Sirolimus-Eluting Stent Treatment for Complex Proximal Left Anterior Descending Artery Stenoses: 7-Month Clinical and Angiograph

Proximal left anterior descending artery (LAD) stenoses are considered to have special prognostic implications.¹ Medically treated patients with isolated proximal LAD stenosis have a significantly worse prognosis than patients with lesions in other locations.² Stenting is an accepted treatment with excellent short-term results, yet previous studies have shown that proximal LAD stenoses per se have higher rates of restenosis than stenoses in other coronary segments after angioplasty,³ as well as after stenting.^4,5 Bypass surgery utilizing the internal mammary artery is superior with regard to the need for target vessel revascularization (TVR) and freedom from angina in isolated proximal LAD stenoses,⁶ as well as multivessel disease with significant involvement of the proximal LAD.⁷ This is particularly true for complex stenoses of the proximal LAD, where stenting is usually ineffective due to an unacceptably high restenosis rate.⁶ Therefore, high-grade involvement of the proximal LAD, either in isolation or as part of multivessel coronary artery disease, remains a frequent indication for surgical revascularization. The sirolimus-eluting stent (SES) has substantially reduced the rates of clinical and angiographic restenosis in randomized trials^8,9 as well as in clinical registries.^10,11 These effects were also observed among the LAD subgroups studied in the SIRIUS Trial and the RESEARCH Registry.^9,11 It still remains unclear, however, whether these favorable results apply to LAD stenoses among high-risk patients with complex lesion morphologies, a subset that has not yet been adequately studied. Methods Design and population. The study population was a defined subgroup of patients with significant proximal LAD stenoses and one or more additional risk factors for restenosis. These risk factors were diabetes mellitus, long lesions (greater than or equal to 20 mm), and bifurcated lesions requiring double guidewires (Types 1A, 2A, 3A and 1B), ostial lesions, chronic total occlusions, heavily calcified lesions and in-stent restenosis. Lesions were considered significant when they had greater than or equal to 50% DS angiographically and an objective evidence of ischemia and/or typical anginal symptoms. All lesions greater than or equal to 70% were considered significant. This was also true for non-LAD lesions in multivessel coronary artery disease (CAD) with significant involvement of the proximal LAD. Between November 2002 and January 2004, 80 consecutive patients fulfilling these criteria were enrolled in this open-cohort, single-center study. All patients were treated by one or more Cypher^™ sirolimus-eluting stent (Cordis Corporation, Johnson & Johnson, Miami, Florida) for the proximal LAD. Proximal LAD stenosis was defined according to segment 6 of the American Heart Association/American College of Cardiology (AHA/ACC) classification of coronary artery segments.¹² Long lesions starting within and extending beyond the mentioned segment were also included in the study. The patients were adequately informed of the alternative surgical treatment and written, informed consent was obtained from them. SES procedures and concomitant medications. Stenting was performed either directly or after lesion preparation to facilitate stent deployment according to the operator’s discretion. For the 80 proximal LAD stenoses, a total of 89 Cypher stents were used. The stent length was chosen so as to cover the whole lesion, especially the proximal and distal edges. In cases where multiple stents were placed, adequate overlapping was done. Angiographic success was defined as residual stenosis 36 mm, who had chronic total occlusions or bifurcated lesions for 6 months. Quantitative coronary angiography. Baseline, postintervention and 7-month off-line QCA were performed by a single, blinded, trained physician using the Cardiovascular Measurement System (Medis, Medical Imaging System). Optimal views of the lesion were obtained at baseline and the same projections were performed at 7-month follow-up. At all occasions angiograms were performed after administration of 100–200 mcg of intracoronary nitroglycerine. The analysis segment included the stent and 5 mm at either end. In bifurcated lesions, QCA was done only for side branches greater than or equal to 2.0 mm in diameter. Manual editing was required in most cases to avoid oversizing of the proximal reference diameter for side branches. The minimal lumen diameter (MLD) was determined by edge detection, while the reference lumen diameter (RLD) was automatically calculated by the interpolation method. The percent diameter stenosis (% DS) was calculated from the MLD and the RLD. Acute gain (in millimeters) was defined as the increase in MLD immediately after intervention, while late loss was defined as the decrease in MLD at follow-up compared to postintervention. The late loss index was calculated