The Association Between the Extent of Coronary Artery Disease and Major Bleeding Events After Percutaneous Coronary Intervention: From the ACUITY Trial

Abstract: Objective. We sought to evaluate the relation between the extent of coronary artery disease (CAD) and bleeding risk in patients undergoing percutaneous coronary intervention (PCI) for non-ST segment elevation acute coronary syndrome (NSTEACS). Background. Patients with severe CAD undergoing PCI for NSTEACS are at high risk for recurrent adverse events. Hemorrhagic events after PCI are associated with high rates of morbidity and mortality. Despite sharing many common risk factors, the relationship between the extent of CAD and bleeding after PCI remains understudied. Methods. The SYNTAX score (SS) was used to quantify the extent and severity of CAD. We stratified 2627 patients from the ACUITY PCI cohort into SS groups based on score tertiles from the ACUITY trial (<7, 7-12, and >12). Thirty-day major bleeding rates were determined for each group. Results. When stratified by ACUITY tertiles, 30-day major bleeding rates were significantly greater in the highest SS tertile (>12) than in the intermediate and lowest tertiles (P<.01). By multivariable analysis, the SS (by augmentation of 1 point) remained independently associated with 30-day major bleeding (hazard ratio = 1.03; 95% confidence interval, 1.01-1.04; P<.01). Conclusion. The results of this large-scale study suggest that in addition to its previously described association with adverse ischemic events, the extent of CAD, as assessed by the SS, was independently associated with major bleeding after PCI for NSTEACS.

J INVASIVE CARDIOL 2015;27(4):203-211

Key words: coronary artery disease, bleeding, acute coronary syndromes, percutaneous coronary intervention

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Although the application of an early invasive strategy for non-ST segment elevation acute coronary syndrome (NSTEACS) patients results in significantly improved clinical outcomes, the rates of adverse outcomes are still substantial.^1,2 Iatrogenic major bleeding, one of the most frequently encountered complications after percutaneous coronary intervention (PCI), has been associated with increased rates of adverse outcomes and mortality.^3-6 Analyses of several studies have revealed clinical predictors of major bleeding events in patients with NSTEACS.^3,7,8 However, to date, the relationship between the extent of coronary artery disease (CAD) and bleeding after PCI has yet to be established. The Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score (SS), developed to assess severity and extent of CAD,⁹ is a powerful tool for predicting adverse ischemic outcomes in patients presenting with acute coronary syndromes.^10-12 As increased coronary disease burden is very much related to systemic factors such as peripheral vascular disease and chronic kidney disease, we expected patients with more extensive CAD to be at greater risk for bleeding events. Therefore, we sought to evaluate this relationship between extent of CAD and bleeding events after PCI in the large-scale Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.

Methods

Study protocol. The ACUITY trial design has previously been described in detail.¹³ In brief, ACUITY was a multicenter, prospective, randomized trial of 13,819 patients with moderate- and high-risk NSTEACS who were treated with an early invasive strategy. Major inclusion criteria were age ≥18 years with unstable angina symptoms lasting ≥10 minutes in duration within 24 hours of randomization and ≥1 of the following: new ST-segment depression or transient elevation of at least 1 mm, cardiac biomarker elevations, known CAD, or all 4 other variables as part of the Thrombolysis in Myocardial Infarction (TIMI) risk score for unstable angina.¹⁴ Major exclusion criteria were acute ST-elevation myocardial infarction (STEMI) or shock, bleeding diathesis or recent major bleeding episode, thrombocytopenia, calculated creatinine clearance <30 mL/min, recent antithrombotic or thrombolytic agent administration, and allergy to study drugs or iodinated contrast medium not amenable to pretreatment.

Prior to coronary angiography, patients were randomly assigned to heparin (unfractionated or low molecular weight) plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin monotherapy. Angiography was performed within 72 hours of randomization, and depending on coronary anatomy, patients were triaged to PCI, coronary artery bypass graft (CABG) surgery, or medical therapy. In patients undergoing PCI, stent choice (bare-metal or drug-eluting) was per operator discretion. Dual-antiplatelet therapy with aspirin and clopidogrel was recommended for at least 1 year. An independent clinical events committee, blinded to treatment assignment, adjudicated all major adverse events.

