Background/Purpose:

Studies from our laboratory and others have shown thrombin to be a fibrogenic mediator implicated in the pathogenesis of ILD, including scleroderma-associated ILD (SSc-ILD). Thrombin activity is high in SSc-ILD bronchoalveolar lavage fluid (BALF), and normal lung fibroblasts transform to a myofibroblast phenotype upon exposure to thrombin. Dabigatran etexilate (Pradaxa^®) is a selective thrombin inhibitor approved for the prevention of thromboembolic complications. On the basis of strong preclinical in vitro and animal data demonstrating that thrombin inhibition can ameliorate lung fibrosis, we have conducted a single-site, open-label study to establish the safety of Dabigatran etexilate in SSc-ILD patients.

Methods:

Dabigatran etexilate was administered orally in a dose of 75 mg twice daily for 6 months to 15 patients with SSc-ILD having no contraindication to anticoagulant therapy (ClinicalTrials.gov Identifier NCT02426229). Safety and tolerability of Dabigatran etexilate were monitored by history, PE, questionnaires and laboratory studies during the treatment period. Plasma, BALF, skin and lung fibroblasts were obtained before and after treatment.

Results:

15 patients fulfilling the 2013 ACR/EULAR classification criteria have been enrolled: 13 have completed, 1 subject is still enrolled, and 1 subject was withdrawn due to noncompliance. Baseline characteristics are as follows: 13 females and 2 males; 6 African Americans and 9 Caucasians; 5 limited and 10 diffuse cutaneous SSc; age 47.5 ±9.6 years (mean ±SD); disease duration 4.1 ±3.3 years; modified Rodnan Skin Score 16.0 ±10.3; SSc Health Assessment Questionnaire 1.4 ±0.6; UCLA SCTC GIT score 0.79 ±0.58; Baseline Dyspnea Index 7.9 ±3.1; FVC % predicted 70.6 ±15.4; DLCO % predicted 54.3 ±14.1.

Overall, Dabigatran etexilate has been well tolerated. There have been no serious adverse events. Mild adverse events include: fatigue (n=1), epistaxis (n=3), menorrhagia (n=2) and cystitis (n=1). One moderate adverse event occurred in a subject with headache found to be unrelated to study medication. Monthly laboratory monitoring has shown no clinically significant change in CBC, CMP, PT/INR or PTT, but did show the expected prolongation of thrombin time (TT). Exploratory analysis before and after Dabigatran etexilate treatment revealed that the most profound reduction in thrombin activity was observed in a patient having high BALF thrombin activity at baseline, and this patient also demonstrated the greatest reduction in collagen type I and α-smooth muscle actin in skin fibroblasts, as well as reduction of α-smooth muscle actin in lung fibroblasts.

Conclusion:

Our data suggest that Dabigatran etexilate at a dose of 75 mg twice daily is safe and well tolerated in patients with SSc-ILD. Exploratory analysis suggests that SSc-ILD patients with high BALF thrombin activity may have the greatest potential to benefit from treatment with Dabigatran etexilate. A randomized controlled trial is warranted to establish safety and determine the efficacy of Dabigatran etexilate in patients with SSc-ILD.

Acknowledgements: Funded by NIAMS/NIH R21 AR065089.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-and-suitability-of-a-direct-thrombin-inhibitor-dabigatran-etexilate-in-scleroderma-associated-interstitial-lung-disease-ssc-ild-patients/