대한내과학회지 : 제 75 권제 4 호 2008 특집 (Special Review) - Perspectives of DES 약물방출스텐트의최근동향 울산대학교의과대학, 서울아산병원심장내과 김성환 홍명기 Current status of drug-eluting stents Sung-Hwan Kim, M.D. and Myeong-Ki Hong, M.D., PhD. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea The percutaneous coronary intervention (PCI) has been a great advance in the treatment of coronary artery disease since implantation of bare metal stents (BMS) decreased acute recoil and arterial shrinkage caused by balloon angioplasty. However, neointimal hyperplasia leading to in-stent restenosis after BMS implantation has been emerged a new obstacle. Recent introduction of drug-eluting stents (DES) contributes a powerful breakthrough to PCI. Many large well-controlled randomized trials have shown that DES remarkably reduces restenosis and target vessel revascularization in de novo lesions when compared with BMS. Therefore the application of DES have been expanded to the complex lesions such as left main, multi-vessel, bifurcation, in-stent restenosis, or chronic total occlusion. The safety and effectiveness of DES are still under evaluation with ongoing trials. However, some problems such as very late stent thrombosis remained to be solved. In this review article, we summarize the past, present and future of DES with updated result of clinical trials. (Korean J Med 75:370-382, 2008) Key Words: Drug-eluting stents; Percutaneous transluminal coronary angioplasty 좁아진관상동맥을물리적인방법으로직접넓혀줌으로써치료하려는관상동맥중재술의역사는 1977년 Andreas Gruentzig가세계최초로풍선확장술을시행하면서본격적으로시작되었다 1). 풍선확장술은심장병치료의패러다임을바꾸는획기적인사건이었지만, 급성폐쇄와같은심각한부작용이있었고, 높은재협착율을보여서시술대상은극히제한적이었다. 그이후무수한시행착오끝에 1986년 Puel과 Sigwart 에의해스텐트가사람에게처음으로시술되었고, 스텐트및관련기구의발달, 시술자의경험축적, 새로운항혈소판제사용등으로인해치료성적은괄목할만한성적을거듭하였다. 1993년대규모무작위임상시험이었던 BENESTENT와 STRESS 연구에서스텐트시술이풍선확장술에비해재협착율및재개통술을의미있게줄인다는사실이확인되어, 이후스텐트시술은관상동맥질환표준치료의주된축으로자리매김하게되었다 2, 3). 