TUXEDO-India Trial Quashes Lingering Paclitaxel-Stent Hopes in Diabetics With CAD

October 16, 2015

SAN FRANCISCO, CA — Although paclitaxel-eluting stents have long yielded to everolimus-eluting stents in most patients getting PCI, questions have lingered whether the older type of drug-eluting stent (DES) might give superior results in diabetics. Now, a large study dedicated to that very issue has concluded that there is no such advantage in the coronaries for paclitaxel DES in patients with diabetes[1]. According to its authors, the trial also questions the continued relevance of several influential trials that saw advantages for CABG over PCI in diabetics using outmoded stents.

Dr Upendra Kaul

The trial, called TUXEDO-India, "has clearly put the question to rest, that 'limus' stents, even in the diabetic population, are superior," said Dr Upendra Kaul (Fortis Escorts Heart Institute and Fortis Vasant Kunj, New Delhi, India) at a media briefing prior to his formal presentation of it at TCT 2015. It supports "the current worldwide practice of use of new-generation limus-eluting stents even in patients who require insulin for the management of their diabetes."

In TUXEDO-India, published with Kaul as first author in the New England Journal of Medicine to coincide with his presentation here, the paclitaxel DES (Taxus Element, Boston Scientific) failed to reach significance against the everolimus DES (Xience Prime, Abbott Vascular) in the primary noninferiority analysis (P=0.38) for the end point of target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction (TVMI), or ischemia-driven target vessel revascularization (TVR) after 1 year.

Consistent with that primary outcome, the everolimus stent trounced the paclitaxel stent for the TVF end point in a superiority analysis, the difference driven primarily by TVR and TVMI, with 47% drop in relative risk (RR) (P=0.005). A passel of secondary clinical end points, including the TVF components and stent thrombosis, supported the composite outcomes.

Perhaps more far-reachingly, Kaul said the results also undercut the legacy of the SYNTAX, FREEDOM and BARI 2D trials, which together helped to establish a preference in the guidelines for surgery in revascularizing diabetic patients with extensive CAD. PCI in those trials was accomplished with the older stents. In their publication, Kaul and his coauthors say that the findings "raise the question of whether the results of the FREEDOM and BARI 2D trials would have been different if the trials had been performed with newer-generation drug-eluting stents, especially everolimus-eluting stents."

46 Centers Throughout India

TUXEDO-India randomized 1830 patients with both coronary disease and diabetes at 46 centers to undergo PCI with either the paclitaxel or everolimus DES. Of the group, 11.6% were post-STEMI, 53.2% had ACS or NSTEMI, and 28.5% had chronic stable angina; the rest had silent ischemia. After PCI, patients stayed on dual antiplatelet therapy for at least 12 months.

In the primary 1-year analyses by intention to treat, the paclitaxel stent was nonsignificant for noninferiority (P=0.38), with an RR of 1.89 (95% CI 1.20–2.99). But Xience did meet criteria for superiority, RR 0.53 (95% CI 0.33–0.83, P=0.005).

Clinical Outcomes at 1 Year by Intention-to-Treat Among Patients
End points Taxus, n=914 (%) Xience, n=916 (%) P
TVF 5.6 2.9 0.38 (for noninferiority)
Spontaneous MI 3.2 1.2 0.004
Stent thrombosis 2.1 0.4 0.002
Ischemia-driven TVR 3.4 1.2 0.002
MACE 5.9 3.4 0.01
Cardiac death or TVMI 4.0 2.3 0.03

In subgroup analyses, there was no interaction between type of stent and TVF with regard to age, sex, need for insulin, HbA1c, angina status, target lesion length, number of treated lesions, lesion type, reference-vessel diameter, target vessel, or duration of diabetes, according to the researchers.

"No Role for Paclitaxel-Eluting Stents in CAD"

After Kaul's presentation of TUXEDO-India, TCT codirector Dr Gregg Stone (Columbia University Medical Center, New York) said, "For many years we've understood that limus-eluting DES are superior to paclitaxel-eluting DES in terms of efficacy and possibly even safety. The one possible outlier was in patients with diabetes, in which the different mechanisms of antiproliferative action of limus vs paclitaxel might equalize the playing field and perhaps even favor paclitaxel. But we never had one big dedicated study to answer that question, until today." With this new trial, he said, "It really seems like there's no role for paclitaxel-eluting stents in coronary artery disease anymore."

That's the direction clinical practice has been heading anyway, at least in North America and Europe, Kaul and observers of the trial acknowledged. Also at the press conference, Dr David J Cohen (Saint Luke's Mid America Heart Institute, Kansas City, MO) pointed out that the US guidelines give clinicians lots of discretion in choosing revascularization strategies for individual diabetic patients and that it's already appreciated that the difference between CABG and stenting with contemporary DES in diabetics may not be so pronounced.

As for paclitaxel-eluting coronary stents, "we don't even have them on our shelves anymore," exclaimed Dr John R Laird Jr (University of California Davis Medical Center) at the briefing.

TUXEDO may have more of an impact outside North America or Europe, where the use of cheaper paclitaxel DES is "declining" but the devices are still used "in really large numbers," Kaul said to heartwire from Medscape. Those regions would include India, other parts of Central and South Asia, East Asia, and the Middle East, he said.

Because the original trials pointing to a CABG advantage over PCI in diabetics are "obsolete," according to Kaul, even in those parts of the world, there should now be a substantial shift in perceptions of PCI as being more widely appropriate for diabetic patients. "So those results showing superiority of bypass surgery need to be revisited; it means doing another dedicated study in diabetics with present-generation stents."

Also at the press briefing, Dr Bernard J Gersh (Mayo Medical School, Rochester, MN) said he doesn't think the PCI-vs-CABG implications of SYNTAX, FREEDOM, and BARI 2D have been overturned. The more contemporary data, including TUXEDO-India results, he said, "don't invalidate them, they raise questions." Outcomes differences between CABG and PCI with current stents just might be narrower than previously believed. But he still thinks that in high-risk patients with "very diffuse disease" and diabetes, "bypass surgery remains the treatment of choice."

TUXEDO-India was funded by Boston Scientific; Kaul said it was "investigator initiated." Kaul reports receiving research grants and lecture fees from Boston Scientific and lecture fees from Abbott Vascular. Disclosures for the coauthors are listed on the journal website.

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