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Regarding the JELIS trial, there are major limitations to the study that make generalizability difficult. It was open-label, and open-label trials are notorious for reporting exaggerated treatment effects; and the only significant individual finding from the trial was a reduction in unstable angina, with well over half of the primary endpoint events comprised of these (193 vs 147 events, p=0.014). Therefore, there is an increased likelihood the results were due to performance bias and/or detection bias, resulting from changes in patients’ behavior, physicians’ treatment, or event ascertainment. It was also comprised of a 100% Japanese population of patients with poorly controlled LDL-C (182 mg/dL at baseline); nearly 70% were women; all were given very low dose statin regimens, even for an all-Asian population (pravastatin 10 mg/day or simvastatin 5 mg/day), and around 27% of the subjects discontinued statin use during the study (whether or not more control group subjects discontinued statin use earlier than ethyl ester EPA (EPA-E) group subjects was not disclosed).
Importantly, in JELIS, the MCE composite endpoint itself was different from that in REDUCE-IT. It included revascularization and hospitalization for unstable angina, but did not include strokes. In order to make an apt comparison with the REDUCE-IT trial—ignoring for a moment the numerous differences in populations and background therapies—the same composite endpoint should be used. When this is done, with strokes included, the RRR in JELIS decreases sharply from 19% to just 11.5%, insignificant from 914 events ([324 vs 262 non-stroke MCE; HR 0.81] + [162 vs 166 stroke events; HR 1.02] = blended HR 0.885). Comparing the reported 19% RRR in JELIS with the 25% RRR in REDUCE-IT is therefore misleading.
Not only this, but there was no perceived effect on coronary death (HR 0.94, p=0.81) in JELIS, and all-cause mortality trended worse for treatment group (265 vs 286 events, HR 1.09, p=0.33).
It can only be said that in this open-label, 100% Japanese, 70% female-gender study, 1.8 g/d EPA-E (aka “IPE”) significantly reduced unstable angina in subjects not optimally treated, with the potential for bias to have overinflated the result. JELIS is not a trial that reliably shows IPE can significantly reduce the risk of ASCVD events, particularly not in a patient population similar to that of REDUCE-IT.
Furthermore, a positive result from one study is often not reproduced in later trials. This is one reason that FDA normally requires at least two adequate and well-controlled studies as proof of efficacy and tolerability.
For example, the GISSI-Prevenzione trial, which tested 1 g/d omega-3 ethyl esters (OM3-E) vs control in over 11,000 Italian post-MI subjects, demonstrated a significant 15% RRR in the primary MCE composite, which included all-cause mortality, MI and stroke. The study showed a 20% reduction in death from any cause and a 30% reduction in CV mortality (each also significant) compared with control. There was also a 44% reduction in sudden death (p<0.01). This led to Omacor 1 g/d (aka “Lovaza”) being indicated for secondary prevention (following MI) in major EU member states. The AHA also began recommending 1 g/d omega-3s for secondary prevention, though there was no formal FDA approval for that indication. However, subsequent placebo-controlled trials did not reproduce the positive findings, and as contrary evidence continued to mount, the EMEA eventually decided to retract their approval.
What happened here? Was the result due to the open-label design? It does not seem possible that that could have affected an endpoint like mortality. Was it due to differences in background therapy between GISSI-P and more modern trials? That could be a plausible explanation, as most of the subjects, especially early on in the study (when much of the benefit in mortality was realized), were not on statin therapy. It is possible that the reduction in sudden death in particular was the result of antiarrhythmic and antifibrillatory properties that have been ascribed to omega-3s. These same properties are also ascribed to statins, particularly at higher doses. There were likely untreated targets present due to lack of statin therapy in GISSI-P subjects. Later trials were conducted in an era where all secondary prevention subjects are given moderate to high-intensity statins following an MI (as well as numerous other treatments and cardiac medications). JELIS enrolled all of its subjects between 1996 and 1999, similar to the GISSI-P trial (1993 – 1997). Would the open-label JELIS trial results involving 1.8 g/d of EPA-E repeat in a placebo-controlled test with optimally treated modern-day subjects of Japanese descent randomized over 20 years after the fact? Perhaps not.
Generalizability of study results is crucial in informing drug regulation. 1 g/d OM3-E offers no additional benefit to secondary or primary prevention patients already on extensive background therapy, even though it proved effective in the GISSI-P trial. The JELIS trial subjects and REDUCE-IT trial subjects are too different and were too differently treated to confer anything from the results of one trial to that of the other.
