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Acute Vasodilator Testing in
PAH
Olivier Sitbon, MD
Centre des Maladies Vasculaires Pulmonaires,
Service de Pneumologie et Réanimation Respiratoire,
Hôpital Antoine-Béclère, Université
Paris-Sud, Assistance Publique-Hôpitaux de Paris,
Clamart, France
Vasoconstriction of pulmonary arteries is recognized
as an important component of the pathogenesis of pulmonary
arterial hypertension (PAH). Pure vasodilators alleviate
vasoconstriction with little effect on the fibrotic and
proliferative changes that frequently predominate over
vasoconstriction in PAH. Uncontrolled studies have suggested
that long-term administration of calcium-channel blockers
(CCBs) prolongs survival in the rare subset of responsive
patients (representing around 10% of patients referred
to pulmonary vascular centers), compared with unresponsive
patients. Therefore, the question of the overall efficacy
of administering CCBs is still of concern, as well as
the way of safely identifying the patients who may benefit
from long-term oral treatment. Unfortunately, any clinical
or hemodynamic parameter can predict acute and chronic
responses to CCBs in patients with PAH. It is generally
accepted that patients who may benefit from long-term
use of CCBs can be identified by an acute vasodilator
challenge performed during right heart catheterization
in specialized pulmonary vascular units.
The magnitude of acute vasodilator response that predicts
a favorable outcome with long-term CCB therapy remains
poorly defined. Until recently, a reduction of both mean
artery pulmonary pressure (mPAP) and of pulmonary vascular
resistance (PVR) by at least 20% was used as the criterion
for the initiation of oral CCB therapy. A drop in mPAP
by more than 10 mm Hg without decrease in cardiac output
could be the minimum acceptable response. A decrease in
PVR of 50% relative to baseline value and an mPAP lower
than 30 mm Hg could indicate better clinical outcome.
However, these definitions do not discriminate between
patients with a sustained benefit from CCBs (defined as
being in NYHA functional class I or II with near-normal
hemodynamics after at least one year follow-up) and those
whose condition will fail to improve. In our experience,
only 7% of patients referred to a specialized pulmonary
vascular center with idiopathic PAH will have a sustained
benefit from treatment with CCBs. During acute vasodilator
challenge, these rare patients markedly improve their
pulmonary hemodynamics, achieving an mPAP less than 40
mm Hg, and associated with a normal or high cardiac output.
We therefore consider that a positive response to acute
vasodilator challenge is defined by a substantial reduction
in mPAP (decrease exceeding 10 mm Hg to reach an mPAP
lower than 40 mm Hg) with a normal or high cardiac output.
The occurrence of severe life-threatening hemodynamic
compromise during acute vasodilator challenge with CCBs
is an obvious risk, even when conventional doses of CCBs
are used. Therefore, there is a need for a safe, potent,
and short-acting vasodilator having limited side effects
during acute testing to accurately identify patients who
may benefit from long-term CCB therapy. In the therapeutic
approach of patients with PAH, numerous vasodilator agents
have been used on a short-term basis to evaluate the capacity
of the pulmonary vascular bed to vasodilate. Among them,
prostacyclin, adenosine, and nitric oxide are the most
widely used drugs. Recent data suggest that inhaled iloprost
may be more effective than nitric oxide to decrease PVR.
However, no information is available regarding acute response
to iloprost as a predicting factor to long-term efficacy
of CCB therapy.
With emerging potent oral and inhaled drugs combining
vasodilatory and antiproliferative properties, the issue
of invasive testing for pulmonary vasoreactivity in selecting
treatment may lose its importance. It should be easy to
prescribe oral therapies such as an endothelin receptor
antagonist (bosentan), a prostacyclin analogue (beraprost),
or a phosphodiesterase inhibitor (sildenafil) to all PAH
patients whatever their functional class (except for class
IV) and acute pulmonary vasoreactivity. Although it is
reasonable to think that patients who respond to intravenous
prostacyclin, adenosine, or inhaled nitric oxide are able
to respond to such oral therapies, no study has evaluated
the acute and chronic response to these drugs in vasoreactive
patients. In addition, the cost of these therapies could
be a limitation to their prescription in some PAH patients.
In conclusion, the drugs of choice for testing vasoreactivity
are short-acting agents, intravenous prostacyclin, adenosine,
or inhaled nitric oxide. Long-term treatment with oral
CCBs will be considered only in responders to one of these
three drugs.
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