- Email: [email protected]
Incidence, predictors, and clinical impact of bleeding after transradial coronary stenting and maximal antiplatelet therapy
Incidence, predictors, and clinical impact of bleeding after transradial coronary stenting and maximal antiplatelet therapy Olivier F. Bertrand, MD, PhD, E´ric Larose, DVM, MD, Josep Rode´s-Cabau, MD, Onil Gleeton, MD, Isabelle Taillon, BPharm, MSc, Louis Roy, MD, Paul Poirier, MD, PhD, Olivier Costerousse, PhD, and Robert De Larochellie`re, MD Qué bec City, Qué bec, Canada
Background Bleeding has recently emerged as predictor of early and late mortality after percutaneous coronary intervention (PCI) using femoral approach. Transradial PCI is associated with a lower risk of access-site complications than femoral approach. We evaluated the predictors of bleeding and the impact of major bleeding on death and major adverse cardiac events (MACE) after transradial PCI and maximal antiplatelet therapy. Methods
In the EASY (EArly discharge after transradial Stenting of coronarY arteries) trial, 1,348 patients with acute coronary syndrome were enrolled and underwent transradial PCI. All patients received clopidogrel (90% ≥12 hours pre-PCI) and a bolus of abciximab before first balloon inflation. Univariate and multivariate analyses to identify predictors and prognostic impact of major bleeding on death and MACE (death, myocardial infarction, and target vessel revascularization) were performed.
Results From the study population, 19 (1.4%) patients presented major bleeding. Patients with bleeding were older, had lower creatinine clearance, more often had 3-vessel disease and ≥3 dilated sites, and had longer procedures. Independent predictors of bleeding were creatinine clearance b60 mL/min (odds ratio [OR] 3.26, 95% confidence interval [CI] 1.10-8.67, P = .022), procedure duration (OR 2.95, 95% CI 1.12-8.31, P = .032), and sheath size (OR 5.34, 95% CI 1.44-34.65, P = .029). In patients with major bleeding, the incidence of MACE was higher at 30 days (37% vs 3%), 6 months (42% vs 8%), and 12 months (53% vs 12%; P b .0001 for all comparisons). By multivariate analysis, major bleeding was an independent predictive factor of 1-year mortality and MACE. Conclusion
After transradial PCI and maximal antiplatelet therapy, the incidence of major bleeding remains low. Major bleeding is an independent predictive factor of adverse acute and 1-year outcomes, regardless of the access site. (Am Heart J 2009;157:164-9.)
Potent platelet inhibition and/or thrombin inhibition is now required to optimize percutaneous coronary interventions (PCIs) results. Better clinical outcomes have been associated with pre- and post-PCI clopidogrel treatment.1 For patients with high-risk acute coronary
From the Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie, Québec City, Québec, Canada. This study was designed as investigator-initiated trial and funded by unrestricted grants from Eli-Lilly (Indianapolis, IN), Bristol-Myers-Squibb (New York, NY)/Sanofi-Aventis (Paris, France), Régie Régionale de Québec, and Corporation de l'Institut de cardiologie de Québec (both of Québec City, Québec). O. F. Bertrand and P. Poirier are researchscholars from Quebec Foundation for Health Research. Results have been presented in part during scientific sessions of the American Heart Association (New Orleans, November 8-12, 2008) and published in abstract form (Circulation 2008;118:S638). Registered Clinical Trial #: NCT001169819. Submitted April 6, 2008; accepted September 14, 2008. Reprint requests: Olivier F. Bertrand, MD, PhD, Interventional Cardiology Laboratories, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie, affilié à l'Université Laval., 2725, Chemin Ste Foy, Québec, Canada G1V 4G5. E-mail: [email protected] 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.09.010
syndrome (ACS), further platelet aggregation inhibition with glycoprotein IIb-IIIa receptor inhibitors and rapid catheterization have been recommended following several large international randomized trials.2 Despite catheter miniaturization or use of closure devices, maximization of antiplatelet therapy is still associated with a significant risk of bleeding after PCI, especially with the femoral approach. Great expectation has been placed in the direct antithrombin agent, bivalirudin, to replace glycoprotein IIb-IIIa receptor inhibitors because a significant reduction in the risk of bleeding has been observed with bivalirudin.3,4 Nevertheless, further analyses of PCI trials using femoral approach and state-of-theart antiplatelet or thrombin-inhibition therapies have clearly demonstrated the deleterious impact of bleeding on acute and late outcomes.5,6 Furthermore, several authors have now emphasized the negative clinical impact of bleeding and related issues such as transfusions and anemia on patient outcomes.7,8 Transradial PCI appears associated with a lower risk of access-site complications and transfusions than with femoral approach.9,10 Because there is no previous report
American Heart Journal Volume 157, Number 1
on the relationship between bleeding after transradial coronary stenting, maximal antiplatelet therapy, and clinical outcomes, we have assessed the incidence, predictive factors, and prognostic impact of major bleeding in the EArly discharge after transradial Stenting of coronarY arteries (EASY) trial.
