Anticoagulation in acute cardiac care in patients with chronic kidney disease

Curriculum in Cardiology

Anticoagulation in acute cardiac care in patients with chronic kidney disease Donal Reddan, MB, MHS, Lynda A. Szczech, MD, MSCE, Susan O’Shea, MB, and Robert M. Califf, MD Durham, NC

The number of patients with coexisting chronic kidney disease (CKD) and cardiovascular disease is growing rapidly. Treatment of these patients is challenging, primarily because of a lack of pharmacokinetic and clinical trial data associated with these combined disease entities. In this report, we discuss the cardiovascular disease risk associated with CKD and review the use of anticoagulation for acute cardiovascular disease in patients with CKD. We evaluate the potential role of direct thrombin inhibitors in patients with renal disease who have acute coronary syndromes, with particular focus on the clinical efficacy of bivalirudin. We conclude that direct thrombin inhibitors, including bivalirudin and argatroban, may be promising alternatives to heparin in patients who have renal insufficiency and are therefore at an increased risk for bleeding. In the treatment of patients with advanced renal insufficiency and cardiovascular disease, however, these agents should be used with dose modification to account for altered excretion. (Am Heart J 2003;145:586-94.)

Antithrombotic therapy is important in the management of acute coronary syndromes (ACS). However, in patients with renal insufficiency, the use of these agents is hampered by the absence of reliable pharmacokinetic and clinical trial data. Patients with coexistent cardiovascular and chronic kidney disease (CKD) present a number of treatment dilemmas that arise from lack of data and fear of adverse consequences. We discuss the cardiovascular disease risk associated with CKD, explore the use of anticoagulation in patients with ACS and CKD, and discuss the possible role of the direct thrombin inhibitor bivalirudin in such patients with ACS.

Clinical epidemiology The aging of the US population has led to a significant increase in both cardiovascular disease and renal disease. Currently, in the United States, there are approximately 350,000 patients with end-stage renal disease (ESRD [defined as patients receiving some form of renal replacement therapy]). This ESRD population continues to grow at a rate approaching 7% per year.1 Data from the National Health And Nutrition Examination Survey (NHANES III)2 published in 1998 estimated

From the Duke University Medical Center, Durham, NC. Guest Editor for this manuscript was Richard C. Becker, MD, University of Massachusetts Medical Center, Worcester, Mass. Supported by an educational grant from The Medicines Company, Cambridge, Mass. Submitted March 5, 2002; accepted July 2, 2002. Reprint requests: Donal Reddan, MB, MHS, Duke Institute of Renal Outcomes Research and Health Policy, Box 3646, Duke University Medical Center, Durham, NC 27710. E-mail: [email protected] Copyright 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1067/mhj.2003.168

the prevalence of CKD in the United States to be at least 3 million. This estimate was made on the basis of a CKD definition of baseline serum creatinine concentration ⬎1.7 mg/dL.2 When redefined by use of a serum creatinine concentration of 1.5 mg/dL as the cutoff point, the estimate was closer to 11 million people.2 Data from the Framingham Study suggest that approximately 8% of the population has renal insufficiency,3 and some studies suggest that even greater proportions of certain patient groups, such as older patients and patients from selected populations such as patients who are African American or Hispanic, are at risk for progressive renal insufficiency.4 When patients with cardiovascular disease are selected, there also appears to be an increased proportion of patients with CKD. The Heart Outcomes Prevention Evaluation (HOPE) trial investigators, despite excluding patients with creatinine concentrations ⱖ2.3 mg/dL, found that 11% of the study population had a creatinine concentration ⬎1.4 mg/dL.5 In phase III clinical studies with the direct thrombin inhibitor bivalirudin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), only 25% of patients had normal renal function (glomerular filtration rate [GFR] ⬎90 mL/ min), whereas 46% of patients had mild renal impairment (GFR 60-89 mL/min); 28% of patients had moderate renal impairment (GFR 30-59 mL/min); and ⬍1% of patients had severe renal impairment (GFR ⬍30 mL/ min).6 The consistent use of GFR, measured either directly or indirectly by use of approximation formulas, as opposed to serum creatinine concentration, could lead to even greater numbers of patients being identified as having CKD. The approximation formula currently recommended by the National Kidney Foundation is the equation developed by the Modification of

