ABT-122, a Bispecific Dual Variable Domain Immunoglobulin Targeting Tumor Necrosis Factor and Interleukin-17A, in Patients With Rheumatoid Arthritis With an Inadequate Response to Methotrexate: A Randomized, Double-Blind Study.

OBJECTIVE: Tumor necrosis factor (TNF) and interleukin-17A (IL-17A) may independently contribute to the pathophysiology of rheumatoid arthritis (RA). This study sought to evaluate the safety and efficacy of ABT-122, a novel dual variable domain immunoglobulin targeting human TNF and IL-17A, in patients with RA who have experienced an inadequate response to methotrexate. METHODS: Patients with active RA who were receiving treatment with methotrexate and had no prior exposure to biologic agents (n = 222) were enrolled in a 12-week phase II randomized, double-blind, active-controlled, parallel-group study. Patients were randomized to receive either ABT-122 at dosages of 60 mg every other week, 120 mg every other week, or 120 mg every week or adalimumab at 40 mg every other week, administered subcutaneously. The primary efficacy end point was the proportion of patients achieving a ≥20% improvement response based on the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. RESULTS: Treatment-emergent adverse events were similar across all treatment groups, with no serious infections or systemic hypersensitivity reactions reported with ABT-122. ACR20 response rates at week 12 were 62%, 75%, and 80% with ABT-122 60 mg every other week, 120 mg every other week, and 120 mg every week, respectively, compared with an ACR20 response rate of 68% with 40 mg adalimumab every other week. The corresponding response rates for ACR50 and ACR70 improvement in the ABT-122 dose groups and adalimumab group were 35%, 46%, 47%, and 48%, respectively, and 22%, 18%, 36%, and 21%, respectively. CONCLUSION: Over the 12-week study period, dual inhibition of TNF and IL-17A with ABT-122 produced a safety profile consistent with that of adalimumb used for inhibition of TNF alone. The efficacy of ABT-122 over 12 weeks at dosages of 120 mg every other week or 120 mg every week was not meaningfully differentiated from that of adalimumab at a dosage of 40 mg every other week in patients with RA receiving concomitant methotrexate.

In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494).

BACKGROUND: Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. METHODS: Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. RESULTS: Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. CONCLUSIONS: The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile.

Safety, Tolerability, and Pharmacodynamics of ABT-122, a Tumor Necrosis Factor- and Interleukin-17-Targeted Dual Variable Domain Immunoglobulin, in Patients With Rheumatoid Arthritis.

OBJECTIVE: Tumor necrosis factor (TNF) and interleukin-17 (IL-17) independently contribute to the pathophysiology of rheumatoid arthritis (RA). ABT-122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL-17A. The aim of treatment with ABT-122 is to evoke a greater clinical response than that achieved by targeting either cytokine alone. This study was undertaken to present the pooled safety, tolerability, and exploratory pharmacodynamics of ABT-122 based on 2 phase I, placebo-controlled, multiple ascending-dose studies in patients with primarily inactive RA. METHODS: Patients (n = 44) receiving stable dosages of methotrexate (2.5-25 mg/week) were randomized to receive subcutaneous placebo, ABT-122 1 mg/kg every other week (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses) and were evaluated through 45 days after the last dose (day 92). Serum samples for the assessment of inflammation markers and chemokines were collected at baseline and on postdose days 3, 5, 8, 15, 29, 57, 64, 78, and 92. RESULTS: No clinically significant findings regarding the safety of ABT-122 were observed. The rates of treatment-emergent adverse events (AEs) were similar in patients receiving ABT-122 and those receiving placebo. Only 1 serious AE (and no systemic hypersensitivity reactions or dose-limiting toxicities) was observed in patients treated with ABT-122. The incidence of infections was similar between patients treated with ABT-122 and those receiving placebo, with no serious infection reported. The levels of CXCL9, CXCL10, CCL23, and soluble E-selectin were significantly decreased following ABT-122 treatment relative to placebo treatment. Although patients had essentially inactive RA, exploratory clinical parameters suggested potential antiinflammatory effects following treatment with ABT-122. CONCLUSION: The results of these phase I studies suggest that dual neutralization of TNF and IL-17 with ABT-122 has characteristics acceptable for further exploration of therapeutic potential in TNF- and IL-17A-driven immune-mediated inflammatory diseases.

Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis.

