OVERVIEW
OF PULMONARY ARTERIAL HYPERTENSION (PAH) TREATMENT OPTIONS
Introduction
General medical therapy for pulmonary arterial hypertension
(PAH) includes oral anticoagulants, oxygen, diuretics, and
digoxin. In addition to vasodilator therapies (such as calcium
channel blockers), agents are available that may possess anti-proliferative
activity, including prostaglandins and, more recently, endothelin
receptor antagonists (ERAs). Tracleer™ 
(bosentan), the first representative of this new class (ERA),
is the only oral therapy licensed for the treatment of pulmonary
arterial hypertension (PAH) to improve exercise capacity and
symptoms in patients with grade III WHO Functional Class.
In
patients with pulmonary hypertension with symptomatic progressive
disease who, despite optimal medical treatment, remain severely
ill (modified NYHA functional classes III or IV), a lung transplantation
may be indicated.
Click here to access the EU Summary of
Product Characteristics and UK Prescribing Information
Children
and PAH
The diagnostic work up of a child with PAH is similar to that
of an adult, although other more common causes of pulmonary
hypertension in childhood must be excluded. These include
congenital heart disease, and persistent pulmonary hypertension
of the newborn which has not regressed satisfactorily. Children
can be extremely ill at presentation since they may have deteriorated
swiftly. The management of these patients should be undertaken
in conjunction with an expert.
Treatment
of Pulmonary Arterial Hypertension [Adapted from Hoeper et
al., 2002]
General
Medical Therapy Overview
Oral
anticoagulants
PAH is associated with pulmonary arterial thrombosis and a
hypercoaguable state. Anticoagulation may reduce thrombosis
and slow progression of some forms of the disease. Warfarin
has been shown to be of benefit in primary pulmonary hypertension
(PPH) but there are no published data of its use in other
forms of PAH. However, consideration should be given to contra-indications
to warfarin therapy, such as gastrointestinal haemorrhage,
significant haemoptysis or liver disease with coagulation
abnormalities.
Oxygen
Hypoxaemia causes pulmonary vasoconstriction and so may worsen
pulmonary hypertension. Continuous oxygen has shown symptomatic
improvement in children with PAH. Long-term oxygen therapy,
in particular at night when arterial oxygen saturation falls
significantly, may be helpful, albeit inconvenient.
Diuretics, Digoxin
Right heart failure which manifests at a late state of PAH
gives rise to fluid retention which is improved by diuretics.
Digoxin has been shown to improve cardiac output acutely in
PPH. Its efficacy when administered chronically in this condition
is unknown. Both types of agents therefore can only be regarded
as supportive therapy.
Vasodilator therapy
Calcium
channel blockers
Since vasoconstriction plays an important role in the pathogenesis
of pulmonary hypertension, vasodilators like calcium channel
blockers may be of benefit to some patients. They have been
shown to improve symptoms and haemodynamics in PAH. Patients
who appear responsive to acute vasoreactivity tests (a reduction
in mean pulmonary artery pressure of at least 10 mm/Hg) may
have a favourable response to treatment with oral calcium
channel blockers. However, it is estimated that these “responders”
represent only about 20 percent of all patients with PPH,
and only 10-15 percent of PAH patients are controlled on calcium
channel blockers in the long-term. The efficacy of calcium
channel blockers has not been demonstrated in a controlled
study.
Calcium
channel blockers may cause systemic hypotension and their
negative inotropic effects may be undesirable when right ventricular
function is already damaged.
Prostaglandins
The use of prostacyclin (epoprostenol), a potent endogenous
vasodilator, as a treatment of PAH is supported by a decreased
level of prostacyclin in the pulmonary arteries of patients
with PAH.
Epoprostenol
Epoprostenol, an agent with a short half-life has to be given
by continuous intravenous infusion. Epoprostenol increases
cardiac output and reduces pulmonary vascular resistance during
long-term therapy. It improves measures of quality of life
and exercise capacity. Continuous intravenous administration
of epoprostenol has improved survival in class III and IV
PPH patients. Since tolerance develops to intravenous prostaglandins
the dose requirement increases over time. Potential complications
may arise from the complex pump system, catheter infections,
which can cause worsening of PAH, and catheter thrombosis.
It may be also associated with vomiting, systemic hypotension,
dizziness, syncope, flushing, and headache.
Prostacyclin analogues
The efficacy of prostacyclin therapy has prompted the development
of various analogues.
Treprostinil
Treprostinil is administered as a continuous subcutaneous
infusion by mini-pump and, in a controlled trial, was shown
to improve exercise capacity and haemodynamics in patients
with Class II-IV PAH. Pain and erythema at the local injection
site can be a significant problem in patients and may prevent
some of them from receiving adequate doses. Treprostinil is
currently approved in the US but not in Europe.
