Health equity in heart failure.

The treatment of heart failure (HF) with reduced ejection fraction (HFrEF) has substantially developed over the past decades. More than ever before, the application of appropriate evidence-based medical therapy for HFrEF is associated with remarkable improvements in survival, noteworthy increases in quality of life, and a marked reduction in symptomatic HF sufficient to warrant hospitalization. These enhanced clinical outcomes are driven by the "four pillars" of HF therapy: 1) evidence-based beta blockers, 2) Renin-angiotensin-aldosterone system inhibitors (angiotensin-converting enzyme inhibitors /angiotensin II receptor blockers or angiotensin receptor-neprilysin inhibitors, 3) mineralocorticoid receptor antagonists, and most recently, 4) sodium-glucose cotransporter-2 inhibitors. Despite robust evidence from well-conducted randomized clinical trials, guideline-directed medical therapies with established cardiovascular benefits remain significantly underutilized in clinical practice, particularly among under-represented minority populations. This phenomenon has led to class 1 level recommendations from the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guidelines to address HF disparities among vulnerable populations as follows. In this article, we highlight the difference between health equality and health equity and discuss the need to address equity in the treatment of heart failure, ensuring that the impressive progress made in the treatment of HFrEF is equally beneficial to all individuals. We discuss strategies to reduce and ultimately eliminate disparities in the determinants of health that particularly affect marginalized groups, including the socioeconomic determinants and racism as a threat to public health. Finally, we discuss and propose a combination of the four pillars of ethics with the four pillars of GDMT to optimize and personalize treatment of all patients with HFrEF, to achieve true equity in the treatment of HF.

Relationship Between Medical Therapy, Long-Term Care Insurance, and Comorbidity in Elderly Patients With Heart Failure With Systolic Dysfunction.

BACKGROUND: Although guideline-directed medical therapy (GDMT), including ß-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), improves survival and quality of life, most patients with heart failure with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction are treated with inadequate medications. We investigated the prescription patterns of GDMT in elderly patients with HFrEF and HFmrEF and their characteristics, including the certification of long-term care insurance (LTCI), which represents frailty and disability.Methods and Results: This retrospective cross-sectional study analyzed 1,296 elderly patients with symptomatic HFrEF and HFmrEF with diuretic use (median age 78 years; 63.8% male; median left ventricular ejection fraction 40%). Prescription rates of GDMT were inadequate (ACEi, ARBs, ß-blockers, and MRAs: 27.0%, 30.1%, 54.1%, and 41.9%, respectively). LTCI certification was independently associated with reduced prescription of all medications (ACEi/ARB: odds ratio [OR] 0.591, 95% confidence interval [CI] 0.449-0.778, P=0.001; ß-blockers: OR 0.698, 95% CI 0.529-0.920, P<0.001; MRAs: OR 0.743, 95% CI 0.560-0.985, P=0.052). Patients with LTCI certification also had a high prevalence of polypharmacy and prescription of diuretics. CONCLUSIONS: Vulnerable patients with LTCI may be an explanation for the challenges in implementing GDMT, and communicating is required for favorable heart failure care in this population.

In Situ Gelling Electrospun Ocular Films Sustain the Intraocular Pressure-Lowering Effect of Timolol Maleate: In Vitro, Ex Vivo, and Pharmacodynamic Assessment.

Most common intraocular pressure (IOP) reduction regimens for the management of glaucoma include the topical use of eye drops, a dosage form that is associated with short residence time at the site of action, increased dosing frequency, and reduced patient compliance. In situ gelling nanofiber films comprising poly(vinyl alcohol) and Poloxamer 407 were fabricated via electrospinning for the ocular delivery of timolol maleate (TM), aiming to sustain the IOP-lowering effect of the ß-blocker, compared to conventional eye drops. The electrospinning process was optimized, and the physicochemical properties of the developed formulations were thoroughly investigated. The fiber diameters of the drug-loaded films ranged between 123 and 145 nm and the drug content between 5.85 and 7.83% w/w. Total in vitro drug release from the ocular films was attained within 15 min following first-order kinetics, showing higher apparent permeability (Papp) values across porcine corneas compared to the drug's solution. The fabricated films did not induce any ocular irritation as evidenced by both the hen's egg test on chorioallantoic membrane and the in vivo Draize test. In vivo administration of the ocular films in rabbits induced a faster onset of action and a sustained IOP-lowering effect up to 24 h compared to TM solution, suggesting that the proposed ocular films are promising systems for the sustained topical delivery of TM.

