Correlates of Adverse Events During Saphenous Vein Graft Intervention With Distal Embolic ProtectionA PRIDE Substudy
Ajay J. Kirtane, MD, SM, FACC*,
Eugene R. Heyman, PhD ,
Christopher Metzger, MD, FACC ,
Jeffrey A. Breall, MD, PhD, FACC ,
Joseph P. Carrozza, Jr, MD, FACC||,*
* Center for Interventional Vascular Therapy, Columbia University Medical Center, New York, New York
Montgomery Village, Maryland
The Heart Center, Kingsport, Tennessee
Krannert Institute of Cardiology, Indiana University of Medicine, Indianapolis, Indiana
|| Section of Interventional Cardiology, Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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Abstract
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Objectives: We sought to identify correlates of 30-day adverse events among patients undergoing percutaneous coronary intervention (PCI) of saphenous vein grafts (SVG).
Background: Although the use of distal embolic protection devices during SVG intervention reduces major adverse cardiac events (MACE), many patients still experience MACE despite distal embolic protection, and the major predictors of MACE among these patients are not well-characterized.
Methods: Correlates of 30-day MACE and peri-procedural creatine kinase-myocardial band (CK-MB) elevation were assessed among 631 patients undergoing SVG intervention with distal embolic protection enrolled in the PRIDE (PRotection during saphenous vein graft Intervention to prevent Distal Embolization) study, a randomized comparison of the TriActiv System (Kensey-Nash Corp., Exton, Pennsylvania) with an active control group (Guardwire [Medtronic, Santa Clara, California] or Filterwire [Boston Scientific, Minneapolis, Minnesota]).
Results: Baseline covariates associated with MACE were longer lesion length, greater angiographically assessed estimated plaque volume, and higher SVG degeneration score. Graft age and angina class were not associated with adverse events. Angiographic lesion length was significantly correlated with more complex angiographic metrics such as estimated plaque volume and the SVG degeneration score. In multivariable analyses, angiographic lesion length was the strongest independent correlate of MACE (odds ratio [OR] 2.81 [95% confidence interval (CI) 1.82 to 4.34]/log-increase in lesion length, p < 0.001) with a graded increase in MACE observed with increasing lesion lengths. Similarly, the strongest independent correlate of CK-MB elevation was lesion length (OR 2.54 [95% CI 1.59 to 4.04]/log-increase in lesion length, p < 0.001). The associations between lesion length and both MACE and CK-MB elevation were consistent among the studied embolic protection devices (TriActiv, Guardwire, or Filterwire).
Conclusions: Angiographic lesion length was the strongest correlate of short-term adverse events among patients undergoing SVG intervention with distal embolic protection, with incremental effects noted at even relatively short lesion lengths.
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Abbreviations and Acronyms
| | CI = confidence interval | | CK-MB = creatine kinase-myocardial band | | MACE = major adverse cardiac events | | OR = odds ratio | | PCI = percutaneous coronary intervention | | SVG = saphenous vein graft |
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The percutaneous treatment of diseased saphenous vein grafts (SVGs) represents one of the major current challenges of current percutaneous coronary intervention (PCI). Despite major advances in PCI technique and technology, patients with diseased SVGs still represent one of the highest-risk subgroups of patients undergoing PCI. Percutaneous treatment of SVGs has been associated with a greater incidence of slow flow and higher rates of peri-procedural myocardial infarction, largely owing to distal embolization of the abundant and friable atherosclerotic debris in diseased SVGs.
Although the embolic protection with either balloon occlusion devices or filter-based devices during SVG PCI reduces major adverse cardiac events (MACE), many patients undergoing SVG PCI still experience adverse events (1–5). Prior reports of the major correlates of MACE among patients undergoing contemporary SVG PCI have included a mixed cohort of patients treated both with and without embolic protection (3,6–10) or have been limited by small sample size (11). Therefore we sought to identify correlates of adverse events among a cohort of SVG PCI patients uniformly treated with distal embolic protection.
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Methods
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Data were compiled from 631 subjects undergoing SVG PCI in the PRIDE (PRotection during saphenous vein graft Intervention to prevent Distal Embolization) Study. The PRIDE was a prospective, randomized clinical trial of the TriActiv System (Kensey-Nash Corp., Exton, Pennsylvania) device with an active control (either Guardwire [Medtronic, Santa Clara, California] or Filterwire [Boston Scientific, Minneapolis, Minnesota]) in patients undergoing PCI of an SVG (12). Criteria for inclusion were age  21 years, angina or objective evidence of ischemia, lesion in an SVG (3.0 and  5.0 mm in diameter), Thrombolysis In Myocardial Infarction (TIMI) flow grade 0, and ability to provide informed consent. Patients were excluded if any of the following were present: pregnancy; lesion in a native artery or internal mammary graft; distal shoulder of the lesion within 2.0 cm of the distal anastamosis; left ventricular ejection fraction <25%; sequential grafts, unless the lesion was >2 cm proximal to the branch point; myocardial infarction (creatine kinase [CK] and creatine kinase-myocardial band [CK-MB] more than twice the upper limit of normal within 24 h); allergy to aspirin, clopidogrel, or ticlopidine; treatment of >2 SVGs; and comorbidities limiting life-expectancy to 6 months. The PRIDE study was approved by the institutional review board at each site; all patients provided written informed consent to participate.
