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CETP Inhibition: Past Failures, Future Prospects

Dal-GenE: A Pharmaceutical Trial to Reduce Atherosclerotic Events

Tardif JC, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. The main Dal-OUTCOMES trial results showed that Dalcetrapib showed no significant difference on the primary end point i.e. composite of death from coronary heart disease, a major nonfatal coronary event, or ischemic stroke as compared to placebo (p=0.52). Discovery GWAS in the dal-OUTCOMES trial showed that a  single  region  with  genome-wide  significance  was correlated  with   cardiovascular   events   in the Dalcetrapib group using  Cox   proportional hazards modeling, identifying SNPs  in  the  ADCY9  (Adenylate Cyclase Type 9) gene  on  chromosome  16 from  5 ,543,264  common  genetic  variants. The treatment effect by genotype ADCY9 rs1967309 emerged very different picture in the outcomes in AG patients had neutral impact with Dalcetrapib and placebo whereas AA patients showed significant reduction in the incidence of events with Dalcetrapib (RRR 39%) but GG patients cause harm due to Dalcetrapib as compared to placebo. Dal-Plaque 2 study was independent from Dal-outcomes trial in which 1000 patients were randomized to receive Dalcetrapib showed that the homozygous minor allele patients had regression of atherosclerosis, heterozygous patients had neutral effect and homozygous patients showed major progression of atherosclerosis. Patients with AA and AG genotype showed significant increase in cholesterol efflux than placebo after 12 months whereas patients with GG genotype didn’t show any difference. As per 2018 Circulation paper, ADCY9 genotype inactivation protects from atherosclerosis in mice infected with AAV8-Pcsk9 given a high cholesterol diet. But, ADCY9 inactivation-induced atheroprotection is lost in mice expressing CETP. The recent 2021 study showed the evolutionary interaction between ADCY9 and CETP genotypes on CETP mRNA expression in GEUVADIS group. Meta-analysis supports interaction of CETPi and ADCY9 gene.

A large prospectively conducted clinical trial is required assessing the effects of Dalcetrapib in patients with AA genotype that trial has been existed and conducted from past 4 years called Dal-GenE screened more than 40,000 patients with recent ACS, but failed in GG and AG patients and left with 6147 patients with AA randomized to Dalcetrapib and placebo. The results of the trial will be available in 2022.


A Unified Theory of Cardiovascular and Related Chronic Diseases

Ornish D, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. A whole food plant-based diet is naturally low in fat and refined carbohydrates. The stress management techniques, moderate exercise and psychological support are important lifestyle medicines. Eat well, move more, stress less and love more are the simple lifestyle changes can be powerful to lead healthy life at low cost. Ornish diet is the best heart-healthy diet from 2011. The same diet and lifestyle can be beneficial for the improvement in health. The reason is that these same lifestyle changes can help prevent and reverse the progression of different chronic diseases is that they are different manifestations of same underlying biological mechanisms. Lifestyle Heart study showed that treatment group had reduction in average percent stenosis from 40.7% at baseline to 38.5% at 1 year to 37.3% at 5 years (p<0.01).

Intensive Cardiac Rehabilitation (ICR) program was conducted for reversing heart disease on 10,180 patients. After nine weeks of ICR program, beneficial results were seen in all biomarkers i.e. reduction in lipid parameters, BP, depression, weight. After 12 weeks, this lifestyle program downregulated genes involved in causing chronic inflammation, oxidative stress, angiogenesis, and atherosclerosis and cholesterol metabolism. Gene expression in 501 genes was beneficially affected in only 3 months. RAS oncogenes that promote prostate cancer and breast cancer were downregulated. The Lancet study showed that positive lifestyle changes may reverse ageing on a cellular level.

The same lifestyles changes affect and may even reverse the progression of a wide range of the most common and costly chronic diseases because they share common biological pathways. These biological pathways are directly influenced by what we eat, how we respond to stress, how much exercise we get and how much love and social support we enjoy. This simplifies the lifestyle recommendations to the patients and to the general public.


Edoxaban Versus Dual Antiplatelet Therapy for Valve Thrombosis and Cerebral Thromboembolism after Transcatheter Aortic-valve Replacement: A Randomized ADAPT-TAVR Trial

Park DW, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. The primary objective of the study was to investigate the effect of Edoxaban compared to DAPT for the prevention of leaflet thrombosis and accompanying potential risks of cerebral thromboembolization and neurological or neurocognitive dysfunction in patients without an OAC indication after TAVR. The secondary objective was to determine the casual association of subclinical leaflet thrombosis with cerebral thromboembolism and neurological/neurocognitive function. In , 220 patients without no indication of OAC after successful TAVR were equally randomized to NOAC (Edoxaban) and DAPT (ASA plus Clopidogrel). The primary endpoint was incidence of leaflet thrombosis on 4D, volume-rendered CT at 6 months. The Edoxaban group did not showed statistical difference in primary end point as compared to DAPT. Lesset no. of patients in the Edoxaban group showed reduced leaflet motion Grade ≥3 than DAPT (p=0.15). Edoxaban group showed increase in presence of new cerebral lesions whereas reduction in median number of total new lesions as compared to DAPT. No difference was seen between both groups in neurological and neurocognitive end points and in safety and efficacy outcomes.

The overall incidence of leaflet thrombosis on CT scans was less frequent with Edoxaban therapy than with the DAPT therapy, although did not reach statistical significance. The incidence of new cerebral thromboembolism on brain MRI and new development of neurological or neurocognitive dysfunction were not different between two groups. There was no association between subclinical leaflet thrombosis and temporally related changes of new cerebral thromboembolic lesions and neurological end points.

Five-year Incidence, Timing And Predictors Of Structural Valve Deterioration of Transcatheter And Surgical Aortic Bioprostheses: Insights From The Corevalve US Pivotal And SURTAVI Trials

Transcatheter aortic valve implantation (TAVI) is an established treatment for severe aortic stenosis (AS) in patients of all risk levels. Reardon M, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. The objective of the study was to evaluate the 5-year incidence, outcomes and predictors of hemodynamic structural valve deterioration (SVD) in patients undergoing supraannular, self-expanding TAVI and surgery from the Corevalve US pivotal and SURTAVI trials. TAVI showed significantly lower rate of SVD as compared to surgery in 5 years (2.57% vs 4.38%) (p=0.0095). TAVI showed significantly lower rate of SVD in smaller (≤23 mm) annual diameters as compared to surgery in 5 years (1.39% vs 5.86%) (p=0.049). TAVI showed significantly lower rate of SVD in larger (>23 mm) annual diameters as compared to surgery in 5 years (2.48% vs 3.96%) (p=0.067). Corevalve Evolut pooled analysis showed that patients with higher risk of SVD had worsened clinical outcomes i.e mortality and hospitalization.

In patients with severe AS at intermediate or high surgical risk, the 5-year rate of SVD was 4.38% in patients undergoing surgery and 2.57% in patients undergoing TAVI. The difference in SVD was more profound in patients with smaller annuli (5.86% vs 1.39%), but a trend was also found in patient with larger annuli (3.96% vs 2.48%). The Doppler-derived SVD imparted a near 2-fold risk for all-cause mortality and hospitalization for AV disease or worsening HF at 5 years.


A Randomized Trial to Confirm the Safety and Effectiveness of Chocolate Touch Paclitaxel Coated PTA Balloon Catheter in Above the Knee Lesions

Shishehbor M, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. Chocolate Touch DCB is nitinol constrained balloon designed to reduce vessel trauma and dissections by creating pillow. The distal assembly is coated with paclitaxel to inhibit neointimal formation. The objective of the study was to compare the efficacy and safety of the chocolate touch DCB to the commercially approved lutonix DCB in an international randomized clinical trial. Chocolate Touch, an open-label, randomized, non-inferiority trial in which patients with symptomatic SFA or popliteal arteries were randomized to chocolate touch group (n=152) and Lutonix (n=161). The primary effectiveness endpoint was true DCB success at 12 months and safety endpoint was freedom from major adverse events (MAE) at 12 months. At follow up of 12 months, 142 patients of chocolate touch group and 149 patients of Lutonix group completed the visits. Chocolate touch group showed significant improvement in primary efficacy endpoint as compared to lutonix (78.8% vs 67.7%) (pnon-inferiority<0.0001). Chocolate touch group showed consistent true DCB success at 12 months. At primary safety endpoint, both groups showed no significance difference and lead to non-inferiority. Chocolate touch group showed similar mortality as treated population.

The Chocolate Touch study met its primary effectiveness of True DCB success at 12 months with superior efficacy than Lutonix group.  Chocolate Touch also met its non-inferiority endpoint for safety. No difference in mortality is seen, although the trial was not adequately powered for a mortality endpoint.

Very Mild Perioperative Hypothermia versus Aggressive Warming and Myocardial Injury after Non-Cardiac Surgery: The PROTECT Trial

Sessler D, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. It has been reported by small trial that mild hypothermia (≈35.5°C) results in increased morbid myocardial outcomes. Other trials have also reported that moderate perioperative hypothermia (≈34.5°C) can promote surgical site infections and increase transfusion requirements. As per the international guidelines, it is recommended to keep surgical patients normothermic and active intraoperative warming. The following study primarily hypothesised that aggressive intraoperative warming reduces the incidence of major cardiovascular complications.

The study was conducted as a multi-centre trial in which patients were randomly assigned to routine care (intraoperative core temperature ≈35.5°C) or aggressive warming (≈37°C). The primary outcome assessed was a composite of myocardial injury (troponin elevation, judged due to ischemia), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery.

In this multicentre trial, a total of 5,050 patients were randomized and the mean age was 67 years; a third were female. Final intraoperative temperatures were 35.6±0.3 (SD) and 37.1±0.3°C. The number of cardiovascular complications was found to be similar in patients randomized to 35.5°C and to 37°C: 218/2507 v. 226/2505 patients: RR 1.04 [95% CI: 0.87, 1.25]. At each temperature, serious wound infections [RR 1.13 (95% CI: 0.87, 1.47)], transfusions [RR 1.07 (0.86, 1.32)], duration of hospitalization [HR 0.98 (0.91, 1.05)] and hospital re-admissions [RR 1.19 (0.89, 1.57)] were also similar.

The study concludes that size of PROTECT trial is 10 times more than ten times the size of previous thermoregulatory trials, most of which were conducted two decades ago. Over a 1.5°C range from very mild hypothermia to full normothermia, no outcome varied and keeping the temperature at ≥35.5°C in surgical patients appears sufficient.


Long Term Effect of Renal Denervation on Blood Pressure Reduction in Patients on Antihypertension Medications: 3-year Efficacy Outcomes from the SPYRAL HTN-ON MED Trial

Mahfoud F, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. In SPYRAL HTN-ON Pilot, it was found that renal denervation (RDN) significantly lowered blood pressure (BP) at 6 months in patients with uncontrolled hypertension (HTN) on antihypertension (AH) drugs.

In this trial, patients were randomized in 1:1 to undergo RDN or a sham procedure. The eligible patients had an office systolic BP of 150 to <180 mmHg, diastolic BP >90 mmHg, 24h ambulatory systolic BP (ASBP) of 140 to <170 mmHg, and were administered with 1-3 AH drugs. The study enrolled a total of 80 participants with uncontrolled HTN (n=38 RDN, n=42 sham).

The results of the study show that at the end of 3 years, RDN patients showed greater ABSP reduction compared to sham control patients (-18.7±12.4 mmHg vs. -8.6±14.6 mmHg, p=0.004, respectively and office BP systolic reductions showed a similar trend at 3 years (-20.9±15.3 mmHg vs. -12.5±21.6 mmHg, p=0.073).

Radio frequency RDN patients compared with sham control patients showed significant reductions in ambulatory systolic BP independent of concomitant antihypertensive medications out to 3 years despite similar AH medication burden. Given the long term safety and efficacy, RDN provides an adjuctive treatment modality in the management of hypertension.


Differential Impact of Residual Inflammatory Risk and Residual Cholesterol Risk Among Atherosclerosis Patients with And Without Chronic Kidney Disease: Secondary Analysis of The CANTOS Trial

Ridker P, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. Atherosclerotic disease is jointly contributed by hyperlipidaemia and inflammation and relative contributions of these processes differs in patient groups, with and without patient groups. In CANTOS, 9,151 stable statin treated post-myocardial infarction patients were included to compare the relative contributions of residual cholesterol risk and residual inflammatory risk as determinants of recurrent major adverse cardiovascular events (MACE).

The patients in CANTOS were stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.73m2 and follow up was done for 5 years. Among CANTOS participants with eGFR >60 mL/min/1.73m2, there was a positive association between plasma hsCRP, IL-6, LDLC, and non-HDLC and risks of recurrent MACE (all P-values <0.0001). Among participants with eGFR <60 mL/min/1.73m2, increasing quartiles of hsCRP [P=0.006] and IL-6 [P=0.018]) significantly predicts recurrent MACE.

After adjustment for a wide range of potential confounding factors, the predictive utility of inflammation as compared to hyperlipidemia among patients with eGFR <60 mL/min/1.73m2 remained significant and was particularly striking for cardiovascular and all-cause mortality.

Among atherosclerotic patients with impaired kidney function, residual inflammatory risk may hold a greater importance than residual cholesterol risk. The data available from CANTOS can help in the development of novel agents that target inflammatory processes in this high-risk group of patients.


Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure- Results from the EMPULSE Trial

Kosiborod M, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. Heart failure patients are associated with high burden of symptoms, physical limitations and poor quality of life. SGLT2 inhibitors causes reduction in symptoms in chronic HF, but their effects in acute heart failure are not well characterized.

In this trial, patients with AHF (de novo or decompensated chronic HF, regardless of ejection fraction or diabetes) were randomized to empagliflozin (EMPA) 10 mg daily or placebo (PBO) for 90 days. Assessment of Kansas City Cardiomyopathy Questionnaire (KCCQ) was done at baseline, 15, 30 and 90 days. Analysis of Change (baseline to Day 90) in KCCQ Total Symptom (TSS), Physical Limitations (PLS), quality of life (QoL), clinical summary (CSS) and overall summary (OSS) scores was done.

 A total of 530 patients were randomized with 265 patients in each arm. EMPA-treated pts had a greater improvement in KCCQ TSS, PLS, QoL, CSS and OSS at Day 90 [effect sizes (95% CI): 4.5 (0.3, 8.6), p = 0.035; 4.80 (0.0, 9.6), p = 0.050; 4.7 (0.3, 9.0), p = 0.036; 4.9 (0.8, 8.9), p = 0.02; and 4.4 (0.3, 8.5), p = 0.03, respectively]. Benefits were evident at 15 days and were maintained throughout 90 days.

The study concludes that initiation of EMPA in patients hospitalized for AHF showed improvement in symptoms, physical limitations and quality of life with benefits seen at 15 and maintained through 90 days.


Comparison of Fractional Flow Reserve-guided And Intravascular Ultrasoundguided Percutaneous Coronary Intervention in Intermediate Coronary Artery Stenosis: The FLAVOUR Randomized Clinical Trial

Koo B, presented a study in a session at American College of Cardiology (ACC) on 4th April, 2022. The current standard to define the presence of ischemia in patients with coronary artery disease is fractional flow reserve (FFR) but clinical events still occur after FFR-guided deferral of revascularization. To reduce the risk of adverse events, IVUS-guided percutaneous coronary intervention is most commonly used in comparison with angiography-guided PCI. However, there has not been a solid evaluation about the impact of FFR-guided vs. IVUS-guided PCI on clinical outcomes.

Patients with intermediate stenosis were randomized to either FFR-guided or IVUS-guided PCI in a 1:1 ratio in this international multi-centre study. In the FFR group, PCI was performed according to the predefined criteria for revascularization; FFR ≤ 0.80. In the IVUS group, the predefined criteria were minimal lumen area (MLA) ≤3 mm2 or 3 mm2 < MLA ≤4 mm2 and plaque burden >70%. Primary endpoints assessed were composite of all-cause death, myocardial infarction, and any revascularization at 24 months.

A total of 1682 patients were successfully randomized with the mean age of 65 years. In the FFR group, the rate of target lesion PCI was significantly lower than in the IVUS group (32.9% vs. 57.6%, p<0.001). At the end of 2 years, the primary composite endpoint rate was 8.1% in the FFR group and 8.6% in the IVUS group (hazard ratio, 0.94; 95% CI, 0.67 to 1.31).

The study concludes that FFR group is non-inferior to IVUS group with regards to adverse clinical outcomes during the 2-year follow-up period. Owing to different criteria for revascularization, the FFR group received lesser stents than the IVUS group.

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Artificial Intelligence: New Ways of Diagnosing Valvular Heart Disease

Elias P, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022. Artificial intelligence (AI) often seeks to match MD performance. Electrocardiograms (ECGs) are not diagnostics for aortic stenosis (AS). Cardiologists can’t detect AS from just an ECG. The ECGs were done on patients with echocardiograms and generate labels to diagnose what a human expert cannot. The objective of the study was to develop a deep learning model which analyses ECGs to detect patients with left-sided moderate or severe valvular heart disease (VHD) as determined by echocardiography. Total 617,564 ECGs were performed <1 year prior to echocardiography in 114,215 patients. After excluding 342,509 ECGs, 2,21,255 ECGs were conducted on 43,165 patients in multisite train and one ECG per patient was conducted in multisite validation, multisite train and holdout site test. The ECG model accuracy on test set was AU-ROC 0.88 for aortic stenosis, 0.77 for aortic regurgitation, 0.84 for AS/AR/MR. As per the screening program modeling, positive predictive value of AS,AR, or MR was inversely correlated to sensitivity of model. Saliency mapping determines what features the model uses to make predictions. Red line in the model pull towards positive results and blue line pull towards negative result. This is a true positive with aortic stenosis with the greatest activation in the QRS and T waves, less in the P waves.

Next step in the AI is taking steps to develop this technology further to detect early VHD with conduction of additional multicenter retrospective validation studies and actively enrolling a 200 patient prospective diagnostic trial in patients with no history of VHD. Also, it is developing single lead models for POC testing options. It built the first soup-to- nuts tutorial IntroECG to get deep learning with cardiac data and imaging.

