Brain & NeuroRehabilitation Vol. 7, No. 2, September, 2014 http://dx.doi.org/10.12786/bn.2014.7.2.76 허혈성뇌졸중의이차예방을위한항혈전제치료 부산대학교의과대학신경과학교실조한진ㆍ강태호 Pharmacological Secondary Prevention of Ischemic Stroke Han-Jin Cho, M.D. and Tae-Ho Kang, M.D. Department of Neurology, Pusan National University School of Medicine The causes of ischemic stroke are widely diverse, ranging from large artery atherosclerosis to cardioembolism, and it is important to use preventive therapy toward the goal reducing the future risk of recurrent ischemic stroke, myocardial infarction, and vascular death. Antithrombotic therapy is one of the fundamental medical approaches for secondary prevention of ischemic stroke, which is broadly divided into two general categories, those that exert their effect via platelet inhibition (antiplatelet agents), and those that influence various factors in the clotting cascade (anticoagulants). In general, the clinical guidelines recommend antiplatelet agents for patients with non-cardioembolic stroke, while anticoagulants is indicated for patients with presumed or proven cardioembolic stroke. Many clinical trials have attempted to test the efficacy and safety of antithrombotics in ischemic stroke. This review will discuss on currently available antithrombotic agents that have demonstrated efficacy for secondary prevention of ischemic stroke. (Brain & NeuroRehabilitation 2014; 7: 76-85) Key Words: antiplatelet agent, anticoagulant, secondary prevention, ischemic stroke 서론 뇌경색은재발이흔한병으로발병후 5년간약 25% 정도의환자에게서재발이나타나며뇌경색이재발한경우처음발생했을때보다심한후유증이남을뿐만아니라치명률도높은것으로알려져있다. 1 따라서뇌경색의높은재발률, 증상의심각성, 그리고이로인한사회경제적인손실을고려해보았을때뇌경색의이차예방은매우중요하다고할수있다. 뇌경색의재발을막기위해서는고혈압과당뇨등의위험인자를효과적으로조절하는것도중요하지만, 혈전의생성을억제하기위한항혈소판제나항응고제도필수적으로사용되어야한다. 뇌경색은심혈관질환과는달리다양한발생기전을가지는하나의복합적인질환군이므로각각의발생기전에따라이차예방을위하여사용하는약제도달라져야할것이다. Correspondence to: Han-Jin Cho, Department of Neurology, Pusan National University Hospital, 179, Gudeok-ro, Seo-gu, Busan 602-739, Korea Tel: 051-240-7317, Fax: 051-245-2783 E-mail: chohj75@gmail.com This work was supported by a clinical research grant from Pusan National University Hospital in 2014. 