Chronic dialysis-dependent patients undergoing percutaneous coronary intervention (PCI) are at a greater risk of bleeding and ischemic events. Bivalirudin has been associated with fewer bleeding complications than unfractionated heparin (UFH) in patients undergoing PCI in various clinical settings. These studies, however, have systematically excluded patients dependent on chronic dialysis. We sought to assess the safety, bleeding rates, and in-hospital outcomes of bivalirudin use compared to UFH use alone in patients requiring dialysis and undergoing PCI. A retrospective analysis of 396 dialysis-dependent patients undergoing PCI from January 2000 to March 2009 was performed. Patients treated with a dose-adjusted bivalirudin regimen (n = 267) were compared to those treated with UFH alone (n = 129). The primary end point of major bleeding (hematocrit decrease ≥15%, gastrointestinal or intracerebral bleeding) and the composite end point of in-hospital death, nonfatal Q-wave myocardial infarction, and urgent target vessel revascularization were compared between groups. The baseline characteristics were similar between the 2 groups, except for the proportion of men and nonsmokers and body mass index, which were greater in patients treated with bivalirudin. The rate of major bleeding was similar between the bivalirudin and UFH groups (3.4% vs 3.1%, respectively, p = 0.9). The rate of the composite end point (death, Q-wave myocardial infarction, urgent target vessel revascularization) was not significantly different between the 2 groups (1.8% for bivalirudin vs 0.8% for UFH group, p = 0.7). After adjustment, bivalirudin use was not associated with major bleeding (odds ratio 1.23, 95% confidence interval 0.37 to 4.13, p = 0.7). In conclusion, a dose-adjusted bivalirudin anticoagulation regimen for patients requiring chronic dialysis undergoing PCI seems to be as safe and as effective as UFH use alone. These results do not suggest the superiority of bivalirudin over UFH.
In the era of modern interventional cardiology, chronic renal insufficiency remains associated with a poor clinical outcome after percutaneous coronary intervention (PCI). In particular, the prognosis of chronic dialysis-dependent patients is even worse: the procedural success is reduced, bleeding complications are more frequent, and the incidence of subsequent ischemic cardiac events and mortality is increased. The use of bivalirudin instead of unfractionated heparin (UFH) for intraprocedural anticoagulation has been shown to decrease the incidence of bleeding complications in patients undergoing PCI in a variety of clinical scenarios. This beneficial effect has also been reported in patients with chronic kidney disease. In an analysis of pooled data from multiple randomized trials and a subanalysis of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) study, Chew et al suggested that the use of bivalirudin, instead of UFH, for intraprocedural anticoagulation provides a greater benefit in patients with impaired renal function. However, in these studies, dialysis-dependent patients were systematically excluded. The present study was undertaken to determine whether a similar or greater benefit might accrue if UFH was replaced with bivalirudin in this population subset.
Methods
An ongoing registry of catheter-based coronary procedures is maintained at our institution. From January 2000 to March 2009, all chronic dialysis-dependent patients who underwent PCI were identified. Those undergoing rescue PCI, presenting with cardiogenic shock, or those treated with an intra-aortic balloon pump were excluded from the present analysis. Because the study aimed to compare 2 anticoagulant regimens, patients receiving glycoprotein IIb/IIIa inhibitors were also excluded. The study cohort was composed of 396 patients. Patients treated with bivalirudin (n = 267) were compared to those treated with UFH alone (n = 129).
Coronary stenting was performed using conventional techniques. The interventional strategy was left to the discretion of the operator. In >99%, a femoral approach was used. In all cases, the interventional strategy was at the discretion of the physician who chose the type of implanted stent (either a bare metal stent or a drug-eluting stent), the use of ablative devices, and the antithrombotic regimen. All patients received aspirin 325 mg/day for ≥24 hours before the procedure and continued this regimen indefinitely. Additional antiplatelet therapy with clopidogrel 75 mg/day (after a loading dose of 300 or 600 mg) or ticlopidine 250 mg twice daily was instituted in all patients and was recommended for ≥12 months for patients with acute coronary syndrome, 3 months for stable patients who received a bare metal stent, and 6 months for stable patients who received drug-eluting stent placement.
As recommended by the manufacturer’s instructions, patients receiving renal dialysis therapy who received bivalirudin were given a bolus dose of 0.75 mg/kg followed by an infusion of 0.25 mg/kg/hour for the duration of procedure. If the activated clotting time was <250 seconds at 5 minutes after the start of the infusion, an additional bivalirudin bolus of 0.3 mg/kg was administered. Patients receiving UFH were given a bolus of 50 to 70 U/kg, and additional UFH was given to achieve an activated clotting time >250 seconds. The activated clotting time was routinely measured (Hemocron, International Technidyne, Edison, New Jersey) for all patients before and during PCI and before sheath removal if the patient had not received a closure device.
Blood samples were routinely drawn from all patients before and after the intervention at 6 and 24 hours to assess creatine kinase-MB enzymes. In the case of elevated values, measurements were repeated every 8 hours until the peak value was reached and the values began returning back to normal.
