Table 1. Studies included in this review regarding clinical outcomes of management of Takotsubo syndrome.

ACE, angiotensin-converting enzyme (inhibitors); ALA, alpha-lipoic acid; ARB, aldosterone receptor blocker; CR, cardiac rupture; CRP, C-reactive protein; LMWH, low molecular weight heparin; LV, left ventricular; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; LVOTO, left ventricular outflow tract obstruction; MACE, major adverse cardiac event; MIBG, metaiodobenzylguanidine; MRA, mineralocorticoid receptor antagonists; N/A/, not applicable; OAC, oral anticoagulants; OD, once daily; TIA, transient ischemic attack; TNF, tumor necrosis factor; TTS, Takotsubo syndrome

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Authors, Year of Publication	Study Design: Number of Subjects (n), Area of Study	Treatment Regimen	Primary Measure Studied and Follow-Up Duration	Study Outcomes and Conclusions
Templin et al. 2015	Retrospective observational study: n=1,750 (all TTS)	Beta-blockers and ACE	Outcome measure: MACE. Follow-up: 30 days and 10 years	Study outcome: ACE inhibitor or ARB improve one-year survival. Conclusion: ACE or ARB is beneficial, beta-blockers not beneficial
Santoro et al. 2017	Prospective cohort study: n=12, TTS with LV thrombi	Acute phase (in hospital): LMWH followed by enoxaparin. Long term: OAC (warfarin) for 3 months, discontinuation upon resolution of TTS	Outcome measures: Acute: cerebrovascular embolic event. Long term: new event of stroke, overall survival. Follow-up: 984 days	Study outcomes: Acute phase: LMWH beneficial in stroke prevention. Long term: interruption of OAC after three months with no new stroke, similar survival with or without LV thrombi. Conclusions: LMWH beneficial in acute phase, OAC reasonable use as stroke prophylaxis up to three months
Marfella et al. 2016	Randomized controlled trial: n=48 (all TTS)	ALA 600 mg OD vs placebo	Outcome measures: quantitative MIBG imaging for adrenergic cardiac innervation improvement; Reduction in inflammation marker (CRP, TNF, nitrotyrosine level). Follow-up: one year	Study outcomes: MIBG imaging defect size reduction was greater in ALA treated group compared to placebo; ALA treated group had reduction in inflammation marker compared to placebo. Conclusion: ALA is beneficial
Yeyehd et al. 2016	Observational study: n=117 (all TTS)	Acute phase: Aspirin, Clopidogrel, Fondaparinux, Statin, beta-blockers, ACE/ARB. Discharge: ACE/ARB, beta-blockers, aspirin, clopidogrel, statin + psychological management	Outcome measures: in-hospital mortality; one-year hospital readmission; recurrence of TTS. Follow-up: one year	Study outcomes: no in-hospital mortality; 2.8% re-hospitalization with heart failure; no recurrence of TTS. Conclusion: the standard regime is beneficial, consider discontinued antiplatelet at discharge if TTS diagnosis is certain
Ansari et al. 2018	Observational study: n=114 TTS with hemodynamic instability	With or without catecholamine support in-hospital	Outcome measures: in-hospital mortality; long-term mortality. Follow-up: Four years	Study outcomes: patients require catecholamine support higher in-hospital and long-term mortality; higher 30 day and long-term mortality. Conclusion: catecholamine use for circulatory support possibly exacerbates the risk of mortality
Santoro et al. 2016	Case-controlled study: n=9 TTS with LVOTO	IV esmolol infusion 0.15 0.3 mg/ kg/ min for 24 hours after admission, bisoprolol 1.5 mg daily. Case-controlled study: n=9 TTS with LVOTO	Outcome measures: LVOT pressure gradient; systolic blood pressure. Follow-up: nine months	Study outcomes: esmolol infusion associated with reduction LVOT gradient and systolic blood pressure. Conclusion: esmolol infusion and bisoprolol is possibly beneficial in TTS with LVOTO
