Real-world Data on Treatment Patterns and Bleeding in Cancer-associated Thrombosis: Data from the TROLL Registry.

Background International guidelines are increasingly recommending direct oral anticoagulants (DOACs) as the first-line treatment for cancer-associated thrombosis (CAT). However, data regarding treatment patterns and adherence to guidelines in patients with CAT are scarce. Objectives This study aimed to explore anticoagulant treatment patterns in patients with CAT and to calculate the incidence rates of bleeding events. Methods Patients ≥18 years with active cancer and a first-time venous thromboembolism between 2005 and 2020 were identified through the Venous T hrombosis R egistry in Østf OL d Hospita L . Outcome measures were patterns of anticoagulant treatment during the study period and bleeding events. We calculated overall incidence rates per 100 person-years and 6- and 12-month cumulative incidence of major and clinically relevant nonmajor bleeding (CRNMB) during anticoagulant treatment. Results Median age of 842 CAT patients at the time of thrombosis was 69 years (interquartile range 61-77), and 443 (52.6%) were men. In total, 526 patients (62.5%) had pulmonary embolism and 255 (30.3%) had deep vein thrombosis. Low molecular weight heparin (LMWH) was prescribed to 713 (85.8%) patients, whereas 64 (7.7%) received DOACs and 54 (6.5%) received vitamin K antagonists as the initial anticoagulant treatment. Prescription of DOACs as initial treatment increased from 3.0% in 2013/2014 to 18.0% in 2019/2020. The incidence rate of major bleeding was 6.9 (95% confidence interval [CI] 5.2-9.2) and 10.1 (95% CI 8.0-12.9) in CRNMB. Conclusion Most patients were treated with LMWH. However, a gradual shift in treatment toward DOACs was observed. Overall, bleeding complications were rare and comparable to those reported in randomized trials.

Developing a machine learning model for bleeding prediction in patients with cancer-associated thrombosis receiving anticoagulation therapy.

BACKGROUND: Only 1 conventional score is available for assessing bleeding risk in patients with cancer-associated thrombosis (CAT): the CAT-BLEED score. OBJECTIVES: Our aim was to develop a machine learning-based risk assessment model for predicting bleeding in CAT and to evaluate its predictive performance in comparison to that of the CAT-BLEED score. METHODS: We collected 488 attributes (clinical data, biochemistry, and International Classification of Diseases, 10th Revision, diagnosis) in 1080 unique patients with CAT. We compared CAT-BLEED score, Ridge and Lasso logistic regression, random forest, and Extreme Gradient Boosting (XGBoost) algorithms for predicting major bleeding or clinically relevant nonmajor bleeding occurring 1 to 90 days, 1 to 365 days, and 90 to 455 days after venous thromboembolism (VTE). RESULTS: The predictive performances of Lasso logistic regression, random forest, and XGBoost were higher than that of the CAT-BLEED score in the prediction of bleeding occurring 1 to 90 days and 1 to 365 days after VTE. For predicting major bleeding or clinically relevant nonmajor bleeding 1 to 90 days after VTE, the CAT-BLEED score achieved a mean area under the receiver operating characteristic curve (AUROC) of 0.48 ± 0.13, while Lasso logistic regression and XGBoost both achieved AUROCs of 0.64 ± 0.12. For predicting bleeding 1 to 365 days after VTE, the CAT-BLEED score achieved a mean AUROC of 0.47 ± 0.08, while Lasso logistic regression and XGBoost achieved AUROCs of 0.64 ± 0.08 and 0.59 ± 0.08, respectively. CONCLUSION: This is the first machine learning-based risk model for bleeding prediction in patients with CAT receiving anticoagulation therapy. Its predictive performance was higher than that of the conventional CAT-BLEED score. With further development, this novel algorithm might enable clinicians to perform personalized anticoagulation strategies with improved clinical outcomes.

