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Cập nhật statin ESC 2017
- 1. Statin trong điềutrị rối loạn lipid máu Có gì mới từ ESC 2017? Đại học Y Dược Tp. Hồ Chì Minh Khoa Tim Mạch Can Thiệp BV Chợ Rẫy
- 3. Yếu tố nguycơ xơ vữa huyết khối Yusuf S, et al. Lancet. 2004;364:937--52. Nghiên cứu INTERHEART: 52 nước, gồm Châu Phi, Châu Á, Úc, Châu Âu, Trung Đông, và Nam và Bắc Mỹ 9 yếu tố nguy cơ: 1. Hút thuốc 2. THA 3. Rối loạn lipid máu 4. ĐTĐ 5. Béo phì 6. Chế độ ăn 7. Hoạt động thể lực 8. Rượu 9. Tâm lý Chiếm 90% nguy cơ NMCT cấp Yếu tố có thể điều chỉnh Tương tự trong hầu hết chủng tộc, giới trên thế giới
- 4. Tỉ lệ RLMMcao ở người Việt Nam, đặc biệt ở người cao tuổi Woman Man Hypertension Diabetes Overweight Dyslipidemia Smoking Drinking Low exercise Stress Metabolism Risk Factors Behavorial Risk Factors Nguyen NQ et al, 2012, Int J Hyperten 2012 doi:10.1155/2012/560397
- 7. Đạt LDL-C mụctiêu trong bệnh nhân bệnh động mạch vành Jones PH et al. J Am Heart Assoc. 2012;1:e001800
- 9. Khả năng ứcchế men khử HMG-CoA của statins *P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin IC50 (nM) with 95% confidence limits Rosuva 5.4 100 10 Ceriva * 10.0 Atorva 8.2 Fluva *** 27.6 Simva * 11.2 Prava *** 44.1 IC50 (nM) (log scale)
- 10. Sự thay đổiLDL-C khi tăng liều statin Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 *p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and 20 mg; simvastatin 10 mg, 20 mg and 40 mg †p<0.001 rosuvastatin 20 mg vs atorvastatin 20 mg and 40 mg; simvastatin 20 mg ,40 mg and 80mg ‡p<0.001 rosuvastatin 40 mg vs atorvastatin 40 mg and 80 mg; simvastatin 40 mg and 80 mg # p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg ## p<0.05 atorvastatin 80mg vs rosuvastatin 5mg and 10mg ChangeinLDL-Cfr baseline(%) Dose (log scale) 5 mg 10 mg 20 mg 40 mg 80 mg -27 (n=365) -33 (n=2929) -39 (n=548) -45 (n=479) -50## (n=2072) -55‡ (n=2983) -50† (n=3554) -44* (n=11690) -39 (n=670) -36 (n= 7837) -41# (n=3908) -46 (n=1324) VOYAGER: 37 RCT với 32.258 bệnh nhân
- 11. Tăng mức độtiếp xúc của statin ở người Châu Á 0 0,5 1 1,5 2 0 0,5 1 1,5 2 RSV ATV SIM AUC(0-t) 1.55 (1.21‒ 1.99) Japanese:Caucasian ratio 1.69 (1.32‒ 2.17)1.12 (0.87‒ 1.44) Geometric mean (90% CI) RSV ATV SIM Cmax 1.81 (1.38‒ 2.37) 1.71 (1.31‒ 2.23)1.24 (0.94‒ 1.62) RSV ATV SIM AUC(0-t) 1.86 (1.45‒ 2.39) Chinese:Caucasian ratio 1.53 (1.20‒ 1.96)1.23 (0.96‒ 1.58) RSV ATV SIM Cmax 2.16 (1.65‒ 2.82) 1.60 (1.22‒ 2.08)1.29 (0.98‒ 1.69) Geometric mean (90% CI) Birmingham BK et al. Clin Pharmacol Ther 2008; 83: S15 Bệnh nhân Châu Á Lưu ý đến việc tăng mức độ tiếp xúc với thuốc ở bệnh nhân Châu Á khi không kiểm soát đủ với liều trên 20 mg/ngày.
