100 mg/dL, and in Patients Already
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Conclusions Evolocumab safely reduced cardiovascular events in patients with stable atherosclerotic cardiovascular disease to a similar degree whether the baseline LDL-C was above or below 70 mg/dL, and regardless of whether the background statin was maximal intensity or not. These findings support using evolocumab beyond what is recommended in current guidelines and, more broadly, the value of lowering LDL-C down to levels ~20 mg/dL15 even in those high-risk patients starting below current guideline targets or thresholds for treatment. Funding/Support: This FOURIER trial was supported by a research grant from Amgen, Thousand Oaks, CA. No funding was provided for preparation of this manuscript. Role of the Funder/Sponsor: The FOURIER trial was designed, conducted, and managed in a collaborative effort between the FOURIER Executive and Steering Committees, the FOURIER Investigators, and the sponsor, Amgen. The sponsor played no role in the analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: This work is solely the responsibility of the authors. Additional Contributions: We are indebted to all the patients who participated in the study, the FOURIER Trial investigators, and members of the Data Safety Monitoring, Lipid Monitoring, and Clinical Endpoint Committees. For a full list of the Trial Investigators, please see the Supplemental Appendix Access to Data and Data Analysis: Drs Giugliano and Sabatine had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Data Analysis: The data analysis was conducted by Ms. Sabina Murphy of the TIMI Study Group, Brigham and Women’s Hospital, Boston, MA. References
Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. European heart journal. 2016;37(39):2999-3058. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. Journal of the American College of Cardiology. 2016;68(1):92-125. Orringer CE, Jacobson TA, Saseen JJ, et al. Update on the use of PCSK9 inhibitors in adults: Recommendations from an Expert Panel of the National Lipid Association. Journal of clinical lipidology. 2017. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45. Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. American heart journal. 2016;173:94-101. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017;376(18):1713-1722. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Journal of the American College of Cardiology. 2011;57(16):1666-1675. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine. 2015;372(25):2387-2397. Giugliano RP, Cannon CP, Blazing MA, et al. Baseline LDL-C and clinical outcomes with addition of ezetimibe to statin in 18,144 patients post ACS. Journal of the American College of Cardiology. 2015;65(10S):A4. Group HTRC. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. The New England journal of medicine. 2017. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. Journal of the American College of Cardiology. 2014;64(5):485-494. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL- cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017. Giugliano RP, Wiviott SD, Blazing MA, et al. Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol : A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiol. 2017;2(5):547-555. Sabatine MS, Giugliano RP. Low-Density Lipoprotein Cholesterol Treatment in the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Era: Getting Back on Target. JAMA Cardiol. 2017. Table 1: Patient Characteristics Stratified by Baseline LDL-Ca and Background Statin Intensity
Baseline LDL-C data were not available for one patient. Maximal statin potency indicates either atorvastatin 80 mg or rosuvastatin 40 mg daily. All other statin regimens were considered submaximal. Date shown are n (%) unless otherwise specified aThere were no nominally significant differences between the randomized treatments in either group stratified by baseline LDL cholesterol. There were no nominally significant differences between the randomized treatments in either group stratified by baseline maximal statin potency except for baseline triglycerides and aspirin use in the submaximal subgroup (both p=0.05). bBy trial design, these patients were required to have a non-HDL-C > 100 mg/dL cRace was reported by the patients dPatients could have more than one type of atherosclerosis eCalculated as described by Bohula E et al. Circulation 2016;134: 304-13. fStatin intensity was categorized in accordance with the guidelines of the American College of Cardiology and American Heart Association4 HDL high-density lipoprotein, IQR interquartile range, LDL low-density lipoprotein, NA not applicable, and SD standard deviation SI conversion factors: to convert cholesterol (total, LDL, and HDL) to millimoles per liter, multiply by 0.0259; to convert triglycerides to millimoles per liter, multiply by 0.0113. Table 2 – Safety Outcomes With Evolocumab vs. Placebo Stratified by Baseline LDL-C and Potency of Background Statin
