Atrial Fibrillation Incidence Associated With Exposure to Anticancer Drugs Used as Monotherapy in Clinical Trials

Abstract

Background: The incidence of atrial fibrillation (AF) associated with anticancer drugs in cancer patients remains incompletely defined.

Objectives: The primary outcome was the annualized incidence rate of AF reporting associated with exposure to 1 of 19 anticancer drugs used as monotherapy in clinical trials. The authors also report the annualized incidence rate of AF reported in the placebo arms of these trials.

Methods: The authors systematically searched ClinicalTrials.gov for phase 2 and 3 cancer trials studying 19 different anticancer drugs of interest used as monotherapy, up to September 18, 2020. The authors performed a random-effects meta-analysis to compute summary AF annualized incidence rate with its 95% CI using log transformation and inverse variance weighting.

Results: A total of 191 clinical trials (47.1% were randomized) of 16 anticancer drugs across 26,604 patients were included. Incidence rates could be calculated for 15 drugs administered singly as monotherapy. Summary annualized incidence rates of AF reporting associated with exposure to 1 of the 15 anticancer drugs used as monotherapy were derived; these ranged from 0.26 to 4.92 per 100 person-years. The 3 highest annualized incidence rates of AF reporting were found for ibrutinib 4.92 (95% CI: 2.91-8.31), clofarabine 2.38 (95% CI: 0.66-8.55), and ponatinib 2.35 (95% CI: 1.78-3.12) per 100 person-years. Summary annualized incidence rate of AF reporting in the placebo arms was 0.25 per 100 person-years (95% CI: 0.10-0.65).

Conclusions: AF reporting is not a rare event associated with anticancer drugs in clinical trials. A systematic and standardized AF detection should be considered in oncological trials, particularly those studying anticancer drugs associated with high AF rates. (Incidence of atrial fibrillation associated with anticancer drugs exposure in monotherapy, A safety meta-analysis of phase 2 and 3 clinical trials; CRD42020223710).

Keywords: anticancer drugs; atrial fibrillation; cancer; safety meta-analysis.

Graphical abstract

Figure 1

Study Flow Diagram PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram of systematic review and meta-analysis in ClinicalTrials.gov registries up to September 18, 2020. AF = atrial fibrillation.

Figure 2

AF Incidence Rates by Anticancer Drugs and by Cancer Localization Summary annualized incidence rates of atrial fibrillation (AF) reporting associated with exposure to 1 of 15 anticancer drugs used as monotherapy in clinical trials per 100 observations by anticancer drugs and by cancer localization with ClinicalTrials.gov studies posted up to September 18, 2020 (no AF event was reported for obinutuzumab, and no study was included for anthracyclines and cisplatin). Placebo refers to the summary annualized incidence rates of AF reporting associated with placebo arms of included trials. The color code provides visual information on the summary annualized incidence rate of AF reporting (yellow, the lowest incidences, followed by gold, orange, red, and then purple, the highest incidences). GIST = gastrointestinal stromal tumor; MDS = myelodysplastic syndrome.

Central Illustration

Atrial Fibrillation Incidences for the 5 Anticancer Drugs With Higher Rates Summary annualized incidence rates and 95% confidence intervals of atrial fibrillation (AF) reporting per 100 observations (overall and for study mean age <65 years and mean age 65 years or more, when available) for the 5 anticancer drugs having the highest annualized incidence rates with ClinicalTrials.gov studies posted up to September 18, 2020.

Figure 3

Publication Bias Funnel Plot for the Primary Outcome Funnel plots are presented for each of the 15 anticancer drugs studied.