- Email: [email protected]
Culprit Coronary Lesions Requiring Percutaneous Coronary Intervention After Vascular Surgery Often Arise From In-Stent Restenosis of Bare Metal Stents
Culprit Coronary Lesions Requiring Percutaneous Coronary Intervention After Vascular Surgery Often Arise From In-Stent Restenosis of Bare Metal Stents Santiago Garcia,1 Sara T.N. Murray,1 Thomas E. Moritz,3 Gordon Pierpont,1 Steven Goldman,5 Greg C. Larsen,6 Fred Littooy,4 Herbert B. Ward,2 and Edward O. McFalls,1 Minneapolis, Minnesota; Hines, Illinois; Tuscon, Arizona; and Portland, Oregon
Background: The natural history of coronary artery disease (CAD) after vascular surgery is poorly defined. The aim of this study was to determine the temporal change of coronary artery lesions requiring revascularization with a percutaneous coronary intervention (PCI) after elective vascular surgery and to determine the utility of preoperative biomarkers on predicting those patients at risk for new coronary lesions. Methods: The Coronary Artery Revascularization Prophylaxis Trial tested the long-term survival benefit of coronary artery revascularization before elective vascular surgery. Among randomized patients who subsequently required PCI after surgery, the stenosis of the culprit lesion from the follow-up angiogram was compared with the preoperative vessel stenosis at the identical site on the baseline angiogram. Results: A total of 30 patients underwent PCI for progressive symptoms at a median of 11.5 (interquartiles: 4.5-18.5) months postsurgery. Of 30 patients, 16 (53%) had nonobstructive CAD preoperatively (group 1) with a stenosis that increased from 17 ± 6% to 91 ± 2% (P < 0.01) and 14 (47%) had severe CAD at the culprit site preoperatively (group 2), with a stenosis that increased 89 ± 2% (P ¼ 0.15). The only biomarker that was an identifier of early coronary artery lesion formation in group 1 compared with group 2 patients was a higher baseline homocysteine level (14.6 ± 1.4 vs. 10.6 ± 0.7 mg/dL; P ¼ 0.02). Conclusions: Culprit coronary artery lesions requiring PCI after an elective vascular operation often arise from in-stent restenosis. Therapies that either stabilize existing plaques or prevent restenosis, particularly among patients with elevated homocysteine levels, have the greatest promise for improving postoperative outcomes.
INTRODUCTION 1 Division of Cardiology, University of Minnesota and Minneapolis VA Medical Center, Minneapolis, MN. 2 Division of Cardiothoracic Surgery, University of Minnesota and Minneapolis VA Medical Center, Minneapolis, MN. 3
Cooperative Studies Program Coordinating Center, Hines, IL.
4
Division of Vascular Surgery, VA Medical Center Hines, Hines, IL.
5
Division of Cardiology, Southern Arizona VA Healthcare System and The University of Arizona Sarver Heart Center, Tucson, AZ. 6 Division of Cardiology, Portland VA Medical Center, Portland, OR. Correspondence to: Edward O. McFalls, Division of Cardiology, VA Medical Center, 1 Veterans Drive, Minneapolis, MN 55417, USA, E-mail: [email protected]
Ann Vasc Surg 2010; 24: 596-601 DOI: 10.1016/j.avsg.2010.03.006 Ó Annals of Vascular Surgery Inc.
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Over 400,000 open vascular operations were performed in the United States in the year 2000, and this number is expected to rise as the population ages.1 The prevalence of coronary artery disease (CAD) among these patients is approximately 50%2 and it is not surprising that adverse perioperative cardiac events are common after major aortic and infrainguinal vascular operations.3 Considering that individuals with large-vessel peripheral arterial disease (PAD) have a sixfold increased risk of cardiovascular mortality over 10 years,4 understanding the natural history of CAD in patients with vascular disease remains an important clinical problem.
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Among selected patients with PAD who have undergone elective percutaneous coronary intervention (PCI), a higher than expected rate of target vessel revascularizations has been observed on long-term follow-up.5 These data suggest that the long-term success of revascularization therapies may be problematic in this subset of patients with CAD, related to either a high risk of restenosis after stent deployment or an increased risk of new vulnerable plaque formation in nonobstructive coronary arteries. The Coronary Artery Revascularization Prophylaxis (CARP) trial was a multicentered, randomized controlled trial that showed no longterm survival benefit of preoperative coronary artery revascularization before an elective vascular operation. Over the course of the long-term follow-up, 30 patients returned for clinically driven indications for PCI after the vascular operation. Using this cohort of patients, the aim of the present study was to determine the temporal change of the culprit coronary artery lesion at the time of the follow-up angiogram and PCI compared with the stenosis at the identical site from the preoperative angiogram. We hypothesized that a significant proportion of future culprit lesions in patients with vascular disease who have recurrent ischemia after a vascular operation originate from vessels that were deemed nonobstructive on angiography before the vascular surgery.
