Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis: methodological concerns

From the authors:

We read the correspondence of L. Kawano-Dourado and colleagues related to our article “Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis” with great interest [1]. There is compelling evidence of an association between disturbances in the coagulation system and idiopathic pulmonary fibrosis (IPF); however, results from the ACE-IPF (anticoagulant effectiveness in idiopathic pulmonary fibrosis) randomised controlled trial of the vitamin K antagonist warfarin demonstrated deleterious effects of anticoagulation in IPF [2]. Based on these data, the recent update of the international guideline on IPF gave a strong recommendation against the use of anticoagulants [3]. Yet, the potential risks of medically indicated anticoagulation on mortality and other clinical outcomes in IPF remain unexplored. This is an important clinical question as almost one in every five patients with IPF receives anticoagulants for different indications [4]. In this regard, our post hoc analysis, which describes that patients in the placebo groups treated with anticoagulants in the CAPACITY and ASCEND trials had a higher rate of all-cause and IPF-related mortality compared with non-users, adds further insights in to the potential hazard of anticoagulant use in IPF [1]. We agree with Kawano-Dourado and colleagues that these data should be interpreted in light of the inherent limitations of a post hoc analysis based on a small number of events. However, these data represent, to our knowledge, the largest cohort of IPF subjects in whom this question has been addressed. Furthermore, our data are in line with two retrospective studies in IPF populations that also report a significantly higher risk of mortality in association with the use of anticoagulants for medical indications [5, 6] and this important clinical problem has recently also been highlighted by others [7].

While we agree with Kawano-Dourado and colleagues that, in general, comorbidities significantly affect prognosis in IPF [8], we disagree with their interpretation of the effects of cardiovascular comorbidities and their statement on the attribution to causes of death in our analyses. Given the post hoc nature of our analysis we cannot rule out the possibility of confounding due to differences in unobserved factors, however, on multivariate analysis we did not find an association between observed comorbidities necessitating anticoagulation and death (table 1). With regards attribution of death, this was adjudicated by a blinded clinical investigator in the CAPACITY studies and by a mortality assessment committee in ASCEND [9, 10].

In conclusion, despite the inherent limitations of post hoc analyses our data suggest that anticoagulant use for medically indicated comorbidities may contribute to respiratory worsening and death in IPF. Given that for many indications, e.g. atrial fibrillation, the choice to prescribe anticoagulation is based on an assessment of the balance between potential benefit and risk, and given also that almost 20% of patients with IPF have comorbid indications for anticoagulation further prospective research is urgently needed to elucidate the safest way of managing patients with IPF.

• Received July 25, 2016.
• Accepted July 26, 2016.

• Copyright ©ERS 2016