Real-Life Use of Nilotinib for Chronic Phase CML Demonstrates Similar Efficacy and Rate of Cardiovascular Events As Enestnd

Abstract Introduction: Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) widely used for the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML). ENESTnd, which compared two doses of nilotinib to imatinib for patients with newly diagnosed CML, demonstrated superior rates of major molecular responses (MMRs) at 12 months in patients treated with nilotinib. However, a relative increase in cardiovascular events (CVE) was observed, including ischemic heart disease, stroke, and/or peripheral artery disease among nilotinib-treated patients. Notably, at a median 5-year follow up, 7.5% of patients on nilotinib 300mg twice daily experienced a CVE (Hochaus, Leukemia, 2016) and by 10-years of follow up, approximately 20% of patients treated with nilotinib developed a CVE (Kantarjian, Leukemia, 2021). The baseline Framingham general cardiovascular risk scores and total dose exposure were predictive of patients' risk of developing CVE. In the province of Quebec, Canada, the GQR LMC-NMP (Groupe Québécois de recherche en leucémie myéloide chronique et néoplasie myéloproliférative) has maintained a registry of nearly all patients with CML since 2011. Using this 900+-patient registry, we examined molecular responses and the rate of CVE among patients receiving nilotinib as frontline therapy for CML, to determine if they were similar to those observed in ENESTnd. Methods: We identified all patients with chronic phase CML in the registry who were initiated on nilotinib for chronic phase CML. Baseline patient characteristics included were age, sex, Sokal index, baseline comorbidities, molecular response, cardiovascular complications, duration of exposure to nilotinib, dose adjustment, dose discontinuation and CVE on therapy. Results: In total, 94 patients received nilotinib as frontline treatment starting in 2008 (Table 1). The median age of the population was 58 years, 50.5% were male. The most common cardiovascular comorbidity prior to nilotinib treatment was hypertension (23.4%) followed by elevated cholesterol (21.3%), and prior CVE (12%). Seventeen patients had a low Sokal index, 26 intermediate and 24 high, 25 missing. Sixty-five patients received nilotinib at a total of 600 mg per day, 29 patients had a dose reduction at some point in their treatment and 18 patients were on either 300 or 400 mg daily. The median follow-up time was 67.0 months (range 0.5 to 159), and median nilotinib exposure time was 38.5 months (range 0.5 to 144). Forty-six patients (48.9%) discontinued nilotinib, 6 for a treatment free remission (TFR). While on nilotinib, 63 patients achieved MMR (72.4%) and 43 achieved MR 4.5 (49.6%) by 5 years of treatment, with 52 (55.3%) and 22 (23.4%) patients achieving MMR or MMR4.5 within a year, respectively. There was a total of 7 CVE in 6 patients: six myocardial infarctions and one ischemic stroke (Table 2). No patients developed peripheral artery disease. The mean time of exposure to nilotinib in these 6 patients was 28.6 months. Two patients had a high Sokal index, 3 intermediate and 1 low. One patient received dose-reduced nilotinib. These patients were co-morbid with diabetes (3), hypertension (3), elevated cholesterol (1) and one had a myocardial infarct prior to starting nilotinib, two patients did not have any risk factors. Only one of these patients has remained on nilotinib. All patients with a CVE were alive at the time of this report. Conclusion: We present real world data on the efficacy and safety of nilotinib in the frontline treatment of CML. Our data indicate that molecular responses and toxicities are similar to the ENESTnd trial. Of the 94 treated patients, the rate of MMR and CVE were 72% and 7.4% at 5.5 years of follow up, respectively, which is similar to that observed in ENESTnd, where 77% of patients experienced MMR and 7.5% CVE at this timepoint (Hochaus, Leukemia, 2016). All but one patient with a CVE in our study continued nilotinib, suggesting a reluctance among physicians to continue in the face of CVE. While there were 11 patients with prior CVE, only one of these developed a CVE on nilotinib. Current GQR-LMC CML management guidelines recommend estimation of Framingham score and management of cardiovascular risk factors for all patients with CML. Future follow up of these registry data may demonstrate a decrease in the rate of CVE among nilotinib treated patients, reflecting local adherence to these guidelines. Figure 1 Figure 1. Disclosures Busque: Novartis: Consultancy. Assouline: Eli Lilly: Research Funding; Jewish General Hospital, Montreal, Quebec: Current Employment; Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Johnson&Johnson: Current equity holder in publicly-traded company; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

