WARP试验结果:Warfarin无法减少使用导管之癌症病患的血栓症


  February 17, 2009 — 使用中央静脉导管(central venous catheters,CVCs)之癌症病患运用warfarin预防血栓的一篇大型研究发现,不论与导管有关或整体看来,抗凝血效果未能降低血栓事件发生率,对于整体存活也没有效果。
  
  英国伯明罕大学癌症研究中心的Annie Young小姐所领导的研究团队表示,我们发现,warfarin对于预防导管相关血栓不具可用性。
  
  他们在2月14日的Lancet期刊中结论表示,癌症病患之血栓预防该跳脱使用warfarin的思考了。
  
  Young小姐向Medscape Oncology表示,WARP(warfarin prophylaxis)这项试验的结果,显然符合美国临床肿瘤协会与其它机构的指引,指出不建议在装有CVC的癌症病患使用任何抗凝血剂。
  
  编辑评论中,意大利Padua大学血栓小组的Paolo Prandoni医师表示赞同。他指出,目前现有的证据并不支持常规使用固定剂量的warfarin或者低分子量肝素来预防癌症病患之导管相关上肢深部静脉栓塞。
  
  较新的抗凝血剂或许可望比较有效,但是Prandoni医师写道,主治医师需谨慎决定于特定期间使用现有药物。
  
  【导管增加了原本已经升高的风险】
  已知癌症病患的静脉血栓风险增加,但是癌症病患常规使用血栓预防治疗在医界仍有所争议,如同之前在Medscape Oncology中所报导的。此议题因为各种癌症病患的差异性、其它因素如是否可以走动与是否接受过手术等而益发复杂。
  
  这个已经升高的血栓风险在使用CVC给予化疗制剂下继续增加。Young小姐解释,身体插入导管之后,导管周遭的血流下降,而化疗更是增加风险因素。不过,她表示,疾病本身实际增加多少风险很难得知,且因各种癌症、疾病恶化程度而不同。
  
  使用CVC的癌症病患是否给予血栓预防治疗仍是个争议。Prandoni医师解释,早期研究认为,warfarin可以大幅降低此并发症,因此,在1990年代末期,几乎所有国际指引都建议使用warfarin或肝素进行预防。
  
  Prandoni医师指出,不过,最近的试验都难以显示有可接受的效益。这已经被后设分析确认过,所以最新的指引不再建议有中央静脉管的癌症病患使用全身性预防。他表示,WARP试验提出更多证据显示,此类病患不适合使用全身性warfarin。
  
  Young小姐表示,在某种程度上,以前显示有助益的研究和最近显示无益之新研究间的差异,或许可由导管技术的改善来加以解释。她向Medscape Oncology表示,现在的导管更复杂,材质延展性更佳且有附加装置(如锁闸),导管末端可以加在胸部或手臂,或许有助于使栓塞最少化。
  
  【Warfarin未显示有助益】
  Young小姐等人表示,当他们设计研究时,有些医师认为warfarin有帮助而不愿意指定病患到安慰剂组。这些医师将病患指定到两个warfarin组之一:固定剂量组(1 mg/每天)或者调整剂量以使国际标准化比值维持在1.5-2.0之间。
  
  该试验包括了1,590名各种癌症的病患(主要是大肠直肠癌、上胃肠道癌症、乳癌)且有使用CVC。在随机分组之后平均32天时,有85名(5%)病患发生以X光确认导管相关的血栓事件 。
  
  三组的导管相关血栓比率相似。在预防导管相关血栓上,剂量调整warfarin组优于固定剂量组(13例[3%]相较于34例[7%]; P= .002),但是明显有较多的严重出血事件(7件相较于1件;P= .07)。
  
  研究者指出,合并考量血栓与严重出血后显示,各组之间并无差异。
  
  他们指出,衡量血栓预防以及严重出血风险之后,综合结果显示任何剂量的warfarin都没有帮助。
  
  Young小姐表示,尽管本研究和其它研究的证据显示没有治疗利益,在临床实务上仍有一些装有CVC的癌症病患常规使用血栓预防。根据WARP试验结果,我们建议不要使用warfarin —该跳脱使用warfarin的思考了。她结论表示,这不是一个没有价值的药物,warfarin只是无法好好用在癌症病患上。
  
  Prandoni医师表示,某些病患可以考虑进行血栓预防,例如个人有血栓史或有家族史者、易形成血栓者、那些进行会增加血栓风险的化疗者。对于前述病患,Prandoni 医师建议使用低分子量肝素。
  
  该研究接受英国医学研究委员会与英国癌症研究之资助。研究者宣称没有相关财务关系。

Warfarin Does Not Reduce Thromboses in Cancer Patients With Catheters: WARP Results

By Zosia Chustecka
Medscape Medical News

February 17, 2009 — A large study of warfarin thromboprophylaxis in cancer patients with central venous catheters (CVCs) has found that the anticoagulant did not reduce the rate of thrombotic events, either overall or related to the catheter. There was also no effect on overall survival.