B-type Natriuretic Peptide as a Marker of Different Forms of Systemic Sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune connective tissue disease which affects various tissues and organs, including skin, lungs, kidneys, gastrointestinal tract and cardiovascular system. Cardiac involvement is the most commonly recognized problem and a significant cause of morbidity. The brain natriuretic peptide (BNP) is a previously known marker of elevated cardiovascular risk in SSc, but the levels of BNP in various forms of SSc have not been investigated so far. AIM: The aim of our study was to evaluate the influence of SSc on the function of the right ventricle and the right atrium using the echocardiographic parameters. Moreover, we examined the levels of BNP in different forms of SSc as well as the association of disease severity with the plasma concentrations of BNP. METHODS: We included 42 patients with newly diagnosed SSc and patients whose disease had been diagnosed earlier. SSc patients and non-SSc control patients were examined by using echocardiography and the concentrations of BNP were determined. RESULTS: We analyzed differences in the parameters of right ventricle (RV) function and right atrium (RA) function between SSc patients and healthy controls. The two groups had similar distribution of gender, but SSc patients were significantly older than controls. RV wall thickness was increased in SSc patients (p<0.001), while right ventricular end-systolic area (RVESA; p=0.408) and right ventricular end-diastolic area (RVEDA; p=0.368) did not differ among the examinees. In contrast, RA minor-axis dimension (p=0.001) and the tricuspid annular plane systolic excursion (TAPSE) (p=0.001) were significantly higher in SSc patients. Also, we analyzed differences in brain natriuretic peptide (BNP) concentrations between diffuse cutaneous systemic sclerosis (DSSc) and limited cutaneous systemic sclerosis (LSSc) patients. DSSc patients had significantly higher concentrations of BNP. We found that levels of BNP were in significant positive correlations with age (p=0.007), disease duration (p=0.023), C reactive protein (CRP) (p=0.032), right ventricle fractional area change (FAC) (p=0.022), pulmonary vascular resistance (PVR) and Rodnan score (p=0.019). CONCLUSIONS: Given the obtained results, the laboratory determination of BNP could be useful in differentiating different forms of systemic sclerosis as well as in predicting the severity of the disease and future cardiovascular complications.

Psoriasis is the independent factor for early atherosclerosis: A prospective study of cardiometabolic risk profile.

Background/Aim: Psoriasis as multisystemic inflammatory dis-ease is related with an increased cardiometabolic risk. The aim of the study was to analyze risk biomarkers, peripheral and renal arteries ultrasonography and echocardiography for subclinical atherosclerosis and metabolic disease in 106 subjects (66 psoriasis patients and 40 controls, 20 eczema patients and 20 healthy volunteers). Methods: In all exameenes following parameters were analyzed: body mass index (BMI), C-reactive protein, D-dimer, serum amyloid A (SAA), apolipoprotein (Apo) A1, ApoB, ApoB/Apo A1 index, fasting glucose, C-peptide, fasting insulinemia, homeostatic model assessment-insulin resistance (HOMA-IR), HOMA-ß-cell, lipid profile, serum uric acid concentration (SUAC), 24-h proteinuria and microalbuminuria. Carotid, brachial, femoral and renal arteries ultrasonography, as well as echocardiography was also performed. Results: Five of 66 (7.6%) psoriasis patients had metabolic syndrome (not present in both control groups). The following variables were increased in patients with psoriasis compared to both control groups: BMI (p = 0.012), insulinemia (p < 0.001), HOMA-IR (p = 0.003), HOMA-ß cell (p < 0.001), SUAC (p = 0.006), ApoB/ApoA1 ra-tio (p = 0.006) and microalbuminuria (p < 0.001). Also, increased C-peptide (p = 0.034), D-dimer (p = 0.029), triglycerides (p = 0.044), SAA (p = 0.005) and decreased ApoA1 (p = 0.014) were found in the psoriasis patients compared to healthy controls. HDL cholesterol was decreased in the psoriasis patients compared to the control group of eczema patients (p = 0.004). Common carotid (CIMT) and femoral artery intima-media thickness (FIMT) was significantly greater (p < 0.001) and the maximal flow speed (cm/s) in brachial artery significantly de-creased (p = 0.017) in the patients with psoriasis in comparison to both control groups. In multivariate logistic regression analysis, after the adjustment for confounding variables, the most important predictor of CIMT and FIMT was the diagnosis of psoriasis (p < 0.001).. Conclusion: Cardiometabolic risk biomarkers and ultrasonographic signs of early atherosclerosis are correlated with the diagnosis of psoriasis, and not to generalized eczema. Psoriasis was found to be an independent risk factor for subclinical atherosclerosis

Low On-Treatment Platelet Reactivity Predicts Long-Term Risk of Bleeding After Elective PCI.

