Incidence Of Arterial Thrombotic Events Research Articles

Risk Factors for Pulmonary Embolism in Individuals Infected with SARS-CoV2-A Single-Centre Retrospective Study.

The emergence of SARS-CoV2 has presented itself as a significant global health crisis. The prevalence of thrombotic events is known to be high in these patients, affecting various organ systems, sometimes leading to cutaneous thrombosis, pulmonary embolism (PE), stroke, or coronary thrombosis. The available evidence suggests that thromboembolism, hypercoagulability, and the excessive production of proinflammatory cytokines play a significant role in the development of multiorgan failure. Methodology: This retrospective single-centre study was conducted at "Victor Babes" University of Medicine and Pharmacy from Timisoara, Romania, involving a total of 420 patients diagnosed with COVID-19. We separated them into a CONTROL group that included 319 patients, and an intervention group (PE) with 101 patients that, subsequent to infection with the virus, developed pulmonary embolism. The study included the reporting of demographic data, laboratory findings, and comorbidities. Results: Out of a total of 420 patients, 24% experienced pulmonary embolism, while 21.42% died. Arterial thrombotic events were found to be associated with factors such as age, cardiovascular disease, levels of white blood cells, D-dimers, and albumin in the blood. The findings of the study indicate that there is an independent association between pulmonary thrombosis and hypertension (odds ratio (OR): 1.1; 95% confidence interval (CI): 0.7 to 1.7; p = 0.6463), cancer (OR: 1.1; 95% CI: 0.6 to 2.3; p = 0.6014), and COPD (OR: 1.2; 95% CI: 0.6 to 2.3; p = 0.4927). On the other hand, there is a stronger correlation between PE and obesity (OR: 2.8; 95% CI: 1.7 to 4.6; p < 0.0001), diabetes (OR: 3.3; 95% CI: 2 to 5.3; p < 0.0001), and dyslipidemia (OR: 3.6; 95% CI: 2.3 to 5.8; p < 0.0001) in a multivariable regression logistic model. Conclusions: Patients diagnosed with severe forms of COVID-19 display a comparable incidence of arterial thrombotic events, which have been linked to poor survival rates.

Remdesivir use in severe and critical COVID-19 patients might be associated with lower incidence of arterial thrombotic events

IntroductionVenous thromboembolism (VTE) and arterial thrombotic (AT) events are a striking feature of severe COVID-19, however, relationship of remdesivir use and the risk of thrombotic events is unknown and has not been investigated before. MethodsWe retrospectively analyzed a cohort of 876 consecutive hospitalized severe and critical COVID-19 patients who were treated with remdesivir and compared them to 876 case-matched control patients. All patients were treated in our tertiary-level institution in period from 10/2020 to 6/2021. VTE and AT were diagnosed by objective imaging and laboratory methods. ResultsAfter exclusion of 71 VTE and 37 AT events present at the time of hospital admission, there were a total of 70 VTE (35 in the remdesivir and 35 in the control group) and 38 AT events occurring during hospitalization (13 in the remdesivir and 25 in the control group). There was a similar cumulative post-admission VTE incidence among both remdesivir and matched control patients (P = 0.287). Significantly lower cumulative post-admission AT incidence was observed among patients treated with remdesivir than among matched control patients (1.7% vs 3.3%, HR = 0.51, P = 0.035). Tendency for lower AT rates was evident in subgroups of patients stratified according to the type of AT, as well as according to the intensity of required oxygen supplementation at the time of remdesivir use. ConclusionRemdesivir use in severe and critical COVID-19 patients might be associated with lower occurrence of AT during hospitalization, whereas similar rates of VTE events were observed among both patients treated with remdesivir and control patients.

