Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension

Ann Intern Med. 2002 Apr 2;136(7):515-22. doi: 10.7326/0003-4819-136-7-200204020-00008.


Background: Inhalation of the stable prostacyclin analogue iloprost is being studied for treatment of pulmonary hypertension. The selective phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation.

Objective: To evaluate the safety and effectiveness of oral sildenafil, alone and in combination with inhaled iloprost, for treatment of pulmonary hypertension.

Design: Randomized, controlled, open-label trial.

Setting: Intensive care unit.

Patients: 30 patients with severe pulmonary arterial hypertension (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension due to aplasia of the left pulmonary artery (n = 1), all classified as New York Heart Association class III or IV.

Intervention: All patients received inhaled nitric oxide and aerosolized iloprost (inhaled dose, 2.8 microg). They were then randomly assigned to receive 12.5 mg of oral sildenafil, 50 mg of sildenafil, 12.5 mg of sildenafil plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost.

Measurements: Systemic and pulmonary arterial pressure, pulmonary arterial occlusion pressure, cardiac output, central venous pressure, peripheral arterial oxygen saturation, and arterial and mixed venous blood gases were measured during right-heart catheterization by using a Swan-Ganz catheter.

Results: In rank order of pulmonary vasodilatory potency (maximum reduction of pulmonary vascular resistance and increase in cardiac index), 50 mg of sildenafil plus iloprost was most effective, followed by 12.5 mg of sildenafil plus iloprost. Iloprost alone and 50 mg of sildenafil were almost equally effective but were less potent than the combination regimens, and the least potent treatments were 12.5 mg of sildenafil and nitric oxide. In patients who received 50 mg of sildenafil plus iloprost, the maximum change in pulmonary vasodilatory potency was -44.2% (95% CI, -49.5% to -38.8%), compared with -14.1% (CI, -19.1% to -9.2%) in response to nitric oxide. With administration of 50 mg of sildenafil plus iloprost, the area under the curve for reduction in pulmonary vasodilatory resistance surpassed that of administration of 50 mg of sildenafil alone and iloprost alone combined, the vasodilatory effect lasted longer than 3 hours, and systemic arterial pressure and arterial oxygenation were maintained. No serious adverse events occurred.

Conclusion: Although limited by the small sample and lack of long-term observations, the study shows that oral sildenafil is a potent pulmonary vasodilator that acts synergistically with inhaled iloprost to cause strong pulmonary vasodilatation in both severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
  • Administration, Oral
  • Analysis of Variance
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Hemodynamics / drug effects
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / physiopathology
  • Iloprost / administration & dosage*
  • Iloprost / pharmacokinetics
  • Male
  • Phosphodiesterase Inhibitors / administration & dosage*
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Piperazines / administration & dosage*
  • Piperazines / pharmacokinetics
  • Purines
  • Sildenafil Citrate
  • Sulfones
  • Vasodilator Agents / administration & dosage*
  • Vasodilator Agents / pharmacokinetics


  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Sulfones
  • Vasodilator Agents
  • Sildenafil Citrate
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Iloprost