Biostatistics Unit, Department of Medical Sciences, University of Trieste, Trieste, Italy.
MOX-Modelling and Scientific Computing Laboratory, Department of Mathematics, Politecnico di Milano, Milano, Italy.
PLoS One. 2024 Aug 22;19(8):e0309470. doi: 10.1371/journal.pone.0309470. eCollection 2024.
Low-Density Lipoprotein (LDL) cholesterol is one of the main target for cardiovascular (CV) prevention and therapy. In the last years, Proprotein Convertase Subtilisin-Kexin type 9 inhibitors (PCSK9-i) has emerged as a key therapeutic target to lower LDL and were introduced for prevention of CV events. Recently (June 2022) the Italian Medicines Agency (AIFA) modified the eligibility criteria for the use of PCSK9-i. We designed an observational study to estimate the prevalence of eligible subjects and evaluate the effectiveness of PCSK9-i applying a Target Trial Emulation (TTE) approach based on Electronic Health Records (EHR). Subjects meeting the eligibility criteria were identified from July 2017 (when PCSK9-i became available) to December 2020. Outcomes were all-cause death and the first hospitalization. Among eligible subjects, we identified those treated at date of the first prescription. Inverse Probability of Treatment Weights (IPTW) were estimated including demographic and clinical covariates, history of treatment with statins and the month/year eligibility date. Competing risk models on weighted cohorts were used to derive the Average Treatment Effect (ATE) and the Conditional Average Treatment Effect (CATE) in subgroups of interest. Out of 1976 eligible subjects, 161 (8%) received treatment with PCSK9-i. Treated individuals were slightly younger, predominantly male, had more severe CV conditions, and were more often treated with statin compared to the untreated subjects. The latter exhibited a higher prevalence of non-CV comorbidities. A significant absolute and relative risk reduction of death and a lower relative risk for the first hospitalization was observed. The risk reduction for death was confirmed in CATE analysis. PCSk9-i were prescribed to a minority of eligible subjects. Within the TTE framework, the analysis confirmed the association between PCSK9-i and lower risk of events, aligning with findings from randomized clinical trials (RCTs). In our study, PCSK9-i provided protection specifically against all-cause death, expanding upon the evidence from RCTs that had primarily focused on composite CV outcomes.
低密度脂蛋白（LDL）胆固醇是心血管（CV）预防和治疗的主要靶点之一。近年来，前蛋白转化酶枯草溶菌素/克那霉 9 抑制剂（PCSK9-i）已成为降低 LDL 的关键治疗靶点，并被引入用于预防 CV 事件。最近（2022 年 6 月），意大利药品管理局（AIFA）修改了使用 PCSK9-i 的资格标准。我们设计了一项观察性研究，以评估符合条件的患者的患病率，并应用基于电子健康记录（EHR）的目标试验模拟（TTE）方法评估 PCSK9-i 的有效性。从 2017 年 7 月（PCSK9-i 上市时）至 2020 年 12 月，符合资格标准的患者被确定。结局为全因死亡和首次住院。在符合条件的患者中，我们确定了在首次处方日期接受治疗的患者。包括人口统计学和临床协变量、他汀类药物治疗史以及符合条件的月份/年份日期，估计了逆概率治疗权重（IPTW）。使用加权队列的竞争风险模型得出了感兴趣亚组的平均治疗效果（ATE）和条件平均治疗效果（CATE）。在 1976 名符合条件的患者中，有 161 名（8%）接受了 PCSK9-i 治疗。与未接受治疗的患者相比，接受治疗的患者年龄稍小，主要为男性，CV 状况更严重，且更常接受他汀类药物治疗。后者表现出更高的非 CV 合并症患病率。死亡的绝对和相对风险降低以及首次住院的相对风险降低显著。CATE 分析证实了死亡风险降低。PCSk9-i 仅被开给少数符合条件的患者。在 TTE 框架内，分析结果证实了 PCSK9-i 与较低的事件风险之间的关联，与随机临床试验（RCTs）的结果一致。在我们的研究中，PCSK9-i 提供了针对全因死亡的保护，扩展了 RCT 主要集中在复合 CV 结局的证据。
