Treatment-related biomarkers in pulmonary hypertension patients on oral therapies.

BACKGROUND: Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients. METHODS: This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis. RESULTS: The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (25.9%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p = 0.02 and p = 0.03 respectively), and ET-1 predicted future 6MWD (p = 0.02). ET-1 (p = 0.01) and cGMP/NT-proBNP ratio (p = 0.04) also predicted future 6MWD in the larger cohort (n = 108) of PAH patients with concomitant left heart disease (n = 17), lung disease (n = 20), or CTEPH (n = 13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p = 0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p = 0.03) and PAH patients on ERA therapy (p = 0.01). CONCLUSIONS: ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.

Safety and Tolerability of High-dose Inhaled Treprostinil in Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) has emerging therapeutic options including prostacyclin analogs. Inhaled therapy offers advantages compared with alternative routes of administration. We aimed to determine the safety and tolerability of inhaled treprostinil (iTRE) titrated to target maintenance dose higher than the labeled dose for PAH. Our study included 80 consecutive patients (69% female, 70% White) followed at the Duke University Medical Center prescribed iTRE at dose >9 breaths (54 µg). Etiology of pulmonary hypertension was most frequently PAH (51%) or secondary to lung disease (35%). Median follow-up was 20.3 months (interquartile range 14.2-33.2). Most patients (91%) had titrated iTRE dose to 12 breaths (72 µg) four times daily. Common side effects reported with drug initiation were cough (41%), headache (28%), and throat irritation (8%); most of the side effects improved at follow-up. Overall, 25% patients discontinued iTRE: 9 transitioned to parenteral therapy, 4 had untolerable side effects, 3 died, and 4 had other reasons. Overall, iTRE taken at a higher dose than approved for use in PAH was safe and well-tolerated in our cohort of pulmonary hypertension patients.

Effects of COVID-19 pandemic on the management of pulmonary hypertension.

The coronavirus of 2019 (COVID-19) disrupted delivery of healthcare. Patients with pulmonary hypertension (PH), especially pulmonary arterial hypertension (PAH), require significant resources for both diagnosis and management and are at high risk for decompensation due to disruption in their care. A survey consisting of 47 questions related to the care of patients with PH was designed by the American College of Chest Physicians 2020-2021 Pulmonary Vascular Disease (PVD) NetWork Steering Committee and sent to all members of the PVD NetWork, as well as the multiple other professional networks for PH. Participation was voluntary and anonymous. Responses were collected from November 2020 through February 2021. Ninety-five providers responded to this survey. The majority (93%) believe that care of PH patients has been affected by the pandemic. Sixty-seven percent observed decreased referrals for PH evaluation. Prior to the pandemic, only 15% used telemedicine for management of PH patients compared to 84% during the pandemic. Telemedicine was used most for follow up of selected low-risk patients (49%). While 22% respondents were completely willing to prescribe new PAH therapy via telemedicine, 11% respondents were completely unwilling. Comfort levels differed based on type of medication being prescribed. Over 90% of providers experienced disruptions in obtaining testing and 31% experienced disruptions in renewal or approval of medications. Overall, providers perceived that the COVID-19 pandemic caused significant disruption of care for PH patients. Telemedicine utilization increased but was used mostly in low-risk patients. Some providers had a decreased level of comfort prescribing PAH therapy via telemedicine encounters.

Utilization of risk assessment tools in management of PAH: A PAH provider survey.

