Adigun, Rosalyn

Background: In July 2015, the FDA approved the use of sacubitril/ valsartan in patients with heart failure (HF) and reduced ejection fraction. It was shown in a large clinical trial to reduce the risk of both hospitalization and death compared with enalapril, and has since received a class I recommendation for use in the 2016 ACC/ AHA HF guidelines. However, the use of sacubitril/ valsartan in a clinical practice has not been described. We aimed to assess the uptake and cost of sacubitril/ valsartan in its first year following FDA approval. Methods: Using a large U.S. insurance database, we identified privately insured and Medicare Advantage (MA) patients who filled a first prescription for sacubitril/ valsartan between July 1, 2015 and July 31, 2016. We restricted to persons with medical and pharmacy enrollment for 6 months prior to first fill. For reference, we identified all individuals with a diagnosis of HF on a billing claim (ICD9 428.X or ICD-10 I50.X) in the same time period. Results: There were 314,410 individuals with a diagnosis of HF in the study period. In total, 972 filled a new prescription for sacubitril/ valsartan, and the number of new users steadily increased over time (Figure). The mean age of sacubitril/ valsartan users was 68.1±12.3 years, 32.5% were women, 61.1% were white, and 77% were enrolled in MA plans. Most prescribing clinicians were cardiologists (82.5%). A majority of prescription costs were covered by the health plan (mean $324.05, median $335.38, interquartile range [IQR] $266.56-$370.10). Out-of-pocket (OOP) costs per 30-day prescription filled were variable (mean $101.53, median $45.00, IQR $7.40-$97.49), and were similar in beneficiaries enrolled in MA and commercial plans. By comparison, median OOP costs were $2-4 for lisinopril, losartan, carvedilol, and spironolactone per 30-day prescription. Discussion: These finding suggest that the uptake of sacubitril/ valsartan has been slow in the first year after FDA approval. While the majority of prescription costs are covered by the health plan, OOP costs are still much higher than other guideline-recommended HF medications. Further studies are needed to determine if uptake of sacubril/ valsartan continues to rise and if the higher prescription cost is associated with lower downstream costs of hospitalization and mortality benefit.

Abstract Introduction Cardiopulmonary exercise testing (CPET) has an established role in the clinical evaluation of exercise intolerance and in the risk stratification of patients with heart failure. There is limited data assessing its prognostic utility in the evaluation of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The predisposition of patients with ARVC for ventricular arrhythmias and sudden cardiac death has led to recommendations for exercise restrictions and limits our understanding of how the impairment in oxygen extraction and cardiac output impact disease progression and outcomes in these patients. Purpose We examined the association between CPET indices and event free survival (time to mortality or cardiac transplantation) in patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Methods Patients with definite ARVC based on 2010 task force criteria and genetically positive were enrolled into our institutional ARVC registry. 43 patients underwent CPET and have been included in our analyses. Indications for testing included: Evaluation of exercise-induced palpitations/arrhythmias or syncope (37%), pharmacotherapy optimization (28%), heart failure evaluation (19%), and ARVC management decisions (16%). CPET data (peak oxygen consumption (pVO2), respiratory exchange ratio (RER), and ventilatory efficiency (VE/VCO2) were assessed in patients at time of initial evaluation. Median follow-up time was 4.9 years (IQR 9 years). Results 126 patients were studied (age 43.7+ 15 yrs; 41% women; LVEF 57+ 11%; 15% with LVEF <50%) and 43 underwent CPET evaluation. 41 patients (95%) performed at near maximal effort (RER >1) and no fatal events were reported during testing. During the follow up period, the outcome (death or cardiac transplantation) occurred in 31 patients. On Kaplan Meier analysis, pVO2 ≤14 mL/kg/min was associated with worse outcomes (unadjusted p<0.001). Peak oxygen consumption (pVO2) ≤14 mL/kg/min and ventilatory efficiency (VE/VCO2) >34 were associated with shorter event free survival (HR 5.58, p=0.002 and HR 5.56 p=0.005, respectively). After adjusting for age, sex, and right ventricular function, the association between peak oxygen consumption (pVO2) and event free survival remained significant (p=0.02). Conclusions In patients with ARVC, peak oxygen consumption (pVO2) was a prognostic indicator of worse outcomes. Our findings suggest a potential role for pVO2 in disease surveillance and early assessment for advanced heart failure therapies. Figure 1. KM plot pVO2 & event free survival Funding Acknowledgement Type of funding source: Other. Main funding source(s): Mayo Clinic

Abstract Aims Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF. Methods and results We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6–8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4–0.6, P < 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P < 0.001]. Power reserve showed similar results. Conclusion The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.

