Kexin Type 9 Inhibitor on Carotid Artery Stenting

Journal Pre-proof Effect of preoperative administration of proprotein convertase subtilisin/kexin type 9 inhibitor on carotid artery stenting Yuto Shingai, M.D., Naoto Kimura, M.D., Ph.D., Ryosuke Doijiri, M.D., Ken Takahashi, M.D., Michiko Yokosawa, M.D., Ph.D., Atsushi Kanoke, M.D., Ph.D., Takahiko Kikuchi, M.D., Ph.D., Takayuki Sugawara, M.D., Ph.D., Teiji Tominaga, M.D., Ph.D. PII:

S1878-8750(19)32714-7

DOI:

https://doi.org/10.1016/j.wneu.2019.10.095

Reference:

WNEU 13566

To appear in:

World Neurosurgery

Received Date: 22 April 2019 Revised Date:

14 October 2019

Accepted Date: 15 October 2019

Please cite this article as: Shingai Y, Kimura N, Doijiri R, Takahashi K, Yokosawa M, Kanoke A, Kikuchi T, Sugawara T, Tominaga T, Effect of preoperative administration of proprotein convertase subtilisin/ kexin type 9 inhibitor on carotid artery stenting, World Neurosurgery (2019), doi: https://doi.org/10.1016/ j.wneu.2019.10.095. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

Shingai

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Effect of preoperative administration of proprotein convertase subtilisin/kexin type 9

2

inhibitor on carotid artery stenting

3 4

Yuto Shingai, M.D.1, Naoto Kimura, M.D., Ph.D.1, Ryosuke Doijiri, M.D.2, Ken Takahashi,

5

M.D.2, Michiko Yokosawa, M.D., Ph.D.1, Atsushi Kanoke, M.D., Ph.D.1, Takahiko Kikuchi,

6

M.D., Ph.D.2, Takayuki Sugawara, M.D., Ph.D.1, Teiji Tominaga, M.D., Ph.D.3

7 8

1

9

pan, 2Department of Neurology, Iwate Prefectural Central Hospital, Morioka, Iwate,

Department of Neurosurgery, Iwate Prefectural Central Hospital, Morioka, Iwate, Ja

10

Japan, 3Department of Neurosurgery, Tohoku University Graduate School of Medicine,

11

Sendai, Miyagi, Japan

12 13

Corresponding author: Yuto Shingai, M.D.

14

Address: Department of Neurosurgery, Iwate Prefectural Central Hospital, 1-4-1 Ueda,

15

Morioka, Iwate, Japan

16

E-mail address: [email protected]

17 18

Key words: carotid artery stenting, carotid artery stenosis, low-density lipoprotein

19

cholesterol, proprotein convertase subtilisin/kexin type 9 inhibitor, PCSK9i, statin 1

Shingai

1

Abbreviations

2

CAS: carotid artery stenting

3

CEA: carotid endarterectomy

4

CT: computed tomography

5

CTA: CT angiography

6

LDL: low-density lipoprotein

7

LDL-C: low-density lipoprotein cholesterol

8

MRI: magnetic resonance imaging

9

MRA: magnetic resonance angiography

10

mRS: modified Rankin scale

11

NASCET: North American Symptomatic Carotid Endarterectomy

12

P/M ratio: plaque/muscle ratio

13

PCSK9i: proprotein convertase subtilisin/kexin type 9 inhibitor

14

US: ultrasonography

15

2

Shingai

1

Abstract

2

Background: Perioperative embolic stroke is one of the most serious complications during

3

carotid artery stenting (CAS). Proprotein convertase subtilisin/kexin type 9 inhibitor

4

(PCSK9i) is a low-density lipoprotein (LDL)-lowering drug that inhibits PCSK9, which

5

normally binds to the LDL-C receptor. Its combination with statin significantly decreases

6

LDL-cholesterol levels. PCSK9i is expected to achieve lower LDL-C levels than single use

7

of statin. This study aimed to investigate whether perioperative PCSK9i administration

8

stabilizes carotid artery plaque and reduces perioperative complications of CAS.

9

Methods: Nine patients with symptomatic stenosis [North American Symptomatic Carotid

10

Endarterectomy (NASCET) 50%] or asymptomatic stenosis (NASCET 80%) were included.

11

PCSK9i was administered at least twice (once in 2 weeks) in the outpatient clinic before CAS.

12

Perioperative complications; results from blood tests, magnetic resonance imaging (MRI),

13

MR angiography, and carotid ultrasonography (US); and modified Rankin scale score at

14

discharge were assessed.

15

Results: High intensity on diffusion-weighted imaging was not observed in eight patients.

