Up-titration Of Beta-blockers Research Articles

Effectiveness of a Reminder in Improving Adherence With Outpatient Heart Failure Guideline Prescribing

Lack of guideline adherence in medication prescribing is a concern for heart failure patients with reduced ejection fraction. The purpose of this study is to evaluate the effectiveness of a provider reminder tool with decision support in prescribing for outpatients. A pre-post interventional design was used to measure prescribing and titration of class I medications with implementation of the tool in a convenience sample (N = 120) of consecutive provider-patient encounters. Compliance with renin-angiotensin-aldosterone system inhibitors, beta blockers, and hydralazine–isosorbide dinitrate improved. Compliance to mineralocorticoid receptor antagonists showed significant improvement. Uptitration of beta blockers and renin-angiotensin-aldosterone system inhibitors was achieved.

The Impact of Midodrine on Guideline-Directed Medical Therapy in Patients Admitted With Systolic Heart Failure.

Midodrine is occasionally used off-label to treat hypotension associated with advanced heart failure (HF); however, its association with changes in prescription of guideline-directed medical therapy (GDMT) is unknown. We sought to evaluate the effect of midodrine on the GDMT prescription pattern and clinical outcomes of patients with decompensated systolic HF. We retrospectively identified 114 patients admitted to our hospital in 2020 with decompensated systolic HF who were prescribed midodrine on discharge and compared them with 358 patients with decompensated systolic HF who were not prescribed midodrine. At 6 months, the midodrine group had more initiation or up-titration of beta blockers, renin-angiotensin-aldosterone system inhibitors, and sodium-glucose cotransporter-2 inhibitors compared with the nonmidodrine group. Survival at 6 months was similar between the 2 groups, but the midodrine group had more frequent rehospitalization for HF. Our findings suggest that midodrine is associated with improved GDMT in patients with decompensated HF but may be associated with worse prognosis.

Abstract 13039: A Rare Case of Anomalous Aortic Origin of Right Coronary Artery From Left Coronary Cusp Presenting With Recurrent Atypical Chest Pain

Background: The incidence of anomalous aortic origin of the right coronary artery (AAORCA) is between 0.026% and 0.25%. There is limited data regarding medical versus surgical management. We present a case of AAORCA which did not “qualify” for surgical intervention but remained symptomatic on medical management. Presentation: A 58-year-old female with paroxysmal atrial fibrillation presented for the eighth time in the past two years with recurrent atypical chest pain and lightheadedness. Vital signs and cardiac biomarkers were normal. Work-up: EKG showed normal sinus rhythm. TTE revealed EF 68%. Myocardial perfusion imaging was normal but exercise stress test showed ventricular ectopy, ventricular bigeminy, short bursts of ventricular tachycardia (VT) at peak exercise, and a 7-beat run of VT. A 30-day event monitor revealed a 17-beat run of VT at a rate of 173 bpm (Figure A). Management: Cardiac catheterization showed the dominant right coronary artery (RCA) arising from the left coronary cusp with a shared ostium to the left coronary system (Figure B-D). A coronary CT scan confirmed dominant RCA arising from left coronary cusp (Figure E) with an interarterial course (Figure F) and slit-like appearance of the proximal RCA, with a likely intramural course (Figure G).She was managed conservatively with restriction of vigorous exercise, up-titration of beta-blockers, addition of anti-anginal agents and implantation of loop recorder. Conclusion: The most updated consensus statement for AAORCA recommends surgical intervention for those with signs or symptoms of myocardial ischemia (true angina, findings on provocative testing, aborted sudden cardiac arrest or non-vagally-mediated arrhythmia).Although our patient did not “qualify” for surgical intervention, she continued to experience refractory symptoms. Hence, it is of utmost importance to consider surgical intervention in patients who have failed medical management, for improved quality of life.

