The effectiveness and safety of drug-eluting stents (DES) compared with bare-metal stents (BMS) in saphenous vein graft (SVG) disease remains unclear. In particular, there is a paucity of data on long-term outcomes. In this study, 395 patients enrolled in the National Heart, Lung, and Blood Institute Dynamic Registry who underwent stenting of SVG lesions with BMS (n = 192) from 1999 to 2006 or DES (n = 203) from 2004 to 2006 were analyzed. Patients were followed prospectively for the occurrence of cardiovascular events and death at 3 years. Patients treated with DES were more likely to have diabetes mellitus and other co-morbidities and previous percutaneous coronary intervention. Treated lesions in DES patients were more complex than those in BMS patients. At 3 years of follow-up, the adjusted risk for target vessel revascularization (hazard ratio 1.03, 95% confidence interval 0.65 to 1.62, p = 0.91) and death or myocardial infarction (hazard ratio 0.72, 95% confidence interval 0.49 to 1.04, p = 0.08) was similar in patients treated with DES and those treated with BMS. The combined outcome of death, myocardial infarction, or target vessel revascularization excluding periprocedural myocardial infarction was also similar (adjusted hazard ratio 0.82, 95% confidence interval 0.62 to 1.09, p = 0.16). In conclusion, this multicenter nonrandomized study of unselected patients showed no benefit of DES in SVG lesions, including no reduction in target vessel revascularization, compared with BMS at 3 years. An adequately powered randomized controlled trial is needed to determine the optimal stent type for SVG percutaneous coronary intervention.
Saphenous vein graft (SVG) disease occurs frequently after coronary artery bypass grafting and is a strong predictor of mortality. Percutaneous coronary intervention (PCI) with stent placement is the preferred treatment for SVG disease, but restenosis occurs in >30% of patients treated with bare-metal stents (BMS). Drug-eluting stents (DES) reduce the need for repeat revascularization compared with BMS in native coronary lesions, but studies of DES in SVG lesions have shown mixed results. Furthermore, the safety of DES in SVG lesions has been questioned, with a concern for late stent thrombosis and sudden cardiac death. Given the paucity of long-term data on DES in SVG lesions, we examined a subgroup of patients who underwent SVG PCI with either BMS or DES in a prospective observational multicenter registry with planned 5-year follow-up.
Methods
The National Heart, Lung, and Blood Institute Dynamic Registry is a prospective observational study of consecutive patients who undergo PCI at selected centers in North America. Five enrollment waves of approximately 2,000 consecutive patients each have been collected since 1997. Waves 4 and 5 enrolled patients in the DES era. Stent selection (BMS vs DES) during waves 4 and 5 was at the discretion of the operator. Each clinical center received approval from its institutional review board, and data were compiled and analyzed at the University of Pittsburgh.
In each wave, baseline demographic, clinical, angiographic, and procedural data were collected at the time of the index PCI. In-hospital outcomes were obtained at the site of enrollment. All patients were followed for 1 year after PCI, and patients enrolled in waves 2, 4, and 5 are followed yearly to 5 years. Systematic collection of data on stent thrombosis began in wave 4. During follow-up, coronary angiography was obtained only if clinically indicated for symptoms or objective ischemia. For patients who underwent repeat PCI, lesion-specific data were collected to determine whether target vessel revascularization (TVR) was performed. Patients were interviewed by telephone by trained data coordinators guided by standardized questionnaires.
This analysis includes patients enrolled in waves 2, 4, and 5 who underwent SVG PCI with ≥1 BMS or DES. Waves 1 and 3 patients were excluded because follow-up did not extend beyond 1 year. A total of 6,394 patients were enrolled in waves 2, 4, and 5, and 457 had SVG interventions. Patients with SVG lesions treated with balloon angioplasty only (n = 50) or with a combination of BMS and DES (n = 12) were excluded. The remaining 395 patients were included in this study. In wave 2, 119 patients underwent SVG stenting with BMS. In waves 4 and 5, 73 patients underwent SVG stenting with BMS, and 203 patients underwent SVG stenting with DES. Thus, 192 patients treated with BMS were compared with 203 patients treated with DES. Three-year follow-up rates by recruitment wave ranged from 97% to 100%.
Death included mortality from all causes. Myocardial infarction (MI) was defined by (1) evolutionary ST-segment elevation, development of new Q waves in ≥2 contiguous electrocardiographic leads, or new left bundle branch block pattern on electrocardiography or (2) biochemical evidence of myocardial necrosis, manifested as (a) creatine kinase-MB ≥3 times the upper limit of normal or, if creatine kinase-MB was not available, (b) total creatine kinase ≥3 times the upper limit of normal or (c) troponin value above the upper limit of normal. Repeat PCI included target vessel and non–target vessel interventions. Planned staged PCI procedures after the index procedure were not considered repeat PCI. TVR was defined as a repeat revascularization involving the initially treated vein graft. Native vessel TVR was not included in the TVR end point. Stent thrombosis included only angiographically confirmed (definite) events.
