Efficacy of stenting for unprotected left main coronary artery disease in 297 patients

In the 1990s when there were a growing number of patients with coronary artery disease, randomized clinical trials revealed that the therapeutic effect on percutaneous coronary intervention (PCI) was similar to that of coronary artery bypass graft (CABG) in terms of rates of survival and infarct-free survival.¹ Although the early experience of PCI for unprotected left main coronary artery (LMCA) stenosis showed satisfactory short-term technical success rates, follow-up results suggested high rates of restenosis and repeat revascularization, which led to the repulsion for PCI practice from CABG eligible patients, so lesions in the LMCA are considered as a standard indication for surgical revascularization.^2-4 Recently, with the great progress in interventional techniques and device, stent implantation has been more and more chosen to treat LMCA stenosis. Several studies have shown that stenting for unprotected LMCA stenosis may be a more promising alternative method than CABG in selected patients.^5-7 However most of those results were obtained from multi-center register research. The outcomes of LMCA PCI procedure will vary with different PCI technique strategy from different centers. Up to now, no large sample size research on long-term outcomes of unprotected LMCA PCI has been reported from one single center. The aim of our study is to evaluate the safety and the clinical effects of using bare metal stent (BMS) and drug eluting stent (DES) to treat LMCA stenosis by observing 297 consecutive patients with unprotected LMCA PCI in our center which is the largest single-center sample so far to our knowledge.

Study population
From September 1997 to December 2005, a total of 297 consecutive patients with unprotected LMCA stenosis underwent PCI in our hospital. In our center, DES was available in March 2003, since then some patients with LMCA lesion were treated by DES. Total 34 patients in pre-DES “era” (group I, before the end of 2002) were deployed by BMS only. From 2003 to 2004, 176 patients in DES “era” (group II) were performed LMCA PCI procedure, included 63 patients deployed by DES and 113 patients by BMS. Owing to DES diameter more than 4.0 mm was not available in our area until 2005, part of patients who had a large reference vessel of LMCA lesions in our center were deployed the BMS with diameter of larger than 4.0 mm during 2003 to 2004. The target LMCA lesions with the reference diameter from 2.75 mm to 5.0 mm and the diameter stenosis from 75% to 100% were de novo lesions located in ostium, shaft and distal bifurcations. Procedure success was defined as restoration of thrombolysis in myocardial infarction (TIMI) flow grade 3 with ≤20% residual stenosis by visual estimate.

Angiographic analysis and stenting procedure
Coronary angiography was performed in multi-angle projections to achieve baseline angiographic results, so as to avoid the negligence of the severity of lesion stenosis. Severity of coronary stenosis was measured by the quantitative coronary angiography system (QCA system, Siemens, Germany). Vessel diameter was judged according to the known diameter of the angiographic catheter. Baseline percentage stenosis was estimated by one operator visual measurement.

With PCI to treat LMCA, predilation was usually performed before stenting. Kinds of stents were adopted including BMS (2.5－5.0 mm in diameters), sirolimus-eluting stents (2.75－3.5　mm in dia- meters; Cypher, Johnson and Johnson Cordis, USA), and paclitaxel-eluting stents (2.75－5.0 mm in diameters; TAXUS, BSC, USA). For some patients, special PCI techniques were performed, including direct stenting and predilation by cutting balloon or dual wire balloon. Most lesions at the ostium or shaft without involvement of bifurcations were treated with a single stent. Bifurcation lesions located in distal LMCA were frequently treated according to operators' discretion by one of the following stenting strategies: crossover stenting with single stent directly across the ostial lesions of left anterior descending (LAD) artery or left circumflex (LCX) artery, T stenting, provisional T stenting, kissing stenting and stent crushing. After 2003, more patients with bifurcation lesions and multi-vessel lesions were chosen to implant DES in our center. Majority of the patients underwent postdilation with balloons larger than the deployed stents in diameter. Intra-aortic balloon pumping was deployed in emergency cases or in cases prophylactically selected for hemodynamic support. Ninety-five patients underwent intravascular ultrasound detection before and after LMCA PCI procedure. All patients were advised to have lifetime aspirin therapy. Between 1997 and 2001, ticlopidine was administered to patients both 1－2 days before and 2－3 months after the PCI procedure. From 2002, clopidogrel was prescribed as anti-platelet premedication (300－600 mg/d for loading dose) and postmedication (75 mg/d for 6－9 months). ⁸

