Correspondence Combined therapy with beta-blockers and ACE-inhibitors/angiotensin receptor blockers and recurrence of Takotsubo (stress) cardiomyopathy: A meta-regression study Natale Daniele Brunetti a, ⁎, Francesco Santoro b , Luisa De Gennaro c , Michele Correale d , Antonio Gaglione e , Matteo Di Biase e , John E. Madias f,g a Department of Medical & Surgical Sciences, University of Foggia, Italy b Sankt Georg Asclepios Klinik, Hamburg, Germany c U.O. Cardiologia, Ospedale San Paolo, Bari, Italy d Cardiologia Universitaria, Ospedali Riuniti, Foggia, Italy e Department of Medical & Surgical Sciences, University of Foggia, Italy f Icahn School of Medicine at Mount Sinai, New York, NY, United States g Division of Cardiology, Elmhurst Hospital Center, Elmhurst, NY, United States article info Article history: Received 1 August 2016 Received in revised form 16 December 2016 Accepted 17 December 2016 Available online xxxx Keywords: Takotsubo (stress) cardiomyopathy Combined therapy Beta-blockers ACE-inhibitors/angiotensin receptor blockers Recurrence Meta-regression Prevention A recently published letter [1], after considering the results from a series of meta-analyses showing significant association between rates of prescription of ACE-inhibitors/angiotensin receptor blockers (ACEi/ ARB) after an episode of Takotsubo (stress) cardiomyopathy and lower rates of recurrence in non-randomized studies [2–4], raised the question whether the combined use of beta-blockers (BB), whose rates of prescription were not significantly associated with lower rates of recurrence, and ACEi/ARB may carry a possible preventive benefit. We therefore re-analyzed data reported by Singh et al. [3], considering, in a speculative view, possible rates of association therapy with BB and ACEi/ARB in the reported studies. On the basis of available data, rates of combined prescription of BB and ACEi/ARB ranged from a minimum to a maximum as reported in Table 1 [5]. Each of the studies in Table 1 pro- vides percentages of patients who were prescribed BB, ACEi/ARB, and the % rate of TTS recurrences, but not information about the status of the patients who had a recurrent TTS regarding prescribed BB, or ACEi/ARB, or both. Interestingly, weighting such estimated rates of combined prescription for populations' size [6,7], meta-regression analysis results ranged from clear statistical significance in the less optimistic scenario (minimal theoretical rates of combined prescription, p 0.0146) to borderline significance (p 0.0568) with maximal theoreti- cal rates of combined prescription. Mean theoretical values regression analysis is given in Fig. 1, with a statistical significant p = 0.0255. Re- sults were even more statistically significant, and always significant (p = 0.0067 with minimal and p = 0.0443 with maximal theoretical rates of combined prescription), when including more recent results from Templin et al. [8], which published data from the largest cohort of patient with Takotsubo (stress) cardiomyopathy; mean theoretical values regression analysis is given in Fig. 2, with a statistically significant p = 0.0128. As evident, a reverse correlation between rates of combined prescription of BB and ACEi/ARB and rates of Takotsubo (stress) cardio- myopathy recurrence may be therefore hypothesized. Recurrence rate of TTC ranges from 0 to 10% [9]; although clinical correlates determining recurrence of TTC have not been identified, the recurrence rate is higher in patients with severe LV dysfunction during initial TTC event or youn- ger female patients. There is no consensus about the appropriate treat- ment of patients with TTC but there is a marked increase in prescribing aspirin, BB, ACEi and statins on discharge which would be consistent with what would be expected to be seen in treatment after an acute cor- onary syndrome [10]. At the same time, several are uncertainties re- garding TTC etiology, diagnostics and (partly consequently) therapy [11–12], in particular, the inability of BB therapy to improve survival or prevent recurrence. According to Singh et al., incomplete recovery may be linked to ongoing inflammation and evidence of impaired myo- cardial energetics despite normalization of LV ejection fraction; therapy improving energy efficiency may play some role in future [13]. In the ab- sence of randomized studies evaluating medical therapy in TTS, the treatment for this syndrome remains entirely empirical and should be International Journal of Cardiology xxx (2016) xxx–xxx ⁎ Corresponding author at: Viale Pinto n.1, 71100 Foggia, Italy. E-mail address: natale.brunetti@unifg.it (N.D. Brunetti). IJCA-24302; No of Pages 3 http://dx.doi.org/10.1016/j.ijcard.2016.12.124 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard Please cite this article as: N.D. Brunetti, et al., Combined therapy with beta-blockers and ACE-inhibitors/angiotensin receptor blockers and recurrence of Takotsubo (stress) cardiomyopathy: A meta-regression study, Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.124