A treatment regimen that combines two FDA-approved drugs significantly reduced hospitalizations in patients with pulmonary arterial hypertension (PAH), a type of high blood pressure that affects the arteries in the lungs and causes breathing problems, chest pain, heart failure and death.
The two drugs, ambrisentan and tadalafil, are currently used on their own to treat PAH. This is the first time they have been tested together in a large-scale, randomized clinical trial and the results suggest that the combination is superior to either drug alone: just four percent of patients who received the combination therapy were hospitalized for worsening disease compared to 12 percent of patients who took ambrisentan or tadalafil on their own. The results were reported in the New England Journal of Medicine.
“These results are very exciting because they show that upfront treatment with these two once-daily tablets led to better outcomes for newly diagnosed PAH patients,” said R. James White, M.D., Ph.D., associate professor of Medicine and Pharmacology and Physiology at the University of Rochester School of Medicine and Dentistry and an author of the new study. “This regimen is not a cure and it is not going to work for everybody, but it is a substantial step forward compared to previous therapies that required frequent daily dosing or monthly blood work.”
The main side effects observed more frequently in patients receiving the combination therapy were peripheral edema (swelling of the feet, ankles and legs), headache and nasal congestion. In addition to fewer hospitalizations, patients in the combination group were also able to walk further in a six-minute walk distance test and exhibited less strain on the right side of the heart, which pumps blood through the lungs to pick up oxygen that is delivered to the rest of the body.
PAH affects an estimated 200,000 patients worldwide. According to a study published in the journal CHEST, more than 40 percent of patients diagnosed with the disease die within five years. But, for people who are not treated, average survival is only about three years, according to the American Lung Association.
The disease begins when tiny arteries in your lungs called pulmonary arteries become constricted, making it harder for blood to flow and raising pressure within the arteries. This forces the heart to work harder to pump blood through the lungs, causing the heart muscle to weaken and eventually fail.
White, who treats PAH patients at UR Medicine’s Mary Parkes Center for Asthma, Allergy and Pulmonary Care, says that 50 percent of patients who develop the disease are otherwise healthy and doctors don’t understand why they get it. In the other half of patients, the disease is caused by another medical condition, such as autoimmune diseases like scleroderma, congenital heart disease, HIV/AIDS and chronic liver disease. It is typically thought of as a disease of young females, but men and women of any age can develop PAH.
The study, which was funded by Gilead Sciences, Inc. and GlaxoSmithKline, included 500 patients from 120 centers in 14 countries. Approximately half of the patients received ambrisentan and tadalafil in combination, a quarter received ambrisentan alone and the remaining quarter received tadalafil alone. The University of Rochester was a leading enroller in the U.S., recruiting 15 patients to participate in the study.
“We are very grateful to our community partners in upstate New York and Pennsylvania for entrusting their patients to our care and encouraging their participation in clinical trials. Above all, we are grateful to the patients who participate in clinical trials to advance the care of others,” said Patricia J. Sime, M.D., chief of the Division of Pulmonary and Critical Care Medicine at UR Medicine’s Strong Memorial Hospital. “We are delighted that this new combination therapy may soon be an option for patients with PAH who suffer in so many ways and we look forward to continuing to make advances in patient care and discovery in the years ahead.”
Combination therapy with ambrisentan and tadalafil is currently not approved to treat PAH. In December 2014, Gilead submitted a supplemental new drug application (sNDA) for a label change for ambrisentan involving the use of this combination.
Eli Lilly and Company also provided funding for the study, as well as the supply of tadalafil, brand name Adcirca. Gilead markets ambrisentan under the brand name Letairis® in the U.S. and GlaxoSmithKline markets ambrisentan under the brand name Volibris® outside of the U.S.
White serves as a paid consultant to Gilead and Gilead sponsors both industry- and investigator-initiated research in which he serves as the principal investigator at the University of Rochester. Research coordinators Alison Theuer, R.N. and Karen Frutiger, R.N. assisted White with the current study.