항헤파린-PF4항체[화학발광면역분석법]

Abstract

평가 배경 항헤파린-PF4 항체[화학발광면역분석법]은 헤파린 유도성 혈소판 감소증(Heparin-Induced Thrombocytopenia, 이하 HIT)이 의심되는 환자를 대상으로 화학발광면역검사법을 이용하여 헤파린-PF4 결합체에 대한 항체 유무를 확인하여 헤파린 유도성 혈소판 감소증을 진단하는 검사법이다. 동 기술은 2013년 신의료기술평가결과 신의료기술(제2013-101호)로 평가되었으며, 이후 2015년 3월 개최된 의료행위전문평가위원회 결정에 따라 ‘항헤파린/PF4항체 [화학발광면역분석법]’으로 당해 7월 비급여 목록에 등재(제2015-129호)되었다. 동 기술은 보장성 강화를 위한 검토가 필요하여 2020년 제3차 의료기술재평가위원회(2020.03.20.)에서 재평가 안건으로 선정됨에 따라 신의료기술평가 근거 업데이트를 수행하였다. 이후 제10차 의료기술재평가위원회(2020.10.16.)에서 항헤파린-PF4 항체[화학발광면역분석법]의 안전성 및 유효성 평가 결과를 최종 심의하였다.

평가 방법 항헤파린-PF4 항체[화학발광면역분석법]에 대한 안전성 및 유효성 평가는 체계적 문헌고찰을 통해 수행하였다. 모든 평가방법은 연구목적을 고려하여 “항헤파린-PF4 항체[화학발광면역분석법]평가 소위원회(이하 ‘소위원회’라 한다)”의 심의를 거쳐 확정하였다. 평가의 핵심질문은 1) HIT 의심환자의 진단에 있어 화학발광면역분석법을 활용한 항헤파린-PF4 항체검사의 유효성은 어떠한가? 2) 화학발광면역분석법을 활용한 항헤파린-PF4 항체검사의 비용 또는 비용효과성은 어떠한가? 이었다. 안전성은 본 검사법이 혈액에서 채취하여 체외에서 이루어지는 검사이므로 인체에 직접적 위해를 가가지 않는 것으로 평가하였다. 유효성은 진단정확성(민감도/특이도, 양성/음성예측도, 양성/음성우도비) 및 경제성관련 결과변수로 평가하였다. 문헌검색은 국외 3개, 국내 5개 데이터베이스에서 검색하였으며, 문헌선정 및 배제기준에 따라 두 명의 검토자가 독립적으로 선별하고 선택하였다. 문헌의 비뚤림위험 평가는 QUADAS-2를 사용하여 두 명의 검토자가 독립적으로 수행하여 의견합의를 이루었다. 자료추출은 미리 정해놓은 자료추출 양식을 활용하여 두 명의 검토자가 독립적으로 수행하였으며, 의견 불일치가 있을 경우 제3자와 함께 논의하여 합의하였다. 자료분석은 사전에 정의된 진단정확성 관련 결과변수에 대해 메타분석을 활용하여 결과합성을 수행하였으며, 참조검사 및 4T score 수행여부에 따른 하위군 분석을 통해 민감도분석을 시행하였다.

평가 결과 항헤파린-PF4 항체[화학발광면역분석법] 평가에 선택된 문헌은 총 10편으로 모두 국외문헌이었다. 연구에 포함된 문헌 중 2편은 과거 신의료기술평가보고서에 포함된 문헌으로, 본 평가에도 반영하였다. 문헌의 비뚤림위험 수준은 낮은 것으로 분석되었다.

안전성 동 검사의 안전성은 환자의 채혈과정 외에는 환자에게 직접적인 위해를 가하지 않아 검사 수행에 따른 안전성에는 문제가 없는 것으로 평가하였다.

유효성 유효성은 총 10편의 진단법 평가연구를 근거로 진단정확성을 평가하였다. 세로토닌분비능검사, 혈소판 응집검사, 유세포분석법을 참고표준검사로 하여 분석한 결과, HIT-IgG의 민감도 범위는 0.667에서 1.000, 특이도의 범위는 0.734에서 0.970으로 보고되었으며, HIT-IgGAM의 민감도는 0.667에서 1.000, 특이도는 0.730에서 0.970으로 보고되었다. HIT-IgG 검사의 통합민감도는 0.95(95%CI 0.90, 0.98)이었으며, 통합특이도는 0.94(95%CI 0.92, 0.96)으로 분석되었으며, HIT-IgGAM 검사의 통합민감도는 0.96(95%CI 0.90, 0.99), 통합특이도는 0.82(95%CI 0.80, 0.85)로 분석되어 민감도와 특이도가 높은 검사법으로 확인된다. 비용관련 분석의 경우 2편에서 보고되어 문헌적 근거는 충분하지 않았으나, 동 검사 활용 시 헤파린 유도 혈소판 활성화 검사(Heparin-Induced Platelet Activation test, HIPA) 대비 연간 50건의 검사 건수를 줄여 검사 및 대체 항응고제의 비용을 절감할 것으로 보고하였다.