스텐트시술은 풍선확장술의치명적인단점이었던관상동맥의급성수축 (acute recoil) 과협착 (arterial shrinkage) 을줄였지만, 아급성혈전증 (subacute stent thrombosis) 과스텐트내신생내막형성 (neointimal hyperplasia) 이라는새로운문제점을야기시켰다. 이후고압력풍선을이용한스텐트안착 (apposition) 기술발달과함께이중항혈소판제 ( 아스피린 + 티클로피딘혹은클로피도그렐 ) 를이용한약물요법의발전으로스텐트혈전증의빈도는매우줄어들게되었다 4, 5). 스텐트를관상동맥에시술하게되면, 확장과정에서기계적인혈관손상이발생하고이는혈관평활근세포의증식및이주를불러일으켜서신생내막형성, 즉스텐트내재협착 (in-stent restenosis) 이발생하게된다. 스텐트내재협착발생을예방하기위한많은연구가시행되었고, 이런연구들중에면역억제제로개발되었던 silorimus 와항암제로쓰이는 paclitaxel 이신생내막형성을효과적으로억제함을알게되 - 370 -
- Sung-Hwan Kim, et al: Current status of drug-eluting stents - A B Figure 1. Rate of angiographic restenosis in patients with SES (A) or PES (B) as compared with those with BMS. Pivotal trials show drug-eluting stents remarkably reduce restenosis rate in de novo lesions. BMS, bare-metal stents; SES, sirolimus-eluting stents; PES, paclitaxel-eluting stents. 었다. 문제는이러한약물을전신적으로투여하는경우, 스텐트내에만약물농도가유지되는것이아니어서심각한전신적합병증을유발할가능성이크다는점이었다. 이런단점혹은합병증을극복하게위해약물을스텐트에코팅하여관상동맥에국소적으로약물농도를높이고자하는시도가있었다. 이러한시도의결과물로약물방출스텐트 (drugeluting stent) 가탄생하였지만 6), 약물이초기에한꺼번에유리되어버리는경향이있어신생내막형성이진행되는동안적절한약물농도를유지할수가없었다 7). 이러한약물동력학적인한계를극복한것이바로약물유리속도를조절할수있는중합체 (polymer) 기술의개발이었다. 이렇게기존의한계를극복한스텐트, 중합체, 약물의세가지조합이이루어짐으로해서비로소약물방출스텐트가임상에본격적으로이용되기시작하였다. 약물방출스텐트의탄생은, 이렇듯기존의한계를뛰어넘고자하는수많은노력들의집합체였고, 그이전에일반스텐트 (bare metal stents) 가등장했던것이상으로관상동맥질환의치료에획기적인변화를가져왔다. 단순병변 (de novo lesion) 에대한약물방출스텐트의초기임상시험결과 ( 그림 1) 1. Sirolimus-Eluting Stents (Cypher R, Cordis, Johnson & Johnson) Sirolimus 는체내에서 FKBP12 binding protein과 mammalian target of rapamycin (mtor) 에순차적으로결합하여, G1에서 S phase로의세포주기과정을차단하여혈관평활근증식을억제하는효과를나타낸다. Cypher R 는약물방출스 텐트중에서가장먼저임상시험이시도되었다. 8) 30명에게시도된소규모연구이기는하지만, 이연구자들은시술 4개월시점에서재협착이전혀관찰되지않았을뿐아니라, 1 년후추적관찰에서도혈관내경이거의변화없이유지되는놀라운결과를발표하였고, 단지 14개월시점에서 1예의심근경색이발생했다는초기결과를보고하였다 9). RAVEL (Randomized Study with the Sirolimus-eluting Bx Velocity Balloon Expandable Stent) 연구는약물방출스텐트와일반스텐트를비교한최초의무작위연구인데, 시술후 6개월추적관찰결과, 일반스텐트에서는 26.3% 의재협착율을보인반면, Cypher R 에서는재협착이전혀없는획기적인결과를보였다 10). 