- Email: [email protected]
intrathoracic cancer and radiation therapy
IJCA-28366; No of Pages 5 International Journal of Cardiology xxx (xxxx) xxx
Contents lists available at ScienceDirect
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Short communication
National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior history of mediastinal/intrathoracic cancer and radiation therapy Rupak Desai a,⁎, Aakash Desai b, Shabber A. Abbas c, Upenkumar Patel d, Snehal Bansod e, Nanush Damarlapally f, Rajkumar Doshi g, Sejal Savani h, Kishorbhai Gangani i, Rajesh Sachdeva a,j,k, Gautam Kumar a,l a
Division of Cardiology, Atlanta VA Medical Center, Decatur, GA, USA Department of Internal Medicine, University of Connecticut School of Medicine, UCONN Health, Farmington, CT, USA c R-Endocrinology, Hamilton Township, NJ, USA d Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA e Department of Internal Medicine, St John Episcopal Hospital, Far Rockaway, NY, USA f Department of Health Sciences, Coleman College of Health Sciences, Houston, TX, USA g Department of Internal Medicine, University of Nevada School of Medicine, Reno, NV, USA h Public Health, New York University, New York, NY, USA i Department of Internal Medicine, Texas Health Arlington Memorial Hospital, Arlington, TX, USA j Division of Cardiology, Morehouse School of Medicine, Atlanta, GA, USA k Division of Cardiology, Medical College of Georgia, Augusta, GA, USA l Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA b
a r t i c l e
i n f o
Article history: Received 17 January 2020 Received in revised form 11 February 2020 Accepted 13 February 2020 Available online xxxx Keywords: Takotsubo syndrome Takotsubo cardiomyopathy Stress-induced cardiomyopathy Intrathoracic cancer Mediastinal cancer Radiation therapy/radiotherapy
a b s t r a c t Background: Radiation therapy (RT) for cancers in thoracic/mediastinal region has been linked with heart damage following years of radiation exposure. However, prevalence of takotsubo syndrome (TTS) in patients with prior intrathoracic/mediastinal malignancies treated with RT has never been analyzed on a large scale. Methods: We identified adult hospitalizations with prior mediastinal/intrathoracic cancer and RT and TTS using ICD-9 CM codes and the National Inpatient Sample (2007–2014) after excluding current admissions for chemotherapy. We then assessed the prevalence, odds, trends and in-hospital outcomes of TTS-related admissions in patients with vs. without prior intrathoracic cancer and RT. Results: We identified a total of 5,991,314 hospitalizations with prior intrathoracic/mediastinal malignancies and RT (~73 yrs., 85.2% female), of which 7663 (0.13%, 128 per 100,000) were diagnosed with TTS (~74 yrs., 95.8% females, 88.1% white). Higher odds and rising trends in TTS per 100,000 hospitalizations (from 31 to 241) were seen among patients with prior intrathoracic malignancies and RT as compared to those without (from 19 to 104) (ptrend b 0.001). All-cause in-hospital mortality (4.6% vs 2.8%; OR 1.45; 95%CI 1.29–1.63, p b 0.001), cardiogenic shock (4.3% vs 0.2%), cardiac arrest (3.1% vs 0.9%), arrhythmia (34.3% vs 24.6%), stroke (3.6% vs 2.8%), respiratory failure (14.5% vs 4.6%), and median length of stay and hospital charges were significantly higher in the TTS cohort. Conclusions: This study showed higher odds and increasing trends in TTS-related admissions with worse inhospital outcomes among patients with prior intrathoracic/mediastinal cancer and RT, irrespective of the time interval from cancer diagnosis or RT to TTS occurrence. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Takotsubo Syndrome (TTS) is characterized by severe left ventricular (LV) systolic dysfunction in response to emotional, physical, or
⁎ Corresponding author at: Division of Cardiology, Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA. E-mail address: [email protected] (R. Desai).
medical stress [1]. TTS has been increasingly recognized in patients with cancer, which could be related to emotional stress of diagnosis, chronic inflammation or the physical stress of various cancer treatments, including chemotherapy [2,3]. TTS has also been linked with radiation therapy (RT) for cancer [4]. However, the risk and burden of TTS in adult patients with prior intrathoracic/mediastinal RT has never been reported in the literature. We assessed the prevalence, risk, trends and outcomes of TTS-related admissions in the survivors with prior history of mediastinal/intrathoracic cancer and RT in the United States (US).
https://doi.org/10.1016/j.ijcard.2020.02.036 0167-5273/© 2020 Elsevier B.V. All rights reserved.
