Cost-effectiveness of Icosapent Ethyl for High-risk Patients With Hypertriglyceridemia Despite Statin Treatment

Key Points

Question  What is the cost-effectiveness of icosapent ethyl from a US health care perspective for high-risk patients with hypertriglyceridemia despite statin treatment?

Findings  This economic evaluation including 8179 patients found that icosapent ethyl at a cost of $4.16 to $9.28 per day had a high probability of costing less than $100 000 per quality-adjusted life-year gained. At the lower cost, treatment with icosapent ethyl may be a dominant strategy, offering better outcomes at lower cost.

Meaning  This study suggests that, for high-risk patients with hypertriglyceridemia despite statin treatment, icosapent ethyl may be cost-effective at commonly accepted willingness-to-pay thresholds.

Importance  The Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT) demonstrated the efficacy of icosapent ethyl (IPE) for high-risk patients with hypertriglyceridemia and known cardiovascular disease or diabetes and at least 1 other risk factor who were treated with statins.

Objective  To estimate the cost-effectiveness of IPE compared with standard care for high-risk patients with hypertriglyceridemia despite statin treatment.

Design, Setting, and Participants  An in-trial cost-effectiveness analysis was performed using patient-level study data from REDUCE-IT, and a lifetime analysis was performed using a microsimulation model and data from published literature. The study included 8179 patients with hypertriglyceridemia despite stable statin therapy recruited between November 21, 2011, and May 31, 2018. Analyses were performed from a US health care sector perspective. Statistical analysis was performed from March 1, 2018, to October 31, 2021.

Interventions  Patients were randomly assigned to IPE, 4 g/d, or placebo and were followed up for a median of 4.9 years (IQR, 3.5-5.3 years). The cost of IPE was $4.16 per day after rebates using SSR Health net cost (SSR cost) and $9.28 per day with wholesale acquisition cost (WAC).

Main Outcomes and Measures  Main outcomes were incremental quality-adjusted life-years (QALYs), total direct health care costs (2019 US dollars), and cost-effectiveness.

Results  A total of 4089 patients (2927 men [71.6%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive IPE, and 4090 patients (2895 men [70.8%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive standard care. Treatment with IPE yielded more QALYs than standard care both in trial (3.34 vs 3.27; mean difference, 0.07 [95% CI, 0.01-0.12]) and over a lifetime projection (10.59 vs 10.35; mean difference, 0.24 [95% CI, 0.15-0.33]). In-trial, total health care costs were higher with IPE using either SSR cost ($18 786) or WAC ($24 544) than with standard care ($17 273; mean difference from SSR cost, $1513 [95% CI, $155-$2870]; mean difference from WAC, $7271 [95% CI, $5911-$8630]). Icosapent ethyl cost $22 311 per QALY gained using SSR cost and $107 218 per QALY gained using WAC. Over a lifetime, IPE was projected to be cost saving when using SSR cost ($195 276) compared with standard care ($197 064; mean difference, –$1788 [95% CI, –$9735 to $6159]) but to have higher costs when using WAC ($202 830) compared with standard care (mean difference, $5766 [95% CI, $1094-$10 438]). Compared with standard care, IPE had a 58.4% lifetime probability of costing less and being more effective when using SSR cost and an 89.4% probability of costing less than $50 000 per QALY gained when using SSR cost and a 72.5% probability of costing less than $50 000 per QALY gained when using WAC.

Conclusions and Relevance  This study suggests that, both in-trial and over the lifetime, IPE offers better cardiovascular outcomes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.

The Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT) evaluated the efficacy of icosapent ethyl (IPE) in reducing cardiovascular events among high-risk patients with cardiovascular disease (CVD) or diabetes and another risk factor.^1,2 For total primary events (first and subsequent), there was a 30% relative risk reduction from 89 to 61 events per 1000 patient years (P < .001) among those randomly assigned to receive IPE.^3-6

Although REDUCE-IT demonstrated the efficacy and safety of IPE in reducing cardiovascular events among high-risk patients, whether these benefits provide good value (ie, is IPE worth what it costs?) has not been thoroughly explored. We conducted a cost-effectiveness study of REDUCE-IT participants to estimate the incremental in-trial and lifetime health gains, health care costs, and cost-effectiveness of adding IPE, 4 g/d, to statin therapy.

