평가 배경 

F-18 플루트메타몰 뇌 양전자방출 단층촬영(F-18 flutemetamol (FMM) brain positron emission tomography (PET)) 검사는 인지장애(의심) 환자를 대상으로 F-18 플루트메타몰을 주입한 후 뇌 양전자방출 단층촬영 또는 양전자방출전산화단층촬영을 시행하여 베타아밀로이드 신경반 밀도를 측정하고 평가함으로써 알츠하이머 질병 및 기타 원인의 인지장애를 감별 및 판별하기 위한 검사이다. F-18 플루트메타몰 뇌 PET 검사는 2015년 신의료기술평가 원스탑 서비스로 신청되었던 건으로(2015.5.16.), 2015년 제11차 신의료기술평가위원회(2015.11.27.)에서 유사 기술인 F-18 플로르베타벤 뇌 양전자방출 단층촬영(F-18 Florbetaben Brain PET)과 식약처 허가사항이 동일하고 아밀로이드 친화성(amyloid affinity)이 수용가능한 수준으로 안전성 및 효과성이 있는 기술로 심의되어 보건복지부 고시(제2016-22호, 2016.2.4.) 후 비급여로 등재되었다(2016.11.1.). 보건의료 자원의 효율적 사용도모와 의료기술의 최적 사용을 유도하기 위해 최신 근거를 평가할 필요가 있는 안건으로 제안되었으며, 2021년 제10차 의료기술재평가위원회(2021.10.15.)에서 의료기술재평가 안건으로 선정되어 재평가를 수행하였다. 

평가 방법

F-18 플루트메타몰 뇌 PET 검사의 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가 목적을 고려하여 “F-18 플로르베타벤/F-18 플루트메타몰 뇌 양전자단층촬영 소위원회(이하 ‘소위원회’라 한다)”의 논의를 거쳐 확정하였다. 소위원회는 핵의학과 2인, 정신건강의학과 2인, 신경과 2인, 영상의학과 1인, 근거기반의학 1인 등 총 8인으로 구성하였다.

평가의 핵심질문은 “인지장애(의심) 환자에서 알츠하이머 질병 및 기타 원인의 인지장애 진단 및 예측목적의 F-18 플루트메타몰 뇌 양전자방출 단층촬영 검사가 임상적으로 안전하고 효과적인가?”이었고, 안전성은 검사 및 F-18 플로르베타벤 약물 관련 이상반응을 결과지표로, 효과성은 진단정확성, 진단변화, 예측정확성, 치료변화와 비용 등을 결과지표로 평가하였다.

체계적 문헌고찰은 핵심질문을 토대로 국외 3개, 국내 5개 데이터베이스에서 검색하여 문헌선정 및 배제기준에 따라 두 명의 검토자가 독립적으로 선별하고 선택하였다. 문헌의 비뚤림위험 평가는 Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2)를 사용하였고, 자료추출은 문헌의 연구국가, 대상자 특성, 안전성 지표, 효과성 지표 등을 사전에 정한 양식에 추출하였다. 비뚤림위험 평가와 자료추출은 두 명의 검토자가 독립적으로 수행하였으며, 의견 불일치한 경우 논의하여 합의하였다. 자료분석은 정량적 분석(quantitative analysis)이 가능한 경우 통합정확도를 제시하였고, 정량적 분석이 불가능한 경우 정성적(qualitative review) 분석과 숲 그림(forest plot)을 제시하였다. 본 평가는 소위원회의 결론을 검토하여 의료기술재평가위원회에서 최종심의 후 권고등급을 제시하였다.

평가 결과

F-18 플루트메타몰 뇌 PET 검사의 최종 선택문헌은 8편이었고, 모두 안전성과 효과성 등 임상적 결과지표를 보고하였고, 비용 결과를 보고한 문헌은 없었다. F-18 플루트메타몰 뇌 PET 검사는 대부분 문헌에서 참고표준인 임상진단과 비교해 세부 진단 감별 및 인지장애 관련 진단정확도를 확인하는 보조검사로 활용되었다. 비뚤림위험 평가결과, ‘환자 선택’과 관련된 비뚤림위험 및 적용가능성에 대한 우려가 높은 연구는 주로 환자-대조군 연구였고, 그 외 ‘중재검사’, ‘참고표준검사’, ‘연구진행과 시점’ 등은 비뚤림위험이 낮았다. 

