In quantitative coronary angiography, mean reference vessel diameter, minimal luminal diameter, lesion length, percentage of diameter stenosis, and late luminal loss were analyzed using the computer-assisted automated edge detection method.
- 3 - D. Definitions
According to coronary angiographic morphologies, coronary artery aneurysm (CAA) was defined as a localized or diffuse dilatation of a major epicardial, stented coronary artery that exceeded 1.5 times a diameter of the adjacent reference vessel at late angiography. Peri-stent contrast staining (PSS) was defined as contrast staining outside the Peri-stent contour extending to ≥20% of stent diameter measured by quantitative coronary angiography. Lesion complexity was classified according to the American Heart Association / American College of Cardiology lesion type classification. Stent fractures were defined as angiographic evidence of separation of the stent struts evaluated in multiple projections. Major adverse cardiovascular events included binary in-stent restenosis, target lesion revascularization, myocardial infarction, stent thrombosis and death.
E. Statistical analysis
Categorical data were presented as counts and percentages and compared using Pearson chi-square test, and continuous data were expressed as mean ± SD and compared using the Student t test. In order to find the independent risk factors for development of CAA or PSS, multivariable logistic regression analysis was performed. Kaplan-Meier survival analysis with log-rank significance was used for event-free survival. Cox’s regression proportional hazard ratio analysis was performed to find independent risk factors contributing for major adverse cardiovascular events. Statistical analyses were performed with SPSS 13.0 (SPSS Inc, Chicago, IL). 2-tailed p< .05 was considered statistically significant.
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III. RESULTS
A. Baseline Characteristics
There are no significant differences in baseline clinical characteristics including gender, and hypertension, smoking history in addition to laboratory findings such as cholesterol and high sensitivity C - reactive protein levels, creatinine between groups with and without CAA.
However patients with CAAs or PSS group were younger and tended to have diabetes mellitus less frequently.
Table 1. Baseline clinical characteristics between patients with and without CAAs or PSS
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Values are expressed as lesions number (percentage) or mean ± SD.
B. Angiographic findings
The CAAs and PSS were developed frequently with a drug-eluting stent compared with bare-metal stent. There was predilection among lesions of the left anterior descending artery (58 lesions, 77%) compared with the proportion of native lesions in patients without CAAs.
Whereas other angiographic characteristics such as reference vessel size, minimal lumen diameter, diameter stenosis, and stent diameter did not differ significantly between groups.
Stent length was longer in patients with CAA or PSS compared to patients without that abnormal lesion. It was interesting that Sirolimus-eluting stent was the most commonly used stent type in both groups but there were significant predominance in CAA/PSS group.
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Table 2. Angiographic characteristics between patients with and without CAAs and PSS
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Values are expressed as lesions number (percentage) or mean ± SD.
LAD, Left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.
DS, diameter stenosis; MLD, minimal luminal diameter
- 8 - BMS, bare metal stent; DES, drug-eluting stent
C. Risk Factors of CAAs & PSS
The independent risk factors for CAA or PSS identified by the multivariable logistic regression analysis were age, diabetes and stent fracture under adjustment of gender, hypertension, dyslipidemia, smoking status, stent length, stent type.
Table 3. Risk factors of CAA and PSS
OR 95% CI P value
Age 0.97 [0.94, 0.99] 0.014
Sex 1.4 [0.7, 2.6] 0.36
Diabetes 4.5 [1.3, 14.8] 0.015
Hypertension 0.6 [1.3, 14.8] 0.12
Dyslipidemia 0.8 [0.3, 2.1] 0.6
Smoking status 2.1 [0.8, 5.3] 0.12
Stent fracture 22.2 [10.5, 46.9] <0.001
Stent length 1.02 [0.6, 1.8] 0.014
Stent type 0.7 [0.3, 1.8] 0.53
Stent length: using longer stents more than 30mm Stent type: drug eluting stent
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D. Clinical outcome : CAA/PSS group versus non-CAA/PSS group
The follow-up angiographic study revealed binary restenosis were 19 cases (35%) in CAA/PSS group, whereas there were 529 patients (21%) experienced binary instent restenosis in non-CAA/PSS group (p=0.02). All cause mortality was 3.6% in CAA/PSS group but there was no event of cardiac death. Total major cardiovascular events composed binary restenosis, myocardial infarction, death was increased in CAA/PSS group, but there was no difference in all cause mortality between CAA/PSS and non-CAA/PSS group.
Table 4. Clinical coutcome : CAA/PSS vs. non-CAA/PSS group
Patients
Values are expressed as number (percentage)
- 10 -
Survival analysis using Kaplan-Meier analysis showed significant difference in event-free survival between groups according to having CAA/PSS.
