Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 496–500
doi: 10.1111/jcpt.12170
Transition from intravenous or subcutaneous prostacyclin therapy to inhaled treprostinil in patients with pulmonary arterial hypertension: a retrospective case series C. Y. Enderby* PharmD, M. Soukup* PharmD, M. Al Omari† MD, T. Zeiger‡ RRT and C. Burger‡ MD *Department of Pharmacy, Mayo Clinic, Jacksonville, FL, †Department of Cardiovascular Disease, Mayo Clinic, Jacksonville, FL, and ‡Department of Pulmonary Medicine, Mayo Clinic, Jacksonville, FL, USA
Received 25 March 2013, Accepted 7 April 2014
Keywords: epoprostenol, prostacyclin, pulmonary arterial hypertension, transition, treprostinil
logues. Prostacyclins vasodilate the pulmonary vasculature. Clinical benefits of prostacyclin therapy include improved exercise capacity, quality of life, haemodynamic profile and survival.2 Currently available parenteral prostacyclins include epoprostenol and treprostinil. Continuous infusion of the parenteral prostacyclins, epoprostenol intravenous (IV) and treprostinil IV or subcutaneous (SQ) has been associated with complications including central line infections and infusion site pain.3–7 The advent of inhaled prostacyclin formulations represents a therapeutic option for the treatment of PAH. Inhaled prostacyclins are an attractive alternative to the other available prostaglandin analogue formulations by obviating the use of continuous infusions and its associated risks.8–10 Treprostinil’s longer effective half-life of 4 h11–13 compared with the other available prostacyclins (epoprostenol 3–6 min,14,15 iloprost 20–30 min16) makes it a favourable agent for administration via the inhaled route. As a result, inhaled treprostinil requires fewer treatment sessions compared with the other available inhaled prostaglandin, iloprost.13,16,17 Inhaled treprostinil (Tyvasoâ; United Therapeutics Corp, Research Triangle Park, NC, USA) is available as a sterile formulation administered to achieve a goal dose of nine breaths (54 mcg) per treatment session four times daily during waking hours via an Optineb oral inhalation device.13 Published evidence describing the process of conversion from IV or SQ prostacyclin therapy to the inhaled formulation of treprostinil is limited. Product information provides recommendations for initiating prostacyclin-na€ıve patients on inhaled treprostinil but does not provide dosing guidelines for changing patients previously established on systemic prostacyclin therapy to inhaled treprostinil.13 The purpose of this report is to describe an inpatient protocol for transitioning patients from IV or SQ prostacyclin therapy to inhaled treprostinil in patients with PAH. The clinical assessment from outpatient follow-up after successful transition is also provided.
SUMMARY What is known and objective: Inhaled treprostinil represents an attractive alternative to the other available prostacyclin formulations by obviating the use of continuous infusions and its associated risks. Published evidence describing the process of transition from infusion prostacyclin therapy to inhaled treprostinil is limited. The purpose of this report is to describe an inpatient protocol for transitioning patients with pulmonary arterial hypertension (PAH) from intravenous (IV) or subcutaneous (SQ) prostacyclin therapy to inhaled treprostinil. Methods: A retrospective case cohort study was performed evaluating medical records of three patients undergoing transition from IV/SQ continuous infusion prostacyclin therapy to inhaled treprostinil. The transition protocol and clinical data were collected prospectively. Results and discussion: Haemodynamics, six-min walk distance (6MWD), World Health Organization (WHO) functional class, modified Borg Dyspnea Score and brain natriuretic peptide prior to and after transition remained similar. All patients were receiving concomitant oral PAH medications prior to and after conversion. Adverse effects during the change were mild. No patients discontinued inhaled treprostinil following transition. At long-term follow-up, functional class remained stable at WHO functional class II or better. Patient 1 and Patient 3 demonstrated stable to modest improvement in 6MWD, whereas Patient 2 had a slight decrease in 6MWD. The transition to inhaled treprostinil from IV/SQ infusion prostacyclin therapy appears to be safe in carefully selected patients. What is new and conclusion: Our report describes a standard method used to transition patients from IV/SQ infusion prostacyclin to inhaled treprostinil. WHAT IS KNOWN AND OBJECTIVE Pulmonary arterial hypertension (PAH) is a debilitating and potentially life-threatening disease of the pulmonary vasculature which can result in right heart failure.1 Pharmacological treatments are designed to lower the pulmonary arterial pressures, thereby reducing right ventricular afterload. One class of medications approved for PAH treatment includes prostacyclin or its ana-
METHODS A case cohort study was performed after approval by the Mayo Clinic Institutional Review Board. Patients undergoing transition from IV/SQ continuous infusion prostacyclin to inhaled treprostinil from July 2010 through November 2011 were included. The transition protocol and clinical data were collected prospectively. Retrospective review and analysis were performed for purposes of reporting the results. The medical records of three patients undergoing clinical transition from continuous infusion prostacyclin
Correspondence: C. Y. Enderby, Department of Pharmacy, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Tel.: +1 904 956 1719; fax: +1 904 956 1724; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
496
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Transition to inhaled treprostinil