Randomization was stratified by intention to administer a glycoprotein IIb/IIIa receptor antagonist before intervention. Patients received aspirin before the procedure and either heparin or bivalirudin during the procedure. After the procedure, aspirin and either clopidogrel or ticlopidine were administered for a minimum of 1 month. Cardiac enzymes were routinely assessed every 8 h for 24 h. Patients were assessed clinically at 30 days.
For this analysis, subjects included were those in Cohort 2 of the trial (randomized comparison of TriActiv System vs. Guardwire or Filterwire). Subjects in Cohort 1 (randomized comparison of TriActiv System vs. no embolic protection) were not included. All angiographic data were assessed offline by an independent core laboratory with quantitative coronary angiography methodology that has been described previously (3). The primary end point for this analysis was the occurrence of 30-day MACE (cardiac death, myocardial infarction [any post-procedure CK-MB level 3 x the upper limit of normal], or target lesion revascularization) on a per-patient level. The MACE was adjudicated by an independent clinical events committee blinded to device assignment. Peri-procedural myocardial infarction (as defined earlier) was a secondary end point.
Statistical analysis.
Continuous variables are reported as means with SDs and categorical variables as rates or proportions. The t test was used to compare continuous variables, and the chi-square test was used for comparisons of categorical variables. Variables that were not normally distributed were appropriately transformed (e.g., lesion length was left-skewed and was therefore log-transformed with natural logarithms). Logistic regression multivariable analyses were performed, including candidate covariates associated with the outcome of interest (MACE, CK elevation) with p < 0.05 in univariate analyses. Stepwise selection was used to develop final models. All analyses were performed by an independent study statistician (ERH) with SAS Version 8.2 (SAS Institute, Cary, North Carolina).
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Results
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The mean patient age was 69 years, with 82% male and 41% diabetic subjects (Table 1). The mean graft age was 12 years, and treated grafts had a mean reference diameter of 3.3 mm, a mean percent diameter stenosis of 65%, and a mean lesion length of 14 mm. Angiographic thrombus was present in 58% of lesions, and 11% of grafts had abnormal TIMI flow grade. Coronary stents were successfully delivered in 585 of 631 (92.7%) patients. After PCI, the mean residual diameter stenosis was 14%, with 11% of grafts having abnormal TIMI flow grade. Device success was observed in >99% of cases, with no significant differences between treatment groups in the overall cohort (p = 0.68 for comparison with TriActiv System vs. active control).
Adjudicated MACE was observed in 67 (10.6%) patients, with CK-MB elevation occurring in 56 of 549 (10.2%) patients. The univariate correlates of MACE and CK-MB elevation are shown in Table 2. The only baseline covariates associated with MACE were history of cigarette smoking, lesion length, estimated plaque volume, and SVG degeneration score. The baseline covariates associated with peri-procedural CK-MB elevation were very similar and included female gender, history of cigarette smoking, lesion length, estimated plaque volume, and SVG degeneration score. Of note, neither graft age nor angina class at presentation was associated with adverse peri-procedural outcomes (Table 1).
A strong and graded association between increasing lesion length and the incidence of MACE and CK-MB elevation was observed (Fig. 1). Lesion length was significantly correlated with estimated angiographically estimated plaque volume as well as the SVG degeneration score (r = 0.83 for plaque volume; r = 0.49 for SVG degeneration score). Because lesion length, SVG degeneration score, and angiographic plaque volume were highly correlated, only the covariate with the strongest association with the study end points (lesion length) was included in final multivariable models to avoid multicollinearity.
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Figure 1 Association Between Lesion Length and Rates of Adverse Outcomes
The figure depicts the relationship between increasing lesion length and the rates of adverse peri-procedural events (major adverse cardiac events [MACE] and creatine kinase-myocardial band [CK-MB] elevation). ULN = upper limit of normal.
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In multivariable analyses, lesion length remained the strongest independent correlate of MACE (odds ratio [OR] 2.81 [95% confidence interval (CI) 1.82 to 4.34]/log-increase in lesion length, p < 0.001). Similarly, the most significant independent correlate of peri-procedural CK-MB elevation >3 x the upper limit of normal was lesion length (OR 2.54 [95% CI 1.59 to 4.04]/log-increase in lesion length, p < 0.001). The association between lesion length and either MACE or CK-MB elevation was significant and consistent among the 3 different types of distal embolic protection device used in the trial and regardless of whether the use of glycoprotein IIb/IIIa inhibitors was planned (all p values for interaction not significant).
