The Impact of Hypoglycemia on Productivity Loss and Utility in Patients With Type 2 Diabetes Treated With Insulin in Real-world Canadian Practice: Protocol for a Prospective Study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) imposes a substantial burden owing to its increasing prevalence and life-threatening complications. In patients who do not achieve glycemic targets with oral antidiabetic drugs, the initiation of insulin is recommended. However, a serious concern regarding insulin is drug-induced hypoglycemia. Hypoglycemia is known to affect quality of life and the use of health care resources. However, health economics and outcomes research (HEOR) data for economic modelling are limited, particularly regarding utility values and productivity losses. OBJECTIVE: This real-world prospective study aims to assess the impact of hypoglycemia on productivity and utility in insulin-treated adults with T2DM from Ontario and Quebec, Canada. METHODS: This noninterventional, multicenter, 3-month prospective study will recruit patients from 4 medical clinics and 2 endocrinology or diabetes clinics. Patients will be identified using appointment lists and enrolled through consecutive sampling during routinely scheduled consultations. To be eligible, patients must be aged ≥18 years, diagnosed with T2DM, and treated with insulin. Utility and productivity will be measured using the EQ-5D-5L questionnaire and Institute for Medical Technology Assessment Productivity Cost Questionnaire, respectively. Questionnaires will be completed 4, 8, and 12 weeks after recruitment. Generalized estimating equation models will be used to investigate productivity losses and utility decrements associated with incident hypoglycemic events while controlling for individual patient characteristics. A total of 500 patients will be enrolled to ensure the precision of HEOR estimates. RESULTS: This study is designed to fill a gap in the Canadian evidence on the impact of hypoglycemia on HEOR outcomes. More specifically, it will generate productivity and utility inputs for the economic modeling of T2DM. CONCLUSIONS: Insulin therapy is expensive, and hypoglycemia is a significant component of economic evaluation. Robust HEOR data may help health technology assessment agencies in future reimbursement decision-making. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/35461.

Real-world evidence: a practical toolbox for collecting health state utilities.

Health state utilities (HSU) data collected in real-world evidence studies are at risk of bias. Although numerous guidance documents are available, practical advice to avoid bias in HSU studies is limited. Thus, the objective of this article was to develop a concise toolbox intended for investigators seeking to collect HSU in a real-world setting. The proposed toolbox builds on existing guidance and provides practical steps to help investigators perform good quality research. The toolbox aims at increasing the credibility of HSU data for future reimbursement decision making.

Review of real-world evidence studies in type 2 diabetes mellitus: Lack of good practices.

OBJECTIVES: Unlike randomized controlled trials, lack of methodological rigor is a concern about real-world evidence (RWE) studies. The objective of this study was to characterize methodological practices of studies collecting pharmacoeconomic data in a real-world setting for the management of type 2 diabetes mellitus (T2DM). METHODS: A systematic literature review was performed using the PICO framework: population consisted of T2DM patients, interventions and comparators were any intervention for T2DM care or absence of intervention, and outcomes were resource utilization, productivity loss or utility. Only RWE studies were included, defined as studies that were not clinical trials and that collected de novo data (no retrospective analysis). RESULTS: The literature search identified 1,158 potentially relevant studies, among which sixty were included in the literature review. Many studies showed a lack of transparency by not mentioning the source for outcome and exposure measurement, source for patient selection, number of study sites, recruitment duration, sample size calculation, sampling method, missing data, approbation by an ethics committee, obtaining patient's consent, conflicts of interest, and funding. A significant proportion of studies had poor quality scores and was at high risk of bias. CONCLUSIONS: RWE from T2DM studies lacks transparency and credibility. There is a need for good procedural practices that can increase confidence in RWE studies. Standardized methodologies specifically adapted for RWE studies collecting pharmacoeconomic data for the management of T2DM could help future reimbursement decision making in this major public health problem.

Contemporary disease management in Quebec.

Health or disease management (DM) has emerged as a promising solution to improve the quality of healthcare and patient outcomes in a cost-efficient way. This solution is particularly relevant in the care of our increasing, and aging, patient populations with multiple chronic diseases. This article reviews the recent history and current status of DM in the province of Quebec and summarizes its evolving perspectives and future prospects. Most DM projects in Quebec have developed from a public-private partnership, and they have addressed several disease states. The results of completed programs confirmed the presence of care gaps--the differences between best and usual care in several disease states. They also identified process changes leading to improved practices and enhanced professional satisfaction among stakeholders. Priorities identified for further research include increased knowledge of the underlying causes of care gaps and greater concentration on the measurement of clinical, humanistic and fiscal outcomes and their causal links to DM structures and processes. Although still embryonic in Quebec and Canada, the available evidence suggests that DM partnerships are practical and functional vehicles to expedite knowledge creation and transfer in the care of whole populations of patients. Future projects offer the promise of updated knowledge and continuously improved care and outcomes.

