Risk Of Arterial Thrombotic Events Research Articles

Atrial Fibrillation in Patients with Myelofibrosis

Background: Atrial fibrillation (AF) is the most common arrythmia (1-2% of the general population) and is associated with high risk of arterial thrombotic events. AF is not well characterized in the context of myeloproliferative neoplasms (MPN). Recent studies imply that thrombotic risk stratification among MPN AF patients may be suboptimal using the standard CHA2DS2VASC score, and true predictor of thrombotic risk may be presence of myelofibrosis instead. Clinical context in which AF occurs in myelofibrosis patients had not been investigated so far, but such analysis is needed to better understand why is the presence of myelofibrosis in particular the main predictor of thrombotic events among AF MPN patients. We aimed to evaluate prevalence and clinical associations of AF among patients with myelofibrosis. Methods: We retrospectively investigated a cohort of 154 patients with overt myelofibrosis treated in 6 Croatian hematology centers in period 2004-2022. Diagnoses were reassessed according to the 2016 WHO criteria for primary myelofibrosis (PMF) and the 2008 IWGMRT criteria for secondary myelofibrosis (SMF). Presence of AF documented in medical records and clinical correlations of AF status with main disease related characteristics were analyzed. Results: Among a total of 154 patients, 86 had PMF, 35 had post polycythemia vera (PV) and 33 had post essential thrombocythemia (ET) SMF. Median age was 69 years. There were 91 (59%) males, 111 (75%) patients were JAK2, 9 (7.3%) CALR and 4 (3.3%) MPL mutated. AF was present in 15 (9.7%) patients with myelofibrosis which was significantly more frequent than anticipated in the general population of similar age (P<0.001). There were no significant associations of AF with neither etiology of myelofibrosis, age, sex, mutational status, degree of bone marrow fibrosis, spleen size, history of thrombosis, estimated glomerular filtration rate, hemoglobin, WBC nor platelet count (P>0.05 for all analyses). DIPSS score did not differ between AF and non-AF PMF patients, but MYSEC-PM score was significantly higher among AF SMF patients (P=0.029). AF in comparison to non-AF patients more frequently had constitutional symptoms (87% vs 54%, P=0.015), positive bleeding history (27% vs 6%, P=0.004), heart failure (47% vs 12%, P<0.001), obesity (21% vs 4%, P=0.010), lower MCHC (313 vs 318 g/L, P=0.031), higher urea (median 8.5 vs 6.8 g/L, P=0.009) and higher CHA2DS2VASC score (4 vs 3 points, P=0.003). AF more frequently received anticoagulants and diuretics than non-AF patients (P<0.05), whereas similar rates of cytoreductive therapy and aspirin were utilized. Despite all myelofibrosis patients with AF patients having CHA2DS2VASC score ≥2 points, only 60% of them received anticoagulant therapy, 27% received aspirin and 73% received cytoreductive therapy. No significant difference in survival and thrombosis was observed between AF and non-AF myelofibrosis patients (P>0.05 for all analyses) although study may be underpowered for these analyses. Summary/Conclusion: AF is frequent in patients with myelofibrosis and might be associated with higher frequency of constitutional symptoms, particular cardiovascular comorbidities and consistently high predetermined CHAD2DS2VASC risk. Nevertheless, unexpectedly low proportion of patients receives anticoagulant therapy, possibly due to anticipated risk of bleeding and cytopenias common in myelofibrosis patients. It remains a question whether suboptimal treatment or presence myelofibrosis itself might be a risk factor for unfavorable outcomes among AF MPN patients.

Anticoagulation for the Prevention of Arterial Thrombosis in Ambulatory Cancer Patients: Systematic Review and Meta-Analysis.

The risk of arterial thrombotic events (ATEs) is high among patients on systemic anticancer therapies. Despite the efficacy of anticoagulants in the prevention of cancer-associated venous thromboembolism, it is unknown whether anticoagulation is effective to prevent ATEs. This study sought to examine the efficacy and safety of anticoagulants in ATE prevention among ambulatory cancer patients. We performed a systematic review using Medline, Embase, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to May 21, 2022, and included studies comparing oral or parenteral anticoagulation with no anticoagulation among ambulatory patients receiving systemic anticancer therapy with no other indication for anticoagulation. The primary outcome was ATE (myocardial infarction, ischemic stroke, intra-abdominal arterial embolism, or peripheral artery occlusion). The secondary outcomes were major and nonmajor bleeding and all-cause mortality. Fourteen randomized trials involving low-molecular-weight heparins, direct oral anticoagulants, and warfarin were included. ATEs were captured as coefficacy endpoints or adverse events. Anticoagulant use was not associated with a reduction in ATEs compared with placebo or standard treatment (RR: 0.73, 95% CI: 0.50-1.04; P = 0.08; I2=0%). RRs of major and minor bleeding were 1.56 (95% CI: 1.12-2.17) and 2.25 (95% CI: 1.45-3.48) with anticoagulant use. In 13 trials that reported all-cause mortality, risk of death was not reduced with anticoagulants (RR: 0.99; 95% CI: 0.95-1.02; P = 0.38; I2 = 0%). Anticoagulants did not reduce ATE risk among ambulatory patients on systemic anticancer therapy and were associated with increased bleeding. Based on the current data, anticoagulants have a limited role in ATE prevention in this population as a whole.

