Therapy For Heart Failure With Reduced Ejection Fraction Research Articles

Initiation and sequencing of guideline-directed medical therapy for heart failure across the ejection fraction spectrum.

Strong evidence supports the importance of rapid sequence or simultaneous initiation of quadruple guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) for substantially reducing risk of mortality and hospitalization. Barring absolute contraindications for each individual medication, employing the strategy of rapid sequence, simultaneous, and/or in-hospital initiation at the time of HF diagnosis best ensures patients with HFrEF have the opportunity to benefit from proven medications and achieve large absolute risk reductions for adverse clinical outcomes. However, despite guideline recommendations supporting this approach, implementation in clinical practice remains persistently low, with less than one-fifth of eligible patients being prescribed the quadruple GDMT regimen. Additionally, for heart failure with mildly reduced or preserved ejection fraction (HFpEF), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and non-steroidal mineralocorticoid receptor antagonists (MRA)constitute foundational therapy for all eligible patients with significant clinicalbenefits within just weeks of medication initiation. Nonetheless, the burden of symptoms, functional limitations, and hospitalizations remains substantial for many of these patients, even with SGLT2iand non-steroidal MRA therapy. Additional evidence supports consideration of adjunctive therapies for HF with EF > 40% that can be tailored to the patient phenotype, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) for patients with obesity, as well as angiotensin receptor-neprilysin inhibitors (ARNI) for patients with EF below normal. This article reviews the evidence-based sequencing of GDMT for HF across the spectrum of EF, emphasizing the rationale and benefits of early up-front initiation of quadruple medical therapy for HFrEF, rapid initiation of SGLT2i for HF regardless of EF, and prompt phenotype-specific tailored approach to adjunctive therapies for HF with EF > 40%.

Implementation of guideline-recommended therapies in heart failure with reduced ejection fraction according to heart failure duration: An analysis of 55 581 patients from the Swedish Heart Failure (SwedeHF) Registry.

Guidelines recommend immediate initiation of all four class I guideline-directed medical therapies, renin-angiotensin system inhibitors (RASI) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) following the diagnosis of heart failure (HF) with reduced ejection fraction (HFrEF). The extent to which this occurs in new-onset HFrEF is unclear. We assessed guideline-recommended therapies during the first year following a HFrEF diagnosis. The Swedish HF Registry was linked to additional national registries. In patients with HFrEF (ejection fraction <40%), clinical characteristics and HF treatment from when they were available and recommended in guidelines were assessed according to time from HF diagnosis (<3, 3 to <6, 6-12 and >12 months). Of 55 581 patients with HFrEF enrolled between 2000 and 2021, 54%, 5.8%, 4.8% and 36% had an HF duration of <3, 3 to <6, 6-12 and >12 months, respectively. Patients with shorter HF duration were younger, had lower New York Heart Association class and had fewer cardiovascular comorbidities. Within 3 months, 3 to <6 months, 6-12 months and >12 months from HF diagnosis, 93%, 92%, 90% and 89% were on RASI or ARNI, 9.8%, 17%, 19% and 22% on ARNI alone, 35%, 43%, 44% and 46% on MRA, 92%, 92%, 92% and 91% on beta-blockers, and 26%, 30%, 19% and 28% on SGLT2i, respectively. Additionally, 18% received cardiac resynchronization therapy/implantable cardioverter-defibrillator >12 months after diagnosis. Most patients received RASI and beta-blockers in the first months following HFrEF diagnosis. Use of ARNI, MRA and SGLT2i was limited, both in the early and later time periods. Our findings suggest that strategies to improve guideline-directed use of HFrEF therapies remain urgently needed.

Quality of life in patients with heart failure and improved ejection fraction: one-year follow-up with ARNI and SGLT2i

