Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.

OBJECTIVE: Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTS: LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONS: In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

Downregulation of miR-17~92 Expression Increase Paclitaxel Sensitivity in Human Ovarian Carcinoma SKOV3-TR30 Cells via BIM Instead of PTEN.

To better understand the molecular mechanisms of paclitaxel resistance in ovarian carcinoma, we evaluated the expression of miRNAs using miRNA microarray between human ovarian carcinoma SKOV3 cells and paclitaxel resistant SKOV3-TR30 cells. Results showed that 69 miRNAs were upregulated while 102 miRNAs were downregulated in SKOV3-TR30 cells. Using real-time PCR, we further clarified that miR-17~92 was overexpressed in SKOV3-TR30 cells compared with that in SKOV3 cells. We then established stable virally transduced SKOV3-TR30-m-PTIP-Sponge all SKOV3-TR30 cells and its vector-only control SKOV3-TR30-m-PTIP-GFP cells. Real time-PCR revealed that SKOV3-TR30-m-PTIP-Sponge all cells expressed approximately 6.18-fold lower levels of miR-17~92 compared with the control group. Decreased expression of miR-17~92 resulted in cell cycle arrest in the G2/M phase and growth inhibition. After the transduction, the BIM protein level was increased in SKOV3-TR30 cells and luciferase reporter assays revealed that miR-17~92 binds directly to the 3'-UTR of BIM. Results of luciferase reporter assays accompanied with Western Blot showed that although miR-17~92 binds directly to the 3'-UTR of PTEN, the PTEN protein expression level was upregulated slightly while the result is of no statistical significance. Our results showed that miR-17~92 could be a causal factor of the downregulation of BIM in SKOV3-TR30 cells and thus induce the paclitaxel resistance in SKOV3-TR30 cells.

Economic evaluation of clopidogrel plus aspirin for secondary prevention of cardiovascular events in Canada for patients with established cardiovascular disease: Results from the CHARISMA trial.

BACKGROUND: The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial found a statistically significant reduction in cardiovascular events when clopidogrel was added to aspirin in a prespecified subgroup of patients with established cardiovascular disease. However, the economic implications of such a strategy for the Canadian health care system are unknown. METHODS: For each patient in the CHARISMA trial with established cardiovascular disease, costs were estimated by multiplying resource utilization by unit costs derived from populations of Canadian patients in 2008 dollars. Changes in life expectancy due to nonfatal events were estimated with parametric regression models based on the Saskatchewan Health database. RESULTS: For patients with established cardiovascular disease, a strategy of clopidogrel plus aspirin for median duration of 28 months was associated with a 12.5% relative reduction in cardiovascular death, myocardial infarction, or stroke compared with aspirin alone (6.9% vs 7.9%, P =.048). Mean cost per patient was CAD$1,488 higher for clopidogrel plus aspirin, and life expectancy increased by 0.057 years. The resulting incremental cost-effectiveness ratio for adding clopidogrel was CAD$25,969 per life-year gained or CAD$21,549 per quality-adjusted life-year. These results were sensitive to the cost of clopidogrel but relatively insensitive to plausible variations in discount rate, costs other than clopidogrel, and the prognostic impact of nonfatal events. CONCLUSION: Among the subgroup of patients with established cardiovascular disease in the CHARISMA trial, adding clopidogrel to aspirin increases life expectancy at a cost generally considered acceptable in Canada.

Cost-effectiveness of clopidogrel plus aspirin versus aspirin alone for secondary prevention of cardiovascular events: results from the CHARISMA trial.

