High Risk Of Thromboembolic Events Research Articles

Abstract 4134384: Sotagliflozin, a Dual Inhibitor of Sodium-Glucose Transporters 1 and 2, Elicits Cardioprotective Effects Through Attenuation of Platelet Activation and Thrombosis

Sodium-glucose cotransporter (SGLT) inhibitors are used in the treatment of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). In the SCORED trial, sotagliflozin (SOTA), a dual SGLT1/2 inhibitor, demonstrated significant reductions in both myocardial infarction (MI) and stroke in patients with T2DM and CKD. These results suggest a cardiovascular (CV) benefit of SOTA in patients with T2DM and CKD who are at increased risk of thromboembolic disease. To investigate the underlying mechanism of CV protection, we evaluated the effects of SOTA on platelet activation and thrombus formation, in both in vivo and ex vivo models, to understand its effects on MI and stroke. Washed human platelets treated with SOTA were stimulated with various agonists and platelet activation was assessed via lumi-aggregometry and flow cytometry. In whole blood, SOTA was evaluated for its potential to reduce platelet adhesion and thrombus formation in the perfusion flow chamber and Total Thrombus formation Analysis System (TTAS) assays. In vivo , mice dosed with SOTA were assessed for thrombus formation at the site of injury in real-time in the cremaster arteriole injury model. To determine the effect of SOTA on hemostasis, we assessed coagulation parameters ex vivo in human whole blood using thromboelastography. Finally, bleeding time was measured in vivo in mice dosed with SOTA using the tail bleeding assay. In washed platelets, SOTA inhibits platelet activation and aggregation in a dose-dependent manner. Similarly, a dose-dependent decrease in platelet adhesion and thrombus formation was observed in whole blood assays. In vivo , platelet accumulation and fibrin formation were decreased in mice dosed with SOTA, however no effect is observed in coagulation parameters or bleeding time. SOTA inhibits platelet activation and thrombus formation with no impact on coagulation parameters or bleeding potential. These findings highlight a potential mechanism through which SOTA reduces the risk of stroke and MI in patients with T2DM and CKD, underscoring the importance of further investigation into the role of SOTA in CV protection, particularly in patients suffering from both T2DM and CKD at high risk of thromboembolic events.

The triglyceride-glucose index is a marker of thromboembolic events in atrial fibrillation patient under oral anticoagulation therapy

Abstract Background Atrial fibrillation (AF) increases the risk of stroke and thromboembolism; and appropriate risk stratification is central for better targeted patient management. The triglyceride-glucose (TyG) index indirectly assesses insulin resistance, and has been associated with cardiovascular risk. Purpose To investigate whether the TyG index could be a biomarker for assessing the risk of thromboembolic events in patients with AF. Methods We performed an observational prospective cohort study including outpatients diagnosed with AF starting vitamin K antagonist (VKA) or direct-acting oral anticoagulants (DOAC) therapy from January, 2016 to November, 2021. The primary endpoint was a combination of thromboembolic events, considered as the composite of myocardial infarction, and/or venous thromboembolism, and/or ischemic stroke/transient ischemic attack, over 2 years of follow-up. The TyG index was calculated as the natural logarithm (Ln) of the product of baseline plasma glucose and triglyceride using the following formula: Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)]/2. Patients were stratified into tertiles according to their TyG index (ie. first tertile: TyG index <4.59; second tertile: TyG index 4.59-4.83; third tertile: TyG index >4.83). Results We included 2907 patients (median age 77 [70-83] years; 52.5% female). The median TyG index was 4.71 (4.53-4.91), and 34% (989) where in the third tertile of TyG index. During a follow-up of 2 years, 209 (7.2%) patients suffered a thromboembolic event. Compared to patients in the first or second tertiles of TyG index, patients in the third tertile had an increased annual event rate of thromboembolic events (3.40 per 100 patient-years vs. 4.76 per 100 patient-years, p=0.043; and 3.41 per 100 patient-years vs. 4.76 per 100 patient-years, p=0.044), and higher incidence rate ratio (1.41 [95% CI 1.01-1.98], p=0.044 vs. first tertile; 1.40 [95% CI 1.01-1.97], p=0.044 vs. second tertile). Cox regression analyses adjusted for several risk factors demonstrated that the TyG index was an independent predictor for thromboembolic events (aHR 1.82; 95% CI 1.15-2.89; p=0.011). Patients in the third tertile of TyG index presented a 64% higher risk of thromboembolic events (aHR 1.64; 95% CI 1.17-2.29; p=0.004) (Table), with significantly lower event free survival (log-rank test p-value = 0.016) (Figure). Conclusions In this real-world cohort of AF patients under oral anticoagulation therapy, elevated TyG index was an independent risk factor for thromboembolic events. The TyG index is a simple, low-cost indicator, that could be used as a screening tool in everyday clinical practice.

