PDF(Pubmed)
Abstract：
BACKGROUND: Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials.
METHODS: We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.
RESULTS: We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).
CONCLUSIONS: Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.
METHODS: We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.
RESULTS: We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).
CONCLUSIONS: Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.
摘要：
背景：在evolocumab和alirocumab的随机试验中已经确定了基线失衡。我们的目的是定量评估(1)系统基线差异的存在，(2)试验中基线差异与低密度脂蛋白-胆固醇(LDL-c)效应和临床结局的关系.
方法：我们进行了元流行病学研究。PubMed,Embase,监管报告,搜索ClinicalTrials.gov和公司网站进行试验。七个基线特征(平均年龄，LDL-c,BMI,男性百分比，糖尿病患者,吸烟者,和高血压)和五个结果(LDL-c，主要不良心脏事件，严重不良事件,任何不良事件，全因死亡率)被提取。我们计算了(1)基线不平衡的范围和分布(符号检验)，(2)汇总基线差异和异质性(荟萃分析)，(3)围绕连续变量的SDs差异(符号检验和池化)，(4)基线差异与结局的关系(meta回归)。分别和联合分析PCSK9抑制剂组与安慰剂或依泽替米贝的比较。
结果：我们确定了43项试验，共有63,193名参与者。基线特征经常缺失。许多试验显示基线不平衡，但一些大的不平衡。与安慰剂组相比，只有基线BMI显示出统计学上显着的较低的合并平均值（MD-0.16;95％CI-0.24至-0.09）。基线失衡的异质性存在于六个安慰剂和五个依泽替米贝比较中。BMI的异质性具有统计学意义，男性,合并比较中的糖尿病患者和高血压患者。与对照组相比，PCSK9抑制剂组的SD较大具有统计学意义（体征测试年龄0.014；LDL-c0.014；BMI0.049）。Meta回归显示基线年龄失衡的临床相关关系，BMI和糖尿病患者有任何不良事件的风险和死亡的风险。两种关系具有统计学意义：药物组的平均BMI高于对照组，死亡率风险降低（β-0.56；95％CI-1.10至-0.02），和更高比例的糖尿病患者与任何不良事件的风险增加（β0.02;95％0.01-0.04）。
结论：在evolocumab和alirocumab试验中存在异质性基线失衡和系统性不同的SD，因此，研究小组不能被认为是可比的。这些发现引起了人们对随机化程序的设计和实施的担忧。
方法：我们进行了元流行病学研究。PubMed,Embase,监管报告,搜索ClinicalTrials.gov和公司网站进行试验。七个基线特征(平均年龄，LDL-c,BMI,男性百分比，糖尿病患者,吸烟者,和高血压)和五个结果(LDL-c，主要不良心脏事件，严重不良事件,任何不良事件，全因死亡率)被提取。我们计算了(1)基线不平衡的范围和分布(符号检验)，(2)汇总基线差异和异质性(荟萃分析)，(3)围绕连续变量的SDs差异(符号检验和池化)，(4)基线差异与结局的关系(meta回归)。分别和联合分析PCSK9抑制剂组与安慰剂或依泽替米贝的比较。
结果：我们确定了43项试验，共有63,193名参与者。基线特征经常缺失。许多试验显示基线不平衡，但一些大的不平衡。与安慰剂组相比，只有基线BMI显示出统计学上显着的较低的合并平均值（MD-0.16;95％CI-0.24至-0.09）。基线失衡的异质性存在于六个安慰剂和五个依泽替米贝比较中。BMI的异质性具有统计学意义，男性,合并比较中的糖尿病患者和高血压患者。与对照组相比，PCSK9抑制剂组的SD较大具有统计学意义（体征测试年龄0.014；LDL-c0.014；BMI0.049）。Meta回归显示基线年龄失衡的临床相关关系，BMI和糖尿病患者有任何不良事件的风险和死亡的风险。两种关系具有统计学意义：药物组的平均BMI高于对照组，死亡率风险降低（β-0.56；95％CI-1.10至-0.02），和更高比例的糖尿病患者与任何不良事件的风险增加（β0.02;95％0.01-0.04）。
结论：在evolocumab和alirocumab试验中存在异质性基线失衡和系统性不同的SD，因此，研究小组不能被认为是可比的。这些发现引起了人们对随机化程序的设计和实施的担忧。
