Cost‐Effectiveness of Icosapent Ethyl in REDUCE‐IT USA: Results From Patients Randomized in the United States

Abstract

Background

In 3146 REDUCE‐IT USA (Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial USA) participants, icosapent ethyl (IPE) reduced first and total cardiovascular events by 31% and 36%, respectively, over 4.9 years of follow‐up.

Methods and Results

We used participant‐level data from REDUCE‐IT USA, 2021 US costs, and IPE costs ranging from $4.59 to $11.48 per day, allowing us to examine a range of possible medication costs. The in‐trial analysis was participant‐level, whereas the lifetime analysis used a Markov model. Both analyses considered value from a US health sector perspective. The incremental cost‐effectiveness ratio (incremental costs divided by incremental quality‐adjusted life‐years) of IPE compared with standard care (SC) was the primary outcome measure. There was incremental gain in quality‐adjusted life‐years with IPE compared with SC using in‐trial (3.28 versus 3.13) and lifetime (10.36 versus 9.83) horizons. Using an IPE cost of $4.59 per day, health care costs were lower with IPE compared with SC for both in‐trial ($29 420 versus $30 947) and lifetime ($216 243 versus $219 212) analyses. IPE versus SC was a dominant strategy in trial and over the lifetime, with 99.7% lifetime probability of an incremental cost‐effectiveness ratio <$50 000 per quality‐adjusted life‐year gained. At a medication cost of $11.48 per day, the cost per quality‐adjusted life‐year gained was $36 208 in trial and $9582 over the lifetime.

Conclusions

In this analysis, at $4.59 per day, IPE offers better outcomes than SC at lower costs in trial and over a lifetime and is cost‐effective at $11.48 per day for conventional willingness‐to‐pay thresholds. Treatment with IPE should be strongly considered in US patients like those enrolled in REDUCE‐IT USA.

Registration

URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Nonstandard Abbreviations and Acronyms

ICER

incremental cost‐effectiveness ratio

IPE

icosapent ethyl

NIS

National Inpatient Sample

SC

standard care

WAC

wholesale acquisition cost

WTP

willingness to pay

Clinical Perspective.

What Is New?

• This study presents new data on the cost‐effectiveness of icosapent ethyl in patients in the United States at high risk of cardiovascular events.

What Are the Clinical Implications?

• Icosapent ethyl is generally cost‐effective and, in higher‐risk patients, is cost saving by preventing cardiovascular disease events.

• Although specific to icosapent ethyl use with statins, these data might be relevant in statin‐intolerant and statin‐reluctant patients, and in patients taking nonstatin lipid‐lowering therapies.

The REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial) established the substantial efficacy of icosapent ethyl (IPE), 4 g per day, compared with standard care (SC) in reducing atherosclerotic cardiovascular disease events in statin‐stabilized patients with fasting triglyceride levels between 135 and 500 mg/dL and low‐density lipoprotein cholesterol (LDL‐C) <100 mg/dL who also had known cardiovascular disease (secondary prevention cohort) or diabetes plus additional risk factors (primary prevention cohort). ¹ , ² The efficacy of IPE was even greater in REDUCE‐IT USA, a prespecified subgroup of 3146 patients randomized in the United States. ² In REDUCE‐IT USA, IPE resulted in a striking 31% relative risk reduction compared with SC, from 24.7% to 18.2%, for the first occurrence for the primary end point, the composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina, over 4.9 years of median follow‐up (P<0.0001). As in the overall trial, every primary end point component in REDUCE‐IT USA was significantly reduced, including death from cardiovascular causes. While in the overall trial there was a nonsignificant trend toward reduced total mortality with IPE, in REDUCE‐IT USA, there was a statistically and clinically significant 30% relative and 2.6% absolute risk reduction in total mortality (from 9.8% to 7.2%; hazard ratio [HR], 0.70 [95% CI, 0.55–0.90]; P=0.004). In addition, for total primary events (first and subsequent), there was a 36% relative risk reduction (P<0.0001) in patients randomized to IPE compared with SC. ² , ³ , ⁴

