descriptive analysis of secondary patient data was conducted. Enrollment and prescription data were extracted from a patient support program for a cohort of patients prescribed erenumab in Canada between September 2018 and December 2019 and analyzed for persistence, baseline demographics, clinical characteristics, and treatment patterns. Descriptive analyses and unadjusted Kaplan-Meier (KM) curves were used to summarize the persistence and dose escalation/de-escalation at different timepoints. RESULTS: Data were analyzed for 14,282 patients. Median patient age was 47 years, 11,852 (83.0%) of patients were female, and 9443 (66.1%) had chronic migraine at treatment initiation. Based on KM methods, 71.0% of patients overall were persistent to erenumab 360 days after treatment initiation. Within 360 days of treatment initiation, it is estimated that 59.3% (KM-derived) of patients who initiated erenumab at 70 mg escalated to 140 mg, and 4.4% (KM-derived) of patients who initiated at 140 mg de-escalated to 70 mg. CONCLUSIONS: The majority of patients prescribed erenumab remained persistent for at least a year after treatment initiation, and most patients initiated or escalated to a 140 mg dose. These results suggest that erenumab is well tolerated, and its uptake as a new class of prophylactic treatment for migraine in real-world clinical practice is not likely to be undermined by poor persistence when coverage for erenumab is easily available.

A real-world, observational study of erenumab for migraine prevention in Canadian patients.

OBJECTIVES: To assess real-world effectiveness, safety, and usage of erenumab in Canadian patients with episodic and chronic migraine with prior ineffective prophylactic treatments. BACKGROUND: In randomized controlled trials, erenumab demonstrated efficacy for migraine prevention in patients with ≤4 prior ineffective prophylactic migraine therapies. The "Migraine prevention with AimoviG: Informative Canadian real-world study" (MAGIC) assessed real-world effectiveness of erenumab in Canadian patients with migraine. METHODS: MAGIC was a prospective open-label, observational study conducted in Canadian patients with chronic migraine (CM) and episodic migraine (EM) with two to six categories of prior ineffective prophylactic therapies. Participants were administered 70 mg or 140 mg erenumab monthly based on physician's assessment. Migraine attacks were self-assessed using an electronic diary and patient-reported outcome questionnaires. The primary outcome was the proportion of subjects achieving ≥50% reduction in monthly migraine days (MMD) after the 3-month treatment period. RESULTS: Among the 95 participants who mostly experienced two (54.7%) or three (32.6%) prior categories of ineffective prophylactic therapies and who initiated erenumab, treatment was generally safe and well tolerated; 89/95 (93.7%) participants initiated treatment with 140 mg erenumab. At week 12, 32/95 (33.7%) participants including 17/64 (26.6%) CM and 15/32 (48.4%) EM achieved ≥50% reduction in MMD while 30/86 (34.9%) participants including 19/55 (34.5%) CM and 11/31 (35.5%) EM achieved ≥50% reduction in MMD at week 24. Through patient-reported outcome questionnaires, 62/95 (65.3%) and 45/86 (52.3%) participants reported improvement of their condition at weeks 12 and 24, respectively. Physicians observed improvement in the condition of 78/95 (82.1%) and 67/86 (77.9%) participants at weeks 12 and 24, respectively. CONCLUSION: One-third of patients with EM and CM achieved ≥50% MMD reduction after 3 months of erenumab treatment. This study provides real-world evidence of erenumab effectiveness, safety, and usage for migraine prevention in adult Canadian patients with multiple prior ineffective prophylactic treatments.

Trial of early, goal-directed resuscitation for septic shock.

BACKGROUND: Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. METHODS: We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. RESULTS: We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. CONCLUSIONS: In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).

National survey and point prevalence study of sedation practice in UK critical care.