보다많은환자를대상으로시행된무작위연구인 SIRIUS (Sirolimus Eluting Stent in de Novo Coronary Lesions) 연구는각각 550명을 Cypher R 군과일반스텐트군으로무작위배정하였고, 재협착율이각각 8.9% 와 36.3% 로나타나약물방출스텐트의유용성을입증하였고, 이러한결과로 2003 년미국식약청 (FDA) 의승인을받게된다 11). 이후에계속된 E-SIRIUS, C-SIRIUS 연구에서도일관된효과를보였으며, 단순병변 (de novo lesion) 에대한 Cypher R 의효과를검증한이임상연구들을종합한결과, Cypher R 는일반스텐트에비해재협착의상대위험도를 0.11 (0.08-0.15) 로낮추는탁월한성적을보였다 12-14). 2. Paclitaxel-Eluting Stents (Taxus R, Boston Scientific) Taxus R 는 Cypher R 에이어 2004년에미국식약청의승인을받은약물방출스텐트이다. Paclitaxel 은세포내미세관 - 371 -
- 대한내과학회지 : 제 75 권제 4 호통권제 578 호 2008 - (microtubule) 을안정시켜, G1과 M phase로의이행과정을차단하는약물로항암제연구과정에서발견되었다. TAXUS- I 연구는 Taxus R 의안전성을검증하기위한소규모제 1상시험이었으며, 일반스텐트와비교했을때양호한안전성을보였다 15). 이후계속된 TAXUS-II, IV에서재협착율감소에서일관된우수성이입증되었고, 세가지연구를종합하면, Taxus R 는일반스텐트에비해재협착상대위험도를 0.25 (0.17-0.35) 로낮추는결과를보였다 14, 16, 17). 3. Sirolimus-eluting stents versus paclitaxel-eluting stents REALITY 연구는 Cypher R 와 Taxus R 의효과를직접비교한대규모무작위임상연구중하나인데, 일반병변 (de novo lesion) 에대해각각 700여명의환자를 Cypher R 군과 Taxus R 군으로무작위배정하였다. 일차종료점인 8개월후재협착율에서 Cypher R 가 Taxus R 에비해상대위험도가적은것으로나타났으나통계적의미는보이지않았으며 ( 상대위험도 0.84, p=0.31), 재개통술의필요성역시의미있는차이는없었다 (5.0% vs. 5.4%, p=0.8). 1년내주요심장사건발생또한두군에서차이가없는결과를보였다 ( 상대위험도 0.94, p=0.73) 18). 하지만다양한환자군과다양한병변에서두약물방출스텐트를비교한다른무작위임상시험들의결과는위의연구결과와상이한임상결과를보고하기도하였다. 환자대상을특별히구분하지않고다양한환자군에서시행된 SIRTAX 연구는 1012명의환자를 Cypher R 군과 Taxus R 군으로무작위배정하여 9개월후주요심장사건 ( 심장사, 심근경색, 허혈로인한재개통술 ) 을분석하였다. 심장사, 심근경색에서는양군에서유의한차이를보이지않았다. 하지만 Cypher R 군에서 9개월재협착율 (6.6% vs. 11.7%, p= 0.02) 및재개통술의빈도가더낮았고 (4.8% vs. 8.3%, p= 0.03), 이러한차이는일차종료점인 9개월주요심장사건의차이 (6.2% vs. 10.8%, p=0.009) 를보이는원인이되었다 19). 또한 ISAR-DESIRE 연구는재협착병변을가진 300명의환자를각각풍선확장술, Cypher R, Taxus R 군으로 100명씩무작위배정하고 6개월뒤재협착율을관찰하였는데, 약물방출스텐트군이재협착율방지측면에서풍선확장술군에비해단연우월한성적을보였다. 특히 Cypher R 와 Taxus R 를비교하였을때, Cypher R 가 Taxus R 에비해재협착율이낮은경향을보였을뿐아니라 (14.3% vs. 21.7%, p=0.19), 재개통술의필요성을줄이는효과가더좋은것으로나타났다 ( 상대위험도 0.42, p=0.02) 19, 20). 