Beraprost
Beraprost is administered orally and has been tested in various
uncontrolled and controlled studies. In studies, beraprost
improved exercise tolerance and haemodynamics in PPH patients
but has to date failed to show a significant benefit in PAH
related to connective tissue diseases. In a controlled study,
exercise tolerance and Borg dyspnoea index also improved.
Beraprost
has a relatively short half-life, requiring frequent dosing
and its side effects, such as headache, flushing, jaw pain
and diarrhoea, could limit the ability of a patient to receive
sufficient doses.
Iloprost
Iloprost, a prostaglandin administered by nebuliser or intravenously,
has also been shown to improve exercise tolerance and pulmonary
haemodynamics. Both methods of administration appear to be
effective, however, the inhalation strategy may offer the
additional benefit of allowing lower doses of the drug to
be used, which might result in fewer systemic side effects.
The short half-life requires frequent inhalations of six to
12 times over 24 hours. Inhalations can take up to 15 mins,
although this is being improved to around 5 mins with newly
available inhalation devices.
Although
the oral and inhaled routes are obviously more convenient
than either s.c. or i.v. administration, the need for frequent
administration is a significant drawback.
Balloon
atrial septostomy
Balloon atrial septostomy is a palliative interventional procedure
which creates a left-to-right interatrial shunt which alleviates
the high pressures to which the right heart is subjected in
severe disease. In selected patients it results in an immediate
fall in right ventricular end diastolic pressure and systemic
oxygen saturation, and is accompanied by an increase in cardiac
output. It may improve survival while the patient is awaiting
lung transplantation. Atrial septostomy is well tolerated
despite the fall in systemic oxygen saturation, but it carries
a high mortality in critically ill patients. Precise indications
are uncertain owing to limited data and there are no randomised
trials. Balloon atrial septostomy has to be performed in experienced
centers.
Endothelin receptor antagonists (ERAs)
ERAs are a new class of agents for the treatment of PAH. They
have an innovative mode of action i.e. antagonism of the deleterious
effects of endothelin-1 (ET-1).
ENDOTHELIN RECEPTOR ANTAGONISM (ERA)
ENDOTHELINSCIENCE.COM
ET-1
is one of the most potent and long-lasting endogenous vasoconstrictors
which also promotes inflammation, induces fibrosis, activates
the secretion of several neurohormones, and stimulates myocardial
hypertrophy.
In
pathological conditions elevated levels of ET-1 can mediate
deleterious effects via two receptors – ETA and
ETB. ETA receptors are found in vascular
smooth muscle cells and cardiomyocytes, ETB receptors
in smooth muscle cells, endothelial cells and fibroblasts.
The elevation of both plasma and tissue ET-1 and ET-1 receptor
levels is seen in diseases such as PAH. The extent of the
plasma elevation correlates with disease severity and can
predict subsequent mortality.
Taken
together, these findings point to an important role for ET-1
in the pathophysiology of PAH. This provides the rationale
for the use of endothelin receptor antagonists in therapy.
Tracleer™
(bosentan)
Tracleer is the first of the ERAs to be available and is the
only oral treatment licensed for PAH (taken as a twice-daily
tablet), to improve exercise capacity and symptoms of patients
with grade III WHO Functional Class.
Click here to access the EU Summary of
Product Characteristics and UK Prescribing Information
Tracleer
is a dual endothelin receptor antagonist, with a high affinity
for both types of endothelin receptors (ETA and
ETB) and so blocks the deleterious effects of endothelin
mediated by ETA and ETB in pathological
situations.
Tracleer
improves cardiopulmonary haemodynamics - it reduces pulmonary
vascular resistance and pulmonary arterial pressure, without
significant systemic hypotensive effects. Cardiac output increases,
and exercise capacity is improved, alleviating symptoms.
In
clinical studies, treatment with Tracleer significantly increased
the time to clinical worsening and improved WHO functional
class, it may also have potential in delaying disease
progression. In the studies, time to clinical worsening was
defined as the combined endpoint of death, lung transplantation,
hospitalisation for PAH, worsening PAH or initiation of intravenous
therapy. These benefits may lead to a substantial improvement
in patient quality of life.
Since
Tracleer treatment is associated with an increased incidence
of reversible, dose-related elevations in liver aminotransferases,
liver function monitoring is essential prior to initiation
of treatment and monthly thereafter. In addition, liver aminotransferase
levels must be measured two weeks after any dose increase.
