New Resolute Coronary Stent Shows Good Diabetes and Safety Outcomes

NEW ORLEANS – Presuming that the Resolute zotarolimus-eluting coronary stent enters the U.S. market within the next year, interventionalists likely will rely on data from two key studies to weigh how it matches up against its main competition, the Xience V/Promus everolimus-eluting coronary stent.

Two features seemed to especially capture the attention of the cardiologists who reported the data at the annual meeting of the American College of Cardiology and those who heard it: the impressive performance of the zotarolimus-eluting stent (ZES) in patients with diabetes, and the long-term safety of the ZES compared with the everolimus-eluting stent (EES) for stent thrombosis.

The two studies included the RESOLUTE All Comers trial, which compared the ZES against the EES in a randomized trial of 2,292 European patients for whom follow-up now extends to 2 years. The second study, RESOLUTE US, evaluated the new ZES in a series of 1,402 U.S. patients with a high, 34% prevalence of diabetes; this study had a special focus on the stent’s performance in the 150 narrow, 2.25-mm-diameter arteries included in the series.

The roughly 2,500 ZES recipients included in these two studies form about half of the 5,227 total patient worldwide experience with the stent to date, and constituted what Medronic, the company developing the Resolute ZES, submitted to the Food and Drug Administration on April 1 for marketing approval and labeling.

One major take on these data by experts was that the ZES showed good overall performance that matched well with the performance of the EES.

"I think Xience/Promus and Resolute represent the state of the art for current-generation drug-eluting stents. Choosing between them would be very difficult. They seemed to be fairly equivalent for most of the important safety and efficacy metrics. They are both superb," said Dr. Martin B. Leon, director of the Center for Interventional Vascular Therapy at Columbia University in New York, and lead investigator for the RESOLUTE US study.

But other interventionalists hearing the data from both studies weren’t as completely convinced.

"My initial take on the data is that [the ZES] doesn’t seem to be better than the Xience stent, which is a very good stent and the dominant stent we use [in the United States] at this time," commented Dr. Abhiram Prasad, an interventional cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. "Solely on the basis of these data, I don’t think I would foresee a major shift in our use of the Xience stent," he said in an interview.

Safety concerns with the ZES date back to the initial, 12-month follow-up report, the first indication that the ZES fell short, compared with the EES on the rate of stent thrombosis in the RESOLUTE All Comers trial. The New England Journal of Medicine report last year documented 18 patients (1.6%) with definite or probable stent thrombosis in the ZES arm, compared with 8 cases (0.7%) of definite or probable stent thrombosis in the EES group, a significant difference (N. Engl. J. Med. 2010;363:136-46).

The new, 24-month follow-up data provided some reassurance on safety, in that the stent thrombosis gap between the two stents stayed stable. During an extra year of follow-up, three new cases of definite or probable stent thrombosis occurred in each of the two treatment arms, said Dr. Patrick W. Serruys, professor of interventional cardiology at Erasmus University and the Thoraxcentrum, Rotterdam, and lead investigator for the RESOLUTE All Comers trial. Aside from this one early safety deviation, the ZES and EES continued to show virtually identical efficacy performance through the 2 years of study, he showed in the updated data. Concurrently with his report at the meeting, the results appeared in an article published in the Lancet (Lancet 2011 April 4 [doi:10.1016/S0140-6736(11)60404-2]).

Dr. Serruys, as well as others, chalked up the early difference in stent thrombosis rates to chance, and to some isolated poor performance in certain sites undertaking the coronary interventions.

"Numerically, the stent thrombosis is very small, a difference of 21 versus 11 patients in more than 2,000 total patients. It could be the play of chance," Dr. Serruys said.

The RESOLUTE US results seemed to add to the safety assurance. In those 1,402 patients, 2 cases (0.1%) of stent thrombosis occurred during 12 months of tracking. Concurrently with Dr. Leon’s report, the RESOLUTE US results appeared in an article in the Journal of the American College of Cardiology (J. Amer. Coll. Cardiol. 2011 April 4 [doi:10.1016/j.jacc.2011.03.005]).