본종설에서는국내에서사용되고있는항혈소판제및항응고제에대한연구결과들을정리하여기술하고, 이를바탕으로하여제시된국내뇌졸중진료지침에대하여살펴보고자한다. 본론 1) 항혈소판제뇌경색의발생기전중죽상경화성뇌경색 (atherosclerotic infarction) 이나열공성뇌경색 (lacunar infarction) 은심혈관질환과마찬가지로혈소판의응집및활성화를억제하는것이중요하므로효과적인이차예방을위해서항혈소판제를사용하게되며, 메타분석결과일과성허혈발작및뇌경색환자에서항혈소판제치료는대조군과비교하여뇌경색의재발, 심혈관질환의발생, 혈관성질환으로인한사망률을급성기에는 11%, 장기적으로는 22% 정도감소시키는것으로조사되었다. 2 현재까지다양한항혈소판제들이개발되어사용되고있으며뇌졸중임상연구센터에서발간한뇌졸중진료지침에는이러한항혈소판제사용에대한국내권고사항이제 76
조한진ㆍ강태호 : 허혈성뇌졸중의이차예방을위한항혈전제치료 시되어있고가장최근에는 2013년 3월에개정판이제작된바있다 (Table 1). (1) 아스피린아스피린은뇌경색의이차예방을위하여가장먼저사 용되었고현재도가장보편적으로이용되고있는항혈소판제이다. 아스피린의 acetyl기는혈소판의막과결합하여 cyclooxygenase-1을비가역적으로억제함으로서강력한혈소판활성인자인 thromboxane A2의형성을억제한다 Table 1. Current Recommendations for Antithrombotic Therapy in Patients with Ischemic Stroke from Korean Clinical Practice Guidelines for Stroke Antithrombotics Antiplatelet agent Anticoagulants Recommendation For patients with non-cardioembolic ischemic stroke or TIA, aspirin (50 300 mg) can be given to prevent stroke recurrence and further vascular events. For patients with non-cardioembolic ischemic stroke, aspirin or clopidogrel monotherapy can be given as initial therapy. For patients allergic to aspirin, clopidogrel is reasonable as alternative antiplatelet agent. Ticlopidine is more effective than aspirin in the prevention of stroke recurrence. However, caution should be used with the occurrence of side effect such as neutropenia. Cilostazol monotherapy can be used for patients with non-cardioembolic ischemic stroke, especially lacunar stroke. For patients unable to be treated by aspirin and clopidogrel, cilostazol or triflusal may be used as alternative antiplatelet agent. For patients who have higher bleeding risk, cilostazol or triflusal is recommended to prevent stroke recurrence. The addition of aspirin to clopidogrel increases the risk of hemorrhage and is not routinely recommended for ischemic stroke