Methods Study population and study design The details of the EASY trial have been previously described.11 Briefly, patients referred for coronary angiography and possible PCI were enrolled from October 2003 to April 2005. Because of the study design, contraindication for same-day discharge such as ST-elevation myocardial infarction (MI) within 72 hours and history of left ventricular ejection fraction ≤30% or abciximab administration were exclusion criteria. Except for a secondary branch in bifurcation lesions or redilatation for in-stent restenosis, that is, brachytherapy, all lesions had to be stented. The protocol was approved by Health Canada and the Laval Hospital Ethics Review Board. All patients signed an informed consent form for participation in the trial. The study was a randomized controlled, open-label study comparing same-day home discharge and bolus-only of abciximab (n = 504) to overnight hospitalization and bolus followed by 12-hour infusion of abciximab (n = 501) after uncomplicated transradial coronary stenting. In case of angiographic or clinical complications, patients were excluded from same-day discharge after PCI and received abciximab bolus and infusion (n = 343). Abciximab was administered as a 0.25-mg/kg bolus before first balloon angioplasty, and infusion was given for a total of 12 hours at 0.125 μg/kg per minute to a maximum of 10 μg/min. All patients were pretreated with aspirin and clopidogrel before diagnostic angiography. After radial or ulnar sheath insertion, a bolus of 70 U/kg heparin was given intravenously.12 Vascular sheaths were removed at the end of the procedure, and a bracelet (Hemostop, Zoom Inc, Québec City, Québec, Canada) remained in place until hemostasis was completed, usually within 2 hours. Cardiac biomarkers and complete blood counts were evaluated on blood samples collected immediately before the procedure, after PCI (4-6 hours), and the next day (12-24 hours). Study personnel contacted all patients the day after PCI, at 30 days, at 180 days, and at 365 days.
Study end points Major adverse cardiac event (MACE) rate including death, MI, and target vessel revascularization (TVR) was calculated at 30 days, 6 months, and 12 months after the index procedure. End-point adjudications and classifications at all time points were made by a clinical events committee blinded to study groups. Q-wave MIs were classified using the Minnesota code. For non–Q-wave MIs, periprocedural MIs were classified when any post-PCI creatine kinase–MB (CK-MB) value was ≥3 × ULN, that is, 30 μg/mL in our laboratory. After hospital discharge, non-Q MIs were classified using the American College of Cardiology/European Society of Cardiology nomenclature, that is, using any Tn-I or Tn-T value or CK/CK-MB values above upper limits of normal.13 Major bleeding was graded using REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-
Bertrand et al 165
2 ) classification.3 Briefly, these include intracranial, intraocular, or retroperitoneal hemorrhage, clinically overt blood loss with a decrease in hemoglobin N3 g/dL, any decrease in hemoglobin N4 g/dL without overt bleeding, or transfusion of 2 or more units of blood products. Local hematomas were graded according to a specific scale: type I, ≤5 cm diameter; type II, ≤10 cm diameter; type III, N10 cm but not above the elbow; type IV, extending above the elbow; type V, anywhere with ischemic threat of the hand. Access-site complications other than hematomas included fistulas, pseudoaneurysms, complication requiring surgery, or local infection requiring antibiotics.
Statistical analysis Categorical variables were expressed as numbers and percentages and continuous variables as mean ± SD. Baseline and procedural characteristics were compared using Fisher exact test or χ2 test for categorical variables and Student t test for continuous variables. Potential predictors of bleeding were selected with stepwise, backward, and forward procedures with logistic regression analyzes. Survival curves were constructed using Kaplan-Meier techniques, and comparisons were made using logrank test. Cox proportional hazard model was used to assess the relative risks of major bleeding on clinical outcomes at 12 months. Stepwise selection was used to identify potential predictors, which were entered into the model at P b .20 and retained at P b .05. The area under the receiver operating characteristic curve for our predictive model of major bleeding was 0.77, indicating good predictive ability despite the low incidence of events. A probability value b0.05 was considered significant. Statistical tests were performed using JMP 7.0 (SAS institute, Cary, NC).
Results From the 1,348 patients enrolled in the trial, 19 (1.4%) met the criteria of major bleeding according to the REPLACE-2 definitions (Table I). As previously reported, there was no difference in the incidence of major bleeding between abciximab bolus-only and bolus + infusion in the randomized groups, whereas more bleeding occurred in patients not randomized after PCI to same-day discharge.11,14 Patients with major bleeding were older and less likely with dyslipidemia, and their creatinine clearance was lower compared with patients without major bleeding. Furthermore, patients with major bleeding had more dilated sites, the use of larger sheath (6F) was more frequent, and the procedure lasted longer (Table II). Gender, weight, non–ST-elevation MI, low-molecular weight heparin or glycoprotein IIb-IIIa receptor inhibitors before PCI, baseline hemoglobin, final activated clotting time, and the percentage of type B2/C lesions did not influence the incidence of post-PCI major bleeding. Independent predictors of major bleeding were moderate to severe kidney failure defined by creatinine clearance b60 mL/min (odds ratio [OR] 3.26, 95% confidence interval [CI] 1.10-8.67, P = .022), procedure duration N1 hour (OR 2.95, 95% CI 1.12-8.31, P = .032), and sheath size ≥6F (OR 5.34, 95% CI 1.44-34.65, P = .029). Patients with major bleeding had higher early and late
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166 Bertrand et al
Table I. Baseline characteristics
Table II. Procedural characteristics
Major bleeding
Age (y) Male Diabetes Dyslipidemia Hypertension Family history Tobacco use Previous MI Previous PCI Previous CABG Clopidogrel ≥12 h LMWH prior GPIIb/IIIa inhibitor prior ACS: unstable angina ACS: non–ST elevation MI BMI (kg/m2) Weight (kg) Hemoglobin (g/dL) Platelet (109/L) Creatinine clearance (mL/min)
Major bleeding
Yes (n = 19, 1.4%)
No (n = 1329, 98.6%)
P
Yes (n = 19) No (n = 1329)
66 ± 9 12 (63) 4 (21) 13 (68) 12 (63) 12 (63) 9 (47) 4 (21) 2 (11) 2 (11) 18 (95) 2 (11) 1 (5)
60 ± 10 1038 (78) 229 (17) 1139 (86) 679 (51) 948 (71) 430 (32) 595 (45) 259 (19) 83 (6) 1200 (90) 321 (24) 66 (5)
.010 .16 .56 .046 .36 .45 .22 .060 .56 .34 1.00 .28 1.00
13 (68)
890 (67)
1.00
5 (26)
328 (25)
.79
27 ± 5 75 ± 20 138 ± 12 280 ± 120 69 ± 23
28 ± 5 81 ± 16 140 ± 13 238 ± 58 91 ± 38
.46 .23 .47 .15 b.001
Data are mean ± SD or number (percent of total). CABG, Coronary artery bypass grafting; LMWH, low-molecular-weight heparin; BMI, body mass index; non–STelevation MI, baseline Tn-T value N upper reference limit, that is, 0.03 μg/L.
