September 1, 2008 (Munich, Germany) — One-year follow-up from the much anticipated Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial indicates that drug-eluting stents (DES) are statistically inferior to CABG, at least for the primary composite end point of all-cause death, cerebrovascular event, MI, and repeat revascularization. But the combined rate of "hard" end points--death, MI, and stroke--were no different between the two trial groups, and secondary-end-point findings, showing a statistically lower risk of stroke among PCI-treated patients and a statistically higher risk of revascularization, will no doubt be interpreted differently by interventionalists and surgeons.
Speaking with the press at the European Society of Cardiology Congress 2008, the interventional co-primary investigator for the study, Dr Patrick W Serruys (Erasmus University Medical Center, Rotterdam the Netherlands), suggested that people "shouldn't leave the room thinking that PCI is inferior" just because it did not pass the test for noninferiority. "It's basically up to the patient to assess the different risks," he said.
But as surgical co-principal investigator for SYNTAX, Dr Friedrich W Mohr (University of Leipzig, Germany), pointed out, almost one-third of patients considered for randomization in SYNTAX were deemed ineligible for PCI, primarily due to complex disease or anatomy. So while the results for the randomized trial may be variously interpreted by different physician specialties, the reality remains that even in the DES era, one-third of patients should not be considered for a percutaneous approach. Indeed, the so-called SYNTAX score, evolved for the trial, offers a grading system, based on patient anatomy, to help surgeons and interventionalists make this decision.
Mohr, more forcefully than Serruys, emphasized that the results are "quite clear."
"We did not meet the noninferiority test, so that says that CABG is the treatment of choice--that's clear from those data. And I didn't expect to see that at one year. The advantages of CABG surgery very often appear in the years thereafter, and this needs to be taken into account," Mohr said.
Serruys, by contrast, acknowledged that, "technically speaking," the test for noninferiority was not met. But he stressed that, until very recently, tackling left main disease was "taboo" for stenting, and the vast majority of triple-vessel-disease cases were sent directly to surgery. "I think this will now change. Based on the results, you will see more PCI for main-stem and three-vessel disease, although in which proportion is difficult to say. . . . You have to realize that we never touched main-stem and three-vessel disease before, and now we have something that shows the same safety profile for PCI and CABG in these cases."
SYNTAX Trial and Results
Conducted at 62 European sites and 23 sites in the US, SYNTAX randomized 1800 patients to either CABG (n=897) or PCI (n=903) with the Taxus DES, with a primary end point of 12-month major adverse cardiac and cerebrovascular events (MACCE), defined as all-cause death, cerebrovascular event, MI, and repeat revascularization (PCI and/or CABG). Secondary outcome measures included overall MACCE at different follow-up periods, rates of individual end points, and quality-of-life and cost-effectiveness measures. Patients who were deemed ineligible for CABG or ineligible for PCI were entered into one of two "nested" registries: 1077 into the CABG registry and 198 into the PCI registry. To be enrolled in the trial at all, patients needed to have left main disease, with or without additional coronary disease, or three-vessel disease in all three vascular territories.
At one year, MACCE were significantly more common among PCI-treated patients than among CABG-treated patients, a 7.7% difference that did not meet the prespecified margin of noninferiority of 6.6%. The difference was driven primarily by increased repeat revascularization procedures in the DES group. But without repeat procedures, the combined rates of all-cause death/cerebrovascular events/MI were almost identical between the two groups, whereas the stroke rate, by contrast, was higher in the CABG-treated patients. Of note, however, stroke rates were analyzed on an intention-to-treat basis and, according to Mohr, almost half of the strokes in the CABG arm actually occurred prior to surgery, but postrandomization, while patients were awaiting a surgery date.
Main results from SYNTAX randomized trial
|End Point||CABG (%)||DES (%)||p|
Of note, symptomatic graft-occlusion and stent-thrombosis rates were nearly identical between the two groups, at 3.4% and 3.3% respectively.
| Registry Insights
One of the unique features of SYNTAX was its truly "all-comers" design. Patients were randomized if both the interventional cardiologist and surgeon who were part of the "heart team" agreed that the patient was eligible for either approach; if one of the revascularization strategies was not appropriate, the patient was enrolled in either the PCI or CABG registry. As such, the CABG registry was made up primarily of patients whose anatomy was deemed too complex for percutaneous revascularization, whereas the much smaller PCI registry was made up of patients with too many comorbidities for open-heart surgery. Presenting primary- and secondary-outcome results for patients enrolled in the two "nested" registries, Mohr offered new insights into how patients fared who were not eligible for randomization. In the CABG registry, patients did extremely well, with lower rates of death, MI, revascularization, and MACCE, than those seen among CABG-treated patients in the randomized trial, despite having some of the most complex lesion anatomy in the SYNTAX study. By contrast, patients in the PCI registry did considerably worse than their PCI counterparts in the randomized study.
"In patients who are not eligible for PCI, CABG is an excellent option," Mohr concluded. But by contrast, in patients not eligible for CABG, PCI was described by Mohr merely as a "viable option."