Figure 1. Kaplan-Meier event-free survival curve according to CAA/PSS.
E. Clinical outcome : CAA versus PSS group
The follow-up angiographic study revealed instent restenosis in 23 lesions (46.9%) in CAA group and 6 lesions (20.7%) in the PSS group, respectively (P=0.02). Target lesion revascularization tended to occur more frequently in the CAA group than in the PSS group.
There was no event of cardiac death in CAA/PSS group but cases with acute myocardial Log-rank P=0.001
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infarction caused by stent thrombosis were 5 lesions in CAA/PSS group. Patients in CAA group experienced more frequent MACE compared with PSS group.
Table 5. Clinical outcome of CAA and PSS : Comparison of CAA vs PSS
Lesions
CAA N=49
PSS N=29
p-value
Binary instent restenosis 23 (46.9%) 6 (20.7%) 0.02
Stent thrombosis 4 (6.1%) 1 (3.4%)
MACE 24 (49%) 6 (38.5%) 0.013
Values are expressed as number (percentage)
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IV. DISCUSSION
Although the published incidence of stent-associated CAA after DES implantation ranges from 0.3% to 6%, the true overall incidence of CAA or PSS in the real world practice remains unknown because of insufficient data and study design (Aoki et al., 2008). In our study, CAAs were rarely detected (1.5% per lesion, 2.1% per patient) during the angiographic follow-up. There is a concern that CAAs develop more commonly after DES compared to BMS implantation, available data including that from our review show that there is significantly frequent CAA/PSS formation in DES lesions compared to BMS lesions (Bavry et al., 2007; Aoki et al., 2008; Paulista et al., 2008; James et al., 2009). Especially patients undergoing PCI with sirolimus-eluting stent had dominantly CAA or PSS(Stabile et al., 2004; Virmani et al., 2004). CAA/PSS lesions could be regarded as representing an abnormal vessel wall response and PSS could be regarded as a continuum of pathological process in vessel wall at the site of DES implantation (Rab et al., 1991; Bell et al., 1992;
Nebeker et al., 2006). The title the larger, the better in the BMS era might have caused more vascular injury due to the high-pressure balloon(Hill et al., 1983; Bell et al., 1992; Aoki et al., 2008); however, in the DES era, the high-pressure balloon was not routinely applied and it may have the effect of less vascular injury compared to the previous stent even though DES have the other factors such as polymeric and drug-related reactions (Köster et al., 2000;
Stabile et al., 2004; Hong et al., 2006; Bavry et al., 2007; Alfonso et al., 2009).
Several mechanisms of CAA/PSS formation after DES implantation have been proposed, yet remained to be shown as relevant in most cases. Previous studies have shown that coronary arteries might be damaged by the toxic effects of drugs and polymers in DES(Rab et al.,
- 13 -
1991; Bell et al., 1992; Slota et al., 1997; Cook et al., 2009). Virmani et al reported some cases in which late thrombosis with malapposition and aneurysmal change occurs, especially in association with a hypersensitivity reaction to SESs(Virmani et al., 2004). Based on the fact that sirolimus is eluted from the stent struts for only 6 weeks (with a half life in the tissue of 60 hours), it seems unlikely that sirolimus itself can induce long-term alterations of the vessel wall(Köster et al., 2000; Hillen et al., 2002; Hong et al., 2006; James et al., 2009).
There might be different mechanism for occurrence of CAA/PSS, the reason why CAA/PSS developed in younger and non-diabetic patients compared than non-CAA/PSS group.
Procedural factors such as longer stent length might be related with lesion complexity as well as more “stent” effect on vessel wall. In the TAXUS VI trial, involving long and complex lesions, in 1.4% of patients in the paclitaxel-eluting stent arm late acquired aneurysms developed compared with patients in bare-metal stent arm (Dawkins et al., 2005;
Nebeker et al., 2006).
Survival analysis showed significant difference in event free survival between CAA/PSS and non-CAA/PSS groups. The major cardiovascular adverse events including instent restenosis were significantly increased in CAA/PSS group compared with non-CAA/PSS group. Previous IVUS studies showed that CAA after DES implantation may be associated with DES restenosis and DES thrombosis (Hong et al., 2006; Alfonso et al., 2009).
In current analysis, DES restenosis was more increased in CAA/PSS group but all cause mortality was not increased compared with patients in non-CAA/PSS group. Several reports about clinical outcome of CAA revealed that asymptomatic patients with CAA had benign course under continued dual antiplatelet therapy and did not experience life-threatening
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problems, as our data revealed that no cardiac mortality related with CAA/PSS (Alfonso et al., 2009; Ahn et al., 2010).