379 Contemporary use of guideline directed medical therapy in dilated cardiomyopathy: therapeutic optimization and prognostic benefits

Abstract Aims Therapy with antineurohormonal drugs at target doses has a prognostic benefits in heart failure with reduced ejection fraction. Dilated cardiomyopathy (DCM) represents a particular setting where the possible benefit of target doses of antineurohormonal drugs is unexplored. Methods and results All patients enrolled from 1/1/1992 to 1/3/2020 in the Trieste Muscle Heart Disease register affected by DCM with data on the dosage of therapy available both enrollment and at follow-up visit (i.e., 6–12 month) were included. The population was divided according to the percentage of recommended dose prescribed (0–49%, 50–99%, 100%) of both renin-angiotensin system inhibitors (RASi) and beta blockers (BB). A composite of death/heart transplant/hospitalization for heart failure was considered as the primary endpoint; a composite of sudden cardiac death/major ventricular arrythmias/defibrillator intervention was evaluated as a secondary endpoint. Prognostic associations were explored with uni- and multivariate analyses, Cox regressions, Kaplan–Meier, cumulative incidence curves and propensity score matching. 826 patients were included. At baseline 789 (96%) were taking a RASi and 627 (76%) a BB. The target dose of RASi was prescribed in 29% and 36% of patients at enrolment and at follow-up visit, respectively. The percentage of patients taking the maximum recommended dose of BB was 10% at baseline and 17% after optimization. Predictors of reaching target dose for RASi were BMI < 25 kg/m2, male sex [HR: 1.798 (95% CI: 1.073–3.012), P = 0.026] and higher systolic blood pressure [HR per mmHg 1.038 (95% CI: 1.025–1.051), P < 0.001]. Target dose predictors of BB were age [HR per year 0.527 (95% CI: 0.347–0.802), P = 0.003] and highest systolic blood pressure [HR per mmHg 1.024 (95% CI: 1.013–1.035), P < 0.001]. After adjustment target dose of RASi or BB did not show a significant association with the risk of primary outcome occurrence compared to those taking less than 50% (P = 0.550 for RASi and P = 0.921 for BB). The incidence of arrhythmic events was significantly lower in patients taking 100% of recommended dose of BB compared to those taking less than 50% (P = 0.009), after adjustment for confounders. The target dose of RASi was not associated with an arrhythmic events risk change (P = 0.688). Conclusions In DCM a significant number of patients do not tolerate maximal therapy doses, mainly due to hypotension. The achievement of the target dose of RASi and BB, after adjustment for confounders had a neutral effect on the incidence of heart failure-related events. Uptitration of BB to the recommended dose has a strong protective effect on arrhythmic events.

Heart failure treatment in patients with cardiac implantable electronic devices: Opportunity for improvement.

BackgroundHeart failure and reduced ejection fraction (HFrEF) is the predominant indication for cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator (ICD) implantation. The care gap and opportunity to optimize guideline-directed medical therapy (GDMT) is unclear.ObjectiveWe sought to define uptake, eligibility, dose, and adherence to GDMT in patients with CRT/ICD and HFrEF.MethodsMEDLINE was searched from 2000 to July 2021 for major randomized trials, registries, and cohort studies evaluating GDMT in this population. Thirty-eight studies focused on medical therapy in patients with CRT/ICD devices (CRT = 23, ICD = 11, and both = 4).ResultsIn the pivotal device trials, ACEI/ARB and beta-blocker use was high (mean 94%, range 41%–99%; and 83%, range 27%–97%, respectively), but mineralocorticoid receptor antagonists were modest (mean 45%, range 32%–61%), in keeping with guidelines of that era. Similar results were found in observational registries. CRT was associated with beta-blocker uptitration, while the effects on ACEI/ARB were less consistent. For beta blockers, 57%–68% of patients were uptitrated, increasing the mean percent of target dose achieved by 24% from baseline to follow-up. In one study, adherence increased, for ACEI/ARB from 37% to 55% and beta blockers 34% to 58%. Only 1 study assessed potential eligibility at implant for sacubitril-valsartan (72%) or ivabradine (28%), and no study examined sodium-glucose cotransporter-2 inhibitors. Increased uptake, titration, and dose was associated with reduced mortality, hospitalization, and device therapies.ConclusionPatients with HFrEF and ICD/CRT are undertreated with respect to GDMT, and there is opportunity to optimize therapy to improve morbidity and mortality.