"This is one of the lowest 1-year stent thrombosis rates ever reported," noted Dr. Leon. "I take from this that it’s a safe stent. There was anxiety when RESOLUTE All Comers suggested a higher than expected stent thrombosis rate compared with Xience. The [RESOLUTE US] data help us realize that we need data density to get our hands around stent thrombosis. I’m not sure that 0.1% is the correct number either. By chance you’ll see study variations."

The pattern of some of the earliest cases of stent thrombosis in RESOLUTE All Comers suggested that it may have been caused more by operator failings and less by problems with the stent itself. During the study’s first 30 days, stent thrombosis occurred in nine ZES patients and one EES patient, making up most of the differential that wound up haunting the ZES arm through the next 2 years. "Stent thrombosis during the first 30 days is procedure related," and generally the stent itself plays no role, said Dr. Alan C. Yeung, professor of medicine and director of cardiac catheterization at Stanford (Calif.) University in Palo Alto.

"Whether it’s a real difference or a play of chance remains undetermined," commented Dr. Mitchell W. Krucoff, a professor of medicine and interventional cardiologist at Duke University in Durham, N.C. "These types of differences [21 patients versus 11 patients] are not certain at a statistical level." He called the question of a safety difference between the two stents "an open question," adding that "all the rest is superimposable" between the ZES and EES.

So if the ZES hopes to wrest any market share from the EES when it hits the U.S. market, it may need to have something to distinguish it, and that something may be an FDA-approved indication for treatment of coronary stenoses in patients with diabetes. At least that’s what Medtronic is hoping for. The company included that application in its submission to the FDA, Jason Fontana, Ph.D., senior director for clinical communication at Medtronic, said in an interview. If the ZES gets this indication, it will make the device unique. No other coronary stent now on the U.S. market carries that indication in its label.

"The diabetes subgroup was large enough, and the diabetes analysis was prespecified" in RESOLUTE US, Dr. Leon said in an interview. "If you include this subgroup, and the RESOLUTE All Comers diabetes subgroup, you have a robust enough population to justify consideration for approval, I think," he said.

"The results were quite substantial," with a 3.0% rate of target-lesion revascularization among the patients with diabetes, compared with a 2.0% rate for the entire main cohort of the study. "Usually you see more of a bump in patients with diabetes," he said. "To see a 3% repeat revascularization rate in patients with diabetes is very encouraging. I think if the stent gets this indication it may have an impact. It’s an important consideration."

But even if the diabetes indication works out, will interventionalists be swayed by that, or by the data?

"An issue is, to what extent can a single trial address a subgroup?" said Dr. Krucoff. "To what degree is there statistical guidance that in the real world [the ZES] would live up to this measure?"

"I don’t think I’d put a lot of emphasis of my decision-making on the [RESOLUTE US] data, because a problem with all [stenting] studies is that the rates are constantly improving, so the new device can appear to be better," said Dr. Prasad. "The study did not use a SYNTAX score to give us an idea of how complex the patients were. Unless we know about the complexity of the disease in the diabetes patients, I’m not sure we can call it a superior performance than what one would expect in today’s practice. Even if [the ZES] was approved for use in patients with diabetes, I don’t think in my practice I’d pick it to use in those patients. They’d need to do a randomized study in patients with diabetes to convince me" that it was better than the EES, Dr. Prasad said.

Dr. Serruys said he had no disclosures. Dr. Prasad said he had no disclosures. Dr. Leon said that he serves as an unpaid consultant to Abbott, Boston Scientific, and Medtronic. Dr. Yeung said that he serves on the scientific advisory board of Medtronic; he is also a consultant for Abbott Vascular, Boston Scientific, and Cordis, and has received research grants from Boston Scientific, Edwards, and Medtronic. Dr. Fontana is an employee of Medtronic. Dr. Krucoff said that he has been a consultant to or has received honoraria from Abbott, Biosensors, Cardiomind, Cordis Johnson & Johnson, Medtronic, Merck, Micelle, OrbusNeich, Prescient, Sanofi-Aventis, and Terumo.