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
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R. Desai et al. / International Journal of Cardiology xxx (xxxx) xxx
2. Methods
4. Discussion
We queried the National Inpatient Sample (NIS) (2007 to 2014), a part of the Healthcare Cost and Utilization Project (HCUP) funded by the Agency for Healthcare Research and Quality (AHRQ) [5], which incorporates nearly 35 million weighted inpatient discharges per year. The NIS provides a sample from 20% of hospital stays of all nonfederal US community hospitals (excluding rehabilitation and long-term acute care hospitals) and represents 95% of the general population in the US. It contains de-identified data; therefore, the study was exempt from an institutional review board approval. Adult hospitalizations for TTS were identified using the International Classification of Diseases, Ninth Revision; Clinical Modification (ICD-9CM) code 429.83 with a prior history of intrathoracic/mediastinal cancer and RT (ICD-9-CM code V15.3). Prior intrathoracic/mediastinal cancers included malignant neoplasm of esophagus (V10.03), or trachea, bronchus and lung (V10.1), or other respiratory and intrathoracic organs (V10.2), or larynx (V10.21), or nasal cavities, middle ear, and accessory sinuses (V10.22), or breast (V10.3) or Hodgkin's disease (V10.72). We excluded the cases undergoing chemotherapy during current admissions (using ICD-9 CM procedure codes 00.10, 00.15, 17.70, 99.25, 99.28) from our sample. Primary outcomes were the prevalence, risk and trends in TTSrelated hospitalizations in patients with prior mediastinal/intrathoracic cancer and RT. Co-primary outcomes were the all-cause in-hospital mortality and cardiac complications such as acute myocardial infarction (AMI), arrhythmias, in-hospital cardiac arrest (IHCA), cardiogenic shock, venous thromboembolism and respiratory failure in TTS cohorts with vs. without previous intrathoracic malignancies and RT. Secondary outcomes studied were the mean length of stay (LOS) in days, hospitalization charges, and discharge status in TTS cohort with vs. without previous history of intrathoracic cancer and RT. We utilized discharge and sampling weights to conduct statistical analyses to generate nationally illustrative estimates. We used Pearson's Chi-square test for categorical and Student's t-test for the continuous variables. A two-tailed p b 0.05 was considered to determine the statistical significance. We used SPSS v22 (IBM Corp., Armonk, NY) to perform all statistical analyses.
Our study is the first attempt at quantifying the risk and burden related to the occurrence of TTS in adult inpatients with past mediastinal/intrathoracic cancer with radiation exposure. A prior history of intrathoracic cancer with RT independently increased the risk of TTSrelated admissions. There was nearly 8-fold increase (from 31 to 241) in the mean prevalence of TTS cases per 100,000 hospitalizations with prior intrathoracic/mediastinal cancer and RT from 2007 to 2014. This represents an annual increase of 12.9 patients per 100,000. This might be reflective of the growing elderly population in the US as evidenced by the high percentage of 65 or older aged patients (68%) with TTS as identified in this study. We also believe that increased awareness of this condition among physicians and improvement in diagnostic modalities over the years may have contributed towards rising trends in prevalence of TTS. The gender predisposition in favor of females observed in our study is in accordance with the prior literature [6]. Overall, the rate of TTS might seem low, but it is in fact ~7 times higher (0.13%) than the prevalence of TCM (0.02%) typically seen in general inpatient population [7]. In terms of the all-cause inhospital mortality, we observed almost two-fold increased mortality rate in the TTS group (4.6% vs 2.8%). Both cohorts with and without TTS were comparable in major areas albeit with a few notable differences. These included a significantly higher female prevalence (85.2% vs 50.3%), a significant increase in prevalence of baseline comorbidities, and a relatively higher non-elective admission rate in the TTS cohort. Each of these is consistent with prior studies and underscores the already higher health burden of TTS patients as a group [2,3,6]. TTS and its association with cancer has been a topic of much discussion lately. Chemotherapeutic agents, chronic inflammation and emotional stress related factors have been implicated. RT as a precipitant of TTS has been recently recognized as another risk factor [8]. The increased risk of premature cardiovascular disease in patients post-RT has been well established [9]. RT can affect almost any cardiovascular structure ranging from pericardium, vascular tree, endocardium, myocardium or the conduction system leading to a wide spectrum of diseases including coronary vascular disorders, acute or chronic pericarditis, valvular disease, and cardiomyopathy [10–12]. RT-associated heart damage usually ensues following years of radiation exposure and is linked mainly with RT for cancers in thoracic/mediastinal region e.g. breast cancer, Hodgkin's lymphoma, lung cancer, soft tissue tumors, head/neck or mandible tumors and esophageal cancer. Hence, we utilized cases with prior history of such mediastinal/intrathoracic malignancies to conduct our analyses. However, lack of stratification of radiation doses becomes important especially given that radiation doses of b30 Gy, together with modern-day, multiple-portal, cardiac shielded RT do reduce the overall cardiotoxicity [13]. Whether the development of TTS in these hospitalized patients is related to their prior exposure to RT is a natural question and requires much further elaborate studies to decipher. It is certainly plausible that a proportion of these patients may have an enhanced predisposition to developing TTS as the radiation-induced damage to cardiac tissue is well-documented [14,15]. However, what is clear from our study is that indeed there is a clinical and economic burden upon patients with prior mediastinal/intrathoracic cancer and RT who experience TTS as compared to patients who do not. Our study was limited by the availability of data parameters. For instance, we were not able to stratify for RT dose, regions exposed, duration of exposure, time since first exposure or obtain information on ballooning patterns on echocardiography. Moreover, we did not have information specifying the target radiation anatomical region of the body. Also, we did not include all cancer but only
3. Results We identified a total of 7663 (0.13%, 128 per 100,000) TTS (~74 yrs., 95.8% females, 88.1% white)-related admissions out of overall 5,991,314 hospitalizations recorded among patients with prior intrathoracic/mediastinal malignancies and RT (mean age:~73 [63–82] yrs., 85.2% female) from 2007 to 2014 [Table 1]. Using logistic regression, we found that the unadjusted odds of TTSrelated admissions in patients with prior history of intrathoracic/mediastinal cancer and RT was 2.14 [95%CI 1.09–2.19, p b 0.001]. The odds adjusted for demographics including age, sex, race, type of admission (elective/non-elective) and year of admission remained significant at 1.05 [95%CI 1.02–1.07, p b 0.001] while those adjusted for aforementioned demographics plus all baseline cardiac and extra-cardiac comorbidities including metastatic and non-metastatic cancers were 1.03 [95% CI 1.01–1.06, p = 0.009] (Table 1). From 2007 to 2014, rising trends in TTS per 100,000 hospitalizations (from 31 to 241) were seen RT for prior mediastinal/intrathoracic malignancies as compared to those without (from 19 to 104), more rapid ascent among females (p b 0.001) [Fig. 1]. In-hospital outcomes including all-cause mortality (4.6% vs 2.8%; OR 1.45; 95%CI 1.29–1.63, p b 0.001), cardiogenic shock (4.3% vs 0.2%), cardiac arrest (3.1% vs 0.9%), arrhythmia (34.3% vs 24.6%), stroke (3.6% vs 2.8%), respiratory failure (14.5% vs 4.6%), median length of stay (4 vs 3 days) and hospital charges ($36,656 vs $24,749) were significantly higher in the cohort with TTS.
