Role for Omecamtiv Mecarbil in Pts with EF <35%

KEY POINTS:

  • An experimental new therapeutic for heart failure, omecamtiv mecarbil is a novel, selective cardiac myosin activator that was previously shown in the GALACTIC-HF trial to improve heart failure (HF) outcomes amongst patients with heart failure with reduced ejection fraction (HFrEF)
  • This extended analysis of the GALACTIC-HF trial showed that omecamtiv mecarbil exerts a greater relative and absolute therapeutic benefit in patients with worsening ejection fraction (EF), in keeping with the drug’s mechanism of selectively improving cardiac function
  • The relative and absolute benefits from omecamtiv mecarbil significantly improved with progressively lower EF
  • No clear benefit of omecamtiv mecarbil among patients with EF >30% was shown, with more research into this subgroup forthcoming
  • The potential role for omecamtiv mecarbil is to be additive to other guideline-directed medical therapies (GDMT) for all patients with LVEF <35% and 1+ heart failure hospitalization in the prior year

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Hospital-level Intervention Did Not Improve Outcomes or Quality in HFrEF

Key Points:

  • CONNECT-HF, one of the largest heart failure (HF) implementation science trials performed to date, was performed to evaluate how the principles of audit and feedback with personalized feedback by HF and quality improvement experts might impact HF outcomes
  • Results showed that this hospital-level intervention did not meaningfully improve clinical outcomes or quality of care delivery at 12 months compared to usual care
  • According to the investigators, new approaches are needed to improve care above current quality improvement efforts for patients with HFrEF and next steps include finding alternative QI systems that do improve HF outcomes and rigorously studying those practices

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Pirfenidone Shown to Decrease Fibrosis in Patients with HFpEF

Key Points:

Myocardial fibrosis has previously been associated with death and repeat hospitalization in patients with heart failure with preserved ejection fraction.

In a phase II clinical trial, Pirfenidone, an oral antifibrotic agent used in the treatment of idiopathic pulmonary fibrosis, was found to significantly decrease myocardial fibrosis when compared to placebo. Dr. Christopher Miller of the University of Manchester presented the results of the PIROUETTE trial (NCT02932566) at a Late Breaking Clinical Trial session at the 2021 American College of Cardiology Scientific Sessions meeting. Given its effect in reducing pulmonary fibrosis, investigators hypothesized that the TGF-B1 antagonist would work similarly in the myocardium and hoped for a clinical benefit in volume status and quality of life as well.
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Sacubitril/Valsartan Not More Effective Than Valsartan alone in Advanced HF: LIFE trial

Key Points:

  • This is the first study to assess the effects of Sacubitril/Valsartan in patients with advanced heart failure with reduced ejection fraction.
  • No difference was found between Valsartan and Sacubitril/Valsartan when assessing the change in NT-proBNP levels from baseline in this sicker population.
  • The two drugs had similar efficacy and tolerability profiles, with the exception of higher rates of hyperkalemia in the Sacubitril/Valsartan arm.

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REHAB-HF: A Novel Physical Rehabilitation Intervention For Older Patients With ADHF

Key Points:

  • Elderly frail patients with acute decompensated heart failure hospitalizations benefit from cardiac rehabilitation
  • Tailored rehabilitation led to a large, significant improvement in Short Physical Performance Battery (SPPB) score which was relatively uniform across pre-specified subgroups
  • Rehabilitation intervention patients saw large, significant, clinically meaningful improvements in 6-minute walk distance, quality-of-life, Fried Frailty score, and depression

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Are ACE Inhibitors or Beta-Blockers Cardioprotective During Adjuvant Treatment for Early-Stage Breast Cancer?

New results were presented from the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) trial at ACC 2021 on May 16 and published concurrently in Circulation .  The authors found that medications administered in addition to surgery, adjuvant breast cancer (BC) therapy with anthracylines with or without anti-human epidermal growth factor receptor 2 (HER2) therapy, and radiotherapy may not significantly attenuate the reduction in left ventricular ejection fraction (LVEF), nor improve cardiac troponins in early-stage BC patients.
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PRADA: Cardioprotective Agents May Not Be Required During Breast Cancer Tx

Adjuvant breast cancer therapy, while beneficial in prolonging survival, has been shown to have harmful effects on the heart, prompting some providers to prescribe neurohormonal blocking agents to attenuate the myocardial damage. The original PRADA trial showed that candesartan and metoprolol helped prevent a decline in LVEF in patients on adjuvant therapy. To date, however, smaller studies have not shown a similar benefit to neurohormonal blockade. In a late breaking clinical trial session on May 16 at the 2021 American College of Cardiology Scientific Sessions meeting, Dr. Siri Lagethon Heck of Akershush University Hospital in Oslo, Norway, presented the long-term follow up results of the PRADA trial. Continue reading