Arterial Thrombosis in Patients with Acute Myeloid Leukemia: Incidence and Risk Factors.

Patients with hematological malignancies have an increased risk of arterial thrombotic events (ATEs) after diagnosis, compared to matched controls without cancer. However, data about incidence and risk factors for ATE development in patients with acute myeloid leukemia (AML) are missing. The objectives of this study were to determine the incidence of ATE in non-promyelocytic-AML patients and to define the potential risk factors for ATE development. We conducted a retrospective cohort study of adult patients with newly diagnosed AML. The primary outcome was the occurrence of confirmed ATE, defined as myocardial infarction, stroke or critical limb ischemia. Out of 626 eligible AML patients, 18 (2.9%) patients developed ATE in the median time of 3 (range: 0.23-6) months. Half of these patients died due to ATE complications. Five parameters were predictors of ATE: BMI > 30 (p = 0.000, odds ratio [OR] 20.488, 95% CI: 6.581-63.780), prior history of TE (p = 0.041, OR 4.233, 95% CI: 1.329-13.486), presence of comorbidities (p = 0.027, OR 5.318, 95% CI: 1.212-23.342), presence of cardiovascular comorbidities (p < 0.0001, OR 8.0168, 95% CI: 2.948-21.800) and cytogenetic risk score (p = 0.002, OR 2.113, 95% CI: 1.092-5.007). Our study showed that patients with AML are at increased risk of ATE. The risk was increased in patients with cardiovascular comorbidities, previous thrombosis, adverse cytogenetic risk as well as BMI > 30.

Arterial events in cancer patients treated with apixaban for venous thrombosis

IntroductionIn a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. MethodsTotal 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. ResultsAT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1–8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·109/L, p < 0.01). Clinical factors associated with AT were pancreatic cancer (OR 13.7, 95 % CI 4.3–43.1), ovarian cancer (OR 19.3, 95 % CI 2.3–164.4), BMI <25 percentile (OR 3.1, 95 % CI 1.1–8.8) and previous VT (OR 4.4, 95 % CI 1.4–13.7). Pancreatic cancer had a cumulative incidence of AT of 36 % compared with 0.8 % for all other cancers at 6 months (p < 0.01). Non-steroidal anti-inflammatory drugs (OR 4.9, 95 % CI 1.0–26) and antiplatelet treatment (OR 3.8, 95 % CI 1.2–12.2) were associated with AT. ConclusionIn cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT.The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

The Risk of Stroke and Myocardial Infarction in Multiple Myeloma: A Population-Based Study in the United States

Background: Multiple myeloma is defined by an aberrant increase in monoclonal immunoglobulins, accounting for approximately 10% of all hematologic malignancies. Patients with multiple myeloma have a high risk of arterial and venous thrombosis, which is hypothesized to be due to the interplay of patient comorbidities, therapy, and tumor-related factors. Real-world studies evaluating the association of multiple myeloma and arterial thrombosis in the United States (US) are scarce. Therefore, we conducted a study to assess the risk of stroke and myocardial infarction in this population of patients. Methods: We performed a retrospective study by querying a US-based database (Explorys, IBM) that retrieves patient records from 26 healthcare systems across 50 states, representing around 80 million patients. The database employs Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT) for diagnosis codes. From 1999 through 2022, we identified patients diagnosed with multiple myeloma who were 18 years or older. We also evaluated the following risk factors for stroke and myocardial infarction; sex, age > 65 years, hypertension, hyperlipidemia, diabetes mellitus, smoking status, and atrial fibrillation. A multivariable logistic regression accounting for all covariates was investigated to test for the risk of stroke and myocardial infarction. Results were reported in odds ratio (OR) and 95% confidence interval (CI), and the result was considered statically significant if the p-value was less than 0.001. Results: A total of 70,434,190 patients were included. 67,920 patients had multiple myeloma; 77% were aged > 65, and 52% were male. 19% had obesity, 67% had hypertension, 53% had hyperlipidemia, 31% had diabetes, and 21% had atrial fibrillation. A total of 600 patients had stroke with a prevalence of 0.88% and 5,370 patients had myocardial infarction with an incidence of 7.9%. After adjusting for confounding risk factors, the risk of stroke was significantly higher in the multiple myeloma group compared to patients without multiple myeloma (OR 1.51, 95% CI 1.43-1.59) see table 1. The risk of myocardial infarction was also significantly higher among patients with multiple myeloma (OR 1.36, 95% CI 1.32-1.39) see table 2. Conclusion: This is the largest real-world study in the US evaluating the risk of arterial thrombotic events in patients with multiple myeloma. Our study showed 51% and 36% higher odds of having a stroke and myocardial infarction, respectively. Given the enormity of the risk, physicians should consider optimizing modifiable risk factors in all patients with multiple myeloma. Further prospective studies are warranted to identify and risk stratify patients at the highest risk and explore the impact of different treatment regimens used in multiple myeloma. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Renal Function and Risk of Arterial Thrombotic Events in Patients Positive for Lupus Anticoagulant

