COMMENTARY

AHA 2014: Lipids, Platelets, and CT Angiography Trials

Melissa Walton-Shirley, MD; E. Magnus Ohman, MD

Disclosures

December 29, 2014

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Long-term DAPT After Stent

Melissa Walton-Shirley, MD: I am Dr Melissa Walton-Shirley, from the 2014 American Heart Association (AHA) meeting in Chicago. I am here with Dr Magnus Ohman from Duke University. It's the first day of the meeting, and it has been all about lipids and platelets.

I would like to start by asking you about the DAPT [Dual Antiplatelet Therapy] study.[1,2]

E. Magnus Ohman, MD: It has been a very important trial for interventional cardiologists because we have been wondering how long we should use dual antiplatelet therapy after stenting, and particularly after drug-eluting stents. This is the largest trial to date, almost five times larger than the previous trials. The investigators did a fantastic job. They followed patients for up to 30 months and randomly assigned patients to stop the prasugrel or clopidogrel at 12 months or to continue with dual therapy. According to the guidelines, stopping is our approach now rather than continuing. The lingering question is continuing beyond a year after stent thrombosis. We have heard incidentally that patients stop their therapy and then they have stent thrombosis. However, we never figured out whether we should assume the bleeding risk that is associated with long-term therapy and continue that therapy in all of our patients. This trial addresses that issue.

Dr Walton-Shirley: The question that I am asked every day in the office setting is, "Doctor, can I stop my clopidogrel? Can I stop my prasugrel?" I always tell the patient, "You are doing pretty well on this medication. You have some significant risk factors. I don't feel comfortable stopping." Is this a practice-changing trial? Are you going to change what you do for patients next Monday when you go back to work?

Is 30 Months Too Long?

Dr Ohman: Any trial today has a little wrinkle, as does this trial. There was a highly significant, very powerful reduction in stent thrombosis and myocardial infarction, so on the plus side, longer dual therapy seems to work. There was a signal of some long-term bleeding, as you would expect, because giving therapy long-term has a downside. The tiebreaker is in the middle, which is mortality. All-cause mortality was borderline statistically significantly higher in those who continued to take it for 30 months, but not cardiovascular mortality.

What in these drugs drives noncardiovascular mortality? This is an area that is quite complicated, because we don't think that these drugs promote cancer, yet we have this signal, so there will be an interesting balance. For people who are healthy, I would tend to go longer, because the data tell me that this is relatively safe and there is a benefit. I don't know what to do about the signal for noncardiovascular mortality. Seeing all of the data would be helpful in this field. There is also the Paris registry[3] (a study by Roxana Mehran) in which she looked at long-term clopidogrel. In practice, if the patient is doing well, we continue it. If necessary, we will stop it temporarily for a tooth extraction, for example, and then restart it. She showed that if you have to stop it short-term for good reasons, but you think that overall the patient is doing well, then it is safe to do so. However, this trial begs the question: Isn't 30 months a long time?

Dr Walton-Shirley: It's interesting. I have been doing the right thing but for the wrong reason. I always looked at patients and said, "Well, you have a significant burden of atheroma. You have several vessels that we have not treated mechanically. Perhaps you should stay on the medication." They are looking at the subset analyses, and the hint is that it is their risk-factor profile—their vulnerable plaque—that places patients at risk. It makes you wonder whether it may be secondhand smoke exposure or other issues that weren't teased out in that trial.

Dr Ohman: The very positive signal here in myocardial infarction, that is beyond stent thrombosis, is helpful because the stent is just 20 mm in a coronary artery.

Dr Walton-Shirley: It's a scaffold.

Dr Ohman: Yes, and we only have a very short distance there, whereas we have close to 320 mm of coronary vessels and we are just treating a very short area. So there may be more to these drugs long-term. There will be a trial[4] coming out at the American College of Cardiology that is looking at long-term ticagrelor. There was no ticagrelor in the DAPT trial, only clopidogrel and prasugrel, so the ticagrelor trial will be helpful in giving us another signal long-term. Is it beneficial, and what is the risk? We had the TRILOGY ACS trial[5] that I was involved with. We also showed a long-term signal, so there may be something to what you are saying—namely that spontaneous plaque rupture may be the factor. When patients have that and are on one of these agents, they are pretty safe.

Dr Walton-Shirley: Another interesting caveat is when we list the number of patients with diabetes in any trial. I wonder how many of those patients have been glucose challenged. We probably have many more people with diabetes in these trials than we think we have, which could also skew the data. It's an interesting conversation about the future.

