Sangeeta Joshi, MD Sangeeta Joshi is a fellow for the Division of Pulmonary and Critical Care Medicine. Center for Pulmonary Vascular Disease, Duke University Medical Center , Victor F Tapson, MD Victor Tapson is the Professor of Medicine and Director, Center for Pulmonary Vascular Disease, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center

Originally printed in:
» US Respiratory Disease 2007 - October 2007

Pulmonary circulation plays a pivotal role in the cardiopulmonary functions of gas exchange and oxygen transport, but is vulnerable to injury from developmental or acquired disorders affecting the heart and/or lungs. One of the most serious and potentially devastating chronic disorders of the pulmonary circulation is pulmonary hypertension (PH). This hemodynamic abnormality has diverse etiologies, challenging physicians both diagnostically and therapeutically. Most specialists in this field still accept the definition of PH as outlined by the National Institutes of Health (NIH) Registry on Primary Pulmonary Hypertension (now termed idiopathic pulmonary arterial hypertension, IPAH), as a mean pulmonary artery pressure (mPAP) >25mmHg with a pulmonary capillary wedge or left atrial pressure <15mmHg as measured by cardiac catheterization.¹ The classification of PH was most recently revised in 2003, based on the 2003 World Health Organization (WHO) meeting in Venice, Italy. Appropriate classification, combined with determination of severity, aids in directing therapy.

Irrespective of its etiology, PH is a serious and often progressive disorder that can result in right ventricular dysfunction, impairment of exercise tolerance, and death. The pathogenesis is complex, still incompletely understood, and thought to be affected by genetic and environmental factors that alter vascular structure and function. Dramatic advances in the treatment of PAH have occurred over the past 15 years based on improved understanding of its pathogenesis in the research laboratory and extensive PAH clinical trials. These efforts have led to US Food and Drug Administration (FDA) approval of three prostanoids (epoprostenol, treprostinil, and iloprost), two endothelin receptor antagonists (bosentan and ambrisentan), and a phosphodiesterase-5 inhibitor (sildenafil). Not all countries, however, have access to all of them. Calcium channel blockers have proven effective, but only in the minority of patients who are ‘vasodilator responders’ at rightheart catheterization. Our focus will primarily be Group I patients—i.e. those with PAH—and how prostanoid therapy is used in these individuals.

Prostacyclins
Eicosanoids are the 20-carbon essential fatty acids derived from arachidonic acid. This family of biologically active mediators includes the prostacyclins (prostaglandin I2, PGI2), thromboxanes, and leukotrienes. Epoprostenol and the structurally related compounds treprostinil, iloprost, and beraprost are collectively referred to as prostanoids. Prostacyclins are produced in endothelial cells from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. These drugs are potent vasodilator agents that inhibit platelet aggregation. Epoprostenol has been studied extensively in the laboratory, and recent observations suggest its role as a mediator of vascular remodeling.³

The parenteral prostacyclins include intravenous (IV) iloprost (not available in the US), IV epoprostenol, and subcutaneous and IV treprostinil. These are generally reserved for patients with more advanced disease. An approach to choosing PH therapy is outlined in Table 1, offering a general guide as to when more aggressive (parenteral) prostanoid therapy should be considered.

These drugs cause characteristic adverse effects, particularly when administered parenterally. These include headache, flushing, nausea, diarrhea, jaw pain, and, particularly with more long-term treatment, leg or foot pain. Dose escalation can often be slowed and/or a lower dose can be targeted, which may alleviate or better control these symptoms. Chronic leg and foot pain can often be controlled with gabapentin; narcotics are rarely needed. Parenteral prostacylins should be administered by physician/nursing teams with expertise in this area. Patients must be closely monitored by outpatient visits and by telephone.

Epoprostenol
This was the first prostanoid shown to be promising based on laboratory studies. It is unstable at normal body pH and has a very short half-life, requiring continuous IV infusion through a central venous catheter. Side effects can include jaw pain, headache, flushing, nausea, diarrhea, and vomiting. This drug has been used in severe PAH by the continuous IV route since the early to mid-1990s. Patients are generally admitted to the hospital to begin this drug, and a central catheter is placed for delivery. The drug is initiated and intense teaching is undertaken regarding the drug and its side effects, use of the delivery pump, and central-line care. Patients are taught to be vigilant for line infections and remain in contact with their physician/nursing team regarding the above issues. The target dose of IV epoprostenol is in the range of 40ng/kg/min; it generally takes more than six weeks to achieve this.

Clinical Trials
There have been three randomized, controlled studies comparing prostacyclin with conventional treatment. In 1996, Barst et al. reported a 12-week prospective, randomized, multicenter trial comparing the effects of continuous IV infusion of epoprostenol plus conventional therapy with those of conventional therapy alone in 81 patients with severe IPAH who were functional class III or IV. The conventional therapy included oral calcium channel blockers, anticoagulation, diuretics, digoxin, and oxygen. Exercise capacity improved in the 41 patients treated with epoprostenol—median 6-minute walk test (6MWT) distance 362m at 12 weeks versus 315m at baseline—and decreased in the 40 patients treated with conventional therapy alone—median 6MWT distance 204m at 12 weeks versus 270m at baseline (p=0.002 for comparison of the treatment groups). There were also improvements in quality of life, hemodynamics, and survival.⁴ In 2000, Badesch et al.² reported a multicenter, randomized, controlled, open-label 12-week trial of long-term IV epoprostenol treatment in 111 patients with moderate to severe PAH occurring in the setting of the scleroderma spectrum of disease. Exercise capacity improved with epoprostenol—median 6MWT distance 316m at 12 weeks compared with 270m at baseline—but decreased with conventional therapy—median 6MWT 192m at 12 weeks compared with 240m at baseline. The difference between treatment groups in the median distance walked at week 12 was 108m (95% confidence interval (CI) 55.2–180; p=0.001). Hemodynamics also improved; however, a survival advantage was not demonstrated. Trends suggesting greater improvement in severity of Raynaud’s phenomenon and fewer new digital ulcers were seen in the epoprostenol group.⁵ Two large, long-term observational series have documented an improvement in survival in patients with IPAH treated with epoprostenol compared with either historical control subjects or predicted survival based on the NIH Registry equation.^6,7