Reviews. Lack of Efficacy of Drug Therapy in Preventing Takotsubo Cardiomyopathy Recurrence: A Meta-analysis

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1 Reviews Lack of Efficacy of Drug Therapy in Preventing Takotsubo Cardiomyopathy Recurrence: A Meta-analysis Francesco Santoro, MD; Riccardo Ieva, MD; Francesco Musaico, MD; Armando Ferraretti, MD; Giuseppe Triggiani, MD; Nicola Tarantino, MD; Matteo Di Biase, MD; Natale Daniele Brunetti, MD Cardiology Department, University of Foggia, Foggia, Italy Address for correspondence: Natale Daniele Brunetti, MD Cardiology Department, University of Foggia Viale Pinto Foggia, Italy natale.brunetti@unifg.it Background: Efficacy of chronic drug therapy in prevention of stress-induced cardiomyopathy recurrences is not well established. We therefore aimed to evaluate in this meta-analysis whether pharmacological treatment can effectively prevent takotsubo cardiomyopathy (TTC) recurrences, according to available studies. Hypothesis: There is no evidence for preventing TTC recurrence by drug therapy. Methods: After a PubMed search, we conducted a meta-analysis of available studies (clinical nonrandomized registries) on efficacy of drug therapy in preventing recurrence of TTC. Results: A total of 23 (4.5%) TTC recurrences occurred in the 511 patients included in the analysis. Seven studies on the effects of β-blockers on prevention of TTC recurrence were evaluated; the odds ratio (OR) was 0.44 and the 95% confidence interval (CI) was In 5 studies on the effects of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the OR was 0.42 and the 95% CI was ; in 3 studies on statins, the OR was 0.74 and the 95% CI was ; and in 4 studies on aspirin, the OR was 0.33 with a 95% CI of (P value not significant in all cases). Conclusions: A meta-analysis of the efficacy of different medications through the clinical TTC registries available showed no clinical evidence for a standard drug treatment in the chronic management of TTC. β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, and aspirin do not seem to significantly reduce recurrences of TTC. Randomized, adequately powered studies are needed to further assess this issue. Introduction Takotsubo cardiomyopathy (TTC) is a rapidly reversible form of acute heart failure occurring mainly in postmenopausal women after an episode of physical or emotional stress 1 and is associated with a typical left ventricular (LV) contraction pattern. 2 Increased catecholamine levels were thought to be the primary precipitator of the condition, 3 but the exact mechanism is still not well elucidated. 4,5 The initial treatment for TTC is usually the same as adopted for acute heart failure, except for contraindication to β-adrenergic inotropes 6 ; data on the efficacy of chronic pharmacological therapy, however, are scanty. Despite its relatively good long-term prognosis, 7 recurrences of TTC are not infrequent, with a rate ranging from 5% to 11.4% within the first 4 years and an incidence per year of 2.4%. 8,9 β-blockers are commonly used chronically to prevent TTC recurrence, but, given the rarity of TTC, there are no randomized studies supporting this approach. We therefore conducted a meta-analysis of currently available studies to evaluate whether drug therapy can effectively prevent TTC recurrences. The authors have no funding, financial relationships, or conflicts of interest to disclose. 434 Methods Data Sources and Study Selection Two investigators (F.S., N.D.B.) independently searched PubMed, BioMed, CardioSource, ClinicalTrials.gov, and ISI Web of Science for the time period of January 1990 to October Search keywords were takotsubo syndrome, apical ballooning syndrome, takotsubo cardiomyopathy, stress cardiomyopathy, long-term follow-up, chronic treatment, and pharmacological treatment. No language restriction was used. Studies were included if they enrolled patients with a diagnosis of TTC based on Mayo Clinic criteria: (1) transient hypokinesis, akinesis, or dyskinesis of the LV mid segments, with or without apical involvement; the regional wall-motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often, but not always, present; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new electrocardiographic abnormalities, either ST-segment elevation and/or T-wave inversion, or modest elevation in cardiac troponin; and (4) absence of pheochromocytoma myocarditis. 11 Inclusion criteria also required a median follow-up of 3 years and recording of pharmacological treatment at discharge and immediately Received: January 4, 2014 Accepted with revision: March 4, 2014

