Samuel Z Goldhaber, MD; Laura Mauri, MD, MSc


December 09, 2014

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Samuel Z Goldhaber, MD: This is Dr Sam Goldhaber for the Clotblog at on Medscape, speaking to you from the American Heart Association Scientific Sessions in Chicago.

We are very fortunate to have today Dr Laura Mauri, who has just presented the results of DAPT, the Dual Antiplatelet Therapy trial,[1,2] which received great coverage. It has many lessons for us in the world of cardiology for the management of coronary artery disease. Can you give us the background on this 10 000-patient, randomized, controlled trial? When did you get the idea to do this study, and how did you get all of the different companies to cooperate and support the study, so you would have the resources to carry it out?

Laura Mauri, MD: It's a very interesting trial, the idea for which dates back to 2006 when there was a concern about late stent thromboses occurring more than a year after placement of drug-eluting stents. These unexpected stent thromboses were occurring after patients had discontinued antiplatelet therapy. It wasn't clear at that time whether keeping patients on aspirin plus clopidogrel would prevent these events. I participated in a US Food and Drug Administration [FDA] advisory committee meeting and some randomized trials that were helpful in understanding that the rates of stent thrombosis were fairly low and not that different from those for bare-metal stents, but the patients in those trials were pretty simple. Unanswered questions in clinical practice were whether stents were safe and whether dual antiplatelet therapy would be helpful if taken for longer periods of time.

Dr Goldhaber: In those days, wasn't there a big controversy about bare-metal stents vs drug-eluting stents? Didn't you write a pivotal paper in the New England Journalof Medicine[3]?

Dr Mauri: Yes, there was concern then, and following that meeting we looked at the data from an observational series of all the patients who were treated with percutaneous coronary intervention in Massachusetts, and there was no difference in mortality. We couldn't look at stent thrombosis specifically.

Dr Goldhaber: There was no difference between bare-metal and drug-eluting stents?

Dr Mauri: That's right. Some interesting observational studies, including an important cohort from Duke University[4] indicated that patients with drug-eluting stents seemed to do better when they stayed on antiplatelet therapy beyond a year. These findings, in large part, influenced the guidelines to extend dual antiplatelet therapy to 12 months, but this was done in the absence of randomized data. Over the years, several trials have been done, many of which were small, and underpowered to look at stent thrombosis. The DAPT study was a very large study. We enrolled 26 000 patients in the trial.

Dr Goldhaber: You reported approximately 10 000. How did you get from 26 000 to 10 000, and are you following the others in a registry?

Dr Mauri: The drug-eluting-stent patients who were randomized were the primary analysis population. We took patients who reached 12 months without any severe bleeding or recurrent myocardial infarction and randomly assigned them to continue on either clopidogrel or prasugrel plus aspirin or aspirin alone. Those patients [constituted] a set of about 10 000 patients. We entered more patients than that, because some patients (about 3000) had been treated with bare-metal stents, and others had events [during the first year]. Because of a strong feeling that there might be a benefit to continuing antiplatelet therapy longer, some patients and their physicians were not comfortable with randomization. The trend toward a preference for shorter-duration therapy is logical because we want to avoid bleeding risk, and we are worried about cost, but there has been a shift back and forth without any large enough trials.

Dr Goldhaber: How did you get eight or more companies to work together to cooperate and let you do this trial?

Dr Mauri: It is a credit to the FDA, which had the foresight to think that it would be important to answer this as a public-health question, so they solicited support from these companies. They posed the question to the manufacturers of stents that we needed to understand how long these patients should be on dual antiplatelet therapy. Because stent thrombosis is unusual, it is very difficult for one entity to conduct a trial, and we wanted the results to be broadly generalizable. In the end, four different stent manufacturers and four different pharmaceutical manufacturers participated under a public-private partnership with the FDA and the Harvard Clinical Research Institute.

Dr Goldhaber: Can you summarize, for the Clotblog audience, some of the pivotal findings?

Dr Mauri: The two co–primary endpoints were stent thrombosis and major adverse cardiovascular and cerebrovascular events (death, myocardial infarction, and stroke). There were highly significant reductions with continued thienopyridine—a 71% reduction in relative risk for stent thrombosis and a 29% reduction for major adverse cardiovascular and cerebrovascular events, which was mostly driven by myocardial infarction. Patients who continued the thienopyridine beyond a year had about half of the risk of myocardial infarction compared with patients who took aspirin alone.