Dr Ohman: Absolutely. Obviously this is a very large trial, and these were just the first-line results. We are going to learn a lot more about all of these issues. The question about clopidogrel vs prasugrel, and other questions, are yet to come. We have much more to learn.

Driving Down the LDL

Dr Walton-Shirley: Let's switch gears now to IMPROVE-IT.[6] This was a long-awaited trial. Many of us in the community have not prescribed ezetimibe for about 5 years. I always explain to my patients that we just don't know the answer. I keep looking for the big mortality benefit with any of these medications, but in fact the data state that this may be a fairly marginal benefit for some patients. Tell me your slant: Low-density lipoprotein cholesterol (LDL-C) lowering is important, but how important and to what level? Tell me about that.

Dr Ohman: Last year we had what I call the "guideline debacle." We had new prevention and cholesterol guidelines and we started saying, "Okay, just go with statins and don't worry." We did away with the levels. We said, "It doesn't matter what the level is," whereas as physicians we always wondered whether that was really sensible. The data were very good focusing on the statins in this trial, because they uptitrated and achieved a level that was the lowest of any trial that I have seen for secondary prevention.

Dr Walton-Shirley: The LDL-C was in the 50 mg/dL range.

Dr Ohman: It is remarkable, and they have a reduction in the primary endpoint. You can argue that they included urgent revascularization and revascularization procedures in that endpoint, but if you include death from myocardial infarction and stroke, the things that you and I care about for our patients, it's a significant benefit. Remember that what is funny about this trial is that 40% of the patients in both arms actually stopped the treatment because it was a blinded long-term trial. People don't like taking medication. It is hard to keep people on tablets. Was this 40% dropout rate consistent with your practice?

Dr Walton-Shirley: Sure. Just last week I was asked again to change a patient's prescription from ezetimibe and simvastatin combination to just simvastatin. It was insurance company–driven of course. The number needed to treat (NNT) was 50, so there is a significant cost issue as well.

Dr Ohman: The question that remains is: Could you achieve 50 mg/dL with rosuvastatin or one of the other agents? Yes, you probably could, but this trial is important because it shows us that getting even lower with titration, with the combination therapy, actually improves outcomes, and that is pretty important. It was safe too, which is the other aspect that everybody worries about in this field. What do we do with guidelines? We need to revisit them. Obviously we will have to learn more about this trial. Remember, 40% didn't take their medication. If you look at what happens to the patients in the on-treatment analysis, it was even more powerful. Fewer patients, but more powerful, so it tells a very consistent story. You and I have to go back and measure our levels and see where we are.

Dr Walton-Shirley: I may have to change my attitude about this entire situation. I'm going to have to think about it.

CT Angiography in Diabetes

Dr Walton-Shirley: Did you see anything else at this meeting that you found interesting?

Dr Ohman: There was a randomized trial[7] of CT angiography among high-risk diabetic patients. It was from Intermountain Health Practice and all at one site, where they randomly assigned nearly 1000 patients to CT angiography (if they had diabetes) or to continue usual care. The principle here was to determine whether it would help to understand the burden of disease. This goes back to your question about the burden of disease in a patient with diabetes who has no cardiovascular symptoms and no cardiovascular history. The trial was neutral. It didn't show any benefit with CT angiography, but an important part of the trial showed that 70% of the patients with diabetes who had a CT angiography had moderate disease or greater. The diabetic patients had a lot of events because they have a lot of disease.

Dr Walton-Shirley: It requires a conversation about the true definition of primary vs secondary prevention, because when we find that large burden of atheroma, is it truly primary prevention anymore? It depends on what you are referencing, but I see the same thing with calcium scoring in patients who walk into my office with a calcium score of 9000 HU. The patient's father had a heart attack, but the patient has no symptoms. What do we do with that patient? This is a fascinating topic.

Dr Ohman: We have much to learn about these data. Of importance, they are going to follow the patients for 10 years. They have now about 3.5 years of follow-up, so they are going to go long-term, which will be fascinating to see. The more you know about your patients, the better patients will do.

Dr Walton-Shirley: Absolutely, and the more trust patients will have that you will guide them correctly. It will be up to us to try to tease out these data and take the information back into our offices next week. Thank you very much for coming today. Thank you to our viewers for joining us today on theheart.org for Medscape Cardiology.

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