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Effect of Peripheral Arterial Disease in Patients Undergoing Percutaneous Coronary Intervention With Intracoronary Stents
ORIGINAL ARTICLE
PERCUTANEOUS CORONARY INTERVENTION
Effect of Peripheral Arterial Disease in Patients Undergoing Percutaneous Coronary Intervention With Intracoronary Stents MANDEEP SINGH, MD; RYAN J. LENNON, MS; DAWOOD DARBAR, MD; BERNARD J. GERSH, MBCHB, DPHIL; DAVID R. HOLMES, JR, MD; AND CHARANJIT S. RIHAL, MD OBJECTIVE: To compare the short-term and long-term outcomes of patients with coronary artery disease and peripheral arterial disease (PAD) who underwent intracoronary (IC) stent implantation during percutaneous coronary intervention (PCI) with the outcomes of patients with isolated coronary artery disease but without PAD who underwent IC stent implantation. PATIENTS AND METHODS: We analyzed the outcomes of 7696 patients who underwent IC stent implantation during PCI at the Mayo Clinic in Rochester, Minn, between January 1996 and December 2002. Outcomes of 6299 patients (82%) with isolated coronary artery disease and without PAD who underwent IC stent implantation (group 1) were compared with outcomes of 1397 patients (18%) with coronary artery disease and PAD (group 2) who underwent PCI with IC stent implantation. RESULTS: Patients in group 2 were older (71.1±10.2 years vs 65.0±12.0 years; P<.001) and had a higher prevalence of hypertension (79% vs 61%; P<.001), diabetes mellitus (33% vs 20%; P<.001), hyperlipidemia (76% vs 70%; P<.001), and history of smoking (70% vs 63%; P<.001) compared with group 1. Prevalence of multivessel disease was higher in group 2 (79% vs 68%; P<.001). Procedural success was significantly lower in group 2 (95% vs 97%; P<.001). In-hospital complications were higher in group 2: death (3% vs 1%; P<.001), any myocardial infarction (MI) (8% vs 5%; P<.001), death/MI/coronary artery bypass grafting (CABG)/target vessel revascularization (11% vs 7%; P<.001), and blood loss requiring transfusion (11% vs 5.8%; P<.001). After adjustment for other risk factors, the odds ratio for in-hospital death was 1.84 (95% confidence interval [CI], 1.16-2.90; P=.009), and for death/MI/CABG/target vessel revascularization, the odds ratio was 1.25 (95% CI, 1.00-1.55; P=.048) in patients with PAD treated with IC stents. Median follow-up was 3.1 years. Six-month, 1-year, and 2-year Kaplan-Meier estimates of survival free of death/MI/CABG/target vessel revascularization were 84%, 77%, and 69%, respectively, for group 2 and were significantly worse compared with group 1 (89%, 85%, and 80%, respectively; P<.001). This effect remained after adjustment for other risk factors (hazard ratio, 1.36; 95% CI, 1.22-1.51). CONCLUSIONS: Compared with patients who had isolated coronary artery disease but no PAD, patients with coronary artery disease and PAD had lower procedural success and higher inhospital major cardiovascular complications, including higher blood loss requiring transfusion, after PCI with stent implantation. On follow-up, the short-term and long-term outcomes of patients with PAD were worse, with higher mortality, MI, and need for repeated target vessel revascularization.
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ata from the Bypass Angioplasty Revascularization Investigation (BARI) have shown that patients with combined coronary artery disease and peripheral arterial disease (PAD) who undergo myocardial revascularization are at high risk of lower procedural success and higher in-hospital compliFor editorial cations, with a significantly worse comment, see page 1107 long-term prognosis compared with patients with isolated coronary artery disease.1 Also, patients with PAD have a significantly higher risk of major periprocedural complications after either coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) than do patients without additional noncoronary disease.2 Rates of complications, in particular abrupt closure, were higher after PTCA.2 Since the BARI study, new percutaneous revascularization techniques such as intracoronary (IC) stent implantation have been introduced. This technique has improved procedural success and has reduced the likelihood of abrupt closures and the need for repeated revascularization procedures after PTCA in patients without PAD.3,4 However, whether IC stenting has resulted in a lower risk of periprocedural complications and has improved the long-term prognosis of patients with concomitant coronary artery disease and PAD needs to be determined. Therefore, the major objective of this study was to compare the short-term and long-term outcomes of patients with coronary artery disease and PAD who underwent IC stent implantation with the outcomes of patients with isolated coronary artery disease but without PAD who underwent IC implantation. PATIENTS AND METHODS We analyzed the Mayo Clinic PTCA Registry, which prospectively codes demographic, clinical, and angiographic
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BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; CHF = congestive heart failure; CI = confidence interval; IC = intracoronary; MI = myocardial infarction; OR = odds ratio; PAD = peripheral arterial disease; PCI = percutaneous coronary intervention; PTCA = percutaneous transluminal coronary angioplasty
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From the Division of Cardiovascular Diseases and Internal Medicine (M.S., D.D., B.J.G., D.R.H., C.S.R.) and Division of Biostatistics (R.J.L.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Darbar is now with the Vanderbilt University Medical Center, Nashville, Tenn. Address reprint requests and correspondence to Charanjit S. Rihal, MD, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2004 Mayo Foundation for Medical Education and Research
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PERCUTANEOUS CORONARY INTERVENTION
