By Omid Kiamanesh, MD, FRCPC (biography and no disclosures)
What I did before
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide.1 Despite current preventive efforts, half of middle-aged persons without any cardiovascular risk factors have ASCVD detectable by non-invasive imaging.2
The rate of atherosclerotic plaque development is linearly proportional to the level of circulating atherogenic proteins.3 Therefore, atherosclerotic plaque volume is primarily determined by cumulative exposure to low-density lipoprotein-cholesterol (LDL-C), which can be estimated by age (years) x LDL-C level.4 These plaques develop in early adulthood and can progress to a threshold mass beyond which the plaque is vulnerable, and an individual is at risk of an atherosclerotic event.4,5 This minimum threshold correlates with a cumulative exposure of 125 mmol LDL-years.4
Accordingly, the benefit of lowering LDL-C is a function of the duration and absolute reduction of LDL-C. Simply put, when it comes to LDL-C, ‘the lower, the earlier, the better.’ Over 25 cardiovascular outcome trials have confirmed the efficacy of this approach by showing a 22% reduction in major atherosclerotic events per 1 mmol/L reduction in LDL-C.4 Intensive lowering of LDL-C by up to 85% is safe and achievable using a combination of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i).6 However, despite dramatic lowering of LDL-C to < 0.8 mmol/L, the rate of major atherosclerotic events in persons with ASCVD remains high at 5.3% at 1-year.7 Clearly there is significant residual ASCVD risk that persists beyond lowering LDL-C.8
Lowering triglycerides (TG) has emerged as another strategy to reduce ASCVD risk. Triglyceride-rich lipoproteins include chylomicrons, very-low-density lipoprotein, and intermediate-density lipoprotein. Along with LDL, they comprise circulating apoB particles (which are estimated by non-HDL cholesterol). Collectively, apoB molecules play an active role in atherogenesis by carrying their contents (including TG and LDL-C) across the vascular endothelium, which in turn cause inflammation, oxidation, and atherosclerosis.9 Because apoB molecules are atherogenic, it stands to reason that any method to reduce the number of apoB molecules will reduce ASCVD risk. In fact, a Mendelian randomization analysis showed that TG lowering and LDL-C lowering gene variants were associated with a similarly lower risk of ASCVD per unit reduction of apoB.10 However, randomized trials of therapies to lower TG had not produced a cardiovascular outcome benefit.8,11
Recently, a landmark study was published using icosapent ethyl for cardiovascular risk reduction in patients with hypertriglyceridemia.12 Icosapent ethyl is a high-concentration formulation of eicosapentaneoic acid (EPA) which, along with docosahexaenoic acid (DHA), is an active ingredient in omega-3 fatty acids.
For ASCVD risk reduction, I recommend primordial and primary prevention to all patients. That is to say that, at a minimum, everyone should engage in lifestyle interventions with a proven benefit to prevent ASCVD risk factors and the development of ASCVD. In all patients, I perform a comprehensive risk assessment (discussed elsewhere) and establish a goal LDL-C level.6,13 In select patients, I use lipid-modifying therapy for primary or secondary prevention of ASCVD. As discussed, lowering LDL-C remains the bedrock of this strategy.
To achieve the goal LDL-C, I sequentially initiate lipid-modifying therapy using a high-intensity statin, ezetimibe, and PCSK9 inhibitor. I base this pragmatic sequence on the efficacy, cost, and ease-of-use of these therapies.
Given the prior absence of data supporting a strategy of lowering TG to reduce ASCVD risk, I limited my use of lipid-modifying therapy to lower TG for the prevention of pancreatitis in those with severe hypertriglyceridemia (TG > 10 mmol/L).
What changed my practice
The REDUCE-IT trial is a randomized-controlled trial that aimed to evaluate the potential benefits of icosapent ethyl and was recently published in the New England Journal of Medicine.12 REDUCE-IT showed that among 8179 patients with established cardiovascular disease (71%) or diabetes with an additional risk factor (29%) with mixed dyslipidemia while on statin therapy (LDL-C >1.0 to ≤2.6 mmol/L and TG ≥1.7 to <5.6 mmol/L), icosapent ethyl results in a 25% relative risk reduction in major adverse cardiovascular events (number needed to treat [NNT] = 21) and 20% relative risk reduction in cardiovascular death (NNT = 111) when compared with placebo at 4.9 years.12 This effect was enhanced in those with higher vascular risk based on triglycerides > 2.3 mmol/L and HDL-C < 0.9 mmol/L (hazard ratio 0.68, 95% CI [0.53–0.88]).12
Importantly, the treatment benefit was observed across all baseline triglyceride levels and was consistent irrespective of the attained triglyceride level.12 There was no difference in the overall rate of adverse events or the rate of adverse events leading to treatment discontinuation. Icosapent ethyl resulted in higher rates of atrial fibrillation (5.3% vs 3.9%) and peripheral edema (6.5% vs. 5.0%), but lower rates of anemia (4.7% vs. 5.8%) and diarrhea (9.0% vs 11.1%) when compared with placebo. These findings led to updated recommendations for the use of icosapent ethyl in updated guidelines by the European Society of Cardiology, National Lipid Academy, and American Heart Association.6,14,15 At the time of writing, an update of the Canadian Cardiovascular Society guidelines is in progress.