Opportunities for clinician education in the pharmacotherapy of stable heart failure

Abstract Introduction Heart failure (HF) is a commonly encountered clinical entity in the developed world, and is estimated to cost 660m euro annually to the Irish exchequer. Evidence supporting the benefit of multi disciplinary care in reduction of readmission rates has prompted the establishment of specialist HF clinics, resulting in improved medication adherence and early recognition and treatment of mild decompensation, thus averting the need for hospital admission. In contrast, the role of the hospital generalist and the general practitioner in the management of stable HF is under-emphasised despite evidence that optimal medical therapy reduces readmission and its attendant costs. The aim of this survey was to assess knowledge of pharmacotherapeutic options amongst generalists, and identify opportunities for education, in order to further optimise guideline-directed medical therapy while the patient awaits specialist input. Methods We distributed a 14 item questionnaire regarding indications for HF medications (as per ESC guidelines) to doctors in medicine and general practice throughout Ireland. Results There were 127 responses from 27 centres (117 analysed). Median years of practice was 4. Table 1 depicts the breakdown of clinicians who correctly identified HFrEF as an indication for each of the major drug classes. More than 20% of clinicians at all grades failed to identify HFrEF as an indication for beta blocker therapy. There was a higher level of knowledge amongst junior doctors in the prescription of mineralocorticoid receptor antagonists (p≤0.05) but no statistical difference in knowledge of other drug classes. Only 26% of participants who felt comfortable with initiation and up-titration of beta blockers (N=89) correctly identified an optimal target heart rate of less than 70 beats per minute. Twenty-four percent of respondents (N=28) were unaware of a specialist HF service that catered to their institution. Ninety-seven percent (N=113) felt that their practice would benefit from further education on HF pharmacotherapy. Conclusion The high prevalence of HF in Ireland and costs associated with admission for decompensation necessitates a sound knowledge of its management amongst generalists. Results of this survey suggest a need, and indeed a demand, for further education and support surrounding pharmacotherapy of stable heart failure. Funding Acknowledgement Type of funding sources: None.

July 2021 at a glance: focus on blood volume distribution, haemodynamics and adherence to therapy.

July 2021 at a glance: focus on blood volume distribution, haemodynamics and adherence to therapy.

Role of Guideline Directed Medical Therapy Doses and Optimization in Patients Hospitalized With Decompensated Systolic Heart Failure

Despite significant advances in evidence-based treatments for heart failure with reduced ejection fraction (HFrEF), the use of guideline directed medical therapy (GDMT) at recommended doses remains suboptimal. We examine the usage and modification of inpatient GDMT and its effect on outcomes in patients hospitalized with a diagnosis of acute on chronic HFrEF between 2013 and 2018. Overall use and modification of GDMT, which included heart failure appropriate beta-blockers (BB), renin-angiotensin system inhibitors (RASi) and aldosterone blockers (MRA) during the hospitalization were collected. Target dosages were based on guideline recommendations. Primary endpoints included 30-day hospitalization-free survival and 1-year survival. Among 1,655 patients, discharge use of BB, RASi, and MRA was 73.4%, 55.9% and 13.8%, respectively. Upon discharge, ≥50% target dose of BB, RASi, and MRA was used in 25.3%, 15.6%, and 13.7%, respectively. In multivariable analyses, there was a statistically significant improvement in 1-year survival and 30-day hospitalization-free survival in patients discharged on increasing number of medication classes optimized at ≥50% target dose (per extra medication, HR 0.74, 0.64-0.86, p <0.001, and HR 0.73, 0.62-0.86, p = 0.0002), respectively. Initiation and/or uptitration of BB and RASi was associated with improved 30-day hospitalization-free survival and 1-year survival, (HR 0.73 (0.57-0.92), p = 0.0087; HR 0.62 (0.46-0.82), p <0.001) for BB and (HR 0.77 (0.62-0.95), p <0.001; HR 0.62 (0.48-0.80), p <0.001) for RASi, respectively. In conclusion, inpatient optimization of GDMT in acute HFrEF is feasible and associated with improved 30-day hospitalization-free survival and 1-year survival.

Association between up-titration of medical therapy and total hospitalizations and mortality in patients with recent worsening heart failure across the ejection fraction spectrum.

The role of neurohormonal inhibition in chronic heart failure (HF) is well established. There are limited data on the effect of up-titration of renin-angiotensin inhibitors (RASi) and beta-blockers (BBs) on clinical outcomes of patients with worsening HF across the left ventricular ejection fraction (LVEF) spectrum. We analysed data from 2345 patients from BIOSTAT-CHF (80.9% LVEF <40%), who completed a 3-month up-titration period after recent worsening of HF. Patients were classified by achieved dose (% of recommended): ≥100%, 50-99%, 1-49%, and none. Recurrent event analysis using joint and shared frailty models was used to examine the association between RASi/BB dose and all-cause and HF hospitalizations. In the 21 months following up-titration, 512 patients died and 879 (37.5%) had ≥1 hospitalization. RASi up-titration was associated, incrementally, with reduced risk of all-cause hospitalization at all achieved dose levels compared to no treatment [hazard ratio (95% confidence interval): ≥100%: 0.60 (0.49-0.74), P < 0.001; 50-99%: 0.56 (0.46-0.68), P < 0.001; 1-49%: 0.71 (0.59-0.86), P < 0.001]. This association was consistent up to an LVEF of 49% (P < 0.001), and when considering only HF hospitalizations. Up-titration of BBs was associated with fewer all-cause hospitalizations only when LVEF was <40% (overall P < 0.001), but with more HF hospitalizations when LVEF was ≥50%. Up-titration of both RASi/BBs was associated with lower mortality in LVEF up to 49%. After recent worsening of HF, up-titration of RASi and BBs was associated with a better prognosis in patients with LVEF ≤49%. Up-titration of BBs was associated with a greater risk of HF hospitalization when LVEF was ≥50%.

Implication of Ivabradine in Up-titrating Beta-blocker in a Patient with Advanced Heart Failure.

Titration of beta-blockers is a gold-standard therapy in patients with heart failure and a reduced ejection fraction but is sometimes challenging to administer, given symptomatic hypotension. Ivabradine is a recently introduced selective If channel inhibitor that purely reduces the heart rate. We encountered a patient with advanced heart failure in whom a beta-blocker could not be up-titrated given his symptomatic hypotension. Following the initiation of ivabradine, an increase in blood pressure due to heart rate optimization, probably via an improvement in the cardiac output, allowed for the further up-titration of carvedilol, followed by a successful clinical course. Ivabradine might be a novel therapeutic tool to facilitate the up-titration of beta-blockers in patients with heart failure and hypotension.

Heart Rate Reduction Following Beta- Blocker Up-Titration is Associated With Patients with Heart Failure with Reduced Ejection Fraction

Introduction Lower resting heart rate (HR) is associated with favorable outcomes in patients with heart failure with reduced ejection fraction (HFrEF, ≤40%). Clinical trials supported the benefits of beta-blockers in HFrEF patients have implied that targeting a lower resting HR ( Hypothesis Greater reduction in resting HR with beta-blocker uptitration is associated with improved outcomes in patients with HFrEF. Methods We identified HFrEF patients with at-least 3 follow-up visits for purpose of beta-blocker up-titration, with serially documented resting HR that defined “hypo-responder” or “hyper-responder” if their changes were in the lowest or highest quartile, respectively. Primary outcome was composite of all-cause mortality or heart failure (HF) hospitalization. Results In our cohort of 997 patients (median age 62.7 [IQR 53, 73] years), 246 were hyper-responders (median HR decrease of 22 [IQR 17, 31] bpm, 77% achieved target HR Conclusions Greater reduction in resting HR following beta-blocker up-titration was associated with decreased risk of all-cause mortality and HF hospitalization.