data on all patients who undergo percutaneous coronary intervention (PCI) at the Mayo Clinic in Rochester, Minn. We reviewed PCI procedures performed between January 1996 and December 2002. Patients who refused to allow use of their records for research were excluded per Minnesota state law. If a patient had multiple qualifying PCIs during the study period, only the earliest was included. Baseline data collected included information on atherosclerosis in noncoronary vascular beds. After selecting all patients who had undergone PCI over the 7-year period, we divided the patients into 2 groups: group 1 consisted of 6299 patients with isolated coronary artery disease but no evidence of PAD who had undergone IC stent implantation; group 2 consisted of 1397 patients with coronary artery disease and evidence of PAD in whom an IC stent was used. The study was approved by the Mayo Foundation Institutional Review Board. FOLLOW-UP Patients were contacted by telephone at 6 and 12 months after their procedure and yearly thereafter. At each contact, information was obtained pertaining to vital status, myocardial infarction (MI), angina symptoms, and occurrence of additional revascularization procedures. Refused calls were treated as missing, ie, no contact. Records from other hospitals were obtained when possible. DEFINITIONS USED Peripheral arterial disease was defined as presence of claudication, history of peripheral arterial surgery, presence of abdominal aortic aneurysm, disease of the cranial and extracranial arteries defined as a history of stroke or transient ischemic attacks, history of carotid surgery, or presence of carotid disease documented by ultrasonography, angiography, or carotid bruit. Acute MI was considered to have occurred when at least 2 of the following 3 criteria were met: (1) chest pain lasting longer than 30 minutes, (2) persistent electrocardiographic changes suggestive of ischemia, and (3) 2-fold or greater elevations in serum creatine kinase levels with a corresponding increase in the MB isoform. Multivessel disease was defined as the presence of 70% or greater stenosis of the luminal diameter in a major epicardial artery, with 50% or greater stenosis in a second major epicardial vessel (2-vessel disease) or in both of the other epicardial vessels (3-vessel disease). Procedural success was defined as residual stenosis less than 50% in at least 1 lesion without in-hospital death, Q-wave MI, or CABG. STATISTICAL ANALYSES Demographic and baseline clinical characteristics were compared for patients with and without noncoronary ath1114
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erosclerosis. The Student t test was used to compare continuous variables, χ2 tests to compare proportions, KaplanMeier estimates to describe follow-up survival rates, and the log-rank test to compare survival curves. All hypothesis tests were 2-tailed with a 0.05 type I error rate. Multiple logistic regression was used to assess the likelihood of an in-hospital complication associated with the presence of PAD, adjusting for other risk factors. Similarly, Cox proportional hazards models were used to estimate the increased risk of adverse events on follow-up in patients with PAD. The set of covariates used for risk adjustment was age, sex, date of procedure, preprocedural shock, acute MI, Canadian Heart Class III or higher angina, diabetes mellitus, hypertension, body mass index, history of cholesterol level greater than 240 mg/dL, history of congestive heart failure (CHF), current CHF status, smoking history, history of MI, prior PCI, prior CABG, chronic renal disease, peptic ulcer disease, tumor, metastatic cancer, multivessel disease, American College of Cardiology/American Heart Association lesion class IIb or c, thrombus in any lesion, and use of glycoprotein IIb/ IIIa inhibitors. RESULTS Over a 7-year period, 7696 patients underwent IC stent implantation at our institution. Peripheral arterial disease was identified in 1397 patients (18%), of whom lower-extremity vascular disease was present in 772 (55%) and cerebrovascular disease in 835 (60%). Of the 7696 patients, 160 (2%) had a nonfemoral vascular access site for PCI. BASELINE CHARACTERISTICS Baseline characteristics of the 2 groups are shown in Table 1. In general, patients in group 2 with PAD had adverse prognostic characteristics; they were older and had a higher prevalence of hypertension, diabetes mellitus, history of smoking, prior MI, hyperlipidemia, CHF, and prior revascularization. PROCEDURAL SUCCESS AND COMPLICATION RATES There was a higher prevalence of multivessel disease in group 2. Among patients in group 2, procedural success was significantly lower than among patients in group 1 (95% vs 97%; P<.001). Group 2 prevalences were significantly higher than those of group 1 (P<.001) for in-hospital death (3% vs 1%), any MI (8% vs 5%), and in-hospital death/MI/CABG/target vessel revascularization (11% vs 7%). The prevalences of stroke (0.6% vs 0.3%; P=.02) and transient ischemic attack (0.4% vs 0.1%; P=.004) were significantly higher in group 2 (Table 2).
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PERCUTANEOUS CORONARY INTERVENTION
Glycoprotein IIb/IIIa inhibitors were used less frequently in group 2 patients compared with group 1 patients (48% vs 56%; P<.001). Despite that, the need for blood transfusion due to excessive blood loss was higher in group 2 (11% vs 5.8%; P<.001). The complications related to vascular access were low and similar in the 2 groups (Table 3). FOLLOW-UP Median follow-up was 3.1 years; 94% of patients were followed up for at least 6 months. The follow-up was complete in 85% of the study group at 12 months and in 75% at 18 months. The values for 6-month, 1-year, and 2year survival free of death (Figure 1), death/MI (Figure 2), or death/MI/CABG/target vessel revascularization (Figure 3) were worse in group 2. Six-month, 1-year, and 2-year Kaplan-Meier estimates of survival free of death/MI/ CABG/target vessel revascularization were 84%, 77%, and 69%, respectively, for group 2 and were significantly worse compared with group 1 (89%, 85%, and 80%, respectively; P<.001). INFLUENCE OF PAD AND YEAR OF TREATMENT OUTCOME After adjustment for concomitant risk factors, patients with PAD treated with IC stents had an 84% increase in the odds of in-hospital death (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.16-2.90; P=.009) and 25% higher odds for in-hospital composite end points of death/MI/CABG/target vessel revascularization (OR, 1.25; 95% CI, 1.00-1.55; P=.048). The presence of PAD was a significant risk factor for cardiovascular mortality and morbidity on followup. The risks of death (hazard ratio, 1.48; 95% CI, 1.261.73; P<.001) and the composite event of death/MI/CABG/ target vessel revascularization (hazard ratio, 1.36; 95% CI, 1.22-1.51; P<.001) were higher in group 2 compared with group 1. To assess improvement over time of patients with PAD who had undergone stent implantation, we estimated similar models with these patients, again including procedure date in the covariate set. We observed significant reduction over time in in-hospital events of death (OR per year, 0.88; 95% CI, 0.68-0.99; P=.04) and the composite of death/MI/ CABG/target lesion revascularization (OR per year, 0.88; 95% CI, 0.79-0.97; P=.01). ON
DISCUSSION The present study provides data on the effect of IC stent implantation in a high-risk group of patients with combined coronary artery disease and PAD. Peripheral arterial disease is a significant risk factor for lower proceMayo Clin Proc.