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Diet in Renal Disease (MDRD) Study Group.7 This formula differs from the more commonly used Cockcroft and Gault formula8 in that it incorporates serum albumin and blood urea nitrogen levels and also is adjusted for patient race. Patients with CKD have a higher prevalence of cardiovascular risk factors, and standard cardiovascular medications such as ␤-blockers, angiotensin– converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, aspirin, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are considerably under-prescribed to these patients (Table I).9 The etiology of cardiovascular disease in renal insufficiency is complex. Several factors underlie the increased risk, including greater prevalence and consequences of traditional coronary risk factors such as diabetes mellitus, lipid abnormalities, and hypertension.10-14 CKD has also been linked to alterations in components of vascular integrity, culminating in both bleeding risk and a thromboinflammatory state.15,16 Evidence supports chronic endothelial injury associated with elevated tissue plasminogen activator (tPA) and von Willebrand factor release.17 Uremia is also associated with elevated plasma levels of thrombin–antithrombin complex, fibrinopeptide A, and D-dimer, implicating an increase in thrombin generation.18 Similarly, heightened factor VII coagulant activity correlates with the increased cholesterol and triglyceride levels and thrombin generation.19 These risk factors are often coexistent and synergistic in their potentiation of atherosclerosis.20 Disorders of left ventricular structure and function are commonly associated with renal disease.21 Patients with CKD are also at considerable increased risk of adverse outcomes after cardiovascular events.22 In 1999, the first-year mortality rate for patients with ESRD was estimated to be 20%; approximately 50% of deaths were cardiac in origin.1 Patients with ESRD who experience myocardial infarction (MI) have an approximate 60% mortality rate during the subsequent year.23 Patients with ESRD who undergo surgical revascularization for peripheral vascular disease have a substantially increased mortality rate when compared with control subjects without ESRD.24 Available data suggest that a gradient of outcomes may exist for patients with coronary artery disease (CAD) and CKD, which is a function of the severity of renal insufficiency. In the Multiple Risk Factor Intervention Trial (MRFIT), change in creatinine concentration at 6 years was an independent risk factor for coronary heart disease and all-cause mortality.25 In MRFIT, a ⱖ18-␮mol/L increase in creatinine concentration in 6 years was associated with a 9.45% mortality rate (per 1000 person-years) in men with coronary heart disease and a 19.75% mortality rate for all causes. An increase in creatinine concentration of 0.09 to 18.00 ␮mol/L was associated

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Table I. Cardiovascular risk for patients with renal disease Population

Risk associated with renal insufficiency

Reference

ESRD Increase in overall mortality Increase in mortality after MI Inferior outcomes in patients undergoing PCI Increase in mortality after revascularization for PVD

1 23 27,28

Increase in risk for cardiac and all-cause mortality Doubling of 30-day mortality after CABG Increased mortality in coronary care unit A 40% increased risk for reaching primary outcome of cardiovascular death, MI, or stroke

25

24

CKD

26 22 5

ESRD, End-stage renal disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; CKD, chronic kidney disease; CABG, coronary artery bypass grafting.

with a 4.93% mortality rate in men with coronary heart disease and a 9.52% mortality rate for all causes.25 The largest study of CAD in patients with CKD compared outcomes in 3271 patients undergoing coronary artery bypass grafting (CABG) whose serum creatinine concentration was ⬍1.5 mg/dL and 631 patients whose serum creatinine concentration was 1.5 to 3.0 mg/dL.26 Patients in the higher creatinine level group were observed to have a 30-day mortality rate after CABG that was 2 times higher. Among patients admitted to the coronary care unit, an increase in mortality hazard has been demonstrated for those with renal dysfunction, with graded decrements in survival across increasing renal dysfunction strata.22 Inferior outcomes have also been demonstrated in patients with ESRD who are undergoing percutaneous coronary intervention (PCI).27,28 Multiple studies have compared CABG with PCI in patients with ESRD.29-32 Most of these analyses suggest that CABG may be the preferred therapy in ESRD. Two recent analyses suggested that patients with ESRD undergoing CABG procedures had better survival rates and fewer subsequent MIs than did patients with ESRD undergoing PCI.33,34 Recently, the HOPE trial investigators demonstrated a 40% increase in risk of reaching the primary outcome of cardiovascular death, MI, or stroke associated with mild levels of renal insufficiency (creatinine concentration ⬎1.4 mg/dL).5

Anticoagulation in CKD and ACS Since the 1960s, antithrombotic agents have been used in both medical and interventional therapeutic

