Alirocumab in Acute Myocardial Infarction: Results From the Virginia Commonwealth University Alirocumab Response Trial (VCU-AlirocRT)

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 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.

INTRODUCTION

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 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 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 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.

Statistical Analysis

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; 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).

TABLE 1.

Individual Patient Data

	Subject (#)	Age (yrs)	Sex	Race	HTN	DM	Statin (Pre), Dose (mg)	Statin (Post), Dose (mg)	LDL-C, Baseline, mg/dL	LDL-C, ≤72 h, mg/dL	LDL-C, 14 d, mg/dL
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

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

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).

FIGURE 1.

Changes in LDL-cholesterol and PCSK9 levels.

TABLE 2.

Biomarker Data

	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)
≤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)
≤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.

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

FIGURE 2.

Changes in inflammatory biomarkers. IL-10, interleukin-10; TNF-α, tumor necrosis factor-α.

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 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.

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 experience are needed to validate these findings and to determine whether this treatment strategy has a sustained benefit on clinical outcomes.