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Medtronic Stent Data for Diabetic Patients Published
JACC: Cardiovascular Interventions Article Describes How the Resolute Integrity Zotarolimus-Eluting Stent Was Approved by the FDA for Use in Diabetics
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Medtronic's Resolute Integrity zotarolimus-eluting coronary stent
Medtronic's Resolute Integrity zotarolimus-eluting coronary stent
April 18, 2013 -- A little over a year ago, the FDA granted approval to Medtronic's Resolute Integrity zotarolimus-eluting coronary stent specifically for use in diabetic patients, currently the only drug-eluting stent to carry such an indication.

This week the peer-reviewed Journal of the American College of Cardiology: Cardiovascular Interventions published an article detailing the two-year pooled analysis of outcomes from Medtronic's international RESOLUTE Global Clinical Program of over 5,100 patients: how this data showed positive results for the interventional treatment of patients with diabetes, and how these outcomes led the FDA to approve the Resolute Integrity for use in diabetic patients.

Stents and Diabetes: A Complex Circle
Diabetes is a major risk factor for coronary artery disease (CAD), and coronary artery disease is the cause of death for almost 60% of diabetic patients. Compounding the problem is that it has been difficult to treat diabetic patients for CAD because they tend to have smaller coronary arteries and elevated blood-sugar levels, which can increase the rate of procedural complications and long-term safety risks.

Historically, long-term outcomes in diabetic patients who have been treated with angioplasty and stents have not equalled those for non-diabetic patients. Restenosis occurred more often, more frequent re-interventions became necessary and late stent thrombosis seemed to occur more often in diabetic patients. As a result, open heart coronary bypass graft surgery (CABG) is sometimes the recommended treatment, especially in complex coronary disease.

New Stents: New (and Equivalent) Outcomes
The outcomes from the pooled Resolute trials, however, show an entirely new picture: at two-years there were no statistically significant differences in any measures of outcomes between non-diabetic patients and those diabetic patients who were not insulin-dependent.

A performance goal was pre-determined in conjunction with the FDA in order to gain approval for the diabetic indication. A target vessel failure rate of 14.5% at 12 months in "less complex patients" was set, based on a number of previously published studies of drug-eluting stent outcomes in diabetic patients. The cohort of less complex patients was specified by the FDA in order to compare the Resolute's performance with other devices: in previous trials, complex diabetic patients were usually excluded, and so the authors analyzed this "less complex" cohort separately. The Resolute's TVF rate in these patients was only 7.8%, almost half that of the performance goal! Thus the FDA approved the new indication for use in diabetic patients.

Outcomes in More Complex Patients
However, several of the Resolute studies were real-world all-comers trials, and included the types of complex cases previously excluded in studies of diabetics (patients with acute myocardial infarction within 72 hours of the procedure, lesion length greater than 27 mm, more than two lesions/vessel, in-stent restenosis, unprotected left main lesions, bifurcation lesions, total occlusions, bypass grafts, thrombus, left ventricular ejection fraction lower than 30%, etc. So the authors also looked at the two year outcomes for the entire diabetic cohort, both more and less complex clinical and anatomical features, both insulin-dependent and non-insulin-dependent diabetics.

At two years, there was no statistically significant differences between the non-diabetic and diabetic patients who were not insulin-dependent across all measures of safety and efficacy. Stent thrombosis rates were also low in the entire patient cohort (0.8% for non-diabetics vs 1.2% for all diabetics, including insulin dependent). Late stent thrombosis rate, occurring after 30 days, one of the original concerns with drug-eluting stents, was very low (0.3% vs 0.4%).

Prof. Dr. Sigmund Silber
Prof. Dr. Sigmund Silber

Where there was a difference in outcomes, however, was in the insulin-dependent diabetics. A little more than a quarter of diabetics cannot be treated with medication and lifestyle modification alone and must take insulin -- and, for these patients, event rates were predictably higher, although significantly better than those seen with first generation drug-eluting or even bare metal stents. Commenting on this, the authors, headed by Prof. Dr. Sigmund Silber, director of the Heart Center at the Isar in Munich, Germany, concluded that, "...there is still an opportunity to improve the treatment of CAD in patients taking insulin, and coronary artery bypass surgery should be strongly considered as an alternative revascularization strategy in these patients—especially with multivessel disease—as recommended by European and U.S. guidelines."

Multiple Uses of the Resolute Pooled Dataset
While the conclusion of the analysis, that "patients with diabetes not taking insulin had similar clinical outcomes as patients without diabetes in all patient groups" is, of course, the central message, of additional interest is the way in which the five prospectively planned and harmonized studies of the RESOLUTE Global Clinical Program, some of which were begun over six years ago, were designed to yield a rich dataset: information about real world clinical scenarios and patient populations not seen in sufficient numbers in many previous stent trials.

An indication of how much more data is now being looked at in these studies is the fact that the number of diabetic patients in the RESOLUTE Program far exceeds the total number of patients of all types that were studied in the original Cypher or Taxus first generation drug-eluting stent trials.

