Bahiru Ehete, de Cates Angharad N, Farr Matthew Rb, Jarvis Morag C, Palla Mohan, Rees Karen, Ebrahim Shah, Huffman Mark D
Internal Medicine; Division of Cardiology, Northwestern University, 201 E. Huron St. Galter 19-100, Chicago, Illinois, USA, 60611.
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK, CV4 7AL.
Cochrane Database Syst Rev. 2017 Mar 6;3(3):CD009868. doi: 10.1002/14651858.CD009868.pub3.
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD.
To determine the effect of fixed-dose combination therapy on all-cause mortality, fatal and non-fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed-dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health-related quality of life, and costs.
We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions.
We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure-lowering and one lipid-lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre-existing ASCVD.
Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I < 50%) and random-effects models when heterogeneity was high (I ≥ 50%). We used the GRADE approach to evaluate the quality of evidence.
In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89, I = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence).
AUTHORS' CONCLUSIONS: The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes.
动脉粥样硬化性心血管疾病（ASCVD）是全球死亡和残疾的主要原因，然而ASCVD危险因素控制和二级预防率仍然很低。将降血压、降胆固醇和抗血小板治疗组合成固定剂量的单片复方制剂（即多效药丸）已被提议作为减轻全球ASCVD负担的一种策略。
确定固定剂量联合治疗对全因死亡率、致命和非致命ASCVD事件以及不良事件的影响。我们还试图确定固定剂量联合治疗对血压、血脂、依从性、停药率、健康相关生活质量和成本的影响。
我们在2016年9月更新了之前对CENTRAL、MEDLINE、Embase、ISI科学网以及DARE、HTA和HEED的检索。我们还在2016年9月检索了两个临床试验注册库。我们没有设置语言限制。
我们纳入了固定剂量联合治疗的随机对照试验，该治疗至少包含一种降压成分和一种降脂成分，与18岁及以上成年人的常规治疗、安慰剂或活性药物对照进行比较，治疗持续时间不限，无论是否存在预先存在的ASCVD均无限制。
三位综述作者独立选择纳入研究并提取本次更新的数据。我们使用Cochrane“偏倚风险”评估工具评估偏倚风险。对于二分数据，我们计算风险比（RR），对于连续数据，我们计算平均差（MD），当异质性较低（I²<50%）时使用固定效应模型，当异质性较高（I²≥50%）时使用随机效应模型，并给出95%置信区间（CI）。我们使用GRADE方法评估证据质量。
在初始综述中，我们确定了9项随机对照试验，共7047名参与者，本次更新纳入了另外4项试验（n = 2012名参与者；平均年龄范围62至63岁；30%至37%为女性）。13项试验中的8项评估了固定剂量联合（FDC）治疗在无ASCVD病史人群中的效果，中位随访时间从6周至23个月不等。最近的试验通常规模更大，随访时间更长，偏倚风险更低。主要偏倚风险与参与者和研究人员缺乏盲法有关，这是干预措施所固有的。与对照人群（安慰剂、常规治疗或活性药物对照）相比，固定剂量联合治疗对死亡率（FDC = 1.0%，对照 = 1.0%，RR 1.10，95%CI 0.64至1.89，I² = 0%，5项研究，N = 5300）以及致命和非致命ASCVD事件（FDC = 4.7%，对照 = 3.7%，RR 1.26，95%CI 0.95至1.66，I² = 0%，6项研究，N = 4517）的影响尚不确定（低质量证据）。这些结局的事件发生率较低，以及将固定剂量联合与常规治疗及单一药物进行比较的证据间接性表明，应谨慎看待这些结果。干预组（32%）和对照组（27%）的不良事件都很常见，随机接受固定剂量联合治疗的参与者报告不良事件的可能性高16%（RR 1.16，95%CI 1.09至1.25，11项研究，6906名参与者，中等质量证据）。干预组和对照组之间收缩压的平均差为-6.34 mmHg（95%CI -9.03至-3.64，13项试验，7638名参与者，中等质量证据）。干预组和对照组之间总胆固醇和低密度脂蛋白胆固醇的平均差（95%CI）分别为-0.61 mmol/L（95%CI -0.88至-0.35，11项试验，6565名参与者，低质量证据）和-0.70 mmol/L（95%CI -0.98至-0.41，12项试验，7153名参与者，中等质量证据）。在血压和血脂比较中存在高度的统计学异质性（所有I²≥80%），无法解释，因此应谨慎看待这些结果。与常规治疗相比，固定剂量联合治疗使多药治疗策略的依从性提高了44%（26%至65%）（4项试验，3835名参与者，中等质量证据）。
固定剂量联合治疗对全因死亡率或ASCVD事件的影响尚不确定。报告这些结局的试验数量有限，且纳入的试验主要旨在观察ASCVD危险因素水平的变化而非临床事件，这可能部分解释了纳入试验中观察到的危险因素差异未转化为临床结局差异的现象。与安慰剂、活性对照或常规治疗相比，固定剂量联合治疗与不良事件适度增加相关，但可能与多药治疗方案的依从性改善有关。正在进行的固定剂量联合治疗长期试验将有助于证明危险因素的短期变化是否能够维持，并基于这些变化导致临床事件出现预期差异。