Abstract Introduction A baseline Heart Failure (HF) with reduced Ejection fraction (HFrEF) &amp;lt;=40% that improved for &amp;gt;=10 points and a second measured left ventricle ejection fraction (LVEF) &amp;gt;40%, can be considered as HF with improved ejection fraction (HFimpEF). The novel therapy for HFrEF and HFimpEF are sacubitril/valsartan (ARNI- angiotensin receptor/neprilysin inhibitor) and Sodium-glucose cotransporter-2 inhibitors (SGLT2i). Purpose Our study aimed to evaluate ARNI and SGLT2i therapy on the health status of HFrEF patients, as well as the prognostic impact of HFimpEF in terms of quality of life and outcomes (mortality and rehospitalization due to HF) during a one-year follow-up. Methods In this prospective study, we included 376 hospitalized HFrEF patients, in whom ARNI and SGLT2i were initiated into regular therapy. A 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) was performed at discharge and after one year. The primary prognostic endpoints were all-cause mortality and HF rehospitalization. Results Initially, about two-thirds of the study population were men (71%), mean age of 61.0±11.5 years, mean LVEF 27.5±5.2 % and mean KCCQ overall summary (KCCQ-OS) score of 48.5±12.5, while quality of life KCCQ-QoL 37.4±10.2. After one year LVEF was increased by 35.6±7.1 %. The total number of 143 patients (38%) met the criteria for HFimpEF, with the improvement of mean LVEF (45.2±8.6 %., p&amp;lt;0.001). Overall, HFimpEF patients experienced an average 5.3 ± 18.6-point improvement in the KCCQ-OS compared with 2.5 ± 17.4 points for non-HFimpEF group (differences in mean changes of 2.9 [95% CI: 1.4 to 4.7). This is largely due to improvements in the domain of KCCQ-QoL (5.8 ± 29.7 points vs. 2.9 ± 22.2 points, respectively). During one year of follow-up, combined SGLT2i + ARNI therapy was represented statistically significantly more in HFimpEF compared to the non-HFimpEF group (86% vs. 34%, p&amp;lt;0.0005), where 45% took only one medicine and 21% none. The HFimpEF group had a significantly better outcome in terms of all-cause mortality (2.8% vs. 18.9%, p&amp;lt;0.005) and HF rehospitalization (3.5% vs. 40%, p&amp;lt;0.0001). The one-year KCCQ-12 was independently associated with outcomes; the hazard ratio for the integrated endpoints (mortality and HF rehospitalization) was 1.08 (95% CI: 1.05–1.11, p = 0.005). Conclusions In routine clinical practice, initiation of the ARNI and SGLT2i therapy was associated with significant improvements in the health status of HFrEF patients, but also change to HFimpEF. The one-year quality of life in patients with heart failure and improved ejection fraction was superior to baseline and compared to the non-HFimpEF group. HFimpEF was associated with a better outcome. All HF patients should undergo KCCQ-12 because it is an independent predictor of outcome.

Optimal Medical Therapy and Outcomes Among Patients With Chronic Heart Failure With Reduced Ejection Fraction

BackgroundOptimal medical therapy (OMT) scoring may stratify clinical risk in real-world chronic heart failure with reduced ejection fraction (HFrEF) by integrating use and dosing of guideline-directed medical therapy (GDMT) for HFrEF. ObjectivesThe purpose of this study was to characterize patients and associated long-term clinical outcomes by OMT score-derived treatment groups. MethodsCHAMP-HF (Change the Management of Patients with Heart Failure) included U.S. outpatients with chronic HFrEF receiving ≥1 GDMT. OMT subgroups were defined as suboptimal (score <3), acceptable (score = 3), and optimal (score ≥4) by baseline use and dose of GDMT, as proposed by the HF Collaboratory consortium. Cox proportional hazard analyses were used to assess for all-cause and cardiovascular death across subgroups, after adjusting for demographic and clinical covariates. ResultsThe authors studied 4,582 participants enrolled in CHAMP-HF with available 2-year follow-up. Median age was 68 years, 1,327 (29%) were women, and 2,842 (62%) were White, non-Hispanic. Median OMT score across the population was 4 (Q1-Q3: 2-5), and 1,628 (35%) had suboptimal, 665 (14%) had acceptable, and 2,289 (50%) had optimal therapy. Participants with optimal treatment were younger, had higher annual household income, and were enrolled from practices with dedicated HF clinics (all P < 0.001) than participants with acceptable or suboptimal treatment. Participants with optimal treatment had lower all-cause death (adjusted HR: 0.77; 95% CI: 0.64-0.92) and cardiovascular death (adjusted HR: 0.79; 95% CI: 0.65-0.96) than those with suboptimal treatment. ConclusionsAcross a large cohort of chronic ambulatory HFrEF, OMT scores stratified risk of all-cause and cardiovascular death.

Wearable defibrillator to improve accuracy in selecting candidates to implantable defibrillator: A real-world experience.

The indication for implantable cardioverter defibrillator (ICD) for sudden cardiac death (SCD) prevention relies mostly on left ventricular ejection fraction (LVEF)≤35%. The use of a wearable cardioverter defibrillator (WCD) in the case of dynamic alterations of LVEF may help avoid an improper early ICD implant when a favourable evolution in the post-acute phase is observed and may help reduce costs. This parallel cohort retrospective study included patients with heart failure with reduced ejection fraction (HFrEF) at high risk of arrhythmias recruited in the acute phase and divided into an early ICD cohort and a WCD cohort for primary prevention during the waiting period established by European Society of Cardiology guidelines. A total of 41 consecutive patients were enrolled: 26 in the WCD group and 15 in the early ICD group. Age, LVEF at baseline, causes of HFrEF and drug therapy in the two cohorts were similar. During the waiting period after the inclusion, three patients (11.5%) in the WCD cohort and four (26.7%) in the early ICD cohort developed relevant ventricular arrhythmias (P=0.22); none of them had subsequent LVEF recovery. At the end of the waiting period, 13 patients (50%) in the WCD group and 7 (46.7%) in the early ICD group experienced LVEF recovery (P=0.84). The average cost per patient at the end of the waiting period was €23934 in the early ICD cohort versus €19167 in the WCD cohort (-19.9%). This cost savings from WCD use appears even higher when projected over a 10year period (-41.2%). WCD may represent a cost-effective strategy to more accurately select candidates for the primary prevention ICD implant among high-risk patients with HFrEF. ICD use provides effective protection from SCD and reduces costs compared with an extensive early ICD implant.