BACKGROUND: ABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation. METHODS: ABT-494 single (1-48 mg or placebo; n = 56) and multiple (3-24 mg or placebo twice daily for 14 days; n = 44) doses in healthy subjects, as well as multiple doses (3-24 mg or placebo twice daily for 27 days; n = 14) in subjects with rheumatoid arthritis (RA) on a background of methotrexate were evaluated. Pharmacokinetic samples were collected and safety and tolerability were assessed. RESULTS: ABT-494 followed bi-exponential disposition, with a terminal elimination half-life of 6-16 h and a functional half-life, calculated from maximum observed plasma concentration (C max) to trough plasma concentration (C trough) ratio at steady state, of 3-4 h. ABT-494 exposure was approximately dose proportional over the 3-36 mg dose range, with no significant accumulation with repeated dosing. In subjects with RA, no pharmacokinetic interaction between ABT-494 and methotrexate was observed. The fraction of ABT-494 dose eliminated in urine as unchanged ABT-494 was 14-25 %. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE (15.6 % for ABT-494 vs. 16.7 % for placebo) after multiple twice-daily administration to healthy subjects. No clinically significant changes in laboratory parameters, vital signs, or electrocardiogram findings in healthy or RA subjects were observed. CONCLUSIONS: The favorable pharmacokinetics, safety, and tolerability results from these studies supported further evaluations of ABT-494 in phase IIb dose-ranging trials in RA and Crohn's disease. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifier: NCT01741493.

Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study.

This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 ± 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet. Images were reviewed centrally using a streamlined semiautomatic approach. Quantitative volumetric measurements on plaque morphology (lumen, wall, and outer wall) and plaque tissue composition [lipid-rich necrotic core (LRNC), calcification, and fibrous tissue] were obtained. Inter-scan reproducibility was summarized using the within-subject standard deviation, coefficient of variation (CV) and intraclass correlation coefficient (ICC). Good to excellent reproducibility was observed for both morphological (ICC range 0.98-0.99) and compositional (ICC range 0.88-0.96) measurements. Measurement precision was related to the size of structures (CV range 2.5-4.9 % for morphology, 36-44 % for LRNC and calcification). Comparable measurement variability was found between the two platforms on both plaque morphology and tissue composition. In conclusion, good to excellent inter-scan reproducibility of carotid MRI can be achieved in multicenter settings with comparable measurement precision between platforms, which may facilitate future multicenter endeavors that use serial MRI to monitor atherosclerotic plaque progression.

Extended-release niacin therapy and risk of ischemic stroke in patients with cardiovascular disease: the Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglycerides: Impact on Global Health Outcome (AIM-HIGH) trial.

BACKGROUND AND PURPOSE: In Atherothrombosis Intervention in Metabolic Syndrome with low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial, addition of extended-release niacin (ERN) to simvastatin in participants with established cardiovascular disease, low high-density lipoprotein cholesterol, and high triglycerides had no incremental benefit, despite increases in high-density lipoprotein cholesterol. Preliminary analysis based on incomplete end point adjudication suggested increased ischemic stroke risk among participants randomized to ERN. METHODS: This final analysis was conducted after complete AIM-HIGH event ascertainment to further explore potential relationship between niacin therapy and ischemic stroke risk. RESULTS: There was no group difference in trial primary composite end point at a mean 36-month follow-up among 3414 patients (85% men; mean age, 64±9 years) randomized to simvastatin plus ERN (1500-2000 mg/d) versus simvastatin plus matching placebo. In the intention-to-treat analysis, there were 50 fatal or nonfatal ischemic strokes: 18 (1.06%) in placebo arm versus 32 (1.86%) in ERN arm (hazard ratio [HR], 1.78 [95% confidence interval {CI}, 1.00-3.17; P=0.050). Multivariate analysis showed independent associations between ischemic stroke risk and >65 years of age (HR, 3.58; 95% CI, 1.82-7.05; P=0.0002), history of stroke/transient ischemic attack/carotid disease (HR, 2.18; 95% CI, 1.23-3.88; P=0.0079), elevated baseline Lp(a) (HR, 2.80; 95% CI, 1.25-6.27 comparing the middle with the lowest tertile; HR, 2.31; 95% CI, 1.002-5.30 comparing the highest with the lowest tertile; overall P=0.042) but a nonsignificant association with ERN (HR, 1.74; 95% CI, 0.97-3.11; P=0.063). CONCLUSIONS: Although there were numerically more ischemic strokes with addition of ERN to simvastatin that reached nominal significance, the number was small, and multivariable analysis accounting for known risk factors did not support a significant association between niacin and ischemic stroke risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120289.

Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure.

BACKGROUND: This study evaluated the efficacy and safety of levosimendan, a positive inotropic drug with vasodilator effects, given intravenously to patients with acutely decompensated heart failure (ADHF). METHODS: We performed 2 sequential trials, the first to develop a new measure of efficacy in 100 patients, and the second to use this measure to evaluate levosimendan in an additional 600 patients. Patients admitted with ADHF received placebo or intravenous levosimendan for 24 h in addition to standard treatment. The primary endpoint was a composite that evaluated changes in clinical status during the first 5 days after randomization. RESULTS: In the 600-patient trial, more levosimendan than placebo patients (58 vs. 44) were improved at all 3 pre-specified time points (6 h, 24 h, and 5 days), whereas fewer levosimendan patients (58 vs. 82) experienced clinical worsening (p = 0.015 for the difference between the groups). These differences were apparent, despite more frequent intensification of adjunctive therapy in the placebo group (79 vs. 45 patients). Improvements in patient self-assessment and declines in B-type natriuretic peptide levels with levosimendan persisted for 5 days and were associated with reduced length of stay (p = 0.009). Similar findings were present in the 100-patient pilot trial. Levosimendan was associated with more frequent hypotension and cardiac arrhythmias during the infusion period and a numerically higher risk of death across the 2 trials (49 of 350 on a regimen of levosimendan vs. 40 of 350 on a regimen of placebo at 90 days, p = 0.29). CONCLUSIONS: In patients with ADHF, intravenous levosimendan provided rapid and durable symptomatic relief. As dosed in this trial, levosimendan was associated with an increased risk of adverse cardiovascular events. (Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Chronic Heart Failure; NCT00048425).

Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy.

BACKGROUND: The purpose of this research was to compare the effects of niacin extended-release in combination with simvastatin (NER/S) versus atorvastatin monotherapy on high-density lipoprotein (HDL) particle number and size in patients with hyperlipidemia or dyslipidemia from the SUPREME study. METHODS: This was a post hoc analysis of patients (n = 137) who completed the SUPREME study and who had lipid particle number and size measurements at both baseline and at week 12 by nuclear magnetic resonance spectroscopy. Following ≥4 weeks without lipid-modifying therapy (washout period), the patients received NER/S 1000/40 mg/day for 4 weeks followed by NER/S 2000/40 mg/day for 8 weeks, or atorvastatin 40 mg/day for 12 weeks. Median percent changes in HDL particle number and size from baseline to week 12 were compared between the NER/S and atorvastatin treatment groups using the Wilcoxon rank-sum test. Distribution of HDL particle subclasses at week 12 was compared between the treatment groups using the Cochran-Mantel-Haenszel test. RESULTS: Treatment with NER/S resulted in a significantly greater percent reduction in small HDL particle number at week 12 compared with atorvastatin monotherapy (-1.8% versus 4.2%, P = 0.014), and a numerically greater percent increase in large HDL particle number (102.4% versus 39.2%, P = 0.078) compared with atorvastatin monotherapy. A significantly greater percent increase in HDL particle size from baseline at week 12 was observed with NER/S compared with atorvastatin (6.0% versus 1.3%, P < 0.001). NER/S treatment also resulted in a significant shift in HDL particle size from small and medium at baseline to large at week 12 (P < 0.0001). CONCLUSION: Treatment with NER/S resulted in larger favorable changes in number and size of HDL particle subclasses compared with atorvastatin monotherapy, including a numerically greater increase in number of large HDL particles, and a significantly greater decrease in number of small HDL particles compared with atorvastatin monotherapy. In addition, NER/S treatment resulted in a significant change in HDL particle size distribution from small and medium to large.

Niacin extended-release therapy in phase III clinical trials is associated with relatively low rates of drug discontinuation due to flushing and treatment-related adverse events: a pooled analysis.