The primary safety end point was in-hospital major bleeding. The primary ischemic end point was the composite of in-hospital death, Q-wave myocardial infarction, and urgent target vessel revascularization. Death was defined as all causes of mortality. Q-wave myocardial infarction was defined as new pathologic Q waves in ≥2 contiguous leads associated with creatine kinase-MB ≥2 times the upper limit of normal. Urgent target vessel revascularization was defined as unplanned ischemia-driven percutaneous or surgical revascularization of the treated vessel. Procedural success was defined as the attainment of both Thrombolysis In Myocardial Infarction flow grade 3 and residual stenosis <30%. Stent thrombosis was defined as evidence of angiographic thrombus of the target lesion on either angiography or autopsy. Major bleeding was defined as a decrease in hematocrit of ≥15% and/or the occurrence of gastrointestinal bleeding and/or intracerebral bleeding. Bleeding was also classified according to the criteria of the Thrombolysis In Myocardial Infarction study group. Coronary artery bypass graft-related bleeding was excluded from these definitions. Gastrointestinal bleeding was defined as evidence of an upper (coffee-ground emesis or endoscopy demonstrating active bleeding) or lower (melena or endoscopy demonstrating active bleeding) gastrointestinal tract bleeding. Major hematoma was defined as hematoma measuring ≥4 cm or that requiring transfusions or necessitating prolonged hospitalization.
All data collection, management, and analyses were performed by a dedicated data coordinating center (Data Center, Cardiovascular Research Institute, Washington, DC). The data center staff, who were unaware of the study objectives, abstracted the demographic, clinical, and procedural information by hospital chart review. They also recorded in-hospital outcomes. Source documentation of all reported clinical events was obtained, and their nature was then adjudicated by independent physicians not involved in the study. Continuous variables are presented as the mean ± SD except for the laboratory characteristics, which are presented as the median (twenty-fifth to seventy-fifth percentiles) because of the nongaussian distribution. Categorical variables are expressed as percentages. Student’s t test and the Mann-Whitney U test were used to compare continuous variables, and the chi-square test or Fischer’s exact test was used to compare categorical variables, as appropriate. A multivariate logistic regression analysis was used to identify predictors of the primary safety end point, major bleeding. The variables included in the univariate model were age, male gender, diabetes mellitus, systemic hypertension, current smoker, body mass index, initial presentation with ST-elevation myocardial infarction (primary angioplasty), and bivalirudin use. The final multivariate model included body mass index (the only variable with p <0.20 in the univariate model) and bivalirudin use. All statistical analyses were performed using Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina). Statistical significance was assumed at p <0.05.
Results
Of the 396 patients receiving chronic dialysis included in the present study, 267 (67.4%) received bivalirudin as an anticoagulant during PCI, and 129 (32.6%) received UFH. As listed in Table 1 , most baseline characteristics were similar between the 2 groups. Patients in the bivalirudin group were more likely to be men, not a current smoker, and to have a greater body mass index. The mean age was ≈66 years old, ≈63% were diabetic, and almost 98% were hypertensive. More than 40% of patients had a history of myocardial infarction, and approximately 45% had a history of congestive heart failure. The initial PCI indication was stable coronary artery disease in 21% of the patients.
| Variable | Bivalirudin (n = 267) | UFH (n = 129) | p Value |
|---|---|---|---|
| Age (years) | 66.3 ± 10.6 | 65.2 ± 12.1 | 0.360 |
| Men | 152/267 (56.9%) | 59/128 (46.1%) | 0.043 |
| Family history of coronary artery disease ⁎ | 108/250 (43.2%) | 48/117 (41.0%) | 0.695 |
| Diabetes mellitus † | 186/265 (70.2%) | 81/129 (62.8%) | 0.140 |
| Systemic hypertension ‡ | 261/266 (98.1%) | 125/129 (96.8%) | 0.482 |
| Current smoker | 37/267 (13.9%) | 28/129 (21.7%) | 0.048 |
| Body mass index (kg/m 2 ) | 28.2 ± 7.0 | 26.3 ± 5.5 | 0.005 |
| Hypercholesterolemia § | 230/263 (87.5%) | 106/126 (84.1%) | 0.371 |
| Previous myocardial infarction | 97/224 (43.3%) | 49/109 (45.0%) | 0.776 |
| Previous coronary artery bypass grafting or percutaneous coronary intervention | 101/267 (37.8%) | 54/129 (41.8%) | 0.440 |
| Previous cardiac heart failure | 112/261 (42.9%) | 57/123 (46.3%) | 0.528 |
| Stable coronary artery disease ¶ | 61/267 (22.8%) | 21/129 (16.3%) | 0.131 |
| Acute coronary syndrome | 206/267 (77.2%) | 108/129 (83.7%) | 0.146 |
| ST-segment elevation myocardial infarction (primary percutaneous coronary intervention) | 29/267 (10.9%) | 11/129 (8.5%) | 0.470 |
| Left ventricular ejection fraction (%) | 44 ± 16 | 40 ± 15 | 0.076 |
| Normal creatine kinase-MB | 211/267 (79.0%) | 100/129 (77.5%) | 0.732 |
| Hematocrit (%) | 35.6 (31.5–40.1) | 34.6 (30.6–38.9) | 0.238 |
| Platelet (10 3 /mm 3 ) | 214 (167–265) | 224 (173–276) | 0.268 |
| Glucose (mg/dl) | 115 (89–146) | 113 (86–160) | 0.779 |
| Creatinine (mg/dl) | 6.0 (4.0–8.2) | 6.7 (5.1–8.8) | 0.011 |
| Creatinine clearance ∥ (ml/min) | 12.1 (8.7–17.3) | 9.9 (7.6–13.2) | 0.001 |
| Normal creatine kinase-MB | 211/267 (79.0%) | 100/129 (77.5%) | 0.732 |
⁎ Defined as family history of CAD (myocardial infarction, angina pectoris, revascularization, and sudden unexplained death) in first-degree relative.
