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Journal Club

Journal Club. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Gregson J, Pocock SJ, Ballantyne CM; REDUCE-IT Investigators. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT.

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Journal Club

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  1. Journal Club Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Gregson J, Pocock SJ, Ballantyne CM; REDUCE-IT Investigators. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J Am Coll Cardiol. 2019 Jun 11;73(22):2791-2802. doi: 10.1016/j.jacc.2019.02.032. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019 Jan 3;380(1):23-32. doi: 10.1056/NEJMoa1811403. Harrington D, D'Agostino RB Sr, Gatsonis C, Hogan JW, Hunter DJ, Normand ST, Drazen JM, Hamel MB. New Guidelines for Statistical Reporting in the Journal. N Engl J Med. 2019 Jul 18;381(3):285-286. doi: 10.1056/NEJMe1906559. 埼玉医科大学　総合医療センター　内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田　昌文　 Matsuda, Masafumi 2019年8月1日　8:30-8:55 ４階　カンファレンス室

  2. 油脂の加工・精製でできるもの

  3. n−3 fatty acids (popularly referred to as ω−3 fatty acids or omega-3 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon–carbon double bond in the n−3 position; that is, the third bond from the methyl end of the fatty acid. eicosapentaenoic acid (EPA). docosahexaenoic acid (DHA).

  4. 2010年10月21日 we show that the G protein-coupled receptor 120 (GPR120) functions as an ω-3 FA receptor/sensor. Cell 142, 687–698, September 3, 2010

  5. eicosapentaenoic acid (EPA). 1800mg/day

  6. EPA・DHA摂取量が多いほどDPP-4阻害薬の効果が高いEPA・DHA摂取量が多いほどDPP-4阻害薬の効果が高い 魚摂取量 EPA摂取量 DHA摂取量 （%） （%） （%） 1.0 r=-0.616p＜0.01 r=-0.618p＜0.01 r=-0.678p＜0.01 1.0 1.0 0.5 0.5 0.5 0.0 -0.5 0.0 0.0 HbA1c（NGSP）変化量 -1.0 -0.5 -0.5 -1.5 -1.0 -1.0 -2.0 -1.5 -1.5 -2.5 （g/日） （mg/日） （mg/日） -2.0 -2.0 0 0 0 200 300 40 600 400 80 900 600 120 1200 800 160 薬物治療を行っていない72例の糖尿病患者を対象に、DPP-4阻害薬を4ヵ月間投与し、食事内容の違いがHbA1cの低下効果に及ぼす影響を検討した。 Iwasaki M et al., J Diabetes Invest 2012; 3: 464.

  7. 血中EPA・DHA濃度はDPP-4阻害薬の効果予測マーカーとなり得る血中EPA・DHA濃度はDPP-4阻害薬の効果予測マーカーとなり得る 血中EPA濃度 血中DHA濃度 血中アラキドン酸濃度 （%） （%） （%） r=-0.675p＜0.01 r=-0.729p＜0.01 r=-0.323p=0.165 1.0 1.0 1.0 0.5 0.5 0.5 0.0 0.0 0.0 HbA1c（NGSP）変化量 -0.5 -0.5 -0.5 -1.0 -1.0 -1.0 -1.5 -1.5 -1.5 （μg/mL） （μg/mL） （μg/mL） -2.0 -2.0 -2.0 0 0 0 100 50 100 200 100 300 150 200 400 200 500 250 300 薬物治療を行っていない72例の糖尿病患者を対象に、DPP-4阻害薬を4ヵ月間投与し、HbA1cに及ぼす影響について 検討した。そのうち無作為に選択された患者における投与前の血中EPA・DHA濃度とDPP-4阻害薬による血糖低下作用との関係についても検討した。 Iwasaki M et al., J Diabetes Invest 2012; 3: 464.

