Impact of selexipag use within 12 months of pulmonary arterial hypertension diagnosis on hospitalizations and medical costs: A retrospective cohort study.

BACKGROUND: Oral selexipag, a prostacyclin pathway agent (PPA), is effective in patients with pulmonary arterial hypertension (PAH). The objective of this study is to assess the impact of initiating oral selexipag within 12 months of diagnosis on health outcomes. METHODS: This retrospective cohort study used data from Optum's de-identified Clinformatics® Data Mart Database. PAH patients between 1 October 2015 and 30 September 2019 were included. Patients were also required to have received PAH medication within 12 months of their initial diagnosis. Study groups included patients who initiated selexipag within 12 months of PAH diagnosis (SEL ≤ 12) and those who did not initiate any PPA within 12 months of PAH diagnosis (No PPA ≤ 12). Inverse probability of treatment weighting was used to remove potential confounding between groups. Cox and Poisson regression models were used to compare hospitalization and disease progression. Generalized linear model with gamma distribution and log link was used to compare costs. RESULTS: SEL ≤ 12 had lower rate of all-cause hospitalizations (rate ratio: 0.76, 95% confidence interval [CI]: 0.60, 0.96) versus no PPA ≤ 12, but no differences in PAH-related hospitalization rate (rate ratio: 1.03, 95% CI: 0.79, 1.33) or risk of disease progression (hazard ratio: 1.01, 95% CI: 0.71, 1.44). SEL ≤ 12 incurred lower all-cause (mean difference: -$23 623; 95% CI: -35 537, -8512) and PAH-related total medical costs (mean difference: -$12 927; 95% CI: -19 559, -5679) versus no PPA ≤ 12. CONCLUSION: Selexipag initiation within 12 months of PAH diagnosis demonstrated reductions in all-cause hospitalization rate and medical costs.

Modeling of Acute Pulmonary Arterial Hypertension in Pigs Using a Stable Thromboxane A2 Analogue (U46619): Dose Adjustment and Assessment of Hemodynamic Reactions.

U46619, a synthetic analogue of thromboxane A2 was used for modeling acute stable and reversible pulmonary arterial hypertension. Administration of U46619 in high doses led to vascular collapse and inhibition of cardiac function. The doses of U46619 were empirically selected that allow attaining the target level of pulmonary hypertension without systemic hemodynamic disturbances. The possibility of attaining the target level of pulmonary hypertension and reversibility of changes after termination of U46619 infusion make this model attractive for evaluation of the efficiency of different therapeutic methods of treatment of pulmonary hypertension in large animals.

The Critical Choice of Animal Models in Nanomedicine Safety Assessment: A Lesson Learned From Hemoglobin-Based Oxygen Carriers.

Intravenous injection of nanopharmaceuticals can induce severe hypersensitivity reactions (HSRs) resulting in anaphylactoid shock in a small percentage of patients, a phenomenon explicitly reproducible in pigs. However, there is a debate in the literature on whether the pig model of HSRs can be used as a safety test for the prediction of severe adverse reactions in humans. Given the importance of using appropriate animal models for toxicity/safety testing, the choice of the right species and model is a critical decision. In order to facilitate the decision process and to expand the relevant information regarding the pig or no pig dilemma, this review examines an ill-fated clinical development program conducted by Baxter Corporation in the United States 24 years ago, when HemeAssist, an αα (diaspirin) crosslinked hemoglobin-based O2 carrier (HBOC) was tested in trauma patients. The study showed increased mortality in the treatment group relative to controls and had to be stopped. This disappointing result had far-reaching consequences and contributed to the setback in blood substitute research ever since. Importantly, the increased mortality of trauma patients was predicted in pig experiments conducted by US Army scientists, yet they were considered irrelevant to humans. Here we draw attention to that the underlying cause of hemoglobin-induced aggravation of hemorrhagic shock and severe HSRs have a common pathomechanism: cardiovascular distress due to vasoconstrictive effects of hemoglobin (Hb) and reactogenic nanomedicines, manifested, among others, in pulmonary hypertension. The main difference is that in the case of Hb this effect is due to NO-binding, while nanomedicines can trigger the release of proinflammatory mediators. Because of the higher sensitivity of cloven-hoof animals to this kind of cardiopulmonary distress compared to rodents, these reactions can be better reproduced in pigs than in murine or rat models. When deciding on the battery of tests and the appropriate models to identify the potential hazard for nanomedicine-induced severe HSR, the pros and cons of the various species must be considered carefully.

