Chemotherapeutic Agents and the Risk of Ischemia and Arterial Thrombosis

  • Saamir A. HassanEmail author
  • Nicolas Palaskas
  • Peter Kim
  • Cezar Iliescu
  • Juan Lopez-Mattei
  • Elie Mouhayar
  • Rohit Mougdil
  • Kara Thompson
  • Jose Banchs
  • Syed Wamique Yusuf
Coronary Heart Disease (S. Virani and S. Naderi, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Coronary Heart Disease


Purpose of Review

Numerous chemotherapeutic agents have been associated with the development of ischemia and arterial thrombosis. As newer therapies have been developed to treat cancer, some of these chemotherapy drugs have been implicated in the development of vascular disease. In this review, we will summarize the most common chemotherapeutic drug classes that may play a role in the development of ischemic heart disease.

Recent Findings

Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors have a number of cardiovascular toxicities. The possible mechanisms of action of these drugs leading to ischemic complications are varied but include endothelial dysfunction, platelet aggregation, reduced levels of nitrous oxide (NO), and elevated levels of reactive oxygen species (ROS), and vasospasm. While some drugs act through multiple pathways that result in the development of ischemic heart disease, others such as the antimetabolites and antimicrotubules appear to primarily cause vasospasm. Furthermore, while aromatase inhibitors increase the risk of heart disease in comparison to tamoxifen in large studies, this finding likely occurs because of a protective role of tamoxifen on cardiovascular risk factors rather than a direct effect of aromatase inhibitors.


Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors can lead to ischemic complications in patients with cancer. Many of these drugs have proven to be effective in improving cancer prognosis, but their possible cardiovascular effects have to be carefully monitored and treated. Treatment of ischemic complications in the setting of cancer therapy should focus on the optimal medical management of known cardiovascular risk factors and follow an evidence-based approach.


