==== Front J Arrhythm J Arrhythm 10.1002/(ISSN)1883-2148 JOA3 Journal of Arrhythmia 1880-4276 1883-2148 John Wiley and Sons Inc. Hoboken 10.1002/joa3.12418 JOA312418 Original Article Original Articles Sickle cell disease‐associated arrhythmias and in‐hospital outcomes: Insights from the National Inpatient Sample PATEL et al.Patel Upenkumar MBBS, MPHhttps://orcid.org/0000-0002-4403-0768 1 drupenpatel1989@gmail.comupatel@numc.edu Desai Rupak MBBShttps://orcid.org/0000-0002-5315-6426 2 Hanna Bishoy MD 3 Patel Dhruval MBBS 4 Akbar Shahzad MD 1 Zubair Mohammed MD 1 Kumar Gautam MD 2 5 Sachdeva Rajesh MD 2 3 6 1 Department of Internal Medicine Nassau University Medical Center East Meadow NY