Clinical outcomes in patients with acute coronary syndromes randomized in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial who underwent percutaneous coronary intervention (PCI) of saphenous vein grafts (SVGs) were examined. The ACUITY trial assessed the safety and efficacy of bivalirudin alone versus bivalirudin plus a glycoprotein (GP) IIb/IIIa inhibitor versus heparin plus a GP IIb/IIIa inhibitor in 13,819 patients with moderate- and high-risk acute coronary syndromes, 7,789 of whom underwent PCI. A total of 329 patients (4.2%) underwent PCI of SVGs in ACUITY. The primary end points at 30 days were composite ischemia or major adverse cardiac events (death, myocardial infarction, or unplanned target vessel revascularization), major bleeding (unrelated to coronary artery bypass grafting), and net adverse clinical events (composite ischemia or major bleeding). The rates of ischemic, bleeding, and net clinical end points were similar with bivalirudin monotherapy, bivalirudin plus a GP IIb/IIIa inhibitor, and heparin plus a GP IIb/IIIa inhibitor. Net adverse clinical outcome rates at 30 days were 22%, 26%, and 22% (p = 0.67), respectively, for the 3 groups. Major adverse cardiac event rates at 1 year were 37%, 37%, and 43% (p = 0.95), respectively. Minor bleeding unrelated to coronary artery bypass grafting at 30 days was significantly lower with bivalirudin alone compared with heparin plus a GP IIb/IIIa inhibitor (26% vs 38%, p = 0.05). In conclusion, bivalirudin is an effective anticoagulant in PCI of SVGs in acute coronary syndromes, with similar rates of major adverse cardiac events and net adverse cardiac events and lower minor bleeding complications in comparison with heparin plus a GP IIb/IIIa inhibitor or bivalirudin plus a GP IIb/IIIa inhibitor.
Percutaneous coronary intervention of saphenous vein grafts (SVGs) is considered a high-risk subset, and scarce information exists regarding contemporary antithrombotic regimen in SVG intervention. The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial was a prospective, open-label, randomized, multicenter trial of 13,819 patients with unstable angina and non–ST elevation myocardial infarctions who an underwent early invasive management strategy. In this trial, the pharmacologic management strategy was randomized among bivalirudin alone, bivalirudin plus a glycoprotein (GP) IIb/IIIa inhibitor, or heparin plus a GP IIb/IIIa inhibitor. A total of 329 patients in the trial underwent percutaneous coronary intervention of SVGs, and we sought to examine their clinical outcomes in this analysis.
Methods
The design of the ACUITY trial has been described in detail previously. Briefly, inclusion criteria for the study were age >18 years with symptoms of unstable angina or non–ST elevation myocardial infarction. Major exclusion criteria included acute ST elevation myocardial infarction or shock; bleeding diathesis or major bleeding episode within 2 weeks; thrombocytopenia; calculated creatinine clearance <30 ml/minute; recent administration of abciximab, warfarin, fondaparinux, fibrinolytic agents, bivalirudin, or ≥2 doses of low–molecular mass heparin; and allergy to study drugs or iodinated contrast that could not be adequately premedicated. The study was approved by the institutional review board or ethics committee at each participating center, and all patients gave written informed consent.
Patients were assigned to 1 of 3 antithrombin regimens: heparin (either unfractionated heparin or enoxaparin) plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. In the 2 groups in which patients were assigned to a GP IIb/IIIa inhibitor–based regimen, they were randomized once again in a 2 × 2 factorial design to upstream GP IIb/IIIa inhibitor initiation in all patients immediately after randomization versus deferred GP IIb/IIIa inhibitor initiation for selective use in the catheterization laboratory starting immediately before percutaneous intervention. The provisional use of a GP IIb/IIIa inhibitor was permitted before angiography in patients randomized to the deferred use of a GP IIb/IIIa inhibitor or bivalirudin monotherapy for severe breakthrough ischemia and during percutaneous intervention in bivalirudin monotherapy patients for prespecified procedural complications.
