Introduction

Takotsubo cardiomyopathy, named after the Japanese term for “octopus pot” because of its characteristic temporary ballooning of the left ventricle, was first described in 1990 [1]. Although initially considered a benign and reversible condition, it is currently recognized as a critical condition associated with life-threatening arrhythmias, systemic thromboembolism, heart failure, cardiac shock, and death [2–5]. It is estimated to occur in 1–4% of patients presenting with possible acute coronary syndrome, with a mortality rate of 3–6%, which is comparable to that of the syndrome [3–6]. During the first 30 days after admission, major adverse cardiac and cerebrovascular events occurred in 7.1% of cases, with stroke and transient ischemic attack being the most frequent [5]. Although the use of antithrombotic therapy has been discussed, no clinical research has specifically focused on Takotsubo cardiomyopathy [7–9]. According to an expert consensus of the European Society of Cardiology, anticoagulation with heparin is recommended for high-risk patients, including those with severely reduced ejection fraction and apical ballooning [9]. Direct oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, may serve as alternatives to heparin. Unlike heparin, DOACs do not require injections or routine monitoring [10], rendering them a more practical option. In addition, their oral administration, predictable anticoagulant effect without dose adjustment, and avoidance of prolonged intravenous access may simplify inpatient management and facilitate earlier discharge. However, evidence supporting the use of DOACs for Takotsubo cardiomyopathy is limited. Therefore, in this study, we compared the prognosis and clinical outcomes of patients treated with DOACs and those of patients treated with heparin using data of a Japanese inpatient cohort. Additionally, we assessed the efficacy and safety of each anticoagulation treatment strategy.

Methods

This retrospective study used data extracted from a nationwide diagnostic and procedural combination (DPC) database, which is comparable to the diagnosis-related group payment system in the United States. It was initiated in 2002 as a nationwide reimbursement system for acute inpatient care in Japan and currently covers nearly all acute care hospitals in the country [2,11,12]. Diagnostic codes in the database are classified using the International Classification of Diseases, 10th revision (ICD-10), and grouped into the following six distinct categories: main disease, reason-for-admission diagnosis, most-consuming diagnosis, second-consuming diagnosis, comorbidities identified at admission, and complications arising after admission. Over 20 validation studies of algorithms using diagnoses and medication codes have been reported [13–15]. In particular, the validity of the algorithm for Takotsubo cardiomyopathy diagnosis using the database has been established with a positive predictive value of 1.00 [14]. Further details of the database used in this study are provided in the Supporting Information. This study adhered to the ethical guidelines outlined in the Declaration of Helsinki. The requirement for informed consent was waived because the database contains anonymous information. The data for this research were accessed on October 4, 2023. This study was approved by the Review Board of the Institute of Science Tokyo (M2000-788).

Setting and participants

Patients diagnosed with Takotsubo cardiomyopathy between April 2012 and March 2021 were enrolled in this retrospective cohort study (Fig 1). Takotsubo cardiomyopathy cases were identified using ICD-10 code I51.8, extracted from the reason-for-admission diagnosis, main diagnosis, or most resource-consuming diagnosis category. Among them, patients who underwent coronary angiography on the day of admission and who were initiated on anticoagulation therapy with either DOACs or heparin within the first 2 days of admission and continued through day 2 were included. The exclusion criteria for this study were as follows: age younger than 20 years; a diagnosis of myocarditis (ICD-10 code I40) or pheochromocytoma (ICD-10 code D35.0) based on the Mayo Clinic diagnostic criteria [16]; planned admission; subsequent hospitalizations for Takotsubo cardiomyopathy after the index hospitalization; and undergoing percutaneous coronary intervention, as outlined in a previously validated study [14]. Additionally, patients receiving both DOACs and heparin on day 2 who could not be assigned to either treatment group were excluded. Subsequently, patients were classified into the DOAC and heparin groups based on the anticoagulant therapy received.

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Fig 1. Study flow chart.

