心血管复方药片可改善依从性和高血压

《美国医学会杂志》(JAMA)9月3日在线发表的UMPIRE研究显示，使用含降压药、他汀类药和抗血小板药的固定剂量联合治疗(即复方药片)可显著改善用药依从性并轻微改善高血压和高胆固醇血症(JAMA 2013;310:918-29)。

在这项开放标记研究中，英国伦敦帝国学院国际循环健康中心的Simon Thom医生及其同事从印度的28个诊所纳入1,000例患者，并从英格兰、爱尔兰和荷兰纳入1,004例患者。1,771例患者已确诊心血管疾病(CVD)，233例患者发生CVD事件的估计5年风险≥15%。患者被随机分入2个复方药片组和1个对照组。在第1个复方药片组中，589例患者接受含75 mg阿司匹林、40 mg辛伐他汀、10 mg赖诺普利和50 mg阿替洛尔的复方药片治疗。在第2个复方药片组中，413例患者接受含75 mg阿司匹林、40 mg辛伐他汀、10 mg赖诺普利和12.5 mg氢氯噻嗪的复方药片治疗。对照组1,002例患者接受常规治疗。中位随访时间为15个月(范围：12~24个月)。

结果显示，1个月后，2个复方药片组的依从率为97.3%，而对照组为68.3%。研究结束时，2个复方药片组的依从率为86.3%，而对照组为64.7%。具有统计学显著性的绝对差异为21.6%。

2个复方药片组的血压降幅(2.6 mmHg)和LDL胆固醇水平降幅(4.2 mg/dl)轻微，但与对照组相比具有显著性。在包括吸烟者和CVD事件最高危患者在内的所有亚组患者中，观察到的治疗效应相似且具有统计学显著性。

从使用复方药片中获益最大的亚组是36%的基线时未服用所有推荐药物的患者。这些患者的依从率从23%增至77%；中位血压显著降低4.9 mmHg，LDL胆固醇降低6.7 mg/dl。

体重、腰围和BMI在随访期间未发生改变，研究结束时各组的这些指标也无差异。随访结束时，两组在自报参与剧烈体力活动的时间、参与锻炼项目、到糖尿病诊所就诊和参与戒烟项目方面也无差异。在使用复方药片的患者中观察到肌酐和尿酸水平显著增加，但钠、钾、丙氨酸转氨酶、天冬氨酸转氨酶和血糖水平无改变。

复方药片组和常规治疗组的严重不良事件发生率相似(11.8% vs. 10.2%)，两组在所有主要子分类的不良事件方面也无显著差异。共85例患者发生CVD事件，其中复方药片组5.0%，对照组3.5%。复方药片组和对照组的死亡例数相似，分别为17例和15例。

由于仅有85起CVD事件，因此该研究没有足够效能检出两组之间在CVD转归方面的任何有意义差异。然而，鉴于血压和胆固醇转归方面观察到的获益程度，预计数年后，复方药片组患者的冠状动脉疾病和卒中发生率将降低15%。

UMPIRE研究获欧洲委员会和Dr. Reddy’s Laboratories资助。Thom医生声明无经济利益冲突；其他研究者声明与药企存在诸多联系。

随刊述评：复方药片的优势仍未获证实

哈佛医学院、布里格姆妇女医院老年病科的J. Michael Gaziano医生表示，该复方治疗策略的确切优势在很大程度上仍未获证实，除非有严谨数据表明复方药片确可改善临床CVD转归，而不仅仅是依从率。

该研究的一个缺点是两个干预组的患者可到诊所免费获取复方药片，而常规治疗组患者需支付药费。费用上的差异也可能影响了依从率。此外，虽然整个研究人群基线时的用药依从性较好，并且知道如何获取药物，但干预组患者自己拿药要比对照组更容易。Gaziano医生声明无经济利益冲突(JAMA 2013;310:910-1)。

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By: MARY ANN MOON, Cardiology News Digital Network

Use of a single "polypill" containing drugs to lower blood pressure, cholesterol, and platelet aggregation markedly improved medication adherence and modestly improved hypertension and hypercholesterolemia, according to a report published online Sept. 3 in JAMA.

The results are from the UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) study. UMPIRE is the first randomized trial to assess the long-term use of a fixed-dose combination therapy containing antiplatelet, statin, and BP-lowering drugs among patients who either had established cardiovascular disease or were at high risk – the group in whom 40% of all cardiovascular events occur, said Dr. Simon Thom of the International Centre for Circulatory Health, Imperial College London, and his associates.

