Spironolactone for Pulmonary Arterial Hypertension

INTRODUCTION:

Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival.
Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering
stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a
central role both in the pathogenesis and progression of PAH. Inflammation appears to drive
this dysfunctional endothelial phenotype, propagating cycles of injury and repair in
genetically susceptible patients with idiopathic PAH (IPAH) and patients with
disease-associated PAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles
of injury and repair and thereby delay or prevent RV failure and death has not been tested.
Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist, has
been shown to improve endothelial function and reduce inflammation. Current management of
patients with severe PAH and NYHA/WHO class IV symptoms includes use of MR antagonists for
their diuretic and natriuretic effects once clinical right heart failure has developed. We
hypothesize that initiating therapy with spironolactone at an earlier stage of disease in
subjects with PAH could provide additional benefits through anti-inflammatory effects and
improvements in pulmonary artery endothelial function.

OBJECTIVES:

Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in a
randomized, double blinded, placebo-controlled study of early treatment with spironolactone
to investigate its effects on exercise capacity, clinical worsening, and vascular
inflammation in vivo.

METHODS:

The total number of PAH subjects enrolled will be up to 70. Subjects will undergo 1) standard
clinical examinations including 6-minute walk distance and echocardiography; 2)
cardiopulmonary exercise testing; 3) plasma profiling of inflammatory and neurohormonal
markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5)
high-resolution MRI-based determination of pulmonary vascular and RV structure and function.
Safety and tolerability of spironolactone in PAH will be assessed with periodic monitoring
for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for
untoward effects.

- INCLUSION CRITERIA:

1. WHO Group 1 PH patients on either no medical therapy or stable medical therapy
for at least the past 4 weeks (defined as no new PAH-specific therapy, no change
in the dose of current PAH-specific therapy and no change in NYHA/WHO functional
classification within the past 4 weeks) are eligible. The following parameters on
RHC are required to meet the hemodynamic definition of PAH:

1. mean pulmonary artery pressure of > 25 mmHg at rest,

2. pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a left
ventricular end-diastolic pressure of less than or equal to 12 mmHg) and

3. pulmonary vascular resistance of > 3 Wood units (240 dyn.s.cm(-5).

If clinically indicated at the time of enrollment, then a RHC will be performed at the NIH
Clinical Center upon study entry under a procedural consent.

2) Females who are able to become pregnant (i.e., are not postmenopausal, have not
undergone surgical sterilization, and are sexually active with men) must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to
and for the duration of study participation.

EXCLUSION CRITERIA:

1. Patients with WHO Group 1 PH and evidence of right heart failure as defined by:

1. NYHA/WHO class IV symptoms and

2. Echocardiographic evidence of severe RV dysfunction and

3. Clinical evidence of right heart failure which may include, but is not limited to
elevated jugular venous pressure, ascites, and lower extremity edema

2. Patients with WHO Group 1 pulmonary hypertension and a prior diagnosis of cirrhosis
with portal hypertension as evidenced by a history of ascites, hepatic encephalopathy
and/or varices prior to enrollment

3. Patients with WHO Group 1 pulmonary hypertension and evidence of active infection,
(HIV patients with two consecutive viral loads of < 500 on their most recent
determinations within the past 12 months will be considered to have inactive
infection)

4. Patients with WHO Group 1 pulmonary hypertension who have taken spironolactone or
eplerenone within the last 30 days

5. Known or suspected allergy to spironolactone

6. Pregnant or breastfeeding women (all women of childbearing potential will be required
to have a screening urine or blood pregnancy test)

7. Age <18 years

8. Inability to provide informed written consent for participation in the study

9. Chronic kidney disease (an estimated glomerular filtration rate of < 35
mL/min/1.73m(2) of body surface area)

10. Serum potassium at the time of enrollment of > 5 mEq/L

11. Concurrent use of an ACE inhibitor and angiotensin II receptor blocker

OR

Patients currently taking the maximum recommended dose of an ACE inhibitor or an
angiotensin II receptor blocker [For patients taking one of these medicines
(ACE-Inhibitors or ARBs), the investigators agree to do due diligence by consulting a
clinical center pharmacist and/or a standard pharmacy reference (i.e. Micromedex) to
certify whether or not the patient is on a maximum dose of the drug.]

12. Women currently taking drospirenone-containing oral contraceptives

Exclusion Criteria for MRI

These contraindications include but are not limited to the following devices or conditions:

1. Implanted cardiac pacemaker or defibrillator

2. Cochlear Implants

3. Ocular foreign body (e.g. metal shavings)

4. Embedded shrapnel fragments

5. Central nervous system aneurysm clips

6. Implanted neural stimulator

7. Any implanted device that is incompatible with MRI

8. Unsatisfactory performance status as judged by the referring physician such that the
subject could not tolerate an MRI scan. Examples of medical conditions that would not
be accepted would include unstable angina and severe dyspnea at rest

9. Subjects requiring monitored sedation for MRI studies

10. Subjects with a condition precluding entry into the scanner (e.g. morbid obesity,
claustrophobia, etc.)

11. Subjects with severe back-pain or motion disorders who will be unable to tolerate
supine positioning within the MRI scanner and hold still for the duration of the
examination.

EXCLUSION CRITERIA FOR GADOLINIUM BASED MRI STUDIES ONLY:

1. History of severe allergic reaction to gadolinium contrast agents despite pre-
medication with diphenhydramine and prednisone

2. Chronic kidney disease (an estimated glomerular filtration rate of < 60
mL/min/1.73m(2) of body surface area)