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Expert Consensus Document on Pulmonary Hypertension Released

Introduction
The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) released an expert consensus document on pulmonary hypertension in April 2009.¹ The document covers epidemiology and classification of pulmonary hypertension, screening and diagnostic assessments, and includes an evidence-based treatment algorithm. The consensus document has been published in the Journal of the American College of Cardiology (JACC) and Circulation, and is available on-line at http://www.acc.org.

Epidemiology and Classification
The prevalence of pulmonary arterial hypertension (PAH) is estimated to be approximately 15 people per million.¹ Idiopathic PAH occurs in approximately 6 people per million and is more prevalent in women; with a female to male ratio of 1.7:1. The disease can also be hereditary, known as familial PAH, which has been attributed to a mutation in the bone morphogenic protein receptor-2 (BMPR2). Familial PAH has been reported in approximately 6% to 10% of patients with PAH. Other causes of PAH include congenital heart disease, connective tissue diseases, drugs and toxins, human immunodeficiency virus (HIV) infection, portal hypertension, hemoglobinopathies, and myeloproliferative disorders. The World Health Organization (WHO) has grouped PAH into 5 categories. A summary of these categories is presented in Table 1.

Screening and Diagnosis
Periodic screening for PAH should occur in patients who are at risk for developing this condition such as patients with genetic substrates (BMPR2 mutation), risk factors (e.g., scleroderma spectrum of diseases, patients with portal hypertension who are undergoing evaluation for liver transplantation), or those with suggestive symptoms of PAH.¹ The most common presenting symptoms include dyspnea on exertion, fatigue, chest pain, syncope, palpitations, and lower extremity edema. Severity of symptoms are classified based on the WHO functional classes I to IV, with I being mild symptoms and IV being the most severe symptoms. Physical examination findings can help determine if a patient has PAH. For example, physical signs that suggest moderate to severe disease include a holosystolic murmur that increases with inspiration, increased jugular ‘v’ waves, pulsatile liver, diastolic murmur, and hepatojugular reflux. A chest x-ray and electrocardiogram may also be helpful in identifying markers that are suggestive of PAH.

If PAH is suspected based on history, risk factor assessment, and physical examination, an echocardiogram is the most appropriate study to be done.¹ An echocardiogram can provide an estimate of right ventricular systolic pressure, assessment of functional and morphologic cardiac adverse effects, and help identify cardiac causes of PAH. A diagnosis of PAH requires confirmation with a complete right heart catheterization. Hemodynamic findings of a catheterization in patients with PAH include a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg; a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure (LVEDP) less than or equal to 15 mm Hg; and a pulmonary vascular resistance (PVR) greater than 3 Wood units.

Most patients should also undergo acute vasodilator testing, which is usually performed during the diagnostic catheterization.¹ A response to an acute vasodilator test helps identify patients with a better prognosis and those who are more likely to have a sustained beneficial response to oral calcium channel blockers (CCBs). The consensus document recommends that acute vasodilator testing be performed in all patients with idiopathic PAH who might be considered potential candidates for long-term CCB therapy. However, the document clearly states that patients with overt right heart failure or hemodynamic instability should not undergo vasodilator testing.

Three agents are currently used for vasodilator testing: inhaled nitric oxide, intravenous (IV) epoprostenol, and IV adenosine.¹ The consensus document stated that inhaled nitric oxide was the preferred vasodilator, with the other 2 agents as acceptable alternatives. The optimal dose of nitric oxide has not been established, but common practice is to use doses of 20 to 40 ppm for 5 minutes. Sodium nitroprusside, CCBs, or nitrates should not be used for acute vasodilator testing because the safety and efficacy of these agents in this setting has not been established. A positive response to the test is defined as a reduction in mPAP of at least 10 mm Hg to an absolute mPAP of less than 40 mm Hg without a decrease in cardiac output.

Treatment Algorithm
The goals of treatment for PAH include improving symptoms, quality of life, and survival.¹ The prognosis of PAH is poor, with 15% of patients treated with appropriate therapies dying within 1 year. All patients should be treated with general measures, which include low level aerobic exercise, a sodium restricted diet (less than 2400 mg/day), and routine immunizations such as the influenza and pneumococcal vaccinations. In addition, some patients may require supplemental oxygen to maintain oxygen saturation above 90%. Women with PAH should avoid becoming pregnant, as the hemodynamic fluctuations that occur during pregnancy can be devastating.

Per the committee’s consensus, warfarin should be given to all patients with idiopathic PAH without contraindications to the drug, as an improvement in survival with warfarin therapy has been observed in this patient population.¹ The warfarin dose should be titrated to an International Normalized Ratio (INR) of 1.5 to 2.5. Anticoagulation should also be given to patients with other forms of PAH who have more advanced disease, such as those on continuous IV therapy (see next paragraph). Diuretics are used to manage right ventricular fluid overload.

Patients with a positive response to acute vasodilator testing should be treated with oral CCB therapy.¹ Long-acting nifedipine, diltiazem, or amlodipine are the most commonly used CCBs to treat PAH. Patients who did not have a positive response to acute vasodilator testing and are considered lower risk based on clinical assessment (WHO class II or early class III) should be treated with oral therapy with either endothelin receptor antagonists (bosentan or ambrisentan) or phosphodiesterase (PDE)-5 inhibitors (sildenafil or tadalafil). Tadalafil was recently approved by the Food and Drug Administration for PAH. Patients considered high risk based on clinical assessment (WHO class IV) should be given continuous treatment with IV prostacyclin therapies (epoprostenol or treprostinil). Epoprostenol is the preferred treatment for the most critically ill patients because this agent has been shown to improve exercise capacity, hemodynamics, and most importantly, prolong survival. Inhaled iloprost is another prostacyclin, but patients must inhale this medication 6 times per day, which may impact adherence. Treprostinil may also be delivered via a continuous subcutaneous infusion. Combination therapy should be considered when patients fail to respond to initial monotherapy. Patients who progress despite optimal medical therapy should be evaluated for lung transplantation and/or atrial septostomy.

Follow-up
Patients with PAH must be monitored closely.¹ Office visits should be more frequent for patients with advanced disease and those on IV or combination therapy. These patients should be evaluated every 3 months, or more frequently if needed. Patients who are less ill on oral therapy should be evaluated every 3 to 6 months. The consensus document emphasized the important role nurses have in managing patients with PAH at specialty centers and the key roles pharmacists who are working in specialty pharmacies that dispense medications for PAH play in educating patients about their therapies.

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