Open-Label Two-Dose Pilot Study of Landiolol for the Treatment of Atrial Fibrillation/Atrial Flutter in Caucasian Patients.

BACKGROUND: We investigated for the first time the suitability of landiolol, an ultra-short-acting ß1-specific ß-blocker, for the treatment of atrial fibrillation/atrial flutter (AF/AFL) in Caucasian patients.Methods and Results:The 20 study patients received landiolol as a continuous infusion (starting dose 40 µg/kg/min) with (B+CI) or without (CI) a preceding bolus dose (100 µg/kg/min administered over 1 min) in a prospective open-label study. The primary endpoint was the proportion of patients with sustained heart rate (HR) reduction ≥20% or to <90 beats/min within 16 min of starting the CI. Secondary endpoints were the pharmacodynamics, pharmacokinetics, AF/AFL symptoms, safety and tolerability of landiolol. At 16 min, HR was reduced in all patients treated with landiolol. The primary endpoint was met by 60% of patients in the CI group and 40% in the B+CI group without a significant group difference. Overall reduction of AF/AFL symptoms at 16 min was 72%. Safety and local tolerability of landiolol were excellent, and no serious adverse events occurred. CONCLUSIONS: Continuous infusion of landiolol with a starting dose of 40 µg/kg/min is suitable for the acute treatment of tachycardic AF/AFL in Caucasian patients. Administration of a preceding bolus seems unnecessary.

Pharmacokinetics and Pharmacodynamics of Low-, Intermediate-, and High-Dose Landiolol and Esmolol During Long-Term Infusion in Healthy Whites.

The pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of esmolol and landiolol, a new fast-acting cardioselective ß-blocker, were compared for the first time in Caucasian subjects in a prospective clinical trial. Twelve healthy volunteers received landiolol and esmolol by continuous infusion for 24 hours in a randomized crossover study using a dose-escalation regimen. Blood concentrations of drugs and metabolites, heart rate, blood pressure, ECG parameters, and tolerability were observed for 30 hours and compared. Drug blood concentrations and areas under the curve were dose-proportional. The half life of landiolol (4.5 minutes) was significantly shorter than that of esmolol (6.9 minutes). Volume of distribution and total clearance were lower for landiolol. Heart rate reduction was faster and more pronounced with landiolol and retained throughout the administration period; effects on blood pressure were not different. Landiolol turned out to be superior to esmolol with respect to pharmacokinetic and pharmacodynamic profile and local tolerability.

Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera.

In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.

Pharmacodynamic and -kinetic Behavior of Low-, Intermediate-, and High-Dose Landiolol During Long-Term Infusion in Whites.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of long-term administration of landiolol, a fast-acting cardioselective ß-blocker, were investigated for the first time in white subjects in a prospective clinical trial. Blood concentrations of landiolol and its metabolites, heart rate (HR), blood pressure (BP), and electrocardiogram parameters were studied in 12 healthy volunteers receiving continuous infusions of a new 12-mg/mL formulation of landiolol using a dose-escalation regimen (10 µg/kg BW/min for 2 hours, 20 µg/kg BW/min for 2 hours, 40 µg/kg BW/min for 20 hours, 6 hours follow-up). Landiolol blood concentrations were dose proportional. Time until steady state decreased with increasing doses. Pharmacokinetic parameters were t1/2 = 4.5 minutes, VD = 366 mL/kg, and total body clearance = 53 mL·kg·min. Maximal blood concentrations of the inactive main metabolite M1 were 10-fold higher than those of landiolol, with t1/2 = 126 minutes, VD = 811 mL/kg, and total body clearance = 4.5 mL·kg·min. HR reduction from baseline was fast (significant after 16 minutes) and sustained throughout the administration period. Systolic and diastolic BP reductions and electrocardiogram parameter changes were less pronounced and became significant only occasionally. Recovery after discontinuation of infusion was fast with little (HR) or no (BP) rebound. The new formulation showed excellent local and general tolerability.

Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group.

PURPOSE: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective ß1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. FINDINGS: Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. IMPLICATIONS: Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. TRIAL REGISTRATION: NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7.

Single-Phase Versus Multiphase CT Angiography in Middle Cerebral Artery Clot Detection-Benefits for Less Experienced Radiologists and Neurologists.