Acute effect of propranolol on resting energy expenditure in hyperthyroid patients.

Objective: Hyperthyroidism is a common endocrine disorder which leads to higher resting energy expenditure (REE). Increased activity of brown adipose tissue (BAT) contributes to elevated REE in hyperthyroid patients. For rapid control of hyperthyroid symptoms, the non-selective ß-blocker propranolol is widely used. While, long-term treatment with propranolol reduces REE it is currently unclear whether it can also acutely diminish REE. Design: In the present prospective interventional trial we investigated the effect of propranolol on REE in hyperthyroid patients. Methods: Nineteen patients with overt primary hyperthyroidism were recruited from the endocrine outpatient clinic. REE was measured by indirect calorimetry before and after an acute dose of 80mg propranolol and during a control period, respectively. Additionally, skin temperature was recorded at eleven predefined locations during each study visit, vital signes and heart rate (HR) were measured before and after administration of propranolol. Results: Mean REE decreased slightly after acute administration of 80mg propranolol (p= 0.03) from 1639 ± 307 kcal/24h to 1594 ± 283 kcal/24h. During the control visit REE did not change significantly. HR correlated significantly with the level of free T3 (R2 = 0.38, p=0.029) free T4 (R2 = 0.39, p=0.026). HR decreased 81 ± 12 bpm to 67 ± 7.6 bpm 90 minutes after oral administration of propranolol (p<0.0001). Skin temperature did not change after propranolol intake. Conclusions: In hyperthyroid patients a single dose of propranolol reduced heart rate substantially but REE diminished only marginally probably due to reduced myocardial energy consumption. Our data speak against a relevant contribution of BAT to the higher REE in hyperthyroidism. Clinical trial registration: ClinicalTrials.gov, identifier (NCT03379181).

Beta-blocker efficacy across different cardiovascular indications: an umbrella review and meta-analytic assessment.

BACKGROUND: Beta-blockers are widely used for many cardiovascular conditions; however, their efficacy in contemporary clinical practice remains uncertain. METHODS: We performed a prospectively designed, umbrella review of meta-analyses of randomised controlled trials (RCTs) investigating the evidence of beta-blockers in the contemporary management of coronary artery disease (CAD), heart failure (HF), patients undergoing surgery or hypertension (registration: PROSPERO CRD42016038375). We searched MEDLINE, EMBASE and the Cochrane Library from inception until December 2018. Outcomes were analysed as beta-blockers versus control for all-cause mortality, myocardial infarction (MI), incident HF or stroke. Two independent investigators abstracted the data, assessed the quality of the evidence and rated the certainty of evidence. RESULTS: We identified 98 meta-analyses, including 284 unique RCTs and 1,617,523 patient-years of follow-up. In CAD, 12 meta-analyses (93 RCTs, 103,481 patients) showed that beta-blockers reduced mortality in analyses before routine reperfusion, but there was a lack of benefit in contemporary studies where ≥ 50% of patients received thrombolytics or intervention. Beta-blockers reduced incident MI at the expense of increased HF. In HF with reduced ejection fraction, 34 meta-analyses (66 RCTs, 35,383 patients) demonstrated a reduction in mortality and HF hospitalisation with beta-blockers in sinus rhythm, but not in atrial fibrillation. In patients undergoing surgery, 23 meta-analyses (89 RCTs, 19,211 patients) showed no effect of beta-blockers on mortality for cardiac surgery, but increased mortality in non-cardiac surgery. In non-cardiac surgery, beta-blockers reduced MI after surgery but increased the risk of stroke. In hypertension, 27 meta-analyses (36 RCTs, 260,549 patients) identified no benefit versus placebo, but beta-blockers were inferior to other agents for preventing mortality and stroke. CONCLUSIONS: Beta-blockers substantially reduce mortality in HF patients in sinus rhythm, but for other conditions, clinicians need to weigh up both benefit and potential risk.

