Cardiovascular Risk Associated With Ibrutinib Use in Chronic Lymphocytic Leukemia: A Population-Based Cohort Study

2021 ◽  
pp. JCO.21.00693
Author(s):  
Husam Abdel-Qadir ◽  
Nasruddin Sabrie ◽  
Darryl Leong ◽  
Andrea Pang ◽  
Peter C. Austin ◽  
...  
Keyword(s):  
Health Care ◽  
Cohort Study ◽  
Chronic Lymphocytic Leukemia ◽  
Index Date ◽  
Population Based ◽  
Lymphocytic Leukemia ◽  
Administrative Databases ◽  
Time Varying ◽  
Significant Difference ◽  
Ischemic Events

PURPOSE Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous system ischemic events. The magnitude of these risks remains poorly quantified. METHODS Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate. RESULTS We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI. CONCLUSION Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke.

Autoimmune Cytopenia in Chronic Lymphocytic Leukemia: Effect on Outcome and Survival, a Population Based Analysis in British Columbia, Canada

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1945-1945 ◽  
Author(s):  
Alaa A Alzaki ◽  
Alina S Gerrie ◽  
Tanya L. Gillan ◽  
Steven Huang ◽  
Miriam Ahmed ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Population Based ◽  
Lymphocytic Leukemia ◽  
Time Interval ◽  
Poor Prognostic Factor ◽  
Significant Difference ◽  
Positive Direct ◽  
Time To First Treatment

Abstract Background: Among Chronic Lymphocytic Leukemia (CLL) patients (pts), 4-10% are diagnosed with autoimmune cytopenias (AC) at some point during the course of their disease. This is less common than cytopenias related to bone marrow infiltration (10-20%). Infiltrative cytopenias (IC) are clearly a poor prognostic factor. However, the effect of AC on survival and prognosis of CLL pts remains understudied. Objectives: To determine the prevalence of AC and IC among CLL pts and their effect on overall survival (OS) and time to first treatment (TTFT) compared to patients without cytopenia. Furthermore, the effect of different treatment modalities including chemotherapy and chemo-immunotherapy on the disease course was evaluated in patients with AC. Methods: A population-based retrospective analysis through an electronic search of pts within the Providence Health Care CLL database between 1978 and 2013 was carried out. The diagnostic criteria for autoimmune hemolytic anemia (AIHA) were positive direct antiglobulin test and laboratory evidence of hemolysis, for immune thrombocytopenia (ITP) the exclusion of other etiologies of thrombocytopenia and for pure red cell aplasia (PRCA) anemia with low reticulocyte count and bone marrow evidence of decreased erythropoiesis. Infiltrative cytopenia diagnosis was confirmed by bone marrow biopsy based on lymphocyte percentage and cellularity. Anemia was defined as hemoglobin <100 g/L. Thrombocytopenia was defined as platelets <100 x 109/L. Baseline features of pts with AC and IC were compared using Chi-squared analysis for categorical and the Kruskal-Wallis test for continuous variables. Overall survival was calculated from the date of initial treatment to the date of death from any cause. Time to first treatment (TTFT) was defined as the time interval between the date of diagnosis and date of first CLL treatment. Survival analysis was performed by the Kaplan–Meier method using IBM SPSS statistics for windows. Results: Among 754 pts with CLL, 80 (10.6%) developed cytopenias (anemia and thrombocytopenia). Of those, 50 (6.6%) had IC and 30 (4%) had AC. There was no significant difference between the 2 groups in terms of age, gender, hemoglobin, platelets, LDH, WBC and lymphocyte count at diagnosis. The time to development of cytopenias for the IC and AC groups was similar with median of 3 and 4 years (yrs) from diagnosis, respectively. Within the AC group 16 pts had AIHA, 8 had ITP, 5 had both (Evan's Syndrome) and 1 had PRCA. The median OS was 12.2 yrs (5.9–18.3) and 13 yrs (1.6-24.3) for IC and AC, respectively (p=0.260). However, when compared to CLL pts without cytopenias (median not reached), the AC group had worse OS (p< 0.005) (Fig 1). For the IC and AC groups, the median TTFT was 6.5 yrs (4.5-8.5) and 8.2 yrs (4.1–12.3), respectively (p=0.191). For the CLL pts without cytopenias TTFT was 8.1 yrs (2-12.2), similar to the AC group (p=0.88) (Fig 2). For AC pts, the OS was not significantly different based on treatment received: alkylator based therapy vs. chemo-immunotherapy (p= 0.885). The effect of concomitant hypo-gammaglobulinemia on OS and treatment outcome was studied.Of the 30 pts with AC, 26 had a serum protein electrophoresis done. Of those, 10 (38.5%) had normal results and 16 (61.5%) had low gammaglobulin levels (IgG< 6 g/L); the mean OS was 18.1 yrs and 15.7 yrs respectively (median not reached), (P=0.433). Conclusion: The prognosis of pts with autoimmune and infiltrative cytopenias was similar.However, CLL pts with AC had worse OS compared to those without cytopenias. There was no significant difference in TTFT between AC and IC or when compared to CLL pts without cytopenias. For the AC group, neither treatment with chemotherapy vs. chemo-immunotherapy nor having concomitant hypo-gammaglobulinemia had an effect on outcome. To our knowledge, there are limited population based studies addressing the importance of determining the etiology of cytopenias in CLL pts and the effect of AC on survival. CLL immune complications need to be studied further especially in the context of novel agents and their effects on immune reconstitution. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Epidemiology of pheochromocytoma and paraganglioma: population-based cohort study