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
R. Desai et al. / International Journal of Cardiology xxx (xxxx) xxx
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Table 1 Baseline characteristics of adult hospitalizations with vs. without takotsubo syndrome in patients with prior mediastinal/intra-thoracic cancer and radiation therapy, 2007–2014. Variables Age (years) at admission
Female Race
Non-elective admission Location/teaching status of hospital
Median [IQR] 18–44 45–64 ≥65 White African American Hispanic Asian or Pacific Islander Native American Others Rural Urban nonteaching Urban teaching
No TTS (5,983,651)
TTS (7663)
Overall (5,991,314)
p
73 [63–82] 3.1% 24.3% 72.6% 85.2% 81.3% 10.0% 4.7% 1.5% 0.4% 2.0% 76.3% 10.7% 40.3% 49.0%
74 [66–81] 0.8% 21.4% 77.8% 95.8% 88.1% 5.8% 2.3% 1.6% 0.2% 1.9% 89.5% 5.4% 33.7% 60.8%
73 [63–82] 3.1% 24.3% 72.6% 85.2% 81.3% 10.0% 4.7% 1.5% 0.4% 2.0% 76.3% 10.7% 40.3% 49.1%
0.043 b0.001
Comorbidities Hypertension 62.4% 66.7% Diabetes, uncomplicated 21.2% 15.6% Diabetes, chronic complications 3.4% 2.0% Dyslipidemia 35.3% 48.1% Obesity 8.3% 6.0% Smoking 26.9% 35.4% Peripheral vascular disease 6.7% 7.3% Chronic obstructive pulmonary disease 26.4% 30.7% Renal failure 11.2% 8.0% Prior MI/PCI/CABG 13.1% 15.9% Valvular heart disease 5.5% 6.0% Outcomes All-cause in-hospital Mortality 2.8% 4.6% Cardiogenic shock 0.2% 4.3% In-hospital cardiac arrest 0.9% 3.1% Venous thromboembolism 3.2% 2.7% Arrhythmia 24.6% 34.3% Stroke 2.8% 3.6% Respiratory failure 4.6% 14.5% Length of stay (days), Median[IQR] 3 [2–6] 4 [2–7] Hospital charges ($), median [IQR] $24,749 [13,565 45,426] $36,656 [22,371-66,758] Odds of TTS-related admissions with prior history of intrathoracic/mediastinal cancer and radiation therapy Regression model Odds Ratio 95% CI [LL-UL] Unadjusted 2.14 1.09–2.19 a Adjusted 1.05 1.02-1.07 Adjustedb 1.03 1.01-1.06
b0.001 b0.001
b0.001 b0.001
62.4% 21.2% 3.4% 35.4% 8.3% 26.9% 6.7% 26.4% 11.2% 13.1% 5.5%
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 0.026 b0.001 b0.001 b0.001 0.034
2.8% 0.2% 0.9% 3.2% 24.6% 2.8% 4.6% 3 [2–6] $24,763 [13,573-45,453]
b0.001 b0.001 b0.001 0.015 b0.001 b0.001 b0.001 b0.001 b0.001 p b0.001 b0.001 0.009
p b 0.05 indicates statistical significance. TTS = takotsubo syndrome, IQR = interquartile range MI = myocardial infarction, PCI = percutaneous coronary intervention, CABG = coronary artery bypass grafting. a Regression model was adjusted for demographics including age, sex, race, type of admission and year of admission. b Regression model was adjusted for variables included in model 1 plus all baseline comorbidities including alcohol abuse rheumatoid arthritis/collagen vascular diseases, chronic pulmonary disease, depression, diabetes, drug abuse, hypertension, dyslipidemia, previous myocardial infarction or revascularization, smoking, liver disease, obesity, peripheral vascular disorders, solid tumor without metastasis, metastatic cancer, psychoses, renal failure and valvular heart disease.