We designed the trial so that we could detect whether stents or the other vessels would be the driving force for events. We worry about our patients having recurrent heart attacks that had nothing to do with the stent. That is our primary focus when we counsel our patients, right? So we designed the trial with both of those end points in mind, and most of the myocardial infarctions had nothing to do with the stent. This is an interesting concept, because it goes beyond what stent you should use but is really about what medications you should use.

Dr Goldhaber: It affects public-health policy, too, when we think of the broad population of patients with multivessel coronary disease. As an interventionalist, would you explain a little about stent biology? How can there still be thrombosis on the stent several years after it has been inserted?

Dr Mauri: It's rare, but we do see it. That's what we saw in this trial. The risks for stent thrombosis are highest immediately after the procedure, when the risks are mechanical and have to do with residual dissection, how the stent was deployed, or the characteristics of the vessel. Over time, that risk diminishes significantly. We saw rates of stent thrombosis of 1.4% and 0.4% over the 18-month period that we followed the patients. It is still not very well understood why this happens, and it may be different factors, but now that we have a large data set of hundreds of cases, we will be able to dive into it more deeply.

Dr Goldhaber: The dramatic reduction in stent thrombosis with dual antiplatelet therapy and the dramatic reduction in non–stent-related ischemic heart disease events weren't reflected in the total mortality, were they?

Dr Mauri: The overall mortality rates in the study were very low, which is great for our patients who are treated with coronary stents, but we didn't expect to see a difference in mortality. You are right that we saw a small unexpected difference in mortality that favored the placebo arm by 0.5%. When we first saw that, it raised some concerns because we really didn't expect it. We convened a separate clinical-events committee to review all of the deaths and understand what they were related to. Some of them were related to bleeding (but very few proportionally), and most of the difference was in noncardiovascular deaths related to cancer.

Dr Goldhaber: Was this just the play of chance?

Dr Mauri: It could be. We saw that there were patients who had cancer at the time of enrollment in the treatment arm, and funny things can happen in large trials. We did a few things that were reassuring. The patients who were treated with bare-metal stents (who are also going to be presented at this meeting) were also randomized, and in that group we didn't see any mortality difference. You wouldn't expect a drug to act differently in one type of stent vs another. Dr Yeh, Dr Elmariah, and other colleagues of mine did a meta-analysis[5] of all of the trials looking at thienopyridine plus aspirin vs aspirin alone, with 69 000 patients worth of data, 130 000 patient-years of follow-up. It's remarkable how much information there is, and much of it is very long-term. These were not just patients with coronary artery disease, but also patients with peripheral surgical revascularization who were treated with extended therapy. There was no impact on noncardiovascular mortality. That finding in the DAPT trial may be a wrinkle that we have to think about, but it may also be a false-positive finding.

Dr Goldhaber: Looking at the event reduction in the curves that you published in the New England Journal of Medicine paper,[2] it seemed that in terms of the reduction in both stent-related and non–stent-related myocardial infarction, the benefit of dual antiplatelets seemed to persist throughout the trial.

Dr Mauri: Yes, it did. It was remarkable. We were stunned at how strong the effect was. It was much more than what we had designed the trial for. In retrospect, if we had stopped the study 3 months after patients were randomized, we would have had a positive trial, and that is an important thing to think about. You would probably see even larger differences with a well-powered trial, and over the time period beyond one year, these curves continued to diverge, especially for recurrent myocardial infarction.

Dr Goldhaber: From looking at the graph in your paper, a further benefit appeared at 21 months. My final question is whether we should consider continuing indefinite duration dual antiplatelet therapy in patients at low bleeding risk?

Dr Mauri: We have to think about it. The best answer is maybe. We need to talk about it with our patients. We can say that continuing therapy will reduce the risk for heart attack. Beyond 30 months, we are not as sure, because we haven't studied it in randomized trials, but it may be a lot like taking a statin to prevent heart attack. These may be medications that have ongoing benefit.

Dr Goldhaber: What you have done is monumental. Thank you so much for sharing your findings and giving us some of the background colorful history. This is Dr Sam Goldhaber signing off for the Clotblog.


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