378 pissn : , eissn : Original Article J Korean Orthop Assoc 2016; 51:

378 pissn : 1226-2102, eissn : 2005-8918 Original Article J Korean Orthop Assoc 2016; 51: 378-386 https://doi.org/10.4055/jkoa.2016.51.5.378 www.jkoa.org 고관절골절수술에서수술전 Enoxaparin 혈전예방요법대수술후 Enoxaparin 혈전예방요법 : 수술전 Enoxaparin 사용은안전한가? 문남훈 장재훈 박진섭 * 박기영 박용건 부산대학교병원정형외과, * 순환기내과 Preoperative Enoxaparin versus Postoperative Enoxaparin Thromboprophylaxis in Hip Fracture Surgery: Is Preoperative Enoxaparin Safe to Use? Nam Hoon Moon, M.D., Jae-Hoon Jang, M.D., Jin Sup Park, M.D.*, Ki Young Park, M.D., and Young Gun Park, M.D. Departments of Orthopaedic Surgery and *Cardiology, Pusan National University Hospital, Busan, Korea Purpose: The purpose of this study was to evaluate the safety and efficacy of pre- and postoperative initiation of enoxaparin in treatment of hip fracture. Materials and Methods: In this study, we enrolled 629 consecutive patients with hip fracture who Pusan National University Hospital between March 2009 and March 2014. Of these patients, 414 patients (65.8%) met the final inclusion criteria. Enoxaparin was administered subcutaneously at 40 mg once daily starting 48 hours after surgery in 156 patients (group A), and immediately after admission in 258 patients (group B). The incidence of symptomatic venous thromboembolism (VTE) and risk of bleeding during hospitalization period were compared between groups. Results: The incidence of symptomatic VTE during the hospitalization period was 7.1% (11 patients) in group A and 5.4% (14 patients) in group B. No significant difference in the rate of symptomatic VTE was found between the groups (unadjusted odds ratio [OR], 0.756; 95% confidence interval [CI], 0.334 1.710; adjusted OR, 0.554; 95% CI, 0.212 1.449). The incidence of symptomatic deep-vein thrombosis and pulmonary embolism (including fatal and non-fatal) did not significantly differ between groups. However, fatal pulmonary thromboembolism developed in two cases in group A and one patient expired postoperatively due to pulmonary hemorrhage in group B. Major bleeding and all-cause death did not differ between groups. Conclusion: Preoperative starting chemical thromboprophylaxis may be considered in the elderly patients with hip fracture who have risk factors for venous thromboembolism. Key words: venous thromboembolism, hip fractures, low molecular weight heparin Received April 7, 2016 Revised May 3, 2016 Accepted June 1, 2016 Correspondence to: Jae-Hoon Jang, M.D. Department of Orthopaedic Surgery, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea TEL: +82-51-240-7248 FAX: +82-51-247-8395 E-mail: ansskagns@daum.net *This research was supported by grant from Pusan National University Hospital, 2016. 서론 미국흉부의학회 (American College of Chest Physicians, ACCP) 의정맥혈전색전증에대한 9차예방지침개정안에따르면, 주요정형외과수술을시행받는환자에서정맥혈전색전증예방을위한 The Journal of the Korean Orthopaedic Association Volume 51 Number 5 2016 Copyright 2016 by The Korean Orthopaedic Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