or TIA patients. For patients with ischemic stroke or TIA with persistent or paroxysmal AF, anticoagulation with adjusted-dose warfarin (INR 2.0 3.0) is recommended unless contraindicated. For patients unable to take oral anticoagulants, aspirin 300 mg is recommended. For patients who have an ischemic stroke while taking anticoagulants, sustained use of anticoagulants with an increased target INR (INR 2.5 3.5) or adding antiplatelet agent may be considered. TIA: transient ischemic attack, AF: atrial fibrillation, INR: international normalized ratio. Fig. 1. Platelet activation pathway and actions of antiplatelet agents. AA: arachidonic acid, ADP: adenosine diphosphate, AMP: adenosine monophosphate, COX: cyclooxygenase, GP: glycoprotein, PDE: phosphodiesterase, TP: thromboxane receptor, TXA2: thromboxane A2. 77
Brain & NeuroRehabilitation 2014; 7: 76-85 (Fig. 1). 복용후 1시간이내에혈소판응집을비가역적으로억제하며반감기는 15 20분으로짧지만혈소판은새로운 cyclooxygenase를생성하지못하기때문에혈소판의혈관내수명인 7 10일동안억제효과는지속된다. 하지만매일 10% 정도의혈소판이새로만들어지므로지속적인복용이필요하다. 아스피린은뇌경색환자의이차예방에있어서뇌경색, 심근경색, 그리고혈관성사망의발생률을대조군대비 13% 정도감소시켜주었으나다른동맥경화성혈관질환들에서 19% 정도의감소를보이는것에비해그효과는다소낮게나타났다. 3 하지만아스피린 160 300 mg을뇌경색발생 48시간이내에투여하였을때대조군과비교하여 2 4주이내에나타나는뇌경색의재발을 31% 정도유의하게감소시킨반면뇌출혈의빈도는 20% 증가시켰으나통계적인유의성은없었다. 4-6 아스피린은현재까지뇌경색의급성기에투여했을때뇌경색의재발을감소시키는효과가입증된유일한항혈소판제로급성기부터사용하여약제의변경없이일관되게약제를유지할수있다는장점이있다. 이를바탕으로국내뇌졸중진료지침에서도급성기뇌경색환자에게아스피린 160 300 mg을증상발생 24 48시간이내에경구투여할것을권고하고있다. 뇌경색환자들을대상으로아스피린의용량을어느정도사용하는것이좋은가에대해많은연구들이이루어져왔는데, 메타분석결과를살펴보면뇌경색의재발, 심근경색의발생, 혈관성사망을억제해주는아스피린의효능은 50 mg부터 1500 mg 사이에는차이가없었다. 7 하지만아스피린을지속적으로사용하는데있어문제가되는위장장애증상이 300 mg 이상에서흔하게발생할뿐만아니라가장주의를요하는위장관출혈이나뇌출혈이 300 mg 이상에서그빈도가갑자기증가하게되므로 50 300 mg 사이의용량을사용하는것이가장이상적이며국내의실정을고려하면 100 300 mg을사용하는것이적당하다. 8,9 (2) Thienopyridine 계열항혈소판제혈소판내부에존재하는고밀도과립 (dense granule) 에서분비되는 adenosine diphosphate (ADP) 는 G단백질의일종인 P2Y 1 과 P2Y 12 수용체를통하여혈소판을활성화시키며, P2Y 12 수용체의경우 P2Y 1 수용체에비하여혈소판활성화를더강하게유발시키는것으로알려져있다. Thienopyridine 계열항혈소판제인클로피도그렐과티클로피딘은간의 cytochrome P450을통하여대사되어 P2Y 12 수용체를비가역적으로억제함으로서혈소판응집억제효과를나타낸다 (Fig. 1). CAPRIE 연구는뇌경색, 심근경색, 말초혈관질환의과거력을가진 19,000명의환자를대상으로클로피도그렐 75 mg과아스피린 325 mg을무작위배정하여뇌경색, 심근경색및혈관성사망의발생률을비교한연구로클로피도그렐이아스피린대비 8.7% 정도의상대위험도감소효과를보여주었다 (p=0.043). 