THE "CLOT" THICKENS: HYPERKALEMIA DUE TO ACUTE LIMB ISCHEMIA IN COVID-19

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been implicated in a devastating inflammatory response resulting in thromboembolic events. Upwards of 40% of patients have been reported to have venous thromboembolism while the incidence of arterial thrombotic events, including acute limb ischemia (ALI), is estimated to be lower at 5%. This case highlights the importance of early recognition and treatment of ALI in COVID-19 to prevent significant morbidity and mortality. CASE PRESENTATION: A 59-year-old man with hypertension and pre-diabetes presented to our facility with tachypnea and hypoxia with oxygen saturation of 80%. He was placed on high flow nasal cannula but required intubation due to respiratory failure. Initial laboratory values revealed D-dimer 460 ng/mL, C-reactive protein 109 mg/L, ferritin 3,282 ng/mL, and creatine kinase 700 U/L. Right soleal vein thrombosis was identified on lower extremity ultrasound and he was started on intravenous heparin with therapeutic levels. On hospital day 4, he became acutely hypotensive and hyperkalemic to 7.9 mmol/L. Physical exam was notable for cold lower extremities with mottling while laboratory values showed lactate 4.1 mmol/L, D-dimer greater than 10,000 ng/mL, ferritin 23,712 ng/mL, and creatine kinase 21,078 U/L. Upon evaluation with lower extremity arterial duplex, there was no Doppler signal detected in the bilateral common femoral, superficial femoral, popliteal, posterior tibial, and anterior tibial arteries. A subsequent CT angiogram revealed extensive bilateral pulmonary emboli, acute total occlusion of the aorta beginning distal to the renal arteries, and extensive lower limb muscle stranding suggestive of ischemic injury. He was taken to the operating room and underwent emergent thrombolysis and thrombectomy. Unfortunately, he suffered severe reperfusion injury and expired shortly after the procedure. DISCUSSION: ALI presents with the 6 Ps: pain, pallor, paralysis, paresthesia, poikilothermia, and pulselessness. In COVID-19, it is estimated that 71% of arterial thrombotic events involve the lower extremities. Patients at risk are noted to be males over the age of 60 with diabetes and hypertension. Diagnosis can be made with duplex ultrasound, CT angiography, or MR angiography. After initiating therapeutic anticoagulation, vascular surgery should be consulted for management options such as catheter-directed thrombolysis, mechanical thrombectomy, or open surgery. CONCLUSIONS: This case highlights the significance of arterial thrombotic events in COVID-19 and the importance of early recognition of ALI. Unexplained hyperkalemia should be thoroughly investigated as it can be a presentation of myonecrosis secondary to ALI. Prompt initiation of anticoagulation and vascular surgery consult are vital in limiting morbidity and mortality. REFERENCE #1: Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098. DISCLOSURES: No relevant relationships by Talha Demirci, source=Web Response No relevant relationships by Himanshu Deshwal, source=Web Response No relevant relationships by ron goldenberg, source=Web Response

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.

Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors.

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.

Cardiovascular risk factors and arterial thrombotic events in congenital heart disease patients.

As congenital patients get older, it can be hypothesised that cardiovascular risk factors increase. Retrospective study of congenital heart disease (CHD) patients attended between January 2008 and September 2018. Cardiovascular risk factors, myocardial infarction, stroke, peripheral vascular disease, and analytical data such as serum glucose and lipid profile were determined. Eight hundred and eighteen CHD patients and 1955 control patients matched for age and sex were studied. CHD patients were distributed in simple (462 patients), moderate (228 patients) and great (128 patients) complexity. Median age in CHD patients was 33 (25-41) years oldand 56% were male. CHD patients were significantly more hypertensive and diabetic but less dyslipidemic and smokers than patients in the control group. Twenty-seven (3.3%) CHD patients had an arterial thrombotic event: 3 coronary, 22 neurological and 2 peripheral vascular disease. No significant differences were seen in the incidence of myocardial infarction between the control and the CHD groups. However CHD patients had a significant higher incidence of arterial thrombotic events (coronary, neurological and peripheral vascular events) at the expense of strokes and transient ischaemic attacks (22 vs 2 events in CHD and control patients, respectively). Also, no significant differences were seen in age, sex, BMI, arterial hypertension, diabetes mellitus, dyslipidemia, smoking habit, serum glucose, total and LDL cholesterol, statin treatment, myocardial infarction and arterial thrombotic events according to CHD complexity. Being older and having arterial hypertension, diabetes mellitus, dyslipidemia and smoking habit were more frequent among CHD patients with arterial thrombosis. Congenital heart diseases are more hypertensive and diabetic but less dyslipemic and smokers than patients in the control group. CHD patients have a higher incidence of neurological events but not of myocardial infarction in relation to the control population.

