Abstract
Introduction
Takotsubo syndrome (TTS) is an acute heart failure syndrome, featured by transient left ventricular systolic dysfunction. Recurrences of TTS are not infrequent and there is no standard preventive therapy. The aim of this study was to evaluate in a network meta-analysis if beta-blockers (BB) and ACE inhibitors/angiotensin receptor blockers (ACEi/ARBs), in combination or not, can effectively prevent TTS recurrences.
Methods
We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for clinical studies published between January 2010 and September 2022. We considered all those studies including patients receiving medical therapy with BB, ACEi/ARBs. The primary outcome was TTS recurrence.
Results
We identified 6 clinical studies encompassing a total of 3407 patients with TTS. At 40±10 months follow-up, TTS recurrence was reported in 160 (4.7%) out of 3407 patients. Mean age was 69.8±2 years and 394 patients (11.5%) out of 3407 were male. There were no differences in terms of TTS recurrence when comparing ACEi/ARBs versus control (OR 0.83; 95% CI 0.47 to 1.47, p=0.52); BB versus control (OR 1.01; 95% CI 0.63 to 1.61, p=0.96) and ACEi/ARBs versus BB (OR 0.88; 95% CI 0.51 to 1.53, p=0.65).
Combination of BB and ACEi/ARBs was also not effective in reducing the risk of recurrence versus control (OR 0.91; 95% CI 0.58 to 1.43, p=0.68) vs ACEi/ARBs (OR 0.79; 95% CI 0.46 to 1.34, p=0.38)) and vs BB (OR 0.77; 95% CI 0.49 to 1.21, p=0.26).
Conclusions
Our study did not find sufficient statistical evidence regarding combination therapy with BB and ACEi/ARBs in reduction of TTS recurrence.
Keywords: cardiomyopathies, meta-analysis
Introduction
Takotsubo syndrome (TTS) is an acute heart failure syndrome, featured by transient left ventricular (LV) systolic dysfunction. It is mainly found in postmenopausal woman after a physical or emotional stress.1 2 The precipitating mechanism is still not well elucidated; however, increased catecholamine levels could be the main driver of cardiac toxicity and transient LV dysfunction.3–5
Its initial management is similar to that of the acute heart failure, except for beta-adrenergic inotropes.6 Data on long-term pharmacological therapy are mainly based on observational registries and no randomised trials have been published so far. Therefore, there is no standard therapy suggested. Templin et al found that the ACE inhibitors (ACEi) or angiotensin receptor blockers (ARBs) were associated with improved survival at 1 year and there was no evidence of any survival benefit for the use of beta-blockers (BB).7 However, in this study therapy was recorded only at-hospital discharge and follow-up of the cohort was available for 70% of patients.
Recent data from European registries showed that BB could be associated with survival benefit among patients with TTS with hypertension8 and cardiogenic shock.9
Recurrences of TTS are not infrequent, with a rate ranging from 4% to 11.4% within the first 4 years.10–12 No drugs have shown potential benefit in terms of recurrences reduction.13 However, in a meta-regression study from Brunetti et al, there was a reverse correlation between rates of combined prescription of BB and ACEi/ARBs and rates of TTS recurrence.14
We therefore aimed to evaluate in a network meta-analysis whether pharmacological treatment with BB and/or ACEi/ARBs can effectively prevent TTS recurrences.
Methods
Data sources and selection
Two investigators (FS, NDN) independently searched PubMed, CENTRAL, BioMedCentral, Cardiosource, ClinicalTrials.gov and ISI Web of Science (January 2010–September 2022). Search keywords were: TTS, apical ballooning syndrome, Takotsubo cardiomyopathy, stress cardiomyopathy, long-term follow-up, recurrence, pharmacological treatment. No language restriction was used.
