Emergent Versus Elective Percutaneous Stent Implantation in the Unprotected Left Main: Long-Term Outcomes from a Single-Center Registry

Abstract: Background. Unprotected left main (ULM) coronary disease is considered by contemporary guidelines a class I indication for surgery. However, percutaneous coronary intervention (PCI) is often carried out in the ULM in either emergent or high-risk elective procedures. The aim of this study was to evaluate ULM-PCI as a feasible and safe procedure in the emergent setting, and to analyze outcomes in both scenarios. Methods. Angiographic and clinical data were collected retrospectively for all patients who underwent emergent or elective PCI on ULM at our center from January 2006 to June 2009. All patients were followed up with a clinical visit or telephone interview. Main outcomes included major adverse cardiac events (MACE) and its individual components: cardiac death, myocardial infarction (MI) and target lesion revascularization. These were analyzed at the longest follow-up available. Results. A total of 98 consecutive patients with significant LM disease were included. Fifty-seven of them were treated as a planned procedure (elective group) and 41 as an emergent procedure (emergent group). Procedural success was achieved in 100% of cases in the elective group and in 88% of the emergent group (p = 0.011). Higher use of drug-eluting stents (DES) was recorded in the elective group (75% versus 45% in the emergent group; p <0.002). The emergent group presented a higher in-hospital mortality (24% versus 2% in the elective group; p <0.001). At a mean follow-up of 626 ± 380 days, the overall MACE rate was similar betweeen the two groups (23% in the emergent group versus 17% in the elective group; p = 0.52). Independent predictors of MACE after discharge follow-up were postprocedure minimal diameter and DES use. Conclusions. Emergent PCI of the ULM exhibits worse in-hospital outcomes as compared to elective procedures. However, after discharge, long-term outcomes remain comparably good between groups.

J INVASIVE CARDIOL 2011;23(10):392–397

Key words: unprotected left main, PCI, emergent procedure
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The optimal revascularization strategy for unprotected left main (ULM) coronary disease is a subject of ongoing debate. According to recent guidelines, coronary artery bypass graft surgery (CABG) remains the gold standard treatment for ULM stenosis.¹ However, in high-risk patients, in the setting of an acute coronary syndrome (ACS), percutaneous coronary intervention (PCI) of the ULM appears to be a reasonable, practical, and widely available treatment option. A complete occlusion of the LM is usually associated with cardiogenic shock. Therefore, it represents a life-threatening condition requiring urgent revascularization, often in conjunction with the use of left ventricular assist devices. A subtotal ULM stenosis may present as unstable angina with subendocardial ischemia and rhythm instability, refractory to medical treatment.² In those emergent scenarios, CABG has not been properly evaluated, as this condition is a frequent exclusion criterion from major clinical trials.³

The aim of our study was to evaluate the outcomes of ULM-PCI in both the emergent setting and the elective scenario and identify the predictors of major adverse events at long-term follow-up.

Patients and Methods

Study population. Between January 2006 and June 2009, all consecutive patients who underwent PCI of the ULM in our center were included. No exclusion criteria were applied. All patients were categorized as elective or emergent according to clinical indication of the PCI. The basis for PCI revascularization in elective patients was in common agreement within the Heart Team, composed of a clinical cardiologist, an interventional cardiologist, and a heart surgeon. All patients presented with suitable anatomy for stenting and contraindication for surgery because of the presence of comorbidity. All PCI performed in patients with ULM and recovery of cardiac arrest, ACS with ST elevation, or ACS with hemodynamic or rhythm instability were considered emergent, whereas the rest were classified as elective procedures.

All clinical and procedural data were retrospectively collected. Patients were followed by telephone or clinical visit; no patient was lost during follow-up.

Procedure. All interventions were performed following standard techniques. PCI strategy, the use of periprocedural glycoprotein IIb/IIIa inhibitors, the route of arterial access, the use of thrombectomy devices, the use of predilation devices, intravascular ultrasound guidance, and prophylactic intra-aortic balloon pump or left ventricular assist device (Impella 2.5 LP) were left to the discretion of the operator. Unfractionated heparin was administered according to body weight in the catheterization laboratory before the procedure. Bare-metal stent (BMS) or drug-eluting stent (DES) use was left to the discretion of the operator. After the procedure, patients underwent dual antiplatelet therapy for a minimum of 1 month to a maximum of 12 months, according to the type of stent implanted (BMS or DES) or clinical indication.