Background: Patients with lupus anticoagulant (LA) are at risk for arterial and venous thromboembolic events. Recent work suggests that LA positive patients who experience thrombotic events in different vascular beds constitute distinct subgroups. To risk stratify patients, further work is needed to better characterize predictors for thromboembolic events in these subgroups.Aims: The aim of this study was to identify baseline characteristics and laboratory parameters associated with the development of arterial or venous thrombotic events.Methods: Patients with at least 2 previous positive LA tests were serially monitored for thrombotic events within the prospective Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Patients without clinical follow-up were excluded from this analysis. Statistical analysis was performed with RStudio (Version 1.1.442).Results: One-hundred-eighty-seven patients were followed (Table 1) for a median of 11.4 years and 1865 follow-up visits (median visit/patient=9). Fifty-seven prospective thrombotic events (TE), including 27 arterial thrombotic events (ATE) and 30 venous thrombotic events (VTE), were observed. This corresponded to 10-year prospective ATE, VTE and overall thrombosis incidences of 13.9% [95%CI: 8.3, 19.6], 18.8% [12.2, 25.4], and 32.0% [24.1, 39.8], respectively. (Figure 1). Thirty-seven of the 57 events occurred in patients with a prior history of thrombosis (“recurrent thrombosis”).In univariable competing risk analysis, age (subdistribution hazard ratio (SHR) = 1.02, 95% CI: 1.00-1.05, p=0.019), body mass index (BMI, 1.05, 1.00-1.11, p=0.042), history of ATE (3.14, 1.45-6.81, p=0.0038), active smoking (2.16, 1.00-4.62, p=0.049), diabetes (4.16, 1.47-11.8, p=0.0073), VKA use at baseline (0.42, 0.18-0.97, p=0.042), aCL IgM positivity (2.48, 1.05-5.83, p=0.038), aβ 2GPI IgM positivity (2.86, 1.18-6.93, p=0.020), mean platelet volume (1.17, 1.06- 1.30, p=0.0024), creatinine (3.76, 1.32- 10.7, p=0.013), and estimate glomerular filtration rate (eGFR, 0.98, 0.96-0.99, p=0.0011) were associated with prospective risk of ATE (Table 2). Conversely, the prospective risk of VTE was univariably associated only with prior history of VTE (3.26, 1.40-7.68, p=0.0061).After adjusting for traditional arterial thrombotic risk factors (age, sex, BMI, active smoking, diabetes,), history of ATE (SHR = 3.97, 95% CI: 1.71-9.025, p=0.0014), prior history of both ATE and VTE (3.87, 1.06-14.16, p=0.041), creatinine (3.93, 1.22-12.66, p=0.022), and eGFR (CKD-EPI, 0.96, 0.96-0.99, p=0.0037) remained independently associated with prospective risk of ATE (Table 2).In detail, the 10-year cumulative risk of ATE was 24.9% [95%CI: 8.8, 41.0], 15.0% [5.8, 24.2], and 6.7% [2.2, 13.8] in patients with a baseline eGFR less than 60 mL/min/1.73m 2, between 60 and 89 mL/min/1.73m 2, and greater than or equal to 90 mL/min/1.73m 2, respectively (Gray's test, p=0.019, Figure 2).Conclusion: Approximately 14% of patients persistently positive for LA experienced an ATE over 10 years. After adjusting for traditional arterial risk factors, decreased renal function was associated with an increased prospective risk of ATE. Notably, decreased renal function was not associated with development of VTE and the association with ATE was also independent of underlying SLE, LLD, or rheumatic disease (data not shown). Clinically, LA positive patients with decreased renal function may represent a subgroup that might benefit from more aggressive anti-thrombotic therapy or anti-thrombotic prophylaxis. [Display omitted] DisclosuresPabinger: Bayer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Daiichi Sanchyo: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NovoNordisk: Consultancy, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding.

