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No Stent Thrombosis Seen When Plavix and Aspirin Stopped Early
New Analysis of Medtronic's 5,000 Patient RESOLUTE Drug-Eluting Stent Clinical Program Shows No Increased Risk with Premature Cessation of Dual Antiplatelet Therapy
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Resolute Stent in Artery
Resolute Stent in Artery
March 14, 2013 -- San Francisco -- Important news for stent patients and cardiologists alike: data from a new analysis of Medtronic's (NYSE: MDT) RESOLUTE global drug-eluting stent program show very low occurrence of stent thrombosis when dual antiplatelet therapy (DAPT) is interrupted or discontinued after one month.

Current U.S. guidelines and Instructions For Use (IFU) for all drug- eluting stents, including Medtronic's, call for one year of DAPT to prevent stent thrombosis, a potentially fatal complication that occurs when blood clots form inside the stent and block flow to the heart.

But almost 1 in 6 of the 5,000 patients in the pooled clinical trials for the Resolute zotarolimus-eluting stent either completely stopped or interrupted DAPT for at least 14 days, and did so anytime from one month to less than one year after stent implantation. And in those patients, there were not just low occurrences of stent thrombosis at one year: there were none.

These data are particularly robust because most of the patients in the pooled trials were "All Comers" and of this patient cohort one-third were diabetics, one-third had prior angioplasties (PCI), 40% were urgent PCIs (myocardial infarction or acute coronary syndrome), and 25% had experienced prior heart attacks.

Ajay Kirtane, MD
Ajay Kirtane, MD

Results of this analysis of the 4,896 patient global RESOLUTE Clinical Program were presented on Monday in San Francisco at the Annual Scientific Sessions of the American College of Cardiology by Dr. Ajay Kirtane of NewYork-Presbyterian Hospital/Columbia University Medical Center.

Dr. Kirtane said, "While most physicians would expect patients who interrupted their dual antiplatelet therapy after as few as 30 days following drug-eluting stent implantation to be at a much greater risk for stent thrombosis, this was not observed with the Resolute stent. These data should be very reassuring to physicians as well as to patients in whom this newer generation stent is implanted."

Two weeks ago the European CE Mark for the Resolute Integrity zotarolimus-eluting stent was updated to reflect these data, stating that "...patients who interrupt or discontinue DAPT medication one month or more after stent implantation are considered at low risk and showed no increased risk for stent thrombosis."

Reason Why Patients Stop DAPT Before One Year
Data from the RESOLUTE program showed that over 1,000 of the almost 5,000 patients who received a Resolute drug-eluting stent (DES) in these pooled trials discontinued DAPT before one year was up. A variety of reasons were given for these interruptions: patients needed to have non-cardiac-related surgery (e.g. hip or knee replacement) or a medical procedure such as a colonoscopy or biopsy -- procedures in which uncontrolled bleeding might occur if the patient was on antiplatelet therapy; patients experienced serious adverse reactions to the antiplatelet medications or bleeding complications; patients had completed their script (in Europe, for example, only six months of DAPT is prescribed); or patients just didn't want to take the medications any more -- there are minor and annoying adverse reactions to these drugs, such as bruising, gastrointestinal discomfort, rash, etc.

Why is DAPT Recommended for One Year?
Because it can be fatal, stent thrombosis has been a major concern for cardiologists and their patients since the first bare metal stents became available in the early 1990's. To prevent blood clots inside these stents, a combination of aspirin and a thienopyridine, such as clopidogrel (Plavix), was prescribed for 4-6 weeks after implantation, the time it took for the inner tissue lining of the artery, known as the endothelium, to grow over the metal stent struts and minimize the danger of thrombosis. However, in about 20% of cases, too much tissue grew back, forming a sort of scar, blocking the blood flow. This reblocking, called restenosis, often required a repeat procedure. So drug-eluting stents were developed to retard this tissue growth. They did so very effectively but, since these newer stents also slowed the healing of the endothelium, the period of DAPT was lengthened to six months.