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Pegylated Interferon-Alpha 2a in Combination with Nilotinib As First-Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (Nilopeg trial). Four-Year Follow-up Results

Blood ◽

10.1182/blood.v126.23.1578.1578 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1578-1578 ◽

Cited By ~ 1

Author(s):

Franck E. Nicolini ◽

Gabriel Etienne ◽

Viviane Dubruille ◽

Lydia Roy ◽

Françoise Huguet ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Phase ◽

Pegylated Interferon ◽

Molecular Response ◽

Advisory Committees ◽

Molecular Responses ◽

Log Reduction

Abstract Background & aims In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy. Methods In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center [all expressed in % on the international scale (IS)]. All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR). Results Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8-52.8) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had "major" BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at "6", and "12" months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI). The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1. The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 [1.03-1.16]), 24 months (p=0.005, OR = 1.08 [1.02-1.14]) and 48 months (p=0.024, OR = 1.09 [1.01-1.17], but not with the mean doses of nilotinib [p=0.84, OR = 0.99 [0.99-1.01], p=0.087, OR = 1 [0.99-1.01], and p=0.88, OR = 1 [0.99-1.01] respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke). Conclusion Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred. However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress. Figure 1. Cumulative incidence of MR4.5 Figure 1. Cumulative incidence of MR4.5 Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Rea:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria.

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Sortilin levels correlate with major cardiovascular events of diabetic patients with peripheral artery disease following revascularization: a prospective study

10.21203/rs.3.rs-31908/v2 ◽

2020 ◽

Author(s):

Federico Biscetti ◽

Elisabetta Nardella ◽

Maria Margherita Rando ◽

Andrea Leonardo Cecchini ◽

Nicola Bonadia ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Cardiovascular Events ◽

Vascular Complications ◽

Diabetic Patients ◽

Operating Characteristics ◽

Peripheral Artery ◽

Baseline Serum ◽

Increased Risk ◽

Artery Disease

Abstract Background: Peripheral artery disease (PAD) represents one of the most relevant vascular complications of type 2 diabetes mellitus (T2DM). Moreover, T2DM patients suffering from PAD have an increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Sortilin, a protein involved in apolipoproteins trafficking, is associated with lower limb PAD in T2DM patients.Objective: To evaluate the relationship between baseline serum levels of sortilin, MACE and MALE occurrence after revascularization of T2DM patients with PAD and chronic limb-threatening ischemia (CLTI).Research Design and Methods: We performed a prospective non-randomized study including 230 statin-free T2DM patients with PAD and CLTI. Sortilin levels were measured before the endovascular intervention and incident outcomes were assessed during a 12-month follow-up.Results: Sortilin levels were significantly increased in individuals with more aggressive PAD (2.25 ± 0.51 ng/mL vs 1.44 ± 0.47 ng/mL, p < 0.001). During follow-up, 83 MACE and 116 MALE occurred. In patients, who then developed MACE and MALE, sortilin was higher. In particular, 2.46 ± 0.53 ng/mL vs 1.55 ± 0.42 ng/mL, p < 0.001 for MACE and 2.10 ± 0.54 ng/mL vs 1.65 ± 0.65 ng/mL, p < 0.001 for MALE. After adjusting for traditional atherosclerosis risk factors, the association between sortilin and vascular outcomes remained significant in a multivariate analysis. In our receiver operating characteristics (ROC) curve analysis using sortilin levels the prediction of MACE incidence improved (area under the curve [AUC] = 0.94) and MALE (AUC = 0.72).Conclusions: This study demonstrates that sortilin correlates with incidence of MACE and MALE after endovascular revascularization in a diabetic population with PAD and CLTI.