Arterial Thrombotic Events in CML Patients Treated with First-Line Nilotinib: Incidence, Management and Impact on the Long Term Outcome — a Gimema CML WP Analysis

Background: Nilotinib has better efficacy compared to imatinib, with higher chances of achieving treatment-free remission. However, nilotinib is associated to a higher incidence of arterial thrombotic events (ATEs), limiting its use in selected patients.Aims: To investigate the characteristics of ATEs and their impact on the long-term outcome of CML patients treated with nilotinib first-line.Methods: We retrospectively analyzed 345 patients ≥ 18 years of age (18-49 years, 147 patients; 50-64 years, 109 patients; > 64 years, 89 patients) with CP CML enrolled in multicenter prospective clinical trials of the GIMEMA CML WP investigating nilotinib as first-line treatment (Clinical.Trials.gov: NCT00481052; NCT00769327; NCT01535391). The median age at CML diagnosis was 53 (18 - 86) years. The median follow-up was 58 (22-82) months; total nilotinib exposure: 1043 patient-years. We analyzed the rate, type, management, and outcome of ATEs; moreover, we compared the molecular response rates and the long-term outcome of patients with or without ATEs.Definitions: ATEs: peripheral arterial obstructive disease (PAOD), ischemic heart disease (IHD), significant carotid stenosis and ischemic stroke, or other significant ischemic events; major molecular response (MMR): BCR-ABL≤ 0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies.Results: Incidence and characteristics of ATEs: 30/345 (8.7%) patients had ATEs during treatment with nilotinib. Most common ATEs were IHD (4.1%), PAOD (2.3%), and (asymptomatic) carotid stenosis (1.1%). The median age at CML diagnosis of these patients was 64 (43-85) years, and the median age at ATEs was 67 (47 - 89) years. In patients of 18-49, 50-64, and > 64 years of age the rate of ATEs was 2%, 11%, and 15.7%, respectively; ATEs / 100 patient-years: 0.53, 2.7, and 3.6, respectively (relative risk in patients > 64 years vs. patients of 18-49 years: 6.7). The median duration of nilotinib treatment at ATE was 25 (1- 78) months: 87% and 60% of patients had achieved a MMR and MR4, respectively. These rates were comparable to those observed in patients without ATEs (MMR: 83%; MR4: 64%).Management of ATEs: 50% of patients received medical treatment only, while the remaining required invasive interventions, including coronary angioplasty with stent positioning (30%), lower limbs amputations (10%), and peripheral vascular by-passes (7%). Overall, 70% of patients were hospitalized; 80% of patients (7% of the whole cohort) permanently discontinued nilotinib because of ATEs. Nilotinib dose reduction was performed in most of the remaining patients.Outcome of ATEs: the median follow-up after ATE was 15 (1 - 58) months (total patient-years after ATEs: 52). No patient died for ATEs. The 5-year progression-free survival and overall survival were similar in patients with or without ATEs (PFS: 96% vs. 92%, p=0.55; OS: 96% vs. 93%, p=0.79)Summary: After a median follow-up of almost 5 years, 8.7% of patients treated in first-line with nilotinib had ATEs. In patients > 64 years the relative risk of ATEs was 6.7 times higher compared to patients < 50 years of age. For the management of ATEs, half of the patients received medical treatment only; the remaining patients required invasive procedures, including major surgeries in 20% of cases. Importantly, no patient died for ATEs, and ATEs did not significantly affect response rates and long-term outcome of CML patients treated with nilotinib first-line. DisclosuresGugliotta:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Breccia:TEVA: Speakers Bureau. Tiribelli:Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Fava:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Soverini:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Incyte Biosciences: Consultancy. Martinelli:Pfizer: Consultancy; Celgene: Consultancy; Johnson&Johnson: Consultancy; Roche: Consultancy; Ariad/Incyte: Consultancy; Amgen: Consultancy. Pane:Novartis: Honoraria, Speakers Bureau. Saglio:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Baccarani:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Rosti:Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Fibrinolysis in Acute and Chronic Cardiovascular Disease.

The formation of an obstructive thrombus within an artery remains a major cause of mortality and morbidity worldwide. Despite effective inhibition of platelet function by modern antiplatelet therapies, these agents fail to fully eliminate atherothrombotic risk. This may well be related to extensive vascular disease, beyond the protective abilities of the treatment agents used. However, recent evidence suggests that residual vascular risk in those treated with modern antiplatelet therapies is related, at least in part, to impaired fibrin clot lysis. In this review, we attempt to shed more light on the role of hypofibrinolysis in predisposition to arterial vascular events. We provide a brief overview of the coagulation system followed by addressing the role of impaired fibrin clot lysis in acute and chronic vascular conditions, including coronary artery, cerebrovascular, and peripheral vascular disease. We also discuss the role of combined anticoagulant and antiplatelet therapies to reduce the risk of arterial thrombotic events, addressing both efficacy and safety of such an approach. We conclude that impaired fibrin clot lysis appears to contribute to residual thrombosis risk in individuals with arterial disease on antiplatelet therapy, and targeting proteins in the fibrinolytic system represents a viable strategy to improve outcome in this population. Future work is required to refine the antithrombotic approach by modulating pathological abnormalities in the fibrinolytic system and tailoring therapy according to the need of each individual.