Effect of sacubitril/valsartan on hospital readmissions in heart failure with reduced ejection fraction in Saudi Arabia: A multicenter retrospective cohort study.

Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that has been shown in multiple clinical trials to have clinical benefits and is recommended by major clinical management guidelines as a first-line treatment for heart failure with reduced ejection fraction (HFrEF). The most significant benefit that was observed in clinical trials is its effect in reducing hospital readmissions. However, little evidence supports its effectiveness in practice, especially in Saudi Arabia. A multicenter retrospective cohort study was conducted using the patient medical records at 2 tertiary hospitals in Saudi Arabia. Eligible patients were adults (≥18 years old) with a confirmed diagnosis of HFrEF who were discharged on either sacubitril/valsartan or angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) in addition to the other recommended therapy for HFrEF. The primary endpoint was the all-cause 30-day readmission rate. The secondary endpoints included all-cause readmissions at 60-day, 90-day, and 12 months. Additionally, 30-day, 60-day, and 90-day readmissions due to HF were evaluated. A total of 398 patients were included in our analysis; 199 (50.0%) received sacubitril/valsartan (group 1), and 199 (50.0%) received ACEI/ARB (group 2). Our results showed that all-cause 30-day readmissions in group 1 were significantly lower than in group 2 (7% vs 25.0%, RR 0.28, 95% Cl 0.16-0.49; P < .001). Additionally, the secondary outcomes showed significantly fewer 60-day, 90-day, and 12-month all-cause readmissions were identified in group 1 compared to group 2 (11% vs 30.7%, RR 0.36, 95% CI 0.23-0.56; P < .001), (11.6%. vs 32.6%, RR 0.35, 95% CI 0.23-0.55; P < .001) and (23.6% vs 51.2%, RR 0.46, 95% CI 0.35-0.62; P < .001), respectively. Furthermore, HF readmissions at 30-day, 60-day, and 90-day in group 1 were significantly lower than in group 2 (P < .05). Sacubitril/valsartan for the treatment of HFrEF is associated with a significantly lower rate of all-cause readmission as well as HF readmissions compared to ACEI/ARB. These benefits extend up to 12 months post-discharge.

INDEPENDENT EFFECT OF SGLT2I ON DIASTOLIC FUNCTION IN HFREF POPULATION

Abstract Background Scientific literature reinforces the role of diastolic dysfunction in patients with heart failure with reduced ejection fraction (HFrEF) as an independent prognostic indicator of all–cause mortality. In this context, E/e’ ratio plays a central role in diastolic dysfunction assessments and diagnosis. Despite the introduction of several novel medical therapies for HFrEF that led to improvement in mortality and HF hospitalization, the effect of the combined treatment with Sacubitril/Valsartan (SV) and Sodium Glucose Transporter 2 inhibitors (SGLT2i) on E/e’ ratio has not been addressed yet. Aim We aimed to evaluate the effect of SV alone vs SV+SGLT2i on E/e’ ratio in a real–life population of HFrEF outpatients. Methods This is an observational monocentric study including patients treated with either SV alone or with SV+SGLT2i from 2018 to 2023. E/e’ ratio was measured at baseline, at 6 and 12 months. Results 178 HFrEF patients (mean age 69 years±11, left ventricular ejection fraction (LVEF) 31±6%) in optimal medical therapy were enrolled. 121 of them received SV and 58 received SV+SGLT2i. Baseline E/e’ ratio was similar in the two groups (median value 11,2 [IQR 8;16] in SV group and 10,9 [IQR 8;16] in SV+SGLT2i group, p=0.45). At follow up, only SV+SGLT2i group showed a significative decrease in E/e’ ratio after therapy initiation while SV group showed a E/e’ ratio similar to baseline (E/e’ ratio median value 8,5 [IQR 7;12] vs 11,8 [IQR 8;15] respectively, p=0.035). Moreover, after 12 months most patients receiving SV+SGLT2i didn‘t required diuretic administration compared to those treated with only SV (43% vs 16% respectively; p=0,0002). Conclusions Among patients with HFrEF, treatment with SGLT2i+SV was associated with a significative reduction of E/e’ ratio and of diuretic administration. This result might suggest a favorable independent effect of SGLT2i on diastolic function and myocytes relaxation and might provide new evidence on the positive results observed on hard endpoints.