Outcomes of "diabetes-friendly" vs "diabetes-unfriendly" ß-blockers in older nursing home residents with diabetes after acute myocardial infarction.

AIMS: To assess whether nursing home (NH) residents with type 2 diabetes mellitus (T2D) preferentially received "T2D-friendly" (vs "T2D-unfriendly") ß-blockers after acute myocardial infarction (AMI), and to evaluate the comparative effects of the two groups of ß-blockers. MATERIALS AND METHODS: This new-user retrospective cohort study of NH residents with AMI from May 2007 to March 2010 used national data from the Minimum Data Set and Medicare system. T2D-friendly ß-blockers were those hypothesized to increase peripheral glucose uptake through vasodilation: carvedilol, nebivolol and labetalol. Primary outcomes were hospitalizations for hypoglycaemia and hyperglycaemia in the 90 days after AMI. Secondary outcomes were functional decline, death, all-cause re-hospitalization and fracture hospitalization. We compared outcomes using binomial and multinomial logistic regression models after propensity score matching. RESULTS: Of 2855 NH residents with T2D, 29% initiated a T2D-friendly ß-blocker vs 24% of 6098 without T2D (P < 0.001). For primary outcomes among residents with T2D, T2D-friendly vs T2D-unfriendly ß-blockers were associated with a reduction in hospitalized hyperglycaemia (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.21-0.97), but unassociated with hypoglycaemia (OR 2.05, 95% CI 0.82-5.10). For secondary outcomes, T2D-friendly ß-blockers were associated with a greater rate of re-hospitalization (OR 1.26, 95% CI 1.01-1.57), but not death (OR 1.06, 95% CI 0.85-1.32), functional decline (OR 0.91, 95% CI 0.70-1.19), or fracture (OR 1.69, 95% CI 0.40-7.08). CONCLUSIONS: In older NH residents with T2D, T2D-friendly ß-blocker use was associated with a lower rate of hospitalization for hyperglycaemia, but a higher rate of all-cause re-hospitalization.

Registry-based randomised clinical trial: efficient evaluation of generic pharmacotherapies in the contemporary era.

Randomised clinical trials are the gold standard for testing the effectiveness of clinical interventions. However, increasing complexity and associated costs may limit their application in the investigation of key cardiovascular knowledge gaps such as the re-evaluation of generic pharmacotherapies. The registry-based randomised clinical trial (RRCT) leverages data sampling from nationwide quality registries to facilitate high participant inclusion rates at comparably low costs and, therefore, may offer a mechanism by which such clinical questions may be answered. To date, a number of studies have been conducted using such trial designs, but uncritical use of the RRCT design may lead to erroneous conclusions. The current review provides insights into the strengths and weaknesses of the RRCT, as well as provides an exploratory example of how a trial may be designed to test the long-term effectiveness of beta blockers in patients with myocardial infarction who have preserved left ventricular systolic function.

Dynamic tissue perfusion assessment reflects associations between antihypertensive treatment and renal cortical perfusion in patients with chronic kidney disease and hypertension.