16

Changes in carotid plaque characteristics were found with MRI and/or carotid US in seven

17

patients. The plaque/muscle ratio decreased in three patients. The carotid plaque became

18

hyperechoic in two patients, and the fibrous cap was seen more clearly on carotid US. Two

19

patients had findings of stabilized plaque on MRI and carotid US, which indicates that plaque 3

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1

transformation was more stable.

2

Conclusion: Lowering LDL-C level could reduce ischemic complication, and low LDL-C

3

level affects plaque stability and anti-thrombus formation. PCSK9i can possibly stabilize

4

carotid plaque and reduce perioperative complications of CAS.

5

4

Shingai

1

[Introduction]

2

In addition to antiplatelet therapy, carotid artery stenosis treatment includes revascularization

3

treatments such as carotid artery stenting (CAS) and carotid endarterectomy (CEA). However,

4

CEA in high-risk patients is difficult; thus, in practice, many patients tend to undergo CAS.

5

However, CAS has been shown to be involved in postoperative cerebral stroke, in contrast to

6

CEA,1-3 which is regarded as a problem associated with the procedure.

7

Conversely, reports have indicated that fewer perioperative complications were seen after

8

CAS among patients who received oral statins than among those who did not receive statins4;

9

moreover, there is a decreased incidence of asymptomatic cerebral infarction due to

10

preoperative combined administration of cilostazol and statin,5 emphasizing the importance

11

of preoperative statin administration in patients scheduled to undergo CAS. However, in the

12

clinical context, some patients fail to achieve adequate control of LDL-cholesterol (LDL-C)

13

levels, such as those whose LDL-C level does not decrease even after statin administration

14

and for whom drug doses cannot be increased due to the side effects of statin.

15

Proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is a non-statin preparation

16

that can reduce LDL-C level. The binding of PCSK9 to LDL receptors present on the surface

17

of hepatocytes prompts the endocytosis of LDL receptors, which reduces the number of these

18

receptors. The LDL receptor takes LDL-C from the blood into the hepatocytes, and the

19

decrease in the number of these receptors leads to increases in blood LDL-C levels. By 5

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inhibiting the binding of PCSK9 to the LDL receptors, PCSK9i increases the number of LDL

2

receptors on the surface of the hepatocytes, ultimately lowering the blood LDL-C levels.6 A

3

phase III clinical trial in Japan showed that when used together with statin, PCSK9i reduced

4

the LDL-C by 62.5% (89.9 mg/dL) compared to the baseline,7 and it is expected to more

5

proactively improve hypercholesterolemia. A report in the field of cardiovascular medicine

6

claimed that use of PCSK9i combined with statin led to the retraction of the coronary

7

plaque.8 However, there are almost no relevant reports in the field of neurology. Thus, we

8

conducted a pilot study by administering pre-CAS patients with PCSK9i to determine

9

whether PCSK9i administration helps stabilize carotid plaque in carotid artery stenosis and

10

reduces perioperative complications of CAS.

11 12

6

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[Material and Methods]

2

Population

3

This study was approved by an independent ethics committee in Iwate Prefectural Central

4

Hospital and was conducted in compliance with the approved research protocol. Of the

5

patients with carotid artery stenosis admitted to our hospital between December 2016 and

6

May 2018 who were scheduled for CAS, we targeted those with symptomatic stenosis [North

7

American Symptomatic Carotid Endarterectomy (NASCET) 50%] or asymptomatic stenosis

8

(NASCET ≥80%), who provided consent. The exclusion criteria were as follows:

9

contraindications to magnetic resonance imaging (MRI) (wearing a pacemaker, vigorous

10

body motions, etc.); pregnancy, potential pregnancy, or breast-feeding; terminal illness with

11

prognosis of >6 months; and unfit to be a study subject as decided by the investigator.

12 13

Surgical Methods

14

Any one of the methods or a combination of carotid ultrasonography (US), carotid MR

15

angiography (MRA), carotid CT angiography (CTA) or cerebral angiography was used to

16

diagnose carotid artery stenosis. We obtained written consent from patients who met the

17

selection criteria, and consenting patients were administered alirocumab, a PCSK9i. It was

18

given in combination with the HMG-CoA reductase inhibitor that the patients had been

19

taking and given at a normal dose of 75 mg once in 2 weeks subcutaneously. As this was a 7

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pilot study and few cases were included, we did not establish a control group and statistical

2

analysis was not carried out. Alirocumab was administered during the first examination and 2,

3

4, and 6 weeks later. We evaluated changes in LDL-C levels via blood tests performed during

4

the first examination and 4 weeks later. Plaque properties were assessed by carotid US and

5

carotid MRI. CAS was performed at least 4 weeks after administering the drugs, and patients

6

were examined for perioperative complications of CAS and outcomes at the time of their

7

discharge from hospital by modified Rankin scale (mRS).

