P4608BET-inhibition with Apabetalone in Post-ACS Patients with Diabetes: Design and Baseline Characteristics of the BETonMACE trial

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K K Ray ◽  
S J Nicholls ◽  
M Sweeney ◽  
J Johansson ◽  
N Wong ◽  
...  
Keyword(s):  
Renal Function ◽  
Major Adverse Cardiovascular Events ◽  
Dependent Manner ◽  
Double Blind ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
Low Hdl ◽  
History Of ◽  
Baseline Characteristics

Abstract Background Diabetes (DM) is associated with increased risk of macro/microvascular disease and cognitive decline. Inflammation and vascular calcification may be contributing factors. Bromodomain and extraterminal (BET) proteins coordinate gene transcription and modify the transcriptional response to hyperglycemia, and inflammation. Apabetalone competitively and selectively inhibits binding between BET proteins and acetyl-lysine marks on histone tails: normalizing transcriptional profiles to physiological levels; reducing in vitro alkaline phosphatase (ALP) transcription and in vivo plasma ALP in a dose-dependent manner. Phase 2 trials with apabetalone show improved renal function in the chronic kidney disease (CKD) subgroups. Furthermore, treatment showed a 55% reduction in CVD events with more pronounced benefit among patients with DM, low HDL-cholesterol (HDL-C) and high sensitivity C-reactive protein (hsCRP). Methods The double-blind, placebo controlled phase 3 BETonMACE trial is testing the hypothesis that apabetalone 100 mg b.i.d., added to standard care, reduces major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction or stroke) in patients with DM, acute coronary syndrome (ACS) within the preceding 7–90 days, low HDL-C (<40 mg/dL in men; <45 mg/dL in women), and estimated glomerular filtration rate (eGFR) >30 mL/min/1.7m2. The trial will continue until at least 250 MACE, providing 80% power to detect a 30% reduction. Secondary endpoints include changes in eGFR in patients with baseline eGFR 30 to <60 mL/min/1.7m2, inflammatory markers, lipids, and ALP. In addition the Montreal Cognition Assessment (MoCA) test was performed in patients ≥70 years of age at baseline and annually. Results Enrollment of 2425 patients across 13 countries and 195 centers is now complete. Baseline characteristics [median (IQR)] include LDL-C 65.0 (36) mg/dL, HDL-C 33.0 (7) mg/dL, HbA1c 7.3 (2.3) %, hsCRP 2.8 (4.9) mg/L, mean blood pressure 129/76 mmHg, and CKD in 266 patients (10.8%). Background care was based on guideline recommendations. Diabetes medications include metformin (79%), insulin (36%), sulfonylureas (28%), DPP4 inhibitors (11%), SGLT2 inhibitors (9.7%) and GLP1 receptor agonists (0.3%). The CKD subpopulation vs. total population differed significantly from the whole population with regard to age (71 vs. 62 y. o.), male sex (58% vs. 75%), history of hypertension (46% vs. 88%), history of stroke (1.5% vs. 7.5%), and current smokers (6.1% vs. 13%). In the 70 year and older (n=466, 19%) population 54% (n=243) showed a baseline MoCA score 25 and lower suggesting cognitive impairment. Summary The BETonMACE trial is testing the hypothesis that selective BET-inhibition with apabetalone, added to established, evidence-based treatment, reduces MACE in high-risk patients with DM, recent ACS, and low HDL-C. The study will also assess apabetalone's effect on renal function and cognition.

scholarly journals Contrast Associated Acute Kidney Injury and Mortality in Older Adults with Acute Coronary Syndrome: A Pooled Analysis of the FRASER and HULK Studies

2021 ◽  
Vol 10 (10) ◽  
pp. 2151
Author(s):  
Rita Pavasini ◽  
Matteo Tebaldi ◽  
Giulia Bugani ◽  
Elisabetta Tonet ◽  
Roberta Campana ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Multivariable Analysis ◽  
Kidney Injury ◽  
Coronary Intervention ◽  
Pooled Analysis ◽  
Coronary Syndrome ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Short Term Mortality