Study selection
Two investigators (FS, NDN) independently performed study selection. Studies were included if they enrolled patients through the TTS diagnostic criteria of European Society of Cardiology—Heart Failure Association or INTERTAK: (1) transient regional wall motion abnormalities of the left or right ventricle, frequently preceded by a stressful trigger and usually extending beyond a single epicardial coronary artery distribution; (2) absence of culprit coronary artery disease at coronary angiogram; (3) new and reversible electrocardiography abnormalities during hospitalisation; (4) elevated cardiac troponin and serum natriuretic peptide levels.15 16
Two hundred eleven studies were identified through database search and 46 duplicates were removed. One hundred sixty-five unique records were screened and 111 of them were excluded. Fifty-four full-text articles were assessed for eligibility but only six met all the inclusion criteria8 17–21 (figure 1).
Figure 1.
Flow chart of study selection.
Data extraction
Reviewers extracted the data with regard to inclusion criteria, total number of patients, duration of follow-up, pharmacological treatment at the moment of discharge, during follow-up and at the time of TTS recurrence. In case of missing data, the senior authors of the included studies were contacted to retrieve unpublished data. All senior authors contacted (six out of six) reported additional data required.
Risk of bias and quality assessment
The risk of bias was assessed according to the Cochrane Collaboration’s recommendations (low, medium or high risk of bias). The Grading of Recommendations, Assessment, Development and Evaluation tool was used to access the quality of evidence of the studies selected (high, moderate, low or very low).
Network meta-analysis
Using Review manager (V.5.4–1), a network meta-analysis was performed. ORs and 95% CIs for direct comparisons between pharmacological treatments were calculated and represented in a ranking plot for each outcome. We deemed statistical significance at p<0.05. Control was used as the comparator arm in three subanalyses. Statistical heterogeneity between trials was assessed using I2 statistic. Forest plots for the analysed outcome and network graph that compare the six interventions (including control) were obtained, and they illustrate ORs and 95% CIs for direct comparisons.
Results
Study selection
A systematic search identified a total of 54 records after exclusion of duplicates. After screening, six full-text papers were included (table 1). In total, these studies enrolled 3407 patients (11.5% male) with mean age of 69.8±1.9 years (figure 1). One study included fewer than 100 patients, 4 studies included between 230 and 825 patients and 1 study included >1500 patients. The mean follow-up duration was 40±10 months. Age was comparable among studies (mean age=69.2±2).
Table 1.
Clinical features of the studies included in the network meta-analysis
| Study | Patients | Study features | Mean age | Male (%) | Follow-up (months) | Recurrence (%) |
| Nishida et al 18 | 251 | Observational | 69 | 26.6 | 31 | 2.7 |
| Matabuena Gomez-Limon et al 17 | 66 | Observational | 67 | 4.5 | 48 | 7.5 |
| Arcari et al 19 | 234 | Observational | 72 | 8.1 | 44 | 3.4 |
| Silverio et al 8 | 825 | Observational | 72 | 9.6 | 24 | 4.3 |
| Arcari and Nuṅez et al 21 | 1593 | Observational | 70 | 9.9 | 41 | 4.8 |
| Xenogiannis et al 20 | 436 | Observational | 69 | 15.3 | 53 | 5.9 |
Outcomes
TTS recurrence was reported in 6 studies that enrolled 3407 patients incurring a combined total of 160 (4.7%) events.
Beta-blockers
The effects of BB on prevention of TTS recurrence were evaluated in a pooled analysis that included 1558 patients, of whom 74 (4.7%) suffered recurrence. Among those with TTS recurrence, BB were prescribed in 35 of 74 (47.3%) patients. The recurrence rate was 4.92% (n 35/711) in those treated with BBs compared with 4.60% (n 39/847) in controls (OR 1.01; 95% CI 0.63 to 1.61, p=0.96) (online supplemental figure 1).
heartjnl-2023-322980supp001.pdf (282.3KB, pdf)
ACE inhibitors/angiotensin receptor blockers
The effects of ACEi/ARBs on prevention of TTS recurrence were evaluated in a pooled analysis that included 1333 subjects, of whom 60 (4.5%) suffered recurrence. Among those with TTS recurrence, ACEi/ARBs were prescribed in 21 of 60 (35%) patients. The recurrence rate was 4.41% (n=21/476) in those treated with ACEi/ARBs compared with 4.55% (n=39/857) in controls (OR 0.83; 95% CI 0.47 to 1.47, p=0.52) (online supplemental figure 2).