† Defined as any history of diabetes mellitus and/or use of hypoglycemic drugs; included new diagnosis during index hospitalization with fasting glucose level of ≥1.26 g/L on ≥2 different occasions.
‡ History of systemic hypertension diagnosed and/or treated with medication or currently being treated with diet and/or medication by a physician.
§ Included patients with previously documented diagnosis of hypercholesterolemia; patients could be treated with diet or medication; and a new diagnosis could be made during this hospitalization by elevated total cholesterol >160 mg/dl; did not include elevated triglycerides.
¶ Included patients with silent ischemia and stable angina.
The angiographic and procedural characteristics are summarized in Table 2 . The differences were few between groups in terms of angiographic and procedural characteristics. Treated restenotic lesions were more frequent in the UFH group, and drug-eluting stent use was more frequent in the bivalirudin group. Angiographic success was similarly high in the bivalirudin and UFH groups (97.3% vs 95.6%, respectively). No difference was found in the rate of procedural complications. The bivalirudin mean dose was 97 ± 7 mg (total dose including the bolus and infusion). The UFH mean dose was 4,885 ± 2,451 U. In the bivalirudin group, 13 patients (4.8%) also received a small amount of UFH (192 ± 383 U). The maximum activating clotting time recorded was 323 ± 63 seconds in the bivalirudin group and 292 ± 144 in the UFH group (p = 0.02).
| Variable | Bivalirudin (n = 267) | UFH (n = 129) | p Value |
|---|---|---|---|
| Patient based | |||
| Bivalirudin use | 267/267 (100%) | 0 | — |
| Unfractionated heparin use | 13/267 (4.8%) | 129/129 (100%) | <0.001 |
| No. of narrowed coronary arteries | 2.16 ± 0.83 | 2.12 ± 0.89 | 0.757 |
| No. of stents implanted | 1.44 ± 0.96 | 1.67 ± 1.04 | 0.088 |
| Maximum activated clotting time (s) | 323 ± 63 | 292 ± 144 | 0.021 |
| Closure device used | 124/262 (47.3%) | 34/90 (37.8%) | 0.116 |
| Length of hospital stay (days) | 6.2 ± 6.5 | 7.0 ± 7.6 | 0.280 |
| Lesion based | |||
| Target coronary vessel | |||
| Left main | 12/493 (2.4%) | 1/230 (0.4%) | 0.072 |
| Left anterior descending | 173/493 (35.1%) | 86/230 (37.4%) | 0.548 |
| Left circumflex | 123/493 (24.9%) | 52/230 (22.6%) | 0.494 |
| Right | 158/493 (32.0%) | 71/230 (30.9%) | 0.751 |
| Saphenous vein graft | 25/493 (5.1%) | 20/230 (8.7%) | 0.060 |
| Internal mammary | 2/493 (0.4%) | 0 | — |
| Type (ACC/AHA class) | |||
| Type B1/B2 | 323/477 (67.7%) | 151/223 (67.7%) | 1.000 |
| Type C | 126/477 (26.4%) | 56/223 (25.1%) | 0.714 |
| Restenotic lesion | 11/492 (2.2%) | 15/230 (6.5%) | 0.004 |
| Rotational atherectomy | 12/493 (2.4%) | 6/230 (2.6%) | 0.888 |
| Angiographic success | 477/490 (97.3%) | 218/228 (95.6%) | 0.220 |
| Drug-eluting stent | 297/464 (64.0%) | 103/220 (46.8%) | <0.001 |
| Stent length (mm) | 19.3 ± 6.6 | 19.6 ± 6.2 | 0.742 |
| Stent diameter (mm) | 3.21 ± 1.81 | 3.09 ± 0.96 | 0.792 |
| No reflow | 1/481 (0.2%) | 1/225 (0.4%) | 1.000 |
| Dissection | 3/483 (0.6%) | 0 | 0.556 |
| Abrupt closure | 1/485 (0.2%) | 0 | 1.000 |
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