Management and outcome of gastrointestinal bleeding in patients taking oral anticoagulants or antiplatelet drugs

Background

Non-vitamin K dependent oral anticoagulants (NOACs) significantly decrease overall major bleeding rates compared with vitamin K antagonists (VKAs) but there is conflicting evidence regarding the relative risk of gastrointestinal bleeding. Since data regarding the types, the management, and the outcome of NOAC-associated gastrointestinal bleeding are scarce, we aimed to fill this gap by comparing cases of gastrointestinal bleeding associated with NOAC, VKA, or antiplatelet therapy.

Methods

All major gastrointestinal bleeding events documented in the prospective Dresden NOAC registry were identified, and bleeding location, lesion type, endoscopic treatment, use of blood and coagulation factor transfusion, length of stay, and in-hospital mortality were compared with historical data from a large cohort of consecutive gastrointestinal bleeding patients.

Results

In the 143 NOAC therapy cases, upper gastrointestinal tract bleeding was seen in 44.1%, lower gastrointestinal tract bleeding was seen in 42.0%, and no lesion could be identified in the remaining 14.0%. In contrast, upper gastrointestinal tract bleeding was commoner in the 185 VKA therapy cases (53.0%) and in the 711 antiplatelet therapy cases (68.1%). Among cases with upper gastrointestinal tract bleeding during VKA or antiplatelet therapy, 54.1% and 61.4% respectively presented with ulcers, compared with 27.0% for NOAC therapy. In contrast, hemorrhoid bleeding was the predominant lesion type for lower gastrointestinal tract bleeding with NOAC therapy, with a rate of 33.3%, compared with 10.6% with VKA therapy and 8.7% with antiplatelet therapy. NOAC-associated gastrointestinal bleeding resulted in comparatively low resource consumption, shorter hospitalization, and low in-hospital mortality (1.6%) compared with gastrointestinal bleeding historically seen with use of VKAs (in-hospital mortality 5.6%) or antiplatelet agents (in-hospital mortality 11.9%).

Conclusions

Gastrointestinal bleeding in NOAC recipients is different from that seen with VKA or antiplatelet therapy and has a better short-term prognosis.

     

New predictive model for acute gastrointestinal bleeding in patients taking oral anticoagulants: A cohort study

Background and Aim

The study developed a predictive model of long‐term gastrointestinal (GI) bleeding risk in patients receiving oral anticoagulants and compared it with the HAS‐BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratios, Elderly, Drugs/alcohol concomitantly) score.

Methods

The study periodically followed a cohort of 508 patients taking oral anticoagulants (66 direct oral anticoagulants users and 442 warfarin users). Absence of GI bleeding at an initial examination and any subsequent GI bleeding were confirmed endoscopically. The bleeding model was developed by multivariate survival analysis and evaluated by Harrell's c‐index.

Results

During a median follow‐up of 31.4 months, 42 GI bleeds (8.3%) occurred: 42.8% in the upper GI tract, 50.0% in the lower GI tract, and 7.1% in the middle GI tract. The cumulative 5 and 10‐year probability of GI bleeding was 12.6% and 18.5%, respectively. Patients who bled had a significantly higher cumulative incidence of all‐cause mortality (hazard ratio 2.9, P < 0.001). Multivariate analysis revealed that absence of proton pump inhibitor therapy, chronic kidney disease, chronic obstructive pulmonary disease, history of peptic ulcer disease, and liver cirrhosis predicted GI bleeding. The c‐statistic for the new predictive model using these five factors was 0.65 (P < 0.001), higher than the HAS‐BLED score of 0.57 (P = 0.145).

Conclusions

Gastrointestinal bleeding increased the risk of subsequent mortality during follow‐up of anticoagulated patients, highlighting the importance of prevention. The study developed a new scoring model for acute GI bleeding risk based on five factors (no‐proton pump inhibitor use, chronic kidney disease, chronic obstructive pulmonary disease, history of peptic ulcer disease, and liver cirrhosis), which was superior to the HAS‐BLED score.     