- 12. Nồng độ Rosuvastatin40mg trong huyếtNồng độ Rosuvastatin 40mg trong huyết tương cao hơn 2 lần ở người châu Átương cao hơn 2 lần ở người châu Á -200-200 00 200200 400400 600600 800800 10001000 12001200 14001400 MalayMalayIndianIndianChineseChineseCaucasianCaucasian n=35n=35n=35n=35n=36n=36n=36n=36 RosuvastatinAUC(0-t)ng.h/mL AUCAUC 11 2.32.3 1.61.6 1.91.9 Liều đơn 40 mg (u) Edmind Lee et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environmentClin Pharmacol Ther 2005;78:330
- 13. Quy tắc của6 37 19 35 27 28 18 12 12 6 12 0 10 20 30 40 50 60 Atorvastatin 10/80 Fluvastatin 20/80 Simvastatin 20/80 Pravastatin 20/40 Lovastatin 20/80 46 6 32 11 Rosuvastatin 10/20 Pitavastatin 1/4 Illingworth DR. Med Clin North Am 2000;84-23- Mỗi lần gấp đôi liều statin sẽ dẫn đến việc giảm khoảng 6% nồng độ LDL- C Chất ức chế enzyme HMG-CoA Reductase Tác động phụ thuộc liều
- 15. Thoái triển mảngxơ vữa tùy thuộc vào loại statin Tsujita K, et al. J Am Coll Cardiol 2015;66:495–507 LDL-C: 75 mg/dl
- 16. Tác động củaLDL-C trên tiến triển mảng xơ vữa Nicholls S et al. JAMA 2007;297:499-508
- 17. IBIS-4: Thoái triểnxơ vữa trong NMCT cấp với statin liều cao kéo dài Raber L, et al. European Heart Journal 2014; 1-11. doi:10.1093/eurheartj/ehu373 Lumen Area Plaque Area Baseline Plaque Area Lumen Area Follow up (13 tháng) Rosuva 40mg Thể tích mảng XV toàn bộ đoạn khảo sát Thể tích mảng XV đoạn 10 mm nặng nhất n= 84 BN, 146 sang thương IVUS/RF Integrated Biomarkers and Imaging Study-4 p<0.001 -2 -1 0 p value: follow-up vs. baseline -2.94 P=0.007 -0.9 %Thayđổitrungbình -3
- 18. COSMOS: Thoái triểnxơ vữa trên BN châu Á đạt được với liều thấp hơn Takayama T, et al. Circ J 2009; 73(11): 2110-2117 Lumen Area Plaque Area Baseline Plaque Area Lumen Area Follow up (19 tháng) Rosuva 16,9mg (%) Thể tích mảng XV Thể tích lòng mạch Thể tích mạch máu p<0.0001 p=0.4673 -10 -5 0 5 10 p value: follow-up vs. baseline +7.25 p<0.0001 -5.07 +0.76 %Thayđổitrungbình N=126
- 19. Đáp ứng kémvới statins gây tiến triển mảng xơ vữa Kataoka Y, et al. Arterioscler Thromb Vasc Biol. 2015;35:990-995 Phân tích tổng hợp từ 7 n/c ngẫu nhiên tiến cứu sử dụng IVUS đánh giá sự tiến triển/thoái triển mảng xơ vữa (n=647) REVERSAL, CAMELOT, ACTIVATE, ASTEROID, ILLUSTRATE, PERISCOPE, và STRADIVARIUS. Thời gian từ 18-24 tháng. P<0.001 P<0.001 P<0.001 P=0.45 Đáp ứng kém với statin: giảm LDL-C < 15%
- 21. Liều statin theokhuyến cáo Hội TM VN 2015
- 22. Tăng gấp đôiliều Statin đem lại hiệu quả giảm thêm chỉ 6% Bays HE et al. Expert Opin Pharmacother 2003;4:779-790 1-STEP COADMINISTRATIONStatin at starting doseStatin at starting dose 15–18% + Ezetimize+ Ezetimize 10mg10mg % Reduction in LDL-C 3-STEP TITRATIONStatin at starting doseStatin at starting dose 1st1st 2nd2nd 3rd3rd Doubling 5–6% 5–6% 5–6% % giảm LDL-C Phối hợp ức chế kép liều thấp giảm thêm 18% 1-STEP COADMINISTRATION High or moderate intensity statin (± EZ) 59% + Ức chế+ Ức chế PCSK9PCSK9 Phối hợp ức chế PCSK9 giảm thêm 59%
