Author + information
- Received May 26, 2009
- Revision received June 3, 2009
- Accepted June 8, 2009
- Published online August 1, 2009.
- Davide Capodanno, MD⁎,‡,⁎ (, )
- Piera Capranzano, MD⁎,‡,
- Maria Elena Di Salvo, MD⁎,
- Anna Caggegi, MD⁎,
- Davide Tomasello, MD⁎,‡,
- Glauco Cincotta, MD⁎,
- Marco Miano, MD⁎,
- Martina Patané, MD⁎,
- Claudia Tamburino, MD⁎,
- Salvatore Tolaro, MD§,
- Leonardo Patané, MD∥,
- Antonio Maria Calafiore, MD† and
- Corrado Tamburino, MD⁎,‡
- ↵⁎Reprint requests and correspondence:
Dr. Davide Capodanno, Department of Cardiology, Ferrarotto Hospital, University of Catania, via Citelli 6, 95124 Catania, Italy
Objectives The purpose of our study was to investigate the utility of the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) score in aiding patient selection for percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in a large contemporary registry of patients undergoing revascularization of left main coronary artery.
Background The SYNTAX score has been developed as a combination of several validated angiographic classifications aiming to grade the coronary lesions with respect to their functional impact, location, and complexity.
Methods Between March 2002 and December 2008, 819 patients with left main coronary artery disease underwent revascularization in 2 Italian centers. We compared clinical outcomes of PCI versus CABG in patients with SYNTAX score ≤34 and patients with SYNTAX score >34.
Results The rates of 2-year mortality were similar between CABG and PCI in the group of patients with SYNTAX score ≤34 (6.2% vs. 8.1%, p = 0.461). Among patients with SYNTAX score >34, those treated with CABG had lower rates of mortality (8.5% vs. 32.7%, p < 0.001) than those treated with PCI. After statistical adjustment, revascularization by PCI resulted in a similar risk of death compared with CABG in patients with SYNTAX score ≤34 (hazard ratio: 0.81, 95% confidence interval: 0.33 to 1.99, p = 0.64) and in a significantly higher risk in patients with SYNTAX score >34 (hazard ratio: 2.54, 95% confidence interval: 1.09 to 5.92, p = 0.031).
Conclusions A SYNTAX score threshold of 34 may usefully identify a cohort of patients with left main disease who benefit most from surgical revascularization in terms of mortality.
The rapid widespread and extensive use of drug-eluting stents (DES) has led to a renewed interest for the treatment of complex, off-label coronary lesions such as unprotected left main (1). The encouraging results obtained with DES supported the rationale for the use of percutaneous coronary intervention (PCI) as a safe and effective revascularization alternative to coronary artery bypass grafting (CABG) in patients with unprotected left main coronary artery disease (CAD) and suitable lesion anatomy (2–6).
The SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) score has been recently developed as a combination of several previously validated angiographic classifications aiming to grade the coronary anatomy with respect to the number of lesions and their functional impact, location, and complexity (7). The prognostic utility of the SYNTAX score has been recently validated in different settings, including patients with 3-vessel (8,9) or left main CAD (10,11) undergoing either PCI or CABG. However, the SYNTAX score has been originally proposed as an aid to decision making for PCI patient selection more than as a predictive tool for stratifying individual outcomes of patients undergoing either procedure.
In this perspective, the quest for the optimal threshold to distinguish patients who benefit most from surgical revascularization from those who may be safely treated with PCI is of clinical interest. In a previous study, we demonstrated that a SYNTAX score >34 optimally identifies patients with higher risk of death after left main PCI (10). The aim of this study was to investigate the utility of a SYNTAX score threshold of 34 in aiding patient selection for PCI or CABG in a large contemporary registry of patients undergoing revascularization of unprotected left main coronary artery (ULMCA).
The CUSTOMIZE (Appraise a CUSTOMIZEd strategy for left main revascularization) registry holds data from 2 participating centers that performed PCI or CABG for revascularization treatment of consecutive patients with ULMCA disease (defined as the presence of lesions with stenosis of at least 50% of vessel diameter) between March 2002 and December 2008. Patients who had undergone previous CABG were excluded. The local ethics committee at each center approved the use of clinical data for this study, and all patients provided written informed consent. The authors wrote the manuscript, and are responsible for the completeness and accuracy of data gathering and analysis.
