Nonsevere Hypoglycemia Episode Clinical and Economic Outcomes: A Comparison between Sulfonylurea and Sodium-Glucose Cotransporter 2 Inhibitor as Add-On to Metformin from a Canadian Perspective.

BACKGROUND: Nonsevere hypoglycemia episodes (NSHEs) are associated with clinically adverse outcomes, lower health-related quality of life, increased burden of disease, and reduced work productivity. OBJECTIVE: To estimate prevalence of NSHEs and associated economic outcomes attributable to sulfonylurea (SU) versus sodium-glucose cotransporter 2 inhibitor (SGLT2i) initiation after metformin over one year for Canadian patients with type 2 diabetes (T2DM). METHODS: Risk difference for NSHEs was calculated for SU and SGLT2i from RCT data. Estimation of NSHEs attributable to SU utilization in Canada was calculated from published data. Both direct and indirect costs associated with NSHEs were obtained from previous published studies in literature. RESULTS: The number of patients with T2DM and exposure to SU in Canada in 2016 was estimated to be 1,246,438. The average underreported NSHEs in clinical settings were estimated at 67.7%. Risk difference for NSHEs for SU versus SGLT2i was estimated at 26.7%. Estimation of excess NSHEs attributable to SU utilization versus SGLT2i in Canada was estimated at 130,434 events per year (sensitivity analysis: minimum 80,680 and maximum 624,465). Total indirect costs including loss-of-work productivity and out-of-pocket costs secondary to excess NSHEs due to SU utilization versus SGLT2i after metformin were estimated at CDN$8.6M (M = millions) for 2016 (sensitivity analysis: minimum CDN$5.3M and maximum CDN$81.2M). CONCLUSION: NSHE, which is a forgotten variable in economic evaluations for healthcare reimbursement models, occurs frequently in real-world clinical settings but is infrequently reported. NSHEs can lead to a significant loss-of-work productivity and out-of-pocket costs.

The Prevalence and Risk for Herpes Zoster Infection in Adult Patients With Diabetes Mellitus in the Canadian Primary Care Sentinel Surveillance Network.

OBJECTIVES: Herpes zoster (HZ) is a common infection in Canada that can result in serious and long-term complications. People with diabetes may be at an increased risk for HZ. The objectives of this study were to develop and validate a case definition of HZ diagnosis based on electronic medical records; determine a prevalence estimate for HZ in adult patients in the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) and assess the association between HZ and diabetes. METHODS: This was a retrospective cross-sectional study. Patients 18 years of age or older who had made at least 1 visit to their primary health-care providers within the past 2 years in the CPCSSN were included. These data came from a 2015 extract of CPCSSN data, and a subsample of 289 patients was used to validate our case definition. Prevalences were estimated for the overall population and for people with diabetes, chronic obstructive pulmonary disease, cancer or HIV. Risk ratios were modelled for these conditions. RESULTS: The sensitivity, specificity, positive predictive value and negative predictive values for HZ were 100%, 73.8%, 83.9% and 100%, respectively. The 1-year prevalence of HZ in the CPCSSN data was 0.32%. The prevalence of HZ was higher in females (0.35%) than in males (0.28%). People with diabetes have an increased risk for HZ infection (RR 2.64, 95% CI 2.34, 2.99). CONCLUSIONS: People with diabetes have an increased risk for the diagnosis of HZ infection in the primary care setting in Canada. Women over the age of 65 years with diabetes and/or other chronic conditions are at greatest risk for developing HZ.

Non-severe Hypoglycemia Risk Difference between Sulfonylurea and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2-I) as an Add-On to Metformin in Randomized Controlled Trials.