안전성

F-18 플루트메타몰 뇌 PET 검사의 안전성 대해 보고한 문헌은 8편 중 5편이었고, 2편은 부작용 발생하지 않았고, 3편에서 플루트메타몰 약물 관련 부작용을 보고하였으나(열성홍조, 두통 1명, 혈종 발생 등), 모두 증상이 경미하고, 특별한 처치없이 해결되었다. 또한, 심각한 부작용을 보고한 문헌은 없었다.

효과성 

F-18 플루트메타몰 뇌 PET 검사의 알츠하이머병 치매(Alzheimer's dementia, AD) 관련 진단정확도는 5편에서 보고하였고, 민감도 0.68~0.97, 특이도 0.55~1.00, ROC 곡선의 아래 면적(Area under the receiver operating characteristic (ROC) curve, AUC)은 0.74~0.95이었다. 통합민감도 0.86 (95% 신뢰구간(Confidence interval, CI) 0.74~0.94), 통합특이도 0.78 (95% CI 0.57~0.91), 통합AUC 0.90 (95% CI 0.87~0.92)이었다. 알츠하이머병 치매가 아닌 기타 치매, 전두측두엽 치매 등의 진단정확도 결과(3편), 민감도 0.21~0.50, 특이도 0.55~1.00, AUC 0.35~0.74이었고, 경증인지장애(Mild cognitive impairment, MCI)의 진단정확도 결과(4편), 민감도 0.13~0.83, 특이도 0.85~1.00, AUC 0.54~0.95였고, 주관적 인지감퇴(Subjective cognitive decline, SCD)의 진단정확도 결과(2편), 민감도는 0.50~0.60, 특이도 1.00, AUC 0.93이었다.

F-18 플루트메타몰 뇌 PET 검사 후 진단변화에 대해 보고한 문헌은 4편이었고, AD 환자에서 18.1~19.5%, 전두측두엽 치매 환자에서 14.3%, 비알츠하이머병 치매 환자에서 30%, 기타 치매 환자에서 5.3~55.0%, MCI 환자에서 42.9~51.1%, SCD 환자에서 50.0~60.0%가 진단이 변경되었다. 

F-18 플루트메타몰 뇌 PET 검사의 예측정확도는 1편에서 보고하였고, 3년 치매 예측결과, 민감도 0.64, 특이도 0.69, AUC 0.67이었고, 치매발생에 대한 Cox 비례위험모형의 모든 모형에서 베타아밀로이드 양성은 통계적으로 유의하게 치매 발생 위험이 높은 것으로 나타났다(Hazard ratio (HR) 2.09~2.51).

F-18 플루트메타몰 뇌 PET 검사 후 베타아밀로이드가 양성인 경우 질병진행 가능성 등을 고려하여 치료계획에 반영하였고, 치매관련 약물복용이 34명에서 109명(75명, 218% 증가)으로 증가하거나 환자의 24%에서 약물처방을 변경하였고, 37%에서 치료계획이 변경되었다고 보고하였다.

결론 및 제언

F-18 플루트메타몰 뇌 PET 검사 소위원회는 재평가 결과에 근거하여 다음과 같이 결론을 도출하였다. 

F-18 플루트메타몰 뇌 PET 검사는 핵의학 약물 관련 홍조 등 이상반응이 발생하였으나, 증상이 경미하였고, 모두 회복되었다. 효과성 지표인 진단정확도는 알츠하이머병 치매 관련 진단정확도는 0.74~0.95, 통합AUC 0.90인데 반해 비알츠하이머병 치매진단 정확도는 0.35~0.74, 경증인지장애는 0.54~0.95, 주관적 인지감퇴는 민감도가 0.50~0.60으로 낮았다. F-18 플루트메타몰 뇌 PET 검사로 인한 진단변화는 증상이 경미한 주관적 인지감퇴(SCD) 환자에서 가장 많이 확인되었고, 알츠하이머병 치매 환자 18~19.5%에서 진단이 변경되었다. 3년 치매 예측정확도는 0.67이었고, 베타아밀로이드 양성인 경우 치매발생위험이 2배 이상 높았다. 또한, F-18 플루트메타몰 뇌 PET 검사 결과가 양성인 경우 치료계획에 반영되거나 약물 복용이 증가하였다. 