BACKGROUND: Bleeding after percutaneous coronary interventions (PCI) is an important complication with impact on prognosis. AIM: To evaluate the predictive value of enhanced platelet responsiveness to dual antiplatelet therapy with aspirin and clopidogrel, for bleeding, after elective PCI. METHODS AND RESULTS: We performed multiple electrode aggregometry (MAE) platelet functional tests induced by arachidonic acid (ASPI) and adenosine-diphosphate (ADP) before PCI, and 24 hours after PCI, in 481 elective PCI patients who were followed-up for an average of 15.34 ± 7.19 months. Primary end point was the occurrence of any bleeding, while ischemic major adverse cardiovascular event (MACE) was a secondary endpoint. The incidence of total, BARC ≤ 2, and BARC ≥ 3 bleeding, according to BARC classification, was 19, 18, and 1%, respectively. Groups with any, and BARC ≤ 2 bleeding, had a lower average value of MAE ADP test after 24 hours, compared to the group without bleeding: 45.30 ± 18.63 U versus 50.99 ± 19.01 U; P = 0.005; and 45.75 ± 18.96 U versus 50.99 ± 18.99 U; P = 0.01; respectively. Female gender (HR 2.11; CI 1.37-3.25; P = 0.001), previous myocardial infarction (HR 0.56; CI 0.37-0.85; P = 0.006), lower body mass (HR 0.78; CI 0.62-0.98; P = 0.03), and MAE ADP test after 24 hours (HR 0.75; CI 0.61-0.93; P = 0.009) were the independent predictors for any bleeding by Cox univariate analysis. After adjustment, MAE ADP test after 24 hours, was the only independent predictor for any (HR 0.7; CI 0.56-0.87; P = 0.002), and BARC ≤ 2 (HR 0.71; CI 0.56-0.89; P = 0.003) bleeding, by Cox multivariate analysis. CONCLUSION: MAE ADP test before and after PCI, was associated with any, and BARC ≤ 2 bleeding after elective PCI.

The importance of sleep apnea index determination using 24 h ECG analysis in patients with heart rhythm disorders.

BACKGROUND/AIM: A possible cause of malignant heart rhythm disorders is the syndrome of sleep apnea (periodic cessation of breathing during sleep longer than 10 seconds). Recent 24 h ECG software systems have the option of determination ECG apnea index (AI) based on the change in voltage of QRS complexes. The aim of the study was to determine the significance of AI evaluation in routine 24-hour Holter ECG on a group of 12 patients. METHODS: We presented a total of 12 consecutive patients with previously documented arrhythmias and the history of breathing disorders during night. They were analyzed by 24 h ECG (Medilog AR 12 plus Darwin), that is able to determine AI. RESULTS: We presented a case series of 12 patients, 8 men and 4 women, mean age 58.75 years and the average AI 5.78. In the whole group there was a trend of increasing prevalence of complex rhythm disorders with increasing of AI and increased frequency of arrhythmias in the night phase vs. day phase. CONCLUSION: Determination of AI using routine long term (24 h) ECG analysis is important because sleep apnea can be successfully treated as an etiological or contributing factor of arrhythmias.

Correlation between the Finnish Diabetes risk Score and the severity of coronary artery disease.

BACKGROUND/AIM: The FINish Diabetes RIsk SCore (FINDRISC) which includes age, body mass index (BMI), waist circumference, physical (in) activity, diet, arterial hypertension, history of high glucose levels, and family history of diabetes, is of a great significance in identifying patients with impaired glucose tolerance and a 10-year risk assessment of developing type 2 diabetes in adults. Due to the fact that the FINDRISC score includes parameters which are risk factors for coronary artery disease (CAD), our aim was to determine a correlation between this score, and some of its parameters respectively, with the severity of angiographically verified CAD in patients with stable angina in two ways: according to the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score and the number of diseased coronary arteries. METHODS: The study included 70 patients with stable angina consecutively admitted to the Clinic of Cardiology, Military Medical Academy, Belgrade. The FINDRISC score was calculated in all the patients immediately prior to angiography. Venous blood samples were collected and inflammatory markers [erythrocyte sedimentation rate (ESR), leucocytes, C-reactive protein (CRP), total cholesterol, HDL cholesterol, triglycerides and fasting glucose] determined. Coronary angiography was performed in order to determine the severity of coronary artery disease according to the SYNTAX score and the number of affected coronary vessels: 1-vessel, 2-vessel or 3-vessel disease (hemodynamically significant stenoses: more than 70% of the blood vessel lumen). The patients were divided into three groups regarding the FINDRISC score: group I: 5-11 points; group II: 12-16 points; group III: 17-22 points. RESULTS: Out of 70 patients (52 men and 18 women) enrolled in this study, 14 had normal coronary angiogram. There was a statistically significant positive correlation between the FINDRISC score and its parameters respectively (age, body mass index-BMI, waist circumference) and the severity of CAD according to the SYNTAX score (p < 0.001) and the number of diseased coronary arteries (p < 0.001). The patients with higher FINDRISC score (groups II and III) had more severe and extensive-CAD according to the SYNTAX score than the group I. The odds ratio with 95% confidence intervals (CI) between the group III and the group I was 5.143 (95% CI 1.299-20.360, p = 0.002) and between the group II and the group I 5.867 (95% CI 1.590- 21.525, p = 0.007). There were no differences in odds ratio for multivessel disease according to FINDRISC score between the group II and the group III [1.141; (95% CI 0.348-3.734). In the group I mean SYNTAX score was 5.18, and more than 70% of patients had normal coronary angiogram. In the group II mean SYNTAX score was 17.06, and more than 70% of patients had 2-vessel disease and 3-vessel disease, and in the group III mean SYNTAX score was 18.89, and 2-vessel and 3-vessel disease had 36.36% and 31.82% patients, respectively. In multiple regression analysis, where SYNTAX score was dependent variable, and age, BMI, waist circumference, FINDRISC score were independent variables, we found that only FINDRISC score was independent predictor of SYNTAX score. CONCLUSION: The obtained results suggest a statistically significant correlation between the FINDRISC score and its parameters (age, BMI, waist circumference) and the severity of CAD according to the SYNTAX score and the number of diseased coronary arteries. The FINDRISC score may be useful in identifying patients at the high risk for coronary artery disease.

