Acute Nonvariceal Upper Gastrointestinal Bleeding in Patients Using Anticoagulants: Does the Timing of Endoscopy Affect Outcomes?

This was a retrospective cohort study that consecutively included all patients admitted to the Emergency Department (ED) for UGIB and underwent endoscopy in a University-Affiliated Hospital between January 2011 and June 2020. The present study was approved by the local Ethics Committee for Health.

All adult patients (≥ 18 years old) with suspicion of having UGIB at presentation and submitted to endoscopy were included, namely those who presented with hematemesis, melena, hematochezia with hemodynamic instability, or detection of hematic content in a nasogastric tube. In the situation that more than one UEG was performed during the same admission, only the findings of the index endoscopy were included. In addition, patients with one or more of the following items were excluded from the study: not receiving anticoagulants; gastrointestinal variceal bleeding source; documentation of a bleeding cause in the lower or mid gastrointestinal tract; UGIB in an inpatient setting; and ED presentation due to recurrent bleeding from a previous episode of acute UGIB.

Only NVUGIB patients, including those with a definite diagnosis (namely peptic ulcer disease, mucosal erosive disease of the esophagus/stomach, malignancy, Mallory–Weiss syndrome, Dieulafoy’s lesion, angiodysplasias) or without an identifiable cause in endoscopy and taking anticoagulants were considered in the final sample. Patients were then divided into two groups according to the timing of endoscopy: the early endoscopy group (≤ 24 h after presentation) and the delayed endoscopy group (> 24 h after presentation).

According to the recommendations of our department and to the emergency department protocol of our hospital, all patients started intravenous PPI as soon as UGIB was suspected. Following endoscopy, patients with high-risk endoscopic stigmata according to Forrest classification continued on intravenous infusion of PPI for 72 h [13]. Moreover, Forrest IIb stigmata was treated with clot removal followed by endoscopic hemostasis if underlying high-risk stigmata was found [13]. Otherwise, patients received oral PPI, if needed, as indicated by endoscopic findings. Immediate assessment of hemodynamic status was performed with prompt intravascular volume replacement using crystalloid fluids if hemodynamic instability existed. In hemodynamically stable patients with NVUGIB and no history of cardiovascular disease, a restrictive red blood cell transfusion strategy with a hemoglobin threshold of ≤ 7 g/dL prompted red blood cell transfusion. A post-transfusion target hemoglobin concentration of 7–9 g/dL was considered. In patients with a history of acute or chronic cardiovascular disease, a more liberal red blood cell transfusion strategy was followed with a hemoglobin threshold of ≤ 8 g/dL leading to transfusion. A post-transfusion target hemoglobin concentration of ≥ 10 g/dL was considered. Intravenous erythromycin was administered before endoscopy in patients with clinically severe or ongoing active UGIB [10]. The antithrombotic management policy was carried out in accordance with the protocol of the hematology department of our hospital, ensuring that the patient was optimized for the endoscopy without unnecessarily delaying the procedure. In patients taking low-dose aspirin as monotherapy for primary cardiovascular prophylaxis, aspirin was temporarily interrupted and restarted after careful re-evaluation of its clinical indication. For patients taking low-dose aspirin as monotherapy for secondary cardiovascular prophylaxis, aspirin was not interrupted. Patients on dual antiplatelet therapy for secondary cardiovascular prophylaxis had aspirin uninterrupted, while the second antiplatelet agent was interrupted and restarted within 5 days. Patients taking VKA or enoxaparin had these anticoagulants withheld. In patients with hemodynamic instability, low-dose vitamin K was supplemented with intravenous prothrombin complex concentrate (PCC) or fresh frozen plasma if PCC was not available. In patients taking DOAC, the anticoagulant was withheld. For patients with severe ongoing bleeding, the use of a DOAC reversal agent or intravenous PCC was considered.

Several data were retrospectively collected from electronic medical records.

On presentation, demographic data (age and sex), clinical presentation (hematemesis, melena, hematochezia), Glasgow Coma Scale (GCS) score, history of syncope, vital signs [heart rate (HR), systolic and diastolic blood pressure (SBP and DBP, respectively)], laboratory values [i.e., hemoglobin, platelets, creatinine, urea, albumin, and international normalized ratio (INR)], as well as comorbidities (namely, chronic liver disease (CLD), congestive heart failure (CHF), chronic kidney disease (CKD) and disseminated neoplasia] were retrieved. Data were also obtained regarding the use of certain drugs that could be related to bleeding, such as acetylsalicylic acid (ASA) and other antiplatelet agents, nonsteroidal anti-inflammatory drugs (NSAID), anticoagulants (including DOAC, VKA and enoxaparin), steroids, and selective serotonin reuptake inhibitors (SSRI), as well as could drugs that could decrease the probability of bleeding (PPI or H2RA). Date and time of presentation and endoscopy, endoscopic findings, namely etiology of bleeding and stigmata of recent bleeding (for PUD, Forrest classification), and length of hospital stay (days) were recorded [13]. Forrest Ia, Ib, and IIa were considered high-risk stigmata according to Forrest Classification [10].

