원저 ISSN 2093-9272 일산병원학술지 2017;16(2):67-72 국민건강보험공단노인코호트자료를이용한알츠하이머병에서뇌졸중발생위험률에대한연구 국민건강보험일산병원신경과 1, 연구분석팀 2 이지은 1, 김동욱 2, 이준홍 1 Association between Alzheimer Disease and Risk of Stroke: A 12-year Nationwide Cohort Study Ji Eun Lee 1, Dong Wook Kim 2, Jun Hong Lee 1 Department of 1 Neurology and 2 Research & Analysis Team, National Health Insurance Service Ilsan Hospital, Goyang, Korea Background: To investigate the risk of stroke in patients within 3 years of newly diagnosed Alzheimer`s disease (AD) compared non-ad patients among elderly populations aged 60 and above in South Korea between 2003 and 2013. Methods: This retrospective, nationwide, longitudinal population-based study used National Health Insurance Service-National Elderly cohort (NHIS-elderly) Database to define patients with AD from 2003 to 2013 based on having KCD (Korean Classification of Diseases) code G30 and F00. We performed a 1:5 case-control matched analysis using propensity score matching, which were based on age, sex and household income. We conducted Cox proportional hazards regression analysis to estimate the risk of ischemic and hemorrhagic stroke in AD. Results: AD patients have a greater risk of developing stroke than those without AD. In the cohort study, the adjusted hazard ratios (HRs) for total stroke, ischemic stroke and hemorrhagic stroke were 2.87 (95% CI, 2.707-3.042), 2.546 (95% CI, 2.393-2.709) and 1.998 (95% CI, 1.624-2.458), respectively. Conclusion: Our data show that AD is significantly increased risk of stroke development. Key Words: Alzheimer disease, Population study, Stroke 서론 노인인구가증가하면서동반되는노인성질환이증가하는데, 대표적인질환이치매와뇌졸중이다. 특히이중알츠하이머병은가장흔한신경퇴행성질환으로 65세이상에선 13% 이상, 85세이상의노인에서는 35-50% 정도의유병률을보이고있으며, 1-3 신경세포의조기퇴행성소실로발생하는질환이다. 뇌졸중역시나이가증가함에따라발생률이증가하는질환으로 2012년뇌졸중사망률은 100,000명당 51,1명으로높은사망률을보이고있으며, 4 치매와더불어고령인구의삶의질 책임저자 : 이준홍 10444 경기도고양시일산동구일산로 100 국민건강보험일산병원신경과전화 : (031)900-0225, 팩스 : (031)900-0343 E-mail : jhlee@nhimc.or.kr 을결정하는데영향을많이주어전세계적인주요건강문제가되고있다. 뇌졸중발생과고혈압, 이상지질혈증, 비만, 당뇨와흡연과같은인자들은확실한인과관계를갖는것으로알려져있으며, 최근에치매와뇌경색의발생관계에대한여러연구들이진행되었다. 이중알츠하이머병은뇌경색발생률에는별영향이없으나, 뇌출혈의발생위험도만약 1.3-1.4배정도증가시켰다는연구결과도있고, 5,6 최근몇몇연구에서는알츠하이머병환자에서뇌경색의발생률의위험도가증가하는다음과같은연구결과들을보였다. 이탈리아의한인구기반연구에서는중등도중증치매환자에서각각 1.2와 2.2배정도뇌졸중의위험도를높였으며, 7 잠재적교란요인을제거한스웨덴연구에서는약 2.6배뇌졸중의위험도를높였다. 8 가장최근에진행한타이완의 5년간의추적인구기반연구에의하면약 2배의뇌졸중위험도를높인결과를보였다. 9 본연구에서는국내최초로국민건강보험공단노인코호트 Volume 16 Number 2 December 2017 67