OBJECTIVE: To determine the incremental cost-effectiveness of clopidogrel plus aspirin (C + A) compared with aspirin (A) alone during the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial from a US payer perspective. BACKGROUND: Although the CHARISMA trial did not find a benefit of adding clopidogrel to aspirin in its overall study cohort, a benefit was suggested in a prespecified subgroup of patients with established cardiovascular (CV) disease. The cost-effectiveness of dual antiplatelet therapy in this population is unknown. METHODS: Medical resource utilization was assessed prospectively, and costs for hospitalizations, physician services, outpatient care, and medications were assigned using 2007 US dollars. Life expectancy was estimated contingent on fatal and nonfatal CV events using statistical models of long-term survival from the Saskatchewan Health database. RESULTS: C + A was associated with a 12.5% relative reduction in CV death, myocardial infarction, or stroke compared with A alone (6.9% vs. 7.9%, P = 0.048) over a median 28 months of follow-up. Severe or moderate bleeding events were higher in patients receiving C + A versus A alone (3.6% vs. 2.5%, P < 0.001). Mean cost/patient was $2607 higher for C + A, while projected life expectancy increased by an average of 0.072 years due to fewer in-trial events. The resulting incremental cost-effectiveness ratio (ICER) for C + A was $36,343/year of life gained. Findings were insensitive to discount rate, life expectancy projections, post-event costs, and indirect costs from lost productivity; the ICER was most sensitive to the cost of clopidogrel. Bootstrap analysis demonstrated that the ICER for C + A remained <$50,000/life-year gained in 70.6% of bootstrap replicates and <$100,000/life-year gained in 87.4%. CONCLUSIONS: Among patients with established CV disease, adding clopidogrel to aspirin appears to increase life expectancy modestly at a cost generally considered acceptable within the US health-care system.

Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes.

OBJECTIVES: The aim of this study was to determine the economic impact of several anticoagulation strategies for moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients managed invasively. BACKGROUND: The ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial demonstrated that bivalirudin monotherapy yields similar rates of ischemic complications and less bleeding than regimens incorporating glycoprotein IIb/IIIa receptor inhibitors (GPI) for moderate- and high-risk NSTE-ACS. METHODS: In ACUITY, 7,851 U.S. patients were randomized to: 1) heparin (unfractionated or enoxaparin) + GPI; 2) bivalirudin + GPI; or 3) bivalirudin monotherapy. Patients assigned to GPI were also randomized to upstream GPI before catheterization or selective GPI only with percutaneous coronary intervention. Resource use data were collected prospectively through 30-day follow-up. Costs were estimated with standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule. RESULTS: At 30 days, ischemic events were similar for all groups. Major bleeding was reduced with bivalirudin monotherapy compared with heparin + GPI or bivalirudin + GPI (p < 0.001). Length of stay was lowest with bivalirudin monotherapy or bivalirudin + catheterization laboratory GPI (p = 0.02). Despite higher drug costs, aggregate hospital stay costs were lowest with bivalirudin monotherapy (mean difference range: $184 to $1,081, p < 0.001 for overall comparison) and at 30 days (mean difference range: $123 to $938, p = 0.005). Regression modeling demonstrated that hospital savings were primarily due to less major and minor bleeding with bivalirudin ($8,658/event and $2,282/event, respectively). CONCLUSIONS: Among U.S. patients in the ACUITY trial, bivalirudin monotherapy compared with heparin + GPI resulted in similar protection from ischemic events, reduced bleeding, and shorter length of stay. Despite higher drug costs, aggregate hospital and 30-day costs were lowest with bivalirudin monotherapy. Thus bivalirudin monotherapy seems to be an economically attractive alternative to heparin + GPI for patients with moderate- and high-risk NSTE-ACS. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).

Cost-effectiveness of sirolimus-eluting stents compared with vascular brachytherapy for the treatment of in-stent restenosis.