When novel health care interventions are demonstrated to be highly efficacious, as is IPE, formal cost‐effectiveness analysis is critical to ensure that the cost of the intervention is justified by the incremental improvements in quantity or quality of life, especially when those interventions are somewhat expensive, as is the high‐dose highly purified and branded agent, IPE. In a prior analysis of the overall REDUCE‐IT results from 11 geographically diverse countries, we found that IPE priced at $4.16 per day is likely to be either highly cost‐effective or even dominant (ie, better health outcomes and lower total costs) and at $9.28 to be cost‐effective at accepted willingness‐to‐pay thresholds both within trial and over the lifetime (prices in 2019 USD). ⁵ However, because efficacy as well as drug and hospitalization costs and reimbursement decisions may vary substantially between countries, a cost‐effectiveness analysis of the US patient subgroup of REDUCE‐IT promises to be of great interest to US medical decision‐makers to determine the net value of IPE from a US health sector perspective. Thus, we conducted a cost‐effectiveness study using patient‐level data from REDUCE‐IT USA to estimate the value of adding 4 g/day IPE to statin therapy in US patients eligible for REDUCE‐IT.

METHODS

Study Design and Participants

Because of the sensitive nature of the data collected for this study, requests to access the data set from qualified researchers trained in human subject confidentiality protocols may be sent to the corresponding author.

The details of design and methods of REDUCE‐IT, the REDUCE‐IT USA substudy, and the REDUCE‐IT cost‐effectiveness analysis have been previously published. ² , ³ , ⁵ , ⁶ , ⁷ REDUCE‐IT data may be requested from the steering committee chairperson, and detailed methods for the cost‐effectiveness analysis may be requested from the corresponding author. The study was performed under institutional review board approval, and all subjects gave informed consent. Briefly, between 2011 and 2016, patients were randomized to 4 g/d IPE or SC at 473 sites in 11 countries. Statin‐stabilized patients were eligible with fasting triglycerides ≥135 and <500 mg/dL and LDL‐C>40 and ≤100 mg/dL. The cost‐effectiveness study on all 8179 patients was based on the event rates in trial, which were then projected over a lifetime, with an observed cost of IPE of $4.16 per day. ⁵ The REDUCE‐IT USA cost‐effectiveness study used the same methods as the original REDUCE‐IT cost‐effectiveness study, although costs for medications and events have been updated to 2021 costs for the current study.

Analytic Approach and Perspective

This REDUCE‐IT USA cost‐effectiveness analysis followed the Consolidated Health Economic Evaluation Reporting Standards (see Supplemental Material). ⁸ , ⁹ The perspective was from a US health care sector. ⁹

Cardiovascular and Serious Adverse Events

Cardiovascular events and safety data in trial came from participant‐level data, and included the following events: cardiovascular and all‐cause mortality; cardiac arrest; MI; stroke; percutaneous coronary revascularization; coronary artery bypass surgery; hospitalization for heart failure, atrial fibrillation, ventricular tachycardia, peripheral arterial disease requiring intervention, and unstable angina; syncope; and major bleeding (Tables S1 and S2). ³ Other outcomes and serious adverse events were not included as they did not differ in incidence between the study arms.

To avoid double costing of hospitalizations, the incidence of multiple events in this cost‐effectiveness study varies from the REDUCE‐IT USA clinical publication by requiring 3 days separation to count as separate events. If multiple events occurred within 3 days, cost was attributed to the event with the highest cost. ³ , ⁶ , ⁷

Estimation of Cost

Base case event costs were derived from the National Inpatient Sample (NIS). ¹⁰ , ¹¹ The NIS contains charges that can be reduced to costs using a cost/charge ratio but does not include professional costs. Professional costs were estimated by percentage share. ¹² Background costs adjusted for age were included for all patients along with additional chronic care costs for MI and stroke. Average health spending per capita expenditure in 2020, the latest date with available data, was $12 530, with $12 947 for men and $13 055 for women aged 65 to 84 years and $24 220 for men and $22 390 for women aged ≥85 years. ¹³ IPE net cost (SSR Health) of $4.59 per day, which accounts for discounts and rebates, and RedBook wholesale acquisition cost (WAC) of $11.48 per day were used to characterize the base case. ¹⁴ , ¹⁵ All costs were inflated to 2021 US dollars using the Personal Consumption Expenditure index. ¹⁶

Diagnostic and procedure codes (Table S3) were used to identify events, which then could be costed using NIS costs (Table S4). IPE was considered highly cost‐effective if the incremental cost‐effectiveness ratio (ICER) was <$50 000 per quality‐adjusted life‐year (QALY) gained and intermediate if between $50 000 and $150 000 per QALY gained. ¹⁷