BACKGROUND: The present study was designed to (1) establish current sedation practice in UK critical care to inform evidence synthesis and potential future primary research and (2) to compare practice reported via a survey with actual practice assessed in a point prevalence study (PPS). METHODS: UK adult general critical care units were invited to participate in a survey of current sedation practice, and a representative sample of units was invited to participate in a PPS of sedation practice at the patient level. Survey responses were compared with PPS data where both were available. RESULTS: Survey responses were received from 214 (91 %) of 235 eligible critical care units. Of these respondents, 57 % reported having a written sedation protocol, 94 % having a policy of daily sedation holds and 94 % using a sedation scale to assess depth of sedation. In the PPS, across units reporting a policy of daily sedation holds, a median of 50 % (IQR 33-75 %) of sedated patients were considered for a sedation hold. A median of 88 % (IQR 63-100 %) of patients were assessed using the same sedation scale as reported in the survey. Both the survey and the PPS indicated propofol as the preferred sedative and alfentanil, fentanyl and morphine as the preferred analgesics. In most of the PPS units, all patients had received the unit's reported first-choice sedative (median across units 100 %, IQR 64-100 %), and a median of 80 % (IQR 67-100 %) of patients had received the unit's reported first-choice analgesic. Most units (83 %) reported in the survey that sedatives are usually administered in combination with analgesics. Across units that participated in the PPS, 69 % of patients had received a combination of agents - most frequently propofol combined with either alfentanil or fentanyl. CONCLUSIONS: Clinical practice reported in the national survey did not accurately reflect actual clinical practice at the patient level observed in the PPS. Employing a mixed methods approach provided a more complete picture of sedation practice in terms of breadth and depth of information.

Why try to predict ICU outcomes?

PURPOSE OF REVIEW: To describe why the prediction of ICU outcomes is essential to underpin critical care quality improvement programmes. RECENT FINDINGS: Recent literature demonstrates that risk-adjusted mortality is a widely used and well-accepted quality indicator for benchmarking ICU performance. Ongoing research continues to address the best ways to present the results of benchmarking through either direct comparison among institutions (e.g., by funnel plots) or indirect comparison against the risk predictions from a risk model (e.g., by process control charts). There is also ongoing research and debate regarding event-based outcomes (e.g., hospital mortality) versus time-based outcomes (e.g., 30-day mortality). Beyond benchmarking, ICU outcome prediction models have a role in risk adjustment and risk stratification in randomized controlled trials, and adjusting for confounding in nonrandomized, observational research. Recent examples include comparing risk-adjusted outcomes according to 'capacity strain' on the ICU and extending propensity matching methods to evaluate outcomes of patients managed with a pulmonary artery catheter, among others. Risk models may have a role in communicating risk, but their utility for individual patient decision-making is limited. SUMMARY: Risk-adjusted mortality has strong support from the critical care community as a quality indicator for benchmarking ICU performance but is dependent on up-to-date, accurate risk models. ICU outcome prediction can also contribute to both randomized and nonrandomized research and potentially contribute to individual patient management, although generic risk models should not be used to guide individual treatment decisions.

Burden of Treatment Resistant Depression (TRD) in patients with major depressive disorder in Ontario using Institute for Clinical Evaluative Sciences (ICES) databases: Economic burden and healthcare resource utilization.

INTRODUCTION: The burden of treatment-resistant depression (TRD) in Canada requires empirical characterization to better inform clinicians and policy decision-making in mental health. Towards this aim, this study utilized the Institute for Clinical Evaluative Sciences (ICES) databases to quantify the economic burden and resource utilization of Patients with TRD in Ontario. METHODS: TRD, Non-TRD Major Depressive Disorder (Non-TRD MDD) and Non-MDD cohorts were selected from the ICES databases between April 2006-March 2015 and followed-up for at least two years. TRD was defined as a minimum of two treatment failures within one-year of the index MDD diagnosis. Non-TRD and Non-MDD patients were matched with patients with TRD to analyze costs, resource utilization, and demographic information. RESULTS: Out of 277 patients with TRD identified, the average age was 52 years (SD 16) and 53% were female. Compared to Non-TRD, the patients with TRD had more all-cause visits to outpatient (38.2 vs. 24.2) and emergency units (2.7 vs. 2.0) and more depression-related visits to GPs (3.06 vs. 1.63) and psychiatrists (5.88 vs. 1.95) (all p < 0.05). The average two-year cost for TRD patients was $20,998 (CAD). LIMITATIONS: This study included patients with only public plan coverage; therefore, overall TRD population and cash and private claims were not captured. CONCLUSIONS: Patients with TRD exhibit a significantly higher demand on healthcare resources and higher overall payments compared to Non-TRD patients. The findings suggest that there are current challenges in adequately managing this difficult-to-treat patient group and there remains a high unmet need for new therapies.