Typical profile of a patient with atrial fibrillation in the Russian population based on medical registries. A systematic review

Aim. To compare clinical and anamnestic characteristics of patients with atrial fibrillation (AF) included in three large international stu­dies assessing the efficacy and safety of therapy with direct oral anti­coagu­lants, with the profile of a typical Russian patient with AF in clinical practi­ce, established by medical registries in the Russian Federation (RF).Material and methods. A systematic review of scientific publications was con­ducted. The search was conducted in the E-library and Google Scholar databases. Publications from 8 registries of patients with AF, con­ducted in the Russian Federation from 2012 to 2023, were found, which present the clinical and anamnestic characteristics of patients. All studies included in the analysis meet the generally accepted require­ments for medical registries. The systematic review protocol was pre­viously recorded in the PROSPERO electronic database (CRD42024512425).Results. A Russian patient with AF is a patient with a large number of cardiovascular pathologies and a high risk of thromboembolic events. According to the analysis, Russian patient with AF has an average age of ~70 years. Most patients have a diagnosis of hypertension, heart failure, while from one third to half of patients have a diagnosis of chronic kidney disease. From 20 to 30% of patients have a history of myocardial infarction and every fifth patient has type 2 diabetes.Conclusion. In all countries around the world, including the Russian Fe­deration, for many years, medical registries have been one of the main sources of information on the characteristics of patients with AF and the disease course. They can supplement the available data from randomized clinical trials with real-world data. Comparison of clinical and anamnestic characteristics of patients in randomized clinical trials of direct oral anticoagulants with characteristics of patients in the Russian registries shows that patients included in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K An­tagonism for Prevention of Stroke and Embolism Trial in Atrial Fib­rillation (ROCKET AF trial) were most similar to Russian patients with AF.

Thromboembolism adverse event profiles of thrombopoietin receptor agonists: a real-world, pharmacovigilance study

ABSTRACT Background Thrombopoietin receptor agonists (TPO-RAs) are currently approved for the treatment of thrombocytopenia in different conditions. The relationship between TPO-RAs and thromboembolic events (TEEs) remains controversial. Research design and methods We extracted TPO-RAs adverse reaction reports after their marketing until now, using the FDA adverse event reporting system (FAERS). Positive signals were detected by reporting odds ratios (RORs). And the Weibull shape parameter test was utilized to analyze the time-to-onset profiles. Result Thromboembolic events accounted for 8.97% among TPO-RAs reports. Increased reporting of TEEs was related to TPO-RAs treatment compared with the entire FAERS database [ROR = 2.65 (2.56, 2.73)]. In addition, venous thrombotic events [ROR = 4.13 (3.92, 4.35)] were reported more frequently than arterial events ROR = 1.81 (1.7, 1.93)]. Age over 60 years [odds ratio (OR) = 1.10 (1.01, 1.20), p = 0.029] and weight over 80 kg [OR = 1.36 (1.17, 1.58), p < 0.001] of patients might have higher risk of TEEs during TPO-RAs therapy. Conclusion Evidence from the real world suggested that TPO-RAs were associated with higher incidence of TEEs, particularly venous thrombosis. The risk of TPO-RAs-associated TEEs mostly happened in the early stages of treatment and decreased over time.

Particularities of a Cardiac Amorphous Left Ventricular Tumor in a Patient with Coronary Artery Disease—Diagnostic and Therapeutic Challenges: A Case Report and Literature Review

Background: Cardiac calcified amorphous tumors (CATs) are rare non-neoplastic formations containing amorphous fibrinous material and calcifications. In our research, we present the case of a 42-year-old male patient who developed, during his 6-months monitoring for coronary artery disease, a left ventricular (LV) CAT raising diagnostic challenges. Methods: To gather additional information on CATs, we researched the international medical literature for scientific articles published with the full text in English, on PubMed, ResearchGate, Clarivate, and Google Scholar between 2020 and 2024. Results: Compared to most described cases, our patient was a young male, without mitral annular calcification or chronic renal disease, but he was suffering from chronic peripheral and coronary artery disease, and genetic testing revealed a higher risk for thromboembolic events. During 6 months, he developed a LV CAT of 4.5/3.5/3 cm. Although we found in the medical literature 16 case reports of patients with CAT, only six authors could specify a precise postoperative evolution of the CAT, most of them sustaining that if completely removed, it would not relapse, an aspect observed also in our patient during 3 years of follow-up. Conclusions: CATs are rare heart tumors with slow growth, but with a high embolization risk that raises diagnostic and therapeutic challenges.

