REDUCE-IT Eligibility and Preventable Cardiovascular Events in the US Population (from the National Health and Nutrition Examination Survey [NHANES])

•We projected the preventable CVD events from the REDUCE-IT trial.•We identified 319 persons (3.0 M) to fit key REDUCE-IT eligibility criteria.•We estimate preventing 71,391 primary CVD outcomes.•Many US adults with known CVD or DM can benefit from icosapent ethyl. The reduction of cardiovascular events with icosapent ethyl–intervention (REDUCE-IT) trial showed in persons with prior cardiovascular disease (CVD) or diabetes mellitus (DM) that icosapent ethyl (IPE) reduced CVD events by 25%. We projected the preventable initial and total CVD events if REDUCE-IT trial eligibility criteria were applied to US adults. We identified US adults with available REDUCE-IT inclusion criteria from NHANES Surveys 1999-2016 and estimated primary (CVD death, nonfatal myocardial infarction, stroke, revascularization, or unstable angina) and secondary composite (CVD death, nonfatal MI or stroke) events using REDUCE-IT published event rates in the IPE and placebo groups, the difference being the number of preventable events. From 11,445 adults aged ≥45 years (representing 111.1 million [M]), a total of 319 persons (3.0 M) fit key REDUCE-IT eligibility criteria: triglycerides of 135 to 499 mg/dL, HbA1c <10%, blood pressure <200/100 mm Hg, and on a statin with LDL-C of 40 to 99 mg/dL. 63% had prior CVD and 37% had DM + ≥1 risk factor (primary prevention cohort). If these persons are given IPE for the REDUCE-IT median trial period of 4.9 years, we estimated preventing a total 349,817 (71,391/year) primary CVD outcomes of which 146,011 (29,798/year) were initial events. Most (24,151) preventable events were from the secondary prevention cohort. Using FDA eligibility criteria, an estimated 4.6 million persons would be eligible for IPE, with 60,544 preventable primary CVD outcomes annually from REDUCE-IT USA event rates. In conclusion, many CVD events in US adults with known CVD or DM and well-controlled LDL-C on statin therapy can be prevented with IPE. The reduction of cardiovascular events with icosapent ethyl–intervention (REDUCE-IT) trial showed in persons with prior cardiovascular disease (CVD) or diabetes mellitus (DM) that icosapent ethyl (IPE) reduced CVD events by 25%. We projected the preventable initial and total CVD events if REDUCE-IT trial eligibility criteria were applied to US adults. We identified US adults with available REDUCE-IT inclusion criteria from NHANES Surveys 1999-2016 and estimated primary (CVD death, nonfatal myocardial infarction, stroke, revascularization, or unstable angina) and secondary composite (CVD death, nonfatal MI or stroke) events using REDUCE-IT published event rates in the IPE and placebo groups, the difference being the number of preventable events. From 11,445 adults aged ≥45 years (representing 111.1 million [M]), a total of 319 persons (3.0 M) fit key REDUCE-IT eligibility criteria: triglycerides of 135 to 499 mg/dL, HbA1c <10%, blood pressure <200/100 mm Hg, and on a statin with LDL-C of 40 to 99 mg/dL. 63% had prior CVD and 37% had DM + ≥1 risk factor (primary prevention cohort). If these persons are given IPE for the REDUCE-IT median trial period of 4.9 years, we estimated preventing a total 349,817 (71,391/year) primary CVD outcomes of which 146,011 (29,798/year) were initial events. Most (24,151) preventable events were from the secondary prevention cohort. Using FDA eligibility criteria, an estimated 4.6 million persons would be eligible for IPE, with 60,544 preventable primary CVD outcomes annually from REDUCE-IT USA event rates. In conclusion, many CVD events in US adults with known CVD or DM and well-controlled LDL-C on statin therapy can be prevented with IPE. The reduction of cardiovascular events with icosapent ethyl–intervention (REDUCE-IT) trial,1Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Ballantyne CM REDUCE-IT InvestigatorsCardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.N Engl J Med. 2019; 380: 11-22Crossref PubMed Scopus (1517) Google Scholar preceded by the Japan EPA Lipid Intervention Study (JELIS) trial done in Japan2Yokoyama M Origasa H Matsuzaki M Matsuzawa Y Saito Y Ishikawa Y Oikawa S Sasaki J Hishida H Itakura H Kita T Kitabatake A Nakaya N Sakata T Shimada K Shirato K Japan EPA lipid intervention study (JELIS) InvestigatorsEffects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis [published correction appears in Lancet. 