Real-world persistence with liraglutide 3.0 mg for weight management and the SaxendaCare® patient support program.

OBJECTIVE: Weight management medications can significantly increase patients' chances of achieving a clinically meaningful weight loss if patients persist with treatment. This retrospective observational study of de-identified medical records of 311 patients is the first real-world study examining persistence with liraglutide 3.0 mg in Canada, and also investigates associations between the SaxendaCare® patient support program and persistence and weight loss. METHODS: Overall persistence was assessed, as well as associations of enrollment in SaxendaCare®, persistence and weight loss. RESULTS: Overall mean (standard deviation) persistence with liraglutide 3.0 mg was 6.3 (4.1) months, and 67.5% (n = 210) and 53.7% (n = 167) of patients persisted for ≥4 and ≥ 6 months, respectively. Enrollment in SaxendaCare® was associated with significantly longer persistence with liraglutide 3.0 mg and greater weight loss. Patients enrolled in SaxendaCare® (n = 119) persisted for 7.9 (4.0) versus 5.2 (3.8) months for those not enrolled (n = 184) (p < 0.001), and had significantly greater percent weight loss after 6 months regardless of the duration of their persistence (-7.9% vs -5.5% from baseline, p < 0.01). CONCLUSIONS: These findings suggest that, in clinical settings, persistence with liraglutide 3.0 mg can exceed 6 months, and that enrolling in SaxendaCare® may be associated with comparatively longer persistence and, regardless of persistence, greater weight loss.

Weight loss and persistence with liraglutide 3.0 mg by obesity class in the real-world effectiveness study in Canada.

OBJECTIVE: Liraglutide 3.0 mg is associated with clinically significant weight loss in clinical trials, but real-world data are lacking. In this analysis, weight loss and persistence outcomes with liraglutide 3.0 mg were assessed across obesity classes, in a real-world clinical setting. METHODS: Secondary analysis of an observational, retrospective study of liraglutide 3.0 mg for weight management (as adjunct to diet and exercise) at six Wharton Medical Clinics in Canada. Patients were categorized by body mass index (BMI, kg/m2) into obesity class I (BMI 30-34.9); class II (BMI 35-39.9); and class III (BMI ≥40). Change in weight, categorical weight loss, time to maintenance dose (defined as the time to reach the full liraglutide 3.0 mg maintenance dose) and persistence were assessed for each class and for differences between classes. RESULTS: Of 308 patients, 70 (22.7%) had obesity class I, 83 (26.9%) obesity class II and 155 (50.3%) obesity class III. Similar percentage change in weight was observed between obesity classes (mean [standard deviation, SD]: -7.0% [6.0], -6.6% [6.0] and -6.1% [5.0], respectively; p = .640), and similar proportions achieved ≥5% weight loss (60.4%, 62.0% and 55.3%, respectively; p = .717) at 6 months. Mean time to maintenance dose (SD) was 64.2 (56.4) d, 76.4 (56.3) d and 71.4 (54.5) d for obesity classes I, II and III, respectively (p = .509). Persistence with medication was also similar between obesity classes (p = .358). CONCLUSIONS: These findings suggest that real-world treatment with liraglutide 3.0 mg, regardless of obesity class, is associated with similar clinically significant weight loss, time to maintenance dose and medication persistence.

Seizure frequency, healthcare resource utilisation and mortality in childhood epilepsy: a retrospective cohort study using the THIN database.

