https://orcid.org/0000-0002-2782-1322
Abstract
A case of successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil for treatment of pulmonary arterial hypertension (PAH) is reported.
PAH is a chronically progressive disease characterized by pulmonary artery luminal narrowing that causes increased pulmonary artery pressures leading to right ventricular failure. Parenteral prostacyclin analogues, such as epoprostenol and treprostinil, are direct vasodilators and are cornerstones of therapy for patients with severe disease that have been proven to reduce mortality and increase exercise tolerance. These agents must be administered continuously via intravenous or subcutaneous devices and are high-risk medications due to their potent vasodilatory actions. Chronic use of these medications requires constant attention from both providers and patients because of potential complications including central venous catheter infection, thromboembolism, therapy interruptions, and other undesirable consequences. This case report describes management of a 35-year-old male patient on high-dose outpatient intravenous epoprostenol (101 ng/kg/min; dosing weight, 47 kg) for treatment of PAH who was admitted to the hospital with a malfunctioning central venous catheter. Surrounding manipulation of the central catheter, the patient experienced an ischemic stroke that led to cognitive disability resulting in a lack of ability to manage his previously used home infusion device. The patient was successfully transitioned from intravenous epoprostenol to subcutaneous treprostinil (discharge dose, 200 ng/kg/min) over 5 days by infusing both medications simultaneously and adjusting doses based upon patient-reported symptoms.
This successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil demonstrates the importance in considering patient-specific factors during high-risk medication transitions, the value of a patient-directed flexible prostacyclin transition plan, and the benefit of institutional training and education in ensuring the safe use of parenteral prostacyclin analogues.
Parenteral prostacyclins are an important part of therapy for high-risk pulmonary arterial hypertension (PAH) but require close management by patients and providers.
Patient- and medication-specific factors (tactile ability, home distance to PAH center, medication half-life, etc) should drive clinicians’ decisions on choice of parenteral prostacyclin therapy for PAH treatment.
If necessary, transitioning between parenteral prostacyclin therapies can be done safely through utilizing patient-reported symptoms, a dual infusion method, and a well-trained treatment team.
Pulmonary arterial hypertension (PAH) is a disease state characterized by elevated pulmonary arterial pressures with subsequent remodeling of the pulmonary vasculature, culminating in right ventricular failure, which frequently leads to death in this population.1-3 Targeted therapeutics for PAH work to decrease pulmonary arterial pressures, reduce pulmonary vascular resistance, and delay the progression to right heart failure. The most potent PAH therapeutics currently approved by the US Food and Drug Administration (FDA) are parenteral agents that act within the prostacyclin pathway implicated in both PAH disease pathogenesis and the progression of right ventricular failure.2,4-5 Parenteral medications targeting the prostacyclin pathway include both epoprostenol and treprostinil, which differ significantly in their pharmacokinetics.6,7 Epoprostenol undergoes rapid hydrolysis in circulation, resulting in an short in vitro half-life of 6 minutes, and can only be administered via continuous intravenous (IV) infusion.6 In comparison, treprostinil is primarily hepatically metabolized, exhibits a half-life approximately 40 times longer than epoprostenol (ie, approximately 4 hours), and is appropriate for either IV or subcutaneous administration.7 Prostacyclins are highly effective in improving outcomes in PAH.2,4 However, administration through an implanted central catheter is associated with a number of risks, including catheter failure, infection, and thromboembolism, which may necessitate transition to alternative routes of administration.8 There is significant practice experience (including package insert guidance and other primary literature) describing the dose conversion between epoprostenol and treprostinil. 7,9-13 However, the dose equivalency is not clearly understood, which makes target dose determination difficult to estimate except on the basis of patient-specific factors. This case report details the process of a successful multidisciplinary, patient response–guided transition from high-dose IV epoprostenol to high-dose subcutaneous treprostinil.