mortality than patients without bleeding (Table III). However, most of this effect occurred during the first 30 days after PCI (11% vs 0%, P b .0001) (Figure 1, A). Major bleeding was a strong independent predictive factor of 1-year mortality (hazard ratio [HR] 4.43, 95% CI 2.04-8.42, P = .0009). The other independent predictive factor of 1-year mortality was procedure duration N1 hour (HR 1.97, 95% CI 1.06-3.90, P = .032). The incidence of MACE in patients with major bleeding was higher at 30 days (37% vs 3%), 6 months (42% vs 8%), and 12 months (53% vs 12%; P b .0001 for all comparisons). Again, most of this effect was marked in the first 30 days (Figure 1, B). Major bleeding was an independent predictive factor of MACE at 1 year (HR 2.41, 95% CI 1.42-4.35, P = .001). Other independent predictors were procedure duration N1 hour, severe thrombocytopenia post-PCI (b50,000/mm3), and number of dilated sites ≥3 (Figure 2). Other variables included in the model, diabetes, non–ST-elevation MI, tobacco use, lesion type B2/ C, hematomas, clopidogrel ≥12 hour, and sheath size ≥6F, were not independent predictors (Table IV).
Discussion Our unique findings can be summarized as follows: after transradial PCI and maximal antiplatelet therapy,
1-Vessel 2-Vessel 3-Vessel 1 dilated site 2 dilated sites ≥3 dilated sites Patients with ≥1 B2/C lesion Drug-eluting stents Procedure duration (min) Final ACT, sec Catheter sheath 5F 6F 7F Post-PCI severe thrombocytopenia
10 (53) 4 (21) 5 (26) 11 (58) 2 (11) 6 (32) 15 (79) 0 (0) 79 ± 46 292 ± 62
790 (59) 419 (32) 120 (9) 832 (63) 368 (28) 129 (10) 779 (59) 349 (26) 48 ± 25 311 ± 66
2 (11) 17 (89) 0 (0) 1 (5.3)
626 (47) 693 (52) 10 (1) 7 (0.5)
P
b.033
b.01 .10 .006 .009 .21
.005 .11
ACT, Activated coagulation time. Data are mean ± SD or number (percent of total). Major bleeding included overt blood loss with a N3 g/dL drop in hemoglobin, any decrease in N4 g/dL hemoglobin without overt bleeding, or transfusion of 2 or more units of blood products.3 Severe thrombocytopenia was defined as platelets count b50,000/μL post-PCI.
(1) the incidence of major bleeding remains low (1.4%); (2) predictors of major bleeding are mostly procedure related; (3) major bleeding are not access-site related; (4) major bleeding is a strong independent predictor of 1-year death and MACE. It remains difficult to compare bleeding rates across studies in ACSs and after PCI because different definitions have been applied.15 The thrombolysis in myocardial infarction (TIMI) definition initially designed for thrombolytic trials in acute ST-elevation MI is now considered too conservative in post-PCI trials.15 Overall, new definitions for major bleeding are based on lower level of hemoglobin drop and include access-site hematomas and blood products transfusion.3,16 Several trials with transradial PCI have reported a lower incidence of access-site bleedings compared with standard femoral approach. A recent meta-analysis has shown that transradial PCI was associated with a dramatic risk reduction of access-site complications compared with femoral approach.9 However, studies with transradial approach have not used predefined bleeding criteria, which prevent direct comparison with femoral studies. In our study, major bleeding was defined using the recently proposed REPLACE-2 classification, and access-site complications were categorized using a predefined hematomas scale.11 This allows comparison with recent trials using femoral approach in similar clinical scenarios and evaluating the clinical impact of new antithrombotic regimens. It is noteworthy that the major bleeding incidence in this trial compares favorably with the heparin + glycoprotein IIbIIIa receptor inhibitors (GPI) arm (4.1%) and bivalirudin
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Bertrand et al 167
Table III. Major adverse cardiac events
Figure 2
Major bleeding
Composite 30 d 6 mo 1y Death 30 d 6 mo 1y MI 30 d 6 mo 1y TVR 30 d 6 mo 1y
Yes (n = 19)
No (n = 1329)
P
7 (37) 8 (42) 10 (53)
44 (3) 108 (8) 164 (12)
b.0001 b.0001 b.0001
2 (11) 2 (11) 3 (16)
0 (0) 2 (0.2) 8 (0.6)
b.001 .001 b.001
4 (21) 4 (21) 4 (21)
42 (3) 46 (3) 53 (4)
.003 .004 .007
6 (32) 7 (37) 8 (42)
3 (0.2) 65 (5) 112 (8)
b.0001 b.0001 b.0001
Events are expressed as numbers of patients (percent of total). Major bleeding included overt blood loss with a N3 g/dL drop in hemoglobin, any decrease in N4 g/dL hemoglobin without overt bleeding, or transfusion of 2 or more units of blood products.3 Composite end points: death, MI, or TVR.
Hazard ratios of major adverse cardiac events at 1 year.
