Compared to unfractionated heparin (UFH), bivalirudin decreases bleeding during percutaneous coronary interventions (PCIs). We sought to investigate the association between periprocedural bleeding and 1-year mortality as a function of antithrombotic therapy with bivalirudin or UFH. This analysis of the association between bleeding with bivalirudin or UFH and 1-year mortality included the 4,570 patients with negative biomarkers enrolled in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 3) trial. Major or minor bleeding occurred in 555 patients (12.1%): 225 patients treated with bivalirudin (9.8%) and 330 patients treated with UFH (14.5%, p <0.001). There were 82 deaths (1.8%) within the first year after PCI: 29 deaths occurred in patients who had bled, and 53 deaths occurred in patients who had not bled (Kaplan-Meier estimates of 1-year mortality 5.2% and 1.3%, odds ratio 4.12, 95% confidence interval 2.59 to 6.54, p <0.001). One year after PCI, there were 15 deaths in patients who bled with bivalirudin versus 14 deaths in patients who bled with UFH (Kaplan-Meier estimates of 1-year mortality 6.7% vs 4.2%, odds ratio 1.61, 95% confidence interval 0.76 to 3.40, p = 0.20). Major bleeding occurred in 70 patients (3.0%) treated with bivalirudin and 104 patients treated with UFH (4.5%, p = 0.008). One-year mortality was 11.4% (n = 8) in patients with major bleeding with bivalirudin versus 4.8% (n = 5) in patients with major bleeding with UFH (p = 0.10). In conclusion, these data suggest that in patients with negative biomarkers undergoing PCI, bivalirudin decreases bleeding after PCI compared to UFH, without affecting 1-year mortality in those who had bled.
Several studies across a wide spectrum of patients have unequivocally demonstrated that bleeding complications are strongly associated with short- and long-term mortality after percutaneous coronary intervention (PCI). As recently shown by our group and others, peri-PCI bleeding is at least as strong as a correlate of mortality as myocardial infarction. Because of the strength of association between bleeding and mortality, inclusion of bleeding as a component of a quadruple end point together with death, myocardial infarction, and urgent revascularization to assess outcome after PCI has been proposed. Use of bivalirudin, a direct thrombin inhibitor, to provide anticoagulant/antithrombotic protection during PCI procedures in patients undergoing PCI for treatment of a variety of clinical syndromes has been associated with significantly fewer bleeding complications than heparin and a IIb/IIIa inhibitor and than heparin alone, yet was not associated with a decrease of ischemic complications or mortality in most trials in which it has been studied. However, the discrepancy between the impact of bivalirudin treatment on bleeding complications and ischemic complications and subsequent mortality remains unclear. The objective of this post hoc analysis of the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 3) trial was to investigate the association between periprocedural bleeding and 1-year mortality after administration of bivalirudin versus unfractionated heparin (UFH) in patients undergoing PCI.
Methods
This study included 4,570 patients with negative biomarkers undergoing PCI in the setting of the ISAR-REACT 3 trial enrolled from September 2005 to January 2008. The trial included 3,868 patients (84.6%) with stable coronary artery disease and 702 patients (15.4%) with an acute coronary syndrome. Details of the trial design, patient eligibility, and laboratory measurements were reported in the primary publication. Briefly, all study participants received aspirin 325 to 500 mg and a 600-mg loading dose of clopidogrel ≥2 hours before the PCI procedure. Patients were randomized to receive a 0.75-mg/kg bolus of bivalirudin followed by an infusion at 1.75 mg/kg/hour for the duration of the procedure (n = 2,289 patients) or a 140-U/kg bolus of UFH followed by a placebo infusion for the duration of the procedure (n = 2,281 patients). Patients (n = 42) at 1 center received an initial dose of heparin 100 U/kg and additional boluses of heparin or placebo thereafter if the activated clotting time was <250 seconds. Double blinding was achieved by use of identical-appearing vials in the 2 study groups. Postprocedural therapy included aspirin 80 to 325 mg/day indefinitely and clopidogrel 75 to 150 mg/day until discharge (but no longer than 3 days) followed by 75 mg/day for ≥1 month after placement of a bare-metal stent or 6 months after a drug-eluting stent. Other cardiac medications were left to the judgment of a patient’s physician. Written informed consent was obtained from all patients. The study was carried out in accordance with the Declaration of Helsinki and approved by institutional ethics committees of participating centers.
The primary end point of this analysis was the association between periprocedural bleeding and 1-year mortality after treatment with bivalirudin versus UFH in patients with negative biomarkers undergoing PCI as part of ISAR-REACT 3. Major bleeding was defined according to criteria used in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial: intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss resulting in a decrease in hemoglobin >3 g/dl; any decrease in hemoglobin >4 g/dl; or transfusion of ≥2 U of packed red blood cells or whole blood. Minor bleeding was defined as clinically overt bleeding that did not meet criteria for major bleeding.
The follow-up protocol after discharge consisted of a telephone interview at 1 month after the procedure, a visit at 6 months, and a telephone interview at 12 months. Information about death was obtained from hospital records, death certificates, or telephone contact with relatives of a patient or attending physician. Patients were advised to present to the outpatient clinic or their referring physicians if they developed chest pain or other cardiac symptoms. In such cases, appropriate clinical, laboratory, and electrocardiographic examinations were performed.
Data are presented as mean ± SD or count (percentage). Categorical data are compared with chi-squared test or Fisher’s exact test when cell values were <5. Continuous data are compared using the Wilcoxon rank-sum test. Survival analysis was performed by applying the Kaplan-Meier method. Differences in survival were assessed with log-rank test. Analyses were performed using S-PLUS (Insightful Corp., Seattle, Washington). A 2-sided p value <0.05 was considered to indicate statistical significance.
