Impact of Interventricular Interaction on Ventricular Function: Insights From Right Ventricular Pressure-Volume Analysis.

BACKGROUND: Interventricular interactions may be responsible for the decline in ventricular performance observed in various disease states that primarily affect the contralateral ventricle. OBJECTIVES: This study sought to quantify the impact of such interactions on right ventricular (RV) size and function using clinically stable individuals with left ventricular assist devices (LVADs) as a model for assessing RV hemodynamics while LV loading conditions were acutely manipulated by changing device speed during hemodynamic optimization studies (ie, ramp tests). METHODS: The investigators recorded RV pressure-volume loops with a conductance catheter at various speeds during ramp tests in 20 clinically stable HeartMate3 recipients. RESULTS: With faster LVAD speeds and greater LV unloading, indexed RV end-diastolic volume increased (72.28 ± 15.07 mL at low speed vs 75.95 ± 16.90 at high speed; P = 0.04) whereas indexed end-systolic volumes remained neutral. This resulted in larger RV stroke volumes and shallower end-diastolic pressure-volume relationships. Concurrently, RV end-systolic pressure decreased (31.58 ± 9.75 mL at low speed vs 29.58 ± 9.41 mL at high speed; P = 0.02), but contractility, as measured by end-systolic elastance, did not change significantly. The reduction in RV end-systolic pressure was associated with a reduction in effective arterial elastance from 0.65 ± 0.43 mm Hg/mL at low speed to 0.54 ± 0.33 mm Hg/mL at high speed (P = 0.02). CONCLUSIONS: Interventricular interactions resulted in improved RV compliance, diminished afterload, and did not reduce RV contractility. These data challenge the prevailing view that interventricular interactions compromise RV function, which has important implications for the understanding of RV-LV interactions in various disease states, including post-LVAD RV dysfunction.

Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality.

OBJECTIVE: A post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). METHODS: Two different models of survival were employed; the inverse probability of censoring weighting (IPCW) and the rank-preserving structural failure time (RPSFT) models both allow construction of a pseudo-placebo group, thereby allowing for long-term survival evaluation of patients with PH-ILD receiving inhaled treprostinil. Time-varying stabilised weights were calculated by fitting Cox proportional hazards models based on the baseline and time-varying prognostic factors to generate weighted Cox regression models with associated adjusted HRs. RESULTS: In the INCREASE trial, there were 10 and 12 deaths in the inhaled treprostinil and placebo arms, respectively, during the 16-week randomised trial. During the OLE, all patients received inhaled treprostinil and there were 29 and 33 deaths in the prior inhaled treprostinil arm and prior placebo arm, respectively. With a conventional analysis, the HR for death was 0.71 (95% CI 0.46 to 1.10; p=0.1227). Both models demonstrated significant reductions in death associated with inhaled treprostinil treatment with HRs of 0.62 (95% CI 0.39 to 0.99; p=0.0483) and 0.26 (95% CI 0.07 to 0.98; p=0.0473) for the IPCW and RPSFT methods, respectively. CONCLUSION: Two independent modelling techniques that have been employed in the oncology literature both suggest a long-term survival benefit associated with inhaled treprostinil treatment in patients with PH-ILD.

Transmission of yellow fever vaccine virus through blood transfusion and organ transplantation in the USA in 2021: report of an investigation.

BACKGROUND: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients. METHODS: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by the organ donor. FINDINGS: We identified one read from yellow fever virus in cerebrospinal fluid from the recipient of a kidney using metagenomic next-generation sequencing. Recent infection with yellow fever virus was confirmed in all four organ recipients by identification of yellow fever virus RNA consistent with the 17D vaccine strain in brain tissue from one recipient and seroconversion after transplantation in three recipients. Two patients recovered and two patients had no neurological recovery and died. 3 days before organ procurement, the organ donor received a blood transfusion from a donor who had received a yellow fever vaccine 6 days before blood donation. INTERPRETATION: This investigation substantiates the use of metagenomic next-generation sequencing for the broad-based detection of rare or unexpected pathogens. Health-care workers providing vaccinations should inform patients of the need to defer blood donation for at least 2 weeks after receiving a yellow fever vaccine. Despite mitigation strategies and safety interventions, a low risk of transfusion-transmitted infections remains. FUNDING: US Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority, and the CDC Epidemiology and Laboratory Capacity Cooperative Agreement for Infectious Diseases.