NEW ORLEANS – Presuming that the Resolute zotarolimus-eluting coronary stent enters the U.S. market within the next year, interventionalists likely will rely on data from two key studies to weigh how it matches up against its main competition, the Xience V/Promus everolimus-eluting coronary stent.

Two features seemed to especially capture the attention of the cardiologists who reported the data at the annual meeting of the American College of Cardiology and those who heard it: the impressive performance of the zotarolimus-eluting stent (ZES) in patients with diabetes, and the long-term safety of the ZES compared with the everolimus-eluting stent (EES) for stent thrombosis.

The two studies included the RESOLUTE All Comers trial, which compared the ZES against the EES in a randomized trial of 2,292 European patients for whom follow-up now extends to 2 years. The second study, RESOLUTE US, evaluated the new ZES in a series of 1,402 U.S. patients with a high, 34% prevalence of diabetes; this study had a special focus on the stent’s performance in the 150 narrow, 2.25-mm-diameter arteries included in the series.

The roughly 2,500 ZES recipients included in these two studies form about half of the 5,227 total patient worldwide experience with the stent to date, and constituted what Medronic, the company developing the Resolute ZES, submitted to the Food and Drug Administration on April 1 for marketing approval and labeling.

One major take on these data by experts was that the ZES showed good overall performance that matched well with the performance of the EES.

"I think Xience/Promus and Resolute represent the state of the art for current-generation drug-eluting stents. Choosing between them would be very difficult. They seemed to be fairly equivalent for most of the important safety and efficacy metrics. They are both superb," said Dr. Martin B. Leon, director of the Center for Interventional Vascular Therapy at Columbia University in New York, and lead investigator for the RESOLUTE US study.

But other interventionalists hearing the data from both studies weren’t as completely convinced.

"My initial take on the data is that [the ZES] doesn’t seem to be better than the Xience stent, which is a very good stent and the dominant stent we use [in the United States] at this time," commented Dr. Abhiram Prasad, an interventional cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. "Solely on the basis of these data, I don’t think I would foresee a major shift in our use of the Xience stent," he said in an interview.

Safety concerns with the ZES date back to the initial, 12-month follow-up report, the first indication that the ZES fell short, compared with the EES on the rate of stent thrombosis in the RESOLUTE All Comers trial. The New England Journal of Medicine report last year documented 18 patients (1.6%) with definite or probable stent thrombosis in the ZES arm, compared with 8 cases (0.7%) of definite or probable stent thrombosis in the EES group, a significant difference (N. Engl. J. Med. 2010;363:136-46).

The new, 24-month follow-up data provided some reassurance on safety, in that the stent thrombosis gap between the two stents stayed stable. During an extra year of follow-up, three new cases of definite or probable stent thrombosis occurred in each of the two treatment arms, said Dr. Patrick W. Serruys, professor of interventional cardiology at Erasmus University and the Thoraxcentrum, Rotterdam, and lead investigator for the RESOLUTE All Comers trial. Aside from this one early safety deviation, the ZES and EES continued to show virtually identical efficacy performance through the 2 years of study, he showed in the updated data. Concurrently with his report at the meeting, the results appeared in an article published in the Lancet (Lancet 2011 April 4 [doi:10.1016/S0140-6736(11)60404-2]).

Dr. Serruys, as well as others, chalked up the early difference in stent thrombosis rates to chance, and to some isolated poor performance in certain sites undertaking the coronary interventions.

"Numerically, the stent thrombosis is very small, a difference of 21 versus 11 patients in more than 2,000 total patients. It could be the play of chance," Dr. Serruys said.

The RESOLUTE US results seemed to add to the safety assurance. In those 1,402 patients, 2 cases (0.1%) of stent thrombosis occurred during 12 months of tracking. Concurrently with Dr. Leon’s report, the RESOLUTE US results appeared in an article in the Journal of the American College of Cardiology (J. Amer. Coll. Cardiol. 2011 April 4 [doi:10.1016/j.jacc.2011.03.005]).