Definitions. ULM was defined as stenosis in the LM in the absence of any patent bypass graft to the left system.⁴Procedural success was defined as LM revascularization with <30% of residual diameter stenosis by quantitative coronary angiography and no major procedural adverse events (death, myocardial infarction [MI], emergent target vessel revascularization [TVR] or acute stent thrombosis).⁵Hemodynamic instability was defined as the presence of hypotension (systolic blood pressure <90 mmHg) associated with signs of global or regional hypoperfusion without meeting all of the criteria for cardiogenic shock. Rhythm instability was defined as the presence of malignant ventricular arrhythmias despite use of anti-arrhythmic agents.

The outcomes of the patients were assessed by measuring the rates of major adverse cardiac events (MACE) as a combination of cardiac death, MI, and TVR, and its individual components. Death was classified as cardiac and non-cardiac. Any death was considered cardiac unless a non-cardiac cause could be adjudicated.

Acute myocardial infarction (AMI) was defined as the appearance of new pathological Q-waves in >2 contiguous ECG leads together with an increase in creatine kinase levels to at least twice the upper normal limit or an increase in troponin levels to at least three times above the upper normal limit. TVR was defined as any revascularization performed on the treated segment.

Stent thrombosis was defined and categorized according to the Academic Research Consortium into early (within 30 days), late (more than 30 days to 1 year after stent implantation), and very late (more than 1 year after stent implantation) and into definitive, probable, and possible.⁶

Cerebrovascular events, including stroke (ischemic or hemorrhagic), transient ischemic attacks, and reversible ischemic neurological deficits, were adjudicated by a neurologist and confirmed by computed tomography scanning.

The Charlson comorbidity index predicts the 10-year mortality for a patient who may have a range of 22 possible comorbid conditions, such as heart disease, AIDS, or cancer. Each condition is assigned a score of 0 to 6 depending on the risk of dying associated with this condition. Then the scores are summed up and given a total score that predicts mortality.⁷

Quantitative coronary angiography analysis. Offline analysis of the stented segment pre- and post-PCI by quantitative coronary angiography (QCA) was performed. Minimal luminal diameter, reference vessel diameter, and percent of stenosis were obtained using a guide catheter as reference. Acute gain has been obtained from a difference between minimal luminal diameter post- and pre-PCI.⁶

Statistical analysis. Continuous variables are presented as mean ± standard deviation and categorical variables as percentages. Continuous variables were compared using independent sample t-test or Mann-Whitney U test where appropriate. Categorical variables were compared with Chi-square or Fischer´s statistics test where appropriate.

Cumulative survivals of composite and individual MACE were illustrated by the Kaplan-Meier method. Event-free survival curves were compared by the log-rank test. A landmark analysis of patients surviving at discharge was performed. Analysis of independent predictors of MACE was performed with a Cox multivariable proportional hazard regression analysis. An exploratory univariate analysis was used to identify variables to be used in the Cox model. Only variables with p <0.2 in the bivariate analyses were entered in the Cox regression model. All variables analyzed were adjusted for possible confounding factors. Proportional hazards assumption was tested exploring the time-dependence of covariates all at once. The results are presented as hazard ratios (HR) with exact 95% confidence intervals (CI) and exact p-values. Statistical significance was accepted for a two-sided value of p <0.05. Analysis was performed with SPSS, version 13 (SPSS Inc.).

Results

Baseline characteristics. During the study period, a total of 156 consecutive patients were treated due to LM disease. Of these, all patients who presented with ULM disease were included in this registry (n = 98; 63%). Fifty-seven patients were considered elective PCI (elective group) while 41 patients were emergently treated (emergent group). Baseline clinical characteristics are summarized in Table 1. Overall, patients presented a high-risk profile: mean age was 69.6 ± 12 years, 39% had diabetes, 25% had renal impairment, and 39% had previous AMI. Patients from the elective group were significantly older and presented with a higher incidence of hypertension, previous AMI, previous PCI, and CABG compared to emergent patients. Conversely, patients from the emergent group had higher Euroscores and obviously higher incidence of ST-elevation MI and recovered cardiac arrest at the time of the index procedure. According to the Charlson comorbidity index, no difference was found between the two groups.⁷ There were 14 patients who presented with cardiogenic shock, 2 (3.5%) of the elective group; and 12 (29%) included in the emergent group (Table 1).

Angiographic and procedural data. Angiographic and procedural data are summarized in Table 2. There was no difference between groups regarding localization of LM disease. In the emergent group, there was a higher use of intra-aortic balloon pump (IABP) and thrombectomy devices during PCI procedures. The Impella 2.5 left ventricular assist device was only used in high-risk elective procedures. In the elective group, there was a higher DES implantation rate and a higher procedural success rate (98.9% versus 89.1%; p = 0.017).

