A phase II, Multicentre, Randomised, Double-Blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Efficacy of Amiselimod in Patients with Moderate to Severe Active Crohn's Disease.

BACKGROUND AND AIMS: Amiselimod is an oral selective S1P1 receptor modulator with potentially fewer adverse effects than fingolimod. We evaluated the safety, tolerability, and clinical efficacy of amiselimod in participants with moderate to severe active Crohn's disease. METHODS: This was a phase IIa, multicentre, randomised, double-blind, parallel group, placebo-controlled study comparing amiselimod 0.4 mg with placebo over a 14-Week treatment period. The primary endpoint of the study was the proportion of participants with clinical response (Crohn's Disease activity Index [CDAI] 100) from baseline at Week 12. RESULTS: A total of 180 patients were screened and 78 were randomised [40 to amiselimod 0.4 mg and 38 to placebo]. There was no significant difference in the proportion of patients achieving CDAI 100 at Week 12 on amiselimod 0.4 mg and on placebo [48.7% vs. 54.1%, respectively] (odds ratio [OR] [95% confidence interval]: 0.79 [0.31, 1.98]). The results from the secondary endpoint analyses supported the results of the primary endpoint analysis. Treatment with amiselimod 0.4 mg was generally well tolerated, with 71.8% of participants completing the 14-week treatment period. Seven participants had serious adverse events and four discontinued treatment in the amiselimod group. CONCLUSIONS: Amiselimod 0.4 mg for 12 weeks was not superior to placebo for the induction of clinical response [CDAI 100] in Crohn's disease. Treatment with amiselimod 0.4 mg was generally well tolerated and no new safety concerns related to amiselimod were reported in this study.

Concentration profiles and safety of topically applied betulinic acid and NVX-207 in eight healthy horses-A randomized, blinded, placebo-controlled, crossover pilot study.

The naturally occurring betulinic acid (BA) and its derivative NVX-207 show anticancer effects against equine malignant melanoma (EMM) cells and a potent permeation in isolated equine skin in vitro. The aim of the study was to determine the in vivo concentration profiles of BA and NVX-207 in equine skin and assess the compounds' local and systemic tolerability with the intent of developing a topical therapy against EMM. Eight horses were treated percutaneously in a crossover design with 1% BA, 1% NVX-207 or a placebo in a respective vehicle twice a day for seven consecutive days with a seven-day washout period between each formulation. Horses were treated at the neck and underneath the tail. Concentration profiles of the compounds were assessed by high-performance liquid chromatography in the cervical skin. Clinical and histopathological examinations and blood analyses were performed. Higher concentrations of NVX-207 were found in the skin compared to BA. Good systemic tolerability and only mild local adverse effects were observed in all three groups. This study substantiates the topical application of BA and NVX-207 in further clinical trials with horses suffering from EMM; however, penetration and permeation of the compounds may be altered in skin affected by tumors.

Ex Ante Economic Evaluation of Arg389 Genetically Targeted Treatment with Bucindolol versus Empirical Treatment with Carvedilol in NYHA III/IV Heart Failure.