Whether contrast-associated acute kidney injury (CA-AKI) is only a bystander or a risk factor for mortality in older patients undergoing percutaneous coronary intervention (PCI) is not well understood. Data from FRASER (NCT02386124) and HULK (NCT03021044) studies have been analysed. All patients enrolled underwent coronary angiography. The occurrence of CA-AKI was defined based on KDIGO criteria. The primary outcome of the study was to test the relation between CA-AKI and 3-month mortality. Overall, 870 older ACS adults were included in the analysis (mean age 78 ± 5 years; 28% females). CA-AKI occurred in 136 (16%) patients. At 3 months, 13 (9.6%) patients with CA-AKI died as compared with 13 (1.8%) without it (p < 0.001). At multivariable analysis, CA-AKI emerged as independent predictor of 3-month mortality (HR 3.51, 95%CI 1.05–7.01). After 3 months, renal function returned to the baseline value in 78 (63%) with CA-AKI. Those without recovered renal function (n = 45, 37%) showed an increased risk of mortality as compared to recovered renal function and no CA-AKI subgroups (HR 2.01, 95%CI 1.55–2.59, p = 0.009 and HR 2.71, 95%CI 1.45–5.89, p < 0.001, respectively). In conclusion, CA-AKI occurs in a not negligible portion of older MI patients undergoing invasive strategy and it is associated with short-term mortality.

684 Cardiac troponins and adverse outcomes in European patients with atrial fibrillation: a report from the ESC-EHRA EORP atrial fibrillation general long-term registry

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Marrco Vitolo ◽  
Vincenzo Livio Malavasi ◽  
Marco Proietti ◽  
Igor Diemberger ◽  
Laurent Fauchier ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Regression Analysis ◽  
Cox Regression ◽  
Adverse Outcomes ◽  
Cox Regression Analysis ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
History Of ◽  
Cardiac Troponins

Abstract Aims Cardiac troponins (cTn) have been reported to be predictors for adverse outcomes in atrial fibrillation (AF), patients, but their actual use is still unclear. To assess the factors associated with cTn testing in routine clinical practice and to evaluate the association of elevated levels of cTn with adverse outcomes in a large contemporary cohort of European AF patients. Methods and results Patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry were stratified into three groups according to cTn levels as (i) cTn not tested, (ii) cTn in range (≤99th percentile), and (iii) cTn elevated (&gt;99th percentile). The composite outcome of any thromboembolism/any acute coronary syndrome (ACS)/cardiovascular (CV) death, defined as major adverse cardiovascular events (MACE) and all-cause death were the main endpoints. 10 445 (94.1%) AF patients were included in this analysis [median age 71 years, interquartile range (IQR): 63–77; males 59.7%]. cTn were tested in 2834 (27.1%). Overall, cTn was elevated in 904 (8.7%) and in-range in 1930 (18.5%) patients. Patients in whom cTn was tested tended to be younger (P &lt; 0.001) and more frequently presenting with first detected AF and atypical AF-related symptoms (i.e. chest pain, dyspnoea, or syncope) (P &lt; 0.001). On multivariable logistic regression analysis, female sex, in-hospital enrollment, first-detected AF, CV risk factors, history of coronary artery disease (CAD), and atypical AF symptoms were independently associated with cTn testing. After a median follow-up of 730 days (IQR: 692–749), 957 (9.7%) composite endpoints occurred while all-cause death was 9.5%. Kaplan–Meier analysis showed a higher cumulative risk for both outcomes in patients with elevated cTn levels (Figure) (Log Rank tests, P &lt; 0.001). On adjusted Cox regression analysis, elevated levels of cTn were independently associated with a higher risk for MACE [hazard ratio (HR): 1.74, 95% confidence interval (CI): 1.40–2.16] and all-cause death (HR 1.45, 95% CI: 1.21–1.74). Elevated levels of cTn were independently associated with a higher occurrence of MACE, all-cause death, any ACS, CV death and hospital readmission even after the exclusion of patients with history of CAD, diagnosis of ACS at discharge, those who underwent coronary revascularization during the admission and/or who were treated with oral anticoagulants plus antiplatelet therapy. Conclusions Elevated cTn levels were independently associated with an increased risk of all-cause mortality and adverse CV events, even after exclusion of CAD patients. Clinical factors that might enhance the need to rule out CAD were associated with cTn testing.