결론 및 제언 항헤파린-PF4 항체[화학발광면역분석법] 소위원회에서는 이러한 문헌적 근거를 토대로 다음과 같이 평가하였다. 항헤파린-PF4 항체[화학발광면역분석법] 검사는 헤파린 유도성 혈소판 감소증이 의심되는 환자를 대상으로 헤파린-PF4 결합체에 대한 항체 유무를 확인하여 헤파린 유도성 혈소판 감소증을 신속히 진단할 수 있는 검사로 안전성, 유효성, 경제성에 대한 근거가 있는 검사법으로 평가하였다. 이에 의료기술재평가위원회는 항헤파린-PF4 항체[화학발광면역분석법] 검사를 권고함(권고등급 Ⅰ-a)으로 심의하였다(2020.10.16.).

주요어 헤파린 유도성 혈소판 감소증, 항헤파린-PF4 항체, 화학발광면역분석법, 면역검사.

Background of Assessment The anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay] is a method for diagnosing heparin-induced thrombocytopenia by checking the presence of antibodies to the heparin-PF4 conjugate using a chemiluminescence immunoassay in patients with suspected heparin-induced thrombocytopenia (hereinafter HIT). This technology was evaluated as a new health technology (No. 2013-101) as a result of the 2013 New health Technology Assessment, and 'Anti-heparin/PF4 Antibody [chemiluminescence Immunoassay]' was subsequently registered as a non-benefit item in July (No. 2015-129) according to the decision of the Medical Practice Assessment Committee held in March 2015. The new health technology assessment basis was updated as this technology was selected as a re-assessment agenda at the 3rd Health Technology Reassessment Committee (2020.03.20.) in 2020 as it needed to be reviewed to strengthen coverage. Afterward, the safety and effectiveness assessment results of the anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay] were finally deliberated at the 10th Health Technology Reassessment Committee (2020.10.16.).

Assessment Method The safety and effectiveness assessment of anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay] was conducted through a systematic literature review. All assessment methods were determined after deliberation by the “anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay] assessment subcommittee (hereinafter referred to as the ‘subcommittee’)” in consideration of the research purpose. The key questions in the assessment are 1) How effective is the anti-heparin platelet factor 4 antibody test using chemiluminescence immunoassay in the diagnosis of HIT-suspected patients? 2) What is the cost or cost-effectiveness of anti-heparin platelet factor 4 antibody test using chemiluminescence immunoassay? For safety, it was evaluated that this test method does not directly harm the human body because it is an in vitro test that is collected from blood. Effectiveness was evaluated with diagnostic accuracy (sensitivity/specificity, positive/negative predictive value, positive/negative likelihood ratio) and economic-related outcome variables. A literature search was conducted in 3 overseas databases and 5 domestic databases, and two reviewers independently screened and selected them according to the literature inclusion and exclusion criteria. Evaluation of the risk of bias in the literature was performed independently by two reviewers using QUADAS-2 and consensus was reached. Data extraction was performed independently by two reviewers using a pre-determined data extraction format, and in case of disagreement, it was agreed upon by discussion with a third party. For data analysis, the results were synthesized using meta-analysis on the pre-defined outcome variables related to diagnostic accuracy. Sensitivity analysis was performed through subgroup analysis according to whether the reference test and 4T score were performed.

Assessment Results A total of 10 pieces of literature were selected for the assessment of anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay], all of which were foreign documents. Two of the articles included in the study were documents included in the past new health technology assessment reports and were also reflected in this assessment. The level of risk of bias in the literature was analyzed to be low.

Safety As for the safety of this test, it was evaluated that there was no problem with the safety of the test because it did not directly harm the patient except for the blood sampling process.

Effectiveness Effectiveness was evaluated based on a total of ten diagnostic method evaluation studies. As a result of analysis using serotonin secretion test, platelet aggregation test, and flow cytometry as reference standard tests, the sensitivity range of HIT-IgG was reported to be 0.667 to 1.000, the specificity range was 0.734 to 0.970, the sensitivity of HIT-IgGAM was 0.667 to 1.000, and the specificity was reported from 0.730 to 0.970. The combined sensitivity of the HIT-IgG test was 0.95 (95% CI 0.90, 0.98), the combined specificity was analyzed as 0.94 (95% CI 0.92, 0.96). The combined sensitivity of the HIT-IgGAM test was 0.96 (95% CI 0.90, 0.99), and the combined specificity was analyzed as 0.82 (95% CI 0.80, 0.85), confirming that the test method has high sensitivity and specificity. In the case of cost-related analysis, the literature evidence was not sufficient, as reported in only two documents. However, it was reported that the use of this test would reduce the cost of testing and alternative anticoagulants by reducing the number of tests per year by 50 cases compared to the heparin-induced platelet activation test (HIPA).

Conclusion and Suggestions The anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay] subcommittee evaluated the following based on the literature evidence. The anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay] is a test that can quickly diagnose heparin-induced thrombocytopenia by checking the presence of antibodies to the heparin-PF4 conjugate in patients with suspected heparin-induced thrombocytopenia. It was evaluated as a test method with evidence for safety, effectiveness, and economic feasibility. Therefore, the Health Technology Reassessment Committee recommended an anti-heparin platelet factor 4 antibody [chemiluminescence immunoassay] test (recommendation grade I-a). (2020.10.16.)

Keywords: Heparin-Induced Thrombocytopenia, Anti-Heparin Platelet Factor 4 Antibody, Chemiluminescence Immunoassay