Arterial Thrombotic Events in Adult Inpatients With COVID-19

ObjectiveTo evaluate the clinical course of and risk factors for arterial thrombotic events in adult inpatients with coronavirus disease 2019 (COVID-19). MethodsAll consecutive adult patients admitted for COVID-19 infection in a referral center in France and discharged from the hospital between April 1 and April 30, 2020, were included. All arterial thrombotic events that occurred through discharge were considered for analysis. Epidemiologic, demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records with use of a standardized data collection form. ResultsOverall, 531 COVID-19+ patients were analyzed. Among them, 30 (5.6%) experienced arterial thrombotic events. Arterial thrombotic events in the setting of COVID-19 infection happened at a median of 11 (5-20) days after the first symptoms of infection; occurred in high-risk patients according to traditional cardiovascular risk factors; had an atypical pattern, such as thrombosis of the aorta, upper limb, or renal arteries or cerebral microvasculopathy in 7 (23.3%) cases; and were associated with an in-hospital mortality rate of 40%. Arterial thrombotic events increased the risk of death by 3-fold in COVID-19+ patients (hazard ratio, 2.96; 95% CI, 1.4 to 4.7; P=.002). A subdistribution survival hazard model showed that a concentration of D-dimer above 1250 ng/mL increased the risk of arterial thrombotic events in COVID-19+ patients by more than 7 (subdistribution hazard ratio, 7.68; 95% CI, 2.9 to 20.6; P<.001). ConclusionA dramatically high rate of in-hospital death was observed in patients who suffered arterial thrombotic events in the setting of COVID-19 infection. A D-dimer level above 1250 ng/mL at entry may identify COVID-19+ patients at risk for arterial thrombotic events.

Frequency of Arterial Thromboemobolic Events in Patients with Cancer Associated Venous Thromboembolism

Background:Patients with cancer are at high risk of both venous thromboembolism (VTE) and arterial events, however, little is known about the association between venous and arterial thromboembolic events in patients with cancer. In this study, we evaluated the incidence and relative risk of subsequent arterial thromboembolism in patients with a confirmed diagnosis of acute cancer-associated VTE. Methods:We conducted a retrospective cohort study at the Cleveland Clinic Taussig Cancer Institute of cancer patients with confirmed VTE who were referred to a centralized thrombosis clinic between January 2017-October 2019 with at least 6 months of follow-up. Arterial thrombotic events (ATE), including myocardial infarction, peripheral arterial thrombosis, and ischemic stroke, were identified by manual review of electronic medical records. The cumulative incidence rate of each ATE event was calculated. Results:The study population comprised 294 patients with a median age of (63.5) years (range 27-90), and 49.7 % were male. The cumulative incidence rate of overall ATE during the 6-month, 1-year, and 2-year follow-up period was 3.07%, 3.42%, and 3.42%, respectively. A total of 10 patients who experienced arterial events of whom 7 had ischemic stroke, 2 had myocardial infarction, 2 had peripheral arterial thrombosis where one patient had two arterial events of myocardial infarction and peripheral arterial thrombosis(Table 1 shows the incidence rates of arterial events). Amongst patients with ATE, 30 % were active smokers (n=3), 90% had hypertension (n=9), 20% had diabetes mellitus (n=2), 50% had a family history of coronary artery disease (n=5), 40% were on statin and daily aspirin use (n=4), 40% were obese with BMI &amp;gt;30 (n=4). 40% of ATE patients(n=4) were on a therapeutic anticoagulant therapy at the time of arterial thrombotic event (3 on enoxaparin, 1 on apixaban) Conclusion:Cancer patients with acute VTE have a substantial increased risk of subsequent arterial thromboembolism particularly in the first six months after VTE. Ischemic stroke was the most frequent arterial event and ATE events occured despite therapeutic anticoagulation in a large subset of our cohort. Further prospective studies are needed to better understand the risk of ATE in cancer patients, and further studies should be designed to mitigate the risk of arterial events in this patient population. Disclosures McCrae: Momenta Pharmaceuticals:Consultancy;Novartis:Honoraria;Rigel:Consultancy;Dova:Consultancy.Khorana:Pharmacyclics:Honoraria;Pharmacyte:Honoraria;Seattle Genetics:Honoraria;Leo Pharma:Honoraria;Medscape:Honoraria;Sanofi:Honoraria;Pfizer:Honoraria;Bayer:Honoraria;Janssen:Honoraria;Array:Other: Research funding (to institution);Merck:Research Funding;BMS:Honoraria, Research Funding;Leap:Research Funding.