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Sortilin levels correlate with major cardiovascular events of diabetic patients with peripheral artery disease following revascularization: a prospective study

Cardiovascular Diabetology ◽

10.1186/s12933-020-01123-3 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Federico Biscetti ◽

Elisabetta Nardella ◽

Maria Margherita Rando ◽

Andrea Leonardo Cecchini ◽

Nicola Bonadia ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Cardiovascular Events ◽

Vascular Complications ◽

Diabetic Patients ◽

Operating Characteristics ◽

Peripheral Artery ◽

Baseline Serum ◽

Increased Risk ◽

Artery Disease

Abstract Background Peripheral artery disease (PAD) represents one of the most relevant vascular complications of type 2 diabetes mellitus (T2DM). Moreover, T2DM patients suffering from PAD have an increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Sortilin, a protein involved in apolipoproteins trafficking, is associated with lower limb PAD in T2DM patients. Objective To evaluate the relationship between baseline serum levels of sortilin, MACE and MALE occurrence after revascularization of T2DM patients with PAD and chronic limb-threatening ischemia (CLTI). Research design and methods We performed a prospective non-randomized study including 230 statin-free T2DM patients with PAD and CLTI. Sortilin levels were measured before the endovascular intervention and incident outcomes were assessed during a 12 month follow-up. Results Sortilin levels were significantly increased in individuals with more aggressive PAD (2.25 ± 0.51 ng/mL vs 1.44 ± 0.47 ng/mL, p < 0.001). During follow-up, 83 MACE and 116 MALE occurred. In patients, who then developed MACE and MALE, sortilin was higher. In particular, 2.46 ± 0.53 ng/mL vs 1.55 ± 0.42 ng/mL, p < 0.001 for MACE and 2.10 ± 0.54 ng/mL vs 1.65 ± 0.65 ng/mL, p < 0.001 for MALE. After adjusting for traditional atherosclerosis risk factors, the association between sortilin and vascular outcomes remained significant in a multivariate analysis. In our receiver operating characteristics (ROC) curve analysis using sortilin levels the prediction of MACE incidence improved (area under the curve [AUC] = 0.94) and MALE (AUC = 0.72). Conclusions This study demonstrates that sortilin correlates with incidence of MACE and MALE after endovascular revascularization in a diabetic population with PAD and CLTI.

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Increased Risk of Cardiovascular Events Associated with TKI Treatment in Chronic Phase Chronic Myeloid Leukemia. Data from Swedish Population-Based Registries

Blood ◽

10.1182/blood.v124.21.3134.3134 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3134-3134 ◽

Cited By ~ 2

Author(s):