ACE inhibitors/angiotensin receptor blockers versus beta-blockers
The effects of BB versus ACEi/ARBs on prevention of TTS recurrence were evaluated in a pooled analysis that included 1187 subjects. The recurrence rate was 4.41% in those treated with ACEi/ARBs (n=21/476) vs 4.92% (n=35/711) in those treated with BB (OR 0.88; 95% CI 0.51 to 1.53, p=0.65) (online supplemental figure 3).
Network meta-analysis
BB and ACEi/ARBs versus control
The combination of BB and ACEi/ARBs versus control was evaluated in 2337 patients. Recurrence rate was 3.88% (n=52/1377) among those treated with BB and ACEi/ARBs and 4.55% with no BB and/or ACEi/ARBs (n=39/857) (OR 0.91; 95% CI 0.58 to 1.43, p=0.68) (online supplemental figure 4).
BB and ACEi/ARBs versus BB
The combination of BB and ACEi/ARBs versus BB was evaluated in 2128 patients. Recurrence rate was 3.88% (n=52/1377) among those treated with BB and ACEi/ARBs and 4.92% (n=35/711) in those treated with BBs (OR 0.77; 95% CI 0.49 to 1.21, p=0.26) (online supplemental figure 5).
BB and ACEi/ARBs versus ACEi/ARBs
The combination of BB and ACEi/ARBs versus ACEi/ARBs was evaluated in 1853 patients. Recurrence rate was 3.88% (n=52/1377) among those treated with BB and ACEi/ARBs and 4.41% with ACEi/ARBs (n=21/476) (OR 0.79; 95% CI 0.46 to 1.34, p=0.38) (online supplemental figure 6) (figures 2 and 3).
Figure 2.
Graphic representation of network meta-analysis and results of direct comparisons of beta-blocker and/or ACEi/ARB regimens for the end point Takotsubo syndrome recurrence. None of the OR reached statistical significance. ACEi, ACE inhibitors; ARBs, angiotensin receptor blockers; pts, patients.
Figure 3.
Forest plot OR for prevention of Takotsubo syndrome prevention with drug therapy. ACEi/ARBs, ACE inhibitors; ARB, angiotensin receptor blockers; BB, beta-blockers.
Publication bias
To assess a potential existence of publication bias in the effect of drug therapy in preventing TTS recurrences, a funnel plot for the effect of treatment with ACEi/ARBs versus BBs on TTS recurrence is given in online supplemental figure S7; Egger’s test did not show any significant bias.
Discussion
This is one of the first network meta-analysis study that focuses on drug therapy for the prevention of TTS recurrences, evaluating single and combined benefit of BBs and ACEi/ARBs.
The present study found that:
rate of TTS recurrence is 4.7% at 40±10 months follow-up;
single drug therapy with ACEi/ARBs or BBs is not associated with reduction of TTS recurrence;
there is not sufficient statistical evidence regarding therapy with BB and ACEi/ARBs in reduction of TTS recurrence.
