The power and the flow: raising the bars in the treatment of pulmonary arterial hypertension

Rationale: The current goal oriented strategy in patients with pulmonary
arterial hypertension (PAH) is to improve exercise capacity which can be
achieved by decreasing pulmonary vascular resistance (PVR) and subsequently
increasing cardiac output (CO). Despite this load reduction, a substantial
proportion of patients show progressive right ventricular (RV) dysfunction
leading to clinical worsening and death. A possible explanation is that current
therapies show a relatively modest reduction in PVR, leaving mean pulmonary
artery pressure (mPAP) unchanged. As a consequence, RV work, defined as the
product of CO and mPAP increases, contributing to progressive RV dysfunction.

Hypothesis: A goal oriented therapeutic strategy in patients with PAH that is
able to preserve RV function will result in improved clinical outcome. RV
function can only be preserved when early and aggressive combination therapy
not only reduces PVR but also mPAP.

The primary goal of the study is to assess whether a goal oriented strategy to
preserve/improve right ventricular function by application of upfront
combination therapy will improve clinical outcome.


Study questions:
1. Will a goal oriented strategy to preserve/improve RV function, measured by
right ventricular ejection fraction (RVEF) be effective?

2. Does early and aggressive combination therapy result in improved RV function
and survival during long term follow-up?

3. Does a strategy to preserve RVEF also translate into improvements of other
clinically meaningful parameters?

4. Can RVEF be replaced by more simple measures?

5. Will a goal oriented strategy to improve RVEF also lead to improvement of
myocardial performances and coupling of the RV to its load?

This is a prospective longitudinal, clinical study. Thirty newly diagnosed
idiopathic or heritable PAH patients with NYHA functional class II or III will
be included.
Maintenance/improvement of RVEF will be our primary outcome parameter and
therefore cardiac magnetic resonance imaging (CMR) will be performed at
baseline and after 4, 8, 12 and 24 months of follow-up. Six-minute walk testing
(6MWT), quality of life questionnaires and blood sampling (NT-proBNP) will be
performed during similar follow-up intervals. In addition, right heart
catheterization (RHC) will be performed at baseline and after 4, 12 and 24
months of follow-up.
Patients with NYHA functional class II at baseline, will start with a single
agent endothelin receptor antagonist (ERA) or phosphodiesterase-5 inhibitor
(PDE 5I). Patients with baseline NYHA functional class III will initially start
on combination therapy consisting of an ERA and a PDE 5I. All therapeutic
decisions will be based on measurements of RVEF by CMR. In case of a
stable/improved RVEF (defined as no decrease in RVEF of more than 3%),
treatment remains unchanged. In case of a deteriorating RVEF, additional
medical treatment will be added. In case of a deteriorating RVEF in a patient
already using triple therapy (ERA, PDE 5 I and prostacyclin (P GI2)), lung
transplantation listing will be discussed. Our hypothesis will be proven to be
correct when the additional medical treatment result in improved RVEF during
the subsequent follow-up measurement.

Not applicable.

Because RHC and MRI are part of our routine clinical assessment protocol at
baseline and during regular one-year follow-up assessment, the present study
requires two MRI measurements (at 4 and 8 months follow-up) and one additional
RHC measurement (at 4 months follow-up) per patient. In addition, blood
sampling and 6MWT are already performed on a regular basis for clinical
purposes.
RHC performed in experienced centres has low morbidity (1.1%) and mortality
rates (0.055%) (Hoeper, JACC, 2006). We consider that the additional
measurements are justified by an expected improvement of patients clinical
symptoms, quality of life and survival by our goal oriented therapeutic
approach in order to preserve/improve RV function during long term follow-up.
Furthermore, the results of the present study will provide essential insights
in the mechanism of RV failure and its depence on pulmonary hemodynamics and
could be of great value in order to improve the treatment strategy for PAH
patients world wide.