|
 Richard
N. Channick, MD
Associate Professor of
Medicine
Pulmonary and Critical Care Division
University of California - San Diego Medical Center
San Diego, California
The past several years have seen dramatic changes in
the therapeutic options and outlook for patients with
pulmonary arterial hypertension (PAH). Increasing experience
with existing therapies, development of new therapies,
and expanding knowledge of how to follow patients undergoing
therapy have ushered in great excitement for patients
and healthcare professionals alike.
This article provides an overview of new therapeutic
strategies in PAH, discussing where current treatments
fit in and what applications of current therapy or new
therapies are on the horizon. A standard approach to following
patients during therapy and making decisions regarding
changes in management is also proposed.
CURRENT THERAPIES
Calcium Channel Antagonists
This class of vasodilating drugs has been utilized in
the treatment of PAH for many years. Medications such
as amlodipine, nifedipine, and diltiazem are readily available
and relatively inexpensive. Although there has never been
a randomized trial of these agents in PAH, early reports
suggested that a subgroup of patients who were acutely
vasoreactive benefited from long-term calcium channel
antagonist therapy.1 Recent
data, however, suggest that only a very small percentage
of patients fall into this group. Sitbon, et al., in a
recent retrospective analysis of more than 500 patients
found that 12 percent of patients were acutely vasoreactive
and thus were given calcium channel blockers.2
Of this group, only one-half were felt to have achieved
a long-term benefit from these agents, with improved functional
status and no need for additional therapy. Analysis of
these data suggested fall in PAP and PVR toward normal
(mean PAP <37 mm Hg, PVR <8 Wood units) during the
acute vasodilator test predicted who would be in this
"favorable" group.
Given that only about five percent of all PAH patients
appear to benefit from calcium channel blockers and that
these agents can have substantial adverse effects, including
symptomatic leg edema and hypotension, empiric therapy
with calcium channel blockers is strongly discouraged.
Bosentan
Bosentan, an endothelin receptor antagonist and the only
approved oral medication in the United State, has quickly
arrived as a mainstay of therapy for PAH. The drug is
currently approved for patients with WHO functional class
3 or 4 status, a result of two randomized, placebo-controlled
trials showing significant efficacy in improving 6-minute
walk distance.3, 4
Additionally, improvement in pulmonary hemodynamics and
functional status and prevention of clinical worsening
were noted. The improvement in hemodynamic and functional
status appears to be sustained, as demonstrated in a recent
report by Sitbon et al.5 in
which these parameters persisted at one-year follow-up.
Additional long-term data have clarified and strengthened
the role of bosentan as first-line therapy in most patients
with PAH. Analysis of 169 patients enrolled in the pivotal
bosentan trials who continued bosentan therapy demonstrated
a three-year Kaplan-Meier estimate of survival of 86 percent,
compared with a predicted survival of 48 percent based
on an NIH equation using baseline hemodynamic parameters.6
In this cohort, at one and two years, the percentage of
patients being maintained on bosentan alone was 85 percent
and 70 percent, respectively. The remainder of the patients
had died, had been switched to another therapy, or had
had additional PAH therapy added. It should be noted that
82 percent of this cohort was in functional class 3 and
nine percent in class 4 at initiation of bosentan therapy.
These data suggest that beginning oral bosentan as sole
first-line therapy is associated with excellent long-term
outcome even if additional or alternative therapy is sometimes
necessary.
Data are now emerging on bosentan as part of a combination
regiment with epoprostenol. One placebo-controlled study,
BREATHE-2, demonstrated that in patients beginning epoprostenol
therapy, concomitant oral bosentan was well tolerated,
and there was a trend toward greater improvement in total
pulmonary resistance with the combination compared with
epoprostenol alone (-36% vs -22%)/7
Beneficial effects of bosentan added to inhaled iloprost
have also been demonstrated. In one study, patients receiving
long-term inhaled iloprost demonstrated further improvement
in VO2max when bosentan was added.8
Clearly, further data are needed before firm recommendations
can be made regarding combination regiments for treating
PAH.
Another new area of study is the potential of transitioning
patients from parenteral to oral therapy. In one recently
published study, four patients who had been receiving
long-term epoprostenol maintenance therapy and who had
achieved near-normal pulmonary hemodynamics were weaned
from epoprostenol to oral bosentan (as well as calcium
channel blockers in three and sildenafil in one).9
Follow-up of at least a year demonstrator continued excellent
functional and hemodynamic status without epoprostenol.
A similar study, recently presented at the American Thoracic
Society's annual conference, found that 14 of 59 patients
were able to be weaned from parenteral prostenoid therapy
after the addition of bosentan.10
Given the potential serious risk of weaning epoprostenol,
however, additional follow-up and experience are necessary
before routine "transitioning" can be recommended.
Finally, data are emerging or being generated regarding
other potential indications for bosentan, such as use
in functional class 1 or 2 patients and in patients with
fibrotic lung disease, HIV, or congenital heart disease.
