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SAN DIEGO – Positive results of the LEADERS FREE II trial in patients with high bleeding risk undergoing percutaneous coronary intervention may pave the way for approval of a new drug-coated stent in the United States and possibly spell the end for bare-metal stents.
The stent studied – a polymer-free umirolimus-coated stent – is currently marketed in Europe as BioFreedom (Biosensors International). It outperformed a very similar bare-metal stent (Gazelle, manufactured by Biosensors Interventional Technologies) in the randomized LEADERS FREE trial, which was conducted outside the United States (N Engl J Med. 2015 Nov 19;373[21]:2038-47). The single-arm LEADERS FREE II (NCT02843633) trial was undertaken to confirm those findings, assess their generalizability in a North American population, and obtain data to support regulatory approval of the stent in the United States, explained presenting author Mitchell W. Krucoff, MD, a professor of medicine and member in the Duke Clinical Research Institute, Duke University, Durham, N.C. All patients received drug-coated stents because it was considered unethical to randomize any to bare-metal stents after the preceding trial. As in that trial, all patients received 1 month of dual-antiplatelet therapy.
Compared with the 1,211 propensity-matched patients treated with bare metal stents in the LEADERS FREE trial, the 1,203 patients treated with drug-coated stents in the LEADERS FREE II trial had a 33% lower risk of primary safety events (a composite of cardiac death and myocardial infarction) and a 37% lower risk of primary efficacy events (clinically driven target lesion revascularization) at 1 year, according to the study’s main results. Secondary outcomes were all similar or better with the drug-coated stents.
“This study demonstrates reproducibility of the randomized LEADERS FREE findings showing superior safety … and superior effectiveness … of the drug-coated stent over the bare-metal stent,” Dr. Krucoff said. “This study also, by enrolling more than half of patients in North America, supports the generalizability of the findings to patients on both sides of the Atlantic.”
Parsing the findings
When asked whether the Food and Drug Administration should approve this stent and whether he would use it for his patients, Dr. Krucoff gave a “yes, but …” reply. “The but here is, we have a lot to learn in this area. These are patients who by and large have been excluded from every pivotal drug-eluting stent study and every pivotal dual-antiplatelet study,” he elaborated. It is therefore unclear, for example, how the stent will perform as more are treated and what the optimal duration of dual-antiplatelet therapy is. Nonetheless, given that these patients make up a sizable share of the PCI [percutaneous coronary intervention] population and that some centers still commonly use bare-metal stents, “I think bringing this stent forward with a label for 30 days [of dual-antiplatelet therapy] in high bleeding risk patients is a yes.”
“To me, the main driving factor for an expeditious [approval] process is, if you put a conservatively critical eye to this, you could say that LEADERS FREE alerts us to a safety signal [about] our intuitive behavior practice of putting bare-metal stents in patients who we know are at high bleeding risk, so we are only going to treat them with 30 days of dual-antiplatelet therapy. There is actually a safety signal that we are potentially doing harm, based on at least one look at this,” Dr. Krucoff added. “There is no question, I think FDA decisions are primarily driven by safety concerns. The unusual thing here is, it’s not a safety concern as a defect in the device, it’s a safety concern relative to our current practice.”
Trial details
On average, the patients enrolled in LEADERS FREE II were generally similar to counterparts enrolled in LEADERS FREE and had an average of 1.74 factors putting them at high risk for bleeding, according to Dr. Krucoff. Of note, it was an all-comers trial in that there was no restriction on coronary anatomy, lesion complexity, or clinical presentation.
Results reported at the meeting, which was sponsored by the Cardiovascular Research Foundation, showed that the rate of the primary safety endpoint – the composite of cardiac death and myocardial infarction at 1 year – was 8.6% with the drug-coated stent and 12.3% with the bare-metal stent, for an absolute risk difference of –3.7% (hazard ratio, 0.67; P for noninferiority less than .0001; P for superiority = .0025).
Findings were significant for each component individually and were generally consistent across patient subgroups, Dr. Krucoff said. Secondary safety endpoints showed “no sign of a safety signal or concern with the drug-coated stent platform with 30 days of dual-antiplatelet therapy.”