Tricuspid Valve Replacement with the Transcatheter Evoque Valve is Safe and Effective at 30 days

Transcatheter tricuspid valve replacement has become a feasible alternative to surgery in patients deemed to be at high risk of adverse events, and in the past decade, various devices have been designed to meet this clinical need. In his Focused Clinical Research session on the opening day of the American College of Cardiology 2021 Scientific Sessions, Dr. Susheel Kodali, director of the Structural Heart & Valve Center at New York-Presbyterian/ Columbia University Medical Center presented the 30-day results from the implantation of the EVOQUE valve, as part of the TRISCEND study. Continue reading

Prospective ARNI Versus Ace Inhibitor Trial to Determine Superiority In Reducing Heart Failure Events After Myocardial Infarction (PARADISE-MI)

KEY POINTS

  • Sacubitril/valsartan did not provide a lower rate of cardiovascular death, heart failure hospitalization, or outpatient development of heart failure when compared to active treatment with ramipril in patients after high-risk myocardial infarction.
  • When examining total adjudicated events and investigator reported primary endpoints, there was a trend toward clinical benefit in patients randomized to sacubitril/valsartan.

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EXPLORER-HCM Trial: Mavacamten Associated With Significant Improvement in Patients’ Health Status in Patients With Symptomatic LV Outflow Tract Obstruction

EXPLORER-HCM presented at the American College of Cardiology 2021 meeting by John A. Spertus, MD, MPH, and simultaneously published in The Lancet, demonstrated that the use of mavacamten, a first-in-class cardiac myosin inhibitor, was associated with a highly significant improvement in patients’ health status. 1 out of 5 patients treated with mavacamten tended to experience a significant improvement in health status. Continue reading

Post-Hoc Analysis of DAPA-HF: Dapagliflozin Use Is Associated With Rapid Reduction of Cardiovascular Death Among Patients With Heart Failure With Reduced Ejection Fraction

A recent study by Dr. David D. Berg, published in JAMA Cardiology, found that the use of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with reducing the risk of cardiovascular death and heart failure hospitalization, emerging very early after randomization. Of note, patients with a recent history of hospitalization due to heart failure worsening tend to benefit more and experienced greater relative and absolute risk reductions when treated with dapagliflozin. Continue reading

REPLACE COVID Trial: Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers Can Be Safely Continued in Patients Admitted to Hospital With COVID-19

A recent trial by Dr. Jordana B Cohen, published in The LANCET, indicated that consistent with international society recommendations, patients admitted to the hospital with COVID-19 can safely continue treatment with renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB)) unless there is a distinct medical contraindication to ongoing therapy.

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EMPEROR-Reduced Trial: Empagliflozin Use Was Associated With a Better Clinical Outcomes Among Patients With Heart Failure and a Reduced Ejection Fraction

A recent study by Dr. Milton Packer, published in Circulation, demonstrated that empagliflozin use has been associated with a reduction in the total number of inpatient and outpatient visits in patients with heart failure and a reduced ejection fraction. These benefits were observed within  12-28 days of treatment initiation and were persisted over the duration of the trial. Continue reading

DAPA Trial: Prophylactic Defibrillator Implantation After Primary Percutaneous Coronary Intervention Lowers Long Term Mortality in Patients at High Risk of Death

Results of the DAPA trial, published in Circulation: Arrhythmia and Electrophysiology, demonstrated that the use of early prophylactic implantable cardioverter defibrillator (ICD) in high-risk post-primary percutaneous coronary intervention (PCI) patients was associated with lower all-cause and cardiac mortality rates. However, the results of this trial should be interpreted with caution, since the trial was stopped prematurely.

The optimal timing of ICD implantation in STEMI patients treated with primary angioplasty is not identified yet. Previous clinical trials have failed to show the benefit of early ICD implantation (4-60 days) in post-MI patients with a low left ventricular ejection fraction (≤35-40%). The risk of sudden cardiac death (SCD) is high within the post STEMI period.  However, ICD implantation after 40 days may not be indicated due to left ventricular remodeling and a potential increase in LVEF post-primary PCI. The Defibrillator After Primary Angioplasty (DAPA) trial evaluated all-cause and cardiac mortality of patients undergoing early prophylactic ICD implantation after PCI for STEMI. Following a recommendation from the data safety board, the trial was terminated early after just 38% of the planned sample size was enrolled due to slow enrollment.

This multicenter, randomized, controlled trial included patients with STEMI who had undergone primary PCI and met at least one of the following criteria: LVEF<30% within 4 days after admission, primary ventricular fibrillation (VF) within 24 hours (during PCI excluded), signs of heart failure on admission (Killip class ≥ 2), and/or thrombolysis in myocardial infarction (TIMI) flow post PCI < 3. The participants were randomized in a 1:1 ratio to receive either ICD implantation or conventional therapy within 30 to 60 days of the STEMI event. The primary endpoint was all-cause mortality at 3 and 9-years. The secondary endpoints of the study included the incidence of sudden cardiac death (SCD) and hospital admission for sustained ventricular tachyarrhythmias or appropriate ICD therapy.

