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Report From the Task Force on
Medical Treatments
Nazzareno Galiè, MD, and Alessandra Manes,
MD
Institute of Cardiology, University of Bologna
Bologna, Italy
The recent clinical trials with novel compounds have
produced a tremendous increase of both knowledge and therapeutic
options in patients with pulmonary arterial hypertension
(PAH). The analysis of placebo-treated groups in the various
trials has allowed a better understanding of the natural
history of PAH on conventional treatment. In fact, signs
of functional and hemodynamic deterioration are detectable
as early as after 3 months in previously stable patients.
The new trials have similar designs, duration, and end
points but relevant differences including the baseline
NYHA functional class and the etiology profiles need to
be taken into account in the comparative evaluation of
these studies. Each new compound presents side effects
that are unpredictable in the individual patient and require
an appropriate attention upon treatment initiation and
maintenance. The lack of effect on mortality can be explained
by the study protocols that were not designed for assessing
this end point and by the overall low mortality of the
study populations as compared with the historical controls.
Extension, open label studies will help us to understand
whether the favorable effects and safety profiles observed
in the randomized phases are maintained over the long
term. Unfortunately, in these cases, the effects on mortality
can be assessed only by comparison with historical controls.
The discussion in the Task Force on Medical Treatments
of the 3rd WSPAH has been focused on the attempt to derive
an evidence-based treatment strategy that includes all
available treatments already approved or tested. The treatment
strategy is targeted to patients in NYHA functional class
III and IV, which is the patient population predominantly
enrolled in clinical trials. For NYHA functional class
I and II patients the most appropriate strategy is yet
to be determined.
The traditional approach to treat patients with oral
anticoagulant drugs and diuretics if needed has been confirmed
even if controlled studies are lacking. The vasoreactivity
test is also mandatory to identify the minority of patients
with a favorable acute response (approximately 20%). In
this group, a chronic treatment with high doses of Ca++-channel
blockers is justified but clinical, functional, and hemodynamic
improvements need to be confirmed after 3 to 6 months
with formal noninvasive and invasive investigations. In
patient nonresponders to acute vasoreactivity tests or
responders with no favorable effect of chronic Ca++-channel
blocker treatment who are in NYHA functional class III
treatment with an endothelin receptor antagonist (ERA)
or with a prostanoid is indicated. Up to now the only
commercially available and approved ERA is the oral dual
antagonist bosentan that has been successfully tested
in two controlled clinical trials. The ETA selective ERA
sitaxentan has been tested in an uncontrolled and a controlled
trial and a second study is ongoing, while the ETA selective
ERA ambrisentan has been tested in an uncontrolled trial
and controlled studies should be implemented soon. Among
prostanoids, treprostinil, administered subcutaneously
has been approved in the USA; it was tested in two controlled
clinical trials and only in one was the primary end point
fulfilled. Iloprost, administered by aerosol, has been
approved in Europe, and it has been tested successfully
in one controlled trial. Beraprost is administered orally
and is approved in Japan; it was tested in two controlled
clinical trials and only in one was the primary end point
fulfilled. The first class of drug and the specific compound
to be initiated are related to different factors including
the approval state, the preferred mode of administration,
the side effect profile, and the specific experience of
the centers. The orally active phosphodiesterase V inhibitor
sildenafil has not yet been approved for the treatment
of PAH patients even though multiple uncontrolled favorable
experiences have been published. The role of this drug
can be better understood after the evaluation of the controlled
clinical study that is currently ongoing. In patients
with NYHA functional class III the continuous intravenous
administration of epoprostenol should be considered (two
controlled clinical trials with favorable results) because
the best effects on survival are observed in this functional
class.
Continuous intravenous administration of epoprostenol
is the treatment of choice in patients in NYHA functional
class IV, and it is approved in the United States and
in Europe. In these cases also bosentan and treprostinil
have an official approval by the FDA but given the small
number of patients included in the clinical trials the
experts consider these treatments as a second choice.
Iloprost administered intravenously is approved in New
Zealand, even though no controlled trials are available.
Continuous intravenous administration of epoprostenol
may be indicated also in NYHA class III patients who have
no favorable response with ERAs or to other prostanoids.
Combination therapy (eg, ERA plus prostanoids) has to
be considered in any case of no improvement or deterioration
with the first treatment even if data on this specific
strategy are few and uncontrolled. Appropriate protocols
for timing and dosing to limit possible side effects of
the combination have still to be implemented.
In case of failure and/or unavailability of medical treatments,
balloon atrial septostomy and/or lung transplantation
are indicated. These procedures should be performed in
experienced centers.
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