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Pulmonary Medicine

New drugs enhance pulmonary hypertension treatment


UCLA specialists treat pulmonary hypertension with an arsenal of new and experimental medications that now include intravenous, subcutaneous and oral vasodilators. Pulmonary hypertension, usually fatal within two years if untreated, affects young patients (average age 35) and strikes women at least twice as often as men. Up until the advent of new medical therapies, the only treatment for pulmonary hypertension was a lung or heart/lung transplant. With new medications, 80 percent of cases do not need transplantation.

Pulmonary hypertension work-up

At UCLA, a thorough examination establishes the diagnosis of primary or secondary causes of pulmonary hypertension and helps direct the course of treatment. In particular, one critical test – the right-heart catheterization – assesses the severity of hemodynamic indices and aids in the determination of the most appropriate initial therapy. An acute pulmonary vasodilator trial can assess the reactivity of the pulmonary vasculature to determine if an oral calcium channel blocker will benefit the patient. Nitric oxide (NO) gas, a short-acting yet potent pulmonary vasodilator, is administered briefly during the catheterization. The patient’s response to the NO can accurately predict if the patient will respond favorably to calcium channel blocker therapy, though a favorable vasodilator response is observed in the minority of patients.

Treatment options

Based on the severity of a patient’s pulmonary hypertension and symptoms, a spectrum of treatments is available. Since vascular research indicates that patients with pulmonary hypertension may be prothrombotic, anticoagulation with warfarin is usually prescribed, unless contraindicated.

Prostacyclin-analog therapy
For severe pulmonary hypertension, the gold standard has been epoprosternol (Flolan®), a prostacylinanalog and potent vasodilator that is diminished in patients with pulmonary hypertension. Administering the drug requires continuous intravenous infusion due to the short duration of action in the body (two to six minutes). Since 2002, a longer-lasting prostacyclin-analog – treprostinil (Remodulin®) – has been approved for this application. This medication is administered through a subcutaneous catheter and miniature insulin pump and usually requires the additional use of topical analgesic gels developed to decrease site pain. Treprostinil is valuable for those patients who are limited in their ability to care for the infusion systems themselves since it may require maintenance every three days; the epoprosternol infusion system requires daily care. Recently, treprostinil has also been re-labeled by the FDA for intravenous administration, which may offer significant advantages over intravenous epoprostenol with respect to the tasks associated with daily drug reconstitution and administration. Currently, a novel study is in development to assess the efficacy of aerosolized delivery of treprostinil in pulmonary hypertension.

Oral therapy
Patients with pulmonary hypertension have a higher level in their blood of endothelin-1 (ET-1), a potent vasoconstrictor. The first endothelin receptor blocker (ERB), bosentan (Tracleer®), is approved for use in patients with World Health Organization Class III-IV primary pulmonary hypertension or pulmonary hypertension related to collagen vascular diseases such as scleroderma. This oral therapy has shown improvement in patients’ symptoms of breathlessness and walking distance, but has the possibility for
hepatoxicity. Bosentan is contraindicated for patients with portal-pulmonary hypertension. Long-term data on the efficacy or survival benefit offered by this drug are very promising. New multi-center placebocontrolled clinical trials are underway and available on several research protocols at UCLA.

Sildenafil therapy
Vasodilators such as NO are produced by the endothelium and act via the second messenger, cGMP, to relax vascular smooth muscle. Sildenafil, which predominantly inhibits phosphodiesterase type 5, may potentiate the vasodilator effects of either innate or exogenous prostacyclin and nitric oxide. A recent “double-blinded, double-dummy” multi-center trial of sildenafil (20,40,80 mg t.i.d. versus placebo) demonstrated improvement in mean six-minute walking distance (45-50 meters) and decreased pulmonary
vascular resistance (310 dyne/sec/cm5) over 12 weeks. These promising results have resulted in the recent FDA recommendation for approval of sildenafil for treatment of pulmonary hypertension. Sildenafil (20 mg) will be relabeled for PAH under the tradename, Revatio®, for this indication. Other PDE-5 inhibitors with a longer pharmacologic half-life are currently under investigation for this indication.

Nebulized iloprost (Ventavis®) therapy
Iloprost is the first FDA-approved inhalational treatment for patients with WHO Group I pulmonary arterial hypertension with functional NYHA Class III-IV symptoms. The drug is administered by a specifically designed Prodose® AAD® Nebulizer System, and requires administration six to nine times each day. This therapy, as demonstrated in a multi-center randomized double-blind placebo-controlled trial, was associated with a statistically significant improvement in a composite primary endpoint compared with
placebo. Combining nebulized iloprost with other vasodilator therapies, such as bosentan (Tracleer®), are also under investigation and have demonstrated promising preliminary results.

Team members

David Ross, M.D.
Director, UCLA Pulmonary Hypertension Program
Medical Director, UCLA Lung and Heart-Lung Transplant Program

Rajan Saggar, M.D.
Clinical Instructor, UCLA Division of Pulmonary, Critical-Care & Hospitalists

Abbas Ardehali, M.D.
Director, UCLA Lung Transplant Program

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