BACKGROUND: Non-severe hypoglycemia reduces well-being, lowers quality of life, reduces productivity and increases treatment costs. The non-severe hypoglycemia rate, attributable to sulfonylurea (SU) utilization compared with newer classes such as SGLT2-I, could be of clinical significance. OBJECTIVES: To explore the non-severe hypoglycemia risk difference (RD) for SU use compared with SGLT2-I in randomized controlled trials (RCTs) as an add on to metformin. METHODS: A search was conducted for RCTs of SGLT2-I. PubMed database were utilized for this search. The search was limited to RCTs reported in English language for canagliflozin, dapagliflozin, and empagliflozin. SU dose comparison was utilized to convert the dose of SUs to glimepiride equivalent doses. RESULTS: Totally, 118 RCTs were reviewed; 6 articles had an arm for a SU as add on to metformin. Six articles belong to 3 RCTs, which reported results for 52 weeks and 104 weeks. Average non-severe hypoglycemia rate for SU arm was 30% (5.5%) [Mean (SD)] for 52 weeks and 35.6% (6.1%) for 104 weeks. RD for non-severe hypoglycemia events for SU compared to SGLT2-I was 26.7% (4.9%) for 52 weeks (p-value less than 0.001) and 30.6% (5.5%) for 104 weeks (p-value less than 0.001). There was a significant correlation between dose of SU and hypoglycemia rate (Pearson correlation 0.995; R-square 99%). CONCLUSIONS: This study illustrated that a large proportion of patients who had exposure to SU in RCTs of SGLT2-I experienced non-severe hypoglycemia compared to SGLT2-I. There was a close relation between SU dose and increased probability of non-severe hypoglycemia events.

Lack of Health-Related Quality of Life and Patient-Centred Outcome Measures in Randomized Controlled Trials Conducted for Diabetes Pharmacotherapy: SGLT-2 Receptor Inhibitors as An Example.

BACKGROUND: Use of SGLT-2 receptor inhibitors has been associated with weight loss and a low rate of hypoglycemia in comparison to sulfonylureas. These factors may improve health-related quality of life for patients with diabetes. OBJECTIVES: To systematically explore randomized controlled trials (RCTs) involving SGLT-2 receptor inhibitors that reported health-related quality of life changes. METHODS: A systematic review of SGLT-2 receptor inhibitors clinical trials, limited to RCTs and English language, was conducted utilizing PubMed databases. RESULTS: One-hundred and eighteen RCTs were reviewed and 62 RCTs meeting the inclusion criteria were assessed. All 62 RCTs reported body mass index (BMI) changes and HgbA1c reduction. Measures of health-related quality-of-life (HRQoL) were reported in only 2 RCTs. Both studies illustrate improvement in HRQoL domains for SGLT-2 receptor inhibitors in comparison to the other arms in the RCTs. CONCLUSIONS: Only a small portion of RCTs involving SGLT-2 receptor inhibitors reported on HRQoL. Because of the potential for weight loss and hypoglycemia avoidance to improve HRQoL, future studies of SGLT-2 receptor inhibitors should measure and report on patient-centred outcomes such as HRQoL.

Sulfonylurea and the Heart: Theoretically a Compounded Question from a Pathophysiological Perspective.

Evidence from literature illustrates that from a pathophysiological perspective, sulfonylureas (SU) may impact the heart three ways: directly by intrinsic properties from a pharmacological receptor perspective, indirectly by adverse effects related to hypoglycemia, and obesity. From a pharmacologlogical receptor perspective, SU can bind to ATP-sensitive potassium channels in cardiomyocytes. Channel binding by SU in cardiac tissue may prevent ischemia myocardial protective mechanisms. From a pathophysiological perspective, obesity is associated with cardiac issues such as pulmonary hypertension, left ventricular hypertrophy, arrhythmia, and atrial fibrillation. From a pathophysiological perspective, hypoglycemia is associated with cardiac sympathetic activation and QT prolongation. With the high prevalence and incidence of diabetes, obesity and aging, future basic and clinical studies should further explore the questions related to the pathophysiology of SU utilization and potential cardiac impact in randomized clinical trials and real-world outcome research settings.

