scholarly journals Classic Cardiovascular Risk Factors and Certain Comorbidities May Contribute to the Risk of Thrombembolic and Bleeding Events in Patients with Classical Myeloproliferative Neoplasms

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5195-5195
Author(s):  
Susanne Isfort ◽  
Andrea Kaifie ◽  
Karla Schmitt ◽  
Edgar Jost ◽  
Tim H. Bruemmendorf ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Number Of Patients ◽  
Category Score

Abstract Background. Thrombembolic (TE) and bleeding (B) events pose a severe risk for patients (pts) with myeloproliferative neoplasms (MPN). Multiple disease-related factors have been identified that contribute to these events, such as the interaction between platelets, leucocytes, and endothelial cells. However, not all pts develop thrombosis or severe bleeding, suggesting that further contributing factors may play a role, including specific comorbidities and cardiovascular risk factors. Aims. The aim of our analysis was to evaluate the association between thromboembolic events, specific comorbidities, and cardiovascular risk factors in MPN pts. Methods. We analyzed clinical data frompts treated at the MPN Center at RWTH Aachen University hospital. All pts were aged ≥18 years and carried a diagnosis of classical BCR-ABL negative MPN (polycythemia vera [PV], essential thrombocythemia [ET], primary and secondary myelofibrosis [MF]), as defined by WHO criteria (2008). In addition, data about MPN disease complications, age, cardiovascular risk factors (smoking habits, arterial hypertension, diabetes mellitus, obesity, and hyperlipoproteinemia) and MPN subtype were included. Comorbidities were scored using three different comorbidity scales (CIRS, Charlson comorbidity index, and ACE-27). Results. 75 MPN pts were included in this analysis, 25 with PV, 19 ET pts and 31 pts with MF (19 pts with PMF, 9 Post-PV-MF pts and 3 pts with Post-ET-MF). Characterization of pts regarding age, sex, thrombembolic/bleeding events as well as median scores in comorbidity scales are shown in Table 1. In addition, pts were divided into a group with (Group TE+B) or without (Group no TE+B) thromboembolic or severe bleeding events. 40 patients (53.3%) had previously experienced a thrombembolic or bleeding event. These pts showed significantly higher median comorbidity scores (CIRS of 6.5 vs. 2.0, p< 0,001, Charlson score of 1 vs. 0, p<0,001, and median ACE-27 of 2 vs. 0, p<0,001). Presence of classic cardiovascular risk factors among groups TE+B vs. no TE+B was heterogeneous (10 vs. 11 (ex-)smokers; 18 vs. 9 pts with arterial hypertension; 9 vs. 14 pts with a BMI > 25; 4 vs. 1 pts with diabetes mellitus; 4 vs. 0 pts with hyperlipoproteinemia). TE+B pts had high scores in certain CIRS categories (each category includes a scale of 0-4) especially in categories regarding cardiac diseases, hypertension, vascular disease & endocrinological disease (see Table 2). Furthermore, more than one third of the TE+B pts had also neurological (16/40 pts. (40%) vs. 3/35 (8.6%) in the no TE+B group) and upper-GI-disease (13/40 pts (32.5%) vs. 8/35 (22.9%) in the no TE+B group). Summary and Conclusions. Given the obvious limitations of this analysis due to small sample numbers, this analysis provides an indication that classic cardiovascular risk factors (especially diabetes mellitus, arterial hypertension, and hyperlipoproteinemia) and additional comorbidities contribute to the risk of thromboembolic and bleeding events in pts with classical MPN. Clinical trials should address whether the improvement of such risk factors in addition to anti-MPN treatment can minimize the risk of such events. Table 1. Characterization of pts Subtype of MPN Number of patients Median age at diagnosis (range) Number of patients that developed thromboembolic events (TE) or bleeding (B)* Number of patients without thromboembolic/bleeding events Median CIRS score(Range 0-56) Median Charlson comorbidity index(Range 0-37) Median ACE-27 score(Range 0-3) Polycythemia vera 25(11m/14f) 58 (31-77) 15 (15 TE, 2 B) 10 6 1 1 Essential Thrombo-cythemia 19(10m/9f) 54 (23-64) 6 (5 TE, 1 B) 13 4 0 1 All Myelofibrosis 31(22m/9f) 63 (29-77) 19 (16 TE, 7 B) 12 5 0 1 Myelofibrosis PMF 19(16m/3f) 61 (29-77) 11 (9 TE, 4 B) 8 4 0 1 Post-PV-MF 9(3m/6f) 63 (42-73) 7 (6 TE, 3 B) 2 8 1 1 Post-ET-MF 3(3m/no f) 68 (68-73) 1 (1 TE) 2 13 2 2 · Few Pts had suffered from both thromboembolic and bleeding events Table 2. Number of pts in the TE+B group in comparison to the no TE+B group in certain CIRS categories subdivided according to score CIRS category (TE+B pts vs. no TE+B pts) Score of 0 per category Score of 1 per category Score of 2 per category Score of 3 per category Score of 4 per category Cardiac disease 20 vs. 30 6 vs. 2 5 vs. 3 9 vs. 0 0 vs. 0 Hypertension 22 vs. 26 2 vs. 0 4 vs. 6 12 vs. 3 0 vs. 0 Vascular disease 21 vs. 32 3 vs. 1 12 vs. 0 3 vs. 1 1 vs. 1 Endocrinological disease 21 vs. 26 0 vs.1 19 vs.7 0 vs.1 0 vs.0 Disclosures Isfort: Pfizer: Honoraria; BMS: Honoraria; Mundipharma: Other: Travel & Accomodation; Roche: Other: Travel & Accomodation; Novartis: Other: Travel & Accomodation; Amgen: Other: Travel & Accomodation; Hexal: Other: Travel & Accomodation. Bruemmendorf:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences, Research Funding; Novartis Foundation: Research Funding; Baxalta/CTI: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences; Janssen Cilag: Other: Travel reimbursement for scientific conferences.