Life Expectancy

Life expectancy was based on a disease simulation Markov model, in which each surviving patient was assumed to face a yearly risk of death, with estimates of this risk based on the age‐, sex‐, and race‐specific risk of death obtained from US life tables calibrated to match the observed 4.9‐year mortality of REDUCE‐IT USA patients. ¹⁸ Posttrial events were estimated by carrying forward the in‐trial event rates, with a multiplicative factor for event rates based on patient age (Table S5). ¹⁹

Quality‐Adjusted Life‐Years

QALYs were estimated by multiplying survival by published estimates of utility (Table S6). ²⁰ , ²¹ , ²² Utility, ranging from 0 (death) to 1 (perfect health status), was determined on the basis of whether a patient experienced nonfatal cardiovascular events, revascularization procedures, or stroke. We recognize that some health states may have a utility of <0.

Statistical Analysis

In‐Trial Analysis

Mean total costs and QALYs were calculated, and the distribution was assessed using 5000 bootstrapped sample patients. ²³ The ICER is defined as incremental costs divided by QALYs gained for IPE compared with SC. The numerical ICER is not calculated where 1 strategy offers better outcome at lower cost (ie, dominance). ⁹ Both costs and QALYs were discounted 3% annually, with sensitivity analyses performed for between 0% and 10% discounting. ²⁴

Lifetime Analysis

A Markov state transition model with a 1‐year cycle based on the 4.9‐year median 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. ¹¹ The structure of the model is shown in Figure S1. In each cycle, patients could experience a fatal or nonfatal MI, stroke, angina, heart failure, or noncardiac death (Table S7).

Sensitivity Analysis

Sensitivity analyses were conducted during the trial and over the lifetime to examine the impact of effectiveness, discontinuation, discounting, adherence, acute disutility, disutility of taking pills, probability adverse event, and cost of the drug, major events, and adverse events. The major event HR, probability of death from an adverse event, and event accelerator are crucial factors in the lifetime model, whereas probability of a major event is applicable to the in‐trial analysis. A lifetime probabilistic sensitivity analysis was also performed. The model assessed the impact of simultaneous changes across all variables over 5000 trial simulations. The ranges and distributions of variables used in the sensitivity analyses are shown in Table S8.

Subgroup Analysis

The analyses were repeated for subgroups defined by age (≥65 versus <65 years), sex, primary versus secondary prevention, baseline diabetes, baseline serum triglycerides (≥200 versus <200 mg/dL, and ≥150 versus <150 mg/dL), and baseline LDL‐C (≥70 versus <70 mg/dL).

RESULTS

REDUCE‐IT USA baseline (Table S9) and outcome data (Tables S1 and S2) are included in the supplement. There were no significant differences in the distribution of baseline characteristics of the 1548 participants randomized to IPE compared with the 1598 participants randomized to SC. The outcomes data for total events significantly favor IPE for all‐cause mortality, cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, peripheral arterial disease, and unstable angina. There was little difference between the groups for hospitalization for heart failure or atrial fibrillation; there was a trend for major bleeding to favor SC. Most event rates and costs favor IPE.

In‐Trial Analysis

In‐trial and lifetime base cases both support the cost‐effectiveness of IPE compared with SC (Table). In‐trial life‐years gained favored IPE compared with SC (4.23 versus 4.10; mean difference, 0.13 [95% CI, 0.02–0.25]). Participants randomized to IPE compared with SC accrued 3.28 versus 3.13 mean QALYs, respectively (mean difference, 0.15 [95% CI, 0.05–0.25]). The cost for IPE compared with SC was $29 420 versus $30 947 for net cost, respectively (mean difference, $1527 decrease [95% CI, $4726 decrease to $1672 increase]), and $36 364 versus $30 947 for WAC (mean difference, $5417 [95% CI, $2211–$8623]). IPE was dominant using net cost and highly cost‐effective with an ICER of $36 208 using WAC. The results are displayed graphically in the cost‐effectiveness plane and cost‐effectiveness acceptability curves, with 99.4% of simulations below the $50 000 willingness‐to‐pay (WTP) threshold for net cost, and 71.8% of simulations below the $50 000 WTP threshold for WAC (Figure 1).

Table .