Objectives, patient population, and angiographic analysis. Our primary objective was to study the relationship between the extent of CAD, as assessed by the SS, and risk of major bleeding after PCI at 30 days. We included only patients from the PCI subgroup in whom quantitative coronary angiography (QCA) was performed by experienced core laboratory technicians who were blinded to randomization and clinical outcomes (Cardiovascular Research Foundation, New York, New York).¹⁵ Because the SS had only been validated for native coronary arteries at the time of our angiographic analysis,¹⁶ patients with prior CABG were excluded.

Three experienced interventional cardiologists (PG, TP, AC) who were also blinded to randomization and clinical outcomes assessed the SS for each angiogram. Lesions causing ≥50% reduction in luminal diameter in vessels with a minimal diameter of 1.5 mm were scored using the SS algorithm as described elsewhere.⁹ The Fleiss kappa statistic (tertile partitioning),¹⁷ determined by each of the three readers independently reading 50 films, was 0.57; the value signifies a moderate level of interobserver agreement, comparable to what was achieved in the SYNTAX trial.¹⁸

Endpoint definitions and statistical analysis. As per protocol,¹³non-CABG surgery major bleeding in ACUITY was defined as intracranial or intraocular bleeding, access-site hemorrhage requiring intervention, hematoma ≥5 cm in diameter, reduction in hemoglobin levels ≥4 g/dL without an overt bleeding source or ≥3 g/dL with an overt source, reoperation for bleeding, or any blood product transfusion. We also adjudicated other major access-site bleeding events, including access-site bleeds that resulted in interventional or surgical correction, hematoma ≥5 cm, retroperitoneal bleeding, or hemoglobin drop ≥3 g/dL with ecchymosis or hematoma <5 cm, oozing blood, or prolonged bleeding (>30 minutes).¹⁹Major bleeds not limited to the access site were defined as non-access site only, both non-access site and access site, or unidentified source of bleeding.²⁰Acquired thrombocytopenia was defined as a nadir platelet count of <150,000/mm³ within 30 days of hospitalization.²¹

We stratified patients by equal tertiles of SS based on the score distribution of the current study population (<7, 7-12, >12). Also, to highlight and parallel results from the pivotal SYNTAX trial, we stratified bleeding events according to the broadly used cut-offs from the SYNTAX trial (<23, 23-32, >32).¹⁰ Hereafter, SS score ranges within these two sets of groups will be referred to as SS <7, SS 7-12, SS >12 and SS <23, SS 23-32, and SS >32, respectively. Continuous data are presented as mean ± standard deviation and were compared using the Student t-test or ANOVA, as appropriate. Binary variables are presented as n/N (%) and compared between groups with the chi-square test. Thirty-day event rates were estimated using Kaplan-Meier methodology and compared using the log-rank test. Multivariable regression analysis using Cox proportional hazard models for 30-day time points was performed to assess whether there was an independent relationship between SS and major bleeding with variable entry/stay criteria of 0.1/0.1. Variables for multivariable analysis were selected through statistical significance after univariate analysis as well as clinical importance for bleeding risk; these included SS (as a continuous variable), age, sex, diabetes, current cigarette smoking, renal dysfunction (creatinine clearance <60 mL/min), baseline white blood cell count, baseline hemoglobin, baseline troponin elevation, prior MI, prior PCI, stent choice (drug-eluting vs bare-metal), bivalirudin monotherapy, and postprocedural thrombocytopenia at 30 days (time-dependent covariate). P-values <.05 were considered to be statistically significant. Statistical analyses were performed using SAS version 9.2 (SAS Institute).

Results

The angiographic substudy of ACUITY included 6921 patients (3826 of these patients received PCI). Patients with a history of CABG (n = 862) and those for whom the SS could not be calculated due to technical reasons (n = 337) were excluded, and analysis was performed on the remaining 2627 patients. SYNTAX scores ranged from 0 to 59, with a mean of 11.5 ± 8.4 and median and interquartile range of 9.^5,16

There were a total of 165 (6.3%) non-CABG major bleeds within the first 30 days after intervention in our study population. Table 1 compares baseline clinical characteristics in patients who did and did not develop non-CABG major bleeding at 30 days. Patients who developed bleeding were more likely to be older, female, and have baseline diabetes, renal dysfunction and lower hemoglobin levels. The rates of cardiac biomarker elevation, ST-segment deviation, and higher TIMI scores were higher in the group that experienced bleeding.

