Heart Failure With Preserved Ejection Fraction: Key Stumbling Blocks for Experimental Drugs in Clinical Trials

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a disease with a high prevalence. Accounting for more than 50% of all heart failure cases, it carries a significant mortality. There is a lack of therapeutic options that show improvement in morbidity and mortality. Certain novel therapies have shown a decrease in heart failure hospitalizations; however, this beneficial effect was more pronounced for heart failure patients with mildly reduced ejection fraction (EF). AREAS COVERED: This review summarizes the pathophysiology of the disease to help elucidate the differences between heart failure with reduced ejection fraction (HFrEF), and HFpEF, which could explain why therapies are successful in one (rather than the other). This review focuses on non-standardized nomenclature across major trials, the challenges of finding a therapeutic agent for such a heterogeneous population, and identification of specific phenotypes that have different outcomes and could be a target for future therapies. EXPERT OPINION: Lack of standardized diagnostic criteria, associated with population heterogeneity, might explain why trials have failed to improve outcomes for patients with HFpEF. Standardizing phenotypes, recapitulating these phenotypes in animal models, and understanding the mechanisms of the disease at the molecular level could be the first steps in identifying promising therapeutic options

Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension (PH) caused by thromboembolic disease with the secondary remodeling of the pulmonary vessels. The primary treatment of CTEPH is pulmonary thromboendarterectomy (PTE). However, some patients are not candidates for PTE because of surgically inaccessible thrombi or high operative risk and can be candidates for balloon pulmonary angioplasty (BPA), an emerging, lower risk treatment. This review discusses the patient selection, the technique, and comprehensive review of reported outcomes following BPA. BPA techniques have improved over the years, and so has its safety profile. Recent data show that after several sessions of BPA, patients who were not eligible for PTE had improvement in their hemodynamic profile, functional capacity, and 6-minute walk distance. Studies have shown that compared to riociguat, BPA has shown significant improvement in the functional capacity and hemodynamic measurements. Reperfusion pulmonary edema is a common complication after PTE and BPA, which may be due to vessel injury rather than pulmonary extravasation. Rates of complications have decreased especially after the use of optical coherence tomography, which helps in proper sizing of the balloons. Patients with CTEPH who are ineligible for PTE should be evaluated for BPA. In addition to medical therapy, BPA has shown promising clinical and hemodynamic outcomes in patients with CTEPH

Anaplasma Phagocytophilum Presenting With Orchitis in a Renal Transplant Recipient

Human granulocytic anaplasmosis (HGA), caused by Anaplasma phagocytophilum, is an emerging tick-borne disease. It is spread by the black-legged deer tick Ixodes scapularis, that serves as the vector for six human pathogens. HGA is still rarely reported in solid organ transplant recipients. In solid-organ transplant recipients, orchitis has been reported secondary to chickenpox, tuberculosis and infections due to Listeria monocytogenes and Nocardia asteroides. Orchitis as a presenting feature of HGA infection has only been reported in animals. We present a unique case of a renal transplant recipient with HGA that presented as orchitis. We also compare the clinical presentation and laboratory findings of our patient with other cases of HGA in transplant recipients. To the best of our knowledge, our patient is one of the first cases of A. phagocytophilum mono-infection causing a classical presentation of orchitis in a transplant patient. This article is protected by copyright. All rights reserved

Impact of Obesity and Underweight Status by Body Mass Index on Mortality Among Hospitalized Patients With Hypertrophic Cardiomyopathy

Introduction: Even though obesity is associated with increased phenotypic expression in patients with hypertrophic cardiomyopathy (HCM), the effect of body mass index (BMI) on in-hospital mortality among hospitalized patients with HCM has not been established. Hypothesis: We hypothesized that among hospitalized patients with HCM, obesity and underweight status are associated with increased mortality Methods: We evaluated the National Inpatient Sample database to identify all adults (age ≥18 years) with HCM hospitalized for any cardiac illness between 2008 and 2017. Using ICD codes for BMI, the study cohort was stratified into underweight (BMI ≤19.9 kg/m2), non-obese (BMI 20.0-29.9 kg/m2), class I obesity (BMI 30.0-34.9 kg/m2), class II obesity (BMI 35.0-39.9 kg/m2) and class III (BMI ≥40.0 kg/m2). Multiple logistic regression analysis was used to analyze the independent association of various BMI categories and in-hospital mortality adjusted for age, sex and medical comorbidities. Results: The survey-weighted sample included a total of 2,392,325 hospitalizations with a mean age of 66.1±12.2 years and 42.0% were females. The patients with class III obesity [adjusted mortality rate (AMR) 3.3%, adjusted odds ratio (AOR) 1.53, 95% confidence interval (CI)-1.29-1.82,p Conclusions: Among patients with HCM, BMI has a non-linear U-shaped relationship with in-hospital mortality. The patients who were underweight and morbidly obese had significantly higher mortality, whereas those patients with class I and class II obesity had lower mortality compared to non-obese patients