Cost‐Effectiveness Results for IPE Compared With SC Using Costs From the NIS

Analysis	Average total cost (2021 USD)			Average LY/QALY			ICER, USD/LY or USD/QALY	IPE dominant, %	IPE dominated, %	Probability of cost‐effectiveness, %
	IPE	SC	∆ (95% CI)	IPE	SC	∆ (95% CI)				<$50 000	<$100 000	<$150 000
LY results (net cost)
In trial	33 806	35 386	−1580 (−5242 to 2081)	4.23	4.10	0.13 (0.02 to 0.25)	Dominant	79.4	0.1	98.7	98.8	98.9
Lifetime	216 243	219 212	−2969 (−9685 to 3747)	13.68	13.27	0.41 (0.33 to 0.49)	Dominant	84.2	0.1	99.4	99.6	99.8
PSA	229 023	231 557	−2534 (−9930 to 4862)	13.71	13.45	0.36 (0.20 to 0.52)	Dominant	70.5	0.1	97.2	98.1	99.3
LY results (wholesale acquisition cost)
In trial	41 904	35 386	6518 (2845 to 10 190)	4.23	4.10	0.13 (0.02 to 0.25)	48 674	0.0	0.9	52.5	87.2	94.1
Lifetime	221 403	219 212	5078 (−862 to 8482)	13.68	13.27	0.41 (0.33 to 0.49)	12 385	14.7	0.1	88.2	95.8	97.1
PSA	236 150	231 557	4593 (−1771 to 10 557)	13.71	13.45	0.36 (0.20 to 0.52)	12 758	12.8	0.1	91.6	97.4	98.8
QALY results using net cost
In trial	29 420	30 947	−1527 (−4726 to 1672)	3.28	3.13	0.15 (0.05 to 0.25)	Dominant	81.3	0.1	99.4	99.5	99.6
Lifetime	216 243	219 212	−2969 (−9685 to 3747)	10.36	9.83	0.53 (0.46 to 0.57)	Dominant	76.7	<0.1	99.7	99.8	99.9
PSA	229 023	231 557	−2534 (−9930 to 4862)	10.51	10.04	0.47 (0.32 to 0.62)	Dominant	77.2	0.1	98.1	98.5	99.5
QALY results using wholesale acquisition cost
In trial	36 364	30 947	5417 (2211 to 8623)	3.28	3.13	0.15 (0.05 to 0.25)	36 208	0.0	0.2	71.8	94.8	97.8
Lifetime	221 403	219 212	5078 (−862 to 8482)	10.36	9.83	0.53 (0.46 to 0.57)	9582	17.3	0.1	91.3	96.0	98.1
PSA	236 150	231 557	4593 (−1771 to 10 557)	10.51	10.04	0.47 (0.32 to 0.62)	9772	16.3	0.1	90.5	95.4	98.0

Lifetime analysis was based on microsimulation, and probabilistic sensitivity analysis used population means for parameters involved. ∆ Indicates difference between IPE and placebo; ICER, incremental cost‐effectiveness ratio; IPE, icosapent ethyl; LY, life‐year; NIS, National Inpatient Sample; PSA, probabilistic sensitivity analysis; QALY, quality‐adjusted life‐year; and SC, standard care.

Figure 1. Cost‐effectiveness for icosapent ethyl (IPE) compared with standard care (SC) during the trial period.

The cost‐effectiveness plane for net cost (A) and wholesale acquisition cost (WAC; B) shows the likelihood of IPE being cost‐effective at the $50 000 willingness‐to‐pay (WTP) threshold when compared with SC among 5000 bootstrapped simulations. Results below the WTP line represent where IPE is cost‐effective, and below the horizonal line a dominant strategy (more effective at lower cost). Acceptability curves for net cost (C) and WAC (D) illustrate the impact on the probability of being cost‐effective (y axis) for various WTP thresholds (x axis). QALY indicates quality‐adjusted life‐year.