Procedural and post-intervention practices
The interventional strategy, as well as the choice of the various devices and the administration of therapies during the procedure, was left to the operator's discretion and standard practice. After the procedure, patients treated with DES were prescribed clopidogrel for at least 6 months. Aspirin was prescribed indefinitely for all patients, irrespective of treatment with PCI or CABG.
Surgical revascularization was performed with the use of standard bypass techniques. Whenever possible, the internal thoracic artery was used preferentially for revascularization of the left anterior descending artery. In patients <70 years of age, arterial revascularization was strongly recommended. Patients could be operated either with or without extracorporeal circulation; in on-pump surgeries the type of cardioplegia was left to surgical judgment. The post-procedure medication regimen was chosen according to local clinical practice.
SYNTAX score calculation
The total SYNTAX score was derived from the summation of the individual scorings for each separate lesion (defined as ≥50% stenosis in vessel ≥1.5 mm). Full details on SYNTAX score calculation are reported elsewhere (7). All angiographic variables pertinent to SYNTAX score calculation were computed by 2 of 3 experienced cardiologists who were blinded to procedural data and clinical outcome on angiograms obtained before the procedure. In case of disagreement, the opinion of the third observer was obtained, and the final decision was made by consensus.
Clinical follow-up data related to medications and clinical status were prospectively collected through scheduled outpatient clinic evaluations. Referring cardiologists, general practitioners, and patients were contacted whenever necessary for further information. All repeated coronary intervention (surgical and percutaneous) and rehospitalization data were prospectively collected during follow-up using the centralized system of the participating institutions or contacting directly the hospitals where the patients were admitted or referred. Angiographic follow-up was suggested at 6 and 9 months after the index procedure in all consenting patients treated with PCI. It was performed at an earlier time if clinically indicated. However, patients who were at high risk for procedural complications of angiography and had no symptoms or signs of ischemia, as well as patients who declined the recommendation, did not undergo routine follow-up angiography. For patients who underwent CABG, angiographic follow-up was recommended only if there were ischemic symptoms or signs during follow-up. All outcomes of interest were confirmed by source documentation collected at each center and were centrally adjudicated by an independent, blinded end points committee.
According to the presence or absence of a SYNTAX score >34, patient characteristics pertaining to the index procedure were compared between treatment types with the use of Student unpaired t test for continuous variables (expressed as mean ± SD) and chi-square test or Fisher exact test for categorical variables (expressed as counts and percentages). Two-year cumulative rates of all-cause mortality were estimated by the Kaplan-Meier method, and the log-rank test was used to evaluate differences between groups. Patients lost to follow-up were considered at risk until the date of last contact, at which point they were censored.
To reduce the effect of selection bias and potential confounding in this observational study, the outcome parameter was adjusted by means of a Cox multivariable proportional hazard regression model for observed differences with respect to variables deemed clinically relevant or statistically significant in the univariate analysis, which were age, hypertension, chronic renal failure, diabetes mellitus, history of previous myocardial infarction, history of previous PCI, peripheral artery disease, acute myocardial infarction, left ventricular ejection fraction, EuroSCORE, bifurcation lesion, left main plus 3-vessel CAD, and SYNTAX score. The assumption of the proportional hazard was verified by a visual examination of the log (minus log) curves, and the linearity assumption was assessed by plotting the Martingale residuals against continuous covariates.
The interaction effect of a SYNTAX score >34 with the revascularization strategy was determined by using a Cox proportional hazard regression analysis with the investigated cutoff, the treatment, their multiplicative interaction term, and adjusting covariates entered in the model.
For all analyses, a 2-sided value of p < 0.05 was considered statistically significant. All data were processed using the Statistical Package for Social Sciences version 15 (SPSS Inc., Chicago, Illinois).
The diagnostic angiograms were available in 819 of 839 patients (97.6%). The remaining patients were excluded from the present analysis, assuming a nonsignificant difference with regards to the prevalence of patients with a SYNTAX score >34.
