Efficacy of vonoprazan against bleeding from endoscopic submucosal dissection-induced gastric ulcers under antithrombotic medication: A cross-design synthesis of randomized and observational studies

Vonoprazan, a potassium-competitive acid blocker, is expected to be superior to proton pump inhibitors (PPIs) in preventing post-endoscopic submucosal dissection (ESD)-induced gastric bleeding. However, the results of randomized controlled trials (RCTs) and observational studies on the efficacy of vonoprazan have been inconsistent. This study aimed to evaluate the effectiveness of vonoprazan in antithrombotic drug users, a population that has been excluded from RCTs. Treatment effects were assessed using cross-design synthesis, which can be adjusted for differences in study design and patient characteristics. We used data from an RCT in Japan (70 patients in the vonoprazan group and 69 in the PPI group) and an observational study (408 patients in the vonoprazan group and 870 in the PPI group). After matching, among the antithrombotic drug users in the observational study, post-ESD bleeding was noted in 8 out of 86 patients in the vonoprazan group and 18 out of 86 patients in the PPI group. After pooling the data from the RCT and observational study, the risk difference for antithrombotic drug users was -14.6% (95% CI: -22.0 to -7.2). CDS analysis suggested that vonoprazan is more effective than PPIs in preventing post-ESD bleeding among patients administered antithrombotic medications.

Direct oral anticoagulants increase bleeding risk after endoscopic sphincterotomy: a retrospective study

Background Bleeding can be a serious adverse event of endoscopic sphincterotomy (EST). However, the risk of EST bleeding between direct oral anticoagulant (DOAC) users and those who received no antithrombotic agents has not been clarified. This study analyzed the risk factors for bleeding after EST in patients on DOAC and evaluated the Japan Gastroenterological Endoscopy Society (JGES) guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Methods We retrospectively analyzed 524 patients treated with EST who received DOAC or no antithrombotic drug from May 2016 to August 2019. We investigated the risk factors for bleeding. DOAC was typically discontinued for ≤ 1-day based on the JGES guideline. Although DOAC therapy recommenced the next morning after EST in principle, the duration of DOAC cessation and heparin replacement were determined by the attending physician based on each patient’s status. Results The number of patients on DOAC (DOAC group) and those not on antithrombotic drug (no-drug group) was 42 (8.0%) and 482 (92.0%), respectively. DOAC was discontinued for ≤ 1-day in 17 (40.0%) patients and for > 1-day in 25 (60.0%). Of the 524 patients, 21 (4.0%) had EST bleeding. The bleeding rate was higher in the DOAC group (14.0%) (p = 0.004). Multivariate analysis showed that bleeding occurred more frequently in patients on DOAC (odds ratio [OR] 3.95, 95% confidence interval [CI] 1.37–11.4, p = 0.011), patients with low platelet counts (< 100,000/µl) (OR 6.74, 95% CI 2.1–21.6, p = 0.001), and elderly patients (> 80 years old) (OR 3.36, 95%CI 1.17–9.65, p = 0.024). Conclusions DOAC treatment, low platelet count, and old age (> 80 years old) are risk factors for EST bleeding. Although the bleeding incidence increased in patients on DOAC who received antithrombotic therapy according to the JGES guidelines, successful hemostasis was achieved with endoscopy in all cases, and no thrombotic events occurred after cessation of DOAC. Thus, the JGES guidelines are acceptable.

Knockdown screening of chromatin binding and regulatory proteins in zebrafish identified Suz12b as a regulator of tfpia and an antithrombotic drug target

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits factor VIIa and Xa in the coagulation cascade. It has been shown that forkhead box P3 protein is a TFPI transcriptional repressor. However, there are no studies on chromatin remodeling that control TFPI expression. We hypothesized that the genome-wide knockdowns of the chromatin binding and regulatory proteins (CBRPs) in zebrafish could identify novel tfpia gene regulators. As an initial step, we selected 69 CBRP genes from the list of zebrafish thrombocyte-expressed genes. We then performed a 3-gene piggyback knockdown screen of these 69 genes, followed by quantification of tfpia mRNA levels. The results revealed that knockdown of brd7, ing2, ing3, ing4, and suz12b increased tfpia mRNA levels. The simultaneous knockdown of these 5 genes also increased tfpia mRNA levels. We also performed individual gene and simultaneous 5-gene knockdowns on the 5 genes in zebrafish larvae. We found that after laser injury, it took a longer time for the formation of the thrombus to occlude the caudal vessel compared to the control larvae. We then treated the larvae and adults with a chemical UNC6852 known to proteolytically degrade polycomb repressor complex 2, where SUZ12 is a member, and observed prolongation of time to occlude (TTO) the caudal vein after laser injury and increased tfpia mRNA levels in larvae and adults, respectively. In summary, our results have identified novel epigenetic regulators for tfpia and exploited this information to discover a drug that enhances tfpia mRNA levels and prolongation of TTO. This discovery provides the basis for testing whether UNC6852 could be used as an antithrombotic drug. This approach could be used to study the regulation of other plasma proteins, including coagulant and anticoagulant factors.

Effectiveness of antithrombotic prophylaxis in paediatric cardiosurgical patients

<p><strong>Aim.</strong> To evaluate the effectiveness of prevention measures for thrombotic catheter-associated events in the perioperative management of patients undergoing cardiac surgery.</p><p><strong>Methods.</strong> A total of 433 paediatric and neonatal patients were included in the study during the period from January to December 2018. All patients received antithrombotic prophylaxis via systemic heparin administration.</p><p><strong>Results.</strong> Thirty-six patients displayed signs of thrombosis during the postoperative period (8.31%): 28 patients had venous thrombosis, while 6 had the Blalock-Taussig shunt thrombosis, and 2 had arterial thrombosis. The mortality rate was higher in the group with registered thrombosis than in the group without thrombosis (p = 0.01).</p><p><strong>Conclusion.</strong> The dosage regimen for children and neonatal patients should be according to age-associated antithrombotic drug standards. It requires an integral approach for evaluating the effectiveness of preventive and therapeutic measures.</p><p>Received 25 August 2020. Revised 18 December 2020. Accepted 22 December 2020.</p><p><strong>Funding:</strong> The study did not have sponsorship.</p><p><strong>Conflict of interest:</strong> Author declares no conflict of interest.</p>

Medical Management in Moyamoya Disease

Medical treatment seems to be not entirely helpful in the treatment of Moyamoya disease. No evidence supports the benefits of any drug treatment in Moyamoya disease. The ischemic or hemorrhagic event in Moyamoya disease is not preventable with any medical treatment. However, most of the physicians still prescribe the antithrombotic drug for Moyamoya patients with an ischemic event. Moreover, the standard guidelines recommend administering antithrombotic medications to treat Moyamoya with the ischemic event, even the risk of hemorrhagic complication. Antihypertensive drugs are routinely prescribed in Moyamoya patients with or without elevated blood pressure. A literature review about medical treatment in Moyamoya disease should help determine its use in this pathologic condition.