Pulmonary arterial hypertension (PAH) is a chronically progressive fatal disease. A goal-oriented approach to achieve low risk status has been associated with improved survival. A variety of risk stratification tools are available, but use is low. We conducted a survey to assess potential reasons for under-utilization. We conducted a survey-based study of global PAH disease specialists with a goal of assessing risk assessment utilization and identifying modifiable barriers to use. The survey was designed by the American College of Chest Physicians' Pulmonary Vascular Diseases (PVD) NetWork. Respondents were global members of the PVD NetWork and Pulmonary Hypertension Association. Survey invitations were sent electronically to all members. Participation was anonymous and no provider or patient level data was collected. Participants from four countries responded with the majority (84%) being from the United States. Our survey found suboptimal use of any risk stratification tool with 71/112 (63%) reporting use. A total of 85% of the respondents had more than 5 years of experience in managing PAH. REVEAL 2.0 and European Society of Cardiology/European Respiratory Society risk tools were the most commonly used. A total of 44 (65%) surveyed felt that use of risk tools led to change in PAH therapies. Only 6 (9%) felt they prompted additional testing or changed the frequency of follow-up. A total of 5 (7%) reported they prompted goals of care/palliative care discussions and 2 (3%) that they triggered lung transplant referral. The vast majority indicated that incorporation of risk tools into electronic medical records (EMR) would improve utilization. PAH risk assessment tools remain under-utilized. Most respondents were experienced PAH clinicians. More than one-third were not routinely using risk tools. Most felt that risk tools led to PAH therapy changes but few reported impacts on other aspects of care. The most commonly identified barriers to use were time constraints and lack of integration with EMR.

United States Pulmonary Hypertension Scientific Registry: Baseline Characteristics.

BACKGROUND: The treatment, genotyping, and phenotyping of patients with World Health Organization Group 1 pulmonary arterial hypertension (PAH) have evolved dramatically in the last decade. RESEARCH QUESTION: The United States Pulmonary Hypertension Scientific Registry was established as the first US PAH patient registry to investigate genetic information, reproductive histories, and environmental exposure data in a contemporary patient population. STUDY DESIGN AND METHODS: Investigators at 15 US centers enrolled consecutively screened adults diagnosed with Group 1 PAH who had enrolled in the National Biological Sample and Data Repository for PAH (PAH Biobank) within 5 years of a cardiac catheterization demonstrating qualifying hemodynamic criteria. Exposure and reproductive histories were collected by using a structured interview and questionnaire. The biobank provided genetic data. RESULTS: Between 2015 and 2018, a total of 499 of 979 eligible patients with clinical diagnoses of idiopathic PAH (IPAH) or familial PAH (n = 240 [48%]), associated PAH (APAH; n = 256 [51%]), or pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis (n = 3 [1%]) enrolled. The mean age was 55.8 years, average BMI was 29.2 kg/m2, and 79% were women. Mean duration between symptom onset and diagnostic catheterization was 1.9 years. Sixty-six percent of patients were treated with more than one PAH medication at enrollment. Past use of prescription weight loss drugs (16%), recreational drugs (27%), and oral contraceptive pills (77%) was common. Women often reported miscarriage (37%), although PAH was rarely diagnosed within 6 months of pregnancy (1.9%). Results of genetic testing identified pathogenic or suspected pathogenic variants in 13% of patients, reclassifying 18% of IPAH patients and 5% of APAH patients to heritable PAH. INTERPRETATION: Patients with Group 1 PAH remain predominately middle-aged women diagnosed with IPAH or APAH. Delays in diagnosis of PAH persist. Treatment with combinations of PAH-targeted medications is more common than in the past. Women often report pregnancy complications, as well as exposure to anorexigens, oral contraceptives, and/or recreational drugs. Results of genetic tests frequently identify unsuspected heritable PAH.

United States Pulmonary Hypertension Scientific Registry (USPHSR): rationale, design, and clinical implications.

Diagnostic World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) and Diagnostic Group 1' pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) are progressive and fatal disorders. Past registries provided important insights into these disorders, but did not include hormonal exposures or genomic data. The United States Pulmonary Hypertension Scientific Registry (USPHSR) will provide demographic, physiologic, anorexigen and hormone exposure, genomic, and survival data in the current therapeutic era for 499 patients diagnosed with PAH, PVOD, or PCH. The USPHSR also will explore the relationship between pharmacologic, non-pharmacologic, and dietary hormonal exposures and the increased risk for women to develop idiopathic or heritable PAH.

