Low vs. High-Dose Proton Pump Inhibitor in the Prevention of Bleeding after Endoscopic Submucosal Dissection: A Multicenter, Non-Inferiority, Randomized, Controlled Clinical Trial

Abstract

Background: High dose continuous proton pump inhibitors (PPIs) (80 mg intravenous bolus dose of a PPI followed by a continuous infusion at 8 mg/h) are widely used for preventing post-endoscopic submucosal dissection (ESD) bleeding based on the clinical guidelines for peptic ulcer bleeding. Artificial ulcers refer to the wound surface after ESD, which is the pathological basement of bleeding. As we know that the pathophysiologic mechanisms of peptic ulcers and artificial ulcers are different, the application of PPIs should be not the same in the two kinds of ulcers. Artificial ulcer after ESD is relatively easy to heal, and the risk of bleeding is lower than peptic ulcer. Therefore, we aim to investigate whether low dose intermittent use of PPIs is sufficient to prevent post-ESD bleeding.

Methods: This multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients (≥18 years) with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose (esomeprazole 40 mg intravenously twice a day for 3 days.) or continuous high-dose (esomeprazole 80 mg bolus injection followed by a continuous infusion at 8 mg/h for 3 days) PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. Randomization was done by an independent statistician using a computer-generated random number, and kept in sealed, opaque envelopes. Endoscopists were blinded to treatment allocation. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%。This study was registered with ClinicalTrials.gov, number ChiCTR-IOR-17012738.

Findings: 526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to intermittent (n=209) or continuous (n=205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 14 (6.7%, 95% CI 3.3%-10.5%) of 209 within 7 days in the intermittent group, and 12 (5.9%, 95% CI 2.9%-9.3%) of 205 in the continuous group (P=0.723). The absolute risk reduction (ARR) was 0.84 (-3.83，5.5). There was no difference in the ulcer healing rate between the two groups one month after ESD (P=0.875).

Interpretation: The intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs.

Trial Registration: Registered at the Clinical Trial Registration site in China (http://www.chictr.org.cn/index.aspx) under the number ChiCTR-IOR-17012738

Funding Statement: This work was supported by Chongqing Science and Technology Commission (2019MSXM001) and Army Medical University (2018XLC2011).

Declaration of Interests: None.

Ethics Approval Statement: The study protocol was approved by the ethics committee of Xinqiao Hospital, Army Medical University (AF/SL-02/1.0). All patients provided written informed consents after ESD.