A Systematic Review of Clinical Practice Guidelines' Recommendations on Levothyroxine Therapy Alone versus Combination Therapy (LT4 plus LT3) for Hypothyroidism.

PURPOSE: Patients with hypothyroidism are increasingly enquiring about the benefit of using combination therapy of levothyroxine (LT4) and liothyronine (LT3) as a potential treatment for hypothyroidism. Combination therapy, however, remains controversial. The purpose of this study was to systematically review available hypothyroidism treatment recommendations from clinical practice guidelines from around the world to identify the consensus regarding combination therapy. SOURCE: Clinical practice guidelines were obtained from searches of PubMed, EMBASE, and MEDLINE, using several combinations of MeSH terms. The search was limited to clinical guidelines in English-language publications, published between January 1, 1990 and May 1, 2015. A quantitative approach was utilized for data synthesis. PRINCIPAL FINDINGS: Thirteen guidelines were identified, including three regarding pregnancy, two regarding pediatric populations and eight regarding adult populations. There were six guidelines from North America, four guidelines from Europe and three guidelines from South America. Twelve of the guidelines were published after 2010. Nine guidelines addressed combination therapy of LT4 plus LT3, and all nine concluded that LT4 therapy alone is the standard of care, with insufficient evidence to recommend widespread combination therapy. Only the 2012 ETA Guidelines and the 2015 BTA Guidelines concluded that combination therapy could be used, although only in certain circumstances and as an experimental treatment. CONCLUSION: This systematic review illustrates that clinical practice guidelines worldwide do not recommend and do not support routine use of combination LT4 and LT3 therapy to treat hypothyroidism.

Sex/Gender-Based Pharmacology and Statin Utilization Amongst Elderly Patients with Diabetes.

PURPOSE: The purpose of this study was to explore the ten-year trends in utilization of bioequivalent doses of statin amongst elderly patients with diabetes according to sex/gender in Ontario, Canada. METHODS: A cohort of patients with diabetes (>65 years) was constructed using the Ontario Diabetes Database Statin utilization data (2003-2012) was obtained from the Ontario Drug Benefit Program for both women and men. Bioequivalent doses for statins were calculated according to the dosing conversion factor in therapeutic interchange programs in clinical practice. Utilization pattern of high potency (Atorvastatin and Rosuvastatin) vs. low potency statins (Simvastatin, Lovastatin, Fluvastatin, Pravastatin) were also analyzed. RESULTS: The average bioequivalent Simvastatin utilization in 2003 was 29.22 mg/day for women and 30.35 mg/day for men. By 2008, this gap in dosing was higher for both women and men and by 2013 it had increased to 47.75 mg/day for women and 52.98 mg/day for men. For average number of day supply per year, there was no significant trend of changes over the 10-year period, although the use of high potency statins increased significantly (P<0.001) for both women and men. No differences were seen for sex/gender; either for the 10-year period or for each year. CONCLUSIONS: There has been significant increase in bioequivalent statin utilization amongst elderly patients with diabetes in Ontario; for both men and women. In a publicly-funded healthcare system such as Ontario, there were no sex/gender differences in the utilization of high potency statin (Atorvastatin and Rosuvastatin) amongst elderly patient with diabetes.

Exploring the Distribution of Prescription for Sulfonylureas in Patients with Type 2 Diabetes According to Cardiovascular Risk Factors Within a Canadian Primary Care Setting.

