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J Cardiovasc Pharmacol. Author manuscript; available in PMC 2021 August 04.
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Published in final edited form as:

J Cardiovasc Pharmacol. 2019 September ; 74(3): 266–269. doi:10.1097/FJC.0000000000000706.

Alirocumab in Acute Myocardial Infarction: Results From the

Virginia Commonwealth University Alirocumab Response Trial
(VCU-AlirocRT)
Cory R. Trankle, MD*, George Wohlford, PharmD†, Leo F. Buckley, PharmD‡, Dinesh
Kadariya, MD*, Krishna Ravindra, BS*, Roshanak Markley, MD*, Tae Shik Park, MD*, Nicola
Potere, MD*, Benjamin W. Van Tassell, PharmD†, Antonio Abbate, MD, PhD*
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*Division of Cardiology, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond,
VA;
†Department
of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia
Commonwealth University, Richmond, VA;
‡Department of Pharmacy Services, Brigham and Women’s Hospital, Boston, MA.

Abstract
Alirocumab improves outcomes in patients with a history of recent acute coronary syndrome, but
treatment acutely at the time of myocardial infarction is untested. We present the results of a
randomized, placebo-controlled, double-blinded pilot study of alirocumab treatment at the time of
non-ST elevation MI (NSTEMI). Twenty patients with type 1 NSTEMI and low-density
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lipoprotein cholesterol (LDL-C) >70 mg/dL despite high intensity statin therapy were randomized
1:1 to one dose of alirocumab 150 mg subcutaneously or placebo within 24 hours of presentation.
LDL-C and inflammatory biomarkers—including C-reactive protein—were obtained at baseline,
72 hours, and 14 days. Median (interquartile range) and number (%) were: age 59 (49, 65) years, 7
(35%) men, 16 (80%) black; baseline characteristics were similar between groups. Alirocumab
significantly reduced LDL-C from baseline to 14 days by 64 mg/dL (−96, −47) compared with
placebo [+1 mg/dL (−25, +16)] (primary endpoint). There were no significant between-group
differences in C-reactive protein changes at any time point (all P > 0.2) or serious adverse events
attributable to the study treatment. In conclusion, alirocumab administration at the time of
NSTEMI significantly reduced LDL-C levels at 14 days, was safe, and had neutral effects on
inflammatory biomarkers. Further studies are warranted to explore the effects on clinical
outcomes.
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Keywords
alirocumab; myocardial infarction; PCSK9; low-density lipoprotein cholesterol

Reprints: Cory Trankle, MD, VCU Pauley Heart Center, Virginia Commonwealth University, PO Box 980053, 1200 E Marshall St,
Richmond, VA 23298 (cory.trankle@vcuhealth.org).
The authors report no other conflicts of interest.
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INTRODUCTION
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Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality
worldwide. Cholesterol-lowering drugs, primarily HMG-CoA reductase inhibitors (statins),
not only reduce low-density lipoprotein cholesterol (LDL-C) but also improve clinical
outcomes when used as an adjunct to AMI therapy.1,2

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have emerged as a new

treatment strategy for LDL cholesterol lowering, and alirocumab treatment reduces
cardiovascular events in patients with a history of acute coronary syndrome (1–12 months
before enrollment) and LDL cholesterol ≥70 mg/dL despite statin therapy.3 Preclinical
studies have suggested effects of PCSK9 inhibitors on non-LDL-C receptors involved in
pathogen clearance, which could have implications for remodeling pathways after AMI.4
The incremental benefit of PCSK9 inhibitors as an adjunct therapy early in the AMI
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treatment course has remained untested. Therefore, we designed a phase IV pilot study to
test the safety, feasibility, and effectiveness of alirocumab treatment for patients hospitalized
for AMI management (NCT02938949).

METHODS
From February 2017 to July 2018, patients at the Virginia Commonwealth University
admitted with non-ST elevation MI (NSTEMI) were consecutively screened for eligibility.
Inclusion criteria included type 1 NSTEMI, treatment with high-intensity statin (atorvastatin
40–80 mg daily or rosuvastatin 20–40 mg daily) before admission, and documented LDL-C
≥70 mg/dL within the previous 12 months. Exclusion criteria included documented familial
hypercholesterolemia, autoimmune or autoinflammatory disorder, recent use of
immunosuppressive medications, cancer within the past 5 years, active infection, previous
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hemorrhagic stroke, and uncontrolled thyroid disorder.