The details of the REDUCE-IT design have been previously published.^3,7,8 In brief, patients were randomized in a double-blinded manner to receive IPE, 4 g/d, or placebo between November 21, 2011, and May 31, 2018, at 473 sites in 11 countries. Eligible patients had statin-stabilized fasting triglyceride levels between 135 and 500 mg/dL (to convert to millimoles per liter, multiply by 0.0113) as well as low-density lipoprotein cholesterol levels between 40 and 100 mg/dL (to convert to millimoles per liter, multiply by 0.0259). At enrollment, patients were required to be receiving statin therapy for 4 weeks or more. This study was conducted with institutional review board approval (for sites in North America, Advarra provided institutional review board approval and for sites outside North America, local institutional review boards provided approval). Patients provided written consent. The data supporting the findings of this study may be made available from the corresponding author on reasonable request. The present study followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline.^9,10 Analyses were performed from a US health care sector perspective.¹⁰

The REDUCE-IT data set included patient-level baseline characteristics as well as all CVD and safety events recorded during the trial follow-up period (eTable 1 and eTable 2A in the Supplement).³ Events over the lifetime were modeled (eTable 2B in the Supplement). Patient-level events included nonfatal and fatal CVD, including myocardial infarction, stroke, and cardiac arrest; revascularization with percutaneous coronary intervention or coronary artery bypass grafting surgery; hospitalization for heart failure, atrial fibrillation, ventricular tachycardia, peripheral arterial disease requiring intervention, or unstable angina; and syncope and major bleeding. Other outcomes and serious adverse events that did not differ between the study groups were not included.

The REDUCE-IT Clinical Endpoint Committee charter prespecified handling conventions for specific event combinations.^3,7,8 To avoid double costing of hospitalizations when closely timed events are likely to be within a single hospitalization, the handling of multiple events in this analysis varies from the charter, requiring 3 days’ separation of time to classify events as separate events. When multiple events occurred within 3 days, the costlier event was included. Competing risk analysis, based on the cumulative incidence function, was applied to estimate the marginal probability of an event in the presence of competing events.¹¹

Patient-level acute and chronic event rates and medication use data from REDUCE-IT were used to inform health care resource use. Event costs were taken from the National Inpatient Sample (eTable 3 and eTable 4 in the Supplement).^12,13 Because the National Inpatient Sample does not include professional costs (eg, physician fees), they were estimated by percentage share.¹⁴ In addition, background costs adjusted for age were included for all patients plus additional costs of chronic care after myocardial infarction and stroke. Total background lifetime costs were estimated from the mean Medicare per-capita expenditure, stratified by age group. In 2014, the latest date with available data, the mean Medicare per-capita expenditure was $9840 for men and $9922 for women aged 65 to 84 years and was $18 408 for men and $17 017 for women aged 85 years or older.¹⁵ The cost of medications was sourced from SSR Health net cost (SSR cost), an estimate of the cost to the consumer after application of discounts and rebates, and, separately, RedBook wholesale acquisition cost (WAC).¹⁶ The SSR cost for IPE is $4.16 per day, for an annual cost of $1518; the WAC for IPE is $9.28 per day, for an annual cost of $3387. Costs were inflated to 2019 US dollars (USD) using the Personal Consumption Expenditure index.¹⁷ In-trial and lifetime costs were estimated as the sum of background health care costs plus the costs of events and medications.

The projection of life expectancy was based on a Markov disease simulation model, in which each surviving patient was assumed to face a continuing risk of death, with estimates based on the age-, sex-, and race- and ethnicity-specific risks of death obtained from US life tables calibrated to the observed 4.9-year mortality for the REDUCE-IT standard care group.¹⁸ The estimated and observed cumulative incidence and hazard ratios for cardiovascular events at the median follow-up period in REDUCE-IT were quantitatively compared to validate the model, including the estimated vs observed life-years lost, obtained by subtracting the survival times recorded in REDUCE-IT from estimated age- and sex-specific life expectancy estimates. Events and hospitalizations after the trial period were estimated by carrying forward the in-trial event rates and mortality in both groups of REDUCE-IT, with a multiplicative factor (multiplier) for event rates based on patient age group (eTable 5 in the Supplement).^19,20 To evaluate the lifetime benefit associated with IPE, we carried forward the proportional hazard ratios from REDUCE-IT.