Epoprostenol
Epoprostenol as continuous intravenous therapy has been
available in the United States since 1995. The beneficial
effects this drug has had on the course of patients with
even severe "end-stage" PAH cannot be overstated.
Reports over the years have confirmed both the short-
and long-term efficacy of epoprostenol.11-14
Three-year survival with epoprostnol has been reported
to be 63 percent by both Sitbon et al.13
and McLaughlin et al.14 Desired
benefits from other therapies should use epoprostenol
as a benchmark.
As experience has been gained, some new approaches to
using epoprostenol have developed. For one, the dosing
level of epoprostenol has decreased significantly, partially
based on findings that some patients can have worsening
symptoms of fatigue due to overdosing of the drug causing
a high cardiac output state.15
Also the myriad of side effects related to epoprostenol
are gaining greater appreciation. Thrombocytopenia, painful
neuropathy of the lower extremities, and significant weight
loss with ascites are all now recognized effects of long-term
treatment with epoprostenol.
In addition, contrary to what was previously thought,
patients often do not develop tolerance to epoprostenol
and, in fact, therapy is sometimes maintained with a constant
dose for years. Although there is no "standard"
dosing of epoprostenol, current experience would suggest
that most patients are receiving 30 to 40 ng/kg/min after
one year of therapy. The caveat of "give enough but
not too much" applies well to epoprostenol therapy.
There are also new data to suggest that the benefit epoprostenol
will have is generally clear by the end of one year of
therapy. Sitbon et al demonstrated that subsequent survival
in patients treated with epoprostenol was correlated with
improvement in total pulmonary resistance of >30 percent
and functional status to class 2 after three months of
epoprostenol therapy.13 This
concept is an important one; the status of a patient prior
to initiation of therapy may be less important than the
response to that therapy. Despite the "downside," epoprostenol
is felt to be first-line therapy for the most severely
ill PAH patients. Although experts differ on who these
patients are, it is generally agreed that a patient with
late class 4 status who is short of breath at rest, who
has syncope, and who has right ventricular failure on
catheterization (high right atrial pressure, low cardiac
output) should receive epoprostenol therapy as soon as
possible.
Treprostinil
The prostacyclin analogue treprostinil is approved as
a continuous subcutaneous infusion for functional class
2, 3, and 4 patients with PAH based on efficacy demonstrated
in a randomized controlled trial of 470 patients demonstrating
a 16-meter 6-minute walk treatment effect.16
Further analysis of these data suggested that most of
the benefit on 6-minute walk distance occurs at higher
doses of the drug (over 12 ng/kg/min). Recently presented
data reported a sustained benefit of treprostinil.17
The potential advantages of subcutaneous treprostinil
over intravenous epoprostenol include avoidance of an
indwelling intravenous catheter, a more portable pump,
no need for reconstitution of the medication, and stability
at room temperature.
The major challenge to treprostinil has been the side
effect of infusion site pain. This symptom has led to
a high rate of discontinuation of therapy, need for opiod
analgesia, and reduced quality of life for some patients.
No clearly effective remedy for this problem has emerged.
Thus, where treprostinil fits in the treatment scheme
is not clear. Given the longer half-life of treprostinil
compared with epoprostenol, the possibility of its use
as an effective intravenous or inhaled therapy is being
examined.
Iloprost
Inhaled iloprost, delivered via a hand-held
nebulizer, has recently been approved in Europe, based
on positive results from a large randomized, placebo-controlled
trial.18 In this 12-week
study of 203 patients, 17 percent of patients receiving
inhaled iloprost met the combined clinical end point of
improvement by one functional class and increase in post-inhalation
6-minute walk distance of at least 10 percent compared
with only 5 percent of placebo patients meeting this end
point.
The drug, in addition, appears to have fewer systemic
effects than intravenous or subcutaneous prostacyclin
preparations. One challenge of this therapy is the need
for six to nine treatments daily, potentially limiting
patient acceptability. Early reports suggest that addition
of oral sildenafil may prolong iloprost's hemodynamic
benefits,19 but further study
is needed. Nevertheless, inhaled iloprost offers the possibility
of an effective inhaled prostacyclin and plans to study
the medication in the United States are underway.
On the basis of existing data and level of evidence,
a treatment algorithm was recently developed at the Third
World Symposium on Pulmonary Hypertension held in Venice,
Italy, the results of which were published in the previous
edition of Advances in Pulmonary Hypertension.
Lung Transplantation
Lung or hear-lung transplantations for treatment
of PAH have been performed since about 1980. The role
of transplantation for this disease, however, is changing.
With the advent of effective medical therapies, it appears
that significantly fewer transplantations are being performed
for PAH. Patients doing "well" on medical therapy
are often placed on the inactive list (status 7). In addition,
recent data confirm that overall 5-year survival after
lung transplantation is 50 to 60 percent, not a clear
advantage over medical therapies. Nevertheless, in patients
in whom medical therapies fail, lung transplantation may
be the only option. Most experts take the approach of
listing patients when they begin parenteral prostenoid
therapy and potentially placing patients on hold if significant
improvement occurs with the medication.
