Paclitaxel-eluting stents for the treatment of chronic total coronary occlusions: A strategy of extensive lesion coverage with drug-eluting stents

Gerald S. Werner, MD, Gero Schwarz, MD, Dirk Prochnau, MD, Michael Fritzenwanger, MD, Andreas Krack, MD, Stefan Betge, MD, Hans R. Figulla, MD

Introduction

The rationale to reopen a chronic total coronary occlusion (CTO) is either the relief of clinical symptoms, the improvement of an impaired left ventricular (LV) function [[1][2]], and/or a possible favorable effect on survival [[3]]. However, the percutaneous coronary intervention (PCI) in CTOs is hampered by a higher rate of target vessel failure (TVF) than in nonocclusive lesions with a specifically high incidence of late reocclusions [[4][5]], which adversely influences LV recovery [[1][2]].

The routine use of coronary bare metal stents (BMSs) in CTOs reduced the TVF as compared to balloon angioplasty, but TVF remained higher than in nonocclusive lesions [[6-8]]. Recent studies showed that the major determinants of TVF in CTOs were procedural parameters such as the number of implanted stents and the stented segment length [[9][10]], but the goal to limit the stent length is difficult to meet because of the often diffusely diseased chronically occluded vessel, and dissections occurring during an often complicated course of the recanalization [[11]]. A solution to this dilemma could be the use of drug-eluting stents (DESs) such as the paclitaxel-eluting Taxus stent, which proved highly effective in reducing restenosis in nonocclusive lesions [[12][13]]. Initial registry reports suggest a considerable reduction of TVF by a sirolimus-eluting stent also in CTOs [[14][15]], and we could recently show a similar clinical benefit for a paclitaxel-eluting stent [[16]]. The present study should further evaluate whether the use of this stent would be safe and effective in a real-world cohort of CTOs with unselected lesion lengths and morphologies, and whether the paclitaxel-eluting stent could be reserved to cover the occlusion site in combination with BMS, or whether an extensive use would be more advisable. In view of the already considerable procedural costs of a recanalization [[17]] and the added need for an average of two Taxus stents, the latter issue is of practical relevance.

Materials and methods

Patients

Between February 2003 and August 2004, a recanalization of a CTO of a major coronary branch (diameter > 2.0mm) was attempted in 97 patients, out of whom procedural success was achieved in 82 patients (85%) with crossing of the occlusion and placement of stents. This consecutive cohort of patients was included in this study and treated by implantation of one or more paclitaxel-eluting stents (Taxus; Boston Scientific, Natick, MA) at the occlusion site, and with additional stents to cover additional lesions or dissections occurring as the consequence of the procedure outside of the occlusion site. The selection of stent type (BMS or Taxus stent) for these additional lesions depended on availability and required lesion length. In general, the goal was to use not more than two Taxus stents for economical reasons.

The duration of the occlusion was > 2 weeks (range, 0.5-240 months; mean, 22 ± 45 months; median, 6.5 months). The indication for revascularization was either chest pain or persistent occlusion after a prior myocardial infarction (MI). Patients with an aneurysm distal to the CTO were excluded. Written informed consent was obtained from all patients. All patients were scheduled for angiographic follow-up after 6 months. All patients are followed clinically for at least 6 months and are under continuous biannual clinical follow-up by a phone interview to inquire any additional events after the repeat angiography.

Matched-Pair Analysis

The study group was compared 1:1 to a matched group of 82 patients drawn from 148 consecutive patients with CTO treated between January 1999 and March 2003 by the same interventional cardiologist using bare metal stents [Coroflex, B. Braun (30 patients); Bestent2, Medtronic (24); Jostent, Jomed (18); Express, Boston Scientific (10)]. Matching criteria were lesion location, stent diameter and number of implanted stents, history of diabetes, and prior MI. To eliminate any bias, the matching was done prospectively at the entry of the Taxus patient into the study.

Hybrid Stenting Subgroup

In the Taxus group, 21 patients received one or more BMS in addition to the Taxus stents positioned to cover the occlusion site. Reasons for additional BMS were either short residual lesions at the edge of the Taxus stents or additional lesions or dissections in the target artery. These 21 patients were analyzed separately with their matching 21 BMS control patients regarding the study endpoints.