Torsten Dahlén ◽

Gustaf Edgren ◽

Martin Höglund ◽

Mats Lambe ◽

Magnus Björkholm ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Events ◽

Research Funding ◽

Chronic Phase ◽

Population Based ◽

Swedish Population ◽

2Nd Generation ◽

Increased Risk ◽

Tki Treatment

Abstract Introduction: The introduction of continuous tyrosine kinase inhibitor (TKI) treatment has dramatically improved progression-free survival for chronic phase chronic myeloid leukaemia (CML) patients. This success, however, has put the issue of long-term drug toxicity and safety into focus. Recent data from clinical studies have indicated an increased risk of cardiovascular events (CVE), including peripheral arterial occlusive disease, in CML patients receiving treatment with the TKIs nilotinib or ponatinib, as compared to imatinib (Giles et al, Leukemia 2013; Kim et al, Leukemia 2013; Cortes et al, New England Journal of Medicine 2013; FDA communication 2013). This study used data retrieved from Swedish population-based registries to estimate the frequency of CVE in CML patients, particularly those treated with imatinib and the 2nd generation TKIs nilotinib and dasatinib. Methods: We identified all incident cases between 2002 and 2012 in the Nationwide Swedish CML register. All patients who were in blast crisis or accelerated phase at time of diagnosis were excluded. All patients were followed untill death, emigration or 31st December 2012. For all CML patients a comparison cohort was established, matched to be of the same age and sex as the CML cohort, with 5 control subjects per CML patient. By means of record linkage with the nationwide Swedish patient register both cohorts were followed for the occurrence of adverse cardiovascular outcomes. Two sets of relative risks (expressed as incidence rate ratios; IRRs) of cardiovascular and venous thromboembolic disease were computed. In a first step CML patients were compared to the control population. In a second step, restricted to CML patients ever treated with TKIs, CML patients on different TKI treatments were compared. Patients could be treated with several TKIs during their follow-up, and events would only be attributable to the TKI used during the time period. Both analyses were adjusted for age, sex and calendar period. The second analysis was also adjusted for Sokal risk score. Results: A total of 896 CML patients were included and followed during a median of 4.2 years (Table I). The main outcome data are presented in Table II. A total of 23 venous thrombotic events (VTE) and 60 arterial thrombotic events were detected in the CML patient cohort during follow-up. Compared with the general population, this corresponded to significantly increased risks. In particular, deep venous thrombosis and “other arterial thromboses” were more common among CML patients (IRR 2.41 95% CI 1.29-4.52 and IRR 3.50 95% CI 1.36-9.04, respectively). Assessing risks associated with particular TKIs, we noted that treatment with any of the 2nd generation TKIs nilotinib or dasatinib, as compared to imatinib, was associated with a significantly increased occurrence of myocardial infarction (IRR 2.98 95% CI 1.05-8.49 and IRR 2.89 95% CI 1.20-7.00, respectively). Notably, there were no differences in the occurrence of CVE between the different patient groups before CML diagnosis. Conclusion: These data, derived from a large population-based Swedish cohort, provide evidence of an increased risk of both venous and arterial thrombotic events among CML patients and that patients on 2nd generation TKIs, as compared to imatinib, may be at increased risk of myocardial infarction. Further analyses will assess whether these differences may reflect patient selection and characterstics, rather than drug-related factors. Meanwhile, risk factors for CVE should be observed and considered in the TKI treatment of CML. Figure 1 Figure 1. Figure 2 Figure 2. * Footnote: the number of events may not add up because of occurrence of more than one type of vascular event in one subject. The number of events in the analysis within the CML cohort is lower than in the comparison with the general population because of exclusion of patients who were never treated with TKIs in the former analysis. Disclosures Björkholm: Novartis: Research Funding; Shire: Research Funding; Merck: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Akinon: Honoraria; Nordic Nanovector: Honoraria. Själander:Novartis: Honoraria. Richter:Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria.

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The Costs and Cardiovascular Benefits in Patients with Peripheral Artery Disease Receiving a Fourth-Generation Synchronous Telehealth Program (Preprint)

10.2196/preprints.24346 ◽

2020 ◽

Author(s):

Jenkuang Lee ◽

Chi-Sheng Hung ◽

Ching-Chang Huang ◽

Ying-Hsien Chen ◽

Hui-Wen Wu ◽

...

Keyword(s):

