置入支架后停用双重抗血小板治疗的风险取决于具体原因

阿姆斯特丹——据欧洲心脏病学会(ESC)2013年会上报告的大型前瞻性观察性PARIS注册研究的数据，并非所有置入冠状动脉支架的患者停止双重抗血小板治疗(DAPT)都会面临更高的支架血栓形成及其他心脏事件风险，具体情况都取决于他们停止治疗的原因。报告者为这项注册研究的负责人Roxana Mehran医生。


Roxana Mehran
 
这项囊括15家中心的国际性注册研究包括5,018例置入冠状动脉支架的患者，研究者在其经皮冠状动脉介入治疗（PCI）后对其前瞻性随访了2年，其中3/4置入了第二代药物洗脱支架。该研究的一大新发现是停用DAPT后心脏事件的风险并不一致，而是因停止治疗的原因而有很大差异。

在PCI后的前2年中，57%的患者暂时性或永久性停用DAPT。研究者们根据停止DAPT的原因将其分入3个预设的试验组之一：“停用”（discontinuation）被定义为医生向被他们判定为心脏事件风险低的患者推荐的停止DAPT，“间断”（interruption）是因手术而暂时性停止用药达14天，“中断”（disruption）是指因出血或不依从治疗而停止DAPT。在2年当中，41%的受试者停用DAPT，14%中断治疗，11%间断用药。停用发生在平均382天的DAPT治疗后，而中断治疗发生于治疗的230天时。停用组中将近90%的患者仅停止了噻吩并吡啶用药，而继续维持阿司匹林治疗；相比之下，间断治疗组和中断治疗组中分别有70%和50%的患者两药都停用。

2年重大不良心脏事件的总发生率为11.5%，其中包括心脏死亡、明确的或很可能的支架血栓形成、心肌梗死（MI）或临床诱发的靶病变血运重建。在医生指导下停用DAPT的患者经校正的风险与仍维持DAPT治疗的患者相比降低37%（P=0.004）。因手术而必须间断DAPT治疗的患者显示有心脏事件风险增加的趋势，但没有统计学意义。中断DAPT与脱离治疗的第一周内风险增加7倍有关，与第8~30天中风险增加2.2倍有关。值得关注的是，所有的心脏事件中有74%、明确的或很可能的支架血栓形成事件中有80%发生于患者维持DAPT治疗期间。

美国心脏协会发言人、Elliott Antman医生指出，PARIS注册研究表明，在直观判断谁能安全撤除DAPT方面，医生们一般都做得很好，但目前真正需要的是规范化的实践指导，而这只能从DAPT试验等大型随机临床试验中得出。但遗憾的是，该研究大约在1年后才能得到结果，这项试验包括15,000例患者，均为置入支架的患者，他们首先全部接受1年的DAPT，然后随机被分入撤除治疗组或维持治疗组。

PARIS注册研究由百时美施贵宝和赛诺菲-安万特公司资助。Mehran医生报告收到赛诺菲-安万特公司和6家以上其他制药公司或医疗器械公司提供的顾问费。发言人是赛诺菲-安万特及其他公司的带薪顾问。

本研究的结果与大会发言同步在线发表于《柳叶刀》上(doi:10.1016/50140-6736(13)61720-1)。

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By: BRUCE JANCIN, Cardiology News Digital Network

AMSTERDAM – Not all coronary stent recipients who halt dual-antiplatelet therapy face an increased risk of stent thrombosis and other cardiac events; it all depends upon the reason they stopped, according to data from the large, prospective observational PARIS registry.

Indeed, patients who discontinue dual-antiplatelet therapy (DAPT) because their physician thinks they no longer need it actually have a significantly lower risk of cardiac events than do those who stay on the medications continuously for 2 full years, PARIS registry chair Dr. Roxana Mehran reported at the annual congress of the European Society of Cardiology.
 
In contrast, stent recipients who halt DAPT because of bleeding or noncompliance are at significantly increased risk during the next 30 days, after which their risk tails off and becomes statistically nonsignificant. This risk is greatest during the first 7 days after ceasing DAPT, when it is increased sevenfold, compared with remaining on DAPT, according to Dr. Mehran, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.