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Table II. Anticoagulants and CKD in acute cardiac care Drug

Metabolism and excretion

FDA indication*

UFH LMWH Hirudin

Liver ⫹ kidney Kidney Kidney

None ACS HIT

Argatroban Bivalirudin

Liver ⫹ kidney Kidney ⫹ proteolytic cleavage

HIT PCI

Studies in CKD 39-44 49-53 66,67,69,71

75 77,83,84

Suggested dosing in CKD No dose adjustment recommended. Use with caution in CKD; consider monitoring anti-factor Xa levels. Dose reduction recommended for patients with renal impairment. Hirudin not recommended for patients with creatinine clearance ⬍30 mL/min. No dose reduction recommended. Dosage adjustment in moderate (30-59 mL/min) or severe (⬍30 mL/min) renal impairment.

UFH, Unfractionated heparin; LMWH, low molecular weight heparin; FDA, US Food and Drug Administration; CKD, chronic kidney disease, ACS, acute coronary syndrome; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention. *Includes indications for acute cardiac care only. Other indications for these anticoagulants are not specified in this table.

approaches for ACS. In general, treatment strategies are aimed at preventing the generation of or blocking the activity of thrombin, which plays a pivotal role in thrombotic events. The approach to anticoagulation for patients with renal impairment and ACS is more complex than that for patients with normal renal function (Table II). Among patients with renal impairment, there is a high prevalence of asymptomatic cardiac ischemia, there may be abnormal findings with baseline electrocardiograms (ECGs), and nonspecific elevation of cardiac enzymes may be present.35 Because patients with renal disease and subgroups of these patients are usually excluded from clinical trials for ACS, knowledge about pharmacokinetics for drugs and the best approach to treating these patients is insufficient.

Heparin Despite the dominant role of unfractionated heparin (UFH) as the mainstay in the treatment of patients with unstable angina and non–ST-segment elevation MI,36,37 surprisingly little is known about the most appropriate dosing in patients with CKD. There is great interindividual variability of the pharmacokinetic parameters of both UFH and low molecular weight heparin (LMWH). At higher doses of UFH, the proportion of drug that is renally cleared increases considerably.38 Heparin is cleared through a combination of rapid saturable and slower first-order mechanisms.39,40 The saturable phase of heparin clearance is attributed to binding to endothelial cell receptors41,42 and macrophages.43 The unsaturable mechanism of clearance is largely renal. At therapeutic doses, a considerable proportion of heparin is cleared through the rapid saturable, dose-dependent mechanism; however, at higher doses, a greater proportion of the drug is cleared renally. The intensity and duration of effect, therefore, rise disproportionately with increasing doses. Highpeak levels and prolonged heparin activity have been

reported in patients with impaired renal function (a blood urea level ⬎8 mmol/L, serum creatinine concentration ⬎120 ␮mol/L, or both) undergoing aortic surgery, which results in an increase in the requirement for blood replacement.44 In the study by House et al,44 the use of protamine to reverse anticoagulation was 4 times greater in the patients with renal impairment or clamping above the renal arteries (␹2 ⫽ 3.84, P ⫽ .05). Granger et al45 also demonstrated that heparin activity, as measured by activated partial thromboplastin time (aPTT), is inversely correlated with patient weight and is strongly associated with an increase in bleeding, mortality, and reinfarction rates. There have also been numerous reports of hyperkalemia caused by UFH,46,47 and it is reasonable to assume that this risk is higher in patients with CKD. However, the US Food and Drug Administration (FDA) labeling for heparin does not carry any warnings about renal insufficiency, and neither the package insert nor standard recommendations on dosing recognize the need for dose-adjustment in cases of renal insufficiency.36,37 Furthermore, despite its widespread use, heparin has no labeled indication for either PCI or ACS.

LMWH The 3 most commonly used LMWHs in the United States are dalteparin, tinzaparin, and enoxaparin. Dalteparin (Fragmin, Pharmacia Corporation, Peapack, NJ) is FDA-approved for the treatment of unstable angina and non–Q-wave MI for the prevention of ischemic complications in patients receiving concurrent aspirin therapy, and its use in such patients has been evaluated in clinical trials.48 Dalteparin is also approved for the prophylaxis of deep venous thrombosis (DVT). Tinzaparin (Innohep, Leo Pharmaceutical Products, Buckinghamshire, United Kingdom) is FDA-approved for the treatment of acute symptomatic DVT when administered in conjunction with warfarin sodium.