A total of 266 patients with primary PCI for STEMI were included in the study with 131 patients allocated to the ICD arm and 135 patients assigned to the conventional therapy arm. After 3-years of follow-up, the primary outcome of interest was significantly lower among patients who received ICD implantation (5%) compared to the conventional therapy group (13%) (Hazard ratio (HR):0.37; [95% CI: 0.15-0.95]; p=0.04). This result remained similar at a median of 9-years follow-up (HR: 0.58; [95% CI: 0.37-0.91]; p=0.02). In terms of cardiac mortality, ICD implantation was associated with fewer deaths (11%) compared to the control group (22%) (HR: 0.52; [95% CI: 0.28-0.99]; p=0.04). Although not statistically significant, the incidence of SCD was also lower in the ICD group (3.1%) compared to the control group (5.9%) (HR 0.45; [95% CI 0.14–1.50]; p=0.19).

The results of this study should be interpreted with consideration of the following limitations. First, the premature termination of the study makes it underpowered for analysis. Second, the study used more than one inclusion criteria, so results should be interpreted with consideration of the patient characteristics. The high treatment crossovers (10.2%) within the first 3 years of the study and the lack of information on treatment crossovers between 3 and 9 years are additional limitations of the trial.  Furthermore, while pharmacotherapy of the participants was similar at baseline, there is a lack of data regarding the follow-up medical therapy which may have impacted the mortality rates.

In conclusion, this prematurely terminated trial suggests that early prophylactic ICD implantation may be associated with a better survival rate in patients at high risk of death after primary PCI for STEMI. The results of this trial should be confirmed in future studies.

Study Shows Aortic Valve Replacement Was Associated With Better Outcomes in Patients with Low-Gradient Aortic Stenosis and Preserved Left Ventricular Ejection Fraction Compared With High-Gradient Aortic Stenosis Analysis of PARTNER 2A randomized trial and SAPIEN 3 registry

A recent study by Dr. Salaun, published in Circulation: Cardiovascular Interventions, demonstrated that aortic valve replacement in patients with the low gradient (LG, defined as mean gradient <40 mmHg) severe aortic stenosis (AS) and preserved ejection fraction (EF) has resulted in better outcomes versus in those with the high gradient (HG, defined as a mean transvalvular gradient (MG) 40 mmHg) AS. Also, the study revealed that patients with classical low flow, low gradient (CLF-LG, defined as MG <40 mmHg and LVEF <50%) AS were at higher risk of death, rehospitalization, or stroke at 2 years.

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DAPA-HF Trial: Compared to Placebo, Dapagliflozin Was Beneficial in Patients with Heart Failure and Reduced Ejection Fraction Regardless of Background Diuretic Therapy

A recent study by Dr. Alice M. Jackson M.D., published in Circulation journal, showed that the use of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with reduced ejection fraction heart failure (HF) is associated with reduced risk of cardiovascular (CV) death or a worsening HF event, and all-cause death. These effects remained consistent among different subgroups of diuretic therapy. 
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Integrated Management of Atrial Fibrillation in Primary Care Demonstrates 45% Reduction in All-Cause Mortality Compared to Usual Care in Elderly Patients

In a recent Dutch study, published in European Heart Journalintegrated care for elderly atrial fibrillation (AF) patients in primary care showed a 45% reduction in all-cause mortality when compared with usual care.

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Cohort Study Showed a Large Number of Patients Receiving Anticancer Therapy Demonstrate Myocardial Injury or Left Ventricular Dysfunction, With Only Few Showing Severe Cardiotoxicity

A recent study by Dr. Lopez-Sendon, published in European Heart Journal, showed that cardiotoxicity in the form of left ventricular dysfunction or myocardial injury affects a large portion of patients receiving high-risk anticancer therapy with only severe form strongly associated with all-cause mortality.

Cardiotoxicity has been known as one of the major side effects of anti-cancer therapy that may present with left ventricular dysfunction and heart failure. Given that the early recognition and treatment of these side effects have been associated with a higher recovery rate, a united diagnostic and management guideline seems necessary.

