左室辅助装置血栓形成发生率骤增

《新英格兰医学杂志》11月27日在线发表的一项研究显示，自2011年3月以来，置入HeartMate II左室辅助装置(LVAD)的晚期心力衰竭患者的泵内血栓形成发生率出现非预期的突然增加(N. Engl. J. Med. 2013 Nov. 27 [doi: 10.1056/NEJMoa1313385]).。

由Thoratec公司生产的HeartMate II是小型的轴流式LVAD，在问世后就迅速成为晚期心力衰竭治疗的一部分。早期试验和上市后批准研究显示，该LVAD的血栓形成发生率为2~4%。但克利夫兰诊所进行的一项质量审查显示，自2011年3月开始，发生率出现明显增加。

克利夫兰诊所的Randall C. Starling医生及其同事随后合并了该诊所的HeartMate II数据(2004年10月~2013年2月)与以下另外2个大手术量心脏病中心的数据：圣路易斯华盛顿大学Barnes-Jewish医院(2004年1月~ 2013年4月)和北卡罗来纳州达拉谟杜克大学医学中心(2005年5月~ 2013年5月)。研究者此次报告的是这期间837例患者置入的895个HeartMate II LVAD的结果。

患者的平均年龄为55岁，21%为女性。研究的主要终点是证实的LVAD血栓形成，定义为置换泵时、紧急移植时、或对接触血液的装置表面、装置的流入导管或流出导管上的血栓进行解剖时观察到血栓形成。共在66例患者中观察到72例此类血栓形成；此外，还有36例疑似血栓形成。

证实的泵内血栓形成发生率起初在几年内均稳定在2.2%，但在2011年3月后急剧增至8.4%。这一模型见于所有3个医学中心和这些中心的所有心脏外科医生。

在2011年3月前，置入装置后至出现泵内血栓形成的中位时间间隔为18.6个月，但这一时间间隔在2011年3月间和此后骤减至2.7个月。

研究者还回顾了在置入568个装置的患者中连续测定的乳酸脱氢酶(LDH)。LDH升高提示存在可能预示即将发生血栓形成的溶血。

LDH水平＞1000 IU/L的发生图与证实的泵内血栓形成的发生图基本重叠。LDH数据显示出LDH水平自2011年3月起置入装置后早期就出现升高的平行趋势。

在所有3个医学中心均观察到，在LVAD血栓形成前几周内，LDH水平从平均540 IU/L升至平均1,490 IU/L。这证实了LDH水平是与LVAD血栓形成相关的溶血的有用临床生物标志物。

在72例泵内血栓形成中，11例通过心脏移植处置，21例通过置换泵处置。在其余40例血栓形成中，2例的处置手段为取出LVAD(因为左室功能已改善)，38例的处置手段为药物治疗，即强化抗凝治疗和溶栓药物。这使一些患者的临床过程得以稳定，但另一些患者认为治疗无效，决定撤除治疗。

在无法通过心脏移植或置换泵处置的患者中，死亡率为48%，这一增加的死亡率在3个医学中心具有一致性。

尚不知道HeartMate II相关血栓形成发生率骤增的原因。在研究期间，3个医学中心的LVAD置入技术均未发生改变，并且研究者未发现泵内血栓形成与进行置入术的外科医生之间存在关联。这期间，HeartMate II的设计出现一些改变，如调整流出桥血管和弯曲离隙、流入导管和软件，但尚未观察到这些改变与泵内血栓形成相关。

研究者表示，流入轴承周围沉积的纤维蛋白和变性蛋白可使流入通路变窄，并增加对红细胞的剪应力(如果沉积量够大的话)，降低泵卸载左室的能力。但仍有待观察是这一因素还是其他因素在发挥作用。目前亟需对患者和装置的易感因素及预防和治疗策略进行进一步研究，以解决这一重要的安全性问题。

研究者补充表示，第4个心脏病中心(宾夕法尼亚大学)在初步分析中观察到类似模式。该中心在2005年11月至2013年9月置入148例患者的150个HeartMate II LVAD中观察到15例血栓性事件，并且事件发生率出现突然且非预期地增加，证实的血栓形成发生率不断增加，这与Starling医生的研究结果相似。

Starling医生声明与Thoratec和HeartWare公司存在联系。其他研究者与Thoratec、HeartWare、Abiomed和Syncardia公司存在联系。

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By: MARY ANN MOON, Cardiology News Digital Network

An abrupt and unexpected increase in pump thrombosis has occurred since March 2011 in patients with advanced heart failure who received the HeartMate II left ventricular assist device, according to a report published online Nov. 27 in the New England Journal of Medicine.

Those who develop LVAD thrombosis are at substantial risk of death and morbidity unless the device is replaced or cardiac transplantation is performed, said Dr. Randall C. Starling of the Cleveland Clinic and his associates.