JE Lee, et al. Association between Alzheimer Disease and Risk of Stroke 자료를활용하여 12년간의추적관찰을통하여알츠하이머병과뇌졸중발생위험과의관련성을알아보고자하였다. 대상및방법 1. 연구데이터베이스 2013년기준으로우리나라국민 51,448,491명중 97.1% 가건강보험제도에가입되어있는것으로알려져있으며, 이중 2002년자격유지자중만 60세이상대상자약 619만명중 60세이상의국민건강보험자료의대표성을만족하는 558,147명을표본으로추출한노인코호트자료를이용하였다. 노인코호트의연령별분포는 60-69세는 343,477명 (61.5 %), 70-79 세는 158,874명 (28.5%), 80세이상에서는 55,796 명 (10.0%) 으로되어있다. 본연구는이중 2002년에서 2013년까지 12년간국민건강보험노인코호트자료 (NHIS-2017-2-551) 를이용하여이루어졌으며, 이기간동안국내에서시행된비급여진료를제외한모든청구자료를참고하였다. 본연구는국민건강보험일산병원기관생명윤리위원회로부터승인된자료이며, 연구의진행은심의를받은이후이루어졌다. 2. 대상노인코호트자료의진단명은국제질병분류 (International Classification of Diseases, 10 th Revision, ICD-10) 를수정한한국표준질병사인분류 (Korean Standard Classification of Diseases, 6 th Revision, KCD-6) 에기초하고있다. 주상병및부상병에알츠하이머병관련코드인 (KCD-6 codes: G30, F00) 으로청구코드에포함되어있으면서, 1년에 1회이상알츠하이머병치료제 (donepezil, rivastigmine, memantine, galantamine) 를처방받은환자중혈관성치매관련코드 (F01) 이포함된경우에는제외하여연구대상자로선정하였다. 이중연구기간동안처음진단된환자들만을대상으로하기위해 2002년 1년사이에발생한알츠하이머병으로외래진료를시행받았거나입원했던환자들은제외하고, 2003년 1월부터 2005년 12월까지 3년간알츠하이머병이발생한사람을환자군으로정의하였다. 비교분석을위해성별, 연령, 가계소득을고려하여대조군을선정하였으며, 환자군과비슷한성향을가진환자들로성향점수매칭 (Propensity Score Matching) 방법을통해 1:5로추출하였다. 또한정확성을높이기위해서추적관찰기간동안대조군에서알츠하이머병이발생한사람들은연구대상자에서제외하였으며, 본연구는알츠하이머병환자에서뇌졸중발생을확인하기위한것으로알츠하이머병이전에뇌졸중이먼저발생한환자들도제외하였다. 뇌졸중발생은뇌졸중 (I60-I64), 허혈성뇌졸중 (I63), 출혈성뇌졸중 (I60-I62) 의세그룹으로구분하여분석하였다. 이러한정의를바탕으로최종연구대상자로선택된사람은알츠하이머병환자군 3,524명, 대조군 19,013명이었다 (Fig. 1). 3. 방법모든자료는 SAS System, version 9.4 (SAS Inc, Cary, NC, USA) 를이용하여분석하였다. 환자군과대조군의차이를보기위해 chi-square 분석을이용하였고, 카플란마이어방법 (Kaplan-Meier method) 으로뇌졸중위험을예측하였다. 여러질환에같이이완되어있거나, 사회인구학적특성을보정한 Cox 비례위험모형 (Cox proportional hazards model) 을이용 Fig. 1. Definition of study cohorts. Among NHIS-Elderly 2002-2013 data, the patients diagnosed as AD in 2002 for a year were excluded (washout period). The patients diagnosed as AD (n=3,524) from January 2003 to December 2005 for 3 years (index period) and the comparison group (n=19,013) extracted using propensity scorematching were enrolled. During an 11-year follow-up period the risk of strokes between two groups were analyzed. NHIS-Elderly: National Health Insurance Service-Elderly cohort, AD: Alzheimer's disease. 68 Korean Journal of National Health Insurance Service Ilsan Hospital
