Alirocumab and plaque volume,calf muscle blood flow,and walking performance in peripheral artery disease: A randomized clinical trial

Abstract

Background:

The distal superficial femoral artery (SFA) is most commonly affected in peripheral artery disease (PAD). The effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab added to statin therapy on SFA atherosclerosis, downstream flow, and walking performance are unknown.

Methods:

Thirty-five patients with PAD on maximally tolerated statin therapy were recruited. Patients were randomized to alirocumab 150 mg subcutaneously (n = 18) or matching placebo (n = 17) therapy every 2 weeks for 1 year. The primary outcome was change in SFA plaque volume by black blood magnetic resonance imaging (MRI). Secondary outcomes were changes in calf muscle perfusion by cuff/occlusion hyperemia arterial spin labeling MRI, 6-minute walk distance (6MWD), low-density lipoprotein (LDL) cholesterol, and other biomarkers.

Results:

Age (mean ± SD) was 64 ± 8 years, 20 (57%) patients were women, 17 (49%) were Black individuals, LDL was 107 ± 36 mg/dL, and the ankle–brachial index 0.71 ± 0.20. The LDL fell more with alirocumab than placebo (mean [95% CI]) (−49.8 [−66.1 to −33.6] vs −7.7 [−19.7 to 4.3] mg/dL; p < 0.0001). Changes in SFA plaque volume and calf perfusion showed no difference between groups when adjusted for baseline (+0.25 [−0.29 to 0.79] vs −0.04 [−0.47 to 0.38] cm³; p = 0.37 and 0.22 [−8.67 to 9.11] vs 3.81 [−1.45 to 9.08] mL/min/100 g; p = 0.46, respectively), nor did 6MWD.

Conclusion:

In this exploratory study, the addition of alirocumab therapy to statins did not alter SFA plaque volume, calf perfusion or 6MWD despite significant LDL lowering. Larger studies with longer follow up that include plaque characterization may improve understanding of the effects of intensive LDL-lowering therapy in PAD (ClinicalTrials.gov Identifier: NCT02959047).

Keywords

atherosclerotic plaque magnetic resonance imaging (MRI)PCSK9 inhibition peripheral artery disease (PAD)

Background

Peripheral artery disease (PAD) is characterized by lower-limb arterial obstruction due to atherosclerosis. Its worldwide prevalence is estimated to be over 200 million people and it continues to rise rapidly, with an increase of 23.5% since 2000.^1,2 There are over 8.5 million people with PAD in the US.¹ The annual rate of cardiovascular (CV) events including myocardial infarction, stroke, and CV death is 5–7%. The adjusted risk of dying of a CV event is twofold higher than those without PAD.^3–9

Alirocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor that effectively reduces low-density lipoprotein (LDL) cholesterol by up to 70% in patients on statins or intolerant to statins.¹⁰ A human immunoglobulin antibody, alirocumab binds with a 1:1 ratio to circulating PCSK9 and, thus, it allows recycling of LDL receptors on hepatocytes that are necessary to clear LDL particles. This injectable agent is generally safe and well-tolerated and has been shown to reduce PAD events in the ODYSSEY Outcomes trial.¹¹ Additionally, intensive LDL lowering with PCSK9 inhibitor evolocumab, added to statin therapy, has been shown to reduce major adverse cardiovascular (MACE; cardiovascular death, myocardial infarction, or stroke) and limb events (MALE; acute limb ischemia, major amputation, or urgent revascularization) in patients with and without symptomatic PAD.¹² Current guidelines recommend addition of PCSK9 inhibitors in patients with elevated CV risk if LDL remains above 100 mg/dL despite treatment with statins and ezetimibe.¹³ Both alirocumab and evolocumab are approved by the US Food and Drug Administration (FDA).

Magnetic resonance imaging (MRI) methods can accurately quantify atherosclerotic plaque in the superficial femoral artery (SFA) in patients with PAD. These measures can be performed with high test-retest reproducibility,¹⁴ and plaque regression with statins has been shown using these techniques in PAD.¹⁵ Additionally, arterial spin labeling (ASL) MRI allows measurement of tissue perfusion by using magnetically labeled arterial blood water protons and without intravenous administration of contrast with reproducible results.¹⁴ To our knowledge, alirocumab’s effect on plaque volume in PAD has not been previously studied. We hypothesized that LDL lowering with alirocumab 150 mg subcutaneously (SQ) every 2 weeks would regress atherosclerotic plaque in the SFA of patients with PAD over 1 year, as well as improve calf muscle perfusion and 6-minute walk test (6MWT) performance when compared to placebo.