PCI and clopidogrel: antiplatelet responsiveness and patient characteristics.

OBJECTIVE: This study on responsiveness to clopidogrel and aspirin evaluates its interaction with: (i) patient characteristics; (ii) procedure characteristics; (iii) antiplatelet dose. METHODS AND RESULTS: After elective PCI, 60 patients receiving aspirin 100 mg daily, and clopidogrel 75 mg daily were monitored with the PFA 100 test and VASP assay. Non-responsiveness to aspirin and clopidogrel was found in 23 (38%) and 18 (30%) of 60 patients, respectively. Seven (12%) patients were dual nonresponders. Non-responders to both aspirin and clopidogrel were more often smokers. Non-responders to clopidogrel, in addition had elevated inflammatory markers (P < 0.05). Dual non-responders had (i) a higher platelet count, LDL, and CRP; (ii) a lower HDL (P < 0.05). Clopidogrel non-responders were receiving 150 mg clopidogrel, with a positive response in 72%. Eighty % of non-responders to 150 mg clopidogrel were also non-responders to aspirin. CONCLUSION: Baseline patient characteristics and clopidogrel dose modify the antiplatelet response. Also, patients resistant to both aspirin and clopidogrel do no benefit from an increased clopidogrel dose.

The influence of bisoprolol dose on ADP-induced platelet aggregability in patients on dual antiplatelet therapy.

PURPOSE: Dual antiplatelet therapy is recommended after acute coronary syndrome or after percutaneous coronary intervention with coronary stent implantation. Many of the patients on dual antiplatelet therapy receive ß-blockers; some of them could have antiaggregatory effect. Bisoprolol is a highly selective adrenoceptor-blocker, which is often used in the settings of percutaneous coronary intervention or acute coronary syndrome in patients on dual antiplatelet therapy. Its antiaggregative effect has not been extensively studied. Therefore, the aim of this study is to investigate the effect of bisoprolol on ADP-induced platelet aggregation in patients on dual antiplatelet therapy. METHODS: Platelet aggregability has been measured in 100 patients on dual antiplatelet therapy with multiplate analyzer using ADP test in blood samples anticoagulated with heparin. ADP test values have been expressed by arbitrary units/minute. In univariate and multivariate regression analyses, we have investigated the influence of bisoprolol and its dose and also different factors, such as risk factors, concomitant drugs and their dosage, laboratory findings, on ADP test values. RESULTS: Univariate regression analysis showed significant correlation between the bisoprolol dose and the ADP test value (P=0.046, B=52.55, 95% confidence interval 0.87-104.23), which was also shown in the multivariate regression analysis (P=0.018; B=57.011; 95% confidence interval 10.455-103.567). CONCLUSION: We have identified a positive correlation between bisoprolol dose and ADP-induced platelet aggregability in patients on dual antiplatelet therapy.

[The importance of tests applied to evaluate the effectiveness of antiplatelet therapy in patients with recurrent coronary stent thrombosis].

