UMPIRE表明多效药丸可改善心血管健康

洛杉矶——大规模全球UMPIRE(使用多效药丸减少心血管事件)试验表明，使用由4种心血管药物组成的固定剂量复方制剂(多效药丸)每日1次，与常规治疗相比不仅能明显降低收缩压和LDL胆固醇水平，而且还能将患者的依从率提高33%。

英国伦敦帝国理工学院的心血管药物与药理学教授Simon Thom博士在美国心脏协会(AHA)2012科学年会上报告了上述结果。Thom博士称UMPIRE试验是一次极大的成功。

UMPIRE试验旨在验证这样一种假设：在已确诊患有动脉粥样硬化性心血管疾病或发病风险高的患者中，将指南推荐的治疗药物制成多效药丸用于二级心血管预防以降低治疗成本和复杂性，是否能提高治疗依从性并改善患者结局。

该试验在印度、都柏林、伦敦和荷兰乌得勒支招募了2,004例患者并将其随机分组：88%在基线时已确诊患有动脉粥样硬化性心血管疾病；29%患有糖尿病。受试者被随机分配至接受多效药丸或者常规治疗，多效药丸由75 mg阿司匹林、50 mg辛伐他汀、10 mg赖诺普利和50 mg阿替洛尔或12.5 mg双氢氯噻嗪组成，选择阿替洛尔还是双氢氯噻嗪取决于医生的偏好；常规治疗则是分开处方这4种药物。多效药丸是免费提供的，而常规治疗则按照当地惯例进行支付。

在为期15个月的中位随访期后，多效药丸组的治疗依从率为86%，而常规治疗组仅为65%，相对差异达到了33%。多效药丸组的收缩压平均为129.2 mmHg，比常规治疗组低2.6 mmHg。多效药丸组的平均LDL胆固醇为84.3 mg/dl，常规治疗组为88.6 mg/dl。多效药丸组的舒张压平均为72.8 mmHg，常规治疗组为75.2 mmHg。

Thom博士报告称，上述所有差异均具有统计学意义，考虑到全球目前不断增加的心血管疾病负担，这也具有十分重要的临床意义。此外，多效药丸组患者基于视觉模拟量表的生活质量自我评分也显著优于常规治疗组。不过，两组患者在HDL胆固醇、甘油三酯或心血管事件发生率方面无显著差异。两个治疗组的不良反应情况也类似。

值得注意的是，61%的UMPIRE受试者基线时已经在服用所有4种试验药物。这在中低收入国家属于罕见的高比例，而多效药丸将来很可能会对这类国家作用最大，也就是说，UMPIRE结果其实还低估了多效药丸用于实际临床实践的真实效益。

作为评论员，澳大利亚墨尔本莫纳什医院的预防医学教授/心血管研究中心主任Andrew M. Tonkin博士表示：“UMPIRE是一项很重要的试验，其结果不仅仅应该引起临床医生的广泛关注，而且对于决策制定也有一定的指导意义。”

虽然之前也有人提出过将多效药丸广泛应用于一级预防，类似于将药丸放进饮用水里的策略，但UMPIRE是首个在已确诊为心血管疾病的患者中开展的多效药丸随机试验，也是到目前为止为数不多的几项随访超过了3个月的试验之一。Tonkin博士说：“我认为UMPIRE明确提示多效药丸可以用于患有动脉粥样硬化性心血管疾病的患者。”

值得注意的是，基线时对试验药物依从不好的患者更可能获益于多效药丸，差异达到了3.4倍。这是一个很重要的发现，因为预计多效药丸将来更可能广泛应用于印度、中国、菲律宾以及世界上其他心血管疾病患者众多但却找不到二级药物预防途径的国家。

Tonkin博士补充道，开发多效药丸的职责不应该仅仅落在制药业身上。“由于多效药丸采用的都是低成本的通用药成分，因此这是一项利润率相当低的投资，大型药企不会对此太感兴趣。”

世界卫生组织(WHO)和欧盟委员会都已公开表示支持使用多效药丸。WHO和英国维康信托基金会(Wellcome Trust)在2002年公布的一份报告中称，只要研究证明多效药丸能改善LDL和收缩压，在保证生物等效性的同时还能提高患者的依从性，就足以支持多效药丸获得监管机构的批准，如今UMPIRE试验已经证实了这一点。

UMPIRE试验由欧盟委员会资助。Thom博士和Tonkin博士均声明无相关经济利益冲突。

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By: BRUCE JANCIN, Cardiology News Digital Network

LOS ANGELES – A once-daily, fixed-dose combination of four cardiovascular drugs – a polypill – boosted patient adherence by 33% while meaningfully reducing both systolic blood pressure and LDL cholesterol compared with usual care in the large international UMPIRE trial.

UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) was designed to test the hypothesis that decreasing the cost and complexity of guideline-indicated medications for secondary cardiovascular prevention would improve treatment adherence and outcomes in patients with established atherosclerotic cardiovascular disease or in those at high risk for it.

And UMPIRE was a resounding success, according to Dr. Simon Thom, professor of cardiovascular medicine and pharmacology at Imperial College, London. He presented the results at the annual scientific sessions of the American Heart Association.

The study comprised 2,004 randomized patients in India, Dublin, London, and Utrecht (the Netherlands): 88% had known atherosclerotic cardiovascular disease at baseline; 29% had diabetes. Participants were randomized to the polypill – composed of 75 mg aspirin, 50 mg simvastatin, 10 mg lisinopril, and either 50 mg atenolol or 12.5 mg hydrochlorothiazide, depending upon physician preference – or to usual care, which included individual prescriptions for the same four medications. The polypill was free, while usual care was paid for in the customary local manner.

After a median 15 months of follow-up, treatment adherence was 86% in the polypill arm, compared with 65% with usual care, a relative 33% difference. Systolic blood pressure averaged 129.2 mm Hg in the polypill group, 2.6 mm Hg lower than with usual care. Mean LDL cholesterol was 84.3 mg/dL in the polypill group and 88.6 mg/dL with usual care. Diastolic blood pressure was 72.8 mm Hg with the polypill, compared with 75.2 mm Hg in the usual care group.

All of these differences were statistically significant and clinically meaningful when extrapolated to the rapidly growing global burden of cardiovascular disease. Moreover, quality of life as self-measured on a visual analog scale was significantly better in patients on the fixed-dose combination, Dr. Thom reported.

There were, however, no significant differences between the two study arms in HDL cholesterol, triglycerides, or cardiovascular event rates.

Of note, 61% of UMPIRE subjects were already on all four individual study medications at baseline. That’s an unusually high proportion in the low- and middle-income countries where the polypill will see greatest future use, and it means the UMPIRE results almost certainly underestimate the true benefits to be expected with use of the polypill in clinical practice, he continued.

Side effects were the same in both treatment arms.

Discussant Dr. Andrew M. Tonkin declared UMPIRE to be "an important trial – and the results should be taken on board not only by clinicians, but should really inform government policies and strategies."

Although there is enthusiasm in some quarters for broad use of the polypill for primary prevention – a sort of let’s-put-it-in-the-drinking-water strategy – UMPIRE was the first polypill randomized trial conducted in patients with established cardiovascular disease, and one of very few to date to run longer than about 3 months.

"I believe that UMPIRE firmly establishes the case for using the polypill in those people with manifest atherosclerotic cardiovascular disease," said Dr. Tonkin.

It’s noteworthy that patients with poor baseline adherence to the study medications were 3.4-fold more likely to benefit from use of the polypill. That’s an important finding because the polypill is expected to see its greatest future use in India, China, the Philippines, and other parts of the world where vast numbers of patients with cardiovascular disease now receive little or nothing in the way of pharmacologic secondary prevention, said Dr. Tonkin, professor of preventive medicine and head of the cardiovascular research unit at Monash Hospital in Melbourne.

Moving forward, he added, the responsibility for developing the polypill cannot rest solely with the pharmaceutical industry.

"This is a very low-margin venture using low-cost generic formulations. Major pharma doesn’t want to get interested in this," said Dr. Tonkin.

Both the World Health Organization and the European Commission are publicly on board for the polypill, he noted.

The WHO and Wellcome Trust stated in a 2002 report that demonstration of bioequivalence and improved adherence as reflected in improvements in LDL and systolic blood pressure, as seen in UMPIRE, should be sufficient for regulatory approval of the polypill.

"That, I think, will not carry water in these days, unfortunately. But a meta-analysis of clinical end point data from the various trials is planned. And there are ongoing and planned future phase III trials," Dr. Tonkin said.

While most of the clinical trials, past and present, have taken place in low-income countries, the polypill is also under study in populations in the United States, Canada, Australia, and other relatively well-off nations, he pointed out.

UMPIRE was funded by the European Commission. Dr. Thom and Dr. Tonkin reported having no financial conflicts.