Incidence of Vascular Thrombotic Events in 183 Consecutive Patients Treated with Nilotinib: A Single Centre Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3147-3147 ◽  
Author(s):  
James Gilbert ◽  
Simona Deplano ◽  
Richard Szydlo ◽  
Renuka Palanicawandar ◽  
Gareth Gerrard ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Side Effects ◽  
Adverse Events ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Advisory Committees

Abstract Introduction The spectrum of adverse events occurring in nilotinib is broadly similar to that of other tyrosine kinase inhibitors but recent reports suggest an increase in the incidence of vascular thrombotic events (VTE) compared to imatinib. Many patients treated with ponatinib, where the association of VTE with treatment is now widely accepted, have previously received nilotinib and it remains unclear as to whether the adverse events are a result of the cumulative use of the two drugs. It is important to clearly delineate the risk of VTE with nilotinib in order to estimate risk and provide better information for patients. Methods We conducted a chart review to identify adverse events in 183 consecutive patients who received nilotinib in our institution from February 2006 until June 2014. Patients were to be considered at risk of side effects in they had received at least 24 hours of treatment. Data were collected from out-patient consultations in which side effects and their severity were self-reported and recorded in the medical case notes. The cohort contained 93 women and 90 men and had a median age of 56 years (range 21-93). 8% of patients received nilotinib as first line therapy: 46% and 39% respectively were treated after failure of imatinib only or imatinib and dasatinib . The remainder were treated for relapse post allogeneic transplant. Of those who were treated after one or two prior tyrosine kinase inhibitors (TKI), 57% and 43% were intolerant or resistant respectively. Results The median duration of treatment with nilotinib was 714 days (range 10 -2816 days). Information was available for pre-existing cardiovascular risk factors in 93% of patients and were present in 59%. We recorded 20 occurrences of VTE in 10% of patients with 9 (5%), 7 (4%) and 4 (2%) episodes of myocardial ischaemia, peripheral arterial occlusive disease and cerebrovascular disease respectively. Only one patient without pre-existing cardiovascular risk factors experienced a VTE, The median age of patients with VTE was 67 years (range 35-79) compared to 55 years (range 21-93) in those without VTE. In contrast to previously reported results VTE were more common (18%) in patients who had received two prior TKI compared to 8% in those who had been treated with a single TKI and 7% who received nilotinib upfront. 75% of VTE occurred in patients who have been treated with nilotinib for more than 2 years but this may in part be because of continuation of treatment at a time of lack of awareness of the association of nilotinib with VTE. The remaining adverse events reported on nilotinib were in accordance with published data. Side effects occurring in >10% of patients are given in the table. Conclusions The incidence of VTE in patients treated with nilotinib in our institution was 10%. VTE was more frequent in older patients, in those with pre-existing cardiovascular risk factors and in those who received prolonged therapy with nilotinib. Without a suitable control group matched for age and cardiovascular risk factors it is difficult to provide an accurate estimate of any potential increased risk of treatment with nilotinib. Nevertheless caution must be exercised in older patients with pre-existing risks for VTE and appropriate counselling and monitoring provided. Table 1Adverse eventIncidence (%)Rash and/or pruritus43Fatigue31Elevated transaminases21Myalgia18Abdominal pain17Headaches17Arthralgia16Nausea14Thrombocytopenia12Neutropenia12Anaemia7 Disclosures Gerrard: Novartis: Research Funding. Foroni:Novartis: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Cardiac and Renal Complications of Carfilzomib Therapy in Patients with Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4491-4491 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
Erasmia Psimenou ◽  
Dimitrios Ziogas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cardiac Toxicity ◽  
Cardiac Events ◽  
Advisory Committees ◽  
Artery Disease ◽  
Higher Doses

