Clinical Outcomes after PCI Involving Very Long Segments of DES Implantation: Single-Center Experience

From the Cardiothoracic Centre, Liverpool, United Kingdom. The authors report no conflicts of interest regarding the content herein. Manuscript submitted July 28, 2008, provisional acceptance given October 8, 2008, final manuscript accepted November 20, 2008. Address for correspondence: M. Andron, MBBS, MRCP, Department of Cardiology, The Cardiothoracic Centre, Thomas Drive, Liverpool L14 3PE, United Kingdom. E-mail: mohammed.andron@lhch.nhs.uk

ABSTRACT: Background. Data on effectiveness and safety following the implantation of very long segments of drug-eluting stents (DES) are lacking. Aim. To describe our experience of consecutive patients undergoing implantation of very long segments of DES (> 50 mm) in de novo coronary lesions. Methods. We evaluated major in-hospital complications, target lesion revascularization (TLR) rates and long-term outcomes in 88 consecutive patients (91 procedures) who underwent a single-vessel intervention with implantation of > 50 mm of overlapping DES to de novo lesions between October 2002 and October 2007. An additional 14 patients with long segments of in-stent restenosis, 10 receiving both DES and bare-metal stents for long-segment disease and 1 with long-segment disease in a saphenous vein graft were excluded from the study. Baseline clinical data, procedural outcomes and completed follow up were collected prospectively. Results. Follow up was 100% complete up to April 30, 2008. The mean follow up was 26.5 months (6–60 months). The mean stent length was 70.6 mm (51–135 mm) and the average number of stents per vessel was 2.7 (2–5 stents). Acute complications included 1 case of acute stent thrombosis which was treated successfully, 1 case of aortic root dissection, and 1 case of retroperitoneal hemorrhage. The rate of non-Q-wave myocardial infarction (CKMB > 3 times normal) was 8%. During follow up, the rate of TLR was 6.5%. Five patients died, 4 of them due to noncardiac conditions. One death was attributed to possible late stent thrombosis (18 months) occurring suddenly 2 days post keloid repair. Two patients had definite very late stent thrombosis at 14 and 17 months. Conclusion. In our experience, the use of very long segments of DES is effective in treating diffuse de novo coronary artery lesions. However, longer-term follow up is necessary and more data are required to determine the optimum duration of dual antiplatelet therapy.

J INVASIVE CARDIOL 2009;21:46–50

__________________________________________
Randomized trials have demonstrated the ability of drug-eluting stents (DES) to virtually eliminate restenosis in simple de novo coronary lesions, without significant short-term safety concerns.^1–5 As a result, the U.S. Food and Drug Administration approved their use for such lesions in April 2003. As a result of these promising results, DES have been widely used “off-label” in clinical practice, and applied to more complex coronary lesions.^6–9 However, data are lacking on the effectiveness and safety following the implantation of very long segments of overlapping DES, even though such deployment is often required in current PCI practice for the treatment of long segments of disease or for “bailout” treatment of long coronary dissections. The aim of this study was to describe the acute and longer-term outcomes in consecutive patients undergoing implantation of very long DES (> 50 mm) in de novo lesions in native coronary arteries.

Patients and Methods

The patient cohort includes a consecutive series of 88 patients who underwent 91 procedures with implantation of overlapping stents, measuring in total > 50 mm in length in a single vessel between October 2002 and October 2007. Fourteen other patients who were treated for in-stent restenosis (ISR), 10 who received both DES and bare-metal stents (BMS), and 1 patient who received several DES in a saphenous vein graft within the same time frame, were excluded from the study. The indication for the use of very long segments of stents was diffuse disease in de novo coronary arteries. None of the patients in the study had stenting for “bailout dissection”. Baseline clinical and procedural characteristics and clinical outcomes were obtained prospectively, and follow up took place in outpatient clinics or by questionnaire if required. The mortality rate was checked using the national strategic tracing service. The cause of death was confirmed by autopsy or by contacting the deceased’s general practitioner or referring specialist. Patients were followed up until April 30, 2008, with a mean follow up of 26.5 months (range 6–60 months). Follow up was 100% complete. All patients received standard oral antiplatelet treatment. This included oral loading with 300–600 mg aspirin and 300–600 mg clopidogrel and the subsequent long-term administration of aspirin 75 mg/day. Clopidogrel 75 mg/day was continued for at least 12 months. All patients were given 70–100 units/kg of unfractionated heparin at the start of the procedure. Glycoprotein IIb/IIIa inhibitors were not used routinely. Definition of stent thrombosis. The Academic Research Consortium’s (ARC) definition of stent thrombosis was used.10 Stent thrombosis (ST) was classified into definite, probable, or possible, and as early (0–30 days), late (31–360 days) (LST), or very late (> 360 days) (VLST). The definition of definite stent thrombosis required the presence of acute coronary syndrome (ACS) with angiographic or autopsy evidence of thrombus or occlusion. Probable stent thrombosis included unexplained deaths within 30 days after the procedure or acute myocardial infarction (AMI) involving the target vessel territory without angiographic confirmation. Possible stent thrombosis included all unexplained deaths occurring at least 30 days after the procedure. Statistics. Continuous variables are presented as mean ± standard deviation. Categorical data are presented as percentages with absolute numbers.