379 Preoperative Enoxaparin vs. Postoperative Enoxaparin 저분자량헤파린 (low-molecular-weight-heparin, LMWH) 의사용에대한내용과관련하여수술전 12시간이전혹은수술후 12시간이후에사용할것을권장하고있다. 1) 그러나상기지침을뒷받침하는관련보고들은약물예방요법을시작하는시기에대해서수술 12시간이전에사용하는것이수술 12시간이후에시작하는것에비해정맥혈전색전증을예방하는효과가더뛰어나지않고, 수술전에약물예방요법을시행할경우혈전색전증의발생빈도를낮추어주는경향이있기는하지만주요출혈의위험이잠재적이득에비해서더크다고결론짓고있다. 2-5) 고관절골절이발생한고령의환자들은높은연령, 하지골절, 부동 (immobilization) 및정형외과적수술과같은혈전색전증의발생에대한위험요인을수반하게된다. 뿐만아니라다수의환자가여러가지내과적질환을동반하는경우가많아수술전후혈전색전증의발생에매우취약한경향이있다. 정맥혈전색전증에대한약물적예방의시작시기와관련된몇몇연구가있지만, 이러한연구들의대부분은수술전에보행이가능한환자들을다수포함하고있다. 6-8) 따라서고관절골절과같이수술전부터보행이불가능한환자에서약물적예방시작시기와관련된효과및안전성에대한비교연구는거의없다. 저자들은고관절골절로수술을시행하는고령환자에서정맥혈전색전증예방과관련된현재까지의연구내용들을바탕으로수술전에시작하는 LMWH가혈전색전증의발생빈도를유의한수준으로줄여줄수있을것으로가정하였다. 이연구의목적은고령의고관절골절환자를대상으로정맥혈전색전증에대하여수술전과수술후에시작하는약물예방요법을각각시행하였을때, 출혈합병증과혈전색전증의발생위험을비교하고자함이다. 대상및방법 1. 연구대상 2009년 3월부터 2014년 3월까지부산대학교병원에서고관절골절로내원하였던 629명의환자를대상으로하였다. 연구포함기준은 (1) 65세이상 (2) 고관절골절로수술을시행하였던환자였다. 연구배제기준은 (1) 최근출혈성뇌졸중이나위장관출혈병력이있는환자, (2) 고에너지손상, (3) 다발성외상, (4) 개방적골절, (5) 병적골절, (6) 10만개미만의저혈소판증 (thrombocytopenia), (7) 크레아티닌이높은경우 (serum creatinine >2.0 mg/dl), (8) 크레아티닌여과율이낮은경우 (Cr clearance <30 ml/min) 였다. 상기연구기준을충족시키는환자는총 414명 (65.8%) 이었다. 환자들은정맥혈전색전증에대한약물예방요법의시작시기에따라서두군으로구분하였다. 2009년 3월부터 2011년 6월까지 156 명 (37.7%) 은 enoxaparin 40 mg을피하로하루한번씩수술후 48 시간부터시작하였다 (A군). 2011년 7월부터 2014년 3월까지 258 명 (62.3%) 은 enoxaparin 40 mg을피하로하루한번씩입원과동시에수술전부터시작하였다 (B군) (Fig. 1). 2. 혈전예방요법모든환자는입원과동시에간헐적압박펌프와압박스타킹을이용한물리적예방법을적용하였으며, 입원기간동안유지하였다. Enoxaparin이표준약물예방약제로사용되었다. A군은 enoxaparin 40 mg을하루한번씩수술후 48시간부터피하주사하였으며 2011년대한고관절학회의고관절골절수술에대한정맥혈전색전증예방권고안에따라서평균입원기간인약 2주간 ( 최단 7일, 최장 35일 ) 투여하였다. 9) B군은입원과동시에 40 mg을 629 Consecutive patients who underwent hip fracture surgeries for the treatment of hip fracture between March 2009 and March 2014 215 Excluded: 1. Inclusion criteria not met: 133 2. Technical problem: 7 3. Open fracture: 3 4. Multiple fracture: 34 5. High energy fracture: 38 414 Elderly patients with lower energy hip fracture Group A: 156 patients 40 mg of enoxaparin was administered subcutaneously once daily starting postoperative day 2(after removal of drain) Group B: 258 patients Same regimen of group A with the addition of 40 mg subcutaneous dose of enoxaparin beginning at the time of admission Figure 1. Flow chart of patient enrollment.