The fixed-dose combination therapy, or polypill, has been proposed as a way to simplify complex medication regimens and reduce costs. However, the benefits and risks have not been examined in high-risk CVD patients until now, the study authors noted.

The clinical trial primarily involved patients who were already adherent to a multiple-pill regimen at baseline. However, in the subgroup of 727 patients who were not taking all the recommended medications at baseline, use of the polypill prompted a threefold rise in adherence rates, from 23% to 77%. It also produced larger reductions in blood pressure and LDL cholesterol levels, the investigators noted.

Dr. Thom and his colleagues performed the open-label study among 1,000 patients at 28 clinics across India and 1,004 patients in England, Ireland, and the Netherlands. All the study subjects either had established CVD (1,771 patients) or a 15% or higher estimated 5-year risk of experiencing a CVD event (233 patients).

The study participants were randomly assigned to receive a polypill containing 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol (589 patients), or a polypill containing 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide (413 patients), or usual care (1,002 patients who served as control subjects). They were followed for 12-24 months, with a median follow-up of 15 months.

After 1 month, adherence rates were 97.3% for both polypill groups, compared with 68.3% for the control group.

At the conclusion of the study, rates of adherence were 86.3% for both polypill groups, compared with 64.7% for the control group, a statistically significant absolute difference of 21.6%, the researchers said (JAMA 2013;310:918-29).

The findings were essentially the same in several sensitivity analyses that used slightly altered definitions of adherence.

Blood pressure levels decreased modestly but significantly (2.6 mm Hg lower) in both polypill groups, compared with usual care, as did LDL-cholesterol levels (4.2 mg/dL lower).

The treatment effects were similar and statistically significant across all subgroups of patients studied, including smokers and patients at the highest risk for a CVD event.

The subgroup that benefitted the most from using a polypill was the 36% of patients who were not taking all their recommended medications at baseline. Their adherence rate improved from 23% to 77%; median blood pressure dropped significantly by 4.9 mm Hg, and LDL-cholesterol declined by 6.7 mg/dL.

"Weight, waist circumference, and BMI did not change during follow-up and did not differ between groups at the end of the study," the investigators noted. Self-reported time engaged in vigorous physical activity, participation in exercise programs, attendance at dietetic clinics, and participation in smoking cessation programs were also similar in both groups at the end of follow-up.

Patients taking a polypill showed a significant increase in creatinine and uric acid levels, but no changes in sodium, potassium, alanine transaminase, aspartate aminotransferase, or glucose levels.

Rates of serious adverse events were similar between patients taking the polypills (11.8%) and those under usual care (10.2%), and there were no significant differences between the two groups in any major subcategory of adverse event. A total of 85 study subjects had a CVD event, including 5.0% of the polypill groups and 3.5% in the control group.

Similarly, a comparable number of deaths occurred among the study subjects, with 17 in the polypill groups and 15 in the control group.

Because there were only 85 CVD events, the study was insufficiently powered to detect any meaningful differences between groups specifically for CVD outcomes. However, given the magnitude of benefit in blood pressure and cholesterol outcomes, it would be expected that patients taking the polypill would show a 15% reduction in coronary artery disease and stroke incidence after a few years, Dr. Thom and his associates said.

The European Commission and Dr. Reddy’s Laboratories funded the UMPIRE study. Dr. Thom reported no financial conflicts of interest; his associates reported numerous ties to industry sources.

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Polypill still unproven

Until rigorous data illustrate that the polypill improves concrete clinical CVD outcomes, not just adherence, "the precise advantage of this strategy remains largely unproven," said Dr. J. Michael Gaziano.

One drawback to the UMPIRE trial is that patients in the two intervention groups were given the polypill for free at clinic visits, while those in the usual care group had to pay for their medications. The difference in cost may well have influenced rates of adherence, Dr. Gaziano said.

Moreover, even though the entire study population generally had good medication adherence at baseline and "a good understanding of how to obtain their medications, they were left to get them on their own, making it much easier for the intervention group to obtain the medications," Dr. Gaziano said.

Dr. Gaziano is in the division of aging at Brigham and Women’s Hospital and Harvard Medical School, Boston. Dr. Gaziano also is an associate editor of JAMA. He reported no financial conflicts of interest. These remarks were taken from his editorial accompanying Dr. Thom’s report (JAMA 2013;310:910-1).