  8. 魚介類供給量と平均寿命の関係 （歳） イタリア 日本 ニュージーランド 豪州 スイス スウェーデン 84 フランス ドイツ アイスランド カナダ ノルウェー スペイン アイルランド オーストリア 82 オランダ ギリシア フィンランド ポルトガル 英国 韓国 デンマーク 80 平均寿命 チェコ 米国 メキシコ 78 ポーランド スロバキア 76 トルコ 74 72 （kg/人/年） 70 0 10 20 30 40 50 60 70 80 90 FAO「Food balance sheets」（日本以外の国）、農林水産省「食料需給表」、WHO「Statistical Information System （WHOSIS）」に基づき水産庁で作成。 平成22年水産白書

  9. In our study, the average daily consumption of ω-3 PUFAs(polyunsaturated fattyacid) from seal oil was ~8 g. We based this estimate on a 30% ω-3 PUFA content of seal oil. Compared with less-than-daily consumption, both daily seal oil (odds ratio [OR] 0.2, 95% confidence interval [CI] 0.1-0.8) and daily salmon consumption (OR 0.5, CI 0.2-1.1) were associated with a lower prevalence of glucose intolerance, controlling for age, ethnicity, body mass index, and sex. The effects were similar when limited to newly discovered cases: OR 0.3, CI 0.1-1.3 for seal oil and OR 0.4, CI 0.1-1.3 for salmon. Consumption of seal oil at least five times per week was required to reduce risk. Adler AI, Boyko EJ, Schraer CD, Murphy NJ.: Lower prevalence of impaired glucose tolerance and diabetes associated with daily seal oil or salmon consumption among Alaska Natives. Diabetes Care. 1994 Dec;17(12):1498-501.

  10. GISSI-Prevenzioneの試験概要 EPA・DHA製剤投与群（n=2,836） 心筋梗塞急性期＊患者 （n=11,324） EPA・DHA製剤＋ビタミンE投与群（n=2,830） ＊心筋梗塞発現後3ヵ月以内 ビタミンE投与群（n=2,830） プラセボ群（n=2,828） 観察期間：3.5年間 【主要評価項目】 • 全死亡 • 非致死性心筋梗塞、非致死性脳卒中 • 心血管死、非致死性心筋梗塞、非致死性脳卒中 【副次評価項目】 • 主要評価項目の各因子 GISSI-PrevenzioneＩnvestigators., Lancet 1999;354:447より作図

  11. GISSI-Prevenzione オメガ3系脂肪酸の心血管系イベントへの影響 （%） （%） 5.0 5.0 5.0 総死亡 突然死 4.0 4.0 4.0 -28%* 3.0 3.0 3.0 発現率 発現率 -34%* 2.0 2.0 2.0 -47%* 1.0 1.0 1.0 -57%* 0 0 0 0 0 0 3 3 3 6 6 6 9 9 9 12 （月） 12 （月） 12 （月） （%） 心血管死 EPA・DHA製剤投与群（n-5,665） EPA・DHA製剤非投与群（n=5,658） *：p＜0.05vs. EPA・DHA製剤非投与群、log-rank検定 -30%* 発現率 心筋梗塞発現後3ヵ月以内の11,323例を対象に、EPA・DHA製剤1g群、ビタミンE300mg群、両薬剤併用群、コントロール群（両薬剤非投与群）の4群に無作為に分け、3.5年間追跡したGISSI-Prevenzioneから、心血管系イベントへの影響について検討した。 -34% Marchioli R et al., Circulation 2002; 105, 1897より作図

  12. 2010年9月2日 Low-dose supplementation with EPA–DHA or ALA did not significantly reduce the rate of major cardiovascular events Figure 2. Kaplan–Meier Curves for Primary and Secondary End Points. Kaplan–Meier curves are shown for the cumulative incidence of major cardiovascular events (the primary end point) and fatal coronary heart disease (a secondary end point) among 4837 patients who had had a myocardial infarction and were assigned to receive a study margarine containing supplemental eicosapentaenoic acid (EPA) combined with docosahexaenoic acid (DHA), a margarine containing alpha-linolenic acid (ALA), a margarine containing both EPA–DHA and ALA, or a placebo margarine. N Engl J Med 2010; 363:2015-2026. DOI: 10.1056/NEJMoa1003603 ...

  13. ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S.: n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18.

  14. 2013年7月25日 Fig 5 Dose-response analysis for curvilinear association between marine n-3 PUFA intake (g/day) and risk of breast cancer. Shaded area represents 95% confidence limits for fitted curve. P=0.21 for non-linearity, which indicates no curvilinear association Zheng JS, Hu XJ, Zhao YM, Yang J, Li D.: Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ. 2013 Jun 27;346:f3706. doi: 10.1136/bmj.f3706.

  15. 2013年6月6日 Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, Marchioli R.: n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013 May 9;368(19):1800-8.

