Yusuf S, Pais P, Afzal R, Xavier D, Teo K, Eikelboom J, Sigamani A, Mohan V, Gupta R, Thomas N
Lancet. 2009 Apr 18;373(9672):1341-51. doi: 10.1016/S0140-6736(09)60611-5. Epub 2009 Mar 30.
The combination of three blood-pressure-lowering drugs at low doses, with a statin, aspirin, and folic acid (the polypill), could reduce cardiovascular events by more than 80% in healthy individuals. We examined the effect of the Polycap on blood pressure, lipids, heart rate, and urinary thromboxane B2, and assessed its tolerability.
In a double-blind trial in 50 centres in India, 2053 individuals without cardiovascular disease, aged 45-80 years, and with one risk factor were randomly assigned, by a central secure website, to the Polycap (n=412) consisting of low doses of thiazide (12.5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin. The primary outcomes were LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinary 11-dehydrothromboxane B2 for the antiplatelet effects of aspirin, and rates of discontinuation of drugs for safety. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00443794.
Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood pressure by 7.4 mm Hg (95% CI 6.1-8.1) and diastolic blood pressure by 5.6 mm Hg (4.7-6.4), which was similar when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure increased with the number of drugs used (2.2/1.3 mm Hg with one drug, 4.7/3.6 mm Hg with two drugs, and 6.3/4.5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0.70 mmol/L (95% CI 0.62-0.78), which was less than that with simvastatin alone (0.83 mmol/L, 0.72-0.93; p=0.04); both reductions were greater than for groups without simvastatin (p<0.0001). The reductions in heart rate with Polycap and other groups using atenolol were similar (7.0 beats per min), and both were significantly greater than that in groups without atenolol (p<0.0001). The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283.1 ng/mmol creatinine, 95% CI 229.1-337.0) compared with the three blood-pressure-lowering drugs plus aspirin (350.0 ng/mmol creatinine, 294.6-404.0), and aspirin alone (348.8 ng/mmol creatinine, 277.6-419.9) compared with groups without aspirin. Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill.
This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk.
低剂量的三种降压药物与他汀类药物、阿司匹林和叶酸（复方制剂）联合使用，可使健康个体的心血管事件减少80%以上。我们研究了复方制剂对血压、血脂、心率和尿血栓素B2的影响，并评估了其耐受性。
在印度50个中心进行的一项双盲试验中，通过一个中央安全网站，将2053名年龄在45 - 80岁、无心血管疾病且有一个风险因素的个体随机分配到复方制剂组（n = 412），该组每天服用低剂量的噻嗪（12.5 mg）、阿替洛尔（50 mg）、雷米普利（5 mg）、辛伐他汀（20 mg）和阿司匹林（100 mg），或其他八个组，每组约200人，分别为单独服用阿司匹林组、单独服用辛伐他汀组、单独服用氢氯噻嗪组、两种降压药物的三种组合组、三种降压药物单独使用组，或三种降压药物加阿司匹林组。主要结局指标为：血脂方面为低密度脂蛋白（LDL），降压药物方面为血压，阿替洛尔作用方面为心率，阿司匹林抗血小板作用方面为尿11 - 脱氢血栓素B2，以及药物停用率（用于安全性评估）。分析采用意向性分析。本研究已在ClinicalTrials.gov注册，注册号为NCT00443794。
与未接受降压药物治疗的组相比，复方制剂使收缩压降低7.4 mmHg（95%CI 6.1 - 8.1），舒张压降低5.6 mmHg（4.7 - 6.4），使用三种降压药物（无论是否加用阿司匹林）时结果相似。血压降低幅度随使用药物数量增加而增大（一种药物时为2.2/1.3 mmHg，两种药物时为4.7/3.6 mmHg，三种药物时为6.3/4.5 mmHg）。复方制剂使低密度脂蛋白胆固醇降低0.70 mmol/L（95%CI 0.62 - 0.78），低于单独使用辛伐他汀时的降低幅度（0.83 mmol/L，0.72 - 0.93；p = 0.04）；两者降低幅度均大于未使用辛伐他汀的组（p < 0.0001）。复方制剂组和其他使用阿替洛尔的组心率降低幅度相似（每分钟7.0次），且均显著大于未使用阿替洛尔的组（p < 0.0001）。与三种降压药物加阿司匹林组（350.0 ng/mmol肌酐，95%CI 294.6 - 404.0）相比，复方制剂组11 - 脱氢血栓素B2的降低幅度相似（283.1 ng/mmol肌酐，95%CI 229.1 - 337.0），与未使用阿司匹林的组相比，单独使用阿司匹林组（348.8 ng/mmol肌酐，95%CI 277.6 - 419.9）的降低幅度相似。复方制剂的耐受性与其他治疗相似，没有证据表明随着一片药中活性成分数量增加耐受性会增加。
这种复方制剂可方便地用于降低多种风险因素和心血管风险。