Chemotherapeutic agents Cancer Ischemia Arterial thrombosis 


Compliance with Ethical Standards

Conflict of Interest

Dr. Kim reports personal fees from Boehringer Ingelheim, outside the submitted work. The other authors declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Fuster V, Voute J. MDGs: chronic diseases are not on the agenda. Lancet. 2005;366(9496):1512–4. Scholar
  2. 2.
    American Cancer Society. Cancer Facts & Figures 2015 Atlanta: American Cancer Society; 2015.Google Scholar
  3. 3.
    Cancer: Fact Sheet (Internet). World Health Organization 2017. Available from:
  4. 4.
    Yusuf SW, Razeghi P, Yeh ET. The diagnosis and management of cardiovascular disease in cancer patients. Curr Probl Cardiol. 2008;33(4):163–96. Scholar
  5. 5.
    Basavaraju SR, Jones TD. Atherosclerotic risks from chemicals: part I. Toxicological observations and mechanisms of atherosclerosis. Arch Environ Contam Toxicol. 1998;35(1):152–64. Scholar
  6. 6.
    Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS. Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad Sci. 2001;947:271–92. discussion 92-3CrossRefPubMedGoogle Scholar
  7. 7.
    Lestuzzi C, Viel E, Picano E, Meneguzzo N. Coronary vasospasm as a cause of effort-related myocardial ischemia during low-dose chronic continuous infusion of 5-fluorouracil. Am J Med. 2001;111(4):316–8. Scholar
  8. 8.
    Bathina JD, Yusuf SW. 5-Fluorouracil-induced coronary vasospasm. J Cardiovasc Med. 2010;11(4):281–4. Scholar
  9. 9.
    Schwarzer S, Eber B, Greinix H, Lind P. Non-Q-wave myocardial infarction associated with bleomycin and etoposide chemotherapy. Eur Heart J. 1991;12(6):748–50.PubMedGoogle Scholar
  10. 10.
    Stefenelli T, Kuzmits R, Ulrich W, Glogar D. Acute vascular toxicity after combination chemotherapy with cisplatin, vinblastine, and bleomycin for testicular cancer. Eur Heart J. 1988;9(5):552–6. Scholar
  11. 11.
    Stefenelli T, Zielinski CC, Mayr H, Scoheithauer W. Prinzmetal’s angina during cyclophosphamide therapy. Eur Heart J. 1988;9(10):1155–7. Scholar
  12. 12.
    Cheriparambil KM, Vasireddy H, Kuruvilla A, Gambarin B, Makan M, Saul BI. Acute reversible cardiomyopathy and thromboembolism after cisplatin and 5-fluorouracil chemotherapy—a case report. Angiology. 2000;51(10):873–8. Scholar
  13. 13.
    Frickhofen N, Beck FJ, Jung B, Fuhr HG, Andrasch H, Sigmund M. Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol: Off J Eur Soc Med Oncol. 2002;13(5):797–801.CrossRefGoogle Scholar
  14. 14.
    Rodeghiero F, Elice F. Thalidomide and thrombosis. Pathophysiol Haemost Thromb. 2003;33(Suppl 1):15–8. Scholar
  15. 15.
    Palumbo A, Palladino C. Venous and arterial thrombotic risks with thalidomide: evidence and practical guidance. Ther Adv Drug Saf. 2012;3(5):255–66. Scholar
  16. 16.
    Robinson ES, Khankin EV, Karumanchi SA, Humphreys BD. Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker. Semin Nephrol. 2010;30(6):591–601. Scholar
  17. 17.
    • 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 Treatment Rev. 2017;53:120–7. A very good review of cardiovascular toxicity associated with angiogensis inhbitors. CrossRefGoogle Scholar
  18. 18.
    • Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28(13):2280–5. A meta-analysis of arterial thrombosis due to tyrosine kinase-based cancer therapies. CrossRefGoogle Scholar
  19. 19.
    Qi WX, Shen Z, Tang LN, Yao Y. Risk of arterial thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: an up-to-date meta-analysis. Crit Rev Oncol Hematol. 2014;92(2):71–82. Scholar
  20. 20.
    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: Off J Am Soc Clin Oncol. 2012;30(8):871–7. Scholar
  21. 21.
    Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 2009;10(10):967–74. Scholar
  22. 22.
    Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer. 2012;12(2):104–20. Scholar
  23. 23.
    Gottdiener JS, Appelbaum FR, Ferrans VJ, Deisseroth A, Ziegler J. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med. 1981;141(6):758–63. Scholar
  24. 24.
    Soultati A, Mountzios G, Avgerinou C, Papaxoinis G, Pectasides D, Dimopoulos MA, et al. Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications. Cancer Treat Rev. 2012;38(5):473–83. Scholar
  25. 25.
    Appelbaum F, Strauchen JA, Graw RG Jr, Savage DD, Kent KM, Ferrans VJ, et al. Acute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity. Lancet. 1976;1(7950):58–62.CrossRefPubMedGoogle Scholar
  26. 26.
    Nuver J, Smit AJ, Sleijfer DT, van Gessel AI, van Roon AM, van der Meer J, et al. Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. Eur J Cancer. 2004;40(5):701–6. Scholar
  27. 27.
    Weijl NI, Rutten MF, Zwinderman AH, Keizer HJ, Nooy MA, Rosendaal FR, et al. Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature. J Clin Oncol: Off J Am Soc Clin Oncol. 2000;18(10):2169–78. Scholar
  28. 28.
    Meinardi MT, Gietema JA, van Veldhuisen DJ, van der Graaf WT, de Vries EG, Sleijfer DT. Long-term chemotherapy-related cardiovascular morbidity. Cancer Treat Rev. 2000;26(6):429–47. Scholar
  29. 29.
    Luke DR, Vadiei K, Lopez-Berestein G. Role of vascular congestion in cisplatin-induced acute renal failure in the rat. Nephrol Dialysis Trans : Off Publ Eur Dialysis Trans Assoc—Eur Renal Assoc. 1992;7(1):1–7.Google Scholar
  30. 30.
    Meinardi MT, Gietema JA, van der Graaf WT, van Veldhuisen DJ, Runne MA, Sluiter WJ, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2000;18(8):1725–32. Scholar
  31. 31.
    Fung C, Fossa SD, Milano MT, Sahasrabudhe DM, Peterson DR, Travis LB. Cardiovascular disease mortality after chemotherapy or surgery for testicular nonseminoma: a population-based study. J Clin Oncol: Off J Am Soc Clin Oncol. 2015;33(28):3105–15. Scholar
  32. 32.
    Quezado ZM, Wilson WH, Cunnion RE, Parker MM, Reda D, Bryant G, et al. High-dose ifosfamide is associated with severe, reversible cardiac dysfunction. Ann Intern Med. 1993;118(1):31–6. Scholar
  33. 33.
    Bleeker JS, Gertz MA, Pellikka PA, Larson DR, Buadi F, Dingli D, et al. Evaluation of pretransplant factors predicting cardiac dysfunction following high-dose melphalan conditioning and autologous peripheral blood stem cell transplantation. Eur J Haematol. 2012;89(3):228–35. Scholar
  34. 34.
    Gil L, Kazmierczak M, Kroll-Balcerzak R, Komarnicki M. Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma. Med Oncol. 2014;31(5):944. Scholar
  35. 35.
    Herrmann J, Yang EH, Iliescu CA, Cilingiroglu M, Charitakis K, Hakeem A, et al. Vascular toxicities of cancer therapies: the old and the new—an evolving avenue. Circulation. 2016;133(13):1272–89. Scholar
  36. 36.
    Saif MW, Shah MM, Shah AR. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf. 2009;8(2):191–202. Scholar
  37. 37.
    Wacker A, Lersch C, Scherpinski U, Reindl L, Seyfarth M. High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients. Oncology. 2003;65(2):108–12. Scholar
  38. 38.
    Sudhoff T, Enderle MD, Pahlke M, Petz C, Teschendorf C, Graeven U, et al. 5-Fluorouracil induces arterial vasocontractions. Ann Oncol: Off J Eur Soc Med Oncol. 2004;15(4):661–4.CrossRefGoogle Scholar
  39. 39.
    Tsavaris N, Kosmas C, Vadiaka M, Efremidis M, Zinelis A, Beldecos D, et al. Cardiotoxicity following different doses and schedules of 5-fluorouracil administration for malignancy—a survey of 427 patients. Med Sci Monit. 2002;8(6):Pi51–7.PubMedGoogle Scholar
  40. 40.
    de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol: Off J Am Soc Clin Oncol. 1992;10(11):1795–801. Scholar
  41. 41.
    JI L, Carhart RL, Graziano SL, Gajra A. Acute coronary syndrome secondary to fluorouracil infusion. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24(18):2959–60.CrossRefGoogle Scholar
  42. 42.
    Cardinale D, Colombo A, Colombo N. Acute coronary syndrome induced by oral capecitabine. Can J Cardiol. 2006;22(3):251–3. Scholar
  43. 43.
    Labianca R, Beretta G, Clerici M, Fraschini P, Luporini G. Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori. 1982;68(6):505–10.PubMedGoogle Scholar
  44. 44.
    Henry D, Rudzik F, Butts A, Mathew A. Capecitabine-induced coronary vasospasm. Case Rep Oncol. 2016;9(3):629–32. Scholar
  45. 45.
    Ozturk B, Tacoy G, Coskun U, Yaman E, Sahin G, Buyukberber S, et al. Gemcitabine-induced acute coronary syndrome: a case report. Med Princ Pract. 2009;18(1):76–80. Scholar
  46. 46.
    Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4(4):253–65. Scholar
  47. 47.
    Ganguly A, Yang H, Cabral F. Paclitaxel-dependent cell lines reveal a novel drug activity. Mol Cancer Ther. 2010;9(11):2914–23. Scholar
  48. 48.
    McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989;111(4):273–9. Scholar
  49. 49.
    Arbuck SG, Strauss H, Rowinsky E, Christian M, Suffness M, Adams J, et al. A reassessment of cardiac toxicity associated with Taxol. J Natl Cancer Inst Monogr. 1993;15:117–30.Google Scholar
  50. 50.
    Schrader C, Keussen C, Bewig B, von Freier A, Lins M. Symptoms and signs of an acute myocardial ischemia caused by chemotherapy with paclitaxel (Taxol) in a patient with metastatic ovarian carcinoma. Eur J Med Res. 2005;10(11):498–501.PubMedGoogle Scholar
  51. 51.
    Gemici G, Cincin A, Degertekin M, Oktay A. Paclitaxel-induced ST-segment elevations. Clin Cardiol. 2009;32(6):E94–6. Scholar
  52. 52.
    Howarth FC, Calaghan SC, Boyett MR, White E. Effect of the microtubule polymerizing agent taxol on contraction, Ca2+ transient and L-type Ca2+ current in rat ventricular myocytes. J Physiol. 1999;516(Pt 2):409–19. Scholar
  53. 53.
    Redana S, Sharp A, Lote H, Mohammed K, Papadimitraki E, Capelan M, et al. Rates of major complications during neoadjuvant and adjuvant chemotherapy for early breast cancer: an off study population. Breast. 2016;30:13–8. Scholar
  54. 54.
    Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, et al. A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma. Br J Haematol. 2017;178(4):547–60. Scholar
  55. 55.
    Takamatsu H, Yamashita T, Kotani T, Sawazaki A, Okumura H, Nakao S. Ischemic heart disease associated with bortezomib treatment combined with dexamethasone in a patient with multiple myeloma. Int J Hematol. 2010;91(5):903–6. Scholar
  56. 56.
    Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2014;372(2):142–52. Scholar
  57. 57.
    Chen-Scarabelli C, Corsetti G, Pasini E, Dioguardi FS, Sahni G, Narula J, et al. Spasmogenic effects of the proteasome inhibitor carfilzomib on coronary resistance, vascular tone and reactivity. EBioMedicine. 2017;21:206–12. Scholar
  58. 58.
    Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, et al. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China continuation study. J Hematol Oncol. 2017;10(1):137. Scholar
  59. 59.
    Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621–34. Scholar
  60. 60.
    American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer Society; 2017.Google Scholar
  61. 61.
    Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol. 2016;34(14):1689–701. Scholar
  62. 62.
    Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol. 2003;86(3–5):225–30. Scholar
  63. 63.
    Mendelsohn ME. Protective effects of estrogen on the cardiovascular system. Am J Cardiol. 2002;89(12a):12E–7E. discussion 7E-8ECrossRefPubMedGoogle Scholar
  64. 64.
    Haas MJ, Raheja P, Jaimungal S, Sheikh-Ali M, Mooradian AD. Estrogen-dependent inhibition of dextrose-induced endoplasmic reticulum stress and superoxide generation in endothelial cells. Free Radic Biol Med. 2012;52(11–12):2161–7. Scholar
  65. 65.
    Haque R, Shi J, Schottinger JE, Chung J, Avila C, Amundsen B, et al. Cardiovascular disease after aromatase inhibitor use. JAMA Oncol. 2016;2(12):1590–7. Scholar
  66. 66.
    Khosrow-Khavar F, Filion KB, Al-Qurashi S, Torabi N, Bouganim N, Suissa S, et al. Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol: Off J Eur Soc Med Oncol. 2017;28(3):487–96.Google Scholar
  67. 67.
    Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Col Cardiol. 2012;60(24):e44–e164.CrossRefGoogle Scholar
  68. 68.
    Yusuf SW, Daraban N, Abbasi N, Lei X, Durand JB, Daher IN. Treatment and outcomes of acute coronary syndrome in the cancer population. Clin Cardiol. 2012;35(7):443–50. Scholar
  69. 69.
    Pereg D, Lishner M. Bevacizumab treatment for cancer patients with cardiovascular disease: a double edged sword? Eur Heart J. 2008;29(19):2325–6. Scholar
  70. 70.
    Velders MA, Boden H, Hofma SH, Osanto S, van der Hoeven BL, Heestermans AA, et al. Outcome after ST elevation myocardial infarction in patients with cancer treated with primary percutaneous coronary intervention. Am J Cardiol. 2013;112(12):1867–72. Scholar
  71. 71.
    Sarkiss MG, Yusuf SW, Warneke CL, Botz G, Lakkis N, Hirch-Ginsburg C, et al. Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer. 2007;109(3):621–7. Scholar
  72. 72.
    Yusuf SW, Iliescu C, Bathina JD, Daher IN, Durand JB. Antiplatelet therapy and percutaneous coronary intervention in patients with acute coronary syndrome and thrombocytopenia. Tex Heart Inst J. 2010;37(3):336–40.PubMedPubMedCentralGoogle Scholar
  73. 73.
    • Iliescu C, Grines CL, Herrmann J, Yang EH, Cilingiroglu M, Charitakis K, et al. SCAI expert consensus statement: evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (Endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencionista). Catheterization Cardiovas Interv: Off J Soc Cardiac Angiogr Interv. 2016;87(5):895–9. Expert consesus statement of how to manage and treat cancer patients who need invasive cardiac procedures. CrossRefGoogle Scholar
  74. 74.
    Chandra S, Lenihan DJ, Wei W, Yusuf SW, Tong AT. Myocardial perfusion imaging and cardiovascular outcomes in a cancer population. Tex Heart Inst J. 2009;36(3):205–13.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Saamir A. Hassan
    • 1
    Email author
  • Nicolas Palaskas
    • 1
  • Peter Kim
    • 1
  • Cezar Iliescu
    • 1
  • Juan Lopez-Mattei
    • 1
  • Elie Mouhayar
    • 1
  • Rohit Mougdil
    • 1
  • Kara Thompson
    • 1
  • Jose Banchs
    • 1
  • Syed Wamique Yusuf
    • 1
  1. 1.Department of Cardiology, Division of MedicineMD Anderson Cancer CenterHoustonUSA

Personalised recommendations