Sildenafil for COPD: A Randomized Crossover Trial

Pulmonary hypertension is common in COPD and associated with increased health care costs and mortality.^1–4 Invasive hemodynamic studies of patients with advanced COPD report a prevalence of PH between 30-50%.^5,6 If the definition of PH is expanded to patients with a mean PA pressure > 20 mmHg (pre-pulmonary hypertension) the prevalence increases to >91%.⁷ The presence of pulmonary hypertension in patients with COPD is associated with a doubling of mortality over 5 years (36% vs. 62%) compared to patients without PH.⁸ While in most cases of pulmonary hypertension associated with COPD (PH-COPD), the pulmonary artery pressures are only mildly elevated there appears to be a subgroup of patients with COPD who have a more severe form of pulmonary hypertension.⁹

The past decade has seen marked improvements in our ability to treat pulmonary arterial hypertension (PAH), or World Health Organization (WHO) group 1 pulmonary hypertension.¹⁰ Currently, there are 8 different FDA approved medications for the treatment of PAH, targeting 3 separate pathways: 1) endothelin, 2) nitric oxide and 3) prostacyclin.¹¹ These medications improve hemodynamics, exercise tolerance, time to clinical worsening and survival.¹² Sildenafil is an oral phosphodiesterase-5 (PDE5) inhibitor which is FDA approved for the treatment of PAH. It inhibits the breakdown of cyclic GMP, resulting in pulmonary artery smooth muscle cell relaxation and vasodilatation.¹³ There is a growing interest in applying PAH specific medications such as sildenafil to the other causes of pulmonary hypertension (WHO class II-V). COPD is classified as WHO class III pulmonary hypertension, or pulmonary hypertension associated with parenchymal lung disease or alveolar hypoventilation.

An inherent difficulty in treating PH-COPD is the risk of inducing ventilation-perfusion (V/Q) mismatch. This occurs due to the non-selective dilation of the pulmonary vasculature to areas of parenchymal damage. Previous small clinical studies have demonstrated this occurrence in PH-COPD. Blanco et al randomized 20 patients to either 20 or 40 mg of oral sildenafil at rest and with exercise, measuring their cardiopulmonary hemodynamic and gas exchange acutely. While they demonstrated a significant decrease in mean pulmonary artery pressure there was also worsened oxygenation and VQ matching at rest.¹⁴ Stolz et al added the oral endothelial receptor antagonist bosentan to patients with PH-COPD. There was no improvement in exercise tolerance and there was worsening in the quality of life score.¹⁵ However, other studies of oral pulmonary artery vasodilators have reported improvements in oxygenation when treating WHO class III pulmonary hypertension.^16,17

It is with this background that Lederer et al have re-examined the use of sildenafil in COPD, however in patients without pulmonary hypertension. Dr. Lederer and colleagues performed a double blind, placebo controlled 2 period crossover study of 10 patients with COPD without pulmonary hypertension. In contrast to previous studies they investigated a more chronic use of the medication, following the patients for 1 month, allowing a 1 week wash out and then re-treating with drug or placebo for another month. By using this cross over design the authors improved their ability to identify significant effects in this small number of patients. There was no significant difference in exercise tolerance as measured by 6-minute walk distance or in oxygen consumption at peak exercise between treatment arms. There was however an increase in the alveolar-arterial gradient in patients taking sildenafil as well as worsened symptoms and worsened quality of life as measured by a number of metrics. Adverse events were also more common in the patients taking sildenafil and the adverse events were more frequent at higher doses.

This study certainly has a number of important limitations. It was small in size and short in duration. Most importantly however, the patients enrolled were not diagnosed with pulmonary hypertension. Pulmonary hypertension is the disease previously targeted by the medication. The authors acknowledge that without the presence of PH, they may have simply demonstrated the ability of a non-selective pulmonary vasodilator to worsen VQ matching. Future studies in this area should target the population of PH-COPD as opposed to COPD without PH. However, this study in combination with those preceding highlight the need for a more thorough evaluation of the pulmonary artery vasodilators before their indiscriminate application to other pulmonary hypertension patient populations.

Well-done clinical studies are needed to determine the true prevalence of PH in patients with COPD, and to then assess the impact of PH-specific therapies on clinical outcomes in this population. Selection of appropriate outcome measures will be critically important, and will need to go beyond short-term effects on oxygenation or cardiopulmonary hemodynamics, and address effects on functional capacity, the occurrence of clinical worsening events, and perhaps survival.