"Our findings show that warfarin does not have a useful role in the prophylaxis of catheter-related thrombosis," say the researchers, headed by Annie Young, PGCSR, from the Institute for Cancer Studies at the University of Birmingham, in the United Kingdom.

"The time has come to move on from warfarin for thromboprophylaxis in patients with cancer," they conclude in the February 14 issue of the Lancet.

The results from the study, known as the WARP (warfarin prophylaxis) trial, clearly fit with guidelines from the American Society of Clinical Oncology and other bodies, which state that the use of any anticoagulant is not recommended in cancer patients with CVCs, Ms. Young commented to Medscape Oncology.

In an accompanying editorial, Paolo Prandoni, MD, from the thromboembolism unit at the University of Padua, in Italy, concurs. He points out that the currently available evidence does not support routine use of either fixed-dose warfarin or low-molecular-weight heparin to prevent catheter-related upper-limb deep vein thrombosis in cancer patients.

There is hope that newer anticoagulants will be more effective but, in the meantime, "the decision to use available drugs for a specific period is left to the discretion of the attending physician," Dr. Prandoni writes.

Catheter Raises an Already-Increased Risk

It is well recognized that cancer patients have an increased risk for venous thromboembolism, but routine use of thromboprophylaxis in cancer patients is still a matter of debate among clinicians, as previously reported by Medscape Oncology. The issue is complicated by the heterogeneity of patients with different cancers, and by additional factors, such as whether or not they are ambulatory and have undergone surgery.

This already-raised risk of thromboembolism is increased further with the use of a CVC to administer chemotherapeutic agents. "The physical presence of the catheter, the decreased blood flow around the catheter, and the chemotherapy are all added risk factors," explained Ms. Young. However, exactly how much more the risk is increased on top of the disease itself is difficult to know, she said, and it varies with the type of cancer and how advanced the disease has become.

Whether or not cancer patients with CVCs should be given thromboprophylaxis has been a matter of some debate. Early studies suggested that warfarin could greatly reduce this complication, Dr. Prandoni explained, and hence, at the end of the 1990s, nearly all international guidelines recommended prophylaxis with either warfarin or heparin.

However, more recent trials have failed to show appreciable benefits, Dr. Prandoni pointed out. This has been confirmed by meta-analyses, and so the latest guidelines no longer recommend systematic prophylaxis in cancer patients with a central venous line. The WARP trial adds to the growing body of evidence suggesting that there is no systematic indication for warfarin in this patient population, he said.

To some extent, the difference between the older studies showing a benefit and the newer ones showing no advantage may be partly explained by the improvements that have been made in catheter technology, said Ms. Young. "Catheters nowadays are particularly sophisticated," she told Medscape Oncology, "with material becoming more malleable and additional devices (e.g., locks) that may be added at the chest or arm end of the catheter, which may help to minimize thrombosis."

No Advantage Shown for Warfarin

Ms. Young and colleagues comment that when they were designing their study, some clinicians were convinced that warfarin was beneficial and did not want to assign patients to the placebo group. Those clinicians assigned their patients to 1 of the 2 warfarin groups: either a fixed dose (1?mg/day), or a dose that was adjusted to maintain an international normalized ratio of between 1.5 and 2.0.

The trial involved 1590 patients with a variety of cancers (mainly colorectal, upper gastrointestinal, and breast) and a CVC. Radiological-confirmed catheter-related thrombotic events occurred in 85 patients (5%) at a median time of 32 days after randomization.

The rate of catheter-related thrombosis was similar in all 3 groups. Dose-adjusted warfarin was superior to fixed-dose warfarin in preventing catheter-related thromboses (13 [3%] vs 34 events [7%]; P?= .002), but it was associated with significantly more major bleeding events (7 vs 1; P?= .07).

"A combined end point of thromboses and major bleeding showed no difference between the comparisons," the researchers note.

"When any benefit of thromboprophylaxis was balanced against the risk of major bleeding, the combined outcome showed no advantage with the use of any dose of warfarin," they add.

Not a trivial drug, and warfarin and cancer are not a good combination.

Ms. Young said that, despite the evidence from this and other studies showing a lack of benefit, there is still some use of routine thromboprophylaxis in cancer patients with CVC in clinical practice. On the basis of the WARP results, "we recommend that warfarin is not used — it is time to move on from warfarin." This is not a trivial drug, and warfarin and cancer are not a good combination, she concluded.

Dr. Prandoni said that selected patients may be considered for thromboprophylaxis, such as those with a personal or family history of thrombosis, carriers of thrombophilia, and those treated with chemotherapy that is known to increase the risk for thromboembolism. For these selected patient populations, Dr. Prandoni recommends the use of a low-molecular-weight heparin.

The study was funded by the UK Medical Research Council and Cancer Research UK. The researchers have disclosed no relevant financial relationships.

Lancet. 2009;373;523-524, 567-557.

    
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