Heart Failure ◽

Acute Coronary Syndrome ◽

Ischemic Stroke ◽

Lower Risk ◽

Cardiovascular Events ◽

Control Group ◽

Peripheral Artery ◽

Coronary Syndrome ◽

Artery Disease

BACKGROUND Patients with peripheral artery disease (PAD) are at high risk for major cardiovascular events (MACE), including myocardial infarction, stroke, and hospitalization for heart failure. We have previously shown the clinical efficacy of a 4th-generation synchronous telehealth program for some patients, but the costs and cardiovascular benefits of the program for PAD patients remain unknown. OBJECTIVE The telehealth program is now widely used by higher-risk cardiovascular patients to prevent further cardiovascular events. This study investigated whether patients with PAD would also have better cardiovascular outcomes after participating in the 4th-generation synchronous telehealth program. METHODS This was a retrospective cohort study. We screened 5062 patients with cardiovascular diseases who were treated at National Taiwan University Hospital and then enrolled 391 patients with the diagnosis of PAD. Of these patients, 162 took part in the telehealth program, while 229 did not and thus served as control patients. Inverse probability of treatment weighting (IPTW) based on the propensity score was used to mitigate possible selection bias. Follow-up outcomes included heart failure hospitalization (HFH), acute coronary syndrome (ACS), stroke, and all-cause readmission during the 1-year follow-up period and through the last follow-up. RESULTS The mean follow-up duration was 3.1 ± 1.8 years for the patients who participated in the telehealth program and 3.2 ± 1.8 years for the control group. The telehealth program patients exhibited lower risk of ischemic stroke than the control group in the first year after IPTW (0.9% vs. 3.5%; hazard ratio [HR] 0.24, 95% CI 0.07–0.80). The 1-year composite endpoint of vascular accident, including acute coronary syndrome and stroke, was also significantly lower in the telehealth program group after IPTW (2.4% vs. 5.2%; [HR] 0.46, 95% CI 0.21–0.997). At the end of the follow-up, the telehealth program group continued to exhibit a significantly lower rate of ischemic stroke than the control group after IPTW (0.9% vs. 3.5%; [HR] 0.52, 95% CI 0.28–0.93). Furthermore, the medical costs of the telehealth program patients were not higher than those of the control group, whether in terms of outpatient, emergency department, hospitalization, or total costs. CONCLUSIONS The PAD patients who participated in the 4th-generation synchronous telehealth program exhibited lower risk of ischemic stroke events over both mid- and long-term follow-up periods. However, larger scale and prospective randomized clinical trials are needed to confirm our findings.

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Sortilin levels correlate with major cardiovascular events of diabetic patients with peripheral artery disease following revascularization: a prospective study

10.21203/rs.3.rs-31908/v1 ◽

2020 ◽

Author(s):

Federico Biscetti ◽

Elisabetta Nardella ◽

Maria Margherita Rando ◽

Andrea Leonardo Cecchini ◽

Nicola Bonadia ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Cardiovascular Events ◽

Vascular Complications ◽

Major Adverse Cardiovascular Events ◽

Diabetic Patients ◽

Operating Characteristics ◽

Peripheral Artery ◽

Increased Risk ◽

Artery Disease

Abstract Background: Peripheral artery disease (PAD) represents one of the most relevant vascular complications of type 2 diabetes mellitus (T2DM). Moreover, T2DM patients suffering from PAD have an increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Sortilin, a protein involved in apolipoproteins trafficking, is associated with lower limb PAD in T2DM patients.Objective: To evaluate the relationship between baseline level of Sortilin levels, MACE and MALE occurrence after revascularization of T2DM patients with PAD and chronic limb-threatening ischemia (CLTI).Research Design and Methods: We performed a prospective non-randomized study including 230 statin-free T2DM patients with PAD and CLTI. Sortilin serum levels were measured before the endovascular intervention and incident outcomes were assessed during a 12-month follow-up.Results: Sortilin levels were significantly increased in individuals with more aggressive PAD (2.25 ± 0.51 ng/mL vs 1.44 ± 0.47 ng/mL, p < 0.001). During follow-up, 83 MACE and 116 MALE occurred. In patients, who then developed MACE and MALE, Sortilin was higher. In particular, 2.46 ± 0.53 ng/mL vs 1.55 ± 0.42 ng/mL, p < 0.001 for MACE and 2.10 ± 0.54 ng/mL vs 1.65 ± 0.65 ng/mL, p < 0.001 for MALE. After adjusting for traditional atherosclerosis risk factors, the association between Sortilin and vascular outcomes remained significant in a multivariate analysis. In our receiver operating characteristics (ROC) curve analysis using Sortilin levels the prediction of MACE incidence improved [area under the curve (AUC) = 0.94] and MALE (AUC = 0.72).Conclusions: This study demonstrates that Sortilin correlates with incidence of MACE and MALE after endovascular revascularization in a diabetic population with PAD and CLTI.

