Drug Criteria & Outcomes: Pulmonary arterial hypertension treatment update: Bosentan (Tracleer) and treprostinil (Remodulin)
By Abby Guest,
PharmD candidate
Harrison School of Pharmacy,
Auburn (AL) University
Pulmonary hypertension is a disease characterized by an increase in blood pressure in the pulmonary artery. High pressure can be defined in one of two ways: pulmonary artery systolic pressure higher than 30 mmHg or pulmonary artery mean pressure higher than 20 mmHg.1 Pulmonary arterial hypertension (PAH) is a commonly used term that includes both primary pulmonary hypertension (etiology is unknown) and secondary pulmonary hypertension (associated with an etiology such as hypertension secondary to HIV, congenital heart disease, use of appetite suppressants, systemic disease, or connective tissue disorders).
PAH is a progressive disease that with time will lead to higher pulmonary pressure and vascular resistance.2 PAH very commonly leads to right-sided heart failure and can be fatal within five years of diagnosis.3 Knowing the fatality of this disease, one can see how important pharmacotherapy becomes with regard to treating PAH. The purpose of this article is to review the standard therapy for PAH as well as to discuss the new therapies that recently have been approved by the U.S. Food and Drug Administration (FDA) for managing this disease state.
Standard therapy for pulmonary arterial hypertension
• Calcium channel blockers (CCBs) and anticoagulants are considered a standard of therapy for patients with PAH. Unfortunately, only about 20% of patients respond to vasodilator therapy with calcium channel blockers. To determine who should receive CCBs, patients are exposed to inhaled nitric oxide during a procedure known as the short-acting vasodilator test. If a patient shows a significant response, determined by a decrease in pulmonary artery pressure, calcium channel blockers remain first-line therapy.4 Long-acting CCBs such as amlodipine (Norvasc), nifedipine (Procardia XL), and diltiazem (Cardia XT) are used most commonly.5
• Anticoagulant therapy becomes important in patients with PAH due to an increased risk of thromboembolism. Poor pulmonary blood flow, dilated right heart chambers, venous insufficiency, and low physical activity are all risk factors for thromboembolism. Warfarin is used in two-thirds of PAH patients, and has been shown in both retrospective and uncontrolled studies to prolong life when the international normalized ratio is kept between 1.5-2.0.1
Because PAH can lead to right-sided heart failure, fluid retention is a common problem seen in these patients, and can be managed with diuretic therapy with an agent such as furosemide (Lasix).1,6
New therapies for pulmonary hypertension
Because only about 20% of patients respond to calcium channel blockers, there is a need for alternative therapy in the other 80%. Also, of the original 20% of patients who initially respond to CCBs, the efficacy is maintained in about 75% of patients over five to 10 years.7 Thus, the majority of patients (80%) used to have no drug therapy options available to manage their PAH. This led to the development of two classes of agents, prostacyclin analogues and endothelin-receptor antagonists, that have revolutionized the treatment of PAH.
Prostacyclin analogues
• Epoprostenol (Flolan) is a prostacyclin I2 analogue that was approved by the Food and Drug Administration (FDA) in 1995 after it was shown to improve patients both clinically and hemodynamically as well as to prolong survival.8 Epoprostenol stimulates vasodilation of all vascular beds and inhibits platelet aggregation by increasing the level of cyclic adenosine monophosphate, but it is thought that epoprostenol may possess an additional mechanism of action.9
Chronically, epoprostenol may provide antiproliferative properties, which would benefit patients by preventing remodeling of the pulmonary artery.7 Epoprostenol is given as a continuous intravenous infusion starting at 2 ng/kg/min via a central venous catheter, and is titrated in increments of 2 ng/kg until an effective dose is achieved. The dosage range is typically 20-40 ng/kg/min.6 Once the drug is initiated, it will be infused continuously 24 hr/day for the remainder of the patient’s life through a programmable ambulatory pump. This portable pump should be small and light to allow patients to continue with their daily activities. Patients should keep a backup infusion pump and IV infusion set to avoid potential interruptions in drug therapy.