380 Nam Hoon Moon, et al. 피하로주사하고수술전 24시간에중단한후, 수술후 48시간에다시시작하여 A군과같은방식으로투여하였다 (Fig. 1). 입원기간동안편측하지부종, 호흡곤란, 흉통과같은정맥혈전색전증관련증상이나징후를평가하였고, 관련증상이있는경우심부정맥혈전증이나폐색전증을발견하기위해서전산화단층정맥조영술을시행하였다. 심부정맥혈전증이나폐색전증이확인되면, 21일간 rivaroxaban 15 mg을경구투여한후 22일부터는 20 mg을 3개월간사용하는항응고요법을시행하였다. 10) 3. 정의및결과측정정맥혈전색전증은심장내과전문의와영상의학과전문의, 정형외과전문의의전산화단층촬영및의무기록에대한확인작업을통해서평가되었다. 주요출혈 (major bleeding) 은다음한가지이상과관련이있는출혈로정의하였다. 1) 치명적인출혈, 2) 주요장기에영향을줄수있는출혈, 3) 고관절골절수술후입원기간중 2 g/dl 이상의혈색소저하가있거나 2개이상의수혈이필요한출혈, 4) 진단과치료를위해침습적방법혹은영상의학적중재술이필요한경우, 5) 순환기계통의부전을초래하는출혈. 경증출혈 (minor bleeding) 은주요출혈로분류되지는않지만환자에의해보고된모든출혈로정의하였다. 본연구의 1차효능결과비교를위해증상을나타내는모든혈전색전증의빈도를비교하였다. 1차안전성결과의비교를위해주요출혈과사망을초래한모든원인을비교하였다. 2차안전성결과의비교를위해경증출혈, 수술전수혈이필요한경우, 술중수혈을포함하여수술후수혈량, 총수혈량, 수술시간, 추정출혈량, 수술후배액량을비교하였다. 추청출혈량은술중배액관으로모인혈액의양과거즈에묻어나온양을임상적으로마취과의사가추정한 estimated blood loss (EBL) 를참고하였다. 4. 통계분석모든연속변수 ( 나이, 체질량지수, 수상일로부터수술일까지의시간, Parker 보행점수 ) 들은정규분포를이루었으며, 두군의비교를위해 independent Student t-test를이용하여통계적유의성을검증하였다. Pearson chi-square test를범주형변수 ( 성별, 골절부위, 30 kg/m 2 이상의체질량지수, 혈전색전증의과거력, 종양, American Surgical Association [ASA] class, 항응고제사용과거력, 항혈소판제제의사용과거력, 골절분류, 수술종류, 마취방법 ) 비교를위해서사용하였다. 1차효능결과의비교를위해서혈전색전증의위험인자로알려진나이, 체중, 체질량지수, ASA class, 수상전보행점수, 혈전색전증의과거력, 종양과거력과같은임상적변수들과함께 multiple logistic regression model을사용하여분석하였다. 두군간의차이를확인하기위해서 95% confidence interval (CI) 과위험도 (risk ratio) 를계산하였다. 안전성결과와혈액학적결과의비교를위해서범주형변수는 Pearson s chi-square test나 Fisher s exact test를연속형변수는 Student s t-test나 Mann-Whitney U-test를사용하였다. 혈전색전증의독립예측인자를확인하기위해서 multiple logistic regression model을이용하였다. 모든통계분석은 IBM SPSS Software Package ver. 21.0 (IBM Co., Armonk, NY, USA) 을사용하였으며, p값이 0.05 이하인경우를유의한수준으로하였다. 결과 두군에속한환자들의통계적특성은 Table 1에기술하였다. 각군의통계적데이터 ( 수술당시나이, 성별, 골절부위, 체질량지수 ), 환자의과거력 ( 혈전색전증의과거력, 수상후수술까지시간, 종양과거력, ASA class, 항혈전제사용력, 항혈소판제제의사용력, 수상전보행점수 ), 골절분류, 수술및마취방법, 수술시간은두군간의유의한차이가없었다 (Table 1). 1. 효용및안전성결과본연구에서모든정맥혈전색전증은전산화단층정맥조영술에의해서확진되었다. 입원기간동안증상을동반하는혈전색전증의발생은 A군에서 7.1% (11 명 ), B군에서 5.4% (14 명 ) 였다. 증상을동반하는혈전색전증의발생빈도는두군간의유의한차이가없었다 (unadjusted odds ratio [OR] 0.756, 95% CI 0.334-1.710; adjusted OR 0.554, 95% CI 0.212-1.449). 증상을동반하는심부정맥혈전증과폐색전증의발생역시두군간의유의한차이는없었다 (Table 2). 주요출혈은 A군에서 2명 (1.3%), B군에서 3명 (1.2%) 이었다. A 군에서는 1예의위장관출혈과수술부위혈종형성이각각 1예씩있었다. B군에서는위장관출혈, 폐출혈로인한대량객혈, 수술부위혈종형성이각각 1예씩있었다. 혈종형성이확인된 A군과 B군의각각 1예에대해서는혈종제거술을시행하였다. 