Improving treatment of right ventricular failure in pulmonary hypertension patients.

Pulmonary hypertension (PH) is a severe disease defined by an elevated mean
pulmonary artery pressure (>= 25 mmHg) and pulmonary vascular resistance (>3
Woods units) caused by narrowing of the pulmonary arteries. The increasing
pulmonary vascular resistance ultimately leads to right ventricular (RV)
failure and death (1).

Although treatment strategies for patients with pulmonary arterial hypertension
(PAH) are optimized in the last decades, this has not led to a normalization of
PVR. As such, almost all patients continue to develop RV failure. Patients with
severe RV failure require hospital admissions for intra venous (IV) loop
diuretics in order to reduce fluid overload. However optimal compensation with
loop diuretics is rather challenging since patients develop diuretic resistance
and deterioration of kidney function. A possible mechanisms of diuretic
resistance are both forward failure and renal venous congestion causing an
increased renal interstitial pressure, resulting in a hypoxic state and
increased hydrostatic pressure in the Bowman*s capsule causing a decrease in
glomerular filtration rate (GFR) (2,3).

Despite the considerable burden on patients and survival, consensus on optimal
treatment on RV failure in PH patients is currently lacking. PH guidelines
recommend the use of diuretics to optimize fluid balance. Vasopressors may be
added to preserve systemic blood pressure. To increase cardiac output, use of
inotropes (dobutamine) is recommended (1). However these recommendations were
based on small studies, mainly including patients with acute RV failure. This
is hardly translatable to the PAH population in which patients develop RV
failure over years. Optimizing treatment strategies for RV failure in these
patients is of utmost importance, to improve bridging strategies to pulmonary
transplantation and increase quality of life.

Terlipressin is an arginine vasopressin analogue with a high sensitivity for
the vasopressin 1 (V1)-receptor (4,5). Activation of the V1-recptor in the
vascular wall initiates vasoconstriction in the peripheral vascular bed. In
rats with hypoxia induced pulmonary vasoconstriction however, arginine
vasopressin is known to decrease pulmonary vascular resistance (PVR) and mean
pulmonary artery pressure (MPAP) (6). Vasopressin analogues are successfully
used in patients with end stage liver failure who develop hepatorenalsyndrome.
In these fluid overloaded patients, administration of vasopressors increased
systemic vascular resistance, diuresis and GFR (7). In the VU University
Medical center terlipressin is added to IV loop diuretics in fluid overloaded
PH patients with an insufficient response to diuretics alone. Figure 1
illustrates an end-stage IPAH patient who received terlipressin 1mg/day during
admission for fluid overload. In this patient weight loss increased and
fluidbalance became more negative after switch from furosemide to terlipressin.

Positive results of vasopressors in RV failing PAH patients were not solely
seen in our hospital. Price et al. showed in two young women that vasopressin
is eligible as treatment of severe hypotension due to IPAH induced RV failure
after delivery by Caesarean section. In one patient Metaraminol, norepinephrine
and dobutamine failed in order to increase systemic blood pressure, but after a
bolus of vasopressin systemic bloodpressure rapidly restored (8).

With these favorable effects of vasopressors in mind, we hypothesize that in
pre-capillary PH patients with severe RV failure, without an adequate response
on oral diuretics addition of the vasopressor terlipressin to diuretic therapy
will increase systemic blood pressure and renal blood flow by its systemic
vasoconstrictive properties. This will result in a reduction of required loop
diuretic dose for initiating a negative fluid balance, shorter admission period
and a better preservation of kidney function.
Since the incidence of decompensation in pre-capillary PH patients admitted the
hospital is low, we will conduct an mono center randomized clinical trial. In
this trial we will test the safety and efficacy of addition of terlipressin to
a standardized loop diuretic regimen.
This study will be the first clinical trial in RV failure due to end-stage
pre-capillary pulmonary hypertension.

To explore efficacy and safety of terlipressin in pre-capillary PH patients
with RV failure requiring hospitalization.

The study design is a prospective open label randomized clinical trial.
We will prospectively include 20 IPAH or CTEPH patients, of whom 10 patients
will be randomized to loop diuretics and terlipressin, and 10 patients to loop
diuretics alone.

In this study we will investigate the effect of a low dose of the vasopressin
analogue terlipressin combined with loop diuretics vs. loop diuretics alone.
Patients who are randomized to the terlipressin arm will be on a dose of 1
mg/day. Terlipressin and the loop diuretics will be administered intravenously.

PAH is characterized by progressive pulmonary vascular remodeling and the
associated increased RV afterload eventually leads to right heart failure and
premature death. Even with maximal treatment, prognosis remains poor: 5 year
survival is about 50%.
In end-stage RV failure patients need hospital admissions in order to reduce
fluid overload.
Evidence on optimal treatment of these patients is lacking. We therefore
believe that this study is of utmost importance. Earlier case reports and our
in hospital experience have not shown any adverse effects of treatment
vasopressors.

Potential risks of terlipressin are coronary vasoconstriction, hyponatremia and
cutaneous ischemia. Benefits of terlipressin are reduction of forward failure
by increasing SVR and thus MAP, resulting in an improved kidney perfusion, GFR
and diuresis. Patient will require lower doses of loop diuretics, decreasing
risks on potential side effects of this drug. Moreover by ameliorating diuresis
target weight will be reached earlier resulting in a shorter hospital admission
period.
Risk of administration of high dose diuretics is tinnitus or hearing loss.
Moreover patients are at risk of kidney function deterioration (increase in
creatinine) and electrolyte disturbances, mainly hypokalaemia. Therefore kidney
function and electrolytes (sodium, potassium, magnesium, and chloride) will be
monitored intensively by blood samples (one sample daily). On the other hand
optimizing volume status will give relief of symptoms, decrease preload and
finally improve kidney function by decreasing renal congestion.