Risk of stroke with reduced dose direct oral anticoagulants vs standard dose anticoagulation after cardioversion of atrial fibrillation: A systematic review and meta-analysis

There is consensus on the safety of standard dose direct oral anticoagulants (DOACs) for stroke prevention in patients undergoing cardioversion of atrial fibrillation (AF), but outcomes of reduced dose DOACs in this setting remain unclear. This systematic review and meta-analysis aimed to compare the rate of cardioversion-associated thromboembolic events between patients taking reduced dose DOACs and those receiving standard dose anticoagulation. A systematic search was conducted for studies published between January 1, 2009, and February 16, 2024 in PubMed, Embase, and Cochrane Central Register of Controlled Trials. The included studies compared the rate of thromboembolic events in patients with AF undergoing cardioversion on reduced dose DOACs with the rate in those on standard dose anticoagulation. Odds ratios were pooled with a random effects model. We identified 2 randomized controlled trials and 8 cohort studies, which included 5212 patients with AF who underwent cardioversion on anticoagulation (1010 patients on reduced dose DOACs and 4202 patients on standard dose anticoagulation). Follow-up ranged from 3 hours to 90 days after cardioversion. There was a numerically higher rate of thromboembolic events in patients undergoing cardioversion on reduced dose DOACs than in those on standard dose anticoagulation (0.69% vs 0.29%; odds ratio 1.98; 95% confidence interval 0.72-5.45; P = .19; I2 = 0%); however, the difference was not statistically significant. Our systematic review and meta-analysis suggests that there is a numerically higher risk of thromboembolic events in patients with AF undergoing cardioversion on reduced dose DOACs than in those on standard dose anticoagulation. However, the difference was not statistically significant. These findings raise concern about the safety of reduced dose DOACs in patients undergoing cardioversion.

Incidence and risk factors for thromboembolic events in pediatric-onset inflammatory bowel disease: A French population-based study

IntroductionPatients with inflammatory bowel disease (IBD) are at higher risk of thromboembolic events (TE). In pediatric-onset IBD, more data on incidence and risk factors of venous (VTE) and arterial events (ATE) at the population level are needed to guide thromboprophylaxis. MethodsAll patients aged ≤ 16 years diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) between 1988 and 2011 in the prospective EPIMAD population-based registry were followed until 2013. Every TE occurring during the follow-up period was included. ResultsA total of 1,344 patients were included: 1,007 with CD and 337 with UC, and a median diagnosis age of 14.3 years. After a median follow-up of 8.3 years, 2 (0.15 %) ATE and 15 (1.1 %) VTE occurred at median age of 20.4 years. The global incidence rate of thromboembolic events was 1.32 per 1000 person-years. Periods of active disease (HR=8.4, p = 0.0002), the 3-month-period following surgery (HR=16.4, p = 0.0002) and hospitalization (HR=21.7, p < 0.0001) were found to be associated with an increased risk of VTE. A lower rate of VTE was found in patients treated with 5-aminosalicylates (HR=0.1, p = 0.002). ConclusionThe risk of TE was low in this population. VTE were strongly associated with active disease, surgery and hospitalization.

Correlation between thromboembolic risk and prevalence of coronary artery disease in patients with atrial fibrillation and impaired renal function

BackgroundAtrial fibrillation (AF) and coronary artery disease (CAD) often co-occur. The prevalence of coincident AF and CAD, the characteristics of such patients, and the correlation with thromboembolic risk in association with renal function are unclear. Methods and ResultsWe studied 435 consecutive patients who underwent contrast-enhanced computed tomography (CT) before catheter ablation for AF. Nineteen patients with inconclusive CT underwent coronary angiography for a calcified coronary artery. Overall, 87 of the 435 patients had CAD (20.0 %: paroxysmal AF, 63.9 %; persistent AF, 35.2 %; and longstanding AF, 0.9 %). Of these, 17.9 % were newly diagnosed with CAD. There was a stepwise increase in CAD prevalence according to the CHADS2 score (10.1 % at 0, 20.1 % at 1, 24.7 % at 2, 35.1 % at 3, and 41.7 % at ≥ 4 points). Of note, in patients with low estimated glomerular filtration rate < 50 mL/min/1.73 m2, the CAD prevalence increased for all CHADS2 scores (15.4 % at 0, 40.0 % at 1, 32.4 % at 2, 38.5 % at 3, and 50.0 % at ≥ 4 points). ConclusionsThe prevalence of coexisting CAD increases with the CHADS2 score. This underscores the importance of screening for coexisting CAD in patients who are at high risk for thromboembolic events, particularly in patients with impaired renal function.

Effectiveness of Direct Oral Anticoagulants and Vitamin K Antagonists in Preventing Stroke in Patients With Atrial Fibrillation and Liver Cirrhosis: A Systematic Review and Meta-Analysis.

