Safety and Efficacy of Istaroxime 1.0 and 1.5 µg/kg/min for Patients With Pre-Cardiogenic Shock.

INTRODUCTION: Istaroxime was shown, in a small study, to increase systolic blood pressure (SBP) in patients with pre-cardiogenic shock (CS) due to acute heart failure (AHF). OBJECTIVES: In the current analysis, we describe the effects of 2 doses of istaroxime 1.0 (Ista-1) and 1.5 µg/kg/min (Ista-1.5). METHODS: The target dose of istaroxime, administered in a double-blind, placebo-controlled fashion, was 1.5 µg/kg/min in the first cohort (n = 24), and it was reduced to 1.0 µg/kg/min in subsequent patients (n = 36). RESULTS: Ista-1 was associated with numerically larger effects on SBP area under the curve, with a 93.6% relative increase from baseline during the first 6 hours with Ista-1 vs 39.5% for Ista-1.5, and with a 49.4% and 24.3% relative increase, respectively, at 24 hours. Compared to placebo, Ista-1.5 had more worsening HF events until day 5 and fewer days alive out of hospital (DAOH) through day 30. Ista-1 had no worsening HF events, and DAOH to day 30 were significantly increased. Effects on echocardiographic measures were similar, although decreases in left ventricular end systolic and diastolic volumes were numerically larger in the Ista-1 group. Ista-1, but not Ista-1.5, showed numerically smaller creatinine increases and larger decreases in natriuretic peptides as compared to placebo. There were 5 serious adverse events in Ista-1.5 (4 of which were cardiac) but only 1 in Ista-1. CONCLUSIONS: In patients with pre-CS due to AHF, istaroxime 1.0 µg/kg/min induced beneficial effects on SBP and DAOH. Clinical benefits appear to be reached at dosages less than 1.5 ug/kg/min.

Safety and efficacy of istaroxime in patients with acute heart failure-related pre-cardiogenic shock - a multicentre, randomized, double-blind, placebo-controlled, parallel group study (SEISMiC).

AIMS: We examined the effects of istaroxime in patients hospitalized for acute heart failure (AHF) related Society for Cardiovascular Angiography and Interventions (SCAI) stage B pre-cardiogenic shock (CS). METHODS AND RESULTS: Sixty patients with AHF without acute myocardial infarction with pre-CS, defined as systolic blood pressure (SBP) <90 mmHg without hypoperfusion, venous lactate ≥2 mmol/L and/or mechanical or inotropic support, were randomized to istaroxime 1.0-1.5 µg/kg/min or placebo for 24 h. The primary endpoint, the adjusted area under the curve (AUC) change in SBP from time of treatment to 6 h, was 53.1 (standard error [SE] 6.88) mmHg × hour versus 30.9 (SE 6.76) mmHg × hour with istaroxime versus placebo (p = 0.017). Adjusted SBP AUC at 24 h was 291.2 (SE 27.5) versus 208.7 (SE 27.0) mmHg × hour (p = 0.025). At 24 h, some echocardiographic measurements improved with istaroxime versus placebo including cardiac index (+0.21 L/min/m2 ; p = 0.016), left atrial area (-1.8 cm2 ; p = 0.008), and left ventricular end-systolic volume (-12.0 ml; p = 0.034). There were no significant differences in pulse pressure, laboratory measurements, serious adverse events or adverse events between the treatment groups except for more nausea, vomiting and infusion site pain in the istaroxime-treated patients. In a post-hoc analysis, patients receiving ≤1.0 µg/kg/min versus 1.5 µg/kg/min had similar increase in blood pressure, but a trend towards less adverse events. CONCLUSION: In a phase 2a study of patients with AHF related pre-CS, istaroxime improved blood pressure and some echocardiography measures related to heart failure and was well tolerated.

Impact of a Weekly Glucagon-Like Peptide 1 Receptor Agonist, Albiglutide, on Glycemic Control and on Reducing Prandial Insulin Use in Type 2 Diabetes Inadequately Controlled on Multiple Insulin Therapy: A Randomized Trial.

