Download PDF
Thromb Haemost 2016; 115(01): 7-24
DOI: 10.1160/TH15-04-0355
Review Article
Schattauer GmbH Schattauer

Assessment of bleeding risk in patients with coronary artery disease on dual antiplatelet therapy

A systematic review
Minka J. A. Vries
1   Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht (MUMC), the Netherlands
,
Paola E. J. van der Meijden
1   Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht (MUMC), the Netherlands
,
Yvonne M. C. Henskens
1   Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht (MUMC), the Netherlands
2   Central Diagnostic Laboratory, MUMC, the Netherlands
,
Arina J. ten Cate-Hoek
1   Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht (MUMC), the Netherlands
,
Hugo ten Cate
1   Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht (MUMC), the Netherlands
› Author Affiliations
Further Information

Publication History

Received: 29 April 2015

Accepted after major revision: 29 June 2015

Publication Date:
22 November 2017 (online)

Also available at
   Permissions and Reprints

Summary

Patients with coronary artery disease are usually treated with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention. Patients on DAPT are at risk of both ischaemic and bleeding events. Although side-lined for a long time, real-life studies have shown that both the incidence and the associated morbidity and mortality of outof-hospital bleeding are high. This indicates that prevention of (postinterventional) bleeding is as important as prevention of ischaemia. For this purpose it is crucial to reliably identify patients with a high bleeding risk. In order to postulate an algorithm, which could help identifying these patients, we performed a systematic review to determine the value of previously proposed prognostic modalities for bleeding. We searched and appraised the following tools: platelet function tests, genetic tests, bleeding scores and questionnaires and haemostatic tests. Most studies indicated that low on-treatment platelet reactivity (LTPR), as measured by several platelet function tests, and the carriage of CYP2C19*17 allele were independent risk factors for bleeding. A bleeding score also proved to be helpful in identifying patients at risk. No studies on haemostatic tests were retrieved. Several patient characteristics were also identified as independent predictors of bleeding, such as older age, female sex and renal failure. Combining these risk factors we propose an algorithm that would hypothetically facilitate identification of those patients at highest risk, warranting prevention measures for bleeding. This could be a starting point for further research concerning the topic.

Keywords

Dual antiplatelet therapy - coronary artery disease - bleeding - prognostic tests
 

  • References

  • 1 Sorensen R. et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009; 374: 1967-1974.
    CrossrefPubMedSearch in Google Scholar
  • 2 Abraham NS. et al. Risk of lower and upper gastrointestinal bleeding, transfusions, and hospitalisations with complex antithrombotic therapy in elderly patients. Circulation 2013; 128: 1869-1877.
    CrossrefPubMedSearch in Google Scholar
  • 3 Hamm CW. et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999-3054.
    CrossrefPubMedSearch in Google Scholar
  • 4 Levine GN. et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011; 124: e574-651.
    CrossrefPubMedSearch in Google Scholar
  • 5 Task Force on the management of STseamiotESoC. Steg PG, James SK. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-2619.
    CrossrefPubMedSearch in Google Scholar
  • 6 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
    CrossrefPubMedSearch in Google Scholar
  • 7 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
    CrossrefPubMedSearch in Google Scholar
  • 8 Mehran R. et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J 2009; 30: 1457-1466.
    CrossrefPubMedSearch in Google Scholar
  • 9 Lamberts M. et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126: 1185-1193.
    CrossrefPubMedSearch in Google Scholar
  • 10 Rao SV. et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005; 96: 1200-1206.
    CrossrefPubMedSearch in Google Scholar
  • 11 Mehran R. et al. Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterisation and urgent intervention triage strategy), and HORIZONS-AMI (harmonizing outcomes with revascularisation and stents in acute myocardial infarction) trials. JACC Cardiovasc Interv 2011; 04: 654-664.
    CrossrefPubMedSearch in Google Scholar
  • 12 Tantry US, Gurbel PA. Assessment of oral antithrombotic therapy by platelet function testing. Nature Rev Cardiol 2011; 08: 572-579.
    CrossrefPubMedSearch in Google Scholar
  • 13 Tantry US. et al. Consensus and Update on the Definition of On-Treatment Platelet Reactivity to ADP Associated with Ischaemia and Bleeding. J Am Coll Cardiol 2013; 62: 2261-2273.
    CrossrefPubMedSearch in Google Scholar
  • 14 Ait-Mokhtar O. et al. High on treatment platelet reactivity. Heart Lung Circ 2012; 21: 12-21.
    CrossrefPubMedSearch in Google Scholar
  • 15 Kubica A. et al. Genetic determinants of platelet response to clopidogrel. J Thromb Thrombol 2011; 32: 459-466.
    CrossrefPubMedSearch in Google Scholar
  • 16 Campo G. et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011; 57: 2474-2483.
    CrossrefPubMedSearch in Google Scholar
  • 17 Lip GY. et al. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace 2011; 13: 723-746.
    CrossrefPubMedSearch in Google Scholar
  • 18 Serebruany V. et al. Correlation of inhibition of platelet aggregation after clopidogrel with post discharge bleeding events: assessment by different bleeding classifications. Eur Heart J 2010; 31: 227-235.
    CrossrefPubMedSearch in Google Scholar
  • 19 Siller-Matula JM. et al. How to improve the concept of individualised antiplatelet therapy with P2Y12 receptor inhibitors--is an algorithm the answer?. Thromb Haemost 2015; 113: 37-52.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Kmet LM LR, Cook LS. Standard quality assessment Criteria for Evaluating primary Research Papers from a variety of fields. Alberta Heritage Foundation for Medical Research 2004.
    PubMed
  • 21 NHS Centres for Review and Dissemination.. Undertaking systematic reviewers of research of effectiveness: CRD’s guidance for those carrying out or commissioning reviews. University of York 2001; 2nd ed. York.
    PubMed
  • 22 Janssen PW, ten Berg JM. Platelet function testing and tailored antiplatelet therapy. J Cardiovasc Transl Res 2013; 06: 316-328.
    CrossrefPubMedSearch in Google Scholar
  • 23 Harrison P. Advances in the monitoring of anti-P2Y12 therapy. Platelets 2012; 23: 510-525.
    CrossrefPubMedSearch in Google Scholar
  • 24 Lordkipanidze M. Advances in monitoring of aspirin therapy. Platelets 2012; 23: 526-536.
    CrossrefPubMedSearch in Google Scholar
  • 25 Mehran R. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123: 2736-2747.
    CrossrefPubMedSearch in Google Scholar
  • 26 Liberati A. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Br Med J 2009; 339: b2700.
    CrossrefPubMedSearch in Google Scholar
  • 27 Soffer D. et al. Impact of angina class on inhibition of platelet aggregation following clopidogrel loading in patients undergoing coronary intervention: do we need more aggressive dosing regimens in unstable angina?. Catheter Cardiovasc Interv 2003; 59: 21-25.
    CrossrefPubMedSearch in Google Scholar
  • 28 Cuisset T. et al. Predictive value of post-treatment platelet reactivity for occur-rence of post-discharge bleeding after non-ST elevation acute coronary syndrome. Shifting from antiplatelet resistance to bleeding risk assessment? EuroIntervention 2009; 05: 325-329.
    PubMedSearch in Google Scholar
  • 29 Bonello L. et al. Relationship between post-treatment platelet reactivity and ischaemic and bleeding events at 1-year follow-up in patients receiving prasugrel. J Thromb Haemost 2012; 10: 1999-2005.
    CrossrefPubMedSearch in Google Scholar
  • 30 Stone GW. et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013; 382: 614-623.
    CrossrefPubMedSearch in Google Scholar
  • 31 Kirtane ASTXK. Is there a therapeutic window for platelet responsiveness among PCI patients? Analysis from the ADAPT-DES study. J Am Coll Cardiol 2013; 62: B48-49.
    PubMedSearch in Google Scholar
  • 32 Patti G. et al. Usefulness of platelet response to clopidogrel by point-of-care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study). Am J Cardiol 2011; 107: 995-1000.
    CrossrefPubMedSearch in Google Scholar
  • 33 Huczek Z. et al. Medium on-treatment platelet reactivity to ADP is favorable in patients with acute coronary syndromes undergoing coronary stenting. Platelets 2011; 22: 521-529.
    CrossrefPubMedSearch in Google Scholar
  • 34 Mangiacapra F. et al. A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMY-DA-PROVE (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity for Outcome Validation Effort) study. JACC Cardiovasc Interv 2012; 05: 281-289.
    CrossrefPubMedSearch in Google Scholar
  • 35 Huczek Z. et al. Increased risk of minor bleeding and antiplatelet therapy cessation in patients with acute coronary syndromes and low on-aspirin platelet reactivity. A prospective cohort study. J Thromb Thrombol 2013; 36: 22-30.
    CrossrefPubMedSearch in Google Scholar
  • 36 Tsukahara K. et al. Impact of high-responsiveness to dual antiplatelet therapy on bleeding complications in patients receiving drug-eluting stents. Circulation J 2010; 74: 679-685.
    CrossrefPubMedSearch in Google Scholar
  • 37 Zhang JH. et al. Relationship between ABCB1 polymorphisms, thromboelastography and risk of bleeding events in clopidogrel-treated patients with ST-elevation myocardial infarction. Thromb Res 2014; 134: 970-975.
    CrossrefPubMedSearch in Google Scholar
  • 38 Breet NJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. J Am Med Assoc 2010; 303: 754-762.
    CrossrefPubMedSearch in Google Scholar
  • 39 Breet NJ. et al. High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events. J Thromb Haemost 2010; 08: 2140-2148.
    CrossrefPubMedSearch in Google Scholar
  • 40 Harmsze AM. et al. The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting. Pharmacogen Genomics 2012; 22: 169-175.
    PubMedSearch in Google Scholar
  • 41 Siller-Matula JM. et al. Phenotyping vs genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. J Thromb Haemost 2012; 10: 529-542.
    CrossrefPubMedSearch in Google Scholar
  • 42 Cuisset T. et al. Platelet reactivity in diabetic patients undergoing coronary stenting for acute coronary syndrome treated with clopidogrel loading dose followed by prasugrel maintenance therapy. Intern J Cardiol 2013; 168: 523-528.
    CrossrefPubMedSearch in Google Scholar
  • 43 Cuisset T. et al. CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome. JACC Cardiovasc Interv 2012; 05: 1280-1287.
    CrossrefPubMedSearch in Google Scholar
  • 44 Grosdidier C. et al. Effect of CYP2C19*2 and *17 genetic variants on platelet response to clopidogrel and prasugrel maintenance dose and relation to bleeding complications. Am J Cardiol 2013; 111: 985-990.
    CrossrefPubMedSearch in Google Scholar
  • 45 Cayla G. et al. Prasugrel monitoring and bleeding in real world patients. Am J Cardiol 2013; 111: 38-44.
    CrossrefPubMedSearch in Google Scholar
  • 46 Cuisset T. et al. Clinical implications of very low on-treatment platelet reactivity in patients treated with thienopyridine: the POBA study (predictor of bleedings with antiplatelet drugs). JACC Cardiovasc Interv 2013; 06: 854-863.
    CrossrefPubMedSearch in Google Scholar
  • 47 Deharo P. et al. Impact of new P2Y12 blockers on platelet reactivity and clinical outcomes after acute coronary syndrome: Insight from a large single center registry. IJC Heart Vessels 2014; 04: 188-192.
    PubMedSearch in Google Scholar
  • 48 Parodi G. et al. Residual platelet reactivity, bleedings, and adherence to treatment in patients having coronary stent implantation treated with prasugrel. Am J Cardiol 2012; 109: 214-218.
    CrossrefPubMedSearch in Google Scholar
  • 49 Gaglia Jr. MA. et al. Nuisance and alarming bleeding do not correlate with on-treatment platelet reactivity. Cardiovasc Revasc Med Mol Interv 2013; 14: 76-80.
    PubMedSearch in Google Scholar
  • 50 Cuisset T. et al. Comparison between initial and chronic response to clopidogrel therapy after coronary stenting for acute coronary syndrome and influence on clinical outcomes. Am Heart J 2012; 164: 327-333.
    CrossrefPubMedSearch in Google Scholar
  • 51 Husted S. et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
    CrossrefPubMedSearch in Google Scholar
  • 52 Pare G. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-1714.
    CrossrefPubMedSearch in Google Scholar
  • 53 Park MW. et al. Impact of the CYP2C19*17 polymorphism on the clinical outcome of clopidogrel therapy in Asian patients undergoing percutaneous coronary intervention. Pharmacogen Genom 2013; 23: 558-562.
    PubMedSearch in Google Scholar
  • 54 Sibbing D. et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121: 512-518.
    CrossrefPubMedSearch in Google Scholar
  • 55 Dai ZL. et al. Relationship between cytochrome P450 2C19*17 genotype distribution, platelet aggregation and bleeding risk in patients with blood stasis syndrome of coronary artery disease treated with clopidogrel. J Chin Integr Med 2012; 10: 647-654.
    CrossrefPubMedSearch in Google Scholar
  • 56 Wallentin L. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-1328.
    CrossrefPubMedSearch in Google Scholar
  • 57 Tang XF. et al. Effect of the CYP2C19 2 and 3 genotypes, ABCB1 C3435T and PON1 Q192R alleles on the pharmacodynamics and adverse clinical events of clopidogrel in Chinese people after percutaneous coronary intervention. Eur J Clin Pharmacol 2013; 69: 1103-1112.
    CrossrefPubMedSearch in Google Scholar
  • 58 Reny JL. et al. Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 2012; 10: 1242-1251.
    CrossrefPubMedSearch in Google Scholar
  • 59 Bouman HJ. et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature Med 2011; 17: 110-116.
    CrossrefPubMedSearch in Google Scholar
  • 60 Kang YH. et al. Association of PON1 genotype and haplotype with susceptibility to coronary artery disease and clinical outcomes in dual antiplatelet-treated Han Chinese patients. Eur J Clin Pharmacol 2013; 69: 1511-1519.
    CrossrefPubMedSearch in Google Scholar
  • 61 Mrdovic I. et al. Simple risk algorithm to predict serious bleeding in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: RISK-PCI bleeding score. Circulation J 2013; 77: 1719-1727.
    CrossrefPubMedSearch in Google Scholar
  • 62 Aradi D. et al. Platelet function testing in acute cardiac care – is there a role for prediction or prevention of stent thrombosis and bleeding?. Thromb Haemost 2015; 113: 221-230.
    Thieme ConnectPubMedSearch in Google Scholar
  • 63 Breet NJ. et al. Is platelet inhibition due to thienopyridines increased in elderly patients, in patients with previous stroke and patients with low body weight as a possible explanation of an increased bleeding risk?. Netherl Heart J 2011; 19: 279-284.
    PubMedSearch in Google Scholar
  • 64 Rodeghiero F. et al. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 08: 2063-2065.
    CrossrefPubMedSearch in Google Scholar