Patients with atrial fibrillation and concurrent liver cirrhosis have been excluded from major clinical trials evaluating direct oral anticoagulants (DOACs) due to safety concerns. This has led to uncertainty regarding the optimal anticoagulant therapy in this population at high risk of thromboembolic events. We conducted a systematic review and meta-analysis to compare the effectiveness and safety of DOACs versus vitamin K antagonists (VKAs) in patients with atrial fibrillation and liver cirrhosis. Databases including Embase, MEDLINE/PubMed, and Web of Science were searched for relevant studies. The primary effectiveness outcome was stroke or systemic embolism, and the safety outcome was major bleeding events. A total of 10 studies were included in the meta-analysis. Compared to VKAs, the use of DOACs was associated with a significantly lower risk of stroke or systemic embolism (RR: 0.78, 95% CI: 0.65-0.92, p=0.005). The risk of all-cause mortality was comparable between the two groups (RR: 0.89, 95% CI: 0.74-1.07, p=0.23). Notably, DOACs demonstrated a significantly lower risk of major bleeding events (RR: 0.67, 95% CI: 0.61-0.73, p<0.01) compared to VKAs. This meta-analysis suggests that DOACs may be a favorable alternative to VKAs for the prevention of thromboembolic events in patients with atrial fibrillation and liver cirrhosis, with a lower risk of stroke or systemic embolism and major bleeding. However, further research is needed to establish optimal dosing strategies and assess the safety and efficacy of DOACs in patients with advanced liver disease.

Atrial high-rate episodes detected by cardiac implantable electronic devices: arrhythmic burden and progression towards de-novo clinical atrial fibrillation

Abstract Background Atrial high rate episodes (AHRE) detected by cardiac implantable electronic devices (CIEDs) are associated with a higher risk of thromboembolic events, but whether oral anticoagulants (OACs) improve patient outcomes is still debated. On the other hand, OACs benefits in patients with clinical atrial fibrillation (AF) are well established. Therefore, the potential progression of AHRE towards clinical AF should be promptly recognized. Purpose To evaluate the incidence of de-novo clinical AF and its potential predictors. Methods Consecutive CIED patients presenting AHRE (with confirmation of an arrhythmia lasting 5 min–23 h 59 min, atrial rate 175/min, with no AF at 12-lead ECG and no prior clinical AF) were retrospectively enrolled. Potential predictors of incident clinical AF were investigated by building six different multivariable Cox’s regression analyses, and the duration of the single longest AHRE episode during follow-up was used as a time-dependent covariate. Results 126 patients (median age 79.7 (73.8-84.6), 34.1% female) had available follow-up data. Detailed patients' characteristics are provided in Figure 1. Over a median follow-up of 1128 (580-1646) days, 41/126 (32.5%) patients developed incident clinical AF. A single longest AHRE episode lasting ≥ 6 hours (h) was found associated with a higher risk of incident clinical AF after adjusting for HATCH score, female sex, and coronary artery disease (CAD) (Hazard ratio (HR) 2.82; 95%CI 1.32-6.04) and also in the model adjusting for CHA2DS2-VASc score and CKD (HR 3.13; 95%CI 11.57-6.25). Similar results were found for a single longest AHRE episode lasting ≥ 12 hours (HR 4.91; 95%CI 2.31-10.42 and HR 4.90; 95%CI 2.50-9.60, respectively), and lasting ≥ 24h (HR 4.40; 95%CI 1.82-10.60 and HR 4.56; 95%CI 2.05-10.14, respectively) (Figure 2). On the other hand, HATCH score and CHA2DS2-VASc score were independently associated with a higher risk of incident clinical AF only in multivariable models adjusting for episodes of AHRE lasting ≥6 h (HR 1.42; 95%CI 1.02-1.97 and HR 1.37; 95%CI 1.03-1.83, respectively) but this association was not confirmed after adjusting for AHRE of longer duration. Conclusions In patients with AHRE, the incidence of de-novo clinical AF is high in a three-year follow-up. Baseline patients’ characteristics (HATCH and CHA2DS2-VASc scores) and AHRE duration during follow-up may help to intensify monitoring and decision-making, being independently associated with incident clinical AF at follow-up.Baseline characteristicsMultivariate Cox's regression analysis

Neoplastic pathologic hip fractures are associated with a higher risk of post-operative bleeding and thromboembolic events

IntroductionSurgical treatment of hip fractures leads to significant post-operative complications. Although pathologic fractures (PF) are associated with worse outcomes, most studies do not differentiate between etiology (neoplastic and non-neoplastic PF). We seek to compare 30-day complication rates between 1) native hip fractures and neoplastic PF, and 2) neoplastic and non-neoplastic PF. Materials and methodsA total of 127,819 patients with hip fractures and 5104 with PF diagnosed from 2005 to 2021 were retrieved from the NSQIP database. We included 1843 patients with neoplastic PF and 3261 with non-neoplastic PF. Demographics, pre-operative labs and co-morbidities, and post-operative outcomes were analyzed. Propensity-score matching was conducted to control for confounders. ResultsPatients with a neoplastic PF had a significantly higher rate of deep venous thrombosis (DVT) (4 % vs 1.2 %, p = 0.001) and pulmonary embolism (PE) (2.4 % vs 0.7 %, p < 0.001), than native hip fractures. Rates of post-operative bleeding were significantly higher in the neoplastic PF group (29.3 % vs 23.9 %, p < 0.001) than non-neoplastic PF. No differences in soft tissue complications were found. When comparing neoplastic and non-neoplastic PF, the former had a higher rate of PE (2.5 % vs 1.0 %, p = 0.015) and post-operative bleeding (27.6 % vs 22.0 %, p = 0.009). Unplanned readmission rates and 30-day mortality rate were also higher in the neoplastic PF group. ConclusionNeoplastic PF of the hip are associated with higher risk of thromboembolic event rates and post-operative bleeding than both native hip fractures and non-neoplastic PF. No differences in rates of soft tissue complications were found between groups.