What I do now
I follow the original approach outlined above until lipid-modifying therapy is optimized to attain the goal LDL-C. Importantly, standard therapies that lower LDL-C have a moderate effect of lowering TG and are proven to reduce ASCVD events in patients with or without an elevated TG level. Therefore, I continue to use these agents first.
If the TG level remains elevated after the goal LDL-C is attained, I exclude reversible causes of hypertriglyceridemia (Table 1) and then consider icosapent ethyl for select patients (per REDUCE-IT Trial inclusion criteria):
- ASCVD or diabetes with an additional risk factor, and
- Optimized therapy for lowering LDL-C, and
- Absence of reversible causes of hypertriglyceridemia, and
- LDL-C >1.0 to ≤2.6 mmol/L and TG ≥1.7 to <5.6 mmol/L
Table 1. Secondary causes of hypertriglyceridemia
| Category | Causes |
| Diet | Alcohol, sugar-containing drinks |
| Insulin resistance | Type 2 diabetes, obesity, metabolic syndrome, inflammatory disease |
| Medications | Estrogens, antipsychotics, glucocorticoids, antiretrovirals |
| Renal disease | Nephrotic syndrome, chronic kidney disease |
A few questions remained unanswered. First, with an armamentarium of powerful and easy to use therapies to lower both LDL-C and TG, it remains unclear whether a patient on a statin who has attained the goal LDL-C would benefit from further lowering LDL-C, lowering TG, or both. This was not addressed by REDUCE-IT, where the use of PCSK9i was prohibited and the use of ezetimibe was low (6%).12 While a combination approach of intensive lowering of LDL-C and TG using novel therapies such as PCSK9i and icosapent ethyl is likely to be effective and safe, the cost of such a strategy is prohibitive to most.
Second, it remains uncertain if other novel lipid-modifying therapies that lower TG can reduce ASCVD risk. Importantly, the findings of REDUCE-IT should not be extrapolated to other formulations of omega-3 fatty acids, as prior studies of lower doses of EPA, combination EPA and DHA, and dietary fish oil supplements were negative. There are ongoing trials of high-dose combination EPA and DHA as well as fenofibrates for ASCVD risk reduction and persons with hypertriglyceridemia.16,17
Conclusion
Despite intensive lowering of LDL-C using lipid-modifying therapy, residual ASCVD risk persists, particularly in those with hypertriglyceridemia. Icosapent ethyl reduces residual ASCVD risk and cardiovascular death in select patients with hypertriglyceridemia while on statin therapy. This novel lipid-modifying therapy is an effective adjunct to the current strategy of lowering LDL-C for the management of ASCVD risk.