Prognostic role of pulmonary hemodynamics before transcatheter aortic valve replacement among patients with severe aortic stenosis.

BACKGROUND: Pulmonary hypertension (PH) frequently co-exists in patients with severe aortic stenosis (AS). In this study, we sought to identify the implications of invasive pulmonary hemodynamics on major adverse cardiac events (MACE), biventricular function and NYHA functional class after transcatheter aortic valve replacement (TAVR). METHODS: Invasive hemodynamics via right heart catheterization (RHC) were performed pre-TAVR. Patients were stratified per mean PA pressure (mPAP), diastolic pulmonary gradient (DPG) and pulmonary vascular resistance (PVR), and followed at 1-month and 1-year intervals up to 6 years. MACE outcomes included cardiovascular death and heart failure hospitalizations post-TAVR. RESULTS: Among 215 patients, Kaplan-Meir estimates demonstrated an increased 1-year risk of MACE from 8% among those without pre-TAVR PH to 27% among patients with pre-existing PH. Specifically, the MACE risk was 32% among PH patients with PVR ≥ 3WU (p = .04) and 53% among PH patients with DPG ≥ 7 mm Hg (p < .01). On univariate Cox regression, RV stroke work index (RVSWI) (HR,1.02; p = .02), and pulmonary hemodynamic index (PHI) (HR,1.27; p = .047) were identified as additional predictors of MACE post-TAVR. On multivariable Cox regression analysis, SvO2 (HR, 0.95; p = .01) and PVR (HR, 1.2; p = .04) were demonstrated as predictive of MACE post-TAVR. A significant improvement in LVEF (2-Factor ANOVA, p < .01) and RV fractional area change (RVFAC%) (p < .01) was noted as assessed at baseline, 1-month and 1-year follow up post-TAVR. There was a significant interaction between pre-TAVR PH status and time post procedure with respect to NYHA functional class (p = .03), that is, the manner and degree of change in NYHA class over time depended on pre-TAVR PH status. CONCLUSIONS: Defining invasive pulmonary hemodynamics, such as mPAP, PVR, and DPG among patients with severe AS undergoing TAVR has significant prognostic implications. Routine risk stratification by utilizing invasive hemodynamics can better identify patients who will have functional improvement and improved outcomes post-TAVR.

Rapidly progressive pulmonary hypertension and right ventricular failure in a heart and kidney transplant recipient.

A 54-year-old man status post heart and kidney transplant presented with dyspnea. Imaging was consistent with lymphangitic carcinomatosis (LC), in the setting of biopsy proven adenocarcinoma. He developed pulmonary hypertension (PH) and died of right ventricular failure (RVF) 3 weeks later. Acute PH with radiographic features of LC in a high-risk patient warrants expedited malignancy investigation.

Incidence of Post-Heart Transplant Chronic Thyroiditis and Its Association With Pretransplant Amiodarone Use.

BACKGROUND: Chronic thyroiditis (CT) is a common cause of thyroid dysfunction and could therefore adversely affect outcomes in patients undergoing heart transplant (HT). The incidence of post-HT CT and whether amiodarone, a commonly used anti-arrhythmic drug in patients with heart failure during pre-HT period, is associated with the development of post-HT CT are unknown. METHODS: A retrospective review of HT recipients from February 2, 2010 to October 16, 2018 was performed. Patients who lacked relevant pre-/post-HT records, underwent thyroidectomy, had pre-HT thyroid dysfunction or thyroiditis within 15 days post-HT, and those on amiodarone during the post-HT period were excluded, yielding a final cohort of 75 patients. RESULTS: Patients had a mean age of 63.3 ± 1.4 years and were predominantly male (90.7%) and white (80%). The incidence of post-HT CT was 32% with the majority (83.3%) manifesting as hypothyroidism. Median time to diagnosis of CT after transplant was 10.2 months (interquartile range, 4-27.4). Additionally, the CT group had higher pre-HT use of amiodarone (non-CT vs CT: 21.6% vs 50%, P = .01), higher prevalence of atrial fibrillation (non-CT vs CT: 23.5% vs 45.8%; P = .05), and more stage IV/V chronic kidney disease (non-CT vs CT: 2% vs 16.7%, P = .02). On multivariate analysis, pre-HT amiodarone use was associated with the development of post-HT CT after adjustment for age, sex, and chronic kidney disease (odds ratio, 3.65; 95% CI, 1.17-11.44; P = .03). CONCLUSION: The incidence of post-HT CT is high and is strongly associated with pre-HT amiodarone use underpinning the importance of closely following the post-HT thyroid profile in these patients.