The study was approved by the institutional review Board at Virginia Commonwealth
University. Patients were approached within 24 hours of their presenting NSTEMI and
provided written informed consent. Baseline lipid profile (including LDL-C), high-
sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-α,
complete metabolic profile, complete blood counts were obtained, as well as serum PCSK9
levels (both free and total levels, measured using an enzyme-linked immunoassay with lower
limits of detection of 31.2 and 156 ng/mL, respectively). After this, subjects were
randomized 1:1 in a double-blinded fashion to an immediate single dose of alirocumab 150
mg subcutaneously or a matched placebo. Repeat labs were obtained at 72 hours (or hospital
discharge, whichever came first) and 14 days when a safety assessment was performed. The
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primary endpoint was a placebo-corrected change in LDL-C at 14 days. Additional

prespecified endpoints included the incidence of adverse events (both related and unrelated
to study medications), placebo-corrected change in hsCRP, IL-6, tumor necrosis factor-α,
free PCSK9, and total PCSK9 levels at 72 hours and 14 days, as well as change in LDL-C at
72 hours.

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Statistical Analysis
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Descriptive summaries of continuous measurements are reported as median and interquartile

ranges; descriptive summaries of categorical measurements are reported as frequencies and
proportions. All analyses were conducted on an intention-to-treat principle. Baseline
continuous and categorical variables were assessed between groups using the Mann–
Whitney U test and Fisher exact test, respectively. The Wilcoxon signed-rank test was used
to analyze within-group changes from baseline and analysis of variance for placebo-
corrected changes from baseline. Unadjusted P values are reported throughout, with
statistical significance set at the two-tailed 0.05 level. The SPSS software 25.0 (IBM, New
York, NY) was used for all analyses.

RESULTS
Overall 205 patients were assessed for eligibility: 106 (52%) were not on a qualifying statin;
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18 (9%) did not meet the LDL-C >70 mg/dL entry criteria; 17 (8%) were not type 1
NSTEMI; 12 (6%) were unable to provide consent; 11 (5%) were late-presentation AMI; 9
(4%) had autoimmune, infectious, or malignancy exclusions; 7 (3%) declined to participate;
and 5 (2%) met other exclusion criteria. Thus, 20 patients were enrolled in the study.
Baseline characteristics are displayed on an individual patient basis in Table 1. Median
(interquartile range) and number (%) were: age 59 (49, 65) years, 7 (35%) men, 4 (20%)
white, and 16 (80%) black. Three (15%) were on rosuvastatin and 17 (85%) on atorvastatin
before admission. Baseline characteristics, including LDL-C and CRP levels, were similar
between groups (all P > 0.05), with the exception of lower lipoprotein (a) levels in the
control arm: 56 (13–195) compared with 215 (114–344) nmol/L in the placebo group (P =
0.043).
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Subjects allocated to placebo had no significant change in LDL-C levels, from 98 (72–160)
mg/dL at baseline to 93 (61–132) and 90 (75–131) mg/dL at 72 hours and 14 days,
respectively (P > 0.1 for both follow-up time points compared with baseline). Those treated
with alirocumab had a significant reduction in LDL-C, from 91 (71–129) mg/dL at baseline
to 73 (36–110) and 28 (14–51) mg/dL at 72 hours and 14 days, respectively (P = 0.02 and P
> 0.01 for placebo-corrected comparisons, respectively; Fig. 1 and Table 2). There were no
significant changes in free or total PCSK9 levels at either time point compared with baseline
in the placebo group (P > 0.2 for all within-group comparisons from baseline). Free PCSK9
levels were reduced to undetectable levels (<31.2 ng/mL) in all patients with available data
in the alirocumab group within 72 hours, with levels still significantly reduced compared
with baseline at 14 days. Total PCSK9 levels rose at each time point in the alirocumab group
(Fig. 1 and Table 2).
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HsCRP levels did not change significantly from baseline in either group (P > 0.2 for all
within- and between-group comparisons; Fig. 2). Interleukin-6 levels were lower at 14 days
compared with baseline (P < 0.05 for both within-group comparisons), but there was no
difference at any time point for between-group changes (P > 0.4 for both comparisons).
Tumor necrosis factor-α and interleukin-10 levels did not significantly change within groups
at either time point compared with baseline, and there were not any within-group differences

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in biomarker levels (all P > 0.1 for within- and between-group comparisons). Biomarker data
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are shown in Table 2.

