Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects

Toni K Choueiri, MD
Guru Sonpavde, MD
Section Editors
Richard M Goldberg, MD
Michael B Atkins, MD
Richard A Larson, MD
Deputy Editors
Diane MF Savarese, MD
Jennifer S Tirnauer, MD


The use of angiogenesis inhibitors in cancer therapy is expanding. Following the recognition of the role of angiogenesis in promoting tumor growth [1], multiple trials have shown that angiogenesis inhibitors yield incremental improvements in outcomes for a variety of advanced solid tumors.

With the expanding use of agents that target the vascular endothelial growth factor (VEGF) signaling pathway in cancer therapy, it is increasingly recognized that they are associated with a wide spectrum of toxicities which, in a small number of cases, may be fatal [2,3]. Given that these agents principally target the tumor vasculature rather than the tumor cells themselves, many of their toxicities are unique and not typically observed with conventional cytotoxic agents.

This topic review will cover cardiovascular adverse effects of the anti-VEGF agents (hypertension, thromboembolic disease, left ventricular dysfunction, myocardial ischemia, prolongation of the QTc interval, and thrombotic microangiopathy). All other (non-cardiovascular) toxicities from VEGF pathway inhibitors as well as thrombotic complications of thalidomide, lenalidomide, and pomalidomide, drugs that have immunomodulatory as well as antiangiogenic activity, are discussed in detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues".)


Several classes of antiangiogenic agents are available. (See "Overview of angiogenesis inhibitors".)

Agents discussed herein include the following monoclonal antibodies and small molecules:


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Dec 11, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285:1182.
  2. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 2011; 305:487.
  3. Schutz FA, Je Y, Richards CJ, Choueiri TK. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol 2012; 30:871.
  4. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet 2016; 388:518.
  5. Sivendran S, Liu Z, Portas LJ Jr, et al. Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Cancer Treat Rev 2012; 38:919.
  6. Henry TD, Annex BH, McKendall GR, et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003; 107:1359.
  7. Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol 1998; 274:H1054.
  8. Madeddu P. Therapeutic angiogenesis and vasculogenesis for tissue regeneration. Exp Physiol 2005; 90:315.
  9. Carmeliet P. Manipulating angiogenesis in medicine. J Intern Med 2004; 255:538.
  10. Robinson ES, Khankin EV, Choueiri TK, et al. Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors. Hypertension 2010; 56:1131.
  11. Sica DA. Angiogenesis inhibitors and hypertension: an emerging issue. J Clin Oncol 2006; 24:1329.
  12. Izzedine H, Ederhy S, Goldwasser F, et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol 2009; 20:807.
  13. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335.
  14. Mir O, Coriat R, Cabanes L, et al. An observational study of bevacizumab-induced hypertension as a clinical biomarker of antitumor activity. Oncologist 2011; 16:1325.
  15. Shah SR, Gressett Ussery SM, Dowell JE, et al. Shorter bevacizumab infusions do not increase the incidence of proteinuria and hypertension. Ann Oncol 2013; 24:960.
  16. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012; 30:3499.
  17. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931.
  18. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006; 24:1363.
  19. Bamias A, Manios E, Karadimou A, et al. The use of 24-h ambulatory blood pressure monitoring (ABPM) during the first cycle of sunitinib improves the diagnostic accuracy and management of hypertension in patients with advanced renal cancer. Eur J Cancer 2011; 47:1660.
  20. 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.
  21. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012; 30:134.
  22. Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res 2011; 17:3841.
  23. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381:303.
  24. US Food and Drug Administration. FDA approves Cometriq to treat rare type of thyroid cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm330143.htm (Accessed on December 03, 2012).
  25. An MM, Zou Z, Shen H, et al. Incidence and risk of significantly raised blood pressure in cancer patients treated with bevacizumab: an updated meta-analysis. Eur J Clin Pharmacol 2010; 66:813.
  26. Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 2009; 48:9.
  27. Wu S, Chen JJ, Kudelka A, et al. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 2008; 9:117.
  28. Qi WX, Lin F, Sun YJ, et al. Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis. Cancer Chemother Pharmacol 2013; 71:431.
  29. Motzer RJ HT, Reeves J, et al. Randomized, open label, phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (mRCC); Results of the COMPARZ trial. Proc European Society of Medical Oncology Congress LBA8, Vienna, Austria September 28-October 2, 2012.
  30. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383:31.
  31. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372:621.
  32. Hamnvik OP, Choueiri TK, Turchin A, et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer 2015; 121:311.
  33. Maitland ML, Kasza KE, Karrison T, et al. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res 2009; 15:6250.
  34. Azizi M, Chedid A, Oudard S. Home blood-pressure monitoring in patients receiving sunitinib. N Engl J Med 2008; 358:95.
  35. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst 2010; 102:596.
  36. Schneider BP, Li L, Shen F, et al. Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. Br J Cancer 2014; 111:1241.
  37. Sibertin-Blanc C, Mancini J, Fabre A, et al. Vascular Endothelial Growth Factor A c.*237C>T polymorphism is associated with bevacizumab efficacy and related hypertension in metastatic colorectal cancer. Dig Liver Dis 2015; 47:331.
  38. Dahlberg SE, Sandler AB, Brahmer JR, et al. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 2010; 28:949.
  39. Schneider BP, Wang M, Radovich M, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 2008; 26:4672.
  40. Ryanne Wu R, Lindenberg PA, Slack R, et al. Evaluation of hypertension as a marker of bevacizumab efficacy. J Gastrointest Cancer 2009; 40:101.
  41. Scartozzi M, Galizia E, Chiorrini S, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 2009; 20:227.
  42. Goodwin R, Ding K, Seymour L, et al. Treatment-emergent hypertension and outcomes in patients with advanced non-small-cell lung cancer receiving chemotherapy with or without the vascular endothelial growth factor receptor inhibitor cediranib: NCIC Clinical Trials Group Study BR24. Ann Oncol 2010; 21:2220.
  43. Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011; 103:763.
  44. Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol 2013; 36:319.
  45. Donskov F, Michaelson MD, Puzanov I, et al. Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients. Br J Cancer 2015; 113:1571.
  46. Wick A, Schäfer N, Dörner N, et al. Arterial hypertension and bevacizumab treatment in glioblastoma: no correlation with clinical outcome. J Neurooncol 2010; 97:157.
  47. Hurwitz HI, Douglas PS, Middleton JP, et al. Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies. Oncologist 2013; 18:273.
  48. Duffaud F, Sleijfer S, Litière S, et al. Hypertension (HTN) as a potential biomarker of efficacy in pazopanib-treated patients with advanced non-adipocytic soft tissue sarcoma. A retrospective study based on European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 trials. Eur J Cancer 2015; 51:2615.
  49. Rini BI, Cohen DP, Lu D, et al. Hypertension (HTN) as a biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (abstract). American Society of Clinical Oncology (ASCO) 2010 Genitourinary Cancers Symposium.
  50. Langenberg MH, van Herpen CM, De Bono J, et al. Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors. J Clin Oncol 2009; 27:6152.
  51. Houk BE, Bello CL, Poland B, et al. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol 2010; 66:357.
  52. Piccirillo JF, Tierney RM, Costas I, et al. Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA 2004; 291:2441.
  53. Bair SM, Choueiri TK, Moslehi J. Cardiovascular complications associated with novel angiogenesis inhibitors: emerging evidence and evolving perspectives. Trends Cardiovasc Med 2013; 23:104.
  54. Zangari M, Fink LM, Elice F, et al. Thrombotic events in patients with cancer receiving antiangiogenesis agents. J Clin Oncol 2009; 27:4865.
  55. Mir O, Mouthon L, Alexandre J, et al. Bevacizumab-induced cardiovascular events: a consequence of cholesterol emboli syndrome? J Natl Cancer Inst 2007; 99:85.
  56. Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res 2001; 49:568.
  57. González-Pacheco FR, Deudero JJ, Castellanos MC, et al. Mechanisms of endothelial response to oxidative aggression: protective role of autologous VEGF and induction of VEGFR2 by H2O2. Am J Physiol Heart Circ Physiol 2006; 291:H1395.
  58. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 2007; 96:1788.
  59. Tebbutt NC, Murphy F, Zannino D, et al. Risk of arterial thromboembolic events in patients with advanced colorectal cancer receiving bevacizumab. Ann Oncol 2011; 22:1834.