2007 Jul 21;370(9583):220].Lancet. 2007; 369: 1090‐1098Google Scholar are the only clinical trials to show benefit in reducing atherosclerotic cardiovascular disease (ASCVD) events beyond statin therapy. JELIS involved treatment with 1.8 g/day of pure EPA, but had higher mean plasma EPA levels in participants and lower statin dosages than typically used in the United States; however, there was a significant 19% reduction in CVD events. The REDUCE-IT trial showed a 25% and 30% reduction in initial and total events of the primary composite end point of ASCVD events, respectively, with 4 g/day of IPE in persons with either ASCVD or diabetes mellitus (DM) and additional risk factors who had triglycerides of 135 to 499 mg/dL and well-controlled LDL-C on a statin.1Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Ballantyne CM REDUCE-IT InvestigatorsCardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.N Engl J Med. 2019; 380: 11-22Crossref PubMed Scopus (1517) Google Scholar,3Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Gregson J Pocock SJ Ballantyne CM REDUCE-IT InvestigatorsEffects of icosapent ethyl on total ischemic events: from REDUCE-IT.J Am Coll Cardiol. 2019; 73: 2791-2802Crossref PubMed Scopus (164) Google Scholar Significant reductions were also demonstrated for a many secondary end points. Prescription IPE (Vascepa) was recently approved by the Food and Drug Administration (FDA) for the reduction of CVD events in persons with known ASCVD or DM with risk factors on maximally tolerated statin therapy with triglycerides of ≥150 mg/dl.4FDA approves use of drug to reduce risk of cardiovascular events in certain adult patient groups. Available at:https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups. Accessed June 3, 2020.Google Scholar Not established is the number of US adults who could potentially benefit from IPE based on REDUCE-IT eligibility criteria or FDA indications, and the number of potentially preventable ASCVD events. We estimated the number of US adults potentially eligible for IPE, and more importantly the number of ASCVD events that could be prevented with its use. We identified US adults aged 20 years and over with available REDUCE-IT inclusion criteria using data from National Health and Nutrition Examination Survey (NHANES) 1999-2016. NHANES is a population-based cross-sectional evaluation of noninstitutionalized US individuals with biennial examinations from 1999 to present. This survey collects information regarding participants’ demographic characteristics, medical history, clinical examination, laboratory tests, and prescription medication. Details regarding NHANES methodology have been described previously.5NHANES Survey Methods and Analytic Guidelines. Available at: https://wwwn.cdc.gov/nchs/nhanes/analyticguidelines.aspx. Accessed June 3, 2020.Google Scholar Specific REDUCE-IT eligibility criteria utilized in our study included fasting triglycerides of 135 to 499 mg/dL, hemoglobin A1c (HbA1c <10%), blood pressure <200/100 mmHg and already on statin treatment with LDL-C between 40 and 99 mg/dL. The specific inclusion criteria for primary prevention cohort (those without prior ASCVD) were (1) diabetes mellitus (type 1 or type 2) requiring treatment with medication and (2) men and women aged 50 years or over and at least one of the following additional risk factors for CVD: men ≥55 years of age or women ≥65 years of age, cigarette smoker or stopped smoking for at least 3 months, hypertension (defined as blood pressure ≥ 140 mmHg systolic or ≥90 mmHg diastolic) or on antihypertensive medication, HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women, or