- 23. NC phòng ngừa tiênphát NC phòng ngừa thứ phát 50 70 110 130 150 170 19090 210 %bệnhnhânmắccácbiếncốtimmạch LDL cholesterol CARE-Rx 4S-Rx LIPID-PL 4S-PL CARE-PL LIPID-Rx AFCAPS-Rx WOSCOPS-Rx WOSCOPS-PL AFCAPS-PL 25 20 15 10 5 0 ASCOT-PL ASCOT-Rx HPS-Rx HPS-PL HPS LRC-PL LRC-Rx POSCH-PL POSCH-Rx PL: non statin trials Rx: Statin trials (mg/dL) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L) TNT-80A TNT-10A Rosenson RS. Exp Opin Emerg Drugs 2004; 9(2):269-279, LaRosa JC et al. N Engl J Med 2005; 352: 1425-1435 LDL- C càng thấp càng tốt: Giảm biến cố TMGiảm thấp LDL-C làm giảm biến cố tim mạch: Hạ thấp vẫn có lợi và an toàn ?
- 24. Nghiên cứu IMPROVE-IT:Statin + Ezetimibe Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12 Patients stabilized post ACS ≤ 10 days: LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx) Standard Medical & Interventional Therapy Ezetimibe / Simvastatin 10 / 40 mg Simvastatin 40 mg Follow-up Visit Day 30, every 4 months Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (≥ 30 days after randomization), or stroke N=18,144 Uptitrated to Simva 80 mg if LDL-C > 79 (adapted per FDA label 2011) *3.2mM **2.6mM 90% power to detect ~9% difference
- 25. Nghiên cứu IMPROVE-IT:thay đổi LDL-C Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
- 26. Nghiên cứu IMPROVE-IT:tiêu chí chính -ITT Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12 Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke Simva — 34.7% 2742 events EZ/Simva — 32.7% 2572 events HR 0.936 CI (0.887, 0.988) p=0.016 7-year event rates NNT= 50
- 27. Tăng gấp đôiliều Statin đem lại hiệu quả giảm thêm chỉ 6% Bays HE et al. Expert Opin Pharmacother 2003;4:779-790 1-STEP COADMINISTRATIONStatin at starting doseStatin at starting dose 15–18% + Ezetimize+ Ezetimize 10mg10mg % Reduction in LDL-C 3-STEP TITRATIONStatin at starting doseStatin at starting dose 1st1st 2nd2nd 3rd3rd Doubling 5–6% 5–6% 5–6% % giảm LDL-C Phối hợp ức chế kép liều thấp giảm thêm 18% 1-STEP COADMINISTRATION High or moderate intensity statin (± EZ) 59% + Ức chế+ Ức chế PCSK9PCSK9 Phối hợp ức chế PCSK9 giảm thêm 59%
- 28. Statin cường độmạnh và sự an toàn Escobar C et al. vascular Health and Management 2008;4:525-533
- 32. LDL rất thấpvà nguy cơ tim mạch: Vai trò của thuốc PCSK9 Sabatine MS | Opening Session 400-14. Sabatine MS et al. Am Heart J 2016;173:94-101; http://www.ahjonline.com/article/S0002-8703(15)00686-9/references FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk Evolocumab SC 140 mg q2w or 420 mg qm Placebo SC q2w or qm LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Randomized Double blind
- 33. LDL rất thấpvà nguy cơ tim mạch: Vai trò của thuốc ức chế PCSK9 Sabatine MS | Opening Session 400-14. Sabatine MS et al. Am Heart J 2016;173:94-101; http://www.ahjonline.com/article/S0002-8703(15)00686-9/references FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk 59% mean reduction (95%CI:58-60),P=0.00001 Absolute reduction: 56 mg/dl (95%CI:55-57) Weeks LDLcholesterol(mg/dl) Placebo Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 0 10 20 30 40 50 60 70 80 90 100 Months from randomization CVdeath,MI,stroke,hospitalizationforUA,or coronaryrevascularization Placebo Evolocumab 0% 0 16% 14.6% 12.6% 6 12 18 24 30 HR 0.85 (95% CI, 0.79; 0.92) P<0.0001 14% 12% 10% 8% 6% 4% 2% BN bệnh tim mạch: ức chế PCSK9 giảm biến có TM ở BN đang sử dụng statin. Lợi ích đạt được với giảm LDL thấp hơn đích điều trị hiện tại.
