Department of General Practice and Elderly Care Medicine, University of Groningen, University Medical Centre Groningen (UMCG), PO Box 196, Groningen, AD, 9700, The Netherlands.
BMC Med Res Methodol. 2024 Jun 22;24(1):137. doi: 10.1186/s12874-024-02260-z.
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.
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.
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).
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.
在依洛尤单抗和阿利西尤单抗的随机试验中已经确定了基线不平衡。我们的目的是定量评估（1）是否存在系统的基线差异，以及（2）基线差异与试验中低密度脂蛋白胆固醇（LDL-c）和临床结果的关系。
我们进行了一项荟萃流行病学研究。检索了 PubMed、Embase、监管报告、ClinicalTrials.gov 和公司网站，以寻找试验。提取了 7 个基线特征（平均年龄、LDL-c、BMI、男性百分比、糖尿病患者、吸烟者和高血压患者）和 5 个结局（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）。我们计算了（1）基线失衡的范围和分布（符号检验），（2）汇总的基线差异和异质性（荟萃分析），（3）连续变量周围标准差的差异（符号检验和汇总），以及（4）基线差异与结局的关系（荟萃回归）。分别分析和合并了 PCSK9 抑制剂组与安慰剂或依折麦布的比较。
我们确定了 43 项试验，共纳入 63193 名参与者。基线特征经常缺失。许多试验显示出较小的基线不平衡，但也有一些较大的不平衡。只有药物与安慰剂组的基线 BMI 存在统计学上的显著差异（MD-0.16；95%CI-0.24 至-0.09）。在安慰剂和依折麦布的比较中，有 6 项和 5 项存在基线失衡的统计学显著异质性。在联合比较中，BMI、男性、糖尿病患者和高血压患者的异质性具有统计学意义。PCSK9 抑制剂组与对照组之间的标准差明显更大（年龄符号检验 0.014；LDL-c 0.014；BMI 0.049）。荟萃回归显示，年龄、BMI 和糖尿病患者的基线不平衡与任何不良事件风险和死亡率风险存在临床相关关系。两个关系具有统计学意义：药物与对照组相比，BMI 平均值较高，死亡率降低（β-0.56；95%CI-1.10 至-0.02），糖尿病患者比例较高，任何不良事件风险增加（β0.02；95%CI0.01 至 0.04）。
依洛尤单抗和阿利西尤单抗试验中存在基线不平衡和系统的标准差差异，因此不能假设研究组具有可比性。这些发现引起了人们对随机分组过程设计和实施的关注。
