Yvetter C. Terrie, BSPharm, RPh

Arming patients with essential knowledge about pulmonary arterial hypertension empowers them to make informed decisions about their health.

Pulmonary hypertension (PH) is a condition characterized by increased pressure in the pulmonary arteries. In general, it affects an estimated 2 to 3 times as many women as men.

 PH usually develops between 20 and 60 years of age; however, it can occur at any age.

According to Centers for Disease Control and Prevention (CDC) statistics, between 2000 and 2002, 807,000 patients were hospitalized with PH; 61% were female, and 66% were 65 years or older.

 Statistics from the CDC also report that PH led to 15,688 deaths and 260,000 hospitalizations in 2002.

 Prior to 1995, individuals with PH lived, on average, less than 3 years after diagnosis; however, with emerging therapies, survival rates and quality of life for those living with this condition have improved.

Currently, the World Health Organization (WHO) divides PH into 5 WHO groups, depending on the etiology.1 Group 1 is classified as pulmonary arterial hypertension (PAH) and groups 2 through 5 are called PH. This article will focus on PAH, a rare progressive disease characterized by sustained increases in pulmonary vascular resistance (PVR) that ultimately results in right ventricular failure. 3-7 PAH is defined as having a mean pulmonary artery pressure greater than 25 mm Hg with a pulmonary capillary wedge pressure, left atrial pressure, or left ventricular end-diastolic pressure of 15 mm Hg or less, and a PVR greater than 3 Wood units, as measured by cardiac catheterization.

PAH is considered a complex, multidisciplinary medical condition that, if left untreated, can be lifethreatening.

 Better understanding and recent medical advances have led to increasing awareness and new therapies to combat this condition.

Results from one study suggest that an estimated 15 in 1 million adults have PAH, with 6 cases per million being idiopathic in nature.

Idiopathic PAH (IPAH) occurs more commonly in women than in men.

The WHO first defined the classifications of PH in 1973, and they have been revised over the years. The classifications of PH were most recently updated at the 4th World Symposium on Pulmonary Hypertension in Dana Point, California, in 2008.

 PH was divided into 5 WHO groups depending upon the cause. The first group, or WHO Group 1, is otherwise known as PAH.

 PAH is classified into subgroups, including idiopathic, heritable, and PAH associated with other conditions.

 PAH specifically affects the pulmonary arteries of the lungs, causing them to tighten, stiffen, and narrow.

Patients in Groups 2 to 5 are classified as non-PAH or PH. Group 1 adds the criterion of pulmonary capillary wedge pressure of 15 mm Hg or less and PVR greater than 3 Wood units.6-10 More indepth information regarding the updated clinical classification of PH can be found in the June 30, 2009, online edition of the Journal of the 

Risk Factors and Symptoms Associated with PAH 

Risk factors for PAH include having a familial history of PAH, congenital heart disease, connective tissue disease such as lupus or scleroderma, portal hypertension, sickle cell disease, thyroid disease, or human immunodeficiency virus (HIV), and use of certain pharmacologic agents and toxins.

Statistics report that the prevalence of PAH is 0.5% in HIV-infected patients, 20% to 40% in patients with sickle cell disease, and 16% in patients with systemic sclerosis.11 When the cause is unrelated to any identifiable disorder, these cases are classified as IPAH.6-8 IPAH is more common in young women, with a mean age of diagnosis of 36 years; however, it can occur at any age.11

During the early stages of PAH, patients are typically asymptomatic and diagnosis is often delayed, because many other conditions present with comparable symptoms.

 Patients with PAH may present with fatigue, exertional dyspnea, and occasionally, chest discomfort, palpitations, and syncope.

Dyspnea is the most frequently reported symptom among patients with PAH.

 Patients with advanced PAH may present with clinically evident right-sided heart failure, dizziness, syncope, edema, or cyanosis. 

Early diagnosis and management can improve prognosis; however, diagnosis of PAH in the early stages is often considered a clinical challenge because symptoms such as dyspnea, dizziness, and fatigue are nonspecific.

 Frequently, PAH goes unrecognized until it is relatively advanced.