surgery and as part of the randomization process, the baseline stenosis before vascular surgery was considered to be the stenosis recorded by the interventional cardiologist after the PCI. The stenosis severity from each angiogram was determined from the catheterization laboratory that had been completed by the Principal Investigator and Research Coordinator from each site. Of those patients who underwent preoperative PCI with deployment of a bare metal stent (BMS), the baseline stenosis was the stenosis at the culprit site after the intervention. Baseline clinical characteristics, serum biomarkers, and angiographic data were obtained through the Cooperative Studies Statistical Center at the Hines VA Medical Center. A postoperative myocardial infarction (MI) was defined as a troponin I 0.1 mg/d obtained from the core laboratory assessment of daily cardiac biomarkers for the first 4 days after vascular surgery in all patients. Demographic and baseline clinical characteristics were compared for patients according to preoperative lesion severity. Categorical variables are presented as a percentage, and continuous data are presented as means and standard errors, or medians with interquartile range when specified. Chi-square tests were used for statistical comparisons and all tests were two-sided, with statistical differences considered at P < 0.05.
METHODS
RESULTS
The CARP trial was a multicenter, randomized trial involving 18 Veterans Affairs Medical Centers that tested the long-survival benefit of coronary artery revascularization before elective vascular surgery.6 Full details of the study design have been previously published.7 A total of 462 CARP patients underwent their intended vascular surgery after randomization and 30 returned for PCI at some time after the vascular surgery for progressive cardiac symptoms. A ‘‘culprit lesion’’ on the follow-up angiogram was specified for each patient returning for PCI as the vessel with the most severe stenosis requiring intervention that was felt to be responsible for the progressive symptoms. The site of the culprit lesion on the follow-up angiogram was then compared with the identical site from the preoperative coronary angiographic study. Patients were divided into two groups on the basis of the severity of the culprit lesion from the preoperative angiogram. On the basis of the review of the preoperative coronary angiogram, group 1 patients had a nonobstructive stenosis (<70%) and group 2 patients had a severe stenosis (70%) at the site of the culprit lesion. In the event that a PCI was performed on a patient before vascular
A total of 30 patients underwent PCI at a median of 11.5 (interquartiles: 4.5-18.5) months postsurgery, and the stenosis of the culprit vessel at baseline and at the time of the follow-up is demonstrated for all patients in Fig. 1. Of the 30 patients, 16 (53%) had nonobstructive CAD preoperatively (group 1) with a stenosis that had increased from 17 ± 6% to 91 ± 2% (P < 0.01) at follow-up. Ten patients had a culprit lesion that involved the site of a BMS that was deployed just before the vascular operation as part of the randomization assignment. Of the 30 patients, 14 (47%) who underwent PCI after vascular surgery had a severe stenosis at the culprit site on the preoperative angiogram (group 2), and on the follow-up study, had increased slightly from 84 ± 2% to 89 ± 2% (P ¼ 0.15). The clinical characteristics in groups 1 and 2 patients are shown in Table I and demonstrate no differences in preoperative demographics, cardiac risk variables, or vascular surgical indications. Twelve of the 16 patients in group 1, and 3 of the 14 patients in Group 2 underwent preoperative coronary artery revascularization as part of the assigned randomization (P < 0.01). This demonstrates that the major
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Stenosis (%)
80 70 60 50 40 30 20 10 0
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+ + + + + + + + + + + + + Baseline
+ + + + + + +
Follow-up
Target Vessel for Revascularization Fig. 1. The severity of the stenosis of the culprit lesion that required PCI during the follow-up angiogram is shown for all 30 patients, as well as the stenosis from the identical site obtained from the baseline coronary angiogram before the vascular operation. The red represents those individuals from group 1 (N ¼ 16) in whom the stenosis of the culprit lesion at baseline was deemed nonobstructive (<70%), whereas the black triangles represent those individuals from group 2 (N ¼ 14) in whom the stenosis of the culprit lesion at baseline was deemed severe (70%).
differences between groups 1 and 2 were more frequent preoperative revascularizations, particularly related to PCI with BMS deployment. After the vascular operation, there were no intergroup differences in the incidence of a perioperative MI, as determined by surveillance of troponin I levels in the first 4 postoperative days. There was also no difference in postoperative left ventricular function at 3 months after surgery. The time of coronary angiography after vascular surgery as well as the characteristics of the culprit vessel was also not dissimilar between groups (Table I). Standard clinical biomarkers were obtained after randomization and before vascular surgery in both groups 1 and 2, and showed no differences related to creatinine, hemoglobin, hemoglobin A1C, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, and C-reactive protein levels (Table II). In comparison with patients who had no change in the culprit lesion (group 2) however, patients with new lesions in the culprit vessel (group 1) had a 38% higher level of homocysteine levels before surgery (Fig. 2).