Angiography was performed by protocol <72 hours after randomization, after which the decision was declared and recorded for primary treatment, either with percutaneous coronary intervention, coronary artery bypass graft surgery, or medical management. All antithrombin agents were routinely discontinued per protocol at the completion of angiography or percutaneous coronary intervention. Aspirin (300 to 325 mg orally or 250 to 500 mg intravenously) was administered daily during hospitalization. The initial dosing and timing of clopidogrel were left to investigator discretion per local standards, although a loading dose of ≥300 mg was required no later than 2 hours after percutaneous coronary intervention in all patients. Clopidogrel 75 mg/day was recommended for 1 year in all patients after percutaneous coronary intervention, and aspirin 75 to 325 mg/day was recommended indefinitely.
The end points of the trial have been described previously. Briefly, 3 primary end points were composite ischemia or major adverse cardiac events (MACEs), major bleeding not related to coronary artery bypass graft surgery, and net adverse clinical events (NACEs). Major bleeding was defined as intracranial or intraocular bleeding, hemorrhage at the access site requiring intervention, hematoma with a diameter of 5 cm, a reduction of hemoglobin level ≥4 g/dl without a source or ≥3 g/dl with a source, reoperation for bleeding, or transfusion of a blood product. Types of minor bleeding included ecchymoses, epistaxis, gastrointestinal bleeding, genitourinary bleeding, bleeding at the puncture site, and hemopericardial and pulmonary bleeding.
Of 7,789 percutaneous coronary interventions in ACUITY, 329 patients (4%) underwent percutaneous intervention of SVGs and constituted the focus of this analysis. Although patients who underwent SVG intervention represented a prespecified subgroup for analysis, the ACUITY trial was not powered for formal noninferiority or superiority analysis of this or any subgroup. Statistical comparisons were conducted for the purpose of hypothesis generation. All analyses used the intention-to-treat population. Categorical variables were compared using chi-square or Fisher’s exact tests. Continuous variables were compared using the nonparametric Wilcoxon’s rank-sum test. Medians and interquartile ranges are presented for continuous variables. The power analysis and sample size determination method for the ACUITY trial has been described previously.
Results
Of a total of 329 patients who underwent percutaneous coronary intervention of SVGs in the ACUITY trial, 114 (34%) were randomized to bivalirudin alone, 114 (34%) to bivalirudin plus a GP IIb/IIIa inhibitor, and 101 (31%) to heparin plus a GP IIb/IIIa inhibitor (control). Diagnoses of non–ST elevation myocardial infarctions on presentation (increased creatine kinase-MB isozyme or troponin) were documented in 168 patients (54%); 169 (61%) had high-risk Thrombolysis In Myocardial Infarction (TIMI) scores, and 98 (36%) had intermediate-risk score. Baseline characteristics were similar among all 3 randomized groups and are listed in Table 1 . The rates of clopidogrel preloading were similar in all 3 arms and similar to the original ACUITY study: 66% in the heparin plus GP IIb/IIIa inhibitor arm, 69% in the bivalirudin plus GP IIb/IIIa inhibitor arm, and 75% in the bivalirudin alone arm (p = 0.32).