Abstract Carfilzomib (CFZ) combinations have shown activity in phase 2 and 3 studies in multiple myeloma (MM) patients but also a small but consistent signal of cardiac and renal toxicity. The aim of our study was to analyze potential cardiac and renal toxicity of CFZ combinations in consecutive MM patients. The analysis included 60 patients treated with different combination of CFZ in a single center (University of Athens, Greece): 48 (80%) had relapsed or refractory (RRMM) and 12 (20%) had newly diagnosed MM (NDMM). All had baseline evaluation of cardiovascular risk factors and echocardiography with a LVEF ≥40%. Regimens included Kd in 31 (52%), KRd in 17 (28%) and KMP in 12 (20%) patients. CFZ dose was 20/27 in 27 (45%) patients, 20/36 in 12 (20%) and 20/56 in 21 (35%). Median age was 72 (range 39-76) years and 65% were males. Median number of prior therapies was 2 (range 0-7). Median baseline eGFR was 88 ml/min (range 16 to> 120 ml/min), 33% had eGFR <60 ml/min and 7% had eGFR <30 ml/min. Median duration of CFZ therapy was 10 (range 1-43) cycles. During therapy with CFZ, 7 (12%) patients had a reduction in LVEF ≥20% within a median of 6 months (range 1-13 months) from initiation of CFZ. In 6/7 patients, dyspnea of grade (gr) ≥2 was also present and was associated with a significant increase of NTproBNP (median 2412, range 2219-10162 pg/ml) without increase in troponins. With discontinuation because of disease progression or other unrelated reasons as a competing event, the incidence of LVEF reduction ≥20% was 5% at 3 months, 8% at 6 months, 10% at 12 months and 12% at 15 months. The respective CFZ discontinuation rate unrelated to cardiac toxicity was 17%, 35%, 41% and 49%, respectively (Figure). Among cardiovascular risk factors (age, smoking, hypertension, hypelipidemia, diabetes, renal dysfunction) only peripheral artery disease was associated more often with cardiac events (3/7, 43% vs 4/53,8%, p=0.02). The use of ACE-I, ARBs or CCBs was not associated with cardiac events, however, the use of b-blockers was more common in patients who had LVEF reduction (3/10, 30% vs 4/50, 8%, p=0.048); patients on b-blockers also experienced LVEF reduction earlier [2% vs 20% at 3 months, 6% vs 20% at 6 months and 6% vs 30% at 12 months (p=0.02)], while non-toxicity discontinuation at 12 months was 44% vs 57% (p=0.66). There was no association with prior anthracycline exposure or prior HDT and the dose of CFZ was not associated with cardiac event frequency or timing. Baseline parameters of cardiac function assessed by echocardiography did not show correlation with cardiac events. Further evaluation in all patients who had EF reduction established the diagnosis of coronary artery disease (CAD) in 3/7. In all patients LVEF improved after holding CFZ (<28 days) and 6/7 patients continued therapy with CFZ with dose reduction; only in one patient reinstitution of CFZ was associated with repeated reduction of LVEF. We also evaluated the effects of CFZ in renal function, excluding renal dysfunction associated with disease progression. Per CTCAE v4.03, 22 (37%) patients had a creatinine increase ≥gr 1 (18% gr1, 17% gr2 and 2% gr3). According to the same criteria for acute kidney injury (AKI), 17 (28%) patients experienced AKI ≥gr 1 (gr1 in 25% and gr3 in 3%) while 21 (35%) had a reduction of their eGFR by ≥25%, which was transient in 13/21 (62%). These events occurred mostly early, within the 1st cycle in 9/21 (43%). Two patients, both in CR, developed TTP, one after 22 and the other after 8 cycles of CFZ. Higher doses of CFZ were associated with higher frequency of eGFR reduction ≥25% (22% vs 33% vs 52% for 20/27, 20/36 and 20/56 doses respectively, p=0.093). Age >65 years was not associated with higher risk of AKI (25% vs 35% for those <65 years, p=0.3). Among patients with baseline eGFR <60 ml/min (n=20), 11 (55%) patients improved their eGFR to >60 ml/min. In conclusion, cardiac toxicity after CFZ occurred in 12% of patients, but was essentially unpredictable and reversible in all patients; standard cardiovascular risk factors were not predictive of cardiac toxicity. However, in about half of the patients was associated with underlying CAD, indicating that further investigation is needed regarding the effects of CFZ to vascular function and endothelium. Decrease in eGFR and low grade AKI is common but transient, and can be associated with higher doses of CFZ. Importantly, 55% of patients with moderate CKD improved their renal function after treatment with CFZ. Figure Figure. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Kastritis:Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