BACKGROUND: A growing body of evidence generated from observational studies and meta-analyses has begun to illustrate the potential adverse cardiovascular (CV) risk profile associated with sulfonylurea (SU) use. Specifically, the use of an SU has been demonstrated to be associated with increased mortality and a higher risk of stroke with more CV events associated with SU use having been reported in subgroups of patients with a history of CV disease, elderly and a higher body mass index. OBJECTIVE: The objective of the current study was to explore the distribution of established atherosclerotic CV disease and CV risk factors amongst patients with diabetes on an SU using a Canadian primary care dataset for the 2013 calendar year. METHODS: The Canadian Primary Care Sentinel Surveillance Network (CPCSSN), which is a multi-disease surveillance system based on primary care electronic medical record data, was utilized for this research study. Patients with a diagnosis of diabetes and exposure to an SU were identified. Distribution/prevalence of CV risk profile amongst this sub-cohort was explored. RESULTS: In analyzing the CPCSSN database for the 2013 calendar year, 6150 patients were identified as having diabetes, at least one visit with their family doctor, and on an SU. For this sub-cohort, demographic data was as follows: age [mean (SD)] 65.4(12.8) years-old; 56.4% male and mean BMI 31.3(10.0). Established atherosclerotic CV disease was observed in 16.8% of the patients with the following distribution: 13.2% had ischemic heart disease/myocardial infarction or coronary artery disease; 2.4% had stroke; and 2.3% had peripheral vascular disease. Regarding the aggregation of CV risk factors, a large proportion (65%) of patients without established atherosclerotic CV disease presented with 2 or more CV risk factors including: hypertension (62%), dyslipidemia (33%), active smoking (13%), and obesity (43%). Almost half of the cohort (45%) were males older than 55 years of age or females older than 60 years of age with at least one of the following risk factors: dyslipidemia, hypertension or current smoking, but without established cardiovascular disease. A large proportion of patients (19.5%) had a diagnosis of cardiac-specific issues including ischemic heart disease/myocardial infarction/coronary artery disease, heart failure (not due to ischemic heart disease/myocardial infarction/coronary artery disease), or arrhythmia. Almost 82% of patients had either established atherosclerotic CV disease or 2 or more CV risk factors without established atherosclerotic CV disease. CONCLUSION: This study illustrated that in this dataset of Canadian patients with diabetes in a primary care setting, a substantial proportion of patients treated with an SU in 2013 had established CV disease and/or an aggregation of multiple CV risk factors. In light of recent data reporting on an association between SU utilization and CV events and increased mortality, pharmacovigilance programs should actively monitor SU utilization in patients with diabetes and a high risk CV profile in real world clinical settings.

Challenges in pharmacotherapeutics education for diabetes in real-world clinical settings: views from family medicine and internal medicine residents.

PURPOSE: Pharmacotherapy for diabetes in real-world clinical settings is very complex and is posing a challenge for residents in training. The purpose of this study was to explore the views of residents in Canada regarding educational priorities for pharmacotherapy in diabetes management. METHODS: A questionnaire was developed to explore different domains of pharmacotherapy in diabetes management, including different clinic>al settings, combination pharmacotherapy with different classes of medications and patients' characteristics, including comorbidities and cardiovascular risk factors. The questionnaire and the letter of invitation was sent to residents through their program directors. The results were gathered through an online survey system. Due to the study design, response rate could not be determined. For data analysis, SPSS Software was used for statistical analysis. Chi-square testing was utilized for comparisons of proportions. RESULTS: Thirty-four residency programs in Canada were contacted and 165 residents completed the study. A significant number of the residents (59%) viewed combination pharmacotherapy for diabetes management as the most important educational priority (p < 0.001). Regarding insulin therapy, combination of insulin with another class of agents was recognized as the most important educational priority by 51% of residents (p < 0.001). Among all classes of medication for blood glucose management the education on the use of newer class of medication such as GLP1 agonists, DPP4 inhibitors and SGLT2 inhibitors was recognized as a priority by 77% of residents (p < 0.001). CONCLUSION: This study provides new data and insights into residents' views on diabetes pharmacotherapy. Educational curriculums may incorporate these views from residents on the educational priorities that were identified in this study.

Thyroid stimulating hormone suppression post-therapy in patients with Graves' disease: a systematic review of pathophysiology and clinical data.

