DES for SVG Stenosis — We All Want to Do It, But Are
We There Yet?

More than 400,000 coronary artery bypass graft (CABG) operations are performed annually in the United States, with the saphenous vein graft (SVG) as the major type of conduit.¹ However, surgical revascularization is not definitive, and recurrent angina occurs in 5–10% of patients per year.² While progression of native coronary atherosclerosis explains some of the symptom recurrence, disease of the grafts is a major problem — over 50% of SVGs are severely diseased or occluded after 10 years.^3,4 Because re-do CABG is associated with significant morbidity and mortality, SVGs now represent 10–15% of the targets for percutaneous coronary intervention (PCI) in most institutions.⁵ However, the optimal stent type for SVG lesions remains undefined. Use of bare-metal stents (BMS) in the Saphenous Vein De Novo (SAVED) trial resulted in improved procedural outcomes and a reduced rate of major adverse cardiac events (MACE) compared to balloon angioplasty, but was associated with a restenosis rate of 37% at the mandated 6-month angiographic follow up.⁶

The problem of restenosis in SVGs would seem to have an easy solution: drug-eluting stents (DES), which have been shown to significantly reduce restenosis in native coronary arteries.^7,8 Despite frequent use in clinical practice, the data supporting PCI of SVGs using DES are limited, and the current guidelines give DES a Class IIb recommendation in this setting.⁹ The Reduction of Restenosis in SVG with Cypher sirolimus-eluting stent (RRISC) trial is the only randomized comparison of BMS versus DES to date, and is limited by being a single-center study with a small sample size, underpowered for clinical endpoints.¹⁰ Late lumen loss, restenosis rate and repeat target lesion and vessel revascularization were significantly reduced at 6 months in patients with sirolimus-eluting stents (SES), but longer-term follow up (up to 3 years) revealed that this difference was no longer present and, notably, the patients with SES had significantly higher late mortality.¹¹ The observational studies involving SES,^12–14 paclitaxel-eluting stents (PES),^15–17 or both,^18,19 have been characterized by small sample sizes, often at single centers with short follow up (most around 6 months), and the biases inherent in the observational design. Another retrospective study compares patients treated with SES versus those treated with PES, demonstrating similar procedural success and MACE rates with follow up to 6 months, but with no BMS control group.²⁰

In this issue of the journal, Ellis et al compared patients receiving SES for de novo SVG lesions with matched controls receiving BMS.²¹ They addressed the limitations of previous trials by enrolling a larger number of patients from multiple centers, choosing clinically-driven target vessel revascularization (TVR) as the primary endpoint, and following patients for 12 months. Entry criteria were slightly broader than for the RRISC trial, and the current study had more diabetic patients (39% vs. 15% in RRISC), more hypertensive patients (83% vs. 57%), and younger SVGs (mean 119 vs. 150 months). A trend towards reduced TVR (6.8% vs. 11.8%) and binary restenosis (7.4% vs. 13.6%) at 12 months was seen in patients who received SES, but neither endpoint reached statistical significance. Importantly, there was no difference in mortality between groups at 12 months. The authors conclude that SES “appear to modestly reduce TVR without apparent safety risk compared with BMS” and “in conjunction with other available studies, the data support Cypher use” in treating SVG stenosis. However, several important limitations of the study should be noted.

First, the study enrolled fewer patients than specified by the power calculation, increasing the likelihood of Type II (beta) error. Unfortunately, the power to detect a difference was also compromised by the surprisingly low rate of restenosis in the BMS group. The binary restenosis rate for BMS was 13.6%, compared to 30.6% in the RRISC trial, and the TVR rate was 11.8%, compared to 27% (even with 6 more months of follow up). However, the restenosis and TVR rates for SES of 7.4% and 6.8% at 12 months, respectively, are comparable to those seen in the RRISC trial (11.3% and 5.3% at 6 months).¹⁰ The lower restenosis rate with BMS implantation is not explained, but may be due in part to a lack of mandated angiographic follow up.