OBJECTIVE: The principle of replacing prandial insulin lispro with a once-weekly glucagon-like peptide 1 receptor agonist (GLP-1RA) for type 2 diabetes inadequately controlled on a multiple daily insulin injections regimen was tested with albiglutide. RESEARCH DESIGN AND METHODS: In this treat-to-target study, basal plus prandial insulin was optimized over 4 weeks before participants were randomized (1:1) to albiglutide plus optimized basal insulin glargine and lispro (dose reduced by 50% at randomization; subsequently, lispro injections were fully discontinued 4 weeks later) (n = 402) or to continued optimized lispro plus optimized glargine (n = 412). RESULTS: Mean ± SD HbA1c at baseline, 7.8 ± 0.6% (61 ± 7 mmol/mol) in the albiglutide + glargine group and 7.7 ± 0.6% (60 ± 7 mmol/mol) in the lispro + glargine group, was reduced at week 26 to 6.7 ± 0.8% (49 ± 8 mmol/mol) and 6.6 ± 0.8% (48 ± 8 mmol/mol), respectively (least squares [LS] difference 0.06% [95% CI -0.05 to 0.17]; noninferiority P < 0.0001). In the albiglutide + glargine group, 218 participants (54%) replaced all prandial insulin without reintroducing lispro up to week 26. Total daily prandial insulin dose was similar at baseline but was lower by 62 units/day (95% CI -65.9 to -57.8; P < 0.0001) at week 26 in the albiglutide + glargine group, and the total number of weekly injections was also reduced from 29 to 13 per week. Less severe/documented symptomatic hypoglycemia (57.2% vs. 75.0%) occurred in the albiglutide + glargine group with meaningful weight differences (LS mean ± SE -2.0 ± 0.2 vs. +2.4 ± 0.2 kg; P < 0.0001) vs. lispro + glargine. Gastrointestinal adverse events were higher with albiglutide + glargine (26% vs. 13%). CONCLUSIONS: A once-weekly GLP-1RA was able to substitute for prandial insulin in 54% of people, substantially reducing the number of prandial insulin injections; glycemic control improved, with the added benefits of weight loss and less hypoglycemia in the GLP-1RA arm. Replacing prandial insulin with a weekly GLP-1RA can simplify basal plus prandial insulin treatments and achieve better outcomes in type 2 diabetes.

Efficacy and safety of an albiglutide liquid formulation compared with the lyophilized formulation: A 26-week randomized, double-blind, repeat-dose study in patients with type 2 diabetes mellitus.

AIMS: Compare the efficacy and safety of albiglutide from a ready-to-use, single-dose, auto-injector system with the lyophilized product in patients with type 2 diabetes mellitus (T2DM). METHODS: In this phase 3 study, 308 patients between 18 and 80 years with T2DM and experiencing inadequate glycemic control on their current regimen of diet/exercise alone or in combination with metformin were randomized 1:1 to weekly injections for 26 weeks with an active albiglutide auto-injector and placebo lyophilized dual-chamber cartridge (DCC) pen injector (n = 154) or active albiglutide lyophilized DCC pen injector and placebo liquid auto-injector (n = 154). Participants received liquid or lyophilized albiglutide 30 mg for 4 weeks, and then 50 mg for the remaining 22 weeks. Change in HbA1c and fasting plasma glucose (FPG), pharmacokinetics, and safety were assessed. RESULTS: In the albiglutide liquid and lyophilized drug product groups, 55.6% (85/153) and 45.5% of patients (70/154) had a baseline HbA1c ≥ 8.0%, respectively. The model-adjusted least squares (LS) mean change in HbA1c from baseline at week 26 was -1.1% (95% CI: -1.3, -1.0) and -1.2% (95% CI: -1.3, -1.0; noninferiority P = 0.0002) in the albiglutide liquid and lyophilized product groups, respectively. Similarly, the model-adjusted LS mean change in FPG from baseline at week 26 in the albiglutide liquid and lyophilized product groups was -2.2 (95% CI: -2.6, -1.8) mmol/L and -1.9 (95% CI: -2.3, -1.5) mmol/L, respectively. No new safety concerns were identified. CONCLUSION: Change from baseline in HbA1c for albiglutide liquid was noninferior to lyophilized drug product in patients with T2DM.

A Randomized, Double-Blind, Single-Dose, Crossover Study to Demonstrate the Bioequivalence of 2 Formulations of Albiglutide in Healthy Adult Participants.

Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual-chamber cartridge (DCC) single-dose pen-injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2-period, randomized, crossover, double-blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed. Participants received injections from each type of pen-injector, one containing albiglutide 50 mg and one containing placebo, followed by an 8-week washout period between regimens: albiglutide 50-mg liquid formulation from an auto-injector and lyophilized placebo from a DCC pen-injector (Regimen A), or placebo liquid from an auto-injector and lyophilized albiglutide 50 mg from a DCC pen-injector (Regimen B). Geometric mean total exposures (area under the drug concentration-time curve [AUC](0-t) [1345.4 vs 1426.9 (µg · h/mL)], AUC(0-∞) [1376.2 vs 1454.6 (µg · h/mL)], and maximum concentration of drug in blood plasma [4968.5 vs 5314.7 ng/mL]) were comparable between Regimens A and B. Ratios of geometric least square means (90% confidence interval) were 95.3% (89.49-101.52) for AUC(0-∞) , 95.1% (89.12-101.49) for AUC(0-t) , and 93.2% (86.76-100.17) for maximum concentration of drug in blood plasma, falling within the 90% confidence interval of 0.80 to 1.25 for bioequivalence. No new safety concerns were observed.

Inflammatory Biomarkers Interleukin-6 and C-Reactive Protein and Outcomes in Stable Coronary Heart Disease: Experiences From the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial.

BACKGROUND: Evaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population. METHODS AND RESULTS: Overall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were 2.1 (interquartile range, 1.4-3.2) ng/L and 1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97; P<0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53-3.04; P<0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14-2.04; P<0.05); all-cause mortality (HR, 2.11; 95% CI, 1.62-2.76; P<0.0001); and risk of hospitalization for heart failure (HR, 2.28; 95% CI, 1.34-3.89; P<0.001). Cancer death was doubled in the highest IL-6 quartile group (HR, 2.34; 95% CI, 1.20-4.53; P<0.05). High-sensitivity C-reactive protein was associated with both cardiovascular and non-cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments. CONCLUSIONS: IL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Biomarker-Based Risk Model to Predict Cardiovascular Mortality in Patients With Stable Coronary Disease.

BACKGROUND: Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD). OBJECTIVES: This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD. METHODS: In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study. RESULTS: During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This "ABC-CHD" model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts. CONCLUSIONS: This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903).

Associations between tooth loss and prognostic biomarkers and the risk for cardiovascular events in patients with stable coronary heart disease.

BACKGROUND: Underlying mechanisms behind the hypothesized relationship between periodontal disease (PD) and coronary heart disease (CHD) have been insufficiently explored. We evaluated associations between self-reported tooth loss- a marker of PD- and prognostic biomarkers in 15,456 (97%) patients with stable CHD in the global STABILITY trial. METHODS AND RESULTS: Baseline blood samples were obtained and patients reported their number of teeth according to the following tooth loss levels: "26-32 (All)" [lowest level], "20-25", "15-19", "1-14", and "No Teeth" [highest level]. Linear and Cox regression models assessed associations between tooth loss levels and biomarker levels, and the relationship between tooth loss levels and outcomes, respectively. After multivariable adjustment, the relative biomarker increase between the highest and the lowest tooth loss level was: high-sensitivity C-reactive protein 1.21 (95% confidence interval, 1.14-1.29), interleukin 6 1.14 (1.10-1.18), lipoprotein-associated phospholipase A2 activity 1.05 (1.03-1.06), growth differentiation factor 15 1.11 (1.08-1.14), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.18 (1.11-1.25). No association was detected for high-sensitivity troponin T 1.02 (0.98-1.05). Some attenuation of the relationship between tooth loss and outcomes resulted from the addition of biomarkers to the multivariable analysis, of which NT-proBNP had the biggest impact. CONCLUSIONS: A graded and independent association between tooth loss and several prognostic biomarkers was observed, suggesting that tooth loss and its underlying mechanisms may be involved in multiple pathophysiological pathways also implicated in the development and prognosis of CHD. The association between tooth loss and cardiovascular death and stroke persisted despite comprehensive adjustment including prognostic biomarkers. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov; NCT00799903.