Lifetime Analysis

The lifetime analysis necessarily required estimation of survival, event rates, adherence, and costs. Although there is uncertainty inherent in these estimates, the model simulation closely matched the in‐trial results (Figure S2; Table S10). The model simulation can then be applied to both fatal and nonfatal events (Table S11). In the lifetime analysis, life‐years gained favored IPE compared with SC (13.68 versus 13.27; mean difference, 0.41 [95% CI, 0.33–0.49]). IPE increased QALYs by 0.53 (10.36 versus 9.83 [95% CI, 0.46–0.57]). Using net cost, IPE decreased health care costs by $2969 ($216 243 versus $219 212 [95% CI, $9685 decrease to $3747 increase]) and dominated SC, with lower costs and better quality‐adjusted survival in 76.7% of simulations, as illustrated in the cost‐effectiveness plane and cost‐effectiveness acceptability curves (Figure 2). Compared with SC, IPE‐treated participants had an ICER of <$50 000 per QALY gained in 99.7% and <$100 000 per QALY gained in 99.8% of simulations. Using WAC, IPE increased health care costs over the lifetime by $5078 ($221 403 versus $219 212 [95% CI, $862 decrease to $8482 increase]) and had an ICER of $9582, as shown in the cost‐effectiveness plane and acceptability curves (Figure 2).

Figure 2. Cost‐effectiveness for icosapent ethyl (IPE) compared with standard care (SC) over the lifetime.

The cost‐effectiveness plane for net cost (A) and wholesale acquisition cost (WAC; B) shows the likelihood of IPE being cost‐effective at the $50 000 willingness‐to‐pay (WTP) threshold when compared with SC among 5000 bootstrapped simulations. Results below the WTP line represent where IPE is cost‐effective, and below the horizonal line a dominant strategy (more effective at lower cost). Acceptability curves for net cost (C) and WAC (D) illustrate the impact on the probability of being cost‐effective (y axis) for various WTP thresholds (x axis). QALY indicates quality‐adjusted life‐year.

Threshold Analysis

The daily cost of IPE that will result in an ICER below selected WTP thresholds is shown in Figure 3. During the trial period, IPE was dominant priced at or below $5.98 per day, cost‐effective at the $50 000 WTP threshold when priced at or below $13.52 per day, and cost‐effective at the $100 000 WTP threshold priced at or below $20.96 per day. Over the lifetime, IPE is cost‐effective at the $50 000 WTP threshold when priced at or below $13.00 per day and cost‐effective below the $100 000 WTP threshold priced at or below $20.40 per day.

Figure 3. Icosapent ethyl threshold analysis.

The impact of drug cost on willingness to pay (WTP) is shown during the trial period (A) and over the lifetime (B) for common WTP thresholds. Icosapent ethyl prices based on net cost (SSR Health), Veterans Administration (VA) federal supply, National Average Drug Acquisition Cost (NADAC) generic, NADAC brand, Medicare Part D, and wholesale acquitision cost (WAC) are shown.

Sensitivity Analyses

Tornado diagrams for the sensitivity analyses are shown in Figure 4. During the trial period and over the lifetime, the ICER was primarily sensitive to the price of IPE. The lifetime probabilistic sensitivity analysis (Table; Figure S3) showed that, using net cost, IPE was a dominant strategy in 77.2% of simulations and cost‐effective in 98.1%, 98.5%, and 99.5% of simulations at the $50 000, $100 000, and $150 000 per QALY gained thresholds, respectively. Using WAC, IPE had an ICER of $9772 and was cost‐effective in 90.5%, 95.4%, and 98.0% of simulations at the $50 000, $100 000, and $150 000 thresholds, respectively.

Figure 4. Tornado diagrams illustrate the impact on the incremental cost‐effectiveness ratio (ICER) when varying the value of variables across a range of values.

During the trial period, the ICER is most sensitive to the price of icosapent ethyl (IPE) when using net cost (A) and wholesale acquisition cost (WAC; B). Over the lifetime, the drug cost is similarly influential when using net cost (C) and WAC (D). In the tornado diagrams, the blue bar represents the low value, and the green bar represents the high value; they are separated by the ICER at the central line. For example, during the trial period using net cost (A), the ICER is dominant when IPE is priced at the low value of $3 per day and between $160 000 and $170 000 per quality‐adjusted life‐year (QALY) gained when priced at the high value of $20 per day.

Subgroup Analysis

In trial, using net cost, the ICER for IPE compared with SC was ≤$50 000 per QALY gained in all subgroups and dominant for men, the secondary prevention cohort, and all participants regardless of age, baseline diabetes, baseline LDL‐C, or baseline triglycerides. Using WAC, IPE remains under the $50 000 WTP threshold for all subgroups, except participants qualifying for primary prevention and participants with baseline LDL‐C ≥70 mg/dL (Table S12).

