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Risks and Benefits of Antiplatelet Therapy in Uremic Patients
Risks and Benefits of Antiplatelet Therapy in Uremic Patients Jeffrey B. Washam and George L. Adams Patients with renal insufficiency are at an increased risk for cardiovascular morbidity and mortality. Despite being at a substantial risk for thrombotic events, patients with renal insufficiency also experience a greater number of hemorrhagic complications associated with antiplatelet therapy than individuals with normal renal function. This review focuses on the benefits and risks of antiplatelet therapy in patients with impaired kidney function suffering from an acute coronary syndrome. Q 2008 by the National Kidney Foundation, Inc. All rights reserved. Index Words: Uremia; Antiplatelet therapy; Acute coronary syndrome
I
n addition to those patients already receiving chronic renal replacement therapy, an estimated 8% of Americans aged 20 or older (15.5 million adults) have physiologic evidence of chronic kidney disease defined as a moderately or severely reduced glomerular filtration rate (GFR).1 The 2 leading causes of end-stage renal disease (ESRD) are diabetes mellitus and hypertension,2 known risk factors for coronary artery disease (CAD). Cardiovascular disease is the leading cause of death among patients with renal failure.3 The mortality rate in dialysis patients approaches 9% per year, markedly higher than that of age-matched nonuremic patients.4,5 Mild to moderate renal insufficiency (RI) is also associated with increased cardiovascular morbidity and mortality in patients with hypertension, heart failure, CAD, and acute coronary syndromes (ACS) and in those undergoing percutaneous or surgical revascularization.6-10 Renally impaired patients are known to be at an increased risk for bleeding, most likely related to platelet dysfunction.11,12 This dysfunction is caused by intrinsic as well as external factors that decrease platelet aggregation and impair platelet adhesiveness (Fig 1).
From the Duke Heart Center, Department of Medicine, and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC. Address correspondence to George L. Adams, MD, MHS, Department of Medicine, Duke University Medical Center, Box 31282, Durham, NC 27710. E-mail: [email protected]. edu Ó 2008 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/08/1504-0007$34.00/0 doi:10.1053/j.ackd.2008.07.006
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Intrinsic factors include abnormal expression of platelet glycoproteins, altered release of adenosine phosphate and serotonin from platelet alpha-granules, faulty arachidonic acid and depressed prostaglandin metabolism, decreased platelet thromboxane A2 generation, and abnormal platelet cytoskeletal assembly. Extrinsic factors include the action of uremic toxins, anemia, increased nitric oxide production, von Willebrand factor abnormalities, decreased platelet production, and abnormal interactions between the platelet and the endothelium of the vessel wall. In uremic patients, plasma abnormalities have been shown to contribute to impaired platelet aggregation. Urea and other nitrogenous compounds (guanidinosuccinic acid and phenols)13-15 and fibrinogen fragments16 are culprits to decreased platelet aggregation. Interestingly, fibrinogen fragments impair platelet function by occupying fibrinogen receptors before cell activation, thus preventing the binding of intact fibrinogen to platelets after subsequent stimulation. Managing patients with ACS and RI is challenging. Despite the high prevalence of CAD in renal patients, the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines regarding the management of ACSs with antiplatelet therapy (Fig 2) are mostly based on studies that excluded patients with renal insufficiency. In fact, a recent survey noted that patients with chronic kidney disease were excluded from 75% of published CAD trials.17 As a result, the risk/benefit ratio for the administration of antiplatelet therapy in this population is unclear. This review focuses on the benefits and risks of antiplatelet therapy in patients with
Advances in Chronic Kidney Disease, Vol 15, No 4 (October), 2008: pp 370–377
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Antiplatelet Therapy in Uremic Patients
ADP, serotonin Storage Granule
Altered intracellular Ca+2 mobilization
GP Ib/IX receptor
Decreased activity of vWF
Uremic toxins and fibrinogen fragments
Ca+2 Ca+2 Ca+2 ↑ Nitric Oxide Guanyl Cyclase ↑ Prostacyclin
GP IIb/IIIa receptor
↑ cGMP ↑ cAMP
Fibrinogen
↓ TxA2 , ↓ ADP
Decreased ability of GP IIb/IIIa receptors to bind fibrinogen Increased levels of cyclic glutamine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) reduce the production of Thromboxane A2 and ADP
Figure 1. An overview of factors contributing to platelet dysfunction in uremic patients. Abbreviations: GP, glycoprotein; vWF, von Willebrand factor; TxA2, Thromboxane A2; ADP, adenosine diphosphate.
impaired kidney function suffering from an ACS.
Aspirin Aspirin exerts its antiplatelet effects by inhibiting thromboxane A2-mediated platelet aggregation. Aspirin has been shown to improve outcomes in the ACS population. Accordingly, both the ACC/AHA ST-Elevation Myocardial Infarction (STEMI) and Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) guidelines recommend aspirin administration on presentation and continued indefinitely in this population (Table 1).18,19
Figure 2. A schematic representation of antiplatelet therapy. Abbreviations: ADP, adenosine diphosphate; TXA2, Thromboxane A2; GP, glycoprotein.
For RI patients presenting with an ACS, observational data support the role of aspirin in reducing short-term mortality. An analysis of the Cooperative Cardiovascular Project database revealed a similar 30-day mortality among ACS-ESRD patients (relative ratio ¼ 0.64 [0.5-0.8)] and non-ESRD patients (0.57 [0.55-0.58]) treated with aspirin and betablockers.20 However, these medications were administered less often in patients receiving dialysis. Additionally, McCullough et al21 evaluated the effects of aspirin and betablocker therapy in patients with chronic kidney disease presenting with STEMI. Patients were categorized into quartiles based on estimated creatinine clearance (CrCl). Dialysis patients were categorized separately. Although prescribing rates of aspirin and betablocker declined with worsening renal function, the relative risk reduction for in-hospital mortality was evident across all ranges of renal function. The benefit of the combination of aspirin plus beta-blocker therapy on the age-adjusted relative risk reduction for in-hospital mortality ranged from 64.3% to 80% and was similar across all renal groups. These data support the role of aspirin therapy in patients with RI presenting with an ACS. Ezekowitz et al22 conducted an analysis of registry data to assess the impact of renal function on the outcomes associated with cardiovascular medications in patients with
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Table 1. ACC/AHA (Highlights) Guidelines on Antiplatelet Therapy in ACS Patients Agent Aspirin
Indication
ACC/AHA Guideline Class Recommendation (Level of Evidence)
UA/NSTEMI
I: Administer to patients as soon as possible after presentation and continued indefinitely (A). I: Administer to patients who have not taken aspirin before presentation. The initial dose should be 162 to 325 mg and maintenance dose of 75 to 162 mg and should be given indefinitely (A). I: For post-PCI STEMI stented patients without aspirin resistance, allergy, or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least 1 month after BMS implantation, 3 months after sirolimuseluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which long-term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg daily (B).
STEMI
STEMI/PCI
Clopidogrel
UA/NSTEMI
STEMI
STEMI/PCI
GP IIb/IIIa Inhibitor
UA/STEMI
STEMI/PCI
I: For patients managed by an initial invasive strategy, antiplatelet therapy with either clopidogrel or GP IIb/IIIa inhibitor should be given in addition to aspirin before diagnostic angiography (A) I: For patients managed by an initial noninvasive strategy, clopidogrel should be added to ASA and administered for at least 1 month (A) and ideally up to 1 year (B). I: Clopidogrel should be administered to patients unable to take aspirin (A). I. Clopidogrel 75 mg per day orally should be added to aspirin in STEMI patients regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy. (A) Treatment with clopidogrel should continue for at least 14 days (B). IIa: Long-term maintenance therapy (eg, 1 year) with clopidogrel (75 mg daily) is reasonable in STEMI patients regardless of whether they undergo reperfusion with fibrinolytics or do not receive reperfusion therapy (C). I: For all post-PCI patients who receive a drug-eluting stent, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. For post-PCI patients receiving a BMS, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then, it should be given for a minimum of 2 weeks) (B). I: For patients managed by an initial invasive strategy, antiplatelet therapy with either clopidogrel or GP IIb/IIIa inhibitor should be given in addition to aspirin before diagnostic angiography (A). I. For patients in whom an initial noninvasive strategy is selected, if recurrent ischemia, heart failure, or serious arrhythmia appear, either a GP IIb/IIIa inhibitor (eptifibatide or tirofiban) (A) or clopidogrel (A) should be added to aspirin and anticoagulation before diagnostic angiography. III: Abciximab should not be administered to patients in whom PCI is not planned (A). IIa: It is reasonable to start treatment with abciximab as early as possible before primary PCI (with or without stenting) in STEMI patients (B). IIb: Treatment with tirofiban or eptifibatide may be considered before primary PCI (with or without stenting) in patients with STEMI (C).
Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; ASA, aspirin; BMS, bare metal stent.
congestive heart failure and CAD. A total of 6,427 patients with a diagnosis of congestive heart failure and angiographically proven CAD were grouped based on estimated CrCls. In patients with a baseline estimated CrCl ,60 mL/min, aspirin use was associated with an approximate 25% (P ¼ .006) reduction in mortality at 1 year. These results further support
the efficacy of aspirin in patients with heart disease.
Clopidogrel Clopidogrel belongs to the thienopyridine class of antiplatelet agents. Thienopyridines exert their antiplatelet effect by blocking the
Antiplatelet Therapy in Uremic Patients
binding of adenosine phosphate to the platelet P2Y12 receptor leading to inhibition of platelet activation and aggregation. The ACC/AHA STEMI and UA/NSTEMI guidelines recommend the use of clopidogrel in patients presenting with ACS.18,19,23 Highlights of these recommendations are listed in Table 1. Currently, there are no specific recommendations regarding a need for dose adjustment of clopidogrel for patients with RI. Data from a short-term pharmacodynamic study conducted in hemodialysis patients suggested that the magnitude of platelet aggregation inhibition achieved with clopidogrel was similar to that reported in nonuremic patients.24 In The Clopidogrel for the Reduction of Events During Observation Trial, patients undergoing elective percutaneous coronary intervention (PCI) were randomized to 2 groups; 1 group received a 300-mg loading dose of clopidogrel before PCI followed by 75 mg daily for 1 year, and the second group received clopidogrel 75 mg daily for 28 days. Both groups received aspirin for 1 year. A post hoc analysis of this trial suggested that the beneficial effects of long-term clopidogrel might be reduced in patients with mild to moderate kidney disease. The rates of the composite endpoint of death, myocardial infarction, and stroke at 1 year for patients who did and did not receive clopidogrel based on estimated CrCl were 4.4% versus 10.4% (P , .001) for those patients with CrCl .90 mL/min, 10.3 % versus12.8% (P ¼ .3) for patients with an estimated clearance of 60 to 89 mL/min, and 17.8% versus 13.1% (P ¼ 0.24) for those patients with an estimated clearance ,60 mL/min. In this analysis, there was no association between worsening renal function and the relative risk of bleeding.25 The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial showed the benefit of adding clopidogrel to standard treatment for the composite outcome of cardiovascular death, nonfatal myocardial infarction, or stroke in patients presenting with non–ST-elevation acute coronary syndromes. The mean duration of clopidogrel therapy was 9 months. A post hoc analysis of the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial was conducted to assess the safety and efficacy of clopidogrel in
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patients with renal dysfunction. Patients were categorized into tertiles based on estimated GFRs, with the lower tertile including patients with a GFR ,64 mL/min, the intermediate tertile consisting of patients with GFR of 64 to 81.2 mL/min, and the upper tertile representing patients with an estimated GFR of .81.2 mL/min. Only 1.8% of patients had an estimated GFR ,30 mL/min. Although the authors of this study found no interaction of renal function with clopidogrel therapy (P for heterogeneity ¼ .11), they also showed no significant improvement in the primary outcome with clopidogrel therapy in the lowest GFR tertile (relative ratio ¼ 0.89 [0.76-1.05]). In patients in the lower tertile, a statistically significant increase in the risk of minor bleeding was noted with clopidogrel therapy.26 Based on the current data, the role of clopidogrel in ACS patients with RI is unclear. Clinical trials designed to assess the benefit of clopidogrel on mortality, ischemic endpoints, and risk of bleeding are needed.
Platelet Glycoprotein IIb/IIIa Inhibitors Agents that block the binding of adhesive proteins to glycoprotein (GP) IIb/IIIa complexes inhibit platelet aggregation. Three biochemical types of GP IIb/IIIa inhibitors are available for clinical use: murine-human chimeric antibodies (abciximab), synthetic peptide forms (eptifibatide), and synthetic nonpeptide forms (tirofiban). Selected recommendations from the ACC/AHA UA/NSTEMI and STEMI guidelines for use of GP IIb/IIIa inhibitor therapy are shown in Table 1.18,19 For STEMI, the utility of GP IIb/IIIa inhibitors has not been documented. However, all 3 GP IIb/IIIa inhibitors have been used in conjunction with PCI in STEMI.27-29 Two large randomized trials have assessed the effect of combining abciximab with reduced-dose thrombolytic on clinical outcomes.30,31 Despite reductions in nonfatal ischemic events, no mortality benefit was seen with combination therapy when compared with standard-dose thrombolytic therapy. Importantly, bleeding events were more common in those receiving combination therapies, specifically in those patients of advanced age.
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Abciximab is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. It has a high affinity and specificity for the GP IIb/IIIa receptor on the surface of platelets. In humans, a 0.25-mg/kg intravenous dose achieves greater than 80% blockage of the receptors.32 Its inhibitory effect on platelet function is evident within 10 minutes, measured by increases in bleeding time. It has a short half-life of 10 to 30 minutes but can remain in the circulation platelet bound up to 10 days. The kidneys generally clear Fab fragments. Although renal metabolism is a pathway for the elimination of free abciximab, the removal of platelets by the spleen represents an elimination pathway for platelet-bound abciximab. At this time, no recommendations exist regarding dose adjustment of abciximab in patients with RI. The recommended dosage of abciximab is a 0.25-mg/kg intravenous bolus administered 10 to 60 minutes before the start of PCI followed by a continuous infusion of 0.125 mg/kg/min (to a maximum of 10 mg/min) for 12 hours.32 Eptifibatide is a synthetic cyclic heptapeptide that inhibits platelet aggregation in a dose-and concentration-dependent manner.33 Platelet aggregation inhibition is reversible after the cessation of the infusion. Renal clearance accounts for approximately 50% of total body clearance. The plasma half-life of eptifibatide is approximately 2.5 hours in patients with normal renal function and extends to .6 hours in patients with a CrCl ,30 mL/ min.34 With eptifibatide, dose adjustment is unnecessary for patients with a CrCl .50 mL/min. It is administered as an intravenous bolus of 180 mg/kg, immediately followed by a continuous infusion of 2.0 ug/kg/min. For patients with an estimated CrCl ,50 mL/ min, the infusion dose should be reduced to 1.0 mg/kg/min, whereas the bolus dose is unchanged. Eptifibatide use is contraindicated in hemodialysis patients.33 Tirofiban is a synthetic nonpeptide antagonist of the GP IIb/IIIa receptor. Like eptifibatide, the inhibition of platelet aggregation is dose and concentration dependent and reversible after cessation of the infusion. Its half-life is approximately 2 hours, and renal excretion accounts for 65% of clearance. Tirofiban is administered to patients with normal renal func-
tion as an initial loading intravenous infusion of 0.4 mg/kg/min for 30 minutes followed by a continuous infusion of 0.1 mg/kg/min. The loading infusion and maintenance infusion should be reduced by 50% in patients with a CrCl ,30 mL/min.35 Patients with moderate to severe renal dysfunction have largely been excluded from major clinical trials of GP IIb/IIIa inhibitors in the setting of ACS. Accordingly, Freeman et al36 performed a study to examine the in-hospital outcome and influence of GP IIb/IIIa inhibitor use on patients with ACS across a range of renal function. Results of this study showed that GP IIb/IIIa inhibitor use in this population was associated with both an increased risk of bleeding events (P , .001) and a decrease in the risk of in-hospital mortality (P ¼ .04). Januzzi et al37 also studied the role of tirofiban treatment in ACS patients with RI. Tirofiban treatment reduced the odds of the composite endpoint of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR] 0.68; 95% confidence interval [CI], 0.461.0; P ¼ .05), 7 days (OR, 0.68; 95% CI, 0.520.88; P ¼ .003), 30 days (OR 0.78; 95% CI, 0.63-0.98; P ¼ .03), and 6 months (OR, 0.81; 95% CI, 0.68-0.98; P ¼ .03), irrespective of CrCl. The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined, and there was no unexpected incremental risk of bleeding because of tirofiban among the lowest CrCl categories. An analysis of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/ American Heart Association Guidelines Registry was conducted to assess the rates and outcomes associated with excess dosing of GP IIb/IIIa inhibitors, heparin, and low– molecular-weight heparin in patients presenting with non–ST-segment elevation ACS.38 Excess dosing was noted in approximately 27% of patients treated with a GP IIb/IIIa inhibitor and was associated with a significant increase in the risk of a bleeding event and mortality. Factors associated with excess dosing of GP IIb/IIIa inhibitors included age .75 years, renal insufficiency, female sex, and low body weight. This analysis highlights
Antiplatelet Therapy in Uremic Patients
the importance of taking these factors into consideration when prescribing these agents. The impact of RI on outcomes in patients undergoing PCI with GP IIb/IIIa inhibitor use has also been studied. Best et al39 evaluated the safety of abciximab in patients with renal insufficiency undergoing PCI. This study displayed a trend toward an interaction between CrCl and major bleeding with abciximab (OR ¼ 1.18, P ¼ .06) and no interaction with minor bleeding (OR ¼ 1.01, P ¼ .94). Additionally, a post hoc analysis of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy Trial suggested the benefit of eptifibatide on the composite outcome of death, myocardial infarction, and urgent target vessel revascularization was maintained in patients with an estimated CrCl ,60 mL/min. No increase in bleeding risk was noted with the lower CrCl. Patients with a baseline creatinine .4 mg/dL were excluded from this trial.40 Berger et al41 evaluated whether outcome differences exist between GP IIb/IIIa inhibitors that are renally excreted (tirofiban) or not (abciximab) in patients with mild renal impairment. Their results displayed no interaction between these GP IIb/IIIa inhibitors and CrCl regarding ischemic (tirofiban [OR ¼ 0.93, P ¼.5]) or bleeding events (tirofiban; major bleeding [OR ¼ 1.00, P ¼ .997], minor bleeding [OR ¼ 1.26, P ¼ .13]). The results of these studies need to be confirmed in future randomized clinical trials.
Conclusion Patients with RI are at an increased risk for cardiovascular morbidity and mortality. Despite being at a substantial risk for thrombotic events, patients with RI also experience a greater number of hemorrhagic complications associated with antiplatelet therapy than individuals with normal renal function. Although recommendations have been proposed for the treatment of uremic bleeding,42 the management of bleeding events in ACS patients with RI receiving antiplatelet therapy remains poorly defined. Accordingly, the large RI population represents an ideal patient subset to investigate, on a large scale, patientspecific mechanisms (for thrombosis and hemorrhage) and optional pharmacologic therapies for common, coexisting disease states
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such as ACSs, stroke, and peripheral vascular occlusive disease as well as the bleeding events that are likely to occur. Unfortunately, many phase II and III clinical trials exclude patients with renal insufficiency, whereas others challenge the pharmacokinetic and pharmacodynamic data by using fixed doses in all but those with severe renal failure (CrCl ,30 mL/min) who are traditionally excluded from study entry. It is important that clinical trials begin efforts to address this issue. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative Practice Guidelines for Cardiovascular Disease in Dialysis Patients43 currently recommend treating dialysis patients presenting with ACS the same as those in the nondialysis population with the exception of paying specific attention to medications with altered clearances in kidney failure. Observational data have shown a benefit with the use of certain therapies in this population. However, patients with renal insufficiency are less likely to receive these lifesaving medications when compared with patients without renal insufficiency.21,44,45 Efforts should continue to be focused on improving quality for this population throughout our health care system.
References 1. Coresh J, Selvin E, Stevens LA, et al: Prevalence of chronic kidney disease in the United States. JAMA 298:2038-2047, 2007 2. Kidney and Urologic Disease Statistics for the United States. Bethesda, MD, National Institutes of Diabetes and Digestive and Kidney Diseases, National Kidney and Urologic Diseases Information Clearing Houses, 1997 3. Wolfe RA, Port FK, Webb RL, et al: Introduction to the excerpts from the United States Renal Data System 1999 Annual Data Report. Am J Kidney Dis 34:S1-S3, 1999 4. Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:S112-S119, 1998 5. Rostand SG, Brunzell JD, Cannon RO III, et al: Cardiovascular complications in renal failure. J Am Soc Nephrol 2:1053-1062, 1991 6. Al Suwaidi J, Reddan DN, Williams K, et al: Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation 106:974-980, 2002 7. Szczech LA, Best PJ, Crowley E, et al: Outcomes of patients with chronic renal insufficiency in the bypass angioplasty revascularization investigation. Circulation 105:2253-2258, 2002
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8. Dries DL, Exner DV, Domanski MJ, et al: The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 35:681-689, 2000 9. Herzog CA, Ma JZ, Collins AJ: Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339: 799-805, 1998 10. Rubenstein MH, Harrell LC, Sheynberg BV, et al: Are patients with renal failure good candidates for percutaneous coronary revascularization in the new device era? Circulation 346:957-966, 2000 11. Mezzano D, Tagle R, Panes O, et al: Hemostatic disorder of uremia: The platelet defect, main determinant of prolonged bleeding time, is correlated with indices of activation of coagulation and fibrinolysis. Thromb Haemost 76:312-321, 1996 12. Castillo R, Loranzo T, Escolar G, et al: Defective platelet adhesion vessel subendothelium in uremic patients. Blood 68:337-342, 1986 13. Zwaginga JJ, Ijsseldijk MJW, De Groot PHG, et al: Defects in platelet adhesion and aggregate formation in uremic bleeding disorders can be attributed to factors in plasma. Arterioscler Thromb 11:733-744, 1991 14. Davis JW, McField JR, Phillips PE, et al: Guanidinosuccinic acid on human platelet: Effects of exogenous urea, creatinine, and aggregation in vitro. Blood 39: 388-397, 1972 15. Rabiner SF, Molina F: The role of phenol and phenolic acids on the thrombocytopathy and defective platelet aggregation of patients with renal failure. Am J Med 49:346-351, 1970 16. Kozek-Langenecker SA, Masaki T, Mohammad H, et al: Fibrinogen fragments and platelet dysfunction in uremia. Kidney Int 56:299-305, 1999 17. Charytan D, Kuntz RE: The exclusion of patients with chronic kidney disease from clinical trials in coronary artery disease. Kidney Int 70:2021-2030, 2006 18. Anderson J, Adams C, Antman EM, et al: ACC/ AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-STElevation Myocardial Infarction): Developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society of Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 50:e1-e157, 2007 19. Antman EM, Anbe DT, Armstrong PW, et al: ACC/ AHA guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol 44:671-719, 2004 20. Berger AK, Duval S, Krumholz HM: Aspirin, betablocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction. J Am Coll Cardiol 42:201-208, 2003
21. McCullough PA, Sandberg KR, Borzak S, et al: Benefits of aspirin and beta-blockade after myocardial infarction in patients with chronic kidney disease. Am Heart J 144:226-232, 2002 22. Ezekowitz J, McAlister FA, Humphries KH, et al: The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol 44: 1587-1592, 2004 23. Antman EA, Hand M, Armstrong PW, et al: 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol 51:210-247, 2008 24. Kaufman JS, Fiore L, Hasbargen JA, et al: A pharmacodynamic study of clopidogrel in chronic hemodialysis patients. J Thromb Thrombolysis 10:127-131, 2000 25. Best P, Steinhubl SR, Berger PB, et al: 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 155:687-693, 2008 26. Matyas K, Tonelli M, Mann JFE, et al: Renal function and outcomes in acute coronary syndrome: Impact of clopidogrel. Eur J Cardiovasc Prev Rehabil 14: 312-318, 2007 27. Brenner SJ, Barr LA, Burchenal JEB, et al: Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation 98:734-741, 1998 28. The EPIC Investigatorsa: Use of monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 330:956-961, 1994 29. The IMPACT-II Investigators: Randomized placebo controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 349:1422-1428, 1997 30. Topol EJ: for the GUSTO V Investigators: Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 357:1905-1914, 2001 31. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators: Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomised trial in acute myocardial infarction. Lancet 358:605-613, 2001 32. Centocor BV: ReoPro (Abciximab) packet insert. Leiden, The Netherlands, Centocor BV, 2001 33. Integrellin (eptifibatide) [prescribing information]. Kenilworth, NJ, Schering Corporation, 2005 34. Gretler DD, Guerciolini R, Williams PJ: Pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with normal or impaired renal function. Clin Ther 26:390-398, 2004 35. Aggrastat [package insert]. Baltimore, MD: Guilford Pharmaceuticals, 2004 36. Freeman RV, Mehta RH, Badr WA, et al: Influence of concurrent renal dysfunction on outcomes of patients
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37.
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with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors. J Am Coll Cardiol 41:718-724, 2003 Januzzi JL, Snapinn SM, DiBattiste PM, et al: Benefits and safety of Tirofiban among acute coronary syndrome patients with mild to moderate renal insufficiency: Results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISMPLUS) Trial. Circulation 105:2361-2366, 2002 Alexander KP, Chen AY, Roe MT, et al: Excess dosing of antiplatelet and antithrombin agents in the treatment of non–ST-segment elevation acute coronary syndromes. JAMA 294:3108-3116, 2005 Best PJM, Lennon R, Gersh BJ, et al: Safety of abciximab in patients with chronic renal insufficiency who are undergoing percutaneous coronary interventions. Am Heart J 146:345-350, 2003 Reddan DN, O’Shea JC, Sarembock IJ, et al: Treatment effects of eptifibatide in planned coronary stent implantation in patients with chronic kidney disease (ESPRIT Trial). Am J Cardiol 91:17-21, 2003
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41. Berger PB, Best PJM, Topol EJ, et al: The relation of renal function to ischemic and bleeding outcomes with 2 different glycoprotein IIb/IIIa inhibitors: The Do Tirofiban and ReoPro Give Similar Efficacy Outcome (TARGET) trial. Am Heart J 149:869-875, 2005 42. Hedges SJ, Dehoney SB, Hooper JS, et al: Evidencebased treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 3:138-153, 2007 43. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 45: 16-153, 2005 44. Ezekowitz J, McAlister FA, Humphries KH, et al: The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol 44: 1587-1592, 2004 45. Berger AK, Duval S, Krumholz HM: Aspirin, betablocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction. J Am Coll Cardiol 42:201-208, 2003
I
n addition to those patients already receiving chronic renal replacement therapy, an estimated 8% of Americans aged 20 or older (15.5 million adults) have physiologic evidence of chronic kidney disease defined as a moderately or severely reduced glomerular filtration rate (GFR).1 The 2 leading causes of end-stage renal disease (ESRD) are diabetes mellitus and hypertension,2 known risk factors for coronary artery disease (CAD). Cardiovascular disease is the leading cause of death among patients with renal failure.3 The mortality rate in dialysis patients approaches 9% per year, markedly higher than that of age-matched nonuremic patients.4,5 Mild to moderate renal insufficiency (RI) is also associated with increased cardiovascular morbidity and mortality in patients with hypertension, heart failure, CAD, and acute coronary syndromes (ACS) and in those undergoing percutaneous or surgical revascularization.6-10 Renally impaired patients are known to be at an increased risk for bleeding, most likely related to platelet dysfunction.11,12 This dysfunction is caused by intrinsic as well as external factors that decrease platelet aggregation and impair platelet adhesiveness (Fig 1).
From the Duke Heart Center, Department of Medicine, and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC. Address correspondence to George L. Adams, MD, MHS, Department of Medicine, Duke University Medical Center, Box 31282, Durham, NC 27710. E-mail: [email protected]. edu Ó 2008 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/08/1504-0007$34.00/0 doi:10.1053/j.ackd.2008.07.006
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Intrinsic factors include abnormal expression of platelet glycoproteins, altered release of adenosine phosphate and serotonin from platelet alpha-granules, faulty arachidonic acid and depressed prostaglandin metabolism, decreased platelet thromboxane A2 generation, and abnormal platelet cytoskeletal assembly. Extrinsic factors include the action of uremic toxins, anemia, increased nitric oxide production, von Willebrand factor abnormalities, decreased platelet production, and abnormal interactions between the platelet and the endothelium of the vessel wall. In uremic patients, plasma abnormalities have been shown to contribute to impaired platelet aggregation. Urea and other nitrogenous compounds (guanidinosuccinic acid and phenols)13-15 and fibrinogen fragments16 are culprits to decreased platelet aggregation. Interestingly, fibrinogen fragments impair platelet function by occupying fibrinogen receptors before cell activation, thus preventing the binding of intact fibrinogen to platelets after subsequent stimulation. Managing patients with ACS and RI is challenging. Despite the high prevalence of CAD in renal patients, the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines regarding the management of ACSs with antiplatelet therapy (Fig 2) are mostly based on studies that excluded patients with renal insufficiency. In fact, a recent survey noted that patients with chronic kidney disease were excluded from 75% of published CAD trials.17 As a result, the risk/benefit ratio for the administration of antiplatelet therapy in this population is unclear. This review focuses on the benefits and risks of antiplatelet therapy in patients with
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Antiplatelet Therapy in Uremic Patients
ADP, serotonin Storage Granule
Altered intracellular Ca+2 mobilization
GP Ib/IX receptor
Decreased activity of vWF
Uremic toxins and fibrinogen fragments
Ca+2 Ca+2 Ca+2 ↑ Nitric Oxide Guanyl Cyclase ↑ Prostacyclin
GP IIb/IIIa receptor
↑ cGMP ↑ cAMP
Fibrinogen
↓ TxA2 , ↓ ADP
Decreased ability of GP IIb/IIIa receptors to bind fibrinogen Increased levels of cyclic glutamine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) reduce the production of Thromboxane A2 and ADP
Figure 1. An overview of factors contributing to platelet dysfunction in uremic patients. Abbreviations: GP, glycoprotein; vWF, von Willebrand factor; TxA2, Thromboxane A2; ADP, adenosine diphosphate.
impaired kidney function suffering from an ACS.
Aspirin Aspirin exerts its antiplatelet effects by inhibiting thromboxane A2-mediated platelet aggregation. Aspirin has been shown to improve outcomes in the ACS population. Accordingly, both the ACC/AHA ST-Elevation Myocardial Infarction (STEMI) and Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) guidelines recommend aspirin administration on presentation and continued indefinitely in this population (Table 1).18,19
Figure 2. A schematic representation of antiplatelet therapy. Abbreviations: ADP, adenosine diphosphate; TXA2, Thromboxane A2; GP, glycoprotein.
For RI patients presenting with an ACS, observational data support the role of aspirin in reducing short-term mortality. An analysis of the Cooperative Cardiovascular Project database revealed a similar 30-day mortality among ACS-ESRD patients (relative ratio ¼ 0.64 [0.5-0.8)] and non-ESRD patients (0.57 [0.55-0.58]) treated with aspirin and betablockers.20 However, these medications were administered less often in patients receiving dialysis. Additionally, McCullough et al21 evaluated the effects of aspirin and betablocker therapy in patients with chronic kidney disease presenting with STEMI. Patients were categorized into quartiles based on estimated creatinine clearance (CrCl). Dialysis patients were categorized separately. Although prescribing rates of aspirin and betablocker declined with worsening renal function, the relative risk reduction for in-hospital mortality was evident across all ranges of renal function. The benefit of the combination of aspirin plus beta-blocker therapy on the age-adjusted relative risk reduction for in-hospital mortality ranged from 64.3% to 80% and was similar across all renal groups. These data support the role of aspirin therapy in patients with RI presenting with an ACS. Ezekowitz et al22 conducted an analysis of registry data to assess the impact of renal function on the outcomes associated with cardiovascular medications in patients with
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Table 1. ACC/AHA (Highlights) Guidelines on Antiplatelet Therapy in ACS Patients Agent Aspirin
Indication
ACC/AHA Guideline Class Recommendation (Level of Evidence)
UA/NSTEMI
I: Administer to patients as soon as possible after presentation and continued indefinitely (A). I: Administer to patients who have not taken aspirin before presentation. The initial dose should be 162 to 325 mg and maintenance dose of 75 to 162 mg and should be given indefinitely (A). I: For post-PCI STEMI stented patients without aspirin resistance, allergy, or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least 1 month after BMS implantation, 3 months after sirolimuseluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which long-term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg daily (B).
STEMI
STEMI/PCI
Clopidogrel
UA/NSTEMI
STEMI
STEMI/PCI
GP IIb/IIIa Inhibitor
UA/STEMI
STEMI/PCI
I: For patients managed by an initial invasive strategy, antiplatelet therapy with either clopidogrel or GP IIb/IIIa inhibitor should be given in addition to aspirin before diagnostic angiography (A) I: For patients managed by an initial noninvasive strategy, clopidogrel should be added to ASA and administered for at least 1 month (A) and ideally up to 1 year (B). I: Clopidogrel should be administered to patients unable to take aspirin (A). I. Clopidogrel 75 mg per day orally should be added to aspirin in STEMI patients regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy. (A) Treatment with clopidogrel should continue for at least 14 days (B). IIa: Long-term maintenance therapy (eg, 1 year) with clopidogrel (75 mg daily) is reasonable in STEMI patients regardless of whether they undergo reperfusion with fibrinolytics or do not receive reperfusion therapy (C). I: For all post-PCI patients who receive a drug-eluting stent, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. For post-PCI patients receiving a BMS, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then, it should be given for a minimum of 2 weeks) (B). I: For patients managed by an initial invasive strategy, antiplatelet therapy with either clopidogrel or GP IIb/IIIa inhibitor should be given in addition to aspirin before diagnostic angiography (A). I. For patients in whom an initial noninvasive strategy is selected, if recurrent ischemia, heart failure, or serious arrhythmia appear, either a GP IIb/IIIa inhibitor (eptifibatide or tirofiban) (A) or clopidogrel (A) should be added to aspirin and anticoagulation before diagnostic angiography. III: Abciximab should not be administered to patients in whom PCI is not planned (A). IIa: It is reasonable to start treatment with abciximab as early as possible before primary PCI (with or without stenting) in STEMI patients (B). IIb: Treatment with tirofiban or eptifibatide may be considered before primary PCI (with or without stenting) in patients with STEMI (C).
Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; ASA, aspirin; BMS, bare metal stent.
congestive heart failure and CAD. A total of 6,427 patients with a diagnosis of congestive heart failure and angiographically proven CAD were grouped based on estimated CrCls. In patients with a baseline estimated CrCl ,60 mL/min, aspirin use was associated with an approximate 25% (P ¼ .006) reduction in mortality at 1 year. These results further support
the efficacy of aspirin in patients with heart disease.
Clopidogrel Clopidogrel belongs to the thienopyridine class of antiplatelet agents. Thienopyridines exert their antiplatelet effect by blocking the
Antiplatelet Therapy in Uremic Patients
binding of adenosine phosphate to the platelet P2Y12 receptor leading to inhibition of platelet activation and aggregation. The ACC/AHA STEMI and UA/NSTEMI guidelines recommend the use of clopidogrel in patients presenting with ACS.18,19,23 Highlights of these recommendations are listed in Table 1. Currently, there are no specific recommendations regarding a need for dose adjustment of clopidogrel for patients with RI. Data from a short-term pharmacodynamic study conducted in hemodialysis patients suggested that the magnitude of platelet aggregation inhibition achieved with clopidogrel was similar to that reported in nonuremic patients.24 In The Clopidogrel for the Reduction of Events During Observation Trial, patients undergoing elective percutaneous coronary intervention (PCI) were randomized to 2 groups; 1 group received a 300-mg loading dose of clopidogrel before PCI followed by 75 mg daily for 1 year, and the second group received clopidogrel 75 mg daily for 28 days. Both groups received aspirin for 1 year. A post hoc analysis of this trial suggested that the beneficial effects of long-term clopidogrel might be reduced in patients with mild to moderate kidney disease. The rates of the composite endpoint of death, myocardial infarction, and stroke at 1 year for patients who did and did not receive clopidogrel based on estimated CrCl were 4.4% versus 10.4% (P , .001) for those patients with CrCl .90 mL/min, 10.3 % versus12.8% (P ¼ .3) for patients with an estimated clearance of 60 to 89 mL/min, and 17.8% versus 13.1% (P ¼ 0.24) for those patients with an estimated clearance ,60 mL/min. In this analysis, there was no association between worsening renal function and the relative risk of bleeding.25 The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial showed the benefit of adding clopidogrel to standard treatment for the composite outcome of cardiovascular death, nonfatal myocardial infarction, or stroke in patients presenting with non–ST-elevation acute coronary syndromes. The mean duration of clopidogrel therapy was 9 months. A post hoc analysis of the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial was conducted to assess the safety and efficacy of clopidogrel in
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patients with renal dysfunction. Patients were categorized into tertiles based on estimated GFRs, with the lower tertile including patients with a GFR ,64 mL/min, the intermediate tertile consisting of patients with GFR of 64 to 81.2 mL/min, and the upper tertile representing patients with an estimated GFR of .81.2 mL/min. Only 1.8% of patients had an estimated GFR ,30 mL/min. Although the authors of this study found no interaction of renal function with clopidogrel therapy (P for heterogeneity ¼ .11), they also showed no significant improvement in the primary outcome with clopidogrel therapy in the lowest GFR tertile (relative ratio ¼ 0.89 [0.76-1.05]). In patients in the lower tertile, a statistically significant increase in the risk of minor bleeding was noted with clopidogrel therapy.26 Based on the current data, the role of clopidogrel in ACS patients with RI is unclear. Clinical trials designed to assess the benefit of clopidogrel on mortality, ischemic endpoints, and risk of bleeding are needed.
Platelet Glycoprotein IIb/IIIa Inhibitors Agents that block the binding of adhesive proteins to glycoprotein (GP) IIb/IIIa complexes inhibit platelet aggregation. Three biochemical types of GP IIb/IIIa inhibitors are available for clinical use: murine-human chimeric antibodies (abciximab), synthetic peptide forms (eptifibatide), and synthetic nonpeptide forms (tirofiban). Selected recommendations from the ACC/AHA UA/NSTEMI and STEMI guidelines for use of GP IIb/IIIa inhibitor therapy are shown in Table 1.18,19 For STEMI, the utility of GP IIb/IIIa inhibitors has not been documented. However, all 3 GP IIb/IIIa inhibitors have been used in conjunction with PCI in STEMI.27-29 Two large randomized trials have assessed the effect of combining abciximab with reduced-dose thrombolytic on clinical outcomes.30,31 Despite reductions in nonfatal ischemic events, no mortality benefit was seen with combination therapy when compared with standard-dose thrombolytic therapy. Importantly, bleeding events were more common in those receiving combination therapies, specifically in those patients of advanced age.
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Abciximab is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. It has a high affinity and specificity for the GP IIb/IIIa receptor on the surface of platelets. In humans, a 0.25-mg/kg intravenous dose achieves greater than 80% blockage of the receptors.32 Its inhibitory effect on platelet function is evident within 10 minutes, measured by increases in bleeding time. It has a short half-life of 10 to 30 minutes but can remain in the circulation platelet bound up to 10 days. The kidneys generally clear Fab fragments. Although renal metabolism is a pathway for the elimination of free abciximab, the removal of platelets by the spleen represents an elimination pathway for platelet-bound abciximab. At this time, no recommendations exist regarding dose adjustment of abciximab in patients with RI. The recommended dosage of abciximab is a 0.25-mg/kg intravenous bolus administered 10 to 60 minutes before the start of PCI followed by a continuous infusion of 0.125 mg/kg/min (to a maximum of 10 mg/min) for 12 hours.32 Eptifibatide is a synthetic cyclic heptapeptide that inhibits platelet aggregation in a dose-and concentration-dependent manner.33 Platelet aggregation inhibition is reversible after the cessation of the infusion. Renal clearance accounts for approximately 50% of total body clearance. The plasma half-life of eptifibatide is approximately 2.5 hours in patients with normal renal function and extends to .6 hours in patients with a CrCl ,30 mL/ min.34 With eptifibatide, dose adjustment is unnecessary for patients with a CrCl .50 mL/min. It is administered as an intravenous bolus of 180 mg/kg, immediately followed by a continuous infusion of 2.0 ug/kg/min. For patients with an estimated CrCl ,50 mL/ min, the infusion dose should be reduced to 1.0 mg/kg/min, whereas the bolus dose is unchanged. Eptifibatide use is contraindicated in hemodialysis patients.33 Tirofiban is a synthetic nonpeptide antagonist of the GP IIb/IIIa receptor. Like eptifibatide, the inhibition of platelet aggregation is dose and concentration dependent and reversible after cessation of the infusion. Its half-life is approximately 2 hours, and renal excretion accounts for 65% of clearance. Tirofiban is administered to patients with normal renal func-
tion as an initial loading intravenous infusion of 0.4 mg/kg/min for 30 minutes followed by a continuous infusion of 0.1 mg/kg/min. The loading infusion and maintenance infusion should be reduced by 50% in patients with a CrCl ,30 mL/min.35 Patients with moderate to severe renal dysfunction have largely been excluded from major clinical trials of GP IIb/IIIa inhibitors in the setting of ACS. Accordingly, Freeman et al36 performed a study to examine the in-hospital outcome and influence of GP IIb/IIIa inhibitor use on patients with ACS across a range of renal function. Results of this study showed that GP IIb/IIIa inhibitor use in this population was associated with both an increased risk of bleeding events (P , .001) and a decrease in the risk of in-hospital mortality (P ¼ .04). Januzzi et al37 also studied the role of tirofiban treatment in ACS patients with RI. Tirofiban treatment reduced the odds of the composite endpoint of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR] 0.68; 95% confidence interval [CI], 0.461.0; P ¼ .05), 7 days (OR, 0.68; 95% CI, 0.520.88; P ¼ .003), 30 days (OR 0.78; 95% CI, 0.63-0.98; P ¼ .03), and 6 months (OR, 0.81; 95% CI, 0.68-0.98; P ¼ .03), irrespective of CrCl. The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined, and there was no unexpected incremental risk of bleeding because of tirofiban among the lowest CrCl categories. An analysis of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/ American Heart Association Guidelines Registry was conducted to assess the rates and outcomes associated with excess dosing of GP IIb/IIIa inhibitors, heparin, and low– molecular-weight heparin in patients presenting with non–ST-segment elevation ACS.38 Excess dosing was noted in approximately 27% of patients treated with a GP IIb/IIIa inhibitor and was associated with a significant increase in the risk of a bleeding event and mortality. Factors associated with excess dosing of GP IIb/IIIa inhibitors included age .75 years, renal insufficiency, female sex, and low body weight. This analysis highlights
Antiplatelet Therapy in Uremic Patients
the importance of taking these factors into consideration when prescribing these agents. The impact of RI on outcomes in patients undergoing PCI with GP IIb/IIIa inhibitor use has also been studied. Best et al39 evaluated the safety of abciximab in patients with renal insufficiency undergoing PCI. This study displayed a trend toward an interaction between CrCl and major bleeding with abciximab (OR ¼ 1.18, P ¼ .06) and no interaction with minor bleeding (OR ¼ 1.01, P ¼ .94). Additionally, a post hoc analysis of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy Trial suggested the benefit of eptifibatide on the composite outcome of death, myocardial infarction, and urgent target vessel revascularization was maintained in patients with an estimated CrCl ,60 mL/min. No increase in bleeding risk was noted with the lower CrCl. Patients with a baseline creatinine .4 mg/dL were excluded from this trial.40 Berger et al41 evaluated whether outcome differences exist between GP IIb/IIIa inhibitors that are renally excreted (tirofiban) or not (abciximab) in patients with mild renal impairment. Their results displayed no interaction between these GP IIb/IIIa inhibitors and CrCl regarding ischemic (tirofiban [OR ¼ 0.93, P ¼.5]) or bleeding events (tirofiban; major bleeding [OR ¼ 1.00, P ¼ .997], minor bleeding [OR ¼ 1.26, P ¼ .13]). The results of these studies need to be confirmed in future randomized clinical trials.
Conclusion Patients with RI are at an increased risk for cardiovascular morbidity and mortality. Despite being at a substantial risk for thrombotic events, patients with RI also experience a greater number of hemorrhagic complications associated with antiplatelet therapy than individuals with normal renal function. Although recommendations have been proposed for the treatment of uremic bleeding,42 the management of bleeding events in ACS patients with RI receiving antiplatelet therapy remains poorly defined. Accordingly, the large RI population represents an ideal patient subset to investigate, on a large scale, patientspecific mechanisms (for thrombosis and hemorrhage) and optional pharmacologic therapies for common, coexisting disease states
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such as ACSs, stroke, and peripheral vascular occlusive disease as well as the bleeding events that are likely to occur. Unfortunately, many phase II and III clinical trials exclude patients with renal insufficiency, whereas others challenge the pharmacokinetic and pharmacodynamic data by using fixed doses in all but those with severe renal failure (CrCl ,30 mL/min) who are traditionally excluded from study entry. It is important that clinical trials begin efforts to address this issue. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative Practice Guidelines for Cardiovascular Disease in Dialysis Patients43 currently recommend treating dialysis patients presenting with ACS the same as those in the nondialysis population with the exception of paying specific attention to medications with altered clearances in kidney failure. Observational data have shown a benefit with the use of certain therapies in this population. However, patients with renal insufficiency are less likely to receive these lifesaving medications when compared with patients without renal insufficiency.21,44,45 Efforts should continue to be focused on improving quality for this population throughout our health care system.
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41. Berger PB, Best PJM, Topol EJ, et al: The relation of renal function to ischemic and bleeding outcomes with 2 different glycoprotein IIb/IIIa inhibitors: The Do Tirofiban and ReoPro Give Similar Efficacy Outcome (TARGET) trial. Am Heart J 149:869-875, 2005 42. Hedges SJ, Dehoney SB, Hooper JS, et al: Evidencebased treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 3:138-153, 2007 43. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 45: 16-153, 2005 44. Ezekowitz J, McAlister FA, Humphries KH, et al: The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol 44: 1587-1592, 2004 45. Berger AK, Duval S, Krumholz HM: Aspirin, betablocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction. J Am Coll Cardiol 42:201-208, 2003