OBJECTIVE: The Beta-Blocker Evaluation Survival Trial showed no survival benefit for bucindolol in New York Heart Association (NYHA) class III/IV heart failure (HF) with reduced ejection fraction, but subanalyses suggested survival benefits for non-Black subjects and Arg389 homozygotes. We conducted an ex ante economic evaluation of Arg389 targeted treatment with bucindolol versus carvidolol, complementing a previous ex ante economic evaluation of bucindolol preceded by genetic testing for the Arg389 polymorphism, in which genetic testing prevailed economically over no testing. METHODS: A decision tree analysis with an 18-month time horizon was performed to estimate the cost effectiveness/cost utility of trajectories of 100%, 50%, and 0% of patients genetically tested for Arg389 and comparing bucindolol with empirical carvedilol treatment as per prior BEST subanalyses. Incremental cost-effectiveness/cost-utility ratios (ICERs/ICURs) were estimated. RESULTS: Race-based analyses for non-White subjects at 100% testing showed a loss of (0.04) life-years and (0.03) quality-adjusted life-years (QALYs) at an incremental cost of $2185, yielding a negative ICER of ($54,625)/life-year and ICUR of ($72,833)/QALY lost; at 50%, the analyses showed a loss of (0.27) life-years and (0.16) QALYs at an incremental cost of $1843, yielding a negative ICER of ($6826)/life-year and ICUR of ($11,519)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. Arg389 homozygote analyses at 100% testing showed incremental gains of 0.02 life-years and 0.02 QALYs at an incremental cost of $378, yielding an ICER of 18,900/life-year and ICUR of $18,900/QALY gained; at 50%, the analyses showed a loss of (0.24) life-years and (0.09) QALYs at an incremental cost of $1039, yielding a negative ICER of ($4329)/life-year and ICUR of ($9336)/QALY lost; at 0%, the analyses showed a loss of (0.33) life-years and (0.30) QALYs at an incremental cost of $1459, yielding a negative ICER of ($4421)/life-year and ICUR of ($4863)/QALY lost. CONCLUSION: This independent ex ante economic evaluation suggests that genetically targeted treatment with bucindolol is unlikely to yield clinicoeconomic benefits over empirical treatment with carvedilol in NYHA III/IV HF.

Hemodynamic Safety of Continuous Infusion Labetalol Versus Esmolol Combination Therapies for Type B Aortic Dissections.

BACKGROUND: Medical management for type B aortic dissections (TBADs) require aggressive blood pressure and heart rate control to minimize further dissection extension and to restore perfusion to vital organs. Current guidelines recommend ß-blockers (BB) as first-line therapy, however do not differentiate an ideal agent for use. OBJECTIVE: This study evaluated the hemodynamic safety of continuous infusion labetalol compared to esmolol combination (EC) therapies for TBADs. METHODS: This single-center, retrospective analysis identified patients with a TBAD who received high dose continuous intravenous labetalol (HD-CIVL) or EC therapies. Patients who received HD-CIVL or EC therapies for a minimum of 2 hours, during which a minimum of 4 blood-pressure readings were recorded, were included. The primary end point was the incidence of hemodynamic instability with the use of HD-CIVL versus EC therapies. RESULTS: A total of 20 patients receiving HD-CIVL and 22 patients receiving EC therapy were included in the analysis. Ten (50%) of patients receiving HD-CIVL and 7 (32%) of patients receiving EC therapies met the clinical definition of hemodynamic instability (P = .23). Patients experiencing hemodynamic instability were all due to hypotension, with one also being due to bradycardia. Over half the patients in both groups had discontinued therapy ( P = .06) and were administered bolus fluids (P = .27). Only one patient receiving HD-CIVL required vasopressor administration while none in the EC group (P = .48). CONCLUSION: Our study suggests that HD-CIVL is associated with a nonstatistical significant higher incidence of hemodynamic instability compared to an EC regimen in TBADs. Further studies are warranted in this patient population.

