Pharmacological Therapy For Heart Failure Research Articles

Physical Frailty and Use of Guideline-Recommended Drugs in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND Guideline-recommended therapies that improve prognosis remain underused in clinical practice. Physical frailty may lead to underprescription of life-saving therapy. We aimed to investigate the association between physical frailty and the use of evidence-based pharmacological therapy for heart failure with reduced ejection fraction and the impact of this on prognosis. METHODS AND RESULTS The FLAGSHIP (Multicentre Prospective Cohort Study to Develop Frailty-Based Prognostic Criteria for Heart Failure Patients) included patients hospitalized for acute heart failure, and data on physical frailty were collected prospectively. We analyzed 1041 patients with heart failure with reduced ejection fraction (aged 70 years; 73% male) and divided them by physical frailty categories using grip strength, walking speed, Self-Efficacy for Walking-7 score, and Performance Measures for Activities of Daily Living-8 score: categories I (n=371; least frail), II (n=275), III (n=224), and IV (n=171). Overall prescription rates of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and mineralocorticoid receptor antagonists were 69.7%, 87.8%, and 51.9%, respectively. The proportion of patients receiving all 3 drugs decreased as physical frailty increased (in category I patients, 40.2%; IV patients, 23.4%; P for trend<0.001). In adjusted analyses, the severity of physical frailty was an independent predictor for nonuse of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (odds ratio [OR], 1.23 [95% CI, 1.05-1.43] per 1 category increase) and β-blockers (OR, 1.32 [95% CI, 1.06-1.64]), but not mineralocorticoid receptor antagonists (OR, 0.97 [95% CI, 0.84-1.12]). Patients receiving 0 to 1 drug had a higher risk of the composite outcome of all-cause death or heart failure rehospitalization than those treated with 3 drugs in physical frailty categories I and II (hazard ratio [HR], 1.80 [95% CI, 1.08-2.98]) and III and IV (HR, 1.53 [95% CI, 1.01-2.32]) in the multivariate Cox proportional hazard model. CONCLUSIONS Prescription of guideline-recommended therapy decreased as severity of physical frailty increased in heart failure with reduced ejection fraction. Underprescription of guideline-recommended therapy may contribute to the poor prognosis associated with physical frailty.

SA15 Clinical Outcomes of Pharmacological Therapies for Heart Failure in Black Vs. White Populations: A Meta-Analysis of Randomized Controlled Trials of Heart Failure Treatment

Black patients have a disproportionately high prevalence of heart failure (HF) and HF-related cardiovascular (CV) death compared to other racial groups. However, the Black population has been vastly under-represented in most randomized clinical trials (RCT) of HF medications. It remains unclear whether HF medications are comparably effective in the Black population vs. the White population. We conducted a meta-analysis of RCT to evaluate the effect of different pharmacological therapies for HF on the Black vs. White population.

CO49 Comparative Efficacy of Pharmacological Therapies for Heart Failure with Reduced Ejection Fraction: A Network Meta-Analysis of Randomized Controlled Trials

CO49 Comparative Efficacy of Pharmacological Therapies for Heart Failure with Reduced Ejection Fraction: A Network Meta-Analysis of Randomized Controlled Trials

Design of the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor Versus Placebo in Patients With Congenital Systemic Right Ventricle Heart Failure (PARACYS-RV) Trial

The presence of a systemic right ventricle (sRV) with biventricular physiology (biV) is associated with increased patient morbidity and mortality. To date, no pharmacologic therapy for heart failure has been proven effective for patients with systolic dysfunction of the sRV-biV. We designed a randomized, double-blind, placebo-controlled crossover trial to compare sacubitril/valsartan treatment to placebo in adults (aged ≥ 18 years) with moderate-to-severe sRV-biV dysfunction and New York Heart Association functional class II to III symptoms. Two primary efficacy endpoints are assessed in the trial: exercise capacity (submaximal exercise duration) and neurohormonal activation (N-terminal prohormone brain natriuretic peptide). Secondary objectives include assessing a change in the Kansas City Cardiomyopathy Questionnaire score and evaluating the safety and tolerance of sacubitril/valsartan. A 6-week open run-in phase identifies the maximum tolerated dose of sacubitril/valsartan, up to 97 mg/103 mg twice daily. After a 2-week washout period, patients are randomized 1:1 to sacubitril/valsartan treatment vs placebo for a 24-week phase, followed by another 2-week washout period and subsequent crossover to the alternative treatment arm for an additional 24-week phase. Data to assess primary and secondary endpoints are collected at baseline and at the end of each phase. A total of 48 patients is required to provide > 80% power to detect a 30% difference in distance walked and in N-terminal prohormone brain natriuretic peptide levels with sacubitril/valsartan treatment vs placebo, each with a 2-sided P-value of 0.025. In summary, the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor vs Placebo in Patients With Congenital Systemic Right Ventricular Heart Failure Trial (PARACYS-RV) should determine the role of sacubitril/valsartan in treating heart failure in patients with sRV-biV and carries the potential to alter management of this patient population.

Evaluation and Management of Patients with Diabetes and Heart Failure: A Korean Diabetes Association and Korean Society of Heart Failure Consensus Statement.

Diabetes mellitus is a major risk factor for the development of heart failure. Furthermore, the prognosis of heart failure is worse in patients with diabetes mellitus than in those without it. Therefore, early diagnosis and proper management of heart failure in patients with diabetes mellitus are important. This review discusses the current criteria for diagnosis and screening tools for heart failure and the currently recommended pharmacological therapies for heart failure. We also highlight the effects of anti-diabetic medications on heart failure.

Evaluation and Management of Patients With Diabetes and Heart Failure: A Korean Diabetes Association and Korean Society of Heart Failure Consensus Statement.

Diabetes mellitus is a major risk factor for the development of heart failure. Furthermore, the prognosis of heart failure is worse in patients with diabetes mellitus than in those without it. Therefore, early diagnosis and proper management of heart failure in patients with diabetes mellitus are important. This review discusses the current criteria for diagnosis and screening tools for heart failure and the currently recommended pharmacological therapies for heart failure. We also highlight the effects of anti-diabetic medications on heart failure.

Impact of transcatheter edge-to-edge mitral valve repair on central sleep apnoea

AimsSleep-disordered breathing (SDB) and its subtype central sleep apnoea (CSA) are highly prevalent in patients with heart failure and associated with worse prognosis. Whereas pharmacological therapy of heart failure has been shown to ameliorate CSA, results from previous studies on the effect of mitral regurgitation therapy on SDB are contradicting. The aim of this study was to assess the impact of transcatheter edge-to-edge mitral valve repair (TEER) on prevalence and severity of CSA.Methods and resultsWe enrolled 47 patients undergoing TEER for symptomatic mitral regurgitation in a prospective study. Secondary mitral regurgitation and left ventricular ejection fraction < 50% were present in 79% and 68% of patients, respectively. Respiratory polygraphy was performed before TEER in a compensated condition and four weeks after the procedure. 34 patients completed the follow-up. At baseline, 19 (56%) patients showed moderate-to-severe SDB, of whom 13 (68%) were classified as CSA. Both apnoea-hypopnoea index and percentage of recorded time spent in Cheyne-Stokes respiration strongly decreased from baseline to follow-up (median [IQR] 16 [7–30] vs. 7 [4–15] /h, p = 0.007; 6 [0–34] vs. 0 [0–8] %, p = 0.008). Median relative reduction of central apnoea index was 75% (p = 0.023), while obstructive apnoea index did not change significantly. Increase in stroke volume after TEER and high systolic pulmonary artery pressure at baseline predicted a > 50% reduction of both Apnoea-hypopnoea index and Cheyne-Stokes respiration.ConclusionTEER is associated with a significant short-term reduction of CSA and Cheyne-Stokes respiration in high-risk patients, strengthening its value as an effective treatment option for advanced heart failure.Graphical abstract

Pharmacologic Therapy for Heart Failure with Preserved Ejection Fraction.

The management of heart failure with preserved ejection fraction (HFpEF) is rapidly evolving. The pharmacologic treatment of patients with HFpEF includes symptom management with diuretics and optimization of comorbidities, including hypertension, obesity, diabetes mellitus, and atrial fibrillation. Specific therapies, including angiotensin II receptor blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, are well tolerated and can reduce the risk of HF hospitalization, particularly in those on the lower end of the HFpEF left ventricular ejection fraction spectrum. Ongoing trials should continue to inform optimal therapy in this evolving field.

Adherence and discontinuation of optimal heart failure therapies according to age

Abstract Background Guideline-recommended disease-modifying pharmacological therapies for heart failure (HF) with reduced ejection fraction are underutilized, particularly among elderly patients. Purpose We examined adherence with and discontinuation of evidence-based HF pharmacotherapy, comprising of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin-II receptor blockers (ARB), beta-blockers (BB) and mineralocorticoid receptor antagonists (MRA), according to age. Methods Using Danish nationwide registries, we included patients with a first HF diagnosis between 2011 and 2018. Patients were stratified into three age groups, &amp;lt;65 years (reference group), 65–79 years, and ≥80 years. The average daily drug dose was calculated as median proportions of target doses one year after inclusion. Adherence was estimated by the proportion of days covered (PDC), i.e., the total number of days with the drug available for a patient alive for the whole first year of the follow-up period. Discontinuation was defined as a break of &amp;gt;90 days, and the 5-year risk of discontinuation according to age groups was estimated with the Aalen-Johansen estimator. Multivariable Cox regression models were used to evaluate the treatment discontinuation rate according to age groups. Results We included a total of 29,482 patients (&amp;lt;65 9,449 (25.4% female), 65–79 13,746 (33.1%), ≥80 6,287 (46.3%)). Advancing age was associated with lower median proportions of daily target doses (ACEi 100%, 88%, 63%; ARB 75%, 67%, 50%; BB 75%, 56%, 44%), and lower adherence (ACEi/ARB 79.1%, 77.5%, 69.4%; BB 79.1%, 78.6%, 73.8%), in the &amp;lt;65, 65–79 and ≥80 age groups respectively, one year after inclusion. Age ≥80 was associated with a higher 5-year risk of discontinuation; cumulative incidence, ACEi/ARB 41%, 44%, 51%; BB 38%, 35%, 39%, in the same age group order as above (adjusted hazard ratio: ACEi/ARB 1.60 [95% CI, 1.51–1.69]; BB 1.33 [95% CI, 1.25–1.41]). Conversely, the risk of discontinuation of MRAs differed little with age (&amp;lt;65 50%, 65–79 54%, ≥80 56%), although MRA initiation in the most elderly was less frequent (&amp;lt;65 33%, 65–79 33%, ≥80 22%). Conclusion Among a nationwide cohort of HF patients, advanced age was associated with lower proportions of daily target doses, lower adherence, and a higher rate of discontinuation of ACEi/ARB and BBs. Focus on treatment adherence and optimal dosages among elderly HF patients could improve outcomes. Funding Acknowledgement Type of funding sources: None.

Adherence and Discontinuation of Optimal Heart Failure Therapies According to Age: A Danish Nationwide Study.

Background Guideline-recommended disease-modifying pharmacological therapies for heart failure (HF) with reduced ejection fraction are underutilized, particularly among elderly patients. We studied the association of age in adherence and discontinuation of angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers (ACEi/ARB), β-blockers (BB), and mineralocorticoid receptor antagonists. Methods and Results Patients with a first heart failure diagnosis who had initiated ACEi/ARB and BB within 120 days of presentation were included from nationwide registries and divided into 3 age groups: <65 years (reference), 65 to 79, and ≥80. One-year median proportions of daily target doses were calculated. Adherence was estimated by the proportion of days covered. The 5-year risk of discontinuation was assessed with the Aalen-Johansen estimator. Discontinuation rates were evaluated using Multivariable Cox regression. Twenty-nine thousand four hundred eighty-two patients were included. Advancing age was associated with lower median proportions of daily target doses and adherence (ACEi/ARB 79.1%, 77.5%, and 69.4%; BB 79.1%, 78.6%, and 73.8%), in the <65, 65 to 79, and ≥80 age groups, respectively. Age ≥80 was associated with higher discontinuation rates (cumulative incidence, ACEi/ARB 41%, 44%, and 51%; BB 38%, 35%, and 39%; hazard ratio, ACEi/ARB 1.60 [95% CI, 1.51-1.69]; BB 1.33 [95% CI, 1.25-1.41]). The risk of mineralocorticoid receptor antagonists discontinuation differed little with age (50%, 54%, and 56%), although mineralocorticoid receptor antagonists initiation in the most elderly was less frequent (33%, 33%, and 22%). Conclusions In a nationwide cohort of patients with heart failure, advanced age was associated with lower proportions of daily target doses, lower adherence, and higher discontinuation rates of ACEi/ARB and BBs. Focus on treatment adherence and optimal dosages among elderly patients with heart failure could improve outcomes.

PO-700-06 ROLE OF SINUS RHYTHM QRS AMPLITUDE, FRACTIONATION AND DURATION TO IDENTIFY CLINICAL RESPONSE TO MEDICAL TREATMENT IN PATIENTS WITH CARDIAC SARCOIDOSIS AND FDG-PET UPTAKE

Myocardial fibrosis and inflammation in patients with cardiac sarcoidosis (CS) may lead to sinus rhythm abnormalities such as, low QRS amplitude (QRSa), QRS fractionation (QRSf) and longer QRS duration (QRSd). To determine if reduction of myocardial inflammation associated with medical treatment may improve and/or reverse these 12-lead ECG parameters. 23 consecutive patients (pts) with CS referred for VT ablation between 2009 and 2018 with18-fluorodeoxyglucose (FDG) uptake in a positron emission tomographic (PET1) scan at baseline were studied. All pts received high-dose prednisone 40 mg for 4 to 8 weeks followed by a taper and maintenance therapy with methotrexate ± low-dose prednisone, (≤20 mg/day), until clinically stable and resolution of inflammation on PET2 performed up to 2 years after initial. In addition to immunosuppression, pts with reduced LV ejection fraction (13/23pts) received guideline directed pharmacological therapy for heart failure. Based on the PET2 results, pts were divided into PET positive uptake [PET +, (n=12)] and PET negative uptake [PET -, (n=11)]. 12-lead ECGs of pts with native conduction from baseline (ECG1) and at up to 2-years after initial ECG (ECG2) were analyzed for QRSd, ≥2QRSf contiguous leads and QRSa. Baseline findings in patients who had PET2 (+) vs PET2 (-) were similar: sex (men 83% vs 100%), age (55±8.3 vs 55±8 years), average FDG uptake SUV maximum (5.8±2.7 vs 6.9±3.9) and average number of AADs tried before VT ablation (1.6 vs 1.5); all p value >0.05. Baseline 12-lead ECG1 showed similar QRSd, ≥2QRSf contiguous leads and QRSa for PET2 (+) vs PET2 (-). At follow-up ECG2, 7/11 patients (63.3%) PET2 (-) vs 1/12 patients (8.3%) still PET2 (+) showed ECG improvement p=0.009. Figure 1. ECG changes included QRSa increase in Lead 1 ≥.2 mV (>2 SEM) - [PET2 (+) 1 pt vs PET2 (-) 4 pts], QRSd decrease by ≥18 ms (>2 SEM) - [PET2 (+) 0 pts vs PET2 (-) 1 pt] and/or loss of QRS fractionation [PET2 (+) 0 pts vs PET2 (-) 3 pts]. In patients with cardiac sarcoidosis and VT, 12-lead ECG QRS demonstrating reversal of fractionation, increase in QRS amplitude and/or decrease in QRS duration, can help identify a positive response to medical treatment as indexed by negative FDG-PET at follow-up.

A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction

ObjectivesThis study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction. BackgroundThe estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized. MethodsWe performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor–neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]). ResultsWe identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31-0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32-0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36-0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29-0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35-0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34-0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5-7.5 years) compared with no treatment in secondary analyses. ConclusionsIn patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i.

Epigenetic Therapies for Heart Failure: Current Insights and Future Potential.

Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy (“epidrugs”) is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.

Renal protection in chronic heart failure: focus on sacubitril/valsartan.

Chronic kidney disease (CKD) is highly prevalent in patients with chronic heart failure (CHF) and increases the risk of overall and cardiovascular (CV) mortality. Despite evidence supporting the effectiveness of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers, and mineralocorticoid receptor antagonists in decreasing mortality in patients with CHF, CKD hampers the optimization of standard pharmacologic therapy for heart failure. Therefore, other treatment options are needed to optimize treatment outcomes in CHF patients with CKD. The first-in-class angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, has a complementary activity that counteracts the potential unwanted long-term effects of over-activation of the renin–angiotensin–aldosterone system. Sacubitril/valsartan reduced the risk of CV mortality compared to standard therapy with an ACE-I in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial and has been shown to be safe and effective in a broad range of HFrEF patients. However, data on the efficacy and tolerability of sacubitril/valsartan in patients with more advanced CKD are limited. This review discusses the evidence for the role of sacubitril/valsartan in providing additional renal benefit in patients with HFrEF. Data from clinical trials and real-world experience in patients with HFrEF and advanced CKD support the benefits of dual angiotensin/neprilysin inhibition across the breadth of kidney disease stages, including patients with significant renal impairment that was not reported in the pivotal PARADIGM-HF trial, and suggests a central role for the cardiac benefits of sacubitril/valsartan in nephroprotection.

Abstract 13323: Identifying the Culprit Lesion in a Symptomatic Patient With Physiologically Corrected Transposition of the Great Arteries

Introduction: Physiologically corrected transposition of the great arteries [(S,L,L) TGA] is a rare congenital heart disease characterized by atrioventricular and ventriculoarterial discordance. Case Presentation: A 28-year-old man with (S,L,L) TGA, pulmonary valve (PV) stenosis, ventricular septal defect (VSD), and history of Kawasaki disease who presented for a gradual decline in exercise tolerance. Oxygen saturation was 96% at rest and dropped to 86% with ambulation. Hemoglobin was 17.7 g/dl, EKG showed no bradyarrhythmias. On stress test, peak heart rate was 159 beats/minute, and peak VO 2 22.6 ml/kg/min (83%, and 57% of predicted value respectively). Spirometry was normal. Transthoracic echocardiogram revealed biventricular hypertrophy with normal systolic function, a bicuspid PV with severe stenosis (peak and mean gradient of 155 and 90 mmHg respectively), large inlet VSD with bidirectional flow and mild systemic TV regurgitation. Coronary CTA showed no coronary artery aneurysms. Cardiac catheterization suggested hypoxia due to pulmonary-to-systemic shunting across the VSD with Q p /Q s = 0.86 (Figure). Consideration should be given to performing a high-risk surgical repair versus medical management. Conclusions: Natural history, symptoms, and timing of intervention are determined by the associated cardiac anomalies and the progressive dysfunction of the systemic right ventricle (SRV). Anatomic repair to restore the left ventricle as a systemic pump is a very high-risk procedure in adults. Functional repair maintains SRV, repair the VSD, and PV stenosis has a poor late outcome. Medical management ensures iron stores are repleted, provide empirical use of pharmacological heart failure therapy, and referral to heart transplantation when SRV systolic dysfunction ensues. Clinicians need to know the potential complications in both unoperated patients and following various surgical repairs to recommend appropriate treatment options.

Twenty-year time trends in use of evidence-based heart failure drug therapy in Denmark.

European guidelines for heart failure (HF) have continuously incorporated new evidence since the first publication in 1995. We aimed to explore time trends in utilisation of pharmacological treatment for HF and dispensing of recommended dosages among patients with a first-time diagnosis of HF. We performed a historical cohort study of patients with a first-time HF diagnosis from 1997 to 2015, identified in the Danish National Patient Registry. Dispensed pharmacological treatment included angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor blockers (MRAs), digoxin and diuretics. Furthermore, we estimated the proportion of patients receiving the recommended target dosages 1year after the diagnosis. The utilisation increased and correlated with publication of landmark studies, and among patients diagnosed in 2015, approximately two of three received ACEI/ARB and beta-blocker, respectively. Less than half of the patients redeeming prescriptions for ACEIs, ARBs, beta-blockers or MRAs received the recommended target dosages. The utilisation of pharmacological therapy for HF appears to be correlated with the publications of landmark Phase III clinical trials. However, a high proportion of patients do not receive the recommended target dosages. Despite improvements over time, a substantial gap appears to remain between guideline recommendations and pharmacological therapy in routine care.

