To the Editor,
Pulmonary arterial hypertension (PAH) is a severe disease characterized by pulmonary
vascular remodeling, leading to an increase in pulmonary vascular resistance (PVR)
and causing exertional dyspnea, right heart failure, and eventually death. Prostacyclin
analogs and prostacyclin receptor agonists (epoprostenol, treprostinil, iloprost,
selexipag), endothelin receptor antagonists (bosentan, ambrisentan, macitentan), and
phosphodiesterase type-5 inhibitors (sildenafil, tadalafil) are the main drugs to
treat PAH.
1
Besides improving symptoms, exercise capacity, and hemodynamics,
2
intravenous epoprostenol is the only drug shown to reduce mortality in PAH.
1
However, it is administered by continuous intravenous infusion via a long-term central
venous catheter and is therefore cumbersome, expensive, and prone to mechanical and
infectious complications. In France, an activity-based financing system, known as
T2A (tarification à l’activité), is implemented for the funding of public and private
hospitals, based on diagnosis-related categories in which the cost of the drugs is
included.
3
However, in order to be covered, expensive drugs such as epoprostenol need to be prescribed
with respect to the clinical guidelines. We report herein three cases of patients
with PAH from an expert center, in whom epoprostenol treatment was stopped for non-respiratory
purposes. These cases highlight the complexity of a holistic approach in the care
of these patients.
The first patient (Table 1) was a 70-year-old woman diagnosed with anorexigen-associated
PAH. She received sildenafil and inhaled iloprost, switched one year later to intravenous
epoprostenol due to clinical and hemodynamic deterioration. Five years later, she
developed cognitive impairment and depression leading to less hygienic care of the
central venous catheter and subsequent infections. Epoprostenol had to be permanently
discontinued to avoid further complications and because of the additional workload
devolved upon psychiatry nurses who were not qualified for epoprostenol manipulation.
The patient was therefore transitioned to ambrisentan. The patient experienced progressive
clinical worsening of PAH and died three years later of sudden cardiac arrest.
Table 1.
Characteristics of patients with PAH in whom epoprostenol was discontinued.
Patient 1
Patient 2
Patient 3
Age at diagnosis (years)
69
54
54
Associated condition
Anorexigen
Congenital heart disease
Systemic sclerosis
Previous PAH treatment (duration in months)
Sildenafil (15) Inhaled iloprost (12)
Bosentan (6) Tadalafil (34) Treprostinil not tolerated
Ambrisentan (30) Tadalafil (5) Inhaled iloprost (14)
Time from last RHC to epoprostenol discontinuation (months)
23
8
14
Last RHC before epoprostenol discontinuation
mPAP (mmHg)
26
58
48
CI (L/min/m2)
3.6
2.9
2.8
PVR (Wood units)
4.8
10.9
7.5
Epoprostenol dose (ng/kg/min)
30
17
35
Time from initiation to discontinuation (years)
5
5
2
NYHA class before epoprostenol discontinuation
III
III
IV
Survival status
Died after 3 years
Alive after 1 year
Died after 2 days
Cause of death
Right heart failure
N/A
Right heart failure
PH biomarkers (before/after epoprostenol discontinuation)
BNP (ng/L)
123/745
40/150
1009/not done
6MWD (m)
255/230
245/300
120/not done
RVEF (%)
45/38
15/13
45/not done
TAPSE (mm)
22/18
18/14
10/not done
RHC, right heart catheterization; mPAP, mean pulmonary arterial pressure; CI, cardiac
index; PVR, pulmonary vascular resistance; BNP, brain natriuretic peptide; 6MWD, 6-min
walking distance; RVEF, right ventricle ejection fraction as measured by tomographic
scintigraphy; TAPSE, tricuspid annular plane systolic excursion.
The second patient (Table 1) was a 60-year-old woman diagnosed with PAH associated
with congenital heart disease (CHD). Her medical history included a cerebral tumor
at the age of 14 years treated with radiotherapy without histological data. CHD consisted
of a 16-mm ostium secundum atrial defect with bidirectional shunt. The pulmonary flow
over systemic flow (Qp/Qs) was measured at 1.3 suggesting a moderate left-to-right
shunt. The alveolar–arterial gradient in hyperoxia was high (62 kPa) in favor of a
strong right-to-left shunt. Mean pulmonary arterial pressure (mPAP) was measured at
50 mmHg, cardiac index (CI) was at 4 L/min/m2, and PVR was at 6.1 Wood units. After
multidisciplinary discussion and case referral to the National Reference Center for
PAH, closure of the atrial defect was refused. The patient was initially treated with
bosentan and tadalafil then switched to intravenous epoprostenol 3.5 years later because
of worsening dyspnea (NYHA class IV) and hemodynamic severity (CI = 1.6 L/min/m2).
Five years later, she had an ischemic temporal stroke, revealing cerebral cavernomatosis
secondary to cerebral irradiation. The patient had no prior anticoagulant treatment.
