支架置入后短程抗血小板不劣于长程治疗

旧金山——在经导管心血管治疗年会上，来自以开创性支架技术著称的巴西圣保罗Dante Pazzanese心血管病研究所的心脏介入专家Fausto Feres博士及其同事报告称，在一项纳入了3,120例患者的前瞻性临床随机试验中，第二代佐他莫司药物洗脱支架置入后无论是采用3个月还是12个月的双联抗血小板治疗(DAPT)，术后1年的不良事件发生率相似。


Fausto Feres博士

这项名为OPTIMIZE (在现实临床实践中优化Endeavor佐他莫司洗脱支架置入后氯吡格雷治疗的持续时间)的试验在33个临床基地招募接受经皮冠脉介入术加第二代Endeavor佐他莫司洗脱支架置入术的巴西患者。所有患者都存在稳定性或不稳定性心绞痛或者近期有心肌梗死(MI)病史，至少有1处冠脉病变适合接受PCI加Endeavor支架置入治疗，并且原有血管直径至少达到2.5 mm且狭窄>50%。该患者队列主要由稳定性冠状动脉疾病且急性冠脉综合征(ACS)风险较低的患者组成。

该试验排除了因ST段抬高型MI接受直接或拯救性PCI、病灶位于大隐静脉桥、既往已经接受过PCI加药物洗脱支架置入术以及符合其他不常见排除标准的患者。

以1:1的比例将患者随机分配至接受3个月或12个月的阿司匹林加氯吡格雷(75mg/日) DAPT治疗，以降低出现血栓形成事件的风险。现行指南建议患者在支架置入后行12个月的DAPT治疗。每组均有98%的患者提供了1年随访数据。

结果显示，每组均有超过99%的患者完成了3个月的DAPT治疗。支架置入术后1年，3个月组和12个月组分别有6%和97%的患者仍在接受DAPT治疗。

随访1年后，3个月组和12个月组分别有6%和5.8%的患者出现了复合主要终点中的1项或多项不良事件：任何原因导致的死亡、MI、卒中或大出血。而且，复合终点中各单项事件的发生率也没有显著的组间差异。3个月组和12个月组的全因死亡率分别为1.9%和1.7%；MI的发生率分别为0.8%和0.6%；卒中的发生率分别为0.3%和0.1%；大出血的发生率分别为0.2%和0.4%。里程碑分析显示，术后3个月这些终点也没有显著的组间差异。

在这次由美国心脏学会联合主办的会议上，Feres博士报告称，术后1年，3个月组和12个月组明确或疑似支架内血栓形成的发生率分别为0.3%和0.1%，差异没有统计学意义。3个月组和12个月组1年内出血的发生率分别为0.4%和1%，12个月组的出血风险似乎更高。

1年后次要结局也表明，其他临床不良事件的发生率也没有显著的组间差异。3个月组和12个月组分别有8%和7%的患者出现了1项或多项主要冠脉不良事件：死亡、MI、紧急冠状动脉旁路移植术或靶病变血运重建术。每组各有3%的患者死亡，各有3%出现MI，各有4%出现心源性死亡或MI，各有0.3%出现卒中。3个月组和12个月组分别有0.6%和0.9%的患者出现大出血，分别有3.5%和3.2%的患者接受了靶病变血运重建术。

此外，亚组分析也得出了类似的结果。

在这项试验中，两组患者主要结局的发生率均低于预期。研究者预计发生率为9%，但实际上两组都只有6%左右。不过，术后1年，3个月组和12个月组主要冠脉不良事件的发生率分别达到了8.4%和7.5%。

Feres博士说，对于部分出血并发症风险较高的患者，比如老年患者以及有出血事件病史的患者，临床医生认为在达到所建议的治疗时间之前可能必须提前终止DAPT，上述研究结果支持了他们的这种处理方法。

Feres博士在接受采访时提到，先前在意大利和韩国开展的2项短程DAPT治疗研究中，接受药物洗脱支架置入的患者分别接受6个月或12个月的DAPT治疗。还有一项试验比较了3个月和12个月的DAPT治疗，但同时也比较了2种不同的支架。所有研究都表明DAPT治疗12个月可能不总是必要的。