Management of Chronic Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is a commonly seen clinical entity in the family physician's practice. This clinical review focuses on the pharmacologic management of chronic HFrEF. Special attention is paid to the classification of heart failure and the newest recommendations from the American Heart Association concerning the use of guideline-directed medical therapy. β blockers, ACE inhibitors, ARBs, mineralocorticoid receptor antagonists are discussed in detail. The new emphasis on sacubitril-valsartan and SGLT2i's as therapies for HFrEF are reviewed, followed by a brief discussion of more advanced therapies and comorbidity management.

Effects of levothyroxine in subclinical hypothyroidism and heart failure with reduced ejection fraction: An open-label randomized trial

We report a randomized, multicenter, open-label trial (ClinicalTrials.gov: NCT03096613) to investigate the clinical benefits of levothyroxine (L-T4) administration in subclinical hypothyroidism (SCH) patients with heart failure with reduced ejection fraction (HFrEF). Overall, 117 patients were enrolled and received L-T4 plus standard HFrEF treatment (experimental group, N= 57) or standard HFrEF therapy alone (control group, N= 60). The change of 6-min walk test distance in the experimental group was significantly higher than that in the control group at 24weeks (70.08± 85.76m vs. 27.73± 82.00 m, mean difference [95% confidence interval (CI)] 46.90 [12.90, 80.90], p<0.001). Improvements in New York Heart Association (NYHA) classification (p= 0.033) and thyroid function were significant. Adverse event incidence was similar between groups (risk ratio [95% CI]: 0.942 1.053 (0.424, 2.616); p= 0.628). L-T4 addition to HFrEF treatment improved activity tolerance, NYHA class, and thyroid function within 6months, suggesting its potential for combined therapy in HFrEF patients with SCH. Future double-blind, placebo-controlled trials should be performed to confirm these results.

Prevalence and prognostic impact of bone disease in chronic heart failure with reduced ejection fraction.

Chronic heart failure is associated with a bone-catabolic state and increases the risk of osteoporosis and fractures. Prospective studies investigating the clinical relevance of bone disease in heart failure are lacking. We aimed to assess the prevalence and prognostic impact of osteoporosis and vertebral fractures (VFs) in chronic heart failure with reduced ejection fraction (HFrEF). Symptomatic outpatients with chronic heart failure and a previous diagnosis of overtly reduced left ventricular ejection fraction<40% on stable, optimal HFrEF therapy and left ventricular ejection fraction<50% at enrolment were included into a prospective single-centre study. Osteoporosis was determined with dual-energy X-ray absorptiometry and defined as a T-score≤2.5 at any site. VFs were assessed using X-ray of both thoracic and lumbar spine applying the semiquantitative Genant score. We enrolled 205 patients (22% women), with a median age of 66 (IQR 58-74) years. Median left ventricular ejection fraction was 37 (IQR 30-43) % and median N-terminal pro B-type natriuretic peptide was 964 (IQR 363-2173) pg/mL. Osteoporosis, as defined by bone mineral density, and at least one VF were prevalent in 31 (15%) and 29 patients (14%). Osteoporosis or VF were present in 55 patients (27%) and 5 patients (2%) had both osteoporosis and a VF. During a median follow-up of 4.7 (IQR 4.0-5.3) years, 18 patients (9%) died due to cardiovascular (CV) cause, and 46 patients (22%) had a worsening heart failure (WHF) hospitalization. In multivariate Cox regression analyses, presence of VF independently predicted CV death (HR 2.82, 95% CI 1.04-7.65, P=0.042), WHF hospitalizations (HR 2.39, 95% CI 1.18-4.82, P=0.015), and a composite endpoint of CV death and WHF hospitalizations (HR 2.44, 95% CI 1.23-4.82, P=0.011). Osteoporosis was not significantly associated with CV events. In a prospective study, bone disease affected every fourth patient with HFrEF, and patients with VF at baseline had a two-fold risk of subsequent CV death or WHF hospitalization. Prevalent bone disease, particularly VF, should be considered as a clinically relevant comorbidity in HFrEF.

Neighborhood-Level Socioeconomic Status and Prescription Fill Patterns Among Patients With Heart Failure

