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Original Research |

Cardiovascular Events Associated With Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Population-Based Cohort StudyCardiovascular Adverse Events With Tyrosine Kinase Inhibitors

Torsten Dahlén, MD; Gustaf Edgren, MD, PhD; Mats Lambe, MD, PhD; Martin Höglund, MD, PhD; Magnus Björkholm, MD, PhD; Fredrik Sandin, MSc; Anders Själander, MD, PhD; Johan Richter, MD, PhD; Ulla Olsson-Strömberg, MD, PhD; Lotta Ohm, MD, PhD; Magnus Bäck, MD, PhD; Leif Stenke, MD, PhD, on behalf of the Swedish CML Group and the Swedish CML Register Group*
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 14 June 2016.

* For members of the Swedish CML Group and the Swedish CML Register Group, see the Appendix.


From Karolinska University Hospital and Karolinska Institutet, Stockholm; Regional Cancer Centre and Uppsala University Hospital, Uppsala; Umeå University, Umeå; and Skåne University Hospital, Lund, Sweden.

Note: Drs. Dahlén and Edgren had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: The authors acknowledge Swedish hematologists who treat patients with CML and contribute data to the national registers, as well as all personnel working to maintain the registers.

Financial Support: None.

Disclosures: Dr. Dahlén reports grants from Merck outside the submitted work. Dr. Själander reports personal fees from Novartis outside the submitted work. Dr. Richter reports personal fees from Novartis and Ariad and grants from Bristol-Myers Squibb and Pfizer outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2306.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Reproducible Research Statement:Study code and data set: Not available. Statistical code: Available from Dr. Dahlén (e-mail, torsten.dahlen@karolinska.se).

Requests for Single Reprints: Torsten Dahlén, MD, Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden; e-mail, torsten.dahlen@karolinska.se.

Current Author Addresses: Drs. Dahlén, Björkholm, Ohm, and Stenke: Department of Medicine, Division of Hematology, Karolinska University Hospital Solna, SE-17176 Stockholm, Sweden.

Drs. Edgren and Lambe: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden.

Drs. Höglund and Olsson-Strömberg: Department of Medical Science and Division of Hematology, University Hospital, SE-75185 Uppsala, Sweden.

Dr. Sandin: Regional Cancer Centre, Uppsala University Hospital, SE-75185 Uppsala, Sweden.

Dr. Själander: Department Public Health and Clinical Medicine, Umeå University, SE-90185 Umeå, Sweden.

Dr. Richter: Department of Hematology and Vascular Disorders, Skåne University Hospital, Getingevägen 4, SE-22241 Lund, Sweden.

Dr. Bäck: Department of Cardiology, Karolinska University Hospital, Stockholm, SE-17176 Stockholm, Sweden.

Author Contributions: Conception and design: T. Dahlén, G. Edgren, M. Bäck, L. Stenke.

Analysis and interpretation of the data: T. Dahlén, G. Edgren, M. Höglund, M. Björkholm, A. Själander, L. Ohm, M. Bäck, L. Stenke.

Drafting of the article: T. Dahlén, G. Edgren, M. Höglund, L. Stenke.

Critical revision for important intellectual content: T. Dahlén, G. Edgren, M. Lambe, M. Höglund, M. Björkholm, A. Själander, J. Richter, U. Olsson-Strömberg, M. Bäck, L. Stenke.

Final approval of the article: T. Dahlén, G. Edgren, M. Lambe, M. Höglund, M. Björkholm, F. Sandin, A. Själander, J. Richter, U. Olsson-Strömberg, L. Ohm, M. Bäck, L. Stenke.

Provision of study materials or patients: M. Höglund, A. Själander, U. Olsson-Strömberg, L. Stenke.

Statistical expertise: T. Dahlén, G. Edgren, L. Stenke.

Administrative, technical, or logistic support: T. Dahlén, M. Lambe

Collection and assembly of data: T. Dahlén, G. Edgren, M. Lambe, M. Höglund, F. Sandin, J. Richter, U. Olsson-Strömberg, L. Ohm, L. Stenke.


Ann Intern Med. 2016;165(3):161-166. doi:10.7326/M15-2306
© 2016 American College of Physicians
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Background: Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity.

Objective: To investigate the incidence of vascular events in patients with CML treated with first- and second-generation TKIs.

Design: Retrospective cohort study using nationwide population-based registries.

Setting: Sweden.

Patients: All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 age- and sex-matched control individuals per patient.

Measurements: Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons.

Results: 896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1000 person-years, respectively) than in those receiving imatinib (8 per 1000 person-years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred.

Limitations: Patients may have been exposed to multiple TKIs. Data on second- and third-generation TKIs were limited.

Conclusion: An increased risk for arterial and venous vascular events was seen in patients with CML treated with a TKI. Further study is needed to determine whether the risk for myocardial infarction increases with second-generation drugs.

Primary Funding Source: No external funding.

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