Isolated Pulmonary Embolism Is Associated With a High Risk of Arterial Thrombotic Disease: Results From the VTEval Study

Isolated PE is associated with a higher burden of atherosclerotic disease than other manifestations of VTE. We hypothesized that the presence of isolated PE may signal a chronically elevated risk of arterial thrombotic disease. Data from the VTEval Study, a prospective cohort study enrolling individuals with clinical suspicion and imaging-based diagnosis or exclusion of VTE, were analyzed. Patients with PE received whole-leg ultrasonography to assess presence of DVT. Regularized logistic regression identified features that discriminate between isolated PE and other VTE phenotypes at clinical presentation. Survival analyses were performed to evaluate the crude and adjusted 3-year risks of arterial thrombotic disease, recurrent VTE, and death. The sample comprised 510 patients. Isolated PE patients (n= 63) had a distinct clinical profile from patients with other VTE phenotypes (n= 447). COPD, peripheral artery disease, atrial fibrillation, and coronary artery disease were significantly more prevalent among patients with isolated PE. Isolated PE patients had significantly higher risk (incidence rate ratio vsDVT-associated PE, 3.7 (95%CI, 1.3-10.8, P= .009); vsisolated DVT, 4.8 (1.7-14.3, P= .001) of arterial thrombotic events (ie, myocardial infarction, stroke/transient ischemic attack). After adjustment for clinical profile and medication intake, the risk of arterial thrombotic events for patients with isolated PE remained quadruple that of other VTE phenotypes (hazard ratio [HR], 3.8 [1.3-10.9], P= .01). Patients with isolated PE are at higher risk for arterial thrombosis and may require screening for arterial disease and development of novel therapeutic strategies. NCT02156401.

Different unfractionated heparin doses for preventing arterial thrombosis in children undergoing cardiac catheterization.

The role of cardiac catheterization in pediatrics has progressed significantly over the last two decades, evolving from a primary diagnostic tool to a primary treatment modality in children with congenital heart disease. Vascular complications, particularly arterial thrombosis, are among the most common unwanted post-cardiac catheterization events. In 1974, unfractionated heparin proved to be superior to placebo in decreasing the incidence of arterial thrombosis in pediatric patients. However, the optimal dose of unfractionated heparin to be utilized in this setting remains a matter of controversy. This is an update of the review first published in 2014. To evaluate the use of low-dose (< 100 units/kg) versus high-dose (≥ 100 units/kg) unfractionated heparin administered as an intravenous bolus at the time of initiation of cardiac catheterization (that is, immediately after arterial puncture), with or without subsequent heparin maintenance doses, for the prevention of post-procedural arterial thrombosis in children. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 15 October 2019. We planned to undertake reference checking of identified trials to identify additional studies. No language restrictions were applied. We included randomized or quasi-randomized trials that compared low dose to high dose unfractionated heparin administered prior to cardiac catheterization. We selected studies conducted in children aged 0 to 18 years. The first screening of potentially eligible studies was conducted by one of the authors (MLA). The second screening, risk of bias assessment and data extraction were independently conducted by two authors (MLA, LRB). Outcomes (thrombotic events, bleeding complications, other complications) were treated as dichotomous variables. The effect measures used were risk ratio (RR), risk difference (RD) and number needed to treat (NNT), with 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach. We identified no new studies for inclusion in this review. In total, two studies with a total of 492 participants were included. We had concerns about risk of bias for one of the two studies. The certainty of the evidence for our key outcomes was downgraded to moderate due to risk of bias concerns and imprecision. The confidence interval for the risk of arterial thrombotic events was compatible with benefits of either high or low unfractionated heparin dose regimens (RR low-dose versus high-dose 1.06, 95% CI 0.58 to 1.92). Only one of the studies reported the frequency of bleeding events and found no clear difference in the incidence of major or minor bleeding events between arms (RR low-dose versus high-dose 2.96, 95% CI 0.12 to 71.34 for major bleeding events; RR low-dose versus high-dose 1.38, 95% CI 0.46 to 4.13 for minor bleeding). This study also reported on the incidence of deep vein thrombosis when comparing the high versus low dose of heparin and reported a non-significant difference (RR low-dose versus high-dose 0.34, 95% CI 0.01 to 8.28). The other study lacked information about bleeding. Additional side effects of heparin other than bleeding events were not reported in either of the studies. Due to the limitations of the current evidence, small number of included studies, and lack of details reported in one study, we are unable to determine the effects of different dosing regimens of unfractionated heparin for the prevention of vascular thrombosis during cardiac catheterization in children. Further adequately powered, randomized clinical trials are needed.

Portal Vein Thrombosis and Budd-Chiari Syndrome as the Initial Symptom of Polycythemia Vera and Hyperhomocysteinemia

Portal Vein Thrombosis (PVT), commonly associated with cirrhosis of liver and thrombophilia, is one of the causes of severe abdominal pain. In the absence of non-cirrhotic non-malignant extrahepatic portal vein thrombosis, Myeloproliferative Disease (MPD) and an underlying thrombotic disorder should always be suspected and investigated. Hyperhomocysteinemia has been well-documented to increase the risk of arterial thrombotic events, peripheral arterial disease, and stroke. It is also a risk factor for deep-vein thrombosis. In the general population, association with portal vein thrombosis is very unusual, and only a few cases have been reported. We describe a case of Polycythemia Vera (PV) and hyperhomocysteinemia presenting with severe abdominal pain due to portal vein thrombosis. The patient underwent phlebotomy and was prescribed life-long anticoagulant, aspirin, vitamin B6, vitamin B12, and folic acid, then referred to a hematologist.

Acute arterial cardiovascular events risk in patients with primary membranous nephropathy.