"This is one of the lowest 1-year stent thrombosis rates ever reported," noted Dr. Leon. "I take from this that it’s a safe stent. There was anxiety when RESOLUTE All Comers suggested a higher than expected stent thrombosis rate compared with Xience. The [RESOLUTE US] data help us realize that we need data density to get our hands around stent thrombosis. I’m not sure that 0.1% is the correct number either. By chance you’ll see study variations."

The pattern of some of the earliest cases of stent thrombosis in RESOLUTE All Comers suggested that it may have been caused more by operator failings and less by problems with the stent itself. During the study’s first 30 days, stent thrombosis occurred in nine ZES patients and one EES patient, making up most of the differential that wound up haunting the ZES arm through the next 2 years. "Stent thrombosis during the first 30 days is procedure related," and generally the stent itself plays no role, said Dr. Alan C. Yeung, professor of medicine and director of cardiac catheterization at Stanford (Calif.) University in Palo Alto.

"Whether it’s a real difference or a play of chance remains undetermined," commented Dr. Mitchell W. Krucoff, a professor of medicine and interventional cardiologist at Duke University in Durham, N.C. "These types of differences [21 patients versus 11 patients] are not certain at a statistical level." He called the question of a safety difference between the two stents "an open question," adding that "all the rest is superimposable" between the ZES and EES.

So if the ZES hopes to wrest any market share from the EES when it hits the U.S. market, it may need to have something to distinguish it, and that something may be an FDA-approved indication for treatment of coronary stenoses in patients with diabetes. At least that’s what Medtronic is hoping for. The company included that application in its submission to the FDA, Jason Fontana, Ph.D., senior director for clinical communication at Medtronic, said in an interview. If the ZES gets this indication, it will make the device unique. No other coronary stent now on the U.S. market carries that indication in its label.

"The diabetes subgroup was large enough, and the diabetes analysis was prespecified" in RESOLUTE US, Dr. Leon said in an interview. "If you include this subgroup, and the RESOLUTE All Comers diabetes subgroup, you have a robust enough population to justify consideration for approval, I think," he said.

"The results were quite substantial," with a 3.0% rate of target-lesion revascularization among the patients with diabetes, compared with a 2.0% rate for the entire main cohort of the study. "Usually you see more of a bump in patients with diabetes," he said. "To see a 3% repeat revascularization rate in patients with diabetes is very encouraging. I think if the stent gets this indication it may have an impact. It’s an important consideration."

But even if the diabetes indication works out, will interventionalists be swayed by that, or by the data?

"An issue is, to what extent can a single trial address a subgroup?" said Dr. Krucoff. "To what degree is there statistical guidance that in the real world [the ZES] would live up to this measure?"

"I don’t think I’d put a lot of emphasis of my decision-making on the [RESOLUTE US] data, because a problem with all [stenting] studies is that the rates are constantly improving, so the new device can appear to be better," said Dr. Prasad. "The study did not use a SYNTAX score to give us an idea of how complex the patients were. Unless we know about the complexity of the disease in the diabetes patients, I’m not sure we can call it a superior performance than what one would expect in today’s practice. Even if [the ZES] was approved for use in patients with diabetes, I don’t think in my practice I’d pick it to use in those patients. They’d need to do a randomized study in patients with diabetes to convince me" that it was better than the EES, Dr. Prasad said.

Dr. Serruys said he had no disclosures. Dr. Prasad said he had no disclosures. Dr. Leon said that he serves as an unpaid consultant to Abbott, Boston Scientific, and Medtronic. Dr. Yeung said that he serves on the scientific advisory board of Medtronic; he is also a consultant for Abbott Vascular, Boston Scientific, and Cordis, and has received research grants from Boston Scientific, Edwards, and Medtronic. Dr. Fontana is an employee of Medtronic. Dr. Krucoff said that he has been a consultant to or has received honoraria from Abbott, Biosensors, Cardiomind, Cordis Johnson & Johnson, Medtronic, Merck, Micelle, OrbusNeich, Prescient, Sanofi-Aventis, and Terumo.