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Tinzaparin does not have an FDA-approved indication for ACS. Enoxaparin (Lovenox, Aventis Pharmaceuticals, Bridgewater, NJ) has FDA indications for prophylaxis of DVT, inhospital treatment of DVT, prophylaxis of ischemic complications of unstable angina, and non–Q-wave MI when administered concurrently with aspirin. LMWH has the potential benefits over UFH of improved bioavailability and decreased risk for heparininduced thrombocytopenia (HIT) or osteoporosis.37 However, because LMWH is renally cleared, it should be used with caution, if at all, in patients with renal impairment. There are conflicting data on the kinetics of LMWH in patients with renal disease. Several small clinical trials have compared the pharmacokinetics of LMWHs in patients with various degrees of renal insufficiency and healthy control subjects.49-52 Some of these studies have found that, after a single subcutaneous injection of LMWH, the half-life of the drug is significantly prolonged in patients with CKD.49,51 In addition, there are no published multidose pharmacokinetic studies on LMWHs that evaluate a possible accumulation of anticoagulant activity in patients with severe renal impairment. There are, however, numerous reports of hemorrhagic complications that have occurred with the use of LMWH in patients with renal impairment.53 Therefore, when these agents are used in patients with significant renal impairment, dose reduction and careful monitoring of anticoagulant effect are necessary. Because LMWH levels cannot be measured directly, anti-factor Xa levels are measured as a biomarker of LMWH treatment.54 Anti-factor Xa assays are not currently readily available and often can only be performed in a reference coagulation laboratory. The optimal time to perform an anti-factor Xa assay is 4 hours after a subcutaneous injection of LMWH, which corresponds to the peak level.37,55 It is also generally recommended that an anti-factor Xa assay, when needed, be measured after several doses to more closely approximate a “steady-state” level. The target therapeutic range for twice-daily administration is 0.6 to 1.0 IU/mL. Fewer data are available about the monitoring for once-daily dosing regimens, but a range of 1.0 to 2.0 IU/mL has been recommended. Monitoring is not indicated for prophylactic regimens of LMWH, unless there is concern about possible accumulation of the drug (eg, in cases of renal failure). FDA labeling for each of these drugs suggests the need for caution in patients with advanced renal insufficiency. The labeling for dalteparin states that in patients with chronic renal insufficiency who require hemodialysis, the mean terminal half-life of anti-factor Xa activity after a single intravenous dose was considerably longer than that in healthy volunteers, which suggests a significant risk for accumulation in such patients.

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Similar to labeling for dalteparin, the labeling for tinzaparin describes a longer half-life of anti-Xa activity after a single intravenous dose in 6 patients undergoing hemodialysis for chronic renal failure. A population pharmacokinetic analysis determined that tinzaparin sodium clearance on the basis of anti-Xa activity was related to creatinine clearance calculated by the Cockcroft Gault equation.8 (See also page 5 of the NDA on Innohep [tinzaparin sodium injection] available at: http://www.fda.gov/cder/foi/label/2000/20484lbl.pdf.) In this analysis, a reduction in tinzaparin sodium clearance in moderate (GFR 30-50 mL/min) and severe (GFR ⬍30 mL/min) renal impairment was observed. Patients with severe renal impairment exhibited a 24% reduction in tinzaparin sodium clearance when compared with the remainder of the patients in the study. The labeling, therefore, suggests that caution should be used in administering tinzaparin to patients with severe renal impairment: “Consistent with expected age-related changes in renal function, elderly patients and patients with renal insufficiency may show reduced elimination of tinzaparin sodium. Innohep should be used with care in these patients.”56 Results from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE) trial suggested that the lower recurrent ischemic event rate seen with the LMWH enoxaparin is achieved without an increase in major bleeding, but with an increase in minor bleeding complications, mainly because of injection-site ecchymosis.57 In addition, drug accumulation and an increase in bleeding risk have been described in patients with mild renal impairment (GFR 60-70 mL/min).58 In FDA labeling for enoxaparin, it is stated that apparent clearance and Amax (maximum area under the concentration curve) derived from anti-factor Xa values after single and multiple subcutaneous doses in elderly subjects were close to those observed in young subjects.59 In subjects with moderate renal impairment (creatinine clearance 30-80 mL/min), anti-factor Xa activity values were similar to those in healthy subjects. However, mean anti-factor Xa apparent clearance for subjects with severe renal impairment (creatinine clearance ⬍30 mL/min) was approximately 30% lower than the mean anti-factor Xa apparent clearance of control-group subjects. One of the precautions given by the Physicians’ Desk Reference59 states that, “Anti-factor Xa may be used to monitor the anticoagulant effect of Lovenox injection in patients with significant renal impairment. If during Lovenox injection therapy abnormal coagulation parameters or bleeding should occur, anti-factor Xa levels may be used to monitor the anticoagulant effects of Lovenox injection.”