In this specific paper, not only were diabetic patients studied, but a separate analysis delineated the outcomes of insulin-dependent diabetics vs. non-insulin-dependent patients. Previous analyses of the Resolute clinical program have yielded information about outcomes seen with longer stent lengths, leading to CE Mark and FDA approvals of new indications. Another recent study, again using data from the Resolute pool and published online last month in the journal Heart, concluded that overlapping Resolute stents was a safe and effective technique and had comparable outcomes to non-overlapping DES. Like the findings for diabetics, this may represent a paradigm shift for interventional technique and treatment, because overlapping first generation drug-eluting stents has always been associated with increased inflammation, delayed healing and increased adverse outcomes, including death and heart attack.

The overriding message from the Resolute Global Clinical Program dataset is that these newer generation drug-eluting stents have overcome many of the limitations of earlier devices and have in effect eliminated some of the long-held concerns about worse outcomes for most diabetic patients, or when using longer length stents or overlapping stents.

A press release from Medtronic, Inc. about this study follows below. We also urge those interested to read the very detailed analysis in JACC: Cardiovascular Interventions.

American College of Cardiology Journal Publishes Outcomes of Diabetes Patients Treated with Medtronic's Resolute Stent
Implanted Medical Device for Coronary Artery Disease Performed As Well In Study Subjects With Diabetes Who Were Not Taking Insulin As In Those Without Diabetes

April 15, 2013 -- Minneapolis -- The current issue of JACC: Cardiovascular Interventions, a peer-reviewed journal published by the American College of Cardiology, includes an article that describes how the Resolute Integrity drug-eluting stent from Medtronic, Inc. (NYSE: MDT) became the first and only device of its kind to be approved by the U.S. Food and Drug Administration (FDA) with a specific indication for treating the coronary artery disease of patients with diabetes mellitus.

A common comorbidity of coronary artery disease, diabetes affects approximately one-third of patients who receive coronary stents and historically has been associated with adverse clinical outcomes. New research presented in the journal article, however, shows that treatment with the Resolute drug-eluting stent led to similarly positive outcomes for diabetes patients who were not taking insulin and for patients without diabetes. It was sponsored by Medtronic.

Titled "Clinical Outcome of Patients With and Without Diabetes Mellitus After Percutaneous Coronary Intervention with the Resolute Zotarolimus-Eluting Stent" (R-ZES), the article presents the results of two separate analyses of patient-level data from the global RESOLUTE clinical program, which enrolled a total of 5,130 patients who received a Resolute drug-eluting stent as participants in one of five studies conducted in the United States and internationally.

The authors' conclusions state: "The R-ZES is safe and effective in patients with diabetes. Long-term clinical data of patients with non-insulin-treated diabetes are equivalent to patients without diabetes. Patients with insulin-treated diabetes remain a higher risk subset."

Two Analyses, Similar Findings
One analysis reported in the article evaluated the performance of the device in the 878 standard-risk diabetes patients who received it. Prospectively determined in conjunction with the FDA, it set a 12-month target vessel failure (TVF) rate of 14.5 percent as a performance goal.

The actual rate of TVF at 12 months among these standard-risk diabetes patients was significantly lower at 7.8 percent (p<0.001), demonstrating superiority of the Resolute drug-eluting stent over first-generation devices in this patient subset. The results of this analysis led to FDA approval of a unique diabetes indication for the Resolute Integrity drug-eluting stent in February 2012.

This analysis also found low and comparable rates of target lesion failure (TLF) at two years in the patients with non-insulin-treated diabetes when compared to the patients without diabetes (8.0% vs. 7.1%). In addition, it found a predictably higher two-year TLF rate in the patients with insulin-treated diabetes (13.7%).

(Target vessel failure is a composite endpoint that includes cardiac death, myocardial infarction and revascularization attributable to any part of the stented vessel; target lesion failure includes the same components, but only as attributable to the stented segment of the vessel.)

Another analysis reported in the article evaluated the cumulative incidence of TLF at two years for all 5,130 patients, many of whom had complex coronary artery disease.

For this analysis, the patients were first divided into two groups: those with diabetes (1,535; 30%) and those without diabetes (3,595; 70%). The diabetes patients were then divided into two groups: those who were taking insulin (455; 30%) and those who were not taking insulin (1,080; 70%).

This analysis yielded a similar finding. Specifically, it found low and comparable two-year rates of TLF in patients with non-insulin-treated diabetes and patients without diabetes (8.9% vs. 8.4%) -- and a predictably higher rate of TLF at two years in patients with insulin-treated diabetes (16.7%).

"These two analyses offer interventional cardiologists worldwide increased confidence when making treatment decisions about the coronary artery disease of patients with diabetes mellitus, who have historically experienced worse clinical outcomes following coronary stent procedures," said lead author Prof. Dr. Sigmund Silber, director of the Heart Center at the Isar in Munich, Germany.

The strong performance of the Resolute drug-eluting stent in patients with diabetes -- both in clinical studies and real-world clinical practice -- advances the growing body of evidence that warranted the device's unique diabetes indication in the United States.

In collaboration with leading clinicians, researchers and scientists worldwide, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services that deliver clinical and economic value to healthcare consumers and providers around the world.

About Medtronic
Medtronic, Inc. (, headquartered in Minneapolis, is the global leader in medical technology -- alleviating pain, restoring health and extending life for millions of people around the world.

Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic's periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results.


Reported by Burt Cohen, April 18, 2013