Key Points:

• The use of ECLS has increased substantially over the past decade despite stagnant, high mortality in cardiogenic shock.
• This multicenter randomized trial compared ECLS with control in patients with acute MI-related cardiogenic shock. The primary endpoint was 30-day all-cause mortality.
• There were no differences in the primary endpoint of all-cause mortality between ECLS and placebo; however, ECLS resulted in higher rates of moderate-to-severe bleeding and peripheral ischemia requiring intervention.

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Key Points:

• Qiliqiangxin is a traditional Chinese herbal medicine extract which has been approved since 2004 for the treatment of HF in China.
• This multicenter, double-blind, placebo-controlled trial compared qiliqiangxin with placebo amongst patients with HFrEF (EF<40%). The primary endpoint was a composite of CV death and HF hospitalizations.
• Over a median follow-up of 18 months, qiliqiangxin use resulted in a reduction in the composite primary endpoint.

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Key Points:

• Prior data suggest that heart failure with reduced ejection fraction (HFrEF) patients with iron deficiency receiving IV iron supplementation had improvement in exercise capacity and HF hospitalizations, but the long-term safety and efficacy of the treatment is unknown.
• The HEART-FID trial was a double-blind, placebo-controlled event-driven randomized trial assessing whether there would be improvement in the incidence of death and hospitalization for heart failure or 6-minute walk distance with ferric carboxymaltose therapy compared with placebo in patients with heart failure with a reduced ejection fraction and iron deficiency.
• Patients receiving IV ferric carboxymaltose (FCM) had slightly fewer all-cause mortality events, HF hospitalizations and modestly longer 6-minute walk duration. However,there was no apparent difference in the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.
• Overall FCM supplementation is safe and shows potential clinical benefits; further context can be obtained via pooled analysis with other IV FCM trials.

Iron deficiency has a prevalence of nearly 50% among patients with heart failure with reduced ejection fraction (HFrEF) and leads to impaired health-related quality of life, worsening heart failure (HF) symptoms, and adverse outcomes. The mechanism for iron deficiency in HF is not fully understood though thought to be related to reduction in iron intake as well as absorption and mobilization with increased loss as well. Treatment with intravenous (IV) ferric carboxymaltose (FCM) has previously been shown to improve HF patients’ symptoms and functional capacity. Notably, evidence regarding the utility of IV FCM for improving clinical outcomes such as morbidity and mortality is more limited. Information regarding the long-term efficacy and safety of IV iron infusions is also limited. Furthermore, the majority of available data on the subject was obtained in Europe and excluded other geographic HF populations.

The HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency) (NCT03037931) was a multicenter, randomized, double-blind, placebo-controlled trial that sought to assess the efficacy and safety of IV FCM in the treatment of symptomatic patients in HFrEF with iron deficiency over a period of at least 12 months. Over three thousand patients were randomized at 281 study locations in various geographic regions that included North America, Australia, New Zealand, and Europe. Heart failure patients had ejection fraction (EF) ≤40% within 24 months or ≤30% within 36 months of screening and NYHA Class II-IV symptoms on maximally tolerated background therapy for ≥2 weeks before randomization. They had to have documented HF hospitalization within 12 months of enrollment or elevated N-terminal-pro-brain natriuretic peptide within 90 days of randomization. Criteria for iron deficiency were ferritin <100 ng/mL or 100 to 300 ng/mL with a transferrin saturation <20% with hemoglobin >9.0 g/dL and <13.5 g/dL (females) or <15.0 g/dL (males). Importantly, the trial included those patients with and without anemia. Active bleeding or recent blood transfusion was prohibitive for enrollment.

Eligible patients were given an initial 28-day screening period and then randomized in a 1:1 ratio to receive FCM or placebo. They were then given the study drug on day 0 and 7 and followed up with additional study visits at 3 month intervals. Patients were eligible for additional dosing of the drug every 6 months as needed. HEART-FID trial clinical endpoints included a hierarchical composite of death and HF hospitalizations in the first 12 months, and change in 6 minute walk test (6-MWT) distance at 6 months. Notably a significance level of 0.01 was pre-specified for regulatory purposes by the US Food and Drug Administration (FDA).

Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group, and a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12. The mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon–Mann–Whitney P=0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients.

Presented at the 2023 European Society of Cardiology Congress on August 26^th by Dr. Robert Mentz (Duke Clinical Research Institute, Durham, NC) the HEART-FID trial data showed that administration of FCM resulted in modest improvement for the primary hierarchical endpoint which narrowly missed statistical significance (P=0.019).. When reporting the win ratio in order to translate the endpoint into clinical significance, there were 20% more wins with FCM than placebo for all-cause mortality. When assessing heart failure hospitalizations in those without a death event, there were similar wins in both groups. Change in 6MWT slightly benefited the FCM group. There was a similar percentage of treatment emergent adverse events in each group.

Overall Dr. Mentz states that there was “modest improvement” in the FCM group compared to placebo but importantly IV iron supplementation showed “numerical improvements in mortality.” He goes on to say, “FCM is safe and we build on the prior data showing benefit in quality of life and exercise capacity [with FCM]. Each component of the primary endpoint favors FCM.” He believes that the importance of this study is in providing “another tool in our toolkit in addition to quadruple therapy specifically for HFrEF patients with iron deficiency.” He stated that one significant advantage of FCM is that it does not involve another daily medication and can be administered in clinic in a straightforward way to produce net benefit. Overall, FCM can be used clinically for patients with HFrEF and iron deficiency to help them feel and function better with evidence of a clinical outcome benefit as well. The trial results were simultaneously published in The New England Journal of Medicine.

Key Points:

• A high burden of right ventricular pacing among patients with heart failure patients with reduced ejection fraction is known to cause left ventricular dyssynchrony and progressive dysfunction, yet definitive evidence has been lacking to inform the timing of upgrade to CRT devices.
• The BUDAPEST-CRT Upgrade Study randomized 360 patients with LVEF ≤ 35%, NYHA functional classes II–IVa, paced QRS ≥ 150 ms, and RV pacing burden ≥ 20% to either CRT-D (n=215) or traditional ICD (n=145). The primary endpoint was a composite of all-cause mortality, a first HHF event, or <15% reduction in LVESV at 12 months.
• This trial showed a significant reduction in the primary composite endpoint (32.4% in the CRT-D arm versus 78.9% in the ICD arm, aOR = 0.11, 95% CI 0.06-0.19, p-value <0.001), as well as in several individual secondary endpoints. Taken together, these findings support the clinical practice to promptly pursue CRT upgrade among HFrEF patients with intermittent or permanent RV pacing.

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Key Points:

• More than 80% of patients with HFpEF are overweight or obese, but there has not yet been a study examining the use of weight-loss agents in body weight reduction or HF symptomatology in HFpEF.
• In the Step-HFpEF study, subcutaneous once-weekly semaglutide was compared with placebo in patients with HFpEF and obesity. The two primary endpoints were change of KCCQ-CCS and body weight from baseline after 52 weeks of treatment.
• Semaglutide use resulted in a significant reduction in both heart failure symptomatology and body weight at 52 weeks.

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Key Points

• This trial randomizing patients aged 55 or older to colchicine or placebo following non-cardiac thoracic surgery found no difference in the co-primary endpoints of atrial fibrillation or myocardial injury, but post-hoc analyses indicated benefit in composite outcomes without a signal for increased harm.
• Colchicine increased risk of diarrhea, but patients reported that these symptoms were mostly temporary and benign.
• Further research is needed to explore the encouraging and consistent trend of fewer cardiovascular events with colchicine after non-cardiac surgery.

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Key Points

• This trial randomized elderly patients without a known diagnosis of atrial fibrillation with device-detected atrial high-rate episodes (AHREs) and a median CHA2DS2VASC of 4 to edoxaban or placebo.
• The study was stopped early due to safety concerns and trend towards futility for efficacy after enrollment of all planned patients.
• Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not result in lower incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo. Rather, it was associated with a higher incidence of a composite of death or major bleeding.
• The results indicate that patients with AHREs on their implanted device should not be prescribed anticoagulation unless atrial fibrillation is diagnosed on surface ECG. However, the stroke rates in the control arm were lower than expected.