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TABLE 1. Baseline Characteristics* Variable Age, mean ± SD (y) Male Unstable angina Canadian Heart Class (III, IV) MI 24 h before PCI Diabetes mellitus Hypertension Body mass index, mean ± SD (kg/m2) History of cholesterol ≥240 mg/dL CHF on presentation History of CHF Current/former smoker Prior MI Prior PTCA/CABG Moderate/severe renal disease Ejection fraction ≤40%
Group 1 (N=6299)
Group 2 (N=1397)
P value
65.0±12.0 4482 (71) 3791 (60) 3182 (51) 1041 (17) 1227 (20) 3729 (61)
71.1±10.2 966 (69) 855 (61) 801 (57) 153 (11) 463 (33) 1076 (79)
<.001 .14 .48 <.001 <.001 <.001 <.001
29.5±5.5
28.4±5.1
<.001
3986 (70) 482 (8) 669 (11) 3950 (63) 3225 (52) 1725 (27) 128 (2) 585 (9)
974 (76) 256 (18) 344 (26) 962 (70) 822 (60) 632 (45) 105 (8) 232 (17)
<.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001
*Values are number (percentage) unless indicated otherwise. Denominators may vary slightly because of missing data. CHF = congestive heart failure; MI = myocardial infarction; PCI = percutaneous coronary intervention; PTCA/CABG = percutaneous transluminal coronary angioplasty/ coronary artery bypass grafting.
dural success and higher in-hospital complications. On follow-up, adverse cardiovascular outcomes were higher in patients with PAD. In recent years, patients with PAD have experienced a reduction in in-hospital adverse events. IN-HOSPITAL COMPLICATIONS Peripheral arterial disease is recognized as an independent predictor of in-hospital complications, including death, TABLE 2. Procedural Characteristics and In-hospital Outcomes* Variable Multivessel disease ACC/AHA IIb/c Thrombus in any lesion Calcium in any stenosis Glycoprotein IIb/IIIa use Abrupt closure Procedural success In-hospital death In-hospital any MI In-hospital Q-wave MI In-hospital CABG In-hospital death/MI/CABG/ TVR CVA complication TIA complication
Group 1 (N=6299)
Group 2 (N=1397)
P value
4111 (68) 4579 (80) 2072 (35) 2175 (37) 3553 (56) 134 (2) 6122 (97) 65 (1) 331 (5) 67 (1) 41 (1)
1072 (79) 1128 (85) 407 (31) 623 (48) 674 (48) 38 (3) 1323 (95) 43 (3) 105 (8) 16 (1) 10 (1)
<.001 <.001 .01 <.001 <.001 .18 <.001 <.001 <.001 .79 .79
420 (7) 16 (0.3) 4 (0.1)
147 (11) 9 (0.6) 5 (0.4)
<.001 .02 .004
*Values are number (percentage). Denominators may vary slightly because of missing data. ACC/AHA = American College of Cardiology/ American Heart Association; CABG = coronary artery bypass grafting; CVA = cerebrovascular accident; MI = myocardial infarction; TIA = transient ischemic attack; TVR = target vessel revascularization.
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TABLE 3. Bleeding and Related Complications in Patients With and Without Peripheral Arterial Disease* Variable
Group 1 (N=6299)
Group 2 (N=1397)
P value
Retroperitoneal bleeding Pseudoaneurysm Central nervous system bleeding Blood loss requiring transfusion Hypotension Hematoma
19 (0.3) 62 (1.0) 1 (0.0) 363 (5.8) 434 (6.9) 190 (3.0)
2 (0.1) 16 (1.1) 0 (0.0) 151 (10.8) 124 (8.9) 54 (3.9)
.30 .58 .64 <.001 .009 .10
*Values are number (percentage).