Impact of Body Mass Index on Mortality in Hospitalized Patients With Hypertrophic Cardiomyopathy

Although obesity is associated with increased phenotypic expression in patients with hypertrophic cardiomyopathy (HC), the effect of body mass index (BMI) on in-hospital mortality in hospitalized patients with HC has not been established. We evaluated the National Inpatient Sample in the United States to identify all adults with HC hospitalized for cardiac illnesses between 2008 and 2017. Using International Classification of Diseases codes, the study cohort was stratified into underweight (BMI ≤19.9 kg/m), normal weight (BMI 20.0 to 24.9 kg/m), overweight (BMI 25.0 to 29.9 kg/m), class I (BMI 30.0 to 34.9 kg/m), class II (BMI 35.0 to 39.9 kg/m), and class III (BMI ≥40.0 kg/m) obesity. Multiple logistic regression analysis was used to analyze the independent association of various BMI categories and mortality. The study included a total of 2,392,325 hospitalizations (mean age-66.1 ± 12.2 years; 42.0% female). The patients with class III obesity (adjusted mortality rate [AMR] 3.3%, adjusted odds ratio [AOR] 1.53, 95% confidence interval [CI] 1.29 to 1.82, p \u3c0.001) and underweight patients (AMR 4.4%, AOR 2.07, 95% CI 1.74-2.46, p \u3c0.001) had higher in-hospital mortality whereas overweight patients (AMR 1.6%, AOR 0.26, 95% CI 0.19 to 0.34, p \u3c0.001), patients with class I obesity (AMR 0.8%, AOR 0.35, 95% CI 0.27 to 0.45, p \u3c0.001) and patients with class II obesity (AMR 0.8%, AOR 0.34, 95% CI 0.26 to 0.45, p \u3c0.001) had lower mortality compared with patients with normal BMI (AMR 2.9%). In conclusion, BMI has a nonlinear U-shaped relation with in-hospital mortality in patients with HC. The patients who were underweight and morbidly obese had significantly higher mortality, whereas those patients with overweight, class I, and class II obesity had lower mortality than normal BMI

Survival With Continuous Outpatient Intravenous Inotrope Therapy in the Modern Era

BACKGROUND: To describe baseline characteristics and outcomes in the largest known registry of advanced heart failure (HF) patients receiving continuous outpatient intravenous inotrope therapy. Studies evaluating the use of outpatient inotropes for palliation or as a bridge to advanced therapies were performed before current guideline directed medical and device therapy (GDMDT). There are limited data on the modern experience using outpatient inotrope (OI) therapy. STUDY QUESTION: We aimed to study current use and outcomes of OI. STUDY DESIGN: Retrospective database analysis. MEASURES AND OUTCOMES: From 2015 to 2017, 1540 advanced HF patients in a largess nationwide registry received OI with either milrinone or dobutamine. Baseline characteristics of 1149 patients data were retrospectively reviewed. Unadjusted Kaplan-Meier survival estimates censored at the time of transplant or mechanical circulatory support were reported. RESULTS: Of 1149 patients, more patients were treated with milrinone than dobutamine (64.6% vs. 35.4%). Regardless of the indication for OI, estimated 1 and 2-years survival was 61.8% and 41.6%, respectively. Milrinone use was associated with a greater 1-year survival than dobutamine (70.7% vs. 46.2%, P \u3c 0.0001). The superiority of milrinone over dobutamine extended to all indications for OI, including bridge to transplant (85.9% vs. 71.3%, P \u3c 0.0001), bridge to mechanical support (91.4% vs. 71%, P = 0.001), and palliation (73.6% vs. 63.3%, P \u3c 0.001). After adjusting for indication, age, gender and weight, milrinone was associated with lower mortality than dobutamine (HR 0.50, 95% CI 0.39-0.64, P \u3c 0.0001). CONCLUSIONS: In the largest dataset of HF patients receiving OI, survival on OI for palliation in the current era of GDMDT is significantly higher than previously reported. Compared with dobutamine, milrinone was associated with improved survival in all cohorts