Mean SYNTAX score was 26.3 ± 11.6 in patients treated with PCI and 33.1 ± 12.6 in patients treated with CABG (p < 0.001). According to the study definitions, 85 of 342 patients who were treated with PCI (24.9%) and 204 of 477 patients who were treated with CABG (42.8%) presented with a SYNTAX score >34.
Among patients with a SYNTAX score ≤34, those treated with PCI were more likely to have chronic renal failure defined as serum creatinine >2 mg/dl, previous myocardial infarction, peripheral artery disease, history of previous PCI, acute myocardial infarction, lower left ventricular ejection fraction, and a higher EuroSCORE. Conversely, patients treated with CABG were more likely to present with multivessel and left main bifurcation CAD (Tables 1 and 2).⇓ Among patients with a SYNTAX score >34, differences between patients treated with PCI and those treated with CABG were similar to those reported for patients with a SYNTAX score ≤34. In addition, patients treated with CABG more often had hypertension and diabetes mellitus (Tables 1 and 2).
In-hospital rates of major adverse cardiac or cerebrovascular events, defined as death, Q-wave myocardial infarction, stroke, and repeat revascularization, were similar between patients treated with PCI and CABG (3.4% vs. 3.5%, p = 0.929; no differences were also noted with regard to the subcomponent end points.
Long-term follow up
At 2 years, no significant differences in terms of mortality were seen between CABG and PCI in the group of patients with a SYNTAX score ≤34 (6.2% vs. 8.1%, p = 0.461). Within the group of patients with a SYNTAX score >34, patients treated with CABG had lower rates of mortality (8.5% vs. 32.7%, p < 0.001) compared with those treated with PCI (Fig. 1). These findings resulted in a significant interaction between treatment and the investigated SYNTAX score cutoff (p < 0.001).
After adjustment, revascularization by PCI was consistently associated with a similar risk of death compared with CABG in patients with a SYNTAX score ≤34 (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.33 to 1.99, p = 0.64) and with a significantly higher risk in patients with a SYNTAX score >34 (HR: 2.54, 95% CI: 1.09 to 5.92, p = 0.031) (Fig. 2). The adjusted p value for interaction with treatment type was 0.002 when using the SYNTAX score as a binary variable and 0.05 when using the SYNTAX score as a continuous variable.
SYNTAX score and isolated ostial or shaft left main disease
In the subgroup of patients with ostial or shaft left main disease, PCI and CABG were associated with similar mortality rates in patients with SYNTAX score ≤34 (9.1% vs. 12.6%, Δ −3.5%, p = 0.984, adjusted HR: 0.72, 95% CI: 0.21 to 2.46, p = 0.604). Conversely, patients with a SYNTAX score >34 treated with PCI yielded significantly higher mortality rates compared with those treated with CABG (37.4% vs. 8.7%, Δ 28.7%, p = 0.001, adjusted HR: 2.89, 95% CI: 1.07 to 7.85, p = 0.037).
SYNTAX score and left main bifurcation
In the subgroup of patients with left main bifurcation disease, PCI and CABG yielded similar outcomes among patients with SYNTAX score ≤34 (6.9% vs. 4.3%, Δ 2.6%, p = 0.839, adjusted HR: 0.44, 95% CI: 0.11 to 1.71, p = 0.233) and different outcomes among those with a SYNTAX score >34 (30.2% vs. 6.9%, Δ 23.3%, p = 0.006, adjusted HR: 6.09, 95% CI: 1.00 to 36.9, p = 0.049). As a result, the interaction among treatment, SYNTAX score, and the presence of bifurcation disease was not statistically significant (adjusted p = 0.249).
Importantly, among patients with left main bifurcation CAD treated with PCI, no differences were observed between those treated with a 1-stent strategy and those treated with a 2-stent strategy (14.7% vs. 11.7%, p = 0.329). This lack of significant difference was consistent both in the subgroup of patients with SYNTAX score >34 (p = 0.225) and in the subgroup of those with SYNTAX score ≤34 (p = 0.812).