microalbuminuria defined as albumin/creatinine ratio ≥2.5 mg/mol. Inclusion criteria available in NHANES for the secondary prevention cohort were self-reported diagnosis of coronary heart disease, heart attack or stroke (information regarding carotid or peripheral arterial diseases or revascularization were not available). In a secondary analysis, we further calculated the eligible population based on the label approved by the US Food and Drug Administration for IPE: (1) Adults aged 18 and over with elevated triglyceride level (≥150 mg/dL) (2) have either established ASCVD or DM with 2 or more additional risk factors as mentioned above, and (3) statin therapy, but without specified LDL-C inclusion levels. We first identified IPE eligible US adults according to the aforementioned criteria and summarized demographic characteristics and risk factor distributions in comparison to participants in the placebo group from REDUCE-IT and REDUCE-IT USA trial. Next, we estimated the number of anticipated ASCVD events including primary composite end points (cardiovascular death, nonfatal MI, stroke, revascularization, or unstable angina) and secondary composite end point (cardiovascular death, nonfatal MI, or stroke) as well as individual secondary endpoints including (cardiovascular death, revascularization, nonfatal MI, stroke, and total mortality using overall REDUCE-IT initial1Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Ballantyne CM REDUCE-IT InvestigatorsCardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.N Engl J Med. 2019; 380: 11-22Crossref PubMed Scopus (1517) Google Scholar and total3Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Gregson J Pocock SJ Ballantyne CM REDUCE-IT InvestigatorsEffects of icosapent ethyl on total ischemic events: from REDUCE-IT.J Am Coll Cardiol. 2019; 73: 2791-2802Crossref PubMed Scopus (164) Google Scholar published event rates as well as REDUCE-IT USA event rates (for initial events only)6Bhatt DL Miller M Brinton EA Jacobson TA Steg PG Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Olshansky B Chung MK Gibson CM Giugliano RP Budoff MJ Ballantyne CM REDUCE-IT InvestigatorsREDUCE-IT USA: results from the 3146 patients randomized in the United States.Circulation. 2020; 141: 367‐375Crossref PubMed Scopus (70) Google Scholar in the IPE and placebo groups, respectively, with the difference being the number of preventable events. We finally repeated the analysis based on the slightly modified US FDA eligibility criteria utilizing REDUCE-IT USA event rates as described above. NHANES sample weighting was utilized to project estimates to the US population. Both total preventable events based on the REDUCE-IT follow-up period, as well as annualized preventable events are presented. SAS statistical software (SAS Institute, Cary, NC) was used for analyses. A total of 53,348 US adults were identified in our 16 years of NHANES datasets, 21,548 (representing a sample weighted population of 222.2 million) were randomly assigned to morning sessions (with the requirement of fasting for at least 8.5 hours). After applying other exclusion criteria as available in NHANES, including those aged below 45 years old, fasting TG <135 mg/dL or ≥500 mg/dL, HbA1c >10%, SBP ≥200 mm Hg or DBP ≥100 mm Hg, LDL-C outside the range of 40 to 100 mg/dL and not on statin treatment, we identified 319 subjects representing a sample weighted population of 3.0 million US adults who fit REDUCE-IT trial eligibility criteria. Of these, 63% had prior ASCVD (secondary prevention cohort) and 37% had DM and additional risk factors (primary prevention cohort) (Figure 1). Table 1 displays the demographic and clinical factors comparison between our REDUCE-IT eligible US adults in NHANES and the REDUCE-IT placebo group. When compared with the overall placebo group, our eligible sample had a higher proportion of persons aged ≥65 years, fewer men and Caucasians, lower TG levels, and a higher proportion of subjects belonging to the primary prevention cohort. When compared