inhaled treprostinil was initiated at three breaths. Four hours following the inhaled treprostinil dose, the epoprostenol dose was decreased to 7 ng/kg/min (1/3 of the 20 ng/kg/min dose) and the inhaled treprostinil treatment was increased to six breaths. After an additional 4 h had elapsed, the epoprostenol infusion was discontinued and nine breaths of inhaled treprostinil were administered. Three additional inhaled treprostinil treatments of nine breaths were administered at 4- to 6-h intervals. The patient was subsequently discharged on inhaled treprostinil nine breaths (54 mcg) four times daily in combination with bosentan 125 mg twice daily. Patient 2 was on treprostinil for approximately 2 years. She had been maintained on continuous infusion of SQ treprostinil 59 ng/ kg/min for 8 months prior to successful titration down to 196 ng/ kg/min over the course of 4 months. That dose reduction was achieved in a stair-step fashion by decreasing the SQ treprostinil 10 ng/kg/min over 2 weeks as tolerated. With each 10 ng/kg/min reduction, the dose would be held stable for 1 month, after which the patient was evaluated in the pulmonary hypertension clinic with functional class, brain natriuretic peptide (BNP) and 6MWD. She was stable on 196 ng/kg/min and therefore was hospitalized on July 2010 for placement of a pulmonary artery catheter and transition to inhaled treprostinil. The SQ treprostinil dose was decreased to 147 ng/kg/min (2/3 of the 196 ng/kg/min dose), and 2 h following this dose reduction, inhaled treprostinil was initiated at a dose of three breaths every 4 h for a total of three treatments. On day 2 of the transition, the SQ treprostinil was further decreased to 74 ng/kg/min (1/3 of the 196 ng/kg/min dose), 3 h elapsed, and six breaths of inhaled treprostinil was initiated, administered approximately 4 h apart for a total of four treatments. On the third and final day of transition, SQ treprostinil was discontinued, and after 2 h, nine breaths of inhaled treprostinil were given. This treatment was repeated for a total of two doses, and the patient was subsequently discharge on inhaled treprostinil nine breaths four times daily in combination with sildenafil 60 mg and bosentan 125 mg, both twice daily. Patient 3 was on IV treprostinil for 45 years. She had been receiving continuous infusion IV treprostinil at a stable dose of 65 ng/kg/min for 3 years and 8 months. This dose was titrated down over the course of 6 months in a similar stair-step fashion as Patient 2 to a stable dose of 25 ng/kg/min. She was hospitalized on November 2011 for the transition to inhaled treprostinil, and a pulmonary artery catheter was placed for continuous haemodynamic monitoring. The IV treprostinil dose
therapy (epoprostenol or treprostinil) to inhaled treprostinil are included. The transition occurred utilizing an inpatient protocol (Table 1) designed by two of the authors (CB, TZ). The decision to transition from infusion to inhaled prostacyclin was a shared provider and patient decision. In all three cases, there were significant complications of the IV/SQ infusion prostacyclin therapy. The requirements for consideration included World Health Organization (WHO) functional class of I or II, six-min walk distance (6MWD) of at least 380 m, right ventricular systolic function on echocardiogram that was either normal or only mildly reduced and prostacyclin infusion dose rates of 30 ng/kg/min or less. Data analysis was descriptive in nature with no formal hypothesis testing. RESULTS The demographics and baseline PAH medication regimens are presented in Table 2. All three patients were women. The average age was 47 12 years. Patients 1 and 2 had idiopathic PAH, and Patient 3 had associated PAH with limited scleroderma. All were on combination oral and infusion prostacyclin therapy. All three patients in our case series had been receiving IV/SQ prostacyclin for at least 2 years prior to transition and were stable on maintenance dose of epoprostenol 50 ng/kg/min and treprostinil 59 and 65 ng/kg/min, respectively, prior to downward titration in preparation for conversion to inhaled treprostinil. Table 3 describes haemodynamics before and after the change to inhaled treprostinil. Overall, there was no significant clinical worsening of the PAH. All three patients were transitioned from IV/SQ infusion prostacyclin therapy to inhaled treprostinil using the predefined protocol in Table 1. After transition, all patients were discharged on inhaled treprostinil nine breaths (54 mcg) four times daily in combination with their baseline oral PAH medications. Additional details are provided below. Patient 1 was on IV prostacyclins for 5 years. She had been on continuous infusion of epoprostenol 50 ng/kg/min for 3 years, most recently on room temperature stable epoprostenol. Her dose was reduced by 2 ng/kg/min every 3 days as tolerated over the course of a month to 30 ng/kg/min. She was hospitalized for the transition on December 2010, and a pulmonary artery catheter was placed for continuous haemodynamic monitoring. The epoprostenol dose was decreased at a rate of 2 ng/kg/min every hour until 20 ng/kg/min was reached. The epoprostenol dose was further decreased to 13 ng/kg/min (2/3 of the 20 ng/kg/min dose), and
Table 1. Recommended protocol for transition from IV/SQ prostacyclin therapy to inhaled treprostinil Step Step Step Step
1 2 3 4
Step 5
Step 6
Step 7
Eligible patients should be able to tolerate a titration of their home IV/SQ prostacyclin therapy down to a dose of 25 ng/kg/min or less Admit patient to intensive care unit for pulmonary artery catheter placement and monitoring. Obtain a baseline haemodynamic profile To begin transition, decrease the patient’s home IV/SQ prostacyclin therapy by 33% Two hours following IV/SQ prostacyclin dose reduction, initiate inhaled treprostinil at three breaths four times daily during waking hours (given at approximately 4 h intervals). Obtain baseline and follow-up haemodynamic parameters with each inhaled treprostinil treatment On day 2 of transition, decrease the patient’s home IV/SQ prostacyclin therapy by an additional 33% and 2 h following IV/SQ prostacyclin dose reduction and increase inhaled treprostinil to six breaths four times daily during waking hours (given at approximately 4 h intervals). Obtain baseline and follow-up haemodynamic parameters with each inhaled treprostinil treatment On day 3 of transition, discontinue IV/SQ prostacyclin therapy, wait 2 h and increase inhaled treprostinil to nine breaths four times daily during waking hours (given at approximately 4 h intervals). Obtain baseline and follow-up haemodynamic parameters with each inhaled treprostinil treatment Monitor for signs of under- or overdosing of medication (dyspnoea, fatigue, palpitations, syncope, jaw pain, headache, flushing, nausea, diarrhoea or vomiting)
SQ, subcutaneous.