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein. OBJECTIVES: To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy). DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs from the USA; one of these had clinical sites in Germany. Two studies compared emixustat to placebo while the other compared fenretinide to placebo. All assigned one study eye per participant and, combined, have a total of 821 participants with a majority white ethnicity (97.6%). All participants were diagnosed with geographic atrophy due to AMD based on validated imaging modalities. All three studies have high risk of attrition bias mainly due to ocular adverse effects of emixustat and fenretinide. We considered only one study to be adequately conducted and reported with high risk of bias in only one domain (attrition bias). We considered the other two studies to be poorly reported and to have high risk of attrition bias and reporting bias. People with geographic atrophy treated with emixustat may not experience a clinically important change in best-corrected visual acuity (BCVA) between baseline and 24 months compared to people treated with placebo (mean difference (MD) 1.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (CI) -2.34 to 6.14, low-certainty evidence). Emixustat may also result in little or no difference in loss of 15 ETDRS letters or more of BCVA compared with placebo at 24 months (16.4% versus 18%) (risk ratio (RR) 0.91, 95% CI 0.59 to 1.4, low-certainty evidence). In terms of disease progression, emixustat may result in little or no difference in the annual growth rate of geographic atrophy compared with placebo (mean difference MD 0.09 mm2/year (95% CI -0.26 to 0.44, low-certainty evidence). All three studies reported adverse events of both drugs (emixustat: moderate-certainty evidence; fenretinide: low-certainty evidence). The main adverse events were ocular in nature and associated with the mechanism of action of the drugs. Delayed dark adaptation (emixustat: 54.5%; fenretinide: 39.3%) and chromatopsia (emixustat: 22.6%; fenretinide: 25.2%) were the most common adverse events reported, and were the most prevalent reasons for study dropout in emixustat trials. These effects were dose-dependent and resolved after drug cessation. No specific systemic adverse events were considered related to emixustat; only pruritus and rash were considered to be due to fenretinide. One emixustat study reported six deaths, none deemed related to the drug. None of the included RCTs reported the other pre-specified outcomes, including proportion of participants losing 10 letters or more, and mean change in macular sensitivity. We planned to investigate progression to advanced AMD (geographic atrophy or neovascular AMD) in prevention studies, including participants with early or intermediate AMD, but we identified no such studies. Two of the included studies reported an additional outcome - incidence of choroidal neovascularisation (CNV) - that was not in our published protocol. CNV onset may be reduced in those treated with emixustat but the evidence was uncertain (risk ratio (RR) 0.67, 95% CI 0.27 to 1.65, low-certainty evidence), or fenretinide (RR 0.5, 95% CI 0.26 to 0.98, low-certainty evidence) compared to placebo. A dose-dependent relationship was observed with emixustat. AUTHORS' CONCLUSIONS: There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.

Amiselimod, a sphingosine 1-phosphate receptor-1 modulator, for systemic lupus erythematosus: A multicenter, open-label exploratory study.

OBJECTIVE: To evaluate the safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy of amiselimod, an oral selective sphingosine 1-phosphate receptor-1 modulator, in patients with systemic lupus erythematosus (SLE). METHODS: A multicenter, open-label phase Ib trial was conducted in Japan. Patients in Part 1 and Part 2-B received 0.2 mg amiselimod while those in Part 2-A received 0.4 mg amiselimod for 24 weeks. RESULTS: Seventeen subjects received 0.2 or 0.4 mg amiselimod. Amiselimod and amiselimod-P plasma concentrations increased dose-dependently. Peripheral blood lymphocyte count decreased in all patients after amiselimod treatment, with no clear dose response. There were no serious/severe adverse events (AEs) or clinically meaningful cardiac effects. Five subjects were withdrawn from amiselimod treatment following a decrease in lymphocyte count to <200/µl. Anti-double stranded-DNA antibody decreased from baseline to Week 24/end of treatment (EOT), with those in 2 subjects (22.2%) decreasing to within the normal range. Total SLE disease activity index 2000 score decreased by ≥4 at EOT in 7 of 17 subjects. CONCLUSIONS: Amiselimod was generally well tolerated. While no serious AEs or infectious AEs led to discontinuation, low lymphocyte counts of <200/µl were observed as a laboratory abnormality. Our findings suggest the potential efficacy of amiselimod for patients with SLE.Trial registration: ClinicalTrials.gov identifier: NCT02307643.

Left ventricular dysfunction after two hours of polarizing or depolarizing cardioplegic arrest in a porcine model.