However, in 2006 reports from Europe, where drug-eluting stents had been in use for a longer time, raised significant concerns. An increased amount of stent thrombosis was being observed after the six month period, even after one or two years. What was referred to as a "fire storm" erupted and resulted in an special FDA panel where, for two days, device manufacturers and cardiologists from all over the world gave testimony about this issue (note: this reporter and a patient from Angioplasty.Org's Forum also testified).

Because there literally was no data to guide clinicians, the FDA panel decided to err on the side of caution and recommended that DAPT be extended to one year. This decision had significant effects: patients and insurance now had to pay for more Plavix at a cost of over $4/day -- a single decision which added almost half a billion dollars annually to U.S. healthcare expenditures.

Newer Stents Come on the Market; Stent Thrombosis Rates Drop
The concern over stent thrombosis was generated by the first generation of drug-eluting stents. Since 2006, a new generation of drug-eluting stents has come to market of which Medtronic's Resolute is one; others are manufactured by Abbott and Boston Scientific. These newer stents are thinner, more flexible, and are coated with better more biocompatible polymers. Study after study has shown them to be even more effective and safer than the first generation. The rate of stent thrombosis for this second and third generation DES has dropped to all-time lows.

How Long Should a Patient Take Plavix?
Because there has been no major data on which to base any change in recommendations, U.S. guidelines continue to call for one year of DAPT. A major and very large trial, called The DAPT Study, was started in 2009, enrolling over 20,000 patients and testing whether 12 or 30 months of DAPT made a difference in outcomes. But no large study was undertaken to look at durations of less than 12 months. One or two such trials were started, but had difficulty enrolling patients because referring physicians feared their patients might suffer stent thrombosis if they stopped prior to one year.

However, in the case of the RESOLUTE Clinical Program, Medtronic had gathered information about the duration of each patient's DAPT usage. And the analysis of this information, presented this week, now provides some level of comfort for those patients who must or want to stop. While Abbott and Boston Scientific have also gathered similar data in their various clinical trials, their stents have received CE Mark updates of safety after three months of DAPT; because of this latest data, Medtronic's Resolute was for one month.

Doctors React to Kirtane's Presentation
David J. Cohen, MD, FACC
David J. Cohen, MD
The data presented at the American College of Cardiology meeting elicited a number of reactions from panelists and the audience.

Commenting on the fact that at one year there were no stent thromboses in the 14-day interruption/permanent discontinuation cohort, Dr. David Cohen, Director of Cardiovascular Research at Saint Luke's Mid America Heart Institute in Kansas City said, "Zero is a big number. I might be more concerned if it were one or two, but it was zero!"

Dr. Cohen continued, making reference to the large and ongoing DAPT Study, "So we have a $100 million study looking at 12 months of DAPT vs. 30 months. And we have to say to ourselves, 'Are we asking the wrong question?'"

Other cardiologists have expressed similar observations, notably Dr. Eric Topol in his interview with Angioplasty.Org in which he commented on the DAPT Study, "I mean it's just crazy for me to think of the amount of resources that are being expended for mega trials like that. I'm amazed that it's going forward."

Prof. Sigmund Silber
Prof. Sigmund Silber, MD

Moderator of the ACC panel, Dr. Matthew Price, then posed a question to the entire room. He asked who takes their patients off of DAPT after 3 months, 1 month, 6 months." Very few hands were raised at all, meaning most of the audience followed the 12 month guideline. But Prof. Sigmund Silber of the Heart Center at the Isar in Munich reminded everyone that the European guidelines have always been for 6 months and, referring to the events of 2006, "...that the one year recommendation in the United States was really based on panic!"

Dr. Kirtane agreed and added that the original recommendation, extending DAPT duration from 6 months to a year, was based solely on observational studies and the hysteria from the fears of late stent thrombosis discussed during the FDA hearings.

How Will These Data Change Clinical Practice?
The European CE Mark update, as well as Dr. Kirtane's conclusion, state:

"One year data from the RESOLUTE clinical program indicate low stent thrombosis rates for those who interrupted or discontinued DAPT any time after one month. While physicians should adhere to current ESC or ACC/AHA/SCAI guidelines for PCI, patients who interrupted or discontinued DAPT medication one month or more after stent implantation were considered at low risk and showed no increased risk for stent thrombosis."

