研究支持仅对特定患者预防性输注血小板

亚特兰大——美国血液病学会(ASH)年会上公布的多中心随机TOPPS研究支持限制预防性血小板输注的应用范围。

Simon Stanworth博士

这项研究由英国国民卫生服务部血液和移植中心的血液学顾问Simon Stanworth博士及其同事进行，纳入600例正在接受或预期将接受化疗或干细胞移植且预期将出现至少5天血小板减少症的血液系统恶性肿瘤患者。血小板计数低于10×10⁹/L的患者接受预防性血小板输注，其他患者不接受预防性血小板输注。只有在观察到出血体征或症状后、进行有创手术前、或医生认为有必要的情况下才进行治疗性血小板输注。该研究的主要终点为根据世界卫生组织标准定义的2级或2级以上出血。

结果显示，无预防性血小板输注组主要终点事件的发生率为50%(151例/300例)，而预防性血小板输注组为43%(128例/298例)。校正后的组间发生率差值为8.4%，低于该研究设定的置信区间的15.2%上限。然而，预定的亚组分析发现，进行自体干细胞移植(ASCT)的患者(占研究人群的70%)的主要终点事件发生率与接受急性髓性白血病(AML)诱导化疗或异基因骨髓移植等其他治疗的患者存在显著差异(P=0.04)。预防性血小板输注组和无预防性血小板输注组中ASCT亚组患者的≥2级出血发生率非常接近(45% vs. 47%)。但预防性血小板输注组中AML和异基因骨髓移植亚组患者的≥2级出血发生率低于无预防性血小板输注组中的同类患者(38% vs. 58%)。

与预防性血小板输注组相比，无预防性血小板输注组接受输注的患者比例显著更低(89% vs. 59%)，每例患者接受的输注次数更少(平均3.0次 vs. 1.7次)，血小板低于10,000/ml的天数更多(平均3.6天vs. 1.8天；均P＜0.001)。

无预防性血小板输注组患者随访期间出现2~4级出血的天数平均为1.7天，而预防性血小板输注组为1.2天(P=0.004)。无预防性血小板输注组患者发生首次2~4级出血的时间比预防性血小板输注组早2天(危险比=1.30；P=0.02)。

两组在至血小板减少症恢复时间及其他多个观察指标(包括住院天数和不良事件)方面均无显著差异。预防性血小板输注组和无预防性血小板输注组分别有1例(0.3%)和6例(2%)患者发生严重3级或4级出血。差异无统计学显著性，但可以看出后组患者发生这些有时危及生命的事件的风险是前组患者的6倍(比值比=6.05；P=0.13)。无预防性血小板输注组1例患者发生颅内出血。在7例发生3~4级出血的患者中，仅2例患者在发生出血时的血小板计数＜10×10⁹/L，这2例患者均正在接受AML诱导化疗。

在讨论研究结果时，一位与会者指出，亚组间的出血发生率差异较为显著，建议在对AML患者进行预防性血小板输注时应更加注意，因为这些患者在治疗期间由于内皮损伤而可能特别易于发生严重出血事件。Stanworth博士对此表示认同，他表示该研究结果表明，预防性血小板输注在不同患者组中的作用不同，有待进一步研究。未来需要开发新的策略，以最大程度地降低出血风险，并建议对抗纤维蛋白溶解剂和氨甲环酸的作用进行研究。

麻省总医院输血服务中心联合主任Walter Dzik博士在接受采访时表示，根据最新的美国全国血液采集和利用调查报告，2008年美国输注的血小板约为200万，比2006年显著增加16.7%。TOPPS研究发现预防性血小板输注对自体干细胞移植患者无治疗益处，因此不对这类患者进行输注或可节省数以百万美元的医疗费用。TOPPS研究结果将可能改变临床实践，但还将需要一定时间。

TOPPS研究获英国国民卫生服务部血液和移植中心资助。Stanworth博士和Dzik博士均声明无经济利益冲突。

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By: PATRICE WENDLING, Internal Medicine News Digital Network

ATLANTA – The broad use of prophylactic platelet transfusions in adults with hematologic malignancies and severe thrombocytopenia will likely be narrowed in the wake of the randomized, international TOPPS trial.

The primary endpoint of grade 2 or higher bleeding, by World Health Organization criteria, was seen in 50% with no prophylaxis (151 of 300) and 43% receiving a prophylactic platelet transfusion (128 of 298). The adjusted difference in proportions was 8.4%, which fell below the 15.2% upper limit for confidence interval set for TOPPS (Trial of Prophylactic Platelet Transfusions).
 
"This multicenter trial has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis," lead author Dr. Simon Stanworth said at the annual meeting of the American Society of Hematology.

A predefined subgroup analysis, however, found a significant difference in the primary endpoint between patients undergoing autologous stem cell transplantation (ASCT), who comprised 70% of the study population, and those receiving other treatments such as induction chemotherapy for acute myeloid leukemia (AML) or allogeneic bone marrow transplantation (P value = .04).