PURPOSE: Renal cortical perfusion measured in noninvasive, dynamic ultrasonic method is connected with the hemodynamic cardiac properties and renal function. Antihypertensive drugs affect the functioning of the heart and kidneys. The aim of the study was to evaluate the effect of a chronic use of antihypertensive drugs on ultrasound parameters of renal cortical perfusion. METHODS: The study included 56 consecutive patients (49 M + 7 F, age 54.0 ± 13.3) with stable chronic kidney disease and hypertension. Color Doppler dynamic tissue perfusion measurement was used to assess renal cortical perfusion. RESULTS: Patients were treated with a mean of 2.7 ± 1.4 antihypertensive drugs, of which diuretics accounted for 25%, angiotensin-converting enzyme inhibitors (ACE-I) together with angiotensin receptor blockers (ARB) 24%, beta-blockers (BB) 23%, calcium channel blockers 16%, alpha-1 blockers (α1B) 9% and centrally acting drugs 3%. All investigated groups of drugs correlated significantly with parameters of renal perfusion. In multivariable regression analyses adjusted to age, diuretics were connected with the decrease (r = - 0.473) and ACE-I + ARB (r = 0.390) with the improvement of proximal and whole renal cortex perfusion (R2 = 0.28; p < 0.001), whereas BB (r = - 0.372) and α1B (r = - 0.280) independently correlated with worsened perfusion of renal distal cortex (R2 = 0.21, p < 0.01). CONCLUSIONS: The type of antihypertensive therapy had a significant influence on the ultrasound parameters of renal cortical perfusion. Noninvasive, ultrasonic dynamic tissue perfusion measurement method appears to be an adequate tool to assess the impact of drugs on renal cortical perfusion.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

[The benefits of carvedilol therapy in the treatment of patients with high cardiovascular risk]. / A carvedilolterápia elonyei magas cardiovascularis kockázatú betegek kezelése során.

Among the variety of cardiologic pharmacological therapy options, beta-blockers stand on a prominent position. There are several reasons for this. On one hand they have numerous indication rounds, even though professional guidelines have recently tended to de-emphasize them for treatments of hypertension without complication or comorbidity. However, in addition to hypertonic cases associated with cardiac complication, they play a fundamental role in treating heart failure and arrhythmia and the different clinical manifestations (stable angina pectoris, myocardial state) of ischemic heart disease. The decade long development of the pharmacological group made its hemodynamic effects ever more refined. On the other hand we must not neglect the fact that more and more features came to light that positively influence the outcome of cardiovascular diseases. Verification of these latter features in numerous multicentric studies showed how to achieve a beneficial effect on survivability, independent on even hemodynamic effects during beta-blocker therapy.

Management of postoperative atrial fibrillation after cardiac surgery.

PURPOSE OF REVIEW: Postoperative atrial fibrillation (POAF) occurs commonly after cardiac surgery and is associated with a number of adverse outcomes. This article will review the available evidence on the prevention and treatment of atrial fibrillation after cardiac surgery. Using this knowledge, we propose a conceptual framework on the management of patients with POAF during various phases after cardiac surgery. RECENT FINDINGS: Perioperative ß-blockade is the cornerstone in preventing POAF after cardiac surgery. Results from randomized trials do not support routine use of colchicine or corticosteroids to prevent POAF. There is no study examining the impact of rate versus rhythm control on 'hard' clinical outcomes such as mortality or stroke in the cardiac surgical population. Furthermore, there is a paucity of research on the optimal timing and choice of oral anticoagulation among POAF cardiac surgical patients who are at risk for stroke. SUMMARY: In spite of the plethora of therapies available to treat and prevent POAF in the cardiac surgical population, there is little data to address whether they can improve key clinical outcomes such as death or stroke. Guideline recommendations on rate/rhythm control and oral anticoagulation for stroke prevention in the cardiac surgical population are largely extrapolated from studies of nonsurgical atrial fibrillation patients. Further research is needed to address these key atrial fibrillation management issues specific to the cardiac surgical population.

Assessment of the potential drug-drug interaction between carvedilol and clopidogrel mediated through intestinal P-glycoprotein.