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Key Points:

• Among patients undergoing PCI using third-generation DES with ultrathin struts and advanced polymer technology, 3- to 6-month DAPT was noninferior to 12-month DAPT for net adverse clinical events (NACE; defined as the composite of cardiac death, TVMI, CD-TLR, stent thrombosis, or major bleeding) at one year (3.7% vs. 4.1%; HR, 0.93; 95% CI, 0.60 to 1.45; p=0.75).
• The rates of target lesion failure (TLR; defined as the composite of cardiac death, TVMI, or CD-TLR) were comparable (2.4% vs. 2.5%; HR, 0.98; 95% CI, 0.56 to 1.71; p=0.94).
• No significant difference in major bleeding (BARC type 3 or 5) was observed (1.5% vs. 1.9%; HR, 0.82; 95% CI, 0.41 to 1.61; p=0.56).
• NACE, TLR, or major bleeding was not affected by the mode of presentation (stable ischemic heart disease or acute coronary syndrome).

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Key Points:

• In spite of the increase popularity of low-carbohydrate high-fat diet due to purported benefit in a variety of conditions, there is limited data on the effect of LCHF diet on overall lipid profile and risk of ASCVD
• Compared to the standard diet, regular consumption of a self-reported low-carbohydrate, high-fat diet was associated with elevated levels of total cholesterol (6.08 vs. 5.85 mmol/L; p=0.002), LDL cholesterol (3.80 vs. 3.64 mmol/L; p=0.004), and apolipoprotein B (1.09 vs. 1.04 g/L; p<0.001).
• At 11 years, LCHF diet was associated with a two-fold risk of incident major adverse cardiac event (MACE; defined as the composite of angina, myocardial infarction, coronary artery disease, ischemic stroke, peripheral arterial disease, or coronary/carotid revascularization) compared to standard diet (9.8% vs. 4.3%; p<0.001).
• Other covariates linked to a greater MACE risk included diabetes (HR=3.37), current smoking (HR=2.44), and hypertension (HR=1.89).

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Key Points:

• Both inflammatory risk and hyperlipidemia and crucial risk factors for MACE in patients at high risk of CVD.
• In a large collaborative study of patients combining data from the PROMINENT (N = 9,988), REDUCE-IT (N = 8,179) and STRENGTH (N = 13,078) trials, the effect of residual inflammatory risk (as measured by hsCRP) and LDL-C levels on MACE were assessed.
• Residual inflammatory risk as assessed by hsCRP was a stronger determinant of risk for future cardiovascular events and death than residual cholesterol risk as assessed by LDL-C.

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Key Points:

• There have been conflicting data on the role and recommended dosage of anticoagulation in non-critically-ill patients with COVID-19.
• In the open-label FREEDOM COVID study, therapeutic anticoagulation was compared with prophylactic doses of enoxaparin in patients hospitalized for COVID-19. The primary endpoint was a 30-day composite of all-cause mortality, requirement For ICU level-of-care, systemic thromboembolism, or ischemic stroke.
• Therapeutic anticoagulation did not result in any significant differences in the composite endpoint, but it did result in lower 30-day mortality and endotracheal intubation compared with prophylaxis.

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Key Points:

• Sotatercept is a novel activin signaling inhibitor which was designed to target pulmonary vascular remodeling in PAH.
• In the STELLAR study, sotatercept was tested against placebo on a background of baseline PAH therapy in adults with WHO II/III PAH. The primary endpoint was change in 6MWD at 16 weeks.
• Sotatercept resulted in an improvement in 6MWD, PVR, NT-proBNP, and a composite of time to clinical worsening and all-cause mortality at 16 weeks compared to placebo.