High Incidence of Arterial and Venous Thrombosis in Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

To determine the incidence of arterial thrombotic events (ATE) and venous thromboembolism (VTE) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This is a retrospective cohort study presenting the incidence of ATE (coronary events or ischemic stroke) and VTE [pulmonary embolism (PE) or deep venous thrombosis (DVT)] in patients diagnosed with AAV between 2005 and 2014. There were 204 patients with AAV who were identified. Median followup for surviving patients was 5.8 (range 1-10) years, accounting for 1088 person-years (PY). The incidence of ATE was 2.67/100 PY (1.56 for coronary events and 1.10 for ischemic stroke) and for VTE was 1.47/100 PY (0.83 for DVT only and 0.64 for PE with/without DVT). On multivariate analysis, prior ischemic heart disease (IHD) and advancing age were the only independent predictors of ATE. Among patients without prior IHD or stroke, the incidence of ATE remained elevated at 2.32/100 PY (1.26 for coronary events and 1.06 for ischemic stroke). ATE, but not VTE, was an independent predictor of all-cause mortality. Event rates for both ATE and VTE were highest in the first year after diagnosis of AAV but remained above the population incidence during the 10-year followup period. In comparison to reported rates for the UK population, the event rates in our AAV patients were 15-times higher for coronary events, 11-times higher for incident stroke, and 20-times higher for VTE. Patients with AAV have a high incidence of arterial and venous thrombosis, particularly in the first year after diagnosis.

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.

Effect of thromboprophylaxis with anticoagulant drugs on the incidence of arterial thrombotic events in medical inpatients: a systematic review.

Pharmacological prophylaxis of venous thromboembolism (VTE) is recommended for medical inpatients. Since arterial thrombosis (AT) shares some risk factors with VTE, it would be reasonable to assess the efficacy of thromboprophylaxis by considering both VTE and AT as outcome events. We performed a systematic review and meta-analysis of phase III RCTs on thromboprophylaxis in medical inpatients, to evaluate the quality of reporting and the incidence of AT, and the effect of thromboprophylaxis with anticoagulants on AT incidence. Studies were identified by a combined search strategy until May 2015. Differences in outcomes among groups were expressed as pooled odds ratios (OR) and 95 % confidence intervals (CI). Statistical heterogeneity was assessed by I (2) statistic. Twenty phase III RCTs, encompassing 54,742 patients, were included; of these, 3 (15 %) reported on AT as a pre-defined secondary outcome and 8 (40 %) on at least one AT outcome. Raw-unweighed incidence of fatal MI in the three RCTs is 0.37 % in patients receiving unfractionated heparin or enoxaparin, and 0.38 % in controls (OR 0.97, 95 % CI 0.62-1.52; I (2) = 0 %). A non-statistically significant increase in AT is reported in patients on enoxaparin compared to control (OR 1.95, 95 % CI 0.89-4.27; I (2) = 13 %). AT is underreported in RCTs on VTE prophylaxis in medical inpatients. Published data suggest that incidence of fatal MI in these patients may be clinically relevant. Insufficient data are available to draw firm conclusions on the effects of thromboprophylaxis with anticoagulants on AT incidence in this setting.

A Nordic Population-Based Cohort Study of Risk of Arterial Thrombotic and Venous Thromboembolic Events in Patients with Primary Chronic Immune Thrombocytopenia (cITP)