| Variable | Heparin Plus GP IIb/IIIa Inhibitor | Bivalirudin Plus GP IIb/IIIa Inhibitor | Bivalirudin (n = 114) | p Value |
|---|---|---|---|---|
| (n = 101) | (n = 114) | |||
| Mean age (years) | 70 | 68 | 68 | 0.81 |
| Men | 79% | 83% | 78% | 0.69 |
| Diabetes mellitus | 48% | 41% | 40% | 0.45 |
| Insulin requiring | 15% | 13% | 13% | 0.92 |
| Hypertension | 88% | 81% | 83% | 0.38 |
| Current smokers | 18% | 17% | 12% | 0.46 |
| Previous myocardial infarction | 53% | 55% | 60% | 0.59 |
| Previous percutaneous coronary intervention | 70% | 66% | 60% | 0.30 |
| Baseline ST-segment deviation ≥1 mm | 31% | 29% | 31% | 0.95 |
| Elevated cardiac biomarker or ST-segment deviation ≥1 mm | 59% | 66% | 70% | 0.23 |
| Elevated cardiac biomarker (creatine kinase-MB or troponin) | 51% | 53% | 59% | 0.47 |
| TIMI risk score | ||||
| 0–2 | 5% | 2% | 5% | 0.53 |
| 3–4 | 30% | 39% | 36% | 0.44 |
| 5–7 | 65% | 59% | 59% | 0.63 |
| Thrombus | 20% | 17% | 23% | 0.54 |
| Previous aspirin treatment | 100% | 98% | 97% | 0.28 |
| Previous thienopyridine exposure | 66% | 70% | 75% | 0.33 |
Angiography was performed in all patients within a median time of 10.3 hours after admission. The study drug was administered at a median of 4 hours before percutaneous coronary intervention, with no differences among the 3 groups. In the group randomized to heparin plus a GP IIb/IIIa inhibitor, 59 of 101 patients (58%) were treated with unfractionated heparin, while the remaining 42 (42%) received low–molecular weight heparin enoxaparin. Of the patients receiving unfractionated heparin (in conjunction with a GP IIb/IIIa inhibitor), the median maximum activated clotting time during percutaneous coronary intervention was 239 seconds (interquartile range 211 to 291). Eptifibatide was the most common GP IIb/IIIa inhibitor used during percutaneous coronary intervention (97%), with the remainder (3%) divided between tirofiban and abciximab (started upstream). Of the patients receiving GP IIb/IIIa inhibitors, 53% were randomized to early upstream use, and 46% received deferred use at the time of the procedure. Provisional GP IIb/IIIa inhibitors were used in 19 patients (17%) receiving bivalirudin monotherapy, including 5 (4%) for protocol-specified procedural thrombotic complications.
More than 1 lesion per SVG was treated consistently in all groups ( Tables 1 and 2 ). Drug-eluting stents were implanted in 76% of patients (almost equally divided between paclitaxel-eluting and sirolimus-eluting stents), whereas 29% of patients received bare-metal stents. Adjunctive devices such as thrombectomy were used in 9% of patients, and distal protection devices were used in 20% of patients. The device distribution was well matched among the 3 groups. Angiographic and procedural variables did not differ among the groups ( Table 2 ).
| Variable | Heparin Plus GP IIb/IIIa Inhibitor | Bivalirudin Plus GP IIb/IIIa Inhibitor | Bivalirudin (n = 114) | p Value |
|---|---|---|---|---|
| (n = 101) | (n = 114) | |||
| Target SVG location | ||||
| SVG to LAD | 26% | 23% | 33% | 0.24 |
| SVG to LCX | 41% | 45% | 44% | 0.71 |
| SVG to RCA | 37% | 39% | 33% | 0.81 |
| Number of lesions treated | 2.51 ± 1.19 | 2.61 ± 1.40 | 2.69 ± 1.46 | 0.64 |
| Baseline TIMI flow | ||||
| 0/1 | 13% | 17% | 16% | 0.74 |
| 2 | 26% | 25% | 27% | 0.90 |
| 3 | 61% | 59% | 59% | 0.93 |
| Baseline blush grade | ||||
| 0/1 | 23% | 30% | 26% | 0.60 |
| 2 | 16% | 16% | 15% | 0.99 |
| 3 | 61% | 55% | 59% | 0.70 |