  16. Figure 1. Multivariate-adjusted relationship of plasma phospholipid EPA, DPA, and DHA levels with total mortality, evaluated using restricted cubic splines. 健常な高齢者2692人を対象に、長鎖オメガ3多価不飽和脂肪酸（ω3-PUFA）と死亡の関連をコホート研究で検証。血中ω3-PUFA高値が全死亡率の低下と関連し、最低五分位群に対する最高分位群のハザード比はエイコサペンタエン酸0.83、ドコサペンタエン酸0.77、ドコサヘキサエン酸0.80、全ω3-PUFA0.73だった。 2013年4月11日 Mozaffarian D, Lemaitre RN, King IB, Song X, Huang H, Sacks FM, Rimm EB, Wang M, Siscovick DS.: Plasma Phospholipid Long-Chain ω-3 Fatty Acids and Total and Cause-Specific Mortality in Older Adults: A Cohort Study. Ann Intern Med. 2013 Apr 2;158(7):515-25.

  17. Figure 1. Cumulative Incidence of Cardiovascular Events. Panel A shows the Kaplan–Meier event curves for the primary efficacy composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina in the icosapent ethyl group and the placebo group, in a time-to-event analysis. Panel B shows the Kaplan–Meier event curves for the key secondary efficacy composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in the two trial groups, in a time-to-event analysis. In each panel, the inset shows the same data on an expanded y axis. The curves were visually truncated at 5.7 years because a limited number of events occurred beyond that time point; all patient data were included in the analyses. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators.: CardiovascularRisk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792.

  18. From the Academic Medical Center, University of Amsterdam, Amsterdam. In conclusion, after a parade of failed cardiovascular outcome trials of fish oils, REDUCE-IT has shown a substantial benefit with respect to major adverse cardiovascular events. More data are needed to confirm these effects and to inform an understanding of the mechanism of action, the uniqueness of the compound tested, and the potential influence of mineral oil as the comparator. However, the finding that the risks of several cardiovascular outcomes were significantly and consistently lower with icosapent ethyl than with placebo make us hopeful that the use of icosapent ethyl can substantially improve cardiovascular health in patients with statin-controlled LDL cholesterol levels who have elevated triglyceride levels.

  19. A meta-analysis of 10 randomized trials involving 78,000 patients did not show that the groups that received n–3 fatty acids had a lower risk of major adverse cardiovascular events than those receiving placebo,2 nor did ASCEND (A Study of Cardiovascular Events in Diabetes), which tested 1-g capsules containing 840 mg of marine n–3 fatty acids daily in patients with type 2 diabetes.3 In addition, the results of the Vitamin D and Omega-3 Trial (VITAL), a primary-prevention trial involving more than 25,000 participants (also now reported in the Journal), did not show a lower incidence of the primary cardiovascular composite outcome of myocardial infarction, stroke, or cardiovascular death.4 We find it reassuring that the results reported by Bhatt et al. are similar to those of the Japan EPA Lipid Intervention Study (JELIS), an open-label trial that reported that the risk of major adverse cardiovascular events was 19% lower with statin therapy plus 1.8 g of eicosapentaenoic acid daily than with statin therapy alone.5 Arguments over whether there is something unique about icosapent ethyl or the high dose used can be postponed until after the results of the STRENGTH (Statin Residual Risk Reduction With Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial of Epanova (AstraZeneca), another n–3 fatty acid (ClinicalTrials.gov number, NCT02104817opens in new tab), and other ongoing fish-oil studies become available.

  20. a Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts b FACT (French Alliance for Cardiovascular Trials), an F-CRIN network, DépartementHospitalo-Universitaire FIRE, AP-HP, Hôpital Bichat, Université Paris-Diderot, INSERM U-1148, Paris, France c National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom d Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland e Utah Lipid Center, Salt Lake City, Utah f Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia g Amarin Pharma, Inc. (Amarin), Bedminster, New Jersey h Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada i Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, United Kingdom j Department of Medicine, Baylor College of Medicine; Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas J Am Coll Cardiol. 2019 Jun 11;73(22):2791-2802. doi: 10.1016/j.jacc.2019.02.032.

  21. Background In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. These patients are at risk for not only first but also subsequent ischemic events. Objectives Pre-specified analyses determined the extent to which icosapent ethyl reduced total ischemic events.

  22. Methods REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dl (median baseline of 216 mg/dl) and low-density lipoprotein cholesterol >40 and ≤100 mg/dl (median baseline of 75 mg/dl), and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4 g/day or placebo. The main outcomes were total (first and subsequent) primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). As a pre-specified statistical method, we determined differences in total events using negative binomial regression. We also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint frailty analysis.