Methods

Study design

The study was a prospective, two-center, randomized, double-blind, placebo-controlled, stratified, two-arm study of patients with mild–moderate PAD (ankle–brachial index [ABI] 0.4–0.9) who were on maximally tolerated statin therapy or intolerant to statins (ClinicalTrials.gov Identifier: NCT02959047). Patients were randomized 1:1 to receive alirocumab 150 mg SQ or matching placebo treatment every 2 weeks for 1 year. The two enrolling medical centers were University of Virginia Health and Northwestern University. Inclusion criteria included age 35–85 years, clinical diagnosis of PAD, ABI of 0.4–0.9, LDL > 70 mg/dL, either on statins for at least 6 months or statin intolerant. The statin used could be a high-potency statin (rosuvastatin, atorvastatin) or high dose of a lower-potency statin (e.g., simvastatin 40–80 mg, pravastatin 40–80 mg). Exclusion criteria included rest limb pain, critical limb ischemia, known or planned stent in the SFA, known occlusion of the SFA, planned revascularization within the next year, inability to lie flat, known contraindications to MRI including pacemaker, implantable cardioverter defibrillators, certain intracranial aneurysm clips, and claustrophobia, pregnancy, inability to obtain informed consent, and known allergy to alirocumab. The clinical trial was conducted in accordance with the declaration of Helsinki and was approved by the institutional review boards at both sites. All participants provided written informed consent.

Study protocol

After initial screening and documentation of the ABI, patients who met the inclusion criteria were informed about the study and those who provided informed consent were enrolled. There were at least two visits to the study site: the first visit before initiation of treatment with alirocumab or placebo and the second visit after 1 year of treatment. Physical exam including vital signs, questionnaire on medications and medical history, fasting blood draw, 6MWT, and MRI were performed during both visits. Telephone follow-up was performed at intervals of 1–2 months between study visits to confirm medication compliance and to account for any interval events.

Study outcomes

The primary outcome was mean change in superficial femoral plaque volume (measured from the leg with the minimum ABI at baseline or the leg with corresponding ASL measurement) from first visit to the second visit after 1 year of therapy as measured by black blood MRI, expressed in cm.^3,14 Secondary outcome measures included change in calf muscle perfusion in the most symptomatic leg as measured by cuff/occlusion hyperemia arterial spin labeling MRI,¹⁶ expressed in mL/min/100 g; change in 6MWT expressed in feet; change in LDL cholesterol, high-sensitivity C-reactive protein (hsCRP), fibrinogen, and lipoprotein(a) (Lp(a)) after 1 year of treatment.

The 6-minute walk test (6MWT) procedure

Participants walked back and forth along a marked 100-foot hallway for 6 minutes after standardized instructions to complete as many laps as possible. The distance covered in 6 minutes was recorded and the amount of time rested was recorded. Timing of the 6 minutes continued if the subject stopped to rest. The 0–4 ischemic leg pain scale was shown to the subject and explained before the test. The pre, during, and posttest presence of any claudication along with its location, severity (0–4 scale), onset, and dispersal were recorded. If the subject needed to stop for reasons other than claudication, this was noted. The 6MWT was performed at baseline and at the final study visit approximately 12 months later.

Cardiovascular MRI protocol

MRI was performed on a 3.0 Tesla Prisma MR scanner (Siemens Healthineers, Erlangen, Germany) using a specifically designed four-channel superficial femoral artery array coil (Machnet, Leiden, The Netherlands) and a phased array flexible extremity coil. The patient was placed supine on the scanner table, in the foot first position for plaque imaging, and head first for ASL imaging. Both legs were scanned with the plaque imaging protocol. The most symptomatic leg was scanned with the ASL protocol.

Superficial femoral artery (SFA) plaque imaging protocol

A standard multiplane scout was used to localize the upper thigh and groin area. Then, using a noncontrast, time-of-flight MR angiogram, the bifurcation of the common femoral artery into the SFA and deep femoral artery (DFA) was localized. The SFA was the artery imaged for the purposes of this study. A multislice turbo spin echo sequence with saturation pulses to null flowing blood was used to cover 10–15 cm of the proximal SFA, with the first stack starting just above the bifurcation of the common femoral artery to the SFA and DFA to ensure a reproducible anatomical landmark for follow-up images. Each individual acquisition covered five to six slices, each 3 mm thick with a 3 mm gap between images with axial (transverse) orientation; A-P phase-encoding direction and the following imaging parameters: repetition time (TR): approximately 1500–1700 ms; echo time (TE): 8.3 ms; four averages; flip angle: 180º; fat saturation; field of view (FOV): 150 mm; matrix size: 256 × 256; saturation pulses (parallel foot and head): 10 mm gap, 100 mm thick; bandwidth: 250 Hz/px; turbo factor: 8; and echo trains/slice: 32.

