Late Thrombosis in Drug Eluting Stents (DES) Late Thrombosis in Drug Eluting Stents (DES). Meta-Analysis of All Published Case Reports Artang R, Khadim G, Dieter RS Medical College of Wisconsin Milwaukee, WI Please double click on the slide for closer view. Mr. Chairman, ladies and gentlemen Authors have no relationships to disclose

Background Number of Reported Late Stent Thrombosis (LST) in clinical trials with DES Patient number Follow up months Paclitaxel Sirolimus All DES Mauri et al. NEJM 2007 2278 48 11 7 18 Iakovou et al. JAMA 2005 4495 9 10 5 15 Kuchulakanti et al. Circ 2006 2972 12 - 8 The issue of late thrombosis in drug eluting stents is of major concern. The number of the reported definite cases in the randomized and real word trials are actually small, ranging from 8 to 18 cases The study by Mauri et al, is a meta-analysis of major randomized trials recently published The bottom 2 studies are real world trials from Europe and US Beside the link to premature discontinuation of antiplatelet agents additional details surrounding the late stent thrombosis are not specified.

Systematic review of Case reports of Late stent thrombosis Sources: Background Systematic review of Case reports of Late stent thrombosis Sources: Medline search using key word “drug eluting stent” (all languages since 2000-present). ACC, AHA and TCT Abstracts 2003-present We hypothesized that more details could be available in published case reports We did a systematic review of all published case reports of late stent thrombosis by Medline search using the key word “ drug eluting stent “ in any language as well as screening the abstracts from ACC, AHA and TCT meetings since 2003.

Methods: 845 positive matches for “drug eluting stents”, were found, including the randomized and the real world trials. Cases were included only if the following information were available: The stent thrombosis occurred after 30 days. (Late and Very Late) Thrombosis was angiographically verified. (Definite) Time from stent deployment to clinical event. Stent type, diameter and length. Stented vessel. Antiplatelet regimen at the time of event. Reports from collaborating groups were cross-referenced to avoid counting the same case more than once. Data presented as medians and total range In March of 2006, 845 matches were found for the key word DES, including the randomized and real world trials. All matches were screened for case reports of late thrombosis and were included only if the following information were available: - thrombosis occurred at least 30 days after deployment - It was angiographically verified - Time from deployment to clinical event - Stent type, size, diameter, stented vessel and - Antiplatelet regimen at the time of event Reports from collaborating groups were cross referenced to avoid counting the same case more than once.

Event Related to Surgical Procedure Results: Over all Sirolimus Paclitaxel p value Number of patients 36 16 20 ns Age 57 (33-85) 63 (42-85) 54 (33-76) Male Gender 97% 93% 100% MI at presentation 92% 87% 95% Death 8% 12% 5% small sample size Event Related to Surgical Procedure 42% 44% 40% LAD RCA Circ 74% 17% 9% 73% 13% 75% 20% 36 cases were included in this analysis. Median age was 57 97% were males 92% had acute MI at presentation 8% died 42% were related to a surgical procedure ranging from routine elective colonoscopy or dental procedures to open abdominal surgery. 74% occurred in LAD 17% in RCA and 9% in the circumflex artery No statistical difference was observed between the 2 types of stents Artang ACC 2007

Results: 55% 42% 23 3.0 242 7 30 Artang ACC 2007 Over all n=36 Sirolimus n=16 Paclitaxel n=20 p value Clopidogrel & Aspirin discontinued 55% ns Clopidogrel discontinued 42% 40% 45% Stent length mm 23 (8-68) (8-46) 20 (12-68) Stent diameter mm 3.0 (2.25-3.5) (2.5-3.5) Time to event days 242 (39-927) 240 (49-570) 289 Time from disc. dual antiplatelet agents to event days 7 (3-150) 10 (4-45) Time from disc. clopidogrel to event (days) 30 (14-690) 127 (15-84) small sample size In 55% of the cases both antiplatelet agents were stopped In 42% only clopidogrel was stopped In 3% none of the agents were stopped The mean stent length 23 mm Mean stent diameter 3.0 mm The median time from deployment to event was 242 days about 8 months Median time to event if both antiplatelet agents were stopped was 7 days Median time to event if only clopidogrel was stopped was 30 days Again no statistical difference was observed between the 2 types of stents Artang ACC 2007

Results: p < 0.001 Time from disc. antiplatelet agent to event days This figure demonstrates time from discontinuation of antiplatelet regimen to event if both agents were stopped vs if only clopidogrel was stopped. The Y axis is in days. 7 days vs 30 days. This difference was statistically significant. Artang ACC 2007

Results: Artang ACC 2007 Surgical procedure Time from disc. antiplatelet agent to event days All of the cases where the event was related to a surgical procedure occurred in the group were both agents were stopped. Artang ACC 2007

Observation 1 out of 36 cases was a female This may represent selection or publication bias. 30% of the patients included in the RCT were females. Review of the published data from randomized and real world trials: Gender was not specified in patients with LST. Only one out 36 cases was a female This may represent a selection or publication bias. We know that about 30% of the patients who received DES in the randomized trials were females. We went back and reviewed the published data from the randomized and real world trials. And we noticed that gender was not specified among patients with LST. Artang ACC 2007

Limitations: This study is limited due to small number of reported cases. We did however gather 36 cases of definite late and very late stent thrombosis. Risk factors such as diabetes, lesion type, race, procedure time, off label use of DES, and circumstances prior to discontinuation of antiplatelet agents were not available in all references. This study is limited due to small number of cases. We did however gather 36 cases of definite late and very late stent thrombosis in DES. Risk factors such as diabetes, lesion type, race, procedure time, off label use of DES, circumstances prior to discontinuation of antiplatelet regimen were not available in all of references. Artang ACC 2007

Conclusion Discontinuation of dual antiplatelet agents appeared to be associated with earlier onset of stent thrombosis as compared to discontinuation of clopidogrel alone. Efforts should be made to maintain patients with DES on aspirin for routine surgical procedures. In this data set we observed no statistical difference between sirolimus and paclitaxel eluting stents. Gender differences in LST may require further investigation. In conclusion Discontinuation of dual antiplatelet agents appeared to be associated with earlier onset of stent thrombosis as compared to discontinuation of clopidogrel alone. Efforts should be made to maintain patients with DES on aspirin for routine surgical procedures. In this data set we observed no statistical difference between sirolimus and paclitaxel eluting stents Gender differences in LST may require further investigation, Artang ACC 2007

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