Is Sooner Better? The Push to Use Antifibrotics Early in IPF

Aaron B. Holley, MD


June 17, 2019

Nintedanib and pirfenidone reduce the rate of functional vital capacity (FVC) decline in patients with idiopathic pulmonary fibrosis (IPF),[1] with several large, randomized controlled trials (RCTs) showing efficacy for this outcome.[2,3,4] Because IPF is a progressive disease that was considered untreatable before these drugs were approved by the US Food and Drug Administration, the news of their approval was greeted with wild celebrations. Most pulmonary clinics threw out their impulse oscillometry machines, which no one knew how to use anyway, to make room for party favors. Advanced lung disease centers operated with renewed purpose.

In many ways, the hype was and continues to be justified. Since the publication of the original RCTs, meta-analyses using the RCT data show signal for impact on patient-centered outcomes, such as mortality,[5] respiratory hospitalization,[6] and cough.[7] Post hoc analyses have even sought to expand the population eligible to receive these medications beyond the inclusion and exclusion criteria from the original RCTs.[8,9,10]

Most recently, the issue of timing of initiation was addressed in a letter to the editor published online in the Annals of the American Thoracic Society.[11] The controversy over timing is important. On the one hand, some would argue that it's reasonable to start one drug or the other as soon as an IPF diagnosis is made. After all, the disease is progressive, and lung function that is lost will not be recovered.[12] The con to this argument is that progression is variable and unpredictable, and the drugs are expensive (estimated at more than $100,000 per year).[13] A sizable minority of patients will not show decline over the first 1-2 years, making it unlikely they'd benefit from treatment. Unfortunately, they're difficult to identify up front.

In the letter to the editor,[11] data from patients enrolled in the CAPACITY[2] and RECAP[14] trials were analyzed. CAPACITY was one of the aforementioned RCTs that confirmed reduction in FVC with pirfenidone, and RECAP was an open-label extension of the CAPACITY study. Although the authors concluded that their data support drug initiation at diagnosis, I'm less certain. To me, their study proves nothing more than what we already know: (1) FVC at diagnosis is not a good predictor of rate of decline or response to therapy; (2) lung function that is lost will not be recovered; and (3) the effect of treatment, with respect to slowing FVC decline, will not be affected by when it's initiated. This letter is essentially a rehash of the RECAP results and does not add anything new.

Also worth noting, the Funding and Competing Interests section is three times longer than the introduction to the letter. Completing research without industry funding is difficult, but the resulting bias cannot be ignored.

I would exercise caution before we start prescribing pirfenidone or nintedanib to prevent lung fibrosis. These drugs are great, and for symptomatic patients with a reduced FVC, initiating them is a slam dunk. I would say the same for those with significant symptoms or a history of exacerbations or respiratory hospitalizations. However, for those with preserved FVC, with or without mild symptoms, the cost-efficacy and clinical risk-benefit will be hard to determine up front. Is it cost-effective to spend $100,000 to ensure that a patient with preserved FVC and no symptoms doesn't lose an extra 50-100 mL of lung function? Or should we wait and assess the rate of decline? These are hard questions without easy answers, but they need to be asked.

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