title: Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events.
abstract: OBJECTIVE
  To define cardiovascular (CV) risk and reversibility of cardiac events in patients who received sunitinib versus comparator treatment (interferon-alfa or placebo).
  
  
  METHODS
  We performed a retrospective adjudication of comprehensive CV adverse events (AEs) from two phase 3 trials. Components of the comprehensive CV AE end-point comprised hypertension, symptomatic and asymptomatic left ventricular ejection fraction decreases (SD-LVEF; AD-LVEF) and extent of reversibility, heart-failure symptoms, thromboembolic events, dysrhythmia and CV death. Three cardiologists and one oncologist, blinded to treatment allocation, adjudicated suspected CV AEs in the pooled trial database (N=1090).
  
  
  RESULTS
  Incidence rates (IR) for sunitinib versus Interferon-alfa (IFN-α)/placebo were hypertension: 6.9 versus 2.6 (hazard ratio (HR), 3.1; 95% confidence interval (CI), 2.4-4.0); SD-LVEF: 0.4 versus 0.2 (HR, 2.5; 95% CI, 1.0-6.2); AD-LVEF: 1.1 versus 0.8 (HR, 2.1; 95% CI, 1.3-3.4); and composite CV AE end-point: 10.1 versus 4.8 (HR, 2.5; 95% CI, 2.0-3.1), however reversibility, not previously quantified, was found to be clinically meaningful.
  
  
  CONCLUSIONS
  Hypertension and SD-LVEF/AD-LVEF were significantly higher with sunitinib versus IFN-α/placebo. Among patients who experienced a cardiac event, symptomatic and asymptomatic instances of decreased cardiac dysfunction were adjudicated as reversible in 47 of 83 (56%) and 17 of 30 (57%), respectively. Among sunitinib-treated patients, many were able to resume sunitinib dosing following resolution of events, a finding that is important for clinical care. In comparator groups, symptomatic and asymptomatic instances were adjudicated as reversible in 4 of 6 (66.7%) and 11 of 21 (52%), respectively. Thromboembolic, dysrhythmic and/or CV deaths were not significantly higher in sunitinib-treated patients.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address: mewer@mdanderson.org.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ewer
authors.affiliation: Bern University Hospital, Bern, Switzerland.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Suter
authors.affiliation: Vanderbilt Heart and Vascular Institute, Nashville, TN, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lenihan
authors.affiliation: Pfizer Oncology, New York, NY, United States.
authors.forename: Liviu
authors.initials: L
authors.lastname: Niculescu
authors.affiliation: Pfizer Oncology, New York, NY, United States.
authors.forename: Aurora
authors.initials: A
authors.lastname: Breazna
authors.affiliation: Ludwig Center at Harvard, Dana-Farber Cancer Institute Sarcoma Center, and Harvard Medical School, Boston, MA, United States.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000453:epidemiology; D015994:Incidence; D007211:Indoles / Q000009:adverse effects*; D016898:Interferon-alpha / Q000009:adverse effects*; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D011758:Pyrroles / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012307:Risk Factors; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D016898:Interferon-alpha; D011758:Pyrroles; D000077210:Sunitinib
keywords: Cancer treatment-related hypertension; Cardiotoxicity; Reversibility of cardiotoxic events; Sunitinib