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Original research
Tyrosine kinase inhibitors in chronic myeloid leukaemia and emergent cardiovascular disease
  1. Darryl Leong1,2,
  2. Nazanin Aghel2,
  3. Christopher Hillis3,
  4. Deborah Siegal4,
  5. Sarah Karampatos1,
  6. Sumathy Rangarajan1,
  7. Gregory Pond3,
  8. Hsien Seow3
  1. 1 Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
  2. 2 Medicine, McMaster University, Hamilton, Ontario, Canada
  3. 3 Oncology, McMaster University, Hamilton, Ontario, Canada
  4. 4 Medicine, University of Ottawa, Ottawa, Ontario, Canada
  1. Correspondence to Dr Darryl Leong, Population Health Research Institute, McMaster University, Hamilton, ON L8L 2X2, Canada; leongd{at}


Objectives (1) Describe how the risk of major adverse cardiovascular events (MACE) in individuals with chronic myeloid leukaemia (CML) has evolved; (2) evaluate the risk of MACE associated with the prescription of different CML tyrosine kinase inhibitors (TKI).

Methods A population-based retrospective study including all patients (n=4238) diagnosed with CML in Ontario, Canada between 1986 and 2017 and and age-matched and sex-matched individuals who received healthcare but who did not have CML (controls: n=42 380). The cohort was divided into those entering before 2001 vs from 2001 onwards (when TKIs were introduced). We developed competing risks models to compare time-to-event in CML cases versus controls. We adjusted for baseline comorbidities and present subdistribution HRs and 95% CIs. The relationship between TKI use and MACE was assessed by logistic regression.

Results Before 2001 and from 2001 on, patients with CML had a higher crude incidence of MACE than patients without CML (19.8 vs 15.3 and 20.3 vs 12.6 per 1000 person-years, respectively). After adjustment for cardiovascular risk factors, patients with CML had a lower subdistribution hazard for MACE (0.59, 95% CI 0.46 to 0.76) before 2001; but from 2001, the adjusted subdistribution HR for MACE (1.27, 95% CI 0.96 to 1.43) was similar to age-matched and sex-matched patients. The incidence (9.3 vs 13.8 per 1000 person-years) and subdistribution hazard for cardiovascular death (0.43, 95% CI 0.36 to 0.52) were lower in patients with CML than controls before 2001. From 2001 on, the incidence (6.3 vs 5.4 per 1000 person-years) and subdistribution hazard for cardiovascular death (0.99, 95% CI 0.84 to 1.18) were similar to age-matched and sex-matched patients without CML with a higher risk of cerebrovascular events (8.6 vs 5.6 per 1000 person-years; 1.35, 95% CI 1.00 to 1.83) and peripheral arterial events (6.9 vs 3.0 per 1000 person-years; 1.66 95% CI, 1.15 to 2.39) in patients with CML than patients without CML. Compared with imatinib, there was no difference in the risk of MACE among those prescribed dasatinib (OR 0.67, 95% CI 0.41 to 1.10) or nilotinib (OR 1.22, 95% CI 0.70 to 1.97).

Conclusions In a contemporary CML population, the risk of MACE and cardiovascular death is at least as high as among age-matched and sex-matched patients without CML and may be higher for cerebrovascular and peripheral arterial events. No difference in the risk of MACE between imatinib, dasatinib and nilotinib was observed.

  • epidemiology

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  • Contributors DL designed the study, conducted analyses, drafted the manuscript and is responsible for the overall content as guarantor. NA, CH, DS, SK, SR, GP and HS contributed to the interpretation of the analyses and edited the manuscript. HS facilitated access to the data. The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd (BMJPGL) and its Licensees to permit this article (if accepted) to be published in HEART editions and any other BMJPGL products to exploit all subsidiary rights.

  • Funding Funding was provided by the Population Health Research Institute, McMaster University. DL has received support from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Cancer Society and the Cancer Research Society. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). ICES is an independent, non-profit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyse healthcare and demographic data, without consent, for health system evaluation and improvement. Parts of this report are based on Ontario Registrar General information on deaths, the original source of which is ServiceOntario.

  • Disclaimer The opinions, results and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval This study was conducted in accordance with the Declaration of Helsinki and was approved by the Hamilton Integrated Research Ethics Board, Canada. The public was not involved in the design or execution of the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data may be obtained from a third party and are not publicly available. Raw data are available on successful application to the Institute of Clinical and Evaluative Sciences, Ontario, Canada.

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