Abstract 17207: Cardiovascular Risks in Acute Leukemia Patients Treated With Anthracyclines

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Yu Kang ◽  
Srinivas Denduluri ◽  
Bruna M Assuncao ◽  
Marielle Scherrer-Crosbie
Keyword(s):  
Heart Failure ◽  
Ischemic Stroke ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Previous History ◽  
Major Adverse Cardiovascular Events ◽  
Symptomatic Heart Failure ◽  
Coronary Syndrome ◽  
History Of

Introduction: The incidence of acute leukemia has been increasing by about 1.6% per year in the last decade. Anthracyclines remain a standard of care for patients with acute leukemia; survival is increasing at about 1.0% per year. However, little is known about the incidence and risk of major adverse cardiovascular events (MACE) in patients with acute leukemia. Hypothesis: To investigate the incidence of MACE and the risk factors for MACE in patients with acute leukemia treated with anthracyclines. Methods: All adult patients with acute leukemia treated with anthracyclines between January 2005 and April 2018 at the hospital of University of Pennsylvania were studied. MACE were defined as cardiovascular death, symptomatic heart failure, non-fatal acute coronary syndrome, non-fatal ventricular arrhythmia and non-fatal ischemic stroke. Differences between patients with or without MACE were compared by Student’s t test or the Wilcoxon rank comparison. Cox proportional hazard analysis was used to determine significant clinical and echocardiographic parameters associated with MACE. Results: Six hundred and seventy-four patients (234 acute lymphoblastic leukemia (ALL), 440 acute myeloid leukemia (AML), age range: 22 to 93 years) were studied. Seventy-one patients (10.5%) experienced MACEs during a median follow-up period of 16 months (4 to 146 months) after the initiation of chemotherapy. The median time to MACE was 13 months (5 to 107 months). In the patients with MACE,59 (8.8%) developed symptomatic heart failure, 7 (1.0%) died of cardiovascular causes, 3 (0.4%) experienced non-fatal acute myocardial syndrome and 2 (0.3%) had an ischemic stroke. The Table summarizes the characteristics of patients with and without MACE. In a multivariable analysis, a previous history of heart failure (HR: 4.632, P=0.000, 95% CI: 2.572-8.341), leukemia type (HR: 3.155, P=0.002, 95% CI: 1.544-6.446) and baseline LVEF (HR: 0.973, P=0.000, 95% CI: 0.955-0.991) remained associated with MACE. Conclusion: Patients with acute leukemia treated with anthracyclines have a high rate of MACE after chemotherapy. A previous history of heart failure, baseline LVEF and type of leukemia may help to stratify acute leukemia patients at highest risk for MACEs after anthracycline therapy.

P5341Predictive factors of atherosclerotic cardiovascular diseases events in HIV-HVC co-infected patients: results from hepavih ANRS co13 cohort

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
F Boccara ◽  
B K Tan ◽  
M Chalouni ◽  
D Salmon Ceron ◽  
A Cinaud ◽  
...  
Keyword(s):  
Viral Load ◽  
Sustained Viral Response ◽  
Biological Data ◽  
Personal History ◽  
Hiv Viral Load ◽  
Factors Associated ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
History Of