2021 ◽  
Vol 184 (1) ◽  
pp. 19-28
Author(s):  
Alexander A Leung ◽  
Janice L Pasieka ◽  
Martin D Hyrcza ◽  
Danièle Pacaud ◽  
Yuan Dong ◽  
...  
Keyword(s):  
Cohort Study ◽  
Administrative Data ◽  
Laboratory Data ◽  
Population Based ◽  
Incidence Rates ◽  
Primary Objective ◽  
Administrative Databases ◽  
Secondary Objective ◽  
True Frequency ◽  
Clinical Records

Objective Despite the significant morbidity and mortality associated with pheochromocytoma and paraganglioma, little is known about their epidemiology. The primary objective was to determine the incidence of pheochromocytoma and paraganglioma in an ethnically diverse population. A secondary objective was to develop and validate algorithms for case detection using laboratory and administrative data. Design Population-based cohort study in Alberta, Canada from 2012 to 2019. Methods Patients with pheochromocytoma or paraganglioma were identified using linked administrative databases and clinical records. Annual incidence rates per 100 000 people were calculated and stratified according to age and sex. Algorithms to identify pheochromocytoma and paraganglioma, based on laboratory and administrative data, were evaluated. Results A total of 239 patients with pheochromocytoma or paraganglioma (collectively with 251 tumors) were identified from a population of 5 196 368 people over a period of 7 years. The overall incidence of pheochromocytoma or paraganglioma was 0.66 cases per 100 000 people per year. The frequency of pheochromocytoma and paraganglioma increased with age and was highest in individuals aged 60–79 years (8.85 and 14.68 cases per 100 000 people per year for males and females, respectively). An algorithm based on laboratory data (metanephrine >two-fold or normetanephrine >three-fold higher than the upper limit of normal) closely approximated the true frequency of pheochromocytoma and paraganglioma with an estimated incidence of 0.54 cases per 100 000 people per year. Conslusion The incidence of pheochromocytoma and paraganglioma in an unselected population of western Canada was unexpectedly higher than rates reported from other areas of the world.

scholarly journals Gender Inequalities in Diagnostic Inertia around the Three Most Prevalent Cardiovascular Risk Studies: Protocol for a Population-Based Cohort Study

2021 ◽  
Vol 18 (8) ◽  
pp. 4054
Author(s):  
Concepción Carratala-Munuera ◽  
Adriana Lopez-Pineda ◽  
Domingo Orozco-Beltran ◽  
Jose A. Quesada ◽  
Jose L. Alfonso-Sanchez ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Health Care ◽  
Cohort Study ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Disease Incidence ◽  
Population Based ◽  
Gender Inequalities ◽  
Primary Health Care Centers