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A therapeutic range for arterial monitoring of antifactor Xa levels has not been validated.

Thrombin inhibitors The limitations of heparin in the treatment of thrombosis have prompted the development of alternative antithrombotic agents, such as the direct thrombin inhibitors, recombinant(r)-hirudin, bivalirudin, and argatroban. Direct thrombin inhibitors inactivate thrombin by binding with either the active site, exosite, or both of thrombin, thereby preventing it from interacting with its substrates.60 In contrast to heparin, these agents do not require a plasma cofactor to elicit their anticoagulant effects.61 Direct thrombin inhibitors are able to inactivate fibrin– clot-bound thrombin and soluble thrombin. Conceptually, this may be an important antithrombotic effect, because fibrin– clot-bound thrombin is capable of activating platelets and generating fibrin.62 Additionally, direct thrombin inhibitors do not bind to plasma proteins and, as a result, have a more predictable anticoagulant effect.63,64

Recombinant-hirudin Hirudin is considered to be the prototype of direct thrombin inhibitors. Natural hirudin is produced in small amounts by the leech Hirudo medicinalis. Recombinant (r)-hirudin is a 65 amino acid (6979.5 d) molecule derived from yeast cells. Hirudin was approved by the FDA for the prevention of thrombosis in patients with known HIT in March 1998. Hirudin forms a slowly reversible, 1:1 stoichiometric complex with thrombin, in which its globular amino-terminal domain binds to the active site and its carboxy-terminal domain interacts with exosite 1 on thrombin.65 Recombinant hirudin has been tested in the form of desirudin66 and lepirudin67 in ACS. In both trials, patients with serum creatinine concentrations ⬎1.5 mg/dL were excluded, and yet there was an excess of bleeding in both trials that was most pronounced in patients with impaired creatinine clearance. Both trials also showed a modest benefit in the reduction of ischemic events. A systematic overview of all trials with direct thrombin inhibitors confirms these findings.68 Desirudin has been evaluated in a large trial of patients undergoing PCI.64 Renal impairment was not specified as an exclusion criterion in the report of the Hirudin in a European restenosis prevention triaL VERsus heparin Treatment In PTCA patients (HELVETICA) results, but it is possible that a number of patients with renal impairment were excluded, because it is stated in the report that 32% of patients screened were excluded for “a wide variety of reasons.”69 A reduction in ischemic events was observed in the first several days after treatment, but the benefit eroded in the next 6 months.

Hirudin is almost exclusively excreted by the kidneys and prolongs the aPTT in a dose-dependent manner. The risk of drug accumulation and bleeding is high in cases of renal failure, and dose reduction is necessary in patients with renal impairment. r-Hirudin is not recommended for patients with a creatinine clearance of ⬍15 mL/min.70 Formation of antihirudin antibodies is observed in approximately 40% of patients treated with r-hirudin. Although the clinical significance of these antibodies is not known, they may increase the anticoagulant effect of hirudin because of delayed renal elimination of active hirudin–antihirudin antibodies complexes. 71

Argatroban Argatroban (Argatroban-GlaxoSmithKline, Research Triangle Park, NC), a small-molecule synthetic derivative of L-arginine, is a direct thrombin inhibitor that has been approved by the FDA for use as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban has been used successfully in patients with heparin-induced thrombocytopenia in the setting of PCI.72 It has also been compared with heparin in patients receiving thrombolytic therapy for acute MI.73,74 Argatroban prevents and treats thrombosis by blocking the active site of thrombin. The HIT studies were completed on the basis of a historical control analysis, and the acute MI studies were exploratory phase II efforts. Argatroban has a half-life of 40 to 50 minutes. A steady-state anticoagulant effect is reached 1 to 3 hours after intravenous administration and is monitored by measuring the aPTT. Argatroban is primarily eliminated by hepatic metabolism and biliary secretion. Approximately 25% of each argatroban dose is known to be excreted in the kidney. Argatroban is excreted normally in patients with moderate renal failure,75 but lower doses of the drug must be given to patients with hepatic failure. Antibody formation has also not been detected with argatroban. The primary adverse effect of the drug is hemorrhage. Unfortunately, argatroban has not been tested in a large population of patients either undergoing PCI or with ACS. A large meta-analysis of patient data from randomized trials comparing direct thrombin inhibitors with heparin in patients undergoing PCI found that, compared with heparin, direct thrombin inhibitors were associated with a lower risk of the combined end point of death or MI at the end of treatment; this was primarily because of a reduction in MIs.68 Subgroup analyses suggested that the reduction in death or MI was seen with hirudin and bivalirudin, but not with other agents. Compared with heparin, hirudin increased the risk of major bleeding, but there was a reduction in bleeding with bivalirudin.68

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Bivalirudin Bivalirudin (Angiomax, formerly Hirulog, The Medicines Company, Cambridge, Mass) is a semisynthetically produced 20-amino acid polypeptide inhibitor of thrombin. It has been approved by the FDA for use as an anticoagulant in patients with unstable angina who are undergoing PTCA. It was designed by using hirudin as a model and, like hirudin, interacts with both the active site and exosite 1 on thrombin, forming a stoichiometric complex.76 Bivalirudin produces transient inhibition of thrombin60 and has a biological halflife of approximately 25 minutes after intravenous injection, as opposed to hirudin, which has a half-life of approximately 90 minutes.77 Antibody formation against bivalirudin has not been reported. Clinical trials examining the use of bivalirudin and hirudin for ACS have shown both these agents to be superior to heparin for thrombin inhibition. In addition, bivalirudin has been shown to have a significantly decreased incidence of bleeding in patients with ACS and in patients undergoing PCI.78-80 When combined with abciximab in the treatment of patients undergoing elective PCI procedures in a pilot study, the combined incidence of MI, revascularization, or major hemorrhage reported within 7 days was 3.5% (5/144) in bivalirudin patients and 14.1% (9/64) in a comparison heparin/abciximab group.81 The pharmacokinetics and pharmacodynamics of bivalirudin are similar in patients with normal renal function and patients with mild renal impairment. An analysis of renal function in bivalirudin patients was undertaken by using the database of 2 phase III trials that included 4312 patients with unstable angina who were undergoing PTCA and who were treated with bivalirudin versus heparin.82 Patients were stratified into 4 groups: normal renal function (GFR ⬎90 mL/ min); mild renal impairment (GFR 60-89 mL/min); moderate renal impairment (GFR 30-59 mL/min); and severe renal impairment (GFR ⬍30 mL/min). The frequency of major bleeding episodes increased with both heparin and bivalirudin as the degree of renal function deteriorated, except in the group of patients with severe renal impairment who received bivalirudin; the small number of patients in the severe renal impairment group, however, renders interpretation of the results difficult. The rate of major hemorrhage was significantly higher in patients treated with heparin than in patients treated with bivalirudin, regardless of renal function (Table III). Further analysis showed GFR category to be a greater factor than age or sex in accounting for variability in bleeding rates among patients receiving bivalirudin, but GFR did not fully account for the increased bleeding risk in women. Women were significantly more likely than men to have a bleeding event, after adjusting for GFR category

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Table III. Rates of hemorrhage in patients treated with bivalirudin versus heparin Degree of impairment (GFR; mL/min)

Bivalirudin, n/N (%)

Heparin, n/N (%)

None (⬎90 mL/min) Mild (60-⬍89 mL/min) Moderate (30-⬍59 mL/min) Severe (⬍30 mL/min)

6/483 (1.2%) 17/884 (1.9%) 32/529 (6.0%) 0 (0%)

15/481 (3.1%) 74/870 (8.5%) 65/513 (12.7%) 3/15 (20.0%)

The rate of major hemorrhage was significantly higher in patients treated with heparin than in those treated with bivalirudin regardless of renal function. GFR, Glomerular filtration rate. Reprinted with permission from: Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol 2000;12(F Suppl):33-6F.