Venous thromboembolism is a well established risk in patients with primary membranous nephropathy (MN) due to deficiency in natural anti-coagulants. Recent studies suggested a higher risk of arterial thrombotic events as well in this group. To identify that risk in our cohort. We reviewed the data of all patients who had biopsy proven primary MN at our institute between 2003 and 2013. Clinical data were retrospectively reviewed until November 2016. The cardiovascular (CV) events, including acute coronary syndromes and strokes were determined and included only if occurred after the diagnosis of the nephropathy. A total of 204 patients had biopsy proven MN. Follow up information was available for 166 patients. Thirty-one patients (18.6%) developed CV events during follow up. Thirty-eight per cent of total events occurred within 1 year of MN diagnosis. Forty-two per cent of those who developed CV events were not on anti-thrombotic medications and 60% were not on statin therapy. Male gender, age, diabetes and absence of statins therapy were associated with higher rates of CV events in this group. There is an increased risk of arterial events in patients with primary MN. This risk is greatest in the first year of diagnosis. The risk should be highlighted in this group of patients and anti-platelets and statin therapy should be considered especially during the initial phase of the disease.

Unmet Needs in Managing Myocardial Infarction in Patients With Malignancy.

Patients with cancer face a high short-term risk of arterial thromboembolism. One of the most fatal manifestations of arterial thromboembolism is myocardial infarction (MI), and patients with cancer face a 3-fold greater risk of MI than patients without cancer. The individual risk for arterial thrombotic events in patients with cancer is determined by the complex interaction of baseline cardiovascular risk factors, cancer type and stage, chemotherapeutic regimen, and other general contributing factors for thrombosis. Managing MI in patients with cancer is a clinical challenge, particularly due to cancer's unique pathophysiology, which makes it difficult to balance thrombotic and bleeding risks in this specific patient population. When patients with cancer present with MI, a limited proportion are treated with guideline-recommended therapy, such as antiplatelet therapy or invasive revascularization. Despite the limited evidence, existing reports consistently suggest similar clinical benefits of guideline-recommended therapy when administered to patients with cancer presenting with MI. In this review, we briefly summarize the available evidence, clinical challenges, and future perspectives on simultaneous management of MI and cancer, with a focus on invasive strategy.

Arterial thrombosis and cancer

Cancer-associated arterial thrombotic events (ATEs) are increasingly recognized in specific malignancies and in association with the expanding armamentarium of novel chemotherapeutic agents. The improved cancer survival led to cardiovascular complications becoming clinically relevant many years after cancer diagnosis. The pathobiology of ATEs in cancer is complex and the individual patient risk for an ATE entails a multifactorial interaction between the traditional cardiovascular risk factors and comorbidities, the specific malignancy and selected therapy. Treatment with several specific chemotherapeutic agents, immunomodulatory drugs, vascular endothelial growth factor pathway inhibitors, tyrosine kinase inhibitors, and radiotherapy, impart increased risk for ATEs that result from specific therapy-related mechanisms, often involving endothelial injury. Cancer cell-specific prothrombotic properties are important players in the pathogenesis of cancer-associated hypercoagulability. There are distinct biological and molecular processes preferentially activated in specific cancer cells which can trigger ATEs, including platelet activation, increased expression of procoagulants and suppression of fibrinolytic activity. ATEs portend adverse prognosis in cancer patients. Prevention and treatment of cancer-associated ATEs may be improved by greater awareness and careful monitoring for vascular toxicity, aggressive effort to optimize conventional cardiovascular risk factors, and use of antiplatelet and antithrombotic agents in selected patients. These issues are targets for future studies aimed to reduce ATEs in patients with cancer.

A Case of Pulmonary Vein Thrombosis Associated With Treatment of Omalizumab.

Pulmonary vein thrombosis (PVT) is a challenging diagnosis and has been described in association with or as a complication of pulmonary tumors, lung surgeries, atrial myxoma, and after radiofrequency catheter ablation for atrial fibrillation. There are not many reported cases of PVT associated with medication use. We present a case of a 53-year-old male with a history of severe persistent asthma on omalizumab, who presented with shortness of breath and was found to have PVT on computed tomography scan of the chest. The hypercoagulable workup was normal, and the patient did not have a history of malignancy or pulmonary surgeries. Currently, available data suggest an association between omalizumab use and increased risk of arterial thrombotic events. However, on a literature search, we could not find any reported cases of PVT with omalizumab treatment.

