Author Contributions SS and JJN were responsible for the study design and drafting of the manuscript. SSL and MvHS were responsible for data acquisition and statistical analysis. All authors were involved with data interpretation and critical revision of the manuscript content. Funding This study was sponsored by GlaxoSmithKline; pazopanib is an asset of Novartis AG as of March 1, 2015. Role of the Funding Source GlaxoSmithKline provided financial support for the conduct of the research and preparation of the article, including the collection, analysis and interpretation of data and writing of the report. Ethical Approvals and Informed Consent IMPACT data were anonymized and compliant with U.S. Health Insurance Portability and Accountability Act (HIPAA) guidelines; ethical board review was obtained at PHARMO. References 1. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renalcell Table 3. Incidence proportions for cardiovascular events occurring in RCC Patients treated with multiple anti-VEGF therapies in the IMPACT Database Anti-VEGFLine Cardiovascular n Events/ Incidence Proportion of Therapy Event N Total (95% CI) First Line Therapy* 1L Pazopanib CVA, MI, TIA, TP, UA 0/22 n/a 1L Bevacizumab CVA 1/12 8.3% (0.2-38.5) 1L Sorafenib CVA 1/33 3.0% (0.1-15.8) 1L Sunitinib CVA 5/109 4.6% (1.5-10.4) Second Line Therapy or Higher** 2L+ Pazopanib CVA 5/100 5.0% (1.6-11.3) 2L+ Bevacizumab MI 2/38 5.3% (0.6-17.8) 2L+ Sorafenib CVA 1/46 2.2% (0.1-11.5) 2L+ Sunitinib CVA, MI, TIA, TP, UA 0/21 n/a Abbreviations: cerebrovascular accident (CVA), confidence interval (CI), myocardial infarction (MI), renal cell carcinoma (RCC), Torsades de Pointes (TP), transient ischemic attack (TIA), unstable angina (UA), vascular endothelial growth factor (VEGF). *First-Line (IL): Therapy received before another anti-VEGF drug. **Second-Line or Higher (2L+): Therapy received following other anti-VEGF drug(s). The listed therapy was the closest therapy received prior to or carcinoma. N Engl J Med. 2007; 356:125-134. 2. Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: An NCI Treatment Referral Center trial TRC- 0301. J Clin Oncol. 2006; 24:3354-3360. 3. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006; 24:16-24. 4. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355:2542-2550. 5. Shah MA, Ilson D, Kelsen DP. Thromboembolic events in gastric cancer: High incidence in patients receiving irinotecan- and bevacizumabbased therapy. J Clin Oncol. 2005; 23:2574-2576. 6. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004; 22:2184- 2191. 48 Kidney Cancer Journal MI, TIA, TP, UA 0/12 n/a TP 1/33 3.0% (0.1-15.8) MI, TIA, UA 0/33 n/a MI 5/109 4.6% (1.5-10.4) TIA 4/109 3.7% (1.0-9.1) TP 0/109 n/a UA 3/109 2.8% (0.6-7.8) MI 1/100 1.0% (0.03-5.5) TIA 1/100 1.0% (0.03-5.5) TP 1/100 1.0% (0.03-5.5) UA 1/100 1.0% (0.03-5.5) CVA, TIA, TP, UA 0/38 n/a MI 1/46 2.2% (0.1-11.5) TIA 0/46 n/a TP 0/46 n/a UA 1/46 2.2% (0.1-11.5) 7. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2013; 369:722-731. 8. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010:28:1061-1068. 9. Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomized, doubleblind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Can. 2013; 49:1287-1296. 10. McCormack PL. Pazopanib: a review of its use in the management of advanced renal cell carcinoma. Drugs. 2014; 74:1111-1125. 11. Qi WX, Shen Z, Tang LN, Yao Y. Risk of arterial thromboembolic events with vascular endothelial growth factor tyrosine kinase inhibitors: an up-to-date meta-analysis. Crit Rev Oncol Hematol. 2014; 92:71-82. 12. McCormick N, Lacaille D, Bhole V, et al. Validity of Myocardial Infarction Diagnoses in Administrative Databases: A Systematic Review. PLoS ONE. 2014; 9(3):e92286. 13. McCormick N, Bhole V, Lacaille D, et al. Validity of Diagnostic Codes for Acute Stroke in Administrative Databases: A Systematic Review. PLoS ONE. 2015; 10(8):e0135834. KCJ
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