The most widely prescribed oral antiplatelet agent, clopidogrel, shows high interindividual variability resulting in an increased risk of cardiovascular events in the patients with reduced platelet inhibition. The purpose of this study was to investigate the role of the P-glycoprotein (P-gp) efflux pump in limiting the intestinal permeability of clopidogrel and the effect of a ß-blocker, namely, carvedilol, on its intestinal transport. Effective permeabilities (Peff) of clopidogrel and carvedilol were investigated in the proximal jejunum and distal ileum of rats using an in situ intestinal perfusion model. Peff values of clopidogrel and carvedilol were found to be concentration dependent with decreased Peff values at the low perfusate concentrations. Coperfusion with the P-gp inhibitors verapamil (100 µM) and carvedilol (10 µM) significantly increased the Peff of clopidogrel in the jejunum (8.31±0.20 x 10-5 and 6.98±0.75 x 10-5 vs. 3.60±0.51 x 10-5, respectively) and ileum (9.08±2.19 x 10-5 and 8.35±1.58 x 10-5 vs. 3.85±0.15 x 10-5, respectively). However, at the highest concentration tested (30 µM), clopidogrel exhibited 3 and 1.4 times higher Peff than those of metoprolol, an FDA high permeability reference standard, in the jejunum and ileum, respectively. Overall, this study indicates that the efflux function appears not to have a significant impact on the in vivo intestinal absorption of clopidogrel due to the saturation of P-gp, suggesting no clinically relevant interaction between carvedilol and clopidogrel mediated through P-gp at intestinal level.

Long-term stability, reproducibility, and statistical sensitivity of a telemetry-instrumented dog model: A 27-month longitudinal assessment.

INTRODUCTION: ICH guidelines, as well as best-practice and ethical considerations, provide strong rationale for use of telemetry-instrumented dog colonies for cardiovascular safety assessment. However, few studies have investigated the long-term stability of cardiovascular function at baseline, reproducibility in response to pharmacologic challenge, and maintenance of statistical sensitivity to define the usable life of the colony. These questions were addressed in 3 identical studies spanning 27months and were performed in the same colony of dogs. METHODS: Telemetry-instrumented dogs (n=4) received a single dose of dl-sotalol (10mg/kg, p.o.), a ß1 adrenergic and IKr blocker, or vehicle, in 3 separate studies spanning 27months. Systemic hemodynamics, cardiovascular function, and ECG parameters were monitored for 18h post-dose; plasma drug concentrations (Cp) were measured at 1, 3, 5, and 24h post-dose. RESULTS: Baseline hemodynamic/ECG values were consistent across the 27-month study with the exception of modest age-dependent decreases in heart rate and the corresponding QT-interval. dl-Sotalol elicited highly reproducible effects in each study. Reductions in heart rate after dl-sotalol treatment ranged between -22 and -32 beats/min, and slight differences in magnitude could be ascribed to variability in dl-sotalol Cp (range=3230-5087ng/mL); dl-sotalol also reduced LV-dP/dtmax 13-22%. dl-Sotalol increased the slope of the PR-RR relationship suggesting inhibition of AV-conduction. Increases in the heart-rate corrected QT-interval were not significantly different across the 3 studies and results of a power analysis demonstrated that the detection limit for QTc values was not diminished throughout the 27month period and across a range of power assumptions despite modest, age-dependent changes in heart rate. DISCUSSION: These results demonstrate the long-term stability of a telemetry dog colony as evidenced by a stability of baseline values, consistently reproducible response to pharmacologic challenge and no diminished statistical sensitivity over time.

Predicting energy expenditure from photo-plethysmographic measurements of heart rate under beta blocker therapy: Data driven personalization strategies based on mixed models.