Patient case
A 35-year-old male with idiopathic PAH presented to the emergency department (ED) with a malfunctioning Hickman central catheter. The patient’s home PAH regimen included tadalafil 20 mg twice daily (dosed twice daily due to adverse effects, mainly headache), ambrisentan 10 mg once daily, and IV epoprostenol infused at a rate of 101 ng/kg/min, with a dosing weight of 47 kg. The patient had been on IV epoprostenol for 11 years and had a prior history of malfunctioning central lines that required replacement on 6 separate occasions. His primary residence was almost 200 miles away from the nearest Pulmonary Hypertension Association certified center of care (PHA-CCC). His PAH was reasonably well controlled, with an intermediate-risk Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 score of 8, a transthoracic echocardiogram showing subjective dilation of the right ventricle cavity but normal systolic function, and a right heart catheterization procedure from 2 years prior demonstrating a right atrial pressure of 3 mm Hg, pulmonary artery pressure of 66/34 mm Hg (a mean pulmonary artery pressure of 50 mm Hg), pulmonary capillary wedge pressure of 10 mm Hg, and a thermodilution cardiac output of 6 L/min and cardiac index of 3.95 L/min/m2, yielding a pulmonary vascular resistance of 6.7 Wood units (533 dynes/s/cm5).3
The patient presented to a local hospital ED after getting alarms for venous access occlusions and was transitioned from his malfunctioning Hickman catheter to epoprostenol infusion administered via peripheral IV catheter (via home infusion device). He was then transferred to his pulmonary hypertension center’s tertiary care facility. The patient was cared for in a PAH-specific stepdown unit, where nursing staff are continuously trained on the specifics of parenteral prostacyclin administration. Initial attempts to repair the malfunctioning catheter were unsuccessful, and therefore surgical exchange was scheduled for the following day. At the time of admission, the patient was in his usual state of health and asymptomatic. A physical examination was notable for a markedly flushed complexion (relative to the baseline for the patient).
The central venous catheter was exchanged in the operating room on hospital day 2 without complications. However, approximately 6 hours post procedure, the patient’s mental status and respiratory status significantly deteriorated, requiring transfer to the medical intensive care unit (MICU) with subsequent intubation and mechanical ventilation. Evaluation with a head computed tomography (CT) scan revealed multiple cerebral infarctions and bilateral uncal herniation, and the patient was treated with hypertonic and hyperosmolar therapy in consultation with the neurosurgery department. A subsequent magnetic resonance imaging scan of the head confirmed a significant ischemic injury had occurred. Over the next several days, the patient demonstrated significant neurologic recovery, was able to be extubated, and reached near baseline neurological status, with residual short-term memory deficits and persistent mild visual disturbances. Given his significant ischemic stroke, extensive history with central line malfunctions, visual impairments, and reduction in fine motor skills, his ability to prepare and self-administer the epoprostenol infusion became compromised. This deficit, along with distance from the nearest hospital, led the medical team to decide to transition the patient from IV epoprostenol to subcutaneous treprostinil administered via a Remunity infusion device (United Therapeutics Corporation) for patient safety. The Remunity infusion device pump is an ambulatory device specifically designed for administration of subcutaneous continuous treprostinil infusion. One benefit of this device is the ability to receive pharmacy-filled cassettes that do not require admixture by the patient, which was ideal for this patient given his limited dexterity.
A multidisciplinary team including physicians, pharmacists, and nurses assisted in developing a clinical, symptom-based titration strategy with dose steps based on the recommended transition procedure from the treprostinil prescribing information.7 The titration plan involved concomitant administration of IV epoprostenol through the most-recently placed central venous central catheter and IV treprostinil through a temporary peripherally inserted central catheter. The dose of treprostinil was increased every 6 to 24 hours at the discretion of the treating physician team. In response, epoprostenol was only decreased based on patient symptomatology after the treprostinil was increased, which is opposite of package labeling recommendations.7 The patient had extensive experience with prostacyclin titration and was easily able to report any ill effects such as nausea, vomiting, diarrhea, symptomatic hypotension, blurred vision, headache, and excessive flushing. Therefore, it was determined that the patient would help the team in deciding the timing of dose adjustments, which would reflect the effect of the new prostacyclin (treprostinil) before weaning from the previous prostacyclin (epoprostenol).
The doses of each medication and timing of dose transitions are described in Figure 1. Based upon approximate potency equivalencies between epoprostenol and treprostinil, an initial target of treprostinil 150 ng/kg/min was determined. The titration plan was developed based on the target end treprostinil dose modeled after the recommended transition steps described in the treprostinil package insert.6 Treprostinil was started at 10 ng/kg/min (10% of the current epoprostenol dose of 101 ng/kg/min) and was increased by increments of 10-30 ng/kg/min for each titration step. Increases in treprostinil dose were planned to occur every 6 to 24 hours based on patient response, with a preference for dose increases to be completed during the day shift, when there was more ancillary team support available. Epoprostenol was subsequently decreased by roughly 10% increments of the starting epoprostenol dose when the patient expressed symptoms of excessive drug exposure. This patient experienced headache and visual changes, which he self-reported to the bedside nurse, that indicated the need for a dose decrease. The nursing team then communicated to the attending provider and pharmacist, and an epoprostenol dose decrease was ordered. When the initial target of treprostinil 150 ng/kg/min was reached, the epoprostenol dose was still at 20 ng/kg/min. The goal was to continue the transition as previously, with increases in treprostinil of 10 to 30 ng/kg/min and decreases in epoprostenol of 10 ng/kg/min when necessary per patient symptoms. The final dosage of treprostinil was 200 ng/kg/min. Of note, one concentration change to the treprostinil infusion was necessary during the transition to support higher dosing, and this was done at the change from 90 ng/kg/min to 110 ng/kg/min (as described in Figure 1). The total transition was completed over 7 days (in approximately 120 hours). Surprisingly, once the patient was transitioned off of epoprostenol, his physical examination results significantly improved, with a marked decrease in the amount of skin flushing. There was no need for supplemental oxygen or vasopressors during the transition phase due to patient’s stable oxygen saturations and mean arterial pressures throughout. The patient was prepared for discharge, and a transition to the Remunity subcutaneous infusion device was coordinated with the outpatient specialty pharmacy on the day of discharge.