Table IV. Bleeding events Events
Figure 1
Major bleeding GI bleeding Hemoglobin drop CABG related Any transfusion Access-site hematomas Grade I Grade II Grade III Grade IV Thrombocytopenia b100,000/μL b50,000/μL
(n = 1348)
6 (0.4) 9 (0.7) 4 (0.3) 15 (1.1) 128 (9.5) 72 (5.3) 33 (2.5) 21 (1.6) 2 (0.1) 19 (1.4) 8 (0.6)
Events are expressed as numbers of patients (percent of total). Hematoma grade I: ≤5 cm, II: ≤10 cm, III: N10 cm and distal to elbow, grade 4: extending above elbow. There was no intracranial or retroperitoneal bleeding event. GI, gastrointestinal; CABG, coronary artery bypass graft.
Major adverse cardiac events rate at 1 year. Kaplan-Meier estimates of adverse outcomes in patients with and without periprocedural major bleeding.
arm (2.4%) of the REPLACE-2 trial.3 Further studies with bivalirudin and transradial approach are clearly required to evaluate the potential benefits of this new antithrombotic regimen. In previous studies with femoral approach, several baseline patient characteristics been identified as independent predictors of major bleeding.5,6,17 The most frequent and powerful predictors are advanced age, female gender, renal insufficiency, and baseline anemia. In this study, only moderate to severe kidney failure remained an independent baseline predictor of major bleeding after transradial PCI. Procedural predictors of major bleeding after femoral approach have also been identified: increased procedural duration, use of GPI, time to sheath removal, and use of intraortic balloon pump.5,6,17 In our study, longer procedural duration was
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168 Bertrand et al
also identified as an independent predictor. With transradial approach, the sheaths are removed immediately and a bracelet directly applied on the radial artery at the end of the procedure so that delayed access-site bleeding is unlikely. Severe thrombocytopenia, albeit rare, most likely resulted from abciximab therapy.18 A larger sheath size was also an independent predictor of major bleeding. It is important to note that although sheath size was associated with major bleeding, these did not result from access-site bleeding, and therefore, the use of 6F over 5F most probably reflects more complex PCIs. Because of radial artery size, most PCIs using transradial approach are performed using 5F and 6F catheters. Although more frequently used in our study, 6F sheath size was not associated with more local hematomas. Given the important role of procedural factors, meticulous care to avoid excessive “technical” bleeding during PCI should be taken, especially in more complex and longer procedures. It should also be noted that no other access-site complications than hematomas were noted in this study. Major bleeding after PCI can be categorized as intracranial, gastrointestinal (GI)/genitourinary, accesssite related including retroperitoneal hemorrhage or hemoglobin drop without overt bleeding. With current techniques and antithrombotic regimens, the last 2 represent most bleeding events.6 Perhaps pharmacological therapies to prevent periprocedural GI bleeding should be prospectively investigated. Most of the benefit of bivalirudin has been related to access-site– related bleeding. Despite maximal antiplatelet therapy including pretreatment with clopidogrel and abciximab use, transradial PCI remained associated with an extremely low rate of access-site complications and related bleeding. Mortality at 1 year was N10× higher in patients with major bleeding. Major bleeding was also the strongest independent predictor of mortality. This finding is consistent with previous reports using GPI or bivalirudin.6 Furthermore, MACE were N10 × at 30 days and N4× at 1 year in patients with major bleeding. This association between major bleeding and subsequent ischemic events has also been observed in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial.6 Notably, although subacute stent thrombosis has been associated with major bleeding in ACUITY, no early stent thrombosis occurred in our study, which involved clopidogrel pretreatment ≥12 hours in most patients and systematic abciximab use. Among other independent predictors, major bleeding was the strongest predictor of MACE at 1 year. In contrast to prior randomized studies or registry, baseline elevated troponin was not an independent predictor of bleeding or MACE.5,6,19 Because patients presenting with non–ST-elevation MI represented only 25% of the total population, further studies are required to better
evaluate the potential relationship in this selected population. A recent survey confirmed the low rate of transradial PCI in the US compared with transfemoral PCI but also confirmed a significant reduction in the risk of bleeding, especially in older patients, women, and patients presenting in ACS.20
Limitations The absolute rate of major bleeding was low and therefore limited the number of variables that could be entered into the multivariate analysis. Patients included in the EASY trial had to be eligible for same-day discharge and abciximab therapy before procedure. This might have created a selection bias. However, most of the findings are consistent with previous reports using femoral approach and underscore the strong relationship between periprocedural bleeding and clinical outcomes.
Conclusion In patients with maximal antiplatelet therapy and transradial PCI, the incidence of major bleeding appears lower than current experience with transfemoral approach. Regardless of the access site, major bleeding has a severe negative impact on early and late clinical outcomes after PCI. Because transradial access nearly completely abolishes significant access-site complications and related bleeding, further studies with transradial access and newer antithrombin regimen, like bivalirudin, are urgently required to evaluate potential further reduction in the risk of non–access-site-related bleeding. Several periprocedural factors are readily identifiable and should alert the operator that the patient is at higher risk of bleeding.
References 1. Steinhubl SR, Berger PB, Mann III JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20. 2. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879-87. 3. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-63. 4. Stone GW, White HD, Ohman EM, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007;369: 907-19. 5. Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol 2007;100:1364-9.