Pre-clinical assessment of a water-in-fluorocarbon emulsion for the treatment of pulmonary vascular diseases.

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O2) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO2) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20-30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.

Estimating Resting Energy Expenditure by Different Methods as Compared With Indirect Calorimetry for Patients With Pulmonary Hypertension.

BACKGROUND: For patients with pulmonary hypertension, nutrition status is an independent predictor of morbidity and mortality, and energy expenditure can be strongly influenced by lung disease. Indirect calorimetry (IC) is the gold standard for measuring resting energy expenditure (REE), this study aimed to compare the results of REE estimated by different methods with those obtained by IC for patients with pulmonary hypertension. METHODS: In this cross-sectional study (n = 34), REE was estimated by bioelectrical impedance analysis and the predictive equations of Harris-Benedict, Food and Agriculture Organization / World Health Organization, Institute of Medicine, Cunningham, Katch-McArdle, and Mifflin-St Jeor. RESULTS: Mean patient age was 47.0 ± 14.5 years, and 76.5% were women. REE obtained with IC was strongly correlated with all other estimation methods but showed higher mean values: IC 1750.8 ± 434.3 kcal vs bioelectrical impedance analysis, 1549.0 ± 417.8 kcal; Harris-Benedict, 1493.1 ± 337.0 kcal; FAO/WHO, 1536.1 ± 345.0 kcal; Institute of Medicine, 1457.1 ± 293.2 kcal; Cunningham, 1597.3 ± 292.3 kcal; Katch-McArdle, 1447.7 ± 287.0 kcal; and Mifflin-St Jeor, 1388.7 ± 303.9 kcal. The analysis of agreement showed a clinically significant bias of approximately -255 kcal in all estimation methods when compared with IC. CONCLUSION: Although there was a strong correlation between REE estimation methods and IC, there was no agreement between them. All estimation methods underestimated energy needs by about 255 kcal for patients with pulmonary hypertension, and the Cunningham equation had the smallest difference in relation to IC.

Multi-criteria decision analysis (MCDA): testing a proposed MCDA framework for orphan drugs.

BACKGROUND: Since the introduction of the orphan drugs legislation in Europe, it has been suggested that the general method of assessing drugs for reimbursement is not necessarily suitable for orphan drugs. The National Institute for Health and Clinical Excellence indicated that several criteria other than cost and efficacy could be considered in reimbursement decisions for orphan drugs. This study sought to explore the multi-criteria decision analysis (MCDA) framework proposed by (Orphanet J Rare Dis 7:74, 2012) to a range of orphan drugs, with a view to comparing the aggregate scores to the average annual cost per patient for each product, and thus establishing the merit of MCDA as a tool for assessing the value of orphan drugs in relation to their pricings. METHODS: An MCDA framework was developed using the nine criteria proposed by (Orphanet J Rare Dis 7:74, 2012) for the evaluation of orphan drugs, using the suggested numerical scoring system on a scale of 1 to 3 for each criterion. Correlations between the average annual cost of the drugs and aggregate MCDA scores were tested and plotted graphically. Different weightings for each of the attributes were also tested. A further analysis was conducted to test the impact of including the drug cost as an attribute in the aggregate index scores. RESULTS: In the drugs studied, the R 2, that statistically measures how close the data are to the fitted regression line was 0.79 suggesting a strong correlation between the drug scores and the average annual cost per patient. CONCLUSION: Despite several limitations of the proposed model, this quantitative study provided insight into using MCDA and its relationship to the average annual costs of the products.