intrathoracic/mediastinal based on the biological plausibility that cancers and RT of other regions might not have such a higher risk of TTS. Readers should comprehend study findings based on the fact that nearly 75% of the overall study cohort (n = 5,991,314) included female patients with prior history of breast cancer and RT. Outpatient incidence of TTS was not considered and thus, underreporting of TTS is one of the key limitations. Lastly, NIS is a visit-based retrospective database of administrative nature so over-reporting of hospitalizations for same patients during a year cannot be overlooked completely. Despite the limitations, this large-scale dataset enabled us to analyze odds and trends in TTS hospitalizations and outcomes in patients with prior mediastinal/intrathoracic malignancies with RT in the US consistent with our prior analyses [16–19] .
malignancy and RT irrespective of the time interval from RT to TTS occurrence. TTS-related hospitalizations among survivors of mediastinal/intrathoracic cancer with a history of RT added significantly to increased LOS, in-hospital mortality, and healthcare costs as compared to TTS encounters secondary to other triggers. Increased awareness and greater vigilance of healthcare practitioners to the higher risk of TTS and worse in-hospital outcomes in patients with prior intrathoracic malignancies with prolonged radiation exposure may help curtail the TTS incidence and related adverse in-hospital outcomes.
Disclosure None.
5. Conclusions This nationwide population-based study showed higher prevalence, increased odds, and rising trends in TTS-related admissions from 2007 to 2014 in patients with prior mediastinal/intrathoracic
Funding None.
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
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R. Desai et al. / International Journal of Cardiology xxx (xxxx) xxx
Fig. 1. Trends in prevalence of takotsubo syndrome per 100,000 hospitalizations with prior mediastinal/intrathoracic cancer and RT. a. Overall prevalence of TTS in patients with vs. without prior mediastinal/intrathoracic cancer and RT. b. Prevalence of TTS in patients with prior mediastinal/intrathoracic cancer and RT stratified by sex.
CRediT authorship contribution statement Rupak Desai:Conceptualization, Methodology, Software, Formal analysis, Resources, Data curation, Writing - original draft, Writing - review & editing, Visualization.Aakash Desai:Writing - original draft, Writing - review & editing, Resources, Visualization.Shabber A. Abbas: Writing - original draft, Writing - review & editing, Resources. Upenkumar Patel:Writing - original draft, Writing - review & editing. Snehal Bansod:Writing - original draft, Writing - review & editing, Resources.Nanush Damarlapally:Writing - original draft, Writing - review & editing, Visualization, Supervision.Rajkumar Doshi:Methodology, Software, Writing - original draft, Writing - review & editing, Visualization.Sejal Savani:Methodology, Writing - original draft, Writing - review & editing, Visualization.Kishorbhai Gangani:Writing - original draft, Writing - review & editing, Visualization, Supervision.Rajesh Sachdeva:Conceptualization, Methodology, Validation, Resources, Writing - review & editing, Visualization, Supervision, Project
administration.Gautam Kumar:Conceptualization, Methodology, Validation, Writing - review & editing, Visualization, Supervision, Project administration.
Acknowledgment None. References [1] K. Dote, H. Sato, H. Tateishi, T. Uchida, M. Ishihara, Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases, J. Cardiol. 21 (1991) 203–214. [2] A. Desai, A. Noor, S. Joshi, A.S. Kim, Takotsubo cardiomyopathy in cancer patients, Cardio-Oncology 5 (2019) 7. [3] R. Desai, S.A. Abbas, H. Goyal, et al., Frequency of takotsubo cardiomyopathy in adult patients receiving chemotherapy (from a 5-year nationwide inpatient study), Am. J. Cardiol. 123 (2019) 667–673.
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
R. Desai et al. / International Journal of Cardiology xxx (xxxx) xxx [4] S.B. Singh, I.A. Harle, Takotsubo cardiomyopathy secondary in part to cancer-related pain crisis: a case report, J. Pain Symptom Manag. 48 (2014) 137–142. [5] HCUP Databases. Healthcare Cost and Utilization Project (HCUP). December 2019. Agency for Healthcare Research and Quality, Rockville, MD. www.hcup-us.ahrq. gov/nisoverview.jsp. Accessed February 9, 2020. [6] B. Schneider, A. Athanasiadis, C. Stöllberger, et al., Gender differences in the manifestation of tako-tsubo cardiomyopathy, Int. J. Cardiol. 166 (2013) 584–588. [7] A. Deshmukh, G. Kumar, S. Pant, C. Rihal, K. Murugiah, J.L. Mehta, Prevalence of Takotsubo cardiomyopathy in the United States, American heart journal 164 (2012) 66–71(e61). [8] S. Modi, W. Baig, Radiotherapy-induced Tako-tsubo cardiomyopathy, Clin. Oncol. 21 (2009) 361–362. [9] S.W. Yusuf, B.P. Venkatesulu, L.S. Mahadevan, S. Krishnan, Radiation-induced cardiovascular disease: a clinical perspective, Front. Cardiovasc. Med. 4 (2017) 66. [10] K.M. Nielsen, B.V. Offersen, H.M. Nielsen, M. Vaage-Nilsen, S.W. Yusuf, Short and long term radiation induced cardiovascular disease in patients with cancer, Clin. Cardiol. 40 (2017) 255–261. [11] G.A. MacGowan, The challenge of radiation-induced restrictive cardiomyopathy and outcomes after heart transplantation, J. Card. Fail. 22 (2016) 479–480. [12] X.-f. Zhuang, Y.-m. Yang, X.-l. Sun, Z.-k. Liao, J. Huang, Late onset radiation-induced constrictive pericarditis and cardiomyopathy after radiotherapy: a case report, Medicine 96 (2017). [13] B.W. Corn, B. Trock, R.L. Goodman, Irradiation-related ischemic heart disease, J. Clin. Oncol. 8 (1990) 741–750.