Arterial spin labeling (ASL) MRI protocol

For ASL imaging, a phased array extremity wrap coil was placed around the calf of interest. The cuff for the cuff occlusion device was placed around the thigh and connection to the pressure device was confirmed. The calf was centered in the magnet. After scout imaging of the calf, a slice in the mid-calf was chosen for further imaging with ASL before and after occlusion. Baseline ASL acquisitions prior to cuff occlusion were performed with the following parameters: slice groups: 1; number of slices: 2; distance factor: 50%; transverse orientation; A-P phase-encoding direction; phase oversampling: 0%; FOV read: 200 mm; FOV phase: 100%; slice thickness: 10 mm; TR: 4000 ms; TE: 32.0 ms; averages: 1; concatenations: 1; inversion time 2: 1800 ms; inversion time 1: 700 ms; saturation stop time: 1600 ms; flip angle: 90°; fat saturation: strong; measurements: 51; magnitude reconstruction; perfusion mode: proximal inversion with a control for off-resonance effects (PICORE Q2T); flow limit: 100 cm/s; bolus duration: 700 ms; base resolution: 64; phase resolution: 100%; phase partial Fourier: 6/8; interpolation: off; PAD mode: none. Axial steady-state free precession (SSFP) cine imaging of the same calf slice was performed to confirm patent arterial flow. Then, the cuff was inflated to 200–250 mmHg. Repeat axial SSFP cine imaging was performed to ensure adequate arterial occlusion. After 5 minutes of occlusion, the cuff was deflated and ASL image acquisition was performed with the same parameters as above.

Data analysis

SFA plaque volume analysis was performed on VesselMASS software (University of Leiden, Leiden, The Netherlands) as previously described.^14,15 Plaque volume defined as total vessel area minus lumen area multiplied by the slice thickness was calculated for the entire length of the SFA studied.

ASL perfusion analysis was performed on Syngo.via (Siemens Healthineers, Erlangen, Germany) as previously described¹⁶ for images obtained after cuff occlusion. ASL mean flow was calculated by averaging the perfusion values of six calf muscle groups. Regions of interest (ROI) were drawn manually on the motion-corrected EPI images while avoiding large vessels. The ROIs were copied to the relative blood flow maps to obtain perfusion measurements in mL/min/100 g.

Statistical analysis

At randomization, participants were stratified by sex (female/male) and randomized 1:1 to treatment or placebo using a stratified block randomization scheme with varying block sizes. The study was designed to detect a larger decrease in pre/postplaque volume (effect size of 0.9) in the treated arm compared to placebo assuming a two-sample nonparametric Wilcoxon rank sum test. Assuming a 5% level two-sided test with 80% power and a 15% drop-out rate, target accrual was estimated at 54 patients. Differences between the treatment arms were explored using the Wilcoxon rank sum test. Graphical displays and mean change in pre/postdifferences within and between arms were estimated along with 95% CI, and analysis of covariance with baseline measures as a covariate were used to estimate change, adjusting for baseline. Per patient changes in plaque volume were compared to changes in ASL perfusion by linear correlation. Given the reduced sample size, results should be considered exploratory.

Results

Study population

The recruitment phase for the study participants lasted from July 24, 2017 to March 31, 2020, at which time recruitment was halted prematurely due to the COVID-19 pandemic. As shown in Figure 1, a total of 268 patients were screened for recruitment, 150 were ineligible, and 72 patients declined. Forty eligible patients (short of 54 patients planned per power analysis) were enrolled. Five participants were lost to follow up or withdrew after randomization. Thus, data from 35 patients were available for analysis. Of the final study population, 57% were women and age (mean ± SD) was 64 ± 8 years. Seventeen (49%) were Black. The mean LDL was 107 ± 36 mg/dL and 32 patients were on maximally tolerated statins and three were intolerant to statins. The mean ABI was 0.71 ± 0.20 and 0.73 ± 0.20 on the right and left legs, respectively. Eighteen patients received alirocumab and 17 patients received placebo treatment. Characteristics of the study participants are listed in Table 1.