Abstract Introduction Several studies highlighted an increased risk of cardiovascular disease (CVD) in HIV-HCV co-infected patients without clearly identifying specific virologic factors associated with atherosclerotic CVD (ASCVD) events. Purpose Hence, we analyzed data collection from the French nationwide ANRS CO13 HEPAVIH cohort to determine the incidence of ASCVD events in HIV-HCV co-infected patients and the predictive factors associated with its occurrence. Methods The French multicenter nationwide ANRS CO13 HEPAVIH clinic-based cohort collected prospective clinical and biological data from HIV-HCV co-infected patients followed-up in 28 different university hospitals between December 2005 to November 2016. Participants with at least one year of follow-up were included. Primary outcome was the occurrence of major ASCVD events (cardiovascular death, acute coronary syndrome, coronary revascularization and stroke). Secondary outcomes were total ASCVD events including major ASCVD events and minor ASCVD events (peripheral arterial disease [PAD]). Incidence rates were estimated using Aalen-Johansen method and factors associated with ASCVD identified with Cox proportional hazards models. Results A total of 1213 patients were included: median age 45.4 years [42.1–49.0], 70.3% men, current smoking 70.2%, overweight 19.5%, liver cirrhosis 18.9%, chronic alcohol consumption 7.8%, diabetes mellitus (5.9%), personal history of CVD 2.7%, and statins use 4.1%. After a median follow-up of 5.1 years [3.9–7.0], 44 participants experienced at least one ASCVD event (26 major ASCVD event, and 20 a minor event). Incidences for total, major and minor ASCVD events were of 6.98 [5.19; 9.38], 4.01 [2.78; 6.00], and 3.17 [2.05; 4.92] per 1000 person-years, respectively. Personal history of CVD (Hazard Ratio (HR)=13.94 [4.25–45.66]), high total cholesterol (HR=1.63 [1.24–2.15]), low HDL cholesterol (HR=0.08 [0.02–0.34]) and undetectable HIV viral load (HR=0.41 [0.18–0.96]) were identified as independent factors associated with major ASCVD events while cirrhosis status, liver fibrosis and HCV sustained viral response were not. Cumulative incidence of CV events Conclusion HIV-HCV co-infected patients experience a high incidence of ASCVD events both coronary and peripheral artery diseases. Traditional CV risk factors are the main determinants of ASCVD whereas undetectable HIV viral load seems to be protective. Management of cholesterol abnormalities and controlling viral load are essential to modify this high cardiovascular risk. Acknowledgement/Funding Agence Natoinale de Recherche sur le SIDA et les Hépatites virales

scholarly journals Antidepressant Use and the Risk of Major Adverse Cardiovascular Events in Patients Without Known Cardiovascular Disease: A Retrospective Cohort Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Ha Young Jang ◽  
Jae Hyun Kim ◽  
Yun-Kyoung Song ◽  
Ju-Young Shin ◽  
Hae-Young Lee ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Risk Score ◽  
Cardiovascular Events ◽  
Major Adverse Cardiovascular Events ◽  
Cvd Risk ◽  
Hazard Ratios ◽  
Increased Risk ◽  
History Of ◽  
Antidepressant Use ◽  
Cox Proportional Hazard Regression

Aims: Conflicting data exist on whether an association exists between antidepressants and the risk of major adverse cardiovascular events (MACEs) in patients with depression. This may be due to the use of various study designs and residual or unmeasured confounding. We aimed to assess the association between antidepressant use and the risk of MACEs while considering various covariates, including severity of depression and the cardiovascular disease (CVD) risk score.Methods: Patients newly diagnosed with depression with no history of ischemic heart disease and stroke were followed-up from 2009 to 2015. We conducted Cox proportional hazard regression analysis to estimate hazard ratios (HRs) for each antidepressant for MACE risk.Result: We followed-up (median, 4.4 years) 31,830 matched patients with depression (15,915 antidepressant users and 15,915 non-users). In most patients (98.7%), low-dose tricyclic antidepressants (TCAs) were related with a significantly increased risk of MACEs [adjusted HR = 1.20, 95% confidence interval (CI) = 1.03–1.40]. Duration response relationship showed a gradually increasing HR from 1.15 (95% CI = 0.98–1.33; &lt;30 days of use) to 1.84 (95% CI = 1.35–2.51; ≥365 days of use) (p for trend &lt;0.01). High Korean atherosclerotic CVD risk score (≥7.5%) or unfavorable lifestyle factors (smoking, alcohol intake, and exercise) were significantly associated with MACEs.Conclusion: Even at low doses, TCA use was associated with MACEs during primary prevention. Longer duration of TCA use correlated with higher HR. Careful monitoring is needed with TCA use in patients with no known CVD history.