Associations between tooth loss and prognostic biomarkers and the risk for cardiovascular events in patients with stable coronary heart disease

BACKGROUND: Underlying mechanisms behind the hypothesized relationship between periodontal disease (PD) and coronary heart disease (CHD) have been insufficiently explored. We evaluated associations between self-reported tooth loss- a marker of PD- and prognostic biomarkers in 15,456 (97%) patients with stable CHD in the global STABILITY trial. METHODS AND RESULTS: Base line blood samples were obtained and patients reported their number of teeth according to the following tooth loss levels: "26-32 (All)" [lowest level], "20-25", "15-19", "1-14", and "No Teeth" [highest level]. Linear and Cox regression models assessed associations between tooth loss levels and biomarker levels, and the relationship between tooth loss levels and outcomes, respectively. After multivariable adjustment, the relative biomarker increase between the highest and the lowest tooth loss level was: high-sensitivity C-reactive protein 1.21 (95% confidence interval, 1.14-1.29), interleukin 6 1.14 (1.10-1.18), lipoprotein-associated phospholipase A2 activity 1.05 (1.03-1.06), growth differentiation factor 15 1.11 (1.08-1.14), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.18 (1.11-1.25)...

Tooth loss is independently associated with poor outcomes in stable coronary heart disease.

OBJECTIVE: We investigated associations between self-reported tooth loss and cardiovascular outcomes in a global stable coronary heart disease cohort. METHODS: We examined 15,456 patients from 39 countries with stable coronary heart disease (prior myocardial infarction, prior revascularisation or multivessel coronary heart disease) in the STABILITY trial. At baseline, patients reported number of teeth (26-32 (all), 20-25, 15-19, 1-14 and no teeth) and were followed for 3.7 years. Cox regression models adjusted for cardiovascular risk factors and socioeconomic status, determined associations between tooth loss level (26-32 teeth: lowest level; no teeth: highest level) and cardiovascular outcomes. RESULTS: After adjustment, every increase in tooth loss level was associated with an increased risk of the primary outcome, the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (hazard ratio 1.06; 95% confidence interval 1.02-1.10), cardiovascular death (1.17; 1.10-1.24), all-cause death (1.16; 1.11-1.22) and non-fatal or fatal stroke (1.14; 1.04-1.24), but not with non-fatal or fatal myocardial infarction (0.99; 0.94-1.05). Having no teeth, compared to 26-32 teeth, entailed a significantly higher risk of the primary outcome (1.27 (1.08, 1.49)), cardiovascular death (1.85 (1.45, 2.37), all-cause death (1.81 (1.50, 2.20)) and stroke (1.67 (1.15, 2.39)). CONCLUSIONS: In this large global cohort of patients with coronary heart disease, self-reported tooth loss predicted adverse cardiovascular outcomes and all-cause death independent of cardiovascular risk factors and socioeconomic status.

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment.

AIM: Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2 ). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function. METHODS: This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min(-1) 1.73 m(-2) , n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10. RESULTS: Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (Cmax ) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity. CONCLUSIONS: The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.

Physical activity in patients with stable coronary heart disease: an international perspective.

AIMS: Despite the known benefits of regular exercise, the reasons why many coronary heart disease (CHD) patients engage in little physical activity are not well understood. This study identifies factors associated with low activity levels in individuals with chronic CHD participating in the STABILITY study, a global clinical outcomes trial evaluating the lipoprotein phospholipaseA2 inhibitor darapladib. METHODS AND RESULTS: Prior to randomization, 15 486 (97.8%) participants from 39 countries completed a lifestyle questionnaire. Total physical activity was estimated from individual subject self-reports of hours spend each week on mild, moderate, and vigorous exercise, corresponding approximately to 2, 4, and 8 METS, respectively. Multivariate logistic regression evaluated clinical and demographic variables for the lowest compared with higher overall exercise levels, and for individuals who decreased rather than maintained or increased activity since diagnosis of CHD. The least active 5280 subjects (34%) reported exercise of ≤ 24 MET.h/week. A total of 7191 subjects (46%) reported less exercise compared with before diagnosis of CHD. The majority of participants were either 'not limited' or 'limited a little' walking 100 m (84%), climbing one flight of stairs (82%), or walking 1 km/1/2; mile (68%), and <10% were limited 'a lot' by dyspnoea or angina. Variables independently associated with both low physical activity and decreasing exercise after diagnosis of CHD included more co-morbid conditions, poorer general health, fewer years of education, race, and country (P < 0.001 for all). CONCLUSION: In this international study, low physical activity was only partly explained by cardiovascular symptoms. Potentially modifiable societal and health system factors are important determinants of physical inactivity in patients with chronic CHD.

Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia.

Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors).