Editorial

Editorial

A vision for JGIM

Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88–1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

To identify demographic and clinical risk factors associated with gastrointestinal (GI) bleeding among a large cohort of patients with atrial fibrillation (AF) who initiated dabigatran therapy for stroke prevention, and to describe patterns of subsequent anticoagulant use after occurrence of the GI bleeding event. Retrospective cohort study. Large, nationwide United States commercial insurance database. A total of 21,033 patients with nonvalvular AF who initiated dabigatran between October 19, 2010, and December 31, 2012. We used multivariate Cox regression analysis to estimate the effect of baseline demographic and clinical characteristics on the probability of a GI bleeding event. Patterns of anticoagulation use after GI bleeding were also examined descriptively. Of the 21,033 patients receiving dabigatran, 446 (2.1%) experienced a GI bleed during follow-up. GI bleeding rates differed across many baseline characteristics. Male sex was associated with a lower risk (adjusted hazard ratio [aHR] 0.78, 95% confidence interval [CI] 0.64-0.95) of GI bleeding. Compared with patients younger than 55years, those aged 55-64, 65-74, and 75years or older yielded aHRs of 1.54 (95% CI 0.89-2.68), 2.72 (95% CI 1.59-4.65), and 4.52 (95% CI 2.68-7.64), respectively. Renal impairment (aHR 1.67, 95% CI 1.24-2.25), heart failure (aHR 1.25, 95% CI 1.01-1.56), alcohol abuse (aHR 2.57, 95%CI 1.52-4.35), previous Helicobacter pylori infection (aHR 4.75, 95% CI 1.93-11.68), antiplatelet therapy (aHR 1.49, 95% CI 1.19-1.88), and digoxin use (aHR 1.49, 95% CI 1.19-1.88) were also associated with an increased GI bleeding risk. Of the 446 patients who experienced a GI bleed, 193 (43.3%) restarted an anticoagulant, with most (65.8%) filling prescriptions for dabigatran; the mean time was 50.4days until restarting any subsequent anticoagulant. The risk of GI bleeding in patients receiving dabigatran is highly associated with increased age and cardiovascular, renal, and other comorbidities, even after adjusting for other factors. Fewer than 50% of patients restarted an anticoagulant after experiencing a GI bleed. Clinicians should continue to monitor for these risk factors or consider whether alternative therapies may be appropriate.

There is inadequate information on the risk of gastrointestinal (GI) bleeding in patients who are under rivaroxaban and warfarin therapy in Iran. Determining the risk of GI bleeding in patients receiving these two drugs can help to select a more appropriate anti-coagulation prophylaxis in high-risk patients. The aim of this study was to compare the incidence of GI bleeding in patients with atrial fibrillation (AF) and concomitant bleeding risk factors receiving either warfarin or rivaroxaban. In this observational study, 200 patients with AF and bleeding risk factors who referred to Imam Hossein Hospital (Tehran, Iran) were included. The patients were under treatment with either warfarin or rivaroxaban. The incidence of GI bleeding was compared between the two groups monthly for one year. GI bleedings were observed in 61% and 34% of patients treated with warfarin and rivaroxaban, respectively (P = 0.001).Melena was the most common type of GI bleeding in both groups. History of hypertension, history of stroke, consumption of anti-platelet drugs, NSAID consumption, and history of alcohol consumption were associated with more frequent GI bleeding only in warfarin group. The incidence of GI bleeding was lower in AF patients who received rivaroxaban compared to those treated with warfarin. Also, GI bleeding risk does not change according to the consumption of other anti-coagulant drugs and underlying history of hypertension or stroke in patients received rivaroxaban. Therefore, rivaroxaban is suggested as the choice of prophylaxisin patients with AF and concomitant coagulopathy.

A previous FDA study reported a favorable benefit risk for apixaban compared with warfarin for stroke prevention in older non-valvular atrial fibrillation (NVAF) patients (≥ 65years). However, it remains unclear whether this favorable benefit risk persists in other populations including younger users. We examined if a similar benefit risk was observed in the Sentinel System and if it varied by age group. To examine the risk of ischemic stroke, gastrointestinal (GI) bleeding, and intracranial hemorrhage (ICH) in apixaban users compared with warfarin users in Sentinel Distributed Database (SDD). A retrospective new user cohort study was conducted among patients, 21years and older initiating apixaban and warfarin for NVAF, between December 28, 2012, and June 30, 2018, in the SDD. Cox proportional hazard regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI) for each outcome (ischemic stroke, GI bleeding, and ICH) in propensity score matched apixaban users compared with the warfarin users. Subgroup analyses by age (21-64, 65-74, and 75+ years) were conducted. After matching, 55.3% and 58.4% (n = 55,038) of the apixaban and warfarin users were included in the main analysis. GI bleeding was the most common outcome. The HR (95% CI) for GI bleeding, ICH, and ischemic stroke in apixaban users compared with warfarin users were 0.57 (0.50-0.66), 0.53 (0.40-0.70), and 0.56 (0.45-0.71) respectively. The reduced risk of these outcomes in apixaban compared with warfarin users persisted across age groups. In NVAF patients of all ages initiating either apixaban or warfarin for stroke prevention in the Sentinel System, apixaban was associated with a decreased risk of GI bleeding, ICH, and ischemic stroke compared with warfarin. Among patients less than 65years of age, apixaban use was associated with a decreased risk of GI bleeding and ischemic stroke.

ObjectiveThis study aimed to analyze and map scientific literature on Neuroleptic Malignant Syndrome (NMS) and Serotonin Syndrome (SS) from prestigious, internationally indexed journals. The objective was to identify key topics, impactful articles, prominent journals, research output, growth patterns, hotspots, and leading countries in the field, providing valuable insights for scholars, medical students, and international funding agencies.MethodsA systematic search strategy was implemented in the PubMed MeSH database using specific keywords for NMS and SS. The search was conducted in the Scopus database, renowned for its extensive coverage of scholarly publications. Inclusion criteria comprised articles published from 1950 to December 31st, 2022, restricted to journal research and review articles written in English. Data were analyzed using Microsoft Excel for descriptive analysis, and VOSviewer was employed for bibliometric mapping.ResultsThe search yielded 1150 articles on NMS and 587 on SS, with the majority being case reports. Growth patterns revealed a surge in NMS research between 1981 and 1991, while SS research increased notably between 1993 and 1997. Active countries and journals differed between NMS and SS, with psychiatry journals predominating for NMS and pharmacology/toxicology journals for SS. Authorship analysis indicated higher multi-authored articles for NMS. Top impactful articles focused on review articles and pathogenic mechanisms. Research hotspots included antipsychotics and catatonia for NMS, while SS highlighted drug interactions and specific medications like linezolid and tramadol.ConclusionsNMS and SS represent rare but life-threatening conditions, requiring detailed clinical and scientific understanding. Differential diagnosis and management necessitate caution in prescribing medications affecting central serotonin or dopamine systems, with awareness of potential drug interactions. International diagnostic tools and genetic screening tests may aid in safe diagnosis and prevention. Reporting rare cases and utilizing bibliometric analysis enhance knowledge dissemination and research exploration in the field of rare drug-induced medical conditions.

Background The safety and effectiveness of rivaroxaban versus vitamin K antagonists (standard of care [SOC]) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) was evaluated in Europe. Research design and methods Observational studies were conducted in the UK, the Netherlands, Germany, and Sweden. Primary safety outcomes were hospitalization for intracranial hemorrhage, gastrointestinal bleeding, or urogenital bleeding among new users of rivaroxaban and SOC with NVAF; outcomes were analyzed using cohort (rivaroxaban or SOC use) and nested case–control designs (current vs nonuse). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. Results Overall, 162,919 rivaroxaban users and 177,758 SOC users were identified. In the cohort analysis, incidence ranges for rivaroxaban users were 0.25–0.63 events per 100 person-years for intracranial bleeding, 0.49–1.72 for gastrointestinal bleeding, and 0.27–0.54 for urogenital bleeding. Corresponding ranges for SOC users were 0.30–0.80, 0.30–1.42, and 0.24–0.42, respectively. In the nested case–control analysis, current SOC use generally presented a greater risk of bleeding outcomes than nonuse. Rivaroxaban use (vs nonuse) was associated with a higher risk of gastrointestinal bleeding, but a similar risk of intracranial or urogenital bleeding, in most countries. Ischemic stroke incidence ranged from 0.31 to 1.52 events per 100 person-years for rivaroxaban users. Conclusions Incidences of intracranial bleeding were generally lower with rivaroxaban than with SOC, whereas incidences of gastrointestinal and urogenital bleeding were generally higher. The safety profile of rivaroxaban for NVAF in routine practice is consistent with findings from randomized controlled trials and other studies.

Introduction: Bleeding is frequent in patients with atrial fibrillation (AF) undergoing oral anticoagulation (OAC), and may be the first manifestation of underlying cancer. OAC could be usefull as a screening tool to unveil an occult cancer and enhance early diagnosis. Hypothesis: We aim to analyze whether bleeding represents an useful tool to unmasking an occult cancer in AF patients treated with OAC. Methods: We used a cohort including all patients ≥ 75 years-old from the health area of Vigo (Galicia, Spain) with AF between 2014 and 2017 (CardioCHUVI-AF_75 registry). Results: Of 8,753 AF patients evaluated (mean age, 82.7 years; women, 61.7%), 2,171 (24.8%) experienced any (major or non-major) bleeding and 479 (5.5%) were diagnosed with cancer (mean follow-up of 3 years). Among 2,171 who experienced bleeding, 198 (9.1%) were diagnosed with cancer. Patients with bleeding have a 3-fold higher risk of new cancer diagnosis compared with those without bleeding (4.7 per 100 patient/year vs1.4 per 100/patients year; hazard ratio [HR]: 3,72 [95% CI 3.05-4.55]). Gastrointestinal bleeding was associated with a 13-fold higher hazard of new gastrointestinal cancer diagnosis (HR 13.44 [95% CI 9.11-19.85]). Genitourinary bleeding was associated with an 18-fold higher hazard of new genitourinary cancer diagnosis (HR 18.11 [95% CI 12.52-26.20]). And bronchopulmonary bleeding was associated with a 15-fold higher hazard of new bronchopulmonary cancer diagnosis (HR 15.78 [95% CI 6.03-41.28]). For those other bleeding (non-gastrointestinal, non-genitourinary, non-bronchopulmonary), the HR for cancer was 2.31 (95% CI 1.47-3.64). Conclusions: Any gastrointestinal, genitourinary, or bronchopulmonary bleeding was associated with higher rates of new cancer diagnosis in AF patients undergoing OAC. These bleeding events behave as an useful screening tool and should encourage prompt investigation for underlying cancers at those sites.

Annals for Educators - November 2021.

Evaluation of risk factors for stroke/embolism and of complications due to anticoagulant therapy in atrial fibrillation.

Oral anticoagulants (OACs) used to treat nonvalvular atrial fibrillation (NVAF) are frequently associated with complications, especially gastrointestinal hemorrhage (GH). The aim was to determine the use of resources and costs in the in-hospital treatment of GH in a group of patients with NVAF from Colombia. This was a retrospective study of a cohort of patients who were diagnosed with NVAF and treated with an OAC (apixaban, rivaroxaban, dabigatran or warfarin) between 2018 and 2022 and who were hospitalized for GH. Information on diagnoses, GH location, administered medications, procedures, hospital stay, and health care costs was collected, adjusted to 2022. In total, 59 patients from nine different cities were identified, the mean age was 82.9 ± 12.6 years, and most were men (61.0%) who were admitted to nine clinics for GH. Upper GH was the most frequently identified form (78.0%). The most commonly used OACs were apixaban (44.1%), rivaroxaban (35.6%), warfarin (15.3%) and dabigatran (5.1%). The mean hospital stay was 6.4 ± 5.9 days, and 18.3% of the patients were admitted to the intensive care unit. Patients also received medications that increase the risk of bleeding, such as acetylsalicylic acid (45.8%), the antiplatelet inhibitor P2Y12 (15.3%) and systemic glucocorticoids (23.7%). The average direct cost of all hospital care was USD 872 ± 1315 per patient, which corresponds to 13% of the country’s gross domestic product per capita. GH patients with NVAF generates a significant cost for the use of resources such as medications, procedures and care that affect the country’s health system.

Objective We aimed to further investigate the efficacy and safety of low-dose NOACs by performing a meta-analysis of cohort studies. Background Meta-analyses of randomized controlled trials (RCTs) have demonstrated that low-dose non-vitamin K antagonist oral anticoagulants (NOACs) showed inferior efficacy compared with standard-dose NOACs, although they are still frequently prescribed for patients with atrial fibrillation (AF) in the clinical practice. Methods Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and MEDLINE were systematically searched from the inception to September 9, 2021, for cohort studies that compared the efficacy and/or safety of low-dose NOACs in patients with AF. The primary outcomes were ischemic stroke and major bleeding, and the secondary outcomes were mortality, intracranial hemorrhage (ICH), and gastrointestinal hemorrhage (GH). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with the random-effect model. Results Twenty-five publications involving 487856 patients with AF were included. Compared with standard-dose NOACs, low-dose NOACs had comparable risks of ischemic stroke (HR = 1.03, 95% CI 0.96 to 1.11), major bleeding (HR = 1.12, 95% CI 0.97 to 1.28), ICH (HR = 1.09, 95% CI 0.88 to 1.36), and GH (HR = 1.11, 95% CI 0.92 to 1.33), except for a higher risk of mortality (HR = 1.41, 95% CI 1.21 to 1.65). Compared with warfarin, low-dose NOACs were associated with lower risks of ischemic stroke (HR = 0.72, 95% CI .67 to 0.78), mortality (HR = 0.67, 95% CI 0.59 to 0.77), major bleeding (HR = 0.64, 95% CI 0.53 to 0.79), ICH (HR = 0.57, 95% CI 0.42 to 0.77), and GH (HR = 0.78, 95% CI 0.64 to 0.95). Conclusions Low-dose NOACs were comparable to standard-dose NOACs considering risks of ischemic stroke, major bleeding, ICH, and GH, and they were superior to warfarin. Low-dose NOACs might be prescribed effectively and safely for patients with AF. Considering limitations, further well-designed prospective studies are foreseen.