In an additional analysis, the unadjusted rates of the primary safety endpoint were was 8.6% and 9.0% with the drug-coated stent in the LEADERS FREE II and the LEADERS FREE populations, respectively, compared with 12.4% with the bare-metal stent.
The rate of the primary efficacy endpoint – clinically driven target lesion revascularization at 1 year – was 6.1% with the drug-coated stent and 9.3% with the bare-metal stent, for an absolute risk difference of –3.2% (hazard ratio, 0.63; P for superiority = .0111). Findings again were consistently in favor of the drug-coated stent across most patient subgroups, with the exception of patients having renal failure at the time of admission. Secondary efficacy endpoints all significantly favored that stent as well.
The 1-year rates of bleeding overall and by severity were statistically indistinguishable, Dr. Krucoff reported. The rate of severe bleeding – Bleeding Academic Research Consortium (BARC) type 3-5 – was 7.0% with the drug-coated stent and 7.3% with the bare metal stent.
Dr. Krucoff disclosed that he has various affiliations and financial relationships with Abbott Vascular, Biosensors, Boston Scientific, CSI, Medtronic, OrbusNeich, and Terumo. The trial was sponsored by Biosensors.
SAN DIEGO – Positive results of the LEADERS FREE II trial in patients with high bleeding risk undergoing percutaneous coronary intervention may pave the way for approval of a new drug-coated stent in the United States and possibly spell the end for bare-metal stents.
The stent studied – a polymer-free umirolimus-coated stent – is currently marketed in Europe as BioFreedom (Biosensors International). It outperformed a very similar bare-metal stent (Gazelle, manufactured by Biosensors Interventional Technologies) in the randomized LEADERS FREE trial, which was conducted outside the United States (N Engl J Med. 2015 Nov 19;373[21]:2038-47). The single-arm LEADERS FREE II (NCT02843633) trial was undertaken to confirm those findings, assess their generalizability in a North American population, and obtain data to support regulatory approval of the stent in the United States, explained presenting author Mitchell W. Krucoff, MD, a professor of medicine and member in the Duke Clinical Research Institute, Duke University, Durham, N.C. All patients received drug-coated stents because it was considered unethical to randomize any to bare-metal stents after the preceding trial. As in that trial, all patients received 1 month of dual-antiplatelet therapy.
Compared with the 1,211 propensity-matched patients treated with bare metal stents in the LEADERS FREE trial, the 1,203 patients treated with drug-coated stents in the LEADERS FREE II trial had a 33% lower risk of primary safety events (a composite of cardiac death and myocardial infarction) and a 37% lower risk of primary efficacy events (clinically driven target lesion revascularization) at 1 year, according to the study’s main results. Secondary outcomes were all similar or better with the drug-coated stents.
“This study demonstrates reproducibility of the randomized LEADERS FREE findings showing superior safety … and superior effectiveness … of the drug-coated stent over the bare-metal stent,” Dr. Krucoff said. “This study also, by enrolling more than half of patients in North America, supports the generalizability of the findings to patients on both sides of the Atlantic.”
Parsing the findings
When asked whether the Food and Drug Administration should approve this stent and whether he would use it for his patients, Dr. Krucoff gave a “yes, but …” reply. “The but here is, we have a lot to learn in this area. These are patients who by and large have been excluded from every pivotal drug-eluting stent study and every pivotal dual-antiplatelet study,” he elaborated. It is therefore unclear, for example, how the stent will perform as more are treated and what the optimal duration of dual-antiplatelet therapy is. Nonetheless, given that these patients make up a sizable share of the PCI [percutaneous coronary intervention] population and that some centers still commonly use bare-metal stents, “I think bringing this stent forward with a label for 30 days [of dual-antiplatelet therapy] in high bleeding risk patients is a yes.”
“To me, the main driving factor for an expeditious [approval] process is, if you put a conservatively critical eye to this, you could say that LEADERS FREE alerts us to a safety signal [about] our intuitive behavior practice of putting bare-metal stents in patients who we know are at high bleeding risk, so we are only going to treat them with 30 days of dual-antiplatelet therapy. There is actually a safety signal that we are potentially doing harm, based on at least one look at this,” Dr. Krucoff added. “There is no question, I think FDA decisions are primarily driven by safety concerns. The unusual thing here is, it’s not a safety concern as a defect in the device, it’s a safety concern relative to our current practice.”