2 Statistical Analysis The patient was chosen as the individual unit of analysis (as opposed to person-years). The effects of drug therapy on TTC recurrence were determined using fixed-effect and random-effect modeling. Treatment effect was measured using odds ratios (ORs) with 95% confidence intervals (CIs). Statistical testing was 2-tailed, and statistical significance was set at P < We planned a study of independent cases and controls with 1 control per case. Prior data indicate that the incidence of TTC recurrence was 5% to 11%. If the rate of TTC recurrence with drug therapy would be 5% and 7.5% in controls, we would need to study 430 experimental subjects and controls to be able to reject the null hypothesis that rates of recurrence are equal with probability (power) of 80%. The type I error probability associated with this test of this null hypothesis is 5%. Publication bias was evaluated with the funnel plot and the Egger linear regression test. Figure 1. Study design. Table 1. Studies Included in the Meta-analysis Study Authors Year No. of Patients Follow-up, mo Recurrences, No. Recurrences, % Elesber et al Kurisu et al Opolski et al Parodi et al Samardhi et al Caciotti et al Brenner et al Looi et al before recurrence. Recurrence was defined as a new episode of stress cardiomyopathy according to Mayo Clinic criteria. 11 The study design is illustrated in Figure 1. The database search identified 211 studies, and 46 duplicates were removed. The remaining 165 records were screened, and 140 of them were excluded because the median follow-up was shorter than 3 months. Twenty-five full-text articles were assessed for eligibility, but only 8 studies met all the inclusion criteria (Table 1). 7,9,12 17 Results The 511 patients included in the analysis experienced a total of 23 (4.5%) TTC recurrences. β-blockers Seven studies on the effects of β-blockers on the prevention of TTC recurrence were evaluated in a pooled analysis. 7,9,12 16 In aggregate, the pooled studies included 471 subjects. The recurrence rate was 1.81% (6 of 331) in those treated with β-blockers, compared with 2.86% (4 of 140) in controls (OR: 0.44, 95% CI: , P = not significant [NS]; Figure 2A). Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Five studies on the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on prevention of TTC recurrence were evaluated in a pooled analysis. 7,12,13,16,17 In aggregate, the pooled studies included 275 subjects. The recurrence rate was 0.5% (1 of 214) in those treated with ACEIs/ARBs compared with 0% (0 of 61) in controls (OR: 0.42, 95% CI: , P = NS; Figure 2B). Aspirin Four studies on the effects of aspirin on prevention of TTC recurrence were evaluated in a pooled analysis. 7,12,13,16 In aggregate, the pooled studies included 254 subjects. The recurrence rate was 0.5% (1 of 200) in those treated with aspirin compared with 0% (0 of 54) in controls (OR: 0.33, 95% CI: , P = NS; Figure 2C). Data Extraction Reviewers extracted the data with regard to inclusion criteria, total number of patients, duration of follow-up, pharmacological treatment at discharge, and when TTC recurrence occurred. In the case of missing data, the senior authors of the included studies were contacted to retrieve unpublished data. Statins Three studies on the effects of statins on prevention of TTC recurrence were evaluated in a pooled analysis. 7,12,13 In aggregate, the pooled studies included 203 subjects. The recurrence rate was 0% (0 of 107) in those treated with statins compared with 0% (0 of 96) in controls (OR: 0.74, 95% CI: , P = NS; Figure 2D). 435

3 Figure 2. (A) Effect of β-blockade on recurrence of TTC. (B) Effect of ACEI/ARB blockade on recurrence of TTC. (C) Effect of statins on recurrence of TTC. (D) Effect of aspirin on recurrence of TTC. For each study, the size of the box is proportional to the sample size, and the lines denote the 95% CI. For the combined result, the ends of the diamond shape denote the 95% CI. Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CI, confidence interval; DF, degrees of freedom; Q, Cochran s Q; TTC, takotsubo cardiomyopathy. 436