입원기간동안사망한경우는 A군에서 3예 (1.9%), B군에서 6예 (2.3%) 였다. A군중 2예는폐색전증으로인하여사망하였으며, 다른 1예는패혈증으로사망하였다. B군에서는폐출혈로인한사망이 1예있었다. 그러나폐색전증으로인한사망은없었으며, 폐렴으로인한호흡부전이 3예, 패혈증 1예, 심근경색이 1예였다. 주요출혈및입원기간중사망한빈도는두군간의유의한차이가없었다 (Table 3). 경증출혈은 A군에서 7예 (4.5%), B군에서 10예 (3.9%) 였다. 수술전수혈이필요하였던증례와술중수혈을포함한수술후수혈이필요한증례수는 A군에서각각 27예 (17.3%), 117예 (75.0%), B군에서 54예 (20.9%), 188예 (72.9%) 로확인되었다. 평균수혈량 (packed red blood cell) 은 A군에서 1.9 unit, B군에서 2.0 unit였다. 추정출혈량은 A군이 275.0 ml, B군이 256.1 ml였다. 수술후배

381 Preoperative Enoxaparin vs. Postoperative Enoxaparin Table 1. Patient Baseline Characteristics Characteristic Group A (n=156)* Group B (n=258) p-value Age at surgery (yr) 77.9±8.27 (65 96) 77.8±7.15 (65 99) 0.866 Gender (male) 43 (27.6) 85 (32.9) 0.251 Affected hip (right) 77 (49.4) 136 (52.7) 0.508 BMI (kg/m 2 ) 22.2±3.77 (14.2 36.3) 21.8±3.52 (14.9 35.3) 0.334 BMI >30 kg/m 2 9 (5.8) 14 (5.4) 0.883 History of VTE 7 (4.5) 13 (3.2) 0.797 Time from injury to surgery (d) 8.2±6.86 (1 56) 7.4±5.80 (1 45) 0.198 Underlying cancer 21 (13.5) 43 (16.7) 0.382 ASA classification 0.105 I 3 (1.9) 4 (1.6) II 106 (67.9) 153 (59.3) III 47 (30.1) 95 (36.8) IV 0 (0) 6 (2.3) Anticoagulation 0.829 Aspirin 37 (23.7) 63 (24.4) Plavix 6 (3.8) 9 (3.5) Warfarin 4 (2.6) 11 (4.3) Aspirin+Plavix 5 (3.2) 5 (1.2) Parker s mobility score before injury 7.0±1.62 (1 9) 6.7±1.69 (1 9) 0.066 Type of fracture 0.752 Intertrochanteric 78 (50.0) 138 (53.5) Femoral neck 76 (48.7) 116 (45.0) Subtrochanteric 2 (1.3) 4 (1.0) Type of surgery 0.202 Hemiarthroplasty 52 (33.3) 82 (31.8) Total hip arthroplasty 19 (12.2) 19 (7.4) Osteosynthesis 85 (54.5) 157 (60.9) Type of anesthesia 0.539 General 120 (76.9) 191 (74.0) Spinal 25 (16.0) 52 (20.2) Epidural 11 (7.1) 15 (5.8) Operative time (min) 94.6±23.4 (30 200) 90.3±26.3 (30 220) 0.089 Values are presented as mean±standard deviation (range) or number (%). *Postoperative enoxaparin. Same regimen with the addition of preoperative enoxaparin. BMI, body mass index; VTE, venous thromboembolism; ASA, American Society of Anesthesiologists. 액량은 A군이 182.2 ml, B군이 175.0 ml였다. 2차안전성결과는양군간의유의한차이가없었다. 입원기간중프로트롬빈시간 (prothrombin international normalized ratio), 헤모글로빈 (hemoglobin), 헤마토크리트 (hematocrit) 의변화는양군간에유의한차이가없었다 (Table 4). 2. 입원기간중혈전색전증의예측인자 Multiple logistic regression 분석을통한입원기간중혈전색전증의발생에대한예측인자는 30 kg/m 2 이상의체질량지수, 종양과거력, 심부정맥혈전증의과거력, 항응고제의사용력, 수상전보행점수가낮은경우로확인되었다 (Fig. 2).