In the lifetime analysis, IPE was dominant for participants aged ≥65 years, men, those with baseline diabetes, the secondary prevention cohort, participants with baseline triglycerides ≥200 and ≥150 mg/dL, and those with baseline LDL‐C ≥70 mg/dL using net cost. For all other subgroups, using both net cost and WAC, the ICER was ≤$100 000, including primary prevention (Table S13).

DISCUSSION

Our cost‐effectiveness analysis of the REDUCE‐IT USA prespecified patient subgroup shows that from a US health sector perspective, IPE was dominant at $4.59 per day during the trial period, with 81.3% of simulations having better outcome at lower cost, and with the ICER <$50 000 per QALY gained in 99.4% of simulations. ¹⁷ Priced at $11.48 per day, IPE had an ICER of $36 208 per QALY gained and was <$50 000 per QALY gained in 71.8% of simulations. Over a lifetime, IPE priced below $11.48 per day is cost‐effective at a WTP threshold of $50 000 per QALY gained. In 76.7% of simulations, IPE resulted in better total health outcomes and lower total health care costs over a lifetime of treatment at $4.59 per day. At $11.48 per day, the ICER was $9582. At a threshold of <$50 000 per QALY gained, IPE was cost‐effective in 99.7% of simulations using net cost and 91.3% WAC costs. Results were consistent in subgroups and across sensitivity analyses.

Comparison With Other Cost‐Effectiveness Studies of IPE

We previously evaluated the cost‐effectiveness of IPE using the full REDUCE‐IT population. In that study, IPE yielded more QALYs than SC both in trial (3.34 versus 3.27) and over the lifetime (10.61 versus 10.35). Using net costs, total health care costs were modestly higher with IPE versus SC in trial ($18 786 versus $17 273) but lower over the lifetime ($196 090 versus $197 064). IPE had a 69.7% probability of both costing less and being more effective than SC over the lifetime and an 88.9% probability of costing $50 000 or less per QALY gained. ⁵ Although favorable, the results were not as strongly positive in REDUCE‐IT overall, whereas in the US subgroup the clinical results were more favorable. Thus, in REDUCE‐IT USA, the ICER was <$50 000 per QALY gained in the primary prevention cohort and dominant in the secondary prevention cohort, both in trial and over the lifetime, using net cost. With the more conservative WAC, the ICER was moderately cost‐effective for primary prevention and highly cost‐effective for secondary prevention during the trial period. Over the lifetime, the ICER was highly cost‐effective for both primary and secondary prevention using WAC.

Previously, the Institute for Clinical and Economic Review (ICER group) conducted a cost‐effectiveness simulation based on REDUCE‐IT. ²⁵ Using net pricing of $4.44 per day, the ICER was $17 000 per QALY gained. ²⁶ These results are largely consistent with our overall REDUCE‐IT cost‐effectiveness analysis. The ICER group relied on published summary data from REDUCE‐IT, whereas this REDUCE‐IT cost‐effectiveness analysis used participant‐level data from the trial database.

Gao et al ²⁷ evaluated the cost‐effectiveness of IPE from an Australian health care perspective using a Markov model; the ICER was AUD 59 036 per QALY gained (≈42 151 USD). This study differed from ours in that they only considered first events and the costs for events are lower in Australia than in the United States.

In a recent cost‐effectiveness analysis from Germany comparing statin monotherapy with additive lipid‐lowering therapies, IPE was found to be cost‐effective for both primary prevention with an ICER of €18 133 (≈20 100 USD) and for secondary prevention with an ICER of €14 485 (≈16 056 USD) at a cost of $7.28 per day. ²⁸

To our knowledge, this is the first such analysis of REDUCE‐IT focusing on a US population.

Comparison With Other Treatments

IPE was shown to be cost‐effective, consistent with the cost‐effectiveness of statins, which as generic formulations are cost saving for secondary prevention. In contrast, the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor alirocumab costs $7187 per year. ¹⁴ , ²⁹ This resulted in an ICER for alirocumab plus a statin compared with a statin alone of $308 000. In the same study, the ICER for ezetimibe (annual cost of $1411) plus a statin compared with a statin alone was $81 000. For alirocumab to be as cost‐effective as ezetimibe, the annual cost would need to be <$1974, or about 27% of its current US cost.