소위원회는 이를 종합하여 F-18 플루트메타몰 뇌 PET 검사는 인지장애 및 치매 진단에서 보조검사로 주로 활용되며, 비교적 안전한 검사로 평가하였다. 알츠하이머병 치매 진단시 문헌간 이질성이 일부 존재했지만, 통합민감도 0.86, 통합특이도 0.78, 통합 AUC 0.90으로 높은 진단정확도를 보이고, 치료계획 및 추적관찰 등을 고려할 때 효과적인 검사로 평가하였다. 소위원회는 알츠하이머병 외 다른 종류의 치매 및 인지장애 질환에서는 일부 연구들에서 높은 진단정확도를 보고하였으나, 결과가 일관되지 않아 개별 질환별로 결론을 내리기에는 임상근거가 부족하였다고 평가하였다.

또한, 소위원회는 F-18 플로르베타벤 뇌 PET 및 F-18 플루트메타몰 뇌 PET 검사 최적 사용을 위해서는 구체적인 적용 대상과 임상 적용 시기, 의료이용 경로, 비용-효과 등에 대한 추가연구가 필요하다고 제언하였다.

2022년 제5차 의료기술재평가위원회(2022.5.13.)에서는 소위원회 검토 결과를 논의하여 의료기술재평가사업 관리지침 제4조 제10항에 의거 “F-18 플루트메타몰 뇌 양전자방출 단층촬영”에 대해 다음과 같이 심의하였다. 

의료기술재평가위원회는 F-18 플루트메타몰 뇌 PET 검사는 안전하고 알츠하이머병 치매 및 의심 환자에서 진단 및 예측의 보조검사로 효과적이라고 심의하였고, 알츠하이머병외 치매와 인지장애에 서는 근거가 불확실하여 결론 도출에 다양한 이견이 있음을 확인하였다. 또한, 검사비용이 100만원 이상의 고가인 점과 진단의 보조적 검사로 활용되고, 오ㆍ남용의 우려 등에 대한 의견이 있었다. 이러한 의견을 바탕으로 의료기술재평가위원회는 F-18 플루트메타몰 뇌 양전자방출 단층촬영 검사는 알츠하이머병 치매와 의심환자에서 ‘조건부 권고함’으로 심의하였다. 

주요어

F-18 플루트메타몰 뇌 양전자방출 단층촬영 검사, 인지장애, 알츠하이머병 치매, 안전성, 진단정확도 

F-18 Flutemetamol (FMM) Brain positron emission tomography, Cognitive impairment, Alzheimer's dementia, Dementia, Safety, Diagnostic accuracy

Background

The “F-18 flutemetamol (FMM) Brain Positron Emission Tomography (PET)” scan is an imaging technique for differentiated detection and differential diagnosis between Alzheimer's Disease and cognitive impairment of other causes by injecting F-18 flutemetamol (FMM) and conducting brain PET or positron emission computed tomography to measure and assess the β-amyloid neuritic plaque density for patients (suspect) with cognitive impairment. F-18 FMM brain PET was a technology that applied for New Health Technology Assessment One-stop Service in 2015 (May 16, 2015). It was approved as a safe and effective technology at the 11th New Health Technology Assessment Committee (November 27, 2015) considering that the technology has Ministry of Food and Drug Safety (MFDS) labeling identical to that of F-18 florbetaben (FBB) brain PET, a similar technology, and also has acceptable level of amyloid affinity. After notification by the Ministry of Health and Welfare (Notice No. 2016-22, February 4, 2016), the technology was listed as a non-benefit item for national health insurance coverage (November 1, 2016). In order to promote efficient utilization of healthcare resources and induce optimal use of health technology, this technology was proposed as an item that required assessment of the latest evidence. This technology was selected to be subject to health technology reassessment (HTR) at the 10th Health Technology Reassessment Committee in 2021 (October 15, 2021) and HTR for the technology was performed.

Methods

A systematic review was conducted for assessment of the safety and effectiveness of F-18 flutemetamol (FMM) brain PET. All assessment methods were finalized after undergoing the review by the F-18 FBB/F-18 Flutemetamol Brain PET Sub-committee (Hereinafter Sub-committee) in consideration of the purpose of the assessment. The Sub-committee consisted of a total of eight members: two in Nuclear Medicine, two in Neuropsychiatry, two in Neurology, one in Radiology, and one in Evidence-Based Medicine.

The key question for HRT was: “Is F-18 flutemetamol (FMM) brain PET scan clinically safe and effective for diagnosis and prediction of Alzheimer’s disease and cognitive impairment of other causes in patients with cognitive impairment (suspects)?” Assessment was conducted on the safety of the technology with adverse events related to the examination and adverse reactions to F-18 flutemetamol  as outcome measures and the effectiveness of the technology was assessed with diagnostic accuracy, changes in diagnosis, prediction accuracy, changes in treatments, and cost as outcome measures.