Background: ITP is a rare autoimmune disorder characterized by low platelet counts, resulting in an increased risk for bleeding. Paradoxically, patients with cITP may also have an increased incidence of thrombotic or thromboembolic events, but population-based data on this are limited. We estimated the incidence of these events in a prospective cohort study of incident cITP patients in three Nordic countries.Methods: Based on National Health Registry Systems (NHRSs) and medical records in Denmark, Norway, and Sweden, the study cohort included all adults diagnosed with cITP from January 1, 2008 to December 31, 2012 (n=1,821). Arterial thrombotic events (myocardial infarction [MI] and stroke) and venous thromboembolic events (pulmonary embolism and deep vein thrombosis) were identified in the NHRSs. Patients were followed from the latest of cITP diagnosis or April 1, 2009, until the earliest date of the first occurrence of the event of interest, death, emigration, or December 31, 2012. Incidence rates (events per 1,000 person-weeks [PW]) were computed for the entire cohort and stratified by gender, age, splenectomy status, and comorbidity burden.Results: Nearly 60% of the cITP cohort was >50 years in age, and 56% were female. Overall, the incidence of arterial thrombotic events was 0.31 per 1,000 PW (95% confidence interval [CI]: 0.25-0.39) and the incidence of venous thromboembolic events was 0.18 per 1,000 PW (95% CI: 0.13-0.24). For arterial thrombotic events, the risk was higher in males (compared with females), and the risk for both event types increased with increasing age and comorbid burden. Given the small number of patients who underwent splenectomy (n=101), it was difficult to detect any differences in the risk of thrombotic events by splenectomy status, but the incidence of venous thromboembolic events was higher in splenectomized versus non-splenectomized patients (0.27 per 1,000 PW [95% CI: 0.15-0.50] versus 0.16 [95% CI: 0.11-0.23]).Conclusions: Among patients with cITP, the risk of arterial thrombotic events is higher in males than females and increases with increasing age and level of comorbid burden. The risk of venous thromboembolic events is heightened in cITP patients who have undergone splenectomy. Abstract 4845. TableArterial thrombotic eventsVenous thromboembolic eventsN / PWIncidence rate per 1,000 PW (95% CI)N / PWIncidence rate per 1,000 PW (95% CI)Overall (n=1,821)68 / 218,3910.31 (0.25-0.39)39 / 220,8650.18 (0.13-0.24)GenderMale (n=794)39 / 90,5310.43 (0.31-0.59)17 / 92,4080.18 (0.11-0.30)Female (n=1,027)29 / 127,8600.23 (0.16-0.33)22 / 128,4570.17 (0.11-0.26)Age18-50 years (n=751)5 / 96,1190.05 (0.02-0.12)5 / 95,9630.05 (0.02-0.13)51-70 years (n=544)13 / 65,6520.20 (0.11-0.34)13 / 65,5560.20 (0.12-0.34)>70 years (n=526)50 / 56,6210.88 (0.67-1.17)21 / 59,3450.35 (0.23-0.54)Comorbid burdenLow (n=1,243)25 / 154,1810.16 (0.11-0.24)18 / 155,0580.12 (0.07-0.18)Moderate (n=435)29 / 48,3070.60 (0.42-0.86)14 / 49,6940.28 (0.17-0.48)High (n=143)14 / 15,9030.88 (0.52-1.49)7 / 16,1130.43 (0.21-0.91)Splenectomy statusSplenectomized (n=101)10 / 37,1210.27 (0.14-0.50)10 / 36,9570.27 (0.15-0.50)Non-splenectomized (n=1,720)58 / 181,2700.32 (0.25-0.41)29 / 183,9080.16 (0.11-0.23) DisclosuresCetin:Amgen: Employment. Ghanima:Roche: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy. Stryker:Amgen Inc.: Employment, Equity Ownership.

Risk of Arterial Thrombosis Not Increased by Sorafenib or Sunitinib

TO THE EDITOR: In an analysis assessing the risk of arterial thrombotic events (ATEs) with sunitinib or sorafenib in patients with cancer, Choueiri et al reviewed multiple studies using these agents. However, their finding of an increased risk of ATEs rests on their analysis of only three randomized controlled trials comparing sunitinib or sorafenib therapy with placebos, because the expected incidence of ATEs in uncontrolled trials is uncertain. They calculate a relative risk for thrombosis of 2.39 with sunitinib; however, this was not statistically significant (95% CI, 0.12 to 49.41). Their calculated relative risk in one of the three trials, that by Escudier et al, comparing sorafenib with a placebo for renal cell cancer, was statistically significant. However, because the authors failed to distinguish between incidence per treatment episode and incidence per unit of time (the more relevant statistic), their conclusions may be erroneous. In oncology clinical trials such as those reviewed, patients are generally not treated for a predetermined, fixed period of time; rather, they are treated until their cancer shows evidence of progression on computed tomography scans, at which time the patient is removed from the trial, and further adverse events are not recorded beyond 30 days after the end of treatment. Because sunitinib and sorafenib are beneficial oncology drugs, the patients in these trials often continued treatment with the active drug much longer than patients given a placebo; therefore, patients receiving the active drug had more time to develop conditions leading to adverse events, such as arterial thrombi. For example, in the study by Escudier et al, the median treatment duration with sorafenib was 5.8 months, versus 3 months with the placebo. This would translate into an average observation time of 6.8 months for patients treated with sorafenib, versus 4 months for patients who received the placebo.Twelve ATEs were recorded in patients receiving sorafenib during 3,067 patient-months of observation, versus two events in patients receiving the placebo during 1,804 patient-months of observation. The difference here is not significant (Fisher’s exact test, two-tailed, P .097). These three randomized trials show no clear evidence of an increased rate of significant arterial thrombi per patient per month with either sorafenib or sunitinib, compared with placebos. The same authors made the same error of confusing adverse event per treatment episode with the more important statistic of adverse event per unit of time in their article on bleeding with sunitinib and sorafenib, as was described in my letter. In their reply, the authors asserted that adverse effects, such as bleeding or thrombosis, occur early after drug exposure; however, I am unaware of any studies or clinical experience to support that hypothesis. A similar error was also made by Nalluri et al in a meta-analysis of venous thrombosis with bevacizumab, and when they calculated adverse events per unit of time, their results were no longer significant.

Are patients with thrombophilia and previous venous thromboembolism at higher risk to arterial thrombosis?