scholarly journals First-Ever Ischemic Stroke and Incident Major Adverse Cardiovascular Events in 93 627 Older Women and Men

Stroke ◽  
2020 ◽  
Vol 51 (2) ◽  
pp. 387-394 ◽  
Author(s):  
Luciano A. Sposato ◽  
Melody Lam ◽  
Britney Allen ◽  
Salimah Z. Shariff ◽  
Gustavo Saposnik ◽  
...  
Keyword(s):  
Sex Differences ◽  
Heart Disease ◽  
Ischemic Stroke ◽  
Cardiovascular Events ◽  
Population Based ◽  
Major Adverse Cardiovascular Events ◽  
Cardiac Complications ◽  
Coronary Syndrome ◽  
Cardiovascular Comorbidities ◽  
Increased Risk

Background and Purpose— Stroke risk is sex-specific, but little is known about sex differences of poststroke major adverse cardiovascular events (MACEs). Stroke-related brain damage causes autonomic dysfunction and inflammation, sometimes resulting in cardiac complications. Sex-specific cardiovascular susceptibility to stroke without the confounding effect of preexisting heart disease constitutes an unexplored field because previous studies focusing on sex differences in poststroke MACE have not excluded patients with known cardiovascular comorbidities. We therefore investigated sex-specific risks of incident MACE in a heart disease-free population-based cohort of patients with first-ever ischemic stroke and propensity-matched individuals without stroke. Methods— We included Ontario residents ≥66 years, without known cardiovascular comorbidities, with first-ever ischemic stroke between 2002 and 2012 and propensity-matched individuals without stroke. We investigated the 1-year risk of incident MACE (acute coronary syndrome, myocardial infarction, incident coronary artery disease, coronary revascularization procedures, incident heart failure, or cardiovascular death) separately for females and males. For estimating cause-specific adjusted hazard ratios, we adjusted Cox models for variables with weighted standardized differences >0.10 or those known to influence MACE risk. Results— We included 93 627 subjects without known cardiovascular comorbidities; 21 931 with first-ever ischemic stroke and 71 696 propensity-matched subjects without stroke. Groups were well-balanced on propensity-matching variables. There were 53 476 women (12 421 with and 41 055 without ischemic stroke) and 40 151 men (9510 with and 30 641 without ischemic stroke). First-ever ischemic stroke was associated with increased risk of incident MACE in both sexes. The risk was time-dependent, highest within 30 days (women: adjusted hazard ratio, 25.1 [95% CI, 19.3–32.6]; men: aHR, 23.4 [95% CI, 17.2–31.9]) and decreasing but remaining significant between 31 and 90 days (women: aHR, 4.8 [95% CI, 3.8–6.0]; men: aHR, 4.2 [95% CI, 3.3–5.4]), and 91 to 365 days (aHR, 2.1 [95% CI, 1.8–2.3]; men: aHR, 2.0 [95% CI, 1.7–2.3]). Conclusions— In this large population-based study, ischemic stroke was independently associated with increased risk of incident MACE in both sexes.

scholarly journals Glycemic Variability in Diabetes Increases the Severity of Influenza

