Download this article's Factoid (PDF & PPT for Gold Subscribers)

For patients with unprotected left main disease, the relative safety of revascularization with drug-eluting stents (DES) compared with coronary artery bypass graft (CABG) surgery depends on the complexity of the disease as measured by Syntax score, with DES favored for patients with a low score and surgery for those with a high score, according to a registry study published in the May 24, 2011, issue of the Journal of the American College of Cardiology. However, CABG holds the edge in efficacy regardless of disease burden.

Investigators led by Seung-Jung Park, MD, of Asan Medical Center (Seoul, South Korea), evaluated data from 1,146 patients with unprotected left main disease who underwent revascularization with either DES (n = 645) or bypass surgery (n = 501). This cohort represents the second wave of the MAIN-COMPARE registry study covering the period from May 2003 through June 2006, during which all stenting was performed with DES.

Stratification by Syntax Score

Disease burden was determined by calculating Syntax score using information from baseline angiograms. Syntax scores, which are measures of disease complexity based on multiple anatomic and angiographic parameters, were classified as:

• Low: ≤ 22
• Intermediate: 23-32
• High: ≥ 33

The mean Syntax score was lower in the DES group than the CABG group (24.8 ± 10.9 vs. 38.7 ± 13.3; P < 0.001).

Over a median follow-up of 55.1 months, rates of the primary safety outcomes (death and the composite of all-cause death, Q-wave MI, or stroke) were lower in the DES group than the CABG group for patients with low Syntax scores. Among those with intermediate Syntax scores, these safety endpoints were similar for the 2 groups, while among those with high Syntax scores, the incidence of these safety events tended to favor surgery. After multivariate adjustment using inverse probability-of-treatment weighting, however, those differences no longer showed statistical significance.

On the other hand, CABG held an advantage over DES in TVR across all Syntax categories, with the difference becoming significant among patients with intermediate and high scores. This efficacy difference remained significant after adjustment (table 1).

Table 1. Adjusted Five-Year Outcomes by Syntax Score

When the effect of treatment strategy on outcomes was assessed, interaction with Syntax score was seen for death (P for interaction = 0.047) and the composite safety endpoint (P for interaction = 0.08) but not for TVR (P for interaction = 0.45).

In addition, in the DES group, rates of death and the composite endpoint were significantly increased in patients with high Syntax scores compared with those with low or intermediate scores. In the CABG group, however, there was no uniform increase in these safety outcomes according to Syntax score.

Overall, the risks for death and the composite safety endpoint were lower in the DES group than the CABG group, whereas the incidence of TVR was higher in the DES group. However, adjustment for both Syntax score and covariables eliminated the safety differences (table 2).

Table 2. Hazard Ratio for DES Group Relative to CABG Group at 5 Years

  
The authors write that their findings suggest “an important role of the Syntax score as an aid in decision making for patient selection and risk stratification in clinical practice.”

In a telephone interview with TCTMD, David E. Kandzari, MD, of Piedmont Heart Institute (Atlanta, GA), observed that “this is the third observational study to reaffirm the distinction in outcomes between high and low-intermediate Syntax scores for patients with left main disease, further supporting the results of the randomized SYNTAX trial. And [this study] has the added benefit of having the longest-term follow-up.”

In Observational Study, Treatment Rationale Unclear

It is important to keep in mind, however, that—unlike the randomized SYNTAX trial, in which the Syntax score groups were fairly evenly balanced in regard to treatment—in the observational MAIN-COMPARE registry, despite propensity matching, clinical judgment played a major role in decisions about which patients received PCI and which got surgery, Dr. Kandzari noted.

“This is borne out when you look at the patients with low Syntax scores, where there are 5 times more PCI patients than surgery patients. And conversely, in the high Syntax score cohort, there are more than twice as many surgical patients as PCI patients. For this PCI group, for example, you have to wonder whether they had some high-risk characteristics [beyond the Syntax score] that made surgeons unwilling to treat them, and thus whether their mortality might have been high regardless of which therapy they received.”

Jeffrey W. Moses, MD, of Weill Cornell Medical College (New York, NY), was concerned about a potential confounder: the choice of all-cause death rather than cardiac death as an endpoint. “With all-cause death you always wonder whether some ancillary disease process caused the selection of one treatment or the other,” he told TCTMD in a telephone interview. “For example, someone with cancer would be more likely to get PCI than CABG and to die from the cancer. And that’s not accounted for [in this study].”

Does the Syntax Score Need Refinement?

Dr. Kandzari added, “In real-world practice there are many factors other than Syntax score that influence decision making [regarding revascularization strategy], such as patient choice, pulmonary disease, and other comorbidities. In fact, there has been considerable interest in risk models that include both angiographic and clinical characteristics, such as the Clinical Syntax score, to try to refine outcome prediction.

Nonetheless, “even though the Syntax score is limited to angiographic metrics, it seems to do a fairly good job in terms of predictability,” he said.

Dr, Moses made a similar point. “[In effect, the Syntax score] is an aggregate of anatomic and clinical covariates. For example, diabetes puts a patient in the category of diffuse disease, which adds to the score. So certain aspects of underlying disease may already be reflected in the Syntax score.”

Hidden Roles of Chronic Total Occlusion, Complete Revascularization

“One of the drivers of the Syntax score is non-left main disease, and in particular chronic total occlusions,” Dr. Kandzari observed. “[In the scoring algorithm] you have to multiply a chronic total occlusion by 5. But many doctors don’t treat chronic total occlusions, and in general don’t perform complete revascularization with PCI. So when we see high Syntax score patients with higher mortality, we need to ask ourselves whether [that outcome] is due to greater disease burden or the fact that not all their lesions were treated.”

Dr. Moses agreed that the issue is important and needs clarification. “There are data from other studies from which you could infer that [lack of complete revascularization and nontreatment of chronic total occlusions] may be very important factors beyond the Syntax score itself,” he said. “For example, in the SYNTAX trial there are differences in mortality between patients with and without total occlusion. And there are some registry data indicating a strong correlation between incomplete revascularization and Syntax score.”

Drs. Kandzari and Moses agreed that good technique is important in treating left main disease with PCI and the South Korean investigators are very experienced. But they were unconvinced that IVUS guidance, despite its intuitive appeal, plays a leading role in improving survival. On the other hand, use of newer-generation DES does make a difference, Dr. Moses asserted. “From every dataset we have, I don’t think there is any doubt that we have better stents now,” he said. “And it’s not just efficacy—there’s a safety signal with Xience that is very hard to deny. The outcomes [using first-generation stents] are no longer comparable.”

In the end, “the data [from this study] are suggestive, but they set the stage for a true randomized trial,” Dr. Kandzari concluded, adding that the large randomized EXCEL trial [evaluating Xience vs. CABG for left main disease] is forthcoming, although it excludes patients with a Syntax score greater than 32.

Study Details

Among DES patients, 78% received SES and 22% PES. The mean number of stents implanted per lesion was 1.2 ± 0.5, the mean total length of the stents was 32.8 ± 22.0 mm, and the mean stent diameter was 3.4 ± 0.2 mm. Among CABG patients, 46% underwent off-pump surgery, and 96% underwent revascularization of the LAD with an internal thoracic artery. Complete revascularization was achieved in 64% of DES patients and 80% of CABG patients.

Related Stories:

• Syntax Score Incorporating Clinical Variables Improves PCI Risk Prediction
• SYNTAX Score Cut-off Guides Treatment Selection for Left Main Disease
• SYNTAX Scoring Predicts Outcomes in Unprotected Left Main Patients Undergoing PCI