The ACC/AHA/Multisociety cholesterol guidelines recommend adding a non-statin if the LDL-C remains ≥70 mg/dl in patients with high-risk ASCVD,1 effectively creating a target of <70 mg/dL. The 2019 ESC/EAS Dyslipidemia Guidelines go further and recommend an LDL-C goal of <55 mg/dl for patients with very high-risk ASCVD and to consider an even lower goal of <40 mg/dl for patients with multiple cardiovascular events within 2 years despite optimal statin therapy.2 The advent of PCSK9 inhibition allows many patients to achieve even lower LDL-C levels. For example, evolocumab lowered LDL-C by 59% when added to statin therapy in the FOURIER trial, reducing LDL-C from a median of 93 mg/dl to 30 mg/dl.3 Nevertheless, a key question is whether there is evidence of continued clinical benefit with lowering LDL-C below 40 mg/dl.
An analysis from FOURIER showed no significant heterogeneity in clinical benefit of evolocumab between patients with a baseline LDL-C less than vs. greater than or equal to 70 mg/dl, but this analysis did not address the fraction of LDL-C lowering below subsequently published targets.4 Another analysis demonstrated a strong relationship between achieved LDL-C at 1 month and adjusted risk of cardiovascular events.5 However, this was a post-randomization association analysis which carries the risk of confounding. Therefore, in the current analysis, we aimed to determine whether there is continued cardiovascular benefit from lowering LDL-C to <40 mg/dl utilizing comparisons of randomized groups and analyzing in the context of the magnitude of LDL-C lowering below the most recent recommended targets.
To achieve this aim, we performed an exploratory analysis in FOURIER, a cardiovascular outcomes trial comparing evolocumab to placebo in patients with stable ASCVD on optimized statin therapy.3 Major adverse cardiovascular events (MACE) were defined as cardiovascular death, myocardial infarction (MI), or stroke. Median follow up was 2.2 years. We used a Cox proportional hazard regression model to determine the hazard ratio for MACE for evolocumab vs. placebo (normalized per 39 mg/dl [1 mmol/L] reduction in LDL-C) across the range of baseline LDL-C. When LDL-C was <40 mg/dl, ultracentrifugation was performed. Nonetheless, we also performed analogous analyses using apolipoprotein B (apoB) and non-HDL-C given they are metrics of all atherogenic lipoproteins and there are no analytic concerns. Each site’s ethics committee approved the trial protocol and all subjects provided informed consent. Data will not be made publicly available, however interested parties can contact the corresponding authors.
Among 27,564 patients with ASCVD enrolled in FOURIER (mean age 63 years, 75% men), 81% had prior MI, 19% prior ischemic stroke, and 13% PAD. A total of 80% had hypertension, 37% had diabetes, and 28% were smokers. The median baseline LDL-C was 93 mg/dl (IQR 80-109 mg/dl) with 99% on a moderate or high intensity statin regimen. 65% of subjects randomized to evolocumab achieved an LDL-C <40 mg/dl.
In the top of panel A, the achieved LDL-C (y-axis) is plotted as a function of baseline LDL-C (x-axis) in each treatment arm. The shaded area represents the amount of LDL-C lowering that occurred between the treatment arms at a given baseline LDL-C, with blue shading representing LDL-C lowering that occurred above 40 mg/dl and red shading representing LDL-C lowering that occurred below 40 mg/dl. As the baseline LDL-C level went below 93 mg/dl, the mean achieved LDL-C went below 40 mg/dl. Thus, the further baseline LDL-C levels were below 93 mg/dl, the greater the proportion of LDL-C lowering was below 40 mg/dl, ranging from, on average, 0% of the difference between treatment arms at 93 mg/dl, to 38% of the difference between treatment arms when the starting LDL-C was 58 mg/dl.
If there were no benefit of lowering LDL-C below 40 mg/dl, then one would expect the HR to be progressively attenuated (ie, increase toward 1.0) the lower the baseline LDL-C was below 93 mg/dl (ie, toward the left side of the HR curve in the bottom of panel A) because a progressively greater proportion of the LDL-C lowering with evolocumab would be below 40 mg/dl. However, in contrast, we observed a consistent benefit of LDL-C lowering regardless of how low the baseline LDL-C was. Specifically, despite more than 1/3 of LDL-C lowering occurring below 40 mg/dl in subjects with baseline LDL-C of 58 mg/dl, the clinical benefit of LDL-C lowering was not attenuated (p-interaction=0.78), with robust reductions in the risk of MACE (Figure, panel A). A similar pattern was seen for apoB and non-HDL-C lowering (Figure, panels B and C). There was also no attenuation in the absolute risk reduction at lower baseline LDL-C (−2.1% when baseline LDL-C was 70-<90 mg/dl and −1.9% when 90-110 mg/dl).
Figure.