Although there is currently no cure for PH, various treatment options are available that are aimed at decreasing or improving a patient’s symptoms, improving overall quality of life, slowing progression of the disease, and decreasing mortality. 

 Treatments include medications and surgery; patients are also encouraged to make lifestyle changes as their PAH worsens and limits daily activity.

Patients should also be advised to avoid smoking or the use of sympathomimetics, which may exacerbate the condition.

Standard treatment options, sometimes referred to as supportive therapy, include oral anticoagulation, diuretics, and oxygen supplementation. A small percentage of patients may also receive calcium channel blockers (CCBs) as part of their treatment regimen.

 For more than 25 years, CCBs have been used in the treatment of PAH. Although some patients exhibit significant improvement after treatment with CCBs, these agents have been shown to benefit only a small percentage of patients with PAH and have been studied almost exclusively in patients with IPAH.

 Three CCBs most often used in the treatment of patients with PAH are nifedipine, diltiazem, and amlodipine.

 Numerous clinical studies have investigated the use of nifedipine and diltiazem in PAH.

Currently FDA-approved agents for the treatment of PAH include prostacyclin analogues, endothelin receptor antagonists (ERAs), and phosphodiesterase type-5 (PDE-5) inhibitors.

Prostacyclin is a potent vasodilator that maintains low vascular tone, has antiproliferative properties, and prevents platelet aggregation.6-8 The prostacyclin analogues currently approved in the United States are epoprostenol (Flolan), iloprost (Ventavis), and treprostinil (Remodulin).

Endothelin is a potent vasoconstrictor and stimulator of vascular smooth muscle cell proliferation and is believed to be important in the pathophysiology of PAH.

 In the United States, currently available ERAs include ambrisentan (Letairis) and bosentan (Tracleer). A third ERA, sitaxsentan, is undergoing investigation pending approval from the FDA.

PDE-5 inhibitors increase the intracellular concentration of cyclic guanosine monophosphate, increase nitric oxide (which induces relaxation of blood vessels), and create antiproliferative effects on vascular smooth muscle cells.

Sildenafil (Revatio) and tadalafil (Adcirca) are 2 PDE-5 inhibitors currently approved for PAH treatment.

In May 2009, the FDA approved tadalafil, marketed as Adcirca (Eli Lilly), for the treatment of PAH (WHO Group 1) to improve exercise ability.

 Tadalafil is classified as an oral inhibitor of PDE-5, the enzyme responsible for the degradation of cyclic guanosine monophosphate.

 Tadalafil is available as a 20-mg tablet for oral administration and the recommended initial dose is 40 mg once daily with or without food.

In July 2009, the FDA approved treprostinil, which is marketed as Tyvaso (United Therapeutics). Tyvaso, classified as a prostacyclin analogue, directs vasodilation of pulmonary and systemic arterial vascular beds and inhibits platelet aggregation.

 Tyvaso is specifically indicated to increase walk distance in patients with WHO Group 1 PAH and NYHA Class III symptoms.

 Tyvaso, available as a solution designed for oral inhalation, should be dosed in 4 separate, equally spaced treatment sessions per day, during waking hours.

 The treatment sessions should be approximately 4 hours apart.

Combination therapy has been shown to improve pulmonary arterial pressure, but more research is needed. Additional research is also needed to ascertain whether patients with different types of PAH require different treatment protocols.

 Other treatment options for patients with PAH include balloon atrial septostomy and lung transplantation.

The diagnosis of PH may be overwhelming and challenging for many patients. Arming patients with essential knowledge about PAH and the available treatments enables them to make informed choices about their health. In addition to counseling patients on the proper use of their medications, pharmacists can provide patients with pertinent information regarding PH and encourage them to make lifestyle modifications to improve their overall quality of life. Patients with PAH should be reminded to obtain the pneumococcal vaccine and an annual influenza vaccine.

 An excellent patient resource guide entitled “Pulmonary Hypertension: A Patient’s Survival Guide” can be found on the Pulmonary Hypertension Association Web site.

For more information regarding clinical trials investigating PAH, please visit the US National Institutes of Health Clinical Trials Web site. PT

Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia. 

Yvetter C. Terrie, BSPharm, RPh

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