In-hospital clinical outcome. In-hospital clinical outcome is summarized in Table 3. The MACE rate was significantly higher in emergent patients (24% versus 2% in elective patients; p <0.001). During PCI, there was a higher incidence of cardiac death in emergent patients (10% versus 0% in elective patients; p = 0.011) and an overall higher cardiovascular death rate during hospitalization (24% versus 2% in elective patients; p <0.001). No AMI or TVR were recorded during hospitalization. The rate of complete revascularization was similar at the time of discharge between groups.

Long-term clinical outcome. Long-term outcomes are summarized in Table 4. Clinical follow-up was obtained in all patients. Mean follow-up was 626 ± 380 days without differences between groups.

Overall, MACE-free survival was lower in patients with an emergent procedure (p = 0.0006). However, in the landmark analysis from discharge, cumulative incidence of MACE for both groups was not different (p = 0.52) (Figure 1). During follow-up, a total of 11 patients died after discharge: 6 patients (11%) from the elective group and 5 patients (17%) from the emergent group (p = 0.52). Cardiac death accounted for 5 patients (9%) in the elective group and 4 patients (13%) in the emergent group (p = 0.7). Three patients died secondary to a cerebrovascular event (2 of the emergent group) during follow-up. TVR and AMI during follow-up were comparable between groups (6% and 2% in the elective group versus 10% and 3% in the emergent group; p = 0.66 and p = 1, respectively). There was no difference between groups in the rate of stent thrombosis during follow-up.

Predictors of MACE. An exploratory bivariate analysis was performed to identify those clinical and procedural variables associated with MACE (Table 5). Those variables with a p-value <0.2 were entered into the multivariable analysis. This analysis identified the following independent predictors of MACE at long-term follow-up: hypertension (HR, 0.28; 95% CI, 0.80-0.97; p = 0.045), use of DES (HR, 0.1; 95% CI, 0.01-0.30; p <0.001) and post-PCI minimal luminal diameter (HR, 0.22; 95% CI, 0.08-0.59; p = 0.003). Figure 2 shows MACE-free survival of the overall population according to MLD post-PCI index, adjusted for the other two variables.

MACE analysis in the emergent group, according to type of stent implanted. A sub-analysis of MACE was performed within the emergent group according to the type of stent implanted (BMS or DES). Emergent patients who received BMS (n = 24) were admitted to the hospital with a worse clinical condition compared to patients who received DES (n = 17). Killip-Kimball class was worse in patients receiving BMS (50% with a Killip-Kimball class worse than 2 versus 5.3% in patients receiving DES; p = 0.003). The CPK peak value was also higher in patients receiving BMS (3014 ± 3524 versus 760 ± 1469; p = 0.014). In-hospital death rate showed a trend to be higher in patients treated with BMS (7 patients treated with BMS versus 1 treated with DES; p = 0.06). During follow-up, the overall MACE rate was significantly higher in patients receiving BMS (41.2% versus 5.6%; p = 0.018) at the expense of higher incidence of cardiac death (23.5% of patients treated with BMS versus 0% of patients receiving DES; p = 0.04). No significant differences were observed regarding AMI, TVR, or stent thrombosis rates.

Discussion

The main findings of this study include a higher in-hospital MACE rate, mainly attributed to higher cardiovascular mortality, of emergent patients treated by means of PCI for LM disease as compared to those treated electively. For those survivors after hospitalization, long-term (>2 years) outcomes are comparably good between groups.

During recent years, many studies have assessed the outcomes of PCI in the LM, but only a few have reported them in the emergent setting of an ACS.^2,8,9 In our experience, PCI is a feasible and safe therapeutic option for LM disease in an emergent scenario, assuming a lack of other realistic alternatives (i.e., CABG) in “real world” clinical practice. Indeed, short-term outcomes are poorer in the emergent population than those of elective patients. An incidence of 4% of LM disease in patients with ACS has been reported. However, this rate may be an underestimation as many patients may have died before hospital admission.² Revascularization of the LM in the emergent scenario remains a challenge for the interventional cardiologist. CABG is often rejected by the surgeons due to the inherent high risk in this context. Besides, trials comparing PCI versus CABG in LM revascularization have excluded patients admitted to the hospital with ACS.^3,10 For this reason, follow-up of these patients is not well known.¹¹ Montalescot et al showed from an analysis of the GRACE registry that PCI in LM disease patients with ACS has an early hazard: in-hospital mortality rate two- to four-fold higher than the rates usually reported for scheduled PCI on LM.² Palmerini et al, analyzing clinical outcomes from the Gruppo Italiano Studi Emodinamici-Societa Italiana di Cardiologia Invasiva (GISE-SICI), found that patients with ACS have an increased risk of cardiac mortality and myocardial infarction during the first year after PCI compared to stable patients. However, patients with ST-elevation MI and those with cardiogenic shock were excluded from this analysis.¹⁰ Similar findings were observed by Meliga et al in the Drug-Eluting stent for LeFT main (DELFT) registry at 30 days, 1 year and 3 years follow-up, although 19.6% of the entire population was defined as emergent PCI.⁵ There is no current evidence about LMCA PCI in the emergent setting, and current European Society of Cardiology revascularization guidelines do not mention guidance at this point.¹² PCI guidelines should use data from this and other investigators to support a recommendation for PCI of LMCA disease in the setting of STEMI and/or ACS.^13-15 In the recently published COMBAT trial,¹⁶ 600 unprotected LMCA patients were randomized to PCI with sirolimus-eluting stents (300 patients) or to CABG (300 patients). Of them, only 12 (4%) and 19 (6.3%) were defined as unstable angina or recent AMI, respectively, with no definition of the percentage of emergent patients or time from admission to revascularization.