BackgroundWe evaluated adherence to dosing criteria for patients with atrial fibrillation (AF) taking dabigatran or rivaroxaban and the impact of off-label dosing on thromboembolic and bleeding risk.MethodsWe used data for a retrospective cohort from a large U.S. health plan for Medicare beneficiaries age > =65 years with AF who initiated dabigatran or rivaroxaban during 2010–2016. Stroke and major bleeding were quantified in patients who were eligible for low dose but received standard dose, and in patients who were eligible for standard dose but received low dose.ResultsWe identified 8035 and 19,712 patients who initiated dabigatran or rivaroxaban, respectively. Overall, 1401 (17.4%) and 7820 (39.7%) patients who received dabigatran and rivaroxaban met criteria for low dose, respectively. Of those, 959 (68.5%) and 3904 (49.9%) received standard dose. In contrast, 1013 (15.3%) and 2551 (21.5%) of patients eligible for standard dose dabigatran and rivaroxaban received low dose. Mean follow-up for patients eligible for low and standard dose dabigatran and rivaroxaban were 13.9, 15.1, 10.1, and 12.3 months, respectively. In unadjusted analyses, patients eligible for low or standard dose dabigatran and rivaroxaban but receiving off-label dose, had no differences in the rates of ischemic stroke. Among patients who met criteria for standard dose direct oral anticoagulants (DOAC), use of low dose was associated with significantly higher risk of any major bleeding (Dabigatran: HR = 1.44; 95% CI 1.14–1.8, P = 0.002, Rivaroxaban HR 1.34, 95% CI 1.11–1.6, P = 0.002) and gastrointestinal bleeding (Dabigatran: HR = 1.48; 95% CI 1.08–2, P = 0.016). In patients who met criteria for low dose DOACs, there was lower risk of major bleeding (Dabigatran: HR = 0.59; 95% CI 0.43–0.8, P < 0.001), gastrointestinal (Rivaroxaban: HR 0.79; 95% CI 0.64–0.98, P = 0.03) and intracranial bleeding (Dabigatran: HR = 0.33; 95% CI 0.12–0.9, P = 0.001) with standard dosing. After propensity matching, use of off-label doses was not associated with stroke, major, gastrointestinal or intracranial bleeding for either dabigatran or rivaroxaban.ConclusionsWhile a significant number of patients receive higher or lower dose of dabigatran and rivaroxaban than recommended, we found no evidence of significant impact on thromboembolic or hemorrhagic outcomes.

Aim: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. People with AF have a significantly increased risk of thromboembolic events, including stroke, and the main treatment is therefore aimed at preventing thromboembolic events via anticoagulation with warfarin or acetylsalicylic acid. However, the development of new anticoagulation treatments has prompted a need to know the current cost of AF-related thromboembolic events, for future cost-effectiveness comparisons with the existing treatments. In this study, we estimated the cost of thromboembolic events and their prevention among Swedish AF patients in 2010. Methods: The relevant costs were identified, quantified, and valued. The complications included were ischaemic and haemorrhagic stroke, gastrointestinal bleeding, and other types of major bleeding caused by AF. Treatments intended to lower the risk of ischaemic stroke were also included. A societal perspective was used, including productivity loss due to morbidity. Patients with a CHADS2 score of 1 or higher were included. Results: Among the 9 340 682 inhabitants of Sweden, there are 118 000 patients with AF and at least one more risk factor for stroke, comprising 1.26% of the population. Of these patients, 43.3% are treated with warfarin, 28.3% use acetylsalicylic acid, and 28.3% are assumed to have no anticoagulation treatment. The cost of AF-related complications and its prevention in Sweden was estimated at €437 million for 2010, corresponding to €3 712 per AF patient per year. The highest cost was caused by stroke, and the second highest by the cost of monitoring the warfarin treatment. As the prevalence of AF is expected to increase in the future, AF-related costs are also expected to rise. Conclusion: Thromboembolic events cause high costs. New, easily-administered treatments that could reduce the risk of stroke have the potential to be cost-effective.