The Hypertension of Hemophilia Is Associated with Vascular Joint Remodeling and Cannot be Explained By the Usual Cardiovascular Risk Factors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 762-762
Author(s):  
Richard FW Barnes ◽  
Thomas J Cramer ◽  
Afrah S Sait ◽  
Rebecca Kruse-Jarres ◽  
Doris V. Quon ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Maximum Score ◽  
Joint Health ◽  
Blood Pressures

Patients with hemophilia (PWH) have a higher prevalence of hypertension and intracranial hemorrhage than the general male population. However, the etiology of the hypertension, and to what extent blood pressure and associations with cardiovascular risk factors vary from the general population, is incompletely understood. We therefore investigated the prevalence of hypertension as well as the associations of blood pressure measurements with usual cardiovascular risk factors, in a cross-sectional analysis of a cohort of 486 PWH. The PWH (median age 38 years) came from 3 geographically different areas in the United States. They were compared against males from the contemporary National Health and Nutrition Examination Survey (NHANES), matched for age and race in a 1:5 ratio. Subsequently, at the University of California San Diego, a pilot cohort of PWH (n=28; median age 37 years) was examined prospectively for hypertension and associations with hemophilia-specific risk factors pertaining to joint health. PWH had a significantly higher prevalence of hypertension compared to subjects from NHANES. The prevalence of hypertension was 53.4% in PWH compared to 28.8 % in NHANES (p<0.01). In untreated (not taking anti-hypertensive medications) and treated subjects median systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in PWH than in NHANES. Differences in prevalence of hypertension and blood pressure measurements were most pronounced in the youngest age group (18-29 years). In untreated PWH median SBP and DBP were 125 and 78 mmHg (118 and 72 mmHg in NHANES), and in treated PWH 134 and 84 (127 and 76 mmHg in NAHES), respectively; all p-values <0.0001. However, despite higher blood pressures the usual cardiovascular risk profile was better in PWH compared to NHANES, in that body mass index (BMI), total cholesterol, smoking and diabetes were lower and renal function was better. While the usual cardiovascular risk factors were associated with blood pressure in both PWH and NHANES, they did not account for the differences between the two groups. Whether each risk factor was considered by itself, or in combination with the others in multivariate models, the blood pressure differences remained. Therefore, to elucidate to what extent hemophilia-specific factors might play a role in the pathophysiology of hypertension, we assessed hypertension and blood pressures in association with joint health parameters in a pilot cohort of young adult PWH. These patients underwent prospective baseline examination of 6 joints (both elbows, knees and ankles, n=168) for joint pain (Visual Analogue Scale 0-10), radiographic Pettersson score (maximum score 78), clinical Hemophilia Joint Health Score (HJHS, maximum score 120), severity of hemophilia (severe vs mild/moderate), clotting factor usage, and joint vascular perfusion quantified with Power Doppler (PD, maximum score 54) and high resolution musculoskeletal ultrasound. We found that 54% were hypertensive, similar to the larger cohort. In univariate analysis, PD score was the risk factor most strongly associated with hypertension (p = 0.07). After adjustment for confounders, the odds for hypertension increased by 1.29 (95% CI: 1.04, 1.60; p = 0.02) for each unit increase in PD score. Moreover, there was a strong association of PD scores with SBP when adjusted for confounders. In conclusion, our findings demonstrate that PWH not only have a significantly higher prevalence of hypertension, but also significantly higher blood pressures compared to the general population, even when treated with anti-hypertensive medications. The difference in blood pressures could not be explained by the usual cardiovascular risk factors but appeared to be strongly associated with the degree of vascular changes in the joint. Based on previous findings that vascular remodeling is a prominent feature of hemophilic arthropathy and may be mediated systemically, we postulate that vascular remodeling is associated with the etiology of hypertension in hemophilia. These findings warrant further basic and clinical investigation. Disclosures Kruse-Jarres: Octapharma: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria. Quon:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. von Drygalski:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Arterial and Venous Thrombosis: Clinical Evidence for Mechanistic Overlap