Professor Martin T. Rothman, MD
Prof. Martin T. Rothman, MD

Professor Martin T. Rothman, MD, who is VP of Medical Affairs for Coronary and Renal Denervation Business at Medtronic, emphasized this point to Angioplasty.Org, saying:

"Medtronic is not recommending a shorter duration of DAPT with the Resolute Integrity stent based on this analysis, and I encourage physicians to continue practicing according to the current guidelines.... Medtronic has provided this analysis to allow physicians to make 'best' decisions in the difficult circumstance where a patient has to, or wants to, stop therapy. Thus the physician and the patient can feel comfortable that they have the best current information from Medtronic to know whether the action they are about to take is relatively safe. The data strongly suggests that for the patients in the studies from which this data was derived, it was safe to discontinue 'early'."

Interestingly most of the stent thromboses seen in this group of patients occurred within the first 30 days and the vast majority of these patients were on DAPT at the time, giving credence to the observation that early risk is often due to anatomic or suboptimal stent expansion issues and that, by the end of the first month, endothelialization has occurred.

The results of this analysis are but the most recent evidence that the newer second and third generation drug-eluting stents are safer and more effective than their predecessors, and that much of the concern raised seven years ago now has been addressed.

Dr. Kirtane concluded that, "These better results may be due to the fact that doctors have learned more about the proper administration of antiplatelet therapy, or it may be that the devices have gotten better. Frankly, I think it's the devices!"

Medtronic's press release from Monday follows:

With Medtronic Resolute Stent, Interrupting Dual Antiplatelet Therapy After One Month Showed No Increased Safety Risk in Robust Analysis
ACC.13 Presentation Features Unprecedented Data on Nearly 5,000 Patients, Including "All Comers," from Global RESOLUTE Clinical Program

March 11, 2013 -- San Francisco -- Cardiologists at ACC.13 learned today that patients with coronary artery disease who received a Resolute drug-eluting stent from Medtronic, Inc. (NYSE: MDT) as participants in one of several clinical studies and interrupted or discontinued their dual antiplatelet therapy after one month of the implant procedure showed no increased safety risk through one year of follow-up.

This finding comes from a new analysis of nearly 5,000 patients from the global RESOLUTE clinical program, which included two large studies that enrolled "all comers."

Ajay Kirtane, M.D., chief academic officer and director of the interventional cardiology fellowship program at NewYork-Presbyterian Hospital/Columbia University Medical Center, presented the analysis at the 62nd Annual Scientific Session & Expo of the American College of Cardiology (ACC).

"While most physicians would expect patients who interrupted their dual antiplatelet therapy after as few as 30 days following drug-eluting stent implantation to be at a much greater risk for stent thrombosis, this was not observed with the Resolute stent," Dr. Kirtane said. "These data should be very reassuring to physicians as well as to patients in whom this newer generation stent is implanted."

As part of the new analysis, the investigators also examined patients who interrupted their dual antiplatelet therapy after at least one month following the implant procedure for a period of more than 14 days, by which time normal platelet function typically resumes. Interestingly, these patients –– who constituted the vast majority of those who interrupted their dual antiplatelet therapy after one month –– experienced no instances of stent thrombosis (0.0%) through one year of follow-up.

Based on this analysis, Medtronic recently received approval from European regulators to update the CE (Conformité Européenne) mark labeling for the Resolute Integrity drug-eluting stent with new language related to one-month duration of dual antiplatelet therapy. This labeling update applies to product distributed in countries that accept the CE mark. It does not apply to product distributed outside this region, including the United States.

Dual antiplatelet therapy guidelines for patients who receive a drug-eluting stent differ by geographic region, but generally recommend daily compliance for six to 12 months. The applicable guidelines are referenced in the country-specific labeling for each device.

In other data presented at ACC.13, the RESOLUTE Pooled Safety update, which includes data on all 5,130 patients who received a Resolute stent as participants in the program, showed a consistently low rate of stent thrombosis of 1.1 percent out to three years after implant; and in the RESOLUTE US study, which enrolled 1,402 U.S. patients, the stent thrombosis rate out to three years was a low 0.37 percent.

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, March 14, 2013