Michelle L O'Donoghue, MD, MPH; Karol E Watson, MD, PhD


December 11, 2014

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The Long-Awaited Results

Michelle O'Donoghue, MD, MPH: I'm Dr Michelle O'Donoghue of Brigham and Women's Hospital in Boston and an investigator with the TIMI Study Group. Joining me is Dr Karol Watson of the University of California at Los Angeles Medical Center, Codirector of the preventive medicine program. We are at the American Heart Association Scientific Sessions, and one of the biggest talking points has been the results of the Dual Antiplatelet Therapy (DAPT) trial[1,2] which has been eagerly awaited for several years. What was your initial reaction to the results of the DAPT study?

Karol Watson, MD, PhD: This was a fabulously conducted study, and I'm grateful to hear the results. For years, the whole field has been moving toward increasingly shorter durations of dual antiplatelet therapy (DAPT). In the back of my mind, I know the pathophysiology, and it makes more sense that DAPT would be beneficial. I was very eager to hear these results and comforted that what I have been doing is correct. Another thing that I took away from this study was that we focus on DAPT because of its protective effects on stents and stent thrombosis, but we also see a big protective effect on cardiovascular events in the non–stent-related arteries.

Dr O'Donoghue: You raise a good point. The pendulum has been swinging back and forth. For a while, after the first concerns about stent thrombosis emerged, many of us were hesitant to pull back on DAPT. Subsequently, several studies emerged suggesting that we could get away with shorter periods of DAPT.

But many of those studies were smaller, albeit fairly consistent in their results, but the confidence intervals were always quite wide. The results from DAPT are quite compelling. I was struck by the dramatic reduction in cardiovascular events as well as in stent thrombosis, in the range of 70%.

Dr Watson: It was gratifying to see that the stent-thrombosis numbers were small, but there was a great reduction. Small numbers of a devastating catastrophic event are still important. The data on when they discontinued the DAPT and the rapid increase in cardiovascular events was striking. It is what we always worried about. This is very good evidence that DAPT is not only beneficial for a stent but for all of the coronary anatomy.

Rebound Effect?

Dr O'Donoghue: That gave me pause as well. One of the best things about the study design was that they had a period of observation after everyone had discontinued DAPT. It was striking how steep that curve was. It raises the question of whether there is some physiologic rebound for cardiovascular events, not just a regular trajectory.

Dr Watson: That's a good point. Certainly we know that you get very effective platelet inhibition with DAPT, but did that trajectory of the increase in events show that there is a rebound effect, or is it just a loss of platelet-inhibition effect? I don't know.

Dr O'Donoghue: It is an area that we will need to explore further. We can't say anything conclusively on the basis of these observations. I was struck by the steepness of the slope, and it was particularly apparent with the discontinuation of prasugrel [Effient, Lilly/Daiichi-Sankyo] within the group with Taxus Liberté stents.[3] It also gives me pause in thinking about temporary discontinuation of therapy for patients who need to go for surgery or for another reason, whether they are at heightened risk or not, even if it is for a short period of time.

Dr Watson: Exactly. When it is for a life-preserving surgery, it makes sense, but it is usually for a dental cleaning or something else that makes me wonder whether we are doing our patients any great benefit by stopping DAPT or even single antiplatelet therapy.

Non–CV-Mortality Bump

Dr O'Donoghue: What was your reaction to seeing the strong trend toward a higher risk for death for patients who had been continued on more prolonged DAPT?

Dr Watson: An increase in total mortality always gives us pause. In terms of biologic plausibility, there is no explanation for a true increase. It's possible that the increase in cancer was due to the higher incidence at baseline and the play of chance. It is something that we should look at, but when you look at the overall body of evidence for DAPT, there is no evidence for increased mortality.

Dr O'Donoghue: You never want to completely disregard a potential signal toward harm, but at the same time, we have other studies that were combined in a meta-analysis published in Lancet[4] that did not suggest an increase in either cardiovascular or noncardiovascular mortality. If you turn to the earlier studies of DAPT, such as the CHARISMA study,[5] there is no suggestion of an increased risk for vascular or nonvascular death, and it is similar with such studies as CURE.[6] It seems to be the play of chance. It's a bit of a head scratcher.

Dr Watson: We will watch it, but I am very comfortable that there is nothing there. The great benefit that we saw in vascular events was significant.

Dr O'Donoghue: You raised the point, too, that it wasn't all driven by stent thrombosis. We have seen that in other studies. It is consistent with the higher-risk patients within the CHARISMA trial.[7] We also had the study[8] of vorapaxar [Zontivity, Merck Sharpe & Dohme] in patients with stable coronary artery disease showing long-term benefit for platelet inhibition.

Dr Watson: When you think about it, it makes sense. When you have atherosclerotic cardiovascular disease, you have it all over, not just in one lesion. When those 30% to 50% plaques sit there long enough, they are going to rupture now and again. When that happens, you will need an effective antiplatelet agent on board to help prevent the sequelae.

Dr O'Donoghue: The overall the results are reassuring, also for the ongoing PEGASUS trial[9] which is looking at the use of ticagrelor [Brilinta, AstraZeneca] vs placebo in patients who are post-myocardial infarction.

Dr Watson: I definitely agree. It would have been nice if ticagrelor was included in the DAPT trial.

Dr O'Donoghue: The balance between efficacy and safety was relatively reassuring. Some people will still be struck by the increased risk for at least moderate bleeding in the DAPT trial. For me, it is offset by the dramatic reduction in cardiovascular events.

Dr Watson: Right. In our high-risk patients, their major threat to life is atherosclerotic cardiovascular disease. We will always have to consider how to reduce that risk.

Dr O'Donoghue: Many people will be waiting eagerly for the results of PEGASUS next year. DAPT already gives us a lot of information that we can incorporate into our clinical practice.


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