382 Nam Hoon Moon, et al. Table 2. Incidence of Symptomatic VTE during Hospitalization Variable Group A (n=156)* Group B (n=258) Unadjusted OR (95% CI) p-value Adjusted OR (95% CI) p-value Symptomatic VTE 11 (7.1) 14 (5.4) 0.756 (0.334 1.710) 0.502 0.554 (0.212 1.449) 0.229 Symptomatic DVT 7 (4.5) 8 (3.1) 0.681 (0.242 1.916) 0.467 0.551 (0.178 1.699) 0.299 Symptomatic PE 4 (2.6) 6 (2.3) 0.905 (0.251 3.258) 0.878 0.670 (0.132 3.395) 0.629 Non-fatal PE 2 (1.3) 6 (2.3) 1.833 (0.365 9.198) 0.461 1.673 (0.261 10.720) 0.587 Fatal PE 2 (1.3) 0 (0) N/A 0.995 N/A 0.991 Values are presented as number (%) or median (range). *Postoperative enoxaparin. Same regimen with the addition of preoperative enoxaparin. VTE, venous thromboembolism; OR, odds ratio; CI, confidence interval; DVT, deep vein thrombosis; PE, pulmonary embolism; N/A, not available. Table 3. Safety Outcomes Variable Group A (n=156)* Group B (n=258) p-value Primary outcome Major bleeding 2 (1.3) 3 (1.2) 1.000 Death from any cause 3 (1.9) 6 (2.3) 1.000 Secondary outcomes Minor bleeding 7 (4.5) 10 (3.9) 0.761 Preoperative transfusion 27 (17.3) 54 (20.9) 0.375 Postoperative transfusion 117 (75.0) 188 (72.9) 0.633 Mean units of total transfusion 1.9±1.77 (0 9) 2.0±1.83 (0 11) 0.647 Estimated blood loss (ml) 275.0±183.8 (10 1,000) 256.1±184.9 (50 1,000) 0.313 Postoperative drainage (ml) 182.2±143.8 (15 900) 175.0±139.5 (20 1,050) 0.616 Values are presented as number (%) or mean±standard deviation (range). *Postoperative enoxaparin. Same regimen with the addition of preoperative enoxaparin. Table 4. Hematologic Trends Variable Group A (n=156)* Group B (n=258) p-value Preoperative INR 1.08±0.26 (0.87 3.12) 1.09±0.19 (0.87 3.12) 0.725 Postoperative INR 1.07±0.11 (0.92 1.63) 1.08±0.11 (0.91 3.51) 0.190 Initial Hb level (g/dl) 11.5±1.72 (6.9 15.8) 11.2±1.71 (6.7 15.8) 0.115 Preoperative Hb level (g/dl) 10.7±1.60 (6.6 15.0) 10.5±1.45 (6.6 15.0) 0.260 POD 1 day Hb level (g/dl) 10.3±1.25 (7.3 13.6) 10.2±1.27 (7.0 13.6) 0.512 POD 5 days Hb level (g/dl) 10.5±1.12 (7.1 13.5) 10.4±1.30 (6.6 13.9) 0.569 Initial Hct (%) 33.3±4.68 (20.6 46.8) 32.7±4.89 (19.7 46.8) 0.200 Preoperative Hct (%) 31.7±4.60 (20.0 44.9) 31.3±4.22 (20.0 44.9) 0.286 POD 1 day Hct (%) 30.6±3.64 (21.8 40.6) 30.4±3.77 (21.8 40.6) 0.581 POD 5 days Hct (%) 31.4±3.33 (21.6 40.4) 31.0±3.85 (20.0 40.8) 0.260 Values are presented as mean±standard deviation (range). *Postoperative enoxaparin. Same regimen with the addition of preoperative enoxaparin. INR, international normalized ratio; Hb, hemoglobin; POD, postoperative day; Hct, hematocrit.

