Background Beta-blocker Research Articles

Influence of a chronic beta-blocker therapy on perioperative opioid consumption – a post hoc secondary analysis

BackgroundBeta-blocker (BB) therapy plays a central role in the treatment of cardiovascular diseases. An increasing number of patients with cardiovascular diseases undergoe noncardiac surgery, where opioids are an integral part of the anesthesiological management. There is evidence to suggest that short-term intravenous BB therapy may influence perioperative opioid requirements due to an assumed cross-talk between G-protein coupled beta-adrenergic and opioid receptors. Whether chronic BB therapy could also have an influence on perioperative opioid requirements is unclear.MethodsA post hoc analysis of prospectively collected data from a multicenter observational (BioCog) study was performed. Inclusion criteria consisted of elderly patients (≥ 65 years) undergoing elective noncardiac surgery as well as total intravenous general anesthesia without the use of regional anesthesia and duration of anesthesia ≥ 60 min. Two groups were defined: patients with and without BB in their regular preopreative medication. The administered opioids were converted to their respective morphine equivalent doses. Multiple regression analysis was performed using the morphine-index to identify independent predictors.ResultsA total of 747 patients were included in the BioCog study in the study center Berlin. 106 patients fulfilled the inclusion criteria. Of these, 37 were on chronic BB. The latter were preoperatively significantly more likely to have arterial hypertension (94.6%), chronic renal failure (27%) and hyperlipoproteinemia (51.4%) compared to patients without BB. Both groups did not differ in terms of cumulative perioperative morphine equivalent dose (230.9 (BB group) vs. 214.8 mg (Non-BB group)). Predictive factors for increased morphine-index were older age, male sex, longer duration of anesthesia and surgery of the trunk. In a model with logarithmised morphine index, only gender (female) and duration of anesthesia remained predictive factors.ConclusionsChronic BB therapy was not associated with a reduced perioperative opioid consumption.Trial registrationThis study was registered at ClinicalTrials.gov (NCT02265263) on the 15.10.2014 with the principal investigator being Univ.-Prof. Dr. med. Claudia Spies.

Effect of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction treated with beta-blockers: the DELIVER trial

Abstract Background While beta-blockers are not recommended for the treatment of HFpEF according to the latest ESC and AHA/ACC/HFSA guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers might adversely influence clinical outcomes by limiting chronotropic response in HFpEF. Purpose To examine the contemporary use and implications of beta-blocker use in patients with HFmrEF or HFpEF. Methods In the DELIVER trial, a total of 6,263 patients with symptomatic HF with LVEF >40% were randomized to dapagliflozin or placebo across 20 countries. Efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF. Results Overall, beta-blockers were used in 5,177 patients (83%), with wide variation ranging from Mexico (60%) to Poland (93%). Nearly all patients taking beta-blockers had at least 1 potential indication (n = 5,106 [99%]), such as hypertension (n = 4,623 [89%]), atrial fibrillation/flutter (n= 2,969 [57%]), coronary artery disease (n= 2,744 [53%]), or previous LVEF< = 40% that has since improved (n = 991 [19%]). Beta-blocker use was not associated with a higher risk of the primary outcome in covariate-adjusted models (HR 0.68 [95% CI 0.59-0.80]; Left Panel). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR 0.82 [95% CI 0.72- 0.94]) and those not taking beta-blockers (HR 0.79 [95% CI 0.61-1.03]; P for interaction = 0.85), with similar findings for key secondary endpoints (Right Panel). Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use. Conclusions In patients with HFmrEF or HFpEF enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker, with virtually all these patients having at least 1 potential indication for use. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use.

Contemporary Use and Implications of Beta-Blockers in Patients With HFmrEF or HFpEF: The DELIVER Trial

BackgroundAlthough beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF. ObjectivesThis study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF. MethodsIn the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF. ResultsOverall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; Pinteraction = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use. ConclusionsIn patients with HFmrEF or HFpEF who were enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)

Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study

BackgroundBeta-blocker (BB) and calcium channel blocker (CCB) antihypertensive drugs are commonly used in pregnancy. However, data on their relative impact on maternal and foetal outcomes are limited. We leveraged genetic variants mimicking BB and CCB antihypertensive drugs to investigate their effects on risk of pre-eclampsia, gestational diabetes and birthweight using the Mendelian randomization paradigm.MethodsGenetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs) associated with SBP (p < 5 × 10−8) in BB and CCB drug target gene regions were selected as proxies for drug target perturbation. Genetic association estimates for the outcomes were extracted from GWASs on 4743 cases and 136,325 controls (women without a hypertensive disorder in pregnancy) for pre-eclampsia or eclampsia, 7676 cases and 130,424 controls (women without any pregnancy-related morbidity) for gestational diabetes, and 155,202 women (who have given birth at least once) for birthweight of the first child. All studies were in European ancestry populations. Mendelian randomization estimates were generated using the two-sample inverse-variance weighted model.ResultsAlthough not reaching the conventional threshold for statistical significance, genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per 10 mmHg SBP reduction 0.27, 95%CI 0.06–1.19, p = 0.08) and increased risk of gestational diabetes (OR per 10 mmHg SBP reduction 2.01, 95%CI 0.91–4.42, p = 0.08), and significantly associated with lower birthweight of first child (beta per 10 mmHg SBP reduction − 0.27, 95%CI − 0.39 to − 0.15, p = 1.90 × 10−5). Genetically-proxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR 0.62, 95%CI 0.43–0.89, p = 9.33 × 10−3), and was not associated with gestational diabetes (OR 1.05, 95% CI 0.76–1.45, p = 0.76) or changes in birthweight of first child (beta per 10 mmHg SBP reduction 0.02, 95%CI − 0.04–0.07, p = 0.54).ConclusionsWhile BB and CCB antihypertensive drugs may both be efficacious for lowering blood pressure in pregnancy, this genetic evidence suggests that BB use may lower birthweight. Conversely, CCB use may reduce risk of pre-eclampsia and eclampsia without impacting gestational diabetes risk or birthweight. These data support further study on the effects of BBs on birthweight.

Is hypoglycemia really observed in pediatric beta-blocker intoxications? A case–control study

BackgroundBeta-blocker (BB) intoxications are common in both childhood and adulthood. In the case of poisoning, bradycardia, hypotension, ventricular dysrhythmias, mental status changes, seizures, hypoglycemia, and bronchospasm may occur. Effects on the cardiovascular system are commonly seen, but hypoglycemia is not frequently observed in clinical practice. In this study, we aimed to answer the question, “Is hypoglycemia more commonly observed in BB intoxications than in other intoxications?” MethodThis was a case–control study conducted in a pediatric emergency department of a university hospital. The case group (Group 1) consisted of cases with BB poisonings and the control group (Group 2) consisted of cases with selective serotonin receptor inhibitor (SSRI) poisonings. Data were obtained from patient files. We recorded the blood glucose levels (BGLs) of all patients on admission to the emergency department and at the 1-, 6-, and 24-h follow-up. The amounts of BBs received by the cases were compared with the specific toxic doses of each drug. The data obtained were analyzed using the Statistical Package for the Social Sciences 22 (SPSS.22) program. Mean and standard deviation for numerical values and frequency for categorical data are reported; at test, chi-square test, and ANOVA tests were used for the analysis. ResultsThe study comprised 40 patients (Group 1) and 40 controls (Group 2). The mean serum BGLs of patients in Group 1 at admission and at the 1-, 6-, and 24-h follow-up were 107.2 ± 46.3 mg/dl, 86.3 ± 20.1 mg/dl, 88.6 ± 28.4 mg/dl, and 86.5 ± 23.7 mg/dl, respectively. The mean values of Group 2 cases were 100 ± 39.5 mg/dl, 92.1 ± 30 mg/dl, 91±28 mg/dl, and 127.8 ± 60.7 mg/dl, respectively, at admission and at the 1-, 6-, and 24-h follow-up (p = 0.4, p < 0.001, p = 0.7, and p < 0.001, respectively). The mean BGLs of patients who were exposed to propranolol at admission and at the 1-, 6-, and 24-h follow-up were significantly lower than those of the patients who had taken different BBs in Group 1. No linear correlation was found between the percentage of exposure to BB toxic doses and BGLs. ConclusionOur study showed that the BGLs of patients receiving BBs could be lower, but they were not at a level that would have serious consequences. Nevertheless, the BGLs of all cases of intoxication should be monitored closely.

Abstract 10201: Efficacy of Mavacamten in Patients with Symptomatic Hypertrophic Cardiomyopathy: Sub-Group Analyses by Background Beta-Blocker Use from the EXPLORER-HCM and MAVA-LTE Studies