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 496–500 497
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treprostinil. In a multicenter retrospective case series, de Jesus Perez and colleagues22 describe the transition of 18 WHO Group I PAH patients from IV treprostinil (n = 15) or IV epoprostenol (n = 3) to inhaled treprostinil. The mean dose of IV treprostinil and epoprostenol was 73 ng/kg/min and 10 ng/kg/min, respectively. The majority of patients were on dual or triple therapy for PAH. Followup at a mean of 7 months showed no deterioration in 6MWD or BNP but a trend towards worsening New York Heart Association functional class was noted. In the subset of patients who underwent baseline and follow-up right heart catheterizations to monitor haemodynamics, a trend towards worsening cardiac index was noted. Patients reported improvement in symptoms (nausea/ vomiting, myalgia, headache) following the change to inhaled therapy although cough (n = 3) and syncope (n = 3) were new symptoms reported. Four patients were reinstated on parenteral therapy, and two patients required the addition of oral PAH medications. One death occurred secondary to myocardial infarction following a massive gastrointestinal bleed, although it is unclear if this was secondary to inhaled treprostinil therapy. Our report describes a standardized method used in transitioning patients from IV/SQ infusion prostacyclin to inhaled treprostinil. Table 1 describes our proposed general approach to assist practitioners in this process. Specific methods and procedures for transition were not discussed in detail in currently available literature. Additionally, strategies used for transition varied across different centres.22 The conversion to inhaled treprostinil from IV/SQ infusion prostacyclin therapy appears to be safe in carefully selected patients. All three of our patients were clinically stable, on concomitant oral PAH medications, and had been receiving IV or SQ prostacyclin for at least 2 years prior to transition. These three patients were stable on maintenance dose of epoprostenol 50 ng/kg/min and treprostinil 62 3 ng/kg/min prior to downward titration in preparation for the change to inhaled treprostinil. Upon transition, all patients had stable haemodynamics acutely. Haemodynamic monitoring is essential and titration of inhaled and IV/SQ therapy should be individualized according to the patient’s response. The adverse effects noted in our study are consistent with those previously reported for inhaled treprostinil therapy, including throat irritation, cough and fatigue.8,10,23 None of the patients discontinued therapy during the transition period due to adverse effects. The primary reasons for consideration of inhaled treprostinil in these patients were complications of IV/SQ prostacyclin therapy, including recurrent line infections (patients 1 and 3) and recurrent line difficulties including infection and dislodgement (Patient 2). Bloodstream infections are known and potentially serious complications of prostacyclin therapy.3–6,24 Specific guidelines for the prevention of these catheter-related infections have been developed.25 Use of IV/SQ prostacyclin therapy requires proper education of the patient and special procedures for medication preparation and administration. Inhaled treprostinil provided a beneficial alternative to these patients by reducing the infectious risk and other inconveniences associated with their previous IV/ SQ therapy. All three patients had no further episodes of bacteraemia or sepsis from the time the central lines were removed post-transition. It is important to note the long-term effects of this transition as the clinical status of these three patients have been stable at followup. Long-term benefits of inhaled treprostinil use in prostacyclinna€ıve patients with PAH are supported in the TRIUMPH study which followed patients for 24 months.23 Our follow-up data of
was further reduced to 16 ng/kg/min (2/3 of the 25 ng/kg/min dose) prior to inhaled treprostinil administration. Approximately 1 h following IV treprostinil dose reduction, three breaths of inhaled treprostinil were initiated. The patient was initiated on inhaled treprostinil three breaths four times daily, given approximately 5 h apart. On the second day of transition, IV treprostinil was decreased to 8 ng/kg/min (1/3 of the 25 ng/kg/min dose). One hour after the decrease, the inhaled treprostinil dose was increased to six breaths four times per day. Doses were administered every 4–5 h. The IV treprostinil drip was discontinued on the morning of the third transition day, and the inhaled treprostinil dose increased to nine breaths four times daily. Her combination therapy including sildenafil 20 mg three times daily and bosentan 125 mg and diltiazem 240 mg, both twice daily, was continued. Her discharge regimen for PAH was inhaled treprostinil nine breaths four times daily with sildenafil, bosentan and diltiazem. Comparison of baseline WHO functional class, 6MWD, modified Borg Dyspnea Score and BNP to each patient’s 1 month posttransition outpatient follow-up assessment in the pulmonary hypertension clinic is provided in Table 4. Patient 2 required an increase in her inhaled treprostinil dose 2 