이지은외. 국민건강보험공단노인코호트자료를이용한알츠하이머병에서뇌졸중발생위험률에대한연구 하여위험비 (Hazard ratio, HR) 을구하였고, 신뢰구간 (confidence intervals, CIs) 은 95% 로하였으며, 통계학적유의성확인은 0.05로하였다. 결과 1. 알츠하이머병환자군과대조군의임상적특징 노인코호트자료에포함된 558,147 명에서 2003 년 1 월부 터 2005년 12월까지알츠하이머병으로진단되어진료를받은환자는 3,524명이었고, 약 45.4%(1,598명 ) 에서 2013년 12월까지 11년간의추적관찰기간중뇌졸중이발생하였으며, 대조군은같은기간 19,013명중 25.6%(4,874명 ) 가뇌졸중으로진단받아알츠하이머병군에서뇌졸중에이환되는비율이더높았다 (Table 1). 알츠하이머병치매환자에서발생한뇌졸중환자중 92.2% 인 1,474명은허혈성뇌졸중, 7.8% 인 124명은출혈성뇌졸중에이환되었다. 암발생은대조군 Table 1. Baseline Demographic characteristics and comorbidities of patients with AD and comparison groups Variables Stroke No event Event Sex Male Female Age (y) <70 70-75 75-70 80-84 85 Household income relative to the medication <20% 20-40% 40-60% 60-80% >80% Comorbidity Cancer Diabetes Mellitus Hypertension Chronic kidney disease COPD Dyslipidemia Smoking Never Ever or current Alcohol consumption Non-drinkers 2/week 3/week Physical activity Never 1-2/week 3-4/week 5/week AD group No. (%) Comparison group No. (%) (n=3,524) (n=19,013) 1,926 (54.7) 1,598 (45.4) 1,124 (31.9) 2,400 (68.1) 949 (26.9) 763 (21.7) 816 (23.2) 651 (18.5) 345 (9.8) 497 (14.1) 382 (10.8) 433 (12.3) 720 (20.4) 1,492 (42.3) 393 (11.2) 1,462 (41.5) 2,369 (67.2) 93(2.6) 0(0) 1,227 (34.8) 294 (79.5) 76 (20.5) 301 (79.8) 50 (13.3) 26(6.9) 261 (70.4) 54 (14.6) 12(3.2) 44 (11.9) AD: Alzheimer's disease, COPD: Chronic obstructive pulmonary disease 14,913 (74.4) 4,874 (25.6) 6,910 (36.3) 12,103 (63.7) 5,655 (29.7) 4,233 (22.3) 4,175 (22.0) 3,132 (16.5) 1,818 (9.6) 3,619 (19.0) 2,439 (12.8) 2,643 (14.0) 3,943 (20.7) 6,369 (33.5) 3,422 (18.0) 5,636 (29.6) 10,261 (54.0) 239 (1.3) 0(0) 4,183 (22) 1,808 (77.1) 538 (22.9) 1,737 (72.7) 395 (16.5) 256 (10.7) 1,691 (71.3) 281 (11.9) 124 (5.2) 276 (11.6) p-value 0.0014-0.3066 0.0107 0.2077 Volume 16 Number 2 December 2017 69
JE Lee, et al. Association between Alzheimer Disease and Risk of Stroke 에서알츠하이머병환자에비해유의하게많이발생하였으나, 이이외에당뇨, 고혈압, 만성신장질환, 만성폐쇄성호흡기질환, 이상지질혈증을가진환자는알츠하이머병환자에서모두대조군에비해유의하게많았다. 성별로보면뇌졸중은여자가 68.1%(2,400명 ) 으로남자 31.9%(1,124명 ) 에비해유의하게더많이진단되었고, 가계소득에따라구분해보았을때, 상위 80% 이상의환자가 42.34% 로가장많았다. CI, 2.090-3.552) 배높고, 여성의경우에는 2.710 (95%CI, 2.522-2.912) 배뇌졸중발생위험이통계적으로높은결과를보였다. 세부분석에의하면 60대에비해 70세이상에서모두뇌졸중발생위험률이높았으나, 소득수준과는별상관이 2. 