Phenotypic assessment of pulmonary hypertension using high-resolution echocardiography is feasible in neonatal mice with experimental bronchopulmonary dysplasia and pulmonary hypertension: a step toward preventing chronic obstructive pulmonary disease.

Bronchopulmonary dysplasia (BPD) and chronic obstructive pulmonary disease (COPD) are chronic lung diseases of human infants and adults, respectively, that are characterized by alveolar simplification. One-third of the infants with severe BPD develop pulmonary hypertension (PH). More importantly, PH increases morbidity and mortality in BPD patients. Additionally, COPD is a common respiratory morbidity in former BPD patients. The lack of an appropriate small animal model wherein echocardiography (Echo) can demonstrate PH is one of the major barriers to understand the molecular mechanisms of the disease and, thereby, develop rational therapies to prevent and/or treat PH in BPD patients. Thus, the goal of this study was to establish a model of experimental BPD and PH and investigate the feasibility of Echo to diagnose PH in neonatal mice. Since hyperoxia-induced oxidative stress and inflammation contributes to the development of BPD with PH, we tested the hypothesis that exposure of newborn C57BL/6J mice to 70% O2 (hyperoxia) for 14 days leads to lung oxidative stress, inflammation, alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and Echo evidence of PH. Hyperoxia exposure caused lung oxidative stress and inflammation as evident by increased malondialdehyde adducts and inducible nitric oxide synthase, respectively. Additionally, hyperoxia exposure caused growth restriction, alveolar and pulmonary vascular simplification, and pulmonary vascular remodeling. At 14 days of age, Echo of these mice demonstrated that hyperoxia exposure decreased pulmonary acceleration time (PAT) and PAT/ejection time ratio and increased right ventricular free wall thickness, which are indicators of significant PH. Thus, we have demonstrated the feasibility of Echo to phenotype PH in neonatal mice with experimental BPD with PH, which can aid in discovery of therapies to prevent and/or treat BPD with PH and its sequelae such as COPD in humans.

Novel assessment of haemodynamic kinetics with acute exercise in a rat model of pulmonary arterial hypertension.

NEW FINDINGS: What is the central question of this study? The acute effect of exercise at moderately high intensity on already-elevated pulmonary arterial pressures and right ventricular wall stress in a rat model of pulmonary arterial hypertension (PAH) is unknown. What is the main finding and its importance? We show, for the first time, that in a rat model of PAH, exercise induces an acute reduction in pulmonary artery pressure associated with lung endothelial nitric oxide synthase activation, without evidence of acute right ventricular inflammation or myocyte apoptosis. Haemodynamic measures obtained with traditional invasive methodology as well as novel implantable telemetry reveal an exercise-induced 'window' of pulmonary hypertension alleviation, supporting future investigations of individualized exercise as therapy in PAH. Exercise improves outcomes of multiple chronic conditions, but controversial results, including increased pulmonary artery (PA) pressure, have prevented its routine implementation in pulmonary arterial hypertension (PAH), an incurable disease that drastically reduces exercise tolerance. Individualized, optimized exercise prescription for PAH requires a better understanding of disease-specific exercise responses. We investigated the acute impact of exercise on already-elevated PA pressure and right ventricular (RV) wall stress and inflammation in a rat model of PAH (PAH group, n = 12) induced once by monocrotaline (50 mg kg(-1) , i.p.; 2 weeks), compared with healthy control animals (n = 8). Single bouts of exercise consisted of a 45 min treadmill run at 75% of individually determined aerobic capacity (V̇O2max). Immediately after exercise, measurements of RV systolic pressure and systemic pressure were made via jugular and carotid cannulation, and were followed by tissue collection. Monocrotaline induced moderate PAH, evidenced by RV hypertrophy, decreased V̇O2max, PA muscularization, and RV and skeletal muscle cytoplasmic glycolysis detected by increased expression of glucose transporter-1. Acute exercise normalized the monocrotaline-induced elevation in RV systolic pressure and augmented pulmonary endothelial nitric oxide synthase activation, without evidence of increased RV inflammation or apoptosis. Real-time recordings of pulmonary and systemic pressures during and after single bouts of exercise made using novel implantable telemetry in the same animal for up to 11 weeks after monocrotaline (40 mg kg(-1) ) corroborated the finding of acute PA pressure decreases with exercise in PAH. The PA pressure-lowering effects of individualized exercise associated with RV-neutral effects and increases in vasorelaxor signalling encourage further development of optimized exercise regimens as adjunctive PAH therapy.

