Skinny Stent Falls Short in Noninferiority Trial, Troponin 'Noise' Blamed

October 21, 2020

The sirolimus-eluting Slender IDS coronary stent (Svelt Medical Systems), exquisitely skinny to simplify crossing lesions without predilatation, came up short in a randomized noninferiority trial against familiar Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents (DES).

The results came with a big "but," however. The investigators and some observers blamed the novel stent's failure to achieve noninferiority on lofty rates of target-vessel myocardial infarction (TVMI) in both the Slender group and the cohort that received the more well-established stents — rates that unexpectedly approached 9% in both groups.

That was attributed to the study's definition of TVMI, which included periprocedural CK-MB elevation or, as a substitute, troponin levels three times the upper limit of normal, which aren't necessarily rare in the age of high-sensitivity tests for the biomarker.

Because TVMI was part of the primary end point of target-lesion failure (TLF) at 1 year, there were so many primary events in both groups that the OPTIMIZE IDE trial, with its more than 1600 patients, was grossly underpowered for the Slender stent to meet the prospectively defined criteria for noninferiority, investigators say.

After 1 year, the TLF rate overall was 9.9%, driven by an 8.8% rate of TVMI, 90.0% of which were periprocedural. The TLF rate was 10.30% for the 827 patients who received Slender and 9.49% for the 812 patients treated with the other stents. The rates of TVMI were 9.31% and 8.22% (= .48), respectively.

The 25% of patients in whom troponin levels were measured accounted for 80% of TVMIs, reported Dean J. Kereiakes, MD, The Christ Hospital Heart and Vascular Center, Cincinnati, at TCT Connect, the virtual edition of Transcatheter Cardiovascular Therapeutics (TCT) 2020.

So the failure of the Slender stent to show noninferiority in the trial "was not the device. It was the biomarker definition that was used," Kereiakes told | Medscape Cardiology.

The periprocedural MI experience in the trial "should inform any investigational device exemption trials for DES going forward. You won't see this done again," he said.

Too Much of a Good Thing

"I agree with your conclusion," Ajay J. Kirtane, MD, New York–Presbyterian Hospital and Columbia University Irving Medical Center, New York City, said as an invited discussant after Kereiakes formally presented the analysis at the sessions.

"I think, personally, we do not ever draw these enzymes in practice. And in study after study, we are now overreacting to enzymatic 'infarctlets' or biomarker elevations that have zero clinical relevance. Sometimes it's too much of a good thing," he said.

Adverse event rates are so low with contemporary coronary stenting, "we have to have something to power our trials on. But when it's noise, it doesn't actually contribute to a clear discernment of differences between two different platforms."

The Slender stent, Kereiakes agreed, "is not inferior. Clearly, the biomarkers kind of bit us."

His presentation included post hoc analyses by an independent adjudication committee that framed the results in the context of other DES investigational device exemption studies to show Slender as solidly noninferior to its comparators in OPTIMIZE IDE, with a relative risk for the primary end point of 1.09 (95% CI, 0.81 - 1.46; P = .009 for noninferiority).

A separate exploratory analysis that used an enzyme-oriented MI definition from the Society for Cardiac Angiography and Interventions (SCAI), and another that used the OPTIMIZE MI definition with comparable relative noninferiority margins, produced similar results.

"It Probably Would Have Worked"

Expert observers who commented on OPTIMIZE IDE viewed the post hoc analyses favorably, and saw them as confirming Slender noninferiority — unofficially, however, because the trial "missed" its prospectively defined noninferiority primary end point of 12-month TLF, a composite of cardiac death, Q-wave or non-Q-wave TVMI, periprocedural myocardial infarction by CK-MB or the troponin criteria, and clinically driven target-lesion revascularization (TLR).

"It probably would have worked, had there not been such a high level of troponin when you requested CK-MB," said another invited discussant, Donald E. Cutlip, MD, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Three times the upper limit of normal for CK-MB "would have been fine," he said.

"What's important is there wasn't a difference. Both devices had higher MI rates than we're used to seeing, so the real problem came down to the noninferiority margin. Had they been selected based on the event rate that you later found, you would have been okay, or had it been a relative risk margin."