We determined quality-adjusted life-years (QALYs) by multiplying survival, measured in life-years, by utility. Utility was estimated using disability weights from the Global Burden of Disease Study because it was not directly measured in REDUCE-IT.^21-23 Utility was determined by whether a patient experienced nonfatal cardiovascular events, revascularization procedures, or stroke. Utility values for chronic and acute disutility are included in eTable 6 in the Supplement. As a base case, no pill-taking disutility was applied because taking pills has little or no association with utility for most patients,^24,25 and daily pill-taking applies to both groups owing to the eligibility requirement of stable statin therapy.

Statistical analysis was performed from March 1, 2018, to October 31, 2021. We assessed the distribution of incremental costs and QALYs from 5000 bootstrapped samples.²⁶ The cost-effectiveness of IPE was expressed as the incremental cost-effectiveness ratio (ICER) in cost per life-year or QALY gained for IPE compared with standard care. The ICER is not calculated when 1 strategy offers better outcome at lower cost (dominance).¹⁰ Future costs and QALYs were discounted 3% annually,²⁷ and the discontinuation rate was 6% based on the trial results (eFigure 1 in the Supplement). Icosapent ethyl was considered highly cost-effective if the ICER was less than $50 000 per QALY gained and intermediate if it was between $50 000 and $150 000 per QALY gained.²⁸ Statistical analyses were performed using R, version 3.6.2 (R Group for Statistical Computing), Stata, version 16 (StataCorp LLC), and TreeAge Pro 2020, release 1.1 (TreeAge Software Inc).

Using Monte Carlo simulation, a Markov state-transition model (eFigure 2 in the Supplement) based on the 4.9-year median (IQR, 3.5-5.3 years) follow-up of in-trial patient-level data was used to extrapolate costs, life expectancy, and quality-adjusted life expectancy to estimate the ICER over a lifetime horizon.¹³ The simulation was run with half-year cycles. In each cycle, individuals could experience a fatal or nonfatal myocardial infarction, stroke, angina, or heart failure or could die of other causes. The results from REDUCE-IT were used to estimate the risk of death from all causes or CVD, CVD events, and serious adverse events in 10 000 hypothetical patients similar to patients in REDUCE-IT in terms of baseline characteristics. The transition probabilities for the simulation model are presented in eTable 7 in the Supplement. Background mortality based on US life tables was integrated in the simulation model, accounting for the increased risk of death with age.¹⁸ Costs and QALYs after the first year of follow-up were discounted 3% annually.²⁷

Threshold analyses, both in-trial and lifetime, examine the variation in daily cost of IPE for selected willingness-to-pay (WTP) thresholds over the lifetime. Input variable ranges for the sensitivity analyses are shown in eTable 8 in the Supplement. The association of independently changing key variables across a plausible range of values with the ICER is shown in tornado diagrams. In addition, a lifetime probabilistic sensitivity analysis was conducted to assess the association with outcomes of simultaneous changes of all the variables involved.^13,23,27,29 The model was run 5000 times, each taking random draws from prespecified uncertainty distributions of all model inputs.

All analyses were repeated in the following subgroups: age (≥65 vs <65 years), sex, trial recruitment cohort (primary vs secondary prevention), baseline diabetes status, baseline serum triglyceride level (≥200 vs <200 mg/dL and ≥150 vs <150 mg/dL), and baseline low-density lipoprotein cholesterol level (≥70 vs <70 mg/dL).

To further examine the association with outcomes of CVD event costs, an alternative analysis was performed in which we used the Optum Research Database, a large database of commercially insured patients, for patients younger than 65 years and the Medicare Fee Schedule for patients aged 65 years or older (eTable 13 in the Supplement).^30-32 The Optum Research Database reflects commercial insurance and Medicare Advantage, but not Medicare fee-for-service; thus, only commercial enrollees were included. The Optum Research Database provides health care costs based on private payer claims, including insurer and patient payments for health care. Optum Research Database costs include professional costs (eg, physician fees). Medicare costs do not include professional fees, so they were estimated by percentage share.¹⁴ All Optum Research Database and Medicare results are in the eResults, eTables 14-16, and eFigures 5-7 in the Supplement.

