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Macrovascular Residual Risk THROUGH LANDMARK STUDY

19 July 2019
REDUCE-IT: Targeting elevated triglycerides reduces residual cardiovascular risk

The REDUCE-IT (Reduction of Cardiovascular Events with EPA-Intervention Trial) trial showed that in high risk statin-treated patients with residual hypertriglyeridaemia, treatment with icosapent ethyl, a purified ethyl ester of eicosapentaenoic acid (EPA), reduced major cardiovascular events by 25%. Treatment with icosapent ethyl also substantially reduced the burden of total ischaemic events.

Bhatt DL, Steg PG, Miller M et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22. Bhatt DL, Steg PG, Miller M et al. Effects of icosapent ethyl on total ischemic events: From REDUCE-IT. J Am Coll Cardiol 2019;73:2791-802.
Summary
Comments & References
STUDY SUMMARY
Objective:  To investigate whether treatment with icosapent ethyl reduces cardiovascular events in high-risk statin-treated patients with elevated triglycerides (TG).
Study design:  Multicentre, randomised, double-blind, placebo-controlled trial. Eligible patients were randomly allocated to treatment with 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo.
Study population:  REDUCE-IT enrolled 8,179 statin-treated patients with established cardiovascular disease or with diabetes and other risk factors. Eligible patients had TG of 135 to 499 mg/dL (1.52 to 5.63 mmol/L) and low-density lipoprotein cholesterol (LDL-C) levels of 41 to 100 mg/dL (1.06 to 2.59 mmol/L).
Efficacy variables:

· The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularisation, or unstable angina.

. The key secondary end point was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke.    

Methods:

REDUCE-IT was an event-driven trial. The primary analysis evaluated the effect of icosapent ethyl on time to first primary or secondary endpoints. A pre-specified subsequent analysis evaluated the effect of icosapent ethyl on total (first and subsequent) primary and key secondary composite endpoint events. All analyses were intention-to-treat.

A Cox proportional-hazards model which included trial group assignment as a covariate, stratified by cardiovascular risk category, geographic region and use of ezetimibe was used to estimate relative hazards for first primary and secondary endpoints compared with placebo. Differences in total events between the two groups were investigated using negative binomial regression.

Main results:

The baseline characteristics of the two groups were similar. Overall, 70.7% of patients had established cardiovascular disease and 29.3% were primary prevention patients with diabetes and at least one additional risk factor. Median age was 64 years, 28.8% were female. Median LDL-C was 75 mg/dL (1.94 mmol/L) and median TG levels were 216 mg/dL (2.44 mmol/L).

The median duration of follow-up was 4.9 years. After 1 year, TG levels were reduced by 18.3% (39 mg/dL) in the icosapent ethyl treatment group. LDL-C levels were increased by 3.1% (2.0 mg/dL) in the icosapent ethyl treatment group versus 10.2% (7.0 mg/dL) in the placebo group, representing an overall increase of 6.6% (5 mg/dL) on placebo.

Results of the primary and secondary efficacy analyses are summarised below.

Table 1. Hazard ratios (95% CI) for primary and secondary endpoints in REDUCE-IT (hierarchical testing)

Endpoint

Placebo

(N=4090)

Icosapent ethyl (N=4089)

Hazard ratio                  (95% CI)

p-value

 

No. (%) of events

 

 

Primary endpoint

901 (22.0%)

705 (17.2%)

0.75 (0.68-0.83)

<0.001

Key secondary endpoint

606 (14.8%)

459 (11.2%)

0.74 (0.65-0.83)

<0.001

Cardiovascular mortality

213 (5.2%)

174 (4.3%)

0.80 (0.66-0.98)

0.01

All-cause mortality

310 (7.6%)

274 (6.7%)

0.87 (0.74-1.02)

-

 A higher proportion of patients in the icosapent ethyl group than in the placebo group were hospitalised for atrial fibrillation or flutter (3.1% vs. 2.1%, p=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (p=0.06) 

In the subsequent total events analysis, icosapent ethyl treatment reduced total primary endpoint events (61 vs. 89 per 1,000 patient-years versus placebo, rate ratio 0.70; 95% CI 0.62 to 0.78; p <0.0001). Icosapent ethyl treatment also reduced total key secondary endpoint (32 vs. 44 per 1,000 patient-years versus placebo, rate ratio 0.72; 95% CI 0.63 to 0.82; p <0.0001).    
Authors’ conclusion: Among patients with elevated TG despite the use of statins, the risk of ischaemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. Treatment with icosapent ethyl also substantially reduced the burden of total ischaemic events.