OBJECTIVE: To understand the association of seizure frequency with healthcare resource utilisation (HCRU) and mortality in UK children with epilepsy (CWE). DESIGN: Retrospective cohort study. SETTING: Routinely collected data in primary care from The Health Improvement Network UK database. PATIENTS: CWE ≥1 and<18 years of age with a record of seizure frequency were included in mortality analyses from 2005 to 2015 and HCRU analyses from 2010 to 2015. MAIN OUTCOME MEASURES: Frequency of HCRU contacts during the year following latest seizure frequency and mortality (descriptive and Cox proportional hazards regression) from first record of seizure frequency. RESULTS: Higher seizure frequency was related to increased HCRU utilisation and mortality. In negative binomial regression, each category increase in seizure frequency related to 11% more visits to general practitioners, 35% more inpatient admissions, 15% more outpatient visits and increased direct HCRU costs (24%). 11 patients died during 12 490 patient-years follow-up. The unadjusted HR of mortality per higher category of seizure frequency was 2.56 (95% CI: 1.52 to 4.31). Adjustment for age and number of prescribed anti-epileptic drugs at index attenuated this estimate to 2.11 (95% CI: 1.24 to 3.60). CONCLUSION: Higher seizure frequency is associated with greater HCRU and mortality in CWE in the UK. Improvement in seizure control may potentially lead to better patient outcomes and reduced healthcare use.

Real-World Clinical Effectiveness of Liraglutide 3.0 mg for Weight Management in Canada.

OBJECTIVE: Real-world clinical effectiveness of liraglutide 3.0 mg, in combination with diet and exercise, was investigated 4 and 6 months post initiation. Changes in absolute and percent body weight were examined from baseline. METHODS: A cohort of liraglutide 3.0 mg initiators in 2015 and 2016 was identified from six Canadian weight-management clinics. Post initiation values at 4 and 6 months were compared with baseline values using a paired t test. RESULTS: The full cohort consisted of 311 participants, with 210 in the ≥ 4-month persistence group and 167 in the ≥ 6-month persistence group. Average baseline BMI was 40.7 kg/m2 , and weight was 114.8 kg. There was a significant change in body weight 6 and 4 months after initiation of treatment in persistent subjects (≥ 6-month: -8.0 kg, P < 0.001; ≥ 4-month: -7.0 kg, P < 0.001) and All Subjects, regardless of persistence (-7.3 kg; P < 0.001). Percentage change in body weight from baseline was -7.1% in the ≥ 6-month group and -6.3% in the ≥ 4-month group, and All Subjects lost 6.5% body weight. Of participants in the ≥ 6-month group, 64.10% and 34.5% lost ≥ 5% and > 10% body weight, respectively. CONCLUSIONS: In a real-world setting, liraglutide 3.0 mg, when combined with diet and exercise, was associated with clinically meaningful weight loss.

Evaluating the Relationship Between Visual Acuity and Utilities in Patients With Diabetic Macular Edema Enrolled in Intravitreal Aflibercept Studies.

Purpose: The purpose of this study was to explore the relationship between visual acuity and utility (health-related quality of life) in diabetic macular edema (DME) using intravitreal aflibercept data. Methods: The relationship between visual acuity in the best-seeing eye (BSE) and worse-seeing eye (WSE) and utility was explored using ordinary least squares (OLS) and random-effects models adjusted for different covariates (age, age2, sex, body mass index, smoking status, glycated hemoglobin, diabetes severity, comorbidities, and geographic region). Utility was measured using the EuroQoL-five dimensions questionnaire (EQ-5D) and Visual Functioning Questionnaire-Utility Index (VFQ-UI). For each model, coefficients (R2) were reported, and WSE/BSE was expressed as the ratio of coefficients (OLS models). Models were independent of treatment effects, and outcomes from all time points (up to week 100) were included where available. Results: Data from 1320 patients with DME were analyzed. In all models, the association between visual acuity (BSE > WSE) was stronger with VFQ-UI- than EQ-5D-derived utilities. The estimated relationship between VFQ-UI and visual acuity in the BSE and WSE was robust, even with an increasing number of covariates. WSE/BSE coefficient ratios were similar across VFQ-UI OLS models (32%) compared with EQ-5D models (41%-48%). Actual (unadjusted) versus predicted data plots also showed a better fit with VFQ-UI- than EQ-5D-derived utilities. Conclusions: These analyses show that VFQ-UI was more sensitive than EQ-5D-derived utilities for measuring the impact of visual acuity in the BSE and WSE. Visual acuity in the BSE was a major contributor to utility, but WSE is also important though to a lesser degree as shown by the coefficient ratios. These new data will be useful for health technology assessments in DME, where utilities data are lacking.

