The ACE-IPF trial is the first placebo-controlled, double-blind study with an intent-to-treat evaluation of anticoagulation therapy in IPF. In this study, the use of warfarin in patients with progressive IPF was associated with increased mortality when compared with placebo (adjusted hazard ratio, 4.85; 95% confidence interval, 1.38–16.99). Warfarin did not impact QOL measures or secondary endpoints. The DSMB recommended discontinuation of the study based on the low probability of demonstrating study drug efficacy and an excess of mortality in the warfarin treatment arm. The cause of the excess mortality events remains unknown, but the events do not appear to be related to the known safety profile of warfarin.
The ACE-IPF study was stopped before reaching the prespecified interim analysis boundaries for the composite primary endpoint or all-cause mortality. However, a trend of higher mortality in the warfarin group was observed along with similar trends in all-cause hospitalization, respiratory-related hospitalization, and acute exacerbation of IPF. Together, these trends pointed to the possibility that warfarin treatment contributed to a worsening of the underlying respiratory status in these patients. This effect did not appear to be explained by baseline imbalances or influenced by individual centers, and, if proven true, worsening of respiratory status by warfarin is an entirely novel consequence of this therapy.
Point-of-care INR monitoring has been used in prior trials. To our knowledge, this is the first clinical trial to double-blind warfarin therapy based on internet-directed, encrypted INR monitoring at the subject’s home. No patients in our trial were on warfarin at the time of randomization. The time in target range of the INR by this home point-of-care methodology was similar to that achieved in the warfarin-naive cohort of a recent clinical trial over a similar treatment period (15
In contrast to our findings, a prior smaller study demonstrated a significant survival benefit for anticoagulation with prednisolone compared with prednisolone alone in patients with IPF (10
). Our overall trial design included a matched, placebo control group, double blinding, and an intention-to-treat data analysis. Additionally, our treatment protocol did not include low molecular weight heparin or mandated prednisolone in all subjects. It is unknown if the potential effects of corticosteroids or short-term heparin administration may have contributed to the beneficial outcome (16
). Additionally, our trial enrolled patients with a significantly lower DlCO
(mean, 34% vs. 62% predicted), with all deaths in both treatment arms occurring among subjects with enrollment DlCO
less than 45%.
The reduction in D-dimer levels in the warfarin group at 16 weeks is evidence for suppression of thrombosis and fibrinolysis in our IPF population (see
Appendix EC). Despite this biologic effect, the excess mortality and hospitalizations noted in the warfarin-treated group were not a consequence of major and minor bleeding, as assessed by blinded adjudication. Furthermore, INR safety data showed no indication that the deaths were associated with INR values outside the target range (2.0 – 3.0). Thus, we are left with the unexplained clinical observation that respiratory worsening, the common mode of disease progression in patients with IPF, was the most common feature contributing to the excess mortality in the warfarin group. Biologically plausible explanations for our observations include, but are not limited to, worsening of respiratory disease due to alveolar hemorrhage; unexpected detrimental effects of inhibiting the activity of factor II, VII, IX, and X simultaneously or on noncoagulant, vitamin K–dependent proteins; or loss of the beneficial effects of protein C on inflammation and remodeling (4
There were several strengths related to study design and execution. We successfully randomized and blinded the study using an encrypted home INR monitoring system. Also, the observed rates of mortality in both groups had 95% confidence intervals that were comparable to patients with IPF with similar disease severity, supporting the general applicability of our findings to patients with IPF with similar physiologic impairment (18
). Additionally, a central adjudication committee evaluated the key components of the composite endpoint while being blinded to treatment arm.
The study was not designed to address the molecular mechanisms involved in the treatment effect or to address the potential benefits of alternative forms of anticoagulation, such as heparin, or direct inhibitors of either factor Xa or thrombin. Therefore, we are unable to offer evidence of a mechanism for the outcome in this trial or comment on the usefulness of alternative anticoagulants. Last, early discontinuation of the study limited the available information for secondary endpoints.
The excess mortality in the warfarin arm appeared to be due to respiratory worsening (exacerbation or progression), which accounted for greater than two-thirds of the observed deaths. We must emphasize that patients who required anticoagulation for non–IPF-related reasons were excluded from this study. Therefore, our findings do not address the use of warfarin in patients with IPF who have acknowledged indications for anticoagulation. This trial demonstrated the success of the encrypted INR home monitoring system and consequent low frequency of major bleeding events. This study has significantly altered the balance of evidence related to the use of warfarin in patients with IPF. Based on our results, warfarin, as studied in this trial, should not be used for the treatment of progressive IPF.