OBJECTIVES: CT angiography (CTA) is recommended as a standard of stroke imaging. We investigated accuracy and precision of standard or single-phase CTA as compared with novel technique or multiphase CTA in clot detection in the middle cerebral artery. METHODS: Twenty single-phase CTA and twenty multiphase CTA with prevailing M2 occlusion were assessed by 10 radiologists and 10 neurologists blinded to clinical information (7 less experienced and 3 experienced). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated as compared with reading by two seniors. Reliability was calculated using Krippendorff's alpha (K-alpha). RESULTS: Sensitivity, specificity, PPV, and NPV of single-phase CTA compared with multiphase CTA for M2 clot presence were, respectively, .86, .75, .90, and .67 versus .88, .82, .92, and .72. For secondary or distal clots, sensitivity, specificity, PPV, and NPV of single-phase CTA compared with multiphase CTA were .41, .83, .50, and .78 versus .65, .77, .71, and .67. Agreement increased significantly in favor of multiphase CTA for detection of primary clots from moderate (.43) to substantial (.65) in less experienced radiologists and from slight (.10) to moderate (.30) in less experienced neurologists. Agreement significantly increased for distal or secondary clot detection in favor of multiphase CTA from fair (.24) to moderate (.49) in experienced radiologists and from slight (.12) to moderate (.46) in experienced neurologists. CONCLUSIONS: Multiphase CTA is a reliable imaging tool in M2 clot detection and might represent a beneficial imaging tool in clot detection for less experienced physicians.

Incidence of Hospitalized Stroke in the Czech Republic: The National Registry of Hospitalized Patients.

BACKGROUND: Contemporary stroke incidence data are not available in some countries and regions, including in Eastern Europe. Based on previous validation of the accuracy of the National Registry of Hospitalized Patients (NRHOSP), we report the incidence of hospitalized stroke in the Czech Republic (CR) using the NRHOSP. METHODS: The results of the prior validation study assessing the accuracy of coding of stroke diagnoses in the NRHOSP were applied, and we calculated (1) the overall incidence of hospitalized stroke and (2) the incidence rates of hospitalized stroke for the three main stroke types: cerebral infarction (International Classification of Diseases Tenth Revision, CI I63), subarachnoid hemorrhage (SAH I60), and intracerebral hemorrhage (ICH I61). We calculated the average annual age- and sex-standardized incidence. RESULTS: The overall incidence of hospitalized stroke was 241 out of 100,000 individuals. The incidence of hospitalized stroke for the main stroke types was 8.2 cases in SAH, 29.5 in ICH, and 211 in CI per 100,000 individuals. The standardized annual stroke incidence adjusted to the 2000 World Health Organization population for overall stroke incidence of hospitalized stroke was 131 per 100,000 individuals. Standardized stroke incidence for stroke subtypes was 5.7 cases in SAH, 16.7 in ICH, and 113 in CI per 100,000 individuals. CONCLUSIONS: These studies provide an initial assessment of the burden of stroke in this part of the world. The estimates of hospitalized stroke in the CR and Eastern Europe suggest that ICH is about three times more common than SAH, and hemorrhagic stroke makes up about 18% of strokes.

Alcohol consumption at midlife and risk of stroke during 43 years of follow-up: cohort and twin analyses.

BACKGROUND AND PURPOSE: Although alcohol-stroke association is well known, the age-varying effect of alcohol drinking at midlife on subsequent stroke risk across older adulthood has not been examined. The effect of genetic/early-life factors is also unknown. We used cohort and twin analyses of data with 43 years of follow-up for stroke incidence to help address these gaps. METHODS: All 11 644 members of the population-based Swedish Twin Registry born 1886 to 1925 with alcohol data aged ≤60 years were included. The interaction of midlife alcohol consumption by age at stroke was evaluated in Cox-regression and analyses of monozygotic twins were used. Covariates were baseline age, sex, cardiovascular diseases, diabetes mellitus, stress reactivity, depression, body mass index, smoking, and exercise. RESULTS: Altogether 29% participants developed stroke. Compared with very-light drinkers (<0.5 drink/d), heavy drinkers (>2 drinks/d) had greater risk of stroke (hazard ratio, 1.34; P=0.02) and the effect for nondrinkers approached significance (hazard ratio, 1.11; P=0.08). Age increased stroke risk for nondrinkers (P=0.012) and decreased it for heavy drinkers (P=0.040). Midlife heavy drinkers were at high risk from baseline until the age of 75 years when hypertension and diabetes mellitus grew to being the more relevant risk factors. In analyses of monozygotic twin-pairs, heavy drinking shortened time to stroke by 5 years (P=0.04). CONCLUSIONS: Stroke-risk associated with heavy drinking (>2 drinks/d) in midlife seems to predominate over well-known risk factors, hypertension and diabetes, until the age of ≈75 years and may shorten time to stroke by 5 years above and beyond covariates and genetic/early-life factors. Alcohol consumption should be considered an age-varying risk factor for stroke.