Different clinical outcomes were analyzed, namely the need for endoscopic or surgical treatment, length of hospital stay, intermediate/intensive care unit admission, recurrent bleeding, and 30-day mortality. Surgery was performed in patients with persistent bleeding refractory to all modalities of endoscopic hemostasis.

Based on these data, many clinical and endoscopic-based scores were calculated for each patient, namely the pre- and the post-endoscopic Rockall score (RS), the Glasgow-Blatchford (GBS) score, and the AIMS65 [14].

Timing of endoscopy was defined as the time elapsed between presentation in the ED and beginning of endoscopy. In patients with PUD as the source of NVUGIB, Forrest classification was assessed [13].

CLD was considered in patients with a known history, or clinical, laboratory, and imaging evidence of liver disease [15], while CHF was defined as a known history or clinical evidence and echocardiography of CHF [16]. CKD was defined in patients with an estimated glomerular filtration rate < 60 mL/min/1.73 m² for ≥ 3 months calculated using the Modification of Diet in Renal Disease Study equation [17]. Disseminated neoplasm was considered in patients with a malignant tumor in whom metastasis was identified. Therapeutic endoscopic intervention included one or more of the following hemostatic strategies: use of hemoclips, endoscopic elastic ligation, argon plasma coagulation, bipolar electrocoagulation, sclerotherapy, with or without a previous injection of adrenaline. Mortality was defined as death for any cause (overall mortality) occurring within 30 days of hospital admission. The need for surgery was defined as the necessity of undergoing laparotomy/laparoscopic intervention if persistent bleeding occurred, defined as ongoing active bleeding (spurting, arterial pulsatile bleeding, or oozing) that was present at the end of index endoscopy and refractory to standard hemostasis modalities [10]. Recurrent bleeding was defined as the observation of an overt bleeding event (hematemesis or melena) or a decrease of at least 2 g/dL in hemoglobin levels after initial treatment and stabilization [18]. Pre- and post-endoscopic RS, GBS, and AIMS65 scores were calculated according to their description in the original articles [14, 19, 20].

Statistical Package for Social Sciences program version 26 (IBM Corporation, Armonk, NY) was used. A univariable analysis was performed to assess differences between the two groups (early and delayed endoscopy). Categorical variables were described using absolute frequencies and percentages. χ² Test or Fisher’s exact test was used to compare categorical variables. Depending on the normality tests, continuous variables were expressed as mean ± standard deviation (SD) or median and interquartile range (IQR). Means were compared between the distinct groups using independent samples t-test. When applicable, non-parametric tests were performed. In addition, multivariable analysis using a logistic or linear regression analysis was performed to assess if timing of endoscopy had any influence on the outcomes that in univariable analysis were significantly different between early and delayed groups. Statistical significance was defined as P < 0.05.

Table 2 displays the outcome variables according to the time from presentation to endoscopy. Of the outcomes considered, only endoscopic treatment [31 (37.8%) vs. 11 (19.6%), P = 0.025] and intermediate/intensive care unit admission [42 (51.2%) vs. 15 (26.7%), P = 0.005] were significantly different between early and delayed groups, respectively.

After adjusting for confounders, on multivariable analysis, the timing of endoscopy (early/delayed) was still identified as an independent predictive factor for endoscopic treatment, length of hospital stay, and intermediate/intensive care unit admission. Patients who underwent early endoscopy received endoscopic therapy more frequently (OR 2.4; 95% CI 1.1–5.4; P = 0.034), had shorter length of hospital stay [7 (IQR 6) vs. 9 (IQR 7) days, P = 0.042] and higher rate of intermediate/intensive care unit admission (OR 2.7; 95% CI 1.3– 5.9; P = 0.01] than patients having delayed endoscopy (Tables 3, 4, 5). In addition, the GCS at admission was found to be an independent predictive factor for intermediate/intensive care unit admission. Patients with lower GCS score at presentation were more likely to be admitted to the intermediate/intensive care unit (OR 0.6; 95% CI 0.37–0.96; P = 0.032).