Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Speed and distance requirements for community ambulation: A systematic review

Objective: To provide an overview of the research literature on distance and speed requirements for adults to walk outside the home. Data Sources: We conducted a systematic review and searched PubMed, MEDLINE (Ovid), EMBASE, CINAHL, Scopus, PEDro, and The Cochrane Library from 1948 to May 2012, and other sources. Search terms included communities, walk, ambulation, and neighborhood. Study Selection: Full-text peer-reviewed articles written in English, French, or Spanish reporting distance and/or speed requirements for individuals walking outside the home were considered eligible. Two authors independently screened titles and abstracts. One author reviewed full-text articles to determine inclusion. Of the 3191 titles and abstracts screened, 15 studies (.47%) were selected for detailed review.One author appraised methodological quality. Inadequate description of the reliability of the measurement methods and the population of the town/city assessed was noted. Data Extraction: One author extracted data from included studies. A second reviewer independently verified extracted data for accuracy. Data Synthesis: Seven studies examining 24 community sites and crosswalks in the United States, Australia, and Singapore were included. Three sites with the largest mean distance requirements for adults to walk were club warehouses (677m), superstores (183-607m), and hardware stores (566m). Three sites with the lowest mean distance requirements were walking at the front (16m) and back (19m) of the house, and at cemeteries (18m). The average speed required to cross the street in the time of a walk signal varied from .44 to 1.32m/s. Conclusions: Distance and speed requirements for adults to walk in the community environment vary widely. Findings are relevant to judging capacity for community ambulation to carry out essential activities of daily living, educating patients, and setting rehabilitation goals.The study was supported by a Canadian Institutes of Health Research (CIHR) Knowledge Synthesis grant (grant number KRS-108449). KOB was funded by a CIHR fellowship and holds a CIHR New Investigator Award. DB holds a Canada Research Chair. RM holds a CIHR New Investigator Award

Reference values for standardized tests of walking speed and distance: A systematic review

Objective: To provide an overview of the reference values and methodology used to obtain them for time- and distance-limited walk tests. Methods: We performed a systematic review and searched PubMed, MEDLINE (Ovid), EMBASE, CINAHL, Scopus, PEDro, and The Cochrane Library from 1946 to May 2013. Full-text peer-reviewed articles written in English, French or Spanish were considered eligible. Two authors independently screened titles and abstracts. One author determined eligibility of full-text articles, appraised methodological quality, and extracted data. A second author independently verified the accuracy of extracted data. Results: Of the 41 eligible studies reviewed, 25 failed to describe the method used to select participants and 10 had an inadequate sample size. Twenty-five studies provided reference values for one time-limited walk test (6-min walk test (6 MWT)) and 18 studies provided reference values for 15 distance-limited walk tests. Across studies, walk test distances ranged from 3m to 40m. Descriptive values and reference equations for the 6 MWT were reported in 15 and 20 studies, respectively. Across 43 regression equations (median R2=0.46), age (98%) and sex (91%) were most frequently included. The equation yielding the maximum R2 value (0.78) included age, height, weight and percentage of predicted maximum heart rate. Among six unique regression equations for distance-limited walk tests (median R2=0.17), sex (83%), age (67%) and weight (67%) were most frequently included. The equation yielding the maximum R2 value (0.25) included age and sex. Conclusions: Reference values reported for these tests provide a basis for classifying walking capacity as within normal limits, determining the magnitude of deficit, educating clients, setting rehabilitation goals, and planning studies.The study was supported by a Canadian Institutes of Health Research (CIHR) Knowledge Synthesis grant (grant number KRS-108449). NMS and KOB hold a CIHR New Investigator Award. DB and RM hold a Canada Research Chair

Engaging Patients in the Canadian Real-World Evidence for Value in Cancer Drugs (CanREValue) Initiative: Processes and Lessons Learned

The Canadian Real-world Evidence for Value in Cancer Drugs (CanREValue) Collaboration established the Engagement Working Group (WG) to ensure that all key stakeholders had an opportunity to provide input into the development and implementation of the CanREValue Real-World Evidence (RWE) Framework. Two consultations were held in 2021 to solicit patient perspectives on key policy and data access issues identified in the interim policy and data WG reports. Over 30 individuals, representing patients, caregivers, advocacy leaders, and individuals engaged in patient research were invited to participate. The consultations provided important feedback and valuable lessons in patient engagement. Patient leaders actively shaped the process and content of the consultation. Breakout groups facilitated by patient advocacy leaders gave the opportunity for open and thoughtful contributions from all participants. Important recommendations were made: the RWE framework should not impede access to new drugs; it should be used to support conditional approvals; patient relevant endpoints should be captured in provincial datasets; access to data to conduct RWE should be improved; and privacy issues must be considered. The manuscript documents the CanREValue experience of engaging patients in a consultative process and the useful contributions that can be achieved when the processes to engage are guided by patients themselves

Building a National Reassessment Process for Oncology Drugs: Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration through a Simulated Reassessment Exercise

The CanREValue Collaboration established the Reassessment &amp; Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework

Building a National Reassessment Process for Oncology Drugs: Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration through a Simulated Reassessment Exercise

The CanREValue Collaboration established the Reassessment &amp; Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework

Considerations for Developing a Reassessment Process: Report from the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration’s Reassessment and Uptake Working Group

The Canadian Real-world Evidence for Value in Cancer Drugs (CanREValue) Collaboration was established to develop a framework for generating and using real-world evidence (RWE) to inform the reassessment of cancer drugs following initial health technology assessment (HTA). The Reassessment and Uptake Working Group (RWG) is one of the five established CanREValue Working Groups. The RWG aims to develop considerations for incorporating RWE for HTA reassessment and strategies for using RWE to reassess drug funding decisions. Between February 2018 and December 2019, the RWG attended four teleconferences (with follow-up surveys) and two in-person meetings to discuss recommendations for the development of a reassessment process and potential barriers and facilitators. Modified Delphi methods were used to gather input. A draft report of recommendations (to December 2018) was shared for public consultation (December 2019 to January 2020). Initial considerations for developing a reassessment process were proposed. Specifically, reassessment can be initiated by diverse stakeholders, including decision makers from public drug plans or industry stakeholders. The reassessment process should be modelled after existing deliberation and recommendation frameworks used by HTA agencies. Proposed reassessment outcome categories include maintaining status quo, revisiting funding criteria, renegotiating price, or disinvesting. Overall, these initial considerations will serve as the basis for future advancements by the Collaboration

Mapping Canadian Data Assets to Generate Real-World Evidence : Lessons Learned from Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration’s RWE Data Working Group

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8–11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration’s Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada