Guideline-recommended Doses Research Articles

Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study

Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and β blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF. We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and β blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF. Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, p<0·0001) and had lower bodyweights (72 [16] kg vs 85 [18] kg, p<0·0001) and heights (162 [7] cm vs 174 [8] cm, p<0·0001) than did men, although body-mass index did not differ significantly. A similar number of men and women reached guideline-recommended target doses of ACE inhibitors or ARBs (99 [25%] vs 304 [23%], p=0·61) and β blockers (57 [14%] vs 168 [13%], p=0·54). In men, the lowest hazards of death or hospitalisation for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and β blockers, but women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels. These sex differences were still present after adjusting for clinical covariates, including age and body surface area. In the ASIAN-HF registry, similar patterns were observed for both ACE inhibitors or ARBs and β blockers, with women having approximately 30% lower risk at 50% of the recommended doses, with no further benefit at higher dose levels. This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and β blockers than men, and brings into question what the true optimal medical therapy is for women versus men. European Commission.

Safety and Tolerability of Initiating Maximum-Dose Sacubitril-Valsartan in Patients on Target Dose Renin-Angiotensin System Inhibitors.

Aim Sacubitril-valsartan has proven beneficial in heart failure with reduced ejection fraction. Guidelines recommend initiating half-dose sacubitril-valsartan before up-titration even to patients already on target dose angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). To reduce the number of titration steps needed in order to simplify for the patient as well as the clinic, we aimed to investigate the safety and tolerability of switching patients on target dose ACE inhibitors or ARBs directly to maximum-dose sacubitril-valsartan. Methods This prospective cohort study was conducted between April 2016 and November 2017. A total of 66 patients with heart failure and reduced ejection fraction already on guideline-recommended target dose ACE inhibitors or ARBs (equivalent to enalapril 10 mg twice daily) were switched to maximum-dose sacubitril-valsartan (200 mg twice daily). The patients were followed for twelve months. Results Patients had a mean age of 72 ± 10 years, mean systolic blood pressure of 121 ± 17 mmHg, and 92% were male. At 12-month follow-up, nine patients (14%) had discontinued sacubitril-valsartan, four patients (6%) had a dose reduction, and 17 patients (26%) had developed symptomatic hypotension. No angioedema occurred within the 12-month follow-up and there were no hospitalizations or emergency room visits within the first 14 days. ConclusionsSwitching directly from target dose ACE inhibitors or ARBs to maximum-dose sacubitril-valsartan was safe and generally well tolerated.

Clinical correlates and outcome associated with changes in 6-minute walking distance in patients with heart failure: findings from the BIOSTAT-CHF study.

The 6-minute walk test (6MWT) is a simple and inexpensive way of measuring exercise capacity in patients with heart failure (HF) that predicts morbidity and mortality. However, there are few reports from large multicentre cohorts assessing the predictive value of baseline and changing walk distance. In BIOSTAT-CHF, a 6MWT was performed at baseline (n = 1714) and 9 months (n = 1520). Cox proportional hazards models were used to assess the associations between 6MWT distance and the composite of HF hospitalization and/or death. Median follow-up was 21 months. The median (pct25-75 ) of the 6MWT distance at baseline was 300 m (200-388 m). Independent predictors of a shorter 6MWT distance included older age, female sex, higher heart rate, New York Heart Association class III/IV, orthopnoea, ischaemic heart disease, a previous stroke, current malignancy, and higher N-terminal pro-B-type natriuretic peptide (all P < 0.05). Patients in the lowest baseline 6MWT tertile (≤ 240 m) were less likely to receive guideline-recommended doses of disease-modifying therapies (P < 0.05). Compared to patients in the highest baseline 6MWT tertile (> 360 m), those in the lowest and middle tertiles had a worse prognosis [adjusted hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.38-2.18]. Patients with a decrease in the distance walked had a worse prognosis (adjusted HR for each 50 m decrease1.09, 95% CI 1.06-1.12). 6MWT distance was not modified by treatment up-titration nor the 6MWT improved the BIOSTAT-CHF prognostic models. The 6-minute walk test distance at baseline and a decline in walking distance were both associated with worse prognosis but did not improve the prognostic models. 6MWT distance was not modified by treatment up-titration and its use for assessing the benefits of pharmacologic treatment up-titration may be limited.

Hyperkalaemia in Heart Failure-Pathophysiology, Implications and Therapeutic Perspectives.

Hyperkalaemia is a frequent and sometimes life-threatening condition that may be associated with arrhythmia and cardiac dysfunction. Evaluating the prevalence of hyperkalaemia in patients with heart failure (HF) and potential treatments of this condition is essential for patients using renin-angiotensin-aldosterone system inhibitors or angiotensin receptor-neprilysin inhibitor and mineralocorticoid receptor antagonists, which represent the cornerstone and highly proven life-saving therapy. Novel findings from the past few years include data regarding the epidemiology, pathomechanisms, implications and novel therapeutic approaches to counteract hyperkalaemia in patients with HF. Whilst older potassium-binding agents are associated with serious adverse events, novel potassium-binding drugs are effective in lowering potassium levels and are generally well tolerated. Hyperkalaemia represents both a direct risk of cardiovascular complication and an indirect biomarker of the severity of the underlying disease such as neurohormonal activation and renal dysfunction. Novel potassium-binding drugs such as patiromer and sodium zirconium cyclosilicate may help to optimize therapy in HF and achieve guideline-recommended doses.

Prescribing patterns of evidence-based heart failure pharmacotherapy and outcomes in the ASIAN-HF registry: a cohort study.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), β blockers, and mineralocorticoid receptor antagonists (MRAs) are of proven benefit and are recommended by guidelines for management of patients with heart failure and reduced ejection fraction (HFrEF). We aimed to examine the first prospective multinational data from Asia on prescribing patterns of guideline-directed medical therapies and analyse its effect on outcomes. In the prospective multinational ASIAN-HF registry (with enrolment from 46 centres in 11 countries in Asia), we enrolled patients aged 18 years or older, with symptomatic heart failure (stage C, with at least one episode of decompensated heart failure in the past 6 months that resulted in admission to hospital or was treated in an outpatient clinic) and left ventricular systolic dysfunction (ejection fraction ≤40% on baseline echocardiography, consistent with 2016 European Society of Cardiology guidelines). We excluded patients with heart failure caused by severe valvular heart disease, life-threatening comorbidity with a life expectancy of less than 1 year, who were unable or unwilling to give consent, or who had concurrent participation in a clinical trial. Patients were followed up for 3 years for the outcomes of death and cause-specific admittance to hospital. Primary outcomes were uptake of guideline-directed medical therapies (as proportions) by therapeutic class, achieved doses as proportions of guideline-recommended doses, and their association with 1-year composite outcome of all-cause death or admittance to hospital because of heart failure. This study is registered with ClinicalTrials.gov, number NCT01633398. Between Oct 1, 2012, and Dec 31, 2015, we enrolled 5276 patients with HFrEF (mean age 59·6 years [SD 13·2], 77% men, body-mass index 24·9 kg/m2 [5·1], 33% New York Heart Association class III or IV). Follow-up data were available for 4544 (90%) of 5061 eligible patients taking medication for heart failure, with median follow-up of 417 days (IQR 214-735). ACE inhibitors or ARBs were prescribed to 3868 (77%) of 5005 patients, β blockers to 3975 (79%) of 5061, and MRAs to 2998 (58%) of 5205, with substantial regional variation. Guideline-recommended dose was achieved in only 17% of cases for ACE inhibitors or ARB, 13% for β blockers, and 29% for MRAs. Country (all three drug classes), increasing body-mass index (ACE inhibitors or ARBs and MRAs), and in-patient recruitment (ACE inhibitors or ARBs and β blockers) were associated with attainment of guideline-recommended dose (all p<0·05). When adjusted for indication bias, increasing drug doses, from low dose (1-<25% of guideline-recommended dose) upwards were associated with lower hazards of a 1-year composite outcome for ACE inhibitors or ARBs and β blockers compared with non-users. The lowest adjusted hazards were in the group that attained guideline-recommended doses above 50% (hazard ratio [HR] 0·54, 95% CI 0·50-0·58 for ACE inhibitors or ARBs [50-99·9%]; HR 0·47, 0·46-0·50 for β blockers, and HR 0·77, 0·72-0·81 for MRAs [≥100%]). Guideline-directed medical therapies at recommended doses are underutilised in patients with HFrEF. Improved uptake and uptitration of guideline-directed medical therapies are needed for better patient outcomes. National Medical Research Council (Singapore), A*STAR Biomedical Research Council ATTRaCT program, Boston Scientific Investigator Sponsored Research program, and Bayer.

Beta blockers and chronic heart failure patients: prognostic impact of a dose targeted beta blocker therapy vs. heart rate targeted strategy.

Beta blockers improve survival in patients with chronic systolic heart failure (CHF). Whether physicians should aim for target dose, target heart rate (HR), or both is still under debate. We identified 1,669 patients with systolic CHF due to ischemic heart disease or idiopathic dilated cardiomyopathy from the University Hospital Heidelberg and the Clinic of Ludwigshafen, Germany. All patients were treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker and had a history of CHF known for at least 6months. Target dose was defined as treatment with ≥ 95% of the respective published guideline-recommended dose. Target HR was defined as 51-69bpm. All-cause mortality during the median follow-up of 42.8months was analysed with respect to beta blocker dosing and resting HR. 201 (12%) patients met the dose target (group A), 285 (17.1%) met the HR target (group B), 627 (37.6%) met no target (group C), and 556 (33.3%) did not receive beta blockers (Group D). 5-year mortality was 23.7, 22.7, 37.6, and 55.6% for group A, B, C, and D, respectively (p < 0.001). Survival for group A patients with a HR ≥ 70bpm was 28.8% but 14.8% if HR was 50-70bpm (p = 0.054). Achieving guidelines recommended beta blocker dose or to HR control has a similar positive impact on survival. When on target dose, supplemental HR control additionally improves survival.

A Novel Intelligent Two-Way Communication System for Remote Heart Failure Medication Uptitration (the CardioCoach Study): Randomized Controlled Feasibility Trial.

BackgroundEuropean Society of Cardiology guidelines for the treatment of heart failure (HF) prescribe uptitration of angiotensin-converting enzyme inhibitors (ACE-I) and β-blockers to the maximum-tolerated, evidence-based dose. Although HF prognosis can drastically improve when correctly implementing these guidelines, studies have shown that they are insufficiently implemented in clinical practice.ObjectiveThe aim of this study was to verify whether supplementing the usual care with the CardioCoach follow-up tool is feasible and safe, and whether the tool is more efficient in implementing the guideline recommendations for β-blocker and ACE-I.MethodsA total of 25 HF patients were randomly assigned to either the usual care control group (n=10) or CardioCoach intervention group (n=15), and observed for 6 months. The CardioCoach follow-up tool is a two-way communication platform with decision support algorithms for semiautomatic remote medication uptitration. Remote monitoring sensors automatically transmit patient’s blood pressure, heart rate, and weight on a daily basis.ResultsPatients’ satisfaction and adherence for medication intake (10,018/10,825, 92.55%) and vital sign measurements (4504/4758, 94.66%) were excellent. However, the number of technical issues that arose was large, with 831 phone contacts (median 41, IQR 32-65) in total. The semiautomatic remote uptitration was safe, as there were no adverse events and no false positive uptitration proposals. Although no significant differences were found between both groups, a higher number of patients were on guideline-recommended medication dose in both groups compared with previous reports.ConclusionsThe CardioCoach follow-up tool for remote uptitration is feasible and safe and was found to be efficient in facilitating information exchange between care providers, with high patient satisfaction and adherence.Trial RegistrationClinicalTrials.gov NCT03294811; https://clinicaltrials.gov/ct2/show/NCT03294811 (Archived by WebCite at http://www.webcitation.org/6xLiWVsgM)

Nurse-coordinated care improves the achievement of LDL cholesterol targets through more intensive medication titration

BackgroundNurse-coordinated care (NCC) improves the achievement of low-density lipoprotein-cholesterol (LDL-C) targets after an acute coronary syndrome (ACS). We hypothesised that NCC improves achievement of LDL-C targets through more intensive medication...

Treatment of suspected pulmonary embolism in a morbidly obese patient

A case highlighting challenges with enoxaparin dosage and monitoring in obese patients is presented. A morbidly obese 22-year-old Caucasian female (height, 168 cm; weight, 322 kg; body mass index [BMI], 114 kg/m2) who presented to the emergency department with acute-onset dyspnea and hypoxia was empirically initiated on enoxaparin for suspected pulmonary embolism at the institution's standard maximum dosage (160 mg subcutaneously every 12 hours). On hospital day 2, a peak anti-factor Xa (anti-Xa) level of 0.4 IU/mL was documented about 4 hours after the fourth enoxaparin dose. On hospital day 3, the enoxaparin dose was increased to 200 mg, a dose equivalent to 0.62 mg per kilogram of actual body weight (ABW), much lower than the guideline-recommended dose for venous thromboembolism prophylaxis (1 mg/kg). Four hours after her third 200-mg dose of enoxaparin, the patient had an anti-Xa value of 0.64 IU/mL (goal range, 0.5-1.1 IU/mL), with no evidence of bleeding or other adverse drug events. Follow-up anti-Xa testing on hospital day 4 yielded a value of 0.78 IU/mL. The case highlights the need for research to better delineate strategies for enoxaparin dosage and monitoring in the context of extreme obesity. A female patient with a BMI of 114 kg/m2 was safely and effectively treated using an initial twice-daily dose of enoxaparin less than the recommended 1-mg/kg dose based on ABW. Dosage adjustments were made according to anti-Xa levels, and no adverse drug reactions were noted.

Heart rate reduction and exercise performance in recent onset heart failure with reduced ejection fraction: arguments for beta-blocker hypo-response.

Beta blockers reduce all-cause mortality and readmissions in heart failure with reduced ejection fraction (HFrEF), which may be explained by their effect on heart rate (HR). This study assessed the impact of HR reduction with beta blockers on exercise capacity in recent onset HFrEF. Fifty consecutive patients with recent onset HFrEF (<30 days) performed a standardized exercise protocol with respiratory gas analysis at baseline as well as after 6 and 12 months. Patients participated in a quality of care programme aiming to achieve guideline-recommended target doses for beta-blocker therapy. At baseline, 6 and 12 months, 36%, 70% and 62% of patients, respectively, had a resting HR<70 bpm. Beta-blocker dose after 12 months was comparable in patients with resting HR<70 versus ≥70 bpm (P value=0.631). However, with similar dose uptitration, the former versus the latter had a significantly larger HR reduction (17±22 versus 4±15 bpm; P value=0.027). Peak oxygen consumption (VO2max) was significantly higher when resting HR was <70 versus ≥70 bpm (17.5±5.5 versus 14.4±3.3 mL/min/kg, respectively; P value=0.038). Similar results were observed after 6 months. Patients in whom resting HR decreased at follow-up compared to baseline had a 2.0±3.2 mL/min/kg increase in VO2max compared to a 1.2±7.7 mL/min/kg increase in patients who did not demonstrate a lower resting HR (P value=0.033). In recent onset HFrEF, exercise performance was better when resting HR was controlled <70 bpm with beta-blocker therapy. However, despite aggressive dose uptitration, many patients did not achieve this target as they had little HR reduction with beta-blocker therapy.

Muscle wasting and cachexia in heart failure: mechanisms and therapies.

Body wasting is a serious complication that affects a large proportion of patients with heart failure. Muscle wasting, also known as sarcopenia, is the loss of muscle mass and strength, whereas cachexia describes loss of weight. After reaching guideline-recommended doses of heart failure therapies, the most promising approach to treating body wasting seems to be combined therapy that includes exercise, nutritional counselling, and drug treatment. Nutritional considerations include avoiding excessive salt and fluid intake, and replenishment of deficiencies in trace elements. Administration of omega-3 polyunsaturated fatty acids is beneficial in selected patients. High-calorific nutritional supplements can also be useful. The prescription of aerobic exercise training that provokes mild or moderate breathlessness has good scientific support. Drugs with potential benefit in the treatment of body wasting that have been tested in clinical studies in patients with heart failure include testosterone, ghrelin, recombinant human growth hormone, essential amino acids, and β2-adrenergic receptor agonists. In this Review, we summarize the pathophysiological mechanisms of muscle wasting and cachexia in heart failure, and highlight the potential treatment strategies. We aim to provide clinicians with the relevant information on body wasting to understand and treat these conditions in patients with heart failure.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

β-Blockade in Heart Failure With Reduced Ejection Fraction: Does Heart Rate Control Influence Readmissions?

Background: Raised resting heart rate (HR), >70 beats per minute (bpm), has been shown to be a risk factor for adverse cardiovascular outcomes and hospital readmissions, specifically in patients with heart failure with reduced ejection fraction (HFrEF). Given their mortality benefit, β-blockers are recommended in HFrEF, with a goal to titrate to a maximum tolerated dose rather than a specific HR target. Objective: To determine the impact of optimal HR control achievement prior to hospital discharge on hospital readmissions in patients with HFrEF receiving β-blockade. Methods: A retrospective study of patients admitted to 5 adult hospitals within a large urban health-care system, between 2013 and 2015, was conducted. Patients were identified via International Classification of Diseases, Ninth Revision (ICD-9) coding for acute on chronic HFrEF. Results: Of the 225 patients included, 20% achieved optimal HR control (n = 46, HR <70 bpm; n = 179, HR ≥70 bpm) and only 15% received β-blocker titration during hospital admission. Of note, 25% of patients receiving ≥50% target dose (n = 79) and 28% receiving 100% target dose (n = 39) achieved optimal HR control. At 30 days, patients with an HR <70 bpm versus HR ≥70 bpm exhibited similar readmission rates (9% vs 11%, respectively; P > .99) and ED visits (11% vs 8%, respectively; P = .57). Conclusions: Readmission rates were similar among patients with HFrEF despite the majority failing to achieve optimal HR control from β-blockade. However, β-blocker dosing remains suboptimal relative to guideline-recommended target doses. Opportunities exist for inpatient clinicians to optimize β-blockade in an attempt to achieve HR control.

Feasibility and Association of Neurohumoral Blocker Up-titration After Cardiac Resynchronization Therapy

BackgroundCardiac resynchronization therapy (CRT) improves mortality and morbidity on top of optimal medical therapy in heart failure with reduced ejection fraction (HFrEF). This study aimed to elucidate the association between neurohumoral blocker up-titration after CRT implantation and clinical outcomes. Methods and ResultsDoses of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta-blockers were retrospectively evaluated in 650 consecutive CRT patients implanted from October 2008 to August 2015 and followed in a tertiary multidisciplinary CRT clinic. All 650 CRT patients were on a maximal tolerable dose of ACE-I/ARB and beta-blocker at the time of CRT implantation. However, further up-titration was successful in 45.4% for ACE-I/ARB and in 56.8% for beta-blocker after CRT-implantation. During a mean follow-up of 37 ± 22 months, a total of 139 events occurred for the combined end point of heart failure admission and all-cause mortality. Successful, versus unsuccessful, up-titration was associated with adjusted hazard ratios of 0.537 (95% confidence interval 0.316–0.913; P = .022) for ACE-I/ARB and 0.633 (0.406–0.988; P = .044) for beta-blocker on the combined end point heart failure admission and all-cause mortality. Patients in the up-titration group exhibited a similar risk for death or heart failure admission as patients treated with the maximal dose (ACE-I/ARB: P = .133; beta-blockers: P = .709). ConclusionsAfter CRT, a majority of patients are capable of tolerating higher dosages of neurohumoral blockers. Up-titration of neurohumoral blockers after CRT implantation is associated with improved clinical outcomes, similarly to patients treated with the guideline-recommended target dose at the time of CRT implantation.

Adherence to GOLD Guidelines in the Inpatient COPD Population

Purpose: The Global Initiative for Chronic Obstructive Lung Disease guidelines provide recommendations to manage chronic obstructive lung disease (COPD) exacerbations. This study assessed the management of inpatient COPD exacerbations at an urban teaching hospital. Methods: A retrospective cohort analysis of adults admitted between December 2010 and August 2012 with a COPD exacerbation was conducted. Patient demographics, length of stay (LOS), Charlson comorbidity score, inpatient pulmonary medications, and 30-day readmission were collected. Descriptive statistics characterized guideline adherence and readmission. Results: 94 patients were included with median LOS of 3 days (interquartile range [IQR]: 1-5 days) and median Charlson comorbidity score of 6 (IQR: 5-8). All patients received an inhaled short-acting beta agonist, and 52 (55.3%) also received an inhaled short-acting anticholinergic. Seventy-eight (83%) received systemic corticosteroids, of which 3 received guideline-recommended doses. Sixty-four (68.1%) received antibiotics for a pulmonary indication, of which 71.9% received appropriate antibiotics per indication. Of the 94 patients, 2 were managed in complete adherence with GOLD recommendations. A total of 24 (25.5%) patients were readmitted within 30 days of discharge, 9 of these for COPD. Conclusion: COPD exacerbation treatment deviated from GOLD recommendations. This provides opportunities for further optimization of treatment of COPD exacerbations.

The treatment gap in patients with chronic systolic heart failure: a systematic review of evidence-based prescribing in practice.

The extent and impact of under-prescribing of evidence-based pharmacological therapies among heart failure patients with reduced ejection fraction (HFREF) in contemporary practice is unclear. We sought to examine the prescribing patterns of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers (BBs) and mineralocorticoid receptor antagonists (MRAs), and to quantify the estimated 'treatment gap' among HFREF patients in the 'real-world' setting. The MEDLINE, PubMed, EMBASE, CINAHL and CENTRAL databases were searched for registry- or survey-based studies which examined the prescribing rates of ACE inhibitors, ARBs, BBs and MRAs among HFREF patients. Searches were limited to those published in the years 2000-2015. A total of 23 reports, including 83,605 patients, were evaluated. Overall, ACE inhibitors/ARBs, BBs and MRAs were prescribed to 79.8, 81.4 and 36.4% of patients, respectively. The estimated treatment gaps in the overall population were 13.1% for ACE inhibitors/ARBs, 3.9% for BBs and 16.8% for MRAs. The proportion of patients who received ≥50% of the guideline-recommended target doses was 72% for ACE inhibitors, 51% for ARBs, 49% for BBs, 53% for the combination of ACE inhibitors/ARBs and BBs and 83% for MRAs. Prescribing these drugs according to contemporary guidelines was associated with lower mortality risk. Patients who were elderly, female and with comorbidities were less likely to receive optimal treatment as recommended by the guidelines. ACE inhibitors, ARBs, BBs and MRAs are under-prescribed in eligible HFREF patients. Efforts should be made to improve approaches to closing the treatment gap at both systems of care and individual levels.

A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF.

Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure. The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence-based medical therapy. In the follow-up phase, uptitration to guideline-recommended doses was encouraged. By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure.

Optimizing Guideline-Recommended Antibiotic Doses for Pediatric Infective Endocarditis.

The American Heart Association recently published an updated scientific statement on the management of infective endocarditis in childhood. The recommendations included for vancomycin, aminoglycoside, and β-lactam dosing and monitoring are based primarily on expert opinion and do not consider available evidence for dose optimization based on pharmacokinetic and pharmacodynamic principles in pediatric patients. This is concerning because even when clinically necessary, some practitioners may be hesitant to deviate from guideline-recommended doses. In this perspective, we highlight potential areas for improvement in the statement-recommended doses and summarize evidence supporting antibiotic dosing optimization. The addition of a pediatric clinical pharmacist with expertise in antibiotic dosing to the panel would be beneficial for future updates.

Dose Up-Titration Of Neurohormone Blockers For Chronic Heart Failure Treatment In Real Clinical Practice: Data From Single University Centre

Objective. To describe treatment peculiarities of ambulatory chronic heart failure patients’ in one of Lithuania’s university centres, participating in European Society of Cardiology EURObservation Research Programme (EORP) Heart Failure Long- Term Registry. Methods. 240 ambulatory patients with chronic heart failure were entered in European Society of Cardiology EURObservation Research Programme (EORP) Heart Failure Long-Term Registry from our university centre between May 2011 and March 2013. Follow-up data were collected after 12 months. Registered data about heart failure treatment were included to this study. Statistical analysis was performed with SPSS 22 program. Results. In our centre 67,1% of patients received angiotensin converting enzyme inhibitors at target doses, one third (34,3%) had not reached target doses due to symptomatic hypotension. Beta blockers were up-titrated to target doses for 82,5% of patients and the main reasons for failure to reach their target dose were: symptomatic bradycardia (12,7%), symptomatic hypotension (10,7%). Mineralocorticoid receptor antagonists were up-titrated to a target doses just for half of the patients – 52,1% and the most frequent reason for not reaching target doses was hyperkalemia (15,4%). Conclusions. Angiotensin converting enzyme inhibitors, beta-blockers and mineralocorticoid receptors antagonists, except angiotensin receptor blockers, were prescribed in a guideline-recommended doses. The main reasons why the target doses of neurohormone blockers have not been achieved were symptomatic hypotension for angiotensin converting enzyme inhibitors, symptomatic bradycardia for beta-blockers and hyperkalemia for mineralocorticoid receptors antagonists.

Heart rate reduction and exercise performance in recent onset heart failure with reduced ejection fraction: arguments for beta-blocker hypo-response

Objective Beta blockers reduce all-cause mortality and readmissions in heart failure with reduced ejection fraction (HFrEF), which may be explained by their eff ect on heart rate (HR). This study assessed the impact of HR reduction with beta blockers on exercise capacity in recent onset HFrEF.Methods and results Fifty consecutive patients with recent onset HFrEF (< 30 days) performed a standardized exercise protocol with respiratory gas analysis at baseline as well as after 6 and 12 months. Patients participated in a quality of care programme aiming to achieve guidelinerecommended target doses for beta-blocker therapy. At baseline, 6 and 12 months, 36%, 70% and 62% of patients, respectively, had a resting HR < 70 bpm. Beta-blocker dose after 12 months was comparable in patients with resting HR < 70 versus ≥ 70 bpm (P value = 0.631). However, with similar dose uptitration, the former versus the latter had a signifi cantly larger HR reduction (17 ± 22 versus 4 ± 15 bpm; P value = 0.027). Peak oxygen consumption (VO2max) was signifi cantly higher when resting HR was < 70 versus ≥ 70 bpm (17.5 ± 5.5 versus 14.4 ± 3.3 mL/min/kg, respectively; P value = 0.038). Similar results were observed after 6 months. Patients in whom resting HR decreased at follow-up compared to baseline had a 2.0 ± 3.2 mL/min/kg increase in VO2max compared to a 1.2 ± 7.7 mL/min/kg increase in patients who did not demonstrate a lower resting HR (P value = 0.033).Conclusions In recent onset HFrEF, exercise performance was better when resting HR was controlled < 70 bpm with beta-blocker therapy. However, despite aggressive dose uptitration, many patients did not achieve this target as they had little HR reduction with beta-blocker therapy.