DISCUSSION The principal finding of this study is that coronary artery lesions requiring percutaneous
revascularization after elective vascular surgery often arise from nonobstructive disease, and many of those lesions arise from sites of BMS deployment. In comparison with individuals who had no change in the vessel stenosis at follow-up, those patients who developed a new lesion requiring PCI had 38% higher homocysteine levels as the only identifier of risk. These data support prior studies that have shown the utility of cardiac biomarkers in predicting risk of new vulnerable plaques particularly related to the risk of restenosis risk after elective coronary artery interventions. Few studies have addressed the serial changes in coronary arteries after vascular operations. The Cleveland Clinic has shown that some patients with nonfatal MIs after vascular surgery had nonobstructive coronary arteries before the operation, suggesting that vulnerable plaque formation is not uncommon after noncardiac operations.8 This is not surprising, considering that review of angiographic severity of coronary arteries is an inadequate means of accurately predicting the time or location of subsequent coronary artery occlusions that lead to MIs.9 However, the long-term success of revascularization therapies with PCI in patients with vascular disease has not been ideal10 and the present study supports the utility of cardiac biomarkers, particularly homocysteine levels, in predicting patients with vascular disease who might be prone to vulnerable plaque formation after vascular operations. Interestingly, mean homocysteine level, while still in the normal range, was found to be significantly higher in those with PAD and nonobstructive CAD at baseline. Homocysteine has been shown in several studies to be associated with MI or acute coronary syndromes.11-14 Also, in patients with PAD, homocysteine has been associated with endothelial dysfunction.15,16However, a causal relationship between homocysteine levels and cardiovascular disease has not been well defined, and randomized trials have yet to show a convincing clinical benefit by lowering homocysteine levels with vitamin supplementation.17,18 In fact, randomized studies of vitamin supplementation for modifying homocysteine levels and restenosis rates have given conflicting results.19 The median time at which the clinically driven intervention was performed was 11.5 months (IQ range: 4.5-18.5 months) postsurgery, at which time all patients were on the same regimen of aspirin monotherapy. In CARP, all percutaneous interventions were performed with BMSs and one would expect the stent struts to be fully endothelialized by 30 days. Therefore, inadequate platelet
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Table I. Clinical variables of patients undergoing PCI post-vascular surgery who had a preoperative stenosis of the culprit lesion <70% (Group 1) or 70% (Group 2) Preoperative clinical variables
Preoperative cardiac risks Age Body mass index (BMI) Diabetes mellitus Smoker Congestive heart failure Myocardial infarction Hypertension Hyperlipidemia Preoperative coronary anatomy LVEF at baseline (%) Number of diseased vessels Preoperative revascularization Preoperative PCI Culprit vessel stenosis (pre) (%) Presenting vascular problem Aortic aneurysm Claudication Rest pain/Tissue loss Abdominal vascular operation Postvascular surgical follow-up Postoperative MIa LVEF at 3 mo (%) Angiography postsurgery (mo) Vein graft as culprit lesion LAD as culprit lesion Culprit vessel stenosis (post) (%)
Group 1 (N ¼ 16)
Group 2 (N ¼ 14)
P-value
64 ± 2 26.1 ± 0.9 7 (43.8%) 6 (39.6%) 1 (6.2%) 8 (62.5%) 11 (68.9%) 8 (50.0%)
65 ± 1 26.2 ± 1.5 5 (35.7%) 4 (26.9%) 1 (7.1%) 10 (64.3%) 11 (78.9%) 9 (64.3%)
0.720 0.96 0.667 0.532 0.925 0.923 0.560 0.448
55 ± 3 2.1 ± 0.2 12 (75.0%) 10 (62.5%) 17 ± 6
52 ± 3 2.1 ± 0.1 3 (14.3%) 0 (0%) 84 ± 2
0.500 0.984 <0.001 <0.001 <0.001
6 8 2 6
(37.5%) (50.0%) (12.5%) (37.5%)
5 (41.7%) 53 ± 4 12.5 ± 3.6 3 (18.8%) 3 (18.8%) 91 ± 2
5 4 3 4
(35.7%) (28.6%) (35.7%) (28.6%)
0.923 0.247 0.143 0.619
4 (36.4%) 50 ± 4 10.3 ± 2.1 1 (7.1%) 5 (35.7%) 89 ± 2
0.795 0.590 0.599 0.368 0.311 0.552
Means and SEM. a Troponin I greater than the 99th percentile reference cutoff (0.1 mg/L) was used for the diagnosis of a postoperative myocardial infarction (MI) by core lab values that were blinded to investigators. These were available in 23 patients, 12 from Group 1 and 11 from Group 2. Left ventricular ejection fraction (LVEF) was obtained prior to vascular surgery either non-invasively with 2D echocardiography or invasively during left ventricular angiography at the time of the coronary angiogram.