Medication nonadherence is common among patients with heart failure with reduced ejection fraction (HFrEF) and can lead to increased hospitalization and mortality. Patients living in socioeconomically disadvantaged areas may be at greater risk for medication nonadherence due to barriers such as lower access to transportation or pharmacies. To examine the association between neighborhood-level socioeconomic status (nSES) and medication nonadherence among patients with HFrEF and to assess the mediating roles of access to transportation, walkability, and pharmacy density. This retrospective cohort study was conducted between June 30, 2020, and December 31, 2021, at a large health system based primarily in New York City and surrounding areas. Adult patients with a diagnosis of HF, reduced EF on echocardiogram, and a prescription of at least 1 guideline-directed medical therapy (GDMT) for HFrEF were included. Patient addresses were geocoded, and nSES was calculated using the Agency for Healthcare Research and Quality SES index, which combines census-tract level measures of poverty, rent burden, unemployment, crowding, home value, and education, with higher values indicating higher nSES. Medication nonadherence was obtained through linkage of health record prescription data with pharmacy fill data and was defined as proportion of days covered (PDC) of less than 80% over 6 months, averaged across GDMT medications. Among 6247 patients, the mean (SD) age was 73 (14) years, and majority were male (4340 [69.5%]). There were 1011 (16.2%) Black participants, 735 (11.8%) Hispanic/Latinx participants, and 3929 (62.9%) White participants. Patients in lower nSES areas had higher rates of nonadherence, ranging from 51.7% in the lowest quartile (731 of 1086 participants) to 40.0% in the highest quartile (563 of 1086 participants) (P < .001). In adjusted analysis, patients living in the lower 2 nSES quartiles had significantly higher odds of nonadherence when compared with patients living in the highest nSES quartile (quartile 1: odds ratio [OR], 1.57 [95% CI, 1.35-1.83]; quartile 2: OR, 1.35 [95% CI, 1.16-1.56]). No mediation by access to transportation and pharmacy density was found, but a small amount of mediation by neighborhood walkability was observed. In this retrospective cohort study of patients with HFrEF, living in a lower nSES area was associated with higher rates of GDMT nonadherence. These findings highlight the importance of considering neighborhood-level disparities when developing approaches to improve medication adherence.

Heart failure with improved ejection fraction: patients' characters and predictors for improvement

Abstract Introduction Heart failure with improved ejection fraction (HFimpEF) is a relatively new definition, which presents a diagnostic and therapeutic challenge. Little is known about these patients' characteristics and predictors for EF improvement. Purpose Characterizing the profile of HFimpEF patients and evaluate predictors for EF improvement within heart failure with reduced ejection fraction (HFrEF) patients. Methods The cohort included ambulatory HFrEF patients (EF≤40%) who had two consecutive echo exams at least 6 months apart in a single tertiary medical center. Patients who improved their EF from ≤40% to &amp;gt;40% and by ≥10% (improved group) were compared to those who did not (not-improved group). Clinical, electrocardiographic and echocardiographic data were collected and compared between the groups. Results A total of 567 HFrEF patients (72% male, 54.3±14.4 years old) were analyzed. Patients without EF improvement (n = 393) were more likely to be male, had more comorbidities and had higher rates of ischemic cardiomyopathy (ICMP), compared with the improved group (n = 174) (Table). Lack of improvement in EF was also associated with lower EF and higher left and right ventricular diameters in the first echo. In a multivariate analysis model adjusted to all statistically significant variables in the univariate analysis, predictors for lack of EF improvement were male sex (adjusted odds ratio [OR] 1.63, 95% CI 1.02-2.61; P = 0.041), ICMP (OR 3.98, 95% CI 2.03-7.81; P&amp;lt;.001), larger left ventricular end diastolic and end systolic diameters (OR 2.07, 95% CI 1.44-2.98 and OR 1.84, 95% CI 1.36-2.5, respectively; P&amp;lt;.001 for both) and enlarged right ventricle (OR 1.93, 95% CI 1.11-3.36; P = 0.02), while higher EF at baseline was a positive predictor for improvement (OR 0.95, 95% CI 0.92-0.98; P = 0.001) (Figure). Interestingly, NYHA functional class was not associated with EF improvement (OR 1.16, 95% CI 0.87-1.55; P = 0.306). Hospitalization and mortality rates were both higher in the not-improved group (median of 1 (IQR 1-2) vs. 0 (IQR 0-1); P&amp;lt;.001 and 24% vs. 13%; P = 0.001, respectively). Patients in both groups were generally treated with high rates of guideline directed medical therapy (GDMT) for HFrEF. Although no correlation was found between GDMT and EF improvement, these drugs were associated with reduced hospitalization and mortality rates in both groups. Conclusions Improvement in EF among HFrEF patients may be predicted by the HF etiology and echocardiographic parameters. HFimpEF patients have better prognosis compared to HFrEF patients. While GDMT was not associated with EF improvement, it improved outcomes in both HFimpEF and HFrEF regardless of EF.

Quadruple therapy for heart failure before and after electronic cardiac device implantation - are we hitting our targets?