Risk factors for bleeding in patients taking coumarins

Coumarins (e.g., warfarin) are used for the treatment and prophylaxis of venous and arterial thromboembolism. Unfortunately, their use is limited by bleeding. In deciding whether to initiate coumarin therapy, the therapeutic benefits must be weighed against the potential risk of bleeding for each individual patient. The major determinants of coumarin-related bleeding are the intensity of anticoagulant effect as measured by the International Normalized Ratio, patient characteristics, concomitant use of other drugs, and the length of anticoagulant therapy. At the initiation of coumarin therapy, the risk factors for bleeding can be identified by the COUMARINS acronym and by one of the bleeding prediction models. During ongoing therapy with coumarins, the risks and benefits of therapy should be reassessed periodically. This article reviews the current evidence for the prediction and prevention of coumarin-related bleeding.     

Reversal of novel oral anticoagulants in patients with major bleeding

Novel oral anticoagulants (NOACs) that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) are effective therapies for the prevention and treatment of thromboembolism with reduced bleeding complications compared with warfarin for some indications. However, specific antidotes to reverse the anticoagulant activity of NOACs in the event of major bleeding are not available. Evidence supporting non-specific prohemostatic therapies (prothrombin complex concentrate [PCC], activated prothrombin complex concentrate [aPCC], recombinant factor VIIa) in this setting is limited to healthy human volunteers, animal models, and in vitro studies. Clinical outcome data are lacking. Administration of PCC or aPCC may be considered in addition to supportive measures for patients with severe or life-threatening bleeding. Clinical studies are needed to establish the efficacy and safety of these treatments. Target-specific antidotes are in development and hold promise for NOAC reversal, but require further investigation.     

The oncology treatment of patients who use oral anticoagulants is connected with high risk of bleeding complications

The data about risk for bleeding complications during anticoagulation in cancer patients with different oncology treatment are conflicting. To investigate the rate of bleeding in the course of oral anticoagulants, during treatment of malignant diseases, we conducted a retrospective study including 75 patients on stable anticoagulation prior to commencing their different oncology treatment. All patients were treated according to the consiliar decision, made based on the localization and pathohistological findings of the malignant disease. During their treatment the regular laboratory monitoring of INR was done. Every dose of oral anticoagulants, INR changes, as well as the size and localization of bleeding were recorded. During all the malignancy treatment 22 (30%) of patients were overanticoagulated. In 15 (20%) patients it was associated with bleeding, while 3 (4%) of them had to be transfused with fresh frozen plasma to stop the major bleeding. Most bleeding complications occurred in the group of patients treated with chemotherapy or with analgesics in the group with advanced disease. None of the bleeding complications were observed in patients treated with irradiation and surgery alone, where the bridging of oral anticoagulants with low molecular weight heparin was done before surgery. The oncology treatment of patients who take oral anticoagulants was connected with high risk for bleeding especially if chemotherapy as a therapeutic options was used. Therefore physicians should be aware of this risk and carefully monitor the intensity of anticoagulant therapy, especially during the first treatment weeks when the risk of bleeding is greatest.     

Assessing adherence in Thai patients taking combination antiretroviral therapy

In settings where medications and viral load (VL) monitoring are limited by cost, clinicians need reliable ways to assess patient adherence to therapy. We assessed sensitivity and specificity of two self-reported adherence tools (a visual analogue scale [VAS] and the CASE [Center for Adherence Support Evaluation] adherence index), against a standard of detectable VL, with 288 patients from three sites in Thailand. We also assessed predictors of non-adherence. The sensitivity and specificity of the VAS <95% and CASE adherence index ≤11 against a VL >50 copies/mL were 26% and 90%, 19% and 95%, respectively. Against a VL ≥1000 copies/mL sensitivities increased to 55% and 36%, respectively, and specificities were unchanged. Attending a clinic not staffed by HIV specialists (odds ratio [OR] 3.14; 95% confidence interval [CI] 1.19-8.34) and being educated to primary school level or less (OR 2.24; 95% CI 1.01-4.94) were associated with self-reported adherence <95% on the VAS in multivariate analysis. Adherence assessed by the VAS was a more accurate predictor of detectable VL. Policy-makers in resource-limited settings should ensure that treatment centres are staffed with well-trained personnel aware of the importance of good patient adherence.     