stroke, and the composite of death/MI/stroke/CABG. Also, PAD is considered a marker for vascular access complications.5 The association of PAD and in-hospital complications has been documented consistently in the risk score models developed for patients undergoing PCI in the current era.6-9 The present study supports the observations from these models. The likely reasons for such high risk in these patients are adverse baseline and angiographic characteristics, including older age, diabetes mellitus, CHF, lower ejection fraction, renal disease, higher prevalence of multivessel disease, and other characteristics associated with worse in-hospital outcome related to PCIs. Similar conclusions were drawn from the BARI trial in a subset of patients with PAD and coronary artery disease.2 This study is different from the BARI trial in that it is more representative of current PCI treatment, including the use of stents, glycoprotein IIb/IIIa inhibitors, and anti-
platelet agents such as ticlopidine and, more recently, clopidogrel. The need for in-hospital CABG was low (1%), and the need for emergency CABG related to PCI complications was even lower. This is in contrast to earlier studies of patients with PAD who underwent balloon angioplasty and had abrupt closure rates of 9.8%. The abrupt closure rate in the present study was 3% in patients with PAD treated with stents. The rates of referral for emergency CABG have declined since the introduction of IC stents. The ability of stents to limit elastic recoil, seal intimal flaps, and prevent abrupt closure of the target vessel may be an important factor in reducing the need for emergent surgical revascularization.10 Some reduction in in-hospital complications, including death, has been seen in patients with PAD, most notably a reduction in the need for inhospital revascularization. Vascular access complications were low and were similar in the 2 groups, probably because of smaller sheath size, less vigorous anticoagulant regimens, and better operator experience. However, the need for blood transfusions related to blood loss was higher in patients with PAD. On follow-up, patients with PAD continue to have adverse cardiovascular outcome, likely because of the higher prevalence of multivessel disease and poor left ventricular function. Both these variables and other demographic variables have been shown to be significant predictors for adverse long-term outcome.11,12 STUDY LIMITATIONS The present study is a retrospective analysis of a single center’s experience and is therefore subject to biases innate
100
No PAD
90 PAD
80
Percentage
70 60 50 40 30 20 10 0 0.0
0.5
1.0
1.5
2.0
Years
FIGURE 1. Kaplan-Meier curves for survival in patients with and without peripheral arterial disease (PAD) (P<.001).
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100 No PAD 90 80 PAD
Percentage
70 60 50 40 30 20 10 0 0.0
0.5
1.0
1.5
2.0
Years
FIGURE 2. Kaplan-Meier curves for survival free of death/myocardial infarction in patients with and without peripheral arterial disease (PAD) (P<.001).
in such studies. Intracoronary stent implantation techniques have evolved over the study period, and although we have tested year of treatment as 1 of the variables, the full effect of these changes may not be fully apparent from the analyzed data. Moreover, we have not included patients who underwent implantation of drug-eluting stents. Further studies to evaluate the effects of current PCIs on the outcome of patients with PAD and coronary artery disease are warranted. The use of statins, angiotensin-converting enzyme inhibitors, and newer thienopyridines that have fa-
vorably influenced the outcome of patients with PAD were not studied separately in the 2 groups. CONCLUSIONS This study showed that patients with coronary artery disease and PAD who were treated with IC stents had lower procedural success and higher in-hospital complications, including higher blood loss requiring transfusions, compared with patients who had isolated coronary artery
100 90
No PAD
80
Percentage
70 PAD
60 50 40 30 20 10 0 0.0
0.5
1.0
1.5
2.0
Years
FIGURE 3. Kaplan-Meier curves for survival free of death/myocardial infarction/coronary artery bypass grafting/target vessel revascularization in patients with and without peripheral arterial disease (PAD) (P<.001).
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disease but no PAD. Peripheral arterial disease is an independent risk factor for short-term and long-term adverse cardiovascular outcomes, with higher mortality, MI, and need for repeated target vessel revascularization. Results of PCI in patients with PAD in recent years have improved. REFERENCES 1. Sutton-Tyrrell K, Rihal C, Sellers MA, et al. Long-term prognostic value of clinically evident noncoronary vascular disease in patients undergoing coronary revascularization in the Bypass Angioplasty Revascularization Investigation (BARI). Am J Cardiol. 1998;81:375-381. 2. Rihal CS, Sutton-Tyrrell K, Guo P, et al. Increased incidence of periprocedural complications among patients with peripheral vascular disease undergoing myocardial revascularization in the bypass angioplasty revascularization investigation. Circulation. 1999;100:171-177. 3. Fischman DL, Leon MB, Baim DS, et al, Stent Restenosis Study Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994; 331:496-501. 4. Serruys PW, de Jaegere P, Kiemeneij F, et al, Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994; 331:489-495.
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5. Nasser TK, Mohler ER III, Wilensky RL, Hathaway DR. Peripheral vascular complications following coronary interventional procedures. Clin Cardiol. 1995;18:609-614. 6. Singh M, Lennon RJ, Holmes DR Jr, Bell MR, Rihal CS. Correlates of procedural complications and a simple integer risk score for percutaneous coronary intervention. J Am Coll Cardiol. 2002;40:387-393. 7. Moscucci M, Kline-Rogers E, Share D, et al. Simple bedside additive tool for prediction of in-hospital mortality after percutaneous coronary interventions. Circulation. 2001;104:263-268. 8. Holmes DR Jr, Berger PB, Garratt KN, et al. Application of the New York State PTCA mortality model in patients undergoing stent implantation. Circulation. 2000;102:517-522. 9. Holmes DR, Selzer F, Johnston JM, et al. Modeling and risk prediction in the current era of interventional cardiology: a report from the National Heart, Lung, and Blood Institute Dynamic Registry. Circulation. 2003;107:18711876. 10. Goldberg S, Savage MP, Fischman DL. Coronary artery stents. Lancet. 1995;345:1523-1524. 11. Mock MB, Fisher LD, Holmes DR Jr, et al. Comparison of effects of medical and surgical therapy on survival in severe angina pectoris and twovessel coronary artery disease with and without left ventricular dysfunction: a Coronary Artery Surgery Study Registry Study. Am J Cardiol. 1988;61:11981203. 12. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration [published correction appears in Lancet. 1994;344:1446]. Lancet. 1994;344:563-570.
