Practical management of oral treprostinil in patients with pulmonary arterial hypertension: Lessons from ADAPT, EXPEDITE, and expert consensus.

BACKGROUND: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies. STUDY DESIGN AND METHODS: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use. RESULTS: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76 % female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62 % (78/126) of patients reported headache and diarrhea, and 40 % (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61 % headache, 44 % diarrhea, 70 % nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron, were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6. CONCLUSION: Patient selection for, and initiation and titration of, oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help patients reach higher and more efficacious doses of oral treprostinil.

Expert provider survey of longitudinal assessment in patients with pulmonary arterial hypertension.

BACKGROUND: Patients suffering from pulmonary arterial hypertension (PAH) demand frequent assessment to keep pace with a dynamic and sometimes rapidly progressive disease course. To improve our understanding of patient monitoring, we conducted a survey of pulmonary hypertension (PH) providers to establish real-world practice patterns. OBJECTIVE: To evaluate the type and frequency of patient assessment methods employed by expert PH providers following PAH diagnosis METHODS: A descriptive cross-sectional survey of PH providers across the United States was utilized to assess provider practices. Between September 14, 2017 to October 17, 2017, a survey was distributed electronically to PH experts assessing follow-up frequency and testing evaluation of patients with PAH. RESULTS: 40 (11.4%) providers completed the survey, representing cardiologists, pulmonologists, and advanced practice providers at centers who cared for an average of 95 patients per year with PAH. Follow-up testing and clinic evaluation was influenced by severity of patient illness. Frequency of re-assessment of clinic follow-up, six-minute walk test, echocardiogram, brain natriuretic peptide, and right heart catheterization in various clinical scenarios all reflected disparate practice. CONCLUSIONS: Current clinical practice patterns in the monitoring of patients with PAH are variable and do not necessarily reflect guideline-based practices, suggesting the need for further research and improved guidelines on the frequency of follow up and repeat testing.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

RATIONALE: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint. OBJECTIVES: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension. METHODS: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16. RESULTS: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction. CONCLUSION: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Provider recognition and response to echocardiographic findings indicating pulmonary hypertension in the Veterans affairs medical center population.

PH occurs alone or in association with many disorders. Many patients with transthoracic echocardiography (TTE) findings suggesting PH never receive additional evaluation. Patient characteristics and echocardiographic data associated with increased recognition of PH have not been fully evaluated. We evaluated TTE reports at the Cincinnati Veterans Affairs Medical Center from 2005 to 2006 retrospectively for findings highly indicative of PH: Estimated systolic pulmonary artery pressure (sPAP) ≥40 mmHg, increased right atrial or right ventricular (RV) size, or reduced RV function. Only patients with left ventricular ejection fraction (LVEF) ≥50% and no known diagnosis of PH were included. Patient characteristics, TTE findings, provider recognition rates, and subsequent referral for additional evaluation were assessed. A total of 227 of 3,960 (5.7%) TTE reports revealed findings indicating possible PH. Providers acknowledged possible PH in 53 (23.4%) reports. Recognized PH was predicted by increased RV size (odds ratio (OR) = 5.07, P < 0.001), increased right atrial dimension (OR = 6.45, P < 0.001), decreased RV function (OR = 8.86, P < 0.001), and increased PAP (OR = 1.04 corresponding to each unit increase of PAP, P < 0.01). Patients with comorbid obstructive sleep apnea (OSA), interstitial lung disease, and dyspnea were also more likely to be recognized (OR = 3.63, P = 0.021; OR = 10.98, P = 0.004; OR = 2.39, P = 0.007, respectively). The 12-month mortality rate for recognized patients, 11.3% (7/53), was lower than for unrecognized patients, 25.3% (44/174; P = 0.03). Providers recognized less than one in four patients with echocardiographic evidence suggesting PH. Echocardiography reports revealing higher PAP and right heart dilation and dysfunction are associated with increased acknowledgement of possible PH.