Table 2 presents clinical characteristics, angiographic findings, and treatment randomization for patients stratified by extent of CAD (tertiles based on the ACUITY trial SS distribution). Those in the highest ACUITY tertile (SS >12) were more likely to be older and have renal dysfunction, baseline troponin elevation, ST-segment deviation, lower left ventricular ejection fraction (LVEF), and higher TIMI risk scores compared with those with lower scores (SS <7 and SS 7-12). Angiographically, patients in SS >12 were more likely to have longer lesion lengths, thrombus-containing lesions, and severely calcified lesions compared with those in SS <7 and SS 7-12. The SS >12 tertile was also more likely to have diabetes than the lowest tertile. There were no significant differences in postrandomization antithrombotic regimens or intraprocedural glycoprotein IIb/IIIa inhibitor (GPI) use across SS tertiles. Total procedural time was significantly higher in patients with greater CAD burden (ie, higher SS tertiles). There were no significant differences in medical therapy prescribed at discharge.

Among the 2627 patients, there were 165 (6.3%) major bleeding events within 30 days. The rate of major bleeding and its components at 30 days were stratified by extent of CAD (Table 3, Figure 1). In the ACUITY stratification, the SS >12 tertile had a higher rate of major bleeding compared with the lowest and intermediate tertiles at 30 days (8.3% vs 4.9% [P<.01] and 8.3% vs 5.5% [P=.02], respectively). When stratified by the SYNTAX distribution, major bleeding rates were significantly higher in the SS 23-32 and SS >32 groups compared with the lower group at 30 days (10.9% vs 5.6% [P<.01] and 14.1% vs 5.6% [P<.01], respectively). Blood product transfusions were the most frequent of the major bleeding events (Table 3). Patients with SS >12 had a significantly greater transfusion rate compared with the lower tertiles in the ACUITY distribution (P=.03), and the SS >22-32 and SS >32 groups had significantly greater rates than the SS <22 group (P<.01) in the SYNTAX distribution.

In terms of bleeding site, patients with higher SYNTAX scores in both stratifications were significantly more likely to develop bleeds not limited to the access site rather than access-site bleeds after PCI (Table 3). With regard to outcomes other than adjudicated bleeding events, the rate of 30-day acquired thrombocytopenia was significantly greater among the SS >12 tertile compared to the SS <7 and SS 7-12 tertiles (9.7% vs 6.4% [P=.01] and 9.7% vs 5.4% [P<.001]). As shown in Table 4, after adjusting for potential confounders, SS was independently associated with 30-day major bleeding (hazard ratio = 1.03; 95% confidence interval, 1.01-1.04; P<.01).

Patients who developed 30-day non-CABG major bleeding had significantly higher rates of death (4.2% vs 0.6%; P<.001), cardiac death (3.0% vs 0.6%; P<.001), non-cardiac death (1.2% vs 0%; P<.001), myocardial infarction (17.6% vs 6.4%; P<.001), target vessel revascularization (4.9% vs 2.1%; P=.02), target lesion revascularization (4.9% vs 1.6%; P<.01), CABG major bleeding (3.1% vs 0.6%; P<.001), and MACE (24.2% vs 8.8%; P<.001) at 30 days. Additionally, non-CABG minor bleeding (65.1% vs 25.5%; P<.001) and thrombocytopenia (18.8% vs 6.5%; P<.001) were higher at 30 days in the patients who developed non-CABG major bleeding events. At 1 year, patients who developed 30-day non-CABG major bleeds were also more likely to have higher rates of death (10.6% vs 1.9%; P<.001), cardiac death (5.0% vs 1.1%; P<.001), non-cardiac death (4.5% vs 0.6%; P<.001), bleeding-related deaths (0.6% vs 0.0%; P<.001), myocardial infarction (18.9% vs 8.6%; P<.001), and MACE (30.5% vs 17.9%; P<.001). Rates of 1-year target vessel revascularization (9.5% vs 8.0%; P=.34) and target lesion revascularization (8.9% vs 6.7%; P=.20) did not differ between those who developed non-CABG major bleeding and those who did not.