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[14] M.J. Adams, S.E. Lipshultz, Pathophysiology of anthracycline-and radiationassociated cardiomyopathies: implications for screening and prevention, Pediatr. Blood Cancer 44 (2005) 600–606. [15] J.D. Groarke, P.L. Nguyen, A. Nohria, R. Ferrari, S. Cheng, J. Moslehi, Cardiovascular complications of radiation therapy for thoracic malignancies: the role for noninvasive imaging for detection of cardiovascular disease, Eur. Heart J. 35 (2013) 612–623. [16] R. Desai, S.A. Abbas, H.K. Fong, et al., Burden and impact of takotsubo syndrome in myasthenic crisis: a national inpatient perspective on the under-recognized but potentially fatal association, Int. J. Cardiol. 299 (2020) 63–66, https://doi.org/10.1016/j. ijcard.2019.09.054. [17] R. Desai, S. Singh, M. Baikpour, et al., Does obesity affect the outcomes in takotsubo cardiomyopathy? Analysis of the Nationwide Inpatient Sample database, 2010–2014, Clin. Cardiol. 41 (2018) 1028–1034, https://doi.org/10.1002/clc.22999. [18] R. Desai, S. Singh, U. Patel, et al., Frequency of takotsubo cardiomyopathy in epilepsy-related hospitalizations among adults and its impact on in-hospital outcomes: a national standpoint, Int. J. Cardiol. 299 (2020) 67–70, https://doi.org/10. 1016/j.ijcard.2019.07.034. [19] R. Desai, S. Singh, R. Sachdeva, G. Kumar, The first epidemiologic perspective on takotsubo syndrome in patients with Takayasu arteritis and its impact on inpatient outcomes: comment on the report by Lim et al, Arthritis Rheumatol. (2019) https:// doi.org/10.1002/art.41155[Epub ahead of print].
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Short communication
National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior history of mediastinal/intrathoracic cancer and radiation therapy Rupak Desai a,⁎, Aakash Desai b, Shabber A. Abbas c, Upenkumar Patel d, Snehal Bansod e, Nanush Damarlapally f, Rajkumar Doshi g, Sejal Savani h, Kishorbhai Gangani i, Rajesh Sachdeva a,j,k, Gautam Kumar a,l a
Division of Cardiology, Atlanta VA Medical Center, Decatur, GA, USA Department of Internal Medicine, University of Connecticut School of Medicine, UCONN Health, Farmington, CT, USA c R-Endocrinology, Hamilton Township, NJ, USA d Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, USA e Department of Internal Medicine, St John Episcopal Hospital, Far Rockaway, NY, USA f Department of Health Sciences, Coleman College of Health Sciences, Houston, TX, USA g Department of Internal Medicine, University of Nevada School of Medicine, Reno, NV, USA h Public Health, New York University, New York, NY, USA i Department of Internal Medicine, Texas Health Arlington Memorial Hospital, Arlington, TX, USA j Division of Cardiology, Morehouse School of Medicine, Atlanta, GA, USA k Division of Cardiology, Medical College of Georgia, Augusta, GA, USA l Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA b
a r t i c l e
i n f o
Article history: Received 17 January 2020 Received in revised form 11 February 2020 Accepted 13 February 2020 Available online xxxx Keywords: Takotsubo syndrome Takotsubo cardiomyopathy Stress-induced cardiomyopathy Intrathoracic cancer Mediastinal cancer Radiation therapy/radiotherapy
a b s t r a c t Background: Radiation therapy (RT) for cancers in thoracic/mediastinal region has been linked with heart damage following years of radiation exposure. However, prevalence of takotsubo syndrome (TTS) in patients with prior intrathoracic/mediastinal malignancies treated with RT has never been analyzed on a large scale. Methods: We identified adult hospitalizations with prior mediastinal/intrathoracic cancer and RT and TTS using ICD-9 CM codes and the National Inpatient Sample (2007–2014) after excluding current admissions for chemotherapy. We then assessed the prevalence, odds, trends and in-hospital outcomes of TTS-related admissions in patients with vs. without prior intrathoracic cancer and RT. Results: We identified a total of 5,991,314 hospitalizations with prior intrathoracic/mediastinal malignancies and RT (~73 yrs., 85.2% female), of which 7663 (0.13%, 128 per 100,000) were diagnosed with TTS (~74 yrs., 95.8% females, 88.1% white). Higher odds and rising trends in TTS per 100,000 hospitalizations (from 31 to 241) were seen among patients with prior intrathoracic malignancies and RT as compared to those without (from 19 to 104) (ptrend b 0.001). All-cause in-hospital mortality (4.6% vs 2.8%; OR 1.45; 95%CI 1.29–1.63, p b 0.001), cardiogenic shock (4.3% vs 0.2%), cardiac arrest (3.1% vs 0.9%), arrhythmia (34.3% vs 24.6%), stroke (3.6% vs 2.8%), respiratory failure (14.5% vs 4.6%), and median length of stay and hospital charges were significantly higher in the TTS cohort. Conclusions: This study showed higher odds and increasing trends in TTS-related admissions with worse inhospital outcomes among patients with prior intrathoracic/mediastinal cancer and RT, irrespective of the time interval from cancer diagnosis or RT to TTS occurrence. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Takotsubo Syndrome (TTS) is characterized by severe left ventricular (LV) systolic dysfunction in response to emotional, physical, or
⁎ Corresponding author at: Division of Cardiology, Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA. E-mail address: [email protected] (R. Desai).