In the process of systematic review, based on the above key question, three international and five domestic databases were used for literature search and the articles were selected through independent screening process by two reviewers according to the inclusion/exclusion criteria for the related literature. A tool of Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used for risk of bias assessment of the articles. For data extraction, information on countries where the research was carried out, patient characteristics, outcome measures for safety and effectiveness, etc. were extracted using a predefined format. 

Risk of bias assessment and data extraction were conducted independently by two reviewers, and in case of disagreement, the two reviewers held discussions to draw consensus on the matter. For data analysis, pooled accuracy was presented when quantitative analysis was possible, and qualitative review and forest plots were presented otherwise. In this assessment, the conclusion drawn by the Sub-committee was reviewed, upon final review at the Health Technology Reassessment Committee, the grade of recommendation was presented.

Results

There were eight articles on F-18 FMM brain PET scan finally selected through the above process, and all of the articles reported clinical outcome measures such as safety and effectiveness, and there was no article that reported outcome measures related to cost-effectiveness. In most of the literature, F-18 FMM brain PET was used as an adjunct technique for confirming diagnostic accuracy related cognitive impairment and for detailed differential diagnosis in comparison with clinical diagnosis, the reference standard. As a result of risk of bias assessment, studies with high risk of bias related to patient selection were mainly case-control studies, and index test, reference standard, study progress and timepoint showed a low risk of bias.

Safety

Out of eight articles, five publications reported on the safety of F-18 FMM brain PET scan; two articles reported that no adverse events occurred and three articles reported occurrence of adverse drug reactions related to FMM (hot flush, one case of headache, hematoma, etc.) but all of the symptoms were mild and they were resolved without particular treatment. Also, no serious events were reported in all of the articles. 

Effectiveness

The diagnostic accuracy of F-18 FMM brain PET scan related to Alzheimer's dementia (AD) was reported in five articles, with sensitivity in the range of 0.68 - 0.97, specificity of 0.55 to 1.00, and area under the receiver operating characteristic (ROC) curve (AUC) was 0.74 to 0.95. The pooled sensitivity was 0.86 (95% Confidence Interval (CI) in the range of 0.74 to 0.94), pooled specificity was 0.78 (95% CI of 0.57 - 0.91), and pooled AUC was 0.90 (95% CI of 0.87 - 0.92). The diagnostic accuracy of dementia other than AD such as frontotemporal dementia was reported in three articles, with sensitivity 0.21 to 0.50, specificity 0.55 to 1.00, and AUC 0.35 to 0.74. Four articles reported on diagnostic accuracy of mild cognitive impairment (MCI), with sensitivity in the range of 0.13 to 0.83, specificity of 0.85 - 1.00, and AUC of 0.54 to 0.95. Two articles reported on diagnostic accuracy of subjective cognitive decline (SCD), with sensitivity of 0.50-0.60, specificity at 1.00, and AUC at 0.93.

There were four articles that reported changes in diagnosis after the F-18 FMM brain PET imaging, and the diagnosis was changed in 18.1-19.5% of patients with AD, 14.3% of patients with frontotemporal dementia, 30% for non-AD patients, 5.3-55.0% for patients with other types of dementia, 42.9-51.5% for patients with MCI, and 50.0-60.0% for patients with SCD.

The prediction accuracy of the examination using F-18 FMM brain PET was reported in one article. The prediction accuracy of 3-year dementia incidence showed sensitivity of 0.64, specificity of 0.69, and AUC of 0.67. In all models of the Cox proportional hazards model for dementia incidence, β-amyloid positivity was found to be closely associated with high risk of dementia with statistical significance (Hazard ratio (HR) 2.09~ 2.51). 

After the examination using F-18 FMM brain PET, if the result showed β-amyloid positive, this was reflected in the treatment plan by considering the likelihood of disease progression. With regard to changes in treatments, prescription of medication in relation to dementia increased from 34 patients to 109 patients (increase by 75 patients, equivalent to 218% increase in percentage) or the prescription changed in 24% of the patients, and 37% of the patients reported that they had changes in their treatment plans. 

Conclusion and Suggestions

The F-18 FMM Brain PET Sub-committee derived the following conclusions based on the results of reassessment of the technology.