Trial details
On average, the patients enrolled in LEADERS FREE II were generally similar to counterparts enrolled in LEADERS FREE and had an average of 1.74 factors putting them at high risk for bleeding, according to Dr. Krucoff. Of note, it was an all-comers trial in that there was no restriction on coronary anatomy, lesion complexity, or clinical presentation.
Results reported at the meeting, which was sponsored by the Cardiovascular Research Foundation, showed that the rate of the primary safety endpoint – the composite of cardiac death and myocardial infarction at 1 year – was 8.6% with the drug-coated stent and 12.3% with the bare-metal stent, for an absolute risk difference of –3.7% (hazard ratio, 0.67; P for noninferiority less than .0001; P for superiority = .0025).
Findings were significant for each component individually and were generally consistent across patient subgroups, Dr. Krucoff said. Secondary safety endpoints showed “no sign of a safety signal or concern with the drug-coated stent platform with 30 days of dual-antiplatelet therapy.”
In an additional analysis, the unadjusted rates of the primary safety endpoint were was 8.6% and 9.0% with the drug-coated stent in the LEADERS FREE II and the LEADERS FREE populations, respectively, compared with 12.4% with the bare-metal stent.
The rate of the primary efficacy endpoint – clinically driven target lesion revascularization at 1 year – was 6.1% with the drug-coated stent and 9.3% with the bare-metal stent, for an absolute risk difference of –3.2% (hazard ratio, 0.63; P for superiority = .0111). Findings again were consistently in favor of the drug-coated stent across most patient subgroups, with the exception of patients having renal failure at the time of admission. Secondary efficacy endpoints all significantly favored that stent as well.
The 1-year rates of bleeding overall and by severity were statistically indistinguishable, Dr. Krucoff reported. The rate of severe bleeding – Bleeding Academic Research Consortium (BARC) type 3-5 – was 7.0% with the drug-coated stent and 7.3% with the bare metal stent.
Dr. Krucoff disclosed that he has various affiliations and financial relationships with Abbott Vascular, Biosensors, Boston Scientific, CSI, Medtronic, OrbusNeich, and Terumo. The trial was sponsored by Biosensors.
SAN DIEGO – Positive results of the LEADERS FREE II trial in patients with high bleeding risk undergoing percutaneous coronary intervention may pave the way for approval of a new drug-coated stent in the United States and possibly spell the end for bare-metal stents.
The stent studied – a polymer-free umirolimus-coated stent – is currently marketed in Europe as BioFreedom (Biosensors International). It outperformed a very similar bare-metal stent (Gazelle, manufactured by Biosensors Interventional Technologies) in the randomized LEADERS FREE trial, which was conducted outside the United States (N Engl J Med. 2015 Nov 19;373[21]:2038-47). The single-arm LEADERS FREE II (NCT02843633) trial was undertaken to confirm those findings, assess their generalizability in a North American population, and obtain data to support regulatory approval of the stent in the United States, explained presenting author Mitchell W. Krucoff, MD, a professor of medicine and member in the Duke Clinical Research Institute, Duke University, Durham, N.C. All patients received drug-coated stents because it was considered unethical to randomize any to bare-metal stents after the preceding trial. As in that trial, all patients received 1 month of dual-antiplatelet therapy.
Compared with the 1,211 propensity-matched patients treated with bare metal stents in the LEADERS FREE trial, the 1,203 patients treated with drug-coated stents in the LEADERS FREE II trial had a 33% lower risk of primary safety events (a composite of cardiac death and myocardial infarction) and a 37% lower risk of primary efficacy events (clinically driven target lesion revascularization) at 1 year, according to the study’s main results. Secondary outcomes were all similar or better with the drug-coated stents.
“This study demonstrates reproducibility of the randomized LEADERS FREE findings showing superior safety … and superior effectiveness … of the drug-coated stent over the bare-metal stent,” Dr. Krucoff said. “This study also, by enrolling more than half of patients in North America, supports the generalizability of the findings to patients on both sides of the Atlantic.”