medical stress [1]. TTS has been increasingly recognized in patients with cancer, which could be related to emotional stress of diagnosis, chronic inflammation or the physical stress of various cancer treatments, including chemotherapy [2,3]. TTS has also been linked with radiation therapy (RT) for cancer [4]. However, the risk and burden of TTS in adult patients with prior intrathoracic/mediastinal RT has never been reported in the literature. We assessed the prevalence, risk, trends and outcomes of TTS-related admissions in the survivors with prior history of mediastinal/intrathoracic cancer and RT in the United States (US).
https://doi.org/10.1016/j.ijcard.2020.02.036 0167-5273/© 2020 Elsevier B.V. All rights reserved.
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
2
R. Desai et al. / International Journal of Cardiology xxx (xxxx) xxx
2. Methods
4. Discussion
We queried the National Inpatient Sample (NIS) (2007 to 2014), a part of the Healthcare Cost and Utilization Project (HCUP) funded by the Agency for Healthcare Research and Quality (AHRQ) [5], which incorporates nearly 35 million weighted inpatient discharges per year. The NIS provides a sample from 20% of hospital stays of all nonfederal US community hospitals (excluding rehabilitation and long-term acute care hospitals) and represents 95% of the general population in the US. It contains de-identified data; therefore, the study was exempt from an institutional review board approval. Adult hospitalizations for TTS were identified using the International Classification of Diseases, Ninth Revision; Clinical Modification (ICD-9CM) code 429.83 with a prior history of intrathoracic/mediastinal cancer and RT (ICD-9-CM code V15.3). Prior intrathoracic/mediastinal cancers included malignant neoplasm of esophagus (V10.03), or trachea, bronchus and lung (V10.1), or other respiratory and intrathoracic organs (V10.2), or larynx (V10.21), or nasal cavities, middle ear, and accessory sinuses (V10.22), or breast (V10.3) or Hodgkin's disease (V10.72). We excluded the cases undergoing chemotherapy during current admissions (using ICD-9 CM procedure codes 00.10, 00.15, 17.70, 99.25, 99.28) from our sample. Primary outcomes were the prevalence, risk and trends in TTSrelated hospitalizations in patients with prior mediastinal/intrathoracic cancer and RT. Co-primary outcomes were the all-cause in-hospital mortality and cardiac complications such as acute myocardial infarction (AMI), arrhythmias, in-hospital cardiac arrest (IHCA), cardiogenic shock, venous thromboembolism and respiratory failure in TTS cohorts with vs. without previous intrathoracic malignancies and RT. Secondary outcomes studied were the mean length of stay (LOS) in days, hospitalization charges, and discharge status in TTS cohort with vs. without previous history of intrathoracic cancer and RT. We utilized discharge and sampling weights to conduct statistical analyses to generate nationally illustrative estimates. We used Pearson's Chi-square test for categorical and Student's t-test for the continuous variables. A two-tailed p b 0.05 was considered to determine the statistical significance. We used SPSS v22 (IBM Corp., Armonk, NY) to perform all statistical analyses.
Our study is the first attempt at quantifying the risk and burden related to the occurrence of TTS in adult inpatients with past mediastinal/intrathoracic cancer with radiation exposure. A prior history of intrathoracic cancer with RT independently increased the risk of TTSrelated admissions. There was nearly 8-fold increase (from 31 to 241) in the mean prevalence of TTS cases per 100,000 hospitalizations with prior intrathoracic/mediastinal cancer and RT from 2007 to 2014. This represents an annual increase of 12.9 patients per 100,000. This might be reflective of the growing elderly population in the US as evidenced by the high percentage of 65 or older aged patients (68%) with TTS as identified in this study. We also believe that increased awareness of this condition among physicians and improvement in diagnostic modalities over the years may have contributed towards rising trends in prevalence of TTS. The gender predisposition in favor of females observed in our study is in accordance with the prior literature [6]. Overall, the rate of TTS might seem low, but it is in fact ~7 times higher (0.13%) than the prevalence of TCM (0.02%) typically seen in general inpatient population [7]. In terms of the all-cause inhospital mortality, we observed almost two-fold increased mortality rate in the TTS group (4.6% vs 2.8%). Both cohorts with and without TTS were comparable in major areas albeit with a few notable differences. These included a significantly higher female prevalence (85.2% vs 50.3%), a significant increase in prevalence of baseline comorbidities, and a relatively higher non-elective admission rate in the TTS cohort. Each of these is consistent with prior studies and underscores the already higher health burden of TTS patients as a group [2,3,6]. TTS and its association with cancer has been a topic of much discussion lately. Chemotherapeutic agents, chronic inflammation and emotional stress related factors have been implicated. RT as a precipitant of TTS has been recently recognized as another risk factor [8]. The increased risk of premature cardiovascular disease in patients post-RT has been well established [9]. RT can affect almost any cardiovascular structure ranging from pericardium, vascular tree, endocardium, myocardium or the conduction system leading to a wide spectrum of diseases including coronary vascular disorders, acute or chronic pericarditis, valvular disease, and cardiomyopathy [10–12]. RT-associated heart damage usually ensues following years of radiation exposure and is linked mainly with RT for cancers in thoracic/mediastinal region e.g. breast cancer, Hodgkin's lymphoma, lung cancer, soft tissue tumors, head/neck or