Five-Year outcomes of patients enrolled in the REVEAL Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, severe disease characterized by worsening right-sided heart failure, decreasing functional status, and poor survival. The present study characterizes the 5-year survival in the United States of a new and previous diagnosis of PAH in patients stratified by baseline functional class (FC). The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) is a 55-center observational US registry of the demographics, disease course, and management of patients with World Health Organization (WHO) group 1 PAH. METHODS: The REVEAL Registry enrolled newly and previously diagnosed patients aged ≥ 3 months with WHO group 1 PAH consecutively from March 2006 to December 2009. Demographics, disease characteristics, and hemodynamic data were collected at enrollment. Survival analysis was conducted by FC and other subgroups in patients aged ≥ 18 years. RESULTS: Survival differences between previously diagnosed and newly diagnosed patients at 1 year (90.4% vs 86.3%) were maintained to 5 years; 5-year survival for previously diagnosed patients was 65.4% compared with 61.2% for newly diagnosed patients. Previously diagnosed patients in FC I, II, III, and IV had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for newly diagnosed patients in FC I, II, III, and IV, respectively. CONCLUSIONS: Patient survival of advanced PAH remains poor at 5 years despite treatment advances. New York Heart Association FC remains one of the most important predictors of future survival. These observations reinforce the importance of continuous monitoring of FC in patients with PAH. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Comprehensive assessment of right ventricular function in patients with pulmonary hypertension with global longitudinal peak systolic strain derived from multiple right ventricular views.

BACKGROUND: Right ventricular (RV) function is a strong predictor of mortality in pulmonary hypertension (PH), but two-dimensional (2D) echocardiography-derived assessments of RV function that could aid in risk assessment and management of patients with PH are of limited utility. RV longitudinal peak systolic strain (RVLS) derived from 2D speckle-tracking echocardiography is a relatively novel method for quantifying RV function but typically is derived from a single apical four-chamber view of the right ventricle and may have inherent limitations. The objective of this study was to determine the utility of regional and global RVLS calculated from multiple views of the right ventricle to comprehensively assess RV function in a cohort of patients with PH. METHODS: Regional and global RVLS were obtained from multiple views of the right ventricle (centered on the right ventricle-focused apical position) in 40 patients with PH, defined as a mean pulmonary artery pressure ≥ 25 mm Hg, most of whom also had pulmonary capillary wedge pressures ≤ 15 mm Hg and were thus defined as having pulmonary arterial hypertension. This was compared with other 2D echocardiography-derived parameters of RV function and functional parameters. RESULTS: Global RVLS calculated from multiple views had a superior correlation with 6-min walk distance compared with other parameters of RV function, including tricuspid annular plane systolic excursion, RV myocardial performance index, and fractional area change. Although global RVLS calculated from multiple views displayed a similar correlation with 6-min walk distance as global RVLS calculated from a single four-chamber view, analysis of regional strains provided by multiple views identified distinct patterns of RV dysfunction, consisting of global, free wall, or septal dysfunction, that were associated with specific clinical characteristics. CONCLUSIONS: Global RVLS derived from multiple right ventricle-focused views yields a comprehensive quantitative assessment of regional and global RV function that correlates moderately with functional parameters and may be useful in the assessment of PH. Distinct patterns of regional RV dysfunction are associated with different clinical characteristics.

Comorbid conditions and outcomes in patients with pulmonary arterial hypertension: a REVEAL registry analysis.