| Percutaneous intervention strategy | ||||
| BMS | 27% | 30% | 30% | 0.85 |
| DES | 75% | 77% | 78% | 0.80 |
| BMS and DES | 10% | 12% | 12% | 0.93 |
| Thrombectomy use | 9.0% | 5.3% | 12.4% | 0.17 |
| Atherectomy use | 1% | 0.9% | 0.0% | 0.58 |
| Cutting balloon use | 5.0% | 6.2% | 4.4% | 0.83 |
| Distal protection use | 17.0% | 23.9% | 18.6% | 0.41 |
| Final TIMI flow | ||||
| 0/1 | 3% | 3% | 4% | 0.94 |
| 2 | 5% | 5% | 13% | 0.02 |
| 3 | 92% | 93% | 84% | 0.07 |
| Final blush grade | ||||
| 0/1 | 6% | 4% | 7% | 0.76 |
| 2 | 12% | 15% | 17% | 0.69 |
| 3 | 82% | 81% | 76% | 0.63 |
| Complications | ||||
| Spasm | 3% | 0% | 4% | 0.14 |
| Abrupt closure | 4% | 2% | 3% | 0.59 |
| No reflow | 1% | 2% | 2% | 0.88 |
| Perforation | 0% | 1% | 0% | 0.38 |
| Distal embolization | 0% | 2% | 3% | 0.35 |
The proportion of patients with final post–percutaneous coronary intervention TIMI grade 2 flow was greater and TIMI grade 3 flow rates trended lower in the bivalirudin alone arm. There were no significant differences in the rates of angiographic complications at end of the procedure between the 3 treatment groups ( Table 2 ). There were no reported occurrences of catheter-related thrombus in any of the 3 groups. By blinded core laboratory analysis, the baseline and postprocedural rates of myocardial blush were not significantly different in patients who underwent percutaneous coronary intervention with bivalirudin either with or without a GP IIb/IIIa inhibitor compared with heparin plus a GP IIb/IIIa inhibitor.
The rates of ischemic, bleeding, and net clinical end points were similar among the 3 groups at 30 days and 1 year ( Tables 3 and 4 ). NACE rates were similar with bivalirudin monotherapy as with either bivalirudin plus a GP IIb/IIIa inhibitor or heparin plus a GP IIb/IIIa inhibitor among the 3 groups at 30 days: 22 of 114 (25%), 26 of 114 (30%), and 22 of 101 (22%) (p = 0.67), respectively, for the 3 groups. MACE rates at 1 year were also similar with the 3 groups: 41 of 114 (37%), 40 of 114 (37%), and 37 of 101 (43%) (p = 0.95), respectively. Minor bleeding unrelated to cardiac bypass graft surgery was significantly lower with bivalirudin alone compared with heparin plus a GP IIb/IIIa inhibitor (26% vs 38%, p = 0.05).
| Outcome | Heparin Plus GP IIb/IIIa Inhibitor | Bivalirudin Plus GP IIb/IIIa Inhibitor | p Value ⁎ | Bivalirudin Alone (n = 114) | p Value † |
|---|---|---|---|---|---|
| (n = 101) | (n = 114) | ||||
| Major adverse cardiac event | 19% | 20% | 0.84 | 19% | 0.91 |
| Death from any cause | 1% | 4% | 0.22 | 2% | 0.62 |
| Death/myocardial infarction | 18% | 17% | 0.80 | 17% | 0.8 |
| Myocardial infarction | 17% | 13% | 0.45 | 17% | 0.94 |
| Q wave | 5% | 2% | 0.20 | 1% | 0.07 |
| Non–Q wave | 12% | 12% | 0.91 | 16% | 0.42 |
| Unplanned revascularization for ischemia TVR | 4% | 7% | 0.33 | 5% | 0.89 |
| Percutaneous coronary intervention | 4% | 6% | 0.47 | 5% | 0.89 |
| Coronary artery bypass surgery | 0% | 1% | 0.34 | 0% | 0.32 |
| Net adverse clinical event | 22% | 26% | 0.46 | 22% | 0.44 |
| Major bleeding (non-CABG-related) | 7% | 11% | 0.34 | 6% | 0.8 |
| Minor bleeding (non-CABG-related) | 38% | 37% | 0.99 | 26% | 0.05 |
| Thrombolysis In Myocardial Infarction major bleeding | 1% | 5% | 0.13 | 1% | 0.10 |
| Thrombolysis In Myocardial Infarction minor bleeding | 8% | 11% | 0.51 | 9% | 0.83 |
| Thrombocytopenia | 11% | 8% | 0.49 | 7% | 0.32 |
| Stent thrombosis | 2% | 1% | 0.49 | 2% | 0.89 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