한편재협착군을대상으로하 는다른임상시험인 TAXI와당뇨환자만을대상으로한 ISAR-DIABETES 연구에서는양스텐트사이에병변에대한재개통술빈도에유의한차이가없는것으로나타났다 21, 22). 반면에 Long-DES-II 연구는긴병변을대상으로 Cypher R 와 Taxus R 를비교한대규모무작위연구인데, Cypher R 군에서 6 개월뒤재협착율이유의하게낮았을뿐아니라 (3.3% vs. 14.6%, p<0.001), 재개통술역시줄어듦을보고하였다 (2.4% vs. 7.2%, p=0.012) 23). 그리고일부연구들에서는가는혈관, 만성폐쇄성병변및당뇨환자에서도 Cypher R 는 Taxus R 에비해재협착율, 재개통술에서우월한성적을보였다 24-26). 약물방출스텐트를시행받은 1,084명의등록환자군을분석한 T-SEARCH 연구에서는두약물방출스텐트사이에 1년내주요심장사건발생율이의미있는차이가없음을보고하였다 27). 요약하면, Cypher R 는연구에따라통계수준의차이는있지만, 재협착율및재개통술감소측면에서 Taxus R 에비해일관되게우월한성적을보였으나, 사망등주요임상사건의발생은두군에서비슷한것으로보인다. 임상양상에따른약물방출스텐트와일반스텐트비교결과단순병변에서의우월한임상시험결과를바탕으로약물방출스텐트는점차고위험군에게서도시술되기시작하였고, 주목할만한결과를보였다. 1. ST분절상승급성심근경색증안정형협심증환자와는달리, 죽상경화반의파열및혈전생성이병태생리인 ST분절상승급성심근경색증의경우에스텐트라는이물질을삽입하였을때혈전생성을조장할수도있을것이라는우려가스텐트시술초창기에있었다. 그러나여러임상연구를통해급성심근경색증의치료에도일반스텐트시술이풍선확장술에비해재협착방지측면에서우월할뿐아니라 28-30), 적절한시간에만시행될수있다면혈전용해술에비해부작용도적고임상경과가보다우수함이입증되었다 31, 32). 약물방출스텐트는일반스텐트에비해스텐트내혈전증의빈도가높을것이라는우려가있어, 혈전에의한급성심근경색증의경우에도안전하게사용할수있는가에대한의문이제기되었다. 하지만많은임상연구에서약물방출스텐트의우수한효과가보고되었고 33), 특히 2,357명을메타분석한결과는약물방출스텐트는일반스텐트에비해 1년내주요심장사건 (9.3% vs. 17.6%, p<0.0001) 및병변에대한재개통술 (4.8% vs. 12.0%, - 372 -
- 김성환외 1 인 : 약물방출스텐트의최근동향 - p<0.0001) 을현저히줄일뿐아니라, 스텐트내혈전의빈도는일반스텐트에비해증가하지않음을보여서급성심근경색증환자에서도약물방출스텐트를안전하게사용할수있는근거가되었다 34). 이러한우호적인결과들은현재진행되고있는대규모무작위연구및장기추적연구들에서다시금확인할수있을것으로기대된다 35). 2. 당뇨당뇨는스텐트시술후재협착, 주요심장사건의발생을높이는강력한위험인자일뿐만아니라, 긴병변, 다혈관질환으로발현하는경우가많아서중재시술에어려움을겪게되는질환이다. 당뇨환자에대해서스텐트시술성적을비교한메타분석에따르면, 약물방출스텐트는일반스텐트에비해재협착위험율을 80% 이상낮추는것으로나타났다 ( 비교위험도 0.14, p<0.001) 36. ) 당뇨환자만을대상으로시행된최근의무작위연구결과역시재협착율, 주요심장사건의발생에서약물방출스텐트가일반스텐트에비해우월함을입증하였다 37, 38). 해부학적병변분류에따른약물방출스텐트와일반스텐트비교결과 1. 분지부병변 (bifurcation lesions) 분지부병변이란관상동맥이두갈래 ( 혹은세갈래 ) 로갈라지는부위에협착이있는경우를말하는데, 주된혈관 (main branch) 의병변뿐만이아니라, 가지혈관 (side branch) 의크기와혈류공급영역, 협착의정도역시임상경과에영향을주기때문에중재술이쉽지않은분야중의하나이다. 가장중요한논란거리중의하나는주된혈관의병변에대한스텐트삽입후에생기는혹은더심해지는가지혈관의협착을해결하는방법인데, 두분지에두개의스텐트를삽입하는방법과하나의스텐트를삽입하고나머지는풍선확장술을시행하는방법으로크게나뉜다. 몇몇관찰연구와소규모무작위연구결과는두방법에서재협착율에큰차이가없는것으로나타났으나대규모무작위연구결과가필요한상황이고, 스텐트간의비교에서약물방출스텐트는일반스텐트에비해우월한재협착방지효과를보였다 39, 40). 