COMMENT

Despite best evidence-based medicine including statins, high-risk patients including those with atherosclerotic cardiovascular disease and/or type 2 diabetes mellitus remain at high residual cardiovascular risk.1 Elevated TG - a surrogate for increased TG-rich lipoproteins and their remnants - may contribute to this modifiable lipid-related residual cardiovascular risk.2 In support, Mendelian randomisation studies showed that elevated TG‐rich lipoproteins are causally related to increased risk of ischaemic heart disease.3-8 Furthermore, subgroup analyses of statin trials showed that despite statin treatment, patients with elevated TG levels are at higher risk for cardiovascular events.9-11

Previous clinical studies which have specifically investigated TG-lowering therapies such as fibrates, niacin and omega‐3 fatty acids (EPA and docosahexaenoic acid), have had mixed results. In large part this may relate to inadequate patient selection criteria. For example, in the Action to Control Cardiovascular Risk in Diabetes Lipid Study, there were no elevated TG entry criteria, and the median baseline TG was only 1·8 mmol/L (interquartile range 1·3 to 2·6 mmol/L).12

REDUCE-IT is the first trial of current best-evidence-based therapy to support the rationale of targeting elevated TG to reduce residual cardiovascular risk. There are, however, several caveats to bear in mind. In particular, the magnitude of reduction in cardiovascular events with EPA does not equate with the extent of TG reduction (18.3%). This suggests that other mechanism(s) may be implicated; indeed, omega‐3 fatty acids are known to exert several biological actions beyond TG lowering including effects on platelet aggregation, anti-inflammatory activity and anti‐dysrhythmic actions.13 Additionally, the choice of a non-inert placebo (a mineral oil) in REDUCE-IT was a confounder, as it was shown to significantly raise LDL-C levels.

Despite these caveats, the take home message from REDUCE-IT is that targeting elevated TG reduces residual cardiovascular risk in statin-treated high-risk patients. These findings provide a theoretical basis for the ongoing PROMINENT study testing pemafibrate, a novel Selective Peroxisome Proliferator-Activated Receptor Alpha Modulator (SPPARMα) in high risk patients with atherogenic dyslipidaemia (elevated TG and low plasma concentration of high-density lipoprotein cholesterol).14  

References

1. Jernberg T, Hasvold P, Henriksson M et al. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015;36:1163-70.

2. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.

3. Holmes MV, Asselbergs FW, Palmer TM, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 2015;36:539‐50.

4. Musunuru K, Kathiresan S. Surprises from genetic analyses of lipid risk factors for atherosclerosis. Circ Res 2016;118:579‐85.

5. Crosby J, Peloso GM, Auer PL, et al. Loss‐of‐function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22‐31.

6. Jorgensen AB, Frikke‐Schmidt R, Nordestgaard BG, et al. Loss‐of‐function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32‐41.

7. Jorgensen AB, Frikke‐Schmidt R, West AS, et al. Genetically elevated non‐fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826‐33.

8. Varbo A, Benn M, Tybjaerg‐Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427‐36.

9. Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724–30.

10. Faergeman O, Holme I, Fayyad R, et al. Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in End-Points through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease. Am J Cardiol 2009;104:459–63.

11. Kastelein JJ, van der Steeg WA, et al. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation. 2008;117:3002–9.

12. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med. 2010;362:1563–74.

13. Baum SJ, Scholz KP. Rounding the corner on residual risk: Implications of REDUCE-IT for omega-3 polyunsaturated fatty acids treatment in secondary prevention of atherosclerotic cardiovascular disease. Clin Cardiol 2019. doi: 10.1002/clc.23220. [Epub ahead of print]

14. Pradhan AD, Paynter NP, Everett BM et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.

Key words REDUCE-IT; icosapent ethyl; eicosapentaenoic acid; triglycerides; cardiovascular residual risk; cardiovascular outcomes study