Discussion

The present study, drawn from a cohort of 2627 patients who received an invasive strategy of PCI for NSTEACS, is the first to specifically evaluate the relationship between the extent and severity of CAD and major bleeding events after PCI. The main results of this study are as follows: (1) major bleeding after PCI increased proportionally with CAD burden, as assessed and stratified by SS tertiles; (2) CAD burden remained strongly associated with post-PCI major bleeding after multivariate analysis; and (3) those who developed 30-day major bleeding experienced higher rates of short- and long-term adverse events.

The current study is the first to clearly demonstrate that major bleeding increases proportionally with CAD burden. This finding parallels previous reports showing the association between CAD severity (ie, coronary calcification severity) and hemorrhagic events.²² Several potential factors may explain these findings. Well-established bleeding predictors including diabetes, previous PCI, renal insufficiency, antithrombotic regimen, baseline hemoglobin, and acquired thrombocytopenia, were demonstrated in this report to be independent predictors of major bleeding, and most of these were more frequently observed in the highest SS tertiles (Tables 1 and 2).^3,7,8,21 Thus, patients with greater CAD burden, quantified by higher SS, are generally sicker and at higher risk for adverse outcomes. In addition, since those with higher SS have more complex coronary disease, intervening on these patients is more technically challenging. This is suggested by the significantly longer procedural duration in those with higher SS in ACUITY (Table 2) and as previously described.²³ This is especially important, as longer procedures have been demonstrated to be strongly associated with major bleeding after PCI,^7,24 and the extended anticoagulation during these procedures may be one of the many reasons contributing to this phenomenon.

With regard to the types of bleeds, major bleeding not confined to the access site was more frequently associated with extensive CAD burden (highest SS) compared with major access-site bleeding alone (Table 3). While this finding may partially relate to the fact that patients with extensive CAD who are “non-access site bleeders” share common high-risk characteristics, leading simultaneously to more severe CAD and a higher propensity for bleeding, the low number of access-site bleeding events precludes any definite conclusion. Given that non-access site bleeding has been shown to have a much stronger association with mortality and adverse events than access-site bleeding after PCI,²⁰ it appears that the severe CAD tends to be most associated with the type of bleeding events that are thought to lead to worse prognosis (greatest transfusion rate, morbidity, and mortality).^20,25

Importantly, the current analysis identified baseline CAD burden as independently associated with 30-day major bleeding after controlling for a number of important clinical variables (Table 4). When considering its previously described association with and utility for predicting ischemic endpoints,^10-12 the SS is independently associated with what would initially seem to be paradoxical outcomes. In light of reports demonstrating that major bleeding can subsequently increase short- and long-term risks of death and ischemic events,^3,4 there are several potential explanations for the complex interrelationship between these adverse outcomes with the extent of CAD. First, bleeding and ischemic endpoints often share similar risk factors, as many of the aforementioned predictors of bleeding also have prognostic utility for ischemic endpoints.^26-28 Second, bleeding may directly increase the risk of ischemic complications through triggering a number of adverse physiologic effects, including anemia, hypotension, vasoconstriction, ineffective oxygen delivery, platelet dysfunction, activation of prothrombotic pathways, and transfusion requirement.^5,29,30 Third, proinflammatory disease states, such as diabetes and renal insufficiency, may not only contribute to a more extensive CAD burden but also independently lead to thrombotic and hemostatic complications.^26,31,32 Finally, major bleeding after intervention may significantly influence post-PCI medication regimens. Patients who experience major bleeds are more likely to have premature discontinuation of antithrombotic medications.^33,34 As a matter of fact, patients with the most severe CAD (ie, SS >32) less frequently received antiplatelet agents at hospital discharge compared to patients with SS <23 or SS 23-32 (85.5% vs 92.6% vs 94.3%, respectively; P=.03). The most likely explanation for this trend is that antiplatelet agents were discontinued as a result of in-hospital major bleeding, a practice that would greatly increase the risk for further ischemic events.^30,35 With the above points in mind, one can conclude that more appropriate therapies are likely necessary for the population of patients with high SYNTAX scores who are at greater risk for both bleeding and ischemic events.