Introduction: Mavacamten, a selective inhibitor of cardiac myosin, improved symptoms and exercise capacity (pVO 2 ) in adults with obstructive hypertrophic cardiomyopathy (oHCM) (EXPLORER-HCM; NCT03470545). Improvements in pVO 2 were observed regardless of whether patients were receiving beta-blockers (BB), but were greater in those not receiving BB. To examine whether BB lessen the effect of mavacamten on other parameters such as function, echocardiographic parameters, biomarkers and symptoms further sub-group analyses of EXPLORER-HCM and the mavacamten long-term extension (MAVA-LTE; NCT03723655) studies were conducted. Methods: In the phase 3, placebo-controlled EXPLORER-HCM trial, randomization was stratified by BB usage, and pre-specified sub-group analyses were performed. MAVA-LTE is an ongoing study evaluating long-term mavacamten dosing in patients with HCM who completed EXPLORER-HCM or MAVERICK. Sub-group analyses by BB usage for the same endpoints, if available, were performed post hoc including only patients with oHCM. Results: Results are shown in the Table. In EXPLORER-HCM, the majority of patients not taking BB received non-dihydropyridine calcium channel blockers (mavacamten [25/29 patients] or placebo [17/33]); this trend continued in MAVA-LTE. In EXPLORER-HCM, the mean change from baseline in pVO 2 was lower in the sub-group using BB (1.1 ml/kg/min) vs not using BB (2.2 ml/kg/min), while the heart rate-independent parameter, VE/VCO 2 slope (ventilatory efficiency), improved similarly in both groups (-2.4 vs -2.7). Improvements in symptoms (NYHA Class, KCCQ-CSS), LVOT gradients, LAVI, and biomarkers (NT-proBNP and cTnI) were similar between subgroups across both studies. Conclusion: In EXPLORER-HCM, the reduced effect of mavacamten on pVO2 in BB users is likely due to the effect of BB on heart rate response during exercise. Mavacamten benefits were observed across a range of clinically meaningful parameters regardless of BB use.

Beta-blocker and survival in patients with lung cancer: A meta-analysis.

Beta-blocker (BB) is suggested to have anticancer efficacy. However, the potential influence of BB use on overall survival (OS) in patients with lung cancer remains undetermined. We aimed to evaluate the above relationship in an updated meta-analysis. Observational studies comparing OS between users and non-users of BB with lung cancer were identified by search of PubMed, Embase, and Cochrane's Library. A random-effect model was used to pool the results. Ten retrospective cohort studies with 30870 patients were included. Overall, BB use was not associated with significantly improved OS in lung cancer (hazard ratio [HR] = 1.02, 95% confidence interval [CI]: 0.98 to 1.06, p = 0.33) with moderate heterogeneity (I2 = 29%). Stratified analyses showed similar results in patients with non-small cell lung cancer and small cell lung cancer, in studies with BB use before and after the diagnosis of lung cancer, and in studies with or without adjustment of smoking. Use of BB was associated with improved OS in patients with stage III lung cancer (HR = 0.91, 95% CI: 0.85 to 0.98, p = 0.02) and in patients that did not receive surgery resection (HR = 0.78, 95% CI: 0.64 to 0.96, p = 0.02), while use of non-selective BB was associated with worse OS (HR = 1.14, 95% CI: 1.01 to 1.28, p = 0.03). This meta-analysis of retrospective cohort studies does not support a significant association between BB use and improved OS in lung cancer.

Prognostic role of myocardial work in patients with heart failure and reduced ejection fraction treated by sacubitril/valsartan

Abstract Funding Acknowledgements Type of funding sources: None. Background the non-invasive assessment of myocardial work (MW) by pressure-strain loops analysis (PSL) is a relative new tool for the evaluation of myocardial performance. Sacubitril/Valsartan is a treatment for heart failure with reduced ejection fraction (HFrEF) which has a spectacular effect on the reduction of cardiovascular events (MACEs). Purposes of this study were to evaluate 1) the short and medium term effect of Sacubitril/Valsartan treatment on MW parameters; 2) the prognostic value of MW in this specific group of patients. Methods 79 patients with HFrEF (mean age: 66 ± 12 years; LV ejection fraction: 28 ± 9%) were prospectively included in the study and treated with Sacubitril/Valsartan. Echocardiographic examination was performed at baseline, and after 6- and 12-month of therapy with Sacubitril/Valsartan. Results Sacubitril/Valsartan significantly increased myocardial constructive work (CW) (1023 ± 449 vs 1424 ± 484 mmHg%, p &amp;lt; 0.0001) and myocardial work efficiency (WE) [87 (78-90) vs 90 (86-95), p &amp;lt; 0.0001]. During FU (2.6 ± 0.9 years), MACEs occurred in 13 (16%) patients. After correction for LV size, LVEF and WE, global myocardial constructive work (CW) was the only predictor of MACEs [HR 0.99 (0.99-1.00), p = 0.05]. (Table 1). A CW &amp;lt; 910 mmHg (AUC = 0.81, p &amp;lt; 0.0001, Figure 1, left panel) identified patients at particularly increase risk of MACEs [HR 11.09 (1.45-98.94), p = 0.002, log-rank test p &amp;lt; 0.0001] (Figure 2, Right panel). Conclusions in patients with HFrEF who receive a comprehensive background beta-blocker and mineral-corticoid receptor antagonist therapy, Sacubitril/Valsartan induces a significant improvement of myocardial CW and WE. In this population, the estimation of CW before the initiation of Sacubitril/Valsartan therapy allows the prediction of MACEs. Univariable analysis Multivariable analysis HR (95% CI) p-value HR (95% CI) p-value Age, per year 0.99 (0.95-1.04) 0.81 Ischemic cardiomyopathy 1.07 (0.36-3.21) 0.89 LVEDVi*, per ml/m2 1.01 (1.00-1.03) 0.03 LVESVi, per ml/m2 1.01 (1.00-1.03) 0.009 1.01 (0.99-1.02) 0.35 LVEF, per % 0.91 (0.85-0.98) 0.01 1.02 (0.93-1.12) 0.71 CW, per mmHg% 0.99 (0.99-1.00) 0.002 0.99 (0.99-1.00) 0.04 WE, per mmHg% 0.91 (0.86-0.96) 0.001 0.95 (0.88-1.02) 0.16 Predictors of MACEs at univariable and multivariable analysis Abstract Figure 1 A and B