Baseline LDL-C is not available for one patient. 39 patients who did not receive study drug are excluded. Data shown are n (%), unless otherwise indicated. a By trial design, these patients were required to have a non-HDL-C > 100 mg/dL b Nominal P value <0.05 vs. placebo c Patients with prevalent diabetes were excluded There were no significant treatment – subgroup interactions for either LDL-C at baseline or potency of background statin. ALT, alanine aminotransferase; AST, aspartate aminotransferase To convert LDL-C values from mg/dL to millimoles per liter, multiply by 0.0259. Figure Legend Figure. Efficacy Outcomes Stratified by Baseline LDL-C (Panels A and B) and by statin intensity (Panels C and D). Panel A shows the hazard ratios and 95% confidence intervals at 3 years are shown for the primary (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization) and the secondary (cardiovascular death, myocardial infarction, and stroke) efficacy composite endpoints in the total population and in patients with baseline LDL-cholesterol <70 mg/dL mad with non-HDL-C > 100 mg/dL versus LDL-cholesterol > 70 mg/dL. Evolocumab significantly reduced both composite endpoints to a similar degree regardless of the baseline LDL-cholesterol. Panel B shows the cumulative event rate of the key secondary endpoint with evolocumab compared with placebo in patients with baseline LDL-cholesterol <70 mg/dL and non-HDL-C >100 mg/dL. Panel C shows the hazard ratios and 95% confidence intervals at 3 years are shown for the primary (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization) and the secondary (cardiovascular death, myocardial infarction, and stroke) efficacy composite endpoints in the total population and in patients on patient treated with maximal and submaximal background statin therapy. Maximal statin therapy represents either atorvastatin 80 mg or rosuvastatin 40 mg daily. Evolocumab significantly reduced both composite endpoints to a similar degree regardless of the potency of background statin. Panel D shows the cumulative event rate of the key secondary endpoint with evolocumab compared with placebo in patients treated with maximal potency statin. To convert LDL-C values from mg/dL to millimoles per liter, multiply by 0.0259. Figure 1 Figure 1A. Efficacy Outcomes Stratified by Baseline LDL-C Primary Composite Endpoint HR (95% CI) Pinteraction 
All Patients 0.85 (0.79-0.92) Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07) Baseline LDL-C ≥70 mg/dL 0.86 (0.79-0.92) 0.65 0.4 1.0 2.5 Secondary Composite Endpoint All Patients 0.80 (0.73-0.88) 
Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01) Baseline LDL-C ≥70 mg/dL 0.81 (0.73-0.89) 0.44 0.4 1.0 2.5 Evolocumab better Placebo better Figure 1B. Cardiovascular Death, Myocardial Infarction, or Stroke in Patients with Baseline LDL Cholesterol <70 mg/dL 9% 
8% 7.7% 7%
CV Death, MI, Stroke 5% 5.2% 4% 3% 2% 1% 0% 0 6 12 18 24 30 Months from Randomization Figure 1C. Efficacy Outcomes Stratified by Potency of Background Statin Primary Composite Endpoint HR (95% CI) Pinteraction 
All Patients 0.85 (0.79-0.92) On maximum intensity statin 0.86 (0.75-0.98) On less intense statin 0.85 (0.78-0.93) 0.88 0.4 1.0 2.5 Secondary Composite Endpoint All Patients 0.80 (0.73-0.88) 
On maximum intensity statin 0.78 (0.66-0.92) On less intense statin 0.81 (0.72-0.90) 0.71 0.4 1.0 2.5 Evolocumab better Placebo better Figure 1D. Cardiovascular Death, Myocardial Infarction, or Stroke in Patients on Maximal Potency Background Statin 10% 9% 8% 7% CV Death, MI, Stroke 6% 8.9% 6.8% 
5%
3% 2% 1% 0%
0 6 12 18 24 30 Months from Randomization On-Line Supplement – Table of Contents List of Investigators Table S1. Efficacy Outcomes With Evolocumab vs. Placebo Stratified by Baseline LDL-C Table S2. Efficacy Outcomes With Evolocumab vs. Placebo Stratified Potency of Background Statin List of FOURIER Investigators Steering Committee and National Lead Investigators Jose Luis Accini Mendoza (Colombia), John Amerena (Australia), Jolita Badariene (Lithuania), Lesley Burgess (South Africa), Richard Ceska (Czech Republic), Min-Ji Charng (Taiwan), Donghoon Choi (South Korea), Jorge Leonardo Cobos (Chile), Gheorghe Andrei Dan (Romania), Gaetano M. De Ferrari (Italy), Prakash C. Deedwania and Vijay Kumar Chopra (India), Andrejs Erglis (Latvia), Marat Vladislavovich Ezhov (Russia), Jorge Ferreira (Portugal), Slavomíra Filipová (Slovakia), Zbigniew A. Gaciong (Poland), Borislav Georgiev Georgiev (Bulgaria), Robert P. Giugliano (United States), Guillermo Gonzalez-Galvez (Mexico), Ioanna Gouni-Berthold (Germany), Atsushi Hirayama (Japan), Kurt Huber (Austria), Henrik Kjaerulf Jensen (Denmark), Lixin Jiang (China), J. Wouter Jukema (Netherlands), Oleg Kraydashenko (Ukraine), Lawrence A. Leiter (Canada), Basil S. Lewis (Israel), José López-Miranda (Spain), Alberto J. Lorenzatti (Argentina), François Mach (Switzerland), Brendan McAdam (Ireland), Lennart Nilsson (Sweden), Terje R. Pedersen (Norway), Loukianos Rallidis (Greece), Gregorio G. Rogelio (Philippines), José Francisco Kerr Saraiva (Brazil), André Scheen (Belgium), François Schiele (France), Peter S. Sever (United Kingdom), Chung-Wah Siu (Hong Kong), Leslie Tay (Singapore), Gudmundur Thorgeirsson (Iceland), Matti J. Tikkanen (Finland), S. Lale Tokgozoglu (Turkey), Kalman Toth (Hungary), Margus Viigimaa (Estonia), Wan Azman Wan Ahmad (Malaysia) Site Investigators by Country Directory: bitstream -> 10044 bitstream -> Present state of the area 10044 -> A new Method to Determine Dispersive Surface Energy Site Distributions by Inverse Gas Chromatography 10044 -> A case study of japanese language teaching 10044 -> Palaeomagnetic evidence for the persistence or recurrence of geomagnetic main field anomalies in the South Atlantic 10044 -> Blair W. McPhee, a, b, c 10044 -> Inattention blindness in surgery 10044 -> Archie Hughes-Hallett, mrcs 10044 -> Intraoperative ultrasound overlay in robot assisted partial nephrectomy 10044 -> Micronutrient supplementation augments anti-mycobacterial immune responses in tst reactive household contacts 10044 -> Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy 2 Download 0.98 Mb. Share with your friends:
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