Responding to the SYNTAX results, physicians who spoke with heartwire were divided as to whether the results would actually have an impact on referral patterns and clinical practice.
Dr Petr Widimsky (Charles University, Prague, Czech Republic) told heartwire that "both the surgeons and cardiologists can be happy" about the SYNTAX results. "Surgeons, because they have shown that surgery is slightly better, and cardiologists, because they've shown that cardiology is not worse for hard end points," he said. "I think the message for practice goes two ways. One: the importance of a 'heart team' for these types of patients, involving cardiologist and surgeon, to discuss the patient's options.And the second message is that patients should be involved themselves. Because if there are two options that are basically equal, the patient should have the right to decide: it is his chest that will be cut open, or he who will be coming back for a repeat procedure."
Others highlighted the physician and patient decision-making around stroke vs revascularization risk. "By my estimate, you need to perform 12 CABG procedures to avoid one target-lesion revascularization [TLR], and, conversely, the number need to harm for stroke would be about 63 CABG surgeries," Dr David Kandzari (Scripps Clinic, La Jolla, CA) told heartwire . "So the issue is how benign TLR really is going to be considered relative to having a potentially disabling stroke, all against the background of having a minimally invasive vs open surgical procedure. But overall, despite not meeting its primary end point, I really don't think that SYNTAX will markedly impact clinical practice as it exists now, unless certain subgroups are shown to have markedly disparate safety outcomes."
But Dr Antonio Colombo (Columbus Hospital, Milan, Italy) said he expects SYNTAX to "decrease the fear for the people who are skeptical about left main, for example, and severe three-vessel disease. This study shows that, if you do a good job with DES, even complex anatomy, which has traditionally been in the [domain] of surgery, can be done by interventionalists."
And Dr Christian Hamm (University Hospital Eppendorf, Hamburg, Germany), who discussed the results following the presentation, said that while one of the take-home messages from SYNTAX will be that the need for reintervention is still the chief limitation of PCI, the "main-stem mystery, if it ever was one, is more or less abandoned, by this study."
The More Things Change . . .
When the COURAGE results were released last year, showing PCI to be no better than optimal medical therapy in stable angina, interventionalists reacted defensively, then seemed to return to business as usual. Early signs suggest that SYNTAX will be interpreted not as a negative trial, but as an opportunity.
"Like COURAGE, this trial still leaves results open to individual interpretation," Kandzari observed. "Surgeons will focus on the primary end point not being met and higher target-lesion revascularization, whereas the interventionalists will emphasize a significant difference in stroke with no difference in death or MI. It seems that the more trials we conduct to refine clinical practice, the less definitive answers we receive."
| CARDIA: Stents vs CABG in diabetics
Munich, Germany — Physicians still spinning--or being spun--over the SYNTAX results had a second PCI-vs-CABG study to mull over Monday: Dr Akhil Kapur (London Chest Hospital, UK) presented the results from the Coronary Artery Revascularization in Diabetes (CARDIA) trial immediately following the SYNTAX results during today's ESC 2008 hotline session.
Like SYNTAX, the CARDIA trial was designed to demonstrate noninferiority of PCI to CABG, but this study was confined to diabetic patients with multivessel disease. Unlike SYNTAX, CARDIA fell short of its planned recruitment, enrolling only 510 patients out of the intended 600, meaning that the noninferiority parameters set for the trial were not reached due to insufficient power. However, among the 96% to 98% of patients whose events were adjudicated at 12 months, Kapur et al saw no differences in the primary composite end point of death, stroke, and MI. As in SYNTAX, repeat revascularization procedures were significantly higher among the PCI-treated patients, while strokes were numerically higher among CABG-treated patients, although this difference was not statistically significant. One-year survival rates for the two strategies were nearly identical, at 97%.
CARDIA: Results, Intention-to-Treat Analysis
In a subgroup analysis considering only DES vs CABG (DES made up 71% of the stents in the PCI arm), event rates were similar to those of the intention-to-treat analysis, although in this subset, the difference in stroke rates reached statistical significance.
Kapul concluded his presentation by stating that PCI "may now be considered a reasonable strategy in diabetic patients with multivessel disease."
Dr Valentin Fuster (Mount Sinai Medical Center, NY), the discussant for the trial, was more cautious, highlighting the fact that the trial was underpowered to demonstrate noninferiority.
"In fact, the results are inconclusive," he stated. "I'm not sure we can say PCI in these patients is reasonable; I think the decision clearly needs to be individualized to individual patients."
But Fuster, who is also a principal investigator for the ongoing FREEDOM trial, addressing the same question in a larger population of diabetics, nevertheless congratulated the investigators for seeking answers in a group for whom the role of DES has been controversial. "Although their ultimate goal was not achieved, at least there was the willingness to go there," Fuster concluded.
Heartwire from Medscape © 2008 Medscape
Cite this: Shelley Wood. DES Statistically Inferior to CABG for Complex Coronary Disease: SYNTAX - Medscape - Sep 01, 2008.