2. 만성폐쇄성병변 (chronic total occlusion) 일반적으로관상동맥의완전한협착이 3개월이상진행된것으로판단되는경우를말하며, 완전히막혀있기때문 에중재시술자체가쉽지않을뿐아니라, 일반스텐트를시술하였을경우에재협착율이 32~55% 로보고되어, 중재시술분야에서난제중의하나로남아있는분야이다 41, 42). 몇몇관찰연구에서만성폐쇄성병변에약물방출스텐트를시술하였을때, 재협착율이 2~11.1% 임이보고되었고, 무작위비교연구에서도약물방출스텐트가일반스텐트에비해재협착율을뚜렷이감소시킴을확인하였다 (11% vs. 41%, p<0.001) 43). 3. 가는혈관및긴병변 (small vessel disease and long lesions) 가는혈관 ( 직경 2.5 mm 혹은 3 mm 이하 ) 이나긴병변 ( 길이 20 mm 혹은 30 mm 이상 ) 은시술자체도어려울뿐만아니라, 재협착을예측하는강력한독립적인위험인자이다. 가는혈관을대상으로한무작위비교연구에서풍선확장술과비교해서일반스텐트는재협착율의감소에서큰효과를보이지못하였으나 44), 약물방출스텐트는대규모등록환자군연구에서일반스텐트에비해가는혈관에서재협착율을감소시키는결과를보였다 45). 약물방출스텐트와일반스텐트를무작위비교한연구에서도약물방출스텐트가재협착율을훨씬줄여줄뿐아니라 (9.8% vs. 53.1%, p<0.001), 재개통술이나심근경색의발현을의미있게감소시킴을보여주었다 46). 긴병변에서도약물방출스텐트는일반스텐트와비교하여재협착율을줄인다는사실이보고가있기는하지만 47, 48), 분지부혈관폐쇄로인한심근경색증가, 후기혈전증위험, 관상동맥우회수술시혈관이식의어려움등아직해결해야될문제가많이남아있는상황이다. 4. 재협착병변 (in-stent restenosis) 스텐트시술후재협착이발생한병변은기왕에시술된스텐트는그대로있는상태에서치료를해야한다는기술적인측면에더해또다시협착이발생할가능성이여전히높다는점에서중재시술을시행하는의사를난감하게만드는경우중의하나이다. 약물방출스텐트가없었던과거에는재협착병변에대해서혈관내방사선조사요법이권장되었으나 49), 최근에는약물방출스텐트가혈관내방사선조사요법보다재협착의재발및재개통술필요성측면에서우수한성적을보고하고있을뿐아니라 (TAXUS-V ISR, SISR 등 ) 50-52), 시술이간단하다는장점이있어재협착병변의표준치료로자리잡은상황이다. - 373 -
- The Korean Journal of Medicine: Vol. 75, No. 4, 2008 - A B Figure 2. Kaplan-Meier curves for overall survival (A) or freedom from target-vessel revascularization (B) in patients matched for propensity scores who underwent stents implantation or bypass surgery. CABG, coronary-artery bypass grafting. adapted from MAIN-COMPARE registry. Seung KB, et al. stents versus coronary-artery bypass grafting for left main coronary artery disease. N Engl J Med 358:1781-1792, 2008 5. 복재정맥편병변 (Saphenous vein grafts) 1. 보호되지않은좌주간부병변 관상동맥우회술에사용된복재정맥편병변은경피적으로접근이용이하지않을뿐아니라, 혈전을많이포함하고있거나쉽게형성하는경향이있어서, 중재시술이쉽지않을뿐아니라, 성적도좋지못하다. RRISC 연구는복재정맥편에대해스텐트의효과를비교한무작위연구인데, 75명을평균 32개월관찰한결과, 약물방출스텐트군에서일반스텐트군에비해초기재협착율은훨씬줄어드는듯보였지만 (11.4% vs. 30.6%, p=0.02) 53), 장기간관찰에서이러한효과는없어졌을뿐아니라, 오히려사망률이증가하는경향을보였다 (29% vs. 0%, p=0.0007) 54). 