SYNTAX score and complete revascularization
Complete revascularization (defined as the successful treatment of all vessels at least 1.5 mm in diameter with stenosis of 50% or more, as identified by the interventional cardiologist and cardiac surgeon after coronary angiography and estimated post-procedure by the investigators) was obtained in 52.5% versus 11.9% of patients treated with PCI and in 80.7% versus 68.2% of those treated with CABG in the groups with a SYNTAX score ≤34 and >34, respectively (Fig. 3).
When forced into the Cox multivariable proportional hazard regression model, complete revascularization was found to be an independent predictor of mortality (HR: 0.55, 95% CI: 0.31 to 0.98, p = 0.041), but this finding did not affect the prognostic significance of a SYNTAX score >34 (HR: 1.73, 95% CI: 1.01 to 2.97, p = 0.048). Conversely, treatment type was no longer a significant predictor of mortality in the statistical model.
The present study shows that in patients with ULMCA, the presence of a SYNTAX score >34 is associated with a higher risk of death after PCI compared with that of patients treated with CABG. In particular, after adjustment for potential confounders, patients with a SYNTAX score >34 treated with PCI had an almost 3-fold increase in the likelihood of 2-year mortality, whereas no differences between PCI and CABG outcomes were noted among patients with a SYNTAX score ≤34. Overall, these findings support the hypothesis that a SYNTAX score threshold of 34 is clinically useful to select patients with left main disease who benefit most from revascularization by CABG. Importantly, a sensitivity data analysis showed that these findings are consistent irrespective of the disease location (e.g., ostium/shaft or bifurcation) within the left main.
The randomized SYNTAX study has recently demonstrated that CABG remains the standard of care for patients with 3-vessel or left main CAD, as due to lower rates of the combined end point of major adverse cardiac or cerebrovascular events at 1 year (12). However, post-hoc analyses of the left main subgroup, although not powered to assess differences in secondary end points, suggested that some settings may exist, in which the presumptive superiority of CABG over PCI is not evidence based. Therefore, the potential for similar outcomes between PCI and CABG in patients with low or intermediate values of SYNTAX score has also been hypothesized (12).
The SYNTAX score was created ad hoc and proposed to grade patients according to the individual complexity of CAD. To date, few studies validated SYNTAX score use in different clinical settings. Valgimigli et al. (8) demonstrated the prognostic value of the SYNTAX score to stratify clinical outcomes of patients with 3-vessel disease treated with PCI. We provided complementary findings in patients with left main CAD undergoing stenting (10). Lemesle et al. (9) have recently observed that the SYNTAX score fails to stratify the outcomes of patients undergoing surgical revascularization of 3-vessel CAD. However, Birim et al. (11) showed the usefulness of grading coronary complexity with the SYNTAX score to predict 30-day and 1-year outcome after left main CABG. Of note, these latter findings are in contrast with those of the present study, showing that SYNTAX score was unable to identify a significant difference in mortality among surgical patients with left main CAD and different SYNTAX score values according to a pre-specified threshold of 34.
Overall, these results underscore that while lesion anatomy and complexity have demonstrated to be accurate in predicting PCI risk, they are less consistent in predicting CABG risk, especially in the context of 3-vessel CAD. A possible explanation for this might be that, since CABG bypasses the lesion rather than directly treats it, lesion complexity does not represent, per se, a reason for higher risk of clinical events.
However, SYNTAX score has been openly created to be used in the PCI setting with the main goal of selecting those patients who take advantage of a switch from the interventional strategy to the surgical one. This is, to the best of our knowledge, the first study assessing the utility of SYNTAX score in aiding patient selection for PCI or CABG in the real world.
Importantly, statistical adjustment was performed to test the consistency of results. In fact, particularly in the subgroup of patients with a SYNTAX score >34, variables that are known to influence in a great extend the survival of patients with CAD were not well balanced between groups (e.g., reflecting the common practice of treating with PCI patients presenting with acute myocardial infarction or with surgery those presenting with a more advanced and extended CAD. Also, since patients treated with PCI more frequently presented with impaired renal function as well as increased age than those treated with CABG and given that these 2 variables are likely to determine a remarkable impact on survival, both were forced in the model for statistical adjustment regardless of the absence of statistical significance at univariate analysis.