She presented key results from the 15-center, multinational observational PARIS registry, in which 5,018 coronary stent recipients were prospectively followed for 2 years after percutaneous coronary intervention (PCI). Three-quarters of them had received second-generation drug-eluting stents. The novel finding in PARIS was that the risk of cardiac events after cessation of DAPT was not uniform; rather, it varied substantially depending upon the reason for the stoppage.

"Our findings show that in a real world setting, when physicians recommend discontinuation of DAPT – presumably because they feel their patients are stable – there is no increased risk of adverse events. But when patients simply don’t comply or are forced off DAPT because they are bleeding, their risk is significantly increased," Dr. Mehran said.

During the first 2 years post PCI, 57% of patients quit taking DAPT, either temporarily or permanently. Investigators classified them into one of three prespecified groups on the basis of their reason for stopping DAPT: "Discontinuation" was defined as physician-recommended cessation of DAPT for patients thought to be at low risk for cardiac events, "interruption" was a temporary halt for up to 14 days for surgery, and "disruption" of DAPT was cessation owing to bleeding or noncompliance.

Over the course of 2 years, 41% of study participants had DAPT discontinuation, 14% had disruption, and 11% had interruption. Discontinuation occurred after a mean of 382 days on DAPT, while disruption occurred at 230 days. Nearly 90% of patients in the discontinuation group stopped thienopyridine only, continuing on aspirin. In contrast, 70% of patients in the interruption group and 50% in the disruption group halted both drugs.

The 2-year overall rate of major adverse cardiac events – cardiac death, definite or probable stent thrombosis, MI, or clinically driven target lesion revascularization – was 11.5%. The adjusted risk among patients who discontinued DAPT under physician guidance was reduced by 37% compared with the risk among patients who remained on DAPT for 2 years (P = .004). Patients who interrupted DAPT for surgical necessity showed a nonsignificant trend for increased risk of cardiac events. And DAPT disruption was associated with a sevenfold increased risk in the first week off treatment and a 2.2-fold increased risk during days 8-30.

Of note, 74% of all cardiac events and 80% of definite or probable cases of stent thrombosis occurred while patients were on DAPT.

Session cochair Dr. Keith A. A. Fox put Dr. Mehran’s feet to the fire by posing a challenging clinical scenario: What will you advise, he inquired, the next time a colleague asks what to do for a patient who had a coronary stent implanted 3 days ago and has just had a major GI bleed while on DAPT?

"This is what we call ‘the DAPT dilemma,’ " she replied. "It’s a critically important question. We all face it. We now know from PARIS that if we disrupt the treatment due to bleeding, the hazard in that first week is going to be increased sevenfold. So I think we should do everything we can to control the bleeding so we can keep the patient on DAPT, but if we must, then I think stopping one drug would be better than stopping two."

In an interview, American Heart Association spokesperson Dr. Elliott Antman said the PARIS registry shows that in general physicians are doing a fairly good job of intuitively deciding who can safely come off DAPT. But what’s really needed is the sort of well-defined practice guidance that can come only from a large, randomized trial.

Fortunately, he said, the results of such a study, the ongoing DAPT trial, should be available in about a year. This is a 15,000-patient clinical trial in which all stent recipients were placed on DAPT for 1 year, then randomized to come off of DAPT at that point or continue on, noted Dr. Antman, professor of medicine at Harvard Medical School, Boston.

The PARIS registry is funded by Bristol-Myers Squibb and Sanofi-Aventis. Dr. Mehran reported receiving consulting fees from Sanofi-Aventis and more than half a dozen other pharmaceutical and device companies.

Simultaneous with her presentation of the PARIS registry findings in Amsterdam, the results were published online in the Lancet (Sept. 1, 2013 [doi:10.1016/50140-6736(13)61720-1]).

The study was funded by Bristol-Myers Squibb and Sanofi-Aventis. The presenter is a paid consultant to Sanofi-Aventis and other companies.