Introduction Whether thrombophilic disorders, which are established risk factors for venous thromboembolism (VTE), also increase the risk of arterial thrombosis is still unknown. Materials and methods We analyzed data from 1081 consecutive patients (649 F/432 M, 16–93 years of age) with previous VTE registered in the MAISTHRO (MAin-ISar-THROmbosis) database with regard to arterial thrombotic events and contributing risk factors. Screening for thrombophilia included testing for factor V Leiden and prothrombin G20210A mutation, antiphospholipid antibodies and activities of factor VIII, protein C, protein S and antithrombin. Results Of the entire study cohort, 40 patients (3.7%) had a prior myocardial infarction (MI), and 41 (3.8%) suffered a stroke. Other arterial thrombotic events were rare. Elevated factor VIII levels were more prevalent in MI patients than in controls (44.4 vs. 25.9%, p = 0.044), but after adjusting for the traditional cardiovascular risk factors, this relationship was no longer significant. We observed a higher rate of lupus anticoagulant in MI patients with an adjusted odds ratio of 3.3 (95%CI 0.84–12.8, p = 0.090). No difference in any other tested thrombophilia was observed in patients with MI or stroke relative to those without. Conclusion The cumulative incidence of arterial thrombotic events in VTE patients is low, and the inherited thrombophilias do not seem to substantially increase the risk of arterial thrombosis.

Significantly reduced spontaneous thrombolytic activity in older men: a possible explanation for the gender differences in risk of acute coronary syndromes

Background Although incidence of arterial thrombotic events increases with advancing age, the mechanism of such increased risk is poorly understood. There is also a gender difference; coronary heart disease is more common in men than women. The aim of the present study was to investigate the possible contribution from platelet reactivity and spontaneous thrombolysis, determinants of arterial thrombosis, to the increased risk of thromboembolism in aging, but otherwise healthy subjects. Method One hundred and forty-five normal subjects (61 men, 82 women) of age between 19 and 77 years were grouped into groups of young (<30 years); middle aged (31–50 years), and older (>51 years), according to their gender and body mass index (BMI). A new in vitro test [Gorog Thrombosis Test (GTT)] was used to measure in sequence both platelet reactivity [occlusion time (OT)] and spontaneous thrombolysis [lysis time (LT)] from one non-anticoagulated blood sample. Result OT in all women was 315±9.2 s (mean±S.E.M.), in all men OT was 300±10.6 s. The mean LT in all women was 2557±201.5 s, and in all men LT was 2493±198.6 s. Advanced age did not enhance platelet reactivity (OT), but increased BMI did ( P=0.039). Spontaneous thrombolysis (LT) was impaired in older men but not in women (difference between young vs. middle age: P=0.019; young vs. older: P=0.0002). Conclusion Our findings suggest that in men, spontaneous thrombolytic activity is reduced with age, and this may explain the increased frequency and severity of thromboembolic events. Interestingly, in women, spontaneous thrombolytic activity did not change after menopause.

Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction

AbstractWe hypothesized that possession of either of 2 functional coagulation factor XIII polymorphisms, one within subunit A (Val34Leu) and one within subunit B (His95Arg), might modulate the prothrombotic effects of estrogen and help to explain the variation in incidence of arterial thrombotic events among postmenopausal women using hormone replacement therapy. In a population-based case-control study of 955 postmenopausal women, we assessed the associations of factor XIII genotypes and their interactions with estrogen therapy on risk of nonfatal myocardial infarction (MI). The presence of the factor XIIIA Leu34 allele was associated with a reduced risk of MI (odds ratio [OR] = 0.70, 95% confidence interval [95% CI] = 0.51-0.95). The presence of the factor XIIIB Arg95 allele had little association with MI risk. Neither factor XIII polymorphism alone significantly modified the association between the risk of MI and current estrogen use. In exploratory analyses, however, there was a significant factor XIII subunit gene-gene interaction. Compared to women homozygous for both common factor XIII alleles, the Arg95 variant was associated with a reduced risk of MI in the presence of the Leu34 variant (OR = 0.36, 95% CI = 0.17-0.75) but not in the absence of the Leu34 variant (OR = 1.11, 95% CI = 0.69-1.79). Moreover, among women who had at least 2 copies of the variant factor XIII alleles and were current estrogen users, the risk of MI was reduced by 70% relative to estrogen nonusers with fewer than 2 factor XIII variant alleles (P value for interaction = .03). If confirmed, these findings may permit a better assessment of the cardiovascular risks and benefits associated with postmenopausal estrogen therapy. (Blood. 2003;102:25-30)