Steps in dual-infusion transition from epoprostenol to treprostinil. Doses represented as nanograms per kilogram per minute (intravenous infusion rate in milliliters per hour). The dosing weight was 47 kg.
The patient continued to be followed by a pulmonary hypertension provider but had not needed a repeat right heart catheterization at the time of writing. Repeat echocardiograms at both 2 and 8 months post transition showed stable disease control with little to no right heart dilation.
Discussion
This report highlights the case of a patient-response–driven transition from high-dose epoprostenol to high-dose treprostinil. We believe this report is important in understanding more about target doses during a transition between epoprostenol and treprostinil (which differ from those specified in the package insert and other known sources) and understanding patient-directed adjustment of medication dosages, the safety of the dual-prostacyclin infusion method of cross titration, patient-specific factors that provoke a switch between prostacyclin analogues, and adjusting literature-based recommendations for transitions to patient-specific scenarios.
As previously discussed, epoprostenol and treprostinil differ significantly in their pharmacokinetic parameters, which greatly influences provider and patient awareness of safety issues related to parenteral prostacyclin infusion. Epoprostenol has a greater potency and is the only parenteral prostacyclin for which direct data show improvement in mortality.5 However, the longer half-life of treprostinil and its ability to be administered subcutaneously is advantageous in the ambulatory setting by allowing more time for emergency care in the setting of interruption and avoidance of long-term central venous access. Patient-specific reasons for utilizing one agent over the other must take precedence in the decision-making process. Some of these factors include the ability to utilize a specific infusion device (which differs between the IV and subcutaneous routes), the patient-preferred route of administration, the proximity of a patient’s residence to a hospital or PHA-CCC, insurance/payor-preferred options, and specialty pharmacy support mechanisms. In this specific patient case, the patient’s ability to manage an IV device by admixture at home was compromised due to his functional limitations post stroke. This, in addition to his long distance from a PHA-CCC, previous challenges with central access, and known risk for paradoxical embolism, led the care team to pursue a transition to treprostinil subcutaneous infusion with specialty pharmacy–premade reservoirs.
Inpatient administration of the high-risk medication class of prostacyclins requires institution-specific protocols. At the admitting institution in this case, the standard is to utilize hospital devices for prostacyclin infusions (instead of patients’ home infusion devices), and this transition was performed using two CADD-Solis (Smiths Medical, Inc.) infusion devices running concurrently in separate, dedicated central access points during the duration of the transition. The institutional standard redundancy safety plan for epoprostenol infusion was employed by having a backup infusion device in the patient’s room that was programmed to the current rate of prostacyclin therapy and ensured that a backup patient-specific epoprostenol cassette was available to nursing staff on the unit. This process is undertaken in order to prevent potentially fatal complication of rebound pulmonary hypertension if the infusion were to be interrupted for 3 or more half-lives (ie, 15-20 minutes). All of these procedures and processes are described in a readily accessible multidisciplinary guidance document.
The planning of transitions between high-risk medications, especially in the context of PAH, wherein there cannot be any significant time of drug cessation without concerns for adverse effects, starts with identifying the goal end dose of the new medication. This involves comparing relative potencies and therapeutic outcomes between each medication. Based upon a small body of literature, epoprostenol is considered to be anywhere from 1.2 to 2 times more potent than treprostinil.6-7,9-13 Treprostinil prescribing information recommends a dose conversion goal of 110% of the current epoprostenol dose, with as-needed additional dose increases in increments of 5% to 10% per patient response.7 Therefore, when considering the transition to treprostinil in this case, starting at an epoprostenol dose of 101 ng/kg/min, the target treprostinil dose was considered to be in the range of 120 ng/kg/min to 200 ng/kg/min. However, based upon the patient’s familiarity with the disease and drug effects, the final target dose was to be determined based upon patient response during the medication transition phase. Notably, the patient required a transition to the maximum dose of the expected target range, which was significantly higher than doses used in other studies describing real-world transitions. Most recently, Kikuchi et al13 reported their institution’s experience with transition from epoprostenol to treprostinil. Their study found a mean epoprostenol dose prior to transition of 85 ng/kg/min and an average posttransition treprostinil dose of 88 ng/kg/min (mean dose equivalency ratio of 1:1.04), with the highest dose equivalency reported as 130% of the epoprostenol dose and with many patients requiring the same dose or lower of treprostinil versus epoprostenol. This illustrates the patient-specific nature of pulmonary hypertension and the dose equivalency of parenteral prostacyclins. Due to the nature of the patient’s ability to report medication effects, it was also deemed safer to titrate the treprostinil dose prior to the epoprostenol dose, which is in opposition to the package insert–directed transition procedure.7 The effects of epoprostenol subside more quickly due to its short half-life; thus, when the patient experienced effects indicating excessive prostacyclin, the dose of epoprostenol was decreased and ill effects were short-lived. The adjustment of treprostinil as the alternative would have led to longer experience of adverse effects. This case report demonstrates how utilization of the patient response–driven approach allowed for safe determination of patient-specific treprostinil dose equivalency without undue adverse effects or hemodynamic compromise.