Angioplasty Procedure

All patients were on aspirin (100 mg) and received clopidogrel (75 mg) for 6 months starting on the day of the procedure in the Taxus group. In the BMS control group, clopidogrel was given for 4 weeks. A femoral approach was chosen with 6 Fr guiding catheters. The lesions were crossed by dedicated guidewires (Cross-it or Pilot wires, Guidant, or PT Graphix, Scimed, Boston Scientific) always supported by an support catheter (Transit, Cordis, Miami, FL, or 0.014 Support catheter, Spectranetics, Colorado Springs, CO) or a low-profile over-the-wire balloon catheter (Bandit or Maverick, Scimed, Boston Scientific). The balloon dilatation was done sequentially with increasing sizes, and the appropriate stent size was selected after i.c. nitroglycerine. The procedural strategy was to cover the occlusion site completely with one or more stents of the available lengths of 18, 24, 28, or 32 mm, without leaving a dissection or a residual stenosis of > 30% in the adjacent segments. In case of multiple stents, overlapping was assured. A balloon-to-artery ratio of 1.1 with inflation pressures of 12-16 atm was used. Creatinine kinase was measured 12-24 hr after the procedure.

Quantitative Coronary Angiography

The length of the occlusion was assessed from the lesion length visible after the first balloon dilatation. The final result of stent implantation [reference diameter, minimum lumen diameter (MLD), residual stenosis, and length of stented segment] was assessed by quantitative angiography using the least foreshortening projection with the smallest MLD (QCA 4.0; PieMedical Imaging, Maastricht, The Netherlands). Quantitative angiography was repeated at follow-up, and a restenosis was defined as an MLD in the recanalized artery of < 50% of the reference diameter both within the stent and in the adjacent segments of 5 mm proximal and distal. The late loss was calculated at the site of the MLD at follow-up. Biplane LV angiograms were obtained in all patients at the time of the baseline diagnostic angiography and repeated at follow-up. The LV function was analyzed using a standard software program (LVA 4.0; PieMedical Imaging).

Study Endpoints

Primary clinical endpoint was the incidence of a major adverse cardiac events (MACE), defined as cardiac death, periprocedural and late myocardial infarction (MI) with a creatinine kinase elevation above two times upper reference limit, and target lesion revascularization (TLR). In addition, the incidence of TVF was analyzed, defined as > 50% diameter stenosis in the target vessel, not restricted to the stent or the stented segment but encompassing the whole recanalized artery.

Statistics

Data are given as mean ± SD or percentage. Group differences of continuous variables were evaluated by a t-test. Group differences of categorical variables were tested by a chi-square test. A logistic regression analysis was done to assess determinants of TVF. A Kaplan-Meier statistics with log-rank comparison was done to assess MACE in the study and matched group. A level of P < 0.05 was considered significant. All calculations were done with SPSS for Windows (version 11.5; SPSS, Chicago, IL).

Results

Clinical and Periprocedural Observations

The Taxus stents were successfully implanted in all CTOs. The clinical characteristics of the 82 Taxus patients and the 82 BMS patie

nts were similar regarding the matching criteria, with one-third having diabetes (Table I). There was a trend toward more male patients, less previous MI, more hypertension, and a higher number of CTOs of more than 3-month duration in the Taxus group. After the procedure, no subacute stent thrombosis occurred, and no clinically evident Q-wave MI, but a periprocedural creatinin kinase elevation was observed after Taxus in 3.3% and after BMS in 1.7% (Table II). One patient with severely impaired LV function in the control group died during hospitalization from sudden death with confirmed stent patency at autopsy.

Table I. Clinical Data*

* Data are mean ± SD or %.

 

Table II. Hierarchical Incidence of MACE During Hospitalization and 12-Month Follow-Up in Patients With Successful Recanalization of a CTO*

* Frequency of events (%) with number of patients in parentheses. Non-Q-wave MI defined by elevation of troponine I or CK within 24 hr of recanalization.
[a] Comparison between the Taxus and control group: P < 0.001.
[b]  Comparison between the Taxus hybrid and control group: P = 0.06.

A follow-up angiography was scheduled in all patients. It was done in all but 2 nonsurviving atients of the control group and 80 of the Taxus group after 5.0 ± 1.5 months. In the latter group, one symptomatically improved patient refused and one patient with severe LV dysfunction had died.

Taxus vs. Hybrid Approach: Angiographic Analysis

The comparison of the anigographic features of the Taxus and hybrid group shows a similar Taxus stent length of 39 and 42 mm, respectively (Table III), requiring an average of 1.5 stents per lesion. In the hybrid group, one additional BMS (average length, 15 mm) was used to cover additional lesions in the target artery. The total stent length of 57 mm exceeded that of the clinically matched hybrid control group with 48 mm stent length. The reference diameters and postprocedural MLD in the Taxus and hybrid group were similar, but the BMS control groups tended to have slightly lower MLDs and a higher residual stenosis (Table III). At follow-up angiography, the diameter stenoses in the Taxus and hybrid group were significantly lower than in their respective control groups, but MLD at follow-up, diameter restenosis (Fig. 1), and late loss (Fig. 2) were higher in the hybrid group than in the Taxus group.