A053 Early Single-Centre Experience of a Nurse-led Sacubitril/Valsartan Initiation and Titration Clinic: A Retrospective Analysis

Background: Sacubitril/valsartan has changed the landscape of the pharmacological therapy of heart failure with reduced ejection fraction (HFrEF). We present our single-centre nurse-led initiation and titration clinic findings from Waikato Hospital. Method: Our retrospective analysis includes 149 consecutive patients with HFrEF who were commenced on sacubitril/valsartan by the Heart Failure Clinical Nurse Specialist (HF CNS) clinic between 1 October 2018 and 30 September 2019. Statistical analyses for Wilcoxon signed-rank test (two-tailed) were performed using Prism 8. Results: Our cohort of 149 patients were predominantly male (81%) with a median age of 68. The majority were either European (72%) or Māori (25%). Two-thirds (64%) were aetiologically non-ischaemic. Mean systolic blood pressure, mean GFR, mean weight and mean serum K+ were similar at baseline and at 6 month follow-up. 69% achieved target dose and 6% had withdrawal of sacubitril/valsartan. 36% had reduction in loop diuretic dose and 18% had mineralocorticoid antagonist withdrawn. Statistically significant differences were observed with decrease in NYHA Class (z = -7.961; p <.00001), decrease in NT-pro BNP (z = -6.441; p <.00001) and improvement in LVEF (z = -6.052; p <.00001) across the cohort. 10% (n = 15) were hospitalised for HF and 3.4% died (n = 5) within 6 months of commencing sacubitril/valsartan. Conclusion: Our early, single-centre experience with a nurse-initiated and led sacubitril-valsartan clinic has yielded results in keeping with the data from the PARADIGM-HF trial, whereby patients experience an improvement clinically (NYHA Class), biochemically (NT-pro BNP) and echocardiographically () with a favourable adverse effect profile. Further insights will be gleaned with longer-term follow-up in our cohort. [Formula presented]

Rationale and design of a navigator-driven remote optimization of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.

Although optimal pharmacological therapy for heart failure with reduced ejection fraction (HFrEF) is carefully scripted by treatment guidelines, many eligible patients are not treated with guideline‐directed medical therapy (GDMT) in clinical practice. We designed a strategy for remote optimization of GDMT on a population scale in patients with HFrEF leveraging nonphysician providers. An electronic health record‐based algorithm was used to identify a cohort of patients with a diagnosis of heart failure (HF) and ejection fraction (EF) ≤ 40% receiving longitudinal follow‐up at our center. Those with end‐stage HF requiring inotropic support, mechanical circulatory support, or transplantation and those enrolled in hospice or palliative care were excluded. Treating providers were approached for consent to adjust medical therapy according to a sequential, stepped titration algorithm modeled on the current American College of Cardiology (ACC)/American Heart Association (AHA) HF Guidelines within a collaborative care agreement. The program was approved by the institutional review board at Brigham and Women's Hospital with a waiver of written informed consent. All patients provided verbal consent to participate. A navigator then facilitated medication adjustments by telephone and conducted longitudinal surveillance of laboratories, blood pressure, and symptoms. Each titration step was reviewed by a pharmacist with supervision as needed from a nurse practitioner and HF cardiologist. Patients were discharged from the program to their primary cardiologist after achievement of an optimal or maximally tolerated regimen. A navigator‐led remote management strategy for optimization of GDMT may represent a scalable population‐level strategy for closing the gap between guidelines and clinical practice in patients with HFrEF.