Prognostic role of myocardial work in patients with heart failure and reduced ejection fraction treated by sacubitril/valsartan

The non-invasive assessment of myocardial work (MW) by pressure-strain loops analysis (PSL) is a relative new tool for the evaluation of myocardial performance. Sacubitril/Valsartan is a treatment for heart failure with reduced ejection fraction (HFrEF) which has a spectacular effect on the reduction of cardiovascular events (MACEs). Purposes of this study were to evaluate 1) the short and medium term effect of Sacubitril/Valsartan treatment on MW parameters; 2) the prognostic value of MW in this specific group of patients. 79 patients with HFrEF (mean age: 66 ± 12 years; LV ejection fraction: 28 ± 9%) were prospectively included in the study and treated with Sacubitril/Valsartan. Echocardiographic examination was performed at baseline, and after 6- and 12-month of therapy with Sacubitril/Valsartan. Sacubitril/Valsartan significantly increased myocardial constructive work (CW) (1023 ± 449 vs. 1424 ± 484 mmHg%, P < 0.0001) and myocardial work efficiency (WE) [87 (78–90) vs. 90 (86–95), P < 0.0001]. During FU (2.6 ± 0.9 years), MACEs occurred in 13 (16%) patients. After correction for LV size, LVEF and WE, global myocardial constructive work (CW) was the only predictor of MACEs [HR 0.99 (0.99–1.00), Fig. 1 = 0.05]. ( Table 1 ). A CW < 910 mmHg (AUC = 0.81, P < 0.0001, Fig. 1 A) identified patients at particularly increase risk of MACEs [HR 11.09 (1.45–98.94), P = 0.002, log-rank test P < 0.0001] ( Fig. 1 B). in patients with HFrEF who receive a comprehensive background beta-blocker and mineral-corticoid receptor antagonist therapy, Sacubitril/Valsartan induces a significant improvement of myocardial CW and WE. In this population, the estimation of CW before the initiation of Sacubitril/Valsartan therapy allows the prediction of MACEs.

Prognostic role of myocardial work in patients with heart failure and reduced ejection fraction treated by sacubitril/valsartan

Abstract Background The non-invasive assessment of myocardial work (MW) by pressure-strain loops analysis (PSL) is a relative new tool for the evaluation of myocardial performance. Sacubitril/Valsartan is a treatment for heart failure with reduced ejection fraction (HFrEF) which has a spectacular effect on the reduction of cardiovascular events (MACEs). Purposes of this study were to evaluate 1) the short and medium term effect of Sacubitril/Valsartan treatment on MW parameters; 2) the prognostic value of MW in this specific group of patients. Methods 79 patients with HFrEF (mean age: 66±12 years; LV ejection fraction: 28±9%) were prospectively included in the study and treated with Sacubitril/Valsartan. Echocardiographic examination was performed at baseline, and after 6- and 12-month of therapy with Sacubitril/Valsartan. Results Sacubitril/Valsartan significantly increased global myocardial constructive work (CW) (1023±449 vs 1424±484 mmHg%, p&amp;lt;0.0001) and myocardial work efficiency (WE) [87 (78–90) vs 90 (86–95), p&amp;lt;0.0001]. During FU (2.6±0.9 years), MACEs occurred in 13 (16%) patients. After correction for LV size, LVEF and WE, CW was the only predictor of MACEs (Table 1). A CW&amp;lt;910 mmHg (AUC=0.81, p&amp;lt;0.0001, Figure 1A) identified patients at particularly increase risk of MACEs [HR 11.09 (1.45–98.94), p=0.002, log-rank test p&amp;lt;0.0001] (Figure 1 B). Conclusions In patients with HFrEF who receive a comprehensive background beta-blocker and mineral-corticoid receptor antagonist therapy, Sacubitril/Valsartan induces a significant improvement of myocardial CW and WE. In this population, the estimation of CW before the initiation of Sacubitril/Valsartan therapy allows the prediction of MACEs. Funding Acknowledgement Type of funding source: None

Impact of β-blocker therapy on right ventricular function in heart failure patients with reduced ejection fraction. A prospective evaluation.