Table III. Quantitative Angiographic In-Segment Analysis After Recanalization and at Follow-Up

[a] Comparison between the Taxus and control group: P < 0.001
[b] Comparison between the Taxus hybrid and control group: P < 0.01.
[c] P < 0.05.

Taxus vs. Hybrid Approach: Clinical Analysis

The incidence of late reocclusion in the Taxus group was significantly reduced to 1.7% (one patient) as compared to 21.7% in the BMS group (P < 0.001), and the overall TVF was reduced to 11.7% as compared to 55.0% (P < 0.001). The MACE rate at 6 month was 13.3% in the Taxus group as compared to 56.7% in the BMS group (Table II). There were one sudden death in the BMS group. There was no Q-wave MI observed even in patients with reocclusion. In the hybrid group, the clinical events were significantly reduced as compared to the respective BMS control; however, the TLR and binary restenosis were more than double of that of the Taxus-only group. The MACE rate in the hybrid group was almost triple of that of the Taxus group (Fig. 3).

Determinants of Lesion Recurrence in Taxus and BMS Group

The binary logistic regression analysis in the BMS group showed that diabetes (chi-square = 7.7; P = 0.006), the stent length (chi-square = 5.9; P = 0.015), and stent number (chi-square = 5.3; P = 0.021) were significant determinants of TVF, while the duration of occlusion and diameter stenosis were not independent factors. In contrast, in the Taxus group, neither diabetes (chi-square = 1.8; P = 0.18) nor stent length (chi-square = 0.4; P = 0.5) had a significant influence on TVF. However, taking all 81 patients treated with a Taxus stent together, the hybrid approach was the single significant predictor of TVF (chi-square = 7.0; P = 0.008).

The nonocclusive restenosis in the Taxus group were all focal and located adjacent to the proximal or distal edge of the stented segment (Fig. 4). In the BMS group, 69% of restenotic lesions were focal, and 31% had a diffuse restenosis pattern. In the hybrid group, all recurrences were located within the additional BMS stent. All reinterventions in the Taxus and Taxus hybrid groups were done with additional implantation of a Taxus stent to cover the restenotic site (Fig. 5). All patients were reexamined angiographically and had shown an excellent secondary patency without recurrent restenosis except for one patient, who had developed a de novo lesion in the target artery, again treated by a Taxus stent. Thus, the secondary long-term patency free of restenosis or reocclusion was 98.3%. Of the 70 patients from the Taxus and hybrid group without restenosis, 7 underwent a second follow-up angiography (11 ± 3 months after the recanalization) because of uncharacteristic chest symptoms. None of these patients showed a lesion progression at the site of the Taxus stents.

Discussion

Paclitaxel-Eluting Stents for CTOs

The present study showed a considerable reduction of restenosis and reocclusion after recanalization of a CTO with implantation of the paclitaxel-eluting Taxus stent. TVF was reduced by about 80% as compared to a matched control group treated with BMS, and the specific problem of reocclusion was almost eliminated without an increased risk of subacute stent thrombosis.

The clinical efficacy of paclitaxel to reduce neointimal hyperplasia after stent implantation had been shown in studies of type A and B coronary lesions [[12][13]]. The initial application in high-risk lesions of in-stent restenosis was hampered by a higher rate of lesion recurrence than that reported in the former studies [[18]]. However, the detailed analysis of lesions with failed paclitaxel-eluting stent effect had indicated that a full coverage of the dilated lesion and the avoidance of gaps in case of multiple stent implantation might be important to avoid a treatment failure.

We had applied these initial lessons learned from negative experiences in a real-world cohort of consecutive patients with complex type C coronary lesions of CTOs, with no lesion-related exclusion criteria. The Taxus group showed an improved MACE-free survival compared to BMS mainly due to a reduced TLR without an increase of periprocedural enzyme elevation or subacute stent thrombosis. The control group was taken from a similar cohort of the previous time period, also without exclusion criteria regarding the lesion length. In contrast, previous randomized studies of BMS in CTOs excluded more than 50% of the screened patients, which might have contributed to a lower TVF than that observed in our BMS group [[6][7]]. But the TVF in our BMS group was comparable to the largest randomized study with less restrictive inclusion criteria [[8]].

