Association of Baseline Low-Density Lipoprotein Cholesterol and Percentage Low-Density Lipoprotein Cholesterol Reduction With Statins, Ezetimibe, and PCSK9 Inhibition | Cardiology | JAMA Cardiology | JAMA Network
[Skip to Navigation]
Sign In
Figure 1.  Percentage of Low-Density Lipoprotein Cholesterol (LDL-C) Lowering as a Function of Baseline LDL-C
Percentage of Low-Density Lipoprotein Cholesterol (LDL-C) Lowering as a Function of Baseline LDL-C
Figure 2.  Achieved Low-Density Lipoprotein Cholesterol (LDL-C) as a Function of Baseline LDL-C
Achieved Low-Density Lipoprotein Cholesterol (LDL-C) as a Function of Baseline LDL-C

LS indicates least squares.

Table.  Study Populations
Study Populations
1.
Grundy  SM, Stone  NJ, Bailey  AL,  et al.  2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.   J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003 PubMedGoogle ScholarCrossref
2.
Cannon  CP, Blazing  MA, Giugliano  RP,  et al; IMPROVE-IT Investigators.  Ezetimibe added to statin therapy after acute coronary syndromes.   N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489 PubMedGoogle ScholarCrossref
3.
Sabatine  MS, Giugliano  RP, Keech  AC,  et al; FOURIER Steering Committee and Investigators.  Evolocumab and clinical outcomes in patients with cardiovascular disease.   N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664 PubMedGoogle ScholarCrossref
4.
Schwartz  GG, Steg  PG, Szarek  M,  et al; ODYSSEY OUTCOMES Committees and Investigators.  Alirocumab and cardiovascular outcomes after acute coronary syndrome.   N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174 PubMedGoogle ScholarCrossref
5.
Collins  R, Reith  C, Emberson  J,  et al.  Interpretation of the evidence for the efficacy and safety of statin therapy.   Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5 PubMedGoogle ScholarCrossref
6.
Silverman  MG, Ference  BA, Im  K,  et al.  Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.   JAMA. 2016;316(12):1289-1297. doi:10.1001/jama.2016.13985 PubMedGoogle ScholarCrossref
7.
Giugliano  RP, Keech  A, Murphy  SA,  et al.  Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial.   JAMA Cardiol. 2017;2(12):1385-1391. doi:10.1001/jamacardio.2017.3944 PubMedGoogle ScholarCrossref
8.
Mach  F, Baigent  C, Catapano  AL,  et al; ESC Scientific Document Group.  2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.   Eur Heart J. 2020;41(1):111-188. doi:10.1093/eurheartj/ehz455 PubMedGoogle ScholarCrossref
9.
de Lemos  JA, Blazing  MA, Wiviott  SD,  et al; A to Z Investigators.  Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.   JAMA. 2004;292(11):1307-1316. doi:10.1001/jama.292.11.1307 PubMedGoogle ScholarCrossref
10.
Burke  AC, Dron  JS, Hegele  RA, Huff  MW.  PCSK9: regulation and target for drug development for dyslipidemia.   Annu Rev Pharmacol Toxicol. 2017;57:223-244. doi:10.1146/annurev-pharmtox-010716-104944PubMedGoogle ScholarCrossref
11.
Urban  D, Pöss  J, Böhm  M, Laufs  U.  Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis.   J Am Coll Cardiol. 2013;62(16):1401-1408. doi:10.1016/j.jacc.2013.07.056PubMedGoogle ScholarCrossref
12.
Roe  MT, Li  QH, Bhatt  DL,  et al.  Risk categorization using new American College of Cardiology/American Heart Association guidelines for cholesterol management and its relation to alirocumab treatment following acute coronary syndromes.   Circulation. 2019;140(19):1578-1589. doi:10.1161/CIRCULATIONAHA.119.042551 PubMedGoogle ScholarCrossref
13.
Pitt  B, Loscalzo  J, Yčas  J, Raichlen  JS.  Lipid levels after acute coronary syndromes.   J Am Coll Cardiol. 2008;51(15):1440-1445. doi:10.1016/j.jacc.2007.11.075 PubMedGoogle ScholarCrossref
Brief Report
November 13, 2020

