Outlook of Drug-Eluting Stent Implantation for Unprotected Left Main Disease: Insights on Long-Term Clinical Predictors

Unprotected left main coronary artery (LMCA) is one of the most challenging lesion subsets for interventional cardiologists, and is still considered a strict surgical indication as long-term results of recent randomized trials are awaited.

Although no adequately powered randomized comparisons have yet been completed, many registries have assessed the feasibility and safety of LMCA revascularization with bare-metal stents (BMS),^1–4 particularly in good surgical candidates with a low EuroSCORE (an established means to predict early mortality in patients undergoing cardiac surgery). In-stent restenosis remained, however, a major problem limiting long-term outcomes and freedom from major adverse coronary events (MACE) and mortality.^5,6 Specifically, distal left main lesions involving the bifurcation were associated with the worst outcomes.⁴

Randomized trials and large registries in recent years have showed a substantial reduction in restenosis rates with drugeluting stents (DES) in most lesion subsets. Preliminary reports presented favorable outcomes in terms of morbidity and mortality for unprotected LMCA percutaneous coronary intervention (PCI) with DES, even if limited by heterogeneity of populations, settings and techniques.^7–9

The aim of this prospective study was to assess the safety, feasibility and mid-term outcomes of DES implantation for unprotected LMCA in a high-volume, experienced center according to major baseline and procedural differences, including surgical risk (EuroSCORE).

Methods

Study population. From April 2003 to May 2006, 114 consecutive patients with de novo unprotected LMCA stenosis were treated with DES (both sirolimus- and paclitaxel-eluting stents) implantation at our institution. The inclusion criteria were symptomatic LMCA disease or documented myocardial ischemia and angiographic evidence of ≥ 50% diameter stenosis of the LMCA suitable for stent placement. The LMCA was considered unprotected if there were no patent coronary artery bypass grafts to the left anterior descending (LAD) artery or circumflex artery (CX).

The decision to perform PCI instead of surgery was based on a comprehensive evaluation of several factors including suitable anatomy for stenting, patient’s and physician’s preference for a percutaneous approach and contraindications to surgery because of the presence of major comorbidities.

Procedure. Coronary angioplasty and DES implantation were performed according to current standard techniques. Every lesion at the ostium or shaft without involvement of the bifurcation was treated with a single stent. Bifurcation lesions were treated using one of the following three strategies at the operator’s discretion: provisional T-stenting, V-stenting or Crush-stenting. The use of intravascular ultrasound (IVUS) was at the operator’s discretion, with the aim of achieving optimal stent placement. The debulking procedures (rotational atherectomy) were performed only in a few cases to facilitate stent delivery to the target lesions. Postdilatation withadditional high-pressure balloons (> 14 atm) was at the operator’s discretion in order to achieve optimal stent apposition. An intra-aortic balloon pump (IABP) was used in selected cases for hemodynamic support (e.g., in the case of depressed systolic function).

At the beginning of the procedure, a 100 IU/kg bolus of unfractionated heparin was administered to achieve an activated clotting time > 250 seconds. Glycoprotein IIb/IIIa inhibitors were administered at the operator’s discretion. All patients received aspirin (100 mg/day) indefinitely and if not previously taking clopidogrel, patients were loaded with 300 or 600 mg before or immediately at the end of the procedure, followed by 75 mg/day for at least 9 months.

Serial samples for determination of cardiac biomarkers were routinely collected in all patients 6, 12 and 24 hours after the procedure.

Follow up. All patients were clinically evaluated by follow up visit or telephone interview at 6 months from the index procedure; moreover, since the study period was very long, we performed 12-month follow up in suitable patients and a new follow up was scheduled in patients treated more than 1 year before, at the time of the last patient’s 6-month follow up. Angiographic follow up was performed in 46 patients (40.4%) either at the referring physician’s discretion or when noninvasive evaluation or clinical presentation suggested the presence of ischemia.

