Oral sildenafil (Viagra®) improved exercise tolerance, cardiac output and quality of life in 22 patients with primary pulmonary hypertension, according to the results of the first randomized, placebo-controlled, double-blind, crossover study, reported in the April 7, 2004 issue of the Journal of the American College of Cardiology.
"Not only is the response there; the magnitude of the response is nearly 40 percent. So even with only 22 patients, we could demonstrate a highly statistically significant, very powerful result," said B. K. S. Sastry, DM, with the CARE Hospital in Hyderabad, India.
In patients with primary pulmonary hypertension (PPH), vascular resistance and pressure in the pulmonary arteries progressively increases. The condition is uncommon, but it often leads to heart failure and death. The cause is unknown. Current treatments are unsatisfactory. Some drugs offer only small benefits and some require intravenous infusions. Some PPH patients eventually receive lung transplants.
This study builds on the clinical experience of the researchers and published reports that indicated PPH patients who were given sildenafil improved, often by as much as 40 percent on tests of exercise duration. Also, sildenafil generally has fewer side effects than other PPH treatments. Sildenafil, which dilates blood vessels, is primarily used to treat erectile dysfunction.
"In contrast to other treatments, sildenafil is a drug that can be just taken orally, perhaps three times a day, and the magnitude of the benefit is much greater. And the side effect profile is much, much better. For example, with bosentan (a dual endothelin-receptor antagonist), people have a chance of developing serious liver problems," Dr. Sastry said.
Earlier published studies did not compare sildenafil to placebo, so the researchers enrolled 22 patients with PPH who were then randomized to receive either sildenafil (25 to 100 mg three times a day, based on body weight) or placebo treatment. The randomization results were blinded to both patients and the researchers. After six weeks of treatment, the patients were crossed over to the other treatment; that is, those receiving placebo began getting sildenafil and vice-versa. In this way, each patient served as his or her own control.
One patient withdrew while receiving sildenafil. One patient died while receiving placebo. For statistical purposes, both patients were included in the study analysis as if they had not experienced any change in their conditions.
Exercise time on a treadmill, cardiac output on echocardiograms, and responses to a quality of life questionnaire were measured at baseline, at the six-week medication crossover point, and again when the study concluded after 12 weeks.
"And in all three parameters, exercise tolerance, cardiac output, and quality of life, we could demonstrate significant benefit with sildenafil compared to placebo," Dr. Sastry said.
The length of time patients could exercise on a treadmill increased by 44 percent from 475 ± 168 seconds at the end of placebo phase to 686 ± 224 seconds at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 ± 0.9 liters/meter-squared to 3.45 ± 1.1 l/m2 (p < 0.0001). There was significant improvement in the dyspnea and fatigue components of the quality of life questionnaire. Pulmonary artery systolic pressure decreased from 105.23 ± 17.82 millimeters of mercury to 98.50 ± 24.38 mm Hg, but the change was not statistically significant.
Dr. Sastry said larger trials are needed to confirm their results and to check for rare side effects. Also, he said studies involving cardiac catheterization and more objective methods of exercise testing would help provide better data on how sildenafil works in patients with PPH.
Lewis J. Rubin, MD, with the University of California, San Diego School of Medicine, who was not connected with this study, said physicians are looking forward to the results of longer and larger trials that will build on the experience using sildenafil to treat PPH.
"It's an encouraging, but still preliminary study. The strength was the design, a cross-over study which adds to the strength of the observation. The weakness is that it is still a small study with regard to the number of patients, and a short duration of observation," Dr. Rubin said. "The results of an international, placebo-controlled trial in several hundred patients will be available in a few months, and this should shed light on the role of sildenafil in pulmonary hypertension. Of course, long-term data will be critical, but this will be forthcoming as more patients in these trials are treated for longer periods of time with open label studies."