Getting to Optimal Medical Therapy for Hospitalized HFrEF: PRO – It’s a Sprint: Quadruple Therapy by Discharge

Gregg C. Fonarow from Ronald Reagan UCLA Medical Center presented the first topic “Getting to Optimal Medical Therapy for Hospitalized HFrEF: PRO – It’s a Sprint: Quadruple Therapy by Discharge” for the session DEBATE: Optical Medical Therapy for HFrEF, Death of HVAD and Oral Inotropy, at the HFSA Annual Scientific Meeting 2021.

Patients hospitalized with heart failure with reduced ejection fraction (HFrEF) are at substantially high risk for disease progression, HF rehospitalisation and post discharge mortality. In the first 100 days of a HFrEF hospitalization, 50% of patients will be rehospitalized or die. Use of Angiotensin Receptor-Neprilysin Inhibitors (ARNI) +beta blockers + Mineralocorticoid receptor antagonists (MRA) + Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) in HFrEF reduces hospitalizations by > 75%, all-cause mortality by >75%, extends median survival > 6 years (over ACEi + BB), and are safe, well tolerated, with benefits >>> potential risks. It takes about 28-56 weeks till guideline directed medical therapy (GDMT) is fully implemented. Starting from ACE inhibitors continued for 2 to 4 weeks upto 12 weeks followed by beta blockers for another 16 weeks, then starting with MRA for 2 to 4 weeks upto 12 weeks followed by ARNI for 2 to 4 weeks upto 12 weeks and lastly SGLT2-i. In-hospital initiation of GDMT improves treatment rates, adherence, persistence, and clinical outcomes and is Class I guideline recommended. Patients discharged without one or more GDMT, are unlikely to be started as outpatient and as a result at risk for HF events/death which could have been prevented.

The benefits of HFrEF medications are additive/incremental and begin to provide robust clinical benefits within days of initiation. No substantial overlaps have been demonstrated for the key 4 evidence based therapies for HFrEF: ARNI, beta blockers, MRA and SGLT-2i. The optimal approach is to utilize each medication demonstrated to reduce all-cause mortality in combination, so long as not contraindicated or not tolerated, and start all without delay in-hospital. In-hospital initiation is ACC/AHA/HFSA and ESC class I guideline-recommended. A serial or selective post-discharge approach leads to delays and HF hospitalizations/deaths, which could have been prevented, with earlier use.


Chronic Inotropy on Trial: CON – Mounting Evidence for the Role of Digoxin, Omecamtiv, Mecarbil, and IV Inotropes

Milton Packer from Baylor University Medical center presented an illuminating talk on the topic “Chronic inotropy on trial: CON – Mounting evidence for the role of Digoxin, Omecamtiv, Mecarbil, and IV inotropes” at the HFSA Annual Scientific Meeting 2021.

Drugs that improve systolic performance have been classified into three types based on their mechanism of action; calcitropes-alter intracellular calcium, mitotropes- influences energetics and myotropes-affect the molecular motor and scaffolding. There is limited evidence depicting the role of digoxin in improving systolic performance. Some studies also suggest increased heart failure (HF) hospitalization with digoxin withdrawal.  Guidelines recommend that digoxin can be considered in patients with symptomatic HF with reduced ejection fraction (EF) in sinus rhythm despite treatment with an angiotensin-converting enzyme-1, a beta-blocker, and mineralocorticoid receptor antagonists to reduce the risk of hospitalization.

Omecamtiv mecarbil: a novel myosin activator myrotype increases the duration of systole, increases stroke volume, and causes no increase in myocyte calcium, dp/dt max, and MVO2. A recent study has evaluated the efficacy of omecamtiv mecarbil in 8256 patients with HF. The study results showed that with omecamtiv mecarbil, a lower EF quartile (less than 22%) needed to treat or to prevent one HF event or cardiovascular death over 3 years. Omecamtiv mecarbil has been shown to significantly improve New York Heart Association (NYHA) status, reduced HF hospitalization in the last six months and improves the EF in patients with EF ≤ 30. Also, omecamtiv mecarbil was safe and well-tolerated.

Omecamtiv Mecarbil is a useful addition to the four pillars of pharmacological therapy of the HF.