Societal Impact and Endorsement

We have also published a population health impact analysis, including budget impact estimates. ⁵ , ³⁰ We estimated that 3.6 million US adults meet REDUCE‐IT eligibility criteria, and at a daily IPE cost of $4.59, widespread treatment could cost the US health care system $6.0 billion annually. After factoring in $1.8 billion in costs saved attributable to predicted first events, the net cost burden would be $4.3 billion annually. Furthermore, when total (first and recurrent) events were considered, the net cost burden would be only $2.6 billion annually. Some estimates of indirect costs of cardiovascular disease are as high as $98.9 billion annually and are projected to increase to $151.3 billion by 2035. ³¹ In context of these high indirect costs, we believe that the net cost of IPE combined with the cost‐effectiveness data herein strongly support the population‐wide implementation of IPE treatment for REDUCE‐IT eligible people.

In response to the overall REDUCE‐IT data, the American Diabetes Association, the European Society of Cardiology/European Atherosclerosis Society, the National Lipid Association, and the American Heart Association have all recommended that IPE be considered in appropriate participants. ³² , ³³ , ³⁴ , ³⁵ , ³⁶ Interestingly, the results of REDUCE‐IT USA, and thus, the cost‐effectiveness shown in this study, are even more favorable for IPE use. Furthermore, the American College of Cardiology and the American Heart Association have recommended that cost‐effectiveness analyses, such as our analyses of both REDUCE‐IT overall and REDUCE‐IT USA, be incorporated into the clinical practice guidelines. ¹⁷ Results from Cerner real‐world data report that use of IPE remains low in the United States, highlighting the gap between patients eligible for evidenced‐based therapies and the real‐world treated population. ³⁷ Additional research is underway to study implementation of IPE therapy in clinical practice. ³⁸

Strengths and Limitations

A major strength of this study is its use of participant‐level REDUCE‐IT trial data and the inclusion of all (first and subsequent) cardiovascular disease events. The analyses included all cardiovascular events and serious adverse events from the REDUCE‐IT database, where rates differed between the study arms. The use of NIS to estimate cost offers the most detailed contemporary method short of directly assessing all hospital bills. ¹⁰ , ¹² , ¹⁷ The net cost is most appropriate to branded, patent‐protected drugs, accounting for the lower prices actually paid for the drug compared with WAC. ¹⁵ The sensitivity analyses consistently found the ICER to be <$50 000 per QALY gained, confirming the reliability of the results with both participant‐level in‐trial data and extrapolated lifetime analyses. Finally, out of an abundance of caution, we have presented both net cost and WAC in parallel. High‐quality generic IPE may have lower costs than branded IPE, which would only enhance value.

Although the in‐trial analysis used observed, participant‐level data, the lifetime analysis necessarily required estimation of survival, event rates, adherence, and costs. Although there is uncertainty inherent in these estimates, the model simulation closely matched the in‐trial results (Figure S2). Although NIS costs provide a well‐recognized overall approach to assessing hospital costs, this method cannot provide the granularity of detailed line item resource use (which is not available) and associated costs. Another potential limitation of this study is that although our results are favorable, we did not include direct care costs, including outpatient care, rehabilitation, and nursing home costs, nor indirect costs, such as lost employment, travel, or caregiver costs. However, because IPE prevents nonfatal events, these direct and indirect cost are likely to be lower with IPE. There are no special screening costs for initiating IPE therapy beyond standard lipid testing and no special follow‐up laboratory testing. For all these reasons, it is likely that these results, already favoring IPE, are rather conservative. Generalization to populations outside the United States and to patients not eligible for REDUCE‐IT can only be made with caution. ⁷ Most important, this study is dependent on RECUCE‐IT correctly assessing the risks and benefits of IPE.

CONCLUSIONS

The REDUCE‐IT USA cost‐effectiveness analysis has shown that IPE provides excellent value, even being cost saving (dominant) both in trial over the lifetime as well as in most sensitivity analyses and subgroups, and even within the conservative US WTP threshold of $50 000 per QALY gained, both in primary and secondary prevention. These results, coupled with the clinical evidence of efficacy, suggest that IPE therapy should be strongly considered as a statin adjunct of choice across the United States in all patients meeting REDUCE‐IT inclusion criteria.

Sources of Funding

This analysis was supported by an unrestricted grant from Amarin Pharma, Inc, the manufacturer of the drug. The analysis was performed independently by the academic investigators, who had full access to patient‐level data from REDUCE‐IT USA (Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial USA) and take full responsibility for the conduct and integrity of the analysis. One current employee of Amarin (Dr Philip) is a coauthor of this article.