INTRODUCTION: This experimental study compares myocardial function after prolonged arrest by St. Thomas' Hospital polarizing cardioplegic solution (esmolol, adenosine, Mg2+) with depolarizing (hyperkalaemic) St. Thomas' Hospital No 2, both administered as cold oxygenated blood cardioplegia. METHODS: Twenty anaesthetized pigs on tepid (34°C) cardiopulmonary bypass (CPB) were randomised to cardioplegic arrest for 120 min with antegrade, repeated, cold, oxygenated, polarizing (STH-POL) or depolarizing (STH-2) blood cardioplegia every 20 min. Cardiac function was evaluated at Baseline and 60, 150 and 240 min after weaning from CPB, using a pressure-conductance catheter and epicardial echocardiography. Regional tissue blood flow, cleaved caspase-3 activity and levels of malondialdehyde were evaluated in myocardial tissue samples. RESULTS: Preload recruitable stroke work (PRSW) was increased after polarizing compared to depolarizing cardioplegia 150 min after declamping (73.0±3.2 vs. 64.3±2.4 mmHg, p=0.047). Myocardial tissue blood flow rate was high in both groups compared to the Baseline levels and decreased significantly in the STH-POL group only, from 60 min to 150 min after declamping (p<0.005). Blood flow was significantly reduced in the STH-POL compared to the STH-2 group 240 min after declamping (p<0.05). Left ventricular mechanical efficiency, the ratio between total pressure-volume area and blood flow rate, gradually decreased after STH-2 cardioplegia and was significantly reduced compared to STH-POL cardioplegia after 150 and 240 min (p<0.05 for both). CONCLUSION: Myocardial protection for two hours of polarizing cardioplegic arrest with STH-POL in oxygenated blood is non-inferior compared to STH-2 blood cardioplegia. STH-POL cardioplegia alleviates the mismatch between myocardial function and perfusion after weaning from CPB.

Efficacy and safety of intravenous esmolol for cardiac protection in non-cardiac surgery. A systematic review and meta-analysis.

Haemodynamic instability predisposes patients to cardiac complications in non-cardiac surgery. Esmolol, a short-acting cardioselective beta-adrenergic blocker might be efficient in perioperative cardiac protection, but could affect other vital organs, such as the kidneys, and post-discharge survival. We performed a systematic review on the use of esmolol for perioperative cardiac protection. We searched PubMed, Ovid Medline and Cochrane Central Register for Controlled trials. Eligible randomized controlled studies (RCTs) reported a perioperative esmolol intervention with at least one of the primary (major cardiac or renal complications during the first 30 postoperative days) or secondary (postoperative adverse effects and all-cause mortality) outcomes. We included 196 adult patients from three RCTs. Esmolol significantly reduced postoperative myocardial ischaemia, RR =0.43 [95% confidence interval, CI: 0.21-0.88], p = .02. No association with clinically significant bradycardia and hypotension compared to patients receiving control treatment could be confirmed (RR =7.4 [95% CI: 0.29-139.81], p = .18 and RR =2.21 [95% CI: 0.34-14.36], p = .41, respectively). No differences regarding other outcomes were observed. No study reported postoperative renal outcomes. Esmolol seems promising for the prevention of perioperative myocardial ischaemia. However, the association with bradycardia and hypotension remains unclear. Randomized trials investigating the effect of ß1-selective blockade on clinically relevant outcomes and non-cardiac vital organs are warranted. Key messages Short-acting cardioselective esmolol seems efficient in the prevention of perioperative myocardial ischaemia. The possibly increased risk of bradycardia and hypotension with short-acting intravenous beta blockade could not be confirmed or refuted by available data. Future adequately powered trials investigating the effect of ß1-selective blockade on clinically relevant outcomes and non-cardiac vital organs are warranted.

The influence of esmolol on right ventricular function in early experimental endotoxic shock.