- 34. EBBINGHAUS Cognitive Study ofPatients Enrolled in the FOURIER Trial Giugliano RP | LBCT 404-16 Giugliano RP et al, Clin Card 2017;40:59-65 Cognitive assessments by Nadir – Achieved LDL-C and treatment (full population) Primary CANTAB endpoint*: average change from baseline Composite Global Score: average change from baseline Nadir LDL-Achieved (mg/dL) Mean∆ofboxes Mean∆-Zscore 4 2 0 -2 -4 0 0.5 1 -0.5 -1 <25 mg/dL 25-39 mg/dL ≥ 40 mg/dL <25 mg/dL 25-39 mg/dL ≥ 40 mg/dL P=NS across LDL values achieved and also between treatments # pts 0 661 13 206 969 115 Placebo Evolocumab Negative score improvement Lower scores are better *Spatial working memory strategy index of executive function, raw score
- 35. EBBINGHAUS Cognitive Study ofPatients Enrolled in the FOURIER Trial Giugliano RP | LBCT 404-16 Giugliano RP et al, Clin Card 2017;40:59-65 Patient self-report: 23 questions regarding everyday cognition All patients Placebo N=781 mean (SD) Evolocumab N=800 mean (SD) P-value Memory 1.16 (0.39) 1.17 (0.39) 0.81 Executive functioning total score Planning Organization Divided attention 1.11 (0.32) 1.08 (0.31) 1.09 (0.32) 1.15 (1.42) 1.12 (0.32) 1.10 (0.32) 1.10 (0.33) 1.16 (0.41) 0.28 0.20 0.57 0.54 Total score 1.13 (0.33) 1.14 (0.33) 0.42 Patient self-report at end of study as compared to randomization, graded as 1. Better or no change 2. Questionable/ occasionally worse 3. Consistently a little worse 4. Consistently much worse Lower scores represent better cognition P=0.42 P=0.59 16/99011/586 19/9838/618 Investigator reported cognitive adverse events
- 36. Tăng gấp đôiliều Statin đem lại hiệu quả giảm thêm chỉ 6% Bays HE et al. Expert Opin Pharmacother 2003;4:779-790 1-STEP COADMINISTRATIONStatin at starting doseStatin at starting dose 15–18% + Ezetimize+ Ezetimize 10mg10mg % Reduction in LDL-C 3-STEP TITRATIONStatin at starting doseStatin at starting dose 1st1st 2nd2nd 3rd3rd Doubling 5–6% 5–6% 5–6% % giảm LDL-C Phối hợp ức chế kép liều thấp giảm thêm 18% 1-STEP COADMINISTRATION High or moderate intensity statin (± EZ) 59% + Ức chế+ Ức chế PCSK9PCSK9 Phối hợp ức chế PCSK9 giảm thêm 59%
- 37. Khi nào cầnchuyển thuốc ? Beck DL, 2017. Medscape Dữ liệu từ Nghiên cứu MarketScan của công ty Truven Health Analytics: 105,269 bệnh nhân bị ASCVD (tuổi trung bình 65.1 và nam giới 57.2%) cho thấy 53.2% điều trị statins (1,7% statin + eztimibe) và chỉ 25.2% đạt LDL-C dưới 70 mg%. Nghiên cứu mô phỏng, điều trị tích cực trong nhóm BN không điều trị statin: atorvastatin 20 mg, tăng dần 80 mg thêm ezetimibe alirocumab nếu chưa đạt LDL mục tiêu. Chỉ 0.7% thất bại đạt LDL < 70 mg%.
