佐他莫司与西罗莫司洗脱支架血栓风险均低

《柳叶刀》(Lancet)8月27日在线发表且同时在欧洲心脏病学会(ESC)2012年会上公布的一项大型随机对照研究显示，佐他莫司洗脱支架(Z-ES，Endeavor)的支架内血栓形成发生率与西罗莫司洗脱支架(S-ES，Cypher)一样低。在3年内，两组的血栓形成发生率均低于2%。此外，两组在总死亡率、心肌梗死(MI)和心脏性死亡方面均无显著差异(Lancet Aug. 27, 2012 [doi: 10.1016/S0140-6736(12)61336-1])。

PROTECT研究由日内瓦大学的Edoardo Camenzind博士及其同事进行，纳入了8,709例接受择期、非择期或紧急冠状动脉支架置入术的患者。患者的平均年龄为63岁。行支架置入术的最常见原因为心肌梗死(MI)(26%)，其他原因为不稳定型或稳定型心绞痛或无症状心肌缺血。

出院时，96%的患者接受双联抗血小板治疗，这一比例在1年时降至88%，2年时降至37%，3年时降至30%。

随访结束时，Z-ES组明确或可能的支架内血栓形成发生率为1.4%(61例)，与预期值1.5%相差不大，而S-ES组该发生率为1.8%(75例)，低于预期值2.5%；两组差异不显著。两组在次要终点(总死亡率和非致死性MI、或心脏性死亡和非致死性MI)方面也无显著差异。

该研究观察到血栓形成与时间相关。在术后1个月，Z-ES组和S-ES组分别有31例和26例患者出现明确或可能的血栓形成。术后31~360天，Z-ES组和S-ES组的这一数字分别为17例和5例。在随访的最后2年内，Z-ES组和S-ES组的这一数字分别为13例和44例。

在整个研究期间，Z-ES组明确支架内血栓形成发生率低于S-ES组(0.7% vs. 1.2%)，但SES组靶血管血运重建发生率低于Z-ES组(7.1% vs. 8.2%)，但这些差异均不显著。

这些结果也存在时间相关的差异。在研究的第1年内，Z-ES组的靶血管血运重建发生率显著高于S-ES组(5.8% vs. 3.4%)，但在第2~3年，则正好相反(S-ES组4.0% vs. Z-ES组2.9%)。

研究者表示，鉴于支架内血栓形成的临床表现(通常为死亡或MI)较为严重，这类事件任何程度的降低均具有临床意义，因此尽管该研究所观察到的差异轻微，但仍具有重要意义。此外，世界范围内已有数十万患者置入这些支架，因此该研究结果对这些患者也具有参考价值。随访将继续进行2年，这将有助于确定明确的和明确或可能的支架内血栓形成曲线是否会进一步偏离，以及这种偏离是否会导致临床安全性预后方面的差异。

该研究获Endeavor支架生产商美敦力公司资助。Camenzind博士声明无经济利益冲突，但其他研究者声明从美敦力及其他药企和器械生产商获得酬金。

随刊述评：佐他莫司还是西罗莫司？已变成意义不大的问题

德国心脏中心的心血管介入医生Robert A. Byrne博士及其同事表示，自2007年该研究启动以来，研究中所用的这两种支架在世界范围内已被疗效更高且支架内血栓形成发生率更低的新型装置广泛取代。这种转变无疑限制了该研究结果对当前临床实践的指导意义。该研究在主要和次要终点方面均未观察到这两种支架之间存在差异，因此从这方面来讲，研究结果也具有局限性。此外，研究者重点强调两种支架在时间相关的支架内血栓形成发生率方面的差异，这并不可取。这种根据时间得出的结论似乎是永无休止的争议问题。

Byrne博士声明无经济利益冲突，但其同事声明从美敦力及其他药企和器械生产商获得演讲费。

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By: MICHELE G. SULLIVAN, Cardiology News Digital Network

Rates of stent thrombosis were low and similar between patients implanted with zotarolimus-eluting stents and those with sirolimus-eluting stents in a large, randomized controlled trial.

Over a 3-year period, thrombosis occurred in less than 2% of each group. Furthermore, there were no significant between-group differences in overall mortality, myocardial infarction, or cardiac death, Dr. Edoardo Camenzind and colleagues reported in the August 27 online issue of the Lancet. The study results were simultaneously presented at the annual congress of the European Society of Cardiology.

The 1.4% rate of stent thrombosis noted with the zotarolimus stent matched the expected rate of 1.5%, but the rate with the sirolimus stent was lower than anticipated, with an expected rate of 2.5% and an observed rate of 1.8%, wrote Dr. Camenzind of the University of Geneva and his coauthors (Lancet Aug. 27, 2012 [doi: 10.1016/S0140-6736(12)61336-1]).

