CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
The CIAO (Coronary Interventions Antiplatelet-based Only) StudyA Randomized Study Comparing Standard Anticoagulation Regimen to Absence of Anticoagulation for Elective Percutaneous Coronary Intervention
Eugenio Stabile, MD, PhD, FESC, FAHA*,*,
Wail Nammas, MD*,
Luigi Salemme, MD*,
Giovanni Sorropago, MD*,
Angelo Cioppa, MD*,
Tullio Tesorio, MD*,
Vittorio Ambrosini, MD*,
Esther Campopiano, MD*,
Gregory Popusoi, MD*,
Giuseppe Biondi Zoccai, MD and
Paolo Rubino, MD*
* Laboratory of Invasive Cardiology, Division of Cardiology, Clinica Montevergine, Mercogliano, Italy
Interventional Cardiology, Division of Cardiology, S. Giovanni Battista-Molinette Hospital, University of Turin, Turin, Italy
Manuscript received March 26, 2008;
revised manuscript received June 23, 2008,
accepted July 11, 2008.
* Reprints requests and correspondence: Dr. Eugenio Stabile, Cardiac Catheterization Laboratories, Division of Cardiology, Clinica Montevergine, 83013 Mercogliano, Italy (Email: geko50{at}hotmail.com).
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Abstract
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Objectives: We sought to evaluate, in a double-blind, randomized, prospective study, safety and efficacy of elective percutaneous coronary intervention (PCI), with pharmacotherapy consisting of antiplatelet therapy and no anticoagulation therapy.
Background: Available guidelines recommend systemic anticoagulation agent use during PCI. Significant debate remains, however, with regard to the correlation between the effects of systemic anticoagulation therapy and ensuing ischemic and hemorrhagic complications.
Methods: From June 2005 to January 2007, 700 patients undergoing elective PCI of an uncomplicated lesion have been prospectively enrolled in the protocol. Patients should have been on aspirin and thienopyridine therapy and were assigned either to the control arm (70 to 100 UI/kg unfractionated heparin) or to the no-heparin arm. A clinical assessment was obtained before hospital discharge and at 30 days after PCI.
Results: Procedural success was obtained in 100% of the cases. No acute or subacute thrombosis was observed. The absence of anticoagulation therapy was associated with a significant decrease in post-procedural myocardial damage (p = 0.03) and bleeding events (p = 0.048). At 30 days, the primary end point (death, myocardial infarction, or urgent target vessel revascularization) was more frequent in the control arm than in the no-heparin arm (2.0% vs. 3.7%, respectively; absolute risk reduction 1.7% [95% confidence interval: –0.1% to 4.5%], p for superiority = 0.17, p for noninferiority <0.001).
Conclusions: In the treatment of uncomplicated lesions and in the presence of dual antiplatelet therapy, elective PCI can be safely performed without systemic anticoagulation and is associated with a reduced incidence of bleeding complications.
Key Words: percutaneous coronary intervention • no anticoagulation • bleeding
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Abbreviations and Acronyms
| | ACT = activated clotting time | | CABG = coronary artery bypass graft surgery | | CK-MB = creatine kinase-myocardial band | | GPI = glycoprotein IIb/IIIa inhibitor | | PCI = percutaneous coronary intervention | | UFH = unfractionated heparin |
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Despite the development of new intravenous anticoagulant agents that affect thrombin cascade, unfractionated heparin (UFH) remains the most commonly used agent during percutaneous coronary intervention (PCI). Significant debate remains, however, with regard to the correlation between the effects of UFH and ensuing ischemic and hemorrhagic complications.
Currently available guidelines recently recommended that heparin should be administered in doses of 70 to 100 IU/kg and at a target activated clotting time (ACT) between 250 and 350 s, in the absence of a glycoprotein IIb/IIIa inhibitor (GPI). Similarly, a target ACT of 200 s should be achieved when heparin is administered in conjunction with a GPI (1,2).