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Effect of Peripheral Arterial Disease in Patients Undergoing Percutaneous Coronary Intervention With Intracoronary Stents MANDEEP SINGH, MD; RYAN J. LENNON, MS; DAWOOD DARBAR, MD; BERNARD J. GERSH, MBCHB, DPHIL; DAVID R. HOLMES, JR, MD; AND CHARANJIT S. RIHAL, MD OBJECTIVE: To compare the short-term and long-term outcomes of patients with coronary artery disease and peripheral arterial disease (PAD) who underwent intracoronary (IC) stent implantation during percutaneous coronary intervention (PCI) with the outcomes of patients with isolated coronary artery disease but without PAD who underwent IC stent implantation. PATIENTS AND METHODS: We analyzed the outcomes of 7696 patients who underwent IC stent implantation during PCI at the Mayo Clinic in Rochester, Minn, between January 1996 and December 2002. Outcomes of 6299 patients (82%) with isolated coronary artery disease and without PAD who underwent IC stent implantation (group 1) were compared with outcomes of 1397 patients (18%) with coronary artery disease and PAD (group 2) who underwent PCI with IC stent implantation. RESULTS: Patients in group 2 were older (71.1±10.2 years vs 65.0±12.0 years; P<.001) and had a higher prevalence of hypertension (79% vs 61%; P<.001), diabetes mellitus (33% vs 20%; P<.001), hyperlipidemia (76% vs 70%; P<.001), and history of smoking (70% vs 63%; P<.001) compared with group 1. Prevalence of multivessel disease was higher in group 2 (79% vs 68%; P<.001). Procedural success was significantly lower in group 2 (95% vs 97%; P<.001). In-hospital complications were higher in group 2: death (3% vs 1%; P<.001), any myocardial infarction (MI) (8% vs 5%; P<.001), death/MI/coronary artery bypass grafting (CABG)/target vessel revascularization (11% vs 7%; P<.001), and blood loss requiring transfusion (11% vs 5.8%; P<.001). After adjustment for other risk factors, the odds ratio for in-hospital death was 1.84 (95% confidence interval [CI], 1.16-2.90; P=.009), and for death/MI/CABG/target vessel revascularization, the odds ratio was 1.25 (95% CI, 1.00-1.55; P=.048) in patients with PAD treated with IC stents. Median follow-up was 3.1 years. Six-month, 1-year, and 2-year Kaplan-Meier estimates of survival free of death/MI/CABG/target vessel revascularization were 84%, 77%, and 69%, respectively, for group 2 and were significantly worse compared with group 1 (89%, 85%, and 80%, respectively; P<.001). This effect remained after adjustment for other risk factors (hazard ratio, 1.36; 95% CI, 1.22-1.51). CONCLUSIONS: Compared with patients who had isolated coronary artery disease but no PAD, patients with coronary artery disease and PAD had lower procedural success and higher inhospital major cardiovascular complications, including higher blood loss requiring transfusion, after PCI with stent implantation. On follow-up, the short-term and long-term outcomes of patients with PAD were worse, with higher mortality, MI, and need for repeated target vessel revascularization.
D
ata from the Bypass Angioplasty Revascularization Investigation (BARI) have shown that patients with combined coronary artery disease and peripheral arterial disease (PAD) who undergo myocardial revascularization are at high risk of lower procedural success and higher in-hospital compliFor editorial cations, with a significantly worse comment, see page 1107 long-term prognosis compared with patients with isolated coronary artery disease.1 Also, patients with PAD have a significantly higher risk of major periprocedural complications after either coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA) than do patients without additional noncoronary disease.2 Rates of complications, in particular abrupt closure, were higher after PTCA.2 Since the BARI study, new percutaneous revascularization techniques such as intracoronary (IC) stent implantation have been introduced. This technique has improved procedural success and has reduced the likelihood of abrupt closures and the need for repeated revascularization procedures after PTCA in patients without PAD.3,4 However, whether IC stenting has resulted in a lower risk of periprocedural complications and has improved the long-term prognosis of patients with concomitant coronary artery disease and PAD needs to be determined. Therefore, the major objective of this study was to compare the short-term and long-term outcomes of patients with coronary artery disease and PAD who underwent IC stent implantation with the outcomes of patients with isolated coronary artery disease but without PAD who underwent IC implantation. PATIENTS AND METHODS We analyzed the Mayo Clinic PTCA Registry, which prospectively codes demographic, clinical, and angiographic
Mayo Clin Proc. 2004;79(9):1113-1118
BARI = Bypass Angioplasty Revascularization Investigation; CABG = coronary artery bypass grafting; CHF = congestive heart failure; CI = confidence interval; IC = intracoronary; MI = myocardial infarction; OR = odds ratio; PAD = peripheral arterial disease; PCI = percutaneous coronary intervention; PTCA = percutaneous transluminal coronary angioplasty
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From the Division of Cardiovascular Diseases and Internal Medicine (M.S., D.D., B.J.G., D.R.H., C.S.R.) and Division of Biostatistics (R.J.L.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Darbar is now with the Vanderbilt University Medical Center, Nashville, Tenn. Address reprint requests and correspondence to Charanjit S. Rihal, MD, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2004 Mayo Foundation for Medical Education and Research