  23. Abbreviations: CVD = cardiovascular disease, DM = diabetes mellitus, LDL-C = low density lipoprotein cholesterol, MI = myocardial infarction, TG =triglyceride. *Due to the variability of triglycerides, a 10% allowance existed in the initial protocol, which permitted patients to be enrolled with qualifying triglycerides ≥135 mg/dL. Protocol amendment 1 (May 2013) changed the lower limit of acceptable triglycerides from 150 mg/dL to 200 mg/dL, with no variability allowance. †Median trial follow-up duration was 4.9 years (minimum 0.0, maximum 6.2 years)

  24. Figure 1. Proportion of First and Subsequent Primary Composite Endpoint Events, Overall and by Component Analyses are based on the total adjudicated event dataset without accounting for multiple endpoints occurring in a single calendar day by counting as a single event. Of the 1,303 subsequent events, 762 were second events, 272 third events, and 269 fourth or more events. Primary composite endpoint events: cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. Key secondary composite endpoint events: cardiovascular death, nonfatal MI, or nonfatal stroke.

  25. Figure 2. Total (First and Subsequent) and Time to First Primary Composite Endpoint Events and Key Secondary Composite Endpoint Events *No. at risk = number of patients at risk for recurrent events. The number of patients at risk for the first occurrence of an endpoint event were presented previously in Bhatt et al. (20). (A) Primary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. (B) Key secondary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Analyses are based on reduced dataset accounting for statistical handling of multiple endpoints occurring in a single calendar day by counting as a single event. CI = confidence interval; HR = hazard ratio; RR = rate ratio.

  26. Figure 3. Total Primary and Key Secondary Composite Endpoint Events and First, Second, and Third Occurrences The p values are from negative binomial model and Li-Lagakos-modified Wei-Lin-Weissfeld (WLW) models as indicated. Analyses are based on reduced dataset accounting for statistical handling of multiple endpoints occurring in a single calendar day by counting as a single event. Primary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. Key secondary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For the modified WLW analysis, the second event is defined as nonfatal second event or cardiovascular death, and third event is defined as nonfatal third event or cardiovascular death. Due to the low number of fourth or more events, only first, second, and third events are displayed (please see Online Figure 3). CI = confidence interval.

  27. Figure 4. Total Primary and Key Secondary Composite Endpoints and Individual Components or Other Composite Endpoints The p values are from the negative binomial model. Primary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. Key secondary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Analyses are based on reduced dataset accounting for statistical handling of multiple endpoints occurring in a single calendar day by counting as a single event. CI = confidence interval.

  28. Figure 5. Risk Differences for 1,000 Patients Treated For 5 Years With Icosapent Ethyl Versus Placebo for the Primary Composite Endpoint and Individual Components or Other Composite Endpoints Analyses are based on total adjudicated event dataset without accounting for multiple endpoints occurring in a single calendar day by counting as a single event. MI = myocardial infarction.

  29. Results In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%) first primary endpoint events and 1,303 (44.8%) subsequent primary endpoint events occurred (which included 762 second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 vs. 89 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.70; 95% confidence interval: 0.62 to 0.78; p < 0.0001). Icosapent ethyl also reduced totals for each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 vs. 44 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.72; 95% confidence interval: 0.63 to 0.82; p < 0.0001).

  30. Conclusions Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events. (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial [REDUCE-IT]; NCT01492361)

  31. Message 魚油の研究でJELIS研究がやはりすばらしかった。 2g/日必要！　単独のイベントの他に再発も防いでいる！ 今後さらに臨床研究が出てくるようである。 これまで1g/日程度でうまくゆかなかったが、NEJMなど一流雑誌でずっと出版されている。 よほど魚油が余っている？？？　か、やっとこれでお商売できる？？？

  32. From the Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School ( J.E.M., N.R.C., I-M.L., W.C., S.S.B., S.M., H.G., C.M.A., D.G., T.C., D.D., G.F., C.R., V.B., E.L.G., W.C.W., J.E.B.), and the Departments of Epidemiology (J.E.M., N.R.C., I.-M.L., W.C.W., J.E.B.) and Nutrition (E.L.G., W.C.W.), Harvard T.H. Chan School of Public Health — all in Boston. N Engl J Med. 2019 Jan 3;380(1):23-32. doi: 10.1056/NEJMoa1811403.

