Abstract
Oral Antiplatelet Drugs (OAD) have a proven track record in the risk reduction of major cardiovascular events in patients with cardiovascular disease and normal kidney function. However, major gaps exist in our understanding of their effects on thrombosis and bleeding in chronic kidney disease (CKD). Clinical practice guidelines are ambiguous about use of such drugs in CKD patients, because patients with moderate to severe CKD were systematically excluded from clinical trials evaluating the efficacy and safety of OAD. Paradoxically, CKD patients are at high risk of thrombosis and major bleeding events. Thus, choosing the right combination of OAD for cardiovascular protection in these patients is challenging. Patients with CKD exhibit high rates of OAD hyporesponsiveness. It is, therefore, imperative to explore the mechanisms responsible for poor response to OAD in CKD patients in order to use these drugs more safely and effectively. This review explores suggested mechanisms of platelet dysfucntion in CKD patients and the available evidence on the efficacy and safety of oral antiplatelet drugs in patients with renal dysfunction.
Similar content being viewed by others
References
Hoerger TJ et al (2015) The future burden of CKD in the United States: a simulation model for the CDC CKD initiative. Am J Kidney Dis 65(3):403–411
Coresh J et al (2007) Prevalence of chronic kidney disease in the United States. JAMA 298(17):2038–2047
Tsai TT et al (2011) Safety and efficacy of drug-eluting stents in older patients with chronic kidney disease: a report from the linked CathPCI Registry-CMS claims database. J Am Coll Cardiol 58(18):1859–1869
Go AS et al (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351(13):1296–1305
Anavekar NS et al (2004) Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 351(13):1285–1295
Rao SV et al (2013) An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry. JACC Cardiovasc Interv 6(9):897–904
Baber U et al (2015) Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents registry. Circ Cardiovasc Interv 8(6):e001683
Jain N et al (2013) Antiplatelet therapy in the management of cardiovascular disease in patients with CKD: what is the evidence? Clin J Am Soc Nephrol 8(4):665–674
Levey AS et al (2003) National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 139(2):137–147
Shlipak MG et al (2002) Cardiovascular disease risk status in elderly persons with renal insufficiency. Kidney Int 62(3):997–1004
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41
Levey AS et al (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130(6):461–470
Amsterdam EA et al (2014) 2014 AHA/ACC guideline for the management of patients with Non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 64(24):e139–e228
Amsterdam EA et al (2014) 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 130(25):2354–2394
Melloni C et al (2008) Cockcroft-Gault versus modification of diet in renal disease: importance of glomerular filtration rate formula for classification of chronic kidney disease in patients with non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol 51(10):991–996
Boccardo P, Remuzzi G, Galbusera M (2004) Platelet dysfunction in renal failure. Semin Thromb Hemost 30(5):579–589
Gafter U et al (1987) Platelet count and thrombopoietic activity in patients with chronic renal failure. Nephron 45(3):207–210
Linthorst GE et al (2002) Plasma thrombopoietin levels in patients with chronic renal failure. Hematol J 3(1):38–42
Dewanjee MK et al (1994) In vitro and in vivo evaluation of the comparative thrombogenicity of cellulose acetate hemodialyzers with radiolabeled platelets. ASAIO J 40(1):49–55
Remuzzi G et al (1983) Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclooxygenase defect. J Clin Invest 71(3):762–768
Di Minno G et al (1985) Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med 79(5):552–559
Mezzano D et al (1996) Hemostatic disorder of uremia: the platelet defect, main determinant of the prolonged bleeding time, is correlated with indices of activation of coagulation and fibrinolysis. Thromb Haemost 76(3):312–321
Sloand EM et al (1991) Reduction of platelet glycoprotein Ib in uraemia. Br J Haematol 77(3):375–381
Zwaginga JJ et al (1990) High von Willebrand factor concentration compensates a relative adhesion defect in uremic blood. Blood 75(7):1498–1508
Sreedhara R, Itagaki I, Hakim RM (1996) Uremic patients have decreased shear-induced platelet aggregation mediated by decreased availability of glycoprotein IIb-IIIa receptors. Am J Kidney Dis 27(3):355–364
Ibrahim H et al (2016) Detection and quantification of circulating immature platelets: agreement between flow cytometric and automated detection. J Thromb Thrombolysis 42:77–83
Fager AM et al (2010) Properties of procoagulant platelets: defining and characterizing the subpopulation binding a functional prothrombinase. Arterioscler Thromb Vasc Biol 30(12):2400–2407
Li Y et al (2010) Levels of main platelet thrombin receptors in older chronic haemodialysis patients. Chin Med J (Engl) 123(17):2495–2496
Li Y et al (2011) Effects of Salivae Miltiorrhizae Liguspyragine Hydrochloride and Glucose Injection on the levels of main platelet thrombin receptors in chronic haemodialysis patients. Chin J Integr Med 17(8):625–630
Feldman HI, Kobrin S, Wasserstein A (1996) Hemodialysis vascular access morbidity. J Am Soc Nephrol 7(4):523–535
Capodanno D, Angiolillo DJ (2012) Antithrombotic therapy in patients with chronic kidney disease. Circulation 125(21):2649–2661
Polzin A et al (2016) Antiplatelet effects of aspirin in chronic kidney disease patients. J Thromb Haemost 14(2):375–380
Small DS et al (2009) Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease. J Clin Pharm Ther 34(5):585–594
Butler K, Teng R (2012) Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with severe renal impairment. J Clin Pharmacol 52(9):1388–1398
Park SH et al (2009) A comparison of clopidogrel responsiveness in patients with versus without chronic renal failure. Am J Cardiol 104(9):1292–1295
Angiolillo DJ et al (2010) Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy. J Am Coll Cardiol 55(11):1139–1146
Kosoglou T et al (2012) Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease. Eur J Clin Pharmacol 68(7):1049–1056
Schror K (2002) The pharmacology of cilostazol. Diabetes Obes Metab 4(Suppl 2) pp S14–S19
Muller C et al (2012) Association of estimated GFR with platelet inhibition in patients treated with clopidogrel. Am J Kidney Dis 59(6):777–785
Mallikaarjun S, Forbes WP, Bramer SL (1999) Effect of renal impairment on the pharmacokinetics of cilostazol and its metabolites. Clin Pharmacokinet 37(Suppl 2):pp 33–40
Vane JR, Botting RM (2003) The mechanism of action of aspirin. Thromb Res 110(5–6):255–258
Antithrombotic Trialists C et al (2009) Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373(9678):1849–1860
Jardine MJ et al (2010) Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. J Am Coll Cardiol 56(12):956–965
Antithrombotic Trialists C (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324(7329):71–86
Antiplatelet Trialists’ Collaboration (1994) Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 308(6921):pp 81–106
Ethier J et al (2007) Aspirin prescription and outcomes in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 50(4):602–611
McCullough PA et al (2002) Benefits of aspirin and beta-blockade after myocardial infarction in patients with chronic kidney disease. Am Heart J 144(2):226–232
Best PJ et al (2008) The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 155(4):687–693
Keltai M et al (2007) Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil 14(2):312–318
Wiviott SD et al (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357(20):2001–2015
Roe MT et al (2012) Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 367(14):1297–1309
James S et al (2010) Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 122(11):1056–1067
Magnani G et al (2015) Efficacy and safety of vorapaxar as approved for clinical use in the United States. J Am Heart Assoc 4(3):e001505
Morrow DA et al (2012) Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 366(15):1404–1413
Tricoci P et al (2012) Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 366(1):20–33
Lim PS et al (2016) Role of Cilostazol Therapy in Hemodialysis Patients with Asymptomatic Peripheral Arterial Disease: A Retrospective Cohort Study. Biomed Res Int 2016:8236903
Bangalore S et al (2014) Efficacy of cilostazol on platelet reactivity and cardiovascular outcomes in patients undergoing percutaneous coronary intervention: insights from a meta-analysis of randomised trials. Open Heart 1(1):e000068
Park KW et al (2013) Adjunctive cilostazol versus double-dose clopidogrel after drug-eluting stent implantation: the HOST-ASSURE randomized trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Safety & Effectiveness of Drug-Eluting Stents & Anti-platelet Regimen). JACC Cardiovasc Interv 6(9):932–942
Youn YJ et al (2014) Multicenter randomized trial of 3-month cilostazol use in addition to dual antiplatelet therapy after biolimus-eluting stent implantation for long or multivessel coronary artery disease. Am Heart J p. 241–248(2):e1
Levey AS et al (1998) Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 32(5):853–906
Charytan D, Kuntz RE (2006) The exclusion of patients with chronic kidney disease from clinical trials in coronary artery disease. Kidney Int 70(11):2021–2030
Price MJ et al (2011) Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305(11):1097–1105
Collet JP et al (2011) Randomized comparison of platelet function monitoring to adjust antiplatelet therapy versus standard of care: rationale and design of the assessment with a double randomization of (1) a fixed dose versus a monitoring-guided dose of aspirin and clopidogrel after DES implantation, and (2) treatment interruption versus continuation, 1 year after stenting (ARCTIC) study. Am Heart J p. 5–12(1):e5
Plantinga L et al (2011) Nonsteroidal anti-inflammatory drug use among persons with chronic kidney disease in the United States. Ann Fam Med 9(5):423–430
Jankovic SM et al (2009) Nonsteroidal antiinflammatory drugs and risk of gastrointestinal bleeding among patients on hemodialysis. J Nephrol 22(4):502–507
Ibrahim H et al (2014) Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 64(20):2122–2129
Eikelboom JW, Warkentin TE (2014) Immature platelet count: part of the cardiologist’s complete blood count? J Am Coll Cardiol 64(20):2130–2132
Bufalino VJ et al (2011) The American Heart Association’s recommendations for expanding the applications of existing and future clinical registries: a policy statement from the American Heart Association. Circulation 123(19):2167–2179
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Ibrahim, H., Rao, S.V. Oral antiplatelet drugs in patients with chronic kidney disease (CKD): a review. J Thromb Thrombolysis 43, 519–527 (2017). https://doi.org/10.1007/s11239-017-1483-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-017-1483-3