- 41. Xu hướng mớitrong điều trị hội chứng mạch vành: ESC 2017 Borja Ibanez, et al. European Heart Journal. 2017;00:1–66 What is new in 2017 STEMI Guidelines. BMS = bare metal stent; DES = drug eluting stent; IRA = infarct related artery; i.v. = intravenous; LDL = low- density lipoprotein; PCI = percutaneous coronary intervention; SaO2 = arterial oxygen saturation; STEMI = ST-elevation myocardial infarction; TNK- tPA = Tenecteplase tissue plasminogen activator. For explanation of trial names, see list of. a Only for experienced radial operators. b Before hospital discharge (either immediate or staged). c Routine thrombus aspiration (bailout in certain cases may be considered). d In 2012 early discharge was considered after 72h, in 2017 early discharge is 48–72h. e If symptoms or haemodynamic instability IRA should be opened regardless time from symptoms onset. In left and mid panels, below each recommendation, the most representative trial (acronym and reference) driving the indication is mentioned.
- 43. Cám ơn quíđồng nghiệp
Editor's Notes
- #12 [[Propose that this slide would be updated when Long Beach 1 and 2 manuscripts are published]] In an open-label, parallel-group, randomised, three-way crossover study, the pharmacokinetics of single doses of rosuvastatin 20 mg, atorvastatin 40 mg and simvastatin 40 mg in healthy Chinese and Japanese subjects were compared with Caucasian controls. The ratio of Asian:Caucasian data for Cmax and AUC0-t are shown on this slide. Plasma exposure to rosuvastatin, atorvastatin and simvastatin was higher in the Chinese and Japanese groups compared with Caucasian controls. The magnitude of the ethnic effect was not significantly different for atorvastatin and rosuvastatin in these Asian subjects. However, the difference between simvastatin and rosuvastatin was statistically significant. Reference 1.Birmingham BK et al. Increased exposure levels of rosuvastatin, atorvastatin and simvastatin in Chinese and Japanese subjects: a class effect? Clin Pharmacol Ther 2008; 83: S15 [Data from table in abstract]
- #13 I now want to address the PK difference between Asian and non-Asian patients. Because we developed Crestor after the Cerivastatin problem AZ had to do much more clinical trial work than any of the other statins. One areas we looked at was ethnic differences in PK. The data above is from a very impressive study done by Professor Edmund lee in Singapore. This was one of the best studies that has been done in this area and it confirmed observations we had seen in smaller numbers of Japanese patients – plasma levels in Asia patients seems to be about 2x that of non-Asians for the same dose. Prof Lee looked extensively across the literature but there didn’t seem to be any similar studies for other statins. There were hints that other statins such as simvastatin do have this effect as well, but because they were developed so long ago they were never studied in this way.
- #14 The recommended starting dose for each statin results in a mean reduction in the LDL-C level between 19% to 37%. Thereafter, each doubling of the dose results in an approximate 6% further lowering of the LDL-C level. Titration to the maximum approved dose produces a mean reduction of approximately 31% to 51%. There is marked variability in the potency of the available statin medications. In general, fluvastatin is regarded as the least potent and rosuvastatin is regarded as the most potent.