반면무작위연구는아니지만, 360명을 1년간전향적으로관찰한연구결과에따르면, 1년뒤주요임상사건발생은약물방출스텐트와일반스텐트사이에차이가없는것으로나타났다 (17.8% vs. 20.3%, p=0.46) 55). 몇몇관찰연구역시약물방출스텐트군에서일반스텐트군에비해혈전증을포함한심장사건의증가가관찰되지않고재협착율만을줄이는결과를보였는데 56, 57), 복재정맥편에서약물방출스텐트의효과는좀더충분한자료가필요할것으로보인다. 약물방출스텐트와관상동맥우회술간의비교결과전통적으로좌주간부병변과다혈관질환은높은시술위험성과불량한예후로인해관상동맥우회술만이적응이라고생각되어왔으나, 최근들어약물방출스텐트의괄목할만한성적들이보고되기시작하였다. 보호되지않은좌주간부병변이란, 좌주간부관상동맥의영역이관상동맥우회술등으로 보호가되지않은 즉, 해당병변을통한혈류공급이좌심실의생존에절대적인경우를의미한다. 따라서풍선이나스텐트시술과정에서생기는잠시간의혈류공급중단, 시술후급성폐쇄, 재협착등으로인한위험성은다른병변에비해비교할수없이커서, 스텐트가개발되어시술되던초창기보고에따르면, 입원기간동안사망률이 13.7%, 1년내사망률이 20.2% 에이르는매우위험한시술이었다 58). 현재까지도미국심장학회 / 미국심장협회 (ACC/AHA) 와유럽심장학회 (ESC) 진료지침에서는관상동맥우회술을시행하기어려운경우에한하여그적응증을제한하고있고 59, 60), 단지급성관동맥증후군으로혈관조영술을시행하였을때, 혈역학적으로불안정하여응급중재술이필요하다고판단되는경우에만관상동맥중재술을허용하고있다 61). 반면, 좌주간부병변은굵은혈관직경, 짧은병변길이, 적은굴곡등중재술에적합한특성도가지고있어, 중재시술의사들에게는매력적인도전목표가되어왔다 62-64). 시술자경험의축적과함께시술기구, 특히약물방출스텐트의출현은괄목할만한시술성적의향상을가져왔고, 최근에는관상동맥우회술에비견할만한성적을보이기시작하였다 65). 발표된등록환자군연구중에서가장많은환자를포함한것은 MAIN-COMPARE 연구인데, 좌주간부병변에대해스텐트시술을받은 1,102명의환자와관상동맥우회술을시행받은 1,138명의 3년간임상경과를분석하였다. MAIN-COMPARE 연구에서는, 생존률 - 374 -
- Sung-Hwan Kim, et al: Current status of drug-eluting stents - (92.1% vs. 92.2%, p=0.45) 이나주요심장사건이없는경우가 (90.7% vs. 90.8%, p=0.61) 양군사이에차이가없었고, 단지대상혈관에대한재개통술만스텐트시술군에서높았는데 (12.6% vs. 2.6%, p<0.001), 약물방출스텐트는일반스텐트보다재개통술빈도가더낮은결과를보고하였다 ( 그림 2) 66). 현재좌주간부병변에대한두개의대규모무작위임상시험이진행중인데 (SYNTAX, PRECOMBAT), 그결과에따라현재의진료지침에변화가생길가능성도있다고하겠다. 2. 다혈관질환세개의관상동맥중두개이상의혈관에협착이있는다혈관질환에서일반스텐트와관상동맥우회술을비교한메타분석에따르면, 5년생존율, 협심증증상, 재개통술의빈도에서관상동맥우회술이우월한성적을보였으며 67), 최근에발표된대규모무작위연구 (SoS) 에서도 988명을추적관찰한결과 6년생존율에서관상동맥우회술이우월한결과를보였다 (6.8% vs. 10.9%, p=0.022) 68). 현재까지도미국심장학회 / 미국심장협회진료지침은다혈관질환에서관상동맥중재술의역할을제한하고있다 ( 관상동맥증후군의경우, 좌심실기능정상이고, 당뇨가없으며, 시술에적합한해부학구조를가지고있을때 ) 61). 하지만이러한결과들은대부분일반스텐트와관상동맥우회술을비교한연구들이고, 연구당시에비해서시술경험과약물방출스텐트를비롯한기구의발달이현저한지금그대로적용하기는다소제한점이있다고하겠다. 최근들어발표된약물방출스텐트의성적은고무적인데, 3000여명을 3년간추적관찰한등록환자군분석은관상동맥우회술에비해약물방출스텐트군이사망률에는차이가없고 ( 위험율 0.85, p=0.45), 단지재개통술의필요성 ( 위험율 2.81, p<0.001) 만증가했다는결과를보고하였다 69). 