weeks after the conversion due to shortness of breath. Her dose was further increased to 15 breaths four times daily at the 1 month follow-up appointment due to functional changes as well as slight increases in her right heart pressures but preserved right ventricular size and function. Subsequently, her dose has been decreased to 12 breaths four times daily and then again to her current dose of nine breaths four times daily due to systemic hypotension after the addition of diltiazem to her medication regimen for paroxysmal supraventricular tachycardia. At the most recent outpatient followup, all three patients remained on inhaled treprostinil. Patient 1 was 21 months, Patient 2 was 30 months and Patient 3 was 11 months post-transition to inhaled treprostinil. Functional class remained stable at WHO functional class II or better. Patients 1 and 3 demonstrated stable to modest improvement in 6MWD, whereas Patient 2 had a slight decrease in 6MWD. Adverse events reported during the transition phase were mild. Patient 1 experienced mild jaw pain, throat irritation and a generalized feeling of warmth. Patient 3 complained of epistaxis, muscle-like contractions and gas pains. Epistaxis was attributed to the use of oxygen therapy and the gas pains subsided with the use of calcium carbonate and carbonated soda. None of the patients discontinued the transition to inhaled treprostinil due to adverse effects. On subsequent follow-up appointments, Patient 2 complained of a ‘washed out’ feeling (1 h after a dose of 15 breaths), dyspnoea, fatigue and dry cough. DISCUSSION Prostacyclins are one of the primary medications used in the treatment of PAH. Administration of inhaled prostacyclin is an alternative for patients who have experienced or want to avoid difficulties associated with IV/SQ infusion prostacyclin therapy. Inhaled treprostinil is often preferred to iloprost due to less frequent dosing requirements. Published literature is available on initiating inhaled treprostinil in prostaglandin-na€ıve patients as add on therapy,9,10 converting between the IV and SQ prostacyclin formulations18–21 and switching from inhaled iloprost to inhaled treprostinil.17 Limited information exists on transitioning from IV/ SQ infusion prostacyclins to inhaled treprostinil. A single study to date discusses transition from parenteral prostacyclin to inhaled
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 496–500 498
C. Y. Enderby et al.
Transition to inhaled treprostinil
Table 2. Patient demographics and baseline medication history
Patient
Age
Gender
Race
1
44
F
Filipino
2
36
F
Caucasian
3
60
F
Caucasian
Maintenance prostacyclin dose (ng/kg/min)
Duration of prostacyclin therapy (years)
Prostacyclin dose prior to transition (ng/kg/min)
Prostacyclin therapy
Route of prostacyclin
Room temperature stable Epoprostenol (Veletri) Treprostinil (Remodulin) Treprostinil (Remodulin)
IV
5
50
20
SQ
2
59
196
IV
45
65
25
Concomitant PAH medications
Concomitant PAH medication doses
Bosentan
125 mg po BID
Sildenafil Bosentan Sildenafil Bosentan Diltiazem XR
60 mg po BID 125 mg po BID 20 mg po TID 125 mg po BID 240 mg po BID
SQ, subcutaneous; PAH, pulmonary arterial hypertension.
Table 3. Haemodynamics at baseline and after transition from parenteral prostacyclin therapy to inhaled treprostinil Pressure, mmHga Patient
Timeline
RA
PAS
PAD
mPAP
PCWP
TPG
CO, L/min/CI
PVR, dyn s cm
1 1 2 2 3 3
Baseline After Transition Baseline After Transition Baseline After Transition
4 1 7 7 4 6
30 26 40 40 46 36
13 10 20 18 24 20
18 15 26 25 31 25
10 6 12 10 11 9
8 9 14 15 20 11
44/29 52/34 62/39 51/29 35 49
144 138 181 235 457 261
5
RA, right atrial; PAS, pulmonary artery systolic pressure; PAD, pulmonary artery diastolic pressure; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; CO, cardiac output; PVR, pulmonary vascular resistance. a Based on right heart catheterization.
Table 4. Clinical characteristics pre- and post-transition to inhaled treprostinil
Patient
Baseline 6MWD (m)
1 Month Follow-up 6MWD (m)
Baseline WHO
1 Month Follow-up WHO
Baseline Modified Borg Dyspnea Score
1 Month Follow-up Modified Borg Dyspnea Score
Baseline BNP (pg/mL)
1 Month Follow-up BNP (pg/mL)
1 2 3
400 398 541
414 388 572
2 2 1
2 2 1
1 0 05
3 0 05
68 11 63
43 28 58
6MWD, 6-min walk distance; WHO, World Health Organization functional class; BNP, brain natriuretic peptide.
The main limitations of our study include the small number of patients, single centre and retrospective design. Our experience to date involves only three female patients. The transition protocol used in this case series should be applicable to the general PAH population, but this is unproven. Right heart catheterizations were performed while the patients were hospitalized during the transition but were not repeated in follow-up. Nonetheless, the
up to 30 months are longer than the 7-month follow-up reported in the deJesus study.22 All patients in our study were still receiving inhaled treprostinil at their last follow-up visit. Although Patient 2 did require a dose increase in inhaled treprostinil, for a brief period, she is currently on a stable dose of nine breaths four times daily. This provides further evidence of sustained clinical benefit on long-term inhaled treprostinil.