- #16 METHODSThis trial was a prospective, randomized, controlled, multicenter study. Eligible patients who underwent PCI were randomly assigned to atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily. Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol (LDL-C)&lt;70 mg/dl. Serial volumetric intravascular ultrasound was performed at baseline and again at 9 to 12 months to quantify the coronary plaque response in 202 patients. RESULTSThe combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.216.3 mg/dl vs. 73.320.3 mg/dl; p&lt;0.001). For the absolute change in percent atheroma volume (PAV), the mean difference between the 2 groups (–1.538%; 95% confidence interval [CI]:–3.079% to 0.003%) did not exceed the pre-defined noninferiority margin of 3%, but the absolute change in PAV did show superiority for the dual lipid-lowering strategy (–1.4%; 95% CI:–3.4% to–0.1% vs.–0.3%; 95% CI:–1.9% to 0.9% with atorvastatin alone; p¼0.001). For PAV, a significantly greater percentage of patients who received atorvastatin/ezetimibe showed coronary plaque regression (78% vs. 58%; p¼0.004). Both strategies had acceptable side effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events. CONCLUSIONSCompared with standard statin monotherapy, the combination of statin plus ezetimibe showed greater coronary plaque regression, which might be attributed to cholesterol absorption inhibition–induced aggressive lipid lowering.
- #24 Rất nhiều nghiên cứu phòng ngừa tiên phát lẫn thứ phát đã được thực hiện và kết quả từ những nghiên cứu này đã củng cố thêm lý thuyết trên về vai trò của LDL-C đối với việc giảm biến cố tim mạch. Các nghiên cứu càng về sau càng cho thấy lợi ích của việc giảm biến cố tim mạch nhiều hơn khi hạ LDL-C thấp hơn, và đó cũng chính là những nghiên cứu được xem xét nhằm đề ra các mục tiêu điều trị trong các khuyến cáo về điều trị lipid máu. Và rõ ràng, LDL-C chính là mục tiêu nền tảng.
- #29 There is no proof that statins cause life-threatening liver damage. Mild asymptomatic elevations in liver enzymes are found in about 3 patients per 1,000 person-years who participate in clinical trials. Elevations are reversible on stopping the statin and do not cause lasting harm. Liver failure has been reported in 1 person out of 1 million person-years of statin use, as well as in 1 person in 1 million people not taking a statin. Routine liver function monitoring during statin therapy is not needed. The Task Force recommends that statin manufacturers work with the FDA to remove the requirement for liver function monitoring from prescribing information. Though all marketed statins have a small potential for inducing muscle side effects, 5 in 100,000 patients taking a statin have muscle complaints and are found to have an increase in muscle enzymes, suggesting muscle injury. This finding is not statistically significant. 1.5-3.0 percent of patients taking a statin complain of muscle pain, weakness, or cramps. The numbers are similar for patients receiving placebo. Exercise, trauma, falls, accidents, seizures, infections, chills, and alcohol and drug abuse can cause muscle injury. Physicians should carefully identify and address the risk factors for muscle problems before prescribing a statin. Rhabdomyolysis, the most serious potential problem associated with statin therapy, occurs in about 2 of 100,000 patients taking a statin. This is rarely life threatening and is reversible when the statin is stopped. The panel found no evidence that statins, whentaken in approved doses, cause kidney injury. Protein may be found in the urine of patients receiving a statin as frequently as it is found in the urine of patients who do not receive a statin. If protein is found in the urine of patients who are taking a statin, it is not necessary to discontinue the statin. If kidney function worsens in patients taking a statin, discontinuation is not necessary, although a dose adjustment may be indicated.