A report from single-institution studies (3) and a multicenter registry (4) claimed that only minute doses of UFH are needed during uncomplicated stent implantations. More recently, the use of GPI was advocated to perform coronary stenting using minimal heparin dose (5). In a single-center experience (6), nonemergency PCI could be completed without major adverse clinical events in patients receiving aspirin, thienopyridine, and GPI without scheduled anticoagulation therapy. In the REMOVE (Reduction in Major and Minor Adverse Events With Eptifibatide-based Pharmacotherapy in Percutaneous Coronary Intervention) trial (7), antiplatelet therapy including aspirin, clopidogrel, and GPI without anticoagulation therapy appears to decrease bleeding complications after elective PCI. The ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) trial showed that the degree of heparin anticoagulation, as measured by ACT, did not significantly affect the rate of ischemic events. Ischemic complications in this study did not increase at the lowest levels of ACT, whereas bleedings were reduced for the placebo group at lower ACT levels (8).
It has been suggested (9) that in the future, to make a safe procedure even safer, comparisons of UFH even with no antithrombin therapy should continue to focus on reducing the risk of bleeding during PCI. In this study, we evaluated in a double-blind, randomized, prospective study, the safety and efficacy of elective PCI of uncomplicated lesions, with adjunctive pharmacotherapy consisting of antiplatelet therapy alone, without scheduled unfractionated heparin or other antithrombin therapy.
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Methods
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Patient selection.
From June 2005 to January 2007, all patients undergoing elective PCI for treatment of chronic coronary artery disease were screened for enrollment and asked to consent to trial inclusion if a coronary angiogram showed the presence of a single target lesion meeting the following inclusion criteria: 1) located in a native coronary artery segment >2.5 mm in diameter; 2) >70% diameter stenosis; 3) <33 mm in length; 4) noncalcified; 5) without important side branches (<2.5 mm); 6) nonostial or left main; 7) free of visible thrombus; and 8) no chronic occlusion.
Patients were excluded from the study if they had the following: 1) acute coronary syndromes; 2) recent myocardial infarction (<2 weeks); 3) refused to sign informed consent before enrollment; 4) >90 years old; 5) received unfractionated heparin within 12 h, low molecular weight heparin within 24 h, or warfarin within 3 days; 6) an international normalized ratio >1.3; 7) an indication for long-term anticoagulation; and 8) contraindication to aspirin and/or thienopyridines.
The protocol was approved by the hospital Institutional Review Board and the local ethics committee.
Antiplatelet therapy.
All eligible patients were taking aspirin (75 to 160 mg/day) and should have been on ticlopidine therapy (250 mg twice daily) or clopidogrel (75 mg/day) for at least 7 days. Alternatively, patients received clopidogrel preload (300 mg) 24 h before procedure. Use of GPI was allowed at the operator's discretion.
Study design.
Seven hundred patients were enrolled and randomly assigned to control (70 to 100 UI/kg UFH administered before guiding catheter insertion, with the intention of achieving ACT <250 s; additional heparin could be administered at the operator's discretion) (1,2) or to placebo (saline before guiding catheter insertion, same volume amount of hypothetical heparin dose).
Interventional physicians were blinded to the ACT results (obtained by Medtronic ACT II, Minneapolis, Minnesota); an unblinded nurse monitored ACT every 5 min after heparin bolus administration and gave heparin or saline according to the study arm and ACT values. Catheters were flushed with UFH saline (7.5 UI/ ml). No more than 100 ml flushes were allowed per procedure. Contrast agent was uniformly nonionic (Iobitridol, Guerbet, Roissy, France).
Angiographic assessment.
Patient, lesion characteristics, and percutaneous transluminal angiography results were assessed independently by 2 physicians (assisted by edge-detection software provided with the Phillips-Integris Unit, Eindhoven, the Netherlands). Lesions were categorized according to the modified American Heart Association/American College of Cardiology classification (10).
