LOS ANGELES – When it comes to the optimal management of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF), there are more questions than definitive answers, according to Brett E. Fenster, MD, FACC.

“Is PH in IPF a disease marker, an independent treatment target, or both?” he asked attendees at the annual meeting of the American College of Chest Physicians. “I think we have conflicting information about that.”

Dr. Fenster, a cardiologist with National Jewish Health in Denver, noted that while the pathogenesis of PH in IPF is not completely understood, part of it stems from the effects of chronic hypoxia and vasoconstriction causing elevated pulmonary pressures. “There is undoubtedly destruction of the capillary bed from tissue destruction, fibrosis, and vascular lesions that are probably related to inflammation,” he said. “Neovascularization dysregulation occurs, and there’s probably a component of autoimmune disease as well.”

The prevalence of PH is estimated to be 10% in patients with mild to moderate IPF and tends to progress slowly. Common features of PH in IPF patients include shortness of breath, a greater degree of exertional desaturation, and an increased mortality rate.

Dr. Fenster described the ability to detect PH in IPF patients as “more art than science. A lot of different work has been done to look at different testing to get at the patients that may have PH that is a comorbid disease to their IPF. But a lot of times it comes down to assessing their level of dyspnea proportional to their level of disease. In those patients where we think there is something else going on besides their IPF, we’ll oftentimes get an echocardiogram and try to look at their right heart to see if they have features of PH. If it looks like they do, we will circle back and look at the amount of lung disease they have as characterized by their chest imaging, by their pulmonary function testing, and getting a blood gas. If this patient has findings of right heart enlargement, systolic dysfunction, et cetera, that clues us more into looking at PH and referring them to a center that has expertise in that version of PH.”

According to the most recent European Society of Cardiology/European Respiratory Society guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD)/IPF/combined pulmonary fibrosis and emphysema (CPFE) without PH can be considered when the mean pulmonary artery pressure (mPAP) on right heart catheterization is less than 25 mm Hg. The diagnosis of COPD/IPF/CPFE with PH, based on these same guidelines, can be considered when the mPAP is 25 mm Hg or more. A patient may have COPD/IPF/CPFE with severe PH when his or her mPAP exceeds 35 mm Hg, or is 25 mm Hg or greater in the presence of a low cardiac output, the guidelines says (Eur Heart J. 2016;37:67-119). “That begins to separate out a group that may potentially benefit from targeted PH therapy,” Dr. Fenster said.

Current treatment approaches include long-term oxygen, diuretics, transplant, and pulmonary rehabilitation, but Dr. Fenster said there is sparse data on the optimal treatment approach. A study of sildenafil in IPF known as STEP-IPF failed to increase 6-minute walking test distance but improved diffusion capacity of carbon monoxide, quality of life, and arterial oxygenation (N Engl J Med. 2010;363:620-8). A study evaluating riociguat for idiopathic interstitial pneumonitis PH was discontinued early because of increased risk of death and adverse events. More recently, the drug ambrisentan was found to be ineffective at reducing the rate of IPF progression and was linked to an increase in disease progression events, including a decline in pulmonary function test values, hospitalization, and death, in the ARTEMIS-IPF trial (Ann Intern Med. 2013;158:641-9).

Randomized, placebo-controlled studies of bosentan in IPF give researchers pause for hope, Dr. Fenster said. BUILD-1 demonstrated a trend toward delayed time to death, delayed disease progression, improved quality of life, and no clear worsening of IPF (Am J Respir Crit Care Med. 2008;177[1]:75-81), while BUILD-3 showed a significant improvement in forced vital capacity (FVC) and carbon monoxide diffusing capacity (Am J Respir Crit Care Med. 2011;184[1]:92-9). A more recent trial evaluated IV treprostinil in 15 patients with interstitial lung disease and PH (Thorax 2014;69[2]:123-9). Eight of the patients had IPF. “After 12 weeks of treprostinil therapy, almost all of them experienced some degree of improvement in their walk distance,” said Dr. Fenster, who was not involved with the study. “Perhaps more importantly there were significant improvements in almost all parameters from their right heart catheterizations. So when we think about how to treat these patients, we have to weigh the risks and benefits of what we make potentially worse with our IPF therapy, such as worsening hypoxia, V/Q mismatch, disease progression, and volume overload. On the flip side, we might be improving right heart hemodynamics and RV function, which are prognostic in this disease. What’s the net balance of these things in terms of how it translates into functional capacity, quality of life, hospitalization, and mortality? We don’t know.”

According to Dr. Fenster, current data suggest that future IPF PH research should focus on prostanoid pathways and not on the estrogen-receptor and riociguat pathways to determine effective treatments. “We have numerous studies showing potential harm with IPF PH therapy, so we need to very much wade cautiously into this arena,” he said. “There is a potential role for PH therapy in IPF, but we will likely need to study patients with severe PH and IPF to show benefit. I think that’s where we’ll have the most success.”

Dr. Fenster reported having no relevant financial disclosures.

dbrunk@frontlinemedcom.com

Detecting PH in IPF ‘more art than science’