Results

As shown in Table 1, the mean age of the treated patients was 59.5 ± 10.1 years. The majority of patients (66%) had stable angina pectoris. Thirty-four percent of patients had ACS. Diabetes mellitus was present in 14% of the cohort. The treatment of chronic total occlusion (CTO) constituted 17% of the indication for long/overlapping stents. Abciximab was used in 8 patients (9%). The angiographic and procedural characteristics are shown in Table 2. The mean stent length was 70.6 mm ± 18.5 mm (range: 51–135 mm) and the mean number of stents per vessel was 2.7 stents (range: 2–5 stents). Intervention to the right coronary artery (RCA) accounted for 58% of the cases, 36% involved the left anterior descending (LAD), and only 5% were to the circumflex artery. All procedures were technically successful. The stents used were primarily Cypher™ (Cordis Corp., Miami Lakes, Florida) (61%) and Taxus®/Taxus® Liberté stents (Boston Scientific Corp, Natick, Massachusetts) (38%). One patient received a CoStar™ (Johnson & Johnson) stent in addition to several Cypher stents. In-hospital complications are provided in Table 3. One patient had acute ST at 18 hours following elective PCI to the RCA with implantation of 74 mm of overlapped Cypher stents. There was no evidence of edge dissection, the patient was treated successfully with further balloon dilatation and intracoronary abciximab and discharged home after 48 hours. She remained asymptomatic during follow up. One patient had localized aortic root dissection and 1 experienced retroperitoneal bleeding. Both were successfully managed with conservative treatment. The periprocedural non-Q wave MI rate (CKMB > 3 times the upper limit of normal) was 8%. There were no in-hospital deaths or need for emergency coronary artery bypass graft surgery. Long-term outcomes: Five patients died (Table 3) during follow up. The details are shown in Table 4. One patient died suddenly 2 days after surgical repair of a keloid sternotomy scar 18 months after a total of 59 mm of overlapped Cypher stents had been placed in a large obtuse marginal branch of the circumflex artery. He had stopped clopidogrel at 12 months post PCI and was on aspirin alone. The other 4 died from noncardiac causes. One patient with chronic renal failure died at 9 months following septicaemia with Staphylococcus aureus complicated by multiorgan failure. Another patient died at 12 months due to end-stage decompensated liver failure. A third patient died at 19 months due to aspiration pneumonia confirmed at autopsy, and a fourth patient died of chronic monocytic leukemia at 19 months. Three patients had definite ST (Table 5), 1 early (18 hours) (described above) and 2 VLST. Of the latter, 1 occurred at 14 months and was treated medically and one 17 months after being treated for ISR by 2 additional Cypher stents 7 months after the index PCI. This patient was treated successfully by thrombectomy. ISR causing recurrent angina during follow up occurred in 6 patients (6.5%). The details are shown in Table 6. Five cases occurred in Cypher stents and 1 in Taxus stents. Five patients were treated successfully by PCI and further DES implantation and 1 by balloon angioplasty alone.