Adverse events occurred in 1 patient (10%, sepsis) in the placebo group and 4 patients (40%;
1 stroke, 2 admissions for heart failure, and 1 readmission for unstable angina) in the
alirocumab group (P = 0.152); none were believed to be attributable to the study medication.

DISCUSSION
This pilot study highlights the time course of LDL-C reduction as a result of the
neutralization of PCSK9 with alirocumab. To the best of our knowledge, this is the first
evaluation of the administration of a PCSK9 inhibitor in a hospitalized population being
acutely managed for AMI. Within only 72 hours, a statistically significant reduction of LDL-
C was found for those who received treatment; a reduction which was further enhanced at
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day 14. The observation of decreased LDL-C and free PCSK9 in the setting of increased
total PCSK9 confirms that bound PCSK9 accumulates in the plasma circulation but remains
physiologically inactive.

Rapid reduction of LDL-C at the time of NSTEMI may have beneficial effects. Early
administration of statin therapy seems to have benefits related to lowering of both LDL-C
and CRP, with effects that appear to be independent of one another.5 In addition, previous
investigations have determined that initiation of a medication before discharge increases the
likelihood that the clinically indicated therapy will be used afterward in the outpatient
setting.6 With the recent ODYSSEY-Outcomes trial establishing the significant clinical
benefit of alirocumab when started 1–12 months after unstable angina or NSTEMI,3 earlier
administration at the time of the index event may lead to even greater benefit.
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Inflammatory biomarkers are known to acutely rise in the setting of AMI and are predictive
of adverse events. Because there was no signal for a blunted inflammatory response after
AMI, PCSK9 may not be as influential on the clearance of necrotic cellular debris as was
originally hypothesized in preclinical models.4 Previous studies have determined a lack of
correlation between circulating PCSK9 concentrations and CRP levels in healthy
populations,7 and a lack of observed effects in CRP in clinical trials experience using
various PCSK9 antibodies in hypercholesterolemia.8 However, these analyses incorporated
stable patients in the outpatient setting with longer treatment duration and follow-up.

Limitations to this study include small sample size, short follow-up with clinical data only to
14 days, and conduct at a single center. Because of the small sample size, this study may
have been underpowered to detect small effect sizes. Larger studies and real-world
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experience are needed to validate these findings and to determine whether this treatment
strategy has a sustained benefit on clinical outcomes.

Acknowledgments
The study was funded by an investigator-initiated grant from Regeneron/Sanofi. Regeneron laboratory services
performed the PCSK9 level analysis, but otherwise, neither company had a role in the study design, conduct,
analysis, or reporting. It was also supported by a Clinical and Translational Science Award (UL1TR000058 from

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the National Center for Research Resources) to the Virginia Commonwealth University Center for Clinical and
Translational Research. ClinicalTrials.gov Identification Number: NCT02938949.
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REFERENCES
1. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic
events in acute coronary syndromes. J Am Med Assoc. 2001;285:1711–1718.
2. Patti G, Pasceri V, Colonna G, et al. Atorvastatin pretreatment improves outcomes in patients with
acute coronary syndromes undergoing early percutaneous coronary intervention. Results of the
ARMYDA-ACS randomized trial. J Am Coll Cardiol. 2007;49:1272–1278. [PubMed: 17394957]
3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute
coronary syndrome. N Engl J Med. 2018;379:2097–2107. [PubMed: 30403574]
4. Dixon DL, Trankle C, Buckley L, et al. A review of PCSK9 inhibition and its effects beyond LDL
receptors. J Clin Lipidol. 2016;10:1073–1080. [PubMed: 27678423]
5. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy.
N Engl J Med. 2005;352:20–28. [PubMed: 15635109]
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6. Gattis WA, O’Connor CM, Gallup DS, et al. Predischarge initiation of carvedilol in patients
hospitalized for decompensated heart failure: results of the initiation management predischarge:
process for assessment of carvedilol therapy in heart failure (IMPACT-HF) trial. J Am Coll Cardiol.
2004;43:1534–1541. [PubMed: 15120808]
7. Ridker PM, Rifai N, Bradwin G, et al. Plasma proprotein convertase subtilisin/kexin type 9 levels
and the risk of first cardiovascular events. Eur Heart J. 2016;37:554–560. [PubMed: 26508163]
8. Cao YX, Li S, Liu HH, et al. Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels:
a systematic review and meta-analysis of rand-omised controlled trials. BMJ Open.
2018;8:e022348.
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FIGURE 1.
Changes in LDL-cholesterol and PCSK9 levels.
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FIGURE 2.
Changes in inflammatory biomarkers. IL-10, interleukin-10; TNF-α, tumor necrosis factor-
α.
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TABLE 1.