10 하지만뇌경색의과거력을가진 6,431명의환자들만을대상으로분석해보았을때상대위험도의감소는 7.3% 로아스피린과비교하여유의한감소효과는없었다 (p=0.26). 그럼에도불구하고뇌경색이나심근경색의과거력을이미가지고있었던환자, 당뇨가동반된환자, 고지혈증으로투약받던환자, CABG 의기왕력을가진환자의경우아스피린에비해상대위험도의감소가 9.7 20.4% 정도로유의하게관찰되어이러한고위험군의뇌경색환자에게서클로피도그렐을사용하는것은권장할만하다. 11-13 또한안전성의측면에서도클로피도그렐은아스피린의가장큰문제점인위장장애증상이나위장관출혈을유의하게감소시켰다. 따라서국내뇌졸중진료지침에서는아스피린과더불어클로피도그렐을비심장성뇌경색환자에게서일차선택약제로권고하고있다. 클로피도그렐저항성이란클로피도그렐을복용하는환자들의혈소판의기능분석을통하여혈소판의응집력저하가예상보다적은경우를의미하며, 국내보고에따르면급성기뇌경색환자들의클로피도그렐저항성은 18.5% 정도에서관찰된다. 14 뇌경색환자들에게서클로피도그렐의저항성이혈관질환의재발과관련이있다는보고는현재까지없으므로클로피도그렐을복용하는모든환자들에서저항성을검사할필요는없으나, 급성심근경색환자를대상으로한연구에서는클로피도그렐저항성이있는경우혈관질환의재발률이높아지는것으로나와주의가필요하다. 15 티클로피딘은구조나약리작용에있어클로피도그렐과유사하며 250 mg을경구투여했을때 1 3시간이내에혈장최고농도에도달한다. 뇌경색환자를대상으로티클로피딘 500 mg (250 mg 1일 2회 ) 을위약군과비교해보았을때뇌경색, 심근경색및혈관성사망의발생률을 30.2% 정도감소시켰으나, 16 같은용량을아스피린 1,300 mg과비교해보았을때에는뇌경색, 심근경색, 그리고혈관성사망의발생률을 3년간 9% 정도감소시켜유의성에도달하지는못했다. 하지만뇌경색의발생위험은 21% 정도유의하게감소시켜부분적인효과를입증하였다. 17 티클로피딘을사용함에있어가장주의를요하는것은심각한혈액부작용으로중성구감소증 (0.5 2%), 혈소판감소증, 재생불량성빈혈, 혈전성혈소판감소자색반 78
조한진ㆍ강태호 : 허혈성뇌졸중의이차예방을위한항혈전제치료 (thrombotic thrombocytopenic purpura, TTP) 과같은부작용이보고되었다는점이다. 이러한혈액부작용은대개티클로피딘을투여한이후 3개월이내에나타나게되므로첫 3개월간은정기적으로혈액검사를시행하는것이좋다. 최근시행한연구에서티클로피딘을클로피도그렐과비교해보았을때에도혈관질환의감소효과와출혈성부작용에있어서는두약제간에차이가없었지만혈액부작용및간수치의상승이티클로피딘군에서유의하게높게조사되었다. 18 따라서국내뇌졸중진료지침에서도아스피린과비교하였을때뇌경색의이차예방에도움을줄수있으나호중구감소증등의위험성이있으므로투약시주의가필요하다고명시하고있다. (3) 실로스타졸실로스타졸은 phosphodiesterase 3을억제하는기전을통하여혈소판의응집을저하시키면서동시에혈관확장의효과를가지고있는약물로서일본, 한국, 그리고중국에서뇌경색환자를대상으로유용성이대한연구들이나오고있다 (Fig. 1). 중국에서시행된 CASISP 연구에서뇌경색환자를대상으로실로스타졸 200 mg (100 mg 1일 2회 ) 과아스피린 100 mg을무작위배정하여비교한결과뇌경색, 뇌출혈및지주막하출혈의발생률에서유의한차이가나타나지않았다. 19 하지만일본에서시행된 CSPS2 연구를통하여실로스타졸 200 mg과아스피린 81 mg을비교해보았을때뇌경색, 뇌출혈및지주막하출혈의발생률에서실로스타졸이아스피린에비해 26% 의감소효과를보여주어상반된결과를나타내었다. 20 따라서이상의두연구를합친메타분석이시행되었는데뇌경색과심근경색의발생빈도에는아스피린대비유의한차이를보여주지못했던반면뇌출혈의발생에있어서는 74% 의상대위험도감소를보여주었고두개외출혈의발생도실로스타졸군에서 26% 더낮게조사되어출혈성부작용의발생에있어뛰어난안전성을보여주었다. 