Resting heart rate in ambulatory heart failure with reduced ejection fraction treated with beta‐blockers

AimsCurrent guidelines recommend beta‐blocker therapy in chronic heart failure with reduced ejection fraction (HFrEF) titrated according to tolerated target dose. The efficiency of this strategy to obtain adequate heart rate (HR) control remains unclear in clinical practice. The aim of this study was to determine, in a real‐world setting, the proportion of HFrEF patients who fail to achieve beta‐blocker target doses, whether target doses of beta‐blockers have a relationship with the adequacy in reducing resting HR over time.Methods and resultsBeta‐blocker dose and resting HR of consecutive ambulatory patients with a diagnosis of HFrEF (ejection fraction ≤ 35%) in sinus rhythm were reviewed at the first outpatient contact in the Cleveland Clinic Health System from the year 2000 to 2015. Patients who did not receive beta‐blocker therapy, have congenital heart disease and hypertrophic cardiomyopathy, were not in sinus rhythm, or have a history of heart transplant were excluded. Patients were followed up until their last known visit at the Cleveland Clinic. Median resting HR was 71 b.p.m. [inter‐quartile range (IQR) 60–84 b.p.m.] in 8041 patients (median age 65; 68% male) with 67% on carvedilol, 32% on metoprolol succinate, and 1% on bisoprolol. In 3674 subjects (56%), resting HR was ≥70 b.p.m. At final follow‐up after a median of 21 months (IQR 0.1–7.2 years), resting HR was 72 b.p.m. (IQR 60–84 b.p.m.) in the subset of patients with persistently low ejection fraction ≤ 35%. HR ≥ 70 b.p.m. was observed in 55% of this group. Beta‐blocker target dose was achieved in 19%, 5%, and 15% of those receiving carvedilol, metoprolol succinate, and bisoprolol, respectively. In the subset of patients who experienced beta‐blocker up‐titration, reduced mortality or hospitalization due to heart failure was observed in patients who experienced the lowest HR after titration.ConclusionsIn our single‐centre experience, the majority of patients with chronic HFrEF treated with beta‐blocker therapy did not achieve target doses over time, and a substantial proportion had inadequate control of resting HR. There was no relationship between achieved beta‐blocker target dose and resting HR control.

July 2020 at a glance: focus on imaging and cardiomyopathies

Data on epidemiology of cardiomyopathies are limited.1-3 Merlo et al.4 showed a reduction in mortality, heart transplantation, left ventricular (LV) assist device implantation and sudden cardiac death in the last decade, compared with the previous ones, in patients with non-ischaemic dilated cardiomyopathy (DCM). Outcomes were also dependent on specific phenotypes with the poorest in patients with chemotherapy-induced DCM and the best in those with tachycardia-induced DCM. An analysis of the Swedish Heart Failure (HF) Register of the young patients with HF, compared with the others, showed that patients aged <55 years were more likely to have DCM, obesity, congenital heart disease, and a low LV ejection fraction (LVEF). Patients aged <55 years had a five times higher mortality risk compared with control subjects with the highest risk in the youngest ones, 18-34 years old.5 Diabetes is a known risk factor for cardiovascular death in patients with a recent myocardial infarction.6 Shin et al.7 showed the independent prognostic value for HF hospitalizations or cardiovascular death of glycated haemoglobin (A1C) levels (adjusted hazard ratio 1.11, 95% confidence interval 1.01–1.21 per 1% higher A1C) and LVEF in patients with type 2 diabetes and a recent acute coronary syndrome. Cardiac magnetic resonance (CMR) has a major role in the detection and quantification of myocardial fibrosis and adipose tissue, two major determinants of the phenotype and outcomes of patients with HF and preserved ejection fraction (HFpEF).8, 9 Quarta et al.10 review the role of CMR in the management of HFpEF patients. Tayal et al.11 used CMR to evaluate LV reverse remodelling in DCM. Absolute LV contractile reserve by dobutamine stress CMR and female gender predicted LVEF increase over 12 months. Nauta et al.12 retrospectively evaluated the association between LV geometry, clinical and biomarker phenotypes, and therapeutic response in patients with chronic HF. Compared to patients with an eccentric hypertrophy pattern, those with a concentric one had a different clinical and biomarker phenotype and did not benefit from the up-titration of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Left ventricular ejection time (LVET) was an independent predictor of HF in a community-based cohort studied by echocardiography.13 Patel et al.14 explored its prognostic role in 545 HF outpatients stratified by LVEF. LVET was shorter in HF patients with reduced ejection fraction (HFrEF) vs. those with HFpEF and its longer duration was independently associated with better 1-year outcomes in HFrEF but not in HFpEF patients. Left atrial (LA) structure and function are major determinants of outcomes in patients with HF and atrial fibrillation.15, 16 LA diameter predicted 4-year mortality also in HF patients with mitral regurgitation treated by percutaneous repair.17 Impaired LA strain may contribute to reduced exercise capacity.18 Sugimoto et al.19 showed that a blunted LA strain is associated with lower stroke volume and cardiac output response to exercise and worse outcomes in HF patients. Pulmonary hypertension and right ventricular dysfunction are major prognostic markers in HF and valve disease.20-23 Santiago-Vacas et al.24 assessed the long-term trajectories of systolic pulmonary artery pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE) and TAPSE/SPAP ratio in 1557 HF patients. These parameters were independent determinants of outcomes and increasing SPAP and declining TAPSE and TAPSE/SPAP ratio in the preceding period were associated with higher mortality. Sodium–glucose co-transporter type 2 inhibitors were found to reduce HF events25, 26 and are studied in major clinical trials in HF patients.27-30 A pre-specified analysis from the Dapagliflozin And Prevention of Adverse-outcomes in HF (DAPA-HF) study showed the lack of interaction between LVEF and the beneficial effect of dapagliflozin on outcomes in HFrEF patients.31 Breast cancer therapies can lead to late-onset HF.32 A pro-inflammatory state, detected by biomarker measurements, can cause cardiac dysfunction even 10 years after treatment in breast cancer survivors.33 Heart rate is a major prognostic marker, especially in patients in sinus rhythm.34, 35 Anker et al.36 identified elevated resting heart rate as associated with increased levels of HF biomarkers and poor outcomes in treatment-naïve cancer patients.

Concentric vs. eccentric remodelling in heart failure with reduced ejection fraction: clinical characteristics, pathophysiology and response to treatment.

AimsHeart failure is traditionally classified by left ventricular ejection fraction (LVEF), rather than by left ventricular (LV) geometry, with guideline‐recommended therapies in heart failure with reduced ejection fraction (HFrEF) but not heart failure with preserved ejection fraction (HFpEF). Most patients with HFrEF have eccentric LV hypertrophy, but some have concentric LV hypertrophy. We aimed to compare clinical characteristics, biomarker patterns, and response to treatment of patients with HFrEF and eccentric vs. concentric LV hypertrophy.Methods and resultsWe performed a retrospective post‐hoc analysis including 1015 patients with HFrEF (LVEF <40%) from the multinational observational BIOSTAT‐CHF study. LV geometry was classified using two‐dimensional echocardiography. Network analysis of 92 biomarkers was used to investigate pathophysiologic pathways. Concentric LV hypertrophy was present in 142 (14%) patients, who were on average older and more likely hypertensive compared to those with eccentric LV hypertrophy. Network analysis revealed that N‐terminal pro‐B‐type natriuretic peptide was an important hub in eccentric hypertrophy, whereas in concentric hypertrophy, tumour necrosis factor receptor 1, urokinase plasminogen activator surface receptor, paraoxonase and P‐selectin were central hubs. Up‐titration of beta‐blockers was associated with a mortality benefit in HFrEF with eccentric but not concentric LV hypertrophy (P‐value for interaction ≤0.001). For angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, the hazard ratio for mortality was higher in concentric hypertrophy, but the interaction was not significant.ConclusionPatients with HFrEF with concentric hypertrophy have a clinical and biomarker phenotype that is distinctly different from those with eccentric hypertrophy. Patients with concentric hypertrophy may not experience similar benefit from up.‐titration of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers and beta‐blockers compared to patients with eccentric hypertrophy.

Beta-blocker target dosing and tolerability in a dedicated heart failure clinic in Johannesburg.