Tracleer
therapy has been associated with a modest, dose-dependent
decrease in haemoglobin concentrations, occurring within the
first weeks of therapy. It is recommended that haemoglobin
concentrations be recorded prior to initiation of Tracleer
therapy, followed by monthly monitoring during the first four
months of treatment, then quarterly thereafter.
Women
with child bearing potential with PAH should not become pregnant
and therefore should use reliable contraception. Furthermore,
since Tracleer has a teratogenic potential, pregnancy should
not occur during treatment. Therapy with Tracleer should not
be initiated in women of child-bearing potential unless a
pre-treatment pregnancy test is negative. Since oestrogens
and progestogens are partially metabolised by cytochrome P450,
there is a possibility of failure of contraception when Tracleer
is co-administered. Therefore, women of childbearing potential
must use an additional or an alternative reliable method of
contraception when taking Tracleer. Monthly pregnancy tests
during treatment with Tracleer are recommended.
Since
it is not known whether Tracleer is excreted into human milk,
nursing women taking Tracleer should be advised to discontinue
breast-feeding.
The
above information is based on the European Union Summary of
Product Characteristics. For full details see the SPC.
References
-
Gibbs
JSR et al. Recommendations on the management
of pulmonary hypertension in clinical practice. British
Cardiac Society Guidelines and Medical Practice Committee.
Heart (Sept 2001);86(1):i1-i13.
-
Rich
S (Ed). Primary pulmonary hypertension: Executive summary
from the WHO symposium, Evian, France 6-10 Sept 1998
-
Hoeper
et al. New treatments for pulmonary arterial
hypertension. Am J Respir Crit Care Med (2002)165:1209-1216
-
Archer
S, Rich S. Primary pulmonary hypertension: a vascular
biology and translational research 'WORK IN progress'.
Circulation (2000);102 (22):2781-91
-
Coghlan
JG et al. Eur Heart J (1999):95(8)
-
Packer
M. Is it ethical to administer vasodilator drugs to patients
with primary pulmonary hypertension? Chest (1989);95(6):1173-5
-
Barst
R.J. et al., N. Engl. J. Med. (1996) 334:296-302
-
Simonneau
et al.Am J Respir Crit Care Med (2002);165:800-04
-
Nagaya
et al. J Am Coll Cardiol (1999);34:1188-92
-
Galiè
N et al. Effects of beraprost sodium, an oral
prostacyclin analogue, in patients with pulmonary arterial
hypertension: A randomised, double-blind, placebo-controlled
trial. J Am Coll Cardiol (2002) 39(9);1496-502
-
Hoeper
MM et al. N Engl J Med (2000);342:1866-70
-
Olschewski
et al. N Engl J Med 2002;347:322-9
-
Zouki
et al. Br J Pharmacol (1999);127:969-79
-
Xu
et al. J Invest Dermatol (2001);116:417-25
-
Yoshida
et al. Hypertension 1992;20:292-97
-
Liu
et al. Clin Sci (Lond) (1996); 90(2):91-96
-
Love
MP et al. Circulation (1996);94:2131-37
-
Galiè
N, Grigioni F, Bacchi-Reggiani K, Ussia GP, Parlangeli
R, Catanzariti P, et al. Relation of endothelin-1
to survival in patients with primary pulmonary hypertension.
Eur J Clin Invest (1996);26(1):273
-
Pousset
F et al. Eur Heart J (1997);18:254-58
-
Giaid
A, Yanagisawa M, Langleben D et al. Expression
of endothelin-1 in the lungs of patients with pulmonary
hypertension. N Engl J Med (1993) 328:1732-1739
-
Saleh
D, Furukawa K, Tsao MS, Maghazachi A, Corrin B, Yanagisawa
M, et al. Elevated expression of endothelin-1
and endothelin-converting enzyme-1 in idiopathic pulmonary
fibrosis: possible involvement of proinflammatory cytokines.
Am J Respir Cell Mol Biol (1997);16:187-193
-
Ishikawa
S, Miyauchi T, Ueno H, et al. Influence of pulmonary
blood pressure and flow on endothelin-1 production in
humans. J Cardiovasc Pharmacol (1995); 26:429-433
-
Chen
SJ et al. J Appl Physiol (1995) 79:2122-31
-
Channick
RN, Simonneau G, Sitbon O et al. Effects of the
dual endothelin-receptor antagonist bosentan in patients
with pulmonary hypertension: a randomized placebo controlled
study. Lancet (2001)358:1119-1123
-
Rubin
LJ, Badesch DB, Barst RJ et al. Bosentan therapy
for pulmonary arterial hypertension. N Engl J Med
(2002)346:896-903.
|