Figure 1.

Patient flow diagram.

Table 1.

Patient baseline characteristics.

	Alirocumab, n = 18	Placebo, n = 17	Total, n = 35
Age, y	63 ± 7	66 ± 9	64 ± 8
Male sex	8 (44)	7 (42)	15 (43)
Weight, lbs	189 ± 45	191 ± 38	190 ± 41
Systolic blood pressure, mm Hg	130 ± 19	139 ± 19	134 ± 19
Diastolic blood pressure, mm Hg	71 ± 11	74 ± 11	73 ± 11
Left ABI	0.73 ± 0.20	0.72 ± 0.21	0.73 ± 0.20
Right ABI	0.71 ± 0.18	0.70 ± 0.23	0.71 ± 0.20
Total cholesterol, mg/dL	177 ± 38	181 ± 47	179 ± 42
LDL, mg/dL	108 ± 32	106 ± 41	107 ± 36
Triglycerides, mg/dL	131 ± 57	149 ± 85	140 ± 72
Fibrinogen, mg/dL	381 ± 109	390 ± 56	385 ± 86
High-sensitivity CRP, mg/dL	6 ± 7	6 ± 7	6 ± 7
Lipoprotein(a), mg/dL	79 ± 75	84 ± 68	82 ± 71
6-Minute walk distance (feet)	1171 ± 421	914 ± 380	1047 ± 416
On statins	16 (89)	16 (94)	32 (91)
Coronary artery disease	9 (50)	3 (18)	12 (34)
Hypertension	15 (83)	14 (82)	29 (83)
Diabetes mellitus type 2	8 (44)	9 (53)	17 (49)
Hyperlipidemia	16 (89)	16 (94)	32 (91)
History of myocardial infarction	4 (22)	2 (12)	6 (17)
History of PCI	6 (33)	1 (6)	7 (20)
History of CABG	4 (22)	0 (0)	4 (11)
History of leg percutaneous intervention	5 (28)	5 (29)	10 (29)
History of carotid endarterectomy	0 (0)	1 (6)	1 (3)
History of stroke/TIA	3 (17)	6 (35)	9 (26)
History of surgical leg bypass	2 (11)	2 (12)	4 (11)

Values are n (%) or mean ± SD.

ABI, ankle–brachial index; CABG, coronary artery bypass graft; CRP, C-reactive protein; LDL, low-density lipoprotein; PCI, percutaneous coronary intervention; TIA, transient ischemic shock.

Primary and secondary endpoints

Baseline and follow-up image data for SFA plaque volume (Figure 2) and ASL perfusion analysis were available for 27 and 25 patients, respectively. Reasons for loss of data points were multifactorial and included intervention to the SFA between the initial and 1-year visits; poor image quality due to motion despite multiple image acquisition attempts; loss to follow up; and inability to obtain follow-up imaging due to development of claustrophobia or change in medical condition. ASL images could not be obtained in two patients due to inability to tolerate cuff occlusion.

Figure 2.

Example of SFA (arrows) and its associated plaque in a patient treated with placebo (A, B) and in a patient treated with alirocumab (C, D). (A) and (C) show plaque at baseline and (B) and (D) show images after 1 year of treatment.

At 52 weeks, the mean change in total plaque volume was 0.25 cm³ with alirocumab versus −0.04 cm³ with placebo (difference −0.29 cm³ [95% CI −0.96 to 0.37], p = 0.85) (Figure 3). Analysis of calf muscle ASL perfusion using MRI showed no significant change in response to treatment with alirocumab for 1 year even when adjusted for baseline (Figure 4). There was no significant correlation between change in plaque volume and change in ASL perfusion.

Figure 3.

Effects of alirocumab compared to placebo treatment on total mean ± SD plaque volume (cm³) measured from the leg with the minimum ABI at baseline or the leg with corresponding ASL measurement.

Figure 4.

Effects of alirocumab compared to placebo treatment on ASL mean ± SD flow measured from the leg with the minimum ABI at baseline.

Baseline and follow-up data for lab results and the 6MWT were available for 35 and 33 patients, respectively. LDL levels fell more with the addition of alirocumab than with statin therapy alone (−49.8 vs −7.7 mg/dL, p < 0.001), as shown in Table 2. There was a trend towards favorable change in hsCRP and Lp(a) levels with alirocumab, but these were not statistically significant (Table 2). There was no statistically significant difference in change in the 6-minute walk distance (6MWD) between the placebo and alirocumab groups (Table 2).

