Omega-3 “STRENGTH TRIAL Outcome”- shows no significant benefit for patients with high coronary risk. Really? What happened?
Yesterday was the third time I received a message pointing me to a recently published study indicating that the STRENGTH TRIAL RESULTS (2021), financed by AstraZeneca, concluded that EPA-/ DHA-Free Fatty Acids may show no benefit on Major Adverse Cardiovascular Events (MACE) in Patients at High Cardiovascular Risk. WHAT? Wasn´t it the same product in 2013 that showed a 30% reduction in blood triglyceride levels in statin-treated patients with high cardiovascular risk profile (ESPRIT-Trial) [1]? The same product that is now FDA approved and prescribed successfully to these high-risk patients for many years?
Almost 4000 published trials/scientific papers over the last 30 years show numerous health benefits derived from a regular intake of omega-3 fatty acids, in particular DHA (docosahexaenoic acid) and EPA (Eicosapentaenoic acid). Only very recently, in 2019, a significant clinical trial in the omega-3 field called the “REDUCE-IT”- Study was published in the prestigious “The New England Journal of Medicine” [2]. This study carried out by the Harvard University showed an impressive reduction in cardiovascular risk by almost 30% in patients who were already under statin treatment with established cardiovascular disease or diabetes and other risk factors. To make this clear, the risk reduction coming from the omega-3 fatty acid of almost 30% was more than the risk reduction you could expect by taking statins. This particular REDUCE-IT Trial had patients already under statin therapy, so one could think these patients were already well protected. The study showed that even these patients benefited clearly from the omega-3/EPA administration by an additional 30% risk reduction in suffering a Major Adverse Cardiovascular Event (MACE).
In 2020 the first results from the EVAPOTATE-Trial were published [3] that showed that 18 months of treatment with the EPA significantly reduced the plaque formation in patients with atherosclerosis compared to a placebo. This was a further observation explaining the cardiovascular protection properties coming from the omega-3 fatty acid and seen in the REDUCE-IT trial.
Past large clinical trials (GISSI[4,5], JELIS[6], ESPRIT [1], REDUCE-IT [2], ENHANCE-IT[7]) repeatably showed that Omega-3 fatty acids (EPA, DHA, and EPA+DHA) are a safe, and very efficient treatment for lowering blood triglycerides – a major cardiovascular risk factor. To avoid any misunderstandings, the STRENGTH Trial also recorded a significant reduction in the plasma triglyceride levels after the omega-3 treatment. However, they could not see a benefit in reducing cardiovascular risk. This finding is controversial to the recently also published REDUCE-IT and EVAPORATE Trials.
So, what is correct now?
- Do Omega-3 fatty acids reduce elevated plasma triglyceride levels? YES (all studies confirm this)
- Are elevated plasma triglyceride levels considered as a cardiovascular risk factor? YES
- Can omega-3 fatty acids EPA and DHA reduce our Cardiovascular Risk? …. Just looking at the above two questions, I would say “YES,” and the REDUCE-IT study also confirmed this. However, the STRENGTH Trial was not able to prove this. Why not?
| Reduce_IT | STRENGTH | |
| Product/Sponsor | Vascepa/Amarin | Epanova/Astrazenica |
| University | Harvard | Cleveland |
| Study Duration | 2011-2016 | 2014-2020 |
| Primary End-Point | Composite of cv death, nanfatal mycardial infarction, non fatal stroke, coronary revascualarization or unstable angina | Composite of cv death, nanfatal mycardial infarction, non fatal stroke, coronary revascualarization or unstable angina |
| Number of subjects | 8179 | 13078 |
| Subject Type | Under statin treatment with established cardiovascular disease or diabetes and other risk factors | Under statin treatment with high cv risk, hypertriglyceridemia and low levels of HDL-cholesterol |
| Study Design | Randomised, double-blind, multi center placebo controlled | Randomised, double-blind, multicenter, placebo controlled |
| Drug composition | >96.5% EPA, no DHA | 50-60% EPA, 15-25% DHA |
| Chemical form | Ethyl ester (EE) | Free fatty acids (FFA) |
| Delivery form | 1000 mg soft gel | 1000 mg soft gel |
| Enteric coating? | NO | YES |
| Placebo | Mineral oil | Corn OIl |
| Initial "O3-I" treatment | no data | 6,9 |
| End "O3-I" treatment | no data | 9,4 |
| Initial EPA in plasma (µg/ml) treatment | 26,1 | 21,0 |
| 12mo EPA in plasma (µg/ml) treatment | 144,0 | 89,6 |
| EPA in RBC (µg/ml) treatment | no data | 0,6 |
| 12mo EPA in RBC (µg/ml) treatment | no data |
2,81 |
| Initial DHA in plasma (µg/ml) treatment | no data |
61,9 |
| 12mo DHA in plasma (µg/ml) treatment | no data |
90,7 |
| Initial DHA in RBC (µg/ml) treatment | no data |
5,0 |
| 12mo DHA in RBC (µg/ml) treatment | no data |
6,6 |
| Initial TG (mg/dl) | 216,5 |
239 |
| 12mo TG (mg/dl) | 175 |
191 |
| 5 year TG (mg/dl) | 158 |
no data |
| Dose | 2x 2 caps per day (4 gr) |
2x 2 caps per day (4 gr) |
| Primary End-Point Treatment | occurred in 17,2% of patients |
occurred in 12,0% of patients |
| Primary End-Point Placebo Group | occurred in 22,0% of patients |
occurred in 12,2% of patients |
| Conclusion | Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cv death, was significantly lower among those patients who received 4 g EPA-EE per day compared to the placebo group. |
These findings do not support use of this omega-3 free fatty acid formulation to reduce major adverse cv events in patients with high cv risk. |
| Literature | Deepak L. et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England Journal of Medicine, Vol. 380, No.1 (2019), 11-22 |
Nicholls SJ et al. Effect of High Dose Omega-3 Fatty Acids vs Corn OIl on Major Adverse Cardiovascular Events in Patients at High CV Risk. Journal Amarican Medical Associacion (JAMA). doi:10.1001/jama.2020.22258, Published online November 15, 2020 |
Table 1: comparing REDUCE-IT versus STRENGTH TRIAL
The first thing that comes to my head is to compare these two studies directly with each other (see Table 1 above).