Endpoints and definitions. The events analyzed for follow up in this study were death, coronary artery bypass graft surgery (CABG), myocardial infarction (MI), target lesion revascularization (TLR), restenosis and acute, subacute or late stent thrombosis (ST), with the primary endpoint of major adverse cardiovascular events (MACE, i.e., cardiac death, MI or TLR).

Technical success was defined as revascularization in the target lesion with < 30% residual stenosis by visual analysis in the presence of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3. Deaths were classified as either cardiac or non-cardiac. Deaths that could not be classified were considered cardiac-related. Periprocedural MI was defined as a new CK-MB or a troponin I/T rise > 5 times the upper normal limit. Subsequent MI was diagnosed by a rise in the CK level to greater than twice the upper normal limit, with an increased CK-MB fraction. TLR was defined as any revascularization (surgical or percutaneous) performed on the treated segment. Binary restenosis was defined as > 50% luminal narrowing at the segment site (stent and 5 mm proximal and distal, including the ostium of the LAD artery and/or CX artery) demonstrated at the angiographic follow up, regardless of the patient’s clinical symptoms. ST was defined as either TIMI flow grade 0–1, or the presence of flow-limiting thrombus (TIMI flow grade 1–2) occurring in an acute (< 24 hours), subacute (between 24 hours–30 days) and late (> 30 days) period after stent implantation.

The additive European system of cardiac operative risk evaluation (EuroSCORE) was used to stratify the surgical risk of death at 30 days. Patients were scored as high risk in the presence of a EuroSCORE > 6, and as very high risk if the EuroSCORE was > 13.¹⁰ The Mayo Clinic risk score was used to stratify the risk of in-hospital complications (defined as death, Q-wave MI, emergent or urgent CABG or cerobrovascular accident) after PCI. According to this scoring system, patients were stratified as very low risk (0–5), low risk (6–8), moderate risk (9–11), high risk (12–14) and very high risk (≥ 15).¹¹

Statistical analysis. SPSS version 12 software (SPSS Inc., Chicago, Illinois) was used for computations. Continuous data were expressed as mean ± standard deviation and were compared using the Student’s t-test. Categorical variables were expressed as percent (%) and were compared using either chi-squared or Fisher’s exact tests when appropriate, with Bonferroni correction in the case of multiple comparisons. Receiver-operating-characteristic (ROC) curves were analyzed to determine sensitivity and specificity of the EuroSCORE in predicting cardiac or all-cause mortality. The value corresponding to the highest accuracy (i.e., minimal false negative and false positive result) was chosen as the optimal cutoff. The Kaplan-Meier method was used to construct survival curves. The log-rank test was used to compare survival distributions. Comprehensive multivariable logistic regression analyses were conducted for all-cause death, cardiac death and MACE, forcing into the multivariable model all variables significantly (p < 0.05) associated with events at univariate analysis. Results of such logistic regression were presented as odds ratios with a 95% confidence interval and respective p-value. For all tests, a two-tailed p < 0.05 was considered significant.

Results

Patients characteristics. Baseline clinical characteristics are listed in Table 1. Age was 75.2 ± 8.9 years, and 74% of patients were males. The procedure was elective for stable angina in 35 patients (30.7%) and was urgent or emergent in 79 patients (69.3%; 68 patients with unstable angina or non- ST-segment elevation MI, 4 patients with ST-segment elevation MI and 7 patients with MI occurring within < 2 weeks). High surgical risk scores (EuroSCORE > 6) were present in 69 (60.5%) patients.

Angiographic and procedural characteristics. Baseline angiographic and procedural characteristics are shown in Table 2. Thirty-five (30.7%) lesions were located at the ostium of the LMCA, 10 (8.8%) in the mid portion and 69 (60.5%) in the distal portion. Bifurcation lesions were treated in 64 (56.1%) patients.

In-hospital outcomes, clinical and angiographic follow up. In-hospital and clinical events at follow up are shown in Table 3. The technical success rate was 100%. During inhospital stay, there were 4 (3.5%) deaths (Table 4) and no cases of non-fatal MI or emergency CABG. Conversely, increases in CK-MB > 3 but < 5 times the upper normal limit occurred in 5 cases (4.3%).