Regional variation in critical care provision and outcome after high-risk surgery.

PURPOSE: Evidence of variation in mortality after surgery may indicate preventable postoperative death. We sought to determine if regional differences in outcome were present in surgical patients admitted to critical care in the UK. METHODS: We extracted data on admission characteristics, case mix and outcome of all patients admitted to UK critical care units following surgery for the calendar year of 2009. We also used publicly held data on regional population, volume of surgery and bed provision. Multilevel regression analysis was used to adjust for the effects of case mix and regional critical care bed provision on acute hospital mortality. RESULTS: A total of 16,147 patients admitted to critical care following surgery were included in this analysis. Median odds ratio (MOR) was used to describe regional-level variance in acute hospital mortality. Significant variation was identified (MOR 1.14; 95% CI 1.07, 1.28) and persisted following adjustment for case mix (MOR 1.10; 95% CI 1.04, 1.25) and regional critical care bed provision (MOR 1.09; 95% CI 1.04, 1.24). Critical care bed utilisation (surgical critical care admissions per 100,000 surgical procedures) seemed to better explain this observation (MOR 1.03; 95% CI 1.00, 29.26) and was associated with statistically significant reduction in mortality (OR 0.91; 95% CI 0.85, 0.97; p = 0.01). CONCLUSION: Significant regional variation in hospital mortality for patients admitted to critical care following surgery was observed. Critical care bed utilisation seemed to better explain this observation and was associated with improved outcome.

Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness. OBJECTIVES: The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Fifty-six NHS hospitals in England. PARTICIPANTS: A total of 1260 patients who presented at EDs with septic shock. INTERVENTIONS: EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1. MAIN OUTCOME MEASURES: All-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -£725 (95% CI -£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events. LIMITATIONS: Recruitment was lower at weekends and out of hours. The intervention could not be blinded. CONCLUSIONS: There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%. FUTURE WORK: The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36307479. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.

The Protocolised Management in Sepsis (ProMISe) trial statistical analysis plan.

BACKGROUND: The Protocolised Management in Sepsis (ProMISe) trial is an open, multicentre, randomised controlled trial (RCT) of the clinical effectiveness and cost-effectiveness of early, goal directed, protocolised resuscitation compared with usual resuscitation for patients presenting to emergency departments (EDs) in the United Kingdom with early signs of severe sepsis or septic shock. The rationale for the ProMISe trial derives from a single-centre United States RCT that reported a reduction in hospital mortality from 46.5% to 30.5%. OBJECTIVE: To describe the proposed statistical analyses for the evaluation of clinical effectiveness for the ProMISe trial. It is important to complete this plan before inspecting the data, and before completion of two related international studies, so that post-hoc, data-derived decisions are avoided. METHODS: The primary and secondary outcomes were defined precisely, and the approach to safety monitoring and data collection summarised, with a description of the planned statistical analyses including prespecified subgroup and secondary analyses. RESULTS: The primary outcome is all-cause mortality at 90 days. The primary analysis will be reported as a relative risk and absolute risk reduction and tested with the Fisher exact test. Prespecified subgroup analyses will be based on age, baseline Medical Emergency Department Sepsis score, baseline Sequential Organ Failure Assessment score, and time from ED presentation to randomisation. Secondary analyses include adjustment for baseline covariates, estimation of learning curve effects and adjustment for noncompliance. CONCLUSION: In keeping with best practice, we have developed a statistical analysis plan for the ProMISe trial and place it in the public domain before inspecting data from the trial.