Abanador-Kamper et al. 2017	Observational study: n=72 (all TTS)	Different combination antithrombotic therapy (aspirin, P2Y12 antagonist, OAC and LMWH) for 3,6 or 12 months) + Heart failure regimen (ACE, beta-blocker, MRA) at discharge	Outcome measures – MACE: in-hospital/ Long-term mortality, stroke, myocardial infarction, recurrent TTS. Follow-up: 24 months	Study outcomes: moderate MACE, an event rate of 12%, 1% in-hospital mortality, 5% two-year all-cause mortality. Conclusion: beneficial antithrombotic therapy + heart failure regime for at least two months
Isogai et al. 2016	Observational study: n=2,672 (all TTS)	Early beta-blockers use who started on day one or two of hospitalization compared to no beta-blocker treatment during hospitalization (control group)	Outcome measure: 30-day in-hospital mortality. Follow-up: in-hospital until 30-day after admission	Study outcomes: no mortality benefit for early beta-blocker using compared to control group. Conclusion: early beta-blocker not beneficial
Francesco et al. 2014	Meta-analysis: n=8 studies (all TTS studies with a median follow up of three years)	Standard pharmacological therapy (beta-blockers, ACE/ARB, aspirin. and statins)	Outcome measures: recurrence of TTS at follow up. Follow-up: median three years	Study outcomes: All four pharmacological therapies do not significantly reduce recurrence of TTS. Conclusion: beta-blockers, ACE, ARB, aspirin, and statins are not beneficial in reducing recurrence of TTS
Kumar et al. 2011	Systematic review: n=11 case reports of TTS with CR	Use of beta-blockers of patient with cardiac rupture compared to control group	Outcome measures: N/A. Follow up: N/A	Study outcomes: TTS who developed CR associated with lower use of beta-blockers compared to control group (mean: 36% vs 86%), P = .03. Conclusion: beta-blocker use may have protective effect against CR and may be useful in TTS patients
Regnante et al. 2009	Observational study: n=70 (all TTS)	Standard cardiovascular medication (aspirin, beta-blockers, ACE, statin). Discharged with warfarin for TTS with severe apical wall motion abnormalities	Outcome measures: MACE; recurrence of TTS. Follow-up: four years	Study outcomes: long-term use of ACE before TTS onset protective against cardiogenic shock, sustained ventricular arrhythmia and death; beta-blockers not protective against recurrence of TTS. Conclusion: long-term use of ACE may be beneficial/protective against TTS, beta-blockers not beneficial against recurrent TTS
Fazzio et al. 2008	Observational study: n=33 (all TTS)	Beta-blockers, ACE inhibitors, aspirin, or calcium channel blockers compared to control	Outcome measures: LVEF functional improvement; days of hospitalization. Follow-up: 30 days	Study outcomes: no significant difference found between treatment group and control group. Conclusion: All four medications are not beneficial
de Gregorio. 2010	Systematic review: n=36 TTS with LV thrombus	Anticoagulation	Outcome measures: any cardioembolic event (stroke, TIA, renal infarct, peripheral ischemia). Follow-up: N/A	Study outcome: Early anticoagulation treatment with suspected TTS at risk of thromboembolic diseases, irrespective for presence of LV clot. Conclusion: anticoagulation is beneficial in TTS with risk of thromboembolism
Santoro et al. 2013	Case series: n=13 (all TTS)	IV levosimendan 0.1 mcg/kg/min	Outcome measures: LVEF; any adverse event. Follow-up: 441 days	Study outcome: all had improved LVEF on third day and discharge compared to admission; 15% had adverse event. Conclusion: levosimendan possibly beneficial in improving LVEF
Dias et al. 2016	Retrospective study: n=206 (all TTS)	Antiplatelet (single/dual), beta-blockers, ACE, or statin	Outcome measure: MACE (in-hospital heart failure, death, stroke or respiratory failure). Follow-up: until discharge	Study outcome: single or dual antiplatelet therapy independent predictors of lower incidence of MACE. Conclusion: antiplatelet therapy beneficial
Singh et al. 2014	Systematic review and meta-analysis: n=847 (all TTS)	Beta-blockers and ACE	Outcome measure: recurrence rate. Follow-up: N/A	Study outcome: TTS recurrence inversely correlated with ACE prescription and independent of beta-blockers. Conclusion: ACE beneficial