  33. Background • Higher intake of marine n−3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n−3 fatty acids has such effects in general populations at usual risk for these end points is unclear.

  34. Methods • We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n−3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n−3 fatty acids with placebo.

  35. Screening, Randomization, and Follow-up of the Participants.

  36. * Analyses were from Cox regression models that were controlled for age, sex, and randomization group in the vitamin Dportion of the trial. The 95% confidence intervals were not adjusted for multiple comparisons. † This end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. ‡ This end point was a composite of myocardial infarction, stroke, death from cardiovascular causes, or coronary revascularization (percutaneous coronary intervention [PCI] or coronary-artery bypass grafting [CABG]). § These events were not prespecified as primary or secondary end points. ¶ This end point was a composite of myocardial infarction, coronary revascularization (PCI or CABG), and death from coronary heart disease.

  37. Figure 1. Cumulative Incidence Rates of Major Cardiovascular Events and Invasive Cancer of Any Type, According to Year of Follow-up, in the n−3 Group and the Placebo Group. Analyses were from Cox regression models that were controlled for age, sex, and randomization group in the vitamin D portion of the trial (intention-to-treat analyses). The insets show the same data on an enlarged y axis. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group.: Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019 Jan 3;380(1):23-32. doi: 10.1056/NEJMoa1811403.

  38. Figure 2. Cumulative Incidence Rates of Invasive Cancer of Any Type and Major Cardiovascular Events, According to Year of Follow-up, in the Vitamin D Group and Placebo Group. Analyses were from Cox regression models that were controlled for age, sex, and randomization group in the n−3 fatty acid portion of the trial (intention-to-treat analyses). The insets show the same data on an enlarged y axis. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Gordon D, Copeland T, D‘Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group.:Vitamin DSupplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44. doi: 10.1056/NEJMoa1809944.

  39. Figure 2. Hazard Ratios and 95% Confidence Intervals of Major Cardiovascular Events According to Subgroup, Comparing the n−3 Group with the Placebo Group. Analyses were from Cox regression models that were controlled for age, sex, and randomization group in the vitamin D portion of the trial (intention-to-treat analyses). Analyses were not adjusted for multiple comparisons. Race and ethnic group were reported by the participant. Participants with diabetes and hypertension were defined as those receiving treatment for each condition. Parental history of myocardial infarction was defined as early myocardial infarction in a parent (at <60 years of age in father or <65 years of age in mother). Cardiovascular risk factors were smoking, diabetes, hypertension, a high cholesterol level, and parental history of early myocardial infarction.

  40. Results • A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n−3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.24). Invasive cancer was diagnosed in 820 participants in the n−3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P=0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed.

  41. Conclusions • Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. • (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259)

  42. Message 1g/日のn-3ではやはりダメだった。 EPA製剤処方するなら1.8g日で！

  43. From the Department of Data Sciences, Dana–Farber Cancer Institute (D.H.), Boston University (R.B.D.), Harvard T.H. Chan School of Public Health (D.H., D.J.H.), and the Department of Health Care Policy, Harvard Medical School, and the Department of Biostatistics, Harvard T.H. Chan School of Public Health (S.-L.T.N.) — all in Boston; the Department of Biostatistics and Center for Statistical Sciences, Brown University School of Public Health, Providence, RI (C.G., J.W.H.); and Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom (D.J.H.). N Engl J Med. 2019 Jul 18;381(3):285-286. doi: 10.1056/NEJMe1906559.

  44. Some Journal readers may have noticed more parsimonious reporting of P values in our research articles over the past year. For example, in November 2018, we published two reports from the Vitamin D and Omega-3 Trial (VITAL),1,2 a two-by-two factorial, placebo-controlled, randomized trial assessing whether vitamin D or marine n−3 (also known as omega-3) fatty acids prevent cardiovascular disease or cancer. For the n−3 portion of the trial, Manson et al.2 reported 2 prespecified primary outcomes and 22 prespecified and other secondary outcomes — not uncommon in large, expensive randomized or observational studies. The n−3 fatty acids did not significantly reduce the rate of either the primary cardiovascular outcome or the cancer outcome. If reported as independent findings, the P values for two of the secondary outcomes would have been less than 0.05; however, the article reported only the hazard ratios and confidence intervals for the intervention effects for those secondary outcomes, consistent with recently implemented Journal guidelines limiting the use of P values for secondary and other comparisons.

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