BACKGROUND: Sirolimus-eluting stents (SESs) were recently shown to be superior to vascular brachytherapy for the treatment of restenosis within a bare metal stent. No economic comparison of these alternative strategies has yet been reported. METHODS: We conducted a prospective health economic study involving all patients randomized to SES (n = 259) or brachytherapy (n = 125) in the SISR trial. Procedural, hospital, and outpatient costs, as well as physician fees, were estimated through 12 months based on measured resource use and itemized hospital bills. Cost-effectiveness was assessed in terms of the cost per repeat revascularization avoided, cost per major adverse cardiac event avoided, and cost per event-free patient. RESULTS: Although initial device costs were approximately $1100/patient higher in the SES group, this was offset by higher physician fees associated with brachytherapy, such that initial hospitalization costs were similar for the 2 groups. Because SES significantly reduced repeat revascularization procedures and major adverse cardiac event compared with brachytherapy during follow-up, cumulative 12-month costs were significantly lower in the SES group ($16,482 vs $19,435, mean difference -$2953, 95% CI -$5470 to -$792). Sirolimus-eluting stenting was thus both more effective and less expensive than brachytherapy, as confirmed in >98% of bootstrap replications for each of the cost-effectiveness outcomes. CONCLUSIONS: Compared with vascular brachytherapy, SES is an economically dominant strategy for the treatment of in-stent restenosis.

Cost effectiveness of paclitaxel-eluting stents for patients undergoing percutaneous coronary revascularization: results from the TAXUS-IV Trial.

OBJECTIVES: This study sought to compare aggregate medical care costs for patients undergoing percutaneous coronary intervention with paclitaxel-eluting stents (PES) and bare-metal stents (BMS) and to formally evaluate the incremental cost effectiveness of PES for patients undergoing single-vessel percutaneous coronary intervention. BACKGROUND: Although the cost effectiveness of SES has been studied in both clinical trials and decision-analytic models, few data exist on the cost effectiveness of alternative drug-eluting stent (DES) designs. In addition, no clinical trials have specifically examined the cost effectiveness of DES among patients managed without mandatory angiographic follow-up. METHODS: We performed a prospective economic evaluation among 1,314 patients undergoing percutaneous coronary revascularization randomized to either PES (N = 662) or BMS (N = 652) in the TAXUS-IV trial. Clinical outcomes, resource use, and costs (from a societal perspective) were assessed prospectively for all patients over a 1-year follow-up period. Cost effectiveness was defined as the incremental cost per target vessel revascularization (TVR) event avoided and was analyzed separately among cohorts assigned to mandatory angiographic follow-up (n = 732) or clinical follow-up alone (n = 582). RESULTS: The PES reduced TVR by 12.2 events per 100 patients treated, resulting in a 1-year cost difference of 572 dollars per patient with incremental cost-effectiveness ratios of 4,678 dollars per TVR avoided and 47,798 dollars/quality-adjusted life year (QALY) gained. Among patients assigned to clinical follow-up alone, the net 1-year cost difference was 97 dollars per patient with cost-effectiveness ratios of 760 dollars per TVR event avoided and $5,105/QALY gained. CONCLUSIONS: In the TAXUS-IV trial, treatment with PES led to substantial reductions in the need for repeat revascularization while increasing 1-year costs only modestly. The cost-effectiveness ratio for PES in the study population compares reasonably with that for other treatments that reduce coronary restenosis, including alternative drug-eluting stent platforms.

Two-year outcomes after sirolimus-eluting stent implantation: results from the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRIUS) trial.

OBJECTIVES: The purpose of this study was to examine the two-year clinical outcomes in patients enrolled in the Sirolimus-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) study. BACKGROUND: The SIRIUS study was a double-blinded randomized study which demonstrated that sirolimus-eluting stents (SES) significantly improved angiographic results (at 8 months) and clinical outcomes (at 9 and 12 months) compared with bare-metal stents (BMS). METHODS: Patients with de novo native coronary artery lesions randomized to either SES (533 patients) or control BMS (525 patients) were followed for two years. RESULTS: Between one and two years, there were infrequent additional clinical events that were equally distributed between the sirolimus and control groups. After two years, target lesion revascularization was 5.8% and 21.3% in SES and control patients, respectively (p < 0.001), and major adverse cardiovascular events and target vessel failure rates were 10.1% versus 24.4% and 12.0% versus 26.7%, respectively (p < 0.0001 for both). There were no differences in death, myocardial infarction, and stent thrombosis between the two groups. CONCLUSIONS: Clinical outcomes two years after implantation of SES continue to demonstrate significant reduction in the need for repeat target lesion (and vessel) revascularization compared with BMS without evidence for either disproportionate late restenosis or late stent thrombosis.