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-3-SCI-3 ◽  
Author(s):  
Walter Ageno
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Venous Thrombosis ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Abdominal Obesity ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
Advisory Committees ◽  
Increased Risk

Abstract Venous and arterial thromboembolic disorders are usually considered as two separate pathophysiological entities. Over the last years, some clinical evidence challenged this common view. First of all, a number of studies have reported an increased risk of subsequent symptomatic atherothrombosis in patients with venous thromboembolism (VTE), in particular after unprovoked events. In a substudy of the Warfarin optimal duration Italian pulmonary embolism (WODIT PE) trial, the incidence of arterial cardiovascular events in patients affected by unprovoked pulmonary embolism (PE) was significantly higher than in patients with PE secondary to transient risk factors such as surgery, trauma or immobilization. This finding was subsequently confirmed by the results of a large prospective cohort study comparing the incidence of symptomatic atherosclerotic disease in patients with unprovoked VTE and patients with secondary VTE. In a subsequent population-based cohort study from Denmark, the relative risk of cardiovascular events in the first year after deep vein thrombosis (DVT) and after PE was significantly higher than in a control population and remained increased during the subsequent 20 years of follow-up. The results of these and other studies were summarized in a meta-analysis of the literature that confirmed a significantly higher incidence rate ratio of arterial cardiovascular events in patients with unprovoked VTE than in patients with provoked VTE and in controls. A possible explanation for such association between unprovoked VTE and arterial thrombosis could be represented by shared risk factors between these disease entities. Among traditional cardiovascular risk factors, obesity and age have consistently been demonstrated to be independent risk factors also for VTE. Of interest, obesity was also shown to be associated with a significantly increased risk of recurrent VTE. Obesity, and in particular visceral adiposity (abdominal obesity), predisposes to inflammatory and hypercoagulable states thus resulting in a prothrombotic condition that may cause both venous and arterial thrombotic events. A study from Norway found abdominal obesity defined by the measurement of waist circumference to be a better predictor of the risk of VTE than obesity defined by the body mass index. In addition, abdominal obesity is commonly associated with the presence of arterial hypertension, diabetes mellitus, and dyslipidemia. In a meta-analysis of studies on the association between cardiovascular risk factors and VTE, we found all these major arterial risk factors to be significantly associated with venous thrombosis. In addition, we and others found an association between the metabolic syndrome, which is a cluster of cardiovascular risk factors, and VTE. Finally, a large-population based case-control study reported an increased risk of venous thrombosis in both current and ex-smokers compared to those who had never smoked. Although these associations were not fully confirmed by the results of prospective cohort studies, and although the strength of the association was not comparable to that reported for major traditional risk factors for venous thrombosis, these findings may be clinically relevant because cardiovascular risk factors are common, they frequently co-exist, and their co-existence may result in an additive effect. Moreover, most cardiovascular risk factors are modifiable. These observations also raised the question of whether drugs that are effective in preventing arterial thrombosis, such as aspirin and statins, may be also effective for the prevention of venous thrombosis. Two recent randomized controlled trials compared aspirin with placebo for the secondary prevention of VTE after an initial course of anticoagulant therapy. When the results of these two studies were pooled together, there was a statistically significant 32% reduction in the rate of VTE recurrence with no increased risk of major bleeding. In a meta-analysis, we found that statins reduce the risk of a first VTE event by 20%. Other studies have suggested that statins may also play a role in the secondary prevention of VTE, but no randomized controlled trials are available to support this hypothesis. In conclusion, the presence of cardiovascular risk factors should be carefully assessed in patients with unprovoked VTE and their management may concomitantly prevent subsequent atherothrombotic events and reduce the risk of recurrent VTE. Future studies should assess whether the combination of aspirin and statins may result in a substantial reduction of the risk of recurrent VTE. Disclosures Ageno: Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; STAGO: Honoraria. Off Label Use: I will discuss evidences on the role of aspirin and statins for the prevention of venous thromboembolism.