with the REDUCE-IT USA placebo group, our eligible sample had very similar characteristics except for lower TG levels as well.Table 1Demographic characteristics among icosapent ethyl eligible subjects from NHANES 1999-2016, as compared with REDUCED-IT overall and USA placebo groupsVariableNHANES (n=319, N= 3,041,891)REDUCED-IT placebo (n=4,090)REDUCE-IT USA placebo (n=1,598)Age (years) Median (IQR)65.4 (60.2-72.2)64.0 (57.0-69.0)65.0 (59.0-71.0) ≥65 ((n) (weighted)207 (N=1,703,079, 56.0%)1906 (46.6%)866 (54.2%)Men (weighted)205 (N=1,819,563, 59.8%)28995 (70.8%)1070 (67.0%)Whites race (weighted)201 (N=2,566,577, 84.4%)3688 (90.2%)1474 (92.2%)Body mass index (kg/m2) Median (IQR)31.2 (28.2-36.0)30.8 (27.9-34.7)32.2 (28.7-36.6) ≥30 (n) (weighted)178 (N=1,874,264, 61.6%)2362 (57.8%)1053 (65.9%)Cardiovascular risk stratum (n) (weighted) Secondary prevention cohort205 (N=1,908,781, 62.7%)2893 (70.7%)942 (58.9) Primary prevention cohort114 (N=1,133,110, 37.3%)1197 (29.3%)656 (41.1)Diabetes (n) (weighted) Type 15 (N=44,873, 1.4%)30 (0.7%)20 (1.3) Type 2217 (N=2,055,414, 67.6%)2363 (57.8%)1095 (68.5) No diabetes97 (N=941,604, 31.0%)1694 (41.4%)483 (30.2%) Data missing03 (0.1%)0Median triglyceride level (IQR) (mg/dL)180.6 (154.6-222.5)216.0 (175.5-274.0)217.5 (175.0-273.5)Median HDL cholesterol level (IQR) (mg/dL)42.1 (35.0-49.9)40.0 (35.0-46.0)40.0 (34.5-46.5)Median LDL cholesterol level (IQR) (mg/dL)77.1 (65.1-89.9)76.0 (63.0-89.0)73.0 (61.0-85.0)Distribution of triglyceride levels (mg/dL) – (n) (weighted N, %) <15062 (N=545,058, 17.9%)429/4089 (10.5%)172 (10.8%) ≥150 to < 200146 (N=1,400,358, 46.0%)1191/4089 (29.1%)446 (27.9%) ≥ 200111 (N=1,096,475, 36.1%)2469/4089 (60.4%)979 (61.3%)Triglyceride level ≥ 200 mg/dL and HDL cholesterol ≤35 mf/dL – no. (weighted N, %)33 (N=355,427, 11.7%)794 (19.4%)349 (21.8%)Numbers are displayed as weighted median or frequency with projected population and weighted percentage. Open table in a new tab Numbers are displayed as weighted median or frequency with projected population and weighted percentage. Figure 2 and Table 2 show the estimated number initial and total primary and secondary composite outcomes based on our REDUCE-IT eligible sample. If given IPE for 4.9 years, from sample weighted projections we estimate a total of 71,391/year primary and 31,660/year secondary ASCVD outcomes (total events, including initial and recurrent events) could be prevented, of which, 29,798/year and 22,349/year were first events, respectively. Table 2 additionally shows the annual preventable events for the individual secondary endpoints from REDUCE-IT. Table 3 stratifies results for the primary and secondary composite endpoints according to belonging to the primary or secondary prevention cohort in REDUCE-IT, demonstrating that the vast majority of preventable events would occur from eligible secondary prevention subjects. If based on REDUCE-IT USA event rates (initial events only), we estimate preventing 40,351/year primary composite and 27,936/year secondary composite ASCVD outcomes in the United States (Table 4 and Figure 3).Table 2Weighted number and absolute event rate of expected preventable cardiovascular outcomes if on icosapent ethyl, NHANES 1999-2016 (n = 319 weighted to 3.0 M)If not on icosapent ethylIf on icosapent ethylPreventable EventsVariableNo.%Events/yearNo.%Events/yearNo.%Events/yearPrimary composite669,21622.0%136,575523,20517.2%106,777146,0114.8%29,798Total Primary composite1,149,83537.8%234,660800,01726.3%163,269349,81711.5%71,391Key secondary composite450,20014.8%91,878340,69211.2%69,529109,5083.6%22,349Total secondary composite568,83418.7%116,088413,69713.6%84,428155,1365.1%31,660Cardiovascular death or nonfatal myocardial infarction377,19412.4%76,978292,0229.6%59,59685,1732.8%17,382Fatal or nonfatal myocardial infarction264,6458.7%54,009185,5556.1%37,86879,0892.6%16,141Urgent or emergency revascularization237,2677.8%48,422161,2205.3%32,90276,0472.5%15,520Cardiovascular death158,1785.2%32,281130,8014.3%26,69427,3770.9%5,587Hospitalization for unstable