Case-Based Evidence for Cardiovascular Risk Reduction - Episode 4
Deepak Bhatt, MD, MPH: We’re lucky here, in terms of folks involved with the REDUCE-IT trial. I could turn to either Bob or Matt. But Bob, I’ll just turn to you for this 1. Could you, just for the audience, describe the REDUCE-IT study? You of course enrolled lots of patients in there. Perhaps you can review, for the benefit of the audience, what the trial objectives were, the study design, and the outcomes.
Robert Busch, MD: Like Brett, I also feel icosapent ethyl is the darling of cardiology, given all the other treatments we’ve had in the past. The REDUCE-IT trial is the study of over 8000 patients at high risk for heart disease. They either had a cardiovascular event in the past, an MI [myocardial infarction], a stroke or peripheral vascular disease, angioplasty and stents, or some type of ASCVD [atherosclerotic cardiovascular disease] event in the past, or are in the 30% of the patients who were high-risk diabetics. These were diabetics who had an additional risk factor. These patients were well managed.
In fact, they all were on a satin. They had to be on a statin, their LDL [low-density lipoprotein] had to be between 40 and 100 mg/dL. The average was about 75 mg/dL, but what got them into the study is they had the additional risk of having high triglycerides, 135 to 500 mg/dL. Given that additional risk that might be an indicator of persistent risk, half the patients were given icosapent ethyl—2 g twice a day—and the other half were given a placebo.
They were followed for an average of 5 years. The primary end point was a 5-point MACE [major adverse cardiovascular events]: a nonfatal MI, a nonfatal stroke, a cardiovascular death, revascularization, or unstable angina hospitalization. Then there was a 3-point MACE, what we call hard MACE: nonfatal MI, nonfatal stroke, or cardiovascular death. That was the end point. There have been several substudies that Dr Bhatt actually has presented at many cardiovascular meetings that we can get into.
The bottom line, why it’s the darling of all of us and why it’s a game-changing therapy, is that 5-point MACE went down 25% as a primary end point, 3-point MACE, nonfatal MI, nonfatal stroke, cardiovascular death down 26%. Each individual part, the nonfatal MI went down 31%, stroke 28%, and cardiovascular death 20%. To me, as an endocrinologist, what’s unique is many of our trials with some of our heart-smart drugs might lower MI stroke and death, but they don’t lower each individual end point. Even in the trials with PCSK9 inhibitors, where you lowered MI and nonfatal stroke, you didn’t lower cardiovascular death. To lower each individual end point as well as the conglomerate is most impressive, with P values that had many 0s before .1.
The other thing is that the number needed to treat in the primary end point was 21 patients, just looking at the overall population. Dr Bhatt, I’m sure you’ll be discussing some of the substudies done, whether revascularization for patients, total end points rather than first end point, having total events looking at the US population. The most recent 1, looking just at the diabetic population, not only in that primary prevention group but the very high-risk diabetics who already had cardiac events in the past. The results are quite astounding. Basically, it’s a game changer to create an obligation for all of us to look at the triglycerides in patients now.
In the past we looked at them only if they were 500 mg/dL or more to hopefully prevent pancreatitis with a drug therapy. But the patient whose triglycerides are as low as 135 to 500 mg/dL, to have such dramatic events, not because of just the triglyceride lowering but other unique factors about the EPA that lowered each of these individual events, as a whole, was a game changer for all of us. Walking in the exam room, it’s not just, “How is your blood pressure?” and as a diabetic, “How is your A1C [glycated hemoglobin]?” and “Am I using heart-smart drugs?” and “Is your LDL low enough?” This is because with the drugs we have now, we can always try to lower LDL. But to look at triglycerides, it’s an obligation to do something about it by instituting icosapent ethyl.
Deepak Bhatt, MD, MPH: That’s a really nice summary of those trials’ overall results. We’ll come back to the diabetes subgroup and get your particular endocrinology viewpoint on that in a bit. Can you also describe the safety profile and any contraindications for EPA?
Robert Busch, MD: In terms of the safety profile, there was a slightly higher risk of atrial fibrillation and atrial fibrillation hospitalizations, mainly in patients who had preexisting disease. There was a slightly higher rate of bleeding, usually in patients who are on an anticoagulant beforehand. Those would be the major 2 things that we could look out for. I suppose if the patient were allergic to EPA, that would probably be the only contraindication that I would think of with this. So the risk benefit far outweighs this minimal risk.
You can assess the minimal risk if the patient had preexisting atrial fib. Still, these patients had excellent outcomes, less stroke, less V-fib [ventricular fibrillation], V-tach [ventricular tachycardia] arrest as well, despite having the atrial fibrillation. In terms of bleeding outcomes, I don’t believe there was any increase of hemorrhagic strokes, but more minor bleeding type things.
Deepak Bhatt, MD, MPH: Adjudicated hemorrhagic stroke was not significantly different between the 2 arms. There was no significant difference in fatal bleeding. It was really more minor bleeding that was increased. There was no significant excess in GI [gastrointestinal] bleeding. So you got it right. Finally, any comments about the cost effectiveness of icosapent ethyl? There have been a couple of analyses done.
Robert Busch, MD: It was a good analysis. I believe a MedStar analysis talked about that cost effectiveness over a lifetime, that it saves money. If you look at the cost of cardiac disease and the cost of icosapent ethyl and the dramatic decrease of events, particularly the comorbidity of stroke and rehab after stroke or an MI or the other interventional things that have to be done with cardiac disease, it was very cost effective as well.
We have lots of different tools available to lower cardiac risk. This would be 1. It really is an obligation to look at the triglycerides and do something about it as well as to lower the persistent cardiovascular risk that these patients who are well managed on a statin. Perhaps the LDL could have been lower, as we talked about guidelines below 70 or 55 mg/dL. But an average LDL of 75 mg/dL to start with in these patients was not bad, and they were all on a statin to start with.
Deepak Bhatt, MD, MPH: That’s quite a nice summary.
Transcript Edited for Clarity