Defining Heart Failure Based on Symptoms and Signs

Javed Butler from the University of Mississippi Medical Center, USA, presented an enlightening talk on, “defining heart failure based on symptoms and signs” at the HFSA Annual Scientific Meeting 2021.

He started the discussion with the universal definition and classification of heart failure. Universally, heart failure can be defined as symptoms and/or signs of HF caused by structural and/or functional cardiac abnormality corroborated by at least one of the following; elevated natriuretic peptide levels or objective evidence of cardiogenic pulmonary or systemic congestion. It is important to decide which signs or symptoms to be consider as a characteristic of HF. Physiologic changes that occurs normally with aging can be confused with the signs and symptoms of HF. A recent study has reported a high burden of non-cardiac comorbidities (diabetes mellitus, renal insufficiency, hypertension, anemia, obesity, chronic obstructive pulmonary disease) in patients with HF. Currently the natriuretic peptides are the most commonly used biomarker and help in the diagnosis and prognostication of patients with heart failure. However, their role is still debatable.

Now the question is, if not biomarkers, then what signs and symptoms should be considered characteristic of HF. Breathlessness, orthopnoea, paroxysmal nocturnal dyspnea, reduced exercise tolerance, fatigue, tiredness, and increased time to recover after exercise and ankle swelling are some of the typical symptoms of HF. More specific signs of the HF include elevated jugular venous pressure, hepatojugular reflux, third heart sound, laterally displaced apical impulse and cardiac murmur.

Until further research directs us, signs and symptoms should remain part of the definition.


Cardiac Contractility Modulation in Heart Failure: Where is the Therapy Going?

Peter Carson, presented his views on one of the awaited topics of the day, “cardiac contractility modulation in heart failure” at the HFSA Annual Scientific Meeting 2021.

Cardiac contractility modulation (CCM) therapy is delivered by the Optimizer®, a device the size of a pacemaker that delivers precisely timed electric pulses to the heart. CCM therapy delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction. Cardiac contractility modulation signal application is associated with the normalization of phosphorylation of key proteins and the expression of genes coding for proteins involved in the regulation of calcium cycling and contraction. FIX-HF-5 II study was designed to test the longer-term effects of CCM treatment. The study demonstrated that CCM was safe within prespecified boundaries. CCM significantly improved peak VO2 and Minnesota Living with Heart Failure Questionnaire (MLWHFQ) by 0.65 mL kg−1 min−1 [P = .024] and −9.7 points [P < .0001], respectively over optimal medical therapy. The sub-group analysis of this study further demonstrated that CCM effects potentially improve even more in patients with ejection fraction (EF) greater than 35%. In the FIX-HF-5C study, CCM significantly improved exercise capacity at 24 weeks. In addition, a considerable improvement in the secondary endpoints; 11.7 point improvement in MLWHFQ, improvement in New York Heart Association (NYHA) status ≥ 1 in 81% patients, and improvement in 6-min walk test by 33.7  meters (p=0.0093) was noted. Subgroup analysis showed that the improvement in the composite rates of cardiac death and heart failure hospitalizations with CCM was mainly driven by a significant reduction in events for the EF 25% to 35% cohort. Another study, CCM-REF (prospective registry study) was conducted to assess the long-term effects of CCM in patients with EF 40-45%. A significant improvement in the NYHA functional class, quality of life and left ventricular ejection fraction was noted with the CCM therapy. There are mainly three types of CCM systems; CCM rapid, CCM intermediate, and CCM long-term. Dr. Peter discussed the key benefits associated with each type of system.

CCM therapy delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction. It is a safe and effective treatment for patients with medically refractory heart failure.


Staying the Course and Staying Engaged: The Road to Medication Adherence

Meraz Rebecca et al., presented a poster session on the topic “ Staying the course and Staying engaged: The road to medication adherence. The authors aimed to investigate whether positive psychological characteristics (PPC) i.e resilience, hope and patient activation can explain or predict medication non-adherence (MA) in persons with heart failure (HF).  

Qualtrics was utilized for nationwide participant recruitment and data collection in this descriptive correlational cross sectional investigation. Participants (n=174) completed Voila self reported medication non adherence measurement (Part 1), The 14-item Resilience Scale, The Adult Hope Scale, The Patient Activation Measure (short form) and a demographic questionnaire.