Safety of Statin Pretreatment in Intravenous Thrombolysis for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: A recent meta-analysis investigating the association between statins and early outcomes in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) indicated that prestroke statin treatment was associated with increased risk of 90-day mortality and symptomatic intracranial hemorrhage. We investigated the potential association of statin pretreatment with early outcomes in a large, international registry of AIS patients treated with IVT. METHODS: We analyzed prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST) registry on consecutive AIS patients treated with IVT during an 8-year period. Early clinical recovery within 24 hours was defined as reduction in baseline National Institutes of Health Stroke Scale score of ≥10 points. Favorable functional outcome at 3 months was defined as modified Rankin Scale scores of 0 to 1. Symptomatic intracranial hemorrhage was diagnosed using National Institute of Neurological Disorders and Stroke, European-Australasian Acute Stroke Study-II and SITS definitions. RESULTS: A total of 1660 AIS patients treated with IVT fulfilled our inclusion criteria. Patients with statin pretreatment (23%) had higher baseline stroke severity compared with cases who had not received any statin at symptom onset. After adjusting for potential confounders, statin pretreatment was not associated with a higher likelihood of symptomatic intracranial hemorrhage defined by any of the 3 definitions. Statin pretreatment was not related to 3-month all-cause mortality (odds ratio, 0.92; 95% confidence interval, 0.57-1.49; P=0.741) or 3-month favorable functional outcome (odds ratio, 0.81; 95% confidence interval, 0.52-1.27; P=0.364). Statin pretreatment was independently associated with a higher odds of early clinical recovery (odds ratio, 1.91; 95% confidence interval, 1.25-2.92; P=0.003). CONCLUSIONS: Statin pretreatment seems not to be associated with adverse outcomes in AIS patients treated with IVT. The effect of statin pretreatment on early functional outcomes in thrombolysed AIS patients deserves further investigation.

Earlier identification of risks: cumulative probability analysis of time to safety alerts for therapeutic monoclonal antibodies.

OBJECTIVE: Previous analysis of US FDA Medwatch safety alerts for monoclonal antibody therapeutics demonstrated that premarketing clinical trials can predict more than half of safety concerns. We expanded this analysis to assess whether the predictable alerts are detected sooner than the unpredictable alerts. METHODS: Times to alert were compared using Mann-Whitney test, Kolmogorov-Smirnov test, and using curves displaying cumulative frequencies of alerts over time. RESULTS: Until December 31, 2013 inclusive, 76 Medwatch alerts for therapeutic monoclonal antibodies were reported: 43 predictable vs. 33 unpredictable. Predictable alerts were reported at a median (IQR) of 41 (19-77) months after approval vs. 53 (23-73) months for the unpredictable alerts. The mean (SE) was 52.07 (6.69) months and 55.91 (7.06) months for the predictable and unpredictable, respectively. Although the difference of 12 months between medians of time to alert was observed, the difference was not demonstrated as significant. Cumulative frequency curves show that predictable alerts were detected sooner until month 73 after approval, when ~ 80% of alerts were detected. Immunological reactions (such as infusion reactions, anaphylaxis, and reactions due to antibodies) were identified early; all 12 such alerts were released before the curves of cumulative frequencies cross at month 73. On the other hand, reactions occurring after the curves cross are predominantly late-occurring cancers and opportunistic infections. CONCLUSIONS: The results imply that focus on predictable reactions defined as potential risks may play a role in early detection of important safety concerns.

Validation of Stroke Diagnosis in the National Registry of Hospitalized Patients in the Czech Republic.