Clinical follow up was 100% at 6 months over a mean period of 17.1 ± 9.1 months (range 6–38 months). At 6 months, 100% of patients had undergone follow up. In this mid-term follow-up period, we observed 6 (5.2%) deaths, of which 4 (3.5%) were cardiac-related, no cases of non-fatal MI, and 6 (5.2%) TLRs (with PCI in 5 patients and CABG in 1 patient). Late ST occurred in 1 patient (0.9%). The cumulative incidence of MACEs at 6 months was 12.2%.

During the entire follow-up period, there were 9 deaths (7.9%), 4 of which (3.5%) were cardiac-related (Table 4) and there were no non-fatal MIs; 15 patients (13.2%) reported angina and 9 (7.9%) underwent repeat revascularization of the LMCA (7 patients underwent a repeat PCI and 2 patients underwent CABG, 3 and 18 months, respectively, after the index procedure). Eleven patients (9.6%) required a PCI of a non-target vessel during the follow up period. The cumulative incidence of MACE during the follow-up period was 14.9%.

The EuroSCORE was significantly higher among patients with cardiac death, either during the hospital stay or during the follow-up period (23.1 ± 16.5 vs. 8.7 ± 8.1; p < 0.001). A high surgical risk of death (EuroSCORE > 6) was present in all of the patients who died, and in only 61 patients (57.5%) in the survival group (p < 0.001). In particular, the 4 patients who died during their hospital stay, and 3 of the 4 patients who died during follow up, had a very high surgical risk of death (EuroSCORE > 13). Even when all-cause mortalitywas considered, we observed that dying patients were at high risk according to the EuroSCORE system (92.3% vs. 56.4%; p < 0.01; mean 18.3 ± 14.5 vs. 8.6 ± 8.2; p < 0.001). Dying patients did not differ from surviving patients when stratified according to the Mayo Clinic scoring system (10.5 ± 1.4 vs. 10.3 ± 1.9, respectively; p = 0.76). Moreover, 71.4% of patients who experienced a cardiac death were diabetic, whereas only 26.6% of surviving patients where diabetic (p < 0.05).

As expected, patients presenting with an acute coronary syndrome were more likely to experience death (100% of non-surviving patients vs. 67% of survived patients; p < 0.05).

The prevalence of mid or distal LMCA disease was not significantly more common in surviving vs. non-surviving patients (87.5% vs. 67.9; p = 0.2), whereas considering allcause mortality, nonostial disease was more common in dying patients (92.3% vs. 66.3%; p = 0.05). EuroSCORE and admission of unstable coronary disease were not significantly associated with MACEs (p = 0.08 and p = 0.6, respectively). Conversely, most patients with MACE had mid or distal LMCA stenosis (88.2% patients with MACE vs. 66% patients without MACE; p = 0.054). Finally, patients treated with 2 stents had a higher, albeit statistically nonsignificant, rate of MACE in comparison to patients treated with 1 stent (28% vs. 13.6%, respectively; p = 0.1).

Angiographic follow up was performed in 46 (40.4%) patients over a mean of 7.7 ± 4.5 months (range 1–23). Eight (7.0%) cases of in-lesion restenosis were observed. The distribution of restenosis is shown in Table 5.

EuroSCORE and prediction of long-term prognosis. Based on ROC curve analysis, a EuroSCORE with a cutoff of 11 had a sensitivity and specificity of 76.9% and 79.7%, respectively, to predict all-cause mortality (area under the curve 0.812, 95% CI 0.71–0.89). The same cutoff reached 100% and 78.5% of sensitivity and specificity, respectively, to predict cardiac death (area under the curve 0.91, 95% CI 0.82–0.96).

Figure 1 shows cardiac and non-cardiac event rates according to the previously published EuroSCORE cutoff values (Figure 1A), and according to our proposed cutoff (Figure 1B). Kaplan-Meier survival curves demonstrated that patients with a EuroSCORE of 11 had significantly better survival rates than patients with a EuroSCORE > 11 (p < 0.0001) (Figure 2) and significantly lower cardiac mortality (p < 0.0001; Figure 3).

