Prof. Sundeep Mishra helps throws light on the REDUCE-IT trial, presented at the recent annual AHA Session 2018, and explains how it may affect the practice of physicians.

Nutritional supplements whether it be Vitamin E, Vitamin D or fish oils have never been known to directly reduce the cardiovascular risk in large head-to-head, controlled clinical trials. Furthermore, as yet it is only LDL-C reduction that has shown a remarkable CV risk reduction in large clinical trials, any therapy acting beyond LDL-C reduction has shown only minor, if any benefit at all.

In this context, the REDUCE- IT trial which was presented in the recent annual AHA Session 2018 in Chicago and simultaneously published in the New England Journal of Medicine is rather unique.

For the first time it has shown that high dose (4 gm) omega-3 oil, eicosapentaenoic acid (EPA) used in patients with manifest cardiovascular disease (CVD) or diabetes mellitus (DM) + at least 1 more risk factor and relatively high triglyceride levels (150-500 mg%) but normal LDL-C levels (41 to 100 mg%) can significantly and markedly reduce the primary end-point of CV death, MI, stroke, coronary revascularization, or unstable angina. It represents an absolute reduction of 4.8%, a relative reduction of 25%, a remarkable P value of .00000001 (i.e. unbelievable seven zeros) and number needed to treat just 28. This remarkable benefit on the top of ongoing statin therapy has never been witnessed before.

How does this trial affect our practice?

This is a landmark trial, even “the dawn of a new era,” as for the first time it has revealed remarkable benefits of using fish oils in secondary prevention of patients with high triglyceride levels. Many physicians were using fish oils in patients with high triglycerides but the intention was only to bring the triglyceride level to normal and this large benefit in reduction of coronary events even cardiovascular deaths was not expected. This large benefit and relatively minor adverse effects will give confidence to the physicians to use it more often.

The Trial

The REDUCE-IT trial enrolled 8179 patients (70% with established CVD and 30% with DM & one more risk factor), with raised triglycerides but normal LDL-C values. The average triglyceride level at baseline was 216 mg %. The patients were randomized to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or mineral oil (placebo) and followed for a median of nearly 5 years (4.9 years). Results revealed a robust 25% reduction in primary end-point as also 26% reduction in the key secondary endpoint of CV death, MI, or stroke, again highly statistically significant (a P Value of < .0000001). There was a reduction of even cardiovascular death although the effect was a bit modest comparatively (P<0.03). On the other hand, there was a 31% reduction in sudden cardiac death (SCD) and 48% reduction in cardiac arrest, both statistically significant. To put this in context, for long there has been a controversy about beneficial effects of fish oil in reducing SCD in various clinical scenarios but this is perhaps the first time that such clear and definitive benefit has been shown in a large, controlled trial. There was a 20% difference in triglyceride levels between the two groups (an 18% reduction in the fish oil group and a 2% increase in the placebo group).

How to explain remarkable benefit with fish oil

High dose EPA can markedly reduce serum triglyceride, especially if the baseline values are high. In this trial, there was a 20% reduction in triglyceride levels in the fish oil arm. However, this kind of reduction can only account for a possible 5-10% reduction in the event rate but cannot explain 25% reduction in the same. Clearly, some extra-lipid mechanisms are operative. It is known that EPA therapy can stabilize the cell membrane and this may also be the mechanism for reduction of SCDs as well as a reduction in MI, stroke and in elective revascularization. In addition, there could be some anti-thrombotic effect (as evidenced by increased bleeding risk) as well as an anti-inflammatory response (as revealed by lowering of CRP levels).

Why did earlier trials not show this benefit?

There could be many differences between the early trials 9which failed) and the current trial which is a highly positive one. Some of the differences could be:

Earlier trials had used low dose of mixed omega-3 oils (upto 1 g / day) but the current trial used a high dose (4 g0 of purified EPA. A dose of 1 g of fish oil has a trivial impact and is unlikely to markedly reduce serum triglyceride levels especially in those with elevated triglycerides but this is possible with higher doses and may be responsible for improved clinical outcomes.

The subjects in this trial were manifest CAD or DM already on statins but with high triglyceride levels on the background of normal LDL-C levels. This unique patient group may not have been tested earlier.

This trial was really well-conducted trial spanning over a period of nearly 5 years. This kind of design robustness was perhaps lacking in earlier trials.

Limitations of the current trial

The placebo arm received mineral oil, a mild laxative but which could have been responsible for increased CVD risk. In the placebo arm, LDL-C increased by 10% to 84mg% and CRP increased by 30% giving rise to a suspicion that placebo did not really behave as a placebo, rather caused some CV events and stroke making the EPA arm look really better than it is?

There were some adverse effects in the EPA group which revealed a slight increase in hospitalizations for atrial fibrillation (AF; 3.2% vs. 2.1%; P = .004) and a trend towards an increase in serious bleeding events (2.7% vs. 2.1%; P = .06).
 

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