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6. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol 2007;49:1362-8. 7. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-62. 8. Voeltz MD, Patel AD, Feit F, et al. Effect of anemia on hemorrhagic complications and mortality following percutaneous coronary intervention. Am J Cardiol 2007;99:1513-7. 9. Agostoni P, Biondi-Zoccai GG, de Benedictis ML, et al. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; systematic overview and meta-analysis of randomized trials. J Am Coll Cardiol 2004;44:349-56. 10. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007;69: 73-83. 11. Bertrand OF, De Larochelliere R, Rodes-Cabau J, et al. A randomized study comparing same-day home discharge and abciximab bolus only to overnight hospitalization and abciximab bolus and infusion after transradial coronary stent implantation. Circulation 2006;114: 2636-43. 12. Mangin L, Bertrand OF, De La Rochelliere R, et al. The transulnar approach for coronary intervention: a safe alternative to transradial approach in selected patients. J Invasive Cardiol 2005;17:77-9. 13. Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for measuring the
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clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol 2001;38:2114-30. Bertrand OF, Rodes-Cabau J, Larose E, et al. Early and late outcomes in patients excluded from same-day home discharge after transradial stenting and maximal antiplatelet therapy. Catheter Cardiovasc Interv 2008;72:619-25. Steinhubl SR, Kastrati A, Berger PB. Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs. Am Heart J 2007; 154:3-11. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 2004;148:764-75. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003;92: 930-5. Huxtable LM, Tafreshi MJ, Rakkar AN. Frequency and management of thrombocytopenia with the glycoprotein IIb/IIIa receptor antagonists. Am J Cardiol 2006;97:426-9. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24:1815-23. Rao SV, Ou F, Wang TY, et al. Trends in the prevalence and outcomes of radial and femoral approaches to percutaneous coronary intervention. J Am Coll Cardiol Intv 2008:379-86.
Background Bleeding has recently emerged as predictor of early and late mortality after percutaneous coronary intervention (PCI) using femoral approach. Transradial PCI is associated with a lower risk of access-site complications than femoral approach. We evaluated the predictors of bleeding and the impact of major bleeding on death and major adverse cardiac events (MACE) after transradial PCI and maximal antiplatelet therapy. Methods
In the EASY (EArly discharge after transradial Stenting of coronarY arteries) trial, 1,348 patients with acute coronary syndrome were enrolled and underwent transradial PCI. All patients received clopidogrel (90% ≥12 hours pre-PCI) and a bolus of abciximab before first balloon inflation. Univariate and multivariate analyses to identify predictors and prognostic impact of major bleeding on death and MACE (death, myocardial infarction, and target vessel revascularization) were performed.
Results From the study population, 19 (1.4%) patients presented major bleeding. Patients with bleeding were older, had lower creatinine clearance, more often had 3-vessel disease and ≥3 dilated sites, and had longer procedures. Independent predictors of bleeding were creatinine clearance b60 mL/min (odds ratio [OR] 3.26, 95% confidence interval [CI] 1.10-8.67, P = .022), procedure duration (OR 2.95, 95% CI 1.12-8.31, P = .032), and sheath size (OR 5.34, 95% CI 1.44-34.65, P = .029). In patients with major bleeding, the incidence of MACE was higher at 30 days (37% vs 3%), 6 months (42% vs 8%), and 12 months (53% vs 12%; P b .0001 for all comparisons). By multivariate analysis, major bleeding was an independent predictive factor of 1-year mortality and MACE. Conclusion
After transradial PCI and maximal antiplatelet therapy, the incidence of major bleeding remains low. Major bleeding is an independent predictive factor of adverse acute and 1-year outcomes, regardless of the access site. (Am Heart J 2009;157:164-9.)
Potent platelet inhibition and/or thrombin inhibition is now required to optimize percutaneous coronary interventions (PCIs) results. Better clinical outcomes have been associated with pre- and post-PCI clopidogrel treatment.1 For patients with high-risk acute coronary
From the Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie, Québec City, Québec, Canada. This study was designed as investigator-initiated trial and funded by unrestricted grants from Eli-Lilly (Indianapolis, IN), Bristol-Myers-Squibb (New York, NY)/Sanofi-Aventis (Paris, France), Régie Régionale de Québec, and Corporation de l'Institut de cardiologie de Québec (both of Québec City, Québec). O. F. Bertrand and P. Poirier are researchscholars from Quebec Foundation for Health Research. Results have been presented in part during scientific sessions of the American Heart Association (New Orleans, November 8-12, 2008) and published in abstract form (Circulation 2008;118:S638). Registered Clinical Trial #: NCT001169819. Submitted April 6, 2008; accepted September 14, 2008. Reprint requests: Olivier F. Bertrand, MD, PhD, Interventional Cardiology Laboratories, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie, affilié à l'Université Laval., 2725, Chemin Ste Foy, Québec, Canada G1V 4G5. E-mail: [email protected] 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.09.010
syndrome (ACS), further platelet aggregation inhibition with glycoprotein IIb-IIIa receptor inhibitors and rapid catheterization have been recommended following several large international randomized trials.2 Despite catheter miniaturization or use of closure devices, maximization of antiplatelet therapy is still associated with a significant risk of bleeding after PCI, especially with the femoral approach. Great expectation has been placed in the direct antithrombin agent, bivalirudin, to replace glycoprotein IIb-IIIa receptor inhibitors because a significant reduction in the risk of bleeding has been observed with bivalirudin.3,4 Nevertheless, further analyses of PCI trials using femoral approach and state-of-theart antiplatelet or thrombin-inhibition therapies have clearly demonstrated the deleterious impact of bleeding on acute and late outcomes.5,6 Furthermore, several authors have now emphasized the negative clinical impact of bleeding and related issues such as transfusions and anemia on patient outcomes.7,8 Transradial PCI appears associated with a lower risk of access-site complications and transfusions than with femoral approach.9,10 Because there is no previous report
American Heart Journal Volume 157, Number 1
on the relationship between bleeding after transradial coronary stenting, maximal antiplatelet therapy, and clinical outcomes, we have assessed the incidence, predictive factors, and prognostic impact of major bleeding in the EArly discharge after transradial Stenting of coronarY arteries (EASY) trial.