Second, the duration of follow up, while longer than most of the other observational studies, remains relatively short given recent concerns about the long-term safety of DES.^22–27 Especially worrisome is the finding of 11 deaths (29%) in the SES group compared to 0 deaths in the BMS group after a median follow up of 32 months in the RRISC trial.¹¹ The majority of these deaths occurred after 12 months of follow up (including a definite stent thrombosis at 14.5 months associated with the cessation of dual antiplatelet therapy), stressing the need for follow up on the order of several years.

Finally, the usual criticisms of observational studies can be applied. However, the authors were able to match cases and controls well for characteristics that typically contribute significantlyto the risk of restenosis in native coronary arteries including diabetes mellitus, lesion length and reference vessel diameter. Indeed, matching of vessel diameter (smaller in DES patients) and lesion length (longer in DES patients) was a problem in a recently presented observational study involving a large number of SVG PCIs with 9-month follow up, which also showed a nonsignificant trend towards reduced TVR rate in patients with DES.²⁸ Additionally, in the current study, patients were also matched with controls from the same site and as close in time as possible, thereby minimizing bias arising from changing practice patterns with time and by institution.

Of note, taking advantage of the increased sample size compared to prior studies, the authors attempted to analyze prespecified subgroups for restenosis risk. We agree with the authors, however, that subgroup data should be interpreted with considerable caution. Specifically, no conclusions can be made as to whether there is a difference between SES versus BMS in diabetics, in regards to reference vessel diameter, total stent length or SVG age. In addition, embolic protection was used infrequently in both groups (35% in SES vs. 25% in BMS; p = 0.04), whereas glycoprotein (GP) IIb/IIIa inhibitors were used more frequently in patients receiving BMS versus SES (83% vs. 52%; p < 0.0001).

In conclusion, while this study makes an important contribution and lends support to the strategy of SES use to reduce restenosis in diseased SVGs, concerns will persist regarding possible very late (> 1 year) adverse events and the actual magnitude of benefit. We encourage continued follow up of this study cohort for mortality and other adverse events. Ideally, a multicenter randomized trial with a large sample size powered for clinical outcomes over a long duration of follow up should be performed comparing DES versus BMS in treating SVG stenosis, but this is easier said than done. Of note, this study also confirms a rate of restenosis and TVR in the single-digit percent range for patients undergoing SES implantation in de novo SVG lesions. Until further data are available, it is reasonable to conclude that the question of “DES in SVG stenosis?” is not a simple one to answer. Sure, we all “want to do it, but we are not there yet” with the data! In the meantime, we recommend limiting the use of DES in de novo SVG PCI to those patients at highest risk for restenosis, possibly including patients with long lesions, small reference vessel diameter and diabetes mellitus, and importantly, in patients who are going to be compliant with long-term dual antiplatelet therapies.

References

1. Eagle KA, Guyton RA, Davidoff R, et al. American College of Cardiology; American Heart Association. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.

2. Campeau L, Lesperance J, Hermann J, et al. Loss of the improvement of angina between 1 and 7 years after aortocoronary bypass surgery: Correlations with changes in vein grafts and in coronary arteries. Circulation 1979;60:1–5.

3. Fitzgibbon GM, Leach AJ, Kafka HP, Keon WJ. Coronary bypass graft fate: Long term angiographic study. J Am Coll Cardiol 1991;17:1975–1980.

4. Fitzgibbon GM, Kafka HP, Leach AJ, et al. Coronary bypass graft fate and patient outcome: Angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28:616–626.

5. Baim D. Percutaneous treatment of saphenous vein graft disease: The ongoing challenge. J Am Coll Cardiol 2003;42:1370–1372.

6. Savage MP, Douglas JS Jr, Fischman DL, et al. Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts: Saphenous Vein De Novo Trial investigators. N Engl J Med 1997;337:740–747.