뇌졸중의유형에따른위험도 알츠하이머병환자에서대조군에비해전체뇌졸중발생위험률이 2.87 (95%CI, 2.707-3.042) 배높은것으로나타났다. 콕스비례위험회귀분석에서 11년간의알츠하이머병환자군에서대조군에비해 stroke-free survival rate이통계적으로유의하게낮은결과를보였다 (Fig. 2). 뇌졸중유형에따른발생위험률을분석한결과에의하면허혈성뇌졸중의경우에는알츠하이머병환자에서뇌졸중발생위험률이 2.546 (95%CI, 2.393-2.709), 출혈성뇌졸중의경우에는발생위험률이 1.998 (95%CI, 1.624-2.458) 로대조군에비해높았다 (Table 2). 성별에따른뇌졸중발생위험률을보면남성의경우알츠하이머병환자의뇌졸중발생위험이 3.214 (95% Fig. 2. Stroke-free survival rates for patients with Alzheimer disease and comparison group in South Korea between 2003 and 2005 Table 2. Association of Alzheimer disease with all strokes and ischemic and hemorrhagic strokes. Type of strokes Age group, y AD N(%) HR(95% CI) * p-value All strokes <70 496 3.782 (3.395-4.213) 70-74 371 2.862 (2.538-3.228) 75-79 391 2.637 (2.344-2.965) 80-84 242 2.249 (1.941-2.607) 85 98 2.305 (1.817-2.925) ALL 1,598 2.87 (2.707-3.042) Ischemic stroke <70 464 2.576 (2.299-2.885) 70-74 342 2.54 (2.235-2.887) 75-79 359 2.533 (2.235-2.87) 80-84 221 2.911 (2.476-3.421) 85 88 2.174 (1.664-2.841) ALL 1,474 2.546 (2.393-2.709) Hemorrhagic stroke <70 32 2.44 (1.585-3.757) 70-74 29 2.792 (1.752-4.45) 75-79 32 1.775 (1.166-2.703) 0.0075 80-84 21 2.048 (1.197-3.501) 0.0089 85 10 2.247 (0.99-5.098) 0.0527 ALL 124 1.998 (1.624-2.458) * Adjustments were made for age, sex, hypertension, diabetes, cancer, COPD, CKD, dyslipidemia and household income. HR indicates hazard ratio. p<0.05. 70 Korean Journal of National Health Insurance Service Ilsan Hospital
이지은외. 국민건강보험공단노인코호트자료를이용한알츠하이머병에서뇌졸중발생위험률에대한연구 없었다. 남자의경우에는당뇨, 고혈압, 이상지질혈증이있는경우뇌경색발생률이높아졌으나, 암이동반질환으로있는경우에는오히려뇌경색발생위험비가 0.816 (95% CI, 0.739-0.902) 으로통계적으로유의하게낮았다. 여자의경우에는연령및소득수준에대한영향은남자와비슷한경과를보였으나, 동반질환에대해서는당뇨, 고혈압, 이상지질혈증이있는경우에는뇌경색발생위험률이증가하였으나, 암은통계적으로유의한영향을주진않은결과를보였다. 고찰 이연구는국내최초로국민건강보험노인코호트데이터를이용하여알츠하이머병환자에서뇌졸중발생위험률을본연구였다. 우리는이연구를통하여 11년간의추적관찰기간을통하여알츠하이머병환자에서성별, 연령, 가계소득을고려한대조군에비해고혈압, 당뇨, 이상지질혈증등의뇌졸중발생위험인자등의혼란변수를보정한결과 2.87배뇌졸중발생위험률이높은결과를보였다. 또한성별로분석한결과남자알츠하이머병환자는 3.214배뇌졸중발생위험 률이높고여자의경우에는 2.71배로남자알츠하이머병환자에서여자에비해뇌졸중발생위험률이높았다. 또한뇌졸중유형에따른분석결과에의하면허혈성뇌졸중이 2.546, 출혈성뇌졸중이 1.998로알츠하이머병환자에서출혈성뇌졸중에비해서는허혈성뇌졸중의발생위험률이높았다. 본연구결과와몇몇선행연구결과들에서알츠하이머병환자에서뇌졸중발생위험률을높였다는결과를보였으나, 질병기전에대해서는아직명확히밝혀진것은없다. 뇌졸중과알츠하이머병의연관성은다음과같이생각해볼수있다. 알츠하이머병환자들은동맥경화나뇌혈관장애와같은뇌혈관질환의부담이증가한상태이다. 기존여러연구들에서치매환자들은신경퇴행성질환과뇌혈관장애를동시에갖고있는경우가많아뇌혈류감소, 동맥경화등의악화가결국신경손상을일으켜인지장애, 치매를일으키고이러한것이임상적뇌졸중을일으킬수있다라고설명하고있다. 