21 그럼에도불구하고 CSPS2 연구에포함된환자의 65% 가열공성뇌경색이라는점은논란의여지가있는부분이다. 이러한점을반영하여국내뇌졸중진료지침에서는실로스타졸의단독치료를열공성뇌경색환자의이차예방에사용할것을권고하고있으며, 특히뇌출혈을포함한심각한출혈의위험이있는환자를대상으로사용할것을추천하고있다. (4) 트리플루잘트리플루잘은아스피린과유사한구조를가지고있어 cyclooxygenase를비가역적으로억제시키는효과를나타내는데 (Fig. 1), 아스피린의대사물인살리실산 (salicylic acid) 은혈소판응집을억제시키는효과를가지고있지않은반면트리플루살의대사물은혈소판응집을억제시키는효과를나타낼뿐만아니라 48시간정도의긴반감기를가지고있어작용이오랫동안지속된다. TACIP 연구에서뇌경색환자를트리플루잘 600 mg (300 mg 1일 2회 ) 투여군과아스피린 325 mg 투여군으로나누어비교하였을때뇌경색, 심근경색, 혈관성사망의발생률에유의한차이가없었다. 하지만출혈성합병증의발생은트리플루잘군에서유의하게낮은것으로조사되었으며, 22 같은방법으로시행된 TAPIRSS 연구에서도 TACIP 연구와같은결과가도출되었다. 23 하지만아스피린의낮은약제비용을감안하였을때트리플루잘을일차예방약으로권고하기에는부족한점이있다. 따라서국내뇌졸중진료지침에서는트리플루잘을아스피린이나클로피도그렐을사용하기어려운경우에사용할것을권고하고있고, 실로스타졸과마찬가지로뇌출혈을포함한심각한출혈의위험이있는환자를대상으로사용할것을추천하고있다. (5) 항혈소판제병합치료뇌경색환자의이차예방을위하여항혈소판제를복합적으로투여하는것이단독으로투여하는것와비교하여보다효과적인지를알아보기위한연구가지속적으로시도되어왔으며, 가장많은연구가시행된항혈소판제의조합은클로피도그렐과아스피린의복합사용이다. 하지만클로피도그렐과아스피린의복합사용에대한임상시험의경우기대에미치지못하는결과가보고되었다. 7,599 명의뇌경색환자를대상으로클로피도그렐 75 mg과아스피린 75 mg을복합사용한군과클로피도그렐 75 mg을단독으로사용한군을비교한 MATCH 연구는재발방지에있어유의한효과없이출혈성부작용만이증가하는결과를나타내었고, 24 클로피도그렐 75 mg과아스피린 75 162 mg을복합사용한군과같은용량의아스피린만을사용한군을비교한 CHARISMA 연구에서도복합사용의우월한효과는관찰되지않았다. 25 최근열공성뇌경색환자를대상으로클로피도그렐 75 mg과아스피린 325 mg 의복합사용군과아스피린 325 mg의단독사용군을비교한 SPS3 연구의결과가보고되었는데이전의결과와마찬가지로재발성뇌경색의감소없이출혈성부작용을 2배가량증가시키는것으로나타났다. 26 따라서뇌경색환자의이차예방을위하여클로피도그렐과아스피린의복합투여는특별한상황을제외하고는사용을하지않는것이바람직하다. 다만경동맥또는중대뇌동맥에 50% 이상의협착으로인해발생한뇌경색의경우클로피도그렐과아스피린의복합투여가아스피린단독투여와비교하여혈 79
Brain & NeuroRehabilitation 2014; 7: 76-85 관의안정성을효과적으로회복시킬가능성을보여주었으므로이러한환자들을대상으로치료자의판단에의해선택적으로사용될수는있으나득보다실이더클것인가에대한충분한고려가필요하다. 27,28 (6) 요약아스피린과클로피도그렐은뇌경색의이차예방을위하여일차로사용이가능한약제이며, 아스피린의경우급성기에사용했을때유일하게효과를나타낸약제이므로약제의변경없이지속적으로사용할수있다는장점이있는반면위장출혈의위험성이있어주의가요망된다. 클로피도그렐은아스피린과유사한효능을보이지만출혈성부작용이적고고위험군환자에서아스피린대비우수한효과를나타내는장점이있다. 티클로피딘은뇌경색의재발에있어서아스피린보다우월한효과를보이지만혈액부작용에대한주의가필요하고, 실로스타졸과트리플루잘은아스피린이나클로피도그렐을사용하기어려운경우에사용할수있는데특히출혈의위험성이높은환자에게서사용을고려할수있겠다. 2) 항응고제심장성뇌경색 (cardioembolic infarction) 은전체뇌경색의약 20% 정도를차지하는것으로보고되고있으나 29 인구의고령화및심장질환에대한진단도구의발달로인하여심장성뇌경색의비율은향후더욱증가될것으로판단된다. 