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1
Kanazawa University Health Service Center, Kanazawa, Japan
2
Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
3
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
4
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
5
Department of Neurology, Tokyo Women’s Medical University, Tokyo, Japan
6
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
7
Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan
8
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
9
Department of Community Medicine & Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine,
Osaka, Japan
10
Rinku General Medical Center, Osaka, Japan
Address for correspondence: Atsushi Nohara, Department of Lipidology, Kanazawa University Graduate School of Medical Science, Takara-machi 13-1,
Kanazawa 920-8641, Japan E-mail: a-nohara@med.kanazawa-u.ac.jp
Received: April 22, 2018 Accepted for publication: April 30, 2018
Copyright©2018 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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Nohara et al .
public insurance coverage for PCSK9 inhibitors also for secondary prevention of coronary artery disease in
includes primary prevention in non-familial hypercho- the JAS Guidelines for Prevention of Atherosclerotic
lesterolemia (FH) patients; however, the use of these Cardiovascular Diseases 2017 1). However, it is a remain-
drugs should focus on FH patients, in whom the risk ing issue to be addressed in the future whether PCSK9
of coronary artery disease is particularly high, and pa- inhibitors should also be recommended for patients with
tients with high-risk underlying conditions for second- symptomatic cerebrovascular disorder (athero-throm-
ary prevention of coronary artery disease. botic cerebral infarction) and peripheral arterial dis-
In the current Committee Report, we have pre- ease.
pared drug therapy flowcharts to help identify target
patients for PCSK9 inhibitors and clarify their appro- 2) Use for Patients with Statin Intolerance
priate use in clinical practice. Health insurance coverage for PCSK9 inhibitors
should be extended to high-risk statin intolerant pa-
1) Familial Hypercholesterolemia (FH) Heterozy- tients, and clinical trials to verify whether they can be
gotes used safely in such patients are underway. Also, it is
For the secondary prevention of coronary artery expected that appropriate diagnostic criteria for statin
disease in FH, great efforts should be made to achieve intolerance will soon be drawn up.
an LDL-C level of less than 70 mg/dL. If management
is insufficient with the maximum tolerated statin dose 3) LDL-C Level Thresholds for Consideration of
plus ezetimibe, combination with PCSK9 inhibitors PCSK9 Inhibitors
should be actively considered. Also, it is advisable to In the JAS Guidelines for Prevention of Athero-
judge the LDL-C lowering effect 1-2 months after a sclerotic Cardiovascular Diseases 2017 1), the achieve-
prescription change and to consult a specialist when ment of target LDL-C management levels is not con-
initiating PCSK9 inhibitors. (Fig. 1-A) sidered to be absolutely essential; for example, in pri-
mary prevention of FH heterozygotes, a management
2) Secondary Prevention of Coronary Artery Dis- target level of less than 50% of the pre-treatment level
ease (non-FH) is also permissible depending on individual patient
For the secondary prevention of coronary artery risk. While the LDL-C threshold values for the use of
disease in non-FH patients, patients with acute coro- PCSK9 inhibitors have been proposed in guidance in
nary syndrome and/or diabetes+other high-risk under- Europe 4), they are not stated in JAS Guidelines for
lying condition should be considered to achieve an Prevention of Atherosclerotic Diseases 2017 1). There-
LDL-C level of less than 70 mg/dL 1). If the target fore, setting thresholds for the use of PCSK9 inhibi-
LDL-C management level is not achieved with ezeti- tors will be a task for the future.
mibe combined with statin at the maximum tolerated
dose, the patient may be a FH. Therefore, clinicians 4) Dosing Interval for PCSK9 Inhibitors
should not only consider the use of PCSK9 inhibitors From the viewpoints of medical and medical eco-
but also suspect FH. In addition, it is essential to ade- nomics, it is important to achieve satisfactory cost
quately control traditional cardiovascular risk factors effectiveness with regard to changes in LDL-C levels
such as hypertension, diabetes and smoking, and it is and the medical fees paid by patients and insurers.
advisable to discuss their initiation with a specialist. Therefore, individual adjustment of dosing intervals
(Fig. 1-B) could be studied.
748
Statement for Appropriate Clinical Use of PCSK9 Inhibitors
Figure 1-A
Diagnosis of heterozygous FH
Insufficient effect
* In case of patients with statin intolerance, consider
prescription of another statin or changing dosing
Statin maximum tolerated dose* and or combination with ezetimibe
interval and increase dose as much as possible.
Insufficient effect
** It is advisable to consult a specialist when initiating
Add PCSK9 inhibitor** and/or resin and/or probucol PCSK9 inhibitor.
Insufficient effect
*** As PCSK9 inhibitor will be removed by LDL
apheresis, injection should be administered after
LDL apheresis*** apheresis. LDL apheresis is applicable to FH
heterozygotes for secondary prevention.
Modified from Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017 (in Japanese).
Figure 1-B
YES
FH diagnosis criteria met? To A. FH Flowchart
NO
Secondary prevention of
coronary artery disease in non-FH a. High-risk conditions other than diabetes:
• Non-cardiogenic ischemic stroke
• Peripheral arterial disease
Acute coronary syndrome and/or
diabetes + other high-risk conditiona • Chronic kidney disease
• Metabolic syndrome
NO YES • Multiple major risk factors
• Smoking
LDL-C management target <100 mg/dL LDL- C management target <70 mg/dL
treatment not dependent on LDL receptor function 6) Conditions with Little Evidence for PCSK9 Inhib-
such as MTP inhibitors 6) (after obtaining authoriza- itor Efficacy and Concerns for Long-term Use
tion for treatment of designated intractable disease) and As PCSK9 inhibitors are new agents, there is lit-
LDL apheresis. tle evidence of efficacy for some conditions (heart fail-
ure, renal failure, etc.). Additionally, there are several
749
Nohara et al .
concerns (diabetes, cognitive function, cerebral hem- Co., Ltd., Bayer Yakuhin, Ltd, Nippon Boehringer Ingel-
orrhage, etc.) for the long-term use of PCSK9 inhibi- heim Co., Ltd., Eisai Co., Ltd.. Kayoko Sato; Takeda
tors at present. Therefore, doctors and facilities using Pharmaceutical Company Limited., Astellas Pharma
these drugs should make efforts to obtain the latest Inc.. Atsushi Nohara; Aegerion Pharmaceuticals, Inc..
information. Shizuya Yamashita; Astellas Pharma Inc., Bayer Yakuhin,
Ltd. Kazuhisa Tsukamoto; Mitsubishi Tanabe Pharma
Corporation Affiliation with Endowed Department:
Conclusion Shizuya Yamashita; Izumisano City.
PCSK9 inhibitors should be used for secondary
prevention in patients with coronary artery disease when This is an English version of the Statement for
LDL-C management targets are not achieved with treat- Appropriate Clinical Use of PCSK9 Inhibitors in Japan
ment combining ezetimibe and statins at the maximum published in Japanese in March, 2018. (http://www.
tolerated dose, who include many FH heterozygotes. j-athero.org/topics/pdf/seimei_20180302.pdf )
We have described the types of patients who would
receive great benefit from PCSK9 inhibitors from the
viewpoints of medical and medical economics at the References
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