BACKGROUND: Post-treatment hypothyroidism is common in Graves' disease, and clinical guidelines recommend monitoring for it; however, thyroid stimulating hormone (TSH) can remain suppressed in these patients following treatment. The objectives of this study were to explore the proposed pathophysiology behind the phenomenon of post-therapy TSH suppression and to systematically review existing clinical data on post-therapy TSH suppression in patients with Graves' disease. SOURCE: A systematic literature search was performed using EMBASE and PubMed databases, with several combinations of MeSH terms. Bibliography mining was also done on relevant articles to be as inclusive as possible. PRINCIPAL FINDINGS: A total of 18 articles described possible mechanisms for post-therapy TSH suppression. Several of the studies demonstrate evidence of thyrotroph atrophy and hypothesize that this contributes to the ongoing suppression. TSH receptors have been identified in folliculo-stellate cells of the pituitary as well as astroglial cells of the hypothalamus, mediating paracrine feedback. A few studies have demonstrated inverse correlation between autoantibody titres and TSH levels, suggestive of their role in mediating ongoing TSH suppression in patients with Graves' disease. In addition, five studies were identified that provided clinical data on the duration of TSH suppression. Combined data show that 45.5% of patients recover TSH by 3 months after treatment, increasing to 69.3% by 6 months, and plateauing to 73.8% by 12 months (p>0.0001). Sub-analysis also shows that for patients who are TBII negative, 80.7% recover their TSH by 6 months compared with only 58.7% in those who are TBII positive (p= 0.003). CONCLUSION: Clinical data suggests that TSH recovery is most likely to occur within the first 6 months after treatment, with recovery plateauing at approximately 70% of patients, suggesting that reliance on this assay for monitoring can be very misleading. Furthermore, TBII positivity is associated with lower likelihood of TSH recovery. Pathophysiology behind suppressed TSH involves not only anatomical but also autoimmune mechanisms.

Sex/gender disparities in randomized controlled trials of statins: the impact of awareness efforts.

PURPOSE: Studies have demonstrated gender differences in the burden of cardiovascular outcomes for patients with dyslipidemia. Progress in identification of the sex/gender composition in Randomized Controlled Trials (RCTs) is crucial for understanding the distribution of therapeutics effectiveness in the population according to sex/gender. The purpose of this study was to investigate the evolving pattern of sex/gender disparity in participants of RCTs on statins between 1990 and 2010. A secondary objective was to evaluate changes in the pattern of the average age of participants of RCTs on statins between 1990 and 2010. METHODS: This review focused on RCTs on statins that reported participants' numbers by sex/gender. Studies were identified from an initial PubMed search using several combinations of MeSH terms. The search was limited to the RCTs on adults in English-language publications. The dates for search were set between January 1, 1990 and December 31, 2010. RESULTS: In the 1990s, RCTs on statins with an average of more than 500 participants included 18.6% women [95% Confidence Interval (95% C.I.): 16.31%, 21.13%]. By the first decade of the 2000s, women comprised, on average, 31.45% [29.45%, 32.52% (95% C.I.)] of the total cohort of RCTs with more than 500 participants. Regression analysis illustrated a significant increase in the recruitment of women for RCTs of statins (p-value < 0.01). Furthermore, analysis of the average age of participants illustrated a significant trend (p-value = 0.03) towards an increase in the average age of the participants in RCTs on statin between 1990 and 2010: the average age of participants in the 1990s was 58 years [56, 60 (95% C.I.)] and in the 2000s it was 62 years [56, 60 (95% C.I.)]. CONCLUSION: This study demonstrates significant progress in the inclusion of women in RCTs on statins. This finding reflects the efforts of different agencies and groups to increase the representation of women in clinical trials.

Personalized pharmacotherapy in diabetes care using clinical pharmacology data of basal insulin analogues.

Advancement in technology led to the development of many insulin analogues in the last three decades. These analogues are characterized by various clinical pharmacology properties that can be utilized in clinical practice to tailor insulin therapy for each patient with diabetes, individually. This paper explores the different aspects of clinical pharmacology data on basal insulin analogues that can influence the choice of basal insulin for a personalized pharmacotherapy.