10 그중대표적인것이알츠하이머병발생과상관성이높은 APOE4 allele로 APOE4 는동맥경화의악화와연관있어서 11 실제로 APOE4 transgenic mice 는혈관뇌장벽이쉽게약해져 Table 3. Adjusted Hazards Ratios for AD among patients with all stroke Variables All stroke Male (n=537) All stroke Female (n=1061) p-value HR (95% CI) * HR (95% CI) * p-value AD 3.214 (2.909-3.552) 2.710 (2.522-2.912) Age groups <70 70-74 1.365 (1.219-1.528) 1.253 (1.150-1.365) 75-79 1.739 (1.556-1.943) 1.454 (1.334-1.584) 80-84 1.860 (1.643-2.105) 1.605 (1.455-1.771) 85 1.645 (1.347-2.008) 1.432 (1.250-1.642) Household income relative to the medication 20-40% 0.951 (0.812-1.113) 0.5294 1.020 (0.911-1.141) 0.7351 40-60% 0.972 (0.835-1.132) 0.7177 1.005 (0.900-1.122) 0.9316 60-80% 1.007 (0.880-1.152) 0.9193 1.004 (0.910-1.108) 0.9396 80-100% 0.985 (0.871-1.113) 0.8044 0.958 (0.878-1.046) 0.3384 Comorbidities Diabetes Mellitus 1.339 (1.225-1.464) 1.316 (1.231-1.406) Hypertension 1.793 (1.635-1.966) 1.950 (1.812-2.099) Cancer 0.816 (0.739-0.902) 0.938 (0.854-1.030) 0.1802 Chronic kidney disease 1.218 (0.935-1.585) 0.1436 1.118 (0.876-1.426) 0.3704 Dyslipidemia 1.270 (1.156-1.395) 1.304 (1.217-1.397) * Adjustments were made for age, sex, hypertension, diabetes, stroke, COPD, CKD, dyslipidemia and household income. HR indicates hazard ratio. p<0.05. Volume 16 Number 2 December 2017 71
JE Lee, et al. Association between Alzheimer Disease and Risk of Stroke 서혈관주위의 hemosiderin 을증가시키고, 뇌혈류를감소시키며, 미세혈관의길이를감소시킨결과를보였으며, APOE4 가출혈성뇌졸중및허혈성뇌졸중발생과의연관성이있을것으로생각하고있다. 12,13 또한알츠하이머병환자에서뇌출혈의증가는대뇌아밀로이드맥관병증과의연관성을고려해볼수있다. 대뇌아밀로이드맥관병증은내피세포질의얇아짐, 혈관주의세포의소실및내피단백질들의변성이혈관뇌장벽을손상시켜결국뇌출혈의위험인자로작용한다. 14,15 본연구의가장큰강점은국내에서최초로이루어진국민대다수가참여하고있는국민건강보험가입환자중 60세이상의국민건강보험공단자료의대표성을만족하는표본을추출한노인코호트를대상으로알츠하이머병환자를대상으로진행한연구라는데있다. 또한, 보다진단의정확도를높이기위해 KCD-6 codes에서 G30, F00으로청구코드에포함되어있으면서, 1년에 1회이상알츠하이머병치료제를복용한환자로제한하고진단코드에혈관성치매가포함된경우에는제외한정의를이용하였다는데의의가있다. 그러나본연구에몇가지제한점이있는데첫째, 자료의특성상의무기록이아닌건강보험청구기록을바탕으로이루어져진단명에대한신뢰성을좀더높이고자여러조작적정의를통해알츠하이머병과뇌졸중을정의했음에도불구하고, 두질환진단의정확성에제한점이있다. 둘째, 본연구는건강보험청구기록및건강검진기록을바탕으로진행된연구로서직접의무기록및진찰등을통해뇌졸중및알츠하이머병이진단된것이아니기때문에실제환자수에비해과소혹은과대평가됐을가능성이있다. 특히알츠하이머병중기이상으로진행되면거동이불편하여병원접근성이어려워지는경우가많은데, 이경우에는뇌졸중의발견이대조군에비해잘안되거나, 뇌졸중이생겨도병원을방문하는경우가적었을가능성이있다. 마지막으로알츠하이머병이후에뇌경색관련진단명이건강보험청구기록에들어온시점을발생시점으로하였으므로실제는알츠하이머병이후에뇌경색이발생한것이아니고, 이전에발생했을가능성을배제할순없다. 