Transition from parenteral prostacyclins to selexipag: safety and feasibility in selected patients.

There are limited data regarding the feasibility of transitioning from intravenous prostacyclins to selexipag in pulmonary arterial hypertension patients. We present a case series of successful transitions from intravenous prostacyclins to selexipag in the majority of carefully selected five stable pulmonary arterial hypertension patients using a standardized protocol in the outpatient setting.

Outcomes of patients hospitalized for acute pulmonary embolism by obstructive sleep apnea status.

Pulmonary embolism (PE) is a major cause of cardiovascular morbidity and mortality. Obstructive sleep apnea (OSA) is increasingly recognized in the aging population, especially with the rising obesity epidemic. The impact of OSA on inpatient mortality in PE is not well understood. We used the Nationwide Inpatient Sample databases from 2005 to 2016 to identify 755,532 acute PE patients (age≥18 years). Among these, 61,050 (8.1%) were OSA+. Temporal trends in length of stay, inpatient mortality, and its association with OSA in PE patients were analyzed. The proportion of PE patients who were OSA+ increased from 2005 to 2016. OSA+ PE patients were younger and predominantly men. Despite a higher prevalence of traditional risk factors for inpatient mortality in OSA+ patients, OSA was associated with a lower risk of mortality in PE patients (odds ratio, 95% confidence interval; p: unadjusted 0.56, 0.53-0.58; p < 0.0001 and adjusted 0.55, 0.52-0.58; p < 0.0001). Overall mortality and length of stay in PE patients decreased over time. Relative to OSA- patients, there was a slight increase in mortality among OSA+ PE patients over time, although the length of stay remained unchanged between the two groups. In conclusion, OSA+ PE patients had a lower inpatient mortality compared to OSA- patients despite a higher prevalence of traditional mortality risk factors. Secondary pulmonary hypertension related to OSA with preconditioning of the right ventricle to elevated afterload may potentially explain the protective effect of OSA on mortality in PE. However, mechanistic studies need to further elucidate the links behind this association.

A Case Report of a Patient With Pulmonary Arterial Hypertension Transitioned From Inhaled Iloprost to Selexipag.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance that can lead to right ventricular failure and death. The use of medications that affect the prostacyclin pathway is an important treatment strategy in PAH. Inhaled iloprost is a prostacyclin analogue, and selexipag is an oral, non-prostanoid, prostacyclin IP receptor agonist. Data are limited on transitioning patients from inhaled iloprost to selexipag. In this case report, we describe the successful transition of a 57-year-old female with heritable PAH from inhaled iloprost to selexipag over 8 weeks in an out-patient setting. After initiation of selexipag, the patient's inhaled iloprost dose was gradually reduced and eventually discontinued. The patient tolerated the transition well with stable symptoms, 6-minute walk distance, and pulmonary hemodynamics. Additional studies are needed to better define the comparative efficacy and safety of inhaled iloprost and selexipag.

Impact of transcatheter aortic valve replacement on left ventricular hypertrophy, diastolic dysfunction and quality of life in patients with preserved left ventricular function.

Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and diastolic dysfunction (LVDD). Due to positive impact on transvalvular hemodynamics, transcatheter aortic valve replacement (TAVR) is expected to improve LV remodeling, LVDD and heart failure (HF)-related quality-of-life (QoL). We identified patients with severe AS and LV ejection fraction (LVEF) ≥ 50% who underwent TAVR. We reviewed pre-procedure, 1-month and 1-year post-TAVR transthoracic echocardiograms to assess LV volumetric changes and diastolic function. QoL was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). In 171 patients studied, we found significant improvement in LV mass index (LVMI), LV end-systolic diameter and LV end-diastolic diameter from baseline to 1-month to 1-year post-TAVR. Predictors of LVMI regression included greater change from baseline in mean aortic valve (AV) gradient, peak AV velocity, and improvements in septal and lateral e' velocities and E/e' post-TAVR. The percentage of patients with ≥ grade 2 LVDD decreased from 65% to 53% at 1-month and 49% at 1-year. A significant improvement in symptomatology, as reported by KCCQ score was also noted. There is conceivable reverse LV remodeling post-TAVR, impacted by improvements in mean AV gradient, peak AV velocity, E/e', medial and lateral e' velocities, which occurs immediately post-TAVR and persists up to 1-year post-operatively. This is associated with concomitant improvement in LVDD and HF-related QoL as demonstrated by KCCQ scores.

Reasons for refusing parenteral therapy: a qualitative study of patients with pulmonary arterial hypertension.

While parenteral prostacyclin (pPCY) therapy, delivered either subcutaneously or intravenously, is recommended for pulmonary arterial hypertension patients with severe or rapidly developing disease, some patients refuse this treatment. This study aimed to understand, directly from patients with pulmonary arterial hypertension, why pPCY was refused and, in some cases, later accepted. Interviews were conducted with 25 pulmonary arterial hypertension patients who previously refused pPCY therapy (Group A: Refused/Never initiated (n = 9) and Group B: Refused/Initiated (n = 16)). Patients in both groups believed that pPCY could improve their symptoms, slow disease progression, and provide them a greater ability to perform activities. Reasons for refusal included concern over side effects and the perceived limitations of pPCY on daily activities. Group A perceived their decision as a balance between quality of life and prolonging life and most acknowledged they would reconsider pPCY if other treatment options were exhausted. Group B cited they initiated therapy due to a worsening of symptoms, disease progression, to improve quality of life, to be there for their family, or a desire to live. Following initiation, Group B indicated their experience met expectations with reduced symptoms, slowed disease progression, and perception of improved survival; concerns related to pPCY were described as manageable. Given the efficacy of pPCY therapy, clinicians should apply knowledge of these findings in clinical practice. Patients noted improvements to parenteral pump technologies to include smaller size, water resistance, and implantability may increase their acceptance of this modality. Development efforts should focus on technologies that increase the acceptance of pPCY when indicated.

Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for Use in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Achievement of low-risk status is a treatment goal in pulmonary arterial hypertension (PAH). Risk assessment often is performed using multiparameter tools, such as the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator. Risk calculators that assess fewer variables without compromising validity may expedite risk assessment in the routine clinic setting. We describe the development and validation of REVEAL Lite 2, an abridged version of REVEAL 2.0. RESEARCH QUESTION: Can a simplified version of the REVEAL 2.0 risk assessment calculator for patients with PAH be developed and validated? STUDY DESIGN AND METHODS: REVEAL Lite 2 includes six noninvasive variables-functional class (FC), vital signs (systolic BP [SBP] and heart rate), 6-min walk distance (6MWD), brain natriuretic peptide (BNP)/N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and renal insufficiency (by estimated glomerular filtration rate [eGFR])-and was validated in a series of analyses (Kaplan-Meier, concordance index, Cox proportional hazard model, and multivariate analysis). RESULTS: REVEAL Lite 2 approximates REVEAL 2.0 at discriminating low, intermediate, and high risk for 1-year mortality in patients in the REVEAL registry. The model indicated that the most highly predictive REVEAL Lite 2 parameter was BNP/NT-proBNP, followed by 6MWD and FC. Even if multiple, less predictive variables (heart rate, SBP, eGFR) were missing, REVEAL Lite 2 still discriminated among risk groups. INTERPRETATION: REVEAL Lite 2, an abridged version of REVEAL 2.0, provides a simplified method of risk assessment that can be implemented routinely in daily clinical practice. REVEAL Lite 2 is a robust tool that provides discrimination among patients at low, intermediate, and high risk of 1-year mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Safety and efficacy of transitioning from the combination of bosentan and sildenafil to alternative therapy in patients with pulmonary arterial hypertension.