Impact of Age on Efficacy, Safety, and Long-Term Outcome of Chronic Myeloid Leukemia (CML) Patients Treated in First-Line with Nilotinib: An Analysis of the Gimema CML Working Party

Background: In chronic phase (CP) chronic myeloid leukemia (CML) the disease characteristics at diagnosis, risk distribution, probability of transformation to accelerated/blast phase (AP/BP), and toxicities may vary according to age. Nilotinib has shown better efficacy compared to imatinib, but it has been associated to a higher incidence of arterial thrombotic events (ATEs). Little is known on the efficacy, safety and long-term outcome of nilotinib treated patients in different age groups.Aims: To investigate the efficacy and safety, particularly the cardiovascular safety, of first-line treatment with nilotinib according to age distribution.Methods: We analyzed 345 patients ≥ 18 years of age with CP CML enrolled in clinical trials of the GIMEMA CML WP investigating nilotinib as first-line treatment. Patients were treated with: nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123); nilotinib 300 mg BID (n=149). The median follow-up was 58 months. We divided the patients in 3 groups of age (table): 18-49 years (group A, 147 pts, median age: 39 years); 50-64 years (group B, 109 pts, median age 58 years); and ≥ 65 years (group C, 89 pts, median age 71 years). We analyzed in detail the response rates, events and outcome. Definitions: Major molecular response (MMR): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to AP/BP, or deaths. ATEs: peripheral arterial obstructive disease (PAOD), acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events.Results: EUTOS high risk patients were: 8.8, 5.5, 1.1% in group A, B, and C, respectively (p=0.048). We did not observe significant differences in molecular response rates (table), including BCR-ABL/ABL <10% at 3 months, MMR and MR4 at 12 months, and cumulative incidences by 5 years of MR3 and MR4. Events leading to permanent nilotinib discontinuations occurred in 31%, 29%, and 42% of group A, B, and C, respectively (p=0.049). Overall, 29 ATEs were recorded, with higher rates, as expected, in elderly patients (group A: 2%; B: 11%; C: 15.7%; p=0.006); relative risk for ATEs in group B vs. A: 5; relative risk in group C vs. A: 6.7. ATEs were the reason for permanent nilotinib discontinuation in 2% of pts 18-49 years, 7.3% of pts 50-64 years, and 11.2% of pts > 65 years (p=0.015). Progressions to AP/BP were significantly more frequent in younger (18 - 49 years) patients (6.8%) compared to older (> 50 years) patients (1.5%), p= 0.019. Overall, 19 patients died (group A: 4.8%; B: 2.8%; C: 10%). In patients < 65 years all deaths (10) were leukemia-related, while in patients >65 years, all but one (8/9) deaths were leukemia-unrelated. The 6-year overall-survival was 94%, 97%, and 84% in pts 18-49 years, 50-64 years, and > 65 years of age (p=0.12)Summary/Conclusion: Nilotinib as first-line treatment of newly diagnosed CP CML patients showed high rates of molecular responses in all age groups. However, compared to older patients, significant more progressions occurred in younger (18-49 years) ones; the causes of death in this group were all leukemia-related. In contrast, in elderly patients (>65 years) the causes of death were almost all leukemia-unrelated. ATEs were rare (2%) in patients of 18-49 years, while high rates (> 10%) of ATEs were recorded in those of 50-64 years; as expected, ATEs occurred even more frequently in patients > 65 years. These data suggest that while in patients > 50 years more attention should be focused on the prevention of ATEs, in younger ones more efforts are needed to avoid the progression of CML to accelerated/blast phase. [Display omitted] DisclosuresGugliotta:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Castagnetti:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martinelli:Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Novartis: Speakers Bureau; Amgen: Consultancy; Genentech: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Amgen: Consultancy; Genentech: Consultancy. Saglio:Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Baccarani:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Other: personal fees, Speakers Bureau; Ariad: Honoraria, Other: personal fees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Should aspirin be used for primary prevention of thrombotic events in patients with membranous nephropathy?

Patients with nephrotic syndrome are at increased risk of thrombosis. The risk of venous thrombosis is particularly high in patients with nephrotic syndrome due to primary membranous nephropathy. Recent data provide evidence that these patients also have a high absolute risk of arterial thrombotic events, which is associated with the degree of hypoalbuminemia. In this commentary we discuss whether prophylactic aspirin therapy might be indicated in this patient population.

Cancer associated thrombosis: risk factors and outcomes

Deep vein thrombosis of the leg and pulmonary embolism are frequent diseases and cancer is one of their most important risk factors. Patients with cancer also have a higher prevalence of venous thrombosis located in other parts than in the legs and/or in unusual sites including upper extremity, splanchnic or cerebral veins. Cancer also affects the risk of arterial thrombotic events particularly in patients with myeloproliferative neoplasms and in vascular endothelial growth factor receptor inhibitor recipients. Several risk factors need to interact to trigger thrombosis. In addition to common risk factors such as surgery, hospitalisation, infection and genetic coagulation disorders, the thrombotic risk is also driven and modified by cancer-specific factors including type, histology, and stage of the malignancy, cancer treatment and certain biomarkers. A venous thrombotic event in a cancer patient has serious consequences as the risk of recurrent thrombosis, the risk of bleeding during anticoagulation and hospitalisation rates are all increased. Survival of cancer patients with thrombosis is worse compared to that of cancer patients without thrombosis, and thrombosis is a leading direct cause of death in cancer patients.