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Key Points:

• SGLT2i therapy reduces HF hospitalizations and CV mortality in HFpEF, but the mechanism is not yet clear.
• In this single-center, double-blinded RCT, patients with HFpEF were randomized to dapagliflozin or placebo and underwent exercise and resting hemodynamics at baseline and at 24 weeks.
• Dapagliflozin resulted in reduced resting and exercise PCWP, weight, and plasma volume relative to placebo.

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Key Points:

• The μCor monitor is a novel device that uses radiofrequency signals to assess the wearer’s thoracic fluid index, which can indicate HF complications.
• The BMAD trial enrolled 522 patients with HF within 10 days of hospitalization and fitted them with the μCor monitor, which was worn continuously for 90 days.
• Results showed that patients whose clinicians monitored their thoracic fluid index using the μCor device had a 38% relative risk reduction compared to those in the control arm.

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Key Points 

-Lowering LDL-C is known to reduce the risk of ASCVD

-In patients at very high risk for ASCVD or in those with intolerance to statins, PCSK-9 inhibitors are recommended, however, current PCSK-9 inhibitors are administered subcutaneously, limiting their use

-The findings of this Phase 2 trial suggest that MK-0616, an oral PCSK-9 inhibitor significantly reduced LDL-C at 8 weeks by as much as 60.3% compared to placebo

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Key Points

-HCM is the most common cause of sudden cardiac death in athletes

-In patient diagnosed with HCM, long-established guidelines have advocated against vigorous exercise with the assumption this decreases the risk of sudden death

-The findings of the LIVE-HCM trial, suggest that vigorous exercise is not associated with an increased risk of death, cardiac resuscitation, ICD shock, or cardiogenic syncope

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Key Points

– Prompt identification of patients suffering from ACS requires measurements of the blood level of the cardiac troponin biomarker, which is traditionally dependent on laboratory turn-around times.

– A novel wrist-worn, point-of-care test for estimating high-sensitivity cardiac troponin-I (hs-cTnI) based on transdermal infra-red spectrophotometric sensors, and coupled with a machine-learning algorithm, was trained and externally validated on a cohort of 238 patients presenting with ACS across 5 hospitals in India.
– The externally validated model demonstrated an excellent performance with AUC of 0.92 (95% CI, 0.80-0.98; sensitivity, 0.94; specificity, 0.64), and also predicted obstructive coronary disease and regional wall motion abnormalities. As such, this innovative wearable technology may have important implications in real-world settings for diagnosing patients presenting with ACS inside and outside of a hospital.

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Key Points

-Patients with diagnosed sudden cardiac death (SCD)-predisposing genetic heart diseases (GHDs) have traditionally been restricted from participating in competitive sporting activities.

-This retrospective study was the first to assess the risk of potentially life-threatening arrhythmias among NCAA D1 and professional athletes with a mean age of 22±5 years at the time of return to play.

– Over an average follow-up period of seven years, only three (3) athletes (4%) experienced a non-lethal cardiac episode related to their genetic heart disease, with fainting being the most common event. One of these athletes received an appropriate ICD shock. No athletes died during the study follow-up period.

Individuals diagnosed with sudden cardiac death (SCD)-predisposing genetic heart diseases (GHDs) have traditionally been restricted from participating in competitive sporting activities. There has been a paucity of data available to help clinicians make informed shared-decisions with patients and families. However, the concerns for adverse outcomes after return to play (RTP) include a range of scenarios which include, but are not limited to: cardiogenic fainting or seizures, implantable cardio-defibrillator (ICD) shocks, sudden cardiac arrest or sudden cardiac death. One of the largest, most contemporary studies to address this uncertainty, was a 20-year retrospective Mayo Clinic study on shared decision making (SDM)-mediated return-to-play (RTP). Although this study provided promising evidence of extremely low, non-lethal event rates, it was unfortunately, representative of a very young (<22 year of age) athletic cohort in non-elite level (Division I University or Professional) sporting activities.