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data on all patients who undergo percutaneous coronary intervention (PCI) at the Mayo Clinic in Rochester, Minn. We reviewed PCI procedures performed between January 1996 and December 2002. Patients who refused to allow use of their records for research were excluded per Minnesota state law. If a patient had multiple qualifying PCIs during the study period, only the earliest was included. Baseline data collected included information on atherosclerosis in noncoronary vascular beds. After selecting all patients who had undergone PCI over the 7-year period, we divided the patients into 2 groups: group 1 consisted of 6299 patients with isolated coronary artery disease but no evidence of PAD who had undergone IC stent implantation; group 2 consisted of 1397 patients with coronary artery disease and evidence of PAD in whom an IC stent was used. The study was approved by the Mayo Foundation Institutional Review Board. FOLLOW-UP Patients were contacted by telephone at 6 and 12 months after their procedure and yearly thereafter. At each contact, information was obtained pertaining to vital status, myocardial infarction (MI), angina symptoms, and occurrence of additional revascularization procedures. Refused calls were treated as missing, ie, no contact. Records from other hospitals were obtained when possible. DEFINITIONS USED Peripheral arterial disease was defined as presence of claudication, history of peripheral arterial surgery, presence of abdominal aortic aneurysm, disease of the cranial and extracranial arteries defined as a history of stroke or transient ischemic attacks, history of carotid surgery, or presence of carotid disease documented by ultrasonography, angiography, or carotid bruit. Acute MI was considered to have occurred when at least 2 of the following 3 criteria were met: (1) chest pain lasting longer than 30 minutes, (2) persistent electrocardiographic changes suggestive of ischemia, and (3) 2-fold or greater elevations in serum creatine kinase levels with a corresponding increase in the MB isoform. Multivessel disease was defined as the presence of 70% or greater stenosis of the luminal diameter in a major epicardial artery, with 50% or greater stenosis in a second major epicardial vessel (2-vessel disease) or in both of the other epicardial vessels (3-vessel disease). Procedural success was defined as residual stenosis less than 50% in at least 1 lesion without in-hospital death, Q-wave MI, or CABG. STATISTICAL ANALYSES Demographic and baseline clinical characteristics were compared for patients with and without noncoronary ath1114
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erosclerosis. The Student t test was used to compare continuous variables, χ2 tests to compare proportions, KaplanMeier estimates to describe follow-up survival rates, and the log-rank test to compare survival curves. All hypothesis tests were 2-tailed with a 0.05 type I error rate. Multiple logistic regression was used to assess the likelihood of an in-hospital complication associated with the presence of PAD, adjusting for other risk factors. Similarly, Cox proportional hazards models were used to estimate the increased risk of adverse events on follow-up in patients with PAD. The set of covariates used for risk adjustment was age, sex, date of procedure, preprocedural shock, acute MI, Canadian Heart Class III or higher angina, diabetes mellitus, hypertension, body mass index, history of cholesterol level greater than 240 mg/dL, history of congestive heart failure (CHF), current CHF status, smoking history, history of MI, prior PCI, prior CABG, chronic renal disease, peptic ulcer disease, tumor, metastatic cancer, multivessel disease, American College of Cardiology/American Heart Association lesion class IIb or c, thrombus in any lesion, and use of glycoprotein IIb/ IIIa inhibitors. RESULTS Over a 7-year period, 7696 patients underwent IC stent implantation at our institution. Peripheral arterial disease was identified in 1397 patients (18%), of whom lower-extremity vascular disease was present in 772 (55%) and cerebrovascular disease in 835 (60%). Of the 7696 patients, 160 (2%) had a nonfemoral vascular access site for PCI. BASELINE CHARACTERISTICS Baseline characteristics of the 2 groups are shown in Table 1. In general, patients in group 2 with PAD had adverse prognostic characteristics; they were older and had a higher prevalence of hypertension, diabetes mellitus, history of smoking, prior MI, hyperlipidemia, CHF, and prior revascularization. PROCEDURAL SUCCESS AND COMPLICATION RATES There was a higher prevalence of multivessel disease in group 2. Among patients in group 2, procedural success was significantly lower than among patients in group 1 (95% vs 97%; P<.001). Group 2 prevalences were significantly higher than those of group 1 (P<.001) for in-hospital death (3% vs 1%), any MI (8% vs 5%), and in-hospital death/MI/CABG/target vessel revascularization (11% vs 7%). The prevalences of stroke (0.6% vs 0.3%; P=.02) and transient ischemic attack (0.4% vs 0.1%; P=.004) were significantly higher in group 2 (Table 2).
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Glycoprotein IIb/IIIa inhibitors were used less frequently in group 2 patients compared with group 1 patients (48% vs 56%; P<.001). Despite that, the need for blood transfusion due to excessive blood loss was higher in group 2 (11% vs 5.8%; P<.001). The complications related to vascular access were low and similar in the 2 groups (Table 3). FOLLOW-UP Median follow-up was 3.1 years; 94% of patients were followed up for at least 6 months. The follow-up was complete in 85% of the study group at 12 months and in 75% at 18 months. The values for 6-month, 1-year, and 2year survival free of death (Figure 1), death/MI (Figure 2), or death/MI/CABG/target vessel revascularization (Figure 3) were worse in group 2. Six-month, 1-year, and 2-year Kaplan-Meier estimates of survival free of death/MI/ CABG/target vessel revascularization were 84%, 77%, and 69%, respectively, for group 2 and were significantly worse compared with group 1 (89%, 85%, and 80%, respectively; P<.001). INFLUENCE OF PAD AND YEAR OF TREATMENT OUTCOME After adjustment for concomitant risk factors, patients with PAD treated with IC stents had an 84% increase in the odds of in-hospital death (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.16-2.90; P=.009) and 25% higher odds for in-hospital composite end points of death/MI/CABG/target vessel revascularization (OR, 1.25; 95% CI, 1.00-1.55; P=.048). The presence of PAD was a significant risk factor for cardiovascular mortality and morbidity on followup. The risks of death (hazard ratio, 1.48; 95% CI, 1.261.73; P<.001) and the composite event of death/MI/CABG/ target vessel revascularization (hazard ratio, 1.36; 95% CI, 1.22-1.51; P<.001) were higher in group 2 compared with group 1. To assess improvement over time of patients with PAD who had undergone stent implantation, we estimated similar models with these patients, again including procedure date in the covariate set. We observed significant reduction over time in in-hospital events of death (OR per year, 0.88; 95% CI, 0.68-0.99; P=.04) and the composite of death/MI/ CABG/target lesion revascularization (OR per year, 0.88; 95% CI, 0.79-0.97; P=.01). ON
DISCUSSION The present study provides data on the effect of IC stent implantation in a high-risk group of patients with combined coronary artery disease and PAD. Peripheral arterial disease is a significant risk factor for lower proceMayo Clin Proc.