Association of Baseline Low-Density Lipoprotein Cholesterol and Percentage Low-Density Lipoprotein Cholesterol Reduction With Statins, Ezetimibe, and PCSK9 Inhibition

Author Affiliations
  • 1Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 2TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 3Cardiology Division, University of Texas Southwestern Medical Center, Dallas
  • 4Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 5Deputy Editor, JAMA Cardiology
JAMA Cardiol. 2021;6(5):582-586. doi:10.1001/jamacardio.2020.6184
Key Points

Question  Is the percentage low-density lipoprotein cholesterol (LDL-C) lowering with different pharmacotherapies attenuated in patients starting with lower baseline LDL-C levels?

Findings  In this study of 39 714 patients from 3 randomized clinical trials, there was a higher percentage reduction in LDL-C with evolocumab in patients with lower baseline LDL-C levels, a more modest difference for simvastatin, and no clinically important difference with ezetimibe.

Meaning  These data are encouraging for the use of intensive LDL-C–lowering therapies even in patients starting with relatively low LDL-C levels.

Abstract

Importance  Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels.

Objective  To evaluate the association between baseline LDL-C levels and the percentage LDL-C reduction with a statin, ezetimibe, and a PCSK9 inhibitor.

Design, Setting, and Participants  This secondary exploratory study analyzed data from 3 randomized placebo-controlled clinical trials (Aggrastat to Zocor–Thrombolysis in Myocardial Infarction 21 [A to Z–TIMI 21], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT], and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]) of lipid-lowering therapies (statin, ezetimibe, and a PCSK9 inhibitor) and included participants with atherosclerotic cardiovascular disease. Analyses took place form April to October 2020.

Interventions  In A to Z–TIMI 21, 1:1 randomization to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. In IMPROVE-IT, 1:1 randomization to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. In FOURIER, 1:1 randomization to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo.

Main Outcomes and Measures  The percentage LDL-C reduction at either 1 month (A to Z–TIMI 21, IMPROVE-IT) or 3 months (FOURIER) as a function of baseline LDL-C level. Data were modeled using a generalized linear regression model.

Results  A total of 3187 patients from A to Z–TIMI 21, 10 680 patients from IMPROVE-IT, and 25 847 patients from FOURIER were analyzed. There was a higher percentage reduction in LDL-C levels with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P < .001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P < .001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P = .007).

Conclusions and Relevance  The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels and is 6.6% greater for PCSK9 inhibition. These data are encouraging for the use of intensive LDL-C–lowering therapy even for patients with lower LDL-C levels.

Introduction

Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. Statins remain the cornerstone of LDL-C–lowering therapy, with ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors indicated to achieve further cardiovascular risk reduction in selected patients.1-4 The clinical benefit of LDL-C lowering depends on the magnitude of LDL-C reduction regardless of which agent is used.5,6

With more recent data showing a monotonic relationship between LDL-C and cardiovascular risk reduction that extends to LDL-C values below 38.61 mg/dL (to convert to millimoles per liter, multiply by 0.0259),7 guidelines now call for increasingly lower LDL-C targets.8 As a consequence, further LDL-C–lowering therapy may be added for individuals with relatively lower baseline LDL-C levels. Therefore, we sought to quantify the association between baseline LDL-C levels and the magnitude of LDL-C lowering with a statin, ezetimibe, and a PCSK9 inhibitor.