In REDUCE-IT, 4089 patients (2927 men [71.6%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive IPE, and 4090 patients (2895 men [70.8%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive standard care. The characteristics of the REDUCE-IT trial population are summarized in eTable 1 in the Supplement. In-trial outcomes and costs are shown in eTable 2A in the Supplement, and lifetime outcomes and costs are shown in eTable 2B in the Supplement. The outcomes data for total events (first and subsequent) significantly favor IPE compared with standard care for cardiovascular death, nonfatal myocardial infarction with revascularization, nonfatal ischemic stroke, revascularization, peripheral arterial disease, and unstable angina. Nonfatal myocardial infarction without revascularization, hospitalization for atrial fibrillation or flutter, and major bleeding favor standard care. The Markov simulation model accurately regenerated the cumulative incidence curves and hazard ratios for the primary end point, key secondary end point, and additional end points and components during the 4.9-year follow-up period (eTable 9, eTable 10, and eFigure 3 in the Supplement).

With the use of the SSR cost, the cost of IPE was $18 786, and the cost of standard care was $17 273 (mean difference, $1513 [95% CI, $155-$2870]); with the use of WAC, the cost of IPE was $24 544, and the cost of standard care was $17 273 (mean difference, $7271 [95% CI, $5911-$8630]) (Table). Unadjusted life-years gained favored IPE vs standard care (4.31 vs 4.25; mean difference, 0.06 [95% CI, 0.00-0.12]). Adjusted for utility, patients treated with IPE accrued 3.34 QALYs vs those treated with standard care, who accrued 3.27 QALYs (mean difference, 0.07 [95% CI, 0.01-0.12]). The ICER point estimate was $22 311 per QALY gained using SSR cost and $107 218 per QALY gained using WAC. The cost-effectiveness scatterplots and acceptability curves show that, with the use of the SSR cost, patients treated with IPE had an ICER less than $50 000 per QALY gained in 85.4% of simulations, an ICER less than $100 000 per QALY gained in 95.2%, and an ICER less than $150 000 per QALY gained in 97.1% (Figure 1). With the use of the WAC, patients treated with IPE had an ICER less than $50 000 per QALY gained in 1.0% of simulations, an ICER less than $100 000 per QALY gained in 42.7%, and an ICER less than $150 000 per QALY gained in 74.5%.

With the use of the SSR cost, the cost of IPE was $195 276, and the cost of standard care was $197 064 (mean difference, –$1788 [95% CI, –$9735 to $6159]); with the use of WAC, the cost of IPE was $202 830, and the cost of standard care was $197 064 (mean difference, $5766 [95% CI, $1094-$10 438]) (Table). Unadjusted life-years gained favored IPE vs standard care (14.08 vs 13.94; mean difference, 0.16 [95% CI, 0.08-0.24]). Adjusted for utility, patients treated with IPE accrued 10.59 QALYs compared with those treated with standard care, who accrued 10.35 QALYs (mean difference, 0.24 [95% CI, 0.15-0.33]). The cost-effectiveness scatterplots and acceptability curves show that, with the use of SSR cost, patients treated with IPE had an ICER less than $50 000 per QALY gained in 89.4% of simulations, an ICER less than $100 000 per QALY gained in 98.9%, and an ICER less than $150 000 per QALY gained in 99.9% (Figure 2). With the use of WAC, patients treated with IPE had an ICER less than $50 000 per QALY gained in 72.5% of simulations, an ICER less than $100 000 per QALY gained in 94.8%, and an ICER less than $150 000 per QALY gained in 96.4%. Compared with standard care, IPE had a 58.4% lifetime probability of costing less and being more effective when using SSR cost, an 89.4% probability of costing less than $50 000 per QALY gained when using SSR cost, and a 72.5% probability of costing less than $50 000 per QALY gained when using WAC.

