PDE5 inhibition as a treatment of pulmonary hypertension

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Few options are available for the treatment of pulmonary hypertension. Epoprostenol (Flolan), or prostacyclin, is the single most important advance in the treatment of primary pulmonary hypertension. Inhaled NO has also been established as a selective pulmonary vasodilator although there are problems associated with long-term use of NO inhalation, including its potential toxicity and difficulty in ambulatory inhalation.

In contrast to the rare condition, primary pulmonary hypertension, secondary pulmonary hypertension is a frequent consequence of cardiac disorders, pulmonary disorders (COPD), or both in combination. Both of these groups of conditions are extremely common and the number of patients with secondary pulmonary hypertension is large.

In patients with secondary pulmonary hypertension, management is directed at early recognition and treatment of the underlying disease (while it is still potentially reversible). Given the efficacy of NO in the treatment of pulmonary hypertension and the known expression of PDE5 (the enzyme that metabolizes cGMP produced in response to NO) in the human pulmonary artery this condition is emerging as a possible new indication for PDE5 inhibitors. An early acute clinical study conducted by Dr Evangelos D. Michelakis at the University of Alberta, demonstrated that sildenafil decreased pulmonary vascular resistance as effectively as NO, and increased cardiac output, while wedge pressure was unaffected.

More recently this group has investigated the chronic effects of sildenafil on pulmonary hypertension. Treatment for 3 months with oral sildenafil (50 mg orally every 8 hours) is well tolerated in patients with class III or II disease. Treatment improved disease score to class II or I and 6 minute walk distances increased substantially, whereas the mean pulmonary artery pressure and the pulmonary vascular resistance index significantly decreased. Cardiac parameters also improved; the cardiac index and right ventricular ejection fraction increased while the right ventricular mass decreased.

Despite the small size and nonrandomized nature of this study the therapeutic efficacy is promising. The study population consisted mostly of primary arterial hypertension patients and sildenafil offers a treatment option for these patients that is cheaper and possibly more effective than alternatives. Larger randomized trials are required to confirm this. Furthermore, positive data in additional studies of patients with the much more common secondary arterial hypertension would represent a major advance in this difficult to treat condition. Such studies are eagerly awaited.

Entry date Wednesday, December 17, 2003

Adapted from Michelakis et al, Circulation. 2003 Oct 28;108(17):2066-9. Epub 2003 Oct 20.

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