P1618A polymethoxy flavonoid, Nobiletin, Has a therapeutic potency against the development of heart failure through NBP1 activation

Abstract Introduction Maladaptive hypertrophy is being recognized as a critical event during the development of heart failure. The control of cardiac hypertrophy may be one of the therapeutic strategy for heart failure therapy. In our previous study, we screened natural compound library and found that a natural compound, Nobiletin, could inhibit cardiomyocyte hypertrophy in culture. Nobiletin has various useful effects such as anti-cancer, anti-inflammation, and anti-oxidant and may be applicable to pharmacological therapy for heart failure. Hypothesis We thought that nobiletin might prevent the development of heart failure in vivo and investigated the target molecule of Nobiletin in the heart. Methods and results In primary cardiomyocytes, Nobiletin significantly inhibited phenylephrine (PE)-induced hypertrophic responses such as increases in cell size and hypertrophic gene transcription, such as ANF and BNP. C57BL6 mice were subjected to sham or transarotic constriction (TAC). Oral administrations of Nobiletin (20 mg/kg/day) or vehicle were repeated for 8 weeks. Nobiletin treatment significantly prevented TAC-induced increases in PWT and systolic dysfunction. Nobiletin also suppressed TAC-induced myocardial cell hypertrophy, perivascular fibrosis, and hypertrophic gene transcriptions. To investigate the target molecule of Nobiletin, Nobiletin-binding proteins were purified from rat heart using biotin-conjugated Nobiletin. We identified 162 novel binding protein of Nobiletin by LC/MS-MS. One of them, Nobiletin-binding protein 1 (NBP1) related to cellular metabolic pathway. Pulldown assay demonstrated that biotin-conjugated Nobiletin, but not biotin, directly interacted with recombinant NBP1. In vitro enzyme assay showed that Nobiletin enhanced NBP1 activity. Although NBP1 knockdown could not affect PE-induced hypertrophic response gene transcriptions and cardiomyocyte hypertrophy, NBP1 knockdown failed to exhibit Nobiletin-mediated anti-hypertrophic effects. NBP1-KO mice and WT mice were subjected to sham or TAC and randomly divided into two groups: Nobiletin (20 mg/kg/day) and vehicle. After 8 weeks, Nobiletin significantly improved TAC-induced cardiac hypertrophy and systolic dysfunction in WT mice but not in NBP1-KO mice. Nobiletin also prevented TAC-induced increases in HW/BW rate, myocardial cell hypertrophy, and mRNA levels of ANF and β-MHC in WT mice but not in NBP1-KO mice. Conclusions In this study, we demonstrate that Nobiletin inhibits cardiomyocyte hypertrophy and the development of heart failure in vivo. NBP1 activity is required to exhibit therapeutic potency of Nobiletin for heart failure. These finding suggest that a natural compound, nobiletin, might be a candidate for heart failure agent in human. Acknowledgement/Funding This work was supported by JSPS KAKENHI Grant.

An Integrated System Biology Approach Yields Drug Repositioning Candidates for the Treatment of Heart Failure.

Identifying effective pharmacological treatments for heart failure (HF) patients remains critically important. Given that the development of drugs de novo is expensive and time consuming, drug repositioning has become an increasingly important branch. In the present study, we propose a two-step drug repositioning pipeline and investigate the novel therapeutic effects of existing drugs approved by the US Food and Drug Administration to discover potential therapeutic drugs for HF. In the first step, we compared the gene expression pattern of HF patients with drug-induced gene expression profiles to obtain preliminary candidates. In the second step, we performed a systems biology approach based on the known protein–protein interaction information and targets of drugs to narrow down preliminary candidates to obtain final candidates. Drug set enrichment analysis and literature search were applied to assess the performance of our repositioning approach. We also constructed a mode of action network for each candidate and performed pathway analysis for each candidate using genes contained in their mode of action network to uncover pathways that potentially reflect the mechanisms of candidates’ therapeutic efficacy to HF. We discovered numerous preliminary candidates, some of which are used in clinical practice and supported by the literature. The final candidates contained nearly all of the preliminary candidates supported by previous studies. Drug set enrichment analysis and literature search support the validity of our repositioning approach. The mode of action network for each candidate not only displayed the underlying mechanisms of drug efficacy but also uncovered potential biomarkers and therapeutic targets for HF. Our two-step drug repositioning approach is efficient to find candidates with potential therapeutic efficiency to HF supported by the literature and might be of particular use in the discovery of novel effective pharmacological therapies for HF.