The combination of bosentan and sildenafil is commonly used to treat patients with pulmonary arterial hypertension (PAH); however, there is evidence of a significant drug interaction between these two medications. We sought to evaluate the safety and efficacy of transitioning patients with PAH from the combination of bosentan and sildenafil to alternative therapy. A retrospective database review was performed on 16 patients with PAH who were treated with the combination of bosentan and sildenafil and transitioned to alternative treatment at our center. Invasive and non-invasive patient parameters were collected at baseline and after transition. 56.3% of patients were in World Health Organization functional class (WHO FC) III and a majority of patients (68.7%) were on background prostacyclin therapy. The most common reason for transition was concern for a drug interaction in seven patients (43.8%). The most common transition was bosentan to macitentan in eight patients (50%). Fifteen patients (93.8%) tolerated the transition after a median follow-up of 6.5 months with minor adverse events occurring in four patients (25%). In 11 patients, 6-min walk distance (6MWD) was unchanged comparing baseline to post transition measurements with a median change of +8 m (range: -50 to + 70; P = 0.39). Nine patients (81.8%) had stable (within 15% margin) or significant improvement (increase by ≥15%) in 6MWD after transition. All patients demonstrated stable or improved WHO FC after transition. There were no significant changes after transition in hemodynamics, N-terminal pro-brain natriuretic peptide (NT-proBNP) values, or Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk scores. In our study, transitioning patients from bosentan and sildenafil to alternative therapy was safe and resulted in clinical stability.

Data on clinical and economic burden associated with pulmonary arterial hypertension related hospitalizations in the United States.

A comprehensive description of the contemporary trends in pulmonary arterial hypertension (PAH) related hospitalizations, associated inpatient outcomes and predictors of worse outcomes were reported in our paper recently published in the International Journal of Cardiology [1]. Our observational analysis utilized ten year of national inpatient sample from January 1st 2007 through December 31st 2016. This Data in Brief companion paper aims to report the specific statistical highlights of the entire ten-year PAH cohort including demographics, hospital characteristics, regional variation, prevalence of comorbidities, and multivariable regression analysis used to examine the factors associated with increased inpatient mortality and prolonged length of stay. Additionally, we report trends in the cost (the actual amount of money reimbursed to the hospitals) of PAH related hospitalizations over the past ten years.

National trends and inpatient outcomes of pulmonary arterial hypertension related hospitalizations - Analysis of the National Inpatient Sample Database.

BACKGROUND: Pulmonary arterial hypertension (PAH) is associated with a significant burden of morbidity and mortality. We examined national trends in PAH-related hospitalizations, associated inpatient mortality (IM), length of stay (LOS) and hospitalization charges from 2007 to 2016, as well as predictors of IM and LOS in this population. METHODS: We used the National Inpatient Sample to identify PAH admissions using International classification of diseases (ICD) codes 416.0 (ICD-9) and I27.0 (ICD-10). Records suggestive of secondary causes of pulmonary hypertension were excluded. 6162 (weighted) records with PAH as the primary diagnosis were analyzed. RESULTS: Mean age was 38.7 years, with the majority being females (78.8%). Overall IM was 6.03%, mean LOS 7.6 ± 0.5 days and mean charges $84,100 ± 6200. PAH-related hospitalizations (per million) (27 in 2007 vs. 28 in 2016, p = 0.19) and associated IM (4.5% in 2007 vs. 6.8% in 2016, p = 0.748) as well as LOS (5.9 days in 2007 vs 6.7 days in 2016, p = 0.304) remained unchanged over the decade. Charges increased by 2.4-fold ($43,800 in 2007 to $103,300 in 2016, p = 0.002). While right heart failure, fluid/electrolyte disorders, cardiac arrhythmia and neurological disorders were associated with increased IM, Hispanic race was found to have a survival benefit. Fluid/electrolyte disorders and coagulopathy were associated with increased LOS. CONCLUSION: Despite significant advancements in PAH therapies over the duration of this study, the rate of PAH hospitalizations, and associated IM and LOS remain unchanged. The study identified the predictors of IM and prolonged LOS in PAH population which could be used for additional risk stratification of these patients.