In-trial and lifetime variation in the daily cost of IPE for selected WTP thresholds is shown in Figure 3. In-trial (Figure 3A), IPE is cost-effective at the $50 000 threshold priced at or below $5.84 per day. Over the lifetime (Figure 3B), IPE is dominant when priced at or below $4.80 per day and cost-effective at the $50 000 threshold priced at or below $10.20 per day.

Tornado diagrams show the univariate effect of varying key parameters associated with both effectiveness and cost (Figure 4). Both in-trial and over the lifetime, the ICER was primarily sensitive to the cost of IPE. Results of the lifetime probabilistic sensitivity analysis are shown in the Table as well as eFigure 4 in the Supplement. With the use of SSR cost, IPE was dominant compared with standard care in 47.6% of simulations and cost-effective in 86.2%, 96.9%, and 99.6% of simulations at the $50 000, $100 000, and $150 000 WTP thresholds, respectively. With the use of WAC, IPE was a dominant strategy in 0.9% of simulations and cost-effective in 67.2%, 88.4%, and 94.6% of simulations at the $50 000, $100 000, and $150 000 WTP thresholds, respectively.

For most subgroups, the ICERs indicate that IPE is dominant or cost-effective below a WTP threshold of $100 000 per QALY gained using SSR costs or WAC in-trial (eTable 11 in the Supplement) and over the lifetime (eTable 12 in the Supplement).

In-trial, IPE was estimated to cost $22 311 per QALY gained using the SSR cost and $107 218 per QALY gained using the WAC. In lifetime extrapolation, IPE was projected to cost less and be more effective than standard care using SSR cost, but not using WAC (ICER, $23 866 per QALY gained). In the probabilistic sensitivity analysis, the ICER was less than $50 000 per QALY gained in 86.2% of simulations using SSR cost and 67.2% of simulations using WAC. Although lifetime analysis remains a standard for cost-effectiveness analysis,¹⁰ the in-trial analysis, with a 4.9-year median follow-up, uses real observed data, without the modeling and assumptions necessary for a lifetime analysis. We completed a broad range of analyses investigating posttrial treatment effect, medication and outcome pricing, adherence, and subgroups. The ICER is highly sensitive to the cost of IPE. The SSR cost and WAC offer reasonable boundaries of real-world costs of IPE, as shown in Figure 3.

The cost-effectiveness of IPE, based on SSR cost, is consistent with the cost-effectiveness of statins, which, as generic formulations, are cost saving for secondary prevention. In contrast, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have lower value, given their high annual cost even after discounts.^33-35 In the study by Kazi et al,³³ the annual cost of the PCSK9 inhibitor alirocumab was $7187 (range, $2640-$18 200) based on pricing from SSR Health (net cost)¹⁶ and RedBook (WAC).³⁶ The ICER for alirocumab plus a statin was $308 000 (range, $197 000-$678 000). In the same publication, the ICER for ezetimibe (at an annual cost of $1411) plus a statin was $81 000 (range, $51 000-$215 000). In the present analysis, the cost-effectiveness of IPE was sensitive to the price of the drug.

The Institute for Clinical and Economic Review group used a Markov model simulation based on published summary results from REDUCE-IT³⁷ and found that the ICER for IPE at a net price of $4.44 per day compared with standard care was $17 000 per QALY gained.³⁸ These results are in accord with the present analysis showing that IPE is cost-effective for high-risk populations; although the cost of the drug was similar to the SSR cost in this study, there are differences that likely account for the results. The Institute for Clinical and Economic Review group used published summary data, and the present analysis used patient-level data from the REDUCE-IT trial database, affording a more granular, detailed analysis and making it easier to include and cost all events and reducing the number of assumptions applied in the model. For instance, evaluating the incidence of coronary artery bypass grafting surgery and percutaneous coronary intervention required direct access to patient-level data, and the published summary data did not include repeated events. In addition, the cost of events in the Institute for Clinical and Economic Review group study was drawn from multiple sources across many years; some were state specific and some national, and they date as far back as 2003.

Gao et al³⁹ used a Markov model simulation to evaluate the cost-effectiveness of IPE from an Australian health care perspective, finding an ICER of A$59 036 (approximately $42 151 USD) per QALY gained. That study considered only first events, the costs for events were lower than in the present study, and it is not clear what costs were used for revascularization.