Beta-blocker (β-blocker) therapy has been shown to improve mortality and reduce hospitalizations in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Although the physiological action mechanisms of β-blockers are well described, their effects on right ventricular (RV) function have not been prospectively studied. This prospective study aimed to (a) evaluate whether β-blocker therapy impacts RV remodeling based on echo parameters and (b) determine the predictive echo factors of β-blocker therapy response. From September 2017 to September 2018, HF patients were prospectively enrolled using CIBIS criteria: Class II, III, or IV HF; left ventricular ejection fraction (LVEF) of ≤40%; hospitalized for HF within the previous 12months. Echo evaluation was performed before initiating β-blocker therapy and 3months after optimal dose adjustment. Based on previous studies, patients with (absolute) LVEF≥5% improvement were considered significant β-blocker therapy responders. Overall, 40 patients (pts) completed the study, characterized as follows by age: 70±10years; gender: 10 women; cardiomyopathy etiology: idiopathic in 24 and ischemic in 16; NYHA Class: II in 22 and III in 10; LVEF: 32±5%; and NTProBNP: 2665±2400pg/mL. The final population comprised 32 pts (79%), with eight (21%) excluded: two because of β-blocker therapy intolerance, one lost to follow-up, and five withdrew from the study. Under β-blocker therapy, several echo parameters significantly improved: LVEF from 31.7±9 to 40.5±9 (P<.0001); LV end-diastolic volume (EDV) from 154±54 to 143±45mL (P=.06); LV end-systolic volume (ESV) from 107±49 to 88±37mL (P=.0006); LV ES from 46±11 to 64±13mL (P=.008); LV end-diastolic diameter (EDD) from 57±9 to 54±6mm (P=.04); LV end-systolic diameter (ESD) from 48±10 to 44±7mm (P=.007); and right ventricular systolic pressure (RV SP) from 39±10 to 32±8mmHg (P=.0001). Significant modifications were observed in terms of RV echo parameters: right ventricular (RV) size decreased from 30±4 to 27±5mm (P=.03), while RV systolic function significantly improved based on tricuspid annular plane systolic excursion (TAPSE) (16.5±4 vs. 19±4mm; 0.0006); DTI-derived tricuspid lateral annular systolic velocity wave (S') (10±2 vs. 11.3±3cm/s; P=.03); and RIMP (Tei index) (0.5±0.1 vs 0.46±0.1; P=.04). RV 2D fractional area change (%) did not significantly differ despite a clear improvement tendency (35±6 vs. 37±4%; P=.1). No significant modifications were observed concerning LV diastolic parameters. Overall, β-blocker echo responders (n=23/32; 72%) exhibited the same left and right echo parameters. No echo variables predicted the β-blocker response. In HFrEF pts, β-blocker therapy significantly improves LV and RV systolic remodeling. Accordingly, β-blocker therapy could be applied as soon as possible in HFrEF patients with right ventricular dysfunction so as to limit RV remodeling.

Prognostic Usefulness of Myocardial Work in Patients With Heart Failure and Reduced Ejection Fraction Treated by Sacubitril/Valsartan

The noninvasive assessment of myocardial work (MW) by pressure-strain loops analysis (PSL) is a relative new tool for the evaluation of myocardial performance. Sacubitril/Valsartan is a treatment for heart failure with reduced ejection fraction (HFrEF) which has a spectacular effect on the reduction of cardiovascular events (major adverse cardiovascular events [MACEs]). This study aimed to evaluate the short- and medium-term effect of Sacubitril/Valsartan treatment on MW parameters and the prognostic value of MW in this specific group of patients. Seventy-nine patients with HFrEF (mean age: 66 ± 12 years; LV ejection fraction: 28% ± 9%) were prospectively included in the study and treated with Sacubitril/Valsartan. Echocardiographic examination was performed at baseline, and after 6- and 12-month of therapy with Sacubitril/Valsartan. Sacubitril/Valsartan significantly increased myocardial constructive work (CW) (1023 ± 449 vs 1424 ± 484 mm Hg%, p <0.0001) and myocardial work efficiency (WE) [87 (78to 90) vs 90 (86 to 95), p <0.0001]. During FU (2.6 ± 0.9 years), MACEs occurred in 13 (16%) patients. After correction for LV size, LV ejection fraction and WE, global myocardial constructive work (CW) was the only predictor of MACEs [hazard ratio [HR] 0.99 (0.99 to 1.00), p = 0.04]. A CW <910 mm Hg identified patients at particularly increase risk of MACEs [HR 11.09 (1.45 to 98.94), p = 0.002, log-rank test p <0.0001]. In conclusion, in patients with HFrEF who receive a comprehensive background beta-blocker and mineral-corticoid receptor antagonist therapy, Sacubitril/Valsartan induces a significant improvement of myocardial CW and WE. In this population, the estimation of CW before the initiation of Sacubitril/Valsartan allows the prediction of MACEs.