As regards the Mayo Clinic risk score (MS), Kaplan- Meier survival curves demonstrated no significant differences in all-cause mortality (p = 0.2) (Figure 4) and in cardiac mortality (p = 0.9) (Figure 5) between patients at low-to-moderate risk (MS < 12) and those at high risk (MS ≥ 12).

Finally, comprehensive confirmatory multivariable analysis for cardiac events, including in the model all variables significantly (p < 0.05) associated at univariate analysis with adverse events (specifically, acute coronary syndrome on admission, disease location, EuroSCORE and diabetes), showed that the EuroSCORE was the only multivariable predictor of events (odds ratio 1.08 [95% CI 1.01–1.15], p = 0.016 for all-cause death, 1.09 [1.02–1.17], p = 0.010 for cardiac death and 1.08 [1.08–1.15], p = 0.016 for MACE).

Discussion

Despite the fact that CABG is the guideline-recommended treatment for unprotected LMCA disease, the approval of DES and their substantial reduction of restenosis, has increasingly led to their off-label use in this patient population. However, clinical and angiographic outcomes in these patients critically depend on appropriate patient selection, the anatomic location of the LMCA stenosis and on the technical strategy employed. This study, which reports a detailed analysis of long-term predictors of DES implantation for LMCA disease,thus provides important and timely information.

The European system for cardiac operative risk evaluation (EuroSCORE)¹⁰ has been shown to be a valuable measure for the prediction of immediate (30-day) postoperative death in patients undergoing CABG.^12–14 Recent studies have also demonstrated the ability of the EuroSCORE to predict longterm mortality after cardiac surgery.^15–19 This result is justified by the presence, in this risk scoring system, of important variables (i,e., age, extracardiac arteriopathy, renal function and left ventricular ejection fraction [LVEF]) that have been largely shown to be predictors of long-term outcomes in patients with coronary artery disease.¹⁸ In particular, both the additive and logistic EuroSCORE are predictive of 30-day postoperative death and provide a good estimate of late outcomes after CABG.^18,19 Several studies demonstrated that the EuroSCORE is also predictive of percutaneous procedural mortality. In fact, percutaneous procedural mortality approaches 0% in patients at low risk for cardiac surgery.^2,4,5,20 Low-risk patients in the ULTIMA Registry⁴ (age < 65 years, LVEF > 30%, without cardiogenic shock), of whom 76% received stents, had 1-year mortality of 3.4%. Similarly, Takagi et al⁵ found a 3-year cardiac mortality rate of 4.2% in patients with a low surgical risk, and Park et al,²⁰ in a series of 63 consecutive patients with normal LVEF, had no cardiac deaths and a total mortality rate of 3.1% over an average follow-up period of 19.9 months. Conversely, patients who were not good candidates for cardiac surgery showed a cumulative 1-year mortality rate > 20%.^2,4,5 High-risk patients in the ULTIMA Registry⁴ (LVEF ≤ 30%, mitral regurgitation grade 3 or 4, clinical presentation of MI with cardiogenic shock) reached a 1-year mortality rate as high as 78%.

Consistently in our study, patients (n = 61) with a low surgical risk (EuroSCORE ≤ 6) had no cardiac deaths and a total mortality rate of 2.2%. Patients (n = 53) with a high surgical risk (EuroSCORE > 6) had a cardiac mortality rate of 11.6% (the entire patient population cardiac mortality rate was 7%) over an average follow-up period of 17.1 months. Even if the cardiac mortality rate is higher in this subgroup of patients, it is however lower than that observed in the literature,^2,4,5 considering that our high-risk group comprised patients with acute coronary syndrome at presentation (38 patients with NSTE-ACS and 8 patients with MI) and a low LVEF as well. Moreover, our data demonstrated that the EuroSCORE has good specificity and sensitivity to predict cardiac and allcause mortality in patients with LMCA disease. Particularly in patients with a EuroSCORE ≤ 11, PCI for LMCA stenosis appears safe, with low cardiac and overall mortality. Moreover, our data on mortality after PCI agree with the expected surgery mortality rate predicted by the additive EuroSCORE: 2–5% for patients at low-risk and > 10%, respectively, for patients at high-risk.¹⁰