The use of F-18 FMM brain PET involved occurrence of adverse reactions such as hot flush related to the radiopharmaceuticals used, but the symptoms of the adverse reactions were mild and these were all resolved over time. As for the diagnostic accuracy, one of the outcome measures for effectiveness, the diagnostic accuracy related to AD was in the range of 0.74 to 0.95 with pooled AUC 0.90. On the other hand, the diagnostic accuracy related to dementia not caused by Alzheimer’s disease was in the range of 0.35 to 0.74, and that for MCI was 0.54 to 0.95, and the sensitivity for SCD was low in the range of 0.50-0.60. The changes in diagnosis due to F-18 FMM brain PET were mostly observed in patients with mild symptoms of SCD and 18-19.5% of the patients with AD underwent changes in their diagnosis. The prediction accuracy of 3-year dementia incidence was 0.67, and for those who were β-amyloid positive, the risk of dementia occurrence was more than doubled. In addition, when the result of F-18 FMM brain PET imaging was positive, it was incorporated into the treatment plan or the prescription of administered medication increased.

In comprehensive consideration of the above results, the assessment by the Sub-committee concluded that F-18 FMM brain PET scan is mainly used as an adjunct technique for diagnosis of cognitive impairment and dementia, and that the technology is relatively safe to use. In diagnosis of AD, although there were some discrepancies depending on the literature of previous studies, high diagnostic accuracy was reported with pooled sensitivity 0.86, pooled specificity 0.78, and pooled AUC 0.90; thus the technology was assessed as an effective technique when considering treatment plans and follow-up monitoring/observations for patients. Also, the Sub-committee determined that although some of the existing works reported high diagnostic accuracy for types of dementia other than AD and cognitive impatient, the results were not consistent across these previous studies; thus, it was determined that the technology requires further clinical evidence to draw conclusions for each type of dementia/cognitive impairment.

In addition, the Sub-committee suggested that for optimal application of F-18 FBB brain PET and F-18 flutemetamol brain PET, further studies are needed on specific patient groups for application of the technology, timing of clinical application, route of using medical services, cost-benefit analysis, etc.

Based on the results of the review by the Sub-committee at the 5th Health Technology Reassessment Committee (May 13, 2022) in 2022, the following is the result of the review for “F-18 flutemetamol brain PET” in accordance with Article 4, Paragraph 10 of the Management Guidelines for Health Technology Reassessment Project.

The review by the Health Technology Reassessment Committee determined that F-18 FMM brain PET is a safe technology and is effective as an adjunct technique for diagnosis and prediction for patients with AD and adults with suspected AD. However, for types of dementia other than AD and cognitive impairment, the evidence for the technology was uncertain, leading to different opinions in deriving a conclusion for these cases. 

In addition, there were opinions that expressed concerns about the high cost of examination in its use as an adjunct method for diagnosis, which is more than one million KRW, and also concerns about likelihood of misuse/overuse of the technology. Based on these opinions, the review by the Health Technology Reassessment Committee determined the grade of recommendation for F-18 FMM brain PET as “conditional recommendation” for patients with AD and adults with suspected AD.

Keywords

F-18 Flutemetamol (FMM) Brain positron emission tomography, Cognitive impairment, Alzheimer's dementia, Dementia, Safety, Diagnostic accuracy

요약문 (국문) ⅰ

알기 쉬운 의료기술재평가 Ⅰ

Ⅰ. 서론 1

 1. 평가배경 1

  1.1 평가대상 의료기술 개요 1

  1.2 질병 특성 및 현존하는 의료기술 7

  1.3 가이드라인 및 선행 연구 13

 2. 평가목적 15

Ⅱ. 평가 방법 16

 1. 체계적 문헌고찰 16

  1.1 개요 16

  1.2 핵심질문 16

  1.3 문헌검색 17

  1.4 문헌선정 18

  1.5 비뚤림위험 평가 18

  1.6 자료추출 19

  1.7 자료분석 19

 2. 권고등급 결정 19

Ⅲ. 평가결과 20

 1. 문헌선정 결과 20

  1.1 문헌선정 개요 20

  1.2 선택문헌 특성 21

  1.3 비뚤림위험 평가결과 24

 2. 분석결과 25

  2.1 안전성 25

  2.2 효과성 26

Ⅳ. 결과요약 및 결론 34

 1. 평가결과 요약 34

  1.1 안전성 34

  1.2 효과성 34

 2. 결론 및 제언 35

Ⅴ. 참고문헌 36

Ⅵ. 부록 38

 1. 의료기술재평가위원회 38

 2. 소위원회 39

 3. 문헌검색전략 40

 4. 비뚤림위험 평가 및 자료추출 양식 43

 5. 최종선택문헌 46