BACKGROUND: Stent thrombosis is potentially lethal complication with huge economic burden. The role of insufficient response to antiplatelet therapy is still unclear reason for its occurrence. CASE REPORT: We presented 54-year-old man with recurrent stent thrombosis on the 4th, 9th and 12th day after the primary percutaneous coronary intervention in spite of double antiaggregation therapy (aspirin+clopidogrel). All possible procedural causes were excluded and reimplantation of intracoronary stent was insufficient to resolve the problem, so four platelet tests were performed: flow cytometry, Platelet Function Analyzer-100 test, aggregometry, and determination of gene polymorphism for P2Y12 receptor (directly involved in the mechanism of thienopyridine), and GPIIbIIIa receptor (final receptor in aggregation). The patient was the carrier of the major haplotype H1H1 for P2Y12 receptor and minor A1A2 for GPIIbIIIa receptor. The results of all the performed tests showed insufficient antiplatelet effect of aspirin and sufficient response to thienopyridin (not to clopidogrel, but to ticlopidine). CONCLUSION: Performance of platelet function tests is necessary in the case of major adverse cardiac events especially stent thrombosis, after implantation of intracoronary stent.

Thienopyridine resistance among patients undergoing intracoronary stent implantation and treated with dual antiplatelet therapy: assessment of some modifying factors.

In this open, prospective study we assessed the prevalence of antiplatelet resistance among patients subjected to intracoronary stent implantation. In patients treated with aspirin + thienopyridine (N = 32), platelet reactivity index (PRI) significantly decreased after 2 and 7 days of dual antiplatelet treatment in comparison with the same patients on aspirin monotherapy (P<0.001, both). After 7 days of aspirin + thienopyridine treatment, insufficient antiplatelet response was observed in 28% (9/32) of the patients. High interindividual variability in response to aspirin + thienopyridine treatment emphasizes the significance of thienopyridine resistance, while the influence of statins on such a treatment should be reassessed.

The prognostic value of nailfold capillary changes for the development of connective tissue disease in children and adolescents with primary raynaud phenomenon: a follow-up study of 250 patients.

To assess the prognostic value of capillaroscopy findings for the development of connective tissue disease in children and adolescents with Raynaud phenomenon, we followed up a group of 250 (mean age 15 years) for 1 to 6 years after the first capillaroscopy was performed. Every 6 months they were screened for signs and symptoms of connective tissue disease. Analysis was performed on capillary changes registered 6 months before the development of connective tissue disease. Capillary changes were classified into three types: normal, nonspecific, and sclerodermatous. At the end of the follow-up period, 191 (76%) subjects had primary Raynaud phenomenon, 27 (10.8%) were diagnosed as having undifferentiated connective tissue disease, and 32 (12.8%) fulfilled the criteria for a diagnosis of a specific connective tissue disease. Systemic lupus erythematosus was found in nine (3.6%) patients, rheumatoid arthritis in 10 (4%) patients (six of them with juvenile onset rheumatoid arthritis), and scleroderma spectrum disorders in 13 (5.2%). The mean time for the evolution of Raynaud phenomenon into undifferentiated connective tissue disease or a form of the disease was 2 years. Most of the subjects with primary Raynaud phenomenon (173/191, 91%), undifferentiated connective tissue disease (22/27, 81%), juvenile onset rheumatoid arthritis/rheumatoid arthritis (7/10, 70%), and systemic lupus erythematosus (6/9, 67%) had normal capillary findings. Nonspecific capillary changes occurred in 3 of 10 (30%) patients with rheumatoid arthritis, 2 of 9 (22%) with systemic lupus erythematosus, 4 of 27 (15%) with undifferentiated connective tissue disease, and 18 of 191 (9%) with primary Raynaud phenomenon. Of all the subjects, only 10 (4%) showed sclerodermatous disease type capillary changes 6 months before the expression of a particular disease: eight (62%) of these developed scleroderma spectrum disorders, one expressed systemic lupus erythematosus, and one had undifferentiated connective tissue disease. We concluded that there were no specific capillary changes predictive for future development of systemic lupus erythematosus, juvenile onset rheumatoid arthritis/rheumatoid arthritis, and undifferentiated connective tissue disease in children and adolescents with Raynaud phenomenon. Most of our study subjects with Raynaud phenomenon who developed these diseases had normal capillary findings or nonspecific changes. Children and adolescents who developed scleroderma spectrum disorders showed a sclerodermatous type of capillary changes 6 months before the expression of the disease, indicating that this type of capillary changes in children and adolescents with Raynaud phenomenon highly correlated with further development of scleroderma spectrum disorders.