Guidelines for Hypertension Management Around the Globe: The ESC/ESH Perspective

Dominicazak AF, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022. The objectives of the study were to discuss the diagnosis and role of out-office BP, organ damage, BP threshold and target for treatment, drugs and strategy of treatment. If the BP is 140/90 mmHg, repeat visits to office BP measurement or/and out-of office measurement (ABPM/HBPM) to confirm the diagnosis. Elevated ambulatory BP significantly increases the risk of CV events and mortality. Elevation in BP with organ damage significantly increases the high risk for patients to CVD. According to SCORE, SCORE ≥5% with superoxide dismutases (SOD) present substantially increase the probability of CV death as compared to SCORE ≥5% with no SOD p<0.001. In the younger age group of 18-65 years and age 65-79 years, the BP ≥140/90 mmHg is threshold to treatment. For ≥80 years group, BP ≥160/90 mmHg is considered to treatment and ≥130/ 85 mmHg is considered for very high risk group. According to RT-based meta analyses, lowering SBP to <130 or DBP to <80mmHg significantly reduces the risk of all CV events and CV-cause death. The office BP treatment target range for all age group should be first SBP <140 mmHg and aim for SBP 130 mmHg. Sometimes BP lowers too much while decreasing stroke, CHD and HF risk leads to predominately increase in treatment discontinuation to adverse drug reactions. Initial two-drug combination therapy showed better adherence to treatment, reduced therapeutic inertia, better long-term BP control and reduces CV events. 5 drug classes (ACEIs/ARBs/BBs/CCBs/Ds) have proven ability to reduce BP, CV events in placebo controlled studies. These guidelines recommend that the same 5 classes of drugs should form the basis of antihypertensive therapy.

The core drug-treatment strategy for uncomplicated hypertension is dual combination initial therapy of ACEi or ARB plus CCB or diuretic in 1 pill. Step 2 of therapy will be triple combination of ACEi or ARB plus CCB plus diuretic in single pill. If hypertension is still resistant with treatment, spironolactone or other diuretic, alpha-blocker or beta-blocker is added to the triple combination therapy with 2 pills.


Past, Present, and Future: Addressing the Global Burden of Hypertension and Cardiovascular Disease

Yusuf S, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022. The prevalence of hypertension is about 40-50% in most of countries. 10 years back, PURE study showed that 17 countries showed very high prevalence of hypertension with 40-50% awareness and 40-45% treatment ratio whereas control rate was 10-20% only. Salt substitute and Stroke Study (SSaSS), a cluster, randomized, parallel, open-label trial with 20,995 patients randomized to salt-substitute or regular salt and followed for approx 5 years. Salt substitution group had higher SBP reduction with difference of 3.34 mmHg. Also, salt substitution showed mean 24 hr U Na excretion of 4.3g/d with diiference of 8% and mean 24 hr U K excretion of 1.4g/d with difference of 57%. Salt substitute lowers stroke, major CVD and death in patients as compared to regular salt. PREMIER trial showed that the established behavioral program further lowered SBP by 3.7 mmHg (p<0.01). Combined DASH diet with established behavioral program resulted in further SBP reduction by 0.6 mmHg. Bothe interventions significantly lowered body weight. FDC meta analysis of 18,162 patients overall from TIPS-3, HOPE-3 and PolyIran studies showed that FDC group significantly reduces LDL-C (mean diff- 22.6 mg/dL) and SBP (mean diff- 4.7 mmHg) as compared to control, group. The primary outcome i.e. CV death, MI, stroke, revascularization was significantly reduced by FDC group (p<0.0001). The addition of aspirin to FDC showed superior results in risk reduction of primary outcomes.

Hypertension is poorly detected, treated and controlled worldwide. Improving K intake reduces BP, CVD and mortality. Combination of BP lowering drugs plus statin plus aspirin safely reduces CVD by 50%. Such a low cost community wide strategy can avoid over 10 million CVD events each year globally and is applicable to all economic settings.


Gaps in Guideline-Based Lipid-Lowering Therapy for Secondary Prevention in the United States: A Nationwide Analysis of 227,824 Patients

Kolkailah AA, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022.Statins are specified for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). But, the degree to which statins are used and dosed for secondary prevention in clinical practice is not clear.
Patients with ASCVD that acquired care during 2017-2018 were recognized over 90 health systems in the US using Cerner Real World Data, a de-recognized electronic health record (EHR) dataset. Medication data were analysed to categorize patients into 3 groups according to 2018 ACC/AHA guideline recommendations: not on a statin, on lower-than-recommended statin (low or moderate intensity), and appropriate dose (high intensity).

From 227,824 ASCVD patients incorporated (median age 65 years, 61.7% male, 80.1% white), 41.2% were on appropriate statin treatment, 31.1% were on lower-than-recommended treatment, and 26.7% were on no statin. Patients not on statins or on less-than-recommended statin intensity were more likely to be female and less likely to have private insurance as compared to patients on appropriate treatment (p<0.001). All groups had low usage of non-statin lipid lowering therapy (LLT).

Above half of patients with ASCVD are not on guideline-recommended appropriate statin treatment, few are using evidence-based non-statin LLT, and many are using non-evidence-based LLT. Additional work is urgently required to enhance usage of guideline-based LLT in clinical.

Long-Term Overexpression of BMP9 Prevents Pulmonary Hypertension

Genetic evidence implies bone morphogenetic protein 9 (BMP9) as a culprit gene for pulmonary arterial hypertension (PAH). But, removal or inhibition of BMP9 prevents or even alters PAH. To mark this contradictory, Wang SJ, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022 which developed a BMP9 transgenic rat model (Tg-BMP9) and evaluated the long-term impact of BMP9 on the pulmonary vascular.
Transgenic SD rat lines were developed with overexpression of human BMP9 especially in the liver. The phenotype characteristics of pulmonary artery were evaluated at baseline or exposed to of monocrotaline stimulation for 3 weeks.
The expression of BMP9 protein were frequently up-regulated in both liver and blood in Tg-BMP9 rats. These rats were phenotypically normal for up to 6 months of results. Surprisingly, the monocrotaline-induced pulmonary vascular remodeling were almost completely inhibited using BMP9 overexpressing. In Tg-BMP9 rats, the right ventricular wall thickness (RVAW) and internal diameter (RVID) were reduced by 33% and 45%, respectively. Tg-BMP9 rats showed reduction of mean pulmonary arterial pressure (mPAP) by 20 mmHg. Tg-BMP9 rats showed lesser wall thickness of small pulmonary arteries as compared to in wild-type littermates.

Long-term overexpression of BMP9 does not lead to spontaneous PAH. In comparison, it prevents pathological pulmonary remodeling. The long-term improvement of BMP9 could be a favorable preventive strategy for PAH.

A Comparison of Plant-Based, Mediterranean, Paleolithic and Dash Diets

Cardiovascular disease is the major cause of death in the US. Talreja S, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022 which analysed the effect of four diet programs: plant-based, Mediterranean, Paleolithic and DASH diets on CV risk factors.
Nondiabetic adults (ages 35-85) with one or more risk factors for CVD were enrolled in the study. Participants attended a comprehensive nutrition education program before a 60-day diet intervention in which they kept a daily food log and met weekly with a multi-disciplinary study team. An initial health screen analyzed weight, blood pressure, fasting glucose, A1C, lipids and lipoprotein particles, and was repeated following 60 days and at 6-months follow-up.
279 patients completed the 60-day dietary intervention (58 Vegan, 80 Mediterranean, 76 Paleo, 65 DASH), and 199 returned for 6-month follow-up. Mean age of patient was 56 years, mean BMI 33 kg/m2. Mean FPG, TG and HDL-C were within the normal range at baseline, but LDL-P and BP were increased. Patients lost an average of 9 lbs (4.7% body weight), which was correlated with enhancements in BP over all groups following 60 days on the respective diets. Patients lost the most weight (6.5%) on the Vegan and Paleo diets and exhibited the highest enhancements in lipid risk factors (11-14% reduction in LDL-P; 10-20% reduction in VLDL and TG).

All 4 diets aided weight loss and enhanced BP however showed changing impacts on lipid risk factors. Impacts were highest and sustained in those patients who underwent regular diet support group meetings.


Multisite, Randomized, Controlled Trial of a Supermarket and Web-based Intervention Targeting Nutrition for Cardiovascular Risk Reduction

Steen DL, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022. Dietary interventions may foremost be delivered at grocery stores, which provide convenience, accessibility, full food inventories, and increasingly, in-store registered dietitians, online shopping and delivery services, electronic food purchasing data-guided support tools, and other healthcare services. The effectiveness of interventions controlling these opportunities has not been explored by well designed clinical trials. A multisite, randomized, controlled trial (N=247) was conducted enrolling from a primary care network via each participant’s home grocery store and retail clinic. Two individualized, in-person, dietitian-led, education interventions focused on the Dietary Approaches to Stop Hypertension (DASH) dietary pattern and guided by electronic food purchasing data were evaluated: 1) “Strategy 1” harnessed the in-store environment for education, demonstration and practice and 2) “Strategy 2” harnessed both the in-store and online environments. Participants were allocated 2:2:1 to Strategy 1, Strategy 2, or standard of care (SOC). Two hypotheses were analysed hierarchically to estimate change in DASH score from baseline to 3 months (post-intervention): 1) Strategies 1 and 2 together compared with SOC and 2) Strategy 2 compared with Strategy 1. The interventions elevated DASH score by 4.7 as compared to SOC (0.9, 8.5; p=0.02). Strategy 2 elevated DASH score by 3.8 (0.8, 6.9; p=0.01) as compared to Strategy 1. A pre-specified examination showed that prior to the COVID-19 pandemic, the interventions elevated DASH score by 8.3 (3.4, 13.3; p=0.001) as compared to SOC.

This trial exhibited the effectiveness of two comprehensive, retail based, dietary interventions as well as modern online shopping devices. These findings are timely given the rapid growth and consumer adoption of online shopping as well as retail-based care. This trial shows the chance for academia to cooperate with the rapidly expanding and evolving, retail-based healthcare industry to outline and rigorously analyse nationally scalable, community-based healthcare interventions.


Magnitude And Duration of Effects of A Short-interfering RNA Targeting Lipoprotein(a): A Placebo-controlled Double-blind Dose-ranging Trial (APOLLO Trial)

Nissen S, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022. A genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis (AS) is elevated Lipoprotein(a) [Lp(a)]. As per mendelian randomization studies, elevated Lp(a) levels show positive association with ASCVD and AS.

SLN360 is a 19-mer double-stranded small interfering RNA (siRNA) targeting LPA messenger RNA. Apolipoprotein(a) is encoded in LPA which is a dominant and rate limiting component in the hepatic synthesis of Lp(a). SLN360, an siRNA contains a covalently linked N-acetyl-galactosamine (GalNac) ligand attaches to a receptor expressed on liver cells facilitating concentration of SLN360 in the liver. The APOLLO trial was conducted that included men and women, between the 18-70 years of age, without evidence of ASCVD or AS and an Lp(a) level ≥150 nmol/L (equivalent to approximately 60 mg/dL). The mean age of the participants enrolled was 49.6±13.5 years, 53.1% were female, and median Lp(a) levels were 224 nmol/L (IQR 188-278). Two cohorts were developed with 8 participants in each ((6 active: 2 placebo), were randomized to ascending doses of SLN360 or placebo at 30, 100, 300, or 600 mg subcutaneously. Measurement of plasma concentrations of the drug and Lp(a) were used to determine the pharmacokinetic and pharmacodynamic effects of SLN360 and effects were assessed at multiple time points for the first 24 hours and during follow up for 150 days. Single dose of SLN360 significantly reduces median Lp(a) levels at day 30. SLN360 showed significant reduction in Lp(A) by 98% after 60 days. SLN360 300 mg and 600 mg dose showed significant reduction in LDL-C by 21% and 26% resp. and in ApoB by 21% and 24% resp.

Subcutaneous injection of an siRNA (SLN360) targeting mRNA for the LPA gene lowered lipoprotein(a) upto 98%. >70% and >80% reductions in Lp(a) persisted for 150 days after the 300 mg and 600 mg doses. The highest doses reduced LDL-C and Apo-B by 20-30%. The findings support further development of the therapy.

Patiromer for the Management of Hyperkalemia in Subjects Receiving Renin-angiotensin-aldosterone System Inhibitor Medications for Heart Failure with Reduced Ejection Fraction: Results from the DIAMOND Trial

Butler J, presented a study in a session at American College of Cardiology on 3rd April, 2022. For the treatment of patients with heart failure with reduced ejection fraction (HFrEF), Renin-angiotensin-aldosterone system inhibitors (RAASi) follow a class I indication. However, RAASi therapy is often down titrated or discontinued in patients with history of or current hyperkalemia. The following study hypothesized that treatment with patiromer, a novel potassium binder, can result in lower serum potassium (sK+) levels, thus facilitating guideline directed medical therapy.

The DIAMOND trial was conducted which included 1640 patients with HFrEF with current or history of hyperkalemia where participants were optimized on RAASi therapy including mineralocorticoid receptor antagonist (MRA), and patiromer. Following this, patients were randomized to double-blind in a 1:1 ratio to either continued patiromer treatment or plabo (patiromer withdrawal). The primary endpoint assessed was mean difference in serum potassium from baseline between the two arms for the duration of the trial.

A total of 1194 patients entered the run-in phase, out of which 878 were randomized. Average duration of follow up was 266.6 days. Patiromer showed significantly lesser increase in serum K+ levels as compared to placebo (+0.03 vs +0.13) (p<0.001). Patiromer had lesser no. of hyperkalemia events than placebo (61 vs 85) (p=0.006). Lesser no. of patients with patiromer had reduction of MRA dose below target (61 vs 83) (p=0.006).

Most patients (84.6%) with HFrEF and RAAS related hyperkalemia could achieve optimal doses of RAASi including MRA when treated with patiromer. Patiromer maintained lower serum K+ levels. Patiromer was associated with lower incidence of hyperkalemia events and greater proportion of patients being maintained on MRA at target doses.  Patiromer lead to 35% relative risk reduction in total number of hyperkalemia events.


A Cluster-Randomized PRagmatic Trial Aimed At ImprOving Use of Guideline Directed Medical Therapy in OutPatienTs with Heart Failure: PROMPT-HF

Ghazi L, presented a study in a session at American College of Cardiology (ACC) on 3rd April, 2022. The use of GDMT improves outcomes in patients with HFrEF but uptake remains challenging. The PROMPT-HF trial, pragmatic multicenter EHR-based randomized controlled trial was developed an hypothesis that targeted and tailored EHR alerts recommending GDMT in HFrEF patient can improve guidance adherence.

This trial included 100 clinicians seeing the most HFrEF patients were randomized to the alert vs usual care. The alert notified providers to GDMT recommendations as per their HFrEF patients who were not receiving any of 4 recommended medication classes. The primary outcome assessed was an increase in number of GDMT classes prescribed at 30 days post-randomization.

In the PROMPT-HF trial, a total of 1310 ambulatory HFrEF patients were enrolled over 7 months. At baseline, 84% were receiving BB, 71% ACE-I/ARB/ARNI, 28% MRA and 11% SGLT2i. In the alert arm, proportion of patients in whom GDMT components were added was higher; 117/625 in the usual care arm (18.7%) and 176/685 patients in the alert arm (25.7%) [RR: 1.38 (1.01, 1.87); p=0.04].

Significant higher rates of GDMT for a patient centred EHR-based alert for HFrEF outpatients as compared to usual care. The study indicates that this low cost-intervention can be rapidly integrated into clinical workflow, accelerate adherence to guidelines, and improve clinical outcomes, including mortality.

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Novel and Emerging Therapies: Inclisiran 

Watson K, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. LDL is the causative agent in atherosclerosis and lowering LDL-C decreases events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein which targets the LDL receptor for degradation. Its gain of function mutations causes high LDL-C and loss of function causes low LDL-C. Inhibition of PCSK9 lowers LDL-C levels and statin treatment can upregulated it. As per PCSK9 inhibitor RCTs, ODYSSEY trial showed that Alirocumab significantly reduces the Major adverse cardiovascular events (MACE) (RRR 15%) as compared to placebo in 18,924 patients and FOURIER trial showed that Evolocumab significantly reduces CV death, MI, stroke rate (RRR 15%) as compared to placebo in 27,564 patients. Current PCSK9i are monoclonal antibodies. These drugs are administered as SQ injections every 2-4 weeks. New approach has been introduced in the RNA interference to inhibit PCSK9 synthesis in the liver. Phase I trial of the PCSK9i Inclisiran (using the RNAi approach) 300 mg showed that LDL-C could be reduced ~50% with twice yearly injections for 4-6 months. 2 doses of Inclisiran lowered LDL-C for upto 6 months. In ORION-10 study, 1561 patients on maximally tolerated statin were randomized to Inclisiran or placebo. Inclisiran showed significant reduction in LDL-C ∆% by 58% after 17 months of treatment (p<0.00001). Also, Inclisiran had similar safety and tolerability compared with placebo.

Inclisiran is the first cholesterol-lowering agent in the siRNA class. Twice yearly injection of Inclisiran provides sustained LDL lowering. Increasing the number of effective therapeutic options available is good for the patients.


Novel and Emerging Therapies: Bempedoic Acid 

Virani S, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. In clinical trial setting, as per US guidelines, ~55% patients with high intensity statin treatment showed more than 70 mg/dL LDL-C and as per European guidelines, ~75% patients continued to high cholesterol levels. SWEDEHEART exhibited that 87% of patients receiving high intensity statin treatment in which only 17% of patients had LDL-C below 55 mg/dL and with 100% use of statin showed 21% of patients will get cholesterol target level. In USAGE study, 10,318 patients were surveyed via internet. 88% patients were current statin users. Bempedoic acid (BA) acts in the same cholesterol biosynthesis pathway as statins. Elevated LDL are causally associated with initiation and progression of ASCVD and per 38.7 mg/Dl reduction in LDL-C leads to ASCVD relative risk reduction by 22%. As per CLEAR study, Bempedoic acid significantly reduces LDL-C levels as compared to placebo in 2230 patients with no major adverse events except the increase in uric acid level than placebo. CLEAR study presented at ACC 2019 showed that Bempedoic acid significantly reduced LDL-C level from baseline to week 12 as compared to placebo. Also, Combination of Bemepedoic acid and ezetimibe substantially decreases LDL-C and hsCRP level by 35%. BA is associated with increased risk of tendon rupture or injury with 0.5% in RCT. FDA 2020 has approved Bemepedoic acid and Bemepedoic acid plus ezetimibein for the treatment of heterozygous familial hypercholesterolemia (HeFH) or established ASCVD.

Studies showed 15 to 25% LDL-C reduction on background of statin and higher LDL-C reduction in patients not on statins. Combination of bemepedoic acid and ezetimibe lowers LDL-C by 35%. Also, Bempedoic acid had good safety profile overall with small incidence of tendon rupture and increase in uric acid. The CV outcome studies of the drug is pending.


Antihypertensive Therapy for Mild Chronic Hypertension Improves Pregnancy Outcomes: A Pragmatic Multicenter RCT

Tita ATN, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022 which evaluated the hypothesis that therapy of mild Chronic hypertension (CHTN) vs. no treatment decreases the frequency of adverse pregnancy effects and is safe for the fetus.