Methods Study population and study design The details of the EASY trial have been previously described.11 Briefly, patients referred for coronary angiography and possible PCI were enrolled from October 2003 to April 2005. Because of the study design, contraindication for same-day discharge such as ST-elevation myocardial infarction (MI) within 72 hours and history of left ventricular ejection fraction ≤30% or abciximab administration were exclusion criteria. Except for a secondary branch in bifurcation lesions or redilatation for in-stent restenosis, that is, brachytherapy, all lesions had to be stented. The protocol was approved by Health Canada and the Laval Hospital Ethics Review Board. All patients signed an informed consent form for participation in the trial. The study was a randomized controlled, open-label study comparing same-day home discharge and bolus-only of abciximab (n = 504) to overnight hospitalization and bolus followed by 12-hour infusion of abciximab (n = 501) after uncomplicated transradial coronary stenting. In case of angiographic or clinical complications, patients were excluded from same-day discharge after PCI and received abciximab bolus and infusion (n = 343). Abciximab was administered as a 0.25-mg/kg bolus before first balloon angioplasty, and infusion was given for a total of 12 hours at 0.125 μg/kg per minute to a maximum of 10 μg/min. All patients were pretreated with aspirin and clopidogrel before diagnostic angiography. After radial or ulnar sheath insertion, a bolus of 70 U/kg heparin was given intravenously.12 Vascular sheaths were removed at the end of the procedure, and a bracelet (Hemostop, Zoom Inc, Québec City, Québec, Canada) remained in place until hemostasis was completed, usually within 2 hours. Cardiac biomarkers and complete blood counts were evaluated on blood samples collected immediately before the procedure, after PCI (4-6 hours), and the next day (12-24 hours). Study personnel contacted all patients the day after PCI, at 30 days, at 180 days, and at 365 days.
Study end points Major adverse cardiac event (MACE) rate including death, MI, and target vessel revascularization (TVR) was calculated at 30 days, 6 months, and 12 months after the index procedure. End-point adjudications and classifications at all time points were made by a clinical events committee blinded to study groups. Q-wave MIs were classified using the Minnesota code. For non–Q-wave MIs, periprocedural MIs were classified when any post-PCI creatine kinase–MB (CK-MB) value was ≥3 × ULN, that is, 30 μg/mL in our laboratory. After hospital discharge, non-Q MIs were classified using the American College of Cardiology/European Society of Cardiology nomenclature, that is, using any Tn-I or Tn-T value or CK/CK-MB values above upper limits of normal.13 Major bleeding was graded using REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-
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2 ) classification.3 Briefly, these include intracranial, intraocular, or retroperitoneal hemorrhage, clinically overt blood loss with a decrease in hemoglobin N3 g/dL, any decrease in hemoglobin N4 g/dL without overt bleeding, or transfusion of 2 or more units of blood products. Local hematomas were graded according to a specific scale: type I, ≤5 cm diameter; type II, ≤10 cm diameter; type III, N10 cm but not above the elbow; type IV, extending above the elbow; type V, anywhere with ischemic threat of the hand. Access-site complications other than hematomas included fistulas, pseudoaneurysms, complication requiring surgery, or local infection requiring antibiotics.
Statistical analysis Categorical variables were expressed as numbers and percentages and continuous variables as mean ± SD. Baseline and procedural characteristics were compared using Fisher exact test or χ2 test for categorical variables and Student t test for continuous variables. Potential predictors of bleeding were selected with stepwise, backward, and forward procedures with logistic regression analyzes. Survival curves were constructed using Kaplan-Meier techniques, and comparisons were made using logrank test. Cox proportional hazard model was used to assess the relative risks of major bleeding on clinical outcomes at 12 months. Stepwise selection was used to identify potential predictors, which were entered into the model at P b .20 and retained at P b .05. The area under the receiver operating characteristic curve for our predictive model of major bleeding was 0.77, indicating good predictive ability despite the low incidence of events. A probability value b0.05 was considered significant. Statistical tests were performed using JMP 7.0 (SAS institute, Cary, NC).
Results From the 1,348 patients enrolled in the trial, 19 (1.4%) met the criteria of major bleeding according to the REPLACE-2 definitions (Table I). As previously reported, there was no difference in the incidence of major bleeding between abciximab bolus-only and bolus + infusion in the randomized groups, whereas more bleeding occurred in patients not randomized after PCI to same-day discharge.11,14 Patients with major bleeding were older and less likely with dyslipidemia, and their creatinine clearance was lower compared with patients without major bleeding. Furthermore, patients with major bleeding had more dilated sites, the use of larger sheath (6F) was more frequent, and the procedure lasted longer (Table II). Gender, weight, non–ST-elevation MI, low-molecular weight heparin or glycoprotein IIb-IIIa receptor inhibitors before PCI, baseline hemoglobin, final activated clotting time, and the percentage of type B2/C lesions did not influence the incidence of post-PCI major bleeding. Independent predictors of major bleeding were moderate to severe kidney failure defined by creatinine clearance b60 mL/min (odds ratio [OR] 3.26, 95% confidence interval [CI] 1.10-8.67, P = .022), procedure duration N1 hour (OR 2.95, 95% CI 1.12-8.31, P = .032), and sheath size ≥6F (OR 5.34, 95% CI 1.44-34.65, P = .029). Patients with major bleeding had higher early and late
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166 Bertrand et al
Table I. Baseline characteristics
Table II. Procedural characteristics
Major bleeding
Age (y) Male Diabetes Dyslipidemia Hypertension Family history Tobacco use Previous MI Previous PCI Previous CABG Clopidogrel ≥12 h LMWH prior GPIIb/IIIa inhibitor prior ACS: unstable angina ACS: non–ST elevation MI BMI (kg/m2) Weight (kg) Hemoglobin (g/dL) Platelet (109/L) Creatinine clearance (mL/min)
Major bleeding
Yes (n = 19, 1.4%)
No (n = 1329, 98.6%)
P
Yes (n = 19) No (n = 1329)
66 ± 9 12 (63) 4 (21) 13 (68) 12 (63) 12 (63) 9 (47) 4 (21) 2 (11) 2 (11) 18 (95) 2 (11) 1 (5)
60 ± 10 1038 (78) 229 (17) 1139 (86) 679 (51) 948 (71) 430 (32) 595 (45) 259 (19) 83 (6) 1200 (90) 321 (24) 66 (5)
.010 .16 .56 .046 .36 .45 .22 .060 .56 .34 1.00 .28 1.00
13 (68)
890 (67)
1.00
5 (26)
328 (25)
.79
27 ± 5 75 ± 20 138 ± 12 280 ± 120 69 ± 23
28 ± 5 81 ± 16 140 ± 13 238 ± 58 91 ± 38
.46 .23 .47 .15 b.001
Data are mean ± SD or number (percent of total). CABG, Coronary artery bypass grafting; LMWH, low-molecular-weight heparin; BMI, body mass index; non–STelevation MI, baseline Tn-T value N upper reference limit, that is, 0.03 μg/L.