Analysis descriptive and correlation analysis were performed. A linear regression was calculated to predict medical adherence based on degree of resilience, hope, and activation. Linear regression models were used to show the relationship among the variable. Resilience, hope, and activation were positively correlated with medication adherence (p=<0.01). The model as a whole is significant (F(3, 168)=7.40, p=0.00, r=0.34) and explains 20% of the variance in medication adherence scores. In the final model, resilience (b=-.06, t(168)=-3.01, p<=0.003) and PA (b=-.-48, t(168)=-2.21, p=0.028) make a significant unique contribution to predicting medication adherence.

Resilience makes the strong unique contribution in explaining medical adherence followed by activation and hope. Resilient, hopeful, and activated persons with HF are more likely to take medication as prescribed. Enhancing the positive psychological characteristic of hope and resilience increasing level of patient activation in person with HF may result in improved medical adherence.


Case Report: Cardiomyopathy During A Partial Molar Pregnancy

Yulei Cao presented the findings of an interesting case in the poster session on the topic “cardiomyopathy during a partial molar pregnancy” at the HFSA Annual Scientific Meeting 2021. Molar pregnancies are associated with increased maternal complications, notably hyperemesis gravidum, pre-eclampsia, or the development of gestational trophoblastic neoplasia, but rarely cardiomyopathy. A case of a partial molar pregnancy complicated by new-onset heart failure was presented. 

A 38-year old 17-weeks pregnant female was presented with symptoms of exertional dyspnea, orthopnea, peripheral edema, and rapid weight gain. The patient reported a mild viral illness two months before presentation. She also had several significant life stressors. The patient had seven full-term spontaneous vaginal deliveries, all uncomplicated, as well as spontaneous abortion. Her last delivery was 18 months before her presentation. Her blood pressure was 131/94 and her heart rate was 120 beats per minute. The cardiopulmonary exam showed tachycardia, regular rhythm, normal S1, and S2. Jugular venous pressure was elevated to 12 cm and grade 2+ pitting edema was noted. No wheezes were observed. Other laboratory and diagnostic investigations were done. Examination of products of conception confirmed a partial mole. Multidisciplinary teams from general cardiology, heart failure, and maternal-fetal medicine collaborated to provide care for this patient. She was aggressively diuressed and was started on afterload reduction with hydralazine. She subsequently underwent dilation and evacuation with a Swan-Ganz catheter in place for hemodynamic monitoring. The patient was ultimately discharged on a beta-blocker, diuretic, and sacubitril/valsartan. At the most recent follow-up, her ejection fraction recovered to 62%. The exact mechanism of acute HF in molar pregnancy is unknown, and only a few cases have been described. Removal of the molar pregnancy and initiating guideline-directed medical therapy (GDMT) can lead to myocardial recovery.

Heart failure in the setting of a partial molar pregnancy is a rare but important diagnosis to consider when presenting with dyspnoea. Removal of the molar pregnancy and initiating GDMT can lead to myocardial recovery. The mechanism by which molar pregnancy leads to cardiomyopathy is unclear and warrants additional research.


Risky Business: Angiotensin II Use in A Heartmate 3 LVAD Patient In The Setting Of Refractory Vasoplegia

Mathew C gave an enlightening presentation at the HFSA, 2021 on the topic “Risky Business: Angiotensin II Use in A Heartmate 3 LVAD Patient in The Setting of Refractory Vasoplegia”. The study presented a case of vasoplegia refractory to standard therapy in a patient after Left Ventricular Assist Device (LVAD) placement.

The patient was a 44-year-old man history of stage D idiopathic dilated cardiomyopathy and chronic kidney disease status post HeartMate 3 (HM3) LVAD placement three months ag. The condition was complicated by right ventricular (RV) failure which made him require milrinone infusion. He was prescribed with medications like Dobutamine, Bumetanide, Sildenafil, Levemir and has a social history of smoking.

Talking about his treatment course, he was started on Milrinone, dobutamine, epinephrine, bumetanide drip, and chlorothiazide upon admission. In right heart catheterization, low systemic vascular resistance (SVR) was revealed but the evidence of right ventricular was not found.

Poor urine output was observed and continous dialysis was initiated. The fluid removal was not feasible due to continued Vasoplegia. With the starting of Angiotensin II, SVR improved (Table 1), and fluid was removed with continuous dialysis

Angiotensin II carries risk of thromboembolism risk and the risk of angiotensin II need to be made aware of.