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TABLE 1. Baseline Characteristics* Variable Age, mean ± SD (y) Male Unstable angina Canadian Heart Class (III, IV) MI 24 h before PCI Diabetes mellitus Hypertension Body mass index, mean ± SD (kg/m2) History of cholesterol ≥240 mg/dL CHF on presentation History of CHF Current/former smoker Prior MI Prior PTCA/CABG Moderate/severe renal disease Ejection fraction ≤40%
Group 1 (N=6299)
Group 2 (N=1397)
P value
65.0±12.0 4482 (71) 3791 (60) 3182 (51) 1041 (17) 1227 (20) 3729 (61)
71.1±10.2 966 (69) 855 (61) 801 (57) 153 (11) 463 (33) 1076 (79)
<.001 .14 .48 <.001 <.001 <.001 <.001
29.5±5.5
28.4±5.1
<.001
3986 (70) 482 (8) 669 (11) 3950 (63) 3225 (52) 1725 (27) 128 (2) 585 (9)
974 (76) 256 (18) 344 (26) 962 (70) 822 (60) 632 (45) 105 (8) 232 (17)
<.001 <.001 <.001 <.001 <.001 <.001 <.001 <.001
*Values are number (percentage) unless indicated otherwise. Denominators may vary slightly because of missing data. CHF = congestive heart failure; MI = myocardial infarction; PCI = percutaneous coronary intervention; PTCA/CABG = percutaneous transluminal coronary angioplasty/ coronary artery bypass grafting.
dural success and higher in-hospital complications. On follow-up, adverse cardiovascular outcomes were higher in patients with PAD. In recent years, patients with PAD have experienced a reduction in in-hospital adverse events. IN-HOSPITAL COMPLICATIONS Peripheral arterial disease is recognized as an independent predictor of in-hospital complications, including death, TABLE 2. Procedural Characteristics and In-hospital Outcomes* Variable Multivessel disease ACC/AHA IIb/c Thrombus in any lesion Calcium in any stenosis Glycoprotein IIb/IIIa use Abrupt closure Procedural success In-hospital death In-hospital any MI In-hospital Q-wave MI In-hospital CABG In-hospital death/MI/CABG/ TVR CVA complication TIA complication
Group 1 (N=6299)
Group 2 (N=1397)
P value
4111 (68) 4579 (80) 2072 (35) 2175 (37) 3553 (56) 134 (2) 6122 (97) 65 (1) 331 (5) 67 (1) 41 (1)
1072 (79) 1128 (85) 407 (31) 623 (48) 674 (48) 38 (3) 1323 (95) 43 (3) 105 (8) 16 (1) 10 (1)
<.001 <.001 .01 <.001 <.001 .18 <.001 <.001 <.001 .79 .79
420 (7) 16 (0.3) 4 (0.1)
147 (11) 9 (0.6) 5 (0.4)
<.001 .02 .004
*Values are number (percentage). Denominators may vary slightly because of missing data. ACC/AHA = American College of Cardiology/ American Heart Association; CABG = coronary artery bypass grafting; CVA = cerebrovascular accident; MI = myocardial infarction; TIA = transient ischemic attack; TVR = target vessel revascularization.
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TABLE 3. Bleeding and Related Complications in Patients With and Without Peripheral Arterial Disease* Variable
Group 1 (N=6299)
Group 2 (N=1397)
P value
Retroperitoneal bleeding Pseudoaneurysm Central nervous system bleeding Blood loss requiring transfusion Hypotension Hematoma
19 (0.3) 62 (1.0) 1 (0.0) 363 (5.8) 434 (6.9) 190 (3.0)
2 (0.1) 16 (1.1) 0 (0.0) 151 (10.8) 124 (8.9) 54 (3.9)
.30 .58 .64 <.001 .009 .10
*Values are number (percentage).