Disclosures

Dr Ballantyne has received grant or research support through her institution from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Novartis, Regeneron, Roche Diagnostic, National Institutes of Health (NIH), American Heart Association (AHA), and American Diabetes Association. He has received consulting fees from Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Matinas BioPharma Inc, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi‐Synthelabo. Dr Bellows has received research support through his institution from the NIH. Dr Bhatt is the chair and principal investigator of REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial), with research funding from Amarin to Brigham and Women's Hospital, and discloses the following relationships: Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; Chair: Inaugural Chair, AHA Quality Oversight Committee; Consultant: Broadview Ventures and Hims; Data Monitoring Committees: Acesion Pharma, Assistance Publique–Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY‐DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH‐funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, American College of Cardiology Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE‐DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR‐ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital, who assigned to Lexicon; neither Dr Bhatt nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); site co‐investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; trustee: American College of Cardiology; Unfunded Research: FlowCo and Takeda. Dr Boden served on the Executive Steering Committee for the TRAVERSE Trial, funded by Abbvie, Inc. He has received research grant support from the Clinical Trials Network, Massachusetts Veterans Epidemiology, Research, and Information Center, VA New England Healthcare System; National Heart, Lung, and Blood Institute as national coprincipal investigator for the ISCHEMIA trial; Axio Research, Inc, Seattle, WA; AbbVie; Amarin Pharmaceuticals, Inc; Amgen; AstraZeneca; and Sanofi Aventis. He served on the Board of Directors for Boston VA Research Institute, Inc, and CardioDx, Mountain View, CA. He served on the Data Monitoring Committee for the VA Cooperative Studies Program and was National Coordinator for the STRENGTH trial, with honoraria from the Cleveland Clinic Clinical Coordinating Center. He serves as Associate Editor for Journal of the American College of Cardiology, Clinical Cardiology and has received speaking honoraria from Amgen, AstraZeneca, Janssen Pharmaceuticals, and Regeneron. Dr Bress has received research support to his institution from Amarin and private consulting from Amarin. Dr Brinton is a member of the REDUCE‐IT steering committee; receives research support from Regeneron; has received consulting/advising honoraria from 89bio, Dalcor, Immunovant, Ionis, Merck, New Amsterdam, and Regeneron; and has received speaking honoraria from Amgen, Amryt, CSL Behring, and Kaneka. Dr Derington reports no disclosures. Ms Dolman reports no disclosures. Dr Jacobson reports receiving consulting fees from Amgen, Esperion, Novartis, Regeneron, and Sanofi. Dr Jiao was a current employee of Amarin at the time of the analyses and is a current shareholder of Amarin Pharma, Inc. Dr Kolm reports no disclosures. Dr Juliano was a current employee of Amarin at the time of the analyses and is a current shareholder of Amarin Pharma, Inc. Dr Miller receives consulting/advising honoraria from Amarin, 89bio, and Ionis and is a member of the REDUCE‐IT steering committee. Dr Philip is a current employee of Amarin and stock shareholder of Amarin Pharma, Inc. Dr Steg has received research grant support from Amarin, Bayer, Sanofi, and Servier. He has received speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer‐Ingelheim, Bristol Myers Squibb, Idorsia, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Sanofi, and Servier. Dr Tardif reports receiving grant support and fees from Amarin; grant support and fees from AstraZeneca; grant support from Ceapro; grant support, fees, and minor equity from DalCor Pharmaceuticals; grant support from Esperion; fees from HLS Pharmaceuticals; grant support from Ionis; grant support from Novartis; fees from Pendopharm; grant support and fees from Pfizer; grant support from RegenXBio; and grant support and fees from Sanofi. He reports holding a patent (US 9909178 B2) on pharmacogenomics‐guided CETP inhibition and has a patent pending on the use of colchicine after myocardial infarction (Dr Tardif has waived his rights in the colchicine patent and does not stand to gain financially). Dr Weintraub has received research support from Amarin Corporation, Lexicon Pharmaceuticals, and from the NIH. He provides consulting to Amarin Corporation, Lexicon Pharmaceuticals, AstraZeneca, Janssen, SC Pharma, and The Medicines Company. Dr Zhang receives consulting from Amarin via MedStar Health Research Institute, Washington, DC.

Supporting information

Tables S1–S13

Figures S1–S3