Objective To determine whether echocardiography-derived left ventricular filling pressure influences survival in patients with severe aortic stenosis (AS) undergoing aortic valve replacement (AVR). Methods We retrospectively reviewed 1383 consecutive patients with severe AS, normal ejection fraction and interpretable filling pressure undergoing AVR. Left ventricular filling pressure was determined according to current guidelines using mitral inflow, mitral annular tissue Doppler, estimated right ventricular systolic pressure and left atrial volume index. Cox proportional hazards regression was used to assess the influence of various parameters on mortality. Results Age was 75±10 years and 552 (40%) were female. Left ventricular filling pressure was normal in 325 (23%), indeterminate in 463 (33%) and increased in 595 (43%). Mean follow-up was 7.3±3.7 years, and mortality was 1.2%, 4.2% and 18.9% at 30 days and 1 and 5 years, respectively. Compared with patients with normal filling pressure, patients with increased filling pressure were older (78±9 vs 70±12, p<0.001), more often female (45% vs 35%, p=0.002) and were more likely to have New York Heart Association class III–IV symptoms (35% vs 24%, p=0.004), coronary artery disease (55% vs 42%, p<0.001) and concentric left ventricular hypertrophy (63% vs 37%, p<0.001). After correction for other factors, increased left ventricular filling pressure remained an independent predictor of mortality after successful AVR (adjusted HR 1.45 (95% CI 1.16 to 1.81), p=0.005). Conclusions Preoperative increased left ventricular filling pressure is common in patients with AS undergoing AVR and has important prognostic implications, regardless of symptom status. Future prospective studies should consider whether patients with increased filling pressure would benefit from earlier operation.

Abstract Aims Despite improvements in cardiac haemodynamics and symptoms, long-term mortality remains increased in some patients after aortic valve replacement (AVR). Limited data exist on the prognostic role of left ventricular (LV) chamber stiffening in these patients. Methods and results We performed a retrospective analysis in 1893 patients with severe aortic stenosis (AS) referred for AVR. LV end-diastolic pressure–volume relations (EDPVR, P = αV^β) were reconstructed from echocardiographic measurements of end-diastolic volumes and estimates of end-diastolic pressure (EDP). The impact of EDPVR-derived LV chamber stiffness (CS30, at 30 mmHg EDP) on all-cause mortality after AVR was evaluated. Mean age was 76 ± 10 years, 39% were females, and ejection fraction (EF) was 61 ± 12%. The mean LV chamber stiffness (CS30) was 2.2 ± 1.3 mmHg/mL. A total of 877 (46%) patients had high LV stiffness (CS30 &gt;2 mmHg/mL). In these patients, the EDPVR curves were steeper and shifted leftwards, indicating higher stiffness at all pressure levels. These patients were slightly older, more often female, and had more prevalent comorbidities compared to patients with low stiffness. At follow-up [median 4.2 (interquartile range 2.8–6.3) years; 675 deaths], a higher CS30 was associated with lower survival (hazard ratio: 2.7 for severe vs. mild LV stiffening; P &lt; 0.0001), both in patients with normal or reduced EF. At multivariate analysis, CS30 remained an independent predictor, even after adjusting for age, sex, comorbidities, EF, LV remodelling, and diastolic dysfunction. Conclusion Higher preoperative LV chamber stiffening in patients with severe AS is associated with poorer outcome despite successful AVR.