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 496–500 499
C. Y. Enderby et al.
Transition to inhaled treprostinil
October 2013. Results of this study should provide additional insight into this transition process and patient outcomes.
patients remained symptomatically stable with concomitant stable or improved non-invasive measures of PAH severity such as BNP and 6MWD. Of note, an ongoing prospective, observational trial sponsored by the Los Angeles Biomedical Research Institute in collaboration with United Therapeutics began in August 2010 with an estimated enrolment of 21 patients.26 Primary outcome measurement is number of adverse events at transition, 4 weeks and 12 weeks. Secondary outcomes include clinical worsening over 12 weeks. Criteria for switching patients in this study are mPAP
doi: 10.1111/jcpt.12170
Transition from intravenous or subcutaneous prostacyclin therapy to inhaled treprostinil in patients with pulmonary arterial hypertension: a retrospective case series C. Y. Enderby* PharmD, M. Soukup* PharmD, M. Al Omari† MD, T. Zeiger‡ RRT and C. Burger‡ MD *Department of Pharmacy, Mayo Clinic, Jacksonville, FL, †Department of Cardiovascular Disease, Mayo Clinic, Jacksonville, FL, and ‡Department of Pulmonary Medicine, Mayo Clinic, Jacksonville, FL, USA
Received 25 March 2013, Accepted 7 April 2014
Keywords: epoprostenol, prostacyclin, pulmonary arterial hypertension, transition, treprostinil
logues. Prostacyclins vasodilate the pulmonary vasculature. Clinical benefits of prostacyclin therapy include improved exercise capacity, quality of life, haemodynamic profile and survival.2 Currently available parenteral prostacyclins include epoprostenol and treprostinil. Continuous infusion of the parenteral prostacyclins, epoprostenol intravenous (IV) and treprostinil IV or subcutaneous (SQ) has been associated with complications including central line infections and infusion site pain.3–7 The advent of inhaled prostacyclin formulations represents a therapeutic option for the treatment of PAH. Inhaled prostacyclins are an attractive alternative to the other available prostaglandin analogue formulations by obviating the use of continuous infusions and its associated risks.8–10 Treprostinil’s longer effective half-life of 4 h11–13 compared with the other available prostacyclins (epoprostenol 3–6 min,14,15 iloprost 20–30 min16) makes it a favourable agent for administration via the inhaled route. As a result, inhaled treprostinil requires fewer treatment sessions compared with the other available inhaled prostaglandin, iloprost.13,16,17 Inhaled treprostinil (Tyvasoâ; United Therapeutics Corp, Research Triangle Park, NC, USA) is available as a sterile formulation administered to achieve a goal dose of nine breaths (54 mcg) per treatment session four times daily during waking hours via an Optineb oral inhalation device.13 Published evidence describing the process of conversion from IV or SQ prostacyclin therapy to the inhaled formulation of treprostinil is limited. Product information provides recommendations for initiating prostacyclin-na€ıve patients on inhaled treprostinil but does not provide dosing guidelines for changing patients previously established on systemic prostacyclin therapy to inhaled treprostinil.13 The purpose of this report is to describe an inpatient protocol for transitioning patients from IV or SQ prostacyclin therapy to inhaled treprostinil in patients with PAH. The clinical assessment from outpatient follow-up after successful transition is also provided.
SUMMARY What is known and objective: Inhaled treprostinil represents an attractive alternative to the other available prostacyclin formulations by obviating the use of continuous infusions and its associated risks. Published evidence describing the process of transition from infusion prostacyclin therapy to inhaled treprostinil is limited. The purpose of this report is to describe an inpatient protocol for transitioning patients with pulmonary arterial hypertension (PAH) from intravenous (IV) or subcutaneous (SQ) prostacyclin therapy to inhaled treprostinil. Methods: A retrospective case cohort study was performed evaluating medical records of three patients undergoing transition from IV/SQ continuous infusion prostacyclin therapy to inhaled treprostinil. The transition protocol and clinical data were collected prospectively. Results and discussion: Haemodynamics, six-min walk distance (6MWD), World Health Organization (WHO) functional class, modified Borg Dyspnea Score and brain natriuretic peptide prior to and after transition remained similar. All patients were receiving concomitant oral PAH medications prior to and after conversion. Adverse effects during the change were mild. No patients discontinued inhaled treprostinil following transition. At long-term follow-up, functional class remained stable at WHO functional class II or better. Patient 1 and Patient 3 demonstrated stable to modest improvement in 6MWD, whereas Patient 2 had a slight decrease in 6MWD. The transition to inhaled treprostinil from IV/SQ infusion prostacyclin therapy appears to be safe in carefully selected patients. What is new and conclusion: Our report describes a standard method used to transition patients from IV/SQ infusion prostacyclin to inhaled treprostinil. WHAT IS KNOWN AND OBJECTIVE Pulmonary arterial hypertension (PAH) is a debilitating and potentially life-threatening disease of the pulmonary vasculature which can result in right heart failure.1 Pharmacological treatments are designed to lower the pulmonary arterial pressures, thereby reducing right ventricular afterload. One class of medications approved for PAH treatment includes prostacyclin or its ana-
METHODS A case cohort study was performed after approval by the Mayo Clinic Institutional Review Board. Patients undergoing transition from IV/SQ continuous infusion prostacyclin to inhaled treprostinil from July 2010 through November 2011 were included. The transition protocol and clinical data were collected prospectively. Retrospective review and analysis were performed for purposes of reporting the results. The medical records of three patients undergoing clinical transition from continuous infusion prostacyclin
Correspondence: C. Y. Enderby, Department of Pharmacy, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Tel.: +1 904 956 1719; fax: +1 904 956 1724; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