The actual transition was performed with 2 hospital-managed infusion devices through which all of the inpatient administrations of treprostinil or epoprostenol were provided. These devices (CADD-Solis) were implemented due to their superior safety aspects in backflow prevention, account of volume utilization during line priming, and uniqueness relative to other hospital infusion devices with regard to enhancing the culture of safety and facilitating safe administration of high-risk drugs. In terms of specific concentrations, the cassette concentrations utilized for both agents can be found in Figure 1. The flow rates of these medications is typically slower than those for many other hospital-administered IV medications and range from 0.3 mL/h to 5 mL/h. These rate limitations demand infusion concentration adjustments, especially when dosages are changed by significant amounts. Concentration changes with epoprostenol pose a specific risk because the medication effects can wash out within 2 to 3 half-lives (10-15 minutes) with cessation of administration. Administration of these agents is limited to central access at our institution, not for concern of extravasation but of concern for durability of access. The central venous access devices used at our institution have a required priming volume of 0.5 to 1.5 mL, so priming can take 1 to 3 hours. Therefore, depending on the rate of the infusion, it typically takes longer to get medication to the bloodstream than it takes for previously administered medication to wash out. This is considered by utilizing a dual-infusion method, which continues the current concentration and access while providing the new concentration through separate access until it is estimated that the new access is providing drug to the bloodstream, after which the previous infusion is stopped and the previous access is cleared of drug. The pharmacist contributing to the plan is responsible for assessing the need for concentration changes and providing detailed instructions on the line-priming procedure, when needed. In the case described here, with high doses of both epoprostenol and treprostinil, at least one concentration change was needed. Fortunately, we were able to design titrations that would allow that concentration change to take place with treprostinil instead of epoprostenol. Treprostinil’s longer half-life does not pose a concern of drug cessation during line priming, so our institutional practice is to stop the current access infusion, clear the access of old concentration, and initiate the new concentration through the same access without a dual infusion being necessary. Another note is that each of the doses selected for each step must come out to an infusion rate that is able to be administered by the infusion device, which rounds to 0.1 mL/h. This was important in considering the starting and final doses of each medication and must be confirmed to be acceptable within the dosing parameters of the infusion device.
Additional considerations of importance for transitions of parenteral prostacyclin therapies are assurance of access to the new medication and training on the medical device specific to the new therapy. At our institution, transitions between new therapies are not completed until confirmation of medication access and affordability of co-payment are obtained. The pharmacist is responsible for coordinating the transmission of prescriptions and medical records necessary to the pharmacy for these limited-distribution medications. The inpatient pharmacist communicates directly with the specialty pharmacy for coordination of care relative to medication and insurance approval, co-pay assistance, and device training provided by the specialty pharmacy to the patient.
Conclusion
The successful transition from high-dose IV epoprostenol to high-dose subcutaneous treprostinil described here demonstrated the importance of considering patient-specific factors during high-risk medication transitions, the value of a patient-directed flexible prostacyclin transition plan, and the benefit of institutional PAH training and education to ensure safe use of high-risk medications.
Data availability
No new data were generated or analyzed in support of this article.
Disclosures
Dr. Jose and Dr. Guido receive research funding for an investigator-initiated study from United Therapeutics. Dr. Elwing, in the focus area of pulmonary arterial hypertension, over the last 3 years has served as a consultant for United Therapeutics, Altavant, Aerovate, Bayer, Gossamer Bio, Acceleron/Merck, Janssen/Actelion, Insmed, and Liquida. Dr. Elwing has participated in clinical research funded by Janssen/Actelion, United Therapeutics, Liquidia, Phase Bio, Gossamer Bio, Bayer, Acceleron/Merck, Lung LLC, Altavant, and Aerovate. The other authors have declared no potential conflicts of interest.
Additional information
The authors provided the following information regarding their contributions to this work: J.S. and D.K. extracted and analyzed the data, and all authors drafted the manuscript, revised it critically, and approved its final version.
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