inhibition is unlikely to account for the difference between groups. In the perioperative period, factors such as inflammation, sympathetic surges, and hypercoaguable states may alter coronary plaque composition to the point of becoming a ‘‘vulnerable plaque.’’ This certainly is an important factor related to future cardiac events.20 Polderrmans et al. showed that beta-blockers substantially reduce the risk of death and nonfatal MIs after major vascular operations by a mechanism that remains poorly understood.21 It is possible that beta-blocking agents have an intrinsic protection related to reducing shear stress or enhancing remodeling of vessels that may be vulnerable. In support of this, use of beta-blockers in patients with CAD and serial coronary angiograms was protective against subsequent formation of vulnerable plaques.22 There is accumulating evidence that vulnerable plaque formation and
progression of new coronary artery lesions are systemic processes potentially linked to C-reactive protein.23 In the present study, we did not find differences in C-reactive protein between the patients with and without new coronary artery lesions. However, we recognize that there may be potential for selection bias in our cohort and with small numbers, cannot discount the importance of chronic inflammatory markers in this group of patients.
CONCLUSION Among patients with vascular disease, culprit coronary artery lesions after an elective vascular operation often arise from nonobstructive lesions, particularly among patients who have undergone prior BMS deployment. Therapies that stabilize
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Table II. Clinical variables of patients undergoing PCI post-vascular surgery who had a preoperative stenosis of the culprit lesion <70% (Group 1) or 70% (Group 2) Preoperative biomarkers
Creatinine (mg/dL) Hemoglobin (g/dL) White blood count (103) Total cholesterol (mg/dL) LDL (mg/dL) HDL (mg/dL) C-reactive protein (mg/dL) Glycosylated hemoglobin (mg/dL) Triglyceride (mg/dL)
Group 1 (N ¼ 16)
Group 2 (N ¼ 14)
P-value
1.0 ± 0.1 1.1 ± 0.1 0.616 14.4 ± 0.3 14.6 ± 0.5 0.717 7.4 ± 0.3 7.9 ± 0.6 0.413 167 ± 7
185 ± 10
107 ± 7 39 ± 3 1.0 ± 0.3
113 ± 11 0.671 37 ± 3 0.592 2.4 ± 1.7 0.440
6.6 ± 0.5
6.5 ± 0.3 0.871
158 ± 25
245 ± 52
0.157
0.137
Means and SEM.
18 Homocysteine (mg%)
16
P=0.02
14 12 10 8 6 4 2 0 Group 1 (<70%)
Group 2 (≥70%)
Preoperative Stenosis of Culprit Lesion at Follow-up
Fig. 2. In comparison with patients who had no change in the culprit lesion at the time of the follow-up coronary intervention (group 2), patients who had a significant change in the stenosis from a nonobstructive lesion before surgery (group 1) had homocysteine levels that were 38% higher on the preoperative baseline biomarker assay.
existing plaques as well as those strategies that prevent restenosis after coronary interventions have the greatest promise for improving postoperative outcomes in patients undergoing vascular surgery.
Supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development.
REFERENCES 1. Anderson PL, Gelijns A, Moskowitz A, et al. Understanding trends in inpatient surgical volume: vascular interventions, 1980-2000. J Vasc Surg 2004;39:1200-1208. 2. Hertzer NR, Young JR, Kramer JR. Routine coronary angiography prior to elective aortic reconstruction: results of selective myocardial revascularization in patients with peripheral vascular disease. Arch Surg 1979;114:1336-1344. 3. Krupski WC, Layug EL, Reilly LM, Rapp JH, Mangano DT. Comparison of cardiac morbidity between aortic and infrainguinal operations. J Vasc Surg 1992;15:354-365. 4. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381-386. 5. Singh M, Lennon RJ, Darbar D, Gersh BJ, Holmes DR, Rihal CS. Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents. Mayo Clin Proc 2004;79:1113-1118. 6. McFalls EO, Ward HB, Moritz TE, et al. Coronary artery revascularization before elective major vacular surgery. N Engl J Med 2004;351:2795-2804. 7. McFalls EO, Ward HB, Krupski WC, et al. Prophylactic coronary artery revascularization for elective vascular surgery: study design. Control Clin Trials 1999;20: 297-308. 8. Ellis S, Hertzer N, Young J, Brener S. Angiographic correlates of cardiac death and myocardial infarction complicating major nonthoracic vascular surgery. Am J Cardiol 1996;77: 1126-1128. 9. Little W, Constantinescu M, Applegate R, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78:1157-1166. 10. Singh M, Lennon R, Darbar D, Gersh B, Holmes D, Rihal C. Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents. Mayo Clin Proc 2004;79:113-118. 11. Al-Obaidi MK, Philippou H, Stubbs PJ, et al. Relationships between homocysteine, factor VIIa, and thrombin generation in acute coronary syndromes. Circulation 2000;101: 372-377. 12. Giles WH, Croft JB, Greenlund KJ, Ford ES, Kittner SJ. Association between total homocysteine and the likelihood for a history of acute myocardial infarction by race and ethnicity: results from the Third National Health and Nutrition Examination Survey. Am Heart J 2000;139:446-453. 13. Al-Obaidi MK, Stubbs PJ, Collinson P, Conroy R, Graham I, Noble MIM. Elevated homocysteine levels are associated with increased ischemic myocardial injury in acute coronary syndromes. J Am Coll Cardiol. 2000;36: 1217-1222. 14. Matetzky S, Freimark D, Ben-Ami S, et al. Association of elevated homocysteine levels with a higher risk of recurrent coronary events and mortality in patients with acute myocardial infarction. Arch Intern Med 2003;163: 1933-1937. 15. Stuhlinger MC, Oka RK, Graf EE, et al. Endothelial dysfunction induced by hyperhomocysteinemia: role of asymmetric dimethylarginine. Circulation 2003;108:933-938. 16. Sydow K, Hornig B, Arakawa N, et al. Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc Med 2004;9:93-101.