Women with mild CHTN, singleton and <23 weeks’ gestation were enrolled in the CHAP trial, an open-label multicenter RCT. Participants (center-stratified) were randomized to either treatment (with a first-line antihypertensive for pregnancy to a BP goal <140/90) or no treatment unless BP≥160/105. The centrally adjudicated primary outcome was a composite of preeclampsia with severe features, preterm birth <35weeks, abruption and neonatal/fetal death. The safety outcome was small-for-gestational age (SGA; birth weight (<37weeks) and preeclampsia. 2408 participants were effectively randomized to treatment (n=1208) and no treatment (n=1200) at 61 sites from 2015 to 2021. Groups were similar at baseline; 56% patients were on antihypertensive at enlistment, 48% Black, 28% NH White, 20% Hispanic, 16% diabetic and mean BMI of 37.6. The treatment group showed lower incidence of primary outcome as compared to standard group. Both groups showed similar SGA <10th and <5th percentile. The treatment group exhibited reduced frequency of preeclampsia and preterm birth. Primary results did not vary by therapy status prior to enlistment (p=0.115), race-ethnicity (p=0.609), BMI categories (0.074) or diabetic status (p=0.255).

Mild CHTN treatment in pregnancy to a BP goal <140/90 decreases a composite of adverse pregnancy outcomes (NNT= 14.7) and does not harm fetal growth. CHAP supports treatment of CHTN to BP<140/90 mmHg in pregnancy with continuation of established antihypertensive treatment. Long-term studies will further clarify treatment effects in maternal and childhood outcomes.


Dietary Management of Disorders of Lipid and Lipoprotein Metabolism in Youth 

Liebeskind A, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. The objectives of the study were to identify genetic and acquired lipid disorders that may present in childhood and adolescence, discuss nutrition change that may benefit children with specific lipid disorders and incorporate healthy eating principles for all children to prevent acquire lipid disorders. Familial hypercholesterolemia (FH) is a genetic disorder characterized by moderate to severe elevation in LDL-C that increases chance of CHD. Lipid lowering medications are generally required in addition to focused nutrition and activity in order to reach optimal lipid goals. To acquire nutritions in FH, patients must reduce saturated fat to <7% daily calorie intake (8-20 g/day), avoid trans fat with <200 mg dietary cholesterol daily and increase dietary soluble fiber. Familial combined hyperlipidemia (FCHL) may present as elevated LDL-C, hypertriglyceridemia, mixed hyperlipidemia. FCHL may present in childhood generally in association with metabolic conditions such as T2DM. Nutrition recommendations are similar to those for FH with additional recommendation of reduce simple carbohydrate. Sitosterolemia is an inherited disorder of hyperabsorption and decreased biliary excretion of non-cholesterol sterol leads to accumulation of serum levels. In sitosterolemia nutritional approach, patients should restrict non-cholesterol sterols, limit intake or avoidance of shellfish. Fruits, vegetables and cereal products without germ may be used. Obesity is the most common cause of lipid disorders in children leads to mild to moderate hypertriglyceridemia. To start nutrition for youth, patient’s growth charts, medical history, causes should be reviewed. The child’s current nutritional status should be understand and review the entire family’s readiness to change. Patient’s adequate nutrition status and focus on positive reinforcement should be ensured.

Most Lipids disorders in children are associated with obesity and overweight status. Nutrition and physical activity to reach a healthy weight is essential. For LDL-C related disorders, mediations will likely be needed but a diet lower in saturated fat and higher in fiber can assist. For TG-related disorders, medications are less likely to achieve optimal goals and focused nutrition and physical activity is a mainstay. Dietary recommendations for most youth should emphasize fruits, vegetables, whole grains and varied protein foods. Avoiding added sugar in foods and beverages is always the right answer. Small lifestyle changes made in youth can impact total cholesterol years.


Management of Dyslipidemia During Reproductive Years

Mehta S, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. 8 out of 10 women of childbearing age have never had their cholesterol levels checked, despite clear guidelines to get a first lipid blood test early in adulthood. Previously statins are considered as X category in pregnancy. FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy. But it is still advises most pregnant patients should stop taking statins. Breastfeeding not recommended in patients who require statins. The women with FH showed higher increase in LDL-C level during pregnancy as compared to non-FH women. Pregnancy management in FH considered with healthy lifestyle and stop statins, ezemtimibe, niacin, fibrates, PCSK9i 4 weeks prior to discontinuing contraception. Bile acid sequestrants are only acceptable medication. Lipoprotein apheresis is also considered safe for very high risk women.

Hyperlipidemia assessment and management should not be ignored during the childbearing years. Healthy lifestyle is the key for all patients during their lifetime. Women with FH do benefit from medications and possibly apheresis, however the choice does vary based on pregnancy and lactation status.


Bentracimab Immediately and Significantly Reverses the Antiplatelet Effects of Ticagrelor in Older People

Bhatt D, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. Ticagrelor is an efficacious antiplatelet agent however if bleeding happens there is no way to reverse it. Bentracimab is a human monoclonal antibody fragment outlined to bind ticagrelor.

A double-blind, placebo-controlled, Phase 2b trial in which participants aged 50-80 years pre-treated with ticagrelor and aspirin were randomized to bentracimab bolus plus infusion or placebo. The primary outcome was percent platelet inhibition as evaluated with the VerifyNow PRU test, and the secondary outcome was percent platelet inhibition using the VASP PRI test, both evaluated via 4 hours post dose.

205 participants were enlisted in the study (154 randomized to bentracimab, 51 to placebo). The primary and secondary outcome each demonstrated highly substantial reversal of ticagrelor’s impact (p<0.0001 and p<0.0001, respectively). Platelet function was restored to fundamentally baseline immediately following the bolus, with an impact that was sustained all over the period of infusion. No incidence of platelet rebound was seen evaluated using p selectin levels or mean platelet volume. 37.7% of bentracimab and 41.2% of placebo patients showed at least one treatment-emergent adverse event; none were contemplated associated to bentracimab in the blinded trial.

Bentracimab significantly restored platelet function as measured by multiple assays by binding and eliminating free ticagrelor and ticagrelor active metabolite as compared to placebo. No thrombotic events and no SAEs reported in volunteers randomized to Bentracimab, confirming the safety profile. Bentracimab appears to be a very promising option for ticagrelor reversal.


How Should We Treat Large Thrombus Burden in 2022? (STEMI)

Jolly S, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. In TOTAL study, 10,700 STEMI patients with primary PCI ≤12 hours of symptom onset were enrolled. Patients were equally randomized to manual thrombectomy or PCI alone. Primary outcome was CV death, MI, cardiogenic shock and class IV HF ≤180 days. Patients with thrombectomy showed lesser rate of primary outcome as compared to patients with PCI alone. Patients with stroke showed significantly high rate of death (30.8%) as compared to patients without stroke (p<0.0001). As per ACC/AHA guidelines update, class III indication is for routine thrombus aspiration and class IIb indication for bailout or selective aspiration due to lack of data. In individual Patient Meta analysis of 19,047 patients, thrombectomy showed lower rate of CV death as compared to PCI alone treatment (p<0.16). In patients with high thrombus burden, routine TIA was associated with lower CV death but higher stroke or TIA at 30 days with no difference in mortality at 1 year. CAT RX technology showed 99.5% patients with grade 0 final TIMI thrombus and 97.5% patients with grade 3 final TIMI flow and 99.85 patients with myocardial blush. CHEETAH study showed significant reduction in CV death as compared to thrombectomy and PCI alone treatment.

Manual thrombus aspiration should not be done routinely. Routine thrombus aspiration decreases CV death in patients with high thrombus burden. CAT RX technology can provide satisfactory results in thrombectomy.


 Antithrombotic Management in AF Patients Undergoing PCI: What Do Consensus and Guidelines Say?

Collet JP, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. Jean-Philippe Collet stated that there have been changes between 2018 and 2020 in the guideline recommendations for antithrombotic management of patients with atrial fibrillation undergoing percutaneous coronary intervention.

Recommendations for combining antiplatelet agents and anticoagulants in patients with non-ST-segment elevation acute coronary syndrome requiring chronic anticoagulants:

  • Stroke prevention is recommended in atrial fibrillation patients with >1 non-sex CHA2DS2-VASc stroke factor (score of >1 in males or >2 in females).
  • For patients with 1 non-sex stroke factor oral anti-coagulants should be considered and treatment may be individualized based on net clinical benefit and consideration of patient values and preferences.
  • An early internal carotid artery should be considered in patients at risk for high bleeding, irrespective of anti-coagulant exposure, to expedite treatment allocation (medical vs. PCI vs. CABG) and to determine the optimal antithrombotic regimen.

New key recommendations for antithrombotic treatment include the following:

  • In patients with atrial fibrillation, after a short period of triple antithrombotic therapy, double antithrombotic therapy is recommended as the default strategy using a new oral anticoagulant at the recommended dose for stroke prevention and single oral antiplatelet agent (preferably clopidogrel).
  • Double antithrombotic therapy with an oral anticoagulant and either ticagrelor may be considered as an alternative to triple antithrombotic therapy with an oral anticoagulant, aspirin, or clopidogrel in patients with a moderate or high risk of stent thrombosis, regardless of the type of stent used.

New oral anticoagulants should be preferred over of vitamin K antagonists if not contraindicated; aspirin should be used up to one week post PCI and up to one month in case of high thrombotic risk and acceptable bleeding risk; a combination of new oral anticoagulant plus oral P2Y12 inhibitor with aspirin use limited to the peri-PCI period should be the default strategy.


Prognostic Significance of Pulmonary Hypertension in Patients with Obstructive Hypertrophic Cardiomyopathy after Septal Myectomy

Lee A, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022. The patients with hypertrophic obstructive cardiomyopathy (HOCM) often are associated with concomitant pulmonary hypertension (PH). The study hypothesised that concomitant PH results in increased risk for short-term adverse outcomes after septal myectomy (SM).

A retrospective analysis of 758 patients who underwent SM for HOCM between 2010 and 2020 were evaluated. After excluding patients without pre-op right heart catheterization (RHC) or incomplete RHC data, final sample included 281 patients. Definition of adverse events included composite endpoint such as post-op stroke, TIA, MI, cardiac arrest, prolonged ventilation, reintubation, pneumonia, multi-organ failure and mortality and comparison was made between patients with and without AE.

The results of this study shows that the overall incidence AE was low (n=17, 6%). Among the adverse events (AE), prolonged ventilation was the most common (n=9, 3.2%). It was also found that patients with AE were older (64 vs 57, p=.015) and they were more likely to suffer from chronic lung disease (OR 4.42, 95% CI 1.5-12.8, p=.003).  Patients with AE experienced greater pulmonary artery (PA) systolic pressure, mean PA pressure, PA pulsatility index, PA pulse pressure, transpulmonary gradient and pulmonary vascular on pre-op RHC.

The study concludes that increased severity of concomitant PH in HOCM patients who are undergoing SM results in increased risk of short-term AE. Before SM, screening for and treating PH can reduce the risk of complications.


Higher Cumulative Systolic Blood Pressure is Associated with Poorer Left Atrial Function in the Absence of Left Atrial Enlargement: The Atherosclerosis Risk in Communities (ARIC) Study

Left atrial (LA) function disability can predate LA enlargement and is correlated with adverse cardiovascular disease (CVD) effects. There is no information regarding risk factors for poorer LA function with normal LA size. Hof JV, presented a study in a session at American College of Cardiology (ACC) on 2nd April, 2022 which analyzed the hypothesis that higher cumulative systolic blood pressure (cSBP) is correlated with poorer LA function absent of LA enlargement in ARIC, a community-based cohort study.

3,870 participants (mean age 75 [SD 5] years, 61% female, 19% Black) were assessed excluding those with LA volume index >34 ml/m2 and prevalent atrial fibrillation at ARIC visit 5 (2011-13). 2D speckle tracking echocardiography was used to estimate LA function at visit 5. cSBP over 24 years was measured by averaging SBP at visits 1-5, standardizing by time among visits. Linear regression was used to analyse correlations among cSBP and LA function.

Higher cSBP was correlated with worse LA reservoir and conduit strain, and total and passive emptying fraction following adjusting for demographics and CVD risk factors. All correlations remained substantial after additional adjustment for LV function, except for LA reservoir strain. cSBP was not substantially correlated with LA contractile strain and active emptying fraction.

Higher cSBP is correlated with poorer LA function even in the absence of LA enlargement and independent of LV function. The results underscore SBP as a prevention target and justify additional research to estimate whether SBP decrease inhibits LA function reduction.

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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.

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HFSA 2021 Annual Scientific Meeting September 10 -13, 2021 Day 3 http://digimedupdates.com/hfsa-2021-annual-scientific-meeting-september-10-13-2021-day-3/ http://digimedupdates.com/hfsa-2021-annual-scientific-meeting-september-10-13-2021-day-3/#respond Fri, 08 Oct 2021 13:48:22 +0000 http://digimedupdates.com/?p=3359

International Session – Universal Definition and Classification of HF Joint Session with the Heart Failure Association of the European Society of Cardiology (HFA-ESC) and the Japanese Heart Failure Society (JHFS)

Biykem Bozkurt from Baylor College of Medicine, presented the opening topic “What is New in the Universal Definition of HF? Summary and Future Implications” for the session International Session – Universal Definition and Classification of HF Joint Session with the Heart Failure Association of the European Society of Cardiology (HFA-ESC) and the Japanese Heart Failure Society (JHFS), at the HFSA Annual Scientific Meeting 2021.

Text book definition “Heart failure”: A clinical syndrome caused by the inability of the heart to meet tissue metabolic requirements. Few patients with heart failure (HF) only meet the historical HF definition. The new universal definition of HF is defined as “Heart failure is a clinical syndrome with current or prior symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by at least one of the following: elevated natriuretic peptide levels, objective evidence of cardiogenic pulmonary or systemic congestion by diagnostic modalities such as imaging or hemodynamic measurements. Standardization of HF syndrome definiton may help to enhance appropriate diagnosis and opimisation of Guideline-directed medical therapy and achieve uniformity of care. The new revised classification of heart failure includes patients at risk for heart failure, pre-HF, HF and advanced HF.

The ejection fraction (EF) classification of HF in universal definition classifies HF:

  • HF with reduced EF (HFrEF) [HF with left ventricular ejection fraction (LVEF) ≤ 40%];
  • HF with mildly reduced EF (HFmrEF) [HF with LVEF 41-49%];
  • HF with preserved EF (HFpEF) [HF with LVEF ≥ 50%];
  • HF with improved EF (HFimprEF) [HF with a baseline LVEF ≤ 40, a ≥ 10 point increase from baseline LVEF, and a second measurement of LVEF >40%].

There has been failure of HF treatment in the last two decades. Current standard of care for HFrEF involves beta-blockers, ACEi/ARBs/ARNI, MRA, and SGLT2-inhibitors.

HF syndrome definition has been standardised. New revised classification of HF is easy to understand by patients as well as clinicians. The clinical trajectories terminology has changed from stable HF to persistent HF and recovered HF to HF in remission.


SGLT2 inhibitors: Reviewing their Role in Type 2 Diabetes, Heart Failure and Chronic Kidney Disease

Richard Pratley from Advent Heath Diabetes Institute, Ontario, presented an illuminating talk on the topic” SGLT2 inhibitors: reviewing their role in type 2 diabetes, heart failure, and chronic kidney disease” at the HFSA Annual Scientific Meeting 2021. His talk was focused on identifying the patients with type 2 diabetes (T2D), heart failure (HF), or chronic kidney disease (CKD) who would benefit from a sodium-glucose cotransporter-2 (SGLT2) inhibitor. He talked about the guidelines and specific evidence for the management of cardiovascular (CV) and or renal risk in patients with T2DM. He explained the mechanism of action of SGLT2 inhibitors in T2DM, HF, and CKD. He also mentioned clinical trial data on the use of SGLT2 inhibitors for managing CV and/or renal risk in patients with T2DM.

HF is one of the first manifestations of T2D-related CV disease (CVD). DM is associated with an increased incidence of heart failure and mortality. Intensive glucose control does not reduce the incidence of HF. On the other hand, diabetes is the leading cause of the end-stage renal disease (ESRD). Mortality is increased in patients with T2 D and kidney disease. SGLT2 inhibition reduces renal glucose reabsorption, plasma glucose, body weight, blood pressure, plasma uric acid, albumin excretion and improves renal and CV outcomes. SGLT2 inhibitors improve glomerular loading conditions. Canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin food and drug administration (FDA)-approved SGLT2 inhibitors. Various CV outcome trials (CVOTs) have demonstrated the positive effects of SGLT2 inhibitors. EMPA-REG trial showed that the cumulative incidence of 3-point major cardiovascular events (MACE) was significantly reduced with empagliflozin as compared to placebo. The other CVOTs have also demonstrated positive effects of SGLT2 inhibitors. Guidelines are now transitioning from a gluco-centric focus to one emphasizing patient-relevant outcomes, including CVD, HF, and CKD, and hence supports the use of SGLT2 inhibitors in T2D patients at high risk of CVD, HF, and CKD. 

SLGLT 2 inhibitors have proven benefits to reduce the risk for CVD, HF, and CKD progression and should be considered in high-risk patients regardless of glycemic control.


Restore EF Trial- Impact of Hemodynamic-Supported Revascularization on LVEF

Jason Wollmuth, Director, Complex Coronary Interventions, Providence Heart Institute, Portland, Oregon, presented a captivating talk on the topic, “Restore EF trial- Impact of hemodynamic-supported revascularization on LVEF” at the HFSA Annual Scientific Meeting 2021.

The extent of coronary artery disease (CAD) is associated with prognosis in heart failure. Coronary artery bypass graft (CABG) is associated with sustained reductions in death as well as cardiovascular (CV) hospitalizations in ischemic cardiomyopathy (ICM). CABG has proven to be effective in patients with severe left ventricular dysfunction. In a meta-analysis of observational studies of CABG in patients with left ventricular ejection fraction (LVEF) 35%. A total of 26 studies comprising 4911 patients were included. The operative mortality and 5-year mortality were noted to be 5.3% and 26.4%, respectively. A significant improvement in LVEF was noted with CABG revascularization. The population of complex and high-risk percutaneous coronary intervention (PCI) is growing at a faster rate. PCI after surgical consult grew six times faster than total PCI. The evidence for PCI in ICM is limited. Impella heart pumps mitigate the inherent risks of surgical ineligibility. The PROTECT II and cVAD registry trial including 331 patients reported no difference in the mortality and major adverse cardiac and cerebrovascular events in CABG eligible and ineligible unprotected left main PCI patients. In high-risk Impella-supported PCI patients, a considerable improvement in LVEF has been noted. The “Restore EF” study was a multicenter, single-arm, prospective clinical study conducted in post-Impella supported high-risk PCI patients to validate the best practices. The primary endpoint of the study was LVEF at a 90-day follow-up. A significant improvement in LVEF at 90-day LVEF was noted as compared to pre-PCI LVEF. Follow-up LVEF improvement from baseline was significantly higher in subjects who underwent complete revascularization. The primary endpoint stratified by quartile baseline also showed significant follow-up LVEF improvement for patients with depressed pre-PCI LVEF. There was a 76% and 97% reduction in heart failure and angina symptoms.