색전증의위험성을높일수있는여러가지심장질환들가운데비판막성심방세동 (nonvalvular atrial fibrillation, 이하심방세동 ) 은가장대표적인질환으로뇌경색의약 16% 가심방세동으로인해발생하는것으로조사되고있다. 30-32 따라서본종설에서는심방세동으로인한심장성뇌경색의이차예방에대하여조사해보고자한다. (1) 와파린심방세동으로인한뇌경색은심장내에형성된혈전이뇌혈관으로이동하여발생하게되는데주로좌심방이나좌심방부속기 (left atrial appendage) 에서형성되는경우가많다. 죽상경화성뇌경색이나열공성뇌경색의경우혈소판의활성화가혈전의형성에있어중요한인자로작용하는반면심방세동으로인한혈전은혈액응고계의이상으로인해형성되므로응고계에작용하여혈전형성을억제하는약제가투여되어야한다. 와파린은 1930년대에개발된경구용항응고제로간에서비타민 K 길항제로작용하여응고인자 II, VII, IX, X과같이비타민 K를필요로하는단백질의합성을억제한다. 심방세동이있는환자를대상으로시행된일차예방연구 의메타분석결과를보면대조군에비하여뇌경색발생을 68% 정도유의하게감소시켰고, 33 아스피린 75 325 mg 과비교하였을때에도뇌경색의발생을 52% 정도감소시켰다. 34 이러한와파린의효과는 EAFT 연구를통하여뇌경색의이차예방에서도확인되었는데, 뇌경색환자를대상으로와파린과아스피린 300 mg을투여한결과뇌경색, 심근경색, 전신성색전증, 혈관성사망의상대위험도를아스피린대비 47% 정도감소시켰고뇌경색의발생률만놓고보았을때에는 66% 의상대위험도감소를보였다. 35 이러한항응고제의탁월한효과때문에외국및국내의뇌졸중진료지침에서는심방세동이동반된환자에게서적극적인항응고제의사용을권장하고있다 (Table 1). 와파린의적절한 PT INR 범위는 2.0 3.0으로 PT INR 2.0 이하인경우항응고제의예방효과가현저히감소하게된다. 35-37 한편뇌출혈과같은출혈성부작용은대부분 PT INR 3.0 이상에서발생하므로엄격한 PT INR의조절이매우중요하다. 38 심방세동환자에게있어서항응고제의사용유무는동반된위험인자에의해결정되는데, 향후뇌경색의발생위험을예측할수있도록고안된 CHADS 2 score (congestive heart failure 1점, hypertension 1점, age 75 years 1점, diabetes 1점, stroke 2점 ) 를이용하여 0점인경우아스피린을투여하고 1점인경우출혈의위험성을고려하여와파린또는아스피린중하나를선택하여투여하며 2점이상인경우에는항응고제를필수적으로사용하도록권고하고있다 (Table 2). 39,40 따라서뇌경색이발생한경우에는동반된위험인자가없더라도뇌경색자체만으로항응고제사용의적응증이될수있다. 한편유럽심장학회 (European society of cardiology) 의경우 2012년도진료지침개정판에서 CHA 2DS 2-VASc score (congestive heart failure 1점, hypertension 1점, age 75 years 2 점, diabetes 1점, stroke 2점, vascular disease 1점, age 65 74 years 1점, female 1점 ) 를이용하여 1점이상인경우항응고제를사용하도록하여보다적극적인사용을권장하고있다. 단, 다른위험인자없이여성인이유로 1점이부 Table 2. Prevention of Ischemic Stroke in Patients with Atrial Fibrillation Type Classification Recommendation Nonvalvular CHADS 2 score 2 Warfarin (INR 2.0 3.0) CHADS 2 score = 1 Warfarin (INR 2.0 3.0) or Aspirin CHADS 2 score = 0 Aspirin or No treatment Valvular Rheumatic valve disease Warfarin (INR 2.0 3.0) Mechanical prosthetic valve Warfarin (INR 2.5 3.5) INR: international normalized ratio, CHADS 2: congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke. 80