496
C. Y. Enderby et al.
Transition to inhaled treprostinil
inhaled treprostinil was initiated at three breaths. Four hours following the inhaled treprostinil dose, the epoprostenol dose was decreased to 7 ng/kg/min (1/3 of the 20 ng/kg/min dose) and the inhaled treprostinil treatment was increased to six breaths. After an additional 4 h had elapsed, the epoprostenol infusion was discontinued and nine breaths of inhaled treprostinil were administered. Three additional inhaled treprostinil treatments of nine breaths were administered at 4- to 6-h intervals. The patient was subsequently discharged on inhaled treprostinil nine breaths (54 mcg) four times daily in combination with bosentan 125 mg twice daily. Patient 2 was on treprostinil for approximately 2 years. She had been maintained on continuous infusion of SQ treprostinil 59 ng/ kg/min for 8 months prior to successful titration down to 196 ng/ kg/min over the course of 4 months. That dose reduction was achieved in a stair-step fashion by decreasing the SQ treprostinil 10 ng/kg/min over 2 weeks as tolerated. With each 10 ng/kg/min reduction, the dose would be held stable for 1 month, after which the patient was evaluated in the pulmonary hypertension clinic with functional class, brain natriuretic peptide (BNP) and 6MWD. She was stable on 196 ng/kg/min and therefore was hospitalized on July 2010 for placement of a pulmonary artery catheter and transition to inhaled treprostinil. The SQ treprostinil dose was decreased to 147 ng/kg/min (2/3 of the 196 ng/kg/min dose), and 2 h following this dose reduction, inhaled treprostinil was initiated at a dose of three breaths every 4 h for a total of three treatments. On day 2 of the transition, the SQ treprostinil was further decreased to 74 ng/kg/min (1/3 of the 196 ng/kg/min dose), 3 h elapsed, and six breaths of inhaled treprostinil was initiated, administered approximately 4 h apart for a total of four treatments. On the third and final day of transition, SQ treprostinil was discontinued, and after 2 h, nine breaths of inhaled treprostinil were given. This treatment was repeated for a total of two doses, and the patient was subsequently discharge on inhaled treprostinil nine breaths four times daily in combination with sildenafil 60 mg and bosentan 125 mg, both twice daily. Patient 3 was on IV treprostinil for 45 years. She had been receiving continuous infusion IV treprostinil at a stable dose of 65 ng/kg/min for 3 years and 8 months. This dose was titrated down over the course of 6 months in a similar stair-step fashion as Patient 2 to a stable dose of 25 ng/kg/min. She was hospitalized on November 2011 for the transition to inhaled treprostinil, and a pulmonary artery catheter was placed for continuous haemodynamic monitoring. The IV treprostinil dose
therapy (epoprostenol or treprostinil) to inhaled treprostinil are included. The transition occurred utilizing an inpatient protocol (Table 1) designed by two of the authors (CB, TZ). The decision to transition from infusion to inhaled prostacyclin was a shared provider and patient decision. In all three cases, there were significant complications of the IV/SQ infusion prostacyclin therapy. The requirements for consideration included World Health Organization (WHO) functional class of I or II, six-min walk distance (6MWD) of at least 380 m, right ventricular systolic function on echocardiogram that was either normal or only mildly reduced and prostacyclin infusion dose rates of 30 ng/kg/min or less. Data analysis was descriptive in nature with no formal hypothesis testing. RESULTS The demographics and baseline PAH medication regimens are presented in Table 2. All three patients were women. The average age was 47 12 years. Patients 1 and 2 had idiopathic PAH, and Patient 3 had associated PAH with limited scleroderma. All were on combination oral and infusion prostacyclin therapy. All three patients in our case series had been receiving IV/SQ prostacyclin for at least 2 years prior to transition and were stable on maintenance dose of epoprostenol 50 ng/kg/min and treprostinil 59 and 65 ng/kg/min, respectively, prior to downward titration in preparation for conversion to inhaled treprostinil. Table 3 describes haemodynamics before and after the change to inhaled treprostinil. Overall, there was no significant clinical worsening of the PAH. All three patients were transitioned from IV/SQ infusion prostacyclin therapy to inhaled treprostinil using the predefined protocol in Table 1. After transition, all patients were discharged on inhaled treprostinil nine breaths (54 mcg) four times daily in combination with their baseline oral PAH medications. Additional details are provided below. Patient 1 was on IV prostacyclins for 5 years. She had been on continuous infusion of epoprostenol 50 ng/kg/min for 3 years, most recently on room temperature stable epoprostenol. Her dose was reduced by 2 ng/kg/min every 3 days as tolerated over the course of a month to 30 ng/kg/min. She was hospitalized for the transition on December 2010, and a pulmonary artery catheter was placed for continuous haemodynamic monitoring. The epoprostenol dose was decreased at a rate of 2 ng/kg/min every hour until 20 ng/kg/min was reached. The epoprostenol dose was further decreased to 13 ng/kg/min (2/3 of the 20 ng/kg/min dose), and
Table 1. Recommended protocol for transition from IV/SQ prostacyclin therapy to inhaled treprostinil Step Step Step Step
1 2 3 4
Step 5
Step 6
Step 7
Eligible patients should be able to tolerate a titration of their home IV/SQ prostacyclin therapy down to a dose of 25 ng/kg/min or less Admit patient to intensive care unit for pulmonary artery catheter placement and monitoring. Obtain a baseline haemodynamic profile To begin transition, decrease the patient’s home IV/SQ prostacyclin therapy by 33% Two hours following IV/SQ prostacyclin dose reduction, initiate inhaled treprostinil at three breaths four times daily during waking hours (given at approximately 4 h intervals). Obtain baseline and follow-up haemodynamic parameters with each inhaled treprostinil treatment On day 2 of transition, decrease the patient’s home IV/SQ prostacyclin therapy by an additional 33% and 2 h following IV/SQ prostacyclin dose reduction and increase inhaled treprostinil to six breaths four times daily during waking hours (given at approximately 4 h intervals). Obtain baseline and follow-up haemodynamic parameters with each inhaled treprostinil treatment On day 3 of transition, discontinue IV/SQ prostacyclin therapy, wait 2 h and increase inhaled treprostinil to nine breaths four times daily during waking hours (given at approximately 4 h intervals). Obtain baseline and follow-up haemodynamic parameters with each inhaled treprostinil treatment Monitor for signs of under- or overdosing of medication (dyspnoea, fatigue, palpitations, syncope, jaw pain, headache, flushing, nausea, diarrhoea or vomiting)
SQ, subcutaneous.
