SORT OUT IV at 5 Years: Better Long-term Safety Confirmed for Second Generation Stents

Reassuring long-term data from the SORT OUT IV trial confirm what many operators have long believed: compared with first-generation devices, second-generation everolimus-eluting stents (EES) provide better overall safety and efficacy. Of note, differences detected at 5 years—and in particular a significant difference in stent thrombosis favoring the newer generation stent—were not apparent in earlier follow-up. 

Writing in the February 23, 2016, issue of the Journal of the American College of Cardiology, the researchers say despite how commonly EES are implanted, outcomes data comparing them with SES or other first-generation stents are limited.

“The long-term safety and efficacy of coronary stents in everyday clinical practice need continuous assessment,” say Lisette Okkels Jensen, MD, PhD, of Odense University Hospital (Odense, Denmark), and colleagues. “Increased risk of late and very late stent thrombosis associated with first-generation DES led to recommendations for large-scale randomized clinical endpoint trials encompassing a variety of patient categories and types of coronary lesions.”

When 2-year results from SORT OUT IV were published in 2012, the researchers reported that EES were noninferior to SES, which once were the original “gold standard,” albeit first-generation drug-eluting stent. Even after SES became obsolete, experts have continued to stress the importance of the long-term head-to-head comparison data in confirming superiority of EES.

Differences Not Immediately Apparent

For SORT OUT IV, 2,774 Danish coronary artery disease patients were randomized to receive either Xience V/Promus EES (n = 1,390; Abbott Vascular, Boston Scientific) or Cypher Select+ SES (n = 1,384; Cordis) from August 2007 to June 2009.

The overall rate of composite MACE, the primary endpoint, was lower at 5 years in the EES group than in the SES group. The difference was not apparent in the first year, but emerged thereafter. A similar pattern was also seen for rates of TVR and TLR (table).

Furthermore, the patient-related composite outcome (all death, all MI, or any revascularization) did not differ overall or at any time point, while the stent-related composite outcome (cardiac death, target vessel MI, or ischemia-driven TLR) favored EES over SES, but only from year 1 through 5 (P for interaction = .09). 

Importantly, Academic Research Consortium (ARC)-defined definite stent thrombosis occurred less frequently in the EES group than the SES group (0.4% vs 2.0%; P = .0004). This endpoint also did not differ in the first year, but beyond year 1, EES was associated with lower rates of very late definite stent thrombosis than SES (0.2% vs 1.4%; P = .003). All patients who developed very late definite stent thrombosis were on aspirin monotherapy.  

In a post hoc analysis conducted at the time of stent thrombosis but before TLR, there were no differences in MACE, MI, or TLR rates between the EES and SES groups. According to the study authors, this finding implies that the higher frequency of stent thrombosis events in the SES group was the primary driver of the observed differences in outcomes between the stent groups. Additionally, Jensen and colleagues say the results of SORT OUT IV together with data from other trials that have looked at EES over time, “confirm the fact that the second-generation EES has a better long term safety profile than the first-generation SES.”

Shifting Priorities

In an editorial accompanying the study, Olivier Barthélémy, MD, and Gilles Montalescot, MD, PhD, both of Pitié-Salpêtrière University Hospital (Paris, France), say the study results represent a “paradigm shift,” by demonstrating that in contemporary PCI, stent thrombosis is a chronic complication rather than an acute one.

Commenting on the study to TCTMD, Jeffrey W. Moses, MD, of Columbia University Medical Center (New York, NY), agreed, adding that the study “confirms the incremental incidence of late stent thrombosis in the first-generation stents,” and “is what you’d expect to find from our knowledge of both stents.”

While the overall rate of definite stent thrombosis in the EES group (0.4%) is very low, Moses said the fact that the TVR rate increased by about 1% per year from years 1 to 5 in the EES group still signals that “we’ve licked one problem but we haven’t licked … recurrent events in the target vessel [which are] still an issue.”

In patients with the most complex disease, Moses added, getting event rates as low as possible is important, especially if the case is to be made that PCI outcomes in these patients are comparable to CABG. One way to accomplish this may be by using devices without durable polymers, which increase the risk of stent thrombosis by causing chronic inflammation and delaying endothelial regeneration, he said.

Barthélémy and Montalescot cite the recent LEADERS FREE trial showing that a polymer-free umirolimus-coated stent is safer and more effective than a bare metal stent in high-risk patients. Similarly, the LEADERS trial, which used a biolimus-eluting stent (BES) with a biodegradable polymer, showed superior safety compared with SES, but data from a 2013 meta-analysis hint that safety outcomes may favor EES and ZES over current generation BES, they add.  

So for the moment, Moses said, more work is needed, at least with regard to the polymer technology. But SORT OUT IV, he said, provides reassurance that EES are superior to bare metal stents and first-generation DES and suggests that EES outcomes provide more of a picture of contemporary DES than trials that used first-generation devices.

Sources: 
1. Jensen LO, Thayssen P, Christiansen EH, et al. Safety and efficacy of everolimus-versus sirolimus-eluting stents: 5-Year results from SORT OUT IV. J Am Coll Cardiol. 2016;67:751-762.
2. Barthélémy O, Montalescot G. Moving toward eradication of stent thrombosis. J Am Coll Cardiol. 2016;67:763-765. 

Disclosures:

• Jensen reports research grants from Biosensors, Biotronik, St Jude Medical, and Terumo; and honoraria from Abbott Vascular, Amgen, AstraZeneca, Biotronik, St Jude Medical. 
• Barthélémy reports lecture fees from Sanofi.  
• Montalescot reports consulting fees, and speaking and research grants from multiple drug and device companies.  
• Moses reports serving as a consultant to Abbott and Boston Scientific. 

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