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17. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-1588. 18. Lonn E, Yusuf S, Arnold MJ. Homocysteine lowering with folic acid and b vitamins in vascular disease. N Engl J Med 2006;354:1567-1577. 19. Lange H, Suryapranata H, De Luca G, et al. Therapy and instent restenosis after coronary stenting. N Engl J Med 2004;350:2673-2681. 20. Libby P. Atherosclerosis: disease biology affecting the coronary vasculature. Am J Cardiol 2006;98:3Q-9Q.
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21. Poldermans D, Boersma E, Bax J, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999;341:1789-1794. 22. Heidland U, Strauer B. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001;104:1477-1482. 23. Sano T, Tanaka A, Namba M, et al. C-reactive protein and lesion morphology in patients with acute myocardial infarction. Circulation 2003;108:282-285.
Background: The natural history of coronary artery disease (CAD) after vascular surgery is poorly defined. The aim of this study was to determine the temporal change of coronary artery lesions requiring revascularization with a percutaneous coronary intervention (PCI) after elective vascular surgery and to determine the utility of preoperative biomarkers on predicting those patients at risk for new coronary lesions. Methods: The Coronary Artery Revascularization Prophylaxis Trial tested the long-term survival benefit of coronary artery revascularization before elective vascular surgery. Among randomized patients who subsequently required PCI after surgery, the stenosis of the culprit lesion from the follow-up angiogram was compared with the preoperative vessel stenosis at the identical site on the baseline angiogram. Results: A total of 30 patients underwent PCI for progressive symptoms at a median of 11.5 (interquartiles: 4.5-18.5) months postsurgery. Of 30 patients, 16 (53%) had nonobstructive CAD preoperatively (group 1) with a stenosis that increased from 17 ± 6% to 91 ± 2% (P < 0.01) and 14 (47%) had severe CAD at the culprit site preoperatively (group 2), with a stenosis that increased 89 ± 2% (P ¼ 0.15). The only biomarker that was an identifier of early coronary artery lesion formation in group 1 compared with group 2 patients was a higher baseline homocysteine level (14.6 ± 1.4 vs. 10.6 ± 0.7 mg/dL; P ¼ 0.02). Conclusions: Culprit coronary artery lesions requiring PCI after an elective vascular operation often arise from in-stent restenosis. Therapies that either stabilize existing plaques or prevent restenosis, particularly among patients with elevated homocysteine levels, have the greatest promise for improving postoperative outcomes.
INTRODUCTION 1 Division of Cardiology, University of Minnesota and Minneapolis VA Medical Center, Minneapolis, MN. 2 Division of Cardiothoracic Surgery, University of Minnesota and Minneapolis VA Medical Center, Minneapolis, MN. 3
Cooperative Studies Program Coordinating Center, Hines, IL.
4
Division of Vascular Surgery, VA Medical Center Hines, Hines, IL.
5
Division of Cardiology, Southern Arizona VA Healthcare System and The University of Arizona Sarver Heart Center, Tucson, AZ. 6 Division of Cardiology, Portland VA Medical Center, Portland, OR. Correspondence to: Edward O. McFalls, Division of Cardiology, VA Medical Center, 1 Veterans Drive, Minneapolis, MN 55417, USA, E-mail: [email protected]
Ann Vasc Surg 2010; 24: 596-601 DOI: 10.1016/j.avsg.2010.03.006 Ó Annals of Vascular Surgery Inc.