BACKGROUND: Comorbidities can affect disease progression and/or response to treatment in various conditions. Comorbid conditions are prevalent in patients with pulmonary arterial hypertension (PAH); however, their effect on patient outcomes remains unknown. METHODS: We evaluated the effect on functional class (FC), 6-min walk test distance (6MWD), and survival of the seven most common, comorbid conditions at enrollment in patients with PAH from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry): hypertension, clinical depression, type 2 diabetes mellitus (diabetes), obesity, COPD, sleep apnea, and thyroid disease. RESULTS: Patients with COPD or diabetes had the shortest 6MWD at enrollment (304.5 and 304.6 m, respectively) vs other comorbidities. Adjusted linear regression for 6MWD at enrollment revealed significant reductions among patients who were hypertensive, obese, diabetic, or had COPD (P<.001). A larger proportion of patients who were obese or had COPD were FC III/IV vs FC I/II at enrollment (P<.001). There was a greater risk for death among patients with diabetes (hazard ratio [HR], 1.73; 95% CI, 1.40-2.13; P<.001) or COPD (HR, 1.59; 95% CI, 1.34-1.90; P<.001), but there was a reduced risk for death in patients who were obese (HR, 0.73; 95% CI, 0.61-0.86; P<.001). CONCLUSIONS: Compared with other analyzed comorbidities in patients with PAH, hypertension, obesity, diabetes, and COPD were associated with significantly worse 6MWD; obesity and COPD were associated with worse FC; and diabetes and COPD were associated with increased risk for death. Further investigation of the effects of treating these comorbidities in patients with PAH is warranted. TRIAL REGISTRY: ClinicalTrials.gov; Identifier: NCT00370214; URL: www.clinicaltrials.gov.

Bloodstream infections in patients with pulmonary arterial hypertension treated with intravenous prostanoids: insights from the REVEAL REGISTRY®.

OBJECTIVE: To evaluate the rate of and potential risk factors for bloodstream infections (BSIs) using data from the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension [PAH] Disease Management) REGISTRY(®), which provides current information about patients with PAH. PATIENTS AND METHODS: Patients were enrolled from March 30, 2006, through December 8, 2009, and data on reported BSIs were collected through the third quarter of 2010. Bloodstream infection rates were calculated per 1000 patient-days of risk. RESULTS: Of 3518 patients enrolled, 1146 patients received intravenous (IV) prostanoid therapy for more than 1 day (no BSI, n=1023; ≥1 BSI, n=123; total BSI episodes, n=166). Bloodstream infections rates were significantly increased in patients receiving IV treprostinil vs IV epoprostenol (0.36 vs 0.12 per 1000 treatment days; P<.001), primarily due to gram-negative organisms (0.20 vs 0.03 per 1000 treatment days; P<.001). Multivariate analysis adjusting for age, causes of PAH, and year of BSI found that treatment with IV treprostinil was associated with a 3.08-fold increase (95% confidence interval, 2.05-4.62; P<.001) in BSIs of any type and a 6.86-fold increase (95% confidence interval, 3.60-13.07; P<.001) in gram-negative BSIs compared with treatment with IV epoprostenol. CONCLUSION: Compared with IV epoprostenol therapy, treatment with IV treprostinil is associated with a significantly higher rate of gram-negative BSIs; observed differences in BSI rate did not seem to be due to any other analyzed factors. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00370214.

Inhaled treprostinil for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension is a progressive disease characterized by vascular proliferation and vasoconstriction of the small pulmonary arteries that eventually leads to right-sided heart failure and death. Patients often initially have symptoms such as shortness of breath, fatigue, and edema; later in the disease, presyncope and syncope are common. Patients with progressive pulmonary arterial hypertension despite oral therapy and/or with severe disease typically require treatment with a prostanoid. Inhaled treprostinil (Tyvaso) is a prostacyclin analog indicated for the treatment of pulmonary arterial hypertension to increase walk distance in patients with symptoms classified as New York Heart Association functional class III. Inhaled treprostinil was approved by the Food and Drug Administration in July 2009. This article provides a brief overview of the pathophysiology of pulmonary arterial hypertension and reviews the mechanism of action, key clinical data, and the practical management of inhaled treprostinil in patients with pulmonary arterial hypertension.