The Treatment Effect of an ACE-Inhibitor Based Regimen with Perindopril in Relation to Beta-Blocker use in 29,463 Patients with Vascular Disease: a Combined Analysis of Individual Data of ADVANCE, EUROPA and PROGRESS Trials

IntroductionIn everyday practice, angiotensin converting enzyme inhibitors and beta-blockers are cornerstone treatments in patients with (cardio-)vascular disease. Clear data that evaluate the effects of the combination of these agents on morbidity and mortality are lacking.MethodsIn this retrospective pooled analysis of three large perindopril outcome trials (ADVANCE, EUROPA, PROGRESS), clinical outcomes were evaluated in 29,463 patients with vascular disease. Multivariate Cox regression analyses were performed in patients randomized to a perindopril-based regimen or placebo (treatment effect), and data were stratified according to background beta-blocker treatment. The primary endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and stroke.ResultsThe cumulative incidence of the primary endpoint over mean follow-up of 4.0 years (Sd 1.0) was significantly lower in the beta-blocker/perindopril group (9.6%; 545/5700 patients) as compared to beta-blocker/placebo (11.8%; 676/5718 patients) (p < 0.01). Adding perindopril to existing beta-blocker treatment reduced the relative risk of the primary endpoint by 20% (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.71–0.90), non-fatal myocardial infarction by 23% (HR 0.77; 95% CI 0.65–0.91), and all-cause mortality by 22% (HR 0.78; 95% CI 0.68–0.88) as compared to placebo. Significant treatment benefit was not observed for stroke (HR 0.93; 95% CI 0.75–1.15). Significance was maintained for the primary endpoint and cardiovascular endpoints when data were further stratified by baseline hypertension. However, the mortality benefit was only observed in patients with hypertension with background beta-blocker use.ConclusionsThese data suggest that the beneficial cardioprotective effects of perindopril treatment are additive to the background beta-blockers use.

Abstract 12773: Dose-dependence of Beta-blocker Therapy on Subsequent Mortality in One Year Survivors After Myocardial Infarction

Background: Beta-blocker (BB) therapy after acute myocardial infarction (MI) improves survival. The benefits of long term treatment remain debated. Methods: Of 7058 patients enrolled in the OBTAIN prospective multi-center registry of patients with acute MI, follow-up BB dosing information was available in 2822 patients who survived ≥1 year. BB dose was indexed to the target BB dose used in RCTs (when available), reported as %; only BBs studied in RCTs were included in this analysis. Dosage groups were No BB (n=302), ≤12.5% (n=557), 12.6-25% (n=848), 26-50% (n=687), and &gt;50% (n=428) of target dose respectively. Vital status was obtained by chart review, Social Security Death Index, or direct contact. Adjustment for baseline differences among groups was achieved by propensity score analysis (predicted 1-year BB dose as control variable). Results: In the 5 groups, mean age was 62-64 years, with significant differences in gender, clinical, and MI characteristics. Mean ejection fractions were 47-50%. The figure shows Kaplan-Meier survival curves (unadjusted, p=0.06). Propensity score analysis showed an independent effect of BB dose on mortality (p=0.047). Compared to No BB, only the 12.6-25% dose group had a significant mortality reduction (HR 0.46, 95% CI 0.25-0.86, p=0.014). Conclusions: At one year after MI, continued BB therapy may be associated with lower mortality, but there appears to be a dose-dependence to this effect. Further studies are needed to optimize BB dosing strategies for long-term treatment after MI.