References
- Roth GA, Abate D, Abate KH, et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736-88. doi:10.1016/S0140-6736(18)32203-7 (View)
- Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol. 2017;70(24):2979-2991. doi:10.1016/j.jacc.2017.10.024 (View)
- Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365(22):2078-2087. doi:10.1056/NEJMoa1110874 (View)
- Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141-1156. doi:10.1016/j.jacc.2018.06.046 (View)
- McGill Jr HC, McMahan CA. Determinants of atherosclerosis in the young. Am J Cardiol. 1998;82(10):30-36. doi:10.1016/S0002-9149(98)00720-6 (View with CPSBC or UBC)
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;41(1):111-188. doi:10.1093/eurheartj/ehz455 (Request with CPSBC or view UBC)
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664 (View)
- Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol. 2018;72(3):330-343. doi:10.1016/j.jacc.2018.04.061 (View)
- Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol. 2017;14(7):401-411. doi:10.1038/nrcardio.2017.31 (Request with CPSBC or view UBC)
- Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA. 2019;321(4):364-373. doi: (View)
- Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10 158 incident cases among 262 525 participants in 29 western prospective studies. Circulation. 2007;115(4):450-458. doi:10.1161/CIRCULATIONAHA.106.637793 (View with CPSBC or UBC)
- Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792 (Request with CPSBC or view UBC)
- Anderson TJ, Gregoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016;32(11):1263-1282. doi:10.1016/j.cjca.2016.07.510 (View with CPSBC or UBC)
- Orringer CE, Jacobson TA, Maki KC. National Lipid Association scientific statement on the use of icosapent ethyl in statin-treated patients with elevated triglycerides and high or very-high ASCVD risk. J Clin Lipidol. 2019;13(6):860-872. doi:10.1016/j.jacl.2019.10.014 (View with CPSBC or UBC)
- Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation. 2019;140(12):e673-e691. doi:10.1161/CIR.0000000000000709 (View)
- Ridker P, Pradhan A. Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT). ClinicalTrials.gov. Updated March 11, 2020. Accessed August 26, 2020. https://clinicaltrials.gov/ct2/show/NCT03071692 (View)
- Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). ClinicalTrials.gov. Updated May 15, 2020. Accessed August 26, 2020. https://clinicaltrials.gov/ct2/show/NCT02104817 (View)
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Superb review, thank you! I do however have a problem with using the NNT taken directly from clinical trials, for the following reason two reasons:
Firstly, the NNT taken form the trial results assumes that my patient will be treated for exactly as long as the patients in the clinical trial (5 years in REDUCE-IT). Assuming that the drug effect is maintained (as you imply in your cumulative exposure model), the NNT would in fact decline as treatment is continued.
Secondly, one of the dogmas in interpretations of clinical trials is that one should not generally pay too much attention to sub-group analyses, except as hypothesis-generating observations. In other words, it should be assumed until proven otherwise that the RELATIVE risk reduction (RRR) is a constant. In any event, there was consistent response (RRR) among groups in REDUCE-IT.
NNT is the inverse of absolute risk reduction (ARR), which in turn is equal to RRR multiplied by baseline (placebo group) risk. In other words, ARR = RRR * baseline risk.
In other words, the NNT is as much influenced by the patient as it is by the treatment.
The NNT derived directly from a clinical trial assumes that the patient sitting in front of me has the same risk as the placebo group, and that is, I believe, a faulty assumption.
Therefore, when faced with an individual patient, I try to calculate his personal risk (eg Framingham or whatever), and then multiply that by the RRR from the clinical trial. That would be his personal ARR, and the inverse of that number is what I call his NITNT (“number of identical twins needed to treat”).
2 further pieces of information are needed to put the study results and treatment suggestions in perspective. First, we need to know changes in all cause mortality, not just the change in disease specific mortality. We need all cause mortality as treatments may increase other causes of death even as the cause of interest declines.
Secondly, we need to know how much longer a treated population lives. A gain of a month or two of life expectancy may not be considered of value to some patients considering the costs of a treatment or its side-effects.
very interesting
Its an excellent article which will change mypractice.
Thanks for the concise review of REDUCE-IT. I will certainly give more consideration to the use of icosapent in the future.
It’s worth pointing out that 70% of the subjects had established atherosclerotic disease (coronary, carotid, or peripheral) and so the results may not be truly generalizable to those without any documented plaques.
No change in mortality.
Each of the first two authors has more than 10 lines of disclosures with dozens of entities.
Five authors disclose being “employed by and being a stock shareholder of Amarin Pharma”
I don’t know but I’d be surprised if Amarin Pharma does not benefit from this publication.
Not yet replicated that I know of. I(‘m no expert.)
Are we sure that’s enough to change practice enthusiastically?
this is a very thought provoking article
I thank you all for the thoughtful comments and discussion. I will attempt to answer these questions.
Dr. Auersperg provides excellent comments regarding measures of treatment effect. My preference is to report both relative risk and absolute risk. Relative risk has the advantage of comparing risk between two groups (i.e. the treatment and control group). Absolute risk provides an estimate of the clinical relevance of the effect. The number needed to treat (NNT) was introduced as a more intuitive measure of a treatment effect, often when communicating with a patient. After all, a patient’s outcome is binary. It is calculated as the inverse of the ARR and therefore has the same limitations, namely that it depends on baseline risk and treatment duration. In this article, the NNT is reported as a result of an editorial request; however, the ARR (4.8%) is available in the publication(1). It is incumbent on the reader to know the strengths and limitations of each measure.