NEW ORLEANS – Presuming that the Resolute zotarolimus-eluting coronary stent enters the U.S. market within the next year, interventionalists likely will rely on data from two key studies to weigh how it matches up against its main competition, the Xience V/Promus everolimus-eluting coronary stent.

Two features seemed to especially capture the attention of the cardiologists who reported the data at the annual meeting of the American College of Cardiology and those who heard it: the impressive performance of the zotarolimus-eluting stent (ZES) in patients with diabetes, and the long-term safety of the ZES compared with the everolimus-eluting stent (EES) for stent thrombosis.

The two studies included the RESOLUTE All Comers trial, which compared the ZES against the EES in a randomized trial of 2,292 European patients for whom follow-up now extends to 2 years. The second study, RESOLUTE US, evaluated the new ZES in a series of 1,402 U.S. patients with a high, 34% prevalence of diabetes; this study had a special focus on the stent’s performance in the 150 narrow, 2.25-mm-diameter arteries included in the series.

The roughly 2,500 ZES recipients included in these two studies form about half of the 5,227 total patient worldwide experience with the stent to date, and constituted what Medronic, the company developing the Resolute ZES, submitted to the Food and Drug Administration on April 1 for marketing approval and labeling.

One major take on these data by experts was that the ZES showed good overall performance that matched well with the performance of the EES.

"I think Xience/Promus and Resolute represent the state of the art for current-generation drug-eluting stents. Choosing between them would be very difficult. They seemed to be fairly equivalent for most of the important safety and efficacy metrics. They are both superb," said Dr. Martin B. Leon, director of the Center for Interventional Vascular Therapy at Columbia University in New York, and lead investigator for the RESOLUTE US study.

But other interventionalists hearing the data from both studies weren’t as completely convinced.

"My initial take on the data is that [the ZES] doesn’t seem to be better than the Xience stent, which is a very good stent and the dominant stent we use [in the United States] at this time," commented Dr. Abhiram Prasad, an interventional cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. "Solely on the basis of these data, I don’t think I would foresee a major shift in our use of the Xience stent," he said in an interview.

Safety concerns with the ZES date back to the initial, 12-month follow-up report, the first indication that the ZES fell short, compared with the EES on the rate of stent thrombosis in the RESOLUTE All Comers trial. The New England Journal of Medicine report last year documented 18 patients (1.6%) with definite or probable stent thrombosis in the ZES arm, compared with 8 cases (0.7%) of definite or probable stent thrombosis in the EES group, a significant difference (N. Engl. J. Med. 2010;363:136-46).

The new, 24-month follow-up data provided some reassurance on safety, in that the stent thrombosis gap between the two stents stayed stable. During an extra year of follow-up, three new cases of definite or probable stent thrombosis occurred in each of the two treatment arms, said Dr. Patrick W. Serruys, professor of interventional cardiology at Erasmus University and the Thoraxcentrum, Rotterdam, and lead investigator for the RESOLUTE All Comers trial. Aside from this one early safety deviation, the ZES and EES continued to show virtually identical efficacy performance through the 2 years of study, he showed in the updated data. Concurrently with his report at the meeting, the results appeared in an article published in the Lancet (Lancet 2011 April 4 [doi:10.1016/S0140-6736(11)60404-2]).

Dr. Serruys, as well as others, chalked up the early difference in stent thrombosis rates to chance, and to some isolated poor performance in certain sites undertaking the coronary interventions.

"Numerically, the stent thrombosis is very small, a difference of 21 versus 11 patients in more than 2,000 total patients. It could be the play of chance," Dr. Serruys said.

The RESOLUTE US results seemed to add to the safety assurance. In those 1,402 patients, 2 cases (0.1%) of stent thrombosis occurred during 12 months of tracking. Concurrently with Dr. Leon’s report, the RESOLUTE US results appeared in an article in the Journal of the American College of Cardiology (J. Amer. Coll. Cardiol. 2011 April 4 [doi:10.1016/j.jacc.2011.03.005]).