BACKGROUND AND OBJECTIVE: Niacin is a highly effective agent for increasing low high-density lipoprotein cholesterol (HDL-C) levels. It also has beneficial effects on key pro-atherogenic lipoprotein parameters. However, the side effect of flushing can challenge patient adherence to treatment. In this study, we pooled safety data from available trials of at least 16 weeks' duration to evaluate the impact of flushing on patient adherence to niacin extended-release (NER) therapy. METHODS: Data were pooled from eight NER studies (administered as NER with a maximum dosage of 1000, 1500, and 2000 mg/day, either as monotherapy or in combination with simvastatin 20 or 40 mg/day [NER/S], or lovastatin 20 or 40 mg/day [NER/L]) to evaluate rates of study discontinuation due to flushing or any treatment-related adverse events. RESULTS: While 66.6% of patients experienced flushing, only 5.2% of patients discontinued treatment due to flushing. Of the total number of patients treated with NER (n = 307), NER/S (n = 912), or NER/L (n = 928), 34 (11%), 105 (11%), and 127 (14%) patients discontinued due to any treatment-related adverse event, respectively, while 14 (5%), 43 (5%), and 55 (6%) discontinued due to flushing. Discontinuation for flushing did not differ with regard to maximum dose, or to the presence or type of statin combined with NER. CONCLUSION: Although flushing was common with NER treatment, discontinuation due to flushing occurred in only 5-6% of patients in this pooled analysis. This could be due to several factors, including the fact that all patients in the NER trials were educated about flushing and its management. Translation of methodology employed in these trials into clinical practice may improve long-term adherence to NER therapy, which would enhance the therapeutic benefit of NER for reducing cardiovascular risk.

Important considerations for treatment with dietary supplement versus prescription niacin products.

Niacin is a water-soluble B vitamin (B3) known to have favorable effects on multiple lipid parameters, including raising high-density lipoprotein cholesterol (HDL-C) levels and lowering triglycerides (TGs), lipoprotein(a), and low-density lipoprotein cholesterol (LDL-C). Although LDL-C remains the primary target of lipid-altering therapy, current guidelines emphasize HDL-C and other modifiable lipid factors as key secondary targets. Thus, niacin is considered an important therapeutic option to help reduce the risk of cardiovascular disease in patients with mixed dyslipidemia who, in addition to high LDL-C, have elevated TGs and low HDL-C. Although available prescription niacin products, including immediate-release niacin (IR; Niacor) and an extended-release niacin formulation (Niaspan), have demonstrated safety and efficacy in randomized clinical trials, confusion remains among health care providers and their patients regarding the various commercially available nonprescription dietary supplement niacin products. These dietary supplements, which include IR, sustained-release (SR), and "no-flush" or "flush-free" niacin products, are not subject to the same stringent US Food and Drug Administration regulations as prescription drugs. In fact, both the American Heart Association and the American Pharmacists Association recommend against the use of dietary supplement niacin as a substitute for prescription niacin. Although some dietary supplement IR and SR niacin products have demonstrated a lipid response in clinical trials, products labeled as "no-flush" or "flush-free" that are intended to avoid the common niacin-associated adverse effect of flushing generally contain minimal or no free, pharmacologically active niacin and therefore lack beneficial lipid-modifying effects. To clarify important differences between available prescription and dietary supplement niacin products, this article contrasts current regulatory standards for dietary supplements and prescription drugs and provides an overview of available clinical data from key trials of niacin.

Beneficial association of ß-blocker therapy on recovery from severe acute heart failure treatment: data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial.

OBJECTIVES: Beta-blocker therapy is recommended for most patients with chronic heart failure, although such therapy may be discontinued or reduced during hospitalizations. The aim is to determine whether ß-blocker use at study entry and/or at discharge has an impact on 31- and 180-day survival. DESIGN: Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support study was designed as a randomized, double-blind, active-controlled, multi-center study. SETTING: Multinational. PATIENTS: A total of 1,327 critically ill patients hospitalized with low-output heart failure in need of inotropic therapy. INTERVENTION: Levosimendan versus dobutamine. MEASUREMENTS: All-cause mortality at 31 and 180 days in patients who survived initial hospitalization with/without ß-blocker use at entry and/or at discharge. RESULTS: Patients on ß-blockers at entry and at discharge had significantly lower 31-day (p < .0001) and 180-day (p < .0001) mortality compared to patients without ß-blockers use at both time points. The association was robust when adjusted for age and co-morbidities (p = .006 at 31 days; p = .003 at 180 days). CONCLUSIONS: Those results strongly suggest, in severe acutely decompensated heart failure patients, admitted on ß-blockers, to continue on them at discharge.

