United Therapeutics’s lead product, Remodulin, was approved by the FDA on May 21, 2002 as a continuous subcutaneous infusion for the treatment of the life-threatening disease pulmonary arterial hypertension in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise. To learn more about Remodulin, please click here.

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The following text describes pulmonary arterial hypertension in detail and how this disease is treated.  This text was written by Dr. Stuart Rich, Professor Medicine and Director, Rush Heart Institute Center for Pulmonary Heart Disease, Rush Presbyterian St. Luke’s Hospital in Chicago.

What Do We Know About Pulmonary
Hypertension and How Do We Treat It?

The causes of pulmonary arterial hypertension includes primary pulmonary hypertension, and pulmonary hypertension associated with the collagen vascular diseases, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, anorexigen use, and persistent pulmonary hypertension of the newborn.  These patients share a common histopathology that includes pulmonary vascular abnormalities involving the endothelium, smooth muscle cells, and extracellular matrix.  The most common features are medial hypertrophy, eccentric and concentric intimal fibrosis, recanalized thrombi appearing as fibrous webs, and plexiform lesions.

Pathobiology

There are likely several pathobiologic processes that result in pulmonary arterial hypertension as a final common pathway.  These include inhibition of the voltage regulated potassium channel producing vasoconstriction of the pulmonary artery smooth muscle cells, reduced expression of nitric oxide synthase in the endothelium of the pulmonary arterial bed, increased expression of endothelin and basic fibroblast growth factor, and thrombin deposition related to a procoagulant state.  The types of abnormalities that occur are likely influenced by the patient’s genotype and exposure to risk factors that serve to trigger these processes.

Primary Pulmonary Hypertension

Primary pulmonary hypertension (PPH) is uncommon, with an estimated incidence of 2 cases per million.  There is a strong female predominance, with most patients presenting in the fourth and fifth decadesalthough the age range is from infancy to greater than 60 years.

Genetic Considerations

Familial primary pulmonary hypertension accounts for 12-20% of cases of PPH, and is characterized by autosomal dominant inheritance, variable age of onset, and incomplete penetrance.  The clinical and pathologic features of familial and sporadic PPH are identical.  Heterozygous germline mutations that involve the gene coding the Type II bone morphogenetic protein receptor (BMPR II), a member of the transforming growth factor beta superfamily, have been found to underlie many cases of familial PPH and has been designated as the PPH I gene located on chromosome 2q31.  An interruption in the BMP-mediated signaling pathway will predispose the cells within the small pulmonary arteries to proliferation rather than apoptosis. These observations support the concept that pulmonary arterial hypertension is a result of abnormal proliferation of pulmonary vascular endothelial and smooth muscle cells.  

Natural History

Diagnosis

A thorough diagnostic evaluation to look at all potential causes for pulmonary hypertension should be undertaken.  The most common symptom attributable to pulmonary hypertension is shortness of breath with effort, which is nonspecific.  Other common symptoms are fatigue, angina pectoris that my represent right ventricular ischemia, syncope, near syncope, and peripheral edema.

The chest x-ray generally shows enlarged central pulmonary arteries.  The lung fields may or may not reveal other pathology.  The electrocardiogram usually reveals right axis deviation and right ventricular hypertrophy. The echocardiogram will demonstrate right ventricular enlargement, a reduction in left ventricular cavity size, and a tricuspid regurgitant jet that reflects right ventricular systolic pressure.  Pulmonary function tests are helpful to document underlying obstructive airways disease, or severe restrictive lung disease. Hypoxemia and an abnormal diffusing capacity for carbon monoxide are common findings of pulmonary hypertension of most causes.  A perfusion lung scan will almost always be abnormal in patients with thromboembolic pulmonary hypertension.  However, diffuse patchy filling defects of a non-segmental nature can often be seen in longstanding pulmonary hypertension in the absence of thromboemboli.

Cardiac catheterization is mandatory to accurately measure pulmonary artery pressure and cardiac output, exclude an underlying cardiac shunt, and precisely determine left ventricular filling pressures.  Because of the difficulty in obtaining accurate pulmonary capillary wedge pressures in these patients it is desirable that a left heart catheterization be performed to determine left ventricular end diastolic pressure as the cause of the pulmonary hypertension. It is also recommended that patients with pulmonary arterial hypertension undergo drug testing with a short acting pulmonary vasodilator at the time of cardiac catheterization to determine the extent of pulmonary vasodilator reactivity. (see figure)  Inhaled nitric oxide, intravenous adenosine, and intravenous epoprostenol appear to have similar effects in reducing pulmonary artery pressure acutely with little effect on the systemic vascular bed.  Maximal physiologic effectiveness of the drug is determined at the highest tolerated dose.  Laboratory tests should also be performed, including antinuclear antibody and HIV testing.  Because of the high frequency of thyroid abnormalities in patients with primary pulmonary hypertension it is recommended that a TSH be determined as well.