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Rebecca J. Marshall ◽  
Pornthida Armart ◽  
Katina D. Hulme ◽  
Keng Yih Chew ◽  
Alexandra C. Brown ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glycemic Variability ◽  
Endothelial Barrier ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Severe Influenza ◽  
Increased Risk ◽  
History Of

ABSTRACT People with diabetes are two times more likely to die from influenza than people with no underlying medical condition. The mechanisms underlying this susceptibility are poorly understood. In healthy individuals, small and short-lived postprandial peaks in blood glucose levels occur. In diabetes mellitus, these fluctuations become greater and more frequent. This glycemic variability is associated with oxidative stress and hyperinflammation. However, the contribution of glycemic variability to the pathogenesis of influenza A virus (IAV) has not been explored. Here, we used an in vitro model of the pulmonary epithelial-endothelial barrier and novel murine models to investigate the role of glycemic variability in influenza severity. In vitro, a history of glycemic variability significantly increased influenza-driven cell death and destruction of the epithelial-endothelial barrier. In vivo, influenza virus-infected mice with a history of glycemic variability lost significantly more body weight than mice with constant blood glucose levels. This increased disease severity was associated with markers of oxidative stress and hyperinflammation both in vitro and in vivo. Together, these results provide the first indication that glycemic variability may help drive the increased risk of severe influenza in people with diabetes mellitus. IMPORTANCE Every winter, people with diabetes are at increased risk of severe influenza. At present, the mechanisms that cause this increased susceptibility are unclear. Here, we show that the fluctuations in blood glucose levels common in people with diabetes are associated with severe influenza. These data suggest that glycemic stability could become a greater clinical priority for patients with diabetes during outbreaks of influenza.

GFI1 Is a Tumor Suppressor in Myeloid Progenitors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2942-2942
Author(s):  
Aditya Chaubey ◽  
Shane Hormon ◽  
Chinavenmeni S. Velu ◽  
Tristan Bourdeau ◽  
Jinfang Zhu ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Myeloid Leukemia ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Increased Risk ◽  
Myeloid Leukemias ◽  
Dose Dependent ◽  
Anterior Posterior

Abstract In severe congenital neutropenia (SCN) patients and mice with Growth factor independent-1 (Gfi1) loss of function, arrested progenitors are suspended in a hyperproliferative state while terminal granulpoiesis is blocked. SCN patients are at increased risk for the development of acute myeloid leukemia. We demonstrate that Gfi1 directly targets HoxA9, Pbx1 and Meis1 during normal myelopoiesis. Gfi1−/− progenitors exhibit elevated levels of HoxA9, Pbx1 and Meis1, exaggerated HoxA9-Pbx1-Meis1 activity, and increased persistence in vivo and in vitro. Limiting HoxA9 alleles corrects, in a dose dependent manner, in vivo and in vitro phenotypes observed with loss of Gfi1. Moreover, in a manner conserved in Drosophila anterior/posterior patterning, we demonstrate that these factors can compete for occupancy of DNA sequences encoding composite Gfi1-HoxA9-Pbx1-Meis1 binding sites. Finally, the expression of Gfi1 and HoxA9 are inverse and stratify human myeloid leukemias, suggesting a role for HoxA9- Gfi1 antagonism in human AML. In agreement with this, a myeloproliferative disorder progresses into a rapid, lethal and transplantable myeloid leukemia in a Gfi1−/− setting. We conclude that the lifespan and oncogenic transformation of hematopoietic progenitor cells is regulated through a conserved competition between Gfi1 and HoxA9-Pbx1-Meis1.

