Pulmonary Arterial Hypertension, November 2005

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Pulmonary Arterial Hypertension, November 2005 Journal Scan

FromThe New England Journal of MedicineNovember 17, 2005  ( Volume 353, Number 20 )

Sildenafil Citrate Therapy for Pulmonary Arterial HypertensionGalie N, Ghofrani H, Torbicki A, et al. 
The New England Journal of Medicine.  2005;353(20):2148-2157

The pathophysiology of pulmonary hypertension involves an increased production of vasoconstrictors (endothelin-1) and a decrease in prostacyclin and nitric oxide, which are vasodilators.[1] Over time, this pulmonary endothelial dysfunction causes strain on the right ventricle, leading to right ventricular failure. The end result is eventually death. Long-term therapies have consisted of prostanoids, oxygen, diuretics, and endothelin receptor antagonists (ERAs). Yet treatment is problematic. The prostanoids are often associated with many potential side effects. Routine liver enzyme testing is required when using the ERAs.[2] The role of the nitric oxide pathway has been studied, and inhaled nitric oxide has been used for some time in vasoreactivity testing. Phosphodiesterase type-5 (PDE-5) metabolizes cyclic guanosine monophosphate (cGMP), causing vasoconstriction and the growth of vascular smooth muscle cells. In patients with pulmonary hypertension, PDE-5 is upregulated. The inhibition of PDE-5 enhances the cGMP, allowing for dilation of pulmonary vessels and possibly exerting antiproliferative effects on the vascular smooth muscle cells in the lungs.[3]

This large 12-week study conducted in 53 centers between October 2002 and November 2003 evaluated the effects of 3 different doses of sildenafil (a PDE-5 inhibitor) on patients with pulmonary arterial hypertension, mostly New York Heart Association (NYHA) classes II and III. The patients included in the study had either idiopathic pulmonary arterial hypertension, pulmonary hypertension associated with connective tissue disease, or repaired congential heart disease. Patients were randomized according to distance walked on a 6-minute walk (< 325 m or > 325 m) and the cause of the pulmonary hypertension. Treatment groups received either 20-, 40-, or 80-mg doses of sildenafil or placebo. In the extension study, 80 mg of sildenafil was studied. The primary endpoint was the 6-minute walk distance (6MWD). Also evaluated was NYHA functional class, time to clinical worsening, hemodynamic parameters (mean pulmonary artery pressures), and Borg dyspnea scale. A total of 278 patients were randomized to 1 of the 4 treatment groups, with 265 completing the 12 weeks of study. Idiopathic pulmonary arterial hypertension was the most common type noted, with NYHA class of III for 58% of the patients. All patients receiving sildenafil exhibited an increase in 6MWD at the end of 12 weeks. The 20-mg group demonstrated an increase of 45 m and the 80-mg group improving by 50 m. Hemodynamics varied considerably among the 3 sildenafil groups and the control group. The placebo group demonstrated an increase in hospitalizations for worsening pulmonary hypertension compared with the treatment group. WHO functional class improved to a greater degree in the sildenafil groups.

Overall, an improvement was noted in exercise capacity for the patients taking sildenafil regardless of the cause of PAH evaluation. The improvement in 6MWD compares to that noted with epoprostenol (47 m) and bosentan (44 m). This effect was noted up to 1 year in the extension study.ReferencesHumbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:(Suppl 12):13S-24S.Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436.Tantini B, Manes A, Fiumana E, et al. Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol. 2005;100:131-138.

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