Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study

Abstract

Aims: With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA).

Methods and results: We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed.

Conclusion: This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements.

Clinical trial registration: NCT03530215.

Keywords: Anticancer drugs; Disproportionality analysis; Long QT; Pharmacovigilance; Torsade de pointes; Ventricular arrhythmias.

Graphical Abstract

Evolution of reporting for drug-induced long QT, ventricular arrhythmias, and torsade de pointes associated with anticancer drugs (A) as a function of their classes (B) in VigiBase from inception (1967) to January 2019.

Figure 1

Evolution of the absolute number of long QT syndrome and/or ventricular arrhythmias including torsade de pointe reports over time for each of the 49 culprit anticancer drugs identified using VigiBase (see Table 1). For each drug, the year of Food and Drug Administration approval was added when available (otherwise, NA stands for not available).

Figure 2

Three-level sudden death risk stratification for the 49 liable anticancer drugs associated with isolated drug-induced long QT (low risk), ventricular arrhythmias without sudden death (moderate risk), and ventricular arrhythmias with sudden death (high risk) identified in VigiBase (through 1 January 2019). Absolute number of ventricular arrhythmias (N  _VA) including torsade de pointes (associated (N  _LQT + N  _VA) or not with diLQT reports by drug and sudden death risk level is displayed in (A) and (B), respectively. The corresponding proportion of such cases (N  _VA or N  _LQT + N  _VA) over the total number of overall adverse drug reactions per drug (N  _drug) are displayed in (C) and (D), respectively.

Figure 3

Overlap and overall fatality rate of drug-induced long QT syndrome, torsade de pointe, and ventricular arrhythmia reports associated with the 49 drugs identified in VigiBase (A) with their respective time to onset (B). Overlap in VigiBase for reports of drug-induced long QT and ventricular arrhythmia including torsade de pointes for these 49 drugs as a function of the underlying drug classes (C) with their corresponding time to onset (D). Differences in median time to onset by groups were compared by Wilcoxon tests and Dunn’s post-test. * and ** stands for P ≤ 0.05 and ≤0.0001, respectively. combo, reports containing at least one culprit anticancer drugs from at least two different anticancer drug classes; CT, cytotoxic therapy; HT, hormone therapy; IT, immunotherapy; KI, kinase inhibitor; Misc, miscellaneous.