Table 2.

Initial and 1-year follow-up mean results and change between placebo and alirocumab groups.

End point	Alirocumab			Placebo			Drug – placebo	95% CI of difference
End point	Baseline	Final	Change	Baseline	Final	Change	Drug – placebo	95% CI of difference
TPV	2.61	2.86	0.25	3.07	3.03	−0.04	−0.29	(−0.98, 0.40)
ASL	17.84	18.05	0.22	12.61	16.43	3.81	3.59	(−7.67, 14.86)
6MWD	1188.53	1180.82	−7.71	924.88	890.44	−34.44	−26.73	(−130.40, 76.89)
TC	176.61	125.50	−51.11	180.82	166.47	−14.35	36.76	(13.39, 60.12)
LDL	107.56	57.72	−49.83	106.35	98.65	−7.71	42.13	(22.50, 61.76)
TG	131.17	117.22	−13.94	148.76	117.12	−31.64	−17.70	(−57.48, 22.08)
hsCRP	6.16	5.84	−0.32	6.44	7.63	1.18	1.50	(−5.02, 8.03)
Lp(a)	79.35	75.18	−4.18	84.35	88.71	4.35	8.53	(−0.41, 17.47)
Fibrinogen	380.61	389.89	9.28	389.53	408.18	18.65	9.37	(−59.38, 78.12)

Note that there is a significant difference in TC and LDL change between alirocumab and placebo.

6MWD, 6-minute walk distance (feet); ASL, arterial spin labeling (mL/min/100 g); hsCRP, high-sensitivity C-reactive protein (mg/L); LDL, low-density lipoprotein (mg/dL); Lp(a), lipoprotein(a) (mg/dL); TC, total cholesterol (mg/dL); TG, triglycerides (mg/dL); TPV, total plaque volume (cm³).

Discussion

This study demonstrated that the addition of alirocumab to statin therapy did not reduce SFA plaque volume or improve calf ASL perfusion or 6MWD in PAD, despite a significant reduction in LDL cholesterol. There was no significant plaque progression in either group. The distal SFA is the predominant location affected by atherosclerosis in PAD. Lower LDL and total cholesterol levels have been demonstrated to be associated with greater plaque stability in coronary arteries and a decrease in CV death.¹⁷ However, though hyperlipidemia is a major risk factor for lower-limb atherosclerosis as well, the effects of LDL lowering are not well understood in PAD. MRI measurement of SFA plaque volume in patients with mild to moderate PAD is reliable and reproducible, as shown by our group.¹⁴

The current study and a previous study by our group¹⁵ demonstrated that the effect of LDL reduction on SFA plaque volume in patients with PAD may depend upon prior statin therapy. In the prior study, statin-naïve patients treated with simvastatin (n = 16) or simvastatin and ezetimibe (n = 18) did not demonstrate MRI-measured plaque progression over a 2-year period, whereas those previously on statins receiving open-label ezetimibe (n = 33) demonstrated progression.¹⁵ The vast majority of patients in the present study had been on statins for some time and may have already received the maximal benefit of LDL lowering on plaque volume. If alirocumab was given to a group of statin-naïve patients, changes in plaque volume with therapy may have been more likely.

Studies of coronary plaque volume and components with alirocumab have shown mixed results. The ODYSSEY J-IVUS trial, a randomized, prospective study which enrolled 206 Japanese patients with acute coronary syndrome, showed that there was no reduction in total plaque volume after 36 weeks of therapy with alirocumab.¹⁸ An open-label randomized clinical trial of 61 patients with intermediate coronary artery lesions reported a greater increase in minimum fibrous cap thickness, a greater increase in minimum lumen area, and a greater diminution in maximum lipid arc, promoting a more stable coronary plaque phenotype in addition to lowering LDL cholesterol levels after 36 weeks of treatment with alirocumab as assessed by optical coherence tomography.¹⁹ The PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial involving nine centers in four European countries used multimodality imaging including intravascular ultrasonography (IVUS), near-infrared spectroscopy, and optical coherence tomography on 300 patients undergoing percutaneous coronary intervention for acute myocardial infarction demonstrated greater plaque atheroma volume regression, reduction in maximum lipid core burden, and greater change in minimal fibrous cap thickness after 52 weeks of therapy with alirocumab.²⁰ Gao at al. demonstrated that patients with intermediate coronary lesions treated with alirocumab had a lower rate of calcium score progression.²¹ Thus, plaque characteristics may change more than plaque volume with alirocumab therapy.