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Cardiovascular and Metabolic Risk in Patients with Chronic Myeloid Leukemia in Chronic Phase Receiving First-Line BCR-ABL1 Tyrosine Kinase Inhibitors in the United States: Baseline and Six-Month Follow-up Results from a Prospective Real-World Observational Study

Blood ◽

10.1182/blood-2020-137613 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Michael J. Mauro ◽

Vivian G. Oehler ◽

James E. Thompson ◽

James K. McCloskey ◽

Michael C. Heinrich ◽

...

Keyword(s):

Risk Factors ◽

Real World ◽

Research Funding ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Metabolic Risk ◽

Publicly Traded ◽

The Usa ◽

The Impact

Introduction: Tyrosine kinase inhibitors (TKIs) are the standard-of-care for patients with chronic myeloid leukemia in chronic phase (CML-CP) and are associated with improved outcomes. The risk of cardiovascular (CV) events has emerged as an important consideration during TKI therapy, mostly due to associated complications and the need to understand causality and proper mitigation. While nilotinib has been associated with an increased risk of CV events, few prospective studies have assessed the CV and metabolic risk profile of TKIs administered during routine clinical practice in a real-world setting. Importantly, data regarding the role of baseline CV risk factors at initiation of specific TKIs and subsequent CV events are limited. Here we assess CV and metabolic risk in patients with CML-CP undergoing first-line treatment with TKIs in a real-world setting. Methods: CA180-653 (NCT03045120) is an ongoing, non-interventional, prospective clinical trial characterizing the impact of approved TKIs (bosutinib, dasatinib, imatinib, and nilotinib) on CV and metabolic risk factors following initial TKI therapy in newly diagnosed patients with CML-CP in the USA. Baseline clinical and demographic characteristics, including medical history, vital signs, and evidence of additional comorbid conditions were assessed. CV and metabolic risk factors, as well as CV disease surrogates, were also measured, including ankle brachial index (ABI), echocardiogram (ECHO), electrocardiogram (EKG), and Framingham coronary heart disease score. Metabolic risk variables included fasting blood glucose, HbA1c, and fasting lipid panel. Enrolled patients were analyzed at both baseline and at six months after study enrollment. Results: Between March 2017 and December 2019, 109 patients were enrolled at 16 study sites across the USA. The analysis included patients treated with dasatinib (n = 48), imatinib (n = 47), and nilotinib (n = 14); key characteristics and CV findings are summarized in the Table. In all, 48.9% of patients prescribed imatinib were ≥ 65 years of age, compared with 22.9% of dasatinib and 28.6% of nilotinib patients. Patients treated with dasatinib had a marginally lower proportion of reported baseline CV/metabolic conditions (50.0%) compared to imatinib (53.2%) and nilotinib (57.1%). Interestingly, among patients with baseline Ca2+ scoring, 57.1% of nilotinib patients had coronary artery calcification present at baseline compared to 35.7% of imatinib patients and 28.9% of dasatinib patients. Most patients receiving an ECHO (96%) or EKG (99%) were assessed as normal or presenting clinically not significant abnormalities both at baseline and at the 6-month follow-up. Baseline corrected QT (QTC) scores were similar for dasatinib, imatinib, and nilotinib patients. Among patients with a change in QTC at six months, patients on imatinib had a larger change in median score (13.5 msec) than patients on nilotinib (8.0 msec) or dasatinib (2.0 msec). At six months, changes in ABI scores were small and unlikely to be statistically significant: left ABI scores changed by -0.030, -0.020, and 0.015 for patients on dasatinib, nilotinib, and imatinib respectively; right ABI scores changed by -0.030, 0.055, and 0.060 for patients on dasatinib, imatinib, and nilotinib, respectively. Additional longitudinal data will be presented. Conclusions: These preliminary findings confirm that just over half of patients with CML-CP in the USA have CV/metabolic comorbidities present at baseline, as measured by reproducible and sequentially evaluable studies known to be predictive of systemic vascular disease risk. Measurement of baseline clinical data is vital for assessing CV and metabolic risk in the US oncology settings. CA180-653 was powered to capture the impact of first- and second-generation TKIs on CV and metabolic risk factor outcomes within treatment arms, rather than between treatment arms. Further analysis is ongoing to determine the differential effects of TKIs used in CML-CP, the effect of long-term TKI therapy, and the value of specific CV evaluations to assess optimally and manage risk in patients with CML-CP. Study support:BMS. Table Disclosures Mauro: Sun Pharma/SPARC:Research Funding;Pfizer:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Takeda:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Novartis:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Bristol-Myers Squibb:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding.Oehler:Pfizer:Research Funding;Bristol-Myers Squibb, Takeda:Consultancy.McCloskey:Jazz:Consultancy, Honoraria;AbbVie:Consultancy, Honoraria;Takeda:Consultancy, Honoraria;BMS:Consultancy, Honoraria;Amgen:Consultancy, Honoraria.Heinrich:Novartis:Consultancy, Patents & Royalties: Patent on treatment of GIST licensed to Novartis;Blueprint Medicines:Consultancy;Deciphera:Consultancy, Speakers Bureau.DeGutis:Bristol-Myers Squibb:Current Employment, Current equity holder in publicly-traded company.Tabano:Bristol-Myers Squibb:Current Employment.Khan:Bristol-Myers Squibb:Current Employment, Current equity holder in publicly-traded company.Moslehi:AstraZeneca, Janssen, BMS, Boston Biomedical, Immunocure, Myovant, Boston Biomedical, Deciphera:Consultancy.