Quantification of Cardiac Output with Phase Contrast Magnetic Resonance Imaging in Patients with Pulmonary Hypertension.

OBJECTIVE: The purpose of the study is to compare phase contrast (PC) imaging with invasive measurements of cardiac output (CO) in patients with pulmonary hypertension (PH). MATERIALS AND METHODS: We analyzed 81 cases with PH who underwent cardiac magnetic resonance imaging and right heart catheterization (RHC). Measurement of CO and stroke volume (SV) by cardiac magnetic resonance (CMR) was performed by PC imaging of the proximal aorta (Ao) and pulmonary artery (Pa) and by RHC using the Fick and thermodilution (TD) methods. RESULTS: There was good correlation in CO measurements between PC and RHC; however, there was better correlation with SV measurements; Fick-TD (r=0.85), PC-TD (Ao r=0.77, Pa r=0.79), and PC-Fick (Ao r = 0.73, Pa r = 0.78). Bland-Altman analysis of SV showed that Pa PC had slightly lower standard deviation than Ao PC; PC-Fick (Pa SD = 15.11 vs. Ao SD = 16.4 ml) and PC-TD (Pa SD = 16.99 ml vs. Ao SD = 17.4 ml) while Fick-TD had the lowest (SD = 14.4 ml). Compared to Fick, measurement of SV with Ao PC (‒4.12 ml) and Pa PC (0.22 ml) both had lower mean difference than TD (‒11.1 ml). CONCLUSION: Non-invasive measurement of CO and SV using PC-CMR correlates well with invasive measurement using RHC. Our study showed that PC-CMR had high accuracy and precision when compared to Fick. Among all the modalities, PC-CMR contributed the least amount of variation in measurements.

Identifying potential parameters associated with response to switching from a PDE5i to riociguat in RESPITE.

BACKGROUND: RESPITE evaluated patients with pulmonary arterial hypertension and an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i) who switched to riociguat. This post hoc analysis assessed response to this switch in parameters associated with clinical improvement. METHODS: RESPITE was a 24-week, uncontrolled pilot study (n = 61). Differences in functional, hemodynamic, and cardiac function parameters, REVEAL risk score (RRS), and biomarkers were compared between responders (free from clinical worsening, World Health Organization functional class I/II, and ≥30 m improvement in 6-min walking distance at Week 24) and non-responders. RESULTS: Of 51 patients (84%) completing RESPITE, 16 (31%) met the responder endpoint. At baseline, there were significant differences between responders and non-responders in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15), and RRS, whereas there were no differences in hemodynamics or cardiac function. At Week 24, responders had significant improvements in pulmonary arterial compliance, pulmonary vascular resistance, and mean pulmonary arterial pressure, while non-responders showed no significant change. Cardiac efficiency and stroke volume index significantly improved irrespective of responder status. CONCLUSIONS: NT-proBNP, GDF-15, and RRS were identified as potential predictors of response in patients switching from PDE5i to riociguat. Further prospective controlled studies are needed to confirm the association of these parameters with response.

Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan.

This review aims to elucidate the optimal dosing of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the heart failure (HF) treatment paradigm through examination of the trial population characteristics and the mortality benefit observed in the Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) trial. Considerations regarding the initiation and titration of sacubitril/valsartan, a first-in-class ARNI, will also be addressed. The approval of sacubitril/valsartan heralded the first novel pharmacological class in over a decade for the treatment of heart failure with reduced ejection fraction (HFrEF). The PARADIGM-HF trial showed that treatment with valsartan/valsartan reduced the risk of first occurrence of either cardiovascular death or HF-related hospitalization (composite primary endpoint) by 20% compared with enalapril in patients with HFrEF. The incremental benefits of treatment with valsartan/valsartan over enalapril demonstrated in the PARADIGM-HF trial led to strong recommendations for its use over ACEIs or angiotensin receptor blockers to further reduce morbidity and mortality in the 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America updates to the guidelines for the management of HF. Although the optimal timing for the initiation of valsartan/valsartan has yet to be determined, its early use is likely to have a positive impact on patient outcomes.