The quantitative angiographic parameters in the Taxus group at follow-up showed a late loss in the range of that reported in nonocclusive lesions [[13]]. The rare incidences of focal restenosis at the edges of the stented segment indicate that in these often diffusely diseased arteries, a wider overlap of the drug-eluting stent into the segment adjacent to the original occlusion might be needed.

Rationale for Hybrid Stenting in CTOs

In this real-life cohort of CTOs, the need of long and often several stents to cover the occlusion site is evident. This is encouraged by the absence of a negative effect of stent length on restenosis for the Taxus stent, in contrast to BMS [[9][10]]. Therefore, the solution to overcome the high recurrence rate with BMS in long lesions by focal stenting is now overcome by the effectiveness of DESs [[19]] and the strategy of extensive coverage to avoid edge effects [[20]].

On the other hand, the already higher procedural costs for the PCI of a CTO due to dedicated wires or devices [[21][22]] will further increase by the need for two or three DESs per lesion. These costs are usually not compensated for by reimbursement, and alternative strategies may be explored. One such strategy was recently suggested as a hybrid stenting approach combining DES for the high-risk lesion and BMS for lower-risk lesions [[23]].

In our experience, the limitation of the Taxus stents to the occlusion site and the use of a BMS for remote lesions within the target artery to cover distal dissections or additional distal lesions resulted in a considerably higher TVF and MACE rate as compared to the group with exclusive Taxus stent use. Even though the recurrence rates were still lower as in the matched BMS control group, the higher need for reintervention, specifically the risk of reocclusion, makes this approach not cost-effective.

Study Limitations

Studies in CTOs often contain a limited number of patients because CTOs constitute about 10% of all patients undergoing a PCI. However, the high recurrence rate with BMS provides the statistical power to detect the beneficial effect of the Taxus stent in this study. The comparison with a matched control group is statistically less convincing than a double-blind randomized approach, but precautions were taken to avoid any bias in the matching process, which was done at the time of the procedure, and not at follow-up. Bias was further reduced by using a standardized approach during recanalization, and recruitment of all consecutive patients with a CTO treated in one institution by one experienced investigator.

The angiographic follow-up was timed earlier than in the DES studies for nonocclusive lesions [[12][13]]. This was based on the experience with BMS, where reocclusions occurred frequently, and the earlier follow-up should identify patients at risk for reocclusion. Our preliminary experience in 10% of patients without restenosis undergoing an additional angiography, and the repeat angiography in those treated for focal restenosis, showed no evidence of a late catch-up within the initial Taxus stents.

Clinical Implications

The absolute risk reduction of TVF in CTOs by the Taxus stent is higher than that reported in low-risk nonocclusive lesions or even the more complex lesions included in the recent Taxus VI study (presented at EuroPCR 2004). Our experience and the present analysis strongly support a strategy of more extensive stenting to cover all adjacent lesions with the drug-eluting stent, as there is no adverse influence of stent length on TVF. On the other hand, the combination of the Taxus stent with BMS to cover distal lesions in the recanalized artery should be avoided as this increases the risk of restenosis and reocclusion.