Abstract Background Quadruple therapy is currently recommended pharmacological treatment for heart failure with reduced ejection fraction (HFrEF). It consists of beta-blockers, mineralocorticoid receptor antagonists (MRA), angiotensin converting enzyme inhibitors (ACE-I) – recently suggested to be replaced with angiotensin receptor/neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 inhibitors (SGLT2-I). Patients eligible for implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) implantation should have therapy titrated to evidence-based target doses prior to the procedure, whenever tolerable. Compliance with guidelines as well as distinction in prescription practice before and after device implantation in the era of quadruple HFrEF therapy has not yet been fully researched. Purpose The purpose of this study is to evaluate the use of disease-modifying drugs in corresponding target doses in patients with HFrEF eligible for ICD or CRT implantation, prior to and after the procedure. Methods This is a retrospective observational study which included patients with HFrEF hospitalized for ICD or CRT implantation in a single tertiary centre from January 2021 to January 2023. Data was collected through patients' medical history and phone calls. Results We collected data on a total of 107 patients with HFrEF and ICD or CRT implantation. Most patients received all four classes of guideline-directed therapy before ICD or CRT implantation: beta-blockers (91,6%), MRA (86,0%), ACE-I (31,8%) or ARNI (59,8%) and SGLT2-I (59,8%). Evidence-based target doses were reached for 10,2%, 52,2%, 11,8%, 32,8% and 100% patients receiving beta-blockers, MRA, ACE-I, ARNI and SGLT2i respectively. After hospitalization for device implantation, results pointed to an increase in prescription of beta-blockers (99,1%), MRA (97,2%), and most notably SGLT2-I (87,9%), while more ACE-I (19,6%) were replaced with ARNI (75,7%). Target doses were reached for 19,8%, 72,1%, 28,6%, 37,0%, and 100% patients receiving beta-blockers, MRA, ACE-I, ARNI, and SGLT2-I respectively. Conclusions Most of the examined patients have been receiving all four drug classes prior to device implantation. We noticed a rising trend in recruiting novel heart failure drugs, ARNI and SGLT2-I, after the procedure. However, drug titration was non-compliant with guidelines. There was a slight improvement in up-titration of therapy after the procedure, which could be explained by more common medication adjustments by electrophysiologists during device control sessions as well as better drug tolerability after device implantation. Regardless, a minority of patients received ACE-I, ARNI and beta blockers in target doses. Despite several objective obstacles to adequate administration of disease-modifying drugs, including intolerability and patients’ non-adherence, further effort in up-titrating guideline-directed medical therapy should be applied.Therapy administration practice

Feasibility, efficacy and safety of early and rapid initiation of evidence-based treatment for patients with HFrEF- a real world experience of the "four drugs in four weeks" strategy

Abstract Background Evidence-based treatment for heart failure with reduced ejection fraction (HFrEF) is associated with improved outcomes for patients. However, there is uncertainty as to how treatment with these foundational drugs should best be implemented. Objectives To evaluate whether early and rapid initiation of medications for patients with HFrEF using a 4 x 4 approach (4 pillars of HFrEF therapy in 4 weeks) is feasible, safe, and effective. Methods We recruited consecutive patients from April to July 2021 with a new diagnosis of HFrEF who were either assessed at our urgent HF clinic or had a recent HF hospitalisation. All patients had regular reviews (every 1-2 weeks, combination of telephone and face-to-face) at our hospital-based HF clinic by a HF consultant or senior HF specialist nurse for initiation and up-titration of guideline-recommended therapy including angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor neprilysin inhibitor (ARNI), beta blockers (BB), mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter inhibitor (SGLT2i). Results Of 100 patients approached, 19 patients were considered unsuitable for the 4x4 pathway (79% due to severe frailty or significant comorbidities). 81 patients were enrolled (61% male, median (IQR) age: 73 (67-82) years, median (IQR) NT-proBNP: 3764 (1597-7487) ng/L); 39 (48%) patients achieved "4 drugs at 4 weeks". Of the 42 patients who did not, 33 (79%) had contraindication to one or more of the drug classes at the outset, including renal impairment (28%), bradycardia (18%) and hyperkalaemia (15%). Patients who did not achieve "4 drugs at 4 weeks" were older, more symptomatic, and had higher NTproBNP and worse renal function. During a median follow up of 554 days, 6 (7%) patients died and 31 (38%) experienced the combined outcome of all-cause death / hospitalisation. Patients who did not achieve "4 drugs at 4 weeks", compared to those who did, had a 2.5 fold increased risk of the combined outcome (Figure 1). They were also less likely to be up-titrated to targeted doses of HF medications (Figure 2). There was noticeable improvement in NTproBNP with no significant change in renal function or systolic BP in both groups. Compared to those who did not achieve "4 drugs at 4 weeks", those who did showed larger improvement in LVEF (8% vs 2%) at 6 months. 5 patients (6%) experienced significant side effects during medication up-titration: 4 had symptomatic hypotension and 1 had hyperkalaemia. Conclusion The 4x4 strategy is clinically feasible and safe when implemented in selected patients with HFrEF and may be associated with improved outcomes. Our results support larger studies to further investigate the generalisability and effectiveness of the 4x4 strategy.