mandible tumors and esophageal cancer. Hence, we utilized cases with prior history of such mediastinal/intrathoracic malignancies to conduct our analyses. However, lack of stratification of radiation doses becomes important especially given that radiation doses of b30 Gy, together with modern-day, multiple-portal, cardiac shielded RT do reduce the overall cardiotoxicity [13]. Whether the development of TTS in these hospitalized patients is related to their prior exposure to RT is a natural question and requires much further elaborate studies to decipher. It is certainly plausible that a proportion of these patients may have an enhanced predisposition to developing TTS as the radiation-induced damage to cardiac tissue is well-documented [14,15]. However, what is clear from our study is that indeed there is a clinical and economic burden upon patients with prior mediastinal/intrathoracic cancer and RT who experience TTS as compared to patients who do not. Our study was limited by the availability of data parameters. For instance, we were not able to stratify for RT dose, regions exposed, duration of exposure, time since first exposure or obtain information on ballooning patterns on echocardiography. Moreover, we did not have information specifying the target radiation anatomical region of the body. Also, we did not include all cancer but only
3. Results We identified a total of 7663 (0.13%, 128 per 100,000) TTS (~74 yrs., 95.8% females, 88.1% white)-related admissions out of overall 5,991,314 hospitalizations recorded among patients with prior intrathoracic/mediastinal malignancies and RT (mean age:~73 [63–82] yrs., 85.2% female) from 2007 to 2014 [Table 1]. Using logistic regression, we found that the unadjusted odds of TTSrelated admissions in patients with prior history of intrathoracic/mediastinal cancer and RT was 2.14 [95%CI 1.09–2.19, p b 0.001]. The odds adjusted for demographics including age, sex, race, type of admission (elective/non-elective) and year of admission remained significant at 1.05 [95%CI 1.02–1.07, p b 0.001] while those adjusted for aforementioned demographics plus all baseline cardiac and extra-cardiac comorbidities including metastatic and non-metastatic cancers were 1.03 [95% CI 1.01–1.06, p = 0.009] (Table 1). From 2007 to 2014, rising trends in TTS per 100,000 hospitalizations (from 31 to 241) were seen RT for prior mediastinal/intrathoracic malignancies as compared to those without (from 19 to 104), more rapid ascent among females (p b 0.001) [Fig. 1]. In-hospital outcomes including all-cause mortality (4.6% vs 2.8%; OR 1.45; 95%CI 1.29–1.63, p b 0.001), cardiogenic shock (4.3% vs 0.2%), cardiac arrest (3.1% vs 0.9%), arrhythmia (34.3% vs 24.6%), stroke (3.6% vs 2.8%), respiratory failure (14.5% vs 4.6%), median length of stay (4 vs 3 days) and hospital charges ($36,656 vs $24,749) were significantly higher in the cohort with TTS.
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
R. Desai et al. / International Journal of Cardiology xxx (xxxx) xxx
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Table 1 Baseline characteristics of adult hospitalizations with vs. without takotsubo syndrome in patients with prior mediastinal/intra-thoracic cancer and radiation therapy, 2007–2014. Variables Age (years) at admission
Female Race
Non-elective admission Location/teaching status of hospital
Median [IQR] 18–44 45–64 ≥65 White African American Hispanic Asian or Pacific Islander Native American Others Rural Urban nonteaching Urban teaching
No TTS (5,983,651)
TTS (7663)
Overall (5,991,314)
p
73 [63–82] 3.1% 24.3% 72.6% 85.2% 81.3% 10.0% 4.7% 1.5% 0.4% 2.0% 76.3% 10.7% 40.3% 49.0%
74 [66–81] 0.8% 21.4% 77.8% 95.8% 88.1% 5.8% 2.3% 1.6% 0.2% 1.9% 89.5% 5.4% 33.7% 60.8%
73 [63–82] 3.1% 24.3% 72.6% 85.2% 81.3% 10.0% 4.7% 1.5% 0.4% 2.0% 76.3% 10.7% 40.3% 49.1%
0.043 b0.001
Comorbidities Hypertension 62.4% 66.7% Diabetes, uncomplicated 21.2% 15.6% Diabetes, chronic complications 3.4% 2.0% Dyslipidemia 35.3% 48.1% Obesity 8.3% 6.0% Smoking 26.9% 35.4% Peripheral vascular disease 6.7% 7.3% Chronic obstructive pulmonary disease 26.4% 30.7% Renal failure 11.2% 8.0% Prior MI/PCI/CABG 13.1% 15.9% Valvular heart disease 5.5% 6.0% Outcomes All-cause in-hospital Mortality 2.8% 4.6% Cardiogenic shock 0.2% 4.3% In-hospital cardiac arrest 0.9% 3.1% Venous thromboembolism 3.2% 2.7% Arrhythmia 24.6% 34.3% Stroke 2.8% 3.6% Respiratory failure 4.6% 14.5% Length of stay (days), Median[IQR] 3 [2–6] 4 [2–7] Hospital charges ($), median [IQR] $24,749 [13,565 45,426] $36,656 [22,371-66,758] Odds of TTS-related admissions with prior history of intrathoracic/mediastinal cancer and radiation therapy Regression model Odds Ratio 95% CI [LL-UL] Unadjusted 2.14 1.09–2.19 a Adjusted 1.05 1.02-1.07 Adjustedb 1.03 1.01-1.06
b0.001 b0.001
b0.001 b0.001
62.4% 21.2% 3.4% 35.4% 8.3% 26.9% 6.7% 26.4% 11.2% 13.1% 5.5%
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 0.026 b0.001 b0.001 b0.001 0.034
2.8% 0.2% 0.9% 3.2% 24.6% 2.8% 4.6% 3 [2–6] $24,763 [13,573-45,453]
b0.001 b0.001 b0.001 0.015 b0.001 b0.001 b0.001 b0.001 b0.001 p b0.001 b0.001 0.009
p b 0.05 indicates statistical significance. TTS = takotsubo syndrome, IQR = interquartile range MI = myocardial infarction, PCI = percutaneous coronary intervention, CABG = coronary artery bypass grafting. a Regression model was adjusted for demographics including age, sex, race, type of admission and year of admission. b Regression model was adjusted for variables included in model 1 plus all baseline comorbidities including alcohol abuse rheumatoid arthritis/collagen vascular diseases, chronic pulmonary disease, depression, diabetes, drug abuse, hypertension, dyslipidemia, previous myocardial infarction or revascularization, smoking, liver disease, obesity, peripheral vascular disorders, solid tumor without metastasis, metastatic cancer, psychoses, renal failure and valvular heart disease.