Patient- and lesion-level characteristics pertaining to the index PCI were compared between stent types using Student’s t tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables. Three-year event rates were calculated using the Kaplan-Meier approach, and unadjusted comparisons of survival curves were performed using the log-rank test. Multivariate Cox proportional-hazards modeling was used to estimate 3-year hazard ratios for adverse clinical events according to stent type. Covariate adjustment was performed such that clinical, demographic, and procedural variables were entered individually into outcome-specific models that included an indicator variable for stent type. Confounding variables were assessed in a forward stepwise manner to determine the final adjusted model. The screened variables with p values <0.20 were included initially, and those for which the p values were <0.10 remained in the model. Covariate adjustments for outcomes based on lesion and stent type were performed in a similar fashion. Proportional-hazards assumptions were evaluated and met. Patients who did not experience the outcome of interest were censored at the last known date of contact or at 3 years if contact extended beyond that time. For all analyses, a 2-sided p value ≤0.05 was considered statistically significant.
Results
Selected baseline clinical characteristics of the groups are listed in Table 1 . Patients treated with DES were significantly more likely to present with diabetes mellitus, hypercholesterolemia, hypertension, and previous PCI. Other baseline characteristics were similar between the groups. At the index procedure, 287 lesions (248 SVG and 39 native) were stented in 192 BMS-treated patients, and 295 lesions (256 SVG and 39 native) were stented in 203 DES-treated patients. SVG lesion characteristics are listed in Table 2 . DES-treated lesions were significantly more likely to have previous stents, longer lengths, smaller reference diameters, and more complexity compared with BMS-treated lesions. The results were similar when all lesions (SVG and native) were analyzed.
| Variable | BMS | DES | p Value |
|---|---|---|---|
| (n = 192) | (n = 203) | ||
| Mean age (years) | 70.4 | 69.7 | 0.42 |
| Women | 50 (26.0%) | 38 (18.7%) | 0.08 |
| Race/ethnicity | 0.59 | ||
| White | 171 (89.1%) | 173 (85.2%) | |
| Black | 16 (8.3%) | 20 (9.9%) | |
| Asian | 3 (1.6%) | 5 (2.5%) | |
| Hispanic | 2 (1.0%) | 5 (2.5%) | |
| Smoking status | 0.17 | ||
| Never smoked | 67 (37.0%) | 55 (30.4%) | |
| Current/former smoker | 114 (63.0%) | 126 (69.6%) | |
| Hypertension | 146 (76.4%) | 174 (87.0%) | 0.007 |
| Diabetes | 58 (30.4%) | 91 (44.8%) | 0.003 |
| Hypercholesterolemia ⁎ | 142 (75.9%) | 183 (91.0%) | <0.0001 |
| Renal disease † | 20 (10.5%) | 33 (16.3%) | 0.09 |
| Peripheral vascular disease | 34 (17.8%) | 39 (19.3%) | 0.70 |
| Cerebrovascular disease | 24 (12.6%) | 25 (12.4%) | 0.95 |
| Previous PCI | 73 (38.0%) | 119 (58.6%) | <0.0001 |
| Previous myocardial infarction | 87 (47.8%) | 83 (43.9%) | 0.45 |
| History of congestive heart failure | 40 (21.6%) | 45 (23.1%) | 0.73 |
| Mean left ventricular ejection fraction (%) | 47.8 | 47.9 | 0.61 |
| Triple-vessel coronary disease | 135 (70.3%) | 161 (79.3%) | 0.048 |
⁎ Serum cholesterol >240 mg/dl or receiving medical treatment for high cholesterol.
† Renal failure or insufficiency diagnosed by a physician and treated with medication, low-protein diet, or dialysis.
| Variable | BMS | DES | p Value |
|---|---|---|---|
| (n = 248) | (n = 256) | ||
| Lesion previously treated with stent | 16 (6.5%) | 44 (17.2%) | 0.0002 |
| Reference vessel size (mm) | 3.6 | 3.3 | <0.0001 |
| Mean lesion length (mm) | 13.2 | 18.5 | <0.0001 |
| Lesion characteristics | |||
| Evidence of thrombus | 51 (21.7%) | 46 (18.1%) | 0.32 |
| Calcified | 27 (11.3%) | 26 (10.3%) | 0.73 |
| Ulcerated | 31 (13.1%) | 37 (14.7%) | 0.60 |
| Ostial lesion | 28 (11.3%) | 35 (13.7%) | 0.43 |
| Total occlusion | 7 (2.8%) | 14 (5.5%) | 0.14 |
| Lesion classification ⁎ | 0.001 | ||
| A | 18 (7.7%) | 11 (4.3%) | |
| B1 | 73 (31.3%) | 69 (27.0%) | |
| B2 | 90 (38.6%) | 78 (30.5%) | |
| C | 52 (22.3%) | 98 (38.3%) |
⁎ According to the American College of Cardiology and American Heart Association classification.