현재진행중인대규모무작위연구 (SYNTAX, CARDia, FREEDOM) 결과들이발표되면, 다혈관질환에서약물방출스텐트의역할이좀더분명해지리라생각된다. 약물방출스텐트의문제점약물방출스텐트는거의모든임상양상및병변에서일반스텐트에비해재협착및주요심장사건발생을줄이는우수한성적을보였고, 약물방출스텐트의시대 (The Era of DES) 라는말이생길만큼관상동맥질환의치료행태를변화시켰지만, 장기추적관찰연구가발표되면서몇가지문제점들이알려지기시작하였다. 1. 스텐트혈전증스텐트라는금속이물질이혈액에노출되었을때, 필연적으로혈전형성의위험이증가하게된다. 이를극복하기위해, 스텐트시술초창기부터헤파린, 와파린, 항혈소판제제들이차례로이용되어왔고, 이후혈전발생율은 1990년대초 20% 대에서최근에는 0.2~1.8% 수준으로현격히감소하여임상가들에게별다른주목을받지못하고있었다. 하지만 2003년약물방출스텐트시술 6주후에발생한혈전증사례가보고되고, 2004년시술 1년후에발생한혈전증사례가차례로보고되면서, 약물방출스텐트의안전성에대한논란이확산되게되었다 70, 71). 스텐트혈전증의정의는다양하였고, 연구마다기준이다름으로해서, 결과해석에어려움이있었다. 이에미국식약청이후원하고, 미국, 유럽연구자들이중심이된연구모임인 Academic Research Consortium (ARC) 에서는 2007년스텐트혈전증의정의를제시하였고, 이후많은연구에서표준지침으로따르고있다 72). 이지침에서는스텐트혈전증을임상사건의원인으로볼수있는확신도에따라세가지로나누었고 (definite, probable, possible), 시술로부터임상사건이발생한시점을기준으로 early (1개월이내 ), late (1년이내 ), very late (1년이후 ) 로나누었다. 대규모메타분석에따르면, 시술 1년이내 (early, late) 에서는일반스텐트와약물방출스텐트사이에혈전증의빈도는 0.5% 내외로차이가없는것으로보고되었다 73, 74). 문제는 1년후에발생하는 very late 스텐트혈전증인데 75), 두약물방출스텐트군 (sirolimus-eluting stent, SES; paclitaxel-eluting stent, PES) 에서모두 very late 스텐트혈전증의빈도가일반스텐트 (bare metal stent, BMS) 에비해높음이대규모메타분석을통해보고되었다 (0.6% vs. 0%, SES vs. BMS, p=0.03; 0.7% vs. 0.2%, PES vs. BMS, p=0.03) 76). 무엇보다스텐트혈전증의심각성은, 드물지만일단발생하면심근경색으로발현하는경우가많고이에따라사망률이높아진다는사실인데, 보고에따라다르긴하지만혈전증에의한사망률은 7~45% 까지알려져있다 19, 77-81). 이러한약물방출스텐트안전성우려는 2006년유럽심장학회발표및그이후출판된논문에서약물방출스텐트가일반스텐트에비해사망, 심근경색을증가시킨다는결과로인해정점에이르렀는데 82), 이결과에대해교란변수보정, 통계처리방법등에서많은이의제기가있었고, 이후보고에의하면사망률이나심근경색의발생에서약물방출스텐트와일반스텐트사이에유의한차이가없는것으로나타났다 76, 83, 84). 요컨대, very late - 375 -
- 대한내과학회지 : 제 75 권제 4 호통권제 578 호 2008 - 스텐트혈전증의빈도는약물방출스텐트에서다소높지만, 이러한단점은재협착및재개통술빈도의감소로인한이득으로어느정도상쇄되는것으로해석할수있다. 혈전증의빈도를줄이기위해서는시술시에일반스텐트를사용할수도있는경우 ( 단순병변, 굵은혈관, 짧은병변, 당뇨없을때, 개구부 (ostial) 병변아닐때 ) 는아닌지검토하고, 적절하게항혈소판제제를투여하도록노력해야한다. 현재진행되고있는대규모연구결과들이발표되면보다많은정보를얻을수있을것으로생각된다. 2. 항혈소판제제사용아스피린은관상동맥질환환자에게평생복용하는것이권유되어왔다. 