Evidence shows that objectives for detecting and controlling cardiovascular risk factors are not being effectively met, and moreover, outcomes differ between men and women. This study will assess the gender-related differences in diagnostic inertia around the three most prevalent cardiovascular risk factors: dyslipidemia, arterial hypertension, and diabetes mellitus, and to evaluate the consequences on cardiovascular disease incidence. This is an epidemiological and cohort study. Eligible patients will be adults who presented to public primary health care centers in a Spanish region from 2008 to 2011, with hypertension, dyslipidemia, or/and diabetes and without cardiovascular disease. Participants’ electronic health records will be used to collect the study variables in a window of six months from inclusion. Diagnostic inertia of hypertension, dyslipidemia, and/or diabetes is defined as the registry of abnormal diagnostic parameters—but no diagnosis—on the person’s health record. The cohort will be followed from the date of inclusion until the end of 2019. Outcomes will be cardiovascular events, defined as hospital admission due to ischemic cardiopathy, stroke, and death from any cause. The results of this study could inform actions to rectify the structure, organization and training of health care teams in order to correct the inequality.

scholarly journals Morbidity and Mortality Reduction Associated with Polysomnography Testing in Idiopathic Pulmonary Fibrosis: A Population-Based Cohort Study

2021 ◽  
Author(s):  
Nicholas T Vozoris ◽  
Andrew S Wilton ◽  
Peter C Austin ◽  
Tetyana Kendzerska ◽  
Clodagh M Ryan ◽  
...  
Keyword(s):  
Cohort Study ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Health Outcomes ◽  
Index Date ◽  
Population Based ◽  
Sleep Breathing Disorders ◽  
Breathing Disorders ◽  
All Cause Mortality ◽  
Important Health

Abstract Background: It is not well-known if diagnosing and treating sleep breathing disorders among individuals with idiopathic pulmonary fibrosis (IPF) improves health outcomes. We evaluated the association between receipt of laboratory-based polysomnography (which is the first step in the diagnosis and treatment of sleep breathing disorders in Ontario, Canada) and respiratory-related hospitalization and all-cause mortality among individuals with IPF.Methods: We used a retrospective, population-based, cohort study design, analyzing health administrative data from Ontario, Canada, from 2007-2019. Individuals with IPF were identified using an algorithm based on health administrative codes previously developed by IPF experts. Propensity score matching was used to account for potential differences in 41 relevant covariates between individuals that underwent polysomnography (exposed) and individuals that did not undergo polysomnography (controls), in order minimize potential confounding. Respiratory-related hospitalization and all-cause mortality were evaluated up to 12 months after the index date. Results: Out of 5044 individuals with IPF identified, 201 (4.0%) received polysomnography, and 189 (94.0%) were matched to an equal number of controls. Compared to controls, exposed individuals had significantly reduced rates of respiratory-related hospitalization (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.24-0.75), p=0.003) and all-cause mortality (HR 0.49, 95% CI 0.30-0.80), p=0.004). Significantly reduced rate of respiratory-related hospitalization (but not all-cause mortality) was also observed among those with >=1 respiratory-related hospitalization (HR 0.38, 95% CI 0.15-0.99) and systemic corticosteroid receipt (HR 0.37, 95% CI 0.19-0.94) in the year prior to the index date, which reflect sicker subgroups of persons. Conclusions: Undergoing polysomnography was associated with significantly improved clinically-important health outcomes among individuals with IPF, highlighting the potential importance of incorporating this testing in IPF disease management.

scholarly journals Total Proteome Analysis Identifies Migration Defects As a Major Pathogenetic Factor in IGHV-Unmutated Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 718-718 ◽  
Author(s):  
Gina L Eagle ◽  
Rosalind E Jenkins ◽  
Kathleen J Till ◽  
Jithesh Puthen ◽  
Ke Lin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Computational Analysis ◽  
Lymphocytic Leukemia ◽  
Differentially Expressed ◽  
Differentially Expressed Proteins ◽  
Data Set ◽  
Clinical Behaviour ◽  
Mutational Status ◽  
Significant Difference ◽  
Total Proteome