Effect of drug interactions with non-vitamin-K oral anticoagulants on thromboembolic events in patients with nonvalvular atrial fibrillation.

Few real-world studies have investigated drug-drug interactions (DDIs) involving non-vitamin-K antagonist oral anticoagulants (NOACs) in patients with nonvalvular atrial fibrillation (NVAF). The interactions encompass drugs inducing or inhibiting cytochrome P450 3A4 and permeability glycoprotein. These agents potentially modulate the breakdown and elimination of NOACs. This study investigated the impact of DDIs on thromboembolism in this clinical scenario. Patients who had NVAF and were treated with NOACs were selected as the study cohort from the National Health Insurance Research Database of Taiwan. Cases were defined as patients hospitalised for a thromboembolic event and who underwent a relevant imaging study within 7 days before hospitalisa-tion or during hospitalisation. Each case was matched with up to 4 controls by using the incidence density sampling method. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer or inhibitor or both with NOACs was identified. The effects of these interactions on the risk of thromboembolic events were examined with univariate and multivariate conditional logistic regressions. The study cohort comprised 60,726 eligible patients. Among them, 1288 patients with a thromboembolic event and 5144 matched control patients were selected for analysis. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer resulted in a higher risk of thromboembolic events (adjusted odds ratio [AOR] 1.23, 95% confidence interval [CI] 1.004-1.51). For patients with NVAF receiving NOACs, the concurrent use of cytochrome P450 3A4/ permeability glycoprotein inducers increases the risk of thromboembolic events.

RISK OF THROMBOEMBOLISM IN CHRONIC KIDNEY DISEASE PATIENTS WITH NON VALVULAR ATRIAL FIBRILLATION : A SYSTEMATIC REVIEW

Background: Individuals with CKD are at higher risk for thromboembolic events than those without CKD whilst also at a higher bleeding risk. NVAF often coexist with CKD and heightens the risk of one another. This study aimed to investigate the risk of thromboembolism in CKD patients with NVAF. Methods: This systematic review used Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 as standards. Inclusion criteria for literature eligibility are full-text literature, written in english, and published between 2014 and 2024. Exclusion criteria used for this study were editorials, review articles and identical journal that has been published, and submissions without DOI. Literatures were collected from online reference sources like Pubmed and SagePub. Result: In the PubMed database, the results of our search brought up 45 articles, whereas the results of our search on SagePub brought up 382 articles. The results of the search conducted for the last year of 2014 yielded a total 10 articles for PubMed and 12 articles for SagePub. In the end, we compiled a total of 5 papers, 3 of which came from PubMed and 2 of which came from SagePub. We included five research that met the criteria. Conclusion: The existence of both NVAF and CKD increase the risk of thromboembolic events. There are various modalities to analyze the risk of thromboembolism by assessing risk scores, kidney function, and utilizing transesophageal echocardiography (TEE). In order to prevent ischaemic stroke in NVAF patients, anticoagulants can be administered by in consideration to the kidney function.

A pilot study to evaluate the quality of care in oral anticoagulant and antiplatelet use in patients with permanent atrial fibrillation in Irish general practice

Abstract Aim: The aim of this pilot study is to determine the pattern of oral anticoagulant and antiplatelet use in patients with permanent atrial fibrillation (AF) in Irish general practice. Background: Worldwide, AF is the most common sustained cardiac arrhythmia in adults and poses a significant burden to patients, physicians and healthcare systems. There is a five-fold increased risk of stroke with AF, and AF-related strokes are associated with higher levels of both morbidity and mortality compared to other stroke subtypes. Thankfully, appropriate use of oral anticoagulation (OAC) for AF can reduce the risk of stroke by up to 64%. However, we know that patients are commonly undertreated with OAC, prescribed inappropriate doses of OAC and have prolonged use of an antiplatelet agent in addition to OAC without indication. Methods: A descriptive, cross-sectional observational study was undertaken. Proportionate sampling was used across 11 practices from the Ireland East practice-based research network. The general practitioners completed a report form on each patient provided by the research team by undertaking a retrospective chart review. Findings: Eleven practices participated with a total number of 1855 patients with AF. We received data on 153 patients. The main findings from this pilot project are that: 1. 11% of patients were undertreated with OAC 2. 20 % of patients were on an incorrect non-vitamin K antagonist oral anticoagulant dose 3. 28 patients (18%) were inappropriately prescribed combination antithrombotic therapy Undertreatment and underdosing of OAC expose patients to higher risk of thromboembolic events, bleeding and all-cause mortality. Prolonged combination antithrombotic therapy is associated with serious increased risk of bleeding with no additional stroke protection. This pilot project highlights several gaps between guidelines and clinical practice. By identifying these areas, we hope to develop a targeted quality improvement intervention using the electronic health records in general practice to improve the care that those with AF receive.