BACKGROUND: Stroke is a common cause of mortality and morbidity in Eastern Europe. However, detailed epidemiological data are not available. The National Registry of Hospitalized Patients (NRHOSP) is a nationwide registry of prospectively collected data regarding each hospitalization in the Czech Republic since 1998. As a first step in the evaluation of stroke epidemiology in the Czech Republic, we validated stroke cases in NRHOSP. METHODS: Any hospital in the Czech Republic with a sufficient number of cases was included. We randomly selected 10 of all 72 hospitals and then 50 patients from each hospital in 2011 stratified according to stroke diagnosis (International Classification of Diseases Tenth Revision [ICD-10] cerebrovascular codes I60, I61, I63, I64, and G45). Discharge summaries from hospitalization were reviewed independently by 2 reviewers and compared with NRHOSP for accuracy of discharge diagnosis. Any disagreements were adjudicated by a third reviewer. RESULTS: Of 500 requested discharge summaries, 484 (97%) were available. Validators confirmed diagnosis in NRHOSP as follows: transient ischemic attack (TIA) or any stroke type in 82% (95% confidence interval [CI], 79-86), any stroke type in 85% (95% CI, 81-88), I63/cerebral infarction in 82% (95% CI, 74-89), I60/subarachnoid hemorrhage in 91% (95% CI, 85-97), I61/intracerebral hemorrhage in 91% (95% CI, 85-96), and G45/TIA in 49% (95% CI, 39-58). The most important reason for disagreement was use of I64/stroke, not specified for patients with I63. CONCLUSIONS: The accuracy of coding of the stroke ICD-10 codes for subarachnoid hemorrhage (I60) and intracerebral hemorrhage (I61) included in a Czech Republic national registry was high. The accuracy of coding for I63/cerebral infarction was somewhat lower than for ICH and SAH.

Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study.

OBJECTIVE: Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation. DESIGN: Multicenter, double-masked, randomized, placebo-controlled phase III study. PARTICIPANTS: Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 µg/day/eye) or placebo twice daily for 90 days and were followed up to day 180. MAIN OUTCOME MEASURES: The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL. RESULTS: Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related. CONCLUSIONS: This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.

Factors influencing door-to-imaging time: analysis of the safe implementation of treatments in Stroke-EAST registry.

BACKGROUND: Brain imaging is logistically the most difficult step before thrombolysis. To improve door-to-needle time (DNT), it is important to understand if (1) longer door-to-imaging time (DIT) results in longer DNT, (2) hospitals have different DIT performances, and (3) patient and hospital characteristics predict DIT. METHODS: Prospectively collected data in the Safe Implementation of Treatments in Stroke-EAST (SITS-EAST) registry from Central/Eastern European countries between 2008 and 2011 were analyzed. Hospital characteristics were obtained by questionnaire from each center. Patient- and hospital-level predictors of DIT of 25 minutes or less were identified by the method of generalized estimating equations. RESULTS: Altogether 6 of 9 SITS-EAST countries participated with 4212 patients entered into the database of which 3631 (86%) had all required variables. DIT of 25 minutes or less was achieved in 2464 (68%) patients (range, 3%-93%; median, 65%; and interquartile range, 50%-80% between centers). Patients with DIT of 25 minutes or less had shorter DNT (median, 60 minutes) than patients with DIT of more than 25 minutes (median, 86 minutes; P < .001). Four variables independently predicted DIT of 25 minutes or less: longer time from stroke onset to admission (91-180 versus 0-90 minutes; odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.8), transport time of 5 minutes or less (OR, 2.9; 95% CI, 1.7-4.7) between the place of admission and a computed tomography (CT) scanner, no or minimal neurologic deficit before stroke (OR, 1.3; 95% CI, 1.02-1.5), and diabetes mellitus (OR, .8; 95% CI, .7-.97). CONCLUSIONS: DIT should be improved in patients arriving early and late. Place of admission should allow transport time to a CT scanner under 5 minutes.

Hyperdense cerebral artery computed tomography sign is associated with stroke severity rather than stroke subtype.