SFA plaque characteristics and therefore its clinical manifestations are different from those of coronary arteries. Plaques in SFA are more calcified and stable and less prone to rupture due to more fibrotic components and smooth muscle cells, as well as fewer inflammatory cells and lipids.^22,23 Coronary and carotid artery plaques often have a large lipid core. Our group²⁴ used MRI to demonstrate that only a small proportion of patients with PAD have lipid-rich necrotic plaque, whereas 59% had calcified plaques. In 28 patients with carotid artery disease, MRI demonstrated a significant reduction in % lipid-core volume after 6 months of treatment with alirocumab; however, similar to the present study, there were no significant changes in lumen or wall areas.²⁵ The authors of this study suggest that plaque lipid content may be a more sensitive imaging marker for therapeutic response compared to lumen or wall areas. In the present study, SFA plaque characterization was not able to be performed due to the relatively long scan times of both legs required for plaque volume studies. Thus, this study does not differentiate between arteries that are mainly calcified versus arteries with lipid-rich atherosclerosis.

Mohler et al.²⁶ showed that LDL cholesterol reduction with atorvastatin improved pain-free walking distance in 354 patients after 12 months of treatment. The current study did not show any effects of further LDL-lowering therapy in addition to statin therapy on the 6MWD. Again, the benefits of prior statin therapy may have mitigated against further improvement in the 6MWD with alirocumab. Bonaca et al. showed a significant reduction in MACE and MALE with significant LDL lowering.¹² The present study was not powered to evaluate outcomes and excluded any patients with critical leg ischemia. As suggested by Bonaca et al.,¹² longer exposure time to significant LDL-lowering therapy with PCSK9 inhibitor once patients are already on statins may be needed to see functional improvement.

In summary, possible explanations for the lack of improvement in plaque volume, calf perfusion, and walk performance is that patients who are already on statins may require a longer follow-up period and that a primary endpoint of lipid-rich plaque may have been preferable.

Study limitations

The sample size of this study was smaller than initially planned and has reduced power to detect the initial hypothesized difference between treatment arms. Owing to the COVID-19 pandemic, the study was terminated after a total of 40 patients were enrolled rather than the planned 54 patients. Two patients who underwent revascularization procedures to SFA after enrollment were excluded from MRI image data analysis, which decreased the sample size further. In addition, characterization of plaque components was not performed due to time constraints during imaging. In the future, larger studies should evaluate the effects of significant lipid-lowering therapy with PCSK9 inhibitors on plaque characteristics. This study did not have the statistical power to assess the effects of alirocumab on clinical outcomes in patients with PAD. Also, it must be noted that the time it takes to observe any changes in SFA plaque from alirocumab is not known. Previous studies have reported variable follow-up times ranging between 6 months and 1 year for coronary and carotid arteries. SFA plaques which inherently are more stable may require a longer follow-up time to observe changes.

Conclusions

For patients with PAD in the current study, the addition of alirocumab therapy to maximally tolerated statin therapy did not significantly change SFA plaque volume, calf perfusion, or 6MWD despite significant LDL lowering. However, these results should be interpreted with caution as the study lacked statistical power. Larger studies evaluating not only plaque volume, and calf perfusion, but also plaque characteristics in addition to clinical outcomes in response to therapy with PCSK9-inhibitors may help further our understanding of LDL-lowering therapies on PAD and SFA plaque.

Footnotes

Data sharing statement

All individual participant data collected during the trial, after deidentification, can be shared, as well as the study protocol and statistical analysis plan, beginning 3 months and ending 5 years after article publication for researchers who provide a methodologically sound proposal to achieve aims in the approved proposal. Proposals should be directed to ckramer@virginia.edu. To gain access, data requesters will need to sign a data access agreement.

Declaration of conflicting interests

James C Carr has received institutional research grants and has served on an advisory board and speakers bureau for Siemens Healthineers. The other authors have no conflicts of interest.

Funding

This study was supported by a grant from Regeneron Pharmaceuticals, R01 HL075792, and 5T32EB003841. The study was an investigator-initiated trial. The sponsor had no role in study design or manuscript preparation.

ORCID iDs

Mary M McDermott

Christopher M Kramer

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