Revascularization in patients with low LVEF is challenging with limited randomized trial data. Surgical revascularization has been shown to improve outcomes including death and CV hospitalization with probable improvement in LVEF. Increasingly, surgical turndown patients are being referred for complex PCI and hemodynamic support is often used during revascularization. Early data suggest hemodynamic supported revascularization in patients with low LVEF leads to improvement in LVEF and this was also demonstrated in real-world consecutive patients in the RESTORE-EF trial. Further trials will help to determine the value of percutaneous revascularization and optimal approach in surgical turndown patients.


Multidisciplinary Perspectives on Recognizing, Diagnosing and Managing Polyneuropathy Caused by hATTR Amyloidosis (NO CEUs)

John Eatman from North Kansas City Hospital and Summet Mitter from Mount Sinai Hospital discussed their clinical experience in recognizing, diagnosing, and managing adult patients with polyneuropathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis.  They highlighted the signs and symptoms that may help identify patients with polyneuropathy of hATTR amyloidosis through case-based discussion. 

An amyloidosis is a heterogeneous group of disorders characterized by the deposition of insoluble protein aggregates in tissues. It can be inherited, systemic, or localized. The two types of ATTR amyloidosis are wild-type ATTR amyloidosis and hATTR amyloidosis. More than 120 different TTR gene variants have been identified some of which are more common in certain populations. The red flag symptoms in such patients could be peripheral sensory-motor axonal polyneuropathy, bilateral carpal tunnel syndrome, and lumbar spinal stenosis. hATTR amyloidosis can be misdiagnosed with different polyneuropathy as well as cardiac conditions. Accurate diagnosis is critical for early intervention. Diagnosing hATTR amyloidosis is a multistep process; raise clinical suspicion (red flags/family history of hATTR amyloidosis), identify the signs through diagnostic tools (sensory-motor, autonomic and cardiac), and establishing the diagnosis. A multidisciplinary team approach impacts overall patient management.

ONPATTRO® (patisiran) has been found effective for the treatment of polyneuropathy in patients with hATTR amyloidosis. ONPATTRO® (patisiran) reduces the TTR production in the liver. APOLLO-the largest controlled study in hATTR amyloidosis patients found that ONPATTRO® (patisiran) significantly improved polyneuropathy symptoms. 50% of patients treated with ONPATTRO® (patisiran) experienced a reversal in neuropathy impairment from the baseline. ONPATTRO® (patisiran) significantly improved quality of life. Early treatment led to sustained and durable improvements in quality of life for up to 2 years. ONPATTRO® (patisiran) improved autonomic neuropathy symptoms. In addition, ONPATTRO® (patisiran) improved orthostatic intolerance, gastrointestinal symptoms, and nutritional status.

ONPATTRO® (patisiran) is a useful option for treating polyneuropathy in patients with hATTR amyloidosis as it has been shown to markedly reduce the neuropathic impairment and improves the overall quality of life (patient mobility, self-care, usual activities, pain discomfort).


A Computed Tomography Reconstruction Software to Model Ventricular Assist Device Implantation Position

Andrew S, et al, presented a poster session on the topic “A computed tomography reconstruction software to model ventricular assist device implantation position” at the HFSA Annual Scientific Meeting 2021.

This study aims to develop a program that virtually models a VAD into the 3-dimensional rendering of the myocardium and chest using computed tomography images. A python code process was created with a 4D retrospective cardiac CT dataset and then integrated with high-definition 3D VAD model. Rather than creating a full-fledged viewer and analytics tool, which would be too costly and time-intensive a tool, was created that can be used to complement the capabilities of professional imaging processing software such as 3 dimension or visage. The user can adjust the viewer to better isolates the heart prior to simulated VAD implant placement. The DICOM directories produced by this program can be opened directly in the software already used in daily clinical imaging to allow for more in-depth analysis of desired implant placement and cannula positioning which can aid in pre-operative and intra-operative planning.

The next steps of the project will be to enable VAD implant model to be propagated across the 3D scan time series increase computational efficiency and view clarity as well as output the resulting DICOM directory so that it can be opened in visage or a similar tool. In a future version of the project, an automatic placement feature and fluid dynamic analysis to validate the proposed implant location.


Analysis of Clinical, Biochemical and Echocardiography Criteria for Heart Failure with Preserved Ejection Fraction

Stringer B presented a poster session on the topic “Analysis of Clinical, Biochemical and Echocardiography Criteria for Heart Failure with Preserved Ejection Fraction” at the HFSA Annual Scientific Meeting 2021. He aimed to compare the sensitivities of various clinical, biochemical and echocardiographic criteria used to diagnosis HFpEF on a cohort of admitted HFpEF patients.

It was carried out as a retrospective review  of inpatients with a primary diagnosis of HFpEF over a 2- years. Review of  patient demographics, medical comorbidities and lab results was carried out. Echocardiograms were analyzed, including parameters of diastology to determine H2FPEF, HFA-PEFF scores and American Society of Echocardiography diastolic dysfunction (ASE-DD).
The sensitivity of 94% was found for Brain natriuretic peptide (BNP) greater than 100 pg/mland ASE-DD criteria for diastolic dysfunction had a sensitivity of 58%. H2FPEF risk percentage of ≥90% had sensitivity of 63%. Septal E/e’ of ≥15 had a sensitivity of 57% which increased to 90% when cut-off was lowered to ≥10.

In patients who had E/e’ ≥12 had significantly higher H2FPEF score, HFA-PEFF score and length of stay (p<0.05).

The study shows that current diagnostic criteria for HFpEF have relatively low sensitivity. Diagnostic sensitivity can be improved by lower E/e’ cut-off. The correlation of E/e’ and BNP suggests a relationship between the functional and biochemical entities of HFpEF.             


The Effect of COVID-19 Infection on Tacrolimus Metabolism in Heart Transplant

Gopalan R presented a poster session on the topic “The Effect of COVID-19 Infection On Tacrolimus Metabolism in Heart Transplant” at the HFSA Annual Scientific Meeting 2021. This study aimed to understand how COVID-19 and its treatment affect tacrolimus metabolism in solid organ transplant.

The cornerstone management strategy to balance the immune response with the potential for rejection of the graft has remained reliable on tacrolimus levels. We present a case of a heart transplant recipient with highly elevated tacrolimus levels following COVID-19 infection despite little to no tacrolimus administration and no other known drug-drug interactions. This case presents a 58-year-old male with history of ischemic cardiomyopathy; status post orthotopic heart transplantation. After 2 years, he presented to the ED with complaints of jaw pain, symptoms of urinary retention and 3 days of diarrhoea. The patient had been maintained on tacrolimus 0.5mg BID for 8 months with associated trough levels between the goal range of 4-8ng/mL. T: D ratio remained stable on tacrolimus 0.5mg BID before COVID-19 infection. The ratio rose following infection and remained elevated 8 months later despite reducing the dose to 0.5mg QAD.

A relationship is suggested between SARS-COV-2 viremia with tacrolimus metabolism.


The Persistent Heart Failure and Mortality Burden Following Anterior STEMI Treated with PCI; The Role of SSO2 Therapy

Gopalan R gave an enlightening presentation at the HFSA, 2021 on the topic “The Persistent Heart Failure and Mortality Burden Following Anterior STEMI Treated With PCI; The Role Of SSO2 Therapy”. The study hypothesised that Supersaturated oxygen (SSO2) can improve the outcomes in patients treated with primary PCI. It is an FDA approved therapy to deliver to the left anterior descending coronary artery immediately for STEMI. Comparison of 2005-2008 and 2016-2018 Medicare Data rates of mortality and REHOSP for HF was done using descriptive and regression analysis. 100 IC-HOT participants were matched to a Medicare beneficiary to form a comparison group with similar characteristics also treated with primary PCI.

The eligible Medicare group for comparison with IC-HOT included 10,634 cases. The IC-HOT treatment group was observed to have reduced mortality in comparison with the matched Medicare group at 1 year (0 vs 4.6%, p <0.02). In the Medicare group at 1 year, rehospitalisation for HF in IC-HOT was lower (1.1 vs 9.2%, p <0.05) despite a significant decrease in the 1-year REHOSP for HF from the early to later Medicare cohort. The risk adjusted 1-year and 2-year mortality rates increased from the early to later Medicare cohort with anterior STEMI treated with PCI alone.

There is no improvement observed for mortality and REHOSP for HF for MEDICARE patients. Infarct size reduction with h SSO2 therapy has the potential to favorably impact this growing clinical burden in an aging population.


SGLT2 Inhibitors: Cardiovascular Outcomes from DAPA-HF, Emperor-Reduced and SOLOIST-WHF

Vaduganathan M gave an enlightening presentation on the topic “SGLT2 Inhibitors: Cardiovascular Outcomes from DAPA-HF, Emperor-Reduced and SOLOIST-WHF” under the session “SGLT2 Inhibition and Heart Failure: Translating the Evidence to Clinical Practice (CEUs)” at the HFSA Annual Scientific Meeting 2021. SGLT2 Inhibitors undergoes rapid oral absorption, has long half-lives and no clinically relevant drug-drug interactions.

SGLT2 Inhibitors lose glucose lowering properties in advanced CKD and has limited risk of hypoglycaemia. All FDA approved SGLT2 Inhibitors are highly selective. A meta-analysis of the EMPEROR-reduced and DAPA-HF trials show that SGLT2 inhibitors results in 13% reduced risk of death, 26% reduction in CV death or HF hospitalization, and 38% reduction in kidney outcomes. Only modest decrease in background diuretic doses with SGLT2 inhibitors in HF trials and no anticipatory changes were observed. Bidirectional effects of Emplagliflozin on NYHA class apparent after only one week and the effects were sustained for one year. It takes around 28-56 weeks until the GDMT is fully implemented with various medications in place. An ideal HFrEF therapy consists of:

  • One pill, one per day, with no titration
  • Improves survival and prevents hospitalization
  • Improves quality and functional status
  • Benefits appear rapidly within days to few weeks of initialization
  • Well-tolerated and safe
  • No adverse renal effects observed

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.

SGLT2i represents cornerstone management for treatment of patients with HF and reduced HF and can be initiated during or soon after hospitalization of HF.


SGLT2 Inhibitors: Renal Outcomes

Kosiborod  M gave an exciting presentation on the topic “SGLT2 Inhibitors: Renal Outcomes” under the session “SGLT2 Inhibition and Heart Failure: Translating the Evidence to Clinical Practice (CEUs)” at the HFSA Annual Scientific Meeting 2021. SGLT2 Inhibitors block SGLT-2 and reduce glucose and NA absorption.

In EMPA-REG outcome trial, eGFR decreased over time and cumulative probability of kidney endpoints were significantly lower with Emplagliflozin as compared to placebo. In EMPEROR-Reduced trial, significant eGFR slope decline was found for Emplagliflozin vs placebo. In DAPA-CKD trial, primary composite outcomes such as sustained ≥ 50% eGFR decline, ESKD, renal or CV death is significantly less with DAPA 10 mg as compared to the placebo. There is 39% reduced RRR with DAPA 10 mg as compared to placebo. Coming to the mortality, Dapagliflozin were reported to have 101 all-cause mortality events as compared to 146 events with placebo. In DAPA-HF trial, doubling of serum creatinine was observed in 43 patients of Dapagliflozin as compared to 77 patients of placebo. Cumulative incidence of composite kidney endpoints was 7.7% with Dapagliflozin as compared to 10.4% with placebo. SGLT2 inhibitors reduce progression of kidney disease, including eGFR decline and hard endpoints in T2D, HF, and CKD.

SGLT2i reduces acute kidney injury in patients with HF, CKD and in acute illness and reduce death from any cause in CKD.

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Beyond PVR: Assessing and Managing the Dysfunctional Right Ventricle

Manreet Kanwar, Co-division Director, Advanced Heart failure and Pulmonary hypertension cardiology, Allegheny General Hospital, Pittsburg, discussed about the topic “Beyond PVR: Assessing and managing the dysfunctional right ventricle” at the HFSA, 2021.

Right heart failure is a hemodynamic disorder with changes in pressure or right ventricle (RV) metrics, changes in NT-proBNP, changes in functional class (FC) and 6 minute walking distance (6MWD), changes in weight and subsquent hospitalization. Acute right heart failure (ARHF) can occur because of abruptly increased RV afterload or decresed RV contractility. Chronic (CRHF) most commonly results from gradual increases in RV afterload caused by pulmonary hypertension (PH) most frequently from LH failure. Each of these conditions present unique challenges for the RV.

RV dysfunction is very common in end stage left heart failure and is a key predictor of morbidity and mortality. Practical management of RHF requires determining the aetiology and chronicity; evaluation of hemodynamics; treating predisposing factors; and medical and surgical management based on optimization of preload, afterload and contractility. Evaluation of potential triggers for acute RHF includes progression of underlying pulmonary vascular disease, medication/diet non-adherence, pulmonary embolism, new/worsening pulmonary process or infection, surgery, medical conditions i.e. hyperthyroidism, pregnancy/delivery and arrhythmias. The important considerations of management of RHF includes:

  • Optimal management requires a multifaceted approach addressing RV preload, afterload, and contractility
  • Stabilise the cardiac output and manage rhythm disturbances
  • Lower pulmonary vascular resistance
  • Use of mechanical circulatory support is reserved for patients in acute or chronic RVF refractory to optimal medical therapy and it is used as a bride to recovery or bridge to transplant

In acute decompensated right heart failure, using a combination of strategies to decrease preload, stabilize cardiac output and lower PVR is critical. Treating the etiology is crucial. Temporary mechanical support strategies such as Venoarterial Extracorporeal Membrane Oxygenation and right ventricular assist device may play a role in stabilizing end organ function in critically ill patients.


Rehospitalization Following Inpatient CardioMEMS Implantation: Insights from the Nationwide Readmissions Database

Charles Sherrod, et al., presented a poster session on the topic “Rehospitalization following inpatient CardioMEMS implantation: Insights from the nationwide readmissions database” at the HFSA, 2021.

Heart failure management is costly. Incidence is rising and it will raise the health care expenditure. Patients discharged with a diagnosis of heart failure have a 25% cahnce of 30 day readmission. The CardioMEMS device has been assocaited with lower rates of readmission when placed in the outpatient setting.

Patients who underwent inpatient CardioMEMS implantation between 2016-2018 were identified in the national readmissions database. Those who were transferred to or from another hospital during their index hospitalization whose length of stay (LOS) was < 2 days, whose priamry diagnosis was not for circulatory system disease or who died were excluded. Those who underwent CardioMEMS implantation were propensity matched 5:1 to a hospitalized usual care group on 38 patient and hospital-related factors as well as on discharge month and number of preceding admissions that year. Outcomes included all-cause heart failure readmission at 30, 60, 90 and 180 days, inpatient LOS and cost.

Results observed were all cause, and heart failure readmission rates were similar in the CardioMEMS and usual care cohorts at all time points. Median (interquartile range LOS was 6 days (p=0.42) an median (IQR) cost was $48372 vs $16415 (p<0.001) in the CardioMEMS and usual groups, respectively

Inpatient implantation of the CardioMEMS device was not associated with reduced HF or all-cause readmission. There was no reduction in LOS. Implantation was associated with increased costs.


The SCAI is the Limit: Quantification and Classification of Shock

Jacob C. Jentzer, Director of Research, Cardiac Intensive Care Unit, Mayo Clinic, Rochester MN, USA, talked about the much-needed topic in today’s time “the SCAI is the limit: Quantification and classification of shock.” at the HFSA Annual Scientific Meeting 2021.

He started his presentation with a very valid and important question, “why does shock severity grading matter?” The answer to this question is that the grading of shock severity is vital for predicting the short-term outcomes, triage and transfer decisions, and determining the need to escalate therapies. The Society for Cardiovascular Angiography and Interventions (SCAI) has given shock classification with the severity of shock being escalated from stage A to E. A and B stages are the pre-shock stages whereas stages C, D, and E can be defined as classic cardiogenic shock stage, deterioration stage, and extremis stage, respectively. SCAI stage E is characterized by severe acidosis and markedly elevated lactate levels. The severity of shocks i.e. escalation from stage A to E is associated with short-term mortality and these findings have been reported to be true for all patient subgroups i.e. acute coronary syndrome/ heart failure. Hence shock severity could be defined by several factors; hemodynamics/, end-organ hyperfusion, hemodynamics support, and response to initial therapy. It is of great interest to note that the greater vasopressor dose is associated with the high risk of mortality as the increase in shock severity increases the risk of drug toxicity. Mortality can be predicted by the severity of lactic acidosis. A cut-off value of >5mmol/L for lactate levels is often used however, the high value is worse. All mortality risk factors are not associated with shock severity; only lactate and renal function are related to shock severity.

Older age, cardiogenic arrest and rhythm, worsening shock, poor hemodynamics, abnormal echocardiography, systemic inflammation, acute kidney injury, and phenotypic cluster are some of the mortality risk modifiers i.e. they influence survival across the various SCAI shock stages. Different cardiogenic shock phenotypes are non-congested, cardiorenal, and hemometabolic type and amongst the SCAI stages C, D, and E, the hemometabolic phenotype is associated with greater in-hospital mortality compared to the other two.

The SCAI classification of shock is a comprehensive tool to predict the short-term outcomes, triage and transfer decisions, and to determine the need to escalate therapies in patients with cardiogenic shocks.


The Implicit Bias in Transplant/LVAD Selection Committee Meetings and the Impact on Patient Care

Raymond Givens from the Advanced Heart Failure and Transplant, Emory University School of Medicine, USA, presented his insights on the topic, “The implicit bias in transplant/LVAD selection committee meetings and the impact on patient care” at the HFSA Annual Scientific Meeting 2021.

In the advanced heart failure (HF) therapy evaluation, healthcare physicians consider certain medical and psychosocial factors based on the race and origin of the patients. E.g. black candidates are most likely to be sensitized, have higher panel-reactive antibody (PRA) levels, and are more likely to develop de novo donor-specific antibodies (DSAs). As per a recent study, among HF professionals randomized to standardized vignettes, race figured prominently in thought processes about decision-making. Adherence and social history were important factors in decisions about black patients. Black patients were assumed to be sicker and less likely to be adherent. Providers thought they might have difficulty forming a rapport with the black patient. White patients are more likely to be offered heart transplants whereas black patients are more likely to be offered left ventricular assist devices (LVAD). In another study, children were seen as particular liabilities for women especially black women to whom respondents attached concerns about financial stability. The implicit bias results from cognitive processes outside conscious awareness. Pro-white implicit bias is as prevalent among physicians as the general population and is associated with quality of patient interactions, treatment decisions, quality of care, treatment adherence, and outcomes. Most studies reported that those with high levels of pro-white bias have greater difficulties with patient-provider communication.