by dividing late loss according to acute gain. Restenosis was defined as a stenosis of more than 50% luminal diameter in the analysis segment at follow-up. Procedural success and in-hospital events. Procedural success was defined as an angiographically successful procedure without major adverse cardiac events (MACE) until hospital discharge. MACE included postprocedural Q-wave or non-Q-wave myocardial infarction (MI) defined as the development of new Q-waves (> 0.4 seconds) in the ECG and/or an elevation of cardiac enzymes to greater than twice normal, respectively (an ECG and CK-MB were measured at 6 and 12 hours postprocedure in all patients; death (any cause) or TLR, whether by redo-PCI or coronary artery bypass surgery. TLR was defined as a repeat intervention to treat a stenosis within the analysis segment which included the stent and 5 mm proximal and distal to it. Stent thrombosis was angiographically documented as a complete occlusion (TIMI flow 0) or a flow-limiting thrombus (TIMI flow 1 or 2) of a previously successfully treated artery. Non-TVR procedures in multivessel interventions and cerebrovascular accidents (CVA) were also documented. Late follow-up. Late follow-up was done clinically both by personal visit or telephone for MACE and for freedom from angina as evaluated by the Canadian Cardiovascular Society Classification (CCS).¹³ Non-TVR procedures and CVAs were also documented. Angiographic follow-up for late lumen loss and binary restenosis in the analysis segment was done by QCA. Follow-up was planned at 7 months unless patients had recurrent symptoms or an event requiring earlier angiography. Statistical analysis. All data analyses were performed with the Statistical Package for Social Sciences (SPSS for Windows 11.0, SPSS Inc.) software. Data are expressed as mean ± standard deviation (SD). Categorical variables are expressed as percentages to describe the patient population. P-values Patient and lesion characteristics. Clinical and lesion characteristics are shown in Tables 1 and 2, respectively. Acute coronary syndromes were the presentation in 40% of the cases. A total of 21.3% of all patients were diabetic, 52.5% had Type-B2 and 37.5 % had Type-C lesions. A total of 37.6% patients had single-vessel disease, 27.5% had double-vessel disease and 35% had triple-vessel disease. In 55% of all patients, however, the proximal LAD was the only lesion treated according to the intention-to-treat of the operator, while in 23.7% of the cases, 2 vessels were treated, and in 21.2%, all 3 vessels were treated. Of the 49 non-LAD lesions treated, 29 (59.1%) were treated with Cypher stents. The remaining lesions were treated with bare metal stents. Procedural characteristics. Due to lesion complexity, balloon predilatation was performed in almost half of the cases to facilitate stent deployment; rotational atherectomy was performed in 1 case with a heavily calcified lesion. Postdilatation using a high-pressure balloon was applied in 36.2% of cases. The mean stent inflation pressure was 15.8 atm. In bifurcated lesions with a side branch greater than or equal to 2.0 mm (15.0%), PTCA alone for the side branch was performed in 9 patients, and double stenting in 3 patients (2 using the crush technique and 1 using the modified T-technique). Procedural characteristics are shown in Table 3. Procedural success and in-hospital MACE. Angiographic success was achieved in 98.6% of all cases. Procedural success, however, was achieved in 96.0% of cases. The acute gain was 1.49 ± 0.067 mm. None of the patients died during primary hospitalization, 2 patients (2.5%) developed a non-Q-wave MI and 1 of them was subjected to a repeat percutaneous coronary intervention (PCI) due to TIMI 1 flow in a compromised first diagonal branch; the flow was re-established by dilatation only (Late follow-up and MACE. All patients (100%) underwent clinical and angiographic follow-up at long term. The mean follow-up period was 218 days. Clinical follow-up results are shown in Table 4. At 7 months, none of the patients died and none developed a new MI. Repeat PCI for TLR was performed in 5 patients (6.3%) due to clinical restenosis in 4 of them, and late stent thrombosis in 1 case. The combined MACE rate was 6.3% in the long term. One patient underwent elective CABG, and 4 patients underwent repeat PCI for non-LAD clinical restenoses (non-TVR rate = 6.3%). At follow-up, 81.3% of patients were angina-free in their daily activities. None of the patients developed a CVA. Late lumen loss and angiographic restenosis. Late lumen loss at follow up was 0.19 ± 0.069 mm. The late loss index was 3.3%. Binary restenosis was angiographically detected in 6 patients (7.5%). The QCA results at baseline and at follow-up are presented in Table 5 and Figure 1. Predictors, site and pattern of restenosis. Due to the limited event numbers, no logistic regression analysis was done, yet 4 of the 6 patients with restenosis were diabetic, and all had type-B2 or C lesions. Two were bifurcated lesions treated with PTCA only of the side branch. These 2 patients were symptom-free and were not subjected to a repeat procedure. Furthermore, 1 patient subjected to TLR was initially treated for an ostial lesion, and 2 had long lesions, with 1 patient found to have a total stent length of 61.0 mm. Three restenoses occurred within the proximal 5 mm segment to the stent, one of which was a total occlusion. In 3 patients, the restenosis was focal (8,9 as well as in the everyday practice according to initial registry results.