The reason for the sudden rise in pump thrombosis is not yet known, but it may be related to excess "deposition of material (fibrin and denatured protein) in proximity to the inflow bearing" of the device, which has been observed by clinicians in at least three cardiac centers.

"Our data suggest that the HeartMate II may have a more narrow tolerance with respect to thrombus formation than originally understood, and may be vulnerable to the timing and intensity of anticoagulation," Dr. Starling and his colleagues noted.

The HeartMate II, made by Thoratec, is a small axial-flow LVAD that "rapidly became integral in the treatment of patients with advanced heart failure" after it was introduced. Early trials and postmarketing approval studies reported a 2%-4% incidence of thrombosis. But a quality review at the Cleveland Clinic showed a sudden, marked increase in that rate beginning in March 2011.

Researchers at the Cleveland Clinic then pooled their data on the HeartMate II (from October 2004 to February 2013) with data on the device from two other high-volume cardiology centers: Washington University Barnes-Jewish Hospital, St. Louis (January 2004 to April 2013) and Duke University Medical Center, Durham, N.C. (May 2005 to May 2013). They now report on their findings from 895 HeartMate II LVADs implanted in 837 patients during that time.

The mean patient age was 55 years, and 21% of patients were women.

The primary endpoint of the study was confirmed LVAD thrombosis, defined as a finding at pump replacement, urgent transplantation, or autopsy of a thrombus on the blood-contacting surface of the device, its inflow cannula, or its outflow conduit. A total of 72 such thromboses were found in 66 patients; in addition, 36 cases of suspected thromboses occurred.

The rate of confirmed pump thrombosis was initially stable at roughly 2.2% for several years, then rose steeply after March 2011 to 8.4%. This pattern was seen at all three medical centers and across all the cardiac surgeons at those centers.

The median time interval from implantation to pump thrombosis had been 18.6 months before March 2011, but that rate plummeted to 2.7 months during and after March 2011, Dr. Starling and his associates reported (N. Engl. J. Med. 2013 Nov. 27 [doi: 10.1056/NEJMoa1313385]).

The investigators also reviewed serial measurements of lactate dehydrogenase (LDH) that had been taken in recipients of 568 of the devices. Elevated LDH indicates hemolysis that may herald impending thrombosis.

"The graph of the occurrence of LDH levels above 1000 IU per liter ... was nearly superimposable on the graph of the occurrence of confirmed pump thrombosis. The LDH data showed a parallel tendency for elevations to occur early after implantation beginning in approximately March 2011," they said.

The LDH level typically rose from an average of 540 IU/L to an average of 1,490 IU/L during the weeks leading up to LVAD thrombosis at all three medical centers. This confirms that LDH level is a useful clinical biomarker of hemolysis associated with LVAD thrombosis, the researchers said.

Of the 72 pump thromboses, 11 were managed by heart transplantation and 21 by pump replacement. Of the remaining 40 thromboses, 2 were managed by LVAD removal because left ventricular function had improved, and 38 were managed medically, with augmentation of anticoagulation therapy and thrombolytic agents. This stabilized the clinical course in some patients, but others elected withdrawal of care, citing "futility."

Mortality was 48% among the patients who could not be managed by heart transplantation or pump replacement, and this elevated rate was consistent across the three medical centers.

The reasons for this abrupt, dramatic rise in thromboses associated with the HeartMate II are not known. There were no changes in LVAD implantation techniques at any of the three medical centers during the course of this study, "and we could find no association between pump thrombosis and the surgeon performing the implantation." The design of the HeartMate II was changed during this interval – "modification of the outflow graft and bend relief, inflow conduit, and software" was introduced – but these changes have not been linked to pump thrombosis as yet.

Dr. Starling and his associates did note the deposition of fibrin and denatured protein around the inflow bearing, which could narrow the inflow pathway, "increasing shear stress on the red cells and, if the deposition is large enough, decreasing the ability of the pump to unload the left ventricle." But it remains to be seen whether this or other factors played a role.

"Further investigation of predisposing patient and device factors and preventive and therapeutic strategies are urgently needed to resolve this important safety issue," the investigators said.

They added that a fourth cardiology center, the University of Pennsylvania, Philadelphia, found a similar pattern in a preliminary analysis that was reported as the article went to press. In that report on 150 HeartMate II LVADs implanted in 148 patients between November 2005 and September 2013, there were 15 thrombotic events. "Similar to the findings in our study, the event rate has increased abruptly and unexpectedly, with a rate of confirmed thrombosis that continues to rise," Dr. Starling and his associates said.

Dr. Starling reported ties to Thoratec and HeartWare, and his associates reported ties to Thoratec, HeartWare, Abiomed, and Syncardia.