Real-World Analysis of Thromboembolic Event Rates in Patients in the United States with Polycythemia Vera

Background:Polycythemia vera (PV) is a myeloproliferative neoplasm associated with an increased risk of thromboembolic events (TEs). PV patients are characterized based on their risk for TEs as low-risk (age &amp;lt;60 without prior history of TE) or high-risk (age ≥60 and/or prior history of TE). Observational studies have shown higher rates of TEs in PV patients compared to matched controls (14.3 vs 4.9/1000 patient years, or PY), with rates as high as 40% in patients with PV (Goyal et al., Blood. 2014;124:4840; Griesshammer et al., Ann Hematol. 2019;98:1071-82; Pemmaraju et al., Leuk Res. 2022;115:106809). We assessed the rate of arterial and venous TEs in a large cohort of low- and high-risk PV patients. Methods:We conducted a real-world, retrospective cohort study using Optum's de-identified Market Clarity Data, which includes electronic health records (EHR) on 105 million US patients between 2007-2019. Eligible patients were ≥18 years [yrs] old and required ≥2 PV diagnosis codes with ≥60 days between the first and last diagnosis code in the data period. Patients were indexed at the first diagnosis code of PV preceded by ≥1 year of EHR data (“index”) and required ≥1 year of post-index data or death prior to data period end (12/31/2019). Patients with a pre-index diagnosis of secondary polycythemia, leukemia, myelodysplastic syndrome, myelofibrosis, or stem cell transplant were excluded. Patients were stratified into three groups based on risk status at index: low-risk (age &amp;lt;60 without prior history of TE), age-based high-risk (age &amp;gt;60 without prior history of TE) and event-based high-risk (prior history of TE). As outcomes, TEs were identified at the first occurrence of a diagnosis code for a TE in EHR during the post-index period. Descriptive statistics were used to characterize the proportion of patients with TEs and event rates per 1000 PY. Kaplan-Meier analysis was used to evaluate the probability of TE-free survival among patients in the three risk groups at various time points. Patients were censored at death or last engagement date. Results:The total study cohort included 20,089 PV patients (mean age, 63.0 yrs; 57.8% male; 88.6% Caucasian). Approximately one-third (34.4%; 6909 patients) were low-risk, 49.4% (9924 patients) were age-based high-risk, and 16.2% (3256 patients) were event-based high-risk. Among 17,402 patients with pre-index medication data, 16.0% (n=2777) received hydroxyurea (HU) pre-index. HU usage was highest in age-based high-risk patients (21.8%) followed by event-based high-risk (20.0%) and low-risk patients (5.8%). Median follow-up period was 4.3 yrs (IQR, 2.4-5.9). Incidence of TEs was assessed within patient groups (Table 1). Overall, 25.1% (5035/20,089) of patients with PV experienced at least one TE during the post-index period. Incidence of TEs was highest among event-based high-risk patients (50.2%; 1634/3256), followed by age-based high-risk (25.0%; 2480/9924) and low-risk patients (13.3%; 921/6909). The rate of post-index TEs was more than triple for event-based high-risk patients vs. age-based high-risk patients (206 vs. 68/1000 PY) and nearly 7 times higher vs. low-risk patients (206 vs. 31/1000 PY). The rate of TEs was more than double for age-based high-risk patients vs. low-risk patients (68 vs. 31/1000 PY). Incidence of arterial and venous TEs was assessed across the total cohort (Table 1). The most common arterial events were stroke (7.1%) and MI/ACS (6.4%). The most common venous events were DVT/deep thrombophlebitis (8.1%) and pulmonary embolism (4.5%). Kaplan-Meier analysis indicated that at ≈2.5 yrs (1000 days) post-index, TE-free survival was ≈90% for low-risk, ≈80% for age-based high-risk, and ≈55% for event-based high-risk patients (Figure 1). At ≈5.5 yrs (2000 days) post-index, TE-free survival had fallen to ≈85% for low-risk, ≈70% for age-based high-risk, and ≈40% for event-based high-risk patients. The downward trend continued until the end of the data period. Conclusion: Findings from this real-world analysis indicate that PV patients experience high rates of arterial and venous TEs. Event-based high-risk patients have a substantially lower probability of TE-free survival compared with age-based high-risk and low-risk patients. While patients with a prior history of TE have the highest thromboembolic risk, all patients with PV are at high risk of TE, indicating an unmet need for reduction of thromboembolic risks.