8 9

8

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[Results]

2

Patients

3

A total of nine patients were enrolled in this study. Four patients were symptomatic, while the

4

other five were asymptomatic. All patients were men, with an average age of 75.5 years. Four

5

patients were administered with rosuvastatin as the HMG-CoA reductase inhibitor prior to

6

surgery, while three patients received atorvastatin, and the remaining two were given

7

pitavastatin, which meant that all patients had received strong statins. As perioperative

8

complications, one patient had asymptomatic embolic complication and the other had

9

hyperperfusion syndrome. The mRS at the time of discharge had deteriorated only in one

10

patient (Case 6), which had developed hyperperfusion syndrome (Table 1). In contrast, blood

11

tests showed a significant decline in LDL-C levels in all patients after PCSK9i administration

12

(Fig. 1).

13 14

Findings

15

Of the nine patients, seven had undergone diagnostic imaging after PCSK9i administration,

16

and the findings suggested stabilization of plaque. Cases 1, 4, 6, and 8 showed decreased

17

plaque/muscle (P/M) ratio on carotid MRI. The decrease in P/M ratio was 0.15 points in Case

18

1, 0.29 points in Case 4, 0.11 points in Case 6, and 0.80 points in Case 8 (Fig. 2, Table 2).

19

Furthermore, in Cases 3, 5, 6, and 8, carotid US showed that the plaque was becoming more 9

Shingai

1

hyperechoic and the fibrous cap was clearly observed, which suggested the stabilization of

2

plaques (Fig. 3).

3

In Cases 6 and 8, the P/M ratio was decreased on MRI, and the plaque was becoming

4

hyperechoic in echo images (Fig. 4).

5 6

[Discussion]

7

In this study, we found that PCSK9i administration helps stabilize carotid plaque in carotid

8

artery stenosis, and almost no embolic complications after CAS were reported.

9

Carotid artery stenosis, which is a risk factor for cerebral infarction, is found in 7% of men

10

and 5% of women in the general population over 65 years of age. This disease has a high

11

prevalence.9 In contrast, hypercholesterolemia is a risk factor for cerebral infarction,10 and

12

statin, an LDL-C-lowering drug, has been shown to have a stroke prevention effect of around

13

30% in a meta-analysis of large-scale clinical trials.11

14

In cases with carotid artery stenosis, atorvastatin is associated with a high rate of preventing

15

stroke recurrence (hazard ratio: 0.67)12 and reported to reduce the need for carotid artery

16

revascularization significantly.13 Therefore, statin has been suggested to have a particularly

17

strong stroke prevention effect in carotid artery stenosis. In the study of the coronary artery,

18

statin administration has demonstrated its multifaceted effect on plaque stabilization and

19

antithrombogenic effect,14 while pravastatin administration for carotid artery stenosis has also 10

Shingai

1

been reported to cause significant plaque stabilization.15

2

With this background, we administered the novel LDL-C-lowering drug PCSK9i to patients

3

who could not be administered with statins adequately, and we examined the stabilization of

4

plaque and incidence of cerebral infarction during the perioperative period of CAS. Images

5

revealed plaque stabilization in seven of nine cases, which suggested that PCSK9i

6

administration as a proactive intervention for hypercholesterolemia may help stabilize

7

unstable plaque in carotid artery stenosis. Based on this, even though it is a part of the

8

medical treatment for carotid artery stenosis, we expect that the combined use of PCSK9i in

9

the early phase after disease detection in patients who are unresponsive to statin or in patients

10

who suffer from strong statin side effects can prevent the progression and symptomization of

11

carotid artery stenosis. Furthermore, even for patients with intracranial stenotic lesions, when

12

we consider the fact that the medical treatment provided to those with LDL-C <70 mg/dL in

13

SAMMPRIS more effectively reduced the incidence of cerebral infarction than that in the

14

group with combined stent use,16 proactive LDL-C-lowering treatments using PCSK9i can be

15

effective for preventing cerebral infarction in patients with intracranial/extracranial stenotic

16

lesions. In the field of coronary artery diseases, a report indicated that PCSK9i administration

17

in patients with a history of acute coronary syndrome more effectively reduced the relapse of

18

a cardiovascular event compared to a placebo17; thus, going forward, we expect more results

19

showing the indication and efficacy of PCSK9i for cardiovascular and cerebrovascular 11

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diseases. In contrast, with respect to the lowering target of LDL-C level, the FOURIER study

2

in the field of cardiovascular medicine showed that the low LDL-C level (>20 mg/dL)

3

achieved using evolocumab, a PCSK9i, in combination with a statin in patients for whom

4

recurrence of recent cardiovascular events such as acute coronary syndrome can be a problem,

5

was safe compared to a placebo and efficacious for preventing a relapse, thereby showing that

6

“lower is better.”18 Furthermore, a sub-study of the FOURIER study showed no safety-related

7

problems in the super-low LDL-C group (<20 mg/dL) with levels reduced to 10 mg/dL and a

8

strong relationship between low LDL-C and a decrease in major cardiovascular risks.19 This

9

meant that there is no need to consider a lower limit for the LDL-C target value, at least in

10

terms of safety, at the present time. This also suggests that in the future, the idea that “lower

11

is better” may be also demonstrated in the field of neurology, with respect to cerebral

12

infarction associated with carotid artery stenosis and intracranial stenotic lesions.

