Stress cardiomyopathy (Takotsubo syndrome) in patients who received adrenergic agonist drugs: A pharmacovigilance study using the Japanese Adverse Drug Event Report (JADER) database.

Introduction: Stress cardiomyopathy, or Takotsubo syndrome (TTS), is an acute and reversible syndrome developing in strong association with psychological or physiological stressors. While a surge in the circulating catecholamine level is suspected as one of its pathophysiologies, the contribution of treatment with sympathomimetic drugs to the development of TTS remains uncertain.

Methods: We conducted a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database containing more than 500,000 patient cases recorded between April 2004 and March 2019, to detect TTS ('stress cardiomyopathy') as adverse event signals associated with adrenergic agonist drugs usage by calculating reporting odds ratio (ROR).

Results: Among 306 TTS cases reported to JADER, we identified 58 TTS cases with exposure to adrenergic agonist drugs, predominantly of women (52/58, 89.7%) and those in the median age-decades of the 70s. After adjusting for age in decades and sex, most of the intravenous catecholamines showed significantly higher reporting (lower 95% ROR > 1) for TTS, including adrenaline, noradrenaline, dobutamine, dopamine, phenylephrine, and ephedrine. In addition, peroral midodrine, transdermal tulobuterol, inhaled salbutamol, and inhaled procaterol also showed significantly higher ROR for TTS. We also identified a small number of TTS cases with Parkinson's disease taking midodrine or droxidopa, but not receiving other adrenergic agonists.

Conclusion: The current pharmacovigilance study showed significantly higher RORs for TTS following the use of some of the adrenergic drugs, being mostly consistent with the TTS-related adrenergic drugs reported in earlier literature. A potential association of taking midodrine or droxidopa with the development of TTS was also suggested.