Implicit bias reduction training might yield meaningful outcomes. A cluster-randomized trial at a large university showed positive short-term changes in women faculty perceptions that their ideas were taken seriously. Brain regions implicated in implicit bias include the amygdala, dorsolateral prefrontal cortex, and fusiform gyrus. Propranolol reduces implicit association scores among white subjects who were shown images of black faces. Dr. Raymond mentioned certain recommendations to manage the implicit bias. He also showed a graph that depicted the diversity of HF physicians; the majority of HF physicians were white.

Implicit bias reduction training should be provided to the HF physicians so that advanced HF therapy can be given to every patient, irrespective of their race and origin.

Clinical Outcomes One Year Post-implant in Patients with Left Ventricular Assist Devices and Pre-implant ICD Shocks

David G. Hann gave an enlightening poster presentation at the HFSA Annual Scientific Meeting 2021. His presentation was focused on the topic “clinical outcomes one year post-implant in patients with left ventricular assist devices and pre-implant ICD shocks.”

Implantable cardioverter-defibrillator (ICD) shocks after left ventricular assist device therapy (LVAD) are linked to adverse outcomes and may increase mortality. However, there is limited data on the association of pre-LVAD ICD shocks on post-LVAD clinical outcomes. Thus, the objective of the study was to evaluate if pre-LVAD ICD shocks within one year pre-implant are linked to adverse clinical outcomes up to one year post-LVAD.

The study included patients aged ≥18 years with continuous-flow LVADs and ICDs, retrospectively identified within the UPMC system from 2006-2020. The baseline characteristics were similar between the patients with pre-LVAD ICD shocks and patients without pre-LVAD ICD shocks.

Overall results of the study indicated that although pre-LVAD shocks within one year of LVAD implantation predicted the occurrence of post-LVAD ICD shocks, they were not associated with a composite outcome of death, pump thrombosis, stroke, or heart transplant at one year. Also, pre-LVAD ICD shocks predicted post-LVAD hospitalizations for ICD shocks but patients with pre-LVAD ICD shocks had a decreased incidence of heart failure admissions.

In this retrospective study of patients with pre-existing ICDs, pre-LVAD shocks within one year of LVAD implantation were not associated with a composite outcome of death, pump thrombosis, stroke, or heart transplant at one year.


Referral for Heart Failure

Maya Guglin, Director, Heart Failure, Indiana University School of Medicine, discussed about the topic “Who is the right patient/? When is the right time” under the session “Referral for Heart failure” at the HFSA, 2021.

Dr Maya presented a case of 68-year-old male with history of STEMI (acute totoal LAD occluison) one year ago which resulted in ischemic cardiomyopathy with LVEF 20% presented with increasing shortness of breath and edema. The patient could barely walk across the room. He was on lisinopril, carvedilol and furosemide. He was also recently tapped for ascites, His BP was 96/67 mmHg and heart rate of 104 bpm. He was admitted for fluid overload. The right showed the following values: right atrial pressure: 18 mmHg, pulmonary artery: 82/45/51 mmHg, wedge 40 mmHg, cardiac output: 4L/min, index 2L/ min. His creatinine was 3 mg/dL.

Three critical questions were answered during the course of his treatment.

  1. Is transplant/LVAD indicated?
  2. Are there contraindications?
  3. Transplant or LVAD?

The patient was hospitalised and treated with inotropes, defibrilallator shocks, edema/esclating diuretics in view of heart failure NYHA class III and IV, end organ dysfunction (liver and kidneys), ejection fraction <25%, low blood pressure. Use of pulmonary artery catheter is associated with lower rates of mortality in overall and advanced stages of HF. Contraindications include for transplant severe COPD, systemic illness, malignancy with poor prognosis, liver cirrhosis, dementia or psychiatric illness, social issues (substance abuse, lack of support), pulmonary hypertension for transpant. Contraindication for left ventricular assist device (LVAD) includes RV failure.

Transplant does help in prologning the survival rate of patients with heart failure.


 The Association of Resting Heart Rate with Beta Blocker Up-titration in Patients with Heart Failure and Reduced Ejection Fraction: A Single Center Experience from the Middle East

Mania Y gave a presentation at the HFSA, 2021 on the topic “The Association of Resting Heart Rate with Beta Blocker Up-titration in Patients with Heart Failure and Reduced Ejection Fraction: A Single Center Experience from The Middle East”. He aimed to determine utilization of beta-blocker patterns, predictors of BB dose up titration, and its association with resting HR in a newly established heart failure program in the Middle East.

Beta-blocker therapy is an essential part of guideline-direct medical therapy (GDMT)  for heart failure with reduced ejection fraction (HFrEF). specified target dose or the maximum tolerable BB dose is associated with beneficial effects that might extend beyond those related to HR reduction.

A retrospective chart review was conducted which included 152 patients treated with a BB. Data on patient characteristics and medication use at baseline and 12-month follow-up were collected and compared between patients who did and those who did not achieve BB target dose using appropriate tests.

In this study, patients were treated with 12-months follow up, most commonly with bisoprolol (63.1%), followed by carvedilol (24.3%) and metoprolol (12.5%). More patients achieved BB target dose overtime (32% to 54.6%, p<0.01). Proportion of patients achieving resting HR<70 bpm did not change (35.5% vs. 34.9%, p=0.9).  Patients receiving BB target dose at FU (n=83) were younger and more likely to be diabetic.

Nearly half of HFrEF patients did not achieve BB target dose over a year of FU, with majority of them having uncontrolled resting HR.  


Tafamidis Reduces the Decline in Global Longitudinal Strain and Stroke Volume in Patients with Transthyretin Amyloid Cardiomyopathy

Elliot P gave a presentation at the HFSA, 2021 on the topic “Tafamidis Reduces the Decline in Global Longitudinal Strain and Stroke Volume in Patients with Transthyretin Amyloid Cardiomyopathy” . This study aimed to hypothesise that treatment with tafamidis significantly reduces the worsening of echocardiographic variables in patients with transthyretin amyloid cardiomyopathy (ATTR-CM)

The significant predictors of mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) are echocardiographic measures, including global longitudinal strain (GLS) and stroke volume (SV). In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular-related hospitalizations.

 In this trial, patients were randomized to tafamidis 80 mg (n=176) or placebo (n=177) for 30 months. Echocardiography was conducted at enrolment, and at Months 6, 18, and 30, using a standardized protocol with all images reviewed and analysed by an independent central laboratory.

At month 30, there was a significant reduction in least-squares (LS) mean difference (95% CI) with tafamidis vs placebo for each measure. The decline in SV and GLS was apparent from Month 6 in all patients, while the difference between tafamidis and placebo groups was apparent from Month 18 and through to Month 30. The decline in E/e’ (indicative of elevated LV filling pressures) was apparent from Month 6 and through to Month 30 with placebo but only minimally changed at each time point with tafamidis

Treatment with tafamidis significantly reduced worsening of LV systolic function (GLS, SV) and diastolic function (E/e’) over 30 months in patients with ATTR-CM.


Implementing GDMT in Severe Heart Failure Patients – Easy or Challenging? A Debate (No CEUs)

Albert N and Fonarow G presented a session at the HFSA, 2021 on the topic “Implementing GDMT in Severe Heart Failure Patients – Easy or Challenging? A Debate (No CEUs)”. Nancy Albert and Fonarow G aimed to emphasise on the fact that GDMT should be easy and there are US guidelines and recent consensus pathway which offer specific details about medical therapy.

National guidelines assume that if patients can tolerate medications, we must document patient adverse effects and contradictions, patient preferences, target doses when not supported by RCTs and national guidelines, and titration plan. Implementation/monitoring programs are common in HF clinics, transitional care programs, shared medical appointments, and hospital up titration predischarge.

GDMT in acute HF settings provide helpful systems/tools like prognosis and risk scores, eMR cues and flags, pocket card, and “see something say something” approach. Stakeholders of GDMT in heart failure are system, insurance, provider, industry, family, patient, friends, and community supporters.

Implementation of GDT is easy and success requirements depend on agreeing on what severe HF means, open and honest patient communication, and utilization of resources including pharmacy, screening for cognitive dysfunction, treatment of underlying disease, and assure that providers are fully educated. Reasons for underutilization of GDMT are gaps in knowledge and awareness, lack of systems, therapeutic inertia, uncertainty regarding effectiveness, concerns about side-effects, costs, and value, and various other challenges

GDMT implementation can be challenging in severe patients. The optimal approach to GDMT implementation is to utilize each medication demonstrated to reduce all-cause mortality.


Arrhythmia Assessment with 30-day MCT Patch Challenges Traditional Holter Monitoring

Mahajan R gave a presentation at the HFSA, 2021 on the topic “Arrhythmia Assessment with 30-day MCT Patch Challenges Traditional Holter Monitoring”. She aimed to identify if cardiac monitoring with a 30-day MCT patch provides better patient outcomes than with the 24-hr Holter. To do so, we compared the arrhythmia and ectopy diagnostic yield of both modalities.

It was conducted as a retrospective study to analyse data ECG data recorded from 14,514 patients (male-43%, female-57%, median age-64 years). Patient’s data was also evaluated to identify sinus rhythms -sinus bradycardia (SB) and sinus tachycardia (ST), and any of the following arrhythmias, atrial fibrillation, pause, and Ventricular tachycardia (VT). Mean arrhythmia diagnostic yield of 38.1% in 30-day MCT studies is significantly different from 29.1% in 24-hr Holter studies (p<0.001). A total of 25% critical arrhythmias in patients with MCT patches in contrast to 9.6% in Holter. PVC beats were identified in 85.9% and 65.7%, whereas PAC beats in 92.3% and 78.2% of MCT and Holter studies, respectively

Results demonstrate that 30-day monitoring with MCT patch provides a better diagnostic yield than 24-hr Holter monitoring. Timely diagnosis with MCT patch can aid in early therapeutic intervention resulting in better patient care.

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A Novel Approach Using Continuous Monitoring of Peripheral Edema in Heart Failure Patients Allows Recognition of Acute Decompensation Early in the Window of Intervention

Kessler, et al presented a poster session on “A novel approach using continuous monitoring of peripheral edema in heart fialure patients allows recognition of acute decompensation early in the window of intervention” at the HFSA, 2021.

A continuous relaible quantitative measure of peripheral oedemia would provide fluid status that is essential to management of worsening heart failure. It is hypothesized that continuous accurate measurement of ankle circumference can detect decompensation early in the window of intervention. Six male and six female were enrolled for continuous monitoring of ankle circumference for duration of one to six months. The anklet was worn continuously and circumference was measured every 10 minutes; the cumulative orientation was collected every 10 min. The measurement accuracy was 1 mm. The anklet was a comfortable, waterproof devive with a battery life of 4 months.

Continuous monitoring of ankle circumference using the established criteria for accurate and reliable measurements yeilded the following results. The Daily Swelling Pattern (DSP) is correlated with limb orientation. Well-managed heart failure subjects present a DSP and normal baseline substantially equivalent to healthy normal subjects. Fluid retention presents as deviations from the normal baseline.

Quantification of fluid status provides early recognition of decompensation. Ability to detect and interpret ankle swelling patterns provides the opportunity to improve self-care, optimize therapeutic effectiveness, and respond early in the window of intervention to prevent heart failure hospitalizations.


Significantly Reduced Healthcare Costs with Home Furoscix Versus in Hospital IV Diuresis: Results from the FREEDOM-HF Study

Tucker John presented the much awaited results of the FREEDOM-HF study in the session “Significantly reduced healthcare costs with home furoscix versus in hospital IV diuresis: Results from the FREEDOM-HF study” at the HFSA, 2021.

FUROSCIX is an investigational, proprietary furosemide solution formulated to a neutral pH, designed to allow for subcutaneous infusion via a wearable, pre-programmed on-body infusor, for outpatient self-administration. FUROSCIX is being developed for the treatment of congestion caused by fluid overload in adult patients with New York Heart Association (NYHA) Class II and Class III chronic heart failure (HF) who show diminished response to oral diuretics and do not require hospitalization. FUROSCIX, if authorized, has the potential to give an outpatient therapy option for worsening heart failure caused by congestion. FREEDOM-HF was a prospective clinical study that assessed the 30-day heart failure-related and total expenses of treating congestion in chronic HF patients. FUROSCIX, the Company’s investigational product, was administered to patients after they were discharged from the emergency department and compared to a historical comparator group that was managed in the hospital setting.

Comparators were hospitalized for ≤72 hours and drawn from a claims database that was matched to seven factors associated with HF-related hospitalization and severity. Baseline patient characteristics (important matching factors) were comparable between research groups, as was the prevalence of co-morbidities and HF medication usage. The use of FUROSCIX resulted in a statistically significant decrease in 30-day HF-related and total healthcare expenses. The FUROSCIX treated group ($2,920) had $17,753 less HF-related expenditures than the comparison group ($20,673, p-value <0.0001). Similarly, the average 30-day total healthcare expenses in the FUROSCIX-treated group ($7,090) were $30,568 lower than the comparator group ($37,658, p-value<0.0001).  

There were no major adverse events (SAEs) associated with the study medication, and there were no deaths or withdrawals from the trial as a result of an SAE. The most frequent adverse effects of FUROSCIX were injection site bruising (29%), pain (29%), and dizziness (13%); all were minor in intensity and none resulted in study withdrawal. The cost of FUROSCIX is not included in this study because it has not yet been established.

HF patients with mild to moderate volume overload (despite oral diuretic use) can be safely discharged from the emergency department with subcutaneous FUROSCIX, enabling outpatient decongestion. FUROSCIX use was associated with statistically significant reduced overall and HF-related healthcare costs through a reduction in HF-related hospitalizations.


A Novel Approach Using Remote Speech Analysis in Chronic Ambulatory Heart Failure Patient Allows Early Detection of Clinical Decompensation Leading to Hospitalization or Unplanned IV Diuretics Treatment- Updated New Data

Amir, et.al gave a poster presentation at the HFSA Annual Scientific Meeting 2021 on the topic, “A novel approach using remote speech analysis in chronic ambulatory heart failure patient allows early detection of clinical decompensation leading to hospitalization or unplanned IV diuretics treatment- updated new data.”

Prevention of acute decompensated heart failure (ADFH) hospitalizations has both medical and economic implications, yet remains an unmet need. Voice analysis may remotely detect the increases in pulmonary and upper airway fluid content. The ongoing multicentre observational study was based on the hypothesis that Cordio HearO™ speech analysis may help in identifying clinical worsening of heart failure (HF) before hospitalization. The study included a total of 180 New York Heart Association Class II-III, stable stage C chronic HF patients. The patients recorded 2-5 sentences each day using Cordio HearO™ operating on standard smartphone devices, collected daily over 29 months. The present analysis explored the association between different speech measures parameters and episodes of HF decompensation requiring hospitalization. A total of 63,901 recording days were there. Of the 24 patients’ HF events, 21 (87.5%) were detected by the system with a mean of 22 days (min: 3 days, max: 31 days) before the HF event. The estimated false positive event rate per year was 2.87, one priority every 4.2 months (approx.) per patient. The system issued a notification 22 days (per patient, on average) before HF-related hospitalization occurred. 

Cordio HearO™ novel speech analysis technology may be a useful tool in remote monitoring of HF patients, providing an early warning of impending episodes of decompensation, thus having the potential to reduce ADFH hospitalizations and improve patient quality of life and economic outcomes. 

Cordio HearO™ novel speech analysis technology is a useful system for timely detection of clinical decompensation leading to hospitalization. Ongoing and future studies will continue to define the role of speech measures in the management of HF patients.


Which Patients Benefit from Complete Revascularization?

Cindy L. Grines from the Northside Hospital Cardiovascular Institute, Atlanta, Georgia, USA, presented an informative talk on the topic, “Which patients benefit from complete revascularization?” at the HFSA Annual Scientific Meeting 2021. Cindy L. Grines iterated the need for carefully doing risk-benefit assessment in patients with coronary artery disease (CAD). One of the recent studies showed that incomplete revascularization at Index Hospitalization was linked to the higher 1-year death, myocardial infarction (MI), and repeat revascularization. Incomplete revascularization with percutaneous coronary intervention (PCI) is associated with a lower survival rate whereas complete revascularization from either PCI or coronary artery bypass graft (CABG) has similar long-term survival rates. The patients at high risk and complexities have more difficulty in achieving complete revascularization. PCI results in incomplete revascularization than CABG. More extensive revascularization at the Index procedure with Impella support is associated with improved outcomes and risk-reduction in acute kidney injury. According to the results from a very recent SYNTAX Extended Survival Study, incomplete revascularization is common after PCI, and the degree of incompleteness was associated with 10-year mortality. A 2021 R-IMP-IT study revealed that Impella-supported extensive revascularization is associated with lower rates of death, non-fatal MI, and stroke at 1 year. These results are similar to the Roma-Verona Registry study in which more complete revascularization with Impella was linked to increased survival and improved ejection fraction. Cindy L. Grines discussed the findings of The ISCHEMIA Trial in detail. She briefly talked about the study design in which the stable patients with moderate to severe ischemia were randomized to either invasive strategy (optimal medical therapy + catheterization + optimal revascularization) or conservative strategy (optical medical therapy alone). 

In 1825 patients randomized to invasive strategy group, 43.3% patients had complete revascularization as per anatomic complete revascularization assessment and 58.3% had complete revascularization as per functional complete revascularization assessment. Complete revascularization was associated with a significantly lower incidence of CV death, MI, or hospitalization for arrest, HF, or UA. Complete revascularization was associated with significantly improved long-term outcomes compared to patients who underwent incomplete revascularization. Complete revascularization had been shown to reduce the risk of all cause death/CV death, risk of major cardiovascular events (MACE), risk of MI in patients with the acute coronary syndrome (ACS), and high-risk ST-elevation myocardial infarction (STEMI).

All patients with significant multivessel disease, in whom complete revascularization can be safely performed will benefit from complete revascularization.


The Heart of the Heart Team

David Wohns, presented an enlightening presentation on the topic, “The Heart of the Heart Team” at the HFSA Annual Scientific Meeting 2021.

The Goal of the heart of the heart team program is to share spectrum health best practices and tools for heart team implementation. The heart team is involved in conducting various diagnostic procedures, percutaneous coronary intervention (PCI) as the patient volume suffering from acute myocardial infarction; high-risk ST-elevation myocardial infarction (STEMI) has increased over the years. Cost, trust and multidisciplinary care are what patient looks for while selecting any health system. The value proposition of the heart team includes efficient decision-making, rapid multidisciplinary input, physician empowerment, and patient empowerment, reduced length of stay, positive outcomes, and team building. Dr. David presented a case of a 67-year old male with severe coronary artery disease and progressive multiple sclerosis-wheel bound. As per the computed tomography (CT) surgery consult, he was a poor surgical candidate. Interventional cardiology consultation confirmed that he was a poor PCI candidate. For such a case, the right approach would be to consider rapid improvement events, present as well as the future state, and evaluate who should do what, when, and where. “Why” a particular procedure to be considered in this case should be communicated clearly. The standard areas to be included are Ad hoc PCI, admission from Cath lab, pre-operative testing/consultation with surgery, outpatient optimization before the surgery, communication with the patient, family, and nursing. 