Thrombotic Complications Are Associated with Phlebotomy Therapy in Patients with Chuvash Polycythemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 936-936 ◽  
Author(s):  
Adelina Sergueeva ◽  
Galina Miasnikova ◽  
Ekaterina Lisina ◽  
Mehdi Nouraie ◽  
Sergei A. Nekhai ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
High Rate ◽  
Systolic Pulmonary Artery Pressure ◽  
Risk Of Death ◽  
Increased Risk ◽  
History Of ◽  
Baseline Characteristics

Abstract Background: In Chuvash polycythemia (CP) (Problemi Gematologii I Perelivaniya Krovi 1974, 10:30), impaired degradation of hypoxia inducible factor (HIF)-1α and HIF-2α from a homozygous germline VHLR200W mutation leads to augmented hypoxic responses during normoxia (Nat Genet 2002, 32:614). In addition to elevated hematocrit, CP is marked by leg varices, benign vertebral hemangiomas, decreased systemic blood pressure, increased systolic pulmonary artery pressure, and by the defining phenotypes of thrombosis and early mortality (Blood 2004, 103:3924; Haematologica 2012, 97:193). There is no effective therapy. While phlebotomy has been recommended for idiopathic polycythemia by the British Committee for Standards in Haematology (Br J Haematol 2005, 130:174) and is administered to some CP patients, its benefits are unknown. Phlebotomy-induced iron deficiency inhibits PHD2 enzyme, the principal negative regulator of HIFs, which further augments hypoxic responses. This affects the transcription of many genes (BCMD 2014, 52:35). Hypoxia-regulated IRAK1 is augmented in inflammation and may promote thrombosis (Circ Res. 2013, 112:103). Methods: 165 patients with CP were enrolled in a registry between 2001 and 2009 after providing written informed consent. Survival analysis was used to examine the predictors of new thrombosis and death during the follow-up period. mRNA from peripheral blood mononuclear cells (PBMCs) was profiled by Affymetrix Human Exon 1.0 ST Array in 42 of the subjects. Results: The median age at enrollment was 35 years and 90 participants were females, 25 had a history of one thrombosis, 5 of two thromboses and 3 of three thromboses. In the year prior to study entry, 72 had received phlebotomy therapy (Table 1). In July 2015 the median follow-up was 9.0 years (range 1-14.5). During this follow-up period, 30 (18.2%) participants had one new thrombosis, 6 (3.6%) had two new thromboses and 17 (10.3%) died. The median age of death was 55 years (range 16-76) and deaths were related to thrombotic cerebrovascular accident (n = 4), myocardial infarction (n = 4), mesenteric or portal vein thrombosis (n = 3), other major thromboembolic events (n = 2) and trauma or unknown cause (n = 2). Baseline characteristics of older age, prior thrombosis, pentoxifylline treatment, smoking and splenomegaly were independently associated with greater thrombosis risk during follow-up (P < 0.003). After adjustment for these variables, the estimated probability of new thrombosis at 10 years was 26% in those receiving phlebotomies compared to 12% in those not phlebotomized (log rank P = 0.014) (Figure 1). There was also a trend for increased risk of death with phlebotomy: estimated probability 8.7% versus 3.7% (P = 0.15). Examination of gene transcripts affecting thrombosis by logistic regression identified 12 protective and 16 risk genes at 5% false discovery rate. Upregulation of two mRNAs was of singular significance: 1) IL1RAP, a proximal signaling adaptor of IRAK1 (Immunity 1997, 7: 837) and 2) THBS1, encoding thrombospondin1 (Blood 2015, 125: 399). Both genes have known roles in thrombosis promotion and we previously reported that THBS1 is upregulated in CP (BCMD 2014, 52:35). Further analysis revealed a further upregulation of THBS1 in patients with baseline history of phlebotomy (β=0.41, P=0.046). Conclusion: These findings underscore a high rate of thrombosis and death in patients with CP and reveal a potential role of increased IRAK1/IL1RAP signaling in these complications. They raise the possibility that phlebotomy therapy has a detrimental rather than beneficial effect, possibly contributed to by increased THBS1 expression. Table 1. Baseline characteristics by phlebotomy in the year prior to enrollment. Results in median (interquartile range) or n (%); four without phlebotomy data. No phlebotomy N=89 Received phlebotomy N=72 Age (years) 32 (18-48) 37 (26-49) 0.08 Female gender, n (%) 52 (58%) 34 (47%) 0.16 Smoking, n (%) 18 (20%) 24 (33%) 0.060 History of thrombosis, n (%) 20 (23%) 12 (17%) 0.4 Splenomegaly, n (%) 2 (2.3%) 2 (2.8%) 0.8 ASA treatment, n (%) 27 (30%) 36 (50%) 0.011 Pentoxifylline, n (%) 7 (7.9%) 17 (23.6%) 0.005 BMI (kg/m2) 20.4 (18.3-22.9) 21.6 (19.9-24.6) 0.010 Systolic BP (mm Hg) 109 (100-123) 118 (105-124) 0.6 Diastolic BP (mm Hg) 76 (68-84) 78 (71-83) 0.8 Hemoglobin (g/dL) 18.1 (16.4-21.0) 17.9 (16.0-19.8) 0.5 WBC (per uL) 5.7 (4.6-7.0) 5.5 (4.6-6.7) 0.9 Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Hypertension (HTN) in National Cancer Institute of Canada Clinical Trials Group study BR.24: A randomized, double-blind phase II trial of carboplatin (C) and paclitaxel (P) with either daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo, in patients with advanced non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3527-3527
Author(s):  
R. A. Goodwin ◽  
L. Seymour ◽  
K. Ding ◽  
I. Gauthier ◽  
A. Le Maitre ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cox Regression ◽  
Treatment Algorithm ◽  
Progression Free Survival ◽  
Angiogenesis Inhibitors ◽  
Double Blind ◽  
Minimal Impact ◽  
Kaplan Meier ◽  
History Of ◽  
Baseline Characteristics

