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Abemaciclib increases the risk of venous thromboembolism in breast cancer: Integrate meta-analysis, pharmacovigilance
Manqi Hua1, Fei Xiong1, Shan Chong1
1Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
Background:
Recently, cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have emerged as a novel treatment strategy for breast cancer. However, increasing reports of CDK4/6i-associated venous thromboembolism (VTE) have garnered attention. This study assessed CDK4/6i-associated VTE in breast cancer, and examined the effect of CDK4/6i on platelet/coagulation function for the first time in vitro.
Methods:
PubMed and Embase databases were searched for studies published from the establishment of the database to December 31, 2022 for randomized controlled trials (RCTs) and real-world studies of CDK4/6i in patients with breast cancer, and the data obtained from the included studies were used for meta-analysis. A disproportionality analysis by extracting adverse drug reaction signals of CDK4/6i-associated VTE from the FDA Adverse Event Reporting System (FAERS) database was also conducted. Additionally, the in vitro effect of CDK4/6i on platelet function was assessed based on platelet aggregation tests and flow cytometry, and coagulation function was assessed based on the blood clotting function test.
Findings:
A total of 16,903 patients in 13 RCTs and 6,490 patients in 9 real-world studies were included in the meta-analysis. In RCTs, VTE occurred in 193 (2.1 %) and 55 (0.7 %) patients in the CDK4/6i and control groups, respectively. In real-world studies, the aggregate incidence rate of VTE was 4.2 % (95 % CI: 2.1, 6.3). The meta-analysis of RCTs revealed that abemaciclib (Odds ratio [OR]: 4.40 [95 % CI: 2.74,7.05], p < 0.001) and palbociclib (OR: 2.35 [95 % CI: 1.34, 4.12], p < 0.01) significantly increased the risk of VTE in patients with breast cancer compared to placebo. FAERS database analysis revealed that abemaciclib (reporting odds ratio [ROR]: 1.63 [95 % CI: 1.36, 1.97]; IC025: 0.67) and ribociclib (ROR: 1.17 [95 % CI: 1.0, 1.39]; IC025: 0.18) demonstrated a significantly increased signal of VTE. Similarly, findings from in vitro experiments demonstrated that abemaciclib enhanced agonist-induced platelet activation, especially when collagen was used as the inducer, and this effect became more prominent with increasing its concentration.
Interpretation:
Use of abemaciclib may increase the risk of VTE in patients with breast cancer, which may be partially attributed to the effect of abemaciclib on platelet function. Close monitoring of VTE occurrence is highly recommended while using abemaciclib, especially in patients at a high risk of VTE.
Insights
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) like abemaciclib increase venous thromboembolism (VTE) risk in breast cancer patients. Abemaciclib also enhances platelet activation, potentially contributing to this risk.
Area of Science:
- Oncology
- Pharmacology
- Hematology
Background:
- Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are novel breast cancer treatments.
- Increasing reports link CDK4/6i use to venous thromboembolism (VTE).
Purpose of the Study:
- To assess CDK4/6i-associated VTE risk in breast cancer patients.
- To investigate the in vitro effects of CDK4/6i on platelet and coagulation function.
Main Methods:
- Meta-analysis of randomized controlled trials (RCTs) and real-world studies (up to Dec 2022).
- Disproportionality analysis of VTE adverse event signals from the FDA FAERS database.
- In vitro assessment of CDK4/6i effects on platelet aggregation, flow cytometry, and blood clotting.
Main Results:
- Meta-analysis included 16,903 patients (RCTs) and 6,490 (real-world studies).
- RCTs showed higher VTE rates with CDK4/6i (2.1%) vs. control (0.7%).
- Abemaciclib and palbociclib significantly increased VTE risk in RCTs; abemaciclib and ribociclib showed increased VTE signals in FAERS.
- In vitro, abemaciclib enhanced platelet activation, particularly with collagen.
Conclusions:
- Abemaciclib use may elevate VTE risk in breast cancer patients, potentially via platelet function alteration.
- Close VTE monitoring is recommended for patients on abemaciclib, especially high-risk individuals.
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