Recurrence of TTS following the first episode have been described with a frequency ranging from 4% to 11.4%.10–12 Patients with TTS recurrence may represent a vulnerable subset with unique characteristics. There are no definitive features of patients experiencing recurrence; however, data from the INTERTAK registry showed that patients with history of neurological and/or psychiatric disorders could be more susceptible to recurrence.12
In the context of TTS, no randomised trials have been performed to evaluate which drugs can be effective to prevent or reduce the severity of a recurrence.22 In a large international registry, BB did not show benefit for prevention of TTS recurrence; 60% of patients with recurrence were receiving BBs.11
On the other side, a meta-regression analysis showed a significant correlation between rates of prescription of ACEi/ARBs and rates of recurrence of TTS at follow-up.23 Additionally, another meta-regression analysis found a correlation between higher rates of combined prescription of BB and ACEi/ARBs and lower recurrence rates of TTS.14
However, in the present study there was no sufficient statistical evidence regarding therapy with BB and ACEi/ARBs in reduction of TTS recurrence. These data are in line with a previous meta-analysis that tested also other drugs as calcium antagonist, statin and aspirin that did not prove any benefits for TTS recurrence prevention.13
A potential treatment could be psychological support for those patients that developed a TTS secondary to an emotional event and only in selected case antipsychotic medication. As a matter of fact, 74% of patients with TTS that experienced an emotional stress had a pre-existing anxiety disorder.24 Moreover, in a case series of nine patients that experienced two or more TTS recurrences, Shaw KE et al found that these patients have high prevalence of depression and/or anxiety (about 90%).25 Interestingly, 18 out of 25 (71%) TTS recurrence episode occurred in patients treated with both BB and ACEi/ARBs.
Recently, Scally et al showed that patients with TTS after the acute event could develop a persistent, long-term heart failure phenotype.26 These patients, especially those that experienced during TTS hospitalisation a severe transient LV dysfunction may be qualified as having heart failure with improved ejection fraction27, therefore, could be candidate for therapy with BBs, renin-angiotensin system inhibitors, gliflozin and neprilysin inhibitor. However, randomised prospective trials are needed to confirm this hypothesis.
Altered neuronal connectivity in the hippocampus, amygdala, cingulate gyrus and insula which are important in regulating emotional responses and the autonomic nervous system have been demonstrated in patients with TTS. Therefore, it has been supposed that some patients are predisposed to develop an imbalance of the sympathetic and parasympathetic nervous systems in response to stress triggers.28
The scenario may also be complicated by the fact that recurrences can be triggered by either emotional or physical stressors29 and even different LV ballooning phenotypes can be found.30 The heterogeneity of the population with TTS, and the potential multiple pathways that can lead to the acute and recurrent events, may restrict the efficacy of specific treatments only to some subgroups of patients. Prospective and multicentre studies are definitively needed to assess the optimal pharmacological therapy for the prevention of TTS recurrence.
Limitations
Some limitations of our study should be acknowledged. Although 6 studies encompassing 3407 patients with TTS were included, results of meta-analyses are hypothesis-generating and should be interpreted with caution.
One limitation relates to the primary data of this meta-analysis, which included only observational studies. However, owing to the low incidence of TTS recurrence after the first episode, there are no randomised studies investigating the effect of pharmacological treatments for the prevention of recurrence in this patient population.
Another limitation concerns the paucity of data on drug dose regimens, which did not allow subgroup analyses. Moreover, patients receiving BB and/or ACEi/ARB may have a more severe clinical phenotype than those who were not treated with these drugs.
Conclusions
In this network meta-analysis study, there was no sufficient statistical evidence regarding combination therapy with BB and ACEi/ARBs in reduction of TTS recurrence. Large multicentre registries and randomised controlled trial are needed for a better management of TTS recurrence.
Footnotes
Twitter: @#researchHer
Contributors: FS, NDB, IE ideated the analysis; FS, SS, RC, TM, LC, JAU-M, IJN-G, AS, NDN, IR, RC, JN gathered data; FS wrote the paper; FS, NDB analysed data; NDB, TS, IE revised the paper, NDB and FS are responsible for the overall content as the guarantors.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Data availability statement
Data are available on reasonable request.
Ethics statements
Patient consent for publication
Not applicable.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
heartjnl-2023-322980supp001.pdf (282.3KB, pdf)
Data Availability Statement
Data are available on reasonable request.