Methods

Data from 3 randomized, double-blind, placebo-controlled trials of lipid lowering were used. The Aggrastat to Zocor–Thrombolysis in Myocardial Infarction 21 trial (A to Z–TIMI 21; NCT00251576)9 randomized 4497 patients with an acute coronary syndrome to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT; NCT00202878)2 randomized 18 144 patients stabilized after an acute coronary syndrome to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk trial (FOURIER; NCT01764633)3 randomized 27 564 patients with clinically evident atherosclerotic cardiovascular disease receiving an optimized statin therapy (preferably a high-intensity statin but at least atorvastatin, 20 mg, daily or its equivalent) to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. All trials were approved by all relevant institutional review boards, and written informed consent was obtained from all participants.

For these analyses of LDL-C lowering, the study populations were restricted to patients with LDL-C values at baseline and at follow-up and who were taking study drug through that period. For A to Z–TIMI 21 and for IMPROVE-IT, the analyses were also restricted to patients who were statin-naive (no long-term statin therapy for the past 4 weeks). The outcome of interest for this investigation was the relative reduction in LDL-C level while receiving therapy, which was measured at 1 month in A to Z–TIMI 21 and IMPROVE-IT and at 3 months in FOURIER. Percentage LDL-C reduction was calculated as follows. First, the achieved LDL-C measurements as a function of baseline LDL-C levels were fitted using a generalized linear regression model to generate least square means for each treatment arm at each baseline LDL-C value. The percentage LDL-C reduction corresponding to each baseline LDL-C value was then estimated. The lower and upper confidence limits were estimated using asymptotic Cauchy distribution of the percentage LDL-C reduction with the variance derived using Taylor series expansion. All analyses were performed using SAS version 9.4 (SAS Institute). Two-sided P values less than .05 were considered significant. Analyses took place from April to October 2020.

Results

There were 3187 patients from A to Z–TIMI 21, 10 680 patients from IMPROVE-IT, and 25 847 patients from FOURIER included in these analyses. The data for the study populations are shown in the Table. In brief, the median (interquartile range) baseline LDL-C level was 112.0 (95.0-131.0) mg/dL in A to Z–TIMI 21, 83.0 (67.0-100.0) mg/dL in IMPROVE-IT, and 91.5 (79.5-108.5) mg/dL in FOURIER. In FOURIER, 17 948 (69.4%) were taking a high-intensity statin, 7844 (30.3%) were taking a moderate-intensity statin, and 1365 (5.3%) were taking ezetimibe.

The percentage LDL-C reductions in the overall study populations were 45.2% (95% CI, 44.2%-45.3%) with simvastatin, 40 mg, daily in A to Z–TIMI 21, 25.8% (95% CI, 22.3%-25.8%) with ezetimibe in IMPROVE-IT, and 62.3% (95% CI, 61.7%-62.9%) with evolocumab in FOURIER. The percentage of LDL-C reduction as a function of baseline LDL-C level is shown for simvastatin, ezetimibe, and evolocumab in Figure 1. There was a higher percentage reduction in LDL-C level with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P < .001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P < .001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P = .007). Achieved LDL-C level in the individual treatment arms for the 3 studies is shown in Figure 2. The pattern seen with evolocumab was consistent in patients taking high-intensity statin and in patients taking moderate-intensity (eFigure 1 in the Supplement). We observed a similar effect with apolipoprotein B (eFigure 2 in the Supplement).

Discussion

We evaluated the association of baseline LDL-C with the percentage LDL-C lowering with the 3 major classes of LDL-C–lowering therapy: statins, ezetimibe, and PCSK9 inhibition. Rather than observe any attenuation, the percentage LDL-C lowering was greater in patients starting with lower baseline LDL-C, particularly for PCSK9 inhibition.

PCSK9 is a circulating protein produced by the liver that binds LDL receptor (LDLR) at the hepatocyte surface and targets it for lysosomal degradation.10,11 PCSK9 inhibition leads to less degradation of LDLR and hence greater LDL-C clearance from the circulation. Both LDLR and PCSK9 are regulated transcriptionally by sterol regulatory element-binding protein-2. In healthy individuals, sterol regulatory element-binding protein-2 responds to low intracellular cholesterol levels by increasing transcription of LDLR and PCSK9 production. It may be that in such individuals, PCSK9 inhibition is more effective in lowering LDL-C levels.