Despite the significant clinical benefits of beta-blockers in heart failure with reduced ejection fraction (HFrEF), prescription for and adherence to these agents is reported to be poor. There are few data on the use and tolerance of beta-blocker therapy in patients with HFrEF in South Africa and it is unknown whether these patients would benefit from further heart rate-lowering therapy. Data from all patients with HFrEF attending the heart failure clinic of Charlotte Maxeke Johannesburg Academic Hospital from January 2000 to December 2014 were retrospectively collected. We first determined the rates of beta-blocker intolerance in this population and then categorised the patients according to their most recent dose of beta-blocker (low, moderate or target dose) in order to identify factors associated with beta-blocker intolerance. Lastly, we used the data to identify patients who would be suitable for further treatment with heart rate-lowering therapy. Five hundred patients, with a median follow up of 58.7 months, were identified during the study period. Black South Africans constituted the majority (66.4%) and most patients had HFrEF due to hypertension (32.8%). At the last recorded clinic visit at the end of the study period, 489 patients (97.8%) were taking a beta-blocker with 59.8% prescribed a beta-blocker at target dose. Consistent with previous data, bradycardia was the commonest cause for failing to reach target beta-blocker dose. Only 61 (12%) patients were on no (n = 11) or low (n = 50) dose of beta-blocker at final clinic visit. As per current guidelines, only 10.6% (n = 53) of this cohort of patients would qualify for further treatment with heart rate-lowering therapy. In a dedicated heart failure clinic in South Africa, beta-blockers were well-tolerated in the treatment of HFrEF. The potential role of specific heart rate-lowering therapy in patients treated adequately with heart failure medication and proper up-titration of beta-blockers is relatively small.

Reduced occurrence of appropriate therapy for ventricular arrhythmias after beta-blocker uptitration following implant of a primary prevention CRT-defibrillator

Background: Absence of beta-blocker use independently predicts appropriate therapy. Following cardiac resynchronisation therapy (CRT) implant, reverse remodelling and protection against bradycardia allows for beta-blocker dose uptitration. The differential dosing effects on the occurrence of a first episode of appropriate therapy in primary prevention CRT-defibrillator (CRT-D) patients remains unstudied.Methods and Results: Changes in beta-blocker dose following CRT-D in consecutive primary prevention patients implanted between 2008 and 2015 were retrospectively studied. Beta-blocker dose was expressed as percent of target dose. Uptitration of beta-blocker dose following implant was calculated as the change in percent of target dose between implant and 6-months follow-up. Results from a prospectively maintained database of all device analysis were used to determine the occurrence of appropriate therapy. A total of 162 patients (68 ± 8 years) were studied. One hundred and ten (68%) patients underwent uptitration (mean 47 ± 19% in target dose) and 52 (32%) remained on a stable beta-blocker dose. During 37 ± 22 months follow-up, the cumulative percent of appropriate therapy was 31% in patient receiving no-uptitration versus 10% in the uptitrated patients (p < 0.001). After correction for known predictors of appropriate therapy, uptitration was independently associated with an OR = 0.263 (CI = 0.103–0.675; p = 0.001) for the occurrence of appropriate therapy. Every 1%-increase in target dose for beta-blocker associated with a significant lower risk for appropriate therapy, OR = 0.982 (CI = 0.965–0.999; p = 0.042).Conclusion: Following implantation of a primary prevention CRT-D, uptitration of beta-blockers associated with a reduced occurrence of a first episode of appropriate therapy for ventricular arrhythmias. An inverse dose–response effect was seen between beta-blocker dose and appropriate therapy.

Prognostic significance of changes in heart rate following uptitration of beta-blockers in patients with sub-optimally treated heart failure with reduced ejection fraction in sinus rhythm versus atrial fibrillation