© 2014 John Wiley & Sons Ltd
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treprostinil. In a multicenter retrospective case series, de Jesus Perez and colleagues22 describe the transition of 18 WHO Group I PAH patients from IV treprostinil (n = 15) or IV epoprostenol (n = 3) to inhaled treprostinil. The mean dose of IV treprostinil and epoprostenol was 73 ng/kg/min and 10 ng/kg/min, respectively. The majority of patients were on dual or triple therapy for PAH. Followup at a mean of 7 months showed no deterioration in 6MWD or BNP but a trend towards worsening New York Heart Association functional class was noted. In the subset of patients who underwent baseline and follow-up right heart catheterizations to monitor haemodynamics, a trend towards worsening cardiac index was noted. Patients reported improvement in symptoms (nausea/ vomiting, myalgia, headache) following the change to inhaled therapy although cough (n = 3) and syncope (n = 3) were new symptoms reported. Four patients were reinstated on parenteral therapy, and two patients required the addition of oral PAH medications. One death occurred secondary to myocardial infarction following a massive gastrointestinal bleed, although it is unclear if this was secondary to inhaled treprostinil therapy. Our report describes a standardized method used in transitioning patients from IV/SQ infusion prostacyclin to inhaled treprostinil. Table 1 describes our proposed general approach to assist practitioners in this process. Specific methods and procedures for transition were not discussed in detail in currently available literature. Additionally, strategies used for transition varied across different centres.22 The conversion to inhaled treprostinil from IV/SQ infusion prostacyclin therapy appears to be safe in carefully selected patients. All three of our patients were clinically stable, on concomitant oral PAH medications, and had been receiving IV or SQ prostacyclin for at least 2 years prior to transition. These three patients were stable on maintenance dose of epoprostenol 50 ng/kg/min and treprostinil 62 3 ng/kg/min prior to downward titration in preparation for the change to inhaled treprostinil. Upon transition, all patients had stable haemodynamics acutely. Haemodynamic monitoring is essential and titration of inhaled and IV/SQ therapy should be individualized according to the patient’s response. The adverse effects noted in our study are consistent with those previously reported for inhaled treprostinil therapy, including throat irritation, cough and fatigue.8,10,23 None of the patients discontinued therapy during the transition period due to adverse effects. The primary reasons for consideration of inhaled treprostinil in these patients were complications of IV/SQ prostacyclin therapy, including recurrent line infections (patients 1 and 3) and recurrent line difficulties including infection and dislodgement (Patient 2). Bloodstream infections are known and potentially serious complications of prostacyclin therapy.3–6,24 Specific guidelines for the prevention of these catheter-related infections have been developed.25 Use of IV/SQ prostacyclin therapy requires proper education of the patient and special procedures for medication preparation and administration. Inhaled treprostinil provided a beneficial alternative to these patients by reducing the infectious risk and other inconveniences associated with their previous IV/ SQ therapy. All three patients had no further episodes of bacteraemia or sepsis from the time the central lines were removed post-transition. It is important to note the long-term effects of this transition as the clinical status of these three patients have been stable at followup. Long-term benefits of inhaled treprostinil use in prostacyclinna€ıve patients with PAH are supported in the TRIUMPH study which followed patients for 24 months.23 Our follow-up data of
was further reduced to 16 ng/kg/min (2/3 of the 25 ng/kg/min dose) prior to inhaled treprostinil administration. Approximately 1 h following IV treprostinil dose reduction, three breaths of inhaled treprostinil were initiated. The patient was initiated on inhaled treprostinil three breaths four times daily, given approximately 5 h apart. On the second day of transition, IV treprostinil was decreased to 8 ng/kg/min (1/3 of the 25 ng/kg/min dose). One hour after the decrease, the inhaled treprostinil dose was increased to six breaths four times per day. Doses were administered every 4–5 h. The IV treprostinil drip was discontinued on the morning of the third transition day, and the inhaled treprostinil dose increased to nine breaths four times daily. Her combination therapy including sildenafil 20 mg three times daily and bosentan 125 mg and diltiazem 240 mg, both twice daily, was continued. Her discharge regimen for PAH was inhaled treprostinil nine breaths four times daily with sildenafil, bosentan and diltiazem. Comparison of baseline WHO functional class, 6MWD, modified Borg Dyspnea Score and BNP to each patient’s 1 month posttransition outpatient follow-up assessment in the pulmonary hypertension clinic is provided in Table 4. Patient 2 required an increase in her inhaled treprostinil dose 2 weeks after the conversion due to shortness of breath. Her dose was further increased to 15 breaths four times daily at the 1 month follow-up appointment due to functional changes as well as slight increases in her right heart pressures but preserved right ventricular size and function. Subsequently, her dose has been decreased to 12 breaths four times daily and then again to her current dose of nine breaths four times daily due