Patient selection according to a percutaneous procedural risk score system is also recommended.²¹ The Mayo Clinic risk score, which is known to be a good predictor for cardiovascular complications following PCI, is one of the most valid examples of such systems.²¹ Actually, in our study, the Mayo Clinic risk score was not able to stratify patients with LMCA disease into different levels of post-PCI procedural complication risk. This score classifies as moderate-risk those patients with LMCA disease in association with multivessel disease and age > 50 years. Its application to our population classified almost all patients (91.2%) as moderate or high risk, and only 8.8% of the patients as low risk. Thus, the Mayo Clinic risk score, in our study, does not seem to be a good predictor of post- PCI procedural complication risk within patients with LMCA disease. This is probably due to the fact that the Mayo Clinic risk score considers only five simple clinical factors (age, congestive heart failure, New York Heart Association functional class ≥ III, urgent/emergent PCI, chronic renal disease, and preprocedural cardiogenic shock), and three angiographic variables (LMCA disease, multivessel disease and presence of thrombus in any lesion),²² without considering the patient’s specific features (diabetes mellitus), cardiac factors (LVEF) and lesion characteristics (presence of calcification) that may affect the outcome, especially in highrisk patients such as those with LMCA or multivessel disease.

Beyond surgical risk status, the location of the lesion within the LMCA is a significant predictor of outcome after PCI. Lesions within the ostium or shaft of the LMCA that can be treated with a single stent provide excellent results at follow up, while distal LMCA stenoses are technically challenging and efficacy is limited largely by TLR, most frequently for restenosis within the branch ostia.^7,23,24 In particular, Valgimigli et al²⁵ found that the long-term outcome of patients undergoing PCI for distal lesions is significantly worse compared with that of patients treated for LMCA lesions not located in the distal portion. Accordingly, in our study, patients with mid or distal LMCA stenosis showed higher mortality and MACE rates in comparison with patients with non-distal LMCA stenosis. Thus, it is clear how important it is to define the exact location and extent of involvement of the distal bifurcation, and furthermore, to evaluate lesion morphology (i.e., presence of calcification), the actual length of the lesion and the size of the LMCA to individually tailor the percutaneous procedure in order to achieve excellent outcomes. Our data regarding patients with shaft LMCA lesions are, on the other hand, in contrast with previously published reports. In our study, in fact, this subset of patients had the same outcome as patients with distal lesions. A potential explanation is the different criteria used to define location and extent of LMCA disease, which can be accurately appraised only by IVUS. Indeed, IVUS should be used, at least in selected patients, to assess the exact lesion length and morphology, to optimize the immediate PCI results^24,26 and to safely perform directional coronary atherectomy in LMCA bifurcation lesions.^26,27

Available data regarding the technique of stent deployment, especially for treatment of distal lesions, have failed to demonstrate significantly different outcomes,²⁸ thus, it is currently impossible to draw conclusions on the most appropriatestenting technique. In most studies, operators used singlestent or multiple stent techniques (i.e., kissing-stent, crushstenting) in response to specific lesion characteristics. In our opinion, and in keeping with the recently reported NORDIC study,²⁹ the best treatment for distal lesions is “provisional” stenting. Published data report a higher rate of TLR and MACE for kissing-stent and crush-stenting techniques.^30,31 Further studies focusing specifically on LMCA are, however, warranted.

Conclusion

Baseline surgical risk and clinical characteristics such as diabetes mellitus are important predictors of poor outcomes after DES PCI, independently of distal LMCA location and the technique used. Our current findings extend the previous knowledge about risk stratification for patients undergoing PCI for LMCA disease, and may help to identify the subset of patients with LMCA in whom percutaneous revascularization is most appropriate and likely to provide good mid- and long-term prognosis.

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