Discussion

Early randomized trials of DES included only patients with coronary lesions of modest length, and the stents used were 7,11 A subgroup analysis of 100 patients from the C-SIRIUS trial (lesion length 15–32 mm) found lower rates of ISR compared to BMS12 and a follow up of 96 patients from the RESEARCH registry with a minimum total stent length of 41 mm found DES to be safe and effective for de novo lesions requiring multiple overlapping stents.¹³ The recently reported 2-year follow up of TAXUS VI, which enrolled patients with more complex and longer lesions (mean lesion length: 20.6 mm), found that treatment with the Taxus MR stent was associated with sustained clinical benefits and low rates of target vessel revascularization up to 2 years after device implantation.¹⁴ However, there are still little data on the use of DES in very long segments (> 50 mm) of DES. Our study suggests that the use of long and multiple overlapping DES to treat very long lesions is associated with high procedural success and low complication rates. No cases of intraprocedural ST occurred in contrast to the report by Chieffo et al.¹⁵ However, ST did occur in 3 patients — 1 early and 2 very late, at 14 and 17 months, and 1 patient died suddenly at 18 months shortly after minor surgery on aspirin alone. All of the latter 3 patients had stopped clopidogrel after 12 months. No cases of late ST were seen during dual antiplatelet therapy. One might expect to find an increased incidence of ST in this cohort, as both long stents and overlapping stents have been shown to be independent predictors of early and late ST.¹⁶ If one accepts that the sudden death at 18 months was stent-related, then a VLST rate of 3.4% (3/88) is of concern and requires further study. It is possible that long-term dual antiplatelet therapy beyond the current recommended guidelines of 12 months might result in a lower incidence of ST in this group of patients. This could be the subject of a large randomized clinical trial, and although the DAPT trial (Dual Antiplatelet Therapy Trial) is being planned, it is not specifically for those patients with very long DES segments. This trial will compare outcomes for patients receiving dual antiplatelet therapy for 12 or 30 months, respectively, following DES implantation. Unfortunately, randomization is unlikely to take into account the length of stented segments and the number of overlaps. A large multicenter randomized clinical trial is required to compare long-term outcomes in patients with very long segments of DES (> 50 mm) randomized to receive dual antiplatelet therapy for 12 months or for life with at least 5–10 years of follow up. Intravascular ultrasound was not used routinely in our cases, but it might be useful in such long segments of stenting, especially when one or more overlaps are present, by aiding optimal stent strut deployment.¹⁷ With regard to ISR, which is considered to occur more frequently in long as opposed short stents, its incidence in very long segments of DES (50–135 mm) remains unknown. In our study, 6 patients (6.5%) developed recurrent angina due to ISR between 6 and 38 months after the procedure, and all were successfully treated with further PCI. This may be an underestimate of the incidence, since routine angiography was not performed in our cases and restudy was clinically driven. Moreover, longer-term follow up of our cases (which is ongoing) and of similar, but larger, registry studies will determine whether this incidence will continue to rise. Whether a TLR rate of 6.5% in patients undergoing such long-segment DES implantation would differ from the TLR rate in patients with multiple areas of so-called “spot”-stenting remains unknown and requires a randomized clinical trial to answer the question. Study limitations. Clearly, our study does have limitations. It involves only a small number of patients, follow up is only medium-term and the results are only applicable to de novo lesions in native coronary arteries and not to ISR or vein graft lesions. Moreover, as indicated above, routine follow-up coronary angiography was not performed, and therefore the incidence of ISR could be underestimated. Nevertheless, the study shows that DES implantation in very long segments of disease is safe and complications are few. Concern remains, however, that ISR may continue to appear late after the index procedure and VLST may be more of a problem than in patients with shorter stented segments. Prolonged dual antiplatelet therapy is probably indicated in such cases, but the exact duration of treatment or whether it should be lifelong will need to be determined by a large randomized clinical trial of this specific subset of patients.

References

1. Grube E, Silber S, Hauptman KE, et al. TAXUS I: Six- and twelve-month results from a randomized, double-blind trial on a slow release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38–42. 2. Colombo A, Drzewiecki J, Banning A, et al. TAXUS II Study Group. Randomized study to assess the effectiveness of slow and moderate-release polymer-based paclitaxel-eluting stent for coronary artery lesions. Circulation 2003;108:788–794. 3. Stone GW, Ellis SG, Cox DA, et al. TAXUS IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231. 4. Morice M-C, Serruys PW, Sousa JE, et al. RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780. 5. Moses JW, Leon MB, Popma JJ, et al. SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323. 6. Stone GW, Ellis SG, Cannon L, et al. TAXUS V Investigators. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: A randomized controlled trial. JAMA 2005;294:1215–1223. 7. Dawkins KD, Grube E, Guagliumi G, et al. TAXUS VI Investigators. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: Support for the use of drug-eluting stents in contemporary clinical practice. Circulation 2005;112:3306–3313. 8. Rao SV, Shaw RE, Brindis RG, et al. American College of Cardiology National Cardiovascular Data Registry. On- versus off-label use of drug-eluting coronary stents in clinical practice (report from the American College of Cardiology National Cardiovascular Data Registry [NCDR]). Am J Cardiol 2006;97:1478–1481. 9. Büttner HJ, Neumann FJ. Peeling-off labels: Mounting evidence for benefit of drug-eluting stents with off-label use. J Am Coll Cardiol 2007;50:2037–2038. 10. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020–1029. 11. Marroquin OC, Selzer F, Mulukutla SR, et al. A comparison of bare-metal and drug-eluting stents for off-label indications. N Engl J Med 2008;358:342–352. 12. Schampaert E, Cohen EA, Schlüter M, et al. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110–1115. 13. Degertekin M, Arampatzis CA, Lemos PA, et al. Very long sirolimus-eluting stent implantation for de novo coronary lesions. Am J Cardiol 2004;93:826–829. 14. Grube E, Dawkins KD, Guagliumi G, et al. TAXUS VI 2-year follow-up: Randomized comparison of polymer-based paclitaxel-eluting with bare metal stents for treatment of long, complex lesions. Eur Heart J 2007;28:2578–2582. 15. Chieffo A, Bonizzoni E, Orlic D, et al. Intraprocedural stent thrombosis during implantation of sirolimus-eluting stents. Circulation 2004;109:2732–2736. 16. de la Torre-Hernández JM, Alfonso F, Hernández F, et al. Drug-eluting stent thrombosis: Results from the multicenter Spanish registry ESTROFA (Estudio ESpañol sobre TROmbosis de stents FArmacoactivos). J Am Coll Cardiol 2008;51:986–990. 17. Roy P, Steinberg DH, Sushinsky SJ, et al. The potential clinical utility of intravascular ultrasound guidance in patients undergoing percutaneous coronary intervention with drug-eluting stents. Eur Heart J 2008;29:1851–1857.