The program, “the heart of the heart team” could provide a comprehensive patient presentation, would encourage discussion, communication, and education, and would help in reaching general consensus/recommendations, and helps in establishing a good physician-patient relationship.


Outcomes in Patients On Chronic Inotropic Support Who Are Not Candidates for Advanced Heart Failure Therapies

Sami F, presented a session on the topic “Outcomes in Patients On Chronic Inotropic Support Who Are Not Candidates for Advanced Heart Failure Therapies” at the HFSA, 2021. She aimed to study clinical outcomes in these patients discharged on inotropes while comparing the dobutamine and milrinone cohorts.

In heart failure patients, guideline directed therapy (GDMT) and device implantation have improved outcomes in heart failure patients. There is no proper study which studied the impact of GDMT and device implantation on patients with advanced heart failure, who are not candidates for left ventricular assist device (LVAD) or heart transplant (HT).

A retrospective multi-center study from Jan 2015 to May 2019 was conducted which included 249 patients, hospitalized with refractory stage-D heart failure and discharged on continuous long-term milrinone or dobutamine therapy. Exclusion criteria consisted of patients on who were candidates for HT or LVAD and those discharged on comfort measures.

In this study, overall age of of patients was 64.8 ±13.4 years and majority of them were males. Dobutamine group had 118 patients and milrinone was used in 131 patients. In both the groups, age and baseline comorbidities were similar with more prevalence in dobutamine group (59.4 vs 52.0; p=0.02). Patients on dobutamine had higher baseline cardiac indices than milrinone group (Fick 2.0 vs 1.8; p=0.048, Thermodilution 2.0 vs 1.6; p=0.002). Patients on milrinone had lower 1-year-mortality compared to dobutamine group (58.1% vs 85.0%; p<0.01).

Milrinone cohort had more patients discharged on beta blocker (42.9 vs 8.6; p<0.001). Other GDMT was also more common on discharge in milrinone group, though statistical significance was not reached.

Mortality is found to be high in in patients started on chronic inotropes who are not candidates for LVAD/HT. Better patient outcomes are observed with Milrinone as compared to Dobutamine.


Time to Decongestion Following Heart Failure Hospitalization as Measured by Extracellular Fluid Nadir Using Bioimpedance Spectroscopy (BIS)

Daleiden-Burns A, presented the poster session on “Time to decongestion following heart failure hospitalization as measured by extracellular fluid nadir using bioimpedance spectroscopy (BIS)” at the HFSA, 2021. This study evaluated daily SOZO® Digital Health Platform BIS measurements using ImpediMed’s HF-Dex™ heart failure index to track fluid status and compared these measurements to corresponding weight measurements.

The SOZO fluid analysis for heart failure provides an objective measurement of fluid volume in individuals with heart failure. It makes use of ImpediMed’s HF-DexTM heart failure index to assist doctors in determining the appropriate fluid volume range for their patients. HF-Dex is based on BIS-derived reference ranges that show normal fluid volumes and high fluid volumes that may necessitate additional clinical evaluation.

Following a heart failure-related hospital stay, individuals had their lowest extracellular fluid volume on average after 16.9 days. Patients lost a median of 7.8 % of their extracellular fluid (ECF) volume versus only 3.4 % of their weight over this period, a statistically significant difference (p<0.0001). The poster indicated that regular monitoring of ECF using BIS measures is a more sensitive technique of monitoring fluid status in patients with heart failure than weight.

The study results demonstrate that non-invasive bioimpedance spectroscopy measurements during the weeks following heart failure hospitalization may assist clinicians in tracking the fluid status of heart failure patients. Monitoring extracellular fluid volume during the weeks after heart failure hospitalization may provide a more accurate measure of fluid status in heart failure patients than measuring weight alone.


Linear Association of Body Mass Index and Mortality in Cardiogenic Shock: A Retrospective Analysis

Delfiner M presented a session on the topic “Linear Association of Body Mass Index and Mortality in Cardiogenic Shock: A Retrospective Analysis” at the HFSA, 2021. He aimed to determine if the BMI correlates with cardiogenic shock mortality.

Cardiogenic shock (CS) continues to have high mortality despite advancements in care, including the development of shock teams and standardized protocols. Obesity is highly prevalent across the world and is a risk factor for overall cardiovascular disease. Obesity has not made its way into common risk assessment platforms of CS. Awareness of a potential correlation may improve risk assessment and inform care plans for CS patients.

A retrospective analysis of 92 patients from 2014 to 2019 were cared for by a single quaternary care shock team. The shock team comprised of an advanced heart failure physician, a cardiac intensivist, an interventional cardiologist, and a cardiothoracic surgeon. Each patient was subdivided into cohorts: underweight (BMI < 20 kg/m2) normal weight (BMI between 20 kg/m2 and 25 kg/m2), overweight (BMI between 25 kg/m2 and 30 kg/m2), obese (BMI between 30 kg/m2 and 40 kg/m2), and extremely obese ((BMI greater than 40 kg/m2).

The mean age of patients was 62.0 years (SD 12.3 years) and 35 patients (43%) were female. The mean BMI for the total population was 31.1 kg/m2 (SD 8 kg/m2). The mean BMI of patients who survived was 29.7 kg/m2 (SD 8 kg/m2), compared to 33.7 kg/m2 (SD 7.6 kg/m2) for those that did not survive (p = 0.04).

As per this study, an inverse linear relationship between BMI and survival in CS. It has been observed in epidemiological studies that acute coronary syndrome (ACS) related CS yields higher mortality than non-ACS related CS.

Higher BMI is an incremental risk factor for CS mortality and further studies are required that include larger sizes and the measurement of novel biomarkers for obesity and CS.


New York Heart Association Functional Class and Mortality in Obstructive Hypertrophic Cardiomyopathy

Lakdawala N presented a session on the topic, “New York Heart Association Functional Class and Mortality in Obstructive Hypertrophic Cardiomyopathy” at the HFSA, 2021 on the topic. He aimed to assess the associations between NYHA functional class and mortality among patients with oHCM.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with complex pathophysiology. About two-third of patients with HCM have left ventricular outflow tract (LVOT) obstruction present at rest or with provocation (i.e., obstructive HCM [oHCM]). To assess symptoms and functional limitations among patients with HCM, the New York Heart Association (NYHA) functional class is commonly used.

The study used the data from the Sarcomeric Human Cardiomyopathy Registry (SHaRe), an international registry representing patients from ten HCM specialty centres, up to March 2019. The study cohort consisted of adults with oHCM at least one definite assessment of NYHA functional class. The outcomes were all-cause mortality at 1 year.

In this study, a total of 2495 adult patients had oHCM and at least one definite or indefinite NYHA functional class assessment. On the index date, 38%, 41%, and 21% of patients had NYHA functional classes I, II, and III/IV, respectively. Patients with NYHA functional class I were younger at HCM diagnosis (44 years) compared with class II (49 years) and class III/IV (51 years).

26 patients had died (3 in NYHA functional class I, 8 in class II, and 15 in class III/IV) by the end of 1 year and the risks of mortality increased with worse NYHA functional class. The 1-year probabilities of all-cause mortality were 0.4%, 0.9%, and 3.6% for NYHA functional classes I, II, and III/IV, respectively.

Increased all-cause mortality is associated with worse NYHA functional class in oHCM and proper monitoring of NYHA functional status may improve prognosis.


Do all patients with New-onset Heart Failure need assessments for CAD?

Devore A gave an enlightening presentation at the HFSA, 2021 on the topic, “Do all patients with New-onset Heart Failure need assessments for CAD?” He aimed to discuss the observational data on assessments for CAD and recommend assessments for CAD as quality measure in HF care.

In routine practice, improvements in LVEF are common In CHAMP-HF among 2913 patients with HFrEF, increase in LVEF over time were common over a median of 16 months. He presented a case of 61-year-old male with HFrEF and dilated cardiomyopathy. He was diagnosed with HF and AF 15 years ago and treated with ACEi, BB and MRA. He recently presented to hospital with the episode of acute HF.  He arrived on milrinone and intra-aortic balloon pump as choice of treatment. He had a poor urine output despite escalating diuretics and inotropes and impella 5.5 was placed with improvement in end organ function. He underwent transplant at the end of August.

It has been observed that there is underutilization of coronary artery disease testing among patients hospitalized with new onset HF. Testing for HF among patients hospitalized for new-onset HF was 18% which increased to 27% at 90 days after admission

Medical therapy for CAD is a unique therapeutic way for patients with HF and limited testing of CAD can result in missed opportunity to identify appropriate candidates for revascularization.

New-onset HF assessment should be higher than clinical practice and standardized approaches may improve outcomes.

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Current EASD/ADA and KDIGO Guidelines for Treating Type 2 Diabetes with CKD

Wanner C, presented a session on “Current EASD/ADA and KDIGO Guidelines for Treating Type 2 Diabetes with CKD” at Virtual EASD Annual Meeting 2021 on 1st October 2021.

The guideline recommendations have various grading and level of evidence which are important to consider when applying the guideline recommendations. Grade A denotes that the true effect lies close to that of the estimate of the effect. Grade B denotes that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Grade C denotes that the true effect may be substantially different from the estimate of the effect. Grade D denotes that the estimate of effect is very uncertain, and often will be far from truth. The KDIGO defines five levels of glomerular filtration rate basis which the severity of kidney disease is assessed. The five levels are G1: ≤ 90 mL/min/1.73m2; G2: 60-89 mL/min/1.73m2; G3a: 45-59 mL/min/1.73m2: G3b: 30-44 mL/min/1.73m2; G4: 15-29 mL/min/1.73m2; G5: <15 mL/min/1.73m2.

Risk assessment of patients with CKD and without diabetes or ASCVD classifies patients into high risk and very high-risk patients. The kidney heart risk factor management pyramid is built on the foundation of lifestyle modifications which is common for all patient’s such as exercise, nutrition, smoking cessation, and management of co-morbidities like glycemic control, blood pressure control, and lipid management. Use of medications like SGLT2 inhibitors and RAS blockade is given in majority of patients whereas antiplatelet therapies is given in only some patients. It is recommended that patients with hyper-filtration and diabetes are treated in an individualized manner targeting a SBP to 130 mmHg and  <130 mmHg if tolerated, but not  <120 mmHg. In older people (aged <65 years) the SBP goal is to a range of 130-139 mmHg. A RAAS blocker is recommended for treatment of hypertension in patients with diabetes particularly in the presence of proteinuria, microalbuminuria, or LVH. Tight glucose control targeting HbA1c (<7.0% or < 53 mmol/mol) is recommended to decrease microvascular complications in patients with diabetes. Anti-hyperglycemic therapies in patients with diabetes and CKD includes metformin as the first-line treatement for hyperglycemia in patients with Type 2 diabetes and CKD and eGFR ≥ 30 mL/min/1.73m2. In patients with type 2 diabetes, CKD, and eGFR 30 including an SGLT-2 inhibitor in the antihyperglycemic treatment regimen is recommended. Treatment with an SGLT2 inhibitor (empagliflozin, canagliflozin or dapagliflozin) is associated with a lower risk of renal endpoints and is recommended if eGFR is 30 to < 90 mL/min/1.73m2.

The pillar of management of chronic kidney disease in type 2 diabetes currently stands on lifestyle modifications, reduction in salt intake, glucose and blood pressure control and use of drugs like ACE inhibitor, ARB, SGLT2-inhibitors and MRAs like Finerenone.


Treatment of Hyperglycaemia in ICU: Tight or Not Too Tight?

Van den Berghe G, presented a session on “Treatment of hyperglycaemia in icu: Tight or not too tight?” at Virtual EASD Annual Meeting 2021 on 1st October 2021.

Strict blood glucose control with intensive insulin therapy leads to improved leukocyte function, reduced inflammation, improved cardiac contractility, prevented dyslipidemia, improved liver, kidney mitochondrial ultrastructure and function, protection of central and peripheral nervous system. Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit. Other studies conducted in critically ill patients suggested use of intensive insulin therapy is associated with lower blood glucose levels causing reduced occurences of new kidney injury.

In a prospective, randomised controlled study, we enrolled 700 critically ill patients, 317 infants (aged <1 year) and 383 children (aged >or=1 year), who were admitted to the paediatric intensive care unit (PICU) it was seen that the mean blood glucose concentrations were lower in the intensive group than in the conventional group. Age-adjusted glucose control in PICY lead to shorter ICU stay, reduced inflammation, protection of the heart, and fewer ICU infections. In an another study, despite high incidence of hypoglycemia in PICU study the number of patients with hypoglycemia < 40 mg/dL were 1.4% in usual care and 24.9% in the tight glucose control group. In the NICE-sugar trial an international, randomized trial, it was seen that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. Moreover, no difference in organ function with more cardiovascular deaths and 13 times greater risk of hypoglycemia was noted. This has been attributed to lack of early parenteral nutrition in critically ill patients. Few studies have shown harm from early parenteral nutrition in critically ill patients. No blood glucose control plus early parenteral nutrition leads to reduced mortality and reduced organ failure. Early parenteral nutrition plus blood glucose < 110 mg/dL and late parenteral nutrition plus blood glucose < 110 mg/dL leads to enhanced recovery.

There is a need to redo the randomised clinical trials on strict blood glucose control (80-110 mg/dl vs. tolerating hyperglycemia upto 215 mg/dl) in multiple centers, in the context of no early parenteral nutrition with use of accurate sensors and guided by the LOGIC-insulin algorithm. The “TGC-fast” RCT is recruiting currently ± 8000 patients have been included, aiming for ± 9600 patients by next year.


Care of People with Diabetes Post COVID-19 in Primary Care

Khunti K, presented a session “Care of People with Diabetes Post COVID-19 in Primary Care” at Virtual EASD Annual Meeting 2021 on 1st October 2021. In individuals with COVID-19, the presence of co-morbidities, such as diabetes is associated with increased risk of severe COVID-19. Meta-analyses results for prevalence of co-morbidities and increased risk mortality and severity of disease by co-morbidities in COVID-19 patients. The most common co-occurring chronic diseases were diabetes, cardiovascular disease and stroke with multimorbidity and tested positive for COVID-19. In the practical recommendations for the management of diabetes in patients with COVID-19, outpatient care recommendations states caution of discontinuation of established therapy and utilisation of telemedicine and connected health models if possible to maintain maximal self-containment. A meta-analysis revealed a significantly reduced odd for mortality with the use of metformin in patients with diabetes and COVID-19. A nationwide observational study in England, several glucose lowering treatments such as DPP4I, GLP-1RAs, Metformin, SGLT2i, showed significant effects in decreasing risk of COVID-19 mortality in T2DM patients. DARE-19 trial, a phase 3 trial showed that Dapagliflozin had significant reduction in cardiometabolic risk factors in hospitalised patients with COVID-19. A population based study of England states that risk of COVID-19 related mortality risk was significantly associated with preceding levels of hyperglycemia in T1D and T2D patients. During COVID-19 pandemic, people with diabetes have perceived physical and psychological problems. For the chronic disease management during the pandemic, regular contact with primary care is important, to ensure that comorbidities are actively treated and risk factors are controlled, and to improve adherence to medical therapies. COVID and infection control measures necessitated new models of care mean that remote consultations (online, telephone or video) have replaced face-to-face consultations with primary health care professional. The proportion of newly diagnosed diabetes is also significantly increased in COVID-19 patients indicated by review and meta-analysis studies.

The specific consideration such as inpatient/outpatient services, routine diabetes care, foot and pregnancy services for people with disabilities, etc. should be implemented in the routine care of people with diabetes post-pandemic. Vaccine induces a weaker immunity response in people with poor glycemic control as compared to normal glycemic control.


Associations of Hypoglycaemia and Glycaemic Variability with Cardiac Arrhythmias Using a Long-term Monitoring Approach in Insulin-treated Patients with Type 2 Diabetes

Hyperglycaemic episodes are frequent in insulin treated patients with type 2 diabetes, leading to increased risk of cardiovascular disease and mortality. Andersen A, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting using a long-term monitoring approach.

In the one-year observational study, a total of 71 insulin-treated patients and microvascular complications ([mean±SD] age 66.8±9.6 years, BMI 30.1±4.5 kg/m2, HbA1c 6.8±0.4% [51.0±4.8 mmol/mol]) were included. In these patients, continuous glucose monitoring (118±6 days) and implantable cardiac monitors (ICMs) were employed.

It was observed that time spend in hypoglycaemia was higher during night-time than during day-time. In 12 patients, the ICMs detected 724 episodes of clinically relevant arrhythmias. Out of 724 episodes, atrial fibrillation and pauses accounted for 99% of cases. No association between hypoglycaemia and cardiac arrhythmia was found during daytime. Subject-specific hourly incidence of cardiac arrhythmias tented to increase with the occurrence of hypoglycaemia but only slightly with increasing time in hypoglycaemia during night time.

In insulin-treated patients with T2D, cardiac arrhythmias were common and were associated with glycaemic variability, whereas arrhythmias were not strongly associated with hypoglycaemia.


Prevalence of and Factors Associated with Undiagnosed Stage 3 Chronic Kidney Disease in Patient with Type 2 Diabetes: A Report from REVEAL-CKD

Chronic kidney disease (CKD) is a serious condition which affects 10% of the world’s population but it remains largely under recognized problem in among patients with pre-existing comorbidities. As large number of CKD patients have T2D, Wittbrodt E, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which investigated prevalence and factors associated with undiagnosed stage 3 CKD in patients with T2D.

REVEAL-CKD is a multinational initiative to assess early stage undiagnosed CKD. A total of 66,815 patients with eGFR values indicating stage 3 CKD and pre-existing T2D with mean age of 70 years were included in this study. With increasing age, prevalence of undiagnosed CKD increases and ranged between 38% and 48% in patients with other pre-existing comorbidities.

In comparison to patients with diagnosed CKD, undiagnosed group had more female (46% versus 63%) and a had higher proportion of patients >75 years: 33% versus 38%

The results of the given study suggest that a large proportion of older or female patients with baseline T2D have undiagnosed CKD. These results suggest that an opportunity exists for more proactive CKD diagnosis and monitoring of patients with pre-existing comorbidities.


Type 2 Diabetes, Chronic Kidney Disease and Major Cardiovascular Events in Patients with Established Coronary Artery Disease

The conditions, type 2 diabetes and (T2DM) and chronic kidney disease (CKD) usually coincide which confers high risk of cardiovascular diseases. Saely C, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which assessed the single and joint effects of T2DM and CKD on major cardiovascular events (MACE) in a high-risk population of patients with established coronary artery disease (CAD).