383 Preoperative Enoxaparin vs. Postoperative Enoxaparin Transfusion BMI>30 kg/m 2 Cancer history DVT history Anticoagulant Diagnosis (pertrochanteric fx) Mobility score Anesthesia (general) Operation (osteosynthesis) ASA (I, II) EBL Time from injury to operation BMI Weight Group (group A) Age Sex (male) 0.0001 0.001 0.01 1.0 OR 고찰 10.0 100.0 1,000.0 Figure 2. Independent risk factors for thromboembolism in patients with hip fractures. BMI, body mass index; DVT, deep vein thrombosis; fx, fracture; ASA, American Society of Anesthesiologists; EBL, estimated blood loss; Group A, postoperative enoxaparin; OR, odds ratio. 본연구는 65세이상의고관절골절환자를대상으로수술전부터시작하는 enoxaparin을이용한약물예방요법의효율성과안전성을수술후부터시작하는약물예방요법과비교분석하여적절한약물예방요법의시작시기를알아보고자하였다. 저자들은수술전부터시작하는약물예방요법이수술후부터시작하는약물예방요법에비해서정맥혈전색전증예방에우수한효과가있음을확인할수는없었지만, 수술전부터약물요법을시행한다고하더라도임상적으로유의한수준의출혈합병증이나혈액학적지표의차이가나타나지않는다는사실또한확인할수있었다. 많은연구를통해서 LMWH가주요정형외과수술후발생하는정맥혈전색전증을예방하는데효과적이면서안전한약제임을보고한바가있다. 2,11-15) 이러한연구의상당부분은주요정형외과수술그자체또는수술과관련된부동 (immobilization) 이혈전생성에중요한영향을미칠것이라는데기반을두고있다. 미국과캐나다를포함한북미지역에서는정맥혈전색전증에대한예방요법을고려함에있어예방효과보다출혈과관련된합병증에비중을두는경향이있다. 16,17) Hull 등 5) 은이중맹검무작위비교연구에서 delteparin을이용하여수술전부터약물예방요법을시작하였을때혈전색전증의발생빈도가유의한수준으로감소하였지만, 출혈과관련된합병증또한유의한수준으로증가함을보고한바가있다. 뿐만아니라 Strebel 등 2) 의보고에서는수술전부터약물예방요법을시행한다하더라도혈전색전증의발생빈도를낮추어줄수있다는확실한증거가없을뿐만아니라수 술후주요출혈합병증의발생빈도가증가한다고하였다. 이러한내용을바탕으로혈전색전증과관련된 9차 ACCP 예방지침에서도수술전예방보다는수술후예방이더나은방법이라고결론짓고있다. 1) 약물예방요법의시작시기와관련된메타분석과기획종설에는수술전부터시작하는약물예방요법과수술후부터시작하는약물예방요법사이에일관된차이를얻어내지못하고있으나전반적으로수술전부터시작하는약물예방요법이수술후부터시작하는약물예방요법에비해서장점을보여주지못한다고언급하고있다. 2,4,18) 그러나상기보고들의연구대상은주요정형외과수술을대상으로하고있음에도불구하고, 고관절관절염, 대퇴골두무혈성괴사, 슬관절관절염환자와같이수술전보행이가능한다수의환자들을연구대상에포함시키고있다. 이러한환자들은고관절골절환자와수술전상황에있어상당한차이가있다. 고관절골절환자들은수상과동시에거동이불가능하게되고, 골절과관련된크고작은혈관손상은혈액응고작용을활성화시켜과응고상태 (hypercoagulation) 를초래하게된다. 게다가골절로인한부종과혈관손상은정맥순환을억제하여혈류흐름의변화를초래하게되어소위정맥혈전색전증을유발하게되는 Virchow s triad를수술전부터충족시키게된다. 뿐만아니라대다수의고관절골절환자들은고령이며, 다양한내과적질환을동반하고있다. 이러한점은혈전색전증의고위험인자들이므로, 결과적으로고관절골절환자들은수술전부터혈전색전증의발생에매우취약할수밖에없다. Smith 등 19) 은 24시간이상수술이지연되는대퇴골및고관절골절환자들을대상으로수술전도플러초음파를시행하였다. 이연구에서저자들은수술전부터확인되는심부정맥혈전증의빈도가 14.5% 에달하며, 7일이상지연되는경우심부정맥혈전증의발생빈도가 33.3% 까지증가함을보고한바가있다. 그들은이연구를통해서고관절골절환자에서수술이지연되는경우, 수술전부터정맥혈전색전증에대한평가를적극적으로할필요가있음을강조하였다. 저자들은이렇게수술전정맥혈전색전증발생의취약성이임상적으로영향을줄가능성에주목을하였으며, 수술전부터약물예방요법을시작할경우혈전색전증의예방효과가있고, 수술전부터시작하는약물예방요법이출혈합병증을증가시키지않을것이라고가정하였다. 이러한가정은슬관절및고관절인공관절치환술을시행한환자에서수술 12시간전부터 LMWH를이용한약물예방요법을시행한후효과와안전성을입증하였던 Hull 등 4,5,18) 의보고를기반으로하였다. 저자들은본연구에서증상을나타내는모든정맥혈전색전증 ( 심부정맥혈전증, 폐색전증 ) 을이용하여 1차효율성결과를비교분석하였으나, 양군간의유의한차이를확인할수없었다. 이러한결과는수술전부터 enoxaparin을사용한다하더라도증상을동반하는혈전색전증의예방에효과가없음을나타내는결과로

