CLEAR Outcomes Trial: A Brief Summary

Podcast Transcript

Announcer:

Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Steven Nissen, MD:

It was certainly a fun meeting for us. This was the second ACC meeting in a row where we had the lead off trial. Last year was Milind Desai, this year was our CLEAR outcomes trial. Basically, what we did is we took patients with very well-documented statin intolerance, primary or secondary prevention, LDL above a hundred, randomize them to bempedoic acid or placebo. It was event driven for 1,620 primary events in 4-component MACE and 810 or more events for 3-component MACE and at least 24 months of follow up. The primary endpoint was 4-component MACE, and then we hierarchically tested a series of endpoints. That way we could preserve the study wise alpha, and we could keep going until we reached one with a negative, with a non-significant P-value. This is now the contemporary approach, and it turns out we actually got the order here, right as I will show you.

One of the things that happened when we presented this is that we showed the baseline characteristics, and something almost never happens. The audience broke out into a spontaneous applause when we mentioned that we had 48 percent women in the trial, which got a lot of attention. 30 percent high risk primary prevention, 70 percent secondary prevention, and almost half with diabetes. This drug has modest effects on LDL and CRP. LDL was reduced by about 22 percent and CRP about 22 percent, in six months, which is where we set in the SAP we would measure.

Here is what happened: 4-component MACE hazard ratio was 0.87, highly significant with a good absolute risk reduction and an NNT of 63. Surprisingly perhaps, 3-component MACE was stronger with a hazard ratio 0.85. I would point out this is exactly the same hazard ratio that the PCSK9 inhibitors in both of their trials had, which a lot of people forget about.

Then fatal and nonfatal MI, that was the big effect. Hazard ratios 0.77, really quite good. A 23 percent reduction and coronary revascularization that included PCI and bypass surgery was reduced 19 percent. Also, please notice in all the KM curves, separation occurs within the first year, takes lipid lowering therapy a little while, but the separation does occur relatively early. No effect on cardiovascular death or all-cause mortality. None of the trials over the last 15 years of LDL lowering therapies have shown an effect on mortality. We're really good at keeping people with MIs from dying, although they do, of course, later on in life, have disability and eventually mortality.

There were adverse events, but they were not more common in the bempedoic acid group than the placebo group. And to understand this, this drug is a pro-drug and so when administered it's inactive, but then it gets taken up by the liver, activated, and then it works in the same pathway as HMG CoA reductase, but upstream, so it doesn't really have effects in peripheral tissue, and we didn't see it. People tolerated the drug very well. There's about a 1 percent absolute increase in gout and about a 1 percent absolute increase in cholelithiasis. So, we concluded primarily that 4-component MACE reduced 13 percent, 3-component MACE 15 percent, MI 23 percent, and coronary revascularization 19 percent.

So bottom line, statin intolerant patients, this is a designer drug designed not to have effects in the peripheral tissues, only in the liver, the lowered LDL modestly, and had quite a good effect on outcomes.

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