Abstract The mutational status of the immunoglobulin heavy chain variable region (IGHV) defines two clinically distinct forms of chronic lymphocytic leukemia (CLL) known as mutated (M-CLL) and un-mutated (UM-CLL). Patients with M-CLL usually have a favourable outcome whereas those with UM-CLL develop progressive disease and have shorter survival. However, the molecular mechanisms responsible for the more aggressive clinical behaviour associated with UM-CLL are not well understood. Here we describe the application of isobaric tags for relative and absolute quantification (iTRAQ) based mass spectrometry (MS) to analyse the total proteome of M-CLL and UM-CLL samples. This has enabled us to generate the largest quantity of proteomic information for CLL to date and, in particular, to directly compare the functions of differentially expressed proteins between UM-CLL and M-CLL cells through a systems biology approach. We isolated CLL cells from the peripheral blood from 18 CLL patients (9 UM-CLL, 9 M-CLL) and prepared cellular protein extracts which were digested and subjected to labelling with iTRAQ reagents, as previously described (Kitteringham et al, J Proteomics, 2010;73(8):1612-1631). Principal component analysis was used to assess variance across the data set generated by iTRAQ-MS. Statistical significance of the difference in the levels of expression of proteins between UM-CLL and M-CLL samples was determined using student T-test (2-tailed). Several differentially expressed proteins identified by iTRAQ-MS were also validated by immunoblotting. Computational analysis was performed to examine the functions of the differentially expressed proteins and their associated signalling pathways using the GeneGo pathway maps in the Metacore™ database (Thomson Reuters, NY, USA). Unsupervised clustering, based on the expression of 3521 identified proteins, separated CLL samples into two groups corresponding to IGHV mutational status. We identified 274 proteins that were differentially expressed between UM-CLL and M-CLL subgroups (p<0.05, Figure 1A). Hierarchical clustering based on the relative expression of differentially expressed proteins also separated individual CLL cases into two distinct clusters according to their IGHV status (Figure 1B). Computational analysis showed that 43 cell migration/adhesion pathways were significantly enriched (p<0.05) by 39 differentially expressed proteins, 35 of which were expressed at significantly lower levels in UM-CLL samples. Furthermore, UM-CLL cells under-expressed proteins associated with cytoskeletal remodelling and over-expressed proteins associated with transcriptional and translational activity. Taken together, these findings indicated that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes where they are exposed to proliferative stimuli. In agreement with this hypothesis, analysis of an extended cohort of 120 CLL patients revealed that twice as many patients with UM-CLL than M-CLL had documented lymphadenopathy (50% v 24%; P<0.01). The association between UM-CLL and lymphadenopathy was not simply a reflection of increased tumour burden as there was no significant difference in the leukocyte count between the two groups (medians of 37 x 109/L and 28 x 109/L, respectively; P>0.05). In addition, other pathways that promote cell survival and proliferation in UM-CLL cells were also enriched by the differentially expressed proteins. These include the immune response pathway involving B-cell receptor (BCR) signalling (P=0.006), the endoplasmic reticulum (ER) stress response pathway (P=0.035) and the Wnt signalling pathway (P=0.006). Our study has shown that quantitative analysis of the total proteome by iTRAQ-MS was able to separate individual CLL cases according to IGHV status and explained the more aggressive clinical behaviour of UM-CLL and its particular sensitivity to novel therapeutic agents that induce anatomical displacement from the lymph node microenvironment, such as ibrutinib and idelalisib. Moreover, in keeping with the ability of proteomics to detect alterations in gene expression resulting from both transcriptional and post-transcriptional mechanisms, the study illustrates the considerable potential of iTRAQ-MS coupled with computational analysis to elucidate pathogenetic mechanisms and indicate therapeutic strategies in cancer. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Associations of androgens with health care utilization and costs in women—Perspectives of a population-based cohort study

Maturitas ◽  
2016 ◽  
Vol 89 ◽  
pp. 5-8
Author(s):  
Robin Haring ◽  
Henri Wallaschofski ◽  
Henry Völzke ◽  
Steffen Flessa ◽  
Brian G. Keevil ◽  
...  
Keyword(s):  
Health Care ◽  
Cohort Study ◽  
Health Care Utilization ◽  
Population Based ◽  
Care Utilization
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