BACKGROUND: The hyperdense cerebral artery sign (HCAS) on unenhanced computed tomography (CT) in acute ischemic stroke is a valuable clinical marker, but it remains unclear if HCAS reflects clot composition or stroke etiology. Therefore, variables independently associated with HCAS were identified from a large international data set of patients treated with intravenous thrombolysis. METHODS: All stroke patients undergoing intravenous thrombolysis from the Safe Implementation of Treatments in Stroke-EAST (SITS-EAST) database between February 2003 and December 2011 were analyzed. A general estimating equation model accounting for within-center clustering was used to identify factors independently associated with HCAS. RESULTS: Of all 8878 consecutive patients, 8375 patients (94%) with available information about HCAS were included in our analysis. CT revealed HCAS in 19% of patients. Median baseline National Institutes of Health Stroke Scale (NIHSS) score was 12, mean age was 67 ± 12 years, and 3592 (43%) patients were females. HCAS was independently associated with baseline NIHSS (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.10-1.12), vessel occlusion (OR, 5.02; 95% CI, 3.31-7.63), early ischemic CT changes (OR, 1.63; 95% CI, 1.31-2.04), year (OR, 1.07; 95% CI, 1.02-1.12), and age (10-year increments; OR, .90; 95% CI, .84-.96). Cardioembolic stroke was not associated with HCAS independently of baseline NIHSS. In different centers, HCAS was reported in 0%-50% of patients. CONCLUSIONS: This study illustrates significant variation in detection of HCAS among stroke centers in routine clinical practice. Accounting for within-center data clustering, stroke subtype was not independently associated with HCAS; HCAS was associated with the severity of neurologic deficit.

Factors influencing in-hospital delay in treatment with intravenous thrombolysis.

BACKGROUND AND PURPOSE: Shortening door-to-needle time (DNT) for the thrombolytic treatment of stroke can improve treatment efficacy by reducing onset-to-treatment time. The goal of our study was to explore the association between DNT and outcome and to identify factors influencing DNT to better understand why some patients are treated late. METHODS: Prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST: 9 central and eastern European countries) on all patients treated with thrombolysis between February 2003 and February 2010 were analyzed. Multiple logistic regression analysis was used to identify predictors of DNT ≤ 60 minutes. RESULTS: Altogether, 5563 patients were treated with thrombolysis within 4.5 hours of symptom onset. Of these, 2097 (38%) had DNT ≤ 60 minutes. In different centers, the proportion of patients treated with DNT ≤ 60 minutes ranged from 18% to 84% (P<0.0001). Patients with longer DNT (in 60-minute increments) had less chance of achieving a modified Rankin Scale score of 0 to 1 at 3 months (adjusted OR, 0.86; 95% CI, 0.77-0.97). DNT ≤ 60 minutes was independently predicted by younger age (in 10-year increments; OR, 0.92; 95% CI, 0.87-0.97), National Institutes of Health Stroke Scale score 7 to 24 (OR, 1.44; 95% CI, 1.2-1.7), onset-to-door time (in 10-minute increments; OR, 1.19; 95% CI, 1.17-1.22), treatment center (P<0.001), and country (P<0.001). CONCLUSIONS: Thrombolysis of patients with older age and mild or severe neurological deficit is delayed. The perception that there is sufficient time before the end of the thrombolytic window also delays treatment. It is necessary to improve adherence to guidelines and to treat patients sooner after arrival to hospital.

Blood Pressure Recovery After Dobutamine Antagonism: Partial With Landiolol, None With Esmolol.

We investigated the hemodynamic effects of 2 short-acting ß1 -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 µg/kg/min esmolol or 10 µg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of ß-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes. Landiolol reduced the dobutamine-induced heart rate and blood pressure increases better than esmolol. After discontinuation of ß-blocker administration, heart rate recovered swiftly to preinfusion values in both study arms. Systolic and diastolic blood pressure recovered partially after landiolol but showed a continued reduction after esmolol. No serious adverse events were observed. The heart rate effect is characteristic for ß-blockers, whereas the blood pressure effects are likely due to direct and indirect ß-blocker effects as well as influences on various ion channels. This may explain why landiolol that is devoid of effects on renin and sodium, calcium, and potassium channels behaves different from esmolol with respect to blood pressure recovery.

Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines.

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial.