scholarly journals ASXL1 Mutation Is a Novel Risk Factor for Bleeding in Patients with Philadelphia-Negative Myeloproliferative Neoplasms (MPN)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3637-3637
Author(s):  
Amro Elshoury ◽  
Han Yu ◽  
Wenyan Ji ◽  
James E. Thompson ◽  
Elizabeth A. Griffiths ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasm ◽  
Advisory Board ◽  
Factor V ◽  
Continuous Variables ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Risk Of Bleeding

Abstract Background: Bleeding and thrombosis are prevalent across all myeloproliferative neoplasm (MPN) subtypes and have significant impact on morbidity and mortality. Although risk factors for thrombosis are well established, bleeding risk factors in these patients are poorly characterized. Identifying MPN patients at higher risk for bleeding could guide the duration of anticoagulation for patients with MPN associated thrombosis (balancing the risk between bleeding and thrombosis), select individuals at higher risk for bleeding during prophylactic anticoagulation, and predict for bleeding complications with surgical procedures. Methods: We performed a retrospective analysis of bleeding risk factors among consecutive adult MPN patients treated at Roswell Park Comprehensive Cancer Center. Bleeding events were classified as minor or major events as defined by the International Society of Thrombosis and Hemostasis (ISTH). The primary outcome of interest was time to initial bleeding after MPN diagnosis. Patient characteristics were summarized as range and medians (for continuous variables) and counts with percentages (for categorical variables) (Table 1). Cox regression was used to examine the associations between candidate risk factors with identified bleeding events in univariate and multivariable analyses. Variables with p&lt;0.1 in univariate analyses were selected for multi-variate analysis. A time-dependent variable of thrombosis status was included in the model. A stepwise feature selection based on Akaike Information Criterion was used for model selection. Continuous variables were dichotomized at median for the regression analyses. Results: A total of 170-consecutive adult MPN patients were identified between 2005 and 2021. Median follow-up was 43.5 months (range 0.66-485.72). The rate of bleeding (major and minor) was 4.9/100 patient-years and rate of thrombosis was 5.4/100 patient-years (5.4/100 patient-years for arterial thrombosis and 2.9/100 patient-years for venous thrombosis). In univariable analysis, predictors of bleeding included age &gt; 60 years (HR 2.8; 95% CI 1.47-5.34; p=0.001), diagnoses of primary myelofibrosis (PMF) (HR 2.98; 95% CI 1.29-6.9; p=0.01) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS-MPN) overlap syndrome (HR 4.56, 95% CI1.91-10.88; p=0.0004), prior history of thrombosis (HR 3.3, 95% CI 1.27-8.8; p=0.01) and presence of ASXL1 (HR 4.13, 95% CI 2.13-8.04; p=0.0001), JAK2 V617F (HR 0.58; 95% CI 0.31-1.08; p=0.08) and TET2 mutations (HR 3.46; 95% CI 1.5-7.9; p=0.003). In multivariate analysis, the presence of JAK2 V617F (HR 4.8; 95% CI 1-21.5; p=0.03) and ASXL1 (HR 12.7, 95% CI 1.7-93; p=0.01) mutations were associated with increased risk of bleeding (Figure 2). Patients with polycythemia vera were at lower risk of bleeding (HR -3.5, 95% CI 0-0.8; p=0.03). Since ASXL1 mutation was associated with a higher risk of bleeding, we studied the association between ASXL1 mutation and other clinical variables. Patients with ASXL1 mutations were more likely to have a diagnosis of PMF and MDS-MPN overlap syndrome (p=0.0001), age &gt; 60 years (p=0.0001), risk for thrombosis (p=0.04), lower hematocrit (p=0.009) and platelets (p=0.0003) but higher white blood cell count (WBC) (p= 0.04) (Figure 3). We then studied the correlation between ASXL1 mutation and factor VIII/Von Willebrand complex and factor V, the two most described abnormal coagulation factors in MPN. ASXL1 mutation was not associated with a statistically significant lower VWF Ag (p=0.07) or factor V (p=0.1) that could potentially explain the higher risk of bleeding seen with this mutation (figure 4). Conclusion: ASXL1 mutations are associated with a significantly higher risk of bleeding in adult MPN patients. The risk of bleeding with ASXL1 mutations was independent of prior thrombosis and was not associated with abnormalities in VWF profile or factor V. Confirmation of these findings in additional patients and studies of underlying platelet function to identify the possible mechanism of ASXL1 associated bleeding in these patients are ongoing. Figure 1 Figure 1. Disclosures Elshoury: Bristol Meyers Squibb: Other: advisory board. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Griffiths: Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Novartis: Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Genentech: Research Funding. Wang: Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