Post-procedural patient management.
Femoral sheaths were manually removed as early as "holding area" staff was ready and independently from ACT values. An electrocardiogram was obtained before the procedure, immediately after the procedure, and before discharge. Serum creatine kinase-myocardial band (CK-MB) and a complete blood count were tested before PCI, and at 6, 12, and 24 h after the procedure. Before discharge, a physician evaluated all patients, with special emphasis on arterial access site.
Follow up.
All patients were followed up at 30 days by clinical examination and a structured questionnaire.
Study end points.
Any clinical event has been adjudicated by a committee consensus composed by 3 physicians not involved in patient management and blinded to study groups. Procedural success was considered a <30% residual stenosis and Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 achieved. Clinical success was considered when procedural success was attained without any target vessel related death, acute myocardial infarction, emergency coronary artery bypass graft surgery (CABG), stroke, or urgent vessel revascularization within 7 days of the procedure. The primary end point was defined as the composite of death, acute myocardial infarction, or need for urgent vessel revascularization occurring within 30 days of the index procedure.
Acute myocardial infarction (MI) was defined as: 1) an increase in CK-MB >3 times the upper limit of normal in 2 separate blood samples, or if CK-MB was elevated before the procedure, an increase in CK-MB >3 times the upper limit of normal associated with an increase of >50% above the last pre-procedural level; or 2) new Q waves (0.04 m/s) in >2 contiguous electrocardiography leads. Urgent TVR was defined as repeat PCI of the target vessel or bypass surgery within 30 days.
Secondary end points included bleeding complications, classified according to the TIMI study, GUSTO (Global Utilization of Streptokinase and Tissue-Type Plasminogen Activator for Occluded Coronary Arteries) study, STEEPLE (Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients) trial, and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy Trial) criteria.
For TIMI (11), major criteria included intracranial hemorrhage or clinical bleeding associated with a hemoglobin drop of  5 g/dl (or hematocrit decrease by 15 points or by 10 to 15 points with clinical bleeding) and minor criteria included a hemoglobin drop of 3 g/dl (or hematocrit decrease <10 points) with clinical bleeding or 4 g/dl (or hematocrit decrease by 10 to 15 point) with no clinical bleeding. Clinical bleeding was defined as: 1) a large hematoma; 2) gastrointestinal blood loss; or 3) retroperitoneal bleeding.
For GUSTO criteria (12), mild was defined as non–CABG-related bleeding up to 48 h with no need for transfusion and no hemodynamic compromise. Moderate was defined as non–CABG-related bleeding up to 48 h with transfusion required; and severe or life-threatening was non–CABG-related bleeding up to 48 h with hemodynamic compromise.
For STEEPLE criteria (13), major was defined as bleeding that met at least 1 of the following: fatal bleeding; retroperitoneal, intracranial, intraocular bleeding; bleeding that causes hemodynamic compromise requiring specific treatment; bleeding that requires intervention (surgical or endoscopic) or decompression of a closed space to stop or control the event; clinically overt bleeding; requirement for any transfusion of 1 U packed red cells or whole blood; and clinically overt bleeding causing a decrease in hemoglobin of 3 g/dl (or if hemoglobin level not available, a decrease in hematocrit of 10%). Minor was defined as bleeding that did not meet any of the criteria of major bleeding and that met at least 1 of the following: gross hematuria not associated with trauma; epistaxis that is prolonged, repeated, or requires plugging or intervention; gastrointestinal hemorrhage; hemoptysis; subconjunctival hemorrhage; hematoma >5 cm or leading to prolonged or new hospitalization; clinically overt bleeding causing a decrease in hemoglobin of 2 to 3 g/dl; and uncontrolled bleeding requiring protamine sulphate administration.