결론적으로지난 11년간의알츠하이머병환자의추적관찰을통하여알츠하이머병환자에서뇌졸중의발생률이유의하게높은결과를보였다. 따라서알츠하이머병환자에서는뇌졸중의조기진단과지속적인검진및뇌혈관질환위험인자관리를통하여뇌졸중발생을낮추는것이도움이될것으 로생각된다. REFERENCES 1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119-22. 2. Kukull WA, Ganguli M. Epidemiology of dementia: concepts and overview. Neurol Clin 2000;18:923-50. 3. Ma LL, Yu JT, Wang HF, Meng XF, Tan CC, Wang C, et al. Association between cancer and Alzheimer's disease: systematic review and meta-analysis. J Alzheimers Dis 2014;42:565-73. 4. Kim JS. Stroke becomes the 3rd important cause of death in Korea; is it a time to toast? J Stroke 2014;16:55-6. 5. Zhou J, Yu JT, Wang HF, Meng XF, Tan CC, Wang J, et al. Association between stroke and Alzheimer's disease: systematic review and meta-analysis. J Alzheimers Dis 2015;43: 479-89. 6. Tolppanen AM, Lavikainen P, Solomon A, Kivipelto M, Soininen H, Hartikainen S. Incidence of stroke in people with Alzheimer disease: a national register-based approach. Neurology 2013;80:353-8. 7. Ferrucci L, Guralnik JM, Salive ME, Pahor M, Corti MC, Baroni A, et al. Cognitive impairment and risk of stroke in the older population. J Am Geriatr Soc 1996;44:237-41. 8. Zhu L, Fratiglioni L, Guo Z, Winblad B, Viitanen M. Incidence of stroke in relation to cognitive function and dementia in the Kungsholmen Project. Neurology 2000;54:2103-7. 9. Liu ME, Tsai SJ, Chang WC, Hsu CH, Lu T, Hung KS, et al. Population-based 5-year follow-up study in Taiwan of dementia and risk of stroke. PLoS One 2013;8:e61771. 10. Sahathevan R, Brodtmann A, Donnan GA. Dementia, stroke, and vascular risk factors; a review. Int J Stroke 2012;7:61-73. 11. Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 1997;349:151-4. 12. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, et al. Apolipoprotein E controls cerebrovascular integrity viacyclo philin A. Nature 2012;485:512-6. 13. Chi NF, Chien LN, Ku HL, Hu CJ, Chiou HY. Alzheimer disease and risk of stroke: a population-based cohort study. Neurology 2013;80:705-11. 14. Kalaria RN. Linking cerebrovascular defense mechanisms in brain ageing and Alzheimer's disease. Neurobiol Aging 2009; 30:1512-4. 15. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis. Neurobiol Aging 2009;30:337-52. 72 Korean Journal of National Health Insurance Service Ilsan Hospital