BackgroundIn patients with heart failure with reduced ejection fraction (HFrEF) on sub-optimal doses of beta-blockers, it is conceivable that changes in heart rate following treatment intensification might be important regardless of underlying heart rhythm. We aimed to compare the prognostic significance of both achieved heart rate and change in heart rate following beta-blocker uptitration in patients with HFrEF either in sinus rhythm (SR) or atrial fibrillation (AF).MethodsWe performed a post hoc analysis of the BIOSTAT-CHF study. We evaluated 1548 patients with HFrEF (mean age 67 years, 35% AF). Median follow-up was 21 months. Patients were evaluated at baseline and at 9 months. The combined primary outcome was all-cause mortality and heart failure hospitalisation stratified by heart rhythm and heart rate at baseline.ResultsDespite similar changes in heart rate and beta-blocker dose, a decrease in heart rate at 9 months was associated with reduced incidence of the primary outcome in both SR and AF patients [HR per 10 bpm decrease—SR: 0.83 (0.75–0.91), p < 0.001; AF: 0.89 (0.81–0.98), p = 0.018], whereas the relationship was less strong for achieved heart rate in AF [HR per 10 bpm higher—SR: 1.26 (1.10–1.46), p = 0.001; AF: 1.08 (0.94–1.23), p = 0.18]. Achieved heart rate at 9 months was only prognostically significant in AF patients with high baseline heart rates (p for interaction 0.017 vs. low).ConclusionsFollowing beta-blocker uptitration, both achieved and change in heart rate were prognostically significant regardless of starting heart rate in SR, however, they were only significant in AF patients with high baseline heart rate.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Efficacy of Ivabradine in Combination with Beta-Blockers Versus Uptitration of Beta-Blockers in Patients with Stable Angina (CONTROL-2 Study).

IntroductionHeart rate (HR) reduction is an integral part of antianginal therapy, but many patients do not reach the guideline-recommended target of less than 60 bpm despite high use of beta-blockers (BB). Failure to uptitrate BB doses may be partly to blame. To explore other options for lowering HR and improving angina control, CONTROL-2 was initiated to compare the efficacy and tolerability of the combination of BBs with ivabradine versus uptitration of BBs to maximal tolerated dose, in patients with stable angina.MethodsThis multicenter, open, randomized study included 1104 patients with Canadian Cardiovascular Society (CCS) class II or III stable angina, in sinus rhythm, and on background stable treatment with non-maximal recommended doses of BBs. Consecutive patients were allocated to ivabradine + BB or BB uptitration in a 4:1 ratio.ResultsAt the end of the study (week 16), addition of ivabradine to BB treatment and BB uptitration resulted in reduction in HR (61 ± 6 vs. 63 ± 8 bpm; p = 0.001). At week 16, significantly more patients on ivabradine + BB were in CCS class I than with BB uptitration (37.1% vs. 28%; p = 0.017) and significantly more patients were angina-free (50.6% vs. 34.2%; p < 0.001). Patient health status based on the visual analogue scale (VAS) was also better in the ivabradine + BB group. Adverse events (AEs) were significantly more common with BB uptitration than with the ivabradine + BB combination (18.4% vs. 9.4%, p < 0.001).ConclusionIn patients with stable angina, combination therapy with ivabradine + BB demonstrated good tolerability, safety, and more pronounced clinical improvement, compared to BB uptitration.Trial RegistrationISRCTN30654443.FundingServier.

Heart rate as a prognostic marker and therapeutic target in acute and chronic heart failure

Since increased heart rate (HR) is associated with higher mortality in several cardiac disorders, HR is considered not only a physiological indicator but also a prognostic and biological marker. In heart failure (HF), it represents a therapeutic target in chronic phase. The use or up-titration of beta-blockers, a milestone in HF with reduced left ventricular ejection fraction (LVEF) treatment, is at times limited by patients' hemodynamic profile or intolerance. Ivabradine, a HR-lowering drug inhibiting the f-current in pacemaker cells, has been shown to improve outcome in patients with chronic HF, in sinus rhythm with increased HR beyond beta-blocker therapy. The rationale for this review is to update the role of HR as a prognostic biomarker and a potential therapeutic target in other scenarios than chronic HF; namely, in patients with coexisting atrial fibrillation (AF), in HF with preserved LVEF (HFpEF), in acute HF, and in patients discharged after an episode of acute HF. Preliminary studies and case reports that evaluated the use of ivabradine in the setting of acute HF will be summarized. Recent results of HR reduction in the setting of HFpEF with ivabradine will be presented. Finally, data from large registries and trials that evaluated the prognostic impact of HR in patients with acute HF and sinus rhythm or AF will be reviewed, showing that only patients in sinus rhythm may benefit from HR reduction.