Individual Patient Data

LDL-C, Baseline, LDL-C, ≤72 h, LDL-C, 14 d,

Subject (#) Age (yrs) Sex Race HTN DM Statin (Pre), Dose (mg) Statin (Post), Dose (mg) mg/dL mg/dL mg/dL
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Placebo 1 53 F AA Y Y Atorva 80 Atorva 80 154 133 174

3 48 F AA Y Y Atorva 80 Atorva 80 117 116 116
6 47 F C N N Atorva 80 Atorva 80 89 97 104
7 61 F AA Y N Atorva 80 Atorva 80 81 61 68
9 70 F AA Y Y Atorva 40 Atorva 80 107 90 80
12 53 F AA Y N Rosuva 40 Rosuva 40 178 131 89
13 47 F AA Y N Atorva 80 Atorva 80 208 252 222
14 63 M AA Y Y Atorva 80 Atorva 80 74 64 77
19 70 F AA Y N Atorva 80 Atorva 80 65 61 91
20 59 F AA Y N Atorva 80 Atorva 80 64 56 63
Alirocumab 2 64 F AA N N Atorva 40 Atorva 40 68 n/a 49
4 70 F AA Y N Rosuva 20 Rosuva 40 72 23 11
5 71 M AA N Y Atorva 40 Atorva 40 87 57 42
8 43 F C Y Y Atorva 80 Atorva 80 150 110 56
10 65 M AA Y Y Atorva 40 Atorva 80 85 n/a 27
11 35 M AA Y Y Atorva 80 Atorva 80 95 73 19
15 58 M AA Y N Atorva 80 Atorva 80 124 85 28
16 53 M C N N Atorva 80 Atorva 80 144 118 15
17 56 M AA Y N Rosuva 20 Rosuva 20 57 36 9
18 61 F C Y Y Atorva 40 Atorva 80 123 n/a 56

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AA, African American; C, Caucasian; DM, diabetes mellitus; F, female; HTN, hypertension; M, male; N, no; Y, yes.
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TABLE 2.

Biomarker Data
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Placebo Alirocumab P
LDL-C (mg/dL)
Baseline 98 (72–160) 91 (72–129)
≤72 h 94 (61–132) 73 (36–110) 0.020
14 days 90 (75–131) 28 (14–51) <0.001
PCSK9, free (ng/mL)
Baseline 259 (223–351) 202 (137–374)
≤72 h 308 (233–516) 0 (0–0) <0.001
14 d 347 (267–428) 91 (30–109) <0.001
PCSK9, total (ng/mL)
Baseline 547 (438–744) 391 (254–621)
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≤72 h 511 (381–822) 1565 (1215–1903) <0.001

14 d 601 (473–742) 1975 (1252–3485) 0.002
CRP (mg/L)
Baseline 9.37 (4.76–21.87) 6.90 (3.43–29.50)
≤72 h 12.46 (8.77–38.15) 8.12 (2.77–33.24) 0.299
14 d 6.36 (3.46–13.38) 7.29 (2.81–9.40) 0.744
IL-6 (pg/mL)
Baseline 10.4 (9.2–17.4) 7.2 (4.4–17.7)
≤72 h 9.1 (5.4–12.8) 12.1 (5.4–20.0) 0.465
14 d 4.1 (3.3–6.2) 3.7 (2.9–5.8) 0.619
IL-10 (pg/mL)
Baseline 9.1 (6.7–12.8) 9.1 (4.6–12.3)
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≤72 h 7.2 (5.5–9.3) 9.5 (4.8–12.0) 0.556

14 d 8.6 (6.3–11.9) 7.3 (4.6–11.7) 0.622
TNF-α (pg/mL)
Baseline 1.9 (1.1–2.3) 1.3 (1.0–3.3)
≤72 h 1.5 (1.1–1.9) 1.5 (1.1–3.1) 0.916
14 d 1.4 (1.0–1.7) 1.6 (1.5–3.0) 0.828

P values for placebo-corrected changes from baseline.

IL-10, interleukin-10; TNF-α, tumor necrosis factor-α.

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