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Nintedanib combination therapy no better than monotherapy in some cases of idiopathic pulmonary fibrosis
Nintedanib plus sildenafil produced the same results as ninetdanib alone in patients with idiopathic pulmonary fibrosis and diffusion capacity of the lungs for carbon monoxide of 35% or less, according to results recently published in The New England Journal of Medicine.
“In a post hoc analysis, the benefits of sildenafil treatment appeared to be greater in patients with right ventricular systolic dysfunction than in those without right ventricular systolic dysfunction. The current evidence-based international treatment guidelines for [idiopathic pulmonary fibrosis] give a conditional recommendation against the use of sildenafil, indicating that it is not an appropriate treatment for the majority of patients,” Martin Kolb, MD, a professor of infection and immunity at McMaster University and St. Joseph’s Healthcare in Hamilton Ontario Canada and colleagues wrote.
“Patients with a [diffusion capacity of the lungs for carbon monoxide] that is less than 35% of the predicted value have generally been excluded from clinical trials of treatment for idiopathic pulmonary fibrosis, which has resulted in limited data regarding the efficacy and safety of drugs in this population of patients,” they added.
Researchers randomly assigned 274 such patients older than 40 years in a 1:1 ratio to receive either 150 mg of nintedanib (Ofev, Boehringer Ingelheim) two times daily plus 20 mg of sildenafil three times daily or the same dose and regimen of nintedanib and a placebo for 24 weeks.
Kolb and colleagues found no significant difference in the adjusted mean change from baseline in the St. George’s Respiratory Questionnaire total score at week 12 between the nintedanib-plus-sildenafil group (1.28 points) and the nintedanib group (0.77 points). There were no new safety signals identified in either group and in regards to dyspnea, there was no benefit from sildenafil treatment as determined by the University of California, San Diego Shortness of Breath Questionnaire.
“The strengths of our analyses include the pre-specification of all the reported end points and the minimal amount of missing data. Limitations include the potential underpowering of the trial and its relatively short duration. The side-effect data should be interpreted in light of the observation that more than one third of the patients had received nintedanib before entering the trial and so would have been likely to have had fewer adverse events than a population of patients who had never received nintedanib previously,” Kolb and colleagues wrote.” – by Janel Miller
Disclosures : Kolb reports receiving grants and personal fees from Boehringer Ingelheim, Gilead, GlaxoSmithKline, Prometic, and Roche; grants from Actelion, Alkermes, Pharmaxis and Respivert, personal fees from Genoa, Indalo and Third Pole outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.
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In my 20-plus years of being a pulmonologist, we have studied many drugs for idiopathic pulmonary fibrosis in clinical trials, only to find the placebo did better.
The availability of nintedanib and pirfenidone (Esbriet, Genentech) as approved treatments for idiopathic pulmonary fibrosis have finally provided treatments that delay disease progression. We could still use more medications or combination therapies to fight this disease and certainly have more work to do to unravel the mysteries of what causes and treats idiopathic pulmonary fibrosis.
I wouldn’t be surprised if nintedanib and sildenafil were part of other studies. Though Kolb and colleagues conducted a strong study in terms of the number of patients involved, it was a relatively short-term study, and some of the subgroup analysis showed some potential benefit, unfortunately it is just as likely that sildenafil will not have a role in treating this disease.