Interestingly, bare-metal stent implantation was more prevalent in the highest SS groups of both stratifications. While it may appear counterintuitive to use less-effective stents in patients with more extensive disease, the most recent guidelines recommended bare-metal stents over drug-eluting stents in NSTEACS patients who are at high risk for bleeding complications and therefore cannot adhere to extended dual-antiplatelet therapy regimens.^36,37 Several variables linked with greater CAD burden (ie, higher SS), such as diabetes,^38,39 left main disease, bifurcations, long lesions, and multiple lesions,^40,41 are also indications to consider drug-eluting stents, which are associated with improved efficacy and decreased risk of stent failure.³⁷ Though the goal of targeting prothrombotic pathways without compromising hemostatic mediators continues to be elusive, better risk stratification involving both angiographic and clinical variables, continued development of safer and more effective drugs and devices, and identification of the most appropriate revascularization strategy (CABG vs PCI) may help tailor treatments and improve outcomes in patients at high risk of both bleeding and ischemic events.

Study limitations. This study has some limitations that should be acknowledged. As an observational post hoc analysis, it can only identify correlations and not prove causality. Despite adjustment for potential confounders, unmeasured variables may not have been fully controlled. All these findings, therefore, should be considered hypothesis generating. While our sample size of 2627 in the angiographic cohort of the ACUITY trial allows for a well-powered study, the majority of patients fell below the SS of 23, and the sample sizes for the SS 23-32 and SS >32 subgroups were limited. In addition, we were not able to include patients with a history of CABG due to the fact that the SS had yet to be validated in this population,¹⁶ and so the current findings apply only to patients who received PCI in native coronary arteries. Lastly, because we calculated the SS by visual assessment, interobserver variability may influence the reproducibility of our findings.⁴²

Conclusion

Our findings demonstrate that the burden of CAD, as assessed by the SS, was strongly associated with major bleeding events after PCI for NSTEACS in the large-scale ACUITY trial. Further studies are required to help elucidate the mechanisms behind this relationship.

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^*Joint first authors.

From the ¹New York-Presbyterian Hospital and the Columbia University Medical Center, New York, New York; ²Cardiovascular Research Foundation, New York, New York; ³Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Canada; ⁴Istituto di Cardiologia, University of Bologna, Italy; ⁵Hospital Israelita Albert Einstein and Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Brazil; ⁶Icahn School of Medicine at Mount Sinai, New York, New York. 

Funding: The ACUITY trial was funded by The Medicines Company (Parsippany, New Jersey) and Nycomed (Roskilde, Denmark). 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Madhavan was supported by a grant from the Doris Duke Charitable Foundation to Columbia University to fund a clinical research fellowship. Dr Kirtane reports institutional research grants (to Columbia University) from Medtronic, Abbott Vascular, Boston Scientific, Abiomed, Vascular Dynamics, Eli Lilly, and St. Jude Medical. Dr Généreux reports speaker fees from Abbott Vascular; speaker fees, grant support, and consultant fees from Cardiovascular Systems, Inc. Dr Palmerini reports speaker fees from Abbott Vascular. Dr Mehran reports grants from The Medicines Company, Bristol-Myers Squibb/ Sanofi-Aventis, and Lilly/Daiichi Sankyo; personal fees from Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, Merck, Regado Biosciences, and Sanofi-Aventis. Dr Stone reports consultant fees (outside the submitted work) for Osprey, Reva, Boston Scientific, Astra Zeneca, Eli Lilly/Daiichi Sankyo, InspireMD, TherOx, Atrium, Volcano, InfraReDx, Miracor, Velomedix, CSI, AGA, and Thoratac; stock options in the Biostar family of funds, MedFocus family of funds, Caliber, Guided Delivery Systems, MiCardia, Embrella, and VNT. The remaining authors report no conflicts of interest regarding the content therein. 

Manuscript submitted September 30, 2014 and accepted October 1, 2014.

Address for correspondence: Philippe Généreux, MD, Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 12th Floor, New York, NY 10022. Email: pg2295@columbia.edu