7. Moses JD, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.

8. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patient with coronary artery disease. N Engl J Med 2004; 350:221–231.

9. Smith SC, Feldman TE, Hirshfeld JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention. Circulation 2006;113:e166–286.

10. Vermeersch P, Agostoni P, Verheye S, et al. Randomized double-blind comparison of sirolimus-eluting stent versus bare-metal stent implantation in diseased saphenous vein grafts. J Am Coll Cardiol 2006;48:2423–2431.

11. Vermeersch P, Agostoni P, Verheye S, et al. Increased late mortality after sirolimuseluting stents versus bare-metal stents in diseased saphenous vein grafts. J Am Coll Cardiol 2007;50:261–267.

12. Hoye A, Lemos PA, Arampatzis CA, et al. Effectiveness of the sirolimus-eluting stent in the treatment of saphenous vein graft disease. J Invasive Cardiol 2004;16:230–233.

13. Price MJ, Sawhney N, Kao JA, et al. Clinical outcomes after sirolimus-eluting stent implantation for de novo saphenous vein graft lesions. Catheter Cardiovasc Interv 2005;65:208–211.

14. Chu WW, Rha SW, Kuchulakanti PK, et al. Efficacy of sirolimus-eluting stents compared with bare metal stents for saphenous vein graft intervention. Am J Cardiol 2006;97:34–37.

15. Hoffmann R, Pohl T, Köster R, et al. Implantation of paclitaxel-eluting stents in saphenous vein grafts: Clinical and angiographic follow-up results from a multicentre study. Heart 2007;93:331–334.

16. Wöhrle J, Nusser T, Kestler HA, et al. Comparison of the slow-release polymer-based paclitaxel-eluting Taxus-Express stent with the bare-metal Express stent for saphenous vein graft interventions. Clin Res Cardiol 2007;96:70–76.

17. Ruchin PE, Faddy SC, Muller DWM, et al. Clinical follow-up of paclitaxel-eluting ( TAXUS^™) stents for the treatment of saphenous vein graft disease. J Interv Cardiol 2007;20:258–264.

18. Ge L, Iakovou I, Sangiorgi GM, et al. Treatment of saphenous vein graft lesions with drug-eluting stents: Immediate and midterm outcome. J Am Coll Cardiol 2005;45:989–994.

19. Lee MS, Shah AP, Aragon J, et al. Drug-eluting stenting is superior to bare metal stenting in saphenous vein grafts. Catheter Cardiovasc Interv 2005;66:507–511.

20. Chu WW, Kuchulakanti PK, Wang B, et al. Efficacy of sirolimus-eluting stents as compared to paclitaxel-eluting stents for saphenous vein graft intervention. J Interv Cardiol 2006;19:121–125.

21. Ellis SG, Kandzari D, Kereiakes D, et al. Utility of sirolimus-eluting CYPHER™ stents to reduce 12-month target vessel revascularization in saphenous vein graft stenoses: Results of a multicenter 350 patient case-control study. J Invasive Cardiol 2007;19:404–409.

22. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: An observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48:2584–2591.

23. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356:1030–1039.

24. Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356:1009–1019.

25. Bavry AA, Kumbhani DJ, Helton TJ, et al. Late thrombosis of drug-eluting stents: A meta-analysis of randomized clinical trials. Am J Med 2006;119:1056–1061.

26. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of firstgeneration drug-eluting stents: A cause for concern. Circulation 2007;115:1440–1455.

27. Nordmann AJ, Briel M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting stents vs. bare metal stents in coronary artery disease: A metaanalysis. Eur Heart J 2006;27:2784–2814.

28. Wilson BH, Humphrey AD, Cedarholm JC, et al. Drug-eluting stents are no better than bare metal stents in vein grafts: Results from the strategic transcatheter evaluation of new therapies (STENT) group (Abstr). J Am Coll Cardiol 2007; 49( Suppl B):41B.