The mechanism by which heart rate (HR) control with esmolol improves hemodynamics during septic shock remains unclear. Improved right ventricular (RV) function, thereby reducing venous congestion, may play a role. We assessed the effect of HR control with esmolol during sepsis on RV function, macrocirculation, microcirculation, end-organ-perfusion, and ventricular-arterial coupling. Sepsis was induced in 10 healthy anesthetized and mechanically ventilated sheep by continuous IV administration of lipopolysaccharide (LPS). Esmolol was infused after successful resuscitation of the septic shock, to reduce HR and stopped 30-min after reaching targeted HR reduction of 30%. Venous and arterial blood gases were sampled and the small intestines' microcirculation was assessed by using a hand-held video microscope (CytoCam-IDF). Arterial and venous pressures, and cardiac output (CO) were recorded continuously. An intraventricular micromanometer was used to assess the RV function. Ventricular-arterial coupling ratio (VACR) was estimated by catheterization-derived single beat estimation. The targeted HR reduction of >30% by esmolol infusion, after controlled resuscitation of the LPS induced septic shock, led to a deteriorated RV-function and macrocirculation, while the microcirculation remained depressed. Esmolol improved VACR by decreasing the RV end-systolic pressure. Stopping esmolol showed the reversibility of these effects on the RV and the macrocirculation. In this animal model of acute severe endotoxic septic shock, early administration of esmolol decreased RV-function resulting in venous congestion and an unimproved poor microcirculation despite improved cardiac mechanical efficiency.

Two-year results from a phase 2 extension study of oral amiselimod in relapsing multiple sclerosis.

BACKGROUND: Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis. OBJECTIVE: To assess safety and efficacy of amiselimod over 96 weeks. METHODS: After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results. RESULTS: Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: 'headache', 'lymphocyte count decreased', 'nasopharyngitis' and 'MS relapse' were most common (14.7%-16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12-lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug. CONCLUSION: For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity.

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.

Efficacy of esmolol cardioplegia during hypothermic ischaemia.

OBJECTIVES: Cardioplegic arrest using a polarizing solution has been shown to have beneficial advantages for cardioprotection compared with depolarizing (potassium-based) arrest; most studies, however, have looked at normothermic ischaemia with short infusion intervals (every 10-15 min). This study examines the protective efficacy of an esmolol-based cardioplegia during hypothermic arrest, together with a prolonged infusion interval (30 min) for increased clinical feasibility. METHODS: Isolated Langendorff-perfused hearts were subjected to arrest with St Thomas' Hospital cardioplegia (STH2), or esmolol cardioplegia (single- or multidose infusion at 32°C) for 60-min, 90-min or 120-min global ischaemia at 32°C, and recovery of function (left ventricular developed pressure) measured. A further study examined the protective efficacy of multidose esmolol cardioplegia compared with hypothermia alone at temperatures of 20°C, 28°C and 32°C compared with 37°C for 120 min of ischaemia. RESULTS: Esmolol cardioplegic arrest with multidose infusion at 32°C significantly improved recovery of function (left ventricular developed pressure) compared with 32°C STH2, at each ischaemic duration (88 ± 3 vs 66 ± 3% at 60 min, 82 ± 3 vs 51 ± 3% at 90 min and 73 ± 6 vs 49 ± 4% at 120 min; P < 0.05). At various hypothermic temperatures, esmolol cardioplegia significantly improved protection compared with hypothermia alone (88 ± 4%, 88 ± 3% and 72 ± 3% vs 60 ± 3%, 30 ± 2% and 15 ± 1% at 20°C, 28°C and 32°C, respectively; P < 0.05); however, at 37°C, there was no difference in protection. Contracture during ischaemia mirrored the effects of left ventricular developed pressure recovery. CONCLUSIONS: Esmolol cardioplegia (a polarizing solution), used as a multidose infusion during hypothermia, significantly improved cardioprotection compared with the depolarizing STH2. An increased infusion interval of 30 min indicates improved clinical feasibility.

The use of guideline recommended beta-blocker therapy in primary prevention implantable cardioverter defibrillator patients: insight from Danish nationwide registers.

Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st-time primary prevention ICD and cardiac resynchronization therapy defibrillator (CRT-D) implantations in Denmark from 2007-12 (n = 2935). Use of beta-blocker, type and dose was acquired through the Danish Prescription Registry. According to guideline recommendations, we defined target daily doses as ≥50 mg carvedilol and ≥200 mg metoprolol. Prior to implantation 2427 of 2935 (83%) patients received beta-blocker therapy, with 2166 patients (89%) having initiated treatment 3 months or more prior to implantation. The majority of patients was prescribed carvedilol (52%) or metoprolol (41%). Patients on carvedilol reached target dosages more frequently than patients on metoprolol, with 39% of patients on carvedilol and 26% of patients on metoprolol at the time of implantation (P < 0.001 for all time-points). Increase in proportion of patients reaching target daily doses was observed for both carvedilol and metoprolol after ICD implantation. Carvedilol treatment was a strong predictor for being on target dose of BB at time of implant, as was treatment with angiotensin-converting enzyme inhibitors and/or spironolactone, no history of myocardial infarction, younger age and less pronounced heart failure symptoms. Conclusion: In a real-life setting of primary prevention ICD patients, 39% and 26% of patients were titrated to optimal target dose of carvedilol or metoprolol prior to implantation. A higher proportion of patients on carvedilol reached target dose, as compared with metoprolol.

THE SAFETY AND EFFICACY OF AMIODARONE AND CARVEDILOL COMBINATION IN TREATMENT OF PATIENTS WITH SEVERE CARDIAC RHYTHM DISORDERS.

Different arrhythmias are cause of sudden death in many patients with heart failure. Amiodarone is usually used for prevent this arrhythmias, but it is not drug of choice for treatment the patients with heart failure. We retrospectively analyzed 142 patients with moderate and severe heart failure and history of myocardial infarction. These patients have received amiodarone, carvedilol or combination of these two medications together with standard therapy. In our retrospective analysis, the combination therapy with Amiodarone and Carvedilol had highly significant decrease arrhythmic death compare with carvedilol and amiodarone groups. This therapy is more effective in recovering of sinus rhythm in patients with atrial fibrillation and for control ventricular arrhythmias. The effects of carvedilol on left ventricular remodeling, systolic function and symptomatic status are not affected adversly by concurrent treatment with amiodarone. Carvedilol is an effective additional therapy for the patients with chronic heart failure already receiving Amiodarone. Carvedilol can be added to Amiodarone in patients with severe ventricular rhythm disorders and increased risk of sudden death without expecting of increase adverse events (than either drug alone) or loss of clinical efficacy.

Analysis of Clinical Efficacy and Adverse Effects of ß-Blocking Agents Used Clinically for Chronic Heart Failure.

Clinical efficacy and adverse effects of the ß-blocking agents, carvedilol, bisoprolol, and metoprolol were analyzed theoretically, and then compared quantitatively, for the purpose of determining their proper use for chronic heart failure. Initially, we evaluated occupancy binding to the ß1 and ß2 receptors (Фssß1 and Фssß2) by these drugs. Thereafter, we examined the relationship between Фssß1 values and left ventricular ejection fraction (LVEF) increase rate to determine efficacy. The result showed that the efficacy with carvedilol could be attained with a lower Фssß1 value than the others. Therefore, we constructed a model under the assumption that ß-blocking agents exert both indirect action of LVEF increase through the ß1 receptor and direct action on ryanodine receptor 2. Using the model, it was suggested that these drugs have no differences in regard to the efficacy, while it was clarified theoretically that only carvedilol produces an effect that directly involves ryanodine receptor 2 at clinical doses. We also investigated decreases in heart rate and forced expiratory volume in 1 s as adverse effects of ß-blocking agents using a ternary complex model. It was indicated that carvedilol is less likely to induce a heart rate decrease. Meanwhile, it was also suggested that the risk of an asthmatic attack was higher for carvedilol at clinical doses. Our results are considered useful for selection of a proper ß-blocking agent and its administration at a reasonable dose for successful heart failure therapy.