Conference Coverage

Warfarin found to increase adverse outcomes among patients with IPF



– Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.

Dr. Christopher King, medical director, transplant and advanced lung disease critical care program, Inova Fairfax (Va.) Hospital Michele G. Sullivan/MDedge News

Dr. Christopher King

Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.

“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.

“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”

The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.

In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).

In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).

But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.

They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.

The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.

There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.

Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).

In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).

A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.

The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.

The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.

“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”

Dr. King had no disclosures.

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