The clinical benefit of LDL-C lowering has been shown to be proportional to the absolute LDL-C reduction. Although absolute LDL-C lowering will naturally be less in patients starting with lower vs higher baseline LDL-C, these finding illustrate that it will be somewhat greater than anticipated for statins and PCKS9 inhibitors had one assumed a constant percentage reduction. These findings may help explain why the clinical efficacy of the lipid-lowering therapy in these 3 trials was not attenuated in patients starting with lower baseline LDL-C levels.2,3,9 To put the data in perspective, the additional 6.6% greater LDL-C lowering with evolocumab is what one expects for doubling a statin dose. Such data are encouraging for reaching the progressively lower LDL-C targets that are being set,8 particularly for those defined in the guidelines as being at very high risk.1,12

Limitations

There are limitations to this study. First, patients in A to Z–TIMI 219 and IMPROVE-IT2 had recently had an acute coronary syndrome, which can cause small alterations in lipid values.13 However, such alterations should apply equally to both the experimental and control arms in those trials and would not be expected to change the slope of the curve. Second, although the 3 studies are randomized clinical trials of lipid-lowering therapy vs placebo, the comparisons between patients with different baseline LDL-C levels are exploratory and observational in nature and cannot prove causality, and there was heterogeneity among the 3 studies with respect to the timing of follow-up. However, the timing of assessment reflects the time to steady state lipid levels after adding the medications studied in the respective trials. Third, our findings should be replicated in other studies with PCSK9 inhibitors to determine whether this observation represents a class effect. Lastly further biochemical investigation is needed to confirm our postulated mechanism for these findings.

Conclusions

The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels, and in fact is noticeably greater for PCSK9 inhibition. These data are encouraging for reaching the progressively lower LDL-C targets that are being set.

Back to top
Article Information

Corresponding Author: Marc S. Sabatine, MD, MPH, TIMI Study Group, Brigham and Women’s Hospital, Hale Building, 60 Fenwood Rd, 7th Floor, Ste 7022, Boston, MA 02115 (msabatine@bwh.harvard.edu).

Accepted for Publication: October 15, 2020.

Published Online: November 13, 2020. doi:10.1001/jamacardio.2020.6184

Author Contributions: Dr Sabatine had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: de Lemos, Sabatine.

Acquisition, analysis, or interpretation of data: Marcusa, Giugliano, Park, Cannon, Sabatine.

Drafting of the manuscript: Marcusa.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Park.

Obtained funding: Cannon.

Administrative, technical, or material support: Cannon.

Supervision: Sabatine.

Conflict of Interest Disclosures: Dr Giugliano reports grants from Amgen Research and Anthos Therapeutics to the Brigham And Women’s Hospital during the conduct of the study; personal fees from Amgen, Daiichi Sankyo, Merck, Pfizer, and Servier for continuing medical education lectures and consulting outside the submitted work; and personal fees from American College of Cardiology, Amgen, Amaarin, AstraZeneca, Bristol Myers Squibb, CryoLife, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, GlaxoSmithKline, SAJA Pharmaceuticals, Samsung, and Servier outside the submitted work. Dr Park reports grants from GlaxoSmithKline, Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Machines Company, and Zora Biosciences during the conduct of the study. Dr de Lemos reports personal fees from Amgen during the conduct of the study and from Regeneron Pharmaceuticals and Esperion outside the submitted work. Dr Cannon reports grants from Merck, Amgen, Sanofi, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Pfizer during the conduct of the study; personal fees from Merck, Amgen, Sanofi, Bristol Myers Squibb, Aegerion, Innovent, Pfizer, and Alnylam during the conduct of the study; grants from Boehringer Ingelheim and Janssen outside the submitted work; and personal fees from Boehringer Ingelheim, Janssen, Amarin, Applied Therapeutics, Ascendia, Corvidia, HLS Therapeutics, Kowa, Eli Lilly and Company, and Rhoshan outside the submitted work. Dr Sabatine reports research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, CVS Caremark, DalCor, Dr. Reddy’s Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis. Drs Giugliano, Park, and Sabatine are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, The Medicines Company, and Zora Biosciences. No other disclosures were reported.