항혈소판제제에대한논란의중심은클로피도그렐의복용기간이다. 혈전증에대한우려는클로피도그렐사용기간연장에대한주된근거가되었고, 2005년미국심장학회 / 미국심장협회진료지침에서 12개월복용이이상적이다 이었던부분이 2007년진료지침에서는 약물방출스텐트시술후클로피도그렐은최소한 12개월복용해야한다 로바뀌었다. 이러한장기복용은출혈경향의증가, 비용증가, 수술전후관리의어려움등의문제를불러일으켰는데, 적절한클로피도그렐사용기간에대한문제는좀더연구가필요한상황이라고하겠다. 3. 비용-효과문제일반스텐트에비해값비싼약물방출스텐트의사용이대폭늘어나면서, 자연스레비용- 효과의문제가대두되었다. 여러가지분석결과들이보고되었고, 연구방법의어려움으로명확한결론을내리기는쉽지않은것으로보이지만 85, 86), 연구개발비의환수와경쟁스텐트의출시로최근약물방출스텐트의가격은꾸준히하락하는추세여서, 개발초기에활발했던비용- 효과논란은상당부분가라앉은것으로생각된다. 새로운약물방출스텐트 1세대약물방출스텐트라고불리는 Cypher R 와 Taxus R 이후에최근까지임상및연구용으로미국이나유럽에서승인받은스텐트는 10여종이넘는다 (Cypher Select R, Taxus Liberte R, Endeavor R, ZoMaxx R, Xicence V R, BioMatrix R, CoStar R, Supralimus R, Infinnium R, Nobori R, Janus R, Genous R...). 그중최근임상에쓰이고있거나, 주목받는것은새로운약물을이용한스텐트, 생체흡수형중합체 (bioabsorbable polymer), 생체분해형스텐트 (biodegradable stent), 혈관내피세포부착형스텐트 (endothelial progenitor cell capture stent) 이다. 1. 주목받는새로운약물 - Zotarolimus 와 Everolimus Zotarolimus 는 sirolimus 와마찬가지로 mtor 의기능을차단하는기전을가지고있는데, sirolimus 에비해조직에서의약물농도가높을것으로기대되는약물이다. 기존의약물방출스텐트와비교한최초의연구는 ENDEAVOR III 인데 436명을 8개월관찰한결과, 임상적판단에의한재개통술빈도는큰차이가없었지만 (6.3% vs. 3.5%, p=0.34), 재협착율에서 Cypher R 에비해열등함이관찰되었다 (11.7% vs. 4.3%, p=0.04) 87). Everolimus 역시 sirolimus 유사체이다. 최근에발표된대규모전향적무작위연구인 SPIRIT III 결과에의하면, everolimus-eluting stent (Xience V R ) 와 Taxus R 군에서재협착율은의미있는차이가없었지만 (4.7% vs. 8.9%, p=0.07), 1년내주요심장사건의발생을줄이는것으로보고되어 (6.0% vs. 10.3%, p=0.02), 차세대약물방출스텐트중에서현재까지가장양호한결과를보이고있다 88). 이두가지새로운스텐트는최근식약청의승인을받고, 한국에서도시술되기시작하였다. 2. 새로운스텐트디자인약물방출스텐트에서문제가된혈전증의원인으로, 약물보다는약물전달체인중합체및스텐트자체가지목되었다. 이를극복하기위해최근연구되고있는스텐트에는중합체를줄이거나혹은없애거나, 생체흡수형중합체를사용하거나, 장기적으로스텐트가분해되어없어지도록하는시도가이루어지고있다 89-92). 또한혈관내피전구세포 (endothelial progenitor cell) 을붙잡아서, 스텐트표면의내피세포안착 (reendothelialization) 과시술후혈관치유과정을촉진하려는스텐트도개발되어양호한초기성적을보고하였다 93). 맺음말 1977년시작된관상동맥중재술의역사는부딪친한계에대한도전과이에대한극복의연속이었다. 약물방출스텐트의출현으로관상동맥중재술은눈부신진보를이루었지만, 아직도혈전증, 관상동맥우회술에비해높은재협착율등의문제가있다. 현재진행되고있는장기추적관찰연구 - 376 -
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