Comparison of persistence rates with angiotensin-converting enzyme inhibitors used in secondary and primary prevention of cardiovascular disease.

OBJECTIVES: On average, 50% of patients are noncompliant with drugs for chronic health problems, despite their proven efficacy. It is therefore essential to have real-world data to devise suitable methods for improving persistence with these therapies. To measure and compare persistence rates with the angiotensin-converting enzyme inhibitors (ACEIs) in primary and secondary prevention and their determinants. METHODS: Two cohorts were reconstructed from the Régie de l'assurance maladie du Québec's databases. The subjects had to be newly treated with ACEIs between January 1, 1998 and December 31, 2000. The primary prevention cohort consisted of 4596 hypertensive patients and the secondary prevention cohort of 1620 patients. The cumulative persistence rates were determined by the Kaplan-Meier method. The determinants of nonpersistence were evaluated with a Cox regression model. RESULTS: The 1-year persistence rates for the nonexclusive use of antihypertensive agents by initial prescribed agent: enalapril, fosinopril, lisinopril, quinapril, and ramipril were 66%, 64%, 69%, 65%, and 72% in the secondary prevention cohort, and of 66%, 72%, 71%, 72%, and 75% in the primary prevention cohort. The adjusted 1.5-year nonpersistence rates in primary prevention were higher for quinapril and enalapril than for ramipril. In secondary prevention all of the ACEIs were equivalent in nonpersistence rate. In secondary prevention cohort, having dyslipidemia, respiratory disease, >or=4 different classes of drugs/month increase the rate of persistence. Among, the primary prevention cohort, the fact of having diabetes, dyslipidemia, respiratory disease, using >or=4 different classes of drugs/month or prior hospitalization increased significantly the rate of persistence. For both cohorts, the fact of having high number of oral doses/day or elevated health-care resource utilization decreased significantly the rate of persistence. CONCLUSION: The 1.5-year persistence rate was low compared with the threshold of 80% generally accepted. The high-risk patients were less likely to discontinue their treatment. These results can be of help in devising methods for improving the effectiveness of these drugs in routine practice.

Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib.

INTRODUCTION: Erlotinib (Tarceva) has demonstrated a survival benefit in unselected patients with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy. Because not all patients benefit from erlotinib, epidermal growth factor receptor (EGFR) protein expression may provide a basis for selecting patients for treatment with this EGFR inhibitor. METHODS: Tumor samples from patients who participated in National Institute of Canada Clinical Trials Group Study BR.21 were assayed by immunohistochemistry using Dako EGFR pharmDx kits. EGFR expression was scored as proportion of tumor cells with membrane staining, staining intensity, and combined proportion and intensity scores. All possible cutpoints were examined to determine whether EGFR protein expression status by immunohistochemistry might be useful for predicting patient survival. RESULTS: Three hundred twenty-five patients had evaluable assay results. The prognostic significance of EGFR protein expression was modest. Patients with EGFR-positive tumors who received placebo after failure of chemotherapy had slightly worse survival than patients with EGFR-negative tumors; however, the differences were not statistically significant for any cutpoint for any of the three measures of EGFR protein expression. The treatment benefits from erlotinib relative to placebo were greater for EGFR-positive patients compared with EGFR-negative patients, but they were not significantly different for any cutoff used to define EGFR positivity. Use of very high cutpoints to define patients with EGFR-rich tumors that might be especially sensitive to treatment with erlotinib cannot be supported by these data. CONCLUSIONS: Selection or exclusion of NSCLC patients for erlotinib therapy after failure of standard therapy for advanced or metastatic disease should not be based solely on EGFR protein expression as determined by immunohistochemistry.

Nitric oxide synthase and nitric oxide production in in vivo-derived mast cells.

Nitric oxide (NO) is a potent mediator synthesized by a variety of cells involved in inflammatory reactions. We investigated the expression of NO synthase (NOS) in rat peritoneal mast cells (PMC). Small amounts of eNOS mRNA were detected basally, whereas neither mRNA for iNOS nor nNOS was detected in unstimulated PMC. Following stimulation by antigen, interferon-gamma (IFN-gamma), or anti-CD8 antibody, PMC up-regulated iNOS mRNA expression. In situ RT-PCR confirmed that iNOS mRNA originated from PMC. Production of iNOS protein was confirmed in stimulated PMC by immunohistochemistry. Upon stimulation with antigen, IFN-gamma, or anti-CD8, nitrite production was increased significantly (8.4+/-0.6, 7.6+/-0.9, and 6.6+/-0.9 microM/2x10(5) cells/48 h NO2-, respectively; P<0.01), whereas unstimulated PMC released 2.1 +/- 0.3 microM/2 x 10(5) cells/48 h NO2-. These findings demonstrate that in vivo-derived PMC transcribe and translate mRNA for NOS and produce NO.