On occasion a patient may have marked elevations in pulmonary artery pressure in association with obstructive or interstitial lung disease, essential hypertension, ischemic heart disease, or valvular heart disease.  Although it may appear that the pulmonary hypertension is out of proportion to the underlying associated condition, it likely represents a pulmonary vasoconstrictive response to the associated condition, which is serving as a trigger of the pulmonary arteriopathy.  The distinction is important because the treatment of pulmonary hypertension should always include treating the underlying associated cause.

Treatment 

Because the pulmonary vascular resistance can increase dramatically with exercise patients should be cautioned against participating in activities that demand increased physical stress.  Digoxin may increase cardiac output and lower circulating levels of norepinephrine.  Diuretic therapy relieves peripheral edema and may be useful in reducing right ventricular volume overload in the presence of tricuspid regurgitation.  Resting and exercise pulse oximetry should be measured, as oxygen supplementation will help alleviate dyspnea and right ventricular ischemia in patients whose arterial oxygen saturation is reduced.  Anticoagulant therapy is advocated for all patients on the basis that thrombin deposition occurs in the pulmonary circulation, which can serve as a growth factor to promote the disease process.  One retrospective study and one prospective study demonstrated that the anticoagulant warfarin increases survival of patients with primary pulmonary hypertension.  The dose of warfarin is generally titrated to achieve an INR of 2.0-3.0 of control.

Calcium channel blockers

Patients who have substantial reductions in pulmonary arterial pressure from short acting vasodilators at the time of catheterization may be candidates to receive oral calcium channel blockers.  Typically, patients will require high doses (e.g.; nifedipine 240 mg/day or amlodipine 20 mg/day).  Patients who respond favorably will usually have dramatic reductions in pulmonary artery pressure and pulmonary vascular resistance associated with improved symptoms, regression of right ventricular hypertrophy, and improved survival with chronic therapy.  Less than 20% of the patients appear to respond to calcium channel blockers in the long term.  These drugs can be particularly hazardous when given in patients who are unresponsive, as they can result in hypotension, hypoxemia, tachycardia, and worsening right heart failure.

Prostacyclins

Prostacyclin raises cAMP levels in vascular smooth muscle cells and works via vasodilation, growth inhibition, inhibition of platelet aggregation, and cardiac inotropic effects. Epoprostenol (Flolan) is the best characterized approved treatment of pulmonary arterial hypertension for patients who are Functional Class III or IV and unresponsive to other therapies.  Clinical trials have demonstrated an improvement in symptoms and exercise tolerance, and a reduction in mortality even if no acute hemodynamic response to drug challenge occurs.  Recent reports have documented sustained benefits for more than 10 years in some patients.  The drug can only be administered intravenously and requires placement of a permanent central venous catheter and infusion through an ambulatory infusion pump system.  It generally takes several months to gradually up titrate the dose to optimal clinical efficacy, which is usually between 25-50 ng/kg/min.  Side effects include flushing, jaw pain, and diarrhea, which are generally tolerated by most patients.  The major problem with this therapy has been infection related to the venous catheter which requires close monitoring and diligence on behalf of the patient. 

Recently, treprostinil (Remodulin) has been approved for patients with pulmonary arterial hypertension who are Functional Class II-IV and are unresponsive to conventional therapy.  An analog of epoprostenol, treprostinil has a longer half-life and is stable at room temperature allowing for it to be administered subcutaneously through a small infusion pump that was originally developed for insulin. Clinical trials have demonstrated an increase in exercise capacity using a 6-minute walk test and a reduction of symptoms of dyspnea.  The major side effect with this treatment has been local pain at the infusion site.   Patients who are stable on intravenous epoprostenol can be transitioned to subcutaneous treprostinil, eliminating the need for a chronic indwelling intravenous catheter.

Endothelin receptor antagonists

Endothelin levels are increased in pulmonary hypertension, and cause vasoconstriction, and smooth muscle cell proliferation. The non-selective endothelin receptor antagonist bosentan (Tracleer) was recently approved as an oral treatment of pulmonary arterial hypertension for patients who are Functional Class III and IV, and unresponsive to conventional therapy.  In randomized clinical trials bosentan was shown to improve exercise tolerance as measured by an increase in 6 minute walk distance, improve functional class, and extend time until clinical worsening versus placebo.  Therapy is initiated at a low dose (62.5 mg BID) for the first month, and then increased to 125 mg BID thereafter.  Because of the high frequency of abnormal hepatic function tests associated with drug use, primarily an increase in transaminases, it is recommended that patients have liver function tests monitored monthly throughout the duration of use.  Bosentan is also contraindicated in patients who are currently on cyclosporine A or glyburide. There is no data to support the use of bosentan for other forms of pulmonary hypertension.

Sildenafil

Transplantation

Because of the dramatic effects that intravenous epoprostenol has in stabilizing and improving the clinical course of patients with advanced disease transplantation is considered for patients who, while on epoprostenol, continue to manifest right heart failure.  Acceptable results have been achieved with heart-lung, bilateral lung, and single lung transplant.  The availability of donor organs often influences the choice of procedure.  The re-occurrence of primary pulmonary hypertension has never been reported in a patient who has undergone lung transplantation.

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