Discussion:
Bioavailability and Enteric Coating:
There is no doubt that the free fatty acid (FFA) form of omega-3 used in the STRENGTH Trial has a better bioavailability (especially in the fasted state) than the ethyl ester (EE)-form used in the REDUCE-IT trial. However, looking at the calculated theoretical “Omega-3 Index” of the treatment group in the STRENGTH Trial, that only increased from a baseline of 6,9 to 9,4 at the end of the study, I have serious doubts if the entire part of the administrated EPA and DHA was absorbed. After an administration of 4g/d EPA+DHA over a period exceeding 12 months, I would expect a much higher increase in the EPA+DHA content in the RBC.
I, therefore, could imagine that the enteric coating used on the soft gel surface of the omega-3 drug used in the STRENGTH Trial may have dissolved too late in the subject's intestine (duodenum) where the free fatty acids from the diet (and also this drug) are mainly absorbed and transferred to our bloodstream. Thus, despite a higher bioavailability from the free fatty acid form, the treatment group might have lost a significant part of the administered omega-3 in their feces.
Theoretical Omega-3 Index at Baseline:
The calculated average theoretical Omega-3 Index (O3-I) at baseline in the treatment group of the STRENGTH Trial of 6,9 (so 6,9% EPA + DHA in the RBC membranes) is surprisingly high. Not that it is a very high O3-I, but it is already in a range where a pretty good cardiovascular protection is ongoing. See Figure 1 below. I would have expected a baseline O3-I of 3,5 to a maximum of 4.0. Which, according to my knowledge, is the average Omega-3 Index found in the US population. Let’s assume for a moment that the treatment group in the STRENGTH TRIAL had a baseline Omega-3 Index of 4.0 and that this Index increased to 9.6 after administrating 4g EPA+DHA per day. In that case we could actually expect a significant reduction of the cardiovascular risk. But what was actually observed in that trial is something else.
Figure 1: Omega-3 Index (O3-I) versus relative Cardiovascular Risk)
To dig into this matter even further, as mentioned above, an average starting O3 Index of 6.9 among the Treatment Group is a high baseline Index. It proves that the Treatment Group was already relatively well protected from the beginning of the study. An average Index of 6.9 means that some subjects had an Index below 6.9 but others well above. Same with the endpoint O3-Index. The more I think about it; I question if they should not have chosen subjects with a more "normal" O3 Index found in the US of approx. 3.6. In this case, an increase to 9.4 in the O3-I would have probably also shown a significant reduction in the treated patients' cardiovascular risk.
In my professional lifetime, this would not be the first time this fundamental mistake was made in planning a clinical trial involving omega-3 fatty acids. Suppose the Treatment Group already has good protection from a higher level of EPA and DHA incorporated in their cell membranes at the beginning of the study. In that case, additional supplementation will increase this protection level, but this will not be seen during a relatively short clinical trial period. I repeat: the majority of the US citizens have a baseline O3-I between 3 to 4. I wonder if we could ever see the accurate baseline omega-3 Index of the Treatment- and Placebo Groups of the STRENGTH Trial. If my observation is correct, this could be one of the explanations why this particular trial did not show a significant reduction in the cardiovascular risk of the Treatment Group.
Conclusion:
All major clinical trials of the past have shown that omega-3 (DHA and EPA) reduce elevated plasma triglyceride levels in a very efficient and safe way – with no severe side effects. This finding was also observed in the here discussed STRENGTH TRIAL.
Elevated blood triglyceride concentrations are known to be a cardiovascular risk factor. By lowering high blood triglyceride levels, consequently, the cardiovascular risk should also be reduced. If not, then elevated blood triglycerides should not be considered as a CV risk factor.
The observed outcome of the STRENGTH Trial showing no significant reduction in the cardiovascular risk in the Treatment Group, maybe because the baseline omega-3 levels found in the Treatment Group of 6.9 were so high to start with that these patients were already well protected when they entered into the study. Furthermore, the relatively moderate increase in the calculated Omega3-Index from 6,9 to 9.4 after 12 months supplementation of 4g EPA+DHA per day may indicate an absorption/bioavailability problem – possibly due to the specific enteric coating applied to the drug.
Literature:
[1] Maki KC, Orloff DG, Nicholls SJ, et al. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clin Ther. 2013;35(9):1400-11.e1, 3. doi:10.1016/j.clinthera.2013. 07.420 16.]
[2] Deepak L., et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England Journal of Medicine, Vol. 380, No.1 (2019), 11-22
[3] Matthew J., Budoff MD. Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy – EVAPORATE. Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy - American College of Cardiology (acc.org)
[4] McKenny JM, Sica D. Prescription Omega-3 Fatty Acids for treatment of hypertriglyceridemia. Am J Health Syst Pharm (2007) Mar 15, 64(6): 595-605
[5] GISSI–PrevenzioneInvestigators.Dietarysupplementationwithn-3polyunsaturatedfattyacidsandvitaminE in11 324patientswithmyocardialinfarction:Resultsof theGISSI–Prevenzionetrial.Lancet1999;354:447–55
[6] YokoyamaM et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. The Lancet. (2007), March 31: P1090-1098.