Household income and LDL-C goal attainment in patients with diabetes and dyslipidemia in a Canadian dataset.

PURPOSE: There is evidence of a social disparity pertaining to the epidemiology and burden of illness of diabetes. The purpose of this study was to assess the association between household income strata and therapeutic goal achievement rates for LDL-cholesterol (LDL-C) (< 2.5 mmol/L) in Canadian diabetic patients. METHODS: Data (household income, cardiovascular risk factors, drug profile, clinical and laboratory variables) were obtained from a previous cross-sectional study of diabetic patients who filled a prescription for a lipid-lowering drug in selected pharmacies across Canada. Telephone interviews were conducted. Physicians, identified by the participating patients, were requested to complete a short questionnaire for clinical data. Achievement of LDL-C goals according to the Canadian diabetes guidelines were assessed and incorporated into regression models corresponding to household income strata. RESULTS: Seven household income strata were defined in the cohort (from less than 20,000 CDN$, up to 70,000 CDN$ by increments of 10,000 CDN$). LDL-C goals were attained in 34% of patients in the total cohort. There were no significant differences amongst household income strata for LDL-C goal achievement (p = 0.80). There were no significant differences in patient characteristics (age, sex, BMI) and cardiovascular risks according to the household income strata in this cohort, except age more than 65 in the lower income strata. CONCLUSION: This study demonstrates that household income was not a factor to achieve therapeutic goals for LDL-C for patients with diabetes in this dataset, although goal attainment was less than ideal overall. Future studies should address limitations of this work including small sample size, recruitment bias and lack of data on third party insurance coverage.

Goal attainment for multiple cardiovascular risk factors in community-based clinical practice (a Canadian experience).

BACKGROUND: The primary goal in the clinical management of atherosclerotic cardiovascular (CV) disease is to reduce major CV risk factors. A single risk factor approach has been traditionally used for demonstrating effectiveness of therapeutic interventions designed to reduce CV risk in clinical trials, but a global CV risk reduction approach should be adopted when assessing effectiveness in the clinical practice setting. OBJECTIVES: To explore combined goal achievement for low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose and systolic-diastolic blood pressure, in patients with dyslipidemia on pharmacotherapy in community-based clinical practices across Canada. METHODS: In a cross-sectional study, patients filling a prescription for any antihyperlipidemia therapy in selected pharmacies in Ontario, Quebec, British Columbia and Nova Scotia were recruited. Family physicians of the participating patients were requested to provide information from the patient's medical record. Ten-year CV risk was identified for each patient according to the Framingham criteria. RESULTS: High-risk patients comprised 52% of the patient population; 34% were moderate-risk and 14% were low-risk. Patients had a mean of 2.8 CV risk factors; high-risk 3.7, moderate-risk 2.3 and low-risk 1.2. LDL-C goal attainment was observed in 62%, 79% and 96% of patients in high-risk, moderate-risk and low-risk strata respectively. BP goal was achieved in high-risk patients 58%, moderate-risk 83% and low-risk 95%. Glucose levels were below the threshold in 91% of patients. Complete global CV risk reduction was achieved in only 21%, 66% and 92% of high-risk, moderate-risk and low-risk strata respectively. CONCLUSION: This study illustrates that many patients with dyslipidemia in the Canadian population, and in particular the high-risk patients, did not meet the therapeutic targets for specific CV risk factors according to the Canadian guidelines. Overall, 54% of patients failed to achieve a state of complete global CV risk reduction.

Exploring patient demographic and clinical characteristics associated with lipid-lowering pharmacotherapy use in primary care.