mortality than patients without bleeding (Table III). However, most of this effect occurred during the first 30 days after PCI (11% vs 0%, P b .0001) (Figure 1, A). Major bleeding was a strong independent predictive factor of 1-year mortality (hazard ratio [HR] 4.43, 95% CI 2.04-8.42, P = .0009). The other independent predictive factor of 1-year mortality was procedure duration N1 hour (HR 1.97, 95% CI 1.06-3.90, P = .032). The incidence of MACE in patients with major bleeding was higher at 30 days (37% vs 3%), 6 months (42% vs 8%), and 12 months (53% vs 12%; P b .0001 for all comparisons). Again, most of this effect was marked in the first 30 days (Figure 1, B). Major bleeding was an independent predictive factor of MACE at 1 year (HR 2.41, 95% CI 1.42-4.35, P = .001). Other independent predictors were procedure duration N1 hour, severe thrombocytopenia post-PCI (b50,000/mm3), and number of dilated sites ≥3 (Figure 2). Other variables included in the model, diabetes, non–ST-elevation MI, tobacco use, lesion type B2/ C, hematomas, clopidogrel ≥12 hour, and sheath size ≥6F, were not independent predictors (Table IV).
Discussion Our unique findings can be summarized as follows: after transradial PCI and maximal antiplatelet therapy,
1-Vessel 2-Vessel 3-Vessel 1 dilated site 2 dilated sites ≥3 dilated sites Patients with ≥1 B2/C lesion Drug-eluting stents Procedure duration (min) Final ACT, sec Catheter sheath 5F 6F 7F Post-PCI severe thrombocytopenia
10 (53) 4 (21) 5 (26) 11 (58) 2 (11) 6 (32) 15 (79) 0 (0) 79 ± 46 292 ± 62
790 (59) 419 (32) 120 (9) 832 (63) 368 (28) 129 (10) 779 (59) 349 (26) 48 ± 25 311 ± 66
2 (11) 17 (89) 0 (0) 1 (5.3)
626 (47) 693 (52) 10 (1) 7 (0.5)
P
b.033
b.01 .10 .006 .009 .21
.005 .11
ACT, Activated coagulation time. Data are mean ± SD or number (percent of total). Major bleeding included overt blood loss with a N3 g/dL drop in hemoglobin, any decrease in N4 g/dL hemoglobin without overt bleeding, or transfusion of 2 or more units of blood products.3 Severe thrombocytopenia was defined as platelets count b50,000/μL post-PCI.
(1) the incidence of major bleeding remains low (1.4%); (2) predictors of major bleeding are mostly procedure related; (3) major bleeding are not access-site related; (4) major bleeding is a strong independent predictor of 1-year death and MACE. It remains difficult to compare bleeding rates across studies in ACSs and after PCI because different definitions have been applied.15 The thrombolysis in myocardial infarction (TIMI) definition initially designed for thrombolytic trials in acute ST-elevation MI is now considered too conservative in post-PCI trials.15 Overall, new definitions for major bleeding are based on lower level of hemoglobin drop and include access-site hematomas and blood products transfusion.3,16 Several trials with transradial PCI have reported a lower incidence of access-site bleedings compared with standard femoral approach. A recent meta-analysis has shown that transradial PCI was associated with a dramatic risk reduction of access-site complications compared with femoral approach.9 However, studies with transradial approach have not used predefined bleeding criteria, which prevent direct comparison with femoral studies. In our study, major bleeding was defined using the recently proposed REPLACE-2 classification, and access-site complications were categorized using a predefined hematomas scale.11 This allows comparison with recent trials using femoral approach in similar clinical scenarios and evaluating the clinical impact of new antithrombotic regimens. It is noteworthy that the major bleeding incidence in this trial compares favorably with the heparin + glycoprotein IIbIIIa receptor inhibitors (GPI) arm (4.1%) and bivalirudin
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Table III. Major adverse cardiac events
Figure 2
Major bleeding
Composite 30 d 6 mo 1y Death 30 d 6 mo 1y MI 30 d 6 mo 1y TVR 30 d 6 mo 1y
Yes (n = 19)
No (n = 1329)
P
7 (37) 8 (42) 10 (53)
44 (3) 108 (8) 164 (12)
b.0001 b.0001 b.0001
2 (11) 2 (11) 3 (16)
0 (0) 2 (0.2) 8 (0.6)
b.001 .001 b.001
4 (21) 4 (21) 4 (21)
42 (3) 46 (3) 53 (4)
.003 .004 .007
6 (32) 7 (37) 8 (42)
3 (0.2) 65 (5) 112 (8)
b.0001 b.0001 b.0001
Events are expressed as numbers of patients (percent of total). Major bleeding included overt blood loss with a N3 g/dL drop in hemoglobin, any decrease in N4 g/dL hemoglobin without overt bleeding, or transfusion of 2 or more units of blood products.3 Composite end points: death, MI, or TVR.