scholarly journals Multidimensional Vascular Evaluation in Patients Treated with Tyrosine Kinase Inhibitors (TKIs): From Plaque Formation to Evolution and Follow up on 150 Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 54-54
Author(s):  
Elisabetta Abruzzese ◽  
Rossana Gloria ◽  
Andrea Siani ◽  
Carla Mazzone ◽  
Matteo Molica ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Disease ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Surgical Intervention ◽  
Control Group ◽  
Advisory Committees

Background Among the unresolved issues concerning management of chronic myeloid leukemia (CML) patients, the most feared are long-term adverse events due to TKI treatment. Although TKIs have revolutionized CML outcomes, their use has also been associated with severe side effects including cardiovascular events, of which peripheral arterial occlusive disease (PAOD) is the most frequently reported. In 2010 we began a long-term collaboration with local angiologists and vascular surgeons to investigate, screen and follow patients on TKI therapy. Placque formation, evolution and follow up of 150 patients were studied and are presented here. Methods We analyzed 143 CML and 7 Ph+ Acute Lymphoid leukemia (ALL) patients, all of whom were treated with TKIs. Careful assessment of cardiovascular risk factors (i.e., age, smoking, obesity, diabetes, high blood pressure, high LDL or low HDL cholesterol levels, family history of heart disease or other cardiovascular disease) were done according to the European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) risk charts. A complete vascular screening, including physical examination, and a series of instrumental tests were performed for all patients. Tests included doppler echocardiography (US) of supra-aortic arteries with measurement of pre-bulbar IMT, abdominal arteries and inferior limbs arteries and veins (IL), ABI of the posterior tibial artery and digital photoplethysmography (FPG). Patients needing surgical intervention were referred to a surgeon. The team of hematologists, angiologists and surgeons met periodically to discuss results and intervention approaches. Results Patients included 76 males and 74 females with a median age of 53.7 yo (range 18-85). All patients were treated with a TKI at diagnosis, 87 (58%) with imatinib, 63 (42%) with other TKIs, including ponatinib (2 LLA), and all received TKI therapy for a minimum of 12 months since 2010. For analyses purposes, patients were divided in 7 different age groups at diagnosis (18-30, 31-40, 41-50, 51-60, 61-70, 71-80 and 81-85 years; patients incidence per group was 6%, 18%, 18.6%, 27.4%, 13.3%, 12.7% and 4%, respectively). Each patient in the study received yearly screening, and this increased to every 3-6 mo if abnormalities occurred. Of the 150 patients in the study, 10 (7%) developed severe PAOD (grade 3-4) requiring revascularization. Districts involved were: carotid (5), renal (2) and extremities (14 IL, 1 subclavian). Three patients were polyvascular requiring intervention in multiple regions. 