Table 3 lists the characteristics and in-hospital outcomes of the PCI procedures. Procedural indications were similar in BMS- and DES-treated patients. Distal protection devices, which came into widespread use after wave 2, were used in 18.3% of BMS-treated patients and 32.5% of DES-treated patients (p = 0.001). There was a higher incidence of in-hospital death and MI in the BMS-treated group compared with the DES-treated group (7.3% vs 2.5%, p = 0.03). There was a trend toward a higher rate of MI in BMS-treated patients, but no differences were observed between BMS- and DES-treated patients in the rates of in-hospital Q-wave MI, death, coronary artery bypass grafting, or stroke.
| Variable | BMS | DES | p Value |
|---|---|---|---|
| (n = 192) | (n = 203) | ||
| Primary indication for revascularization | |||
| Asymptomatic coronary artery disease | 11 (5.7%) | 13 (6.4%) | 0.78 |
| Stable angina pectoris | 40 (20.8%) | 45 (22.2%) | 0.75 |
| Unstable angina pectoris | 100 (52.1%) | 93 (45.8%) | 0.21 |
| Acute myocardial infarction | 37 (19.3%) | 43 (21.2%) | 0.64 |
| Cardiogenic shock on presentation | 1 (0.5%) | 2 (1.0%) | 0.60 |
| Glycoprotein IIb/IIIa inhibitors used | 78 (40.6%) | 57 (28.1%) | 0.009 |
| Distal protection device used | 35 (18.3%) | 66 (32.5%) | 0.001 |
| Number of lesions attempted | 0.27 | ||
| 1 | 120 (62.5%) | 138 (68.0%) | |
| 2 | 57 (29.7%) | 46 (22.7%) | |
| ≥3 | 15 (7.8%) | 19 (9.4%) | |
| Attempted stent location | 0.72 | ||
| Graft only | 163 (84.9%) | 175 (86.2%) | |
| Graft + 1 native vessel | 24 (12.5%) | 21 (10.3%) | |
| Graft + 2 native vessels | 5 (2.6%) | 7 (3.4%) | |
| In-hospital outcomes | |||
| Myocardial infarction | 11 (5.7%) | 4 (2.0%) | 0.05 |
| Coronary bypass surgery | 0 (0%) | 0 (0%) | 1.00 |
| Stroke | 0 (0%) | 1 (0.5%) | 0.33 |
| Death | 3 (1.6%) | 1 (0.5%) | 0.29 |
| Death or Q-wave MI | 3 (1.6%) | 2 (1.0%) | 0.61 |
| Death or myocardial infarction | 14 (7.3%) | 5 (2.5%) | 0.03 |
| Procedural success ⁎ | 189 (98.4%) | 200 (98.5%) | 0.95 |
⁎ Defined as partial or total angiographic success, without Q-wave MI, emergency coronary artery bypass grafting, or death.
Rates of complications for SVG lesions, including embolization (1.2% BMS vs 1.6% DES, p = 0.74), major dissection (0.8% BMS vs 1.6% DES, p = 0.44), and perforation (1.6% BMS vs 0.4% DES, p = 0.16), were low and similar between BMS- and DES-treated patients. Thrombosis In Myocardial Infarction (TIMI) flow grade was also similar. Postprocedural TIMI flow grade 3 was seen in 98.0% of BMS-treated SVG lesions and 96.9% of DES-treated SVG lesions (p = 0.57). Angiographic success was high and was achieved in 99.6% of BMS-treated SVG lesions and 98.4% of DES-treated SVG lesions (p = 0.19). Of the patients treated with DES, 29.6% received paclitaxel-eluting stents, 63.1% received sirolimus-eluting stents, and 7.4% of the patients received both types of DES. In-hospital event rates including death and MI did not differ according to DES type.
Cumulative event rates are listed in Table 4 . At 3 years, there were no statistically significant differences in the individual end points of death, MI, repeat PCI, or TVR in DES-treated patients compared with BMS-treated patients. There was a trend toward more repeat coronary artery bypass grafting in BMS-treated patients. The combined safety end point of death and MI occurred in 33.1% of patients treated with BMS and 27.4% of those treated with DES ( Figure 1 ). Among BMS-treated patients, those enrolled in wave 2 (n = 119) compared with those enrolled in waves 4 and 5 (n = 73) had nonsignificantly higher 3-year rates of MI (20.8% vs 15.1%, p = 0.33) and periprocedural MI (9.1% vs 7.2%, p = 0.67). In terms of efficacy, TVR occurred in 22.2% of patients treated with BMS and 23.0% of those treated with DES ( Figure 1 ).
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