4 Figure 3. Funnel plot of standard error by odds ratio to evaluate publication bias for effect of treatment with β-blockers on recurrence of TTC. Abbreviation: TTC, takotsubo cardiomyopathy. Publication Bias Publication bias was evaluated with the funnel plot and the Egger linear regression test using the β-blocker studies, the larger series available; Egger bias = 0.09 (95% CI: 0.25 to 0.44, P = 0.61). The funnel plot shown in Figure 3 indicates large symmetry, and therefore a publication bias is likely excluded. The rate of TTC recurrence found both in the treatment group and in controls was actually lower than expected, so much larger populations would be needed for the detection of significant differences (>4000 subjects). However, given the OR found assessing the efficacy of β-blockers in preventing recurrence of TTC, actual sample size, and P value, the power of the analysis was not negligible (>80%). Discussion This is the first meta-analysis focusing on the possible efficacy of pharmacological therapy in preventing recurrences of TTC. Our data show that (1) there is no evidence that drug therapy might effectively prevent TTC recurrence; (2) β-blockers, the most common medication administered at discharge after TTC occurrence, do not evidently provide benefit in terms of reducing TTC recurrence; and (3) ACEIs, ARBs, statins, and aspirin also are not evidently effective in preventing TTC recurrence. The rationale for β-adrenergic block in TTC was actually based on several observations, and β-blockers are still commonly believed to be the elective therapy after an episode of TTC. Increased circulating levels of catecholamines could be found during the acute phase of stress cardiomyopathy, 3 and, in some case reports, TTC episodes were triggered by β2-agonist drugs administered for the treatment of chronic obstructive pulmonary disease. 18,19 Pauretal,inaninvivo rat model, found that high doses of epinephrine, through the pleiotropicβ2-adrenergic receptor (β2-ar), activated the inhibitory G (Gi)-protein, inducing direct cardiomyocyte depression. 20 There also was a greater proportion of β2-ars/β1-ars in the apex, probably due to a greater concentration of sympathetic innervation in the base of the heart. 21 It has been therefore speculated that, by opposing the actions of catecholamines, β-adrenergic antagonists would prevent or at least attenuate clinical severity of a TTC occurrence. Infusion of β-blockers during the acute phase of stress cardiomyopathy was hence able to reduce the severity of intraventricular gradient in some studies. 22 However, the potential protective effect of β-blockers might be hampered by some paradox phenomena. Propranolol, a β-blocker with higher β2-ar-gi agonism, enhanced the negative effects of epinephrine at both apex and base, whereas carvedilol, with lower β2-ar-gi agonism, had little effect on the apex but decreased the base contraction. 20 In contrast, the β1-ar selective blocker bisoprolol reduced the positive effect of epinephrine at the base but without effect on the apical epinephrine response. Although the negative inotropic effect of epinephrine was enhanced, with the addition of propranolol or carvedilol, there was no increase in mortality. Drugs with high β2-ar-gi agonism (eg, propranolol, carvedilol) should therefore be avoided. 18 Even in myocytes from failing human hearts, the activity of the Gi-protein is increased and β-blockers may have a negative inotropic effect if they have affinity with β2-ar-gi receptors. 23 In the context of TTC, however, no randomized trials have been performed to evaluate which drugs can be effective in preventing or reducing the severity of a recurrence. A retrospective study by Palla et al found that, in 64 patients with TTC diagnosis, of which 16 were taking a β-blocker on presentation (metoprolol succinate [50%], metoprolol tartrate [37.5%], or atenolol [12.5%]), pretreatment with lowdose β-adrenergic antagonist therapy does not affect severity of TTC presentation. 24 An evaluation on TTC pretreatment, before the first episode, was also reported by Kurisu et al, 17 demonstrating on 21 patients that TTC could occur despite treatment with vasoactive agents. Indeed, in this study, 12 patients were receiving calcium channel blockers, 7 nitrates, and 1 a β- blocker. As in this case series, calcium channel blockers were widely used; this class of drugs in this context cannot presumably prevent epicardial coronary spasm, one of the main mechanisms suggested for TTC onset. 4 Moreover, these data on drug pretreatment were also confirmed by TTC registries with a long-term follow-up. In one of the biggest registries, evaluating 134 TTC patients with a follow-up of >4 years, Sharkey et al found that β- blockade drugs in standard dosages and other cardioactive drugs failed to provide absolute protection against either initial or recurrent stress cardiomyopathy events, without any benefit in this condition. 8 Due to the paucity of data, no statements can be made about the other drugs examined (ACEIs, ARBs, statins, and aspirin), which are commonly used for cardiovascular prevention but probably cannot play any role in preventing TTC. During the acute phase of TTC, based on our clinical experience, only a cardioselective β1-receptor blocker with rapid onset and a very short duration of action, such as esmolol, can be administrated to reduce dynamic midventricular obstruction. 25 Diuretics and levosimendan (in subjects with low ejection fraction and additional Mayo Clinic risk factors) can also be used for the acute management of TTC

5 Despite the fact that there is presently no clear evidence supporting the use of any chronic pharmacological therapy for the prevention of TTC recurrence, 2 considerations do present themselves: first, hypertensive crises often accompany episodes of acute stress cardiomyopathy, 19,20,25 so their prevention should be theoretically pursued, even with β-blockers; second, β-blockers and calcium antagonists do not seem to provide evident benefit or protection, whereas α-1 blockers, 27,28 which decrease peripheral vascular resistance, could represent an option to be tested for reducing the severity of a TTC episode. Prospective and multicenter studies, however, are surely needed to demonstrate the real efficacy of drug therapy in preventing the recurrence of TTC. Study Limitations This meta-analysis was entirely based on observational, nonrandomized trials and registries, the only presently available data on this topic. The relatively small number of TTC patients recruited in this meta-analysis, due to the rarity of this type of cardiomyopathy, and the low rates of TTC recurrence surely limit generalizations about the potential lack of efficacy of vasoactive drugs in preventing TTC recurrence. Given the actual rates of TTC recurrence found in the studies, much larger populations are needed to reject the null hypothesis that the recurrence rates for cases and controls are equal. The meta-analysis is therefore probably underpowered for definitive conclusions, although results were characterized by an analysis power >80%. Not all studies assessed the efficacy of all drugs considered in this meta-analysis. Some subjects enrolled in some studies could be assigned neither to the treatment group nor to the control group, and some events could not be exactly assigned. That may have caused some apparent discrepancies in calculations and population amounts. Data given in analyzed studies on drug doses and duration of therapy are sparse and incomplete. Despite all these limitations, our results are the only ones currently available, in the absence of randomized trials, on possible efficacy of drug therapy in preventing recurrence of TTC. Conclusion A meta-analysis of the efficacy of different medications through the clinical TTC registries available showed no clinical evidence for a standard treatment in the chronic management of TTC. β-blockers, ACEIs/ARBs, statins, and aspirin do not seem to significantly reduce recurrences of TTC. Randomized, adequately powered studies are needed to further assess this issue. References 1. Song BG, Yang HS, Hwang HK, et al. The impact of stressor patterns on clinical features in patients with tako-tsubo cardiomyopathy: experiences of two tertiary cardiovascular centers. Clin Cardiol. 2012;35:E6 E Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. 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