- #35 Authors Robert P. Giugliano, Francois Mach, Kenton Zavitz, Anthony Keech, Terje Pedersen, Marc Sabatine, Peter Sever, Christopher Kurtz, Narimon Honarpour, Brian R. Ott, Brigham and Women&apos;s Hospital, Boston, MA, USA, Brown University, Providence, RI, USA Abstract Background:Statins and PCSK9 inhibitors lower LDL-C by upregulating LDL receptor expression. Non-randomized data raised concern that statins may cause memory impairment. Similar questions were raised during the development of PCSK9 inhibitors. We performed a dedicated neurocognitive study of pts enrolled in the FOURIER trial, a randomized, double-blind placebo-controlled cardiovascular outcome trial of the PCSK9 inhibitor evolocumab.Methods: FOURIER enrolled pts with prior MI, prior stroke or symptomatic PAD, treated with maximally tolerated statin. Pts in FOURIER could elect to participate in this prospective assessment of cognitive function (EBBINGHAUS). Key exclusions for EBBINGHAUS were diagnoses of dementia, cognitive impairment, or other significant mental/neurological disorders. Neurocognitive testing was performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB); a validated tablet-based tool that assesses executive function and reaction time. The primary endpoint was the change in spatial working memory strategy index of executive function (SWMsi). The hypothesis was that evolocumab is non-inferior to placebo in the mean change from baseline over time in SWMsi. Pts were tested at baseline, week 24, week 48, every 48 weeks thereafter and at the end of the study. 1500 pts completing the assessments will provide approximately 97% power to demonstrate that the upper 95% confidence limit for the treatment difference in mean change from baseline in SWM strategy index over time is &lt;20% of the common standard deviation of the mean change. An exploratory analysis will compare neurocognitive function in pts with, versus without, at least 1 post-baseline LDL-C value &lt;25 mg/dL.Results: A total of 1974 pts (mean age 63 yrs, 28% women, 71% high-intensity statin, 75% prior MI) participated in the study. The median follow-up was ~19 months. Primary results will be ready for presentation at ACC 2017.Conclusions: EBBINGHAUS primary results will provide a first indication as to whether the addition of evolocumab to statin therapy affects cognitive function over time in pts with stable cardiovascular disease already receiving moderate to high intensity statin.
- #36 Authors Robert P. Giugliano, Francois Mach, Kenton Zavitz, Anthony Keech, Terje Pedersen, Marc Sabatine, Peter Sever, Christopher Kurtz, Narimon Honarpour, Brian R. Ott, Brigham and Women&apos;s Hospital, Boston, MA, USA, Brown University, Providence, RI, USA Abstract Background:Statins and PCSK9 inhibitors lower LDL-C by upregulating LDL receptor expression. Non-randomized data raised concern that statins may cause memory impairment. Similar questions were raised during the development of PCSK9 inhibitors. We performed a dedicated neurocognitive study of pts enrolled in the FOURIER trial, a randomized, double-blind placebo-controlled cardiovascular outcome trial of the PCSK9 inhibitor evolocumab.Methods: FOURIER enrolled pts with prior MI, prior stroke or symptomatic PAD, treated with maximally tolerated statin. Pts in FOURIER could elect to participate in this prospective assessment of cognitive function (EBBINGHAUS). Key exclusions for EBBINGHAUS were diagnoses of dementia, cognitive impairment, or other significant mental/neurological disorders. Neurocognitive testing was performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB); a validated tablet-based tool that assesses executive function and reaction time. The primary endpoint was the change in spatial working memory strategy index of executive function (SWMsi). The hypothesis was that evolocumab is non-inferior to placebo in the mean change from baseline over time in SWMsi. Pts were tested at baseline, week 24, week 48, every 48 weeks thereafter and at the end of the study. 1500 pts completing the assessments will provide approximately 97% power to demonstrate that the upper 95% confidence limit for the treatment difference in mean change from baseline in SWM strategy index over time is &lt;20% of the common standard deviation of the mean change. An exploratory analysis will compare neurocognitive function in pts with, versus without, at least 1 post-baseline LDL-C value &lt;25 mg/dL.Results: A total of 1974 pts (mean age 63 yrs, 28% women, 71% high-intensity statin, 75% prior MI) participated in the study. The median follow-up was ~19 months. Primary results will be ready for presentation at ACC 2017.Conclusions: EBBINGHAUS primary results will provide a first indication as to whether the addition of evolocumab to statin therapy affects cognitive function over time in pts with stable cardiovascular disease already receiving moderate to high intensity statin.