Panel A, top: Achieved LDL-C at 48 weeks as a function of baseline LDL-C. The shaded area represents the amount of LDL-C lowering that occurred between the treatment arms at a given baseline LDL-C, with blue shading representing LDL-C lowering that occurred above 40 mg/dl and red shading representing LDL-C lowering that occurred below 40 mg/dl. The further baseline LDL-C levels were below 93 mg/dl (black dashed line), the greater the proportion of LDL-C lowering that was below 40 mg/dl, ranging from, on average, 0% at 93 mg/dl, to 38% at 58 mg/dl.
Panel A, bottom: Hazard ratio for evolocumab vs. placebo for CV Death, MI, or Stroke per 39 mg/dl (1 mmol/L) reduction in LDL-C as a function of baseline LDL-C. As the proportion of LDL-C lowering below 40 mg/dl increased, there was no evidence of attenuation in treatment effect (p-value for treatment interaction = 0.78).
Panel B: Hazard ratio for evolocumab vs. placebo for CV Death, MI, or Stroke per 39 mg/dl (1 mmol/L) reduction in LDL-C as a function of baseline ApoB. The further baseline apoB levels were below 98 mg/dl (black dashed line), the greater the proportion of apoB lowering that was below 50 mg/dl. As the proportion of apoB lowering below 50 mg/dl increased, there was no evidence of attenuation in treatment effect (p-value for treatment interaction = 0.62).
Panel C: Hazard ratio for evolocumab vs. placebo for CV Death, MI, or Stroke per 39 mg/dl (1 mmol/L) reduction in LDL-C as a function of baseline non-HDL-C. The further baseline non-HDL-C levels were below 147 mg/dl (black dashed line), the greater the proportion of non-HDL-C that was below 70 mg/dl. As the proportion of non-HDL-C lowering below 70 mg/dl increased, there was no evidence of attenuation in treatment effect (p-value for treatment interaction = 0.60).
Over the last two decades, we have seen the guidelines shift to lower and lower LDL-C goals based on clinical trials demonstrating that lower is better. The ESC/EAS dyslipidemia guidelines have selected an LDL-C goal of <40 mg/dl as the next step in this progression. Prior clinical trials have proven that such levels are safe,3 and we have demonstrated in this study that there is continued effectiveness even below 40 mg/dl in patients with high-risk ASCVD.
In conclusion, these data support the ESC/EAS Dyslipidemia Guideline recommendations and suggest that lowering LDL-C well below 40 mg/dl in a wider range of patients with ASCVD would further lower cardiovascular risk.
ACKNOWLEDGMENTS
NAM contributed to study design, literature search, statistical analysis, data interpretation, figures, and drafting of the manuscript. RPG and MSS contributed to study design, statistical analysis, data interpretation, figures, and critical review of the manuscript. JGP contributed to data preparation, study design, and statistical analysis. AR, PS, ACK contributed to data interpretation and critical review of the manuscript. MSS is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
FUNDING
The FOURIER trial was sponsored by Amgen.
Footnotes
DISCLOSURES
NAM reports grant support from the National Institutes of Health and involvement in clinical trials with Amgen, Pfizer, Novartis, and AstraZeneca without personal fees, payments, or increase in salary. RPG reports grants from Amgen and Daiichi Sankyo, during the conduct of the study; personal fees from Akcea, grants and personal fees from Amarin, personal fees from American College of Cardiology, grants and personal fees from Amgen, personal fees personal fees from Bristol Myers Squibb, personal fees from CVS Caremark, grants and personal fees from Daiichi Sankyo, personal fees from GlaxoSmithKline, personal fees from Janssen, personal fees from Lexicon, grants and personal fees from Merck, personal fees from Pfizer, personal fees from Servier, outside the submitted work; and Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital for research he is not directly involved in from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. JGP is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, The Medicines Company, Zora Biosciences. AR is an Amgen inc. employee and stockholder. PS reports research grants and honoraria for speakers bureau- Amgen and Pfizer. ACK reports grants and personal fees from Abbott, personal fees from Amgen, personal fees from AstraZeneca, grants and personal fees from Mylan, personal fees from Pfizer, grants from Sanofi, grants from Novartis, personal fees from Bayer, outside the submitted work. MSS reports research grant support through Brigham and Women’s Hospital from Amgen; AstraZeneca; Bayer; Daiichi-Sankyo; Eisai; GlaxoSmithKline; Intarcia; IONIS; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Poxel; Quark Pharmaceuticals; Takeda; Consulting for Amgen; Anthos Therapeutics; AstraZeneca; Bristol-Myers Squibb; CVS Caremark; DalCor; Dyrnamix; Esperion; Fibrogen; IFM Therapeutics; Intarcia; Ionis; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; and Novo Nordisk; Dr. Sabatine is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Aralez, Roche, and Zora Biosciences.
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