Parsing the findings
When asked whether the Food and Drug Administration should approve this stent and whether he would use it for his patients, Dr. Krucoff gave a “yes, but …” reply. “The but here is, we have a lot to learn in this area. These are patients who by and large have been excluded from every pivotal drug-eluting stent study and every pivotal dual-antiplatelet study,” he elaborated. It is therefore unclear, for example, how the stent will perform as more are treated and what the optimal duration of dual-antiplatelet therapy is. Nonetheless, given that these patients make up a sizable share of the PCI [percutaneous coronary intervention] population and that some centers still commonly use bare-metal stents, “I think bringing this stent forward with a label for 30 days [of dual-antiplatelet therapy] in high bleeding risk patients is a yes.”
“To me, the main driving factor for an expeditious [approval] process is, if you put a conservatively critical eye to this, you could say that LEADERS FREE alerts us to a safety signal [about] our intuitive behavior practice of putting bare-metal stents in patients who we know are at high bleeding risk, so we are only going to treat them with 30 days of dual-antiplatelet therapy. There is actually a safety signal that we are potentially doing harm, based on at least one look at this,” Dr. Krucoff added. “There is no question, I think FDA decisions are primarily driven by safety concerns. The unusual thing here is, it’s not a safety concern as a defect in the device, it’s a safety concern relative to our current practice.”
Trial details
On average, the patients enrolled in LEADERS FREE II were generally similar to counterparts enrolled in LEADERS FREE and had an average of 1.74 factors putting them at high risk for bleeding, according to Dr. Krucoff. Of note, it was an all-comers trial in that there was no restriction on coronary anatomy, lesion complexity, or clinical presentation.
Results reported at the meeting, which was sponsored by the Cardiovascular Research Foundation, showed that the rate of the primary safety endpoint – the composite of cardiac death and myocardial infarction at 1 year – was 8.6% with the drug-coated stent and 12.3% with the bare-metal stent, for an absolute risk difference of –3.7% (hazard ratio, 0.67; P for noninferiority less than .0001; P for superiority = .0025).
Findings were significant for each component individually and were generally consistent across patient subgroups, Dr. Krucoff said. Secondary safety endpoints showed “no sign of a safety signal or concern with the drug-coated stent platform with 30 days of dual-antiplatelet therapy.”
In an additional analysis, the unadjusted rates of the primary safety endpoint were was 8.6% and 9.0% with the drug-coated stent in the LEADERS FREE II and the LEADERS FREE populations, respectively, compared with 12.4% with the bare-metal stent.
The rate of the primary efficacy endpoint – clinically driven target lesion revascularization at 1 year – was 6.1% with the drug-coated stent and 9.3% with the bare-metal stent, for an absolute risk difference of –3.2% (hazard ratio, 0.63; P for superiority = .0111). Findings again were consistently in favor of the drug-coated stent across most patient subgroups, with the exception of patients having renal failure at the time of admission. Secondary efficacy endpoints all significantly favored that stent as well.
The 1-year rates of bleeding overall and by severity were statistically indistinguishable, Dr. Krucoff reported. The rate of severe bleeding – Bleeding Academic Research Consortium (BARC) type 3-5 – was 7.0% with the drug-coated stent and 7.3% with the bare metal stent.
Dr. Krucoff disclosed that he has various affiliations and financial relationships with Abbott Vascular, Biosensors, Boston Scientific, CSI, Medtronic, OrbusNeich, and Terumo. The trial was sponsored by Biosensors.
REPORTING FROM TCT 2018
Key clinical point: The polymer-free umirolimus (Biolimus A9)–coated stent is superior to the bare-metal stent in patients at high bleeding risk when used with a month of dual-antiplatelet therapy.
Major finding: The drug-coated stent reduced 1-year risks of the composite of cardiac death and MI by 33% and clinically driven target lesion revascularization by 37% when compared with matched controls.
Study details: A single-arm trial of 1,203 patients at high bleeding risk undergoing PCI who were given drug-coated stents with 1 month of dual-antiplatelet therapy who were compared with 1,211 propensity-matched historical control patients given bare-metal stents (LEADERS FREE II trial).
Disclosures: Dr. Krucoff has various affiliations/financial relationships with Abbott Vascular, Biosensors, Boston Scientific, CSI, Medtronic, OrbusNeich, and Terumo. The trial was sponsored by Biosensors.