Combination of niacin extended-release and simvastatin results in a less atherogenic lipid profile than atorvastatin monotherapy.

OBJECTIVE: To compare the effects of combination niacin extended-release + simvastatin (NER/S) versus atorvastatin alone on apolipoproteins and lipid fractions in a post hoc analysis from SUPREME, a study which compared the lipid effects of niacin extended-release + simvastatin and atorvastatin in patients with hyperlipidemia or mixed dyslipidemia. PATIENTS AND METHODS: Patients (n = 137) with dyslipidemia (not previously receiving statin therapy or having discontinued any lipid-altering treatment 4-5 weeks prior to the study) received NER/S (1000/40 mg/day for four weeks, then 2000/40 mg/day for eight weeks) or atorvastatin 40 mg/day for 12 weeks. Median percent changes in apolipoprotein (apo) A-1, apo B, and the apo B:A-I ratio, and nuclear magnetic resonance lipoprotein subclasses from baseline to week 12 were compared using the Wilcoxon rank-sum test and Fisher's exact test. RESULTS: NER/S treatment produced significantly greater percent changes in apo A-I and apo B:A-I, and, at the final visit, apo B < 80 mg/dL was attained by 59% versus 33% of patients, compared with atorvastatin treatment (P = 0.003). NER/S treatment resulted in greater percent reductions in calculated particle numbers for low-density lipoprotein (LDL, 52% versus 43%; P = 0.022), small LDL (55% versus 45%; P = 0.011), very low-density lipoprotein (VLDL) and total chylomicrons (63% versus 39%; P < 0.001), and greater increases in particle size for LDL (2.7% versus 1.0%; P = 0.007) and VLDL (9.3% versus 0.1%; P < 0.001), compared with atorvastatin. CONCLUSION: NER/S treatment significantly improved apo A-I levels and the apo B:A-I ratio, significantly lowered the number of atherogenic LDL particles and VLDL and chylomicron particles, and increased the mean size of LDL and VLDL particles, compared with atorvastatin.

Hospital costs for treatment of acute heart failure: economic analysis of the REVIVE II study.

BACKGROUND: Acute heart failure (AHF) is the leading cause of hospital admission among older Americans. The Randomized EValuation of Intravenous Levosimendan Efficacy (REVIVE II) trial compared patients randomly assigned to a single infusion of levosimendan (levo) or placebo (SOC), each in addition to local standard treatments for AHF. We report an economic analysis of REVIVE II from the hospital perspective. METHODS: REVIVE II enrolled patients (N = 600) hospitalized for treatment of acute decompensated heart failure (ADHF) who remained dyspneic at rest despite treatment with intravenous diuretics. Case report forms documented index hospital treatment (drug administration, procedures, days of treatment by care unit), as well as subsequent hospital and emergency department admissions during follow-up ending 90 days from date of randomization. These data were used to impute cost of admission based on an econometric cost function derived from >100,000 ADHF hospital billing records selected per REVIVE II inclusion criteria. RESULTS: Index admission mean length of stay (LOS) was shorter for the levo group compared with standard of care (SOC) (7.03 vs 8.96 days, P = 0.008) although intensive care unit (ICU)/cardiac care unit (CCU) days were similar (levo 2.88, SOC 3.22, P = 0.63). Excluding cost for levo, predicted mean (median) cost for the index admission was levo US $13,590 (9,458), SOC $19,021 (10,692) with a difference of $5,431 (1,234) favoring levo (P = 0.04). During follow-up through end of study day 90, no significant differences were observed in numbers of hospital admissions (P = 0.67), inpatient days (P = 0.81) or emergency department visits (P = 0.41). Cost-effectiveness was performed with a REVIVE-II sub-set conforming to current labeling, which excluded patients with low baseline blood pressure. Assuming an average price for levo in countries where currently approved, there was better than 50% likelihood that levo was both cost-saving and improved survival. Likelihood that levo would be cost-effective for willingness-to-pay below $50,000 per year of life gained was about 65%. CONCLUSIONS: In the REVIVE II trial, patients treated with levo had shorter LOS and lower cost for the initial hospital admission relative to patients treated with SOC. Based on sub-group analysis of patients administered per the current label, levo appears cost-effective relative to SOC.