A total of 1460 patients with angiographically proven CAD over 10.4±4.8 years, of whom 454 (30.8%) had T2DM and 251 (17.1%) had CKD were included in the study.

In comparison to non-diabetic subjects, MACE events occurred more frequently in T2DM patients (40.4% vs 28.7%, p<0.001) and in patients with CKD (eGFR < 60ml/min/1.73m2). While comparing the MACE incidence among patients with neither T2DM nor CKD (25.3%), patients with T2DM but who did not have CKD reported frequent MACE events (35.8%; p<0.001) as well as in non-diabetic patients with CKD (47.6%; p<0.001). MACE events happened most frequently in patients with both, T2DM and CKD (57.4%; p<0.001). In Cox regression analysis, T2DM (HR=1.46 [1.20-1.78]; p<0.001) and CKD (HR=1.81 [1.45-2.27]; p<0.001) were mutually independent predictors of MACE after multivariate adjustment.

T2DM and CKD are mutually independent risk factors for MACE patients in patients with established CAD. CAD patients with both CKD and T2DM are an extremely high risk for MACE.


Remission of Type 2 Diabetes Following a Short-term Intervention with Insulin Glargine and Metformin/Sitagliptin: Results of the REMIT-sita Randomised Controlled Trial

Non-surgical approaches have shown success in inducing remission of type 2 diabetes. However due to limited evidence diabetes remission was reported following a short-term intervention with insulin glargine, metformin/sitagliptin and lifestyle approaches. Gerstein H, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021.

102 patients with type 2 diabetes were segregated in 2 groups (i) a 12-week intensive treatment with insulin glargine and metformin/sitagliptin combined with lifestyle therapy or (ii) control group where the participants with HbA1C10 mmol/l on ≥50% of glucometer readings, re-initiation of diabetes medications ± abnormal FPG or 2-hour plasma glucose on OGTT were included in a randomised trial. To compare the treatment groups with and without FPG/OGTT relapse criteria time-to-relapse analysis was conducted.

In the intervention group, FPG/OGTT criteria included, hazard ratio of relapse was 0.72 (95% CI 0.47; 1.10) when compared to the control group. Hazard ratio of relapse was 0.60 (95% CI 0.39; 0.95), without the FPG/OGTT criteria (supplementary analysis). The results (HR 0.75, 95% CI 0.49; 1.15) were unaffected by the removal of the 2-hour plasma glucose from the relapse criteria.

A sustained diabetes remission may be induced using a short-term intervention with insulin glargine and metformin/sitagliptin. No additional information was obtained by using the 2-hour plasma glucose from OGTT in the relapse criteria.


Metformin Lowers Portal Pressure in Patients with Cirrhosis and Portal Hypertension: A Randomised Clinical Trial

Portal hypertension (PH) is the vital factor of clinical decompensation in patients with liver cirrhosis. In pre-clinical data, metformin decreases portal pressure, however there are no clinical data for this advantageous impact. Thus, Rittig N, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which aimed to analyse the acute impacts of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion in patients with cirrhosis.

A randomized, double-blinded, placebo-controlled parallel study design in which 32 β-blocker naive patients with cirrhosis were assessed before and 90 minutes following an oral single-dose of 1000 mg metformin (n=16) or placebo (n=16). Liver vein catherization was executed to analyse HVGP and indocyanine green (ICG) infusion for analysis of hepatic blood flow.

Metformin group showed higher mean relative change in HVPG as compared to placebo group (-16% vs. 4%) (95%CI: -28 to -4%) (95%CI:-6 to 14%) in the (time x group, p = 0.008). In patients with baseline HVPG ≥ 12 mmHg, metformin-treated group showed clinically substantial enhancements in HVPG (HVPG < 12 mmHg or a > 20% reduction in HVPG) than placebo-treated patients (46% (6/13) vs. 8% (1/13)) (p = 0.07). No changes or differences were seen in systemic blood pressure, heart rate, hepatic plasma- and blood flow, hepatic ICG clearance, hepatic O2 uptake, or inflammation markers among groups.

A single oral metformin dose significantly decreases HVPG in patients with cirrhosis and PH without impacting systemic or liver hemodynamics, or inflammatory biomarkers. This shows a promising view of a safe and inexpensive therapy option that should be analysed in larger scale clinical studies with long-term results in patients with cirrhosis and PH.

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Combination Very Low Dose Sulphonylurea and DPP4 Inhibitor have a Potent Glucose Lowering Effect through Augmentation of Beta Cell Function without Increase in Hypoglycaemia

By 2035, the global prevalence of diabetes will surpass 600 million contributed by low and middle-income countries. Low dose use of sulphonylurea can counteract the negative aspects, particularly hypoglycaemia, weight gain and reduced durability. Cordiner RM, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which hypothesized the potential synergy between low dose SU in combination with a DPP4 inhibitor.

A total of 30 individuals with T2DM (HbA1c <64mmol/l) treated with diet or metformin monotherapy were allocated in a single-centre, open-label, randomised crossover study. Participants completed four, 14-day blocks in a random order: control, gliclazide 20mg once daily (SU), sitagliptin 100mg (DPP4), or combination (SUDPP4). Beta cell function was modelled through the relationship between insulin secretion and glucose concentration. The primary outcomes assessed were the evaluation of treatment on beta cell glucose sensitivity and CGM parameters were assessed as secondary outcomes.

A potent additive glucose lowering effect was shown by linear mixed model estimates mean glucose from area under the curve (mean 95% CI) (mmol/l): Control 11.5 (10.7 – 12.3), DPP4 10.2 (9.4 – 11.1), SU 9.7 (8.9 – 10.5), SUDPP4 8.7 (7.9 – 9.5) (p <0.001) which was mirrored by the glucose sensitivity.

A progressive increase in insulin secretion at the same glucose concentrations (i.e. increased glucose sensitivity) in favour of combination DPP4 and SU was observed.

These results suggest that combination low dose gliclazide with a DPP4 inhibitor shows potent glucose lowering effect and glucose reduction was achieved at gliclazide concentrations far below those achieved with standard therapeutic doses (~600ng/ml vs >5000ng/ml Cmax with 80mg gliclazide daily).


Impact of the Fasting Plasma Glucose Titration Target on the Success of Basal Insulin Titration in Insulin-naive Patients with Type 2 Diabetes: A Systematic Analysis

The algorithms of basal insulin titration differ in their fasting plasma glucose (FPG) targets. Wolters J, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which compared beneficial (glycaemic control) and adverse outcomes (hypoglycaemia, weight gain) of basal insulin titration carried out with FPG titration targets (TT).

A total of 42 publications reporting clinical trials were retrieved from PubMed literature search in 17643 insulin-naïve patients with type 2 diabetes. 61 individual study groups were divided as per FPG TT (a: ≤ 5.0; b: 5.01-5.6; c: ≥ 5.61 mmol/l). Weighted means and their standard deviations were calculated for: FPG, HbA1c, target achievement, incidence of any or severe hypoglycaemic events, and insulin doses.

After titration, i.e. at the study end, achieved FPG and HbA1c were lower with more ambitious titration targets (a. 6.17 [6.11; 6.24]; b. 6.67 [6.63; 6.71]; c. 6.93 [6.79; 7.06] mmol/l and a. 7.08 [7.05; 7.11]; b. 7.19 [7.18; 7.21]; c. 7.32 [7.26; 7.37] %; p < 0.01 for all comparisons).

  • In FPG TT a, HbA1c target achievement (≤ 7.0 or 6.5 %) was highest, intermediate with b, and worst with c (p <0.01).
  • In subgroup a, the basal insulin dose achievement was highest
  • With lower FPG TTs, the incidence of (severe or any) hypoglycaemic episodes was not higher
  • Body weight gain (1 to 2 kg across all subgroups) was not more prominent as well.

Improvement in glycaemic control can be achieved by aiming for a lower FPG titration target without increasing the risk for adverse events like hypoglycaemia or increased body weight.


Indirect Effect of COVID Pandemic on Cardiovascular Hospitalisations

Kunutsor S, presented a session on “Indirect effect of COVID pandemic on cardiovascular hospitalisations” at Virtual EASD Annual Meeting 2021 on 30th September 2021.

A study was conducted to assess the indirect impact of the COVID-19 pandemic on hospitalisations for and the management of cardiometabolic conditions. The study was conducted according to a predefined protocol and PRISMA and MOOSE guidelines. All clinical observational studies were included. These studies evaluated indirect impact of COVID-19 on hospitalisations for cardiometabolic conditions and their management. The studies reported comparisons between the pandemic period vs. pre-pandemic and/or historical period. Most studies published in 2020 and 2021 were included. Except for 12 studies, all reported decline in hospitalisations comparing pandemic with pre-pandemic periods (ranging from 20.2 to 73.0%). Eleven of 12 studies reported no increase or no changes in stroke hospitalisations. The severity of presentation was reported by 26 studies. Measures of severity were assessed by increase in levels of cardiac enzymes, worsened left ventricular ejection fraction (LVEF), higher NIHSS score. Most studies reported severe presentation during pandemic compared with pre-pandemic period. 36 studies reported data on procedures performed in hospital. The procedures included coronary angiography, PCI, thrombolysis, MRI, acute revascularisation. Most studies reported less procedures being performed during pandemic compared with pre-pandemic period. Fifty-five studies reported on delays during presentation and management. Delays reported were time between symptom onset to first medical contact, emergency transport, and consultation-intervention. Most studies reported more delays during pandemic compared with pre-pandemic periods. Most common patient delay was time between symptom onset and first medical contact. The reasons cited for delays in seeking medical care were fear of contracting COVID-19 which added extra burden to healthcare system. Most studies reported a shorter length of stay during pandemic compared with pre-pandemic (1-8 vs. 2-12 days). Most studies reported no change in in-hospital mortality or discharge disposition during pandemic compared with pre-pandemic period. Twenty-three studies reported an increase in worse in-hospital outcomes.

This was a real world study gathering data across 6 continents. Health-seeking behaviour of patients for acute cardiometabolic conditions, their management, and outcomes have all been adversely impacted by the COVID-19 pandemic. Despite this, in-hospital deaths were not significantly affected.

Several potential reasons for the decline in hospitalisations increased severity on presentation and delays in management. Despite the delays, change in the in-hospital mortality suggested care for patients was not compromised. Implications for cardiovascular care are needed. It is important to prepare for future pandemics and educate patients.

 Prediabetes: Innocent or Guilty? Insights from the Maastricht Study

Stehouwer CDA, presented a session on “Prediabetes: Innocent or Guilty? Insights from the Maastricht Study” at Virtual EASD Annual Meeting 2021 on 29th September 2021.

Prediabetes is simply early diabetes and its charge is in terms of its consequences. Prediabetes strongly varies with BMI and age. It occurs at ~25% among 40-75 year old while at age 60, is ~5% if BMI <25 and ~40% if BMI is ≥35. Many studies have evidence that diabetes is strongly correlated with cardiovascular death and supportive evidence from mandelian randomization showed positive association between genetically proxied HbA1c and CHD in non-diabetic people. Diabetes has relevance with comorbidities such as retinopathy, kidney disease, and neuropathy. Also, stroke, dementia, depression, heart failure and even T2DM itself. HbA1c and prediabetes are associated with retinal arteriolar and venular diameters in retinopathy. Vasodilation in retina and skin is impaired in T2D and prediabetes. It is measured with analysis of retinal dynamic vessel and skin laser Doppler flowmetry. In T2D, cerebral white matter hyperintensities (WMH) and volume loss increases are linked to cerebral vessel disease. All the three parameters HbA1c, FPG and 2hPG are related with WMH. cerebral vessel disease predisposes to stroke, cognitive impairment depression. Microvascular function of body is associated with prevalence and 4-y incidence of depressive symptoms. Hyperglycemia is toxin for endothelial and neural cells leads to neuronal dysfunction and neurogeneration. T2D and prediabetes are associated with thinning in corneal and retinal nerve fiber length. Retinal neurodegeneration is associated with brain atrophy and also 7-year incidence of depressive symptoms. The studies exhibited that glucose intolerance and diabetes showed strong correlation with CVD events and microvascular disease. Treatment of prediabetes is necessary to prevent or delay the progression of diabetes.

Diabetes is a progressive macrovascular, microvascular and neuronal disorder that affects many organs and that starts in prediabetes.


Cardiovascular Risk in Prediabetes

Faerch K, presented a session on “Cardiovascular Risk in Prediabetes” at Virtual EASD Annual Meeting 2021 on 29th September 2021.

A prospective study of 22 groups in Europe showed that cardiovascular disease (CVD) is leading factor in mortality in prediabetes patients. The 2H-BG is a better predictor of deaths from all causes and CVD than in FBG with significant difference in rise of impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). According to WHO and ADA, people with IFG and IGT exhibited ~20% increased risk of CVD as compared to their normoglycemic counterparts. The risk can be reduced by ~50% following adjustment for conventional CVD risk factors. FPG is modest and 2h-BG is good predictor of CVD but both had high variability.

In the use of HbA1c to diagnose diabetes and high risk patients, the categorical clinical states pre-diabetes, IFG, and IGT fail to capture the continuum of risk and will be phased out of use as HbA1c measurements replace glucose measurements. As per the ADAG study, less than 40% variance in Hba1c could be explained in people without diabetes. HbA1c is affected by anaemia, iron deficiency, genetics, etc. There was >20% increased risk of CVD was seen in people with prediabetes diagnosed by HbA1c compared to their normoglycemic counterparts .No difference in survival rate was seen between prediabetes and normoglycemic groups after adjusting for previous CVD, soking, TC, HDL-C, SBP. HbA1c is very good predictor of CVD. It is convenient for patients and also accurate and precise. The near 2-fold higher unadjusted risk for CVD in people with prediabetes is driven mainly by abnormal levels of conventional CVD risk factors.

Prediabetes is associated with 20% increased risk of CVD compared to normoglycemic individuals. But, ~50% of the risk is driven by conventional non-glycemic CVD risk factors. Prediabetes is not one entity with different diagnostic criteria and different pathophysiology. A balance between feasibility and convenience on one hand and scientific data on the other hand is needed. The focus should be on developing risk scores for the population without diabetes to target individual at the highest risk of CVD, not only focus on glycemia (prediabetes) using arbitrary cutpoints.


Validation of the Classification for Type 2 Diabetes into Five Subgroups: A Report from the ORIGIN Trial

It has been observed that diabetes could be segregated into five subtypes as per the progression of dysglycemia and the incidence of diabetes consequences which has been found in Swedish individuals with newly diagnosed diabetes. Pigeyre M, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021.

A total of 7,017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were allocated in five predefined diabetes subtypes (namely, severe auto-immune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild age-related diabetes (MARD)). This allocation was done on the basis of: age at diabetes diagnosis, body mass index, glycosylated haemoglobin, fasting C-peptide levels, and presence of glutamate decarboxylase antibodies at baseline.

Difference of cardiovascular and renal outcomes in different subtypes were assessed using Cox regression models for a median follow up of 6.2 years and comparison was done between of glargine versus standard care on hyperglycemia. These five different subtypes were replicated in the ORIGIN trial and similar characteristics were found in Europeans and Latin Americans, in comparison to the initially described clusters in the Swedish cohort. A significant difference was found in the renal outcome, with higher incidence of events in SIRD compared to the MARD subtype (i.e., chronic kidney disease stage 3A: HR=1.47, 95%CI [1.30-1.67]; stage 3B: HR=2.20 [1.80-2.69]; macroalbuminuria: HR=1.48 [1.17-1.86]). After the adjustment for multiple hypothesis testing, no differences were found in incidence of retinopathy and cardiovascular diseases. However, these different diabetes subtypes showed different glycaemic response to glargine in the SIDD subtype compared to the MARD subtype, with a decreased risk of hyperglycemia by 14% (OR=1.37 [1.32-1.43] on glargine; OR=1.51 [1.45-1.58] on standard care;

Characterization of five different diabetes subtypes in a multi-ethnic cohort was enabled by cluster analysis. The incidence of renal events and response to insulin was different between diabetes sub-types. These results suggest the use of precision medicine to predict co-morbidities and treatment responses.


Mental illness, Ethnicity and Civil Status Are Associated with Non-attendance in Diabetic Retinopathy Screening Among People with Type 2 Diabetes

Diabetic retinopathy can results in serious vision loss and blindness, if not managed properly. But, the participation in eye screening is below recommended levels. Petersen GB, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which analysed the factors with non-attendance in screening for diabetic retinopathy in people with type 2 diabetes.

Individual register data from 156,878 people with type 2 diabetes aged 40-70 years was collected in this retrospective, observational study. Each individual was categorised as an attender (at least one registered screening) or a never-attender (no registered screening) on the basis of eye screening history from 2013 till 2018. Baseline characteristics were compared between attender and non-attender using non-parametric tests including  Age, Gender, Ethnicity, Place of residence (region), Civil status, Education, Employment, Income, Diabetes duration and Comorbidity and mental health.

In the attenders, 230,173 screening intervals were analysed and if the person failed to participate in the eye screening within the recommended interval, it was defined as non-attender intervals. About 27% of individuals were recognized as non-attenders, having no registered eye screening. The comparison parameters exhibited that attenders and non-attenders differed significantly on all baseline characteristics. Never-attenders were more frequently divorced, 30% vs. 22% (p<.0001), living in the Capital Region, 36% vs. 28% (p<.0001), mentally ill 10% vs. 5% (p<.0001) and had more comorbidities, 22 % vs. 17 % (p<.0001) as compared to attenders.

This is the first national study which focuses the non-attendance in people with type 2 diabetes for diabetic retinopathy. The findings of the study showed that both never-attendance and non-attendance are frequent in people who are divorced and among people of poorer health. Furthermore, non-attendance is more common between people of non-western decent.

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Why Precision Medicine is The Future Of Diabetes Medicine

Udler M, presented the first topic “Why precision medicine is the future of diabetes medicine” from the session “EASD/ADA Symposium: Optimising Diabetes Diagnosis, Prevention And Care: Is Precision Medicine The Answer” on 29th September 2021.

Precision medicine aims to deliver the right treatments in the right dosage at the right time –every time.  With the global diabetes prevalence rising rapidly, it is crucial to have ideal screening practices and management for at-risk patients with diabetes. As per CDC, around 90% of diabetes patients don’t know they are diabetic. There is a possibility of few patients having cure or remission. However, glycaemic targets are met by <50% of patients adherent to medications. Moreover, majority of people develop worsening beta cell function despite treatment. Hence, it is imperative to identify high-risk individuals and determine the intervention for precision prevention. Depending on definition, around 30% population may have prediabetes. Approxiamtely 5-10% are expected to progress to T2D each year and upto 59% of people diagnosed with prediabetes may spontaneously return to normoglycemia within 1-5 years of follow-up. As per a study conducted by Ahlquvist, patients were stratified into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.

