title: Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors.
abstract: BACKGROUND
  Small-molecule tyrosine kinase inhibitors (TKIs) may provide an effective therapeutic option in patients with hematologic malignancies and solid tumors. However, cardiovascular (CV) events, including hypertension, heart failure, left ventricular systolic dysfunction, and QT prolongation, have emerged as potential adverse events (AEs) with TKI therapy.
  
  
  OBJECTIVE
  We review what is known about the mechanism of action of CV AEs associated with TKI use and discuss therapeutic interventions that may prevent and manage these events in clinical practice.
  
  
  METHODS
  References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Search terms included "cardiac," "cardiovascular," "cancer," and "kinase inhibitor." Related links in the databases were reviewed, along with relevant published guidelines.
  
  
  RESULTS
  Although the link between rising blood pressure (BP) and CV AEs is observed but not proven, good clinical practice supports an aggressive policy on proper long-term BP management. There are insufficient data from randomized controlled clinical trials to show indisputably that aggressive or effective heart failure therapy in patients receiving TKIs will fundamentally change outcomes; however, clinical practice suggests that this is an effective long-term approach. Recognizing that QT prolongation is associated with TKI use facilitates identification of patients at high risk for this CV AE and increases awareness of the need for routine electrocardiograms and electrolyte monitoring for those receiving TKI treatment.
  
  
  CONCLUSIONS
  Regular monitoring, early recognition, and appropriate interventions for CV AEs can help more patients derive the benefit of long-term TKI therapy.
authors.affiliation: Vanderbilt Heart and Vascular Institute, Nashville, Tennessee 37232-8802, USA. daniel.lenihan@Vanderbilt.Edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lenihan
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kowey
mesh_terms: D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology / Q000628:therapy*; D006333:Heart Failure / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000145:classification / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000473:pathology / Q000628:therapy
chemical_list: D047428:Protein Kinase Inhibitors
keywords: Adverse events; Cancer; Cardiac; Cardiovascular; TKIs; Tyrosine kinase inhibitors
references.citation: Circulation. 2008 Jul 1;118(1):84-95
references.pmid: 18591451
references.citation: J Clin Oncol. 2010 Feb 20;28(6):1061-8
references.pmid: 20100962
references.citation: Heart Fail Clin. 2011 Jul;7(3):373-84
references.pmid: 21749889
references.citation: Clin Transl Sci. 2009 Feb;2(1):15-25
references.pmid: 20376335
references.citation: Cardiovasc Res. 2000 Aug;47(2):219-33
references.pmid: 10947683
references.citation: J Cardiovasc Electrophysiol. 2000 Sep;11(9):1048-54
references.pmid: 11021476
references.citation: J Clin Oncol. 2008 Nov 10;26(32):5154-5
references.pmid: 18838702
references.citation: J Clin Oncol. 2007 Aug 1;25(22):3362-71
references.pmid: 17664484
references.citation: J Biopharm Stat. 2010 May;20(3):543-62
references.pmid: 20358435
references.citation: Circulation. 2009 Apr 14;119(14):e391-479
references.pmid: 19324966
references.citation: Prog Cardiovasc Dis. 2010 Sep-Oct;53(2):164-72
references.pmid: 20728704
references.citation: Br J Clin Pharmacol. 2003 Jun;55(6):511-7
references.pmid: 12814443
references.citation: FASEB J. 1999 Jan;13(1):9-22
references.pmid: 9872925
references.citation: JAMA. 2003 Apr 23-30;289(16):2120-7
references.pmid: 12709470
references.citation: Nat Clin Pract Oncol. 2008 Nov;5(11):655-67
references.pmid: 18797437
references.citation: J Am Coll Cardiol. 2010 Jan 19;55(3):213-20
references.pmid: 20117401
references.citation: Nat Med. 2006 Aug;12(8):908-16
references.pmid: 16862153
references.citation: J Clin Oncol. 2012 Mar 10;30(8):871-7
references.pmid: 22312105
references.citation: Am Heart J. 1947 Jan;33(1):14-26
references.pmid: 20280672
references.citation: Am J Cardiol. 1992 Sep 15;70(7):797-801
references.pmid: 1519533
references.citation: Ann Noninvasive Electrocardiol. 2003 Oct;8(4):343-51
references.pmid: 14516292
references.citation: Haematologica. 2012 Jun;97(6):883-9
references.pmid: 22271904
references.citation: Anaesthesia. 1992 Feb;47(2):125-7
references.pmid: 1539780
references.citation: J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62
references.pmid: 17161256
references.citation: J Natl Cancer Inst. 2010 May 5;102(9):596-604
references.pmid: 20351338
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3470-6
references.pmid: 18519779
references.citation: J Clin Oncol. 2006 Mar 20;24(9):1363-9
references.pmid: 16446323
references.citation: Am Heart J. 2002 Nov;144(5):769-81
references.pmid: 12422144
references.citation: Circulation. 2004 Oct 26;110(17):2721-46
references.pmid: 15505110
references.citation: Eur Heart J. 2007 Jun;28(12):1462-536
references.pmid: 17562668
references.citation: Ann Oncol. 2008 May;19(5):927-34
references.pmid: 18056916
references.citation: Lancet. 2007 Dec 15;370(9604):2011-9
references.pmid: 18083403
references.citation: Hypertension. 2009 Sep;54(3):652-8
references.pmid: 19652084
references.citation: Drug Discov Today. 2008 Sep;13(17-18):778-84
references.pmid: 18617014
references.citation: J Card Fail. 2000 Jun;6(2):115-9
references.pmid: 10908085
references.citation: Curr Cardiol Rep. 2009 May;11(3):167-74
references.pmid: 19379636
references.citation: Prog Cardiovasc Dis. 2010 Sep-Oct;53(2):114-20
references.pmid: 20728698
references.citation: N Engl J Med. 2011 Oct 6;365(14):1273-83
references.pmid: 21991949