DOAC, direct oral anticoagulant.

https://doi.org/10.1371/journal.pone.0336960.g001

Results

Patient characteristics

Data from 22,195 hospitalized patients were assessed using the DPC database. After exclusion criteria were applied, 4,813 patients were eligible for the analysis, including 530 in the DOAC group and 4,283 in the heparin group (Fig 1). The baseline characteristics are presented in Table 1. Patients in the DOAC group were older, with a mean (standard deviation) age of 78.1 (9.4) years, than those in the heparin group (74.4 [11.2] years). The prevalence of atrial fibrillation differed between the groups, at 53.2% in the DOAC group and 7.0% in the heparin group. Patients in the DOAC group required fewer medical interventions, such as inotropes, oxygen therapy, mechanical ventilation, and intensive care unit admission, than those in the heparin group. After IPTW, the standardized mean difference of baseline characteristics was < 0.1, indicating an adequate balance between groups.

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Table 1. Patient characteristics before and after IPTW.

https://doi.org/10.1371/journal.pone.0336960.t001

Outcomes

The clinical outcomes of patients are presented in Table 2. After IPTW, the mortality rates were 4.0% in the DOAC group and 3.8% in the heparin group (RR 1.05 [95% CI 0.59–1.88], p = 0.87). The rates of ischemic events were 1.1% in the DOAC group and 2.8% in the heparin group (RR, 0.41 [95% CI 0.15–1.07], p = 0.067). The rate of bleeding events was 0.2% and 0.3% in the DOAC and heparin groups, respectively. The blood transfusion rate was lower in the DOAC group at 1.9%, compared with the heparin group at 5.4% (RR 0.35 [95% CI 0.17–0.69], p = 0.003). The length of hospitalization and associated costs are presented in Table 3. After IPTW was applied, the length of hospital stay was significantly shorter in the DOAC group (median, 11 days; interquartile range. [IQR], 8–17 days) than in the heparin group (median, 13 days; IQR, 9–19 days) (p < 0.001). The total hospitalization cost was significantly lower in the DOAC group (median, $5,181 USD; IQR, $4,000–$7,640 USD) than in the heparin group ($6,084 USD; IQR, $4,536–$8,299 USD) (p = 0.003).

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Table 2. Clinical outcomes of the DOAC and heparin groups.

https://doi.org/10.1371/journal.pone.0336960.t002

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Table 3. Hospitalization lengths and costs for the DOAC and heparin groups.

https://doi.org/10.1371/journal.pone.0336960.t003

Discussion

We compared the clinical outcomes of anticoagulation therapies for high-risk patients with Takotsubo cardiomyopathy. To our knowledge, this is the first study to compare the efficacy and safety of DOACs and heparin in this population. In this study, the DOAC and heparin groups had comparable in-hospital mortality. The risk ratio for ischemic events was 0.41, suggesting a trend towards a lower risk in the DOAC group; however, this difference was not statistically significant. Although both groups had low bleeding event rates, the blood transfusion rate in the DOAC group was significantly lower than that in the heparin group. The propensity score matching analysis and separate analysis of the cohort of patients with atrial fibrillation revealed results consistent with those of the primary analysis. Our findings suggest that DOACs may serve as alternatives to heparin for patients with Takotsubo cardiomyopathy. Compared with heparin, DOACs offer the advantages of not requiring dose adjustment based on activated partial thromboplastin time or prolonged intravenous administration throughout hospitalization [10]. These factors may enable earlier discharge of patients on DOACs, thereby potentially reducing hospitalization costs.

In conditions comparable to severely reduced left ventricle wall motion, such as myocardial infarction and dilated cardiomyopathy, studies on the prevention of left ventricle thrombosis have compared the use of DOACs with warfarin, a traditional oral anticoagulant [25–27]. In a meta-analysis involving 824 patients treated with DOACs and 2,233 patients treated with warfarin, Levine et al. reported no significant differences in mortality, ischemic events, or bleeding complications between the two groups [25], indicating that DOACs may be a comparable option to warfarin.