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P4497Serum ceramides and type 2 diabetes are mutually independent predictors of cardiovascular events in patients with peripheral artery disease

European Heart Journal ◽

10.1093/eurheartj/ehz745.0890 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A Leiherer ◽

A Muendlein ◽

C H Saely ◽

R Laaksonen ◽

M Laaperi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Peripheral Artery Disease ◽

Cardiovascular Events ◽

Atherosclerotic Plaques ◽

Peripheral Artery ◽

Event Risk ◽

Artery Disease ◽

Mutually Independent

Abstract Background Ceramides are enriched in atherosclerotic plaques, and a set of circulating ceramides including Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0) has recently emerged as predictors of cardiovascular outcomes in coronary artery disease patients. Purpose The purpose of this study was to investigate their power to predict cardiovascular events in patients with peripheral artery disease (PAD). Methods We measured the serum concentrations of the above mentioned ceramides in a cohort of 380 patients with sonographically proven PAD, of whom 107 had type 2 diabetes (T2DM). Prospectively, we recorded 221 cardiovascular events over a mean follow-up time of 6.3±2.3 years. Results Cardiovascular event risk was higher in T2DM patients than in those who did not have diabetes (69 vs. 52%, p=0.001). The ceramides Cer(18:1/16:0) and Cer(18:1/24:1) and the respective ratios Cer(18:1/16:0) / Cer(18:1/24:0) and Cer(18:1/24:1) / Cer(18:1/24:0) were significant predictors of cardiovascular events both univariately and after multivariate adjustment including the presence of T2DM (figure). Conversely, T2DM predicted cardiovascular events independently from the investigated ceramides (adjusted HR 1.76 [1.31–2.35], p<0.001). Conclusion We conclude that the investigated ceramides and T2DM are mutually independent predictors of cardiovascular events in PAD patients.

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Association of Health Status Scores With Cardiovascular and Limb Outcomes in Patients With Symptomatic Peripheral Artery Disease: Insights From the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) Trial

Journal of the American Heart Association ◽

10.1161/jaha.120.016573 ◽

2020 ◽

Vol 9 (19) ◽

Author(s):

Jennifer A. Rymer ◽

Hillary Mulder ◽

Kim G. Smolderen ◽

William R. Hiatt ◽

Michael S. Conte ◽

...