This study has some strengths, including that this was a patient-level analysis during the trial period, including all CVD events. In addition to the main end points, additional cardiovascular events and serious adverse events were considered when rates differed between the study groups. Hospital charges reduced to costs by the cost to charge ratio from the National Inpatient Sample with the addition of physician costs were used as a proxy for societal costs.^12,14 To carefully construct a cost model that accurately reflects costs, National Inpatient Sample costing was used for events and both SSR cost and WAC for IPE.¹⁶ The SSR cost accounts for the lower prices actually paid for the drug compared with WAC. The SSR Health pricing model is appropriate for branded drugs, especially if they are still protected by a patent. The incremental effectiveness and cost were sensitive to the cost of the drug as well as events. Otherwise, sensitivity and scenario analyses found little association with the ICER, confirming the robustness of these results.

This study also has some limitations, including that utility was not measured during REDUCE-IT, so published sources were used as a proxy. The lifetime analysis required modeling to estimate survival, event rates, adherence, and costs; there is considerable uncertainty to these values beyond the trial period, although the model performed well compared with the 4.9-year follow-up available (eTable 9 and eFigure 3 in the Supplement), and despite these assumptions, the ICER remained in an acceptable range in a series of sensitivity analyses. Some direct care costs likely to favor IPE, such as rehabilitation or skilled nursing facilities, were not captured in our costing models. We also did not include indirect costs, such as lost employment, travel, or caregiver costs, which would also favor IPE. Although we strive to model costs and benefits for a health care sector perspective, proxies must be used for cost, and there is no perfect source. Also, the costs used in the present study are from the US health care system and cannot be directly applied to other countries. Costs were established for all patients as if all patients had received care in the US. This model assumes similar resource use for US and non-US patients. No geographical interactions were noted in the clinical results of REDUCE-IT.⁸

In this patient-level cost-effectiveness analysis of REDUCE-IT, IPE was projected to be cost-effective compared with standard care, both during the trial and over a lifetime, with an ICER below commonly accepted WTP thresholds. The findings suggest that treatment with IPE may be cost-effective among patients with high cardiovascular risk whose triglyceride levels remain high despite statin therapy.

Accepted for Publication: November 2, 2021.

Published: February 14, 2022. doi:10.1001/jamanetworkopen.2021.48172

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Weintraub WS et al. JAMA Network Open.

Corresponding Author: William S. Weintraub, MD, MedStar Healthcare Delivery Research Network, MedStar Health Research Institute, MedStar Washington Hospital Center, 110 Irving St NW, Washington, DC 20010 (william.s.weintraub@medstar.net).

Author Contributions: Dr Weintraub had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Weintraub, Bhatt, Zhang, Dolman, Bress, King, Steg, Brinton, Tardif, Kolm.

Acquisition, analysis, or interpretation of data: Weintraub, Bhatt, Zhang, Dolman, Boden, Bress, King, Bellows, Tajeu, Derington, Johnson, Andrade, Miller, Jacobson, Tardif, Ballantyne, Kolm.

Drafting of the manuscript: Weintraub, Zhang, Dolman, Bress, Kolm.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Zhang, Bress, Bellows, Tajeu, Johnson, Andrade, Kolm.

Obtained funding: Weintraub, Dolman.

Administrative, technical, or material support: Weintraub, Bhatt, Dolman, Bress.

Supervision: Weintraub, Bhatt, Dolman, Steg, Tardif.