[Value of cardiopulmonary exercise test in assessment of cardiac function of patients with pulmonary hypertension].

OBJECTIVE: To explore the role of peak oxygen consumption in assessment of heart function of patients with pulmonary hypertension. METHODS: From September 2010 to April 2012, 101 patients [29 male, mean age: (32.6 ± 11.4 )years] with pulmonary hypertension diagnosis by right heart catheterization were enrolled. Correlations among peak oxygen consumption, New York Heart Association (NYHA) class, NT-proBNP, 6 minute walking distance (6MWD) and cardiac index are analyzed. RESULTS: There were 44 cases with NYHA class II (43.6%), 49 cases with NYHA class III (48.5%), mean 6MWD was (421 ± 91 )m, NT-proBNP was (1262 ± 816) ng/L, pulmonary vascular resistance was (1031 ± 582) dyn·s(-1)·cm(-5), CI was (3.5 ± 2.3) L·min(-1)·m(-2), peak oxygen consumption was( 13.8 ± 4.1)ml·min(-1)·kg(-1). 6MWD, pulmonary vascular resistance and peak oxygen consumption were related to CI (r = 0.299, -0.541, 0.341, respectively, all P < 0.05), but NYHA class and NT-proBNP were not correlated to CI. Multiple regression analysis demonstrated that peak oxygen consumption (B = 0.135, P = 0.004) but not 6MWD was correlated with CI after adjusting age, sex and pulmonary vascular resistance. ROC analysis found that the sensitivity and specificity using peak oxygen consumption <15.2 ml·min(-1)·kg(-1) as a cut-off value was 92.6% and 57.5%, respectively, for diagnosing severe heart dysfunction. CONCLUSIONS: The correlation between peak oxygen consumption and CI is better than that of NYHA class, 6MWD, and NT-proBNP with CI. Peak oxygen consumption less than 15.2 ml·min(-1)·kg(-1) could be used to detect reduced CI in patients with pulmonary hypertension.

The effects of inhaled nitric oxide on the levels of cGMP plasma and lung tissue in a canine model of smoke inhalation injury.

The effects of inhaled nitric oxide (NO) on pulmonary hypertension and their mechanisms were studied in a canine model of smoke inhalation injury. Twenty-one dogs were randomly divided into three groups: four dogs constituted the normal control group, eight dogs subjected to smoke inhalation followed by O(2) inhalation (FiO(2)=0.45) constituted the injury control group, and nine dogs inhaling a mixture of O(2) and 45ppm nitric oxide after smoke exposure served as the treatment group. The levels of cyclic guanosine monophosphate (cGMP) in arterial plasma of the treatment group were higher than that of the control group at 5, 8, and 12h after smoke exposure, while the levels of cGMP in lung tissue were also significantly higher compared with that of the control group (P<0.01). The levels of cGMP of injury control group were decreased significantly compared with normal controls (P<0.05). Pulmonary vasoconstriction following smoke inhalation was significantly attenuated by inhalation of NO (P<0.05), which exerted no apparent effect on the systemic circulation (P>0.05). Inhalation of NO may lower pulmonary hypertension induced by smoke inhalation injury in dogs. The selective effect of NO on pulmonary circulation may be attributed to an increase in level of cGMP in smooth muscle cells of the lung tissue after inhalation of NO.