The CARDIOTOX (CARDIOvascular TOXicity induced by cancer-related therapies) registry has been established to determine the prevalence of cardiotoxicity markers as well as their association with guideline-based heart failure criteria and treatment in patients receiving chemotherapeutic agents. To achieve this purpose, a total of 865 patients receiving anticancer regimens associated with moderate to high cardiotoxicity were selected and followed for a median of 24 months. Clinical data, blood samples, and echocardiographic features were collected before the initiation of anticancer therapy and then at 3 weeks, 3 months, 6 months, 1 year, 1.5 years, and 2 years afterward. Patients with past or current history of heart failure or reduced left ventricular ejection fraction (< 40%) and those with a history of previous cancer therapy including chemotherapy and radiation therapy were excluded from the study. Cardiotoxicity was defined as any new deterioration from the baseline of myocardial/ventricular function during follow-up periods. Cardiotoxicity was also sub-classified into four stages depending on the worst myocardial dysfunction/injury observed in the follow-up period. Myocardial dysfunction/injury stages include the following: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥ 50%; moderate, LVD with LVEF 40–49%; and severe, LVD with LVEF ≤ 40% or symptomatic heart failure.

The study indicated a high incidence (37.5%) of ventricular dysfunction among the patients, of whom only 3.1% were classified as having severe dysfunction and the majority have been classified as mild (31.6%). All-cause mortality was also observed to be higher among those with severe cardiotoxicity than other groups. According to the author, the relatively low prevalence of severe cardiotoxicity in the study population was due to the exclusion of patients with a previous history of cardiac dysfunction and the improvement in the follow-up of the cancer patients in the context of cardio-oncology service. Severe cardiotoxicity has also been associated with a 10-fold increase in total mortality compared to a less severe form of cardiotoxicity. A classification of cardiotoxicity using current heart failure guidelines is also proposed by the authors for future studies. This study acknowledged the critical role of comprehensive monitoring and follow-up for the development of cardiovascular symptoms and left ventricular dysfunction in patients receiving chemotherapeutic agents with potential cardiotoxicity.

Limitations that are worthy of mentioning include the inclusion of patients with some degree of abnormality in biomarkers and echocardiographic findings at baseline. Secondly, the prevalence of myocardial damage may be underestimated due to a number of missing visits or incomplete data collection during the follow-up period. Future research is warranted to approve the relationship of different stages of cardiotoxicity with clinical outcomes.

Study Shows Hepatitis C Status Not Associated With Adverse Events in Adult Heart Transplant Patients by 1 Year

A recent study by Dr. Kilic, published in the American Heart Association Journal, showed similar adverse outcomes in the 1-year survival, rejection rates, and complications of patients who received a heart transplant using hepatitis C-positive (HCV+) donors whereas those using hepatitis C-negative donors.

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Elevated Coronary Sinus Neuropeptide Y Levels Are Associated With Adverse Outcomes in Patients With Chronic Heart Failure

The study by Dr. Ajijola, published in JAMA Cardiology, found that elevated coronary sinus neuropeptide Y (NPY) level is associated with adverse cardiovascular events in stable patients with chronic heart failure and therefore, it may have prognostic value in this population.

Increased cardiac sympathetic signaling has been associated with adverse cardiovascular outcomes. Biomarkers of the sympathetic system are of significant interest in the assessment of cardiovascular outcomes. NPY is one of the circulating catecholamines, which may predict the risk of death in patients with chronic heart failure.

Dr. Ajijola and his colleagues conducted a prospective observational cohort study at a single-center, tertiary care hospital. They observed 105 patients with stable heart failure undergoing elective cardiac resynchronization therapy (CRT) device implantation between 2013 and 2015. Patients with NYHA class I, severe aortic stenosis, cardiac surgery within prior 90 days, severe obstructive pulmonary disease requiring oxygen or with recent decompensation (< 30 days), current pregnancy, primary pulmonary hypertension, continuous intravenous drug infusion for heart failure, and life expectancy under 6 months were excluded from the study. At the time of the intervention, the coronary sinus blood sample was taken and checked for the NPY levels. Patients were evaluated for major adverse cardiovascular events (MACE) as well as responses to CRT.  Composite endpoint was defined as death, cardiac transplant (OHT), or ventricular assist device (VAD) placement.

The results of the study showed that NPY levels of coronary sinus were associated with prognostic implications in patients with heart failure. 20 out of 105 (19%) patients showed composite endpoints at a median follow-up of 29 months. Also, the NPY levels of greater than 130 pg/mL were associated with worse outcomes compared with those with lower levels (HR, 8.9; 95% CI, 3.1 – 25.7; P < 0.001). The results remained significant even after adjusting for age, eGFR, and LVEF (HR, 9.5; 95% CI, 2.92 – 30.5; P < 0.001).  According to Dr. Ajijola, “Coronary sinus NPY levels may identify patients in whom close clinical monitoring and more aggressive interventions are needed to prevent adverse events. It may also identify those in whom CRT is likely to be ineffective, and such patients may be considered sooner for OHT or VAD.”

This study is limited by some points. First, although NPY levels were irrespective of CRT response, the presence of CRT devices limits the external validity of the study. Second, the sample size was small for formal statistical validation of the study including the NPY thresholds. Future studies are warranted to further validate the results of this study and to clarify the prognostic value of NPY levels.