IMPROVE-IT: Are We Back to 'The Lower the Better' for LDL-C?

Seth Bilazarian, MD; Christopher P. Cannon, MD


December 01, 2014

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IMPROVE-IT: Did It Improve?

Seth Bilazarian, MD: This is Seth Bilazarian at the American Heart Association (AHA) Scientific Sessions in Chicago. I just came from the IMPROVE-IT trial[1] presentation, and I am with Dr Chris Cannon, a principal investigator of the trial. I am excited to talk with him not only about the results, but for myself as a practicing community-based cardiologist and for many in our audience, what do they mean, how do we integrate these data into our practice, and what will patients be asking going forward? For purposes of disclosure, I was an IMPROVE-IT investigator. Could you start by telling us what we found?

Christopher P. Cannon, MD: We studied 18,000 post-acute coronary syndrome (ACS) patients, treated everyone with aggressive statin therapy, and then added ezetimibe (as Vytorin®), which gave about a 15-mg/dL additional lowering of the low-density lipoprotein cholesterol (LDL-C) level. We found a significant reduction (6.4%) in cardiovascular events and about a 10% reduction in cardiovascular death, myocardial infarction (MI), or stroke. So in addition to the known benefits of statins, we now see benefits with a nonstatin drug, ezetimibe. We also saw a very good safety profile, in that there were no differences in safety between the combination of ezetimibe and statin vs simvastatin alone. These are encouraging new data, and we now have to figure out how to incorporate these findings into our practice.

Dr Bilazarian: So what do we do? This was a secondary prevention trial; early post-ACS patients were enrolled. In my practice and in our local hospitals in the Boston area, they seem to use atorvastatin (Lipitor®) 80 mg post-ACS. Going forward, what should we do with these data when patients come back? The current guidelines suggest that we should only check lipid levels to confirm compliance with therapy, but they don't suggest any specific target. Many of us for years have trained ourselves and our patients to "know your number, know your blood pressure, know your LDL, know your body mass index" Now we have to retrain them. Should we retrain them? Give me some insights about what you will do next week with the post-ACS patients returning on statins and at different LDL-C levels. How will you deal with that?

Dr Cannon: I actually saw such a patient on Monday, but I said I can't do anything yet. Of interest, post-ACS is the first population. At discharge should we simply be using high-dose statin plus ezetimibe (Zetia®)? That is what we studied. We saw a benefit, so we would have direct evidence supporting that. I am used to starting patients on high-dose statins, seeing them back in a month or two, and seeing where their LDL-C levels are. If not at goal, then we lower them. Most people still do that, and I think that is the right thing to do.

Dr Bilazarian: The trial didn't use atorvastatin, but is it fair to say that it is appropriate to add ezetimibe? The trial looked at patients whose LDL-C levels were < 100 mg/dL. I assume that that means that we can use it for patients with LDL levels > 100 mg/dL. It is extrapolating the data, but that is what we have to do in practice.

Dr Cannon: At baseline, patients could have LDL-C levels up to 125 mg/dL, so we had a broad range of baseline LDL-C levels. For statin therapy we used simvastatin, but it was a background statin and so we would anticipate that the real difference came from adding ezetimibe, and so this would pertain to whatever background statin you are using. We had an interesting discussion about whether we should simply use both drugs right out of the box in a post-ACS patient at the time of discharge. Some people offered that if the baseline LDL level was relatively high, and they calculated that atorvastatin at 80 mg/dL would give an extra 50% reduction but would not bring the LDL-C level all the way down, they would use both drugs from the beginning.

Do We Have a New LDL-C Target?

Dr Bilazarian: What does "all the way down" mean?

Dr Cannon: That used to be defined as < 70 mg/dL. Now we saw benefits with 54-55 mg/dL, so into the 50s is what I would like to see.

Dr Bilazarian: If the patient's LDL level is > 140 mg/dL, half of that is 70 mg/dL. Clearly, that patient is probably not going to get there with atorvastatin alone, so it might be appropriate to start that patient with both drugs.

Dr Cannon: Yes, right out of the box, and then there is variability in how patients respond. Giving atorvastatin 80 mg or any high-dose statin will have a terrific benefit early on, so if a month or two later you are checking and adding ezetimibe (this was a benefit seen over 6 years), that still seems like a reasonable approach.

What about someone whose MI was a year ago? We had 18,000 patients, only a year after they were enrolled, and we clearly saw ongoing benefit year after year in these patients as they stabilized. These data are directly relevant to that early post-ACS period and the few years following. But in someone who is 10 years post-MI, are the data relevant to them? That is a little bit more of a stretch. Those patients are a lower-risk group and so we would anticipate the same relative benefit, but the absolute benefit is going to be much more modest. In that case, you would have to start thinking twice.