조한진ㆍ강태호 : 허혈성뇌졸중의이차예방을위한항혈전제치료 Fig. 3. Coagulation cascade and actions of new oral anticoagulants. TF: tissue factor. Fig. 2. Choice of anticoagulants from European society of cardiology guidelines. AF: atrial fibrillation, CHA 2DS 2-VASc: congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke, vascular disease, age 65 74 years, female. 여되는경우에는항응고제사용의적응증에서제외된다 (Fig. 2). 41 (2) 새로운경구용항응고제 와파린은많은연구를통하여뇌경색의이차예방효과가입증되었고수십년간널리사용되었지만다양한약제나음식등에의하여농도의변화가심하여 PT INR을적절하게유지하는것이쉽지않을뿐만아니라 PT INR을모니터링하기위하여반복적인혈액검사가시행되어야하는불편함이있어왔다. 이러한와파린의단점을극복하기위하여새로운항응고제가개발되었는데, 이들은응고과정의단계를선택적으로억제하여다른약물이나음식과의상호작용이적고약물효과의정기적인모니터링이필요없다는장점을가지고있다 (Fig. 3). 현재심방세동환자에게서뇌경색과전신성색전증의예방을위하여사용할수있는 3가지의새로운항응고제가국내에허가되어있다. 다비가트란은트롬빈 (thrombin) 을선택적으로억제하여항응고효과를나타내며 110 mg과 150 mg의두가지제형이있다. 경구투여 30분 2 시간이후혈중약물농도가최고에이르며혈장반감기가 7 9시간이므로하루에 2회를투약한다. 다비가트란과와파린의효과를비교한 RE-LY 연구는다비가트란 110 mg을투여한환자군, 150 mg을투여한환자군, 그리고와파린을투여한환자군으로나누어뇌경색또는전신성색전증의예방효과을비교하였는데, 110 mg를투여한경우와파린과비슷한효과를 나타내었고 150 mg을투여한경우에는와파린보다효과가더좋았다. 중대한출혈의발생은 110 mg의경우와파린에비하여약간낮았으나, 150 mg은와파린과비슷하였다. 42 리바록사반은혈액응고인자 Xa를선택적으로억제하는약제로서최고혈중농도는투약후 2 4시간이후에도달한다. 반감기는 9 13시간으로하루에 1회를투약하며심방세동환자를대상으로는 15 mg과 20 mg의두가지제형을사용할수있다. ROCKET AF 연구는심방세동환자를대상으로리바록사반과와파린의뇌졸중및전신성색전증예방효과를비교한연구로리바록사반 20 mg 이기본적으로투여되었으나신기능장애로크레아티닌청소율 (creatinine clearance, CrCl) 이 30 49 ml/min인환자를대상으로는 15 mg이사용되었다. 이연구는다른새로운항응고제를대상으로시행된연구들에비하여 CHADS 2 score가더높은고위험군의환자들을대상으로이루어졌으며리바록사반투여군에서뇌졸중및전신성색전증의발생이와파린투여군과비교하여통계적으로비열등함을증명하였다. 출혈성부작용의발생은리바록사반투여군과와파린투여군사이에차이가없는것으로나타났지만치명적인출혈이나두개내출혈은리바록사반을투약한군에서더적게발생하였다. 43 아픽사반역시리바록사반과마찬가지로혈액응고인자 Xa를선택적으로억제하여항응고효과를나타내며 2.5 mg 과 5 mg의두가지제형을 1일 2회투약한다. ARISTOTLE 연구를통하여아픽사반을투약한군과와파린을투약한군사이의뇌졸중및전신성색전증의발생률을비교하였는데기본적으로는아픽사반 5 mg이투여되었으나 80세이상, 체중 60 kg 미만, 혈장크레아티닌 1.5 mg/dl 이상가운데두가지이상을만족하는환자에게는 2.5 mg이투 81