Energy expenditure have been often estimated using computational models based on heart rate (HR) and appropriate personalization strategies to account for users cardio-respiratory characteristics. However, medications like beta blockers which are prescribed to treat several cardiac conditions have a direct influence on the cardiovascular system and may impact the relationship between HR and energy expenditure during physical activity (AEE). This study proposes to estimate AEE from HR using mixed models (MIX-REG) by introducing a novel method to personalize the prediction equation. We selected as features to represent the individual random effect in the MIX-REG model those subject characteristics which minimized both estimation error (RMSE) and between-subjects error bias variability. Data from 17 patients post-myocardial infarction were collected during a laboratory protocol. AEE was measured using indirect calorimetry and HR using an innovative wrist worn activity monitor equipped with the Philips Cardio and Motion Monitoring Module (CM3-Generation-1), which is an integrated module including a photo-plethysmographic and accelerometer sensor. The presented method showed large AEE estimation accuracy (RMSE = 1.35 kcal/min) which was comparable to that of models personalized using data from laboratory calibration protocols (HR-FLEX) and was superior to multi-linear regression and MIX-REG models trained using a stepwise features selection procedure.

Functional and histological assessment of an experimental model of Takotsubo's cardiomyopathy.

BACKGROUND: Our objectives were to characterize functional and structural features of an experimental model of Takotsubo cardiomyopathy, and its response to beta-blockers. METHODS AND RESULTS: In protocol 1, a dose-finding study: 69 rats received various doses of isoproterenol (ISO) and echocardiographic and histologic parameters were measured on days 2 to 3 or day 8. There were no dose-dependent effects and, out of 69 ISO-treated rats, 40 (58.0%) survived and 29 (42.0%) died within 24 hours. Of survivors, 30 had apical akinesis averaging 12.1 ± 1.6% of the long axis LV circumference. Out of the 40 survivors, 32.5% showed apical akinesis ≥ 10%, 42.5% showed akinesis<10% and 25% showed no apical akinesis. The basal portion of the LV was always preserved. At 24 hours, histology and ultrastructure showed necrosis, vacuolization, lipid droplets, mononuclear cell infiltration, damaged mitochondria, and edema. On day 8, apical akinesis fully resolved but histologic abnormalities were still present. In protocol 2, rats were randomized to Control; ISO100 mg/kg; propranolol+ISO; and metoprolol+ISO groups. Pretreatment with propranolol and metoprolol improved survival to 90% and 100% respectively, compared with 60% in the ISO group, but did not reduce the incidence and extent of akinesis or the structural damage. CONCLUSION: TC can be mimicked in a rat model of ISO exposure that demonstrates apical akinesis on days 2 to 3 with full recovery of systolic regional wall motion abnormality despite the presence of persistent foci of necrosis and fibrosis on day 8. Pretreatment with beta-blockers improved survival but did not affect structural and functional alterations.

Oral ß-blockade in relation to energy expenditure in clinically stable patients with liver cirrhosis: a double-blind randomized cross-over trial.

Elevated resting energy expenditure (REE) is seen in liver cirrhosis and is associated with reduced transplant-free survival. Non-selective ß-blockers reduce REE in acute hypermetabolic conditions. We examined whether non-selective ß-blockers reduce REE in patients with stable liver cirrhosis. Twenty-two stable cirrhotic patients (Child-Pugh grading: 19A, 2B, 1C) were randomized to 3-month treatment with nadolol (titrated to decrease resting pulse rate by 20%) or placebo and after a 1-month washout period crossed to the alternative treatment for a further 3 months. REE was measured by indirect calorimetry and total body protein by neutron activation analysis at the beginning and end of each 3-month period of treatment. A predicted REE was calculated for each patient based on total body protein. A measured to predicted REE ratio >1.22 indicated significantly elevated REE. The primary outcome was REE at the end of 3-month treatment with nadolol compared with placebo. Elevated REE was seen in one patient at study entry. After 3 months on placebo REE was 1506±40 (SEM) kcal/d and on nadolol, 1476±40 kcal/d, a mean reduction of 31±16 kcal/d (P=.076). Total body protein changes were not significant. Nadolol was well tolerated with no increase in the rate of adverse events. In stable cirrhotic patients, nadolol was not associated with reduction in REE. A larger, longer-term study with different eligibility criteria is required to investigate whether this treatment offers benefits additional to its use for prevention of variceal hemorrhage.