In a late-breaking presentation at the American College of Cardiology’s Annual Scientific Session Together With the World Congress of Cardiology today, Katherine A. Martinez (an undergraduate student at Loyola University, Baltimore, MD) and her team presented their study: “Return-to-play For Elite Level Athletes With Sudden Cardiac Death Predisposing Genetic Heart Diseases”, which is the first to assess s the risk of potentially life-threatening arrhythmias among National Collegiate Athletic Association (NCAA) Division I and professional athletes with heart conditions that can increase the risk of sudden cardiac death.

This was a multi-center, retrospective analysis of 76 elite athletes playing at the Division I or professional level treated for GHD at Mayo Clinic, Morristown Medical Center, Massachusetts General Hospital, and Atrium Health Sports Cardiology Center. About half of the elite athletes with GHD who were cleared for RTP (40 patients, 53%) had hypertrophic cardiomyopathy (HCM), and one-quarter (20 patients, 26%) had Long QT Syndrome (LQTS).  Slightly more than half of the athletes (40/76, 52%) had no symptoms prior to their diagnosis and were flagged after an abnormal cardiac evaluation, usually during pre-season screening. Approximately a quarter of athletes were diagnosed after experiencing symptoms suggestive of GHD. The remainder were diagnosed due to family history or an unrelated event. About 28% were female, with a mean age at return to play of 22±5 years. The breakdown of elite level participation was 49 (64%) NCAA D1 level and 27 (36%) at the professional level. Approximately one-third of athletes had an ICD.

The athletes included in the analysis played a range of sports, including basketball, hockey, track and field, triathlon and soccer, representing a variety of racial and ethnic backgrounds. Most athletes three-quarters (55/76, 72%) had been initially disqualified from sports based on their diagnosis but ultimately opted for unrestricted return to play after comprehensive clinical evaluation and implementation of SDM.

Over an average follow-up period of seven years, only three athletes (4%) experienced a non-lethal cardiac episode related to their genetic heart disease, with fainting being the most common event. One of these three patients received an appropriate ICD shock. No athletes died during the study follow-up period.

The results of this study by Katherine A. Martinez and team, provides hope for many patients with GHDs who wish to participate in sporting activities, particularly at the elite level. This study particularly highlights the importance of shared decision-making approaches to clinician-patient interactions as well as the need for multidisciplinary specialist involvement (genetic cardiologists and sports cardiologists among others) in the care of this patient population. This brings focus to the growing importance of an individualized approach to clinical recommendations. The devastating instances of high-profile tragedies naturally influences organizational, clinician and public perceptions of the health risks posed by GHDs in the sporting arena. However, this contemporary analysis stresses the importance of using scientific evidence in informed decision making. Prospective, multi-center data will be prudent to help bolster policy and guideline statements. The authors acknowledged that essential criteria for a comprehensive RTP protocol, must include: patient commitment to adherence to prescribed treatments and follow-up, access to an AED and open communication with relevant stakeholders overseeing elite sporting activities.

In closing, regarding the clinical implications of the study, Katherine Martinez stated: “our study provides scientific evidence, that for athletes competing at an elite level with an ICD, the outcomes are good.”

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Key Points:

• Macitentan and Tadalfil are frequently used in combination for PAH, which opens up the possibility of a fixed-dose combination pill.
• In the DUE study, macitentan/tadalafil FDC therapy was compared against macitentan and tadalafil monotherapy. The primary outcome was PVR reduction at 16 weeks.
• M/T FDC resulted in a significant reduction in PVR at 16 weeks compared to either macitentan or tadalfil monotherapy. There was a non-significant trend towards reduction in 6MWD at 16 weeks.

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Key Points

• Despite an extensive body of evidence supporting the benefit and use of guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF), its implementation remains low
• The IMPLEMENT-HF study explored the efficacy of virtual optimization of GDMT for hospitalized patients, hypothesizing that a dedicated GDMT Team would improve GDMT optimization during admission compared to usual care
• A virtual care team-guided strategy improved GDMT in hospitalized HFrEF patients; this strategy was safe and was not associated with increased hospital length of stay.

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