Conflict of Interest Disclosures: Dr Weintraub reported receiving grants from Amarin during the conduct of the study. Dr Bhatt reported serving as the REDUCE-IT chair and principal investigator during the conduct of the study; and receiving grants from Amarin, AstraZeneca, Bristol Myers Squibb, Eisai, Ethicon, Medtronic, sanofi aventis, The Medicines Company, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Lilly, Chiesi, Ironwood, Regeneron, Idorsia, Synaptic, Fractyl, Afimmune, Ferring Pharmaceuticals, Lexicon, Contego Medical, Owkin, HLS Therapeutics, 89bio, Garmin, Stasys, Faraday Pharmaceuticals, and Abbott; performing unfunded research for FlowCo, Takeda, and Merck; serving on the advisory board for Medscape Cardiology, Elsevier Practice Update Cardiology, Level Ex, Regado Biosciences, and Stasys; serving on the board of directors for Boston VA Research Institute; serving as deputy editor for Clinical Cardiology; serving as a site coinvestigator for Abbott, Biotronic, St Jude Medical (now Abbott), Svelte, CSI, and Philips; receiving grants from and serving on the advisory board for PLx Pharma, Cardax, PhaseBio, Novo Nordisk, Cereno Scientific, CellProthera, MyoKardia/Bristol Myers Squibb, Janssen, and NirvaMed; receiving grants from and serving as a site co-investigator for Boston Scientific; receiving personal fees and nonfinancial support from and serving as a trustee for American College of Cardiology; receiving grants and personal fees from and serving on the advisory board for Boehringer Ingelheim; personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Global, Harvard Clinical Research Institute (now Baim Institute for Clinical Research), Journal of the American College of Cardiology, Cleveland Clinic, TobeSoft, Bayer, Medtelligence/ReachMD, CSL Behring, MJH Life Sciences, Level Ex, K2P, Canadian Medical and Surgical Knowledge Translation Research Group, Arnold and Porter law firm, Piper Sandler, Cowen and Company, and Mount Sinai School of Medicine; personal fees and nonfinancial support from Society of Cardiovascular Patient Care; and nonfinancial support from American Heart Association outside the submitted work. Dr Zhang reported receiving personal fees from MedStar outside the submitted work. Dr Bress reported receiving grants from Amarin during the conduct of the study. Dr King reported receiving personal fees from MedStar Health which were funded by Amarin Corporation during the conduct of the study. Dr Tajeu reported receiving grants from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases and grants and personal fees from the NIH/National Heart, Lung, and Blood Institute during the conduct of the study. Dr Derington reported receiving research funds directly to institution from Amgen Inc and Amarin Corporation outside the submitted work. Mr Johnson and Ms Andrade reported being employees of Optum and that Amarin funded analyses performed by Optum during the conduct of the study. Dr Steg reported receiving personal fees from Amarin during the conduct of the study; personal fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Novartis, Novo Nordisk, Sanofi, and Servier; and grants from Sanofi, Servier, and Bayer outside the submitted work; in addition, Dr Steg had a patent for use of alirocumab to reduce cardiovascular risk issued to Sanofi with no royalties. Dr Miller reported receiving personal fees from Amarin during the conduct of the study and personal fees from Amarin outside the submitted work. Dr Brinton reported receiving personal fees from Amarin during the conduct of the study; and personal fees from Esperion, AstraZeneca, Kowa, and from Pfizer outside the submitted work; grants from Regeneron; and serving as a speaker and/or consultant to 89bio, Amgen, Amryt, Dalcor, Medicure, and Novartis. Dr Jacobson reported receiving personal fees from Amarin during the conduct of the study and personal fees from Amgen, Esperion, Novartis, Regeneron and AstraZeneca outside the submitted work. Dr Tardif reported receiving grants from Amarin and personal fees from HLS Pharmaceuticals during the conduct of the study; and grants and personal fees from AstraZeneca and DalCor Pharmaceuticals; grants from Ceapro, Esperion, Novartis, Pfizer, RegenXBio, and Sanofi; holding minor equity interest in DalCor Pharmaceuticals; and personal fees from Pendopharm, outside the submitted work; in addition, Dr Tardif had a patent for pharmacogenomics-guided cholesteryl ester transfer protein inhibtion issued to DalCor Pharmaceuticals, a patent for use of colchicine after myocardial infarction pending, and a patent for genetic determinants of response to colchicine pending. Dr Ballantyne reported receiving personal fees from Amarin during the conduct of the study; grants from Akcea, Amgen, Arrowhead, Esperion, Ionis, Novartis, and Regeneron; grant/research support (to his institution) and personal fees from Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Esperion, Genentech, Gilead, Illumina, Matinas BioPharma Inc, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, and Sanofi-Synthelabo outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by an unrestricted grant from Amarin Corporation.

Role of the Funder/Sponsor: The sponsor is the manufacturer of the drug. However, the sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The original trial data from REDUCE-IT were provided by the sponsor to the investigators.