"This is one of the lowest 1-year stent thrombosis rates ever reported," noted Dr. Leon. "I take from this that it’s a safe stent. There was anxiety when RESOLUTE All Comers suggested a higher than expected stent thrombosis rate compared with Xience. The [RESOLUTE US] data help us realize that we need data density to get our hands around stent thrombosis. I’m not sure that 0.1% is the correct number either. By chance you’ll see study variations."

The pattern of some of the earliest cases of stent thrombosis in RESOLUTE All Comers suggested that it may have been caused more by operator failings and less by problems with the stent itself. During the study’s first 30 days, stent thrombosis occurred in nine ZES patients and one EES patient, making up most of the differential that wound up haunting the ZES arm through the next 2 years. "Stent thrombosis during the first 30 days is procedure related," and generally the stent itself plays no role, said Dr. Alan C. Yeung, professor of medicine and director of cardiac catheterization at Stanford (Calif.) University in Palo Alto.

"Whether it’s a real difference or a play of chance remains undetermined," commented Dr. Mitchell W. Krucoff, a professor of medicine and interventional cardiologist at Duke University in Durham, N.C. "These types of differences [21 patients versus 11 patients] are not certain at a statistical level." He called the question of a safety difference between the two stents "an open question," adding that "all the rest is superimposable" between the ZES and EES.

So if the ZES hopes to wrest any market share from the EES when it hits the U.S. market, it may need to have something to distinguish it, and that something may be an FDA-approved indication for treatment of coronary stenoses in patients with diabetes. At least that’s what Medtronic is hoping for. The company included that application in its submission to the FDA, Jason Fontana, Ph.D., senior director for clinical communication at Medtronic, said in an interview. If the ZES gets this indication, it will make the device unique. No other coronary stent now on the U.S. market carries that indication in its label.

"The diabetes subgroup was large enough, and the diabetes analysis was prespecified" in RESOLUTE US, Dr. Leon said in an interview. "If you include this subgroup, and the RESOLUTE All Comers diabetes subgroup, you have a robust enough population to justify consideration for approval, I think," he said.

"The results were quite substantial," with a 3.0% rate of target-lesion revascularization among the patients with diabetes, compared with a 2.0% rate for the entire main cohort of the study. "Usually you see more of a bump in patients with diabetes," he said. "To see a 3% repeat revascularization rate in patients with diabetes is very encouraging. I think if the stent gets this indication it may have an impact. It’s an important consideration."

But even if the diabetes indication works out, will interventionalists be swayed by that, or by the data?

"An issue is, to what extent can a single trial address a subgroup?" said Dr. Krucoff. "To what degree is there statistical guidance that in the real world [the ZES] would live up to this measure?"

"I don’t think I’d put a lot of emphasis of my decision-making on the [RESOLUTE US] data, because a problem with all [stenting] studies is that the rates are constantly improving, so the new device can appear to be better," said Dr. Prasad. "The study did not use a SYNTAX score to give us an idea of how complex the patients were. Unless we know about the complexity of the disease in the diabetes patients, I’m not sure we can call it a superior performance than what one would expect in today’s practice. Even if [the ZES] was approved for use in patients with diabetes, I don’t think in my practice I’d pick it to use in those patients. They’d need to do a randomized study in patients with diabetes to convince me" that it was better than the EES, Dr. Prasad said.

Dr. Serruys said he had no disclosures. Dr. Prasad said he had no disclosures. Dr. Leon said that he serves as an unpaid consultant to Abbott, Boston Scientific, and Medtronic. Dr. Yeung said that he serves on the scientific advisory board of Medtronic; he is also a consultant for Abbott Vascular, Boston Scientific, and Cordis, and has received research grants from Boston Scientific, Edwards, and Medtronic. Dr. Fontana is an employee of Medtronic. Dr. Krucoff said that he has been a consultant to or has received honoraria from Abbott, Biosensors, Cardiomind, Cordis Johnson & Johnson, Medtronic, Merck, Micelle, OrbusNeich, Prescient, Sanofi-Aventis, and Terumo.