Monoclonal Gammopathy of Undetermined Significance and the Risk of Thrombotic Events: Results from Istopmm, a Population-Based Screening Study in Iceland

Introduction: Multiple myeloma (MM), Waldenström's macroglobulinemia (WM), and related disorders have been associated with excess risk of thrombosis. Furthermore, medications used to treat these disorders, in particular immunomodulatory agents, have been associated with excess thrombotic risk. Monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor of MM, WM, and related disorders, has also been associated with arterial and venous thrombosis. However, prior studies have been based on cohorts where MGUS was diagnosed as part of the work-up for other unrelated medical disorders. We have shown that these cohort have biased selection of individuals with chronic disease, including autoimmune disease, heart failure, endocrine disorders and more. This selection bias may have led to false associations or overestimation of the relationship of MGUS and thrombotic events. Aim: To evaluate the relationship of MGUS and thrombosis in a screened cohort of individuals with MGUS. Methods: Data were obtained from the Iceland screens, treats, or prevents multiple myeloma study (iStopMM), a population-based screening study for MGUS and a randomized trial of follow-up strategies with the aim of evaluating the benefits and harms of MGUS screening. As part of the study 75,422 Icelandic residents 40 years and older (54% of the underlying population) have provided their informed consent for the study and were screened by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. The cohort was crosslinked to population-based Icelandic government registries that includes all diagnoses made in the universal healthcare system, recorded as international classification of diseases (ICD) 10 codes. The study exposure was MGUS at screening and the outcome was venous and arterial thrombosis, defined as recorded ICD-10 codes. Events recorded within 90 days of each other were considered the same event. We further analyzed subgroups of M protein isotype and light chain (LC) MGUS. We followed participants prospectively after the date of screening to arterial and venous thrombosis as the endpoint and censoring at death, progression to MM, WM, and related disorders, or end of follow-up. Hazard ratios (HR) for time to first thrombotic event were estimated using Cox regression models, while hazard ratios for recurrent thrombotic events were estimated using mixed-effects Cox regression models with a random intercept. Both prospective analyses were adjusted for age as a non-linear variable and sex. In a secondary analysis, M-protein concentration was included as a non-linear variable into similar models that were restricted to those with MGUS with an M-protein. Results: Of the 75,422 screened, 3,353 had MGUS with an M-protein, here termed heavy chain (HC) MGUS, and 315 had LC MGUS. Over a median follow-up of 3.67 to 3.90 years, depending on the outcome of interest, 263 and 3,557 arterial events (20.4 and 13.5 per 1,000 person years) and 260 and 3,092 venous events (20.2 and 11.7 per 1,000 person years) were observed in those with and without MGUS respectively. MGUS was found to be associated with venous thrombotic events (HR: 1.31; 95% CI: 1.08-1.57), in particular deep vein thrombosis (HR:1.46; 95% CI: 1.12-1.90). Of the different MGUS subtypes, this association was only observed in non-IgM MGUS. The results were similar in the recurrent events analysis. IgM MGUS was found to be associated with a higher of peripheral arterial embolic events (HR: 2.86; 95% 1.04-7.85) but this association was not observed in the recurrent event analysis. M-protein concentration was not correlated with the risk of thrombotic events. Discussion: In this large population-based study including more than 75,000 individuals screened for MGUS, we found that MGUS, and particularly non-IgM MGUS, was associated with venous thrombotic events. Interestingly, the size of the M-protein spike was not associated with a higher risk for thromboembolic events. Further studies are needed to identify the underlying mechanisms with the goal of identifying subgroups of the MGUS population that may require interventions to prevent thrombotic events, potentially improving the survival and quality of life of those with MGUS.

Patients with atrial fibrillation and a low risk of thromboembolic events: prescription rate of anticoagulant therapy according to a retrospective analysis

Aim. To conduct a retrospective analysis of the prevalence of main risk factors for thromboembolic events (TEEs) and the prescription rate of anticoagulant therapy (ACT) in patients with atrial fibrillation (AF) and a low CHA2DS2-VASc score in certain Russian regions using artificial intelligence technologies.Material and methods. The information was obtained from the Webiomed predictive analytics platform. The sample included 87601 patients with AF aged 18-74 years (men, 49,5%, mean age, 59,3±12,3 years, mean CHA2DS2-VASc score, 2,3±1,5) who received care in medical organizations in 6 constituent entities of the Russian Federation in the period from 2016 to 2019. CHA2DS2VASc score of 1 and 2 in a man and a woman, respectively, was regarded as a moderate risk, while score of 0 and 1, respectively, as a low risk of TEEs.Results. There were 22337 (25,5%) patients with AF at moderate risk and 18366 (21,0%) patients at low risk of TEEs. With a moderate risk of TEEs, CHA2DS2-VASc score of 1 in 70,4% of cases was determined by hypertension, while in 15,7% — by age 65-74 years, in 9,0% — by heart failure, in 2,9% — by myocardial infarction and/or peripheral arterial disease, in 2,0% — by type 2 diabetes. In patients with AF and a moderate risk of TEEs, ACT was prescribed in 4927 (22,1%) patients, while with a low risk of TEEs — in 1833 (10,0%). Among patients with AF and a high risk of TEEs (n=46898, 53,5%), 1216 (24,6%) patients with ischemic stroke (IS) did not initially have a high CHA2DS2-VASc risk.Conclusion. In clinical practice, among patients with AF aged 18-74 years, there are quite often individuals with CHA2DS2-VASc score of 1 not associated with sex. These patients need an individualized approach in ACT, which is the basis for prospective studies in order to optimize the assessment of cardioembolic IS risk, as well as to analyze the efficacy and safety of long-term ACT.