OPTIMIZE试验的结果同步在线发表在《JAMA》上(JAMA 2013 Oct. 31 [doi: 10.1001/jama.2013.282183])。

Feres博士声明与BioSensors、礼来和美敦力公司之间存在经济利益关系，美敦力公司是Endeavor支架的生产商，也是这项研究的资助方。

专家点评：试验效能不足以改变临床实践

对于这项试验，我的担心在于采用综合了疗效(缺血性事件)和安全性(出血性事件)指标的复合主要终点来进行非劣性比较。虽然选择这类终点可以提高检验效能，但由于其单项成分之间缺乏实际或预期的一致性，所以这是有问题的。当存在一致的差异时，这些单项成分就不足以确定是否存在有临床意义的组间差异。

在OPTIMIZE试验中，3个月治疗组缺血性事件相对增加10%~14%被大出血事件相对减少12%所抵消。在90天里程碑分析中，支架内血栓形成和大出血事件的数据图示也反映了这种相抵消的关系。90天后，两组的事件发生率都绝对增加了0.2%，提示3个月组支架内血栓形成的发生率相对增加4倍，12个月组大出血的发生率相对增加2倍。

事实上，置信区间的上限允许短程治疗组支架内血栓形成的发生率增加35倍，长程治疗组大出血的发生率增加8倍。值得注意的是，OPTIMIZE排除了开始试验前30天内出现了生物标志物阳性ACS的患者，而这类患者出现支架内血栓形成的风险最高；纳入的受试者平均年龄为61岁，这类患者的出现出血事件的风险本身就比较低。

试验所排除的生物标志物阳性ACS患者在当前临床实践中占到了相当大的比例，尤其是考虑到PCI对于ACS和稳定性缺血性心脏病的相对疗效。虽然选择氯吡格雷而不是其他新药可能是由于排除了生物标志物阳性ACS患者，但试验方案没有对负荷剂量进行标准化处理。最后，选择Endeavor支架平台也有点问题，它很难外推至其他药物洗脱支架。Endeavor已经在很大程度上被Resolute取代了，而Resolute的聚合物材料以及药物释放动力学都不同于Endeavor。

关于DAPT治疗最佳持续时间的确切结论，还需要开展校验效能更充分、纳入范围更广、更符合当前临床实际的随机对照试验。

Dean J. Kereiakes, M.D.是美国俄亥俄州心脏和血管中心的心脏介入专家。以上节选自他作为研究评论员在会上的发言。Kereiakes博士声明与Medpace、HCRI和其他企业之间存在经济利益关系。

爱思唯尔版权所有  未经授权请勿转载

By: SHERRY BOSCHERT, Cardiology News Digital Network

SAN FRANCISCO – Adverse event rates 1 year after implantation of a second-generation zotarolimus-eluting coronary stent were similar for 3,120 patients regardless of whether they took 3 months or 12 months of dual-antiplatelet therapy in a prospective trial that randomized 3,120 patients in real-world settings.

Six percent in the 3-month group and 5.8% in the 12-month group developed one or more adverse events that were included in a composite primary endpoint: death from any cause; myocardial infarction; stroke; or major bleeding, Dr. Fausto Feres and his associates reported at the Transcatheter Cardiovascular Therapeutics annual meeting. The results were significant in a noninferiority analysis.

The results should comfort clinicians who think they have to stop dual-antiplatelet therapy (DAPT) earlier than recommended in some patients who are at higher risk for bleeding complications, such as the elderly and patients with a history of hemorrhagic events, said Dr. Feres, an interventional cardiologist at the Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil, an institution known for pioneering stent procedures.

The study tapped 33 clinical sites to enroll Brazilian patients who were undergoing percutaneous coronary intervention (PCI) with the second-generation Endeavor zotarolimus-eluting stent. All patients had stable or unstable angina or a recent MI, at least one coronary lesion suitable for PCI with the Endeavor stent, and a native vessel diameter of at least 2.5 mm with stenosis greater than 50%. The cohort consisted mainly of patients with stable coronary artery disease and a low risk of acute coronary syndrome.

Equal numbers were randomized to 3 or 12 months of DAPT with aspirin and 75 mg/day of clopidogrel to reduce the risk of thrombotic events. Current guidelines call for 12 months of DAPT after stent implantation. One-year follow-up data were available for 98% in each group.

Known as the OPTIMIZE trial (Optimized Duration of Clopidogrel Therapy Following Treatment With the Endeavor Zotarolimus-Eluting Stent in Real-World Clinical Practice), the study found that more than 99% of patients in each group completed 3 months of DAPT. One year after stent implantation, 6% who had been randomized to the 3-month group were still on DAPT, as were 97% of those randomized to the 12-month group.