Dr. Etches discusses the durability of the treatment effect and the presence of adverse effects. I respectfully disagree with these comments. 1) There is no evidence that the treatment effect is not durable. Figure 1 from the REDUCE-IT publication shows Kaplan-Meier curves that are consistent with countless trials of therapies to reduce atherogenic lipoproteins (i.e. LDL), in that the curves separate at 1-year and continue to separate over time(1). This is consistent with our current model of ASCVD. If anything, the (absolute) effect of the therapy only increases with time. 2) The hazard ratio (95% CI) for all-cause mortality is 0.87 (0.74–1.02) with treatment. I would also caution against using all-cause mortality to exclude important adverse effects(1). It is difficult to power a trial for all-cause mortality, even with an effective therapy. The absence of an increased risk of death should not reassure us that there are not important adverse effects. In the case of EPA, the adverse effect profile is favourable reported in Supplementary Table 5(1).
Dr. Weiss emphasized that, as described in the text of this article, 71% of patients had established cardiovascular disease (secondary prevention) and 29% had diabetes plus an additional risk factor(1). This study population is generalizable to many practices. Furthermore, subgroup analyses showed no interaction for risk stratum (primary prevention versus secondary prevention).
Dr. Finucane comments on the financial relationships of this trial and investigators. As with most large randomized trial of new medical therapies, this trial is funded by a pharmaceutical company. The funding source of trials should neither negate or reassure us on the merits of the science – we have to judge the data for what it is. For example, let’s review the major breakthrough life-saving therapies for heart failure with reduced ejection fraction over the past decade. The trials for empagliflozin(2) (EMPEROR-Reduced, NEJM 2020, funded by Boehringer Ingelheim), dapagliflozin(3) (DAPA-HF, NEJM 2019, funded by AstraZeneca), sacubitril/valsartan(4) (PARADIGM-HF, NEJM 2014, funded by Novartis), and eplerenone(5) (EMPHASIS-HF, NEJM 2011, funded by Pfizer) were all funded by pharmaceutical companies. When compared with treatment with beta blocker and ACE inhibitor alone, these therapies will increase the survival of a 55-year-old with HFrEF by a remarkable 6.3 years(6). It is unconscionable to deny a patient the benefits of these therapies based on who funded the trial. Conversely, we must not be falsely reassured by investigator-led, grant-funded studies. Just look at the recent falsification of COVID-19 patient data that resulted in the Surgisphere scandal(7),(8). Clearly, personal and academic conflicts of interest may prevail in the absence of pharmaceutical funding. I implore us all to assess trials based on the merits of their science through a systematic critical appraisal.
Dr. Finucane also comments on the reproducibility of these results. The findings of REDUCE-IT build on the JELIS trial, which compared EPA with statin versus statin alone (there was no placebo group)(9). They are supported by the findings of the subsequent EVAPORATE trial, which showed that EPA results in a 17% reduction in low-attenuation coronary artery plaque volume at 18-months of therapy(10). We have no reason to believe that the findings of REDUCE-IT will be further replicated but, as always, remain vigilant. For the record, I have no disclosures and conflicts of interest.
I thank Dr. Madoonik, Dr. Bhuiyan, and Dr. Puts for their interest and kind works.
Sincerely,
Omid
References:
1. Patel PN, Patel SM, Bhatt DL: Cardiovascular risk reduction with icosapent ethyl. Curr Opin Cardiol 2019; 34:721–727.
2. Packer M, Anker SD, Butler J, et al.: Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med [Internet] 2020; :1–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32865377
3. McMurray JJV, Solomon SD, Inzucchi SE, et al.: Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med Massachusetts Medical Society, 2019; .
4. McMurray JJV, Packer M, Desai AS, et al.: Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014; 371:993–1004.
5. Zannad F, McMurray JJV, Krum H, et al.: Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med 2011; 364:11–21.
6. Vaduganathan M, Claggett BL, Jhund PS, et al.: Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020; 396:121–128.
7. Mehra MR, Ruschitzka F, Patel AN: Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet [Internet] Elsevier, 2020; 395:1820. Available from: https://doi.org/10.1016/S0140-6736(20)31324-6
8. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN: Retraction – Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621. N Engl J Med [Internet] Massachusetts Medical Society, 2020; 382:2582. Available from: http://10.0.4.32/nejmc2021225
9. Yokoyama M, Origasa H, Matsuzaki M, et al.: Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369:1090–1098.
10. Budoff MJ, Bhatt DL, Kinninger A, et al.: Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J [Internet] Oxford University Press (OUP), 2020; . Available from: http://10.0.4.69/eurheartj/ehaa652