Drug-associated Takotsubo syndrome risk profiling: a global pharmacovigilance study

Drug exposure has been reported in association with Takotsubo syndrome, but the breadth and relative strength of these reporting signals across therapeutic classes remain incompletely characterised.

We conducted a retrospective pharmacovigilance study using reports submitted to the Food and Drug Administration Adverse Event Reporting System between 2004 and the second quarter of 2025. Takotsubo syndrome reports were identified and analysed using disproportionality methods, including reporting ORs and Bayesian information components. Sensitivity analyses excluded catecholaminergic agents and selected concomitant therapies.

Among >22 million adverse event reports, 5213 involved Takotsubo syndrome, predominantly affecting women (74.8%) and older individuals (>60 years: 44.4%). Hospitalisation (51.6%) and life-threatening outcomes (21.7%) were frequently reported. Catecholaminergic agents showed the highest reporting disproportionality, notably dobutamine (reporting OR (ROR) (95% CI) 283.83 (226.55 to 355.60)) and norepinephrine (ROR (95% CI) 160.70 (126.42 to 204.28)). After exclusion of these agents, disproportionate reporting persisted across several non-catecholaminergic drug classes, including antineoplastic and central nervous system-active drugs. Immune checkpoint inhibitors (ICIs) accounted for 219 reports and demonstrated disproportionate reporting. However, pairwise comparisons showed lower disproportionality for ICI-only reports than for carboplatin-only or paclitaxel-only reports.

In spontaneous pharmacovigilance reports, Takotsubo syndrome is disproportionately reported with multiple drug classes, most prominently catecholaminergic agents. Disproportionate reporting with ICIs was observed within an oncology population, although with a lower magnitude than carboplatin and paclitaxel. These findings support cautious clinical awareness while highlighting the need for confirmatory observational studies to clarify absolute risk and underlying mechanisms.