Abstract Background Cardiac power output-to-mass (CPOM) ratio is a measure of myocardial performance that incorporates both pressure and flow output, normalized to left ventricular (LV) mass generating that cardiac work. Prior small studies have shown that CPOM predicts outcomes in patients with ischemic cardiomyopathy and reduced LV ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise CPOM and power reserve (increase from rest to peak exercise) in patients with normal EF. Methods and results Retrospective study in 24,783 patients (age 59±13 years, 45% females) with EF≥50% and no significant valve disease or right ventricular (RV) dysfunction, undergoing exercise stress echocardiography between 2004–2018. CPOM was calculated as previously described (0.222 x cardiac output x mean blood pressure / LV mass) and expressed in Watts/100g myocardium. Power reserve was calculated as difference in CPOM between peak stress and rest. All-cause mortality was the primary endpoint. Patients were divided into quartiles of power reserve. Patients with higher power reserve were younger, had higher blood pressure and heart rate, lower LV mass, and lower prevalence of prior myocardial infarction. (Table). During follow-up (median (IQR) 3.9 (0.6–8.3) years), 931 (3.8%) patients died. Progressively lower power reserve was associated with increasing mortality (Figure A). Compared to patients with abnormal stress test, patients with the lowest power reserve but otherwise normal stress test had the same survival as those with infarction/cardiomyopathy or ischemia on stress test (Figure B). Resting CPOM had lower predictive value. After adjusting for age, sex, METs achieved, ischemia/infarction on stress test results, and diastolic function grade, both peak exercise CPOM and power reserve were independent predictors of mortality (p<0.0001), incremental to conventional measures. Conclusion Cardiac power output and reserve measured during exercise stress echo provides independent prognostic information in patients with normal resting EF and no significant valve disease or RV dysfunction. The survival of patients with low power reserve but normal stress test was similar to patients with prior infarction/ cardiomyopathy or ischemia on stress test.

Abstract Background Histoplasma capsulatum is an extremely rare cause of prosthetic valve endocarditis (PVE) and can present with non-specific symptoms leading to a delay in diagnosis with unfavourable outcomes. Case summary A 65-year-old male patient with a history of a bioprosthetic aortic valve replacement and non-obstructive coronary artery disease was admitted for altered mentation, failure to thrive, and a 20-pound unintentional weight loss over the past 4 months. Upon examination, he was lethargic but afebrile and haemodynamically stable. A late peaking ejection murmur was heard on exam. Skin exam was significant for embolic phenomenon involving the extremities. Inflammatory markers and serum calcium were elevated. A bedside echocardiogram showed severe obstruction across the aortic valve prosthesis. Two years prior, he had an echocardiogram with a normal functioning prosthesis. Routine blood cultures were negative and serologic screening was unrevealing. Urine Histoplasma antigen screen was positive on hospital day 3 and on hospital day 10, fungal blood cultures were positive for H. capsulatum. Unfortunately, the patient died shortly afterwards as a result of multiorgan failure from embolic manifestations of the infection. Discussion Based on our patient's findings and those of previously reported cases in the literature, H. capsulatum PVE should be strongly considered in patients from endemic areas with non-specific symptoms and negative routine blood cultures.

Apical ballooning syndrome (ABS) is an under recognised clinical entity characterised by acute reversible left ventricular systolic dysfunction that mimics acute myocardial infarction in the absence of obstructive coronary artery disease; typically occurring in the setting of profound stress.1 ABS disproportionately affects older women and recurrences are infrequent. We, hereby, describe a rare phenomenon of recurrent ABS in an elderly male patient, 10 years apart, presenting with the same left ventricular morphological appearance following non-cardiac surgeries. The case illustrates the importance of considering ABS in the differential diagnosis of perioperative acute myocardial infarction in older men undergoing major surgery.

Abstract Aims Early studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new-generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long-term CAV progression and clinical outcomes in a large contemporary HT cohort. Methods and results We analysed a cohort of 409 adult HT recipients. CAV progression was assessed by serial coronary intravascular ultrasound volumetric measurements of the differences between baseline and last follow-up plaque volume (PV) and plaque index (PV/vessel volume ratio). CAV progression and clinical outcomes were compared between the ES (&lt;2 years after HT) and the LS (&gt;2 years after HT) groups. During a median follow-up of 8.2 years, ES resulted in significantly lower change (Δ) of plaque index (+3.8% ± 1.7% vs. +8.2% ± 3.6%; P = 0.0008) and PV (+0.8 ± 0.3 vs. +1.9 ± 1.2; P = 0.045) compared with LS group. In a Cox proportional hazards regression model and after adjustment for baseline characteristics, ES was associated with a 52% decreased risk of CAV-associated events (hazard ratio 0.48, 95% confidence interval: 0.27–0.91; P = 0.025) and a 42% decreased risk of the composite endpoint of all-cause mortality and CAV-associated events (hazard ratio 0.58, 95% confidence interval: 0.38–0.91; P = 0.019). Conclusions Early initiation of statin therapy after HT results in attenuated CAV progression as well as in decreased CAV-related events and mortality.