13

With respect to perioperative complications of CAS, plaque stabilization is thought to

14

suppress plaque collapse and scattering to distant sites during the procedure and contribute to

15

reducing complications. With regard to Case 5 that developed an embolic complication after

16

surgery during this study, we believe that a surgical mistake (during the surgery, the distal

17

protecting balloon was deflated before the distal protection device sufficiently worked after

18

lesion cross) was the cause of the high-signal regions in the diffusion-weighted image after

19

surgery, which made it painfully clear once again that a reliable surgical technique is essential 12

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for preventing complications. DWI detected 21% embolic stroke after CAS procedure.20 In

2

this study, one out of nine (11.1%) was positive in DWI which is favorable result.

3

Nevertheless, this study has limitations. First, as this was a pilot study at a single institute,

4

there was no control group and the number of patients was limited. Second, we did not study

5

whether plaque stabilization was a natural occurrence. In particular, there are many unclear

6

points about whether plaque stabilization is a result of the multifaceted effect of PCSK9i or

7

because the decrease in blood LDL-C levels promotes the stabilization of carotid plaque. In

8

the future, we believe that a large-scale study on the use of PCSK9i is needed not only in the

9

field of cardiovascular medicine but also in neurology. At the same time, we would need to

10

obtain results from basic research related to the effect of PCSK9i on plaque formation.

11 12

[Conclusion]

13

The use of alirocumab, a PCSK9i, may stabilize unstable plaque and prevent perioperative

14

embolic complications of CAS in patients with carotid artery stenosis. As this study was a

15

pilot study involving only a small number of cases, a large-scale controlled study would be

16

necessary to show the efficacy of PCSK9i for carotid artery stenosis.

17 18

Acknowledgements

13

Shingai

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This research did not receive any specific grant from funding agencies in the public,

2

commercial, or not-for-profit sectors. We would like to thank Editage (www.editage.jp) for

3

English language editing.

4

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19

Table 1 Summary of all cases LDL-C (mg/dL) No.

Age (y)

Statin

Dose

Symptomatic/asympto matic

mRS score

Before administration

After 4 weeks

Admission

Discharge

Complication

Plaque stabilized findings

1

85

Rosuvastatin

2.5 mg

Symptomatic

53.0

25.2

2

2

None

MRI

2

74

Atorvastatin

20 mg

Symptomatic

116.3

56.7

0

0

None

None

3

61

Pitavastatin

2 mg

Asymptomatic

122.8

28.2

1

1

None

US

4

75

Rosuvastatin

5 mg

Asymptomatic

94.4

17.1

0

0

None

MRI

5

84

Pitavastatin

1 mg

Symptomatic

68.3

28.2

4

4

DWI spotty high

US

6

74

Rosuvastatin

2.5 mg

Asymptomatic

137.0

40.5

3

5

Hyperperfusion synd.

MRI, US

7

85

Atorvastatin

5 mg

Asymptomatic

122.6

24.0

0

0

None

MRI

8

83

Atorvastatin

10 mg

Symptomatic

148.0

30.0

1

1

None

MRI, US

9

69

Rosuvastatin

5 mg

Asymptomatic

137.1

21.9

0

0

None

None

MRI, carotid magnetic resonance imaging; mRS, modified Rankin scale; US, carotid artery ultrasonography

Table 2 Plaque/muscle ratio changes based on findings obtained with magnetic resonance imaging P/M ratio No. Pre

Post

1

1.59

1.44

4

1.19

0.90

6

1.80

1.69

8

1.90

1.10

Pre, before administration of proprotein convertase subtilisin/kexin type 9 inhibitor; Post, after administration of proprotein convertase subtilisin/kexin type 9 inhibitor

Shingai

Abbreviations CAS: carotid artery stenting CEA: carotid endarterectomy CT: computed tomography CTA: CT angiography LDL: low-density lipoprotein LDL-C: low-density lipoprotein cholesterol MRI: magnetic resonance imaging MRA: magnetic resonance angiography mRS: modified Rankin scale NASCET: North American Symptomatic Carotid Endarterectomy P/M ratio: plaque/muscle ratio PCSK9i: proprotein convertase subtilisin/kexin type 9 inhibitor US: ultrasonography

1