Abstract 16763: Unchanged Central Aortic Blood Pressure and Increased Myocardial Perfusion in Patients With Stable Coronary Artery Disease Receiving Ivabradine

Background: Treatment of hypertensive patients with beta-blockers reduces heart rate (HR) and increases central blood pressure, implying that the decrease in HR could explain reported increases in cardiovascular risk with beta-blocker. This analysis from a randomized, double-blind study explores whether HR reduction with the I f inhibitor ivabradine had an impact on central blood pressure and coronary perfusion. Methods and results: We included 12 normotensive patients with stable CAD, HR ≥70 bpm (sinus rhythm), and stable background beta-blocker therapy. Patients received ivabradine 7.5 mg bid or matched placebo for two 3-week periods with a crossover design and evaluation by aplanation tonometry. Treatment with ivabradine was associated with a significant reduction in resting HR after 3 weeks versus no change with placebo (-15.8±7.7 versus +0.3±5.8 bpm, p=0.0010). There was no relevant between-group difference in change in central aortic SBP (-4.0±9.6 versus +2.4±12.0 mm Hg, p=0.13) or augmentation index (-0.8±10.0% versus +0.3±7.6%, p=0.87). Treatment with ivabradine was associated with prolongation of diastolic perfusion time by 41% from baseline to 3 weeks (+215.6±105.3 versus -3.0±55.8 ms with placebo, p=0.0005) (Figure) and with a pronounced increase in an index of myocardial viability (Buckberg index, +39.3±27.6% versus -2.5±13.5% with placebo, p=0.0015). There were no safety issues during the study. Conclusion: Heart rate reduction with ivabradine does not modify central aortic blood pressure and is associated with a marked prolongation of diastolic perfusion time and an improvement in myocardial perfusion.

Long-term therapy with ivabradine in combination with beta-blockers in patients with stable angina pectoris and effect of beta-blocker background dose: results from the ADDITIONS 1-year follow-up

Objectives: The non-interventional multicenter ADDITIONS study follow-up evaluated the effectiveness, safety, and effect on quality of life (QoL) of ivabradine (iva) in combination with betablockers over one year. Methods: Resting heart rate (HR), the number of angina attacks, nitrate consumption, and concomitant medications were documented in 901 patients with chronic stable angina treated with iva twice daily in flexible doses in combination with betablockers for one year. QoL was evaluated by the EQ-5D patient questionnaire at each visit. A descriptive statistical analysis was performed. Results: 901 patients (intention to treat, mean age 65.4±10.6 years, 58% male) with chronic stable angina were analyzed. 53% of the patients had undergone a PCI or CABG before and 35% had a history of myocardial infarction. All patients received betablockers (e.g. Metoprolol 41%, mean daily dose (mdd) 109.6 mg; Bisoprolol 39%, mdd 6.9 mg; Nebivolol 13%, mdd 4.9 mg; Carvedilol 7%, mdd 28.9 mg) and concomitant standard medication. At baseline, most patients (49%) were classified CCS grade II, mean HR was 86.1±12.6 bpm, a mean of 1.7±2.2 angina attacks per week were reported, consumption of short-acting nitrates was 2.3±3.2 units per week, and the EQ-5D index was 0.66±0.28. After one year, iva (mean dose 12.53±2.84 mg per day) had reduced HR by 20.7±14.0 bpm to 65.4±8.8 bpm, the number of angina attacks by 1.4±2.5 per week (p<0.0001, Wilcoxon signed rank test), and nitrate consumption by 1.9±3.1 units per week (p<0.0001), had improved EQ-5D index by 0.18±0.27 (p<0.0001), and most patients (63%) were classified CCS grade I. HR reduction and improvement of angina symptoms by iva was similar in three subgroups defined by betablocker background dose (<50%, 50% to 99%, and ≥100% of recommended target dose): see table. View this table: Table 1 Conclusion: Over one year the combination of iva with betablockers in clinical practice not only effectively reduced HR, number of angina attacks, and nitrate consumption, but also improved QoL and CCS class in patients with stable angina. Moreover, the treatment effect of iva on HR and angina symptoms was independent of background betablocker dose.

Effects on Outcomes of Heart Rate Reduction by Ivabradine in Patients With Congestive Heart Failure: Is There an Influence of Beta-Blocker Dose?: Findings From the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) Study

