Dr Deepak Bhatt Highlights Latest REDUCE-IT Data

August 30, 2020

In this most recent analysis of REDUCE-IT, results show a consistent benefit favoring icosapent ethyl versus placebo irrespective of the actual statin type, said Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School.

In this most recent analysis of REDUCE-IT, results show a consistent benefit favoring icosapent ethyl versus placebo irrespective of the actual statin type, said Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School.


The American Journal of Managed Care® (AJMC®):Can you briefly explain how this latest updat adds to the evidence produced by the REDUCE-IT trial?

Dr. Bhatt:
Absolutely, so what we've done in this most recent analysis of REDUCE-IT, that was just presented at the European Society of Cardiology, is examine the outcomes of the patients in the trial as a function of their baseline type of statin. For example, we looked at patients who are on really intense statins, things like atorvastatin and rosuvastatin or more modest types of statins, such as simvastatin or pravastatin even, and just looked to see how the patients did. We also bunched it by hydrophobic and hydrophilic statins. There's some old literature, I'm not sure necessarily how valid it is really, but showing that those different types of statins might have different interactions with different drugs and so forth. But the bottom line was, any way you sliced it there was a benefit, a consistent benefit favoring, icosapent ethyl versus placebo, irrespective of the actual statin type or category of statin.

It further bolsters the results of REDUCE-IT. If this isn't a story that is contingent upon statin use though as a general principle, I would recommend high intensity statins in high risk patients if they can tolerate it. Of course, again, not every patient is going to tolerate very intense statins. For example, if one thought that the only statins that are appropriate at high risk patients are atorvastatin and rosuvastatin, well, the results look terrific in those patients in those particular subgroups. While it's not really appropriate to look at statistical significance in subgroups, really, we're looking for directionality and consistency and it was definitely a consistent story here. But if one wanted to go to that somewhat statistically inappropriate way of looking for or demanding statistical significance within the subgroups, well, then it was, in fact a statistically significant reduction, even if we were looking at just atorvastatin and rosuvastatin which are the most potent stats out there.

AJMC®: How many at-risk patients regularly take statins and what do these results mean for them?

Dr. Bhatt:
Well, it's a great question. How many are actually taking them may be different from how many should be taking them, of course. But essentially, every patient in the secondary prevention universe that is where they have atherosclerosis in their coronary, or cerebral, or peripheral arteries, should be on a statin irrespective of their baseline LDL cholesterol. And then beyond that, in a primary prevention setting, patients with elevated LDL cholesterol should be on the statin, to the exact level depends on their baseline level of risk, whether they have diseases like familial hypercholesterolemia, other risk factors. There are different risk calculators that can be useful in the primary prevention setting to see exactly when a statin should be initiated. So based both on their LDL level, but also their overall cardiovascular level of risk. Between those 2 camps of people, that is secondary and primary prevention, it's, of course tens of millions of people that should be on statins, but how many are actually on it is probably far less than would be optimal. Now, in part that's still due to persisting patterns of undertreatment, which is a bit disappointing and surprising given that statins are now widely available, multiple generics. But I think the other bigger part is statin intolerance or at least perceived statin intolerance. In REDUCE-IT, we, as a matter of protocol insisted that all the patients be on a stabilized dose of statin and tolerating it and continuing it in the trial. So that took the statin question out of there.

But, in real world practice, of course, there are many patients who don't take their statin because they think they're having a side effect, a proportion of those actually are having a side effect. That is if you did a placebo controlled switch on them, as has been done in other studies, it would turn out that they really are having symptoms to the statin and not a placebo. But a fair amount are actually having side effects that aren't related to the drug. That is if you switch them to placebo, the side effects would still have been there. And in part, it's because many things happen at once. Some patients identified as being at high cardiovascular risk or start on a statin but they're also told to exercise. They're exercising for the first time in a few decades. Their muscles ache and they blame the statin and not the new exercise regimen. The other part is there's just a lot of misinformation in social media and on the internet about statins and unfortunately, some people read that and then they believe it and there can be sort of a harmful effect that they believe is there sort of like a placebo or a nocebo type effect. All together that leads to pretty vast rates of under treatment with statins, especially if we follow patients over time. With respect to REDUCE-IT again, we had insisted patients be on statins for the purposes of the trial. The FDA wisely, in terms of their labeling for icosapent ethyl, says the patient should be on maximally tolerated doses of statins. But that includes then a maximally tolerated dose of 0mg. The statins should be used in patients that are high-risk, which is the type of patients where icosapent ethyl would be considered. But having said that, the label doesn't insist on it. If there is a patient that's truly statin intolerant, and in a sense, it almost then doesn't matter if they think they're statin intolerant or they're really statin intolerant. In either case, it's still acceptable for the label to use icosapent ethyl.

AJMC®: Data suggest there are important mechanisms of action for the substantial CV risk reduction observed with icosapent ethyl that are distinct from the LDL receptor pathway. What are the next steps in understanding these mechanisms?

Dr. Bhatt:
There was a separate analysis [presented at ESC] looking at the baseline LDL cholesterol tertiles. In even the lowest tertile of LDL cholesterol, there was still consistent benefit of icosapent ethyl versus placebo. Again, one shouldn't really look for statistical significance in a subgroup, it's just looking for consistency. But for those folks that will do that, nonetheless, it was in fact, a statistically significant reduction in the primary and key secondary endpoint with icosapent ethyl versus placebo, including in that lowest tertile of LDL cholesterol. So that I think is really useful information to physicians, because if they're thinking, Well, does icosapent ethyl work if I blast the LDL down to a really low level? In fact, the answer is, Yes, it does. So, these are completely complimentary pathways. Yes, lower the LDL cholesterol as much as you can, to the extent a patient can tolerate that without side effects with statins, with ezetimibe, with PCSK9 inhibitors, if that works in terms of the cost effectiveness in the healthcare system one is practicing in. But then if their triglycerides are elevated, and per the label, that would be greater than or equal to 150 milligrams per deciliter in the US and that can be a fasting or non-fasting triglyceride there. If they essentially are a REDUCE-IT-like patient, that is secondary prevention or diabetes and high-risk primary prevention, those sorts of patients should also be on icosapent ethyl. Those are distinct pathways towards risk reduction, LDL lowering and then use of icosapent ethyl.

Now, the mechanism that you alluded to, does seem to be distinct from LDL cholesterol lowering, although there are some data that icosapent ethyl or its active ingredient of EPA eicosapentaenoic acid does in fact prevent oxidation of LDL. So there may be some interconnectedness there. But the predominant mode of action of icosapent ethyl is through EPA and downstream effects of EPA that we're just only now being able to disentangle on the basic science level. There are all sorts of downstream mediators created by EPA. So certainly there's an effect on lowering triglycerides, an effect on reducing oxidation of LDL cholesterol. But beyond all that, it does appear that there are things that are produced that are anti-inflammatory, and perhaps not in the conventional way we think of anti-inflammatory such as with CRP or IL-6, I mean, really more fundamental molecules, things like resolvins, and so forth, that do appear to have anti-inflammatory effects that could be providing some of the cardiovascular benefit we see in the REDUCE-IT trial.