IMPORTANCE: DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer. OBJECTIVE: To evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: The VIABLE double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical trial enrolled patients with mCRPC among 177 hospital clinics in the US and Europe between June 2014 and November 2017. Data analyses were performed from December 2019 to July 2020. INTERVENTIONS: Eligible patients were randomized (2:1) to receive DCVAC/PCa (add-on and maintenance) or placebo, both in combination with chemotherapy (docetaxel plus prednisone). The stratification was applied according to geographical region (US or non-US), prior therapy (abiraterone, enzalutamide, or neither), and Eastern Cooperative Oncology Group performance status (0-1 or 2). DCVAC/PCa or placebo was administered subcutaneously every 3 to 4 weeks (up to 15 doses). MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS), defined as the time from randomization until death due to any cause, in all randomized patients. Survival was compared using 2-sided log-rank test stratified by geographical region, prior therapy with abiraterone and/or enzalutamide, and Eastern Cooperative Oncology Group performance status. RESULTS: A total of 1182 men with mCRPC (median [range] age, 68 [46-89] years) were randomized to receive DCVAC/PCa (n = 787) or placebo (n = 395). Of these, 610 (81.8%) started DCVAC/PCa, and 376 (98.4%) started placebo. There was no difference in OS between the DCVAC/PCa and placebo groups in all randomized patients (median OS, 23.9 months [95% CI, 21.6-25.3] vs 24.3 months [95% CI, 22.6-26.0]; hazard ratio, 1.04; 95% CI, 0.90-1.21; P = .60). No differences in the secondary efficacy end points (radiological progression-free survival, time to prostate-specific antigen progression, or skeletal-related events) were observed. Treatment-emergent adverse events related to DCVAC/PCa or placebo occurred in 69 of 749 (9.2%) and 48 of 379 (12.7%) patients, respectively. The most common treatment-emergent adverse events (DCVAC/PCa [n = 749] vs placebo [n = 379]) were fatigue (271 [36.2%] vs 152 [40.1%]), alopecia (222 [29.6%] vs 130 [34.3%]), and diarrhea (206 [27.5%] vs 117 [30.9%]). CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, DCVAC/PCa combined with docetaxel plus prednisone and continued as maintenance treatment did not extend OS in patients with mCRPC and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02111577.

Autologous dendritic cell-based immunotherapy (DCVAC/LuCa) and carboplatin/paclitaxel in advanced non-small cell lung cancer: A randomized, open-label, phase I/II trial.

PURPOSE: To investigate the efficacy and safety of an active cellular immunotherapy (DCVAC/LuCa) and chemotherapy in patients with stage IV non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: SLU01 was a multicenter, open-label, parallel-group, randomized, phase I/II trial. NSCLC patients were randomized in a ratio of 1:1:1 to receive: DCVAC/LuCa and chemotherapy (carboplatin and paclitaxel; Group A); DCVAC/LuCa, chemotherapy, pegylated interferon-α2b, and hydroxychloroquine (Group B); or chemotherapy alone (Group C). DCVAC/LuCa was administered subcutaneously every 3-6 weeks (up to 15 doses). The primary endpoint was overall survival (OS). During the study, enrollment into Group B was discontinued for strategic reasons. RESULTS: Forty-five patients were randomized to Group A, 29 patients to Group B, and 38 patients to Group C. The median OS in the modified intention-to-treat (mITT) population was 3.7 months longer in Group A than in Group C (15.5 vs. 11.8 months; p = 0.0179; hazard ratio = 0.54; 95% confidence interval: 0.32-0.91). This OS effect was consistent across subgroups of the mITT population (females, males, current smokers, former smokers, and patients with non-squamous and squamous cell histology). The most common treatment-emergent adverse events of any grade reported in Groups A, B, and C, respectively, were neutropenia (50.0%, 29.6%, and 20.6%), fatigue (40.0%, 18.5%, and 20.6%), anemia (35.0%, 44.4%, and 32.4%), paresthesia (27.5%, 25.9%, and 17.6%), and alopecia (25.0%, 29.6%, and 41.2%). CONCLUSION: DCVAC/LuCa in combination with carboplatin and paclitaxel extended OS and was well tolerated.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults.

BACKGROUND: To study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry. METHODS: We conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 µg/kg/min landiolol. RESULTS: Dobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20-60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed. CONCLUSION: Landiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects. TRIAL REGISTRATION: Registration number 2010-023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.