Cost effectiveness of pharmacotherapy for the prevention of migraine: a Markov model application.

BACKGROUND: There are few data about the cost effectiveness of prophylactic medications for migraine. Clinical trials have shown several preventive agents to be useful in reducing the frequency of migraine attack while having tolerable side effects. OBJECTIVE: To compare the cost effectiveness of adding preventive treatment to abortive therapy for acute migraine with abortive therapy for acute migraine alone in the primary care setting. METHODS: A Markov decision analytic model with a cycle length of 1 day, a time horizon of 365 days and three health states was used to perform an analysis comparing the cost effectiveness and utility of five treatments for migraine prophylaxis (amitriptyline 75 mg/day, topiramate 100 and 200 mg/day, timolol 20 mg/day, divalproex sodium 1000 mg/day or propranolol 160 mg/day) with treatment of acute migraine alone for the management of migraine in the primary care setting. One-way and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: The expected total annual cost for the use of preventive agents ranged from $US2932 to $US3887, compared with $US3960 for the use of abortive medications only. In the baseline analysis, use of each of the five preventive agents generated more quality-adjusted life-years (QALYs) and incurred lower costs compared with abortive medications only. Monte Carlo Simulation suggested that amitriptyline 75 mg/day was most likely to be considered a cost-effective option versus the other five therapies, followed by timolol 20 mg/day, topiramate 200 mg/day, topiramate 100 mg/day, divalproex sodium 1000 mg/day and propranolol 160 mg/day when the willingness-to-pay (WTP) for society is <$US18 000 per QALY gained. CONCLUSIONS: Preventive medications appear to be a cost-effective approach to the management of migraine in the primary care setting compared with the approach of abortive treatment only. Among those preventive agents, probabilistic sensitivity analysis suggests that, when the societal WTP is <$US18 000 per QALY gained, amitriptyline 75 mg/day is most likely to be considered a cost-effective option.

[Clinical, hemodynamic and neurohumoral effects of switching patients with chronic heart failure from not recommended -adrenoblockers to bisoprolol in ambulatory practice].

At present only bisoprolol, metoprolol succinate, nebivolol, and carvedilol are considered to be beta adrenoblockers with proven efficacy relative to course and prognosis of chronic heart failure (CHF). However in real clinical practice most patients continue to receive preparations which are not recommended for application. Therefore we have conducted this study in order to assess efficacy of switching ambulatory patients from therapy with "not recommended" beta adrenoblockers to bisoprolol which is recommended for the treatment of CHF. We recruited 35 patients with stable class II-III CHF on standard therapy which included beta adrenoblockers not recommended for the treatment of CHF. In all patients at baseline and after 6 months of therapy we assessed clinical status, quality of life with the Minnesota questionnaire and visual analog scale, performed 6 min walk test and echocardiography for evaluation of left ventricular (LV) ejection fraction (EF) and measured level of N terminal fragment of pro brain natriuretic peptide in blood serum. Switching patients from "not recommended" beta adrenoblockers to bisoprolol was associated with significant improvement of clinical status with increase of 6 min walk distance, betterment of parameters of quality of life, and significant rise of LV EF combined with lowering of mean CHF functional class (all <0.01 compared with baseline). There was no significant dynamics of NT proBNP level in the whole group but in the subgroup with NT proBNP values above median significant lowering we noted its significant lowering (<0,05). No significant association between dynamics of main clinico-laboratory parameters and decrease of heart rate was observed. Switch of patients with moderate CHF to bisoprolol from therapy with beta adrenoblockers not recommended for application in this disease was associated with improvement of quality of life, clinical status, and LV systolic function. This was combined with lowering of initially elevated NT proBNP level irrespective of changes of heart rate.