LEADERS FREE II Supports Biolimus Stent for High-Risk Patients

Marlene Busko

September 23, 2018

SAN DIEGO — Results from the pivotal LEADERS FREE II trial suggest that the BioFreedom (Biosensors) polymer-free biolimus A9–coated stent for patients with not only blocked coronary arteries but also a high risk for bleeding is a step closer to potential US regulatory approval.  

As reported earlier, LEADERS FREE showed that in a European population, high-bleeding-risk patients who received this biolimus-coated stent vs a bare metal stent — both with only 30 days of dual antiplatelet therapy (DAPT) — had better 1-year efficacy and safety outcomes. The device has been commercially available in Europe since 2013.

Now, LEADERS FREE II shows similar findings in patients in North American practice.

That is, "by enrolling more than half of the patients in North America, LEADERS FREE II supports the generalizability of the findings of both studies to patients on both sides of the Atlantic," co-principal investigator Mitchell W. Krucoff, MD, from Duke University, Durham, North Carolina, said at a press conference here at Transcatheter Cardiovascular Therapeutics (TCT) 2018.

The trial also sounds an alarm for current practice at some US centers, Krucoff told theheart.org | Medscape Cardiology.

The LEADERS FREE trials suggest, he said, "that our intuitive behavior in practice of putting bare-metal stents in patients whom we know are at high bleeding risks...is actually a safety signal that we're potentially doing harm."

Some US centers are "still putting bare-metal stents in double-digit numbers" of percutaneous coronary intervention (PCIs) in their institutions, he noted, so he feels bringing this stent forward with a label for 30 days of DAPT in high-bleeding-risk patients should be embraced by the US Food and Drug Administration.

However, even if the device is approved, there are still a lot of unanswered questions, he conceded, such as whether this platform is unique or different than other state-of-the-art drug-eluting-stent (DES) platforms, or whether 30 days of DAPT vs 3 months or 6 months is preferable.  

Press conference co-moderator David J. Cohen, MD, from University of Missouri- Kansas City, said it's time to do a trial in high-bleeding-risk patients with thin-strut drug-eluting stents "to see if we can achieve safety and efficacy beyond" what was seen with polymer-free drug-coated stents.

"Absolutely," agreed panel member Antonio Colombo, MD, University of Milan, Italy.

"Right Now, It's About Safety"

To theheart.org | Medscape Cardiology, Colombo elaborated. "This basically confirms the result of LEADERS FREE I, and I think it's a good reason to pull bare-metal stents off the shelf, unless you don't have the biolimus polymer-free eluting stent" available.

Moreover, he feels it is now time to do another trial where the biolimus polymer-free stent is compared with a new-generation thin-strut reabsorbable polymer or even the XIENCE (Abbott) gold standard, second-generation DES, in high-risk-for-bleeding situations, he continued, "because, as you saw, the target lesion revascularization for biolimus is relatively high."

Currently, in Europe, "when we have a high-bleeding-risk patient, we still give a drug-eluting stent and maybe we continue DAPT for a couple of months or 3 months," Colombo said.

Sunil V. Rao, MD, from Duke University, told theheart.org | Medscape Cardiology that "the 10,00-foot takeaway summary of this study is that in a high-bleeding-risk patient who requires PCI, the biolimus A9 BioFreedom stent is preferred over bare-metal stents."

"Until we have more data on contemporary DES in this particular population," he continued, "my personal view is that we probably should be using the drug-coated stent in these patients."

"Right now, in 2018, it's really about the safety," Rao added. "Can we stop DAPT [sooner] in these patients who are high bleeding risk and prevent them from developing stent thrombosis or cardiac death?"

These two trials "showed that this stent will help you achieve that," he said.


LEADERS FREE II aimed to test the reproducibility of LEADERS FREE —that is, the safety and efficacy of this drug-coated stent with 30 days of DAPT in high-bleeding-risk patients — in an independent prospective cohort, Krucoff explained.

It also aimed to see whether the LEADERS FREE findings would apply to North American clinical practice.

The trial had a single-arm prospective design, he pointed out, because, based on LEADERS FREE, it would have been unethical to randomly assign these patients to a bare-metal stent.

It enrolled patients with the same high-bleeding-risk criteria as in LEADERS FREE, which included age 75 years or older, renal disease, anemia, or prior stroke.

Eligible study patients included those "who have been excluded from every pivotal DES study and every pivotal DAPT study," Krucoff noted.

The control group in LEADERS FREE II consisted of the 1189 patients in LEADERS FREE who were in the bare-metal-stent group.

In LEADERS FREE II, the primary safety endpoint was a composite of cardiac death and myocardial infarction (MI) at 1 year, and the primary efficacy endpoint was target-lesion revascularization at 1 year.

Patients in the investigative device group and in the control group were matched for 40 baseline variables and then placed into five quintiles.

The primary safety and efficacy endpoints were the overall averages from the five quintiles.

More than half of the 1203 patients in LEADERS FREE II were enrolled at North American sites (594 patients in the United States and 167 patients in Canada) and the rest were enrolled in Denmark, France, Germany, Italy, and the United Kingdom.

Most patients had more than one bleeding risk factor; overall, patients had an average of 1.74 bleeding risk factors. About two thirds of patients were age 75 years or older, and about a third of patients were receiving anticoagulants.

For the primary efficacy outcome, at 1 year, 12.3% of patients in the bare-metal-stent group vs 8.6% of patients in the drug-coated-stent group had had an MI or had died of cardiac causes (P = .0025 for superiority).

Similar percentages of patients in both groups had stent thrombosis.

For the primary safety outcome, at 1 year, 9.3% of patients in the bare-metal-stent group vs 6.1% of patients in the drug-coated-stent group had target lesion revascularization (P = .0111 for superiority).

More patients in the bare-metal-stent group required urgent target-lesion revascularization (5.6% vs 3.7%).

The efficacy and safety results were better in the drug-coated stent group for all patient subgroups, except that patients with renal failure at admission were more likely to have target-lesion revascularization if they received the drug-coated stent.

"We Have a Lot More to Learn"

"In the United States, if we took bare-metal stents off the shelf tomorrow," Krucoff said, "we have a lot of good drug-eluting stents we can use."

However, "the degree that we can protect patients from thrombotic complications, while reducing...medical thrombotic therapy that triggers bleeding, that's a balance," Krucoff said.

Whether it's the biolimus or the absence of polymer that actually achieves that balance better than a terrific durable polymer or a bioabsorbable polymer, he continued, "I don't think we know the answer... We have a lot to learn, if we're honest."

For Colombo, "the 2% stent thrombosis is a concern" because it is three times higher than in other trials.  

"I totally agree," Krucoff said. "If I'm actively bleeding, my clotting system is very active. So, is 2% good? Is that bad? I think we just need more work" to determine this.  

"This is an important field where we need [more] studies," Colombo agreed, because currently "we are really moving a little bit by personal feeling without any good data."

Krucoff discloses that he receives grant and research support from Abbott Vascular and consulting fess or honoraria from Biosensors, Boston Scientific, CSI, Medtronic, OrbusNeich, and Turumo.

Transcatheter Cardiovascular Therapeutics (TCT) 2018. Presented September 22, 2018.

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