18 patients with no malignancies requiring surgery were used as a control group and matched for sex, age, diabetes, smoking, district and intervention to compare patency rates, morbidity and mortality. At event, these 10 patients were taking imatinib (1), bosutinib (1), nilotinib (5) and ponatinib (3). None of them had a previous PAOD, but all had cardiovascular risk factors (100% were hypertensive). Median age was 66.8 yo (range 46-82) and the median number of PAOD risk factors (age &gt;60, hypertension, diabetes, male gender, nicotine abuse and coronary heart disease) was 2 (range 1-5). Plaque was deemed significant when stenosis was &gt;30%; at this point it developed very rapidly, with signs of arterial thrombosis within a year, requiring intervention. IMT scores (measuring thickness of carotid artery wall) and ABI followed by FPG and their variation over time proved predictive for plaque evolution. No patient died due to complications relating directly to surgical intervention or within 30 days post-surgery. One patient required a major limb amputation at 12 months. Patency rates were similar in the TKI and control group at 12 months (88.2% vs 80%), however the frequency of reintervention (endo or open) was 50% in TKI patients (n=5) and 11% in the control group (n=2; P&lt;0.01). Discussion Multidisciplinary evaluation, comorbidity analysis and cardiovascular risk assessment in CML patients are highly recommended, at diagnosis if possible, to implement a tailored treatment strategy and to identify patients who require strict monitoring of risk factors during treatment. Extensive and detailed information on the 150 patients in this study will be presented with a focus on the onset and characteristics of thrombotic arterial events, medical/surgical interventions, analysis of instrumental parameters (ABI, IMT, FPG) and correlation with clinical data. Disclosures Abruzzese: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria.

Assessing the correlation between diabetes mellitus cardiovascular risk factors and coronary disease

2007 ◽  
Vol 2 (04) ◽  
Author(s):  
P Akritopoulos ◽  
K Akritopoulou ◽  
E Fotiadis ◽  
S Patiakas ◽  
I Kontogiannis ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Coronary Disease

Impact of Metabolic Surgery on Type 2 Diabetes Mellitus, Cardiovascular Risk Factors, and Mortality. Review article.

2020 ◽  
Vol 16 ◽  
Author(s):  
Ricardo Cohen ◽  
Noelia S Sforza ◽  
Romina G Clemente
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Bariatric Surgery ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Cardiovascular Mortality ◽  
Review Article ◽  
Controlled Trials ◽  
Randomized Controlled

Background: The association between obesity and a reduction in life expectancy is well established, and cardiovascular disease is a leading cause of mortality. Bariatric surgery has long been established as the most effective and durable intervention for obesity, and is the only intervention for obesity that consistently improves multiple comorbidities, reduces cardiovascular disease and long-term mortality. The purpose of this review article is to describe the impact of metabolic/bariatric surgery on type 2 diabetes mellitus and cardiometabolic parameters, including cardiovascular mortality. Methods: A systematic literature search of Pubmed, MEDLINE, and Cochrane Central Register was performed. We included randomized controlled trials, metanalysis, case-control trials, and cohort studies that contain data on reductions in cardiovascular risk factors and cardiovascular mortality in subjects who underwent metabolic/bariatric surgery from January 1, 2005, to June 1, 2020. Conclusion: There is sufficient evidence of randomized controlled trials that metabolic/bariatric surgery is associated with a significant improvement of all cardiovascular risk factors. Although studies are showing a reduction of macrovascular events and cardiovascular mortality, these findings come from observational studies and should be confirmed in randomized clinical trials.

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