But the Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial (PROTECT) did show some time-related differences between the two devices, finding more thromboses in the first year with the zotarolimus stent (Z-ES, Endeavor), but more in years 2 and 3 with the sirolimus stent (S-ES, Cypher).

"Interestingly, the pattern of events over time was distributed differentially, with both devices having the same incidence of stent thrombosis, but C-ES having fewer late, but more very late, stent thrombosis than Z-ES," the authors noted. "The higher incidence of late stent thrombosis in the Z-ES group was driven by an increased incidence of definite stent thrombosis."

The study enrolled 8,709 patients who underwent an elective, unplanned, or emergency stenting of coronary arteries. They were a mean of 63 years old. The most common reason for stent placement was acute myocardial infarction (26%). Other reasons for stenting included unstable or stable angina or silent ischemia.

At discharge, 96% were on dual antiplatelet therapy. This number had dropped to 88% at 1 year, 37% at 2 years, and 30% by 3 years.

At the end of follow-up, definite or probable stent thrombosis had occurred in 61 (1.4%) of the Z-ES group and in 75 (1.8%) of the S-ES group – not a significant difference. Nor were there significant differences in any of the main secondary end points of total death and nonfatal MI, or cardiac death and nonfatal MI.

The study revealed a distinct time-associated pattern of thrombosis. In the first month after the procedure, definite or probable thrombosis occurred in 31 of the Z-ES group and 26 of the S-ES group. From days 31 to 360, the numbers were 17 and 5, respectively. During the last 2 years of follow-up, there were 13 definite or probable thromboses in the Z-ES group and 44 in the S-ES group.

Over the entire study period, the Z-ES was associated with a lower incidence of definite stent thrombosis than the S-ES (0.7% vs. 1.2%), but the S-ES had a lower incidence of target vessel revascularization (7.1% vs. 8.2%). None of these differences were significant, however.

Those findings also showed time-related differences. During the first year of the study, significantly more target vessel revascularizations occurred in the Z-ES group (5.8% vs. 3.4%), but that difference was reversed in years 2-3 (4.0% S-ES vs. 2.9% Z-ES).

Although slight, the differences observed in PROTECT are still important, the investigators said: "Given the seriousness of clinical manifestation of stent thrombosis, typically death or myocardial infarction, any reduction has clinical relevance. Furthermore, hundreds of thousands of patients worldwide have been implanted with these devices."

Follow-up on these patients will continue for another 2 years. This "will show whether curves of definite and definite or probable stent thrombosis further diverge and will translate into differences in clinical safety outcomes," Dr. Camenzind and his associates said.

The study was funded by Medtronic, maker of the Endeavor stent. Dr. Camenzind had no financial disclosures but several of his coauthors noted receiving financial remuneration from Medtronic and from other pharmaceutical companies and device manufacturers.

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Zotarolimus or Sirolimus? That Is the (Now Moot) Question

Results of the PROTECT study are academic now, but perhaps still interesting to physicians caring for the millions of patients who still carry the zotarolimus- and sirolimus-eluting stents, Dr. Robert A. Byrne and his colleagues wrote in an accompanying editorial.

"Since the study began in 2007, a significant shift has occurred in interventional cardiology practice, such that both study devices have largely fallen out of use worldwide, being superseded by new devices with increased efficacy and decreased rates of stent thrombosis," wrote Dr. Byrne. "This shift undoubtedly limits the immediate clinical relevance of these findings."

Dr. Byrne and his coauthors also said that PROTECT investigators problematically searched too hard for any interesting tidbits in their secondary analyses.

"The authors report a negative clinical trial with no differences in the primary endpoint. This finding is supported by an absence of difference in the main secondary endpoints. For this reason, the value of all additional analyses presented in the article is restricted, and to highlight differences in the temporal distribution of stent thrombosis between the two devices is inadvisable. This analysis was not prespecified and the probability of a chance finding is high."

The time-driven conclusions can be seeing as a never-ending division problem, they suggested.

"If one notes that stent thrombosis beyond 1 year is higher with [the sirolimus-eluting stent] ... then one must also observe that the number of patients with stent thrombosis up to 1 year is higher with [the zotarolimus-eluting stent]. To take the argument further, one must then question whether it is preferable for a patient to suffer stent thrombosis during the first year or after it: reductio ad absurdum" – arguing on and on that the finding is true because a false result follows from its denial, they wrote.

DR. BYRNE is an interventional cardiologist at Deutsches Herzzentrum, Munich. He had no financial disclosures, but a coauthor disclosed that he has received lecture fees from Medtronic, as well as other device and pharmaceutical companies.