COMMENTARY

Lipid-Lowering, CV Effects of Anacetrapib REVEALed

An Interview With Martin Landray

John M. Mandrola, MD; Martin J. Landray, MB ChB, PhD, FRCP

Disclosures

September 18, 2017

John M. Mandrola, MD: Hi, everyone. This is John Mandrola from theheart.org and Medscape Cardiology. I'm at the European Society of Cardiology (ESC) meeting in Barcelona, Spain, and delighted to be with Professor Martin Landray, who is co-principal investigator of the REVEAL trial.[1] He is also from the University of Oxford. Dr Landray, thank you for being here.

Martin J. Landray, MB ChB, PhD, FRCP: Thank you very much for having me; it's a real pleasure.

REVEAL Trial: Background

Dr Mandrola: The REVEAL study is a randomized controlled trial of anacetrapib versus placebo for cardiovascular outcomes. Tell us about the background.

Dr Landray: We know that patients with cardiovascular disease remain at high risk for cardiovascular events. We have come a long way over the past 20 years with statins, and now intensive doses or high doses of statins are widely used.

The challenge we have with anacetrapib, which is a cholesteryl ester transfer protein (CETP) inhibitor, is that this drug doubles high-density lipoprotein cholesterol (HDL-C) levels. That sounds like it should be a good thing. It also lowers low-density lipoprotein cholesterol (LDL-C) levels, and that almost certainly sounds like it should be a good thing. The challenge is whether those lipid effects translate into a clinical benefit.

Dr Mandrola: You set a pretty high bar for yourself.

Dr Landray: Yes, we set a really challenging bar. I guess we did not want to be criticized that we had just taken people who had inadequately controlled lipids or patients who would have had benefit from an increase in statin dose.

We set the bar at patients who could reach the target with intensive atorvastatin dosing. The mean LDL-C at baseline was 61 mg/dL. With the FOURIER trial[2]—great trial, great drug, quite expensive—the LDL-C at baseline was around 90 mg/dL. This is 30 mg/dL higher than that in REVEAL.

Look at the CANTOS trial,[3] which, of course, used an anti-inflammatory drug. That population was supposed to be people whose LDL-C had been lowered as far as it could go. Their [baseline] LDL-C was 20 mg/dL higher than we saw in this study.

For our baseline, we took patients who were compliant with atorvastatin intensive doses and had a mean LDL-C of 61 mg/dL and asked, "Can we lower the risk of cardiovascular events, specifically coronary events, even further if we add in anacetrapib, despite all that good care?"

Methodology and Results

Dr Mandrola: This was a very large secondary prevention trial. Tell us about the methodology.

We saw that adding anacetrapib on top of atorvastatin in this well-controlled population reduced the risk for major coronary events by 9%.

Dr Landray: There were 30,000 patients with prior vascular disease; 90% or so of them had coronary disease, and about 37% or so had diabetes. It was conducted mainly in Europe; one half of the patients were in Europe, 20% were in North America, and the remaining were in China.

Dr Mandrola: How did it come out?

Dr Landray: It came out well. We saw that adding anacetrapib on top of atorvastatin in this well-controlled population reduced the risk for major coronary events by 9%. Major coronary events were the combination of death from coronary disease, myocardial infarction (MI), and coronary revascularization. We saw similar reductions in events both in what one might term the "hard endpoint"—coronary death and MI—as we did in coronary revascularization.

Dr Mandrola: That is important, because sometimes these composite endpoints are driven by softer endpoints.

Dr Landray: No, we saw real consistency across each of these coronary components.

Dr Mandrola: What happened to HDL-C? What you would expect?

Dr Landray: The lipid effects are pretty much in line with what one would expect. We doubled HDL-C from around 40 mg/dL to around 80 mg/dL. LDL-C in the context of CETP inhibition turns out [to be] quite hard to measure. But we lowered LDL-C probably by about 17% or 18%. The question was: Did those benefits translate into clinical benefit? The answer, of course, is yes.

Dr Mandrola: Safety with this class of drugs is a huge issue. What did you find there?

Safety of Anacetrapib

Dr Landray: The moment we saw a clear result on the primary outcome, the question was all about safety. Way back when we were designing this study, not only did we know that we had to assess efficacy, but it was also really important (given the history of CETP inhibitors, particularly torcetrapib) to assess safety reliably.