^10,11 However, some special settings have not been addressed in the randomized studies conducted to date, and therefore represent a gap between coronary artery bypass graft surgery (CABG) and PCI. One of these indications is the complex proximal LAD stenosis, still a frequent indication for surgical revascularization. The available body of evidence includes the LAD subgroup of the SIRIUS Trial⁹ where the majority of lesions were tubular type-B lesions; ostial, bifurcated, thrombotic and heavily calcified lesions were excluded, which makes the cohort different from that encountered in daily practice and in our present analysis. Also, the RESEARCH Registry,¹¹ which did not analyze the proximal LAD separately and enrolled all patients consecutively, included both complex and noncomplex patients in its LAD subgroup. In our study, all patients were treated for proximal LAD stenoses and all had, in addition, at least one additional known risk factor for restenosis, rendering the cohort at high risk for restenosis. Recent data have shown that SES treatment for isolated proximal LAD stenoses (n = 249) is not associated with a higher rate of TVR at 6 months as compared to proximal left circumflex or right coronary artery stenoses (n = 100) (4.8% versus 6.5%, respectively; p = 0.58).¹⁴ In the present study, we examined a complex subgroup of patients with proximal LAD stenoses treated with SES. Despite the multiplicity of risk factors of restenosis among our study population, TLR rate was 6.3%, which is very comparable with the 4.8% TVR rate cited in previous work among proximal LAD patient groups.¹⁴ Furthermore, it is also comparable to the 5.1% TLR rate among the LAD subgroup of SIRIUS at 9 months⁹ and the 5.1% TVR rate in the RESEARCH Registry at 1 year.¹¹ Angiographically, the late loss in our present study was 0.19 mm in the analyzed segment, which is also similar to the late loss in the SIRIUS proximal LAD subgroup, where it was 0.20 mm in-stent and 0.17 mm in-segment in the sirolimus group (n = 40), and 1.02 mm in-stent and 0.79 mm in-segment in the bare metal stent group (n = 47) (p 9 Our restenosis rate was 7.5 % in the analysis segment, while that in SIRIUS (n = 1058) was 3.2% in-stent and 8.9% in-segment for the sirolimus group, compared to 35.4% in-stent and 36.3% in-segment for the control group (p 9 Regarding data from the pre-DES era, Diegeler and colleagues,⁶ who compared stenting with minimally invasive CABG for stenoses of the isolated proximal LAD, showed a reduction of the MLD from 3.13 ± 1.49 mm postintervention to 1.70 ± 0.87 mm at 6 months in the stent group. Furthermore, the restenosis rate was 56.0% among the type-C lesion subgroup of their stent group, results which are no longer seen with DES. Of note, the restenosis rate in the surgically treated group of Diegeler and coworkers was 5.0%. When re-examining the index procedures of the 3 patients who developed proximal edge restenosis, we believe that the lesions were not adequately covered proximally by SES. Moreover, in the patient who developed late stent thrombosis, it became obvious retrospectively that the stent was malapposed. Although our cohort is nonhomogenous, including both single-vessel and multivessel CAD patients, this shows nonetheless that these results are applicable to significant proximal LAD stenoses, both when isolated, or as part of multivessel CAD. Our present study encompasses a large angiographic cohort of patients with complex proximal LAD lesions treated with SES. It seems to hold true that SES abolishes the higher restenosis rates in the proximal LAD noted previously with bare metal stents as compared to other vessel territories. This could be of significant impact when choosing the appropriate revascularization strategy for patients with significant proximal LAD stenoses, either in isolation, or as part of multivessel CAD. Despite the fact that we cannot recommend a specific initial strategy to deal with special types of lesions, e.g., bifurcated lesions — as this was beyond the scope of this analysis — we can, however, state that SES, once successfully implanted in complex proximal LAD stenoses, appear effective in the long term. Acknowledgment. This study was supported by an educational grant from Cordis Corporation (Johnson & Johnson), Germany. Special thanks to Mrs. Daniela Schuermann-Kuchenbrandt (study nurse) and Mr. Guido Kassner (chief technician) and to all participating patients.

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