Epoprostenol is temperature-sensitive, so cold gel packs must be replaced next to the infusion pump in the bag every eight to 12 hours to provide constant cooling. It also is light-sensitive, so the drug must be protected from light.10 Adverse events that occur with more than 10% incidence include flushing, tachycardia, syncope, fever, chills, anxiety, dizziness, headache, nausea, vomiting, jaw pain, tremor, paresthesias, and flu-like symptoms. Other less common adverse events include hypotension, edema, palpitations, insomnia, depression, abdominal pain, constipation, and rash.9 The annual cost of the drug is estimated to be $60,000-$120,000.11
• Treprostinil (Remodulin), another prostacyclin analogue, recently received FDA approval for use in patients with Class II-IV symptoms (see table below) and acts by the same mechanism described above. This agent allows for both symptomatic and hemodynamic improvement, although the results of the six-minute walk test in the study were not statistically significant when compared to placebo.6 Treprostinil is given as a continuous subcutaneous infusion, with the initial dose starting at 1.25 ng/kg/min. The drug typically is titrated to 20 ng/kg/min. Once treprostinil is initiated, it should be infused without interruption for the remainder of the patient’s life via a microinfusion pump. This is a lightweight pump that can be placed in a bag to allow for easy mobilization. Like epoprostonol, patients should keep a backup pump to avoid interruptions in drug therapy. The most common adverse effects include infusion site pain and infusion site reactions, which were experienced by 80% of patients in clinical trials. Other adverse effects include headache, diarrhea, nausea, rash, jaw pain, vasodilation, dizziness, edema, pruritis, and hypotension.12 The annual estimated cost is $50,000-$90,000.11
Endothelin-receptor antagonists
Bosentan (Tracleer) is a dual endothelin-receptor antagonist that is FDA-approved for the treatment of patients with Class III-IV symptoms (see table above) to increase exercise capacity and decrease the rate of clinical deterioration.10,11 Endothelin recently has been discovered to play a role in the pathogenesis of PAH. Endothelin-1 (ET-1) is a substance that becomes elevated in the plasma and lung tissue in patients with PAH. ET-1 has four main pharmacological actions — vasoconstriction, smooth muscle mitogen, profibrotic effects, and proinflammatory effects — which are mediated through the stimulation of ETA and ETB receptors.4
Bosentan inhibits the effects of ET-1 by blocking both ETA and ETB receptors on the vascular smooth muscle and endothelium. The dose is 62.5 mg PO BID for the first four weeks. If tolerated, the dose should be increased to 125 mg PO BID as a maintenance dose. Bosentan has an 11% incidence of significant elevations in liver transaminases and therefore can be hepatotoxic. Liver function tests should be monitored on a monthly basis. Hemoglobin should be monitored during the first six weeks of therapy due to a possible dose-related decrease. Bosentan is contraindicated in pregnancy, with concurrent glyburide or cyclosporin therapy, and with serum transaminase levels elevated to more than three times the upper limit of normal. Headache is one of the most common side effects and occurs in 16-22% of the population. Other adverse events include nasopharyngitis, flushing, edema, hypotension, palpitations, pruritus, and anemia.13,14 The cost of bosentan is $2,970 for a one-month supply of either dose ($30,000-$36,000/yr).11
Therapy undergoing clinical trials
With the approval of the therapeutic agents already discussed above, more therapeutic opportunities are available for PAH patients. Over the past several years, much research has been aimed at developing newer and better agents for management of this disease state. Due to this research, there are numerous ongoing clinical studies involving new therapies for treatment of PAH. Below is a brief summary of several agents currently being investigated.
Other prostacyclin analogues
Iloprost currently is being studied in the AIR study involving patients in class III and IV (see table, above). This is an aerosolized dosage form requiring six to 12 puffs per day.7
Beraprost is being evaluated in the ALPHABET study, including patients in class II. This is an oral dosage form that will require QID dosing if approved.7
Other endothelin-receptor antagonists
Sitaxsentan currently is being investigated to determine its efficacy in patients with PAH. This agent is different from bosentan in that it is ETA receptor-specific. Sitaxsentan also is available as an oral dosage form.4
BREATHE-2 is investigating the use of combination therapy with epoprostenol and bosentan vs. epoprostenol alone.4
BREATHE-3 is another clinical trial involving the use of bosentan in pediatric patients.4
Conclusions
From the above updated information, it is evident that much progress is being made with the management of this disease state. Several agents are being studied with the hopes of providing not only more convenient dosage forms but also more efficacious therapeutic agents that are likely to become available in the near future. The introduction of the new therapeutic class of endothelin-receptor antagonists may serve as a cornerstone for the development of other new therapies for PAH. With the approval of bosentan and treprostinil as well as ongoing research for other drugs, new therapies may offer PAH patients hope for having better control of symptoms, decreased morbidity and mortality, and an improved quality of life.
References
1. Nauser TD, Stites SW. Diagnosis and treatment of pulmonary hypertension. Am Fam Physician 2001;63:1789-1798.
2. Badesch DB, Bodin F, Channick RN, et al. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist in pulmonary arterial hypertension. Curr Ther Res Clin Exp 2002; 63:227-246.
3. Brashers V. "Alterations of Pulmonary Function." In: Pathophysiology: The Biologic Basis for Disease in Adults and Children. 4th ed. St. Louis: Mosby; 2002:1133-1134.
4. Channick RN, Rubin LJ. Endothelin receptor antagonism: A new era in the treatment of pulmonary arterial hypertension. Advances in Pulmonary Hypertension 2002;1:12-14.
5. Recommendations on management of pulmonary hypertension in clinical practice. Heart 2001;86(Supp 1): i1-i13.
6. Treprostinil (Remodulin) for pulmonary arterial hypertension. Med Lett Drugs Ther 2002;44:80-82.
7. Rubin LJ, Barst R, Galie N. Pulmonary hypertension roundtable. Advances in Pulmonary Hypertension 2002;1:16-23.
8. Barst RJ, Rubio LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The primary pulmonary hypertension study group. N Engl J Med 1996;334:296-302.
9. Epoprostenol. Lexi-Drugs for PDA. Available at: www.lexi.com. Accessed on Oct. 7, 2002.
10. Flolan product information. GlaxoSmithKline. Available at: http://us.gsk.com/products/assets/us_flolan. pdf. Accessed October 2002.
11. American College of Rheumatology. New therapies for pulmonary hypertension in systemic sclerosis. Available at: www.rheumatology.org. Accessed on Oct. 7, 2002.
12. CenterWatch. Drugs Approved by the FDA. Drug Name: Remodulin (treprostinil). Available at: www.centerwatch.com/patient/drugs/dru785.html. Accessed on Oct. 7, 2002.
13. Channick RN, Simmonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomized placebo-controlled study. Lancet 2001;358:1119-1123.
14. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.
The purpose of this article is to review the standard therapy for Pulmonary arterial hypertension (PAH) as well as to discuss the new therapies that recently have been approved by the U.S. Food and Drug Administration (FDA) for managing this disease state.
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