Relationship of late loss in lumen diameter to coronary restenosis in sirolimus-eluting stents.

BACKGROUND: Observed rates of restenosis after drug-eluting stenting are low (<10%). Identification of a reliable and powerful angiographic end point will be useful in future trials. METHODS AND RESULTS: Late loss (postprocedural minimum lumen diameter minus 8-month minimum lumen diameter) was measured in the angiographic cohorts of the SIRIUS (n=703) and E-SIRIUS (n=308) trials. Two techniques, the standard normal approximation and an optimized power transformation, were used to predict binary angiographic restenosis rates and compare them with observed restenosis rates. The mean in-stent late loss observed in the SIRIUS trial was 0.17+/-0.45 mm (sirolimus) versus 1.00+/-0.70 mm (control). If a normal distribution was assumed, late loss accurately estimated in-stent binary angiographic restenosis for the control arm (predicted 35.4% versus observed 35.4%) but underestimated it in the sirolimus arm (predicted 0.6% versus observed 3.2%). Power transformation improved the reliability of the estimate in the sirolimus arm (predicted 3.2% [CI 1.0% to 6.7%]) with similar improvements in the E-SIRIUS trial (predicted 4.0% [CI 1.2% to 7.0%] versus observed 3.9%). In the sirolimus-eluting stent arm, in-stent late loss correlated better with target-lesion revascularization than in-segment late loss (c-statistic=0.915 versus 0.665). CONCLUSIONS: Because distributions of late loss with a low mean are right-skewed, the use of a transformation improves the accuracy of predicting low binary restenosis rates. Late loss is monotonically correlated with the probability of restenosis and yields a more efficient estimate of the restenosis process in the era of lower binary restenosis rates.

Cost-effectiveness of sirolimus-eluting stents for treatment of complex coronary stenoses: results from the Sirolimus-Eluting Balloon Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SIRIUS) trial.

BACKGROUND: Recently, sirolimus-eluting stents (SESs) have been shown to dramatically reduce the risk of angiographic and clinical restenosis compared with bare metal stent (BMS) implantation. However, the overall cost-effectiveness of this strategy is unknown. METHODS AND RESULTS: Between February and August 2001, 1058 patients with complex coronary stenoses were enrolled in the SIRIUS trial and randomized to percutaneous coronary revascularization with either a SES or BMS. Clinical outcomes, resource use, and costs were assessed prospectively for all patients over a 1-year follow-up period. Initial hospital costs were increased by 2881 dollars per patient with SESs. Over the 1-year follow-up period, use of SESs led to substantial reductions in the need for repeat revascularization, including repeat percutaneous coronary intervention and bypass surgery. Although follow-up costs were reduced by 2571 dollars per patient with SESs, aggregate 1-year costs remained 309 dollars per patient higher. The incremental cost-effectiveness ratio for SES was 1650 dollars per repeat revascularization event avoided or 27,540 dollars per quality-adjusted year of life gained, values that compare reasonably with other accepted medical interventions. Under updated treatment assumptions regarding available stent lengths and duration of antiplatelet therapy, use of SESs was projected to reduce total 1-year costs compared with BMSs. CONCLUSIONS: Although use of SESs was not cost-saving compared with BMS implantation, for patients undergoing percutaneous coronary intervention of complex coronary stenoses, their use appears to be reasonably cost-effective within the context of the US healthcare system.