For ACUITY criteria (14), major bleeding was defined as intracranial bleeding; intraocular bleeding; access site hemorrhage requiring intervention; 5 cm diameter hematoma; reduction in hemoglobin concentration of 4 g/dl without an overt source of bleeding; reduction in hemoglobin concentration of 3 g/dl with an overt source of bleeding; reoperation for bleeding; and use of any blood product for transfusion.
Statistics.
Sample size was computed according to a noninferiority design, assuming a 2.5% event rate for the primary end point in the conventional treatment group, aiming for alpha = 5%, beta = 20%, and choosing as the absolute upper noninferiority boundary, not the relative boundary, a margin of tolerance 5.5%, thus yielding 350 patients per group. Continuous variables between groups were compared by the t test for normally distributed values. Proportions were compared by the chi-square test or the Fisher exact test, where appropriate. Absolute risk differences (with 95% confidence intervals [CIs]) were also computed with CI analysis (15). Results are expressed as mean ± SD or n (%) unless otherwise specified. A 2-tailed probability value <0.05 was considered statistically significant for superiority analysis, and a 1-tailed probability value <0.05 was considered statistically significant for noninferiority analysis.
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Results
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A total of 700 patients (350/group) were enrolled. Baseline demographic characteristics are listed in Table 1; baseline lesion and procedural characteristics are listed in Table 2. Treatment groups resulted in being matched with regard to baseline clinical, lesion complexity, and procedural characteristics (Table 2).
The median ACT at the end of PCI was 201 ± 34 s in the control group and 127 ± 25 s in patients receiving no scheduled anticoagulation. Bailout heparin or GPIs were never used. Seventy percent of the patients in each group received a clopidogrel preload the day before the intervention; the remaining patients were chronically on thienopyridine therapy at the time of PCI. The reduced ACT in the no-heparin group resulted in safe early sheath removal and limited time of access site compression.
Quantitative coronary angiography analysis (Table 3) showed similar data between the groups.
Intraprocedural angiographic complications (Table 4) did not result in increased post-procedural myocardial damage. No intracoronary thrombosis was observed; a limited number of procedures, without difference among the groups, required more than 1 stent to be placed; this was done (Table 4) in most of the cases of plaque shift and only in a limited number of cases of flow-limiting coronary dissection.
The primary end point of the study of noninferiority was already reached for the placebo group after 350 patients enrolled for each group. In-hospital major adverse cardiac events are listed in Table 5. Within 30 days, no death occurred in either group. Two patients required urgent vessel revascularization in the control group; both the patients presented with a flow-limiting dissection that required new stent apposition within 2 h from the index procedure; 1 patient in the no-heparin group presented on day 4 to a peripheral hospital with chest pain. In this case, a coronary angiography showed incomplete expansion of a mid left anterior descending artery stent that required new balloon dilation.
The periprocedural myocardial infarction rate was significantly higher in the heparin versus the placebo group (3.1% vs. 1.7%; p < 0.05) (Fig. 1). At 30 days, the primary end point was more frequent in the standard anticoagulation than in the no-anticoagulation group (respectively, 2.0% vs. 3.7%, absolute risk reduction 1.7% [95% CI: –0.1% to 4.5%], p for superiority = 0.17, p for noninferiority <0.001) (Table 4). Of note, no patients experienced a post-procedural Q-wave acute myocardial infarction.
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Figure 1 Post-Procedural Myocardial Damage
Creatine kinase-myocardial band (CK-MB) release after percutaneous coronary intervention (PCI) in patients receiving standard anticoagulation therapy (heparin; purple bars) and in patients receiving no anticoagulation therapy (placebo; hatched bars) (p = 0.034).
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Bleeding incidence is reported in Table 6. A very limited number of bleeding events occurred in the study; nevertheless, a reduced overall incidence of bleeding in the placebo group was observed. No transfusions were required. The statistical value of this observation varied according to the bleeding classification used. The rates of TIMI (major or minor) and ACUITY and GUSTO bleedings were minimal but not significantly different between the groups. The rate of STEEPLE bleedings (major and minor) were significantly reduced in the group receiving placebo.
