Download PDF
Thromb Haemost 2015; 114(06): 1104-1112
DOI: 10.1160/TH15-01-0077
Current controversies
Schattauer GmbH

Solid cancers after antiplatelet therapy: Confirmations, controversies, and challenges

Victor L. Serebruany
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Towson, Maryland, US
,
Vasily Cherepanov
1   HeartDrug™ Research Laboratories, Johns Hopkins University, Towson, Maryland, US
,
Hector A. Cabrera-Fuentes
2   Institute of Biochemistry, Justus-Liebig University, Giessen, Germany
3   Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, Singapore
4   National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
5   Department of Microbiology, Kazan Federal University, Kazan, Russian Federation
,
Moo Hyun Kim
6   Department of Cardiology, Dong-A University Hospital, Busan, Korea
› Author Affiliations
Further Information

Publication History

Received: 27 January 2015

Accepted after major revision: 12 May 2015

Publication Date:
30 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

The role of anticoagulants and antiplatelet agents in tumour growth and prognosis is not new, and currently under intense investigation. Some randomised data strongly suggest that this association exists, but it is complex, and not necessarily pointed at the same direction. The potential mechanisms responsible for such harmful association include a direct hazard of novel antithrombotics on cancer, indirect promotion of tumour growth, easier metastatic dissemination due to instability of platelet-tumour cell aggregates, or/and inability to keep cancer cells locally in situ are considered. The latest randomised evidence ultimately rejected the drug-specific cancer risks, clearly indicating the class-effect. In lay terms “cancers follow bleeding”, which seems to be true for antithrombotic agents in general. Significant excess of solid cancers which was similar after prasugrel in TRITON, and with vorapaxar in TRACER trials was confirmed by the FDA reviews. Later, extra cancer deaths reported following clopidogrel and prasugrel in DAPT, and after ticagrelor in PEGASUS are also of concern. However, there are remaining controversies with regard to published cancer risks after ticagrelor (PLATO), or another vorapaxar trial (TRA2P), while full disclosure of separate clopidogrel and prasugrel cancer data in DAPT is still lacking. In short, if we apply moderate antiplatelet strategies for over two years, or aggressive regimens including triple therapy for much less than one year, the solid cancer risks emerge. Currently, more delicate platelet inhibition, and shorter exposure to dual oral antiplatelet agents should prevail.

Keywords

Prasugrel - clopidogrel - aspirin - ticagrelor - vorapaxar - cancer - clinical trials - duration of antiplatelet therapy - triple antiplatelet therapy
 