Pharmacotherapies in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Network Meta-Analysis

Various pharmacotherapies exist for heart failure with preserved ejection fraction (HFpEF), but with unclear comparative efficacy. We searched EMBASE, Medline, and Cochrane Library from inception through August 2021 for all randomized clinical trials in HFpEF (EF \u3e40%) that evaluated beta-blockers, mineralocorticoid receptor antagonist (MRA), angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Outcomes assessed were cardiovascular mortality, all-cause mortality, and HF hospitalization. A frequentist network meta-analysis was performed with a random-effects model. We included 22 randomized clinical trials (30,673 participants; mean age = 71.7 ± 4.2 years; females = 49.3 ± 7.7%; median follow-up = 24.4 ± 11.1 months). Compared with placebo, there was no statistically significant difference in cardiovascular mortality [beta-blockers; odds ratio (OR) 0.79 (0.46-1.34), MRA; OR 0.90 (0.70-1.14), ACE OR 0.95 (0.59-1.53), ARB; OR 1.02 (0.87-1.19), ARNI; OR 0.97 (0.74-1.26) and SGLT2i; OR 1.00 (0.84-1.18)] or all-cause mortality [beta blockers; OR 0.75 (0.54-1.04), MRA; OR 0.90 (0.75-1.08) ACE; OR 1.05 (0.71-1.54), ARB; OR 1.03 (0.91-1.15), ARNI; OR 0.99 (0.82-1.20) and SGLT2i; OR 1.00 (0.89-1.13)]. The certainty in these estimates was low or very low. There was a significantly reduction in HF hospitalization with the use of SGLT2i [OR 0.71 (0.62-0.82), moderate certainty], ARNI [OR 0.77 (0.63-0.94), low certainty], and MRA [OR 0.81 (0.66-0.98), moderate certainty]; with corresponding P scores of 0.84, 0.68, and 0.58, respectively. In HFpEF, the use of beta-blockers, MRA, ACE/ARB/ARNI, or SGLT2i was not associated with improved cardiovascular or all-cause mortality. SGLT2i, ARNI, and MRA reduced the risk of HF hospitalizations

Pharmacotherapies in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Network Meta-Analysis.

Various pharmacotherapies exist for heart failure with preserved ejection fraction (HFpEF), but with unclear comparative efficacy. We searched EMBASE, Medline, and Cochrane Library from inception through August 2021 for all randomized clinical trials in HFpEF (EF \u3e40%) that evaluated beta-blockers, mineralocorticoid receptor antagonist (MRA), angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Outcomes assessed were cardiovascular mortality, all-cause mortality, and HF hospitalization. A frequentist network meta-analysis was performed with a random-effects model. We included 22 randomized clinical trials (30,673 participants; mean age = 71.7 ± 4.2 years; females = 49.3 ± 7.7%; median follow-up = 24.4 ± 11.1 months). Compared with placebo, there was no statistically significant difference in cardiovascular mortality [beta-blockers; odds ratio (OR) 0.79 (0.46-1.34), MRA; OR 0.90 (0.70-1.14), ACE OR 0.95 (0.59-1.53), ARB; OR 1.02 (0.87-1.19), ARNI; OR 0.97 (0.74-1.26) and SGLT2i; OR 1.00 (0.84-1.18)] or all-cause mortality [beta blockers; OR 0.75 (0.54-1.04), MRA; OR 0.90 (0.75-1.08) ACE; OR 1.05 (0.71-1.54), ARB; OR 1.03 (0.91-1.15), ARNI; OR 0.99 (0.82-1.20) and SGLT2i; OR 1.00 (0.89-1.13)]. The certainty in these estimates was low or very low. There was a significantly reduction in HF hospitalization with the use of SGLT2i [OR 0.71 (0.62-0.82), moderate certainty], ARNI [OR 0.77 (0.63-0.94), low certainty], and MRA [OR 0.81 (0.66-0.98), moderate certainty]; with corresponding P scores of 0.84, 0.68, and 0.58, respectively. In HFpEF, the use of beta-blockers, MRA, ACE/ARB/ARNI, or SGLT2i was not associated with improved cardiovascular or all-cause mortality. SGLT2i, ARNI, and MRA reduced the risk of HF hospitalizations