Antithrombotic therapy with heparin is recommended by the European Society of Cardiology expert consensus for patients with Takotsubo cardiomyopathy classified as high-risk for left ventricle thrombosis, including those with low ejection fraction or apical ballooning type [9]. Recent data from the Swedish national population registry indicated that the use of heparin in patients with Takotsubo cardiomyopathy was associated with reduced 30-day mortality, whereas the use of oral anticoagulants was not significantly correlated with reduced mortality [28]. In contrast, our study adjusted for the timing of anticoagulant initiation and covariates, an approach not applied in the Swedish registry study.

Inflammation plays an important role in the pathogenesis of Takotsubo cardiomyopathy [29]. Ding et al. reported that patients with Takotsubo cardiomyopathy who experienced thrombotic events exhibited significantly elevated inflammatory markers, including C-reactive protein and white blood cell counts [30]. Jafri et al. revealed that heparin has a potential role in reducing pro-inflammatory cytokines, such as interleukin-6 and interleukin-8 [31], whose levels are significantly elevated in Takotsubo cardiomyopathy [32]. These findings suggest an alternative role of heparin as an anticoagulant. Therefore, the comparison between DOACs and heparin remains a critical area of research owing to their different mechanisms and potential benefits.

This study has important strengths in comparing the efficacy and safety of DOACs and heparin in patients with Takotsubo cardiomyopathy. First, we enrolled a cohort of 4,813 patients from nearly all acute care hospitals in Japan, based on the high validity of Takotsubo cardiomyopathy diagnosis in the database. Second, our study design adjusted for the timing of anticoagulant initiation and other covariates, which minimized selection bias. Finally, we applied IPTW to balance baseline characteristics between the DOAC and heparin groups.

However, this study has several limitations. First, the DPC database used in this study did not include detailed laboratory findings or echocardiographic data, such as Takotsubo cardiomyopathy types and left ventricular ejection fraction, or the presence of a thrombus at diagnosis. Furthermore, other potentially influential acute physiological parameters, including precise blood pressure values, detailed arrhythmia characteristics, more granular assessments of overall disease severity, and temporal changes in treatment patterns, were not collected in the database. Therefore, the potential for residual confounding attributable to these specified factors and other unrecognized variables was an important limitation of this study. Second, the accuracy of comorbidity diagnoses and nonfatal outcomes in the database may have been affected by coding errors or misclassifications. Third, the number of patients in the DOAC group differed from that in the heparin group. Although no significant differences in ischemic events were observed between groups, the possibility of insufficient statistical power cannot be ruled out. Fourth, nonfatal outcomes may have been affected by competing risks. Fifth, the database did not include information on pre-admission medications; thus, prior anticoagulant use could not be assessed. Sixth, indication bias was a significant concern, particularly because of the high prevalence of atrial fibrillation in the DOAC group. Because the DPC database does not capture the specific dosing or indication for each prescription, residual indication bias remains a significant concern despite adjustments for baseline diagnoses and other measured comorbidities. A direct comparison of anticoagulation durations in the treatment groups was not appropriate because differences in these durations likely reflected underlying variations in treatment indications and baseline characteristics. Additionally, unfractionated heparin was predominantly used due to limited indications and reimbursement constraints for low-molecular-weight heparin in Japan. As unfractionated heparin is associated with a higher bleeding risk, this may limit the generalizability of our findings. Finally, the DPC data contain only in-hospital outcomes. This limitation is particularly relevant to the shorter hospital stays in the DOAC group, as post-discharge events such as mortality or hospital readmissions could not be assessed. Therefore, further research including pre-hospital information, echographic data, morphological variants of Takotsubo cardiomyopathy, and post-discharge outcomes is needed to validate the findings and provide a more comprehensive understanding of the effect of anticoagulants on patient prognoses.

Conclusion

In this study, the efficacy and safety outcomes of DOACs were not significantly different from those of heparin among patients with Takotsubo cardiomyopathy who required anticoagulation. However, the DOAC group required fewer healthcare resources than the heparin group. Our findings suggest that DOACs may serve as a viable alternative to heparin for patients with Takotsubo cardiomyopathy; however, further research is required to validate these results and explore long-term outcomes.

Supporting information

Acknowledgments

We express our gratitude to the Data Index Corporation (Tokyo, Japan) for providing the Anatomical Therapeutic Chemical classification system dataset.