334P - Cardiovascular events related to CDK4/6 inhibitors: A systematic review and safety meta-analysis of randomized controlled trials

Background

In an era marked by the expanding indications of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), it is particularly essential to confirm the associated risk of cardiovascular adverse events (CVAEs) with CDK4/6i, supported by a high level of evidence.

Methods

We systematically reviewed phase 2 and 3 randomized controlled trials (RCTs) comparing CdK4/6i versus control treatment (placebo and non-placebo) in adults treated for a cancer in the MEDLINE, Cochrane and ClinicalTrials.gov. The primary outcome was the summary risk of CVAE related to CdK4/6i versus any control using a random-effects meta-analysis to obtain Peto odds-ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Cases were extracted up to April 6th, 2024.

Results

We identified 2651 citations and after a systematic review, 106 RCTs were assessed for eligibility. 37 RCTs were included in the safety meta-analysis (n=21014). CDK4/6i significantly increased the risk of torsade de pointes / QT prolongation (TdP/QTprol) (Peto-OR=2.46; CI [1,73; 3.49]; I²=0%), venous thromboembolic events (VTE) (Peto-OR=1.85; CI [1.14; 3.00]; I²=25%), heart failure (HF) (Peto-OR=1.82; CI [1.10; 3.00]; I²=0%) and ischemic stroke (Peto-OR=1.76; CI [1,08; 2.85]; I²=0%) compared to control group. The annualized incidence rates of CVAE in CdK4/6i group were 21.30 (95% CI: 4.46-101.64) for TdP/QTprol, 15.91 (95% CI: 7.96-31.81) for VTE, 5.84 (95% CI: 3.28-10.39) for HF and 11.12 (95% CI: 4.83-25.59) for ischemic stroke per 1000 person-years. To harm one patient with VTE associated with CDK4/6i, 196 patients needed to be treated. Similarly, 419 patients needed to be treated to harm one patient with TdP/QT prolongation, 494 for cerebral arterial ischemia, and 530 for heart failure.

Conclusions

This meta-analysis highlights an increased risk of CVAE associated with CdK4/6i, notably a significant elevation in the risk of TdP/QT prolongation, VTE, HF, and ischemic stroke. These findings should particularly alert clinicians considering the expanded indications for prescribing CDK4/6i.

Clinical trial identification

CRD42024523152.

Editorial acknowledgement

Legal entity responsible for the study

Department of Pharmacology, University Teaching Hospital of Caen-Normandie, France.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.