Active online assessment of patients using new oral anticoagulants: bleeding risk, compliance, and coagulation analysis

Clinicians prescribing new oral anticoagulants (OACs; dabigatran, rivaroxaban, and apixaban) should be aware of the exclusion criteria related to bleeding risks defined in published clinical studies. At least a quarter of patients currently using warfarin have an exclusion criterion that may prevent easy transition to the new OACs. In the summary of product characteristics for dabigatran, as an example, the target populations appear generalized. Due to fixed dosing and predictable pharmacology, routine laboratory monitoring of new OACs is deemed unnecessary. Under special circumstances, however, understanding the extent of thrombin or factor (F) Xa inhibition may aid in evaluating compliance and handling emergency interventions, bleeding complications, or overdoses. Although commonly available global coagulation-time assessments (prothrombin time and activated partial thromboplastin time) are insensitive, they may assist clinical management by indicating a severe accumulation of OACs; moreover, a normal thrombin time (TT) excludes a thrombin-inhibitor effect. In particular circumstances, specific assays (diluted TT, Ecarin clotting time, anti-FIIa or anti-FXa activity) may quantify the anticoagulant effect, but therapeutic ranges for dose adjustment are not yet established. Laboratory results are also influenced by clinical situation: e.g. bleed (consumption of coagulation factors) versus postoperative state (activation of coagulation). Without specific antidotes and evidence-based treatment strategies, new OACs are clinically worrisome in patients with impaired renal or liver function. Postmarketing surveillance and recording of bleeding complications (ICD-10 D68.32) are therefore of major importance.     

Comparison of clinical performance of four gastrointestinal bleeding risk scores in Chinese patients with atrial fibrillation receiving oral anticoagulants

Gastrointestinal bleeding is the most common bleeding complication during anticoagulant therapy. A reliable bleeding risk score can help the clinician assess risk of bleeding in individual patients and select the anticoagulant regimen. This study retrospectively analyzed the data of patients with atrial fibrillation who received anticoagulant therapy from July 2015 to December 2018 at two centers—the Fujian Medical University Union Hospital and Fuzhou Second Hospital Affiliated to Xiamen University. Demographic data, clinical findings, and laboratory results were collected from the hospital records. Patients were followed up for 6 months. The performance of four bleeding risk scores (New Score, RIETE Score, Cuschieri et al. Score, de Groot et al. Score) for prediction of gastrointestinal bleeding was assessed using the area under the curve. A total of 3462 patients (mean age, 66.3?±?11.5 years; 59.6% males; 1055 direct oral anticoagulants users and 2407 warfarin users) were followed up for 6 months. While 99/3462 (2.9%) patients had gastrointestinal bleeding. The area under the curves for the New, RIETE, Cuschieri et al., de Groot et al. scores were 0.652 (95% CI 0.576–0.728), 0.862 (95% CI 0.809–0.914), 0.606 (95% CI 0.527–0.685), and 0.873 (95% CI 0.816–0.929), respectively. Among the four BRSs evaluated, the RIETE score and the de Groot et al. score appear to have the good predictive value, while the NEW score and the Cuschieri et al. score did not sufficiently predict gastrointestinal bleeding risk within the study Chinese population.

     

血清生长分化因子15及ABC出血风险评分在预测老年非瓣膜病心房颤动患者口服非维生素K拮抗剂抗凝药出血风险的临床应用初探

目的 探讨血清生长分化因子15(GDF-15)及以此为基础的ABC(年龄、生物标志物和临床病史)出血风险评分在老年(年龄≥65岁)非瓣膜病心房颤动(NVAF)患者使用非维生素K拮抗剂口服抗凝药物(NOAC)治疗后,随访期间发生出血事件的预测能力,并与传统HAS-BLED出血风险评分比较。方法 选取心血管内科住院收治的、首次诊断为NVAF且接受NOAC治疗的老年患者,采集入选患者的临床资料并分析血清GDF-15水平,计算以GDF-15等心脏生物标志物为基础的ABC出血风险评分及HAS-BLED出血风险评分。对患者出院后进行随访,记录随访期间各种出血事件,按各出血事件的严重程度[重大出血事件、临床相关非重大出血的消化道出血事件(CRNM-GIB)、轻微出血事件、无出血事件]分组,分别评价及比较ABC出血风险评分与HAS-BLED出血风险评分对各种程度出血事件的预测能力。结果 142例老年NVAF患者,CHA₂DS₂-VASc卒中风险评分为(4.86±1.75)分,HAS-BLED出血风险评分为(2.92±0.99)分,经ABC出血风险评分计算预测...     

