Skip to main content
SpringerLink
Log in

Cardiovascular Toxicities of Antiangiogenic Tyrosine Kinase Inhibitors: A Retrospective, Pharmacovigilance Study

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in the management of various solid tumors, particularly renal cell carcinoma (RCC). However, post-marketing data regarding their potential cardiovascular toxicities are scant.

Objective

To identify and characterize cardiovascular adverse events (CVAEs) of VEGFR-TKIs indicated for RCC.

Patients and Methods

Disproportionality analysis of the US Food and Drug Administration adverse event reporting system (July 2014–December 2019) using the reporting odds ratio (ROR) and the lower bound of the Information component (IC) 95% credibility interval (IC025 > 0 is significant).

Results

We identified 51,836 adverse event reports of sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib in the full database [36% women; median age 65 years (range 57–73)]. CVAEs accounted for 11,784 (23%) of the reports, with hypertension [n = 5548 (11%), ROR = 6.55 (95% CI 6.37–6.74), IC025 = 2.48] and hemorrhages [n = 3710 (7.2%), ROR = 1.28 (1.24–1.32), IC025 = 0.28] being the most frequent types. Additional CVAEs were over-reported with VEGFR-TKIs treatment, including aortic dissection [n = 61 (0.1%), ROR = 3.50 (2.71–4.51)], pericardial diseases [n = 173 (0.3%), ROR = 1.98 (1.70–2.30)], cardiomyopathy [n = 61 (0.1%), ROR = 1.89 (1.47–2.43)], heart failure [n = 868 (1.7%), ROR = 1.35 (1.26–1.44)], and venous thromboembolism [n = 604 (1.2%), ROR = 1.33 (1.23–1.45), all IC025 > 0]. The major pericardial disorder was non-malignant pericardial effusion [n = 134 (77%)]. Aortic dissections were also over-reported in patients without concomitant elevated blood pressure [ROR = 2.68 (1.97–3.63), IC025 = 0.91]. Finally, CVAEs were reported more often following lenvatinib and sunitinib treatment compared to other VEGFR-TKIs.

Conclusions

In post-marketing surveillance data, VEGFR-TKIs are associated with increased reporting of various CVAEs, including pericardial diseases, particularly non-malignant pericardial effusion, and aortic dissections. Moreover, VEGFR-TKIs differ in their CVAE reporting patterns. Clinicians should be conscious of these findings in the care of VEGFR-TKIs recipients.

Graphic Abstract

Cardiovascular toxicities of VEGFR-TKIs in the FDA adverse events reporting system (FAERS) database. Post-marketing data of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-associated cardiovascular toxicities are scant. We identified 51,836 safety reports of VEGFR-TKIs (sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib) in the FAERS database, including 11,784 (23%) cardiovascular adverse events (CVAEs). Hypertension, aortic dissections, and pericardial diseases had the highest reporting odds ratios. While the association of VEGFR-TKIs with hypertension is well established, pericardial diseases were not observed to date, and aortic dissection was reported in a small case series.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Levitzki A. Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. Annu Rev Pharmacol Toxicol. 2013;53:161–85.

    Article  CAS  PubMed  Google Scholar 

  2. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79:1283–316.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016;15:385–403.

    Article  CAS  PubMed  Google Scholar 

  4. Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med. 2016;375:1457–67.

    Article  CAS  PubMed  Google Scholar 

  5. Li W, Croce K, Steensma DP, McDermott DF, Ben-Yehuda O, Moslehi J. Vascular and metabolic implications of novel targeted cancer therapies: focus on kinase inhibitors. J Am Coll Cardiol. 2015;66:1160–78.

    Article  PubMed  Google Scholar 

  6. Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat Rev Cardiol. 2020;17(8):474–502.

    Article  CAS  PubMed  Google Scholar 

  7. Totzeck M, Mincu RI, Mrotzek S, Schadendorf D, Rassaf T. Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: a meta-analysis of approximately 29,000 cancer patients. Eur J Prev Cardiol. 2018;25:482–94.

    Article  PubMed  Google Scholar 

  8. Byrne AM, Bouchier-Hayes DJ, Harmey JH. Angiogenic and cell survival functions of Vascular Endothelial Growth Factor (VEGF). J Cell Mol Med. 2005;9:777–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931–9.

    Article  CAS  PubMed  Google Scholar 

  10. Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Hear Fail. 2013;1:72–8.

    Article  Google Scholar 

  11. Sonpavde G, Je Y, Schutz F, Galsky MD, Paluri R, Rosenberg JE, 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;87:80–9.

    Article  PubMed  Google Scholar 

  12. Raschi E, Gatti M, Gelsomino F, Ardizzoni A, Poluzzi E, De Ponti F. Lessons to be learnt from real-world studies on immune-related adverse events with checkpoint inhibitors: a clinical perspective from pharmacovigilance. Target Oncol. 2020;15:449–66.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Salem JE, Manouchehri A, Bretagne M, Lebrun-Vignes B, Groarke JD, Johnson DB, et al. Cardiovascular toxicities associated with ibrutinib. J Am Coll Cardiol. 2019;74:1667–78.

    Article  CAS  PubMed  Google Scholar 

  14. Huang J, Meng L, Yang B, Sun S, Luo Z, Chen H. Safety profile of epidermal growth factor receptor tyrosine kinase inhibitors: a disproportionality analysis of FDA adverse event reporting system. Sci Rep. 2020;10(1):4803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Powles T, Albiges L, Staehler M, Bensalah K, Dabestani S, Giles RH, et al. Updated European Association of Urology Guidelines: recommendations for the treatment of first-line metastatic clear cell renal cancer. Eur Urol. 2018;73:311–5.

    Article  PubMed  Google Scholar 

  16. Angulo JC, Shapiro O. The changing therapeutic landscape of metastatic renal cancer. Cancers. 2019;11:1–13.

    Article  Google Scholar 

  17. Raschi E, Poluzzi E, Salvo F, Pariente A, De Ponti F, Marchesini G, et al. Pharmacovigilance of sodium-glucose co-transporter-2 inhibitors: what a clinician should know on disproportionality analysis of spontaneous reporting systems. Nutr Metab Cardiovasc Dis. 2018;28:533–42.

    Article  CAS  PubMed  Google Scholar 

  18. Bate A, Evans SJW. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf. 2009;18:427–36.

    Article  CAS  PubMed  Google Scholar 

  19. Harpaz R, Dumouchel W, Lependu P, Bauer-Mehren A, Ryan P, Shah NH. Performance of pharmacovigilance signal-detection algorithms for the FDA adverse event reporting system. Clin Pharmacol Ther. 2013;93:539–46.

    Article  CAS  PubMed  Google Scholar 

  20. Norén GN, Hopstadius J, Bate A. Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery. Stat Methods Med Res. 2013;22:57–69.

    Article  PubMed  Google Scholar 

  21. Harpaz R, Odgers D, Gaskin G, Dumouchel W, Winnenburg R, Bodenreider O, et al. A time-indexed reference standard of adverse drug reactions. Sci Data. 2014;1:140043.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19:1579–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Herrmann J. Vascular toxic effects of cancer therapies. Nat Rev Cardiol. 2020;17(8):503–22.

    Article  CAS  PubMed  Google Scholar 

  24. Abdel-Qadir H, Ethier JL, Lee DS, Thavendiranathan P, Amir E. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: a systematic review and meta-analysis. Cancer Treat Rev. 2017;53:120–7.

    Article  CAS  PubMed  Google Scholar 

  25. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hatem R, Bebawi E, Schampaert E. Potential sunitinib-induced coronary artery and aortic dissections. Can J Cardiol. 2017;33:830.e17-830.e18.

    Article  Google Scholar 

  27. Edeline J, Laguerre B, Rolland Y, Patard JJ. Aortic dissection in a patient treated by sunitinib for metastatic renal cell carcinoma. Ann Oncol. 2009;21:186–7.

    Article  PubMed  Google Scholar 

  28. Niwa N, Nishiyama T, Ozu C, Yagi Y, Saito S. Acute aortic dissection in a patient with metastatic renal cell carcinoma treated with axitinib. Acta Oncol. 2015;54:567–8.

    Article  Google Scholar 

  29. Oshima Y, Tanimoto T, Yuji K, Tojo A. Association between aortic dissection and systemic exposure of vascular endothelial growth factor pathway inhibitors in the Japanese Adverse Drug Event Report database. Circulation. 2017;135:815–7.

    Article  PubMed  Google Scholar 

  30. Kust D, Kruljac I, Peternac AŠ, Ostojić J, Prpić M, Čaržavec D, et al. Pleural and pericardial effusions combined with ascites in a patient with severe sunitinib-induced hypothyroidism. Acta Clin Belg. 2016;71(3):175–7.

    Article  PubMed  Google Scholar 

  31. Krauth MT, Herndlhofer S, Schmook MT, Mitterbauer-Hohendanner G, Schlögl E, Valent P. Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily. Haematologica. 2011;96:163–6.

    Article  CAS  PubMed  Google Scholar 

  32. Kelly K, Swords R, Mahalingam D, Padmanabhan S, Giles FJ. Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors. Target Oncol. 2009;4:99–105.

    Article  PubMed  Google Scholar 

  33. Quintás-Cardama A, Kantarjian H, O’Brien S, Borthakur G, Bruzzi J, Munden R, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25:3908–14.

    Article  PubMed  Google Scholar 

  34. Fogli S, Porta C, Del Re M, Crucitta S, Gianfilippo G, Danesi R, et al. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs. Cancer Treat Rev. 2020;84:101966.

    Article  CAS  PubMed  Google Scholar 

  35. Aragon-Ching JB, Ning YM, Dahut WL. Acute aortic dissection in a hypertensive patient with prostate cancer undergoing chemotherapy containing bevacizumab. Acta Oncol. 2008;47:1600–1.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Hahn NM, Stadler WM, Zon RT, Waterhouse D, Picus J, Nattam S, et al. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier oncology group GU 04–75. J Clin Oncol. 2011;29:1525–30.

    Article  CAS  PubMed  Google Scholar 

  37. Pucci G, Milan A, Paini A, Salvetti M, Cerasari A, Vaudo G. Acute blood pressure elevation associated with biological therapies for cancer: a focus on VEGF signaling pathway inhibitors. Expert Opin Biol Ther. 2019;19:433–42.

    Article  CAS  PubMed  Google Scholar 

  38. Shamloo BK, Chhabra P, Freedman AN, Potosky A, Malin J, Smith SW. Novel adverse events of bevacizumab in the US FDA adverse event reporting system database: a disproportionality analysis. Drug Saf. 2012;35:507–18.

    Article  CAS  PubMed  Google Scholar 

  39. Bonnet C, Sibon I. Potential role of anti-VEGF targeted therapies in cervical artery dissection: a case report. Rev Neurol. 2015;171:677–9.

    Article  CAS  PubMed  Google Scholar 

  40. Molina AM, Feldman DR, Voss MH, Ginsberg MS, Baum MS, Brocks DR, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2012;118:1868–76.

    Article  CAS  PubMed  Google Scholar 

  41. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;7:621–51.

    Article  Google Scholar 

  42. Mahé J, de Campaigno EP, Chené A-L, Montastruc J-L, Despas F, Jolliet P. Pleural adverse drugs reactions and protein kinase inhibitors: identification of suspicious targets by disproportionality analysis from VigiBase. Br J Clin Pharmacol. 2018;84:2373–83.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Patras de Campaigno E, Bondon-Guitton E, Laurent G, Montastruc F, Montastruc J-L, Lapeyre-Mestre M, et al. Identification of cellular targets involved in cardiac failure caused by PKI in oncology: an approach combining pharmacovigilance and pharmacodynamics. Br J Clin Pharmacol. 2017;83:1544–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hazell L, Shakir SAW. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2006;29:385–96.

    Article  PubMed  Google Scholar 

  45. Bégaud B, Martin K, Haramburu F, Moore N. Rates of spontaneous reporting of adverse drug reactions in France. J Am Med Assoc. 2002;288:1588.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel

    Adam Goldman, Dana Fourey, Michael Arad & Elad Maor

  2. School of Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Adam Goldman, David Bomze, Dana Fourey, Ben Boursi, Michael Arad & Elad Maor

  3. Unit for Cardiovascular Epidemiology, The Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel

    Rachel Dankner

  4. Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Rachel Dankner

  5. Department of Oncology, Sheba Medical Center, Ramat Gan, Israel

    Ben Boursi

  6. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA

    Ben Boursi

Authors
  1. Adam Goldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Bomze
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rachel Dankner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dana Fourey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ben Boursi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Arad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elad Maor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elad Maor.

Ethics declarations

Funding

No external funding was used in the preparation of this article.

Conflict of interest

AG, DB, RD, DF, BB, MA, and EM declare that they have no conflicts of interest that might be relevant to the contents of this article.

Availability of data and material

The FAERS is a publicly available and anonymized database.

Author contributions

A.G. and D.B. conceived the idea. All authors contributed to the design of the study. A.G. and D.B. acquired the data for the study and performed the analyses. E.M. supervised the study. A.G. wrote the manuscript. All authors interpreted the results and made manuscript revisions. All authors have read and agreed to the published version of the manuscript.

Ethics approval

Since the FAERS is a publicly available and anonymized database, Institutional review board approval and informed consent were waived.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 776 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goldman, A., Bomze, D., Dankner, R. et al. Cardiovascular Toxicities of Antiangiogenic Tyrosine Kinase Inhibitors: A Retrospective, Pharmacovigilance Study. Targ Oncol 16, 471–483 (2021). https://doi.org/10.1007/s11523-021-00817-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-021-00817-2

Search

Navigation