The rate of grade 2 or higher bleeding was very similar among patients undergoing autologous transplantation with or without prophylaxis (45% vs. 47%), while a clear benefit signal was seen in the subgroup of AML and allograft patients receiving treatment plus prophylaxis, compared with no prophylaxis (38% vs. 58%).

"Based on the results, the role of prophylactic platelet transfusions in different patient groups is varied and needs to be considered further," said Dr. Stanworth, a consultant hematologist with National Health Service Blood and Transplant, Oxford (England) University Hospital.

The finding that prophylactic platelets confer no advantage among those getting autologous transplants, however, could open up the opportunity to save millions of dollars in health care costs by skipping this unbeneficial treatment. An estimated 2 million platelets were transfused in the United States in 2008, a significant 16.7% increase from 2006, according to the latest National Blood Collection and Utilization Survey Report.

The results of TOPPS will likely change practice, but it will take time, Dr. Walter Dzik, codirector of the blood transfusion service at Massachusetts General Hospital, Boston, said in an interview.

"It takes quite some time, months to years, for knowledge transfer to occur and for well-established practices to change, but the end result will be to decrease the use of prophylactic platelets in autologous stem cell transplant patients," he said.

Prophylactic platelet transfusions are overused in the United States, in part because many clinicians transfuse their oncologic patients before they reach the recommended platelet prophylaxis threshold of 10 x 109 platelets per liter (Transfusion 2007;47:201-5). Thousands of doses of platelets are also used each year outside of the context of hematology/oncology, in patients undergoing surgery or cardiac procedures, without evidenced-based indications.

During his formal introduction of the plenary abstract, Dr. Dzik said a study published 2 years ago begs the question of whether prophylactic platelets are needed at all, reporting that the number of platelets in a prophylactic transfusion had no effect on the incidence of hemorrhage in patients with hypoproliferative thrombocytopenia (N. Engl. J. Med. 2010;362:600-13).

He pointed out that a recent open-label German trial, however, agrees with the TOPPS data, also finding no advantage from prophylactic platelets in autologous transplants, and all of the advantage resting in allogeneic transplants and AML patients. There was an "unmistakable" reduction in WHO grade 2 bleeding overall, but there was no advantage with the prophylaxis in the amount of red blood cells used per patient, number of days in the hospital, or overall survival (Lancet 2012;380:1309-16). It is against this background that clinicians looked to the TOPPS trial for additional insights, Dr. Dzik observed.

TOPPS enrolled 600 patients with a hematologic malignancy who were receiving or expected to receive chemotherapy or stem cell transplant, and expected to be thrombocytopenic for at least 5 days. Patients were randomly assigned to receive prophylactic platelet transfusion if their platelet count fell below 10x109/L, or no prophylaxis. Therapeutic platelets were given only after documented signs or symptoms of bleeding, prior to invasive procedures or at physician discretion.

Patients in the no-prophylaxis group were significantly less likely to receive a transfusion (59% vs. 89%), received fewer transfusions per patient (mean 1.7 vs. 3.0), and had more days with platelets less than 10,000/microL (mean 3.6 days vs. 1.8 days; all P less than .001, Dr. Stanworth reported.

Patients in the no-prophylaxis group averaged 1.7 days with a grade 2-4 bleed during follow-up vs. 1.2 days in the prophylaxis group (P value = .004), and developed an initial grade 2-4 bleed 2 days earlier than those receiving prophylaxis (hazard ratio 1.30; P = .02).

Still, there was no significant difference between the two groups in time to recovery from thrombocytopenia or a range of other outcomes including number of days in hospital or adverse events, Dr. Stanworth said.

Serious grade 3 or 4 bleeds occurred in one patient in the prophylaxis group (0.3%) and six in the no-prophylaxis group (2%). The difference did not reach statistical significance, but represents a sixfold increase in these sometimes life-threatening events (odds ratio 6.05; P = .13).

One intracranial bleed occurred in the no-prophylaxis group. Only two of the seven patients had a platelet count below 10x109/L at the onset of grade 3-4 bleeding, and both were receiving induction chemotherapy for AML, he said.

During a discussion of the results, an audience member described the difference in bleeding between subgroups as remarkable, and suggested that AML patients should be taken far more seriously with regard to platelet prophylaxis because they may be especially predisposed to serious bleeding events because of endothelial damage during therapy. Dr. Stanworth concurred.

In his conclusion, Dr. Stanworth said there is clearly a need for new strategies to minimize the high burden of bleeding, and suggested that antifibrinolytics and the role of tranexamic acid should be explored.

For his part, Dr. Dzik said, "We need to stop approaching all patients as if they were the same and develop a risk score to identify those patients at higher risk of bleeding. The first question on the score will be ‘Are you an autologous stem cell case?’ and then tailor the degree of hemostatic support to match the risk of the patient."

TOPPS was funded by the National Health Service Blood and Transplant. Dr. Stanworth and Dr. Dzik reported no disclosures.