ORI G I N A L S T U DY Cardiovascular Events and Torsades de Pointes in Patients Using Pazopanib and Other Marketed Anti-VEGF Agents for Metastatic Renal Cell Carcinoma: A Descriptive Study Sumitra Shantakumar1, Samantha St. Laurent2, Myrthe van Herk-Sukel3, Jeanenne J. Nelson4 Affiliations: 1GlaxoSmithKline, Worldwide Epidemiology, Research Triangle Park, NC, USA; 2GlaxoSmithKline, Worldwide Epidemiology, Waltham, MA, USA; 3PHARMO Institute for Outcomes Research, Utrecht, Netherlands; 4GlaxoSmithKline, Collegeville Road, Collegeville, Pennsylvania, 19426-0989, United States Summary Pazopanib is an angiogenesis inhibitor approved by the FDA in 2009 for metastatic renal cell carcinoma (RCC). This observational study describes the frequency of cardiovascular outcomes in adult RCC patients treated with pazopanib. A retrospective cohort study was conducted using data from the United States (Clinformatics™ DataMart Multiplan, IMPACT) and The Netherlands (PHARMO Database Network). The following outcomes were captured via ICD-9 diagnostic codes: myocardial infarction (MI), unstable angina (UA), Torsades de Pointes (TP), cerebrovascular accident (CVA), and transient ischemic attack (TIA). Incidence proportions were evaluated in pazopanib users and a comparator group of RCC patients treated with bevacizumab, sorafenib, or sunitinib. When multiple events occurred for the same cardiovascular outcome in the same patient, only the first event was used. Among 104 RCC patients treated with only pazopanib in the US population, 13 events occurred among 10 patients, as follows: five CVA 4.8% (95% CI: 1.6-10.9%), three events each of MI and TIA 2.9%, (95% CI: 0.6-8.20%, and one event each of TP and UA 1.0% (95% CI: 0.02-5.2%). In comparison, the frequency of events among the comparator group (n=556) were: CVA (2.2%), MI (4.5%), TIA (1.4%), TP (1.6%), UA (1.6%). In the Dutch population, 21 pazopanib users and 96 patients in the comparator group met the eligibility criteria; one pazopanib patient experienced a CVA event and 44 Kidney Cancer Journal one sunitinib user had an UA event. The frequency of selected cardiovascular events among RCC patients was similar for users of pazopanib and similar drugs. Clinical Practice Points As part of pharmacovigilance activities, we evaluated ‘real world’ rates of cardiovascular events in RCC patients treated with pazopanib and other marketed anti-VEGF agents. Based on data from a large administrative claims database in the United States and hospital records in The Netherlands, cardiovascular ischemic events occurred in 0-9.5% of RCC patients treated with pazopanib and other anti-VEGF agents over a mean of 379 days of follow-up. Introduction Pazopanib is an angiogenesis inhibitor approved in 2009 by the United States Food and Drug Administration (FDA) for treatment of metastatic renal cell carcinoma (RCC). The safety profiles of other marketed anti-vascular endothelial growth factor (anti-VEGF) drugs at the time of initial pazopanib approval suggested an increased occurrence of cardiovascular ischemic events and Torsades de pointes (TP).1-6 As pazopanib is used to treat highly vascularized tumors, we designed a descriptive study as part of pharmacovigilance and post-marketing drug safety evaluations in the post-approval period to evaluate the occurrence of cardiac events and TP in RCC patients treated with pazopanib. The primary objective of this study was to estimate the frequency of specific cardiovascular events and TP after drug initiation in adult (18+ years) pazopanib users with RCC and in a comparator group of RCC patients using three other marketed anti-VEGF agents at the time of pazopanib FDA approval in 2009: bevacizumab, sorafenib, Keywords: cardiovascular, ischemia, pazopanib, renal cell carcinoma, Torsades de Pointes Corresponding Author: Sumitra Shantakumar, PhD; Worldwide Epidemiology, Glaxosmithkline R&D; 150 Beach Road, Gateway West, #26-00; Singapore 189720, SINGAPORE Tel: +065-6232-8258; E-mail: sumitra.y.shantakumar@gsk.com
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