  60. www.fda.gov/medwatch/SAFETY/2004/safety04.htm#avastin (Accessed on May 15, 2012).
  61. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99:1232.
  62. Schutz FA, Je Y, Azzi GR, et al. Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes. Ann Oncol 2011; 22:1404.
  63. Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol 2010; 49:287.
  64. Van Cutsem E, Khayat D, Verslype C, et al. Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours. Eur J Cancer 2013; 49:17.
  65. Tang PA, Cohen SJ, Kollmannsberger C, et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res 2012; 18:6023.
  66. FDA-approved manufacturer's package insert for bevacizumab available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=939b5d1f-9fb2-4499-80ef-0607aa6b114e#section-5-5 (Accessed on December 14, 2012).
  67. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f6725df6-50ee-4b0a-b900-d02ba634395d#section-5.6 (Accessed on February 01, 2013).
  68. Common Toxicity Criteria of the National Cancer Institute available online at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (Accessed on May 15, 2012).
  69. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008; 300:2277.
  70. Hurwitz HI, Saltz LB, Van Cutsem E, et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol 2011; 29:1757.
  71. Leighl NB, Bennouna J, Yi J, et al. Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study. Br J Cancer 2011; 104:413.
  72. US Food and Drug Administration (FDA)-approved prescribing information for ramucirumab available online at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477lbl.pdf (Accessed on April 25, 2014).
  73. Choueiri TK, Schutz FA, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol 2010; 28:2280.
  74. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125.
  75. Sternberg CN, Szczylik C, Lee ES, et al. A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC) (abstract #5021). J Clin Oncol 2009; 27:240s.
  76. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf?et_cid=35470087&et_rid=907466112&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2015%2f206947s000lbl.pdf (Accessed on February 20, 2015).
  77. US Food and Drug Administration (FDA)-approved manufacturer's package insert available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=807f988e-117b-4497-934d-73aa78baac71 (Accessed on January 03, 2013).
  78. Patrono C, Coller B, FitzGerald GA, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:234S.
  79. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004; 292:1867.
  80. Stadler WM, Cao D, Vogelzang NJ, et al. A randomized Phase II trial of the antiangiogenic agent SU5416 in hormone-refractory prostate cancer. Clin Cancer Res 2004; 10:3365.
  81. Zangari M, Anaissie E, Stopeck A, et al. Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma. Clin Cancer Res 2004; 10:88.
  82. Heymach JV, Desai J, Manola J, et al. Phase II study of the antiangiogenic agent SU5416 in patients with advanced soft tissue sarcomas. Clin Cancer Res 2004; 10:5732.
  83. Sonpavde G, Je Y, Schutz F, et al. Venous thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2013; 87:80.
  84. Qi WX, Min DL, Shen Z, et al. Risk of venous thromboembolic events associated with VEGFR-TKIs: a systematic review and meta-analysis. Int J Cancer 2013; 132:2967.
  85. Ghatalia P, Morgan CJ, Je Y, et al. Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Crit Rev Oncol Hematol 2015; 94:228.
  86. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007; 370:2011.
  87. Khakoo AY, Kassiotis CM, Tannir N, et al. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer 2008; 112:2500.
  88. Di Lorenzo G, Autorino R, Bruni G, et al. Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol 2009; 20:1535.
  89. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115.
  90. Rock EP, Goodman V, Jiang JX, et al. Food and Drug Administration drug approval summary: Sunitinib malate for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Oncologist 2007; 12:107.
  91. Richards CJ, Je Y, Schutz FA, et al. Incidence and risk of congestive heart failure in patients with renal and nonrenal cell carcinoma treated with sunitinib. J Clin Oncol 2011; 29:3450.
  92. Witteles RM, Telli M. Underestimating cardiac toxicity in cancer trials: lessons learned? J Clin Oncol 2012; 30:1916.
  93. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359:378.
  94. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008; 26:5204.
  95. Haas NB MJ, Ky B, et al. Cardiac safety analysis for a phase III trial of sunitinib or sorafenib or placebo in patients with resected renal cell carcinoma. J Clin Oncol 30, 2012 (suppl; abstr 4500).
  96. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 2007; 7:332.
  97. Hsieh PC, MacGillivray C, Gannon J, et al. Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation 2006; 114:637.
  98. Cheng H, Force T. Why do kinase inhibitors cause cardiotoxicity and what can be done about it? Prog Cardiovasc Dis 2010; 53:114.
  99. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379:1879.
  100. FDA-approved manufacturer's labeling information available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=824f19c9-0546-4a8a-8d8f-c4055c04f7c7#section-6.5or= (Accessed on October 04, 2012).
  101. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol 2011; 29:632.
  102. Floyd JD, Nguyen DT, Lobins RL, et al. Cardiotoxicity of cancer therapy. J Clin Oncol 2005; 23:7685.
  103. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23:792.
  104. Chintalgattu V, Patel SS, Khakoo AY. Cardiovascular effects of tyrosine kinase inhibitors used for gastrointestinal stromal tumors. Hematol Oncol Clin North Am 2009; 23:97.
  105. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147.
  106. FDA-approved manufacturer's package insert for sunitinib available at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=43a4d7f8-48ae-4a63-9108-2fa8e3ea9d9c (Accessed on December 18, 2012).
  107. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b50667e4-5ebc-4968-a646-d605058dbef0 (Accessed on February 01, 2013).
  108. Shah RR, Morganroth J, Shah DR. Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval). Drug Saf 2013; 36:295.
  109. Ghatalia P, Je Y, Kaymakcalan MD, et al. QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Br J Cancer 2015; 112:296.
  110. US FDA drug approval summary for vandetanib in medullary thyroid cancer available online at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022405s000lbl.pdf (Accessed on April 25, 2011).
  111. Zang J, Wu S, Tang L, et al. Incidence and risk of QTc interval prolongation among cancer patients treated with vandetanib: a systematic review and meta-analysis. PLoS One 2012; 7:e30353.
  112. FDA-approved manufacturer's package insert for vandetanib available online at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4dc7f0af-77fb-4eec-46b9-dd1c2dcb4525 (Accessed on January 25, 2013).
  113. Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 2007; 25:3362.
  114. Bello CL, Mulay M, Huang X, et al. Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic- pharmacodynamic evaluation of sunitinib. Clin Cancer Res 2009; 15:7045.
  115. Tolcher AW, Appleman LJ, Shapiro GI, et al. A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer. Cancer Chemother Pharmacol 2011; 67:751.
  116. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008; 358:1129.
  117. Al-Nouri ZL, Reese JA, Terrell DR, et al. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood 2015; 125:616.
  118. Reese JA, Bougie DW, Curtis BR, et al. Drug-induced thrombotic microangiopathy: Experience of the Oklahoma Registry and the BloodCenter of Wisconsin. Am J Hematol 2015; 90:406.