More recently, proposals for prioritizing lung transplant
recipients have been set forth with the goal of transplanting
the "sickest" patients first. As of this writing,
no priority protocol is in place for PAH patients.
NEW APPROACHES TO FOLLOWING
PATIENTS DURING THERAPY
Once one of the above medical therapies is initiated,
determining if that therapy is benefiting the patient
is critical in assessing if that therapy is benefiting
the patient is critical in assessing the need for additional
or alternative therapy, the need for lung transplantation,
or even the need for referral to a pulmonary hypertension
center. What are the most important measures of improvement?
Data are now available that suggest both invasive and
noninvasive markers of prognosis and response to treatment.
As mentioned above, for instance, a fall in total pulmonary
resistance of >30% after three months of epoprostenol
therapy has been shown to predict subsequent five-year
survival.13 It follows then,
that lack of significant fall in total pulmonary resistance
should trigger additional therapy, such as lung transplantation.
noninvasively, a recent report has shown that beta natriuretic
peptide (bNP) levels, which have been shown to be elevated
in PAH patients at baseline, also predict survival, with
levels greater than or equal to 150 picograms/milliliter
being associated with increased mortality.20
Finally, in a recent study, troponin levels correlated
with survival in PAH patients.21
Although exactly how to use these various markers in
making treatment decisions is still evolving, one reasonable
approach would be as follows for a functional class 3
PAH patient:
- Start bosentan therapy.
- Check functional class, exercise capacity, and bNP
levels after three months of therapy. Consider repeat
right heart catheterization to confirm at least 30 percent
improvement in total pulmonary resistance. If favorable
parameters are not met, consider additional therapy
(epoprostenol, treprostinil, iloprost) or referral to
a pulmonary hypertension center for additional options,
including enrollment in a clinical trial.
- Repeat right heart catheterization 6 to 12 months
after therapy to ensure fall in total pulmonary resistance;
if not, consider referral as above.
- In patients given epoprostenol, refer for lung transplantation.
- After one year of epoprostenol therapy, if patient
is in functional class 2 and 6-minute walk distance
is >370 meters, change to inactive status on transplantation
list.
This algorithm is only one potential approach. However,
the concept of beginning with approved oral therapy and
escalating therapy based on defined outcome measures is
an important new advance in treating PAH.
EXPERIMENTAL APPROACHES
The above-mentioned treatments are available in Europe
or the United States and can be characterized as representing
standard therapy. What new treatments are on the horizon?
The following therapies are currently under investigation.
Table
- Summary of Current and Experimental Therapies.
Approved
Oral bosentan (Tracleer®)
Intravenous epoprostenol (Flolan®)
Subcutaneous treprostinil (Remodulin®, approved
in united States and Canada)
Inhaled iloprost (Ventavis®, approved in Europe
only)
Lung transplantation
Experimental
Sildenafil
Sitaxsentan
Ambrisentan
Statins
I-arginine
Vasoactive intestinal peptide
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Sildenafil
Sildenafil, a PDE5 inhibitor, has been suggested as an effective
therapy for PAH. Its mechanism of action is likely enhancement
of endogenous nitric oxide effects via inhibition of cGMP
breakdown. Uncontrolled reports suggest that oral sildenafil
improves functional status, pulmonary hemodynamics, or 6-minute
walk distance.22, 23
However, no convincing long-term benefit of sildenafil has
yet been demonstrated. A large, multi-center, placebo-controlled
trial of sildenafil is nearing completion. Until the results
from this trial are available, sildenafil must be considered
experimental therapy and not used in place of the above-mentioned
approved therapies.
Selective ET-A Antagonists
Two oral endothelin-A receptor antagonists, sitaxsentan
and ambrisentan, are currently under investigation. The
rationale behind selective endothelin-A receptor antagonism
is that the B receptor may serve beneficial roles in increasing
endothelin clearance and possible pulmonary vasodilation.
Whether these benefits are significant in patients with
PAH is not known.
Sitaxsentan was shown in a 12-week trial of 178 patients
to lead to an improvement in 6-minute walk distance of
34 meters.24 Although the
primary end point, improvement in VO2max, was not met,
a second and pivotal trial of this agent is now underway.
Investigators studying ambrisentan recently completed
a phase 2 trial and will soon begin a phase 3 study.
Other agents for which early reports are emerging and
which may represent future therapies include statins,
I-arginine, and vasoactive intestinal peptide. The Table
summarizes current and experimental therapies.
Conclusions
A wealth of new data and experience have emerged on the
treatment of pulmonary arterial hypertension. Randomized
placebo-controlled trials have led to approval of new
therapies with significant benefit to patients in terms
of symptoms, functional capacity, and survival. Refinement
of which therapy should be provided to which patient,
when therapy should be changed or supplemented, what the
role of combination therapies should be, and which experimental
therapies work best, awaits further experience and data.
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