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Over 400,000 open vascular operations were performed in the United States in the year 2000, and this number is expected to rise as the population ages.1 The prevalence of coronary artery disease (CAD) among these patients is approximately 50%2 and it is not surprising that adverse perioperative cardiac events are common after major aortic and infrainguinal vascular operations.3 Considering that individuals with large-vessel peripheral arterial disease (PAD) have a sixfold increased risk of cardiovascular mortality over 10 years,4 understanding the natural history of CAD in patients with vascular disease remains an important clinical problem.
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Among selected patients with PAD who have undergone elective percutaneous coronary intervention (PCI), a higher than expected rate of target vessel revascularizations has been observed on long-term follow-up.5 These data suggest that the long-term success of revascularization therapies may be problematic in this subset of patients with CAD, related to either a high risk of restenosis after stent deployment or an increased risk of new vulnerable plaque formation in nonobstructive coronary arteries. The Coronary Artery Revascularization Prophylaxis (CARP) trial was a multicentered, randomized controlled trial that showed no longterm survival benefit of preoperative coronary artery revascularization before an elective vascular operation. Over the course of the long-term follow-up, 30 patients returned for clinically driven indications for PCI after the vascular operation. Using this cohort of patients, the aim of the present study was to determine the temporal change of the culprit coronary artery lesion at the time of the follow-up angiogram and PCI compared with the stenosis at the identical site from the preoperative angiogram. We hypothesized that a significant proportion of future culprit lesions in patients with vascular disease who have recurrent ischemia after a vascular operation originate from vessels that were deemed nonobstructive on angiography before the vascular surgery.
surgery and as part of the randomization process, the baseline stenosis before vascular surgery was considered to be the stenosis recorded by the interventional cardiologist after the PCI. The stenosis severity from each angiogram was determined from the catheterization laboratory that had been completed by the Principal Investigator and Research Coordinator from each site. Of those patients who underwent preoperative PCI with deployment of a bare metal stent (BMS), the baseline stenosis was the stenosis at the culprit site after the intervention. Baseline clinical characteristics, serum biomarkers, and angiographic data were obtained through the Cooperative Studies Statistical Center at the Hines VA Medical Center. A postoperative myocardial infarction (MI) was defined as a troponin I 0.1 mg/d obtained from the core laboratory assessment of daily cardiac biomarkers for the first 4 days after vascular surgery in all patients. Demographic and baseline clinical characteristics were compared for patients according to preoperative lesion severity. Categorical variables are presented as a percentage, and continuous data are presented as means and standard errors, or medians with interquartile range when specified. Chi-square tests were used for statistical comparisons and all tests were two-sided, with statistical differences considered at P < 0.05.
METHODS
RESULTS
The CARP trial was a multicenter, randomized trial involving 18 Veterans Affairs Medical Centers that tested the long-survival benefit of coronary artery revascularization before elective vascular surgery.6 Full details of the study design have been previously published.7 A total of 462 CARP patients underwent their intended vascular surgery after randomization and 30 returned for PCI at some time after the vascular surgery for progressive cardiac symptoms. A ‘‘culprit lesion’’ on the follow-up angiogram was specified for each patient returning for PCI as the vessel with the most severe stenosis requiring intervention that was felt to be responsible for the progressive symptoms. The site of the culprit lesion on the follow-up angiogram was then compared with the identical site from the preoperative coronary angiographic study. Patients were divided into two groups on the basis of the severity of the culprit lesion from the preoperative angiogram. On the basis of the review of the preoperative coronary angiogram, group 1 patients had a nonobstructive stenosis (<70%) and group 2 patients had a severe stenosis (70%) at the site of the culprit lesion. In the event that a PCI was performed on a patient before vascular
A total of 30 patients underwent PCI at a median of 11.5 (interquartiles: 4.5-18.5) months postsurgery, and the stenosis of the culprit vessel at baseline and at the time of the follow-up is demonstrated for all patients in Fig. 1. Of the 30 patients, 16 (53%) had nonobstructive CAD preoperatively (group 1) with a stenosis that had increased from 17 ± 6% to 91 ± 2% (P < 0.01) at follow-up. Ten patients had a culprit lesion that involved the site of a BMS that was deployed just before the vascular operation as part of the randomization assignment. Of the 30 patients, 14 (47%) who underwent PCI after vascular surgery had a severe stenosis at the culprit site on the preoperative angiogram (group 2), and on the follow-up study, had increased slightly from 84 ± 2% to 89 ± 2% (P ¼ 0.15). The clinical characteristics in groups 1 and 2 patients are shown in Table I and demonstrate no differences in preoperative demographics, cardiac risk variables, or vascular surgical indications. Twelve of the 16 patients in group 1, and 3 of the 14 patients in Group 2 underwent preoperative coronary artery revascularization as part of the assigned randomization (P < 0.01). This demonstrates that the major