BACKGROUND: Lipid-lowering therapeutics, particularly HMG Co-A reductase inhibitors, can be beneficial in primary and secondary cardiovascular prevention. The Canadian population frequently uses these medications but the manner in which they are used in community-based practice is unknown. OBJECTIVES: To assess the patient characteristics associated with lipid lowering drug use in community-based clinical practice across four geographic regions in Canada. To assess amongst lipid-lowering drugs users the proportion of patients that would meet accepted dyslipidemia management guidelines. To assess the community-based effectiveness of anti-hyperlipidemic drugs. METHODS: Patients filling a prescription for any anti-hyperlipidemia therapy in selected pharmacies in Ontario (ON), Quebec (PQ), British Columbia (BC) and Nova Scotia (NS). All eligible patients were interviewed over the telephone. Physicians who were providing healthcare to the participating patients were requested to provide information from the patient's medical record. RESULTS: The mean patient age was > 60 yr in all four provinces. There were some differences amongst the four provinces pertaining to patient characteristics, prescription patterns and therapeutic indicators, but not to outcomes. Anti-hyperlipidemia therapy was associated with a 1.81 mmol/L decrease in LDL-Cholesterol (P < 0.001); however only 73% of patients achieved target LDL-Cholesterol concentrations. A lag time of 1.96 yr (P < 0.0001) was observed from the diagnosis of dyslipidemia until the drug treatment was initiated. Patients had an average of 2.8 cardiovascular (CV) risk factors and 86% of patients had at two or more CV risk factors. Thirty-nine percent (95% CI, 36% - 42%) of the patients were being treated for secondary prevention. Thirteen percent (11-16%) of patients who were being treated for primary prevention had diabetes. Metabolic syndrome was observed in 32% (29-35%) of patients. CONCLUSION: Almost all patients fulfilled guideline requirements for the use of anti-hyperlipidemic therapy. Although the use of pharmacotherapy was associated with a lowering of LDL cholesterol more aggressive management is required to attain target LDL cholesterol concentrations.

Exploring design-related bias in clinical studies on receptor genetic polymorphism of hypertension.

BACKGROUND AND OBJECTIVES: Although several candidate genes of Renin-Angiotensin-Aldosterone System (RAAS) have been investigated, the gene-drug relationship remains unclear. The objective was to appraise the elements of research methodology and explore potential biases, which may be contributing to discordant results in the gene-drug interaction assessment for RAAS. METHODS: Systematic review of studies involving candidate polymorphisms, searching PubMed, and EMBASE. RESULTS: Sixteen studies were identified. Nine studies had a genomic evaluation as the primary question. Six studies investigated more than one gene. A gene-drug interaction was evaluated in two studies and only one of the studies had a placebo arm for accurately exploring the interaction. Almost, 90% of the studies had sample sizes of less than 500 patients. Four studies combined the allele frequencies of the heterozygotes group with one of the homozygotes groups. Almost one quarter of the studies combined different therapeutics in one group. Five studies included patients in one group from previous studies in which selection criteria were not quite similar. CONCLUSION: Most studies contain several methodological limitations. Also biases driven from patient selection, combining different alleles, combining different therapeutics, and combining end points may have occurred in these studies. These limitations and biases may contribute to inconsistency of the results of these studies.

A comparison between integrating clinical practice setting and randomized controlled trial setting into economic evaluation models of therapeutics.

BACKGROUND: Cost-effectiveness analyses generated from randomized controlled trials (RCTs) represent results obtained under ideal experimental conditions (efficacy) and the applicability of these data to real-world settings (effectiveness) may be questionable. OBJECTIVE: To compare cost-effectiveness results obtained from a RCT setting with the results derived from community-based clinical practice. METHODS: Using data from a community-based cohort study and from a RCT, two cost-effectiveness analyses were performed and the incremental cost-effectiveness ratios (ICERs) were calculated for the use of etanercept in the treatment of patients with rheumatoid arthritis. RESULTS: Using an effectiveness-based analysis, the mean quality-adjusted life years (QALYs) gained during the 12-month monitoring period were 0.45 and 0.35 for the treatment and control groups respectively. The ICER for etanercept treatment was 174,200 dollars (CDN) per QALY (95% confidence limits between 119,500 dollars and 285,000 dollars). Incorporating efficacy data obtained from the RCT into the analysis, the mean QALYs gained were 0.56 and 0.35 for the treatment and control groups respectively. This resulted in a substantially lower ICER for etanercept treatment of 82,952 dollars per QALY (95% confidence limits between 66,500 dollars and 103,430 dollars). CONCLUSION: Depending on the type of clinical setting used for the analysis, the resulting ICER for etanercept treatment was very different. These results help to explain the difference in cost-effectiveness reported in previous modeling studies, some based on RCT assumptions and some based on effectiveness setting.