angina115,5923.8%23,59079,0892.6%16,14136,5031.2%7,450Fatal or nonfatal from nonfatal myocardial infarction, or nonfatal end point that was not significant in the from sample from NHANES 1999-2016 was 319 to Numbers are displayed as the population weighted sample based on a median follow-up of 4.9 event rate of expected CVD and was based Figure 4 from approves use of drug to reduce risk of cardiovascular events in certain adult patient groups. Available at:https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups. Accessed June 3, 2020.Google Scholar end point that was not significant in the trial. Open table in a new tab Table number and absolute initial event rate of expected preventable cardiovascular outcomes if on icosapent ethyl by risk NHANES not on icosapent ethylIf on icosapent ethylPreventable not significant for primary or secondary composite outcomes from the trial published by in N= Primary Secondary N= Primary Secondary are displayed as the population weighted sample not significant for primary or secondary composite outcomes from the trial published by approves use of drug to reduce risk of cardiovascular events in certain adult patient groups. Available at:https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups. Accessed June 3, 2020.Google Scholar in analyses. Open table in a new tab Table first preventable primary and secondary composite end point events if on icosapent ethyl based on REDUCE-IT USA NHANES not on icosapent ethylIf on icosapent ethylPreventable secondary death or nonfatal myocardial or nonfatal myocardial or emergency for unstable or nonfatal from nonfatal myocardial infarction, or nonfatal from are displayed as the population weighted sample Open table in a new tab Figure of annual projected initial and preventable primary and secondary composite end point events if on icosapent ethyl based on REDUCE-IT USA NHANES Figure sample from NHANES 1999-2016 was 319 to Numbers are displayed as the population weighted sample based on a median follow-up of 4.9 event rate of expected CVD and was based Figure 4 from approves use of drug to reduce risk of cardiovascular events in certain adult patient groups. Available at:https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups. Accessed June 3, 2020.Google Scholar Numbers are displayed as the population weighted sample Numbers are displayed as the population weighted sample Figure 1 displays the sample based on modified inclusion criteria from the USA FDA label on IPE. A total of projected to 4.6 in the United States were identified in our NHANES 1999-2016 sample as being eligible for IPE based on the FDA estimate of 60,544 and events for primary and secondary composite end respectively, were expected to be prevented if these persons were with IPE. The estimated preventable events for key individual secondary end points of cardiovascular death, MI, and stroke were and respectively. In a total of were also to be preventable annually with IPE treatment, based on the USA data from REDUCE-IT Figure individual preventable events for secondary endpoints are in Table We estimate that at least 3.0 million US adults would be eligible for IPE therapy based on REDUCE-IT eligibility criteria, with million eligible based on FDA total ASCVD events could be prevented annually initial of these preventable events are among those with In FDA the potentially eligible persons and preventable events by and use of REDUCE-IT USA event rates in a number of projected preventable events to a higher risk population initial events prevented analysis further the of the REDUCE-IT trial by the number of US adults potentially eligible for IPE based on the REDUCE-IT criteria, as well as by more FDA In we estimate the preventable ASCVD events from the REDUCE-IT published event overall and among those subjects in the United eligibility data are similar to data from which show of patients being eligible for IPE, the patient population was more to those with coronary DL Y Tardif JC M Steg PG of the REDUCE-IT trial in patients with coronary Am Coll Cardiol. 