and age. Although the dose was unadjusted in this trial, the benefits of bivalirudin over heparin were still evident. Patients with renal impairment were examined specifically in a study that showed similar aPTT profiles for normal (GFR ⱖ90 mL/min), mildly impaired (GFR 60-89 mL/min), and moderately impaired (GFR 30-59 mL/min) renal function with bivalirudin.77 The mean aPTT was higher in groups of patients with severe renal impairment (GFR ⬍30 mL/min) and in patients requiring hemodialysis than in the other 3 groups. The derived maximal effect (Emax) for each group was as follows: normal, 58.3 seconds; mildly impaired, 44.7 seconds; moderately impaired, 58.6 seconds; severely impaired, 79.4 seconds; and dialysis-dependent, 84.4 seconds. For patients with normal renal function, bivalirudin was characterized by rapid plasma clearance (4.58 mL/min/kg) and a small volume of distribution (0.2 L/kg).6 In patients with moderate or severe renal impairment, including those on dialysis, the rate of renal clearance was reduced. Drug half-life ranged from 0.37 to 1.06 hours in patients with normal renal function and increased to between 0.43 and 7.01 hours in patients with severe renal impairment and to 1.33 to 5.62 hours in patients undergoing dialysis.77 Clearance of bivalirudin was found to be markedly reduced in a group of 12 patients undergoing dialysis. A 77% lower clearance rate was noted in patients undergoing dialysis, 1.04 mL/min/kg compared with 4.58 mL/min/kg for patients with normal renal function. In another open-labeled trial, the pharmacokinetics/ pharmacodynamics of bivalirudin were assessed in 30 patients undergoing PTCA who were stratified by renal function.83 Patients were characterized by estimated GFR into groups on the basis of renal function: normal (ⱖ90 mL/min), mildly impaired (60-89 mL/min), and moderately impaired (30-59 mL/min). Plasma clearance of the drug was 3.4 mL/min in normal, 3.5 mL/min in mild, and 2.7 mL/min in severe renal impairment. In addition to significantly reduced clearance, patients

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with renal impairment had higher activated clotting times and increased serum concentrations of bivalirudin.83 Dosage adjustment is therefore advisable in patients with moderate and severe renal impairment because of increased plasma levels and evidence of a strong correlation between aPTT and plasma bivalirudin levels.77 Because patients with renal insufficiency have a higher incidence of major bleeding independent of anticoagulant therapy,6,35 any therapy that may increase this risk needs to be considered carefully. The Hirolog and Early Reperfusion or Occlusion (HERO)-2 study (an open-label randomized trial comparing bivalirudin with heparin in patients undergoing fibrinolysis with streptokinase for acute myocardial infarction) is relevant in this context.84 The findings of the study were that bivalirudin reduced the rate of adjudicated MI but was not associated with a reduction in mortality rate and was associated with an increase in mild and moderate bleeding rates.84

The future There is a notable absence of comprehensive data supporting the use of anticoagulants in the large and growing population of patients with CKD who have ACS or are undergoing PCI. Many of the drugs have not been tested in patients with varying degrees of renal insufficiency and therefore must be used in the absence of adequate dosing information. It is becoming increasingly evident that GFR-based pharmacokinetic studies will be required in the future to support the use of these drugs. The under-appreciated prevalence of CKD mandates such an approach, because a significant proportion of the population either may not be treated with anticoagulants or may receive a dose that could markedly increase the risk of bleeding. The issue of risk related to increased bleeding complications relative to possible benefit in this high-risk population needs to be further explored. It is also important that all large future trials of these agents do not exclude patients with renal insufficiency and prospectively gather data on renal function so that the potential for benefit can be appreciated.

Conclusion CKD is a significant risk factor for cardiovascular disease and for adverse outcomes among patients with cardiovascular disease. Direct thrombin inhibitors appear to be a promising alternative to heparin in the management of cardiovascular disease in cases in which heparin use may be associated with an increase in bleeding risk, such as renal insufficiency. Argatroban is hepatically metabolized, and thus its use is attractive in patients with CKD, but it has not been tested in large PCI or ACS populations. Bivalirudin has the po-

tential advantages of a more predictable dose response, a shorter half-life compared with the other direct thrombin inhibitors, and lack of antibody formation. The results of clinical studies with bivalirudin versus heparin for patients with ACS or patients undergoing PCI have shown that bivalirudin can reduce ischemic events while reducing the risk of bleeding. Further studies to evaluate this and other compounds used in the management of ACS and PCI that measure clinical outcomes are needed to guide clinicians in avoiding untoward harm from improper dosing.

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