Sequelae included aphasia, epilepsy, and transient confusion. Because of the lack
of clinical recovery of the neurological condition, epoprostenol was stopped in order
to facilitate the patient’s admission to a long-term care unit and to avoid any risky
manipulation of the venous catheter. No additional PH treatment was initiated. Six
months later, the patient was alive with no clinically relevant worsening signs of
PAH.
The third case (Table 1) involved a 59-year-old woman with PAH associated with systemic
sclerosis. She had a history of lower-limb amputation secondary to antiphospholipid
syndrome. She was initially treated with ambrisentan, tadalafil, and inhaled iloprost.
Epoprostenol was started two years after diagnosis. Despite this treatment, the patient
had persistent class IV NYHA dyspnea and suffered from several side effects (diarrhea,
headache, and jaw pain) significantly altering her quality of life. The decision to
discontinue epoprostenol and other PAH oral drugs was taken in order to transfer the
patient in a long-term care facility. Unfortunately, she developed fatal acute respiratory
failure two days after epoprostenol withdrawal. In all three patients, the decision
to withdraw epoprostenol was made during an extended meeting with practitioners and
nursing staff. The patients were informed about the purpose of the decision and its
inherent risks.
Social problems affect patients’ health and treatment effectiveness.
4
These three cases underline the complex problem of epoprostenol discontinuation in
patients with an established medical indication for this treatment, in the presence
of independent medical or social situations rendering it difficult to maintain. At
the time of epoprostenol initiation, all three patients had PAH with severe clinical
and hemodynamic features. Obstacles to continuation of epoprostenol appeared several
years later and were all non-PH in nature. Although the use of intravenous epoprostenol
is not well established in PAH associated with CHD, we decided to treat patient 2
with epoprostenol due to the worsening of PAH after the failure of a combination oral
therapy and the intolerance to subcutaneous treprostinil. Several studies have shown
a beneficial effect of intravenous epoprostenol in patients with CHD-PAH without aggravation
of gas exchanges or major side effects.
5,6
The financial aspect of epoprostenol use needs to be considered, especially in long-term
care facilities, where the nurse/resident ratio is generally low, and paramedics unprepared
to manage this drug, which may also prove time-consuming. As the discontinuation of
epoprostenol can sometimes lead to clinical deterioration, the decision may be ethically
challenging for chest physicians. In a recent retrospective study, epoprostenol withdrawal
was done in eight patients with PAH (mainly portopulmonary PAH and PAH associated
with HIV) based on the patient’s request (and not because of major side effects).
7
These patients had persistent improvement of clinical and hemodynamic status (NYHA
class I or II, CI > 2.5 L/min/m2, stable dose of epoprostenol over the last three
months, and lower mPAP and PVR). All patients completed the transition; half of them
experienced mild hemodynamic deterioration without the need to reinitiate epoprostenol.
Two other studies have described transition from epoprostenol to oral agents in nearly
70% of patients with stable PAH.
8,9
However, the cases described in our letter did not share the same severity profile
as they had worsening clinical and/or hemodynamic features of PAH at consecutive evaluations.
After epoprostenol withdrawal, two patients experienced clinical worsening and their
death could be attributed to PAH, although the timeframe was largely variable (2 days
– 3 years). After epoprostenol discontinuation, only one patient was switched to another
PH treatment. However, the remaining two patients had already been treated with endothelin
receptor antagonists and phosphodiesterase type-5 inhibitors.
Patient choice is another essential factor in epoprostenol discontinuation. Our patients
were informed about the possibly life-threatening consequences of epoprostenol discontinuation.
Despite a probably shorter life expectancy, their acceptance was based on the improvement
of their quality of life, with less secondary effects, less hospitalizations for catheter
removal and/or infection, and a higher probability of being accepted in long-term
care facilities. In our center, when patients with similar conditions refuse epoprostenol
withdrawal, the drug is maintained with respect to patient’s choice. Collaboration
with geriatric assessment teams, palliative care teams, and hospital ethics committee
may be useful. A multidisciplinary approach is even more valuable when considering
the changing demographic picture of PAH. Reports from PAH registries have increasingly
shown a rise in the proportion of elderly patients,
10
who have a higher burden of co-morbidities.
11,12
The diagnostic and therapeutical approach in these patients is critical, particularly
when the administration of epoprostenol is considered.
13
A global geriatric assessment is required before the prescription of PAH drugs. The
main therapeutic objective in the elderly is the improvement of symptoms, which depends
on autonomy level and exercise ability. The benefit–risk balance of such treatment
should be clearly discussed with the patients and their family, and help should be
sought from other medical specialties such as cardiogeriatrics. In conclusion, while
epoprostenol discontinuation may be feasible in patients with stable PAH and concomitant
therapy, caution is required in patients with severe PAH because epoprostenol withdrawal
may lead to clinical deterioration and death.