In-hospital and follow-up events
In-hospital and follow-up major adverse cardiac events (MACE) included cardiac death, Q-wave and non-Q-wave acute myocardial infarction (AMI), the need for target lesion revascularization (TLR) either by urgent CABG or by urgent repeat PCI, and in-stent thrombosis. All deaths were considered cardiac origin unless clinically or autopsically documented non-cardiac death. Binary restenosis was defined as ＞50% lesion stenosis at the LMCA, ostium of LAD or LCX vessel according to the result of follow-up angiography, regardless of clinical symptoms. Myocardial infarction (MI) was defined as creatine kinase rose two times more than the upper limit of normal range with elevated CK-MB fraction. TLR was defined as the revascularization either by CABG or repeat PCI for any in-stent lesion in LMCA or any lesions within 5 mm in bifurcations of ostial LAD or LCX closed to LMCA. All the patients were followed up at regular intervals, and the follow-up information was obtained either by collecting the disease history of the rehospitalized patients or by telephone interviews.

Statistical analysis
After analyzed the total patient data, we further compared the baseline, procedural characteristics and one-year follow-up outcomes of patients in pre-DES “era” (group I, before the end of 2002) with those in DES “era” (group II, from the beginning of 2003 to the end of 2004. Patients in 2005 for the time of follow-up less than one year were not included in this group). Continuous variables were expressed as mean±standard deviation (SD) and analyzed by the Student's t test to assess the differences between the groups. Categorical variables were compared with Chi-square test or Fisher exact test. A P value less than 0.05 was considered statistically significant. All data were analyzed by SPSS 11.0 software.

RESULTS

Baseline clinical and angiographic characteristics
Baseline clinical and angiographic characteristics are presented in Table 1. The 297 patients in our study aged from 22 to 87 years, and most of them were male. Twenty-one (7.1%) patients with acute LMCA occlusion admitted as AMI within 12 hours of symptom onset, and 64 patients (21.5%) developed AMI within 4 weeks. Almost a quarter of patients complicated with congestive heart failure and 4.0% cardiogenic shock. Angiogram showed that 37 patients (12.5%) had LMCA lesion only, and the remainder 260 patients (87.5%) had LMCA complicated with multi-vessel disease. The majority of lesions were located in distal part of LMCA. Of the 206 patients with distal LMCA lesions, 152(51.2%) involved LAD, 26(8.8%) involved LCX, and 28(9.4%) involved both ostia of LAD and LCX simultaneously.

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Table 1. Baseline clinical and angiographic characteristics (n=297)

Stenting procedural characteristics
The total procedure success rate of PCI was 99.3% without death during intervention. As shown in 　Table 2, 71 patients (23.9%) had emergent PCI. Of those who needed special PCI techniques, 16 patients underwent direct stenting, 12 received predilation by cutting balloon and 127 by dual wire balloon (Safecut NM, Neich Medical, China). Bifurcation technique strategy for distal LMCA lesions executed in 206 patients (69.4%, 206/297), including crossover single stent deployment in 156 patients (75.7%), T stenting in 4 patients (1.9%), provisional T stenting in 28 patients (13.6%), kissing stenting in 5 patients (2.4%) and stent crushing for 13 patients (6.3%). A total of 368 stents were successfully implanted in 295 patients, of whom 19 were treated by Cypher stents, 119 by TAXUS stents, and the remainder 157 patients by BMS (53.2%). With DES widely usage, the ratio of DES implanted in LMCA lesions prominently increased in our center. In terms of DES use percentage for total 138 DES implanted patients in our center, 22.1% (21/95) of patients were implanted in 2003, 51.9% (42/81) of patients in 2004 and 86.2% (75/87) of patients in 2005, respectively. Stents were not successfully deployed after balloon predilation in two patients as their ostial origins of LCX were severely tortuous. Because of PCI failure, they thereafter successfully received selective CABG at our hospital.

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Table 2. Procedural characteristics (n=297)

In-hospital events and follow-up outcomes
The outcomes of in-hospital and follow-up were presented in Table 3. During their stay in our hospital, 5 (1.7%) patients who were hospitalized for AMI died of LMCA occlusion after PCI procedure. Two of them had successful stenting procedure but died of incurable cardiogenic shock presented previously admitted to catheter lab, another two developed in-stent subacute thrombosis (SAT) and one presented renal failure after PCI procedure. Taken together, including 2 CABG patients, the total in-hospital MACE was 2.0% (6/297). The rate of clinical follow-up reached 98.3% and mean follow-up period was (728.7±452.7) days for these patients. A total of 19 (6.5%) patients died during the follow-up period. Among the 15 patients (5.1%) who were of cardiac death, 7 died of sudden death, 3 of MI and 5 for their TLR during CABG period. The other 4 patients died of non-cardiac reasons, including cancer, stroke, renal failure and traffic accident, respectively. Besides, 4 patients (1.4%) had non-fatal MI, 2 (0.7%) SAT and 16 (5.4%) TLR, so that MACE in follow-up period was 12.5% (37/297). The total incidence of MACE, including in-hospital and post-hospital was 14.5% (43/297) following PCI for LMCA during nearly two-year follow-up. Angiographic follow-up for 108 patients (36.7%) demonstrated that binary in-segment restenosis occurred in 21 (19.4%) patients. Of them, 15 patients were treated by CABG, and the other 6 patients were deployed by DES at restenosis lesions.

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Table 3. In-hospital and follow-up outcomes (n=297)

Clinical, procedural characteristics and the outcome of one-year follow-up between pre-DES and DES patients
After collected the total patient data, we further analyzed patients who had received one-year follow-up after LMCA PCI procedure. Total 34 patients in pre-DES “era” (group I, before the end of 2002) were deployed BMS only, and 176 patients in DES “era” (group II, from the beginning of 2003 to the end of 2004) were deployed either BMS or DES. Baseline clinical and procedural characteristics and one-year follow-up outcomes of the patients in group I and group II are shown in Table 4. No significant differences were found in clinical characteristics between the two groups. However, in group II, there were more patients with diabetes mellitus, cardiogenic shock and congestive heart failure before PCI. Compared to patients in group I, group II patients apparently had more multi-vessel involvement (14.7% vs 81.9%, P<0.001), more bifurcation lesions (32.4% vs 72.2%, P<0.001), and longer mean lesion length [(18.2±9.2) mm vs (26.5±0.9) mm, P<0.01]. The rate of special PCI techniques, such as crossover stenting, T stenting, provisional T stenting, kissing stenting and stent crushing techniques in group II, were performed much higher than that in group I (57.4% vs 38.2%, P<0.05). In addition, the maximum inflation pressure for group II was larger than that for group I (P<0.01). The success rates of PCI procedure and free-MACE rate in-hospital were significantly higher in group II patients than those in group I (100% vs 94.1%, P<0.05; 98.9% vs 90.6%, P<0.05). One-year follow-up outcomes after PCI demonstrated that the incidences of MACE, TLR and angiographic in-segment restenosis in group II patients were all significantly lower than those in group I (P<0.05).

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Table 4. Clinical, angiographic, procedural characteristics and one-year follow–up outcomes of the patients in pre-DES and DES “era”

DISCUSSION

The first report of PTCA applied to LMCA disease was published by Gruntzig in 1978.⁹ Since then, several studies demonstrated the safety and feasibility of using BMS intervention to treat unprotected LMCA stenosis.^10-12 However, clinical follow-up proved that the therapeutic effects of PCI performed in LMCA were inferior to the ones obtained after PCI in other locations. An analysis of several published studies^5,7,10,13 on elective LMCA interventions by stenting in most of the lesions illustrated that in-hospital cardiac mortality rate for elective procedures ranged from 0 to 4%, but it increased to 13.7% when emergency PCI for AMI patients was included.⁶ In the same studies, the long-term outcome of a follow-up time between 7.3 to 25.5 months presented a cardiac mortality rate from 0.7% to 5.7%, an incidence of MI from 0% to 2.6%, and a need for revascularization from 6.8% to 16.4%. In another study published by Park et al,¹¹ 42 relatively younger patients [mean age (54.3±6.7) years] who underwent the same kind of procedures for treatment, had relatively better left ventricular function with > 40% left ventricular ejection fraction, larger reference vessel diameters [mean (4.0±0.5) mm], and only 21% LMCA stenoses in distal bifurcations. Long-term clinical follow-up to these patients showed that the estimated 3-year total survival rate was 80.7% and the cardiac death-free rate was 85.8%. Therefore, it was suggested that PCI could have favorable clinical efficacy in treating some unprotected LMCA lesions, and it could be an alternative method to replace CABG on the basis of better case selection.

Our study showed that the in-hospital outcome of patients treated by PCI for LMCA lesions was satisfactory. The success rate of PCI procedure was 99.3% without procedural deaths. Only four AMI patients (1.3%) died after PCI procedure because of cardiac events and the incidence of total in-hospital MACE was 2.0%. All patients who accepted selective PCI procedure were alive in hospital. During the long term follow-up period of average 2 years, 15 (5.1%) patients were of cardiac death, and the total MACE was 14.5% (43/297) following PCI procedure for LMCA. Obviously, our study is characterized by a wide spectrum of clinical cases (including congestive heart failure and cardiogenic shock) and a variety of anatomic substrates, and more complicated and challenging lesions, such as bifurcation and multi-vessel lesions, all of which are considered to be potential factors leading to the occurrence of restenosis and even cardiac deaths.^14-17 But the long-term outcomes of clinical and angiographic follow-up for this group of patients seem to be similar to or even better than those reported at home and abroad. ^5-7,18

Although we have achieved good initial results and satisfactory follow-up outcomes after PCI for unprotected LMCA, we do believe that the outcomes will vary with different intervention devices and PCI technique strategy as well as the systemically complicated diseases and lesion characteristics. Compared with the patients in the pre-DES “era”, patients with LMCA disease after beginning of 2003 in this group had more severe complicated diseases (e.g. diabetes mellitus, congestive heart failure and cardiogenic shock), and more multi-vessel and bifurcation lesions. However, the follow-up results demonstrate that the one-year follow-up outcomes in DES “era” are greatly improved with lower restenosis and TLR. The following points may account for the improvement. Firstly, before 2003, the success rates of PCI procedure and free-MACE rate in-hospital were significantly lower than that after 2003, which may be due to the limitation of technique level including indication selection and the application of intervention devices, as we were in learning-curve stage for LMCA PCI at that period. Since 2003, along with the PCI volume was increasing in our center, our experience had enriched and skill had elevated in terms of PCI technique for LMCA lesions. It is generally believed that operators' experience and technique are correlated with the incidence of MACE and restenosis of PCI. To some extent, the more PCI cases the operators perform, the lower incidence of restenosis and MACE will have, which may be associated with the appropriate indication selection and operation techniques. Therefore, when PCI for unprotected LMCA is necessary, it is recommended to be performed by experienced centers and operators.¹⁸ Secondly, because of the efforts of so many doctors in worldwide cardiological field during recent years, PCI strategies for LMCA lesion have been greatly improved, for instance, stenting procedure for bigger lumen diameter through post-dilatation by high pressure, special bifurcation techniques and DES implantation for bifurcation lesions, etc. It is proved that the lumen diameter after PCI is closely related to TLR.¹⁹ Not only a proper choice of a stent with a little bigger diameter is necessary, but also a larger balloon inflated at 1621.1－2026.5 kPa for post-dilatation should be executed. Several studies have proved that DES for LMCA bifurcation lesions is superior to BMS in long-term efficacy.^19-21 This viewpoint was also demonstrated by our data that the rates of restenosis and TLR significantly decreased with the wide use of DES in our center. Finally, some studies have already found that acute thrombosis occlusion after LMCA stenting can lead to in-hospital sudden death.^19,20 Therefore, we always emphasize the antiplatelet therapy during perioperative period, for instance, prescription for a loading dose of clopidogrel at 300－600 mg before the procedure.⁸

Our study is only a retrospective summary for our single-center experience, therefore the results we have got may not be very typically compared with those obtained from a multi-center randomized study. Besides, because of the small sample size of DES usage in group II, we have not carried out the subgroup comparison of long-term efficacy between DES and BMS in LMCA lesions after 2003. More randomized and controlled clinical trials are needed to confirm the long-term effects of DES for LMCA lesions.

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