Comparability of The GALACTIC-HF Clinical Trial Population to Real-world Patients Having Heart Failure with Reduced Ejection Fraction

Mefford M gave an enlightening presentation at the HFSA, 2021 on the topic “Comparability of The GALACTIC-HF Clinical Trial Population to Real-world Patients Having Heart Failure with Reduced Ejection Fraction”. This study aimed to investigate the representativeness of the GALACTIC-HF patient population in a general population of HFrEF patients

A total of 12,772 patients with the HF diagnosis between 2014-2018 and identification of HF was done using ICD-9/10 codes. Two mutually exclusive real world cohorts were created such as: a) not taking guideline-directed medical therapy (GDMT), b) taking GDMT and 2 GALACTIC-like cohorts with: c) EF ≤ 35% and d) EF 36-40%.

Overall, 30-day mortality and hospitalization, and 1-year mortality were lower among all cohorts vs. the real-world cohort not taking GDMT. The risk of 1-year hospitalization was observed to be lower among g the real-world cohort taking GDMT vs. the real-world cohort not taking GDMT.

In conclusion, GALACTIC-HF like cohorts had lower 1-year mortality rates but same 1-year hospitalization rates as compared to patients not taking GDMT, indicating the potential benefits of additional treatment.


Heart Failure Clinic No-show Rates and Effect On Heart Failure Hospitalizations: A Real-World Experience from The Middle East

Alsindi F gave an enlightening presentation at the HFSA, 2021 on the topic “Heart Failure Clinic No-show Rates and Effect On Heart Failure Hospitalizations: A Real-World Experience from The Middle East”. The study aimed to determine the frequency and characteristics of f no-show appointments in relation to patient demographics and distance travelled, and evaluate the effect on HF hospitalizations in our newly established advanced HF program in the Middle East-Gulf Region.

The important factor for optimum HF management is adherence to scheduled appointments and identification of adherence patterns can help improve patients’ compliance.  A total of 230 patients were included in this study. A head-to-head comparison was performed between between those who were adherent (no-show rate ≤10%) vs. non- adherent (no-show rate >10%) patients.

The study shows that patients did not appear for 199 out of 1667 appointments attended an average of 6.5± 2 appointments during 12 months’ follow-up. The days that were likely to be missed for appointments were Monday and Wednesday and 57.8% appointments represented afternoon appointments.

Males and smokers were more predominant in the non-adherent group (p=0.02 and p=0.02, respectively)

This study helps formulate future strategic planning to predict and reduce the impact of patient no-show rates and future HF hospitalizations.


Revascularization in Ischemic Cardiomyopathy: The Evidence and Who Benefits?

Velazequz E gave an enlightening presentation at the HFSA, 2021 on the topic “Revascularization in Ischemic Cardiomyopathy: The Evidence and Who Benefits?” Challenging dogma faced by clinicians is that coronary artery bypass grafting reverses severe ischemic left ventricular dysfunction.

In STITICH revascularization hypothesis conduct, 1212 subjects were randomized to CABG+ MED (N=610) and MED (N=602). As per this study, all-cause mortality was lower with CABG as compared to MED. Similarly, cardiovascular mortality also followed the same trend as that of all-cause mortality. CABG leads to earlier and greater benefit in those patients at higher risk. CABG plus medical therapy is favoured when there is increased risk of MI, increased risk of cardiac death, moderate to severe mitral regurgitation, lower LVEF, three vessel coronary disease, and larger LVESVI. 

When comparing PCI and CABG, PCI focuses on revascularization of flow limiting lesions and CABG focuses on establishing distal collateralization. CABG improves survival with less morbidity as compared to GDMT Viability, angina, and ischemia status should not be defined for candidacy for CABG in HFrEF and the mechanism of benefit for CABG are multifactorial. As per 2021 ESC HF guidelines, Dapagliflozin or Emplagliflozin is recommended for patients with HFrEF to reduce the risk of hospitalization and death and SGLT2 inhibitors can be considered as a first line treatment for ASCVD, CKD or HFrEF. PCI is not well studied in HRrEF and more RCTs are required.

Extent of CAD should be assessed and GDMT optimized for all patients presented with HFrEF.