伐瑞拉迪增加ACS后短期内MI风险

一项国际随机临床试验的结果显示，sPLA2抑制剂伐瑞拉迪不但不能降低近期急性冠脉综合征(ACS)患者的心血管事件风险，实际上反而会增加发生心肌梗死(MI)的风险。该研究结果在美国心脏协会(AHA)年会上发布，并同时刊登在《JAMA》在线版上(2013年11月18日 [doi:10.1001/jama.2013.282836])。

伐瑞拉迪是一种非特异性的分泌型磷酸酯酶A2(sPLA2)酶家族的抑制剂，这种酶参与炎症过程，其中一些可见于动脉粥样硬化病变和缺血损伤的心肌区域。在最初的研究中，这种药物可使ACS患者循环中sPLA2水平降低90%以上，并降低LDL胆固醇和C-反应蛋白水平。


Stephen J. Nicholls博士

VISTA-16（通过抑制血管炎症治疗急性冠脉综合征16周）试验是由伐瑞拉迪的生产商Anthera制药公司发起的，由澳大利亚阿德莱德市澳大利亚南方卫生与医学研究所的Stephen J. Nicholls博士及其同事实施，目的是评估该药物在ACS后最初4个月的高危时期内预防CV事件的疗效。3年期间，共纳入17个国家的362个医疗中心的5,145例表现ACS数小时内的患者。这些患者中CV风险因素和明确的动脉粥样硬化疾病的患病率很高，多数已在接受适当的抗血小板药物、他汀、受体阻滞剂、ACE抑制剂或ACE受体阻滞剂治疗。80%的患者在指示事件后接受冠脉再血管化。研究的主要终点为包括CV原因死亡、非致死性MI、非致死性卒中或需要住院治疗的不稳定心绞痛的复合终点。

结果显示，当试验终止时，记录了212例患者的结果，平均接受治疗的时间为13.4 周。接受伐瑞拉迪治疗的患者中有6.1%发生主要终点，安慰剂组的主要终点发生率为5.1%[危险比(HR)为1.25]。次要终点为包括CV原因死亡、MI和卒中的复合终点，伐瑞拉迪和安慰剂组次要终点发生率分别为4.6%和3.8%(HR，1.36)。“主要原因为伐瑞拉迪组MI发生率高于安慰剂组，分别为3.4%和2.2%(HR，1.66)。”

停用研究药物治疗后6个月时，伐瑞拉迪组和安慰剂组的全因死亡率分别为2.7%和2.0%。活性药物治疗组因不良事件或严重不良事件停止治疗的比例为安慰剂组的2倍，分别为2.8%和1.4%。

这一药物确实展现了预期的对炎症和脂肪生物标记物的有益效应，理论上应该转化为ACS后治疗16周期间的斑块破裂倾向性降低。但在对于5,012例参与随机化的患者中的212例患者的结局进行中期分析之后，因活性药物“无益”而提前终止研究。

VISTA-16试验是由Anthera制药公司资助的。Nicholls博士及其合作者披露与多家企业存在利益关系。

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By: MARY ANN MOON, Cardiology News Digital Network

Far from reducing the risk of cardiovascular events in patients with recent acute coronary syndrome, the sPLA2 inhibitor varespladib actually raised the risk of MI in an international randomized clinical trial.

The drug did exert beneficial effects on inflammatory and lipid biomarkers as expected, "which theoretically should have translated to a lower propensity to plaque rupture" in the 16 weeks following ACS. But the study was terminated early "for futility" after an interim analysis of the outcomes for only 212 of the 5,012 randomized patients, said Dr. Stephen J. Nicholls and his associates in the VISTA-16 clinical trial, which was reported simultaneously at the American Heart Association scientific sessions and published online in JAMA (2013 Nov. 18 [doi:10.1001/jama.2013.282836]).

Compared with placebo, varespladib caused an excess of MIs and of the composite outcome of cardiovascular mortality, MI, and stroke. "These findings suggest that short-term sPLA2 inhibition with varespladib is harmful following ACS," said Dr. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, and his colleagues.
 
"Our findings ... reemphasize that identification of a circulating marker of cardiovascular risk does not necessarily imply that pharmacologic suppression or inhibition of the marker will reduce risk," they noted.

Varespladib is a nonspecific inhibitor of the family of secretory phospholipase A2 (sPLA2) enzymes that are involved in inflammation, some of which are present in atherosclerotic lesions and myocardial areas injured by ischemia. In initial studies, the drug reduced circulating levels of sPLA2 by more than 90%, lowered LDL cholesterol, and decreased C-reactive protein in ACS patients.

The VISTA-16 (Vascular Inflammation Suppression to Treat Acute coronary syndrome for 16 weeks) trial, sponsored by Anthera Pharmaceuticals, the maker of varespladib, was designed to assess the drug’s efficacy at preventing CV events during the high-risk period of the 4 months immediately following ACS.

A total of 5,145 patients were enrolled at 362 medical centers in 17 countries over the course of 3 years, within hours of presenting with ACS. They had a high prevalence of CV risk factors and established atherosclerotic disease, and most were already receiving appropriate therapy with antiplatelet agents, statins, beta-blockers, ACE inhibitors, or receptor blockers. Eighty percent underwent coronary revascularization after the index event.

The primary endpoint was a composite of CV mortality, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization. When the trial was terminated, outcomes in 212 patients had been documented after a mean of 13.4 weeks of treatment. The primary endpoint occurred in 6.1% of patients who took varespladib, compared with 5.1% of those who took placebo (hazard ratio, 1.25), the investigators said.

A secondary outcome, a composite of CV mortality, MI, and stroke, occurred in 4.6% of patients who took varespladib and 3.8% of those who took placebo (HR, 1.36).

"This was due primarily to a greater incidence of MI in the varespladib group compared with the placebo group (3.4% vs 2.2%; HR, 1.66)," the researchers said.

Six months after patients had discontinued study treatment, all-cause mortality was 2.7% in the varespladib group and 2.0% in the placebo group.

Twice as many patients taking the active drug (2.8%) as taking placebo (1.4%) discontinued treatment because of adverse or serious adverse events.

The reasons for varespladib’s adverse effect on MI are not yet known. "Whether this represents an adverse effect of the varespladib molecule or a consequence of pan-sPLA2 inhibition remains to be determined," Dr. Nicholls and his associates said.

The VISTA-16 trial was funded by Anthera Pharmaceuticals. Dr. Nicholls and his associates reported numerous ties to industry sources.