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Discussion
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The results of this study demonstrate that elective PCI of uncomplicated coronary lesions can be safely conducted even in the absence of systemic anticoagulation. This procedure is not associated with an increased ratio of periprocedural ischemic events when compared with standard therapy. However, the lack of anticoagulation is associated with a reduced incidence of bleeding events.
Recently published guidelines provide a class I recommendation to administer UFH to patients undergoing PCI with a Level of Evidence C (2). This level of evidence is based only on the consensus opinion of experts, case studies, or standard of care. As stated by the scientific societies endorsing the guidelines, a recommendation with a Level of Evidence C does not imply that the recommendation is weak but that randomized trials are not available (2).
The purpose of this study was to provide a randomized clinical study testing the safety and efficacy of simple lesion elective PCI in the absence of systemic anticoagulation. In our study, the absence of systemic anticoagulation was shown to be noninferior to standard therapy in terms of post-procedural ischemic events. Despite following guidelines-recommended heparin doses in the control group, only a median ACT value of 201 ± 34 s could be achieved. Nevertheless, neither guidewire or guiding catheter thrombosis nor intraprocedural evidence of coronary thrombosis occurred in either of the groups.
The experience with wire thrombus in the OASIS (Optimal Antiplatelet Strategy for Interventions) trials but none in this trial suggests that in a simple and elective procedure, the use of anticoagulation is not crucial. Of note, the OASIS trial enrolled patients undergoing PCI for acute coronary syndromes. This clinical condition sets the procedures in a completely different thrombogenic milieu that predisposes to catheter thrombosis; furthermore, not all OASIS patients were taking aspirin and thienopyridines.
The minimal incidence of bleeding that occurred in this study may be related to the fact that more than 95% of the procedures were conducted through a 5-F system (16). Bleeding events were consistently lower in the group of patients who did not receive systemic anticoagulation. Of note, all events were related to access site complication, and none of them resulted in a surgical procedure or required blood transfusion (17).
Our results are comparable with those reported in a registry (6) and a trial (7), in which the use of an adjunctive therapy based on aspirin, thienopyridine, and GPI without UFH resulted in fewer bleeding complications and maintained efficacy in elective PCI. Of note, in our study, the use of a GPI was left to operator discretion, but in no cases was a GPI used.
A meta-analysis suggested that there were increased ischemic complications among non-GPI patients undergoing PCI with lower ACTs (18). It has to be noted that all of our patients underwent elective PCI to treat chronic coronary artery disease, whereas acute coronary syndromes represented a substantial proportion of the meta-analysis population. The thrombotic milieu of stable and unstable patients is substantially different and justifies different levels of anticoagulation to safely perform coronary interventions in these settings. Other differences are related to procedural duration, in that >1 h was observed in 27% of the meta-analysis cases (average procedural time was 11 min in our study), and to stent use, which was restricted to bailout indications in the meta-analysis and was mandatory in our study.
A study limitation is intraprocedural use of heparinized flush, which was not controlled for. However, given the maximum amount allowed to be used, it is not likely to have significantly affected activated clotting times.
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Conclusions
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The CIAO (Coronary Interventions Antiplatelet-based Only) trial is a single-center, double-blind, randomized study demonstrating that elective PCI of simple coronary lesions in patients pre-treated with double antiplatelet therapy is safe and is associated with reduced bleeding events.
The concept tested, whether anticoagulation is necessary for PCI if dual antiplatelet therapy is utilized, challenges a basic assumption. However, this protocol was conducted with very simple elective procedures in a limited number of selected patients, and this type of adjuvant treatment could probably not be applied to all patients, even stable ones, and certainly not to patients with complex lesions in acute coronary syndromes. Unless a large multicenter trial is performed that confirms these findings, this paper is not intended to provide false reassurance for an operator who decides to try this approach.
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References
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Abstract
Methods