Diagnostic uncertainty may still remain despite a battery of tests. Type 1 diabetes needs to be differentiated from type 2, MODY, and monogenic autoimmune diabetes. For initiating the precision treatment, ADA/EASD Consensus report 2019 which is similar to 2021 ADA standards of care type 2 diabetes treatment algorithm considers individualized factors like HbA1c and goal, vulnerability to hypoglycrmia, weight, cost, ASCVD/HF/CKD disease or risk factors. However, simple individual-level traits (sex, age of diagnosis, baseline BMI and HbA1c) predicted response better than clusters in the initial step towards precision treatment. To understand the precision prognosis, it is important to ascertain the expected disease course and the increased risk of any complications or co-morbidities.

Precision medicine certainly needs to be the future of diabetes medicine because in current practice, the method of screening, recognising the subtype of diabetes and management of diabetes remains suboptimal. Moreover, there is a critical need for truly preventative, disease-modifying, and/or curative treatments. The mission of precision medicine is to treat the cause of disease rather than the symptom which requires better understanding of the disease pathways, refined disease classification and a framework for developing novel, mechanism-directed, and patient-centered therapeutic approaches.


CGM Detected Hypoglycaemia: What Is Its Clinical Relevance?

Iqbal A, presented a session on “CGM detected hypoglycaemia: What is its clinical relevance?” on 29th September 2021.

As per the consensus definition, continuous glucose monitoring (CGM) detected hypoglycaemia includes low interstitial glucose <3.9 mmol/L (70 mg/dL); <3 mmol/L (54 mg/dL) for atleast 15 minutes. A more severe event being a low interstitial glucose <3 mmol/L (54 mg/dL) for atleast 120 minutes. CGM monitoring allows to take steps in self-management as it is comprehensive, it optimises treatment, helps to understand the daily glucose trends, sets the alarms and facilitates lifestyle modification.

There are certain limitations when interstitial glucose (IG) is compared to capillary blood glucose (CBG) such as physiological lag between IG and CBG; under steady state for 4 to 10 mins and more when blood glucose falls rapidly. Also, when in studies CGM reported 19% higher glucose under hypoglycaemia and 8% higher under euglycaemia suggesting the limitation of CGM in detecting accurate period of hypoglycaemia.

Unfortunately, no randomised trials have shown that CGM use can reverse impaired awareness of hypoglycaemia (IAH). Use of CGM for > 6 months in IAH is still associated with upto 6 fold increased risk of severe hypoglycaemia.

As per a study conducted in healthy volunteers, hypoglycaemia causes inflammation and thrombosis. In patients with type 2 diabetes, inflammation and thrombosis can last upto 7 days. In summary, clinical use of CGM reduces hypoglycaemia in T1D and T2D. CGM accuracy in hypoglycaemia is a limitation and use of CGM does not appear to reverse IAH.

Future perspectives involves correlating CGM detected hypoglycaemia (symptomatic and asymptomatic) with patient reported outcomes; need for robust prospective data on CGM detected hypoglycaemia and clinical outcomes; and to explore the consequences of hypoglycaemia using CGM devices.


Hypoglycaemic Unawareness: Strategies to Prevent and Manage it?

Amiel S, presented a session on “Hypoglycaemic unawareness: Strategies to prevent and manage it” on 29th September 2021.

Impaired awareness of hypoglycaemia is defined as loss of subjective awareness of hypoglycaemia and a diminished ability to perceive the onset of hypoglycaemia.

Hypoglycaemia is seen in around 25-40% of people with type 1 diabetes, 10% of people with insulin treated type 2 diabetes. Hypoglycaemia increases the risk of severe hypoglycaemia by 6 to 17 fold. It is also associated with delayed and reduced stress response, which is inducible by level 2 hypoglycaemia and restorable by avoidance of level 2 hypoglycaemia.

The only way hypoglycaemia awareness can be restored is by hypoglycaemia avoidance. Before implementing diabetes technologies in treatment, insulin therapies should be optimized.

To prevent hypoglycaemia, one needs to first ask the patient about hypoglycaemia. Various patient tools and score cards can help to assess the hypoglycaemia. These scores and tools include the GOLD score, Clarke score, DAFNE tool, Pedersen-Bjergaard score. The next step is to check the blood glucose records and subsequently check with the family members.

Blood glucose awareness training is a psychoeducational program. Mühlhauser et al. demonstrated that intensified insulin therapy, when combined with a 5-day teaching program, improved glycaemic control without increasing severe hypoglycaemia.

The pathway for hypoglycaemia prevention involves a structured education in flexible insulin therapt and incorporaton of diabetes teaching and treatment programme therapeutic education as patient education in diabetes has become an integral part of diabetes management.


Diabetes Democracy through Digital Patient Education and Training

The pandemic has presented unique challenges for people with diabetes, who comprise a high-risk group for severe COVID-19 infection. There has been increased emphasis on the importance of self-care activities for people with diabetes to optimise their diabetes management; however this has proven difficult because of restrictions due to lockdown and reduced face-to-face diabetes education. Gupta A, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which explored the impact of digital led patient education and training on the diabetes care.

A systemic review was done of the published evidence for implications of virtual patient education and training in diabetes during COVID-19 era, by searching pubmed-medline, Cochrane library, online databases. Data were analysed using meta-aggregation for the studies conducted till Sept 2020.

1008 patients were of T2DM and 91 were of T1DM. The virtual education and training occurred through telephone, zoom video conferencing app and Medtronic carelink system. The mean impact factor of the journals publishing these studies was 2.8. Prospective study was conducted in 3 phases: before education, after education and in the period of pandemic. Diabetics on oral therapy were included in the study. HbA1c was significantly higher before education compared to post education in COVID-19. BMI was significantly lower after education while QOL was substantially lower in all domain of COVID-19. HCL systems allows T1D patients to improve time in rang (TIR), time below range (TBR), and glycemic variability independently of previous treatment.

Virtual education and training are useful during pandemic that necessitates limiting the access of patients for in person follow up and yet, improving the continuity of care. Digital database intervention for patient education has the potential to translate democratization of diabetes care and enable access to care.


Diabetes Complications among Patients from Metropolitan versus Non-metropolitan Cities in India: One Year Results of LANDMARC

As type 2 diabetes (T2D) develops, it imposes damage to the vasculature. Micro- and macro-vascular complications are the vital reasons of morbidity and mortality correlated with T2D. In India, data are very limited on complications in patients with diabetes from metropolitan and non-metropolitan cities. Hence, Kalra S, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which evaluated micro- and macro-vascular complications in patients from metropolitan versus non-metropolitan cities in the first year of LANDMARC, a 3-year nationwide prospective observational study.

LANDMARC is the first nation-wide, prospective, long-term, multicenter, observational, and longitudinal study incorporating patients with T2D. Patients with T2D who were on ≥2 antihyperglycemic medications were included in the LANDMARC study. Each participant is aimed to be analysed across the 3-year period (March 2018 to March 2021), incorporating 7 visits at 6-months interval.

From the total 6236 enlisted patients, 2378 and 3858 were from metropolitan and non-metropolitan cities, respectively. Age, duration of T2D, and baseline A1C were alike over groups. At 1-year, patients from non-metropolitan showed substantially greater microvascular complications than metropolitan cities (19.08% vs. 10.89%; p<0.0001) (Table). Neuropathy was the most frequent microvascular complication shown in both the groups. Participants from non-metropolitan cities had higher macrovascular complications; and acute coronary syndrome and heart failure were the most frequent.

The present, first-of-its-kind data from India exhibited patterns of disease development between patients with T2D. Findings from this ongoing study showed that patients from non-metropolitan cities may have greater complications, especially microvascular.


Associations Between Chronic Kidney Disease, Prior Cardiovascular Conditions and Increased Mortality in 36.303 Type 1 Diabetes Patients Between 2015-2017

People with type 1 diabetes (T1D) yet have an increased risk of premature death than the general population, generally due to cardiovascular disease. Lyngfelt L, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which explored updated information on the importance of previous heart failure, kidney disease, and atherosclerotic vascular disease for the risk of mortality in a nationwide, registry-based group of T1D.

All T1D patients (n=36 303) were included in the study from the Swedish National Diabetes Register (NDR) during the inclusion period between January 1, 2015 and December 31, 2017. NDR data were associated to data from various national health registries via each patient’s unique personal identification number. The cumulative mortality was explained by Kaplan-Meier curves, and analysed for correlation to prospective risk factors by a Multiple Cox regression model incorporating age, gender, diabetes duration, HbA1c, BMI, SBP, DBP, albuminuria, previous cardiovascular disease (CVD), coronary heart disease, acute myocardial infarction or stroke, heart failure (HF) and eGFR stage as independent parameters.

Mean age at index day was 40.1 years, 55% were men and mean duration of diabetes was 25.8 years. Record of previous CVD, was shown in 8.7%, and prior HF in 1.7%. Normal kidney function (chronic kidney disease (CKD) stage G1; eGFR ≥90) was exhibited in 50%, and 70% were normoalbuminuric. The mean follow-up time was 3.3 years with a minimum patient follow-up time of 1 year. Total 1127 patients were died with an observed crude total mortality rate of 0.92 deaths/person year. In multivariate analysis, the risk in all-cause mortality was HR (hazard ratio) 1.91 (95% CI 1.66-2.20) in patients with prior CVD as compared to persons free of CVD at baseline. In patients with HF adjusted HR was 1.92 (1.66-2.23). Patients with impaired kidney function (moderate, high and very high CKD stages) showed HR 1.47 (1.19-1.80), 2.78 (2.11-3.66), and 3.80 (2.80-5.16), respectively, in multivariate analysis. The cumulative mortality for people with T1D and varying degrees of CKD, were shown with and without previous CVD and HF.

In the registry-based observational study, a previous history of CVD, HF, and CKD all were correlated with an elevated risk of death, and a combination of risk conditions with significantly increased risk for patients with T1D.


Heart failure and Renal Complications in Young- and Usual-onset Type 2 Diabetes among White Caucasians from US and UK

Although people with T2DM are well known to have elevated risk of chronic kidney disease (CKD) and heart failure (HF), the population-level evidence on the risk of these incidents in young- and usual-onset T2DM in various healthcare setups is deficient. Paul S, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which analysed the risk of CKD and/or HF in White Caucasians with T2DM in two different healthcare setups following the same study design. The prospective difference in risk dynamics among male and female over age groups were also analysed.

1491672 and 103233 White Caucasians diagnosed with T2DM among 2000 and 2018 in the age groups of 18-39 /40-49 / 50-59/ 60-69 years were recognized with nationally representative electronic medical records of US and UK. Date of T2DM diagnosis was contemplated as baseline, with first date of CKD or HF diagnosis (CKDHF) or end of follow-up from baseline contemplated as the time to incident. The risk of CKDHF (hospitalisation or physician coded events) was assessed in males and females in different age groups adjusting for time-differing covariates. Adjusted mean time to CKDHF was measured by a propensity score based modelling approach, balancing and adjusting for confounders.

50 /59% were male, 10 /13% showed CKD, 2 /2% showed HF, 48 /55% with hypertension, 39 /31% with dyslipidaemia, 13/15% with cardiovascular disease, and 20 /15% with microvascular disease at T2DM dx in US /UK. 24 /9% were on insulin and 34 /33% exhibited depression prior to CKDHF or end of follow-up. 95% CIs for incidence rates per 1000PY for CKDHF were: (23-24) /(22-24) in 18-39 years, (37-38) /(33-35) in 40-49 years, (53-54) /(53-55) in 50-59 years and (82-83) /(83-86) in 60-69 years in US /UK with mean 4.9-5.1 /7.3-7.5 years of follow-up across all age groups in US /UK. In the youngest age group in US /UK, male showed substantially greater CKDHF rate and 25% (HR CI: 1.20-1.29) /31% (HR CI: 1.14-1.53) greater adjusted risk as compared to female. But, in the 50+ year groups, male showed substantially lower rate and 3-11 / 21-23% lower risk [range of HR CI: 0.88-0.98 /0.73-0.82] as compared to female in US /UK. Adjusted years (CI) to CKDHF in 18-39 years group were 9.7 (9.2, 10.2) /8.9 (8.0, 9.7) in US/UK, only 4.2 / 2.6 years later compared to 5.5 (5.4, 5.6) /6.3 (6.2, 6.5) years in 60-69 years group. The time to event(s) was similar within age groups < 60 years  in US and UK.

Although healthcare systems vary over countries, White Caucasian males and females with young- and usual-onset T2DM showed similar risk paradigm for CKD and HF. This clearly recommends a frequent global approach in the proactive treatment of macro- and microvascular risk concurrently in people with T2DM, especially between young-onset T2DM who progress CKD or HF only 3-4 years later as compared to the usual-onset.


Characteristics and Predictors of Mortality in Diabetes Patients Hospitalised with COVID-19: A Single-centre Cohort Study from Poland

COVID-19 was detected in more than 25 million people in the European Union, and more than 2 million in Poland by the end of March 2021. Based on the previous studies, it is measured that 10-20% of these COVID patients also have diabetes. In the route of COVID-19, diabetes has been identified as a main risk factor for an admission to the intensive care unit, starting of mechanical ventilation and mortality. This is the first attempt of a large-scale examination of the course of COVID-19 in hospitalized patients with diabetes in Poland. Thus, Kania M, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which aimed to specifies the group of diabetic patients hospitalized because of the COVID-19 infection and recognize prospective factors correlated with unfavourable results.

The data was analysed retrospectively of a group of patients admitted because of COVID-19 to the University Hospital in Cracow, Poland from March 6 and October 15 2020. Data was gathered from electronic patients’ records regarding their basic clinical and biochemical variables, therapies and results. Their basic characteristics and predictors of hospital mortality were analysed.

1729 patients from the studied period were included. 23.3% (404 patients) patients showed diabetic prevalence. Diabetic patients were older as compared to the non-diabetic group (median age 71 years, p<0.001), with similar gender distribution (males: 53.8% vs. 50.5%, p=0.24). Patients with diabetes showed longer hospital stay (medians: 18 vs. 16 days, p<0.001), needed more commonly admission into an ICU (16.5% vs. 9.7%, p<0.001), mechanical ventilation (12.1% vs. 8%, p=0.011), and showed greater mortality (19.3% vs. 11.2%, p<0.001). A multivariable logistic model was performed for predictors of mortality. The model incorporated the following parameters – age, sex, glycemia over 10 mmol/l, C-reactive-protein (CRP) level and white blood cells count on admission, history of hypertension, heart failure, ischemic heart disease, inhospital use of dexaven, antiplatelet drugs, anticoagulation therapy, ACEI/sartan, statin, metformin and insulin. Three parameters – older age, higher CRP and dexaven use – were correlated with a higher death rate (OR 1.795%CI 1.03-1.11; 1,005 95%CI 1.001-1.01 and 2.32 95%CI 1.013-5.33 respectively), while metformin use was correlated with lower mortality (OR0.22 95%CI 0.9-0.55).

Diabetes was exhibited in about one fourth of hospitalized patients in the setting. This group of patients with diabetes showed nearly twice as high mortality as compared to non-diabetics. Older age and markers of high inflammatory reactions were recognized as risk factors for mortality.


The Impact of Acute-to-chronic Glycaemic Ratio as a Predictor of COVID-19 Severity and Mortality

Underlying diabetes mellitus (DM) has been contemplated a risk factor for elevated COVID-19 extremity and worse results, incorporating higher mortality. But, no previous studies have evaluated whether the combined analysis of acute and chronic glycaemic levels may have a superior prognostic value than each component alone. Ramon J, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which assessed whether the acute-to-chronic glycaemic ratio (ACR) was correlated with mortality and extreme effects in patients with DM hospitalized for COVID-19.

All patients with DM hospitalized for COVID-19 among March 2020 and May 2020 was registered in an observational cohort study. Demographic and clinical data were gathered, incorporating data on clinical treatment, analytical variables, glycaemic control (glycaemia at admission, HbA1c) and inflammatory markers, extremity scales (MEWS, CURB65) and severity outcomes (length of hospital stay, intensive care unit (ICU) admission, acute respiratory distress syndrome (ARDS), invasive mechanical ventilation (IMV) and mortality. The formula eCGL= (28.7xHbA1c(%))-46.7 was used to measure the chronic glucose levels (CGL) . The ACR (glycaemia at admission/eCGL) were estimated for all patients.

A total of 91 patients were incorporated. Baseline characteristics of the subjects were distinguished for ACR tertiles. Patients in the 3 tertile showed greater glucose levels upon admission and higher concentrations of inflammatory markers. A glucose level at admission >200mg/dL was correlated with ARDS (OR=3.8 (1.4-10.2); p=0.008), IMV (OR=8.6 (1.8-41.5); p=0.008) and ICU admission (OR=9.4 (1.9-45.1); p=0.005) however was not correlated with the length of stay or mortality. By contrast, a Ushape curve correlation was found among the ACR tertiles and mortality. The 1 ACR tertile exhibited a trend towards greater mortality (OR=4.9 (0.9-25.2); p=0.059) and the 3 ACR tertile was substantially correlated with greater mortality (OR=6.0 (1.2-30.7); p=0.032) than the 2 tertile.

The ACR showed a U shaped mortality curve in patients with underlying diabetes. These findings recommend that an unbalance among the acute glycaemia at admission and the chronic metabolic control exhibited greater mortality rates, adding a superior prognostic value than each component alone. By difference, hyperglycaemia at admission was correlated with a greater inflammation status and poor extremity results.


Inside CKD: Modelling the Clinical and Economic Impact of Routine Screening for Albuminuria in People with Type 2 Diabetes

In patients with type 2 diabetes (T2D), early detection of chronic kidney disease (CKD) followed by guideline-recommended interventions is key to slowing CKD development; however adherence to screening recommendations is negligible. Inside CKD models the global burden of CKD by country-specific, patient-level microsimulation models. Power A, presented a study in a session at Virtual EASD Annual Meeting 2021 on 29th September 2021 which modelled the impacts of targeted implementation of urine albumin:creatinine ratio (UACR) estimation and interference in patients with T2D.

The Inside CKD microsimulation was used to model the effect of estimating UACR in routine primary care visits with consecutive intervention in patients with T2D aged ≥ 45 years with a range of kidney functions as compared to current practice. Published country-specific data on demographics, CKD (albuminuria and estimated glomerular filtration rate status), T2D, comorbidities and complications was used to construct the virtual populations.

Preliminary data for 3 countries exhibited that the estimation of UACR with conscutive intervention in patients with T2D would inhibit CKD development to stages 3b to 5 in 164 739 patients in the UK, 964 121 in the US and 156 482 in Canada from 2020 to 2026. correlated cost savings would be £0.14B, US$13.81B and C$2.34B. Furthermore countries will be examined.

Routine UACR estimation with consecutive intervention could prospectively decrease the global burden of CKD and healthcare costs in patients with T2D and enhance patient results.

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