Lastly, this would not by any means be a routine therapy for primary prevention. The caveat here is people who have the sky-high LDL-C levels—for example, those with familial hypercholesterolemia or people with high LDL-C levels (> 100 mg/dL despite therapy). If we want to add something else to get the LDL-C level down, we know that this drug has been seen in another setting to reduce events, so that of all the different options to lower the patient's LDL-C level, that would probably be a next choice. Neil Stone offered that he would consider this a proven therapy in terms of the cholesterol guidelines, so I think we may be turning to ezetimibe (as some of us have been). I have been using it in many patients in whom we couldn't reduce LDL-C levels, and thankfully we know that they have been getting benefit all of these years.

Putting Cost Into the Equation

Dr Bilazarian: We previously thought that 70-75 mg/dL was an acceptable target for LDL-C level, but we know from this trial that we now have a lower target. We should be doing the best for our patients. We care about our patients and we want the best for them. Is 50-55 mg/dL a goal that you are going to try to achieve? In that same patient who is 1-2 years post-MI, post-percutaneous coronary intervention, post-coronary artery bypass graft, is 65 mg/dL good enough on a high-dose statin or would you add ezetimibe? There is a significant cost; even if the patient is well insured, there is a copay. At what point should we be relatively content in a secondary-prevention patient?

Dr Cannon: In part it will depend on the risk status of the patient—for example, closer to a recent event or older age (we saw increasing benefit with increasing age). The patients with diabetes had a gigantic benefit in the study. We used to say in a patient on atorvastatin, "If the patient's LDL-C level is 76 mg/dL, that is pretty close to 70 mg/dL." Now, I know that if we go down to 55 mg/dL, that is going to be better, so I think that aiming for the 50s would be optimal therapy.

Dr Bilazarian: The other question would be, from a practical standpoint, the patient's cost. If the patient is in the mid-70s and you want to try to get him lower, if he is not already on a maximum-dose, high-intensity statin—

Dr Cannon: But that should always be the first step.

Dr Bilazarian: That would be lower-cost and less exposure to multiple drugs. That is a responsible way to handle that.

Dr Cannon: The evidence for statins in general is good. The incremental benefit of high-dose statin vs regular-dose statin plus ezetimibe is similar, but many people have commented that sometimes they want to avoid the highest dose of a statin, so they might add ezetimibe at a lower dose of atorvastain (eg, 40 mg). You will get much more LDL-C lowering with that. There are many good possibilities now that we have some clinical evidence to say that this is actually helping patients.

Boding Well for PCSK9 Inhibitors

Dr Bilazarian: We have learned that a lower LDL-C level is desirable and beneficial. We have learned that a nonstatin therapy is a proven therapy that is not just about statins but about LDL-C lowering. As a trialist and an investigator in PCSK9 inhibition, what does this mean? Were you buoyed in your enthusiasm for PCSK9 inhibitors with these data?

Dr Cannon: It was definitely very encouraging. This is the first time that a nonstatin has done this, and of course the PCSK9s are even more potent. They will achieve another 50% reduction in LDL-C level, so that should translate into big benefits. We will see, but this is very good news for that class of drugs.

Dr Bilazarian: Do you have any last words on what we should do at the end of this week, returning home to the clinic with our patients in whom we are aiming for secondary prevention (LDL levels < 70 mg/dL)? Should we go back to the idea that lower is better? "Know your numbers"? Are we going to begin to enthusiastically endorse that with patients?

Dr Cannon: This does apply more broadly to remind us that it is important to lower cholesterol. Some people say that they are not sure, and there are all kinds of excuses. Here, we are going from low to super-low levels and seeing benefits. People come up with various reasons for not following through, for being noncompliant with their medications. It is a reminder across the spectrum that we have to take cholesterol seriously.

Dr Bilazarian: Thank you for this awesome review and application of what we should be doing with the data from IMPROVE-IT, in which ezetimibe was shown to be an important add-on therapy. More discussion must take place about what the best practice should be going forward, but it certainly gives us enthusiasm that we are headed in the right direction and that a renewed commitment to this strategy is very important. I would like to add my compliments to you and the other leaders of this study, who bore incredible hardship to bring this to a conclusion, pushing on during the years when there was a lot of criticism and suggestion that this was not an appropriate trial to persist with. It is a remarkable achievement that it was brought through to the end. So thank you, Chris, for joining me today and providing some important insights on how we can integrate these data into the practice of secondary prevention. Until next time, I am Seth Bilazarian.


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