When the US Food and Drug Administration reviews OPTIMIZE IDE, "I would think that they would look at the totality the evidence here," said Robert W. Yeh, MD, MSc Beth Israel Deaconess Medical Center, at a media briefing on the trial held during TCT Connect.

There is strong evidence that the end points were "entirely sensitive to the definition of the biomarkers used, and that changes in how hospitals collect different and utilize different laboratory tests have clearly influenced this study," he said.

"The evidence is very clear here that this device performed, I think, equally well to its comparator. And it barely missed, by a very small margin, the P value for noninferiority."

On the other hand, "at the end of the day, you have to base your primary interpretation on the primary end point," said Robert A. Byrne, MB, BCh, PhD, at the briefing. Granted, he said, the regulatory authorities then have to take a look afterward at the totality of the evidence."

"I Was a Bit Puzzled…"

One irony of OPTIMIZE IDE is that its operators didn't take full advantage of the Slender stent's alleged "superpower" — it's exceedingly slim profile meant to facilitate transradial access as well as direct stenting, that is, stenting without predilatation to "prepare" the target lesion for stent expansion.

"Slender IDS has lower crossing profiles than any contemporary DES," states the trial abstract prepared for TCT Connect.

The stent "is mounted on a low-compliant balloon" with an integrated 0.014" guide wire, the abstract further states. The features are said to help the device "reduce the time and cost" of percutaneous coronary intervention (PCI).

"I do worry a little bit about this move toward direct stenting," Kirtane offered during the Q&A after the formal OPTIMIZE IDE presentation. "I think we're seeing a lot more calcified lesions, and the impact of pre- and postdilatation is really, really important. But I'm one who always likes to have more tools at my disposal."

At the same forum, Pieter C. Smits, MD, PhD, Maasstad Hospital, Rotterdam, the Netherlands, pointed out that in the Kereiakes presentation, stenting was direct in only a minority of the patients. "I was a bit puzzled by that." Predilatation was performed in 68.2% of Slender stents and in 72.2% of Xience and Promos stents (= .05).

Many PCI operators "are not sold on direct stenting" because predilatation can improve stenting results in calcified lesions and for other reasons, Kereiakes acknowledged. But direct stenting "is feasible with this device. It's more feasible with this device than many other devices because of the profile and the deliverability."

At the media presentation, Kereiakes said overall resource utilization was lower for patients who had direct stenting in the study. "You don't even need a guide catheter, don't need a predilatation or postdilatation balloon, if you can direct stent with this." Reduced cath lab time and radiation exposure are other potential benefits, he said.

Byrne said he has not used the Slender, but "devices that have an edge in deliverability are likely to be attractive in the current interventional climate, of course. Devices that have an impact in resource utilization are relevant, wherever you're practicing."

TCT Connect is sponsored and run by the Cardiology Research Foundation, which, it frequently notes on the meeting site, "gratefully acknowledges the educational grant support from the 'Major Benefactors' Abbott, Boston Scientific, Edwards, and Medtronic," among other companies. OPTIMIZE IDE was funded by Svelte Medical Systems. Kereiakes disclosed receiving consulting fees or honoraria from Boston Scientific, Caliber Therapeutics/Orchestra Biomed, Elixir Medical, Shockwave, SINO Medical Sciences Technologies, and Svelte Medical Systems; and holding a major equity position in Ablative Solutions. Byrne disclosed receiving a research contract from CeloNova. Yeh disclosed receiving grant support or research contracts from Abbott Vascular, AstraZenca, Boston Scientific, Medtronic, Bard Medical, Cook Medical, and Philips; and receiving consultant fees or honoraria or serving on a speakers Bureau for Boston Scientific, Medtronic, and Abbott Vascular. Kirtane disclosed receiving grant support or research contracts from Medtronic, Abbott Vascular, Boston Scientific, CSI, Siemens, Philips, and ReCor Medical. Cutlip had no disclosures.

Transcatheter Cardiovascular Therapeutics (TCT) 2020: Late-Breaking Clinical Trial Session IV. Presented October 17, 2020.

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