Thread by @skathire

REDUCE-IT trial: when added to statins in its w/ CVD (or T2D+1RF), Rx with 4g purified EPA (Vascepa) (compared to mineral oil placebo) lowered risk CVD events 👇🏽

Vascepa worked but full results expose that we don’t know why

A few thoughts
nejm.org/doi/pdf/10.105…

Difference between 2 groups (Vascepa and mineral oil placebo) in plasma TG was ~40mg/dl and non-HDL-C was ~15.5 mg/dl

But, lipid difference does not explain the 25% RRR

A 15.5 mg/dl delta in non-HDL-C would be expected to alter CVD by only about 10%

👇🏽
nejm.org/doi/full/10.10…

Could it be the antithrombotic or the antiarrhythmic effects

lots of in vitro evidence for these effects
but also some human evidence from this trial

higher bleeding rate in those Rx with Vascepa
lower rate of CV death

jamanetwork.com/journals/jama/…

But, of ~16 mg/dl difference in non-HDL-C between Rx & mineral oil placebo arm:

*4mg due to lowering in Vascepa arm
*12 due to INCREASE non-HDL-C in mineral oil arm

Could placebo increase have led to harm that accentuated the benefit of Vascepa?

From a quantitative analysis, NO (a 12 mg/dl increase in non-HDL-C would explain about 7% RRR)

IMO, the placebo increase doesn’t compromise the integrity of the trial result

Take home:

Vascepa worked but we don’t know why:

most likely a mix of TG-lowering,
antithrombotic,
anti arrhythmic
(and cannot rule out trial issue of LDL rise in placebo)

Should secondary prevention patients with optimal LDL on statin but TG>150 be considered Vascepa?

YES, a reasonable option for patients

But, would love to see confirmation in a second trial

Also, Supplementary Table 4 merits a close review for the Y1 effects on biomarkers in Vascepa and in the mineral oil placebo arms

nejm.org/doi/full/10.10…

Audience @American_Heart late breaker quite convinced by REDUCE-IT results.

By the way, chatting with Rory Collins about REDUCE-IT. His thoughts on trial issues:

1. didn’t seem too bothered by the rise lipids in placebo (he attributed to regression to mean +- mineral oil)

2. seemed super impressed by effect size (25% RRR)

What are implications of REDUCE-IT for triglyceride-rich lipoprotein hypothesis?

1. Benefit of Vascepa not proportional to TG change

2. Benefit of Vascepa did not vary by baseline or achieved TG

So, REDUCE-IT data do not clearly speak to TRL hypothesis

By the way, since the benefit of Vascepa did not vary by baseline TG or achieved TG,

should this medicine be tested in all-comers with ASCVD (without a high TG entry criteria)?