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer.

Cost-effectiveness of ropeginterferon alfa-2b-njft for the treatment of polycythemia vera.

Aim: Patients with polycythemia vera (PV), a rare and chronic blood cancer, are at a higher risk for thromboembolic events, progression to myelofibrosis, and leukemic transformation. In 2021, ropeginterferon alfa-2b-njft (BESREMi®) was approved in the US to treat adults with PV. The purpose of this study is to estimate the cost-effectiveness of ropeginterferon alfa-2b-njft, used as a first- or second-line treatment, for the treatment of patients with PV in the US. Materials & methods: A Markov cohort model was developed from the healthcare system perspective in the United States. Model inputs were informed by the PROUD-PV and CONTINUATION-PV studies and published literature. The model population included both low-risk and high-risk patients with PV. The model compared ropeginterferon alfa-2b-njft used either as first- or second-line versus an alternative treatment pathway of first-line hydroxyurea followed by ruxolitinib. Results: Over the modeled lifetime, ropeginterferon alfa-2b-njft provided an additional 0.4 higher quality-adjusted life years (QALYs) and 0.4life-years with an added cost of USD60,175, resulting in a cost per QALY of USD141,783. The model was sensitive to treatment costs, the percentage of patients who discontinue hydroxyurea, the percentage of ropeginterferon alfa-2b-njft users who switch to monthly dosing, the percentage of ropeginterferon alfa-2b-njft users as 2nd line treatment, and the treatment response rates. A younger patient age at baseline and a higher percentage of patients with low-risk disease improved the cost-effectiveness of ropeginterferon alfa-2b-njft. Conclusion: Ropeginterferon alfa-2b-njft is a cost-effective treatment option for a broad range of patients with PV, including both low- and high-risk patients and patients with and without prior cytoreductive treatment with hydroxyurea.

Efficacy of different variants of endocardial balloon cryoablation in patients with persistent atrial fibrillation

Aim. To study the effectiveness of “extended” cryoballon ablation in patients with a persistent form of atrial fibrillation (AF) and to determine the risk factors for AF recurrence after cryoablation.Methods. The study included 89 patients (62±10 years, 24 [27%] men) with a persistent form of AF. The patients were randomized into two groups: in the 1st, the pulmonary veins (PV) cryoablation was performed (n=48 [53.9%]); in the 2nd, the PV cryoablation was performed in combination with cryoablation of the posterior wall of the left atrium (n=41 [46.1%]). The number of patients at high risk of thromboembolic events predominated in Group 2 (p=0,03). There is a high frequency of taking antiarrhythmic drugs of class III in this group (p=0.018). The follow-up period was 12 months. Clinical efficacy was assessed during a survey and daily ECG monitoring at face-to-face visits after 3, 6 and 12 months.Results. Antral isolation of PV was achieved in all 89 (100%) patients in both groups. In group 2, the average number of applications in the posterior wall of the PV was 10 [9; 13]. The effectiveness of cryoablation in group 1 by the end of the 12-month follow-up period was 54.2%, in group 2 - 56.1%. The complication rate (6.7%) in both groups did not differ statistically (p=0.683). The risk of arrhythmia recurrence didn’t depend on the strategy of cryoablation in postablation period (p=0.834). When conducting a single-factor analysis, a statistically significant effect on the probability of AF recurrence in the period of 3-12 months in group 1 was caused by AF recurrence in the blind period (95% confidence interval (CI): 1.5-27.7, p=0.013), in group 2 belonging to the female sex (95% CI: 1.2-24.6, p=0.032) and AF relapse in the blind period (95% CI: 1.5-128.5, p=0.020). During multivariate analysis in group 2, a statistically significant influence on the risk of AF recurrence in the period of 3-12 months was exerted by belonging to the female sex (hazard ratio (HR) 7.84; 95% CI 1478-42,23; p=0.016) and the presence of early AF recurrence (HR 20.36; 95% CI 1.99-208.23; p=0.011).Conclusion. Extended cryoablation in terms of efficiency and safety was comparable with the standard cryoablation. Early recurrence of AF (in the first 3 months after the intervention) turned out to be an independent risk factor for AF recurrence in the long-term period up to 12 months after cryoablation in both groups.