stroke, and the composite of death/MI/stroke/CABG. Also, PAD is considered a marker for vascular access complications.5 The association of PAD and in-hospital complications has been documented consistently in the risk score models developed for patients undergoing PCI in the current era.6-9 The present study supports the observations from these models. The likely reasons for such high risk in these patients are adverse baseline and angiographic characteristics, including older age, diabetes mellitus, CHF, lower ejection fraction, renal disease, higher prevalence of multivessel disease, and other characteristics associated with worse in-hospital outcome related to PCIs. Similar conclusions were drawn from the BARI trial in a subset of patients with PAD and coronary artery disease.2 This study is different from the BARI trial in that it is more representative of current PCI treatment, including the use of stents, glycoprotein IIb/IIIa inhibitors, and anti-
platelet agents such as ticlopidine and, more recently, clopidogrel. The need for in-hospital CABG was low (1%), and the need for emergency CABG related to PCI complications was even lower. This is in contrast to earlier studies of patients with PAD who underwent balloon angioplasty and had abrupt closure rates of 9.8%. The abrupt closure rate in the present study was 3% in patients with PAD treated with stents. The rates of referral for emergency CABG have declined since the introduction of IC stents. The ability of stents to limit elastic recoil, seal intimal flaps, and prevent abrupt closure of the target vessel may be an important factor in reducing the need for emergent surgical revascularization.10 Some reduction in in-hospital complications, including death, has been seen in patients with PAD, most notably a reduction in the need for inhospital revascularization. Vascular access complications were low and were similar in the 2 groups, probably because of smaller sheath size, less vigorous anticoagulant regimens, and better operator experience. However, the need for blood transfusions related to blood loss was higher in patients with PAD. On follow-up, patients with PAD continue to have adverse cardiovascular outcome, likely because of the higher prevalence of multivessel disease and poor left ventricular function. Both these variables and other demographic variables have been shown to be significant predictors for adverse long-term outcome.11,12 STUDY LIMITATIONS The present study is a retrospective analysis of a single center’s experience and is therefore subject to biases innate
100
No PAD
90 PAD
80
Percentage
70 60 50 40 30 20 10 0 0.0
0.5
1.0
1.5
2.0
Years
FIGURE 1. Kaplan-Meier curves for survival in patients with and without peripheral arterial disease (PAD) (P<.001).
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100 No PAD 90 80 PAD
Percentage
70 60 50 40 30 20 10 0 0.0
0.5
1.0
1.5
2.0
Years
FIGURE 2. Kaplan-Meier curves for survival free of death/myocardial infarction in patients with and without peripheral arterial disease (PAD) (P<.001).
in such studies. Intracoronary stent implantation techniques have evolved over the study period, and although we have tested year of treatment as 1 of the variables, the full effect of these changes may not be fully apparent from the analyzed data. Moreover, we have not included patients who underwent implantation of drug-eluting stents. Further studies to evaluate the effects of current PCIs on the outcome of patients with PAD and coronary artery disease are warranted. The use of statins, angiotensin-converting enzyme inhibitors, and newer thienopyridines that have fa-
vorably influenced the outcome of patients with PAD were not studied separately in the 2 groups. CONCLUSIONS This study showed that patients with coronary artery disease and PAD who were treated with IC stents had lower procedural success and higher in-hospital complications, including higher blood loss requiring transfusions, compared with patients who had isolated coronary artery
100 90
No PAD
80
Percentage
70 PAD
60 50 40 30 20 10 0 0.0
0.5
1.0
1.5
2.0
Years
FIGURE 3. Kaplan-Meier curves for survival free of death/myocardial infarction/coronary artery bypass grafting/target vessel revascularization in patients with and without peripheral arterial disease (PAD) (P<.001).
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disease but no PAD. Peripheral arterial disease is an independent risk factor for short-term and long-term adverse cardiovascular outcomes, with higher mortality, MI, and need for repeated target vessel revascularization. Results of PCI in patients with PAD in recent years have improved. REFERENCES 1. Sutton-Tyrrell K, Rihal C, Sellers MA, et al. Long-term prognostic value of clinically evident noncoronary vascular disease in patients undergoing coronary revascularization in the Bypass Angioplasty Revascularization Investigation (BARI). Am J Cardiol. 1998;81:375-381. 2. Rihal CS, Sutton-Tyrrell K, Guo P, et al. Increased incidence of periprocedural complications among patients with peripheral vascular disease undergoing myocardial revascularization in the bypass angioplasty revascularization investigation. Circulation. 1999;100:171-177. 3. Fischman DL, Leon MB, Baim DS, et al, Stent Restenosis Study Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994; 331:496-501. 4. Serruys PW, de Jaegere P, Kiemeneij F, et al, Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994; 331:489-495.
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5. Nasser TK, Mohler ER III, Wilensky RL, Hathaway DR. Peripheral vascular complications following coronary interventional procedures. Clin Cardiol. 1995;18:609-614. 6. Singh M, Lennon RJ, Holmes DR Jr, Bell MR, Rihal CS. Correlates of procedural complications and a simple integer risk score for percutaneous coronary intervention. J Am Coll Cardiol. 2002;40:387-393. 7. Moscucci M, Kline-Rogers E, Share D, et al. Simple bedside additive tool for prediction of in-hospital mortality after percutaneous coronary interventions. Circulation. 2001;104:263-268. 8. Holmes DR Jr, Berger PB, Garratt KN, et al. Application of the New York State PTCA mortality model in patients undergoing stent implantation. Circulation. 2000;102:517-522. 9. Holmes DR, Selzer F, Johnston JM, et al. Modeling and risk prediction in the current era of interventional cardiology: a report from the National Heart, Lung, and Blood Institute Dynamic Registry. Circulation. 2003;107:18711876. 10. Goldberg S, Savage MP, Fischman DL. Coronary artery stents. Lancet. 1995;345:1523-1524. 11. Mock MB, Fisher LD, Holmes DR Jr, et al. Comparison of effects of medical and surgical therapy on survival in severe angina pectoris and twovessel coronary artery disease with and without left ventricular dysfunction: a Coronary Artery Surgery Study Registry Study. Am J Cardiol. 1988;61:11981203. 12. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration [published correction appears in Lancet. 1994;344:1446]. Lancet. 1994;344:563-570.
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