HFrEF phenotyping in real life

Abstract Background In May 2021 an HFA position paper[1] by Rosano GMC et al. classified patients with heart failure with reduced ejection fraction (HFrEF) into 11 phenotypes based on blood pressure, heart rate, renal function, potassium level and rhythm and assigned them to different prescription attitudes. Aim We aim to investigate the distribution of phenotype frequency in our cohort and their respective outcomes. Methods From 2016 to 2022 we enrolled 900 advanced HFrEF patients with severely reduced ejection fraction (LVEF &amp;lt;35%) in a prospective registry from our tertiary care heart failure unit. Patients were grouped according to the suggested phenotypes. Distribution and outcome for the different groups was analyzed. Results Characteristics of the different phenotypes, the distribution and outcome are shown in Figure 1. 65.8% of patients belong to 5 categories [3, 4, 5, 7b and 9]. Baseline characteristics of these 5 profiles are shown in Table 1. With the exception of Profile 3, which is characterized by a low resting hear rate, these major profiles are all eligible to receive all 4 drugs with class I recommendation at maximal dosages (RASi, BB, MRA, SGLT2i). The 6 remaining categories, all with GDMT limiting features, comprise solely another 3.8% of patients [1.8%, 1.2%, 0.3%, 0.3%, 0.2%, 0%, for the categories 7c, 7a, 1, 2, 6, 8 respectively]. With 30.2% a significant proportion of patients could not be assigned to one profile exclusively mostly because they showed a combination of profile attributes. Thus, of all classifiable HFrEF patients, with 83.4% the majority has no GDMT limiting features and should receive full HFrEF therapy. All-cause mortality did not differ between patient phenotypes [4,5,7b and 9] and the others (p = 0.193), while uncategorizable patients had significantly worse survival (p&amp;lt;0.0001) (Figure 1c). Conclusion The study provides insight into heart failure phenotyping in a real-world setting. Most HFrEF patients are eligible for the 4 class I drugs of HFrEF medication, and only a minority may not be able to receive them. However, nearly one-third of all patients could not be categorized, including those with the poorest survival. Given these findings, the added value of the classification of patients according to this pattern seems limited in routine practice, possibly resulting from the complexity of the clinical picture of HFrEF.Figure 1 BL characteristics

Dapaglifozin in adults with a systemic right ventricle:initial results from the DAPA-SERVE trial

Abstract Background Sodium-glucose Cotransporter-2(SGLT2) inhibitors are currently recommended as first line therapy for all patients with heart failure with reduced ejection fraction (HFrEF).Adults with a systemic right ventricle (sRV) may develop progressive systolic dysfunction during follow-up. Optimal medical therapy for HFrEF remains still to be determined in this complex population. Purpose We aimed to assess safety and evaluate potential clinical benefit of dapagliflozin in patients with a sRV compared to standard medical treatment for HF. Methods Inclusion criteria were:age ≥ 18 years; transposition of the great arteries (TGA) following Senning/Mustard repair or congenitally corrected TGA, sRV EF ≤ 40%, already on optimized medical therapy including sacubitril/valsartan for at least 3 months. Exclusion criteria were: systolic blood pressure (SBP) &amp;lt;90 mmHg, glomerular filtration rate (GFR)&amp;lt;30ml/min and univentricular physiology. All eligible patients attending our tertiary center for adult congenital heart disease were randomly assigned to the treatment or control group. Patients in the treatment arm were prescribed 10 mg dapagliflozin o.d. on top of their medical therapy, while control group continued standard therapy. Patients were scheduled for a structured follow-up including clinical evaluation, blood test, echocardiography, and 6 minute-walking at 6 months from study inclusion for both groups. Results Fifty patients (41±11 years, 54% male, 64% TGA) met the inclusion criteria: 25(50%) were started on 10 mg dapagliflozin. There was no significant difference in terms of age (p=0.4), sex(p=0.1), anatomy(p=0.2) and baseline sRV EF (p=0.2). Up to February 2023, 14 patients in the treatment group and 13 controls completed the 6-month follow-up. Clinical and echocardiographic findings at baseline and at 6-month in the treatment group are summarized in Table1: dapagliflozin was well tolerated and no major adverse events were reported. Treatment did not impact on the systolic blood pressure and renal function. However a significant improvement in the sRV freewall global longitudinal strain(GLS) was found (-15.8±3 Vs -18.3±3; p=0.03). Differences in main echocardiographic indices of sRV systolic function between baseline and follow-up in the two arms are shown in Table2: treatment resulted in significant positive changes of sRV FAC, GLS, and free wall GLS compared to the group on standard therapy. Conclusions Initial results from the ongoing single-centre DAPA-SERVE trial provided reassuring data on the safety profile of dapagliflozin in patients with a sRV. Furthermore, significant improvement of echocardiographic indices of sRV function in patients on dapagliflozin compared to those on standard medical therapy was demonstrated at 6-month. Longer follow-up is warranted to determine the clinical impact of those positive changes and to shed light on the potential benefit of SGLT2 inhibitors use on top of standard therapy in this complex population.