Community-based evaluation of etanercept in patients with rheumatoid arthritis.

OBJECTIVES: Etanercept is one of a new subgroup of biological disease modifying antirheumatic drugs (DMARD) to treat patients with rheumatoid arthritis (RA) who are non-responsive or intolerant to conventional DMARD. We evaluated the effects of etanercept (Enbrel) therapy in patients with RA in community-based clinical practice in Canada. METHODS: Using a cohort design, patients requesting etanercept therapy were stratified into treatment and control arms based upon their individual accessibility to obtain the drug. Patients were interviewed serially during a 12-month period of monitoring. The study measured painful or tender joint count, morning stiffness, pain severity, quality of life measures, medication utilization, health services utilization, and presence of adverse events. RESULTS: The baseline demographic and clinical variables for the treatment group (n = 223) and the control group (n = 208) were similar, except for education, income, and drug plan coverage. In followup, there was greater improvement in most clinical variables in the treatment arm compared to the control arm during the first 6 months, but the magnitude of difference between the 2 groups for some clinical variables decreased or became non-significant during the second 6 months. During the 12 month followup period there were 40 (18%) patient dropouts in the treatment group. CONCLUSION: In a community based setting for the treatment of RA, etanercept can effectively improve the disease state, functional class, work disability, and quality of life during the first 6 months of use. To determine the longterm sustainability of these effects studies with more than 12 months' duration will be required.

Clinical data gap between phase III clinical trials (pre-marketing) and phase IV (post-marketing) studies: evaluation of etanercept in rheumatoid arthritis.

BACKGROUND: There are fundamental differences in design between phase III clinical trials and phase IV post-marketing studies that involve patient characteristics, the clinical setting (environment) and the manner of drug use. As well, many phase IV studies are extensions of randomized clinical trials (RCTs) and suffer from selection bias. OBJECTIVE: To determine if the data obtained from RCTs of etanercept (Enbrel) in the treatment of rheumatoid arthritis would be representative of the effects attainable in community practice. METHOD: An analysis was conducted comparing data from published RCTs of etanercept use in rheumatoid arthritis patients with data collected in a community based cohort study that was not an extension of an RCT. RESULTS: Baseline clinical data, such as tender or painful joint count, patient's global assessment, the heath assessment questionnaire, physical and mental component summary of the SF-36, and rheumatoid arthritis drug profile were significantly different between the patients receiving etanercept in the phase IV community cohort study and the patients enrolled in the RCTs. Differences in the baseline data for the control patients were also noted amongst the RCT studies. The treatment outcome, American College of Rheumatology (ACR) response rate of 20%, 50% and 70% at 6 month, was the same between the cohort study and the RCTs, but at 12 months the clinical response was less for the community based patients than for the RCT patients. At 6 months there were fewer withdrawals involving community-based patients than RCT patients due to less frequent withdrawals associated with lack of efficacy. At 12 months the withdrawal rate due to either a lack of efficacy or from adverse events was similar between data sets. CONCLUSION: The data from the etanercept phase III RCTs may not reflect the characteristics of patients using etanercept in community practice, nor the clinical outcomes observed by RA patients at 12 months. These discrepancies may be derived from methodological differences in study design and patient selection. On the other hand, outcomes such as withdrawal rates at 12 months appear comparable between the two types of populations.