At the end of 4 years of follow-up, all 30,000 patients took their treatment. Even by the end of the study, 85% of patients were still taking the treatment exactly at the same rate as in the placebo group. In this study, we saw that there was no adverse effect on mortality, overall or by specific causes. There was no adverse effect on cancer risk, liver or cognitive function, and so on and so forth.

We did a very wide assessment of safety issues. The only small change we saw in terms of safety was a 0.7-mm Hg rise in systolic [blood] pressure over the course of the 4 years. That is substantially smaller than was seen with, for example, torcetrapib; it was similar to [that with] the other CETP inhibitors. But we saw no excessive hypertension-related clinical events.

We saw a small increase in the number of people who developed stage 3 chronic kidney disease, but again, there was no evidence of any impact of more severe kidney disease (eg, needing dialysis or developing acute kidney injury).

Dr Mandrola: Why do you think anacetrapib is different from the other CETP inhibitors?

Dr Landray: This is the fourth CETP inhibitor to hit a large clinical trial. Torcetrapib had big off-target effects on blood pressure and increased risk for cardiovascular mortality. There has been a lot of work to assess that. Dalcetrapib was the second one to be studied; it actually does not have any effect on LDL-C and only a pretty modest effect on HDL-C. The biochemical effects of evacetrapib and anacetrapib are, broadly speaking, quite similar. I think clinical trial design issues might explain why the REVEAL trial of anacetrapib turned out so well and the ACCELERATE trial[4] of evacetrapib had disappointing results.

Was It the HDL-C Raising or LDL-C Lowering?

Dr Mandrola: What about subgroups? Maybe there are populations of patients that would benefit more?

It's impossible to truly disaggregate the different complicated effects that anacetrapib might have, but my feeling is that this is driven by LDL-C.

Dr Landray: Of course, when you see an overall result, you are always looking for whether this treatment was particularly effective in some group or particularly ineffective in others. We looked at 23 prespecified subgroups and saw similar effects across all of those subgroups. There were similar benefits regardless of being a bit older, a bit younger, a man or a woman, diabetes or not diabetes, higher HDL-C, lower HDL-C, low LDL-C, or very low LDL-C. Across the board, we saw similar proportional reductions. There was no evidence of any different effect in a particular subgroup.

Dr Mandrola: You showed a slide about LDL-C reduction. What is your feeling about where this significant relative risk reduction came from? Was it the LDL-C or HDL-C?

Dr Landray: It's impossible to truly disaggregate the different complicated effects that anacetrapib might have, but my feeling is that this is driven by LDL-C. My reason for saying that is, if you take the classic plot of the effects of statins on the risk for coronary disease against the absolute change in cholesterol levels and plot the REVEAL results, it's pretty much splat-bang on the line.

The doubling of HDL-C—such a huge change—might be expected to reduce risk by about 25%, 30%, or even more. But it's unlikely that that played a major role.

I think what we can take away from this is that HDL-C is quite a good marker of risk. But HDL-C as a target, at least with this drug, seems less appropriate. In other words, I think the risk reductions we saw with anacetrapib, which were undoubted, were largely driven by taking LDL-C from levels that any cardiologist would be proud of—61 mg/dL—even further down. With that, we saw even greater benefit.

Potential Role in Statin Intolerance?

Dr Mandrola: Final question: I'd like you to speculate about the role this drug may have for statin-intolerant patients or patients with familial hyperlipidemia, who might have higher cholesterol.

Dr Landray: Great question. We looked at the toughest example—people with very low cholesterol levels. The groups you described are people with substantially greater levels of LDL-C. With statin-intolerant people or patients who cannot take a statin, I think one would anticipate that the benefits may be even greater than we saw in this study. The other point to make is [that] if we continued this trial for even longer, we also may have seen greater benefits.

I accept that this is speculation. What we see in the trial is a 9% proportional risk reduction in major coronary events. It's reasonable to ask what might have happened if we had taken patients—and we all have lots of them—who have higher levels of LDL-C for one reason or another. Of course, the challenges with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are the huge cost and that some patients do not like injections. Anacetrapib is a once-daily, little white tablet that lowers LDL-C, raises HDL-C, and critically lowers risk on top of a statin.

Dr Mandrola: Thank you for this great discussion; it's an honor to have you.

Dr Landray: Thank you.

Dr Mandrola: That is it from the 2017 ESC Congress.

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