Article
"Development of the European Network in Orphan Cardiovascular Diseases"
„Rozszerzenie Europejskiej Sieci Współpracy ds Sierocych Chorób Kardiologicznych”
Title: Treprostinil use in the treatment of
pulmonary arterial hypertension.
Author: Jakub Stępniewski
Affiliation: Department of Cardiac and Vascular Diseases, John Paul II Hospital, Krakow,
Poland
Background
Pulmonary arterial hypertension (PAH), defined as an elevation of mean pulmonary arterial
pressure ≥ 25mmHg is a chronic diseases impeding every-day activity of affected people and
inevitably leads to premature death. Therefore, management of PAH remains a great
challenge for many caregivers.
Discussion
As a synthetic PGI2 derivative, treprostinil shows biological effects similar to epoprostenol.
[1,2] However, in contrast to epoprostenol, treprostinil sodium is chemically and
metabolically more stable in ambient temperature and neutral pH presenting longer duration
of action with elimination half-life time of approximately 4 hours. [3] These features made
treprostinil suitable for subcutaneous (s.c.) as well as i.v. use. Studies on pharmacokinetics of
s.c. treprostinil confirmed its bioavailability after s.c. infusion, additionally showing that
treprostinil plasma concentration linearly corresponds with dosing rates and reaches its steady
state after about 10 hours. [4]
Before FDA first approved treprostinil for the s.c. treatment of PAH in 2002, the efficacy of
treprostinil s.c. was evaluated in a large randomized, multicenter clinical trial performed on a
group of 470 patients with PAH of different etiologies. [5] 12- week double- blind, placebocontrolled study reported that s.c. treprostinil improves clinical state, exercise capacity and
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: rarediseases@szpitaljp2.krakow.pl
www.crcd.eu
the quality of life of treated patients as well as hemodynamic parameters assessed by RHC. 6minute walk distance (6MWD) increased importantly comparing to placebo group where it
remained unchanged. The extent of improvement was greater in patients in more advanced
stages of PAH (higher WHO FC) at baseline and was dependent on applied dose. Patients
who achieved treprostinil dosing of more than 13.8 ng/kg/min had significantly greater
change in 6MWD in comparison to those receiving smaller doses.
Persistence of aforementioned improvements was observed in several subsequent long-term
trials. In one study 860 PAH patients were followed for up to 4 years in order to state that s.c.
treprostinil therapy was related with a survival rate of 88% at 1 year and 70% at 4 years in
comparison to predicted survival of 69% and 38% respectively. [6] Adverse events were the
reason for interruption of the study for 23% of patients and additional 11% of them were
converted for alternative treatment.
Another retrosepctive study, conducted in three European university hospitals indicated
efficacy of s.c. treprostinil in terms of improvement in 6MWD and clinical state in 99 PAH
and 23 inoperable CTEPH patients. [7] The assessed event- free survival rates at 1 and 3 years
were 83,2% and 69%, respectively, with corresponding overall survival of 88,6% and 70,6%,
respectively.
Recently published data from a prospective registry of 111 PAH patients treated with s.c.
treprostinil confirmed the previously produced reports. [8] 1 year overall survival rate was
84%. After 5 and 9 years the survival was 53% and 33%, respectively. Discontinuation was
observed in 12% of patients due to occurrence side effects mainly drug infusion site reaction
or pain.
Results provided by these studies suggest that the use of continuous s.c. treprostinil in
treatment of PAH is a genuine alternative for i.v. epoprostenol.
In order to verify the feasibility of treprostinil i.v. mode of delivery a randomized clinical trial
with healthy volunteers was designed. [9] Pharmacokinetic assessment of continuous i.v.
infusion was performed and compared with s.c. infusion showing that both routs are
bioequivalent. Additionally, it has been shown, that transitioning from i.v. epoprostenol to i.v.
treprostinil is safe and efficacious in adults and children. [10,11,12] The switching can be
performed either on a rapid (24-48hours) or slow (up to 14 days) fashion. [13] Interestingly,
John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: rarediseases@szpitaljp2.krakow.pl
www.crcd.eu
while the dosing of treprostinil in s.c. infusion is about the same as in i.v. , it has to be at least
two times higher than i.v epoprostenol dose, in order to maintain the clinical benefit. [10,13,
14]
Following this and several consecutive studies on efficacy of i.v. treprostinil the FDA
approved treprostinil to intravenous application as a therapy for PAH in 2004. One of these
trials, an open-label, uncontrolled study demonstrated the positive role of i.v. treprostinil in
amelioration of 6MWD, hemodynamics and dyspnea indices in 16 patients followed for 12
weeks. [15] These observations were confirmed in a randomized, placebo-controlled trial
performed on a group of 44 PAH patients residing the Indian subcontinent. [16]
Correspondingly, an improvement of exercise capacity and clinical status, as well as a
positive trend in improvement of survival in treprostinil group was noted. However, data on
long-term survival analysis of i.v. treprostinil are limited to date.
Conclusion
Treprostinil remain an optional therapy for PAH patients. Their efficacy have been proven in
numerous clinical trials and meta-analyses and as a consequence prostacyclines are
recommended by ESC and ACCF/AHA authorities for the treatment of PAH.
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John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: rarediseases@szpitaljp2.krakow.pl
www.crcd.eu
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John Paul II Hospital in Kraków
Jagiellonian University, Institute of Cardiology
80 Prądnicka Str., 31-202 Kraków;
tel. +48 (12) 614 33 99; 614 34 88; fax. +48 (12) 614 34 88
e-mail: rarediseases@szpitaljp2.krakow.pl
www.crcd.eu