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Discussion
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In this analysis of 631 patients undergoing SVG PCI using distal embolic protection, angiographic lesion length was the only independent correlate of adverse clinical outcomes. Despite the use of embolic protection, the association between lesion length and adverse outcomes was graded and continuous, with >20% rates of peri-procedural MACE observed for lesions >20 mm in length.
The use of embolic protection devices as an adjunct to SVG PCI has been demonstrated to reduce the occurrence of peri-procedural events by approximately 40% (1). Although this represents a significant relative and absolute reduction in adverse events for one of the highest-risk subsets of current PCI, the rate of adverse peri-procedural events remains high even with the use of embolic protection, and these peri-procedural events have been associated with significant morbidity and economic cost (13,14). Thus, identification of patients at the highest risk for peri-procedural complications can lead to appropriate risk-stratification of patients before SVG PCI. Patients with longer lesions in our study were at the highest risk of adverse events. Nonetheless, the observation of a >20% rate of MACE with lesions above 20 mm (a lesion length not traditionally considered extensive for conventional PCI) suggests that there remains significant room for improvement in the percutaneous treatment of SVG lesions, even if greater penetrance of these devices is achieved. A recent report from the American College of Cardiology-National Cardiovascular Data Registry describes <25% use of embolic protection devices for SVG PCI overall (15). Whether higher-risk patients such as those with longer lesions should therefore lower the threshold for the use of an embolic protection device remains to be determined, but longer lesion length was associated with a higher incidence of the use of an embolic protection device in that registry, suggesting that operators might be influenced by this lesion characteristic.
The observed association between lesion length and outcomes in this study parallels that of other studies that have examined risk factors for adverse events in patients undergoing PCI with and without embolic protection (3,9). Longer lesions are thought to be representative of more severe degenerative disease within an SVG (and therefore a larger burden of debris with additionally greater potential to embolize). The observed correlation in this analysis between lesion length and angiographic plaque volume and the semi-quantitative SVG degeneration score validates this theory and is consistent with prior observations that estimated plaque volume and diffuse disease within SVGs is correlated with peri-procedural adverse events as observed almost 15 years ago (16). It is notable that in the present analysis the simple metric of lesion length was the strongest predictor of adverse events, particularly in comparison with more sophisticated angiographic measurements such as plaque volume.
It is unclear why the relationship between lesion length and outcomes persisted in the current study population that was exclusively treated with embolic protection devices with high rates of technical success. Embolization might have occurred with wire or device crossing, and in this respect balloon occlusion devices might have a theoretical advantage over filter-based devices, which typically have larger crossing profiles. Although this study was not adequately powered to detect treatment effects between devices, we did not observe any interaction between lesion length and outcomes among the 3 tested devices. Nonetheless, the occurrence of adverse events even in patients with the shortest lesions in this study—all of whom were treated with embolic protection devices—stresses the high overall risk of this patient population, even when treated with adjunctive embolic protection.
Interestingly, despite a mean graft age of 12 years and the presence of several "high-risk" angiographic features such as a high prevalence of thrombus, we did not observe an association between adverse outcomes and graft age, thrombus, or any other angiographic graft characteristics aside from lesion length. Several risk factors including thrombus and graft age have been described for SVG PCI without distal embolic protection (3,6,7,10). It might be that the use of embolic protection devices with high technical success rates in this study has the ability to mitigate the risk associated with some of the more traditional risk factors for peri-procedural events. Further confirmatory studies are necessary to validate these observations.
Study limitations.
This analysis is a nonrandomized retrospective analysis, and as such it is possible that both identified and unidentified confounders might have influenced the outcomes. The cohort of patients enrolled in PRIDE was a carefully selected clinical trial population that met specific clinical and angiographic inclusion criteria. Thus the results of this trial might not be fully generalizable to unselected patient populations. This study specifically excluded patients with significantly elevated CK-MB at baseline, patients with severely depressed ejection fractions, and patients with the highest-risk acute coronary syndromes, such as ST-segment elevation myocardial infarction. One could anticipate that rates of adverse events would be even higher among these patients, but whether the association we observed between lesion length and outcomes would persist in these patient populations is unknown. In addition, because troponin levels were not systematically or prospectively collected, the definitions of CK-MB elevation and MACE do not include patients with isolated troponin elevations. Finally, whether these results apply to embolic protection devices other than those studied in PRIDE is unknown.
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Footnotes
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This work was supported in part by a grant from Kensey-Nash, Inc.
* Reprint requests and correspondence: Dr. Joseph P. Carrozza Jr., Chief, Section of Interventional Cardiology, Beth Israel Deaconess Medical Center, 1 Deaconess Road, Baker 4, Boston, Massachusetts 02215. (Email: jcarrozz{at}bidmc.harvard.edu).
Manuscript received September 18, 2007;
revised manuscript received December 13, 2007,
accepted January 23, 2008.
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Abstract
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