Hazard ratios of major adverse cardiac events at 1 year.
Table IV. Bleeding events Events
Figure 1
Major bleeding GI bleeding Hemoglobin drop CABG related Any transfusion Access-site hematomas Grade I Grade II Grade III Grade IV Thrombocytopenia b100,000/μL b50,000/μL
(n = 1348)
6 (0.4) 9 (0.7) 4 (0.3) 15 (1.1) 128 (9.5) 72 (5.3) 33 (2.5) 21 (1.6) 2 (0.1) 19 (1.4) 8 (0.6)
Events are expressed as numbers of patients (percent of total). Hematoma grade I: ≤5 cm, II: ≤10 cm, III: N10 cm and distal to elbow, grade 4: extending above elbow. There was no intracranial or retroperitoneal bleeding event. GI, gastrointestinal; CABG, coronary artery bypass graft.
Major adverse cardiac events rate at 1 year. Kaplan-Meier estimates of adverse outcomes in patients with and without periprocedural major bleeding.
arm (2.4%) of the REPLACE-2 trial.3 Further studies with bivalirudin and transradial approach are clearly required to evaluate the potential benefits of this new antithrombotic regimen. In previous studies with femoral approach, several baseline patient characteristics been identified as independent predictors of major bleeding.5,6,17 The most frequent and powerful predictors are advanced age, female gender, renal insufficiency, and baseline anemia. In this study, only moderate to severe kidney failure remained an independent baseline predictor of major bleeding after transradial PCI. Procedural predictors of major bleeding after femoral approach have also been identified: increased procedural duration, use of GPI, time to sheath removal, and use of intraortic balloon pump.5,6,17 In our study, longer procedural duration was
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also identified as an independent predictor. With transradial approach, the sheaths are removed immediately and a bracelet directly applied on the radial artery at the end of the procedure so that delayed access-site bleeding is unlikely. Severe thrombocytopenia, albeit rare, most likely resulted from abciximab therapy.18 A larger sheath size was also an independent predictor of major bleeding. It is important to note that although sheath size was associated with major bleeding, these did not result from access-site bleeding, and therefore, the use of 6F over 5F most probably reflects more complex PCIs. Because of radial artery size, most PCIs using transradial approach are performed using 5F and 6F catheters. Although more frequently used in our study, 6F sheath size was not associated with more local hematomas. Given the important role of procedural factors, meticulous care to avoid excessive “technical” bleeding during PCI should be taken, especially in more complex and longer procedures. It should also be noted that no other access-site complications than hematomas were noted in this study. Major bleeding after PCI can be categorized as intracranial, gastrointestinal (GI)/genitourinary, accesssite related including retroperitoneal hemorrhage or hemoglobin drop without overt bleeding. With current techniques and antithrombotic regimens, the last 2 represent most bleeding events.6 Perhaps pharmacological therapies to prevent periprocedural GI bleeding should be prospectively investigated. Most of the benefit of bivalirudin has been related to access-site– related bleeding. Despite maximal antiplatelet therapy including pretreatment with clopidogrel and abciximab use, transradial PCI remained associated with an extremely low rate of access-site complications and related bleeding. Mortality at 1 year was N10× higher in patients with major bleeding. Major bleeding was also the strongest independent predictor of mortality. This finding is consistent with previous reports using GPI or bivalirudin.6 Furthermore, MACE were N10 × at 30 days and N4× at 1 year in patients with major bleeding. This association between major bleeding and subsequent ischemic events has also been observed in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial.6 Notably, although subacute stent thrombosis has been associated with major bleeding in ACUITY, no early stent thrombosis occurred in our study, which involved clopidogrel pretreatment ≥12 hours in most patients and systematic abciximab use. Among other independent predictors, major bleeding was the strongest predictor of MACE at 1 year. In contrast to prior randomized studies or registry, baseline elevated troponin was not an independent predictor of bleeding or MACE.5,6,19 Because patients presenting with non–ST-elevation MI represented only 25% of the total population, further studies are required to better
evaluate the potential relationship in this selected population. A recent survey confirmed the low rate of transradial PCI in the US compared with transfemoral PCI but also confirmed a significant reduction in the risk of bleeding, especially in older patients, women, and patients presenting in ACS.20
Limitations The absolute rate of major bleeding was low and therefore limited the number of variables that could be entered into the multivariate analysis. Patients included in the EASY trial had to be eligible for same-day discharge and abciximab therapy before procedure. This might have created a selection bias. However, most of the findings are consistent with previous reports using femoral approach and underscore the strong relationship between periprocedural bleeding and clinical outcomes.
Conclusion In patients with maximal antiplatelet therapy and transradial PCI, the incidence of major bleeding appears lower than current experience with transfemoral approach. Regardless of the access site, major bleeding has a severe negative impact on early and late clinical outcomes after PCI. Because transradial access nearly completely abolishes significant access-site complications and related bleeding, further studies with transradial access and newer antithrombin regimen, like bivalirudin, are urgently required to evaluate potential further reduction in the risk of non–access-site-related bleeding. Several periprocedural factors are readily identifiable and should alert the operator that the patient is at higher risk of bleeding.
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