Meeting Presentation: This paper was presented at the American Heart Association Scientific Sessions 2020; November 13, 2020; virtual conference.

Disclaimer: Dr Sabatine is Deputy Editor of JAMA Cardiology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

References
1.
Grundy  SM, Stone  NJ, Bailey  AL,  et al.  2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.   J Am Coll Cardiol. 2019;73(24):e285-e350. doi:10.1016/j.jacc.2018.11.003 PubMedGoogle ScholarCrossref
2.
Cannon  CP, Blazing  MA, Giugliano  RP,  et al; IMPROVE-IT Investigators.  Ezetimibe added to statin therapy after acute coronary syndromes.   N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489 PubMedGoogle ScholarCrossref
3.
Sabatine  MS, Giugliano  RP, Keech  AC,  et al; FOURIER Steering Committee and Investigators.  Evolocumab and clinical outcomes in patients with cardiovascular disease.   N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664 PubMedGoogle ScholarCrossref
4.
Schwartz  GG, Steg  PG, Szarek  M,  et al; ODYSSEY OUTCOMES Committees and Investigators.  Alirocumab and cardiovascular outcomes after acute coronary syndrome.   N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174 PubMedGoogle ScholarCrossref
5.
Collins  R, Reith  C, Emberson  J,  et al.  Interpretation of the evidence for the efficacy and safety of statin therapy.   Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5 PubMedGoogle ScholarCrossref
6.
Silverman  MG, Ference  BA, Im  K,  et al.  Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.   JAMA. 2016;316(12):1289-1297. doi:10.1001/jama.2016.13985 PubMedGoogle ScholarCrossref
7.
Giugliano  RP, Keech  A, Murphy  SA,  et al.  Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial.   JAMA Cardiol. 2017;2(12):1385-1391. doi:10.1001/jamacardio.2017.3944 PubMedGoogle ScholarCrossref
8.
Mach  F, Baigent  C, Catapano  AL,  et al; ESC Scientific Document Group.  2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.   Eur Heart J. 2020;41(1):111-188. doi:10.1093/eurheartj/ehz455 PubMedGoogle ScholarCrossref
9.
de Lemos  JA, Blazing  MA, Wiviott  SD,  et al; A to Z Investigators.  Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.   JAMA. 2004;292(11):1307-1316. doi:10.1001/jama.292.11.1307 PubMedGoogle ScholarCrossref
10.
Burke  AC, Dron  JS, Hegele  RA, Huff  MW.  PCSK9: regulation and target for drug development for dyslipidemia.   Annu Rev Pharmacol Toxicol. 2017;57:223-244. doi:10.1146/annurev-pharmtox-010716-104944PubMedGoogle ScholarCrossref
11.
Urban  D, Pöss  J, Böhm  M, Laufs  U.  Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis.   J Am Coll Cardiol. 2013;62(16):1401-1408. doi:10.1016/j.jacc.2013.07.056PubMedGoogle ScholarCrossref
12.
Roe  MT, Li  QH, Bhatt  DL,  et al.  Risk categorization using new American College of Cardiology/American Heart Association guidelines for cholesterol management and its relation to alirocumab treatment following acute coronary syndromes.   Circulation. 2019;140(19):1578-1589. doi:10.1161/CIRCULATIONAHA.119.042551 PubMedGoogle ScholarCrossref
13.
Pitt  B, Loscalzo  J, Yčas  J, Raichlen  JS.  Lipid levels after acute coronary syndromes.   J Am Coll Cardiol. 2008;51(15):1440-1445. doi:10.1016/j.jacc.2007.11.075 PubMedGoogle ScholarCrossref
×