598 Garcia et al.
100 90
Stenosis (%)
80 70 60 50 40 30 20 10 0
Annals of Vascular Surgery
+ + + + + + + + + + + + + Baseline
+ + + + + + +
Follow-up
Target Vessel for Revascularization Fig. 1. The severity of the stenosis of the culprit lesion that required PCI during the follow-up angiogram is shown for all 30 patients, as well as the stenosis from the identical site obtained from the baseline coronary angiogram before the vascular operation. The red represents those individuals from group 1 (N ¼ 16) in whom the stenosis of the culprit lesion at baseline was deemed nonobstructive (<70%), whereas the black triangles represent those individuals from group 2 (N ¼ 14) in whom the stenosis of the culprit lesion at baseline was deemed severe (70%).
differences between groups 1 and 2 were more frequent preoperative revascularizations, particularly related to PCI with BMS deployment. After the vascular operation, there were no intergroup differences in the incidence of a perioperative MI, as determined by surveillance of troponin I levels in the first 4 postoperative days. There was also no difference in postoperative left ventricular function at 3 months after surgery. The time of coronary angiography after vascular surgery as well as the characteristics of the culprit vessel was also not dissimilar between groups (Table I). Standard clinical biomarkers were obtained after randomization and before vascular surgery in both groups 1 and 2, and showed no differences related to creatinine, hemoglobin, hemoglobin A1C, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, and C-reactive protein levels (Table II). In comparison with patients who had no change in the culprit lesion (group 2) however, patients with new lesions in the culprit vessel (group 1) had a 38% higher level of homocysteine levels before surgery (Fig. 2).
DISCUSSION The principal finding of this study is that coronary artery lesions requiring percutaneous
revascularization after elective vascular surgery often arise from nonobstructive disease, and many of those lesions arise from sites of BMS deployment. In comparison with individuals who had no change in the vessel stenosis at follow-up, those patients who developed a new lesion requiring PCI had 38% higher homocysteine levels as the only identifier of risk. These data support prior studies that have shown the utility of cardiac biomarkers in predicting risk of new vulnerable plaques particularly related to the risk of restenosis risk after elective coronary artery interventions. Few studies have addressed the serial changes in coronary arteries after vascular operations. The Cleveland Clinic has shown that some patients with nonfatal MIs after vascular surgery had nonobstructive coronary arteries before the operation, suggesting that vulnerable plaque formation is not uncommon after noncardiac operations.8 This is not surprising, considering that review of angiographic severity of coronary arteries is an inadequate means of accurately predicting the time or location of subsequent coronary artery occlusions that lead to MIs.9 However, the long-term success of revascularization therapies with PCI in patients with vascular disease has not been ideal10 and the present study supports the utility of cardiac biomarkers, particularly homocysteine levels, in predicting patients with vascular disease who might be prone to vulnerable plaque formation after vascular operations. Interestingly, mean homocysteine level, while still in the normal range, was found to be significantly higher in those with PAD and nonobstructive CAD at baseline. Homocysteine has been shown in several studies to be associated with MI or acute coronary syndromes.11-14 Also, in patients with PAD, homocysteine has been associated with endothelial dysfunction.15,16However, a causal relationship between homocysteine levels and cardiovascular disease has not been well defined, and randomized trials have yet to show a convincing clinical benefit by lowering homocysteine levels with vitamin supplementation.17,18 In fact, randomized studies of vitamin supplementation for modifying homocysteine levels and restenosis rates have given conflicting results.19 The median time at which the clinically driven intervention was performed was 11.5 months (IQ range: 4.5-18.5 months) postsurgery, at which time all patients were on the same regimen of aspirin monotherapy. In CARP, all percutaneous interventions were performed with BMSs and one would expect the stent struts to be fully endothelialized by 30 days. Therefore, inadequate platelet
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Table I. Clinical variables of patients undergoing PCI post-vascular surgery who had a preoperative stenosis of the culprit lesion <70% (Group 1) or 70% (Group 2) Preoperative clinical variables