2019; 73: PubMed Scopus Google Scholar clinical trials with show an 30% to reduction in ASCVD events, many events a of JC MJ T N J B C A The risk reduction a to to reduce risk in patients with J Cardiol. Google Scholar The trial with was the first among to reduction of risk beyond statin therapy, in a very patient population coronary Giugliano RP A H K EA C TA to statin therapy coronary Engl J Med. Scopus Google Scholar This was by 2 major clinical trials of type risk reductions beyond statin therapy for persons with a coronary the of Steg PG M DL C RA A K and and cardiovascular outcomes coronary Engl J Med. PubMed Scopus Google Scholar or atherosclerotic CVD the of Giugliano RP N H T and and clinical outcomes in patients with cardiovascular Engl J Med. PubMed Scopus Google Scholar The REDUCE-IT DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Ballantyne CM REDUCE-IT InvestigatorsCardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.N Engl J Med. 2019; 380: 11-22Crossref PubMed Scopus (1517) Google Scholar was the first trial to a prescription of 25% and 30% risk reductions for initial and total events of the primary composite ASCVD end point in persons with known ASCVD or DM and additional risk Of the benefit was of or triglyceride level (≥150 mg/dL that the risk reduction be to other than triglyceride DL Steg PG Miller M Brinton EA Jacobson TA Jiao L Tardif JC Gregson J Pocock SJ Ballantyne CM REDUCE-IT in first and total ischemic events with icosapent ethyl triglyceride Am Coll Cardiol. 2019; PubMed Scopus Google Scholar a population of patients that benefit from as IPE. a placebo was used in REDUCE-IT, the FDA that was to have significant on the results of the and Available at: Accessed 2020.Google Scholar the results of other including the Study to in Available at: Accessed Scholar which had used a of EPA and had dosages of EPA or inclusion criteria, be compared with REDUCE-IT. study a number of and The NHANES cohort is for type of analysis to the of risk factors and other eligibility criteria as well as the sample that are applied to project to the and US population. NHANES is to self-reported information on ASCVD history, and not have a number of other ASCVD eligibility criteria, information on defined coronary disease, of revascularization, and peripheral arterial disease index was not available for of our NHANES used in which could in of our eligible cohort. our estimates for of the secondary outcomes are based on a number of preventable events estimated to the absolute in ASCVD events based on the REDUCE-IT trial. In conclusion, we estimate 3 million US adults would be eligible for IPE with over total ASCVD events that could be prevented annually initial events) based on the REDUCE-IT trial event rates. In with the slightly risk reductions in REDUCE-IT DL Miller M Brinton EA Jacobson TA Steg PG Ketchum SB Doyle Jr, RT Juliano RA Jiao L Granowitz C Tardif JC Olshansky B Chung MK Gibson CM Giugliano RP Budoff MJ Ballantyne CM REDUCE-IT InvestigatorsREDUCE-IT USA: results from the 3146 patients randomized in the United States.Circulation. 2020; 141: 367‐375Crossref PubMed Scopus (70) Google Scholar including significant reductions in total a number of preventable events and would be preventable based on these if FDA are eligible individuals and preventable events are by the of IPE if applied to eligible patients to of to as well as not by REDUCE-IT. the study and the the analysis and and and and The that have known or that could have to the in This study was in at the of and was by a to the of from the of from and and is on the for and is a to and is a of the for and and are and of with Figure inclusion criteria based on FDA for REDUCE-IT eligible population in NHANES 1999-2016. The additional risk factors and women aged years smoker or stopped smoking for at least 3 or DBP mm or on antihypertensive HDL-C mg/dL for men or for or with Figure of total projected initial and total preventable primary and secondary composite end point events in the United States if on icosapent ethyl, NHANES 1999-2016. with