Pulmonary arterial hypertension: Newer treatments are improving outcomes

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Pulmonary arterial hypertension: Newer treatments are improving outcomes

J Fam Pract. 2004 December;53(12):959-969

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References

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Conventional therapies

Calcium channel blockers. Calcium channel block-ers (CCBs) are useful only for PAH patients who respond to vasodilator testing in a cardiac catheter-ization laboratory (SOR: B). Criteria for vasore-sponsiveness have changed and it is now generally agreed that the mean PA pressure must fall by at least 10 mm Hg to 40 mm Hg with increased or unchanged cardiac output. CCB use for nonrespon-ders leads to higher morbidity and mortality.²⁰

Digoxin. In left ventricular failure, digoxin relieves symptoms, but without mortality benefit (SOR: A).²¹ Only 1 study has shown a hemodynamic benefit in PAH in the intensive-care setting.²² Therefore, experts do not agree that digoxin is useful in right ventricular failure from PAH. Digoxin may be warranted in the presence of concomitant left ventricular dysfunction or digoxin-responsive arrhythmias.

Warfarin. Two retrospective studies have shown a decrease in mortality with warfarin in PAH.^23,24 There is no consensus, though, on the degree of anticoagulation, with recommendations of INR ranging from 1.5 to 4.0.

Diuretics. Judicious use of diuretics is recommended in PAH. Loop diuretics, thiazides, and spironolactone are commonly titrated to achieve symptomatic relief.

Ambulatory oxygen therapy. This option is indicated for resting and exercise-induced hypoxia. Experts usually recommend titration to achieve a PO₂ >60 mm Hg.

Prostanoids: Epoprostenol, treprostinil, iloprost

Prostanoids cause vasodilation, inhibit platelet aggregation, prevent smooth muscle proliferation, decrease inflammation, and increase cardiac output.²⁵ Epoprostenol improves exercise tolerance, hemodynamics and quality of life in patients with IPAH and PAH secondary to scleroderma (SOR: A).^3,26 Treprostinil and iloprost show similar benefits. A survival advantage has only been shown for epoprostenol and treprostinil.²⁷ Epoprostenol is useful in both vasodilator “responders” and “nonresponders.”²⁸

Administration. Epoprostenol is administered with a central venous catheter. Usual starting dose is 2 ng/kg/min or higher with increase by 1 ng/kg/min every 1 to 2 weeks until the desired clinical improvement is manifested, or side effects preclude dose escalation.²⁹

Treprostinil is given subcutaneously and is under investigation as an intravenous agent. The optimal dose for treprostinil is 13.8 ng/kg/min and above.³⁰

Iloprost is delivered via inhalation, although it has also been used intravenously. Iloprost is not approved by the Food and Drug Administration but is available in clinical trials. Inhaled iloprost is short-lived and only provides intermittent hemodynamic benefit.³¹

Side effects. Side effects include jaw pain, nausea, anorexia, diarrhea, flushing, and headache. With the exception of jaw pain, these side effects are dose-related. The risk of catheter sepsis with epoprostenol is 0.1% to 0.4% per patient-year. More serious side effects include arrhythmia with sudden interruption of drug delivery. Treprostinil causes infusion site pain (85%), necessitating discontinuation in 8% of the patients.

Endothelin receptor antagonists: Bosentan, sitaxsentan, ambrisentan

In the lung parenchyma of patients with PH, expression of endothelin-1, a 21-amino-acid peptide, increases.³² Higher levels of serum endothelin-1 correlate directly with severity of PH and poorer outcomes.³³ Endothelin-1 mediates vasoconstriction and smooth muscle proliferation primarily through endothelin type A (ET_A) receptors and vasodilatation mostly through endothelin type B (ET_B) receptors, although a dynamic relationship exists between the two.³⁴

Oral formulation a plus. Bosentan is the only endothelin antagonist currently approved by the FDA. It is a low-molecular-weight, nonpeptide, competitive, dual receptor antagonist. Sitaxsentan and ambrisentan are available in clinical trials only. They are ET_A-selective with the premise that sparing the ET_B receptor, which is responsible for pulmonary vasodilation, will lead to better clinical outcomes. All these compounds can be given orally, a major advantage over prostanoids.

Bosentan improves exercise capacity, hemodynamics, symptoms, and time to clinical worsening.^35,36 Patients studied in bosentan trials had NYHA class III or IV dyspnea due to IPAH, APAH due to scleroderma, and others. Bosentan is not approved by the FDA for functional class II patients, but has been used for such patients.

Indicated for milder PAH. Bosentan outcome data were presented at the American Thoracic Society Meeting (2003) but have not been published so far. At 3 years, 86% of patients were still alive when only 48% were expected based on historical data from the NIH registry.³⁷ Epoprostenol survival at 3 years is about 63%.^16,17 However, only patients with milder PAH receive bosentan, while the more seriously ill ones require prostanoids. This selection may explain the survival difference.

Administration. Recommended starting dose of bosentan is 62.5 mg twice daily for 4 weeks. It is then increased to 125 mg twice daily if there is no elevation of aminotransferases. Bosentan is now known to be safe in children.³⁸ Ambrisentan and sitaxsentan should to be available in 2005 or later.