Acetylsalicylic acid reduces niacin extended-release-induced flushing in patients with dyslipidemia.

BACKGROUND: Niacin extended-release (NER) is safe and effective for treatment of dyslipidemia. However, some patients discontinue NER treatment because of flushing, the most common adverse event associated with niacin therapy. OBJECTIVE: To evaluate the effect of daily oral acetylsalicylic acid (ASA) on NER-induced flushing in patients with dyslipidemia. METHODS: A randomized, double-blind, placebo-controlled, multicenter, 5-week study was conducted (ClinicalTrials.gov identifier: NCT00626392). Patients (n = 277) were randomly assigned to one of six treatment arms and received a 1-week run-in with ASA 325 mg or placebo followed by 4 weeks of ASA 325 mg or placebo 30 minutes before NER at a starting dose of 500 mg or 1000 mg; all patients were titrated to NER 2000 mg at week 3. The primary endpoint was the maximum severity of flushing events during week 1. RESULTS: In week 1, ASA run-in, ASA pretreatment, and a lower starting dosage of NER (500 mg/day) resulted in reductions in mean maximum severity of flushing; 48% fewer patients who received ASA experienced flushing episodes of moderate or greater intensity relative to placebo (absolute rates 15% vs 29%; p = 0.01). Over 4 weeks, ASA reduced the number of flushing episodes/patient/week by 42% relative to placebo. The discontinuation rate due to flushing was lower in the ASA group compared with placebo (1.8% vs 9.4%; p = 0.007). Overall safety was not different between groups. CONCLUSION: These data suggest that a clinically meaningful reduction in the severity and incidence of NER-induced flushing may be achieved with ASA use.

Flushing ASsessment Tool (FAST): psychometric properties of a new measure assessing flushing symptoms and clinical impact of niacin therapy.

BACKGROUND AND OBJECTIVE: A common adverse effect of niacin therapy is flushing, manifested by cutaneous warmth, redness, itching and/or tingling. The Flushing ASsessment Tool (FAST) was developed to assess flushing symptoms and their impact on patients receiving niacin therapy. This study evaluated the reliability, validity and responsiveness of the FAST. The minimal important difference (MID) of the FAST was also examined. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group 8-week study conducted to evaluate the psychometric characteristics of the FAST. The instrument is administered daily using an electronic patient diary. The study was conducted at 41 clinical sites in the US. 276 patients with dyslipidaemia were randomized to treatment and were at least 18 years of age, with fasting laboratory values of low-density lipoprotein cholesterol (LDL-C) <250 mg/dL and one of the following: high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for males or <50 mg/dL for females; or triglycerides (TG) > or = 150 and < or = 400 mg/dL; or LDL-C > or = 70 mg/dL for patients with a history of coronary heart disease (CHD) or CHD risk equivalents, or > or = 100 mg/dL for subjects with two risk factors, or > or = 160 mg/dL for subjects with 0-1 risk factors. Patients were randomized (1 : 1 : 1) to receive niacin extended-release (NER) 500 mg/day in week 1, 1000 mg/day in week 2 and 2000 mg/day in weeks 3-6/aspirin (acetylsalicylic acid [ASA]), NER/ASA placebo, or NER placebo/ASA placebo. RESULTS: FAST test-retest reliability in stable patients during the first 2 weeks was demonstrated for overall flushing severity using patient and physician overall treatment effect (OTE) ratings (intraclass correlation coefficients of >0.7 for mean overall and individual flushing severity scores). Over the 6-week treatment period, FAST scores demonstrated significant correlations with individual symptoms, impact on daily activities and sleep, and dissatisfaction related to flushing (p < 0.01). Changes in FAST scores were associated with treatment satisfaction (p < 0.01) and patient- and physician-rated OTE (p < 0.01). Using patient-rated OTE, the mean maximum flushing severity scores improved 1.85 points in responders and only 0.18 points in non-responders (p < 0.001); responders were defined by improved patient- or physician-rated OTE. Among patients with flushing, mean maximum overall flushing scores differed between patients who subsequently discontinued due to flushing (7.9 points) and those who did not discontinue (4.7 points; p < 0.001). The probable range in this study for a detectable change in flushing symptoms (MID) was 0.29-0.38 points for mean flushing severity and 0.66-0.86 points for maximum flushing severity. CONCLUSION: The FAST exhibited test-retest reliability, good evidence of construct validity, and, overall, flushing severity was responsive to change over time. The FAST is a reliable and valid instrument for assessing the impact of niacin-induced flushing in patients with dyslipidaemia.

Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE.

AIMS: Many chronic heart failure (CHF) patients take beta-blockers. When such patients are hospitalized for decompensation, it remains unclear how ongoing beta-blocker treatment will affect outcomes of acute inotrope therapy. We aimed to assess outcomes of SURVIVE patients who were on beta-blocker therapy before receiving a single intravenous infusion of levosimendan or dobutamine. METHODS AND RESULTS: Cox proportional hazard regression revealed all-cause mortality benefits of levosimendan treatment over dobutamine when the SURVIVE population was stratified according to baseline presence/absence of CHF history and use/non-use of beta-blocker treatment at baseline. All-cause mortality was lower in the CHF/levosimendan group than in the CHF/dobutamine group, showing treatment differences by hazard ratio (HR) at days 5 (3.4 vs. 5.8%; HR, 0.58, CI 0.33-1.01, P = 0.05) and 14 (7.0 vs. 10.3%; HR, 0.67, CI 0.45-0.99, P = 0.045). For patients who used beta-blockers (n = 669), mortality was significantly lower for levosimendan than dobutamine at day 5 (1.5 vs. 5.1% deaths; HR, 0.29; CI 0.11-0.78, P = 0.01). CONCLUSION: Levosimendan may be better than dobutamine for treating patients with a history of CHF or those on beta-blocker therapy when they are hospitalized with acute decompensations. These findings are preliminary but important for planning future studies.

Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: The SUPREME Study.

BACKGROUND: Aggressive treatment of low-density lipoprotein cholesterol (LDL-C) fails to prevent most cardiovascular (CV) events. Concurrent treatment of LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) should be considered in patients with dyslipidemia. OBJECTIVE: The efficacy and safety of a proprietary niacin extended-release and simvastatin (NER/S) combination were compared to atorvastatin monotherapy in a multicenter, Prospective, Randomized (3:2), Open-label, Blinded Endpoint (PROBE) study. METHODS: Following ≥4 weeks without lipid-modifying therapies, 193 patients with dyslipidemia were treated with NER/S (n = 114; 1000/40 mg/day, weeks 1 to 4; 2000/40 mg/day weeks 5 to 12) or atorvastatin (n = 79; 40 mg/day, weeks 1 to 12). RESULTS: Compared to atorvastatin, NER/S had a larger beneficial effect on HDL-C (primary end point: 30.1 ± 2.3% and 9.4 ± 2.6%, respectively; P <.001), TG (P = .02), and lipoprotein(a) (Lp[a]; P <.001), and similar effects on LDL-C and non-HDL-C. Two-thirds of patients treated with NER/S concurrently attained LDL-C (CV risk-adjusted goals), HDL-C (≥40 mg/dL), and TG (<150 mg/dL) targets, compared to one-third of patients treated with atorvastatin (P <.001). Flushing was the most common treatment-emergent adverse event (TEAE) (67.5% NER/S and 10.1% atorvastatin; P <.001). Seventy-five percent of flushing episodes were mild to moderate. More patients treated with NER/S discontinued due to TEAEs (21.1% and 3.8%; P <.001); the most common TEAE was flushing. CONCLUSION: Compared to atorvastatin, NER/S provided superior improvements in HDL-C, TG, and Lp(a) and comparable improvements in non-HDL-C and LDL-C. Treatment with NER/S should be considered for patients with dyslipidemia requiring comprehensive lipid control.

Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial.

CONTEXT: Because acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival. OBJECTIVE: To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival. DESIGN, SETTING, AND PATIENTS: The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004. INTERVENTIONS: Intravenous levosimendan (n = 664) or intravenous dobutamine (n = 663). MAIN OUTCOME MEASURE: All-cause mortality at 180 days. RESULTS: All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P = .40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P<.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group. CONCLUSION: Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00348504.

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases.

Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo via the endothelin A receptor. Treatment with an orally active endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells. Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment.

Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial.

PURPOSE: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma. PATIENTS AND METHODS: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. RESULTS: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P =.13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P =.021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P =.002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan. CONCLUSION: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.