to systemic hypotension after the addition of diltiazem to her medication regimen for paroxysmal supraventricular tachycardia. At the most recent outpatient followup, all three patients remained on inhaled treprostinil. Patient 1 was 21 months, Patient 2 was 30 months and Patient 3 was 11 months post-transition to inhaled treprostinil. Functional class remained stable at WHO functional class II or better. Patients 1 and 3 demonstrated stable to modest improvement in 6MWD, whereas Patient 2 had a slight decrease in 6MWD. Adverse events reported during the transition phase were mild. Patient 1 experienced mild jaw pain, throat irritation and a generalized feeling of warmth. Patient 3 complained of epistaxis, muscle-like contractions and gas pains. Epistaxis was attributed to the use of oxygen therapy and the gas pains subsided with the use of calcium carbonate and carbonated soda. None of the patients discontinued the transition to inhaled treprostinil due to adverse effects. On subsequent follow-up appointments, Patient 2 complained of a ‘washed out’ feeling (1 h after a dose of 15 breaths), dyspnoea, fatigue and dry cough. DISCUSSION Prostacyclins are one of the primary medications used in the treatment of PAH. Administration of inhaled prostacyclin is an alternative for patients who have experienced or want to avoid difficulties associated with IV/SQ infusion prostacyclin therapy. Inhaled treprostinil is often preferred to iloprost due to less frequent dosing requirements. Published literature is available on initiating inhaled treprostinil in prostaglandin-na€ıve patients as add on therapy,9,10 converting between the IV and SQ prostacyclin formulations18–21 and switching from inhaled iloprost to inhaled treprostinil.17 Limited information exists on transitioning from IV/ SQ infusion prostacyclins to inhaled treprostinil. A single study to date discusses transition from parenteral prostacyclin to inhaled
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 496–500 498
C. Y. Enderby et al.
Transition to inhaled treprostinil
Table 2. Patient demographics and baseline medication history
Patient
Age
Gender
Race
1
44
F
Filipino
2
36
F
Caucasian
3
60
F
Caucasian
Maintenance prostacyclin dose (ng/kg/min)
Duration of prostacyclin therapy (years)
Prostacyclin dose prior to transition (ng/kg/min)
Prostacyclin therapy
Route of prostacyclin
Room temperature stable Epoprostenol (Veletri) Treprostinil (Remodulin) Treprostinil (Remodulin)
IV
5
50
20
SQ
2
59
196
IV
45
65
25
Concomitant PAH medications
Concomitant PAH medication doses
Bosentan
125 mg po BID
Sildenafil Bosentan Sildenafil Bosentan Diltiazem XR
60 mg po BID 125 mg po BID 20 mg po TID 125 mg po BID 240 mg po BID
SQ, subcutaneous; PAH, pulmonary arterial hypertension.
Table 3. Haemodynamics at baseline and after transition from parenteral prostacyclin therapy to inhaled treprostinil Pressure, mmHga Patient
Timeline
RA
PAS
PAD
mPAP
PCWP
TPG
CO, L/min/CI
PVR, dyn s cm
1 1 2 2 3 3
Baseline After Transition Baseline After Transition Baseline After Transition
4 1 7 7 4 6
30 26 40 40 46 36
13 10 20 18 24 20
18 15 26 25 31 25
10 6 12 10 11 9
8 9 14 15 20 11
44/29 52/34 62/39 51/29 35 49
144 138 181 235 457 261
5
RA, right atrial; PAS, pulmonary artery systolic pressure; PAD, pulmonary artery diastolic pressure; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary gradient; CO, cardiac output; PVR, pulmonary vascular resistance. a Based on right heart catheterization.
Table 4. Clinical characteristics pre- and post-transition to inhaled treprostinil
Patient
Baseline 6MWD (m)
1 Month Follow-up 6MWD (m)
Baseline WHO
1 Month Follow-up WHO
Baseline Modified Borg Dyspnea Score
1 Month Follow-up Modified Borg Dyspnea Score
Baseline BNP (pg/mL)
1 Month Follow-up BNP (pg/mL)
1 2 3
400 398 541
414 388 572
2 2 1
2 2 1
1 0 05
3 0 05
68 11 63
43 28 58
6MWD, 6-min walk distance; WHO, World Health Organization functional class; BNP, brain natriuretic peptide.
The main limitations of our study include the small number of patients, single centre and retrospective design. Our experience to date involves only three female patients. The transition protocol used in this case series should be applicable to the general PAH population, but this is unproven. Right heart catheterizations were performed while the patients were hospitalized during the transition but were not repeated in follow-up. Nonetheless, the
up to 30 months are longer than the 7-month follow-up reported in the deJesus study.22 All patients in our study were still receiving inhaled treprostinil at their last follow-up visit. Although Patient 2 did require a dose increase in inhaled treprostinil, for a brief period, she is currently on a stable dose of nine breaths four times daily. This provides further evidence of sustained clinical benefit on long-term inhaled treprostinil.
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 496–500 499
C. Y. Enderby et al.
Transition to inhaled treprostinil
October 2013. Results of this study should provide additional insight into this transition process and patient outcomes.
patients remained symptomatically stable with concomitant stable or improved non-invasive measures of PAH severity such as BNP and 6MWD. Of note, an ongoing prospective, observational trial sponsored by the Los Angeles Biomedical Research Institute in collaboration with United Therapeutics began in August 2010 with an estimated enrolment of 21 patients.26 Primary outcome measurement is number of adverse events at transition, 4 weeks and 12 weeks. Secondary outcomes include clinical worsening over 12 weeks. Criteria for switching patients in this study are mPAP