Brain & NeuroRehabilitation 2014; 7: 76-85 여되었다. 그결과아픽사반투여군에서뇌졸중및전신성색전증의발생이와파린투여군에비하여통계적으로우월한효과를보였으나이는뇌출혈의발생이감소되어나타난결과였으며실제뇌경색의발생은양군에서차이가없었다. 심각한출혈은와파린투여군과비교하여유의하게감소되는결과를보여주었다. 44 새로운항응고제를사용함에있어가장주의해야할점은신기능의상태가저하되어있는경우출혈성부작용의위험이높아진다는것이다. 따라서투약전에 CrCl의정도를먼저확인하여약제의투여용량을결정해야하는데, 미국심장협회 (American heart association), 유럽심장학회, 유럽심장리듬협회 (European heart rhythm association) 에서권고하는진료지침에약간씩차이가있어현재까지일관된기준은없는상태이다. 40,41,45 하지만이러한권고사항들을포괄적으로보았을때 CrCl 30 49 ml/min 인경우는용량을줄여서투여하고 CrCl 30 ml/min 미만인경우에는일반적으로투여가권고되지않으며, 만약 CrCl 15 30 ml/min 인환자에게서불가피하게투여해야하는경우라면리바록사반 15 mg을투여하는것이가장안전하다. 또한새로운항응고제를투여한이후정기적으로 CrCl를확인해야하는데 CrCl 50 ml/min 이상인경우는 1년에한번, CrCl 30 49 ml/min 인경우는 6개월에한번정도확인하는것이바람직하겠다. 새로운항응고제는와파린과비교하여많은장점을보여주었으나아직임상에서사용된기간이길지않아수술전후투약방법, 복약과오 (dosing error) 시지도방법, 출혈성부작용이발생했을때대처방법등실제환자를진료하면서마주치는많은문제에대한명확한지침은없는상태이다. 최근유럽심장리듬협회에서임상의들이새로운경구용항응고제를사용함에있어흔히접할수있는문제에대하여실용적인지침을제안한바있으므로환자진료시참조하는것이도움이될것으로생각된다. 45 (3) 요약항응고제는심방세동으로인하여뇌경색이발생한환자의이차예방에탁월한효과를나타내므로 CHADS 2 또는 CHA 2DS 2-VASc score를이용하여적응증이되는경우적극적인투여가권장되며투약시 PT INR 2.0 3.0으로적절하게유지되도록하는것이중요하다. 새로운경구용항응고제가운데유일하게다비가트란 150 mg이와파린과비교하여우월한효과를나타내었고, 다비가트란 110 mg, 리바록사반, 아픽사반의경우는와파린과비슷한정도의효과를보였다. 출혈성부작용에있어서다비가트란 110 mg과아픽사반은와파린보다우수한효과를보였던반면다비가트란 150 mg과리바록사반은와파린과유의 한차이를보이지않았다. 결론 많은연구결과들을통하여항혈전제가뇌경색환자에게서재발성뇌경색, 심근경색, 혈관성사망을감소시키는데효과적이라는것이입증되어왔다. 하지만연구들마다환자의선정기준이나결과변수에차이가있어이연구들에서도출된결과를한마디로요약하여환자들에게일률적으로적용하는것은바람직하지못하다. 따라서이차예방을위한약제의선택은뇌경색의발생원인, 동반된위험인자, 출혈성부작용의위험도, 약제들의특성, 경제적인여건, 복약의순응도등을고려하여환자마다서로다르게적용하는개별화 (individualization) 된치료전략이필요하며, 향후항혈전제를대상으로하는임상연구도뇌경색환자전체를대상으로하는것이아니라특정원인이나위험인자에따라분류된아형에서유효성이있는지를확인하는방향으로시행된다면개별화된치료전략을수립하는데도움이될것으로생각된다. 참고문헌 1) Mohan KM, Wolfe CD, Rudd AG, Heuschmann PU, Kolominsky- Rabas PL, Grieve AP. Risk and cumulative risk of stroke recurrence: a systematic review and meta-analysis. Stroke. 2011;42:1489-1494 2) Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86 3) Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry. 1996;60:197-199 4) CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997;349:1641-1649 5) The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997;349:1569-1581 6) Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R. Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On be- 82
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