Safety and Tolerability of Thrombin Inhibition in Scleroderma‐Associated Interstitial Lung Disease

Abstract

ObjectiveInterstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) (scleroderma) and the leading cause of scleroderma‐related deaths. There exists an unmet need for a new drug therapy for ILD‐complicated SSc. Substantial evidence supports an important role for thrombin in the pathogenesis of SSc‐associated ILD (hereafter SSc‐ILD), and targeting thrombin with a direct thrombin inhibitor could prove to be a novel and effective treatment strategy. As a first step toward designing a clinical trial to test the efficacy of thrombin inhibition in SSc‐ILD, we conducted this study to test the safety and tolerability of dabigatran in patients with SSc‐ILD.MethodsWe performed a prospective, single‐center, open‐label treatment trial with the direct thrombin inhibitor, dabigatran, in patients with SSc‐ILD. Any patient with a history of gastrointestinal hemorrhage or gastric antral vascular ectasia was excluded. Blood monitoring was performed monthly, and patient‐reported outcomes, pulmonary function tests, and skin scores were obtained at baseline and at 3‐ and 6‐month visits. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at baseline and at 6 months for measurement of lung thrombin activity.ResultsOf 15 patients with SSc‐ILD, 14 completed 6 months of treatment with dabigatran at 75 mg taken orally twice daily. Adverse events were uncommon and usually mild or unrelated to the study medication. No serious adverse event was observed. Dabigatran was well tolerated, and we observed no significant gastrointestinal, pulmonary, or other safety issues or intolerability. BAL fluid thrombin activity decreased or remained stable in 13 of 14 (92.8%) subjects.ConclusionDabigatran appears to be safe and well tolerated in patients with SSc‐ILD. A larger randomized controlled trial to test the efficacy of direct thrombin inhibition with dabigatran can be considered.

Direct Oral Anticoagulants and Interstitial Lung Disease: Emerging Clues from Pharmacovigilance

“…Second, alveolar hemorrhage may occur (and manifest as ILD) with apixaban and rivaroxaban, which, respectively, have higher metabolic liability (drug interaction potential) and bleeding risk as compared to dabigatran [1]. Conversely, the lack of consistent disproportionality for dabigatran is in agreement with current evidence and may have a biological rationale: marked anti-inflammatory and antifibrotic effects were demonstrated in a bleomycin model of ILD [7], and preliminary clinical evidence in 15 patients with ILD and systemic sclerosis showed good tolerability of dabigatran without serious adverse events [8].…”

An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

“…Moreover, thrombin was also demonstrated to stimulate fibroblast proliferation and myofibroblast transition [ 10 ]. Dabigatran has been studied in a 6-month, phase 1, prospective, single-centre, open-label study in SSc patients with interstitial lung disease (ILD) [ 11 ]. The dose was 75 mg twice daily.…”

Drug Repurposing Prediction and Validation From Clinical Big Data for the Effective Treatment of Interstitial Lung Disease

“…The usefulness of dabigatran is not limited to the prevention of drug-induced ILD, as ILD is a frequent complication of fibrotic disease such as systemic sclerosis (SSc). A recent, prospective, open-label clinical study indicated that dabigatran appears to be safe and well tolerated in patients with SSc-associated ILD ( Silver et al, 2019 ).…”