References

1. Sirnes PA, Myreng Y, Molstad P, Bonarjee V, Golf S. Improvement of left ventricular ejection fraction and wall motion after successful recanalization of chronic coronary occlusions. Eur Heart J 1998; 19: 273-281.
2. Engelstein E, Terres W, Hofmann D, Hansen L, Hamm CW. Improved global and regional left ventricular function after angioplasty for chronic coronary occlusion. Clin Invest 1994; 72: 442-447.
3. Suero JA, Marso SP, Jones PG, Laster SB, Huber KC, Giorgi LV, Johnson WL, Rutherford BD. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience. J Am Coll Cardiol 2001; 38: 409-414.
4. Ellis SG, Shaw RE, Gershony G, Thomas R, Roubin GS, Douglas JS Jr, Topol EJ, Startzer SH, Myler RK, King SB, 3rd. Risk factors, time course and treatment effect for restenosis after successful percutaneous transluminal coronary angioplasty of chronic total occlusion. Am J Cardiol 1989; 63: 897-901.
5. Violaris AG, Melkert R, Serruys PW. Long-term luminal renarrowing after successful elective coronary angioplasty of total occlusions: a quantitative angiographic analysis. Circulation 1995; 91: 2140-2150.
6. Sirnes PA, Golf S, Myreng Y, Molstad P, Emanuelsson H, Albertsson P, Brekke M, Mangschau A, Endresen K, Kjekshus J. Stenting in chronic coronary occlusion (SICCO): a randomized, controlled trial of adding stent implantation after successful angioplasty. J Am Coll Cardiol 1996; 28: 1444-1451.
7. Rubartelli P, Niccoli L, Verna E, Giachero C, Zimarino M, Fontanelli A, Vassanelli C, Campolo L, Martuscelli E, Tommasini G. Stent implantation versus balloon angioplasty in chronic coronary occlusions: results from the GISSOC trial (Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche). J Am Coll Cardiol 1998; 32: 90-96.
8. Buller CE, Dzavik V, Carere RG, Mancini GB, Barbeau G, Lazzam C, Anderson TJ, Knudtson ML, Marquis JF, Suzuki T, Cohen EA, Fox RS, Teo KK. Primary stenting versus balloon angioplasty in occluded coronary arteries: the total occlusion study of Canada (TOSCA). Circulation 1999; 100: 236-242.
9. Sallam M, Spanos V, Briguori C, Di Mario C, Tzifos V, Dharmadhikari A, Albiero R, Colombo A. Predictors of reocclusion after successful recanalization of chronic total occlusion. J Invas Cardiol 2001; 13: 511-515.
10. Werner GS, Bahrmann P, Mutschke O, Emig U, Betge S, Ferrari M, Figulla HR. Determinants of target vessel failure in chronic total coronary occlusions after stent implantation: the influence of collateral function and coronary hemodynamics. J Am Coll Cardiol 2003; 44: 219-225.
11. Werner GS, Diedrich J, Scholz KH, Knies A, Kreuzer H. Vessel reconstruction in total coronary occlusions with a long subintimal wire pathway: use of multiple stents under guidance of intravascular ultrasound. Cathet Cardiovasc Diagn 1997; 40: 46-51.
12. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, Guagliumi G, Russell ME. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003; 108: 788-794.
13. Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004; 350: 221-231.
14. Hoye A, Tanabe K, Lemos PA, Aoki J, Saia F, Arampatzis C, Degertekin M, Hofma SH, Sianos G, McFadden E, van der Giessen WJ, Smits PC, de Feyter PJ, van Domburg RT, Serruys PW. Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions. J Am Coll Cardiol 2004; 43: 1954-1958.
15. Nakamura S, Muthusamy TS, Bae JH, Cahyadi YH, Udayachalerm W, Tresukosol D. Impact of sirolimus-eluting stent on the outcome of patients with chronic total occlusions. Am J Cardiol 2005; 95: 161-166.
16. Werner GS, Krack A, Schwarz G, Prochnau D, Betge S, Figulla HR. Prevention of lesion recurrence in chronic total coronary occlusions by paclitaxel-eluting stents. J Am Coll Cardiol 2004; 44: 2301-2306.
17. Bell MR, Berger PB, Menke KK, Holmes DR Jr. Balloon angioplasty of chronic total coronary artery occlusions: what does it cost in radiation exposure, time, and materials? Cathet Cardiovasc Diagn 1992; 25: 10-15.
18. Tanabe K, Serruys PW, Grube E, Smits PC, Selbach G, van der Giessen WJ, Staberock M, de Feyter P, Muller R, Regar E, Degertekin M, Ligthart JM, Disco C, Backx B, Russell ME. Taxus III trial: in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation. Circulation 2003; 107: 559-564.
19. Colombo A, De Gregorio J, Moussa I, Kobayashi Y, Karvouni E, Di Mario C, Albiero R, Finci L, Moses J. Intravascular ultrasound-guided percutaneous transluminal coronary angioplasty with provisional spot stenting for treatment of long coronary lesions. J Am Coll Cardiol 2001; 38: 1427-1433.
20. Chieffo A, Tsagalou E, Iakovou I, Melzi G, Airoldi F, Vitrella G, Carlino M, Corvaja N, Ferraro M, Colombo A. Full metal jacket with drug-eluting stents in left anterior descending artery. Am J Cardiol 2004; 94: 221E.
21. Segev A, Strauss BH. Novel approaches for the treatment of chronic total coronary occlusions. J Interv Cardiol 2004; 17: 411-416.
22. Baim DS, Braden G, Heuser R, Popma JJ, Cutlip DE, Massaro JM, Marulkar S, Arvay LJ, Kuntz RE. Utility of the Safe-Cross-guided radiofrequency total occlusion crossing system in chronic coronary total occlusions: results from the Guided Radio Frequency Energy Ablation of Total Occlusions Registry Study. Am J Cardiol 2004; 94: 853-858.
23. Salwan R, Singhania D, Agarwal P, Chandra P, Mathur A, Bhandari S, Kler TS, Seth A. Hybrid stenting vs drug-eluting stents for multivessel angioplasty. Eur Heart J 2004; 25( Suppl): 314.