A possible explanation for the main findings of this study might be that patients treated with CABG benefit from a higher percentage of complete revascularization, both in those with a lower or higher SYNTAX score. However, the well-known gap between PCI and CABG in achieving complete revascularization was doubled among patients with a SYNTAX score >34 compared with those with a SYNTAX score ≤34, with a difference of 56.3% versus 28.2%, respectively. The inability to achieve the goal of complete revascularization in the vast majority of patients with a higher SYNTAX score undergoing PCI, in contrast to similar percentages of complete revascularization among CABG patients, is likely to be the main responsibility for the difference between revascularization treatments in complex CAD. This is consistent with the remark that by forcing complete revascularization into the Cox regression model, the use of PCI no longer represents a predictor of mortality.
Clinical implications of the opportunity to select the optimal treatment just after the angiography, based on the anticipated outcome with the available techniques, are apparent in terms of clinical and economic advantages. However, some potential shortcomings of the SYNTAX score may limit its wide diffusion among interventionalists, since its computation is often perceived as difficult and time consuming. Also, some coronary features that are commonly seen in clinical practice (e.g., presence of patent coronary bypass grafts) are not considered in the scoring system, making the use of the SYNTAX score not always feasible.
In this study, the choice of a dichotomic cutoff was based on the observation that in complex CAD the distribution of SYNTAX score seems more skewed than normally distributed, consistently with previous validation studies (8,10). In these studies, in fact, the intermediate tertile of the SYNTAX score resulted in event rates not well separated from those of lower or higher tertiles. Therefore, the need for a practical and more reliable stratification in 2 groups has been proposed. Of note, the present study confirmed that the interaction effect between treatment type and SYNTAX score is weaker when SYNTAX score is used as a continuous variable than when it is used as a binary one. This substantiates the utility of a dichotomic threshold to discriminate between patients at a lower and higher risk of death. We used a threshold of 34 based on classification and regression tree analysis, as previously reported (10). This value is similar to that of a score of 35 proposed by Valgimigli et al. (8) and with that of 33 used to identify patients in the highest tertile of the SYNTAX study (12).
This is an observational study on current clinical practice. The most important limitation when we sought to determine the outcomes of patients who underwent different strategies for ULMCA revascularization in each group was the lack of a random assignment to PCI or CABG.
Importantly, the number of CABG procedures performed was more than double compared with that of PCI in the subgroup of patients with a SYNTAX score >34, reflecting the common practice of treating with surgery those patients presenting with a more advanced and extended CAD.
In order to partly compensate for the baseline and angiographic imbalance between groups, we performed adjustments for several covariates, making residual selection biases unlikely. However, from a statistical standpoint, the potential for overfitting of the model may not be excluded, since the selection of the variables was based on clinical judgment and univariate analysis. This may have increased the noise of our model. Overall, it is impossible to know if these adjustments are appropriate or if the relevant characteristics have been correctly identified, since only randomization can provide an unbiased estimation of the effects of a treatment.
Finally, patients with a history of previous PCI were not excluded in the present analysis with the intention to provide a reliable perspective on a real-world scenario. However, we acknowledge that in some cases, ULMCA disease may be a consequence of a catheter-induced vascular trauma.
In a large multicenter registry of patients with ULMCA disease undergoing revascularization with PCI or CABG in current clinical practice, a SYNTAX score higher than 34 may usefully identify a cohort of patients who benefit most from surgical revascularization in terms of 2-year mortality. The SYNTAX score is a promising tool to tailor the strategy of revascularization according to the angiographic characteristics of each single patient.
- Abbreviations and Acronyms
- coronary artery bypass grafting
- coronary artery disease
- confidence interval
- drug-eluting stent(s)
- hazard ratio
- percutaneous coronary intervention
- unprotected left main coronary artery
- Received May 26, 2009.
- Revision received June 3, 2009.
- Accepted June 8, 2009.
- American College of Cardiology Foundation
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