2019年8月24日出版的《柳叶刀》杂志刊登了伊朗德黑兰医科大学Reza Malekzadeh研究组的最新成果，他们研究探讨了复方制剂在心血管疾病一级和二级预防中的有效性。

在这项队列研究中，50045名参与者来自伊朗的戈勒斯坦省，年龄40-75岁，随机分配至非药物预防干预组（最低限度护理组）或每日一次服用复方制剂组。非药物预防干预措施包括健康生活方式的教育培训，如低盐、低糖、低脂的健康饮食、锻炼、控制体重、戒烟和戒毒。该研究以两种复方制剂为研究对象。复方制剂组的参与者先服用1号复方制剂（氢氯噻嗪12.5mg，阿司匹林81mg，阿托伐他汀20mg，依那普利5mg)，在随访期间出现咳嗽症状时则改服2号复方制剂，将依那普利5mg替换为缬沙坦40mg。所有参与者均随访了60个月。

主要心血管事件包括急性冠状动脉综合征住院、致命性心肌梗死、猝死、心力衰竭、冠状动脉血管再通术、非致命性和致命性卒中。

2011年2月22日至2013年4月15日，该研究团队将6838名患者纳入研究，最低限度护理组中3417名患者，其中1761名（51.5%）为女性，复方制剂组中3421名患者，1679名（49.1%）为女性，中位依从性为80.5%。随访期间，最低限度护理组中有301名（8.8%）参与者发生重大心血管事件，而复方制剂组中有202名（5.9%），风险比为0.66。既往是否有心血管疾病无明显交互作用。复方制剂组中高依从性的参与者主要心血管事件的风险显著低于最低限度护理组，风险比为0.43。两组间的不良反应发生率相差无几。在5年的随访中，复方制剂组出现10例颅内出血和13例上消化道出血，最低限度护理组则分别出现11例和9例。

综上，复方制剂可有效预防主要心血管事件的发生。患者的药物依从性高，不良反应少，可在中低收入国家大力推广。

研究人员表示，固定剂量联合治疗（复方制剂策略）可减少心血管疾病负担，特别适用于中低收入国家（LMICs）。

附：英文原文

Title: Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial

Author: Gholamreza Roshandel, PhD;Masoud Khoshnia, MD;Hossein Poustchi, PhD;Tom Marshall, PhD;Prof Kar Keung Cheng, FMedSci;Prof Reza Malekzadeh, MD;et al

Issue&Volume: VOLUME 394, ISSUE 10199, P663-671, AUGUST 24, 2019

Summary: 

Background

A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease.

Methods

The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50?045 participants aged 40–75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle—eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome—occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)—was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov, number NCT01271985.

Findings

Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study—3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5–92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55–0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49–0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51–1·12; p interaction=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33–0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up—ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group.

Interpretation

Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs.

DOI: https://doi.org/10.1016/S0140-6736(19)31791-X

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31791-X/fulltext#