Preoperative cardiac risks Age Body mass index (BMI) Diabetes mellitus Smoker Congestive heart failure Myocardial infarction Hypertension Hyperlipidemia Preoperative coronary anatomy LVEF at baseline (%) Number of diseased vessels Preoperative revascularization Preoperative PCI Culprit vessel stenosis (pre) (%) Presenting vascular problem Aortic aneurysm Claudication Rest pain/Tissue loss Abdominal vascular operation Postvascular surgical follow-up Postoperative MIa LVEF at 3 mo (%) Angiography postsurgery (mo) Vein graft as culprit lesion LAD as culprit lesion Culprit vessel stenosis (post) (%)
Group 1 (N ¼ 16)
Group 2 (N ¼ 14)
P-value
64 ± 2 26.1 ± 0.9 7 (43.8%) 6 (39.6%) 1 (6.2%) 8 (62.5%) 11 (68.9%) 8 (50.0%)
65 ± 1 26.2 ± 1.5 5 (35.7%) 4 (26.9%) 1 (7.1%) 10 (64.3%) 11 (78.9%) 9 (64.3%)
0.720 0.96 0.667 0.532 0.925 0.923 0.560 0.448
55 ± 3 2.1 ± 0.2 12 (75.0%) 10 (62.5%) 17 ± 6
52 ± 3 2.1 ± 0.1 3 (14.3%) 0 (0%) 84 ± 2
0.500 0.984 <0.001 <0.001 <0.001
6 8 2 6
(37.5%) (50.0%) (12.5%) (37.5%)
5 (41.7%) 53 ± 4 12.5 ± 3.6 3 (18.8%) 3 (18.8%) 91 ± 2
5 4 3 4
(35.7%) (28.6%) (35.7%) (28.6%)
0.923 0.247 0.143 0.619
4 (36.4%) 50 ± 4 10.3 ± 2.1 1 (7.1%) 5 (35.7%) 89 ± 2
0.795 0.590 0.599 0.368 0.311 0.552
Means and SEM. a Troponin I greater than the 99th percentile reference cutoff (0.1 mg/L) was used for the diagnosis of a postoperative myocardial infarction (MI) by core lab values that were blinded to investigators. These were available in 23 patients, 12 from Group 1 and 11 from Group 2. Left ventricular ejection fraction (LVEF) was obtained prior to vascular surgery either non-invasively with 2D echocardiography or invasively during left ventricular angiography at the time of the coronary angiogram.
inhibition is unlikely to account for the difference between groups. In the perioperative period, factors such as inflammation, sympathetic surges, and hypercoaguable states may alter coronary plaque composition to the point of becoming a ‘‘vulnerable plaque.’’ This certainly is an important factor related to future cardiac events.20 Polderrmans et al. showed that beta-blockers substantially reduce the risk of death and nonfatal MIs after major vascular operations by a mechanism that remains poorly understood.21 It is possible that beta-blocking agents have an intrinsic protection related to reducing shear stress or enhancing remodeling of vessels that may be vulnerable. In support of this, use of beta-blockers in patients with CAD and serial coronary angiograms was protective against subsequent formation of vulnerable plaques.22 There is accumulating evidence that vulnerable plaque formation and
progression of new coronary artery lesions are systemic processes potentially linked to C-reactive protein.23 In the present study, we did not find differences in C-reactive protein between the patients with and without new coronary artery lesions. However, we recognize that there may be potential for selection bias in our cohort and with small numbers, cannot discount the importance of chronic inflammatory markers in this group of patients.
CONCLUSION Among patients with vascular disease, culprit coronary artery lesions after an elective vascular operation often arise from nonobstructive lesions, particularly among patients who have undergone prior BMS deployment. Therapies that stabilize
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Annals of Vascular Surgery
Table II. Clinical variables of patients undergoing PCI post-vascular surgery who had a preoperative stenosis of the culprit lesion <70% (Group 1) or 70% (Group 2) Preoperative biomarkers
Creatinine (mg/dL) Hemoglobin (g/dL) White blood count (103) Total cholesterol (mg/dL) LDL (mg/dL) HDL (mg/dL) C-reactive protein (mg/dL) Glycosylated hemoglobin (mg/dL) Triglyceride (mg/dL)
Group 1 (N ¼ 16)
Group 2 (N ¼ 14)
P-value
1.0 ± 0.1 1.1 ± 0.1 0.616 14.4 ± 0.3 14.6 ± 0.5 0.717 7.4 ± 0.3 7.9 ± 0.6 0.413 167 ± 7
185 ± 10
107 ± 7 39 ± 3 1.0 ± 0.3
113 ± 11 0.671 37 ± 3 0.592 2.4 ± 1.7 0.440
6.6 ± 0.5
6.5 ± 0.3 0.871
158 ± 25
245 ± 52
0.157
0.137
Means and SEM.
18 Homocysteine (mg%)
16
P=0.02
14 12 10 8 6 4 2 0 Group 1 (<70%)
Group 2 (≥70%)
Preoperative Stenosis of Culprit Lesion at Follow-up
Fig. 2. In comparison with patients who had no change in the culprit lesion at the time of the follow-up coronary intervention (group 2), patients who had a significant change in the stenosis from a nonobstructive lesion before surgery (group 1) had homocysteine levels that were 38% higher on the preoperative baseline biomarker assay.
existing plaques as well as those strategies that prevent restenosis after coronary interventions have the greatest promise for improving postoperative outcomes in patients undergoing vascular surgery.
Supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development.
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