In the current analysis, we used the PSS definition proposed by previous study which could be a transit phenomenon in the progression to CAA (Imai et al., 2011). There are several cases which showed progression from PSS to CAA during follow-up of angiography.
Therefore the incidences of instent restenosis or target lesion revascularization tended to be higher in lesions with CAA than in lesions with PSS, suggesting that possible inflammatory reactions underlying CAA/PSS formation might be milder in PSS than CAA, which involved in the restenosis process of DES(Rab et al., 1991; Virmani et al., 2004). Also, cumulative incidence of stent thrombosis (ST) in lesions with CAA/PSS was numerically higher than ordinary post PCI results (Hong et al., 2006). Therefore, it would be reasonable to regard patients with CAA/PSS as being at high risk for subsequent ST. These observations might suggest that common mechanisms such as chronic inflammation might be operative for both VLST and restenosis requiring TLR(Aoki et al., 2008).
There are several important limitations in this study. First, this was a retrospective observational analysis of registry data from a single center with insufficient procedural information such as ballooning or stenting pressure to investigate the relationship of barotraumas to CAA/PSS occurrence. However, because of large volume center, the number of patients enrolled was not small and all patients who came into the cardiovascular center and underwent follow up angiography were included; therefore we could minimize selection bias. Second, the number of patients with PSS as well as CAA was relatively small to evaluate a possible correlation between morphological classification and risk of VLST. Also,
- 15 -
risk stratification for VLST according to the status of antiplatelet therapy could not be conducted because of the small number of patients with CAA/PSS. At last, most importantly, the number of patients with VLST after diagnosis of CAA/PSS, as well as in the non-CAA/PSS group, was very small, rendering the estimation of the incidences of VLST relatively inaccurate. The real incidences and risk factors of VLST and myocardial infarction after CAA/PSS diagnosis should be evaluated in a larger number of patients with scheduled follow-up.
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V. CONCLUSION
In this study, CAA or PSS rarely developed after PCI with rates that have increased in DES implantation group, especially SES. Younger age and non-diabetes were clinical risk factors for CAA/PSS development and stent length was the angiographic predictor of CAA development after DES implantation. The CAAs increased the risk of instent restenosis but not in all cause mortality. PSS is a phenomenon which did not fulfill the definition of CAA which might progress to CAA and related with similar clinical outcome with CAA.
CAA/PSS group did not experience fatal cardiac clinical outcome under prolonged dual antiplatelet therapy. Further Investigations including serial imaging and clinical follow-up are required to determine proper treatment strategies.
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REFERENCES
1. Ahn CM, Hong BK, Kim JY, Min PK, Yoon YW, Lee BK, Kwon HM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y, Shim WH, Cho SY, Kim BK, Oh S, Jeon DW, Yang JY, Jung JH: Incidence and natural history of coronary artery aneurysm developing after drug-eluting stent implantation. Am Heart J 160: 987-994, 2010
2. Alfonso F, Perez-Vizcayno MJ, Ruiz M, Suarez A, Cazares M, Hernandez R, Escaned J, Banuelos C, Jimenez-Quevedo P, Macaya C: Coronary aneurysms after drug-eluting stent
implantation: clinical, angiographic, and intravascular ultrasound findings. J Am Coll Cardiol 53: 2053-2060, 2009
3. Aoki J, Kirtane A, Leon MB, Dangas G: Coronary artery aneurysms after drug-eluting stent implantation. JACC Cardiovasc Interv 1:
14-21, 2008
4. Bavry AA, Chiu JH, Jefferson BK, Karha J, Bhatt DL, Ellis SG, Whitlow PL: Development of coronary aneurysm after drug-eluting stent implantation. Ann Intern Med 146: 230-232, 2007
5. Bell MR, Garratt KN, Bresnahan JF, Edwards WD, Holmes Jr DR:
Relation of deep arterial resection and coronary artery aneurysms after directional coronary atherectomy. J Am Coll Cardiol 20: 1474-1481, 1992
6. Cook S, Ladich E, Nakazawa G, Eshtehardi P, Neidhart M, Vogel R, Togni M, Wenaweser P, Billinger M, Seiler C, Gay S, Meier B,
Pichler WJ, Juni P, Virmani R, Windecker S: Correlation of
intravascular ultrasound findings with histopathological analysis of
- 18 -
thrombus aspirates in patients with very late drug-eluting stent thrombosis. Circulation 120: 391-399, 2009
7. Dawkins KD, Grube E, Guagliumi G, Banning AP, Zmudka K,
Colombo A, Thuesen L, Hauptman K, Marco J, Wijns W, Popma JJ, Koglin J, Russell ME: Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: support for the use of drug-eluting stents in contemporary clinical practice. Circulation 112: 3306-3313, 2005
8. Hill JA, Margolis JR, Feldman RL: Coronary arterial aneurysm
formation after balloon angioplasty. American Journal of Cardiology 52: 261-264, 1983
9. Hillen U, Haude M, Erbel R, Goos M: Evaluation of metal allergies in patients with coronary stents. Contact Dermatitis 47: 353-356, 2002
10. Hong MK, Mintz GS, Lee CW, Park DW, Park KM, Lee BK, Kim YH, Song JM, Han KH, Kang DH, Cheong SS, Song JK, Kim JJ, Park SW, Park SJ: Late stent malapposition after drug-eluting stent implantation: an intravascular ultrasound analysis with long-term follow-up. Circulation 113: 414-419, 2006
11. Imai M, Kadota K, Goto T, Fujii S, Yamamoto H, Fuku Y, Hosogi S, Hirono A, Tanaka H, Tada T, Morimoto T, Shiomi H, Kozuma K, Inoue K, Suzuki N, Kimura T, Mitsudo K: Incidence, risk factors, and clinical sequelae of angiographic peri-stent contrast staining after sirolimus-eluting stent implantation. Circulation 123: 2382-2391, 2011
12. James SK, Stenestrand U, Lindback J, Carlsson J, Schersten F,
Nilsson T, Wallentin L, Lagerqvist B: Long-term safety and efficacy
- 19 -
of drug-eluting versus bare-metal stents in Sweden. N Engl J Med 360: 1933-1945, 2009
13. Köster R, Vieluf D, Kiehn M, Sommerauer M, Kahler J, Baldus S, Meinertz T, Hamm CW: Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet 356: 1895-1897, 2000
14. Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, Davidson CJ, McKoy JM, Raisch DW, Whisenant BK, Yarnold PR, Belknap SM, West DP, Gage JE, Morse RE, Gligoric G, Davidson L, Feldman MD: Hypersensitivity cases associated with drug-eluting coronary stents: A review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol 47: 175-181, 2006
15. Paulista PP, Paulista PH, Centemero MP, Feres F: [Coronary aneurysm after drug-eluting stent implantation]. Rev Bras Cir Cardiovasc 23: 126-128, 2008
16. Rab ST, King SB, 3rd, Roubin GS, Carlin S, Hearn JA, Douglas JS, Jr.: Coronary aneurysms after stent placement: a suggestion of altered vessel wall healing in the presence of anti-inflammatory agents. J Am Coll Cardiol 18: 1524-1528, 1991
17. Slota PA, Fischman DL, Savage MP, Rake R, Goldberg S:
Frequency and outcome of development of coronary artery aneurysm after intracoronary stent placement and angioplasty.
American Journal of Cardiology 79: 1104-1106, 1997
18. Stabile E, Escolar E, Weigold G, Weissman NJ, Satler LF, Pichard AD, Suddath WO, Kent KM, Waksman R: Marked malapposition and aneurysm formation after sirolimus-eluting coronary stent
implantation. Circulation 110: e47-48, 2004
- 20 -
19. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T,
Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD: Localized
Hypersensitivity and Late Coronary Thrombosis Secondary to a
Sirolimus-Eluting Stent. Circulation 109: 701-705, 2004
- 21 - - 국문요약 –
관상 동맥 성형술 후 발생하는 관동맥류의 임상적 결과 및 예측인자 분석
아주대학교 대학원의학과 한 은 진
(지도교수: 탁 승 제)
관상동맥 성형술 후 발생하는 관동맥류 및 스텐트 주변 조영 소견은 관상동맥 성형술 이후 발생하는 주요 임상 사건의 발생, 즉 병변내 재관류 증가, 스텐트 내 혈전증에 의한 급성 심근 경색, 심인성 사망의 빈도가 증가하는 것과 연관된 다는 보고가 있어 주의를 요하였다. 하지만 최근 약물 용출 스텐트 삽입술을 시 행한 환자들의 대규모 임상 연구를 통한 보고에서는 이중 항 혈소판제를 지속적 으로 사용하는 경우 임상 경과가 양호하였던 것을 보고하였다. 실제 의료 환경에 서의 관상동맥 성형술 이후 발생하는 관동맥류 및 스텐트 주변 조영의 발생 빈 도와 발생에 미치는 요인 및 임상 결과를 확인하기 위하여 2003년 1월부터 2010 년 12월까지 아주대학교 병원 순환기내과에 내원하여 관상동맥 성형술을 시행 받은 환자 중 추적 관동맥 조영술을 시행한 환자 2659명을 분석하여 관동맥류 및 스텐트 주변 조영 소견이 나타난 54명의 환자 78 병변을 분석하였다. 관동맥 류 및 스텐트 주변 조영 소견이 나타난 환자는 전체의 2.1%, 병변은 전체 병변의
- 22 -