Abstract 19052: Interferon B1A-Induced Dilated Cardiomyopathy

Introduction: Congestive heart failure is a leading causes of morbidity and mortality. Interferon therapy is a rare cause of dilated cardiomyopathy (DCM) and Heart Failure with Reduced Ejection Fraction (HFrEF). Specifically, interferon Alpha has been associated with cardiotoxicity. Here we describe a case of interferon B1A - induced HFrEF and DCM in a patient who took subcutaneous Interferon B1A for 11 years before developing clinical signs of heart failure. To our knowledge, only four other cases have been reported. Case Description: A 70-year-old man with a history of multiple sclerosis managed with Interferon B1A presented with shortness of breath, orthopnea, and lower extremity edema for 10 days. Physical examination revealed jugular venous distension and pitting edema. Brain natriuretic peptide (BNP) was 1580 pg/mL, troponin was 49 ng/L. Lipid panel, complete blood count, complete metabolic panel, Hemoglobin A1c, and thyroid stimulating hormone were within normal limits. Urine drug screen was negative. Chest X-ray revealed pulmonary vascular congestion and small pleural effusions bilaterally. A Transthoracic echocardiogram revealed mild aortic root dilatation (4.1cm), significant four-chamber dilatation, severely reduced left ventricular (LV) systolic function with an estimated ejection fraction of 20%, diastolic LV dysfunction, and moderately reduced systolic RV function, consistent with HFrEF and DCM (LVIDD 6.1cm). Coronary angiography showed normal coronary anatomy. The patient was started on guideline-directed medical therapy for HFrEF. Close follow-up was arranged to track improvement in systolic function after cessation of interferon b1a and consideration for Cardiac MRI and possible RV biopsy to evaluate for other causes of cardiomyopathy. Discussion/Conclusions: Due to the patient’s negative ischemic workup and absence of risk factors for cardiovascular disease, we strongly suspect that the patient’s cardiomyopathy was due to interferon B1A. With only 4 other cases of interferon B1A-induced DCM reported, it is a rare cause of medication-induced DCM. Interferon B1A should be considered a potential risk factor for developing heart failure, especially in high-risk patients.

Improvement in Left and Right Ventricular Function after Introduction of SGLT2 Inhibitors in Heart Failure Outpatients with Reduced Ejection Fraction.

Type 2 sodium-glucose cotransporter inhibitors (SGLT2i) are among the main therapeutic options for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the effects of SGLT2i on the echocardiographic parameters of left (LV) and right (RV) ventricular function among outpatients with a long history of HFrEF, in optimized therapy. We evaluated consecutive patients affected by HFrEF in whom the SGLT2i therapy was prescribed. Following a baseline evaluation (T0), in which SGLT2i was prescribed, patients were re-evaluated at 3 (T3), 6 (T6), and 12 (T12) months. We considered 60 patients for the analysis with a median history of HFrEF of more than seven years in optimal medical and electrical therapy. After SGLT2i therapy, LV ejection fraction and LV global longitudinal strain improved from baseline at T3, T6, and T12. Analogously, RV global and free wall longitudinal strain improved at T3 and T6. Our study shows that the addition of SGLT2i to the optimized therapy for HFrEF was associated with a significant improvement in both LV and RV function, thus highlighting a possible mechanism responsible for the benefit obtained with this class of drugs.

Call to action for drug interactions between tirzepatide and heart failure guideline-directed medical therapy

BackgroundNo drug interaction between the guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) and glucose-dependent insulinotropic polypeptide (GIP)-glucagon-like peptide-1 (GLP-1) agonists is currently indexed in available drug interaction databases or package inserts for tirzepatide, the first dual GIP/GLP-1 agonist. The objective of our case series is to present 3 patients with HF who required modification in GDMT regimens for HFrEF or loop diuretic therapy after tirzepatide initiation. Case summaryThree patients older than 60 years with HFrEF receiving GDMT agents (angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) were initiated on tirzepatide for weight loss management. After initiating tirzepatide therapy, all 3 patients developed symptomatic hypotension. Two cases had acute kidney injury owing to tirzepatide’s direct vasodilation, natriuresis, reduction in extracellular volume, and weight loss. GDMT regimens and diuretic therapy were significantly modified to improve these adverse reactions. Practice implicationsClinicians must closely monitor vital signs and volume status after initiating tirzepatide for potential need to modify GDMT regimens. Authors request a call to action to index the drug interaction between GDMT agents and tirzepatide in major drug interaction databases for a potential hypotension or dehydration risk.

Tailoring guideline-directed medical therapy in heart failure with reduced ejection fraction: A practical guide.

According to the 2021 European Society of Cardiology guidelines, the four pillars of medical therapy in heart failure with reduced ejection fraction (HFrEF) include sodium-glucose co-transporter-2 inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin-converting enzyme inhibitors or angiotensin receptor-neprilysin inhibitors. However, in clinical practice, concomitant use of all four drug groups in target doses is often limited by their intolerance or fear of potential complications. Herein, we present strategies to initiate or modify HFrEF therapy in frequent but challenging clinical scenarios (symptomatic hypotension, atrial fibrillation, kidney disease or worsening renal function, hyperkalemia) in a way that does not lead to unnecessary reduction or cessation of life-saving treatment.