  • References

  • 1 Coupland LA, Parish CR. Platelets, selectins, and the control of tumour meta-stasis. Semin Oncol 2014; 41: 422-434.
    CrossrefPubMedGoogle Scholar
  • 2 Wiviott SD, Braunwald E, McCabe CH. et al. the TRITON-TIMI 38 Investigators.ugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2007; 357: 2001-2015.
    CrossrefPubMedGoogle Scholar
  • 3 Food and Drug Administration. Briefing document, February 3, 2009 meeting of FDA Cardiovascular and Renal Drugs Advisory Committee on Prasugrel. Available for download at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm181185.pdf Asseessed January 16, 2015.
    PubMedGoogle Scholar
  • 4 Roe MT, Armstrong PW, Fox KA. et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012; 367: 1297-1309.
    CrossrefPubMedGoogle Scholar
  • 5 The FDA ticagrelor review of complete response. Available for download at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000MedR.pdf Accessed January 16, 2015.
    PubMedGoogle Scholar
  • 6 NDA 202–439 Rivaroxaban for acute coronary syndromes May 23, 2012 meeting of FDA Cardiovascular and Renal Drugs Advisory Committee. Available for download at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm305921.pdf Accessed January 16, 2015.
    PubMedGoogle Scholar
  • 7 NDA 294–886. Cross-discipline Team Leader review on Vorapaxar. April 18th, 2014 Available for download at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000SumR.pdf Accessed January 17th, 2015.
    PubMedGoogle Scholar
  • 8 Mauri L, Kereiakes DJ, Yeh RW. et al. DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155-2166.
    CrossrefPubMedGoogle Scholar
  • 9 Murasaki G, Zenser TV, Davis BB. et al. Inhibition by aspirin of N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced bladder carcinogenesis and enhancement of forestomach carcinogenesis. Carcinogenesis 1984; 05: 53-55.
    CrossrefPubMedGoogle Scholar
  • 10 Hasegawa R, St John M, Murasaki G. et al. Effect of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced epithelial proliferation in the urinary bladder and forestomach of the rat. Cancer Lett 1984; 21: 269-275.
    CrossrefPubMedGoogle Scholar
  • 11 Logan RF, Grainge MJ, Shepherd VC. et al. ukCAP Trial Group. aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008; 134: 29-38.
    CrossrefPubMedGoogle Scholar
  • 12 Sadeghi S, Bain CJ, Pandeya N. et al. Australian Cancer Study. Aspirin, nonsteroidal anti-inflammatory drugs, and the risks of cancers of the esophagus. Cancer Epidemiol Biomarkers Prev 2008; 17: 1169-1178.
    PubMedGoogle Scholar
  • 13 Kelly JP, Coogan P, Strom BL. et al. Lung cancer and regular use of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs. Pharmacoepidemiol Drug Saf 2008; 17: 322-327.
    CrossrefPubMedGoogle Scholar
  • 14 Zhang SM, Cook NR, Manson JE. et al. Low-dose aspirin and breast cancer risk: results by tumour characteristics from a randomised trial. Br J Cancer 2008; 98: 989-991.
    CrossrefPubMedGoogle Scholar
  • 15 Chan AT, Giovannucci EL, Meyerhardt JA. et al. aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology 2008; 134: 21-28.
    CrossrefPubMedGoogle Scholar
  • 16 Jacobs CD, Chun SG, Yan J. et al. aspirin improves outcome in high risk prostate cancer patients treated with radiation therapy. Cancer Biol Ther 2014; 15: 699-706.
    CrossrefPubMedGoogle Scholar
  • 17 Choe KS, Cowan JE, Chan JM. et al. aspirin use and the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy. J Clin Oncol 2012; 30: 3540-3544.
    CrossrefPubMedGoogle Scholar
  • 18 Rothwell PM, Wilson M, Price JF. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379: 1591-1601.
    CrossrefPubMedGoogle Scholar
  • 19 Rothwell PM, Fowkes FG, Belch JF. et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377: 31-41.
    CrossrefPubMedGoogle Scholar
  • 20 Cook NR, Lee IM, Zhang SM. et al. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013; 159: 77-85.
    CrossrefPubMedGoogle Scholar
  • 21 Langley RE, Rothwell PM. aspirin in gastrointestinal oncology: new data on an old friend. Curr Opin Oncol 2014; 26: 441-447.
    CrossrefPubMedGoogle Scholar
  • 22 Harris RM, Hawker RJ, Langman MJ. et al. Inhibition of phenolsulphotransferase by salicylic acid: a possible mechanism by which aspirin may reduce carcinogenesis. Gut 1998; 42: 272-275.
    CrossrefPubMedGoogle Scholar
  • 23 Eklou-Kalonji E, Andriamihaja M, Reinaud P. et al. staglandin-independent effects of aspirin on cell cycle and putrescine synthesis in human colon carcinoma cells. Can J Physiol Pharmacol 2003; 81: 443-450.
    CrossrefPubMedGoogle Scholar
  • 24 Gardiner PS, Gilmer JF. he medicinal chemistry implications of the anticancer effects of aspirin and other NSAIDs. Mini Rev Med Chem 2003; 03: 461-470.
    CrossrefPubMedGoogle Scholar
  • 25 Zimmermann KC, Waterhouse NJ, Goldstein JC. et al. irin induces apoptosis through release of cytochrome c from mitochondria. Neoplasia 2000; 02: 505-513.
    CrossrefPubMedGoogle Scholar
  • 26 Ding JH, Yuan LY, Huang RB. et al. aspirin inhibits proliferation and induces apoptosis of multiple myeloma cells through regulation of Bcl-2 and Bax and suppression of VEGF. Eur J Haematol 2014; 93: 329-339.
    CrossrefPubMedGoogle Scholar
  • 27 Mezouar S, Darbousset R, Dignat-George F. et al. Inhibition of platelet activation prevents the P-selectin and integrin-dependent accumulation of cancer cell microparticles and reduces tumour growth and metastasis in vivo. Int J Cancer 2015; 136: 462-475.
    CrossrefPubMedGoogle Scholar
  • 28 Sitia G, Aiolfi R, Di Lucia P. et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A 2012; 109: E2165-2172.
    CrossrefPubMedGoogle Scholar
  • 29 Roop RP, Naughton MJ, Van Poznak C. et al. A randomized phase II trial investigating the effect of platelet function inhibition on circulating tumour cells in patients with metastatic breast cancer. Clin Breast Cancer 2013; 13: 409-415.
    CrossrefPubMedGoogle Scholar
  • 30 Pandey A, Sarangi S, Chien K. et al. Anti-platelet agents augment cisplatin nanoparticle cytotoxicity by enhancing tumour vasculature permeability and drug delivery. Nanotechnology 2014; 25: 445101.
    CrossrefPubMedGoogle Scholar
  • 31 Clopidogrel Prescribing Information. Available for download at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020839s042lbl.pdf Accessed January 17, 2015.
    PubMedGoogle Scholar
  • 32 CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events. Lancet 1996; 348: 1329-1339.
    CrossrefPubMedGoogle Scholar
  • 33 Bhatt DL, Fox KA, Hacke W. et al. Clopidogrel and aspirin versus aspirin Alone for the Prevention of Atherothrombotic Events. N Engl J Med 2006; 354: 1706-1717.
    CrossrefPubMedGoogle Scholar
  • 34 CURE Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Eng J Med 2001; 345: 494-502.
    CrossrefPubMedGoogle Scholar
  • 35 Steinhubl SR, Berger PB, Mann 3rd JT. et al. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
    PubMedGoogle Scholar
  • 36 FDA Drug Safety Communication. FDA reviews long-term antiplatelet therapy as preliminary trial data shows benefits but a higher risk of non-cardiovascular death. Available for download at: http://www.fda.gov/drugs/drugsafety/ucm423079.htm Accessed Jamuary 16, 2015.
    PubMedGoogle Scholar
  • 37 Wallentin L, Becker RC, Budaj A. et al. the PLATO Investigators. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 61: 1045-1057.
    PubMedGoogle Scholar
  • 38 Bonaca MP, Bhatt DL, Cohen M. et al. PEGASUS-TIMI 54 Steering Committee and Investigators. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med. 2015 Epub ahead of print.
    PubMedGoogle Scholar
  • 39 Tricoci P, Huang Z, Held C. et al. the TRACER Investigators. Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes. N Engl J Med 2012; 366: 20-33.
    CrossrefPubMedGoogle Scholar
  • 40 Morrow DA, Braunwald E, Bonaca MP. et al. TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404-1413.
    CrossrefPubMedGoogle Scholar
  • 41 Serebruany VL. Platelet inhibition with prasugrel and increased cancer risks: potential causes and implications. m J Med 2009; 122: 407-408.
    PubMedGoogle Scholar
  • 42 Floyd JS, Serebruany VL. Prasugrel as a potential cancer promoter: review of the unpublished data. rch Intern Med 2010; 170: 1078-1080.
    PubMedGoogle Scholar
  • 43 Apixaban clinical review, The Food and Drug Administration. Available for download at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000MedR.pdf Accessed January 17, 2015.
    PubMed
  • 44 Serebruany VL, Dinicolantonio JJ, Can MM. et al. Unclassified pleomorphic and spindle cell pulmonary neoplasm with brain metastases after prasugrel. Cardiology 2013; 124: 85-90.
    CrossrefPubMedGoogle Scholar
  • 45 Whitley HP, Lindsey W. Sex-based differences in drug activity. Am Fam Physician 2009; 80: 1254-1258.
    PubMedGoogle Scholar