Keyword(s):

Health Status ◽

Lower Extremity ◽

Peripheral Artery Disease ◽

Cardiovascular Events ◽

Major Adverse Cardiovascular Events ◽

Peripheral Artery ◽

Vas Scores ◽

Artery Disease ◽

Lower Extremity Revascularization

Background There are limited data on health status instruments in patients with peripheral artery disease and cardiovascular and limb events. We evaluated the relationship between health status changes and cardiovascular and limb events. Methods and Results In an analysis of the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) trial, we examined the characteristics of 13 801 patients by tertile of health status instrument scores collected in the trial (EuroQol 5‐Dimensions [EQ‐5D], EQ visual analog scale [VAS], and peripheral artery questionnaire). We assessed the association between the baseline health status measurements and major adverse cardiovascular events, major adverse limb events, and lower‐extremity revascularization procedures during trial follow‐up and the association between 12‐month health status change scores and subsequent end points during follow‐up. There were 13 217 (95%) patients with EQ‐5D scores, 13 533 (98%) with VAS scores, and 4431 (32%) with peripheral artery questionnaire scores. Patients in the lowest baseline EQ‐5D tertile (0 to <0.69) were more likely to be female with severe claudication compared with the highest tertile (0.79–1.0; P <0.01). Patients in the lowest VAS (0–60) and peripheral artery questionnaire (0–49) tertiles had lower ankle–brachial indices compared with the highest tertiles (80–100 and 76–108, respectively; P <0.01). There was a significant association between baseline EQ‐5D, VAS, and peripheral artery questionnaire scores and adjusted major adverse cardiovascular events, major adverse limb events, and lower‐extremity revascularization ( P <0.05). Improved EQ‐5D and VAS scores over 12 months were associated with reduced risk of subsequent major adverse cardiovascular events or lower‐extremity revascularization (all P <0.01). Conclusions Although health status instruments are rarely used in clinical practice, these measures are associated with outcomes, including major adverse cardiovascular events, major adverse limb events, and lower‐extremity revascularization. Further research is needed to determine the relationship between changes in these instruments, revascularization, and outcomes.

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Calcification Propensity in Serum and Cardiovascular Outcome in Peripheral Artery Disease

Thrombosis and Haemostasis ◽

10.1055/s-0041-1736444 ◽

2021 ◽

Author(s):

Marija Bojic ◽

Bernhard Bielesz ◽

Daniel Cejka ◽

Gerit-Holger Schernthaner ◽

Clemens Höbaus

Keyword(s):

Cardiovascular Risk ◽

Peripheral Artery Disease ◽

Cardiovascular Mortality ◽

Cardiovascular Events ◽

Study Cohort ◽

Peripheral Artery ◽

Multivariate Adjustment ◽

All Cause Mortality ◽

Artery Disease

AbstractPeripheral artery disease (PAD) has been shown to be linked to elevated cardiovascular risk. The novel T50 test quantifies calcification propensity of serum and has been associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD) and in the general population. This study investigated the association of calcification propensity measured by the T50 test in 287 patients with PAD without severe CKD. Major cardiovascular events (MACEs) including nonfatal stroke and nonfatal myocardial infarction and all-cause death (MACE + ) were evaluated after a median follow-up of 4 years and long-term cardiovascular and all-cause mortality after a median follow-up of 8.7 years by Kaplan–Meier and Cox regression analyses. Mean T50 time was 268 ± 63 minutes in the study cohort (age 69 ± 10 years, 32% women, 47% diabetes). Low T50 values that signify high calcification propensity were significantly associated with the occurrence of MACE+ (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.55–0.94). This association sustained multivariate adjustment for cardiovascular risk factors (CVRFs), Fontaine PAD stage, and prevalent media sclerosis (HR: 0.65; CI: 0.47–0.91). Cardiovascular mortality was significantly associated with T50 after multivariate adjustment for CVRF (HR: 0.72; CI 0.53–0.99), but not all-cause mortality (HR: 0.80; CI: 0.64–1.01). In conclusion, calcification propensity associates with MACE+ and cardiovascular mortality in patients with PAD.

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