This study used the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) database to assess the impact of background beta-blocker dose on response to ivabradine. In systolic heart failure, reduction in relatively high heart rates improves clinical outcomes when achieved with beta-blockers and even more so when the sinus node inhibitor ivabradine also is added. Among patients with systolic heart failure, sinus rhythm, and heart rate ≥70 beats/min on recommended background therapy, maximally tolerated beta-blocker doses were subgrouped as no beta-blocker, <25%, 25% to <50%, 50% to <100%, and 100% of European Society of Cardiology–suggested target doses. The impact of ivabradine on cardiovascular death or heart failure hospitalization (primary endpoint) was analyzed in each subgroup as time-to-first event using Cox models adjusted for heart rate. The statistical models assessed heterogeneity and trend of the treatment effect across subgroups, and an additional analysis was made adjusting for the interaction of randomized treatment with baseline heart rate. The primary endpoint and heart failure hospitalizations were significantly reduced by ivabradine in all subgroups with <50% of target beta-blocker dose, including no beta-blocker (p = 0.012). Despite an apparent trend to reduction in treatment-effect magnitude with increasing beta-blocker dose, no variation in treatment effect was seen in general heterogeneity interaction tests (p = 0.35). Across beta-blocker subgroups, treatment effect was borderline nonsignificant only for the primary endpoint (p = 0.056), and significance was further lost after adjusting for interaction between baseline heart rate and ivabradine effect (p = 0.14). The magnitude of heart rate reduction by beta-blocker plus ivabradine, rather than background beta-blocker dose, primarily determines subsequent effect on outcomes. (Effects of ivabradine on cardiovascular events in patients with moderate to severe chronic heart failure and left ventricular systolic dysfunction. A three-year randomised double-blind placebo-controlled international multicentre study; ISRCTN70429960)

Current status: heart rate as a treatable risk factor

Resting heart is an independent predictor of all-cause mortality and cardiovascular mortality. In patients with coronary artery disease and left ventricular dysfunction, the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) trial showed that a heart rate of 70 b.p.m. or greater is an independent predictor of cardiovascular events. In patients with moderate-to-severe heart failure, the SHIFT (Systolic Heart failure treatment with the If inhibitor Trial) showed also that heart rate was a predictor of cardiovascular death and heart failure hospitalisation. Heart rate plays an important role in the pathophysiology of atherosclerosis. The BEAUTIFUL trial and SHIFT provide evidence for the benefits of heart rate reduction using the new heart rate-lowering agent ivabradine, even in patients on beta-blockers. The BEAUTIFUL trial showed that in patients with a heart rate of 70 b.p.m. or more, ivabradine significantly reduced hospitalisation for fatal and non-fatal myocardial infarction or hospitalisation for heart failure and coronary revascularisation. In the SHIFT, heart rate reduction with ivabradine improved clinical outcomes. Therefore, high heart rate represents an important risk factor the effects of which can be reversed by ivabradine in patients with coronary artery disease or heart failure with or without background beta-blocker therapy.

Nisoldipine Coat-Core

Nisoldipine coat-core is an extended-release once-daily formulation of a dihydropyridine calcium antagonist effective in the treatment of chronic stable angina pectoris. With immediate-release formulations of nisoldipine, plasma drug concentrations that produce therapeutic effects result rapidly, but are not sustained and do not maintain the effects throughout a 12-hour dosage interval. In contrast, with nisoldipine coat-core, a gradual increase in plasma nisoldipine concentrations occurs over 12 hours and therapeutic concentrations are then maintained for the duration of a 24-hour dosage interval. In dosages of 10 to 60 mg once daily, nisoldipine coat-core controls symptoms of angina and improves exercise-induced signs of ischaemia in patients with stable angina. Compared with placebo, daily nisoldipine coat-core doses of > or = 20 mg provide statistically significant increases in total exercise time and time to produce angina and a trend towards an increase in the time to produce 1 mm ST segment depression, in exercise tests conducted approximately 23 hours postdose. When administered in 20 and 40 mg daily doses, nisoldipine coat-core produces improvements in exercise test parameters that are similar to those seen with amlodipine 5 or 10 mg/day or regular-release or sustained-release (SR) diltiazem 240 mg/day. The frequency of daily angina attacks and consumption of short-acting nitrates are also reduced by nisoldipine to a similar extent to that observed with these other agents. After longer term (1 year) administration of 10 to 60 mg daily, improvements in exercise test parameters are maintained, with equivalent anti-ischaemic efficacy seen in patients receiving nisoldipine coat-core alone or with background nitrate or beta-blocker therapy. Adverse events associated with nisoldipine coat-core are typical of the dihydropyridine class of calcium antagonists, with peripheral oedema and headache being most common. Nisoldipine coat-core appears to be associated with fewer deaths than placebo, notably in the DEFIANT-II (Doppler Flow and Echocardiography in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy II) study, where only 1 death occurred with nisoldipine compared with 7 in the placebo group. Nisoldipine should not be taken during phenytoin therapy. In addition, grapefruit juice should be avoided during nisoldipine therapy and nisoldipine should not be taken concurrently with high-fat meals. Thus, the coat-core formulation of nisoldipine appears to have overcome the limitations of the shorter duration of action of immediate-release nisoldipine. Nisoldipine coat-core is well tolerated and once-daily administration produces a long duration of effective anti-ischaemic relief in patients with chronic stable angina pectoris.