384 Nam Hoon Moon, et al. 받아들일수있다. 그러나이것은증상을야기하는혈전색전증의빈도가낮고, 서양인에비해서아시아, 특히한국인의발병빈도가높지않아유의한결과를얻기위한연구대상의수가적었기때문이라고생각한다. 이러한결과에도불구하고저자들은본연구에서수술후부터시작한약물요법군에서두명의치명적인폐색전증이발생하였음에주목하고있다. 이는발생빈도가대단히낮아서통계적으로유의한차이가없었을뿐, 연구대상이늘어난다면충분히유의한결과를얻을가능성이있을것으로기대하고있다. 1차안전성결과는주요출혈과사망을초래한모든원인을이용하였고, 2차안전성결과는경증출혈, 수술전수혈이필요한증례수, 수술중수혈을포함하여수술후수혈이필요한증례수, 총수혈량, 수술시간, 추정출혈량 (EBL), 수술후배액량을이용하여비교분석을하였으나양군간의유의한차이를확인할수가없었다. 저자들은이러한사실을통해서수술전부터약물예방요법을시행한다고하더라도수술 24시간이전에약물을사용을중단한다면, 수술전약물예방요법으로인한출혈합병증을유의한수준으로증가시키지않음은확인할수있었다. 다만경증출혈빈도, 수술전및수술후수혈이필요한환자수, 평균수혈량, 추정배액량모두 enoxaparin을술전에투여한군에서술후에투여한군에비해통계적유의성은없었지만다소낮게확인되었는데, 이것은시간의흐름에따른술자의술기향상, 마취과및임상의사의수혈처방에대한인식변화등과연관되어있을가능성이있으며, 술전 enoxaparin이출혈경향을줄일수있는가능성으로해석하기는힘들것같다. 저자들은치명적인폐색전증의발생빈도가매우낮다는점을감안하고, 이러한치명적인합병증을예방하는것이궁극적인약물예방요법의목적이라고가정한다면, 수술전부터시작하는약물예방요법에서 1차및 2차안전성결과가양군간의유의한차이가없었으므로, 수술전부터약물예방요법을시작하는것이좋다고생각한다. 본연구의제한점은다음과같다. 첫째, 후향적으로이루어진연구이며, 둘째, 연구대상이상대적으로적어유의한결과를얻기가힘들었다. 셋째, 치명적인폐색전증의발생빈도가대단히낮아주어진환자만을대상으로치명적인폐색전증의발생의유의한차이를확인하기힘들었다. 넷째, 증상이있는환자만을대상으로전산화단층정맥조영술을촬영하였기때문에증상이없는정맥혈전색전증에대한평가를할수없었다. 다섯째, 수술방법에따른정맥혈전색전증예방효과와출혈위험성을조사하지못하였다. 결론 본연구에서술전부터약물예방요법을사용한다고하더라도 출혈성합병증발생이의미있게증가하지않았다. 치명적인폐색전증의발생빈도가대단히낮지만한번발생하는경우매우치명적일수있고, 궁극적으로약물예방요법을시행하는목적이치명적인폐색전증을예방하는것이라는점을감안한다면, 정맥혈전색전증의위험인자를동반하는고령의고관절골절환자에서는수술전부터시작하는약물예방요법을고려할필요가있다고생각한다. CONFLICTS OF INTEREST The authors have nothing to disclose. REFERENCES 1. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e278S-325S. 2. Strebel N, Prins M, Agnelli G, Büller HR. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med. 2002;162:1451-6. 3. Raskob GE, Hirsh J. Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest. 2003;124:379S- 85S. 4. Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med. 2001;161: 1952-60. 5. Hull RD, Pineo GF, Francis C, et al; The North American Fragmin Trial Investigators. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. Arch Intern Med. 2000;160:2199-207. 6. Perka C. Preoperative versus postoperative initiation of thromboprophylaxis following major orthopedic surgery: safety and efficacy of postoperative administration supported by recent trials of new oral anticoagulants. Thromb J. 2011;9:17. 7. Hull RD, Pineo GF, Maclsaac S. Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation

385 Preoperative Enoxaparin vs. Postoperative Enoxaparin in patients undergoing elective hip surgery. Thromb Res. 2001;101:V155-62. 8. Lassen MR. Is the preoperative administration of enoxaparin 40mg necessary to optimally prevent the occurrence of venous thromboembolism after hip surgery? A subanalysis of two pooled randomized trials. J Thromb Haemost. 2009;7:889-91. 9. Park YS. Guideline for the prophylaxis of venous thromboembolism in hip surgery patients. J Korean Orthop Assoc. 2011;46:95-8. 10. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-510. 11. Turpie AG, Bauer KA, Eriksson Bl, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: ameta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162: 1833-40. 12. Eriksson BI, Bauer KA, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med. 2001;345:1298-304. 13. Bauer KA, Eriksson BI, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001;345:1305-10. 14. Tsuchie H, Miyakoshi N, Nishi T, Abe H, Segawa T, Shimada Y. A case of incomplete atypical femoral fracture with histomorphometrical evidence of osteomalacia. Acta Med Okayama. 2015;69:59-63. 15. Charters MA, Frisch NB, Wessell NM, Dobson C, Les CM, Silverton CD. Rivaroxaban versus enoxaparin for venous thromboembolism Prophylaxis after hip and knee arthroplasty. J Arthroplasty. 2015;30:1277-80. 16. Kearon C, Hirsh J. Starting prophylaxis for venous thromboembolism postoperatively. Arch Intern Med. 1995;155:366-72. 17. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:381S-453S. 18. Hull RD, Brant RF, Pineo GF, Stein PD, Raskob GE, Valentine KA. Preoperative vs postoperative initiation of low-molecular-weight heparin prophylaxis against venous thromboembolism in patients undergoing elective hip replacement. Arch Intern Med. 1999;159:137-41. 19. Smith EB, Parvizi J, Purtill JJ. Delayed surgery for patients with femur and hip fractures-risk of deep venous thrombosis. J Trauma. 2011;70:E113-6.

386 pissn : 1226-2102, eissn : 2005-8918 Original Article J Korean Orthop Assoc 2016; 51: 378-386 https://doi.org/10.4055/jkoa.2016.51.5.378 www.jkoa.org 고관절골절수술에서수술전 Enoxaparin 혈전예방요법대수술후 Enoxaparin 혈전예방요법 : 수술전 Enoxaparin 사용은안전한가? 문남훈 장재훈 박진섭 * 박기영 박용건 부산대학교병원정형외과, * 순환기내과 목적 : 고관절골절환자에서정맥혈전색전증의예방을위해수술전및수술후시작한 enoxaparin 투여방법의안전성과유효성을 비교분석하고자한다. 대상및방법 : 2009 년 3 월부터 2014 년 3 월까지부산대학교병원에서고관절골절로내원하였던 629 명의환자중연구포함기준을 만족시키는총 414명 (65.8%) 을대상으로하였다. 156명은 enoxaparin 40 mg을수술후 48시간부터피하주사로시작하였고 (A군), 258명은 enoxaparin 40 mg을수술전부터피하주사로시작하였다 (B군). 양군에서정맥혈전색전증의발생빈도와입원기간중출혈위험성을비교분석하였다. 결과 : 증상을동반하는정맥혈전색전증은 A군에서 7.1% (11명), B군에서 5.4% (14명) 이었으며, 두군간의유의한차이는없었다. 증상을동반하는심부정맥혈전증과폐색전증의발생역시두군간의유의한차이는없었으나, A군중 2예는폐색전증으로인하여사망하였고, B군중 1예는폐출혈로사망하였다. 주요출혈및입원기간중사망빈도는두군간에유의한차이가없었다. 결론 : 혈전색전증의위험인자를동반하는고령의고관절골절환자에서는수술전부터시작하는약물예방요법을고려해볼수있다. 색인단어 : 정맥혈전색전증, 고관절골절, 저분자량헤파린 접수일 2016 년 4 월 7 일수정일 2016 년 5 월 3 일게재확정일 2016 년 6 월 1 일책임저자장재훈 49241, 부산시서구구덕로 179, 부산대학교병원정형외과 TEL 051-240-7248, FAX 051-247-8395, E-mail ansskagns@daum.net * 본연구는 2016 년부산대학교병원의임상연구비지원을받았음. 대한정형외과학회지 : 제 51권제 5호 2016 Copyright 2016 by The Korean Orthopaedic Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.