Long-term prognosis in patients continuing taking antithrombotics after peptic ulcer bleeding

AIM To investigate the long-term prognosis in peptic ulcer patients continuing taking antithrombotics after ulcer bleeding, and to determine the risk factors that influence the prognosis. METHODS All clinical data of peptic ulcer patients treated from January 1, 2009 to January 1, 2014 were retrospectively collected and analyzed. Patients were divided into either a continuing group to continue taking antithrombotic drugs after ulcer bleeding or a discontinuing group to discontinue antithrombotic drugs. The primary outcome of follow-up in peptic ulcer bleeding patients was recurrent bleeding, and secondary outcome was death or acute cardiovascular disease occurrence. The final date of follow-up was December 31, 2014. Basic demographic data, complications, and disease classifications were analyzed and compared by t- or χ2-test. The number of patients that achieved various outcomes was counted and analyzed statistically. A survival curve was drawn using the Kaplan-Meier method, and the differencewas compared using the log-rank test. COX regression multivariate analysis was applied to analyze risk factors for the prognosis of peptic ulcer patients. RESULTS A total of 167 patients were enrolled into this study. As for the baseline information, differences in age, smoking, alcohol abuse, and acute cardiovascular diseases were statistically significant between the continuing and discontinuing groups(70.8 ± 11.4 vs 62.4 ± 12.0, P 0.001; 8(8.2%) vs 15(21.7%), P 0.05; 65(66.3%) vs 13(18.8%), P 0.001). At the end of the study, 18 patients had recurrent bleeding and three patients died or had acute cardiovascular disease in the continuing group, while four patients had recurrent bleeding and 15 patients died or had acute cardiovascular disease in the discontinuing group. The differences in these results were statistically significant(P = 0.022, P = 0.000). The Kaplan-Meier survival curve indicated that the incidence of recurrent bleeding was higher in patients in the continuing group, and the risk of death and developing acute cardiovascular disease was higher in patients in the discontinuing group(log-rank test, P = 0.000 for both). Furthermore, COX regression multivariate analysis revealed that the hazard ratio(HR) for recurrent bleeding was 2.986(95%CI: 067-8.356, P = 0.015) in the continuing group, while HR for death or acute cardiovascular disease was 5.216(95%CI: 1.035-26.278, P = 0.028).CONCLUSION After the occurrence of peptic ulcer bleeding, continuing antithrombotics increases the risk of recurrent bleeding events, while discontinuing antithrombotics would increase the risk of death and developing cardiovascular disease. This suggests that clinicians should comprehensively consider the use of antithrombotics after peptic ulcer bleeding.     

Effect of gastroprotective agents on upper gastrointestinal bleeding in patients receiving direct oral anticoagulants

Abstract

Objectives: Direct oral anticoagulants (DOACs) are effective in the prevention and treatment of thromboembolism; however, they are associated with upper gastrointestinal bleeding (UGIB). In this study, we evaluated the efficacy of gastroprotective agents (GPAs) in reducing the risk of UGIB in patients receiving DOACs.

Methods: We retrospectively reviewed the medical records of 2076 patients who received DOACs for the prevention or treatment of thromboembolic events between January 2008 and July 2016. A cumulative incidence analysis using the Kaplan–Meier method was performed to determine the rate of UGIB and its association with GPAs administration.

Results: Of the 2076 patients, 360 received GPAs. Over the follow-up period (1160 person-years), one patient in the GPA group (0.7 per 100 person-years) and 29 patients in the non-GPA group (2.8 per 100 person-years) developed UGIB (p?=?.189). In the multivariate analysis, UGIB was associated with older age (hazard ratio (HR), 1.041; p?=?.048), a history of peptic ulcer or UGIB (HR, 5.931; p?p?=?.014). GPAs administration did not reduce the risk of UGIB (p?=?.289). However, based on the subgroup analysis of 225 patients with concomitant use of antiplatelet agents or a history of peptic ulcer or UGIB, the GPA group (0 per 100 person-years) showed reduced incidence of UGIB compared with the non-GPA group (11.3 per 100 person-years) (p?=?.065).

Conclusions: The prophylactic use of GPAs could reduce the risk of UGIB in patients receiving DOACs who have risk factors, such as concomitant use of antiplatelet agents or a history of peptic ulcer or UGIB.