3527 Background: CED 30 mg/d with C+P increased response rate (RR: 38 vs 16% p < 0.0001) and median progression free survival (PFS: 5.6 vs 5 m, hazard ratio [HR] 0.77) over C+P alone. HTN is a known effect of angiogenesis inhibitors (AI). For BR.24, we describe the incidence of HTN, effects on drug delivery, predictors of its development/worsening, and assess the predictive effect of HTN on efficacy. Methods: Pts received C+P plus either placebo (n =146) or CED (n = 148). HTN as an adverse event (HTN AE: defined as either new onset HTN, or worsening grade HTN in a previously hypertensive pt), was managed with a protocol-defined algorithm. Exploratory analyses characterized the relationship between HTN AE and baseline characteristics and treatment arm. Kaplan Meier curves summarized time to event outcomes and Cox regression models with time dependent covariates correlated HTN AE to outcomes. Results: Rate of pts with a history of HTN were similar: CED 26 %, placebo 33 %. CED pts had significantly higher HTN AE (any: 38 vs 12%, p < 0.0001; grade 3 or 4: 19 vs 2 %). With the treatment algorithm, HTN AE had minimal impact on drug delivery (1 pt interrupted C+P, 11 pts [3.7%] reduced /discontinued CED / placebo). Headache was the only other AE that correlated with HTN AE. Predictors of HTN AE included: CED arm (p < 0.0001), good ECOG (p = 0.02), female (p = 0.006), history of HTN (p = 0.06). CED pts with HTN AE had significantly higher RR (51.8 vs 32.6%, p = 0.025) and PFS (8.5 vs 5.1 m; HR 0.45, 95% CI 0.29 to 0.72, p = 0.0007); similar but not significant findings were observed with placebo (RR 35.3 vs 17.2%, p= 0.098; PFS 5.6 vs 4.9 m; HR 0.84, 95 % CI 0.45–1.54); the interaction term by treatment arm was not significant. Conclusions: CED pts had greater HTN AE, but this did not impact drug delivery. Certain baseline characteristics predicted HTN AE in all pts. Unexpectedly, development of on-study HTN predicted improved outcome in all pts, although to a greater extent for those on CED. Additional evaluation of the role of HTN AE as a predictor of efficacy of both AI and cytotoxics is warranted. [Table: see text]

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