intrathoracic/mediastinal based on the biological plausibility that cancers and RT of other regions might not have such a higher risk of TTS. Readers should comprehend study findings based on the fact that nearly 75% of the overall study cohort (n = 5,991,314) included female patients with prior history of breast cancer and RT. Outpatient incidence of TTS was not considered and thus, underreporting of TTS is one of the key limitations. Lastly, NIS is a visit-based retrospective database of administrative nature so over-reporting of hospitalizations for same patients during a year cannot be overlooked completely. Despite the limitations, this large-scale dataset enabled us to analyze odds and trends in TTS hospitalizations and outcomes in patients with prior mediastinal/intrathoracic malignancies with RT in the US consistent with our prior analyses [16–19] .
malignancy and RT irrespective of the time interval from RT to TTS occurrence. TTS-related hospitalizations among survivors of mediastinal/intrathoracic cancer with a history of RT added significantly to increased LOS, in-hospital mortality, and healthcare costs as compared to TTS encounters secondary to other triggers. Increased awareness and greater vigilance of healthcare practitioners to the higher risk of TTS and worse in-hospital outcomes in patients with prior intrathoracic malignancies with prolonged radiation exposure may help curtail the TTS incidence and related adverse in-hospital outcomes.
Disclosure None.
5. Conclusions This nationwide population-based study showed higher prevalence, increased odds, and rising trends in TTS-related admissions from 2007 to 2014 in patients with prior mediastinal/intrathoracic
Funding None.
Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036
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R. Desai et al. / International Journal of Cardiology xxx (xxxx) xxx
Fig. 1. Trends in prevalence of takotsubo syndrome per 100,000 hospitalizations with prior mediastinal/intrathoracic cancer and RT. a. Overall prevalence of TTS in patients with vs. without prior mediastinal/intrathoracic cancer and RT. b. Prevalence of TTS in patients with prior mediastinal/intrathoracic cancer and RT stratified by sex.
CRediT authorship contribution statement Rupak Desai:Conceptualization, Methodology, Software, Formal analysis, Resources, Data curation, Writing - original draft, Writing - review & editing, Visualization.Aakash Desai:Writing - original draft, Writing - review & editing, Resources, Visualization.Shabber A. Abbas: Writing - original draft, Writing - review & editing, Resources. Upenkumar Patel:Writing - original draft, Writing - review & editing. Snehal Bansod:Writing - original draft, Writing - review & editing, Resources.Nanush Damarlapally:Writing - original draft, Writing - review & editing, Visualization, Supervision.Rajkumar Doshi:Methodology, Software, Writing - original draft, Writing - review & editing, Visualization.Sejal Savani:Methodology, Writing - original draft, Writing - review & editing, Visualization.Kishorbhai Gangani:Writing - original draft, Writing - review & editing, Visualization, Supervision.Rajesh Sachdeva:Conceptualization, Methodology, Validation, Resources, Writing - review & editing, Visualization, Supervision, Project
administration.Gautam Kumar:Conceptualization, Methodology, Validation, Writing - review & editing, Visualization, Supervision, Project administration.
Acknowledgment None. References [1] K. Dote, H. Sato, H. Tateishi, T. Uchida, M. Ishihara, Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases, J. Cardiol. 21 (1991) 203–214. [2] A. Desai, A. Noor, S. Joshi, A.S. Kim, Takotsubo cardiomyopathy in cancer patients, Cardio-Oncology 5 (2019) 7. [3] R. Desai, S.A. Abbas, H. Goyal, et al., Frequency of takotsubo cardiomyopathy in adult patients receiving chemotherapy (from a 5-year nationwide inpatient study), Am. J. Cardiol. 123 (2019) 667–673.
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Please cite this article as: R. Desai, A. Desai, S.A. Abbas, et al., National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior histor..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2020.02.036