The individual components of the combined endpoint did not differ significantly at 1-year follow-up. All-cause mortality was seen in 1.9% and 1.7% of the 3- and 12-month therapy groups; MI rates were 0.8% and 0.6%, respectively; stroke rates were 0.3% and 0.1%; and major bleeding occurred in 0.2% and 0.4%. Landmark analyses also found no significant differences between groups for these endpoints at 3 months.

Rates of definite or probable stent thrombosis at 1 year were 0.3% in the 3-month therapy group and 0.1% in the 12-month group, which was not a significant difference. There was a trend toward higher risk of bleeding at 1 year in patients on 12 months of DAPT, seen in 1% compared with 0.4% of those on 3 months of therapy, Dr. Feres reported at the meeting, cosponsored by the American College of Cardiology.

Secondary outcomes at 1 year showed that rates of other adverse clinical events also did not differ significantly between the two groups. Eight percent in the 3-month group and 7% in the 12-month group developed one or more major adverse coronary events: death, MI, emergent coronary artery bypass grafting, or target lesion revascularization. Three percent in each group died, 3% in each developed an MI, 4% in each had either cardiac death or an MI, and 0.3% in each developed a stroke. Major bleeding occurred in 0.6% of the 3-month group and 0.9% of the 12-month group. Target lesion revascularization rates were 3.5% in the 3-month group and 3.2% in the 12-month group.

Results did not differ by subgroups.

Rates for the primary outcome were lower than expected in both arms of the trial. Investigators expected a 9% rate, not the roughly 6% rate seen in both arms. The rate of major adverse coronary events at 1 year, however, was 8.4% in the 3-month group and 7.5% in the 12-month group.

Two previous studies in Italy and Korea of shortened-duration DAPT for patients receiving drug-eluting stents compared 6 months of therapy with 12 months of therapy. One other previous trial compared 3 months with 12 months of DAPT but compared two different stents, he said. All suggested that 12 months of DAPT may not always be needed, he said in an interview.

The current study excluded patients with primary or rescue PCI for ST-segment elevation MI, lesions located in a saphenous vein graft, patients with a previous PCI with a drug-eluting stent, and other less common exclusion criteria.

The findings from OPTIMIZE were published online concurrently with Dr. Feres’ presentation (JAMA 2013 Oct. 31 [doi: 10.1001/jama.2013.282183]).

Dr. Feres reported having financial relationships with BioSensors, Eli Lilly, and Medtronic, which markets the Endeavor stent and funded the study.

View on the News
Not powered enough to change practice

My concern with this study lies with a noninferiority comparison using a composite primary endpoint that combines both efficacy (ischemic event) and safety (bleeding event) measures. Although this type of endpoint is selected to enhance power, it is problematic because of a lack of actual or expected concordance among its components. When concordant differences are present, the individual components lack power to determine if clinically meaningful differences exist.

In OPTIMIZE, a 10%-14% relative increase in ischemic events with 3 months of DAPT is counterbalanced by a 12% relative decrease in major bleeding. A counterbalance in relationship is graphically depicted in the analysis of stent thrombosis and major bleeding, with a 90-day landmark. Beyond 90 days, the absolute increase in events is 0.2% for both, which represents a fourfold relative increase in stent thrombosis with 3 months of DAPT and a twofold relative increase in major bleeding with longer therapy.

Indeed, the upper boundaries of the confidence intervals allow for a 35-fold increase in stent thrombosis with short treatment and an eightfold increase in major bleeding with longer therapy. This observation must be viewed in the context that OPTIMIZE excluded biomarker-positive acute coronary syndrome (ACS) within 30 days – those patients at greatest risk for stent thrombosis – and included subjects with an average age of 61 years – patients with a lower risk of bleeding events.

The exclusion of biomarker-positive ACS represents a significant portion of contemporary clinical practice, particularly in the context of relative efficacy for PCI and ACS vs. stable ischemic heart disease. Although the choice of clopidogrel vs. novel agents may be justified by exclusion of biomarker-positive ACS, the loading dose was not standardized by protocol. Finally, the Endeavor stent platform is problematic and difficult to extrapolate to other drug-eluting stents. Endeavor has largely been replaced by Resolute, which has a different polymer and drug-release kinetics.

More definitive conclusions about optimal DAPT duration still await the results of adequately powered, more inclusive, and contemporary randomized controlled trials.

Dean J. Kereiakes, M.D., is an interventional cardiologist at the Ohio Heart and Vascular Center, Cincinnati. These are excerpts of his remarks as discussant of the study at the meeting. Dr. Kereiakes reported financial associations with Medpace, HCRI, and other companies.