Results
Bleeding complications occurred in 555 patients (12.1%), i.e., in 225 patients treated with bivalirudin (9.8%) and 330 patients treated with UFH (14.5%, p <0.001). Major bleeding occurred in 70 patients treated with bivalirudin (3.0%) and 104 patients (4.5%, p = 0.008). Minor bleeding occurred 155 patients (6.8%) treated with bivalirudin and 226 patients (9.9%, p <0.001). Baseline characteristics of patients with and without bleeding are listed in Table 1 . Compared to patients who did not bleed, patients who bled were older, more often women, had a lower body mass index, and were more likely to have arterial hypertension, an acute coronary syndrome, and a complex coronary lesion. In contrast, those who bled were less likely to have hypercholesterolemia and previous myocardial infarction. Baseline characteristics of patients who bled with bivalirudin or UFH are listed in Table 2 . Patients who bled after receiving bivalirudin were more likely to have hypercholesterolemia and multivessel disease and had lower left ventricular ejection fractions than patients who bled after UFH.
| Characteristic | With Bleeding | Without Bleeding | p Value |
|---|---|---|---|
| (n = 555) | (n = 4,015) | ||
| Age (years) | 69.1 (63.5, 76.9) | 67.4 (59.9, 73.6) | <0.001 |
| Women | 202 (36%) | 873 (22%) | <0.001 |
| Body mass index (kg/m 2 ) | 26.6 (24.4, 29.3) | 27.2 (24.9, 29.9) | 0.006 |
| Diabetes mellitus | 160 (29%) | 1,094 (27%) | 0.43 |
| Arterial hypertension | 512 (92%) | 3,566 (89%) | 0.014 |
| Current smoker | 67 (12%) | 598 (15%) | 0.08 |
| Hypercholesterolemia (≥240 mg/dl) | 402 (72%) | 3,243 (81%) | <0.001 |
| Previous myocardial infarction | 150 (27%) | 1,273 (32%) | 0.025 |
| Previous coronary artery bypass | 66 (12%) | 468 (12%) | 0.87 |
| Stable angina pectoris | 439 (79%) | 3,429 (85%) | <0.001 |
| Acute coronary syndrome | 116 (21%) | 586 (15%) | <0.001 |
| Serum creatinine (mg/dl) | 0.9 (0.8, 1.1) | 0.9 (0.8, 1.1) | 0.22 |
| Number of narrowed coronary arteries | 0.10 | ||
| 1 | 98 (18%) | 813 (20%) | |
| 2 | 146 (26%) | 1,145 (29%) | |
| 3 | 311 (56%) | 2,057 (51%) | |
| Multivessel coronary disease | 457 (82%) | 3,202 (80%) | 0.15 |
| Complex coronary lesions | 824 (74%) | 4,422 (67%) | <0.001 |
| Left ventricular ejection fraction (%) | 60.0 (53.0, 65.0) | 60.0 (52.0, 65.0) | 0.44 |
| Type of intervention | <0.001 | ||
| Drug-eluting stent | 431 (78%) | 3,353 (83.5%) | |
| Bare-metal stent | 40 (7%) | 259 (6.5%) | |
| Balloon angioplasty | 84 (15%) | 403 (10%) |
| Characteristic | Bleeding With Bivalirudin | Bleeding With UFH | p Value |
|---|---|---|---|
| (n = 225) | (n = 330) | ||
| Age (years) | 69.0 (63.2, 77.5) | 69.3 (63.6, 76.8) | 0.48 |
| Women | 86 (38%) | 116 (35%) | 0.46 |
| Body mass index (kg/m 2 ) | 26.7 (24.2, 29.1) | 26.5 (24.5, 29.4) | 0.89 |
| Diabetes mellitus | 64 (28%) | 96 (29%) | 0.87 |
| Arterial hypertension | 209 (93%) | 303 (92%) | 0.64 |
| Current smoker | 26 (12%) | 41 (12%) | 0.76 |
| Hypercholesterolemia (≥240 mg/dl) | 174 (77%) | 228 (69%) | 0.03 |
| Previous myocardial infarction | 58 (26%) | 92 (28%) | 0.58 |
| Previous coronary artery bypass | 28 (12%) | 38 (11.5%) | 0.74 |
| Stable angina pectoris | 173 (77%) | 266 (81%) | 0.29 |
| Acute coronary syndrome | 52 (23%) | 64 (19%) | 0.29 |
| Serum creatinine (mg/dl) | 0.9 (0.8, 1.1) | 0.9 (0.8, 1.1) | 0.97 |
| Number of narrowed coronary arteries | 0.14 | ||
| 1 | 31 (14%) | 67 (20%) | |
| 2 | 62 (27.5%) | 84 (26%) | |
| 3 | 132 (58.5%) | 179 (54%) | |
| Multivessel coronary disease | 194 (86%) | 263 (80%) | 0.047 |
| Left ventricular ejection fraction (%) | 59.0 (51.0, 64.0) | 60.0 (55.0, 65.0) | 0.03 |
| Complex coronary lesions | 165 (73%) | 225 (68%) | 0.19 |
| Type of intervention | 0.03 | ||
| Drug-eluting stent | 176 (78%) | 255 (77%) | |
| Bare-metal stent | 9 (4%) | 31 (10%) | |
| Balloon angioplasty | 40 (18%) | 44 (13%) |
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