In our report, we found an in-hospital mortality of 24% in patients with emergent ULM PCI compared to 1.8% in patients with elective PCI on LM (p <0.001). This is reasonably explained by the high-risk patient characteristics, given the absence of exclusion criteria in the analysis and thus the inclusion of patients with cardiogenic shock, hemodynamic, and rhythm instability. Moreover, patients included in this analysis reflect an intrinsic higher-risk profile than previous series of ULM stenting: 39% had diabetes, 24% had previous MI, 80% had Euroscore >6, and 58% had unfavorable lesions located at the LM bifurcation. Whether CABG would be a good option in shock patients is still discussed and difficult to evaluate for several reasons.^13-17

ACS secondary to ULM disease accumulates all the risks of the clinical event and revascularization procedure in the first 24 hours. When a patient is admitted to our institution in this scenario, CABG is not scheduled within the first 24 hours. The ULM-CABG procedure is often delayed and performed in lower-risk patients, ruling out those who died from the primary event or developed a contraindication to surgery during the waiting period. Moreover, it is recommended that CABG is scheduled only for patients not requiring immediate revascularization.^18,19

In our analysis, we considered in the emergent group only patients requiring an immediate revascularization so that comparison with LM CABG was impossible. Our results are in agreement with those from the GRACE, GISE-SICI, and DELFT analyses, which also included patients not requiring an immediate revascularization and found an early high-risk mortality of LM patients with ACS on admission.^2,5,9,10,14

Another important finding is that in Cox analysis, independent predictors of death were BMS use and low MLD post-PCI. Indeed, BMS is more often used in emergent scenarios when restenosis is not an issue of concern at the time of PCI; besides, BMS are usually available in larger sizes more suitable for LM disease. Thus, we report the above-mentioned clinical profile resulting in a high mortality rate both at discharge (29.2% versus 5.2%; p = 0.06) and long-term follow-up (23.5% versus 0%; p = 0.04).

On the other hand, MLD post-PCI can well stratify the entire population, according to MACE during the follow-up (Figure 2). The presence of thrombus, hemodynamic instability of the patient, and the adrenergic status may result in underestimation of the ULM.

Conclusions

Recent guidelines have upgraded the indication for ULM-PCI to a class IIb.^12,19 Our registry shows that PCI is a feasible and reasonable therapeautic option for LM disease in an emergent scenario. A less favorable short-term outcome of emergent compared to elective PCI, attributable to ACS in emergent cases, is balanced by a good long-term outcome. However, in a large “real world” population, it has already been shown by the good long-term results observed in emergency patients receiving PCI of LMCA in ACS that this is a reasonable strategy.^20-22 Clinical judgment is the key to decide in which patient with ACS and ULM disease a DES is worth being implanted.

Study limitations. This is a retrospective analysis with all inherent limitations. Our cohort is small and not randomized to draw any conclusions with regard to the potential benefit of one type of stent over the other in emergent cases.

Acknowledgments. We will like to thank Logan J. Kirsch for his valuable comments on this manuscript.

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From the ¹Department of Cardiology, Clinic Thorax Institute, Hospital Clinic de Barcelona, Barcelona, Spain, ²Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands, ³Department of Cardiology, Hospital Vall D´Hebron, Barcelona, Spain, ⁴Department of Cardiology, Hospital del Mar, Barcelona, Spain, ⁵Department of Interventional Cardiology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 25, 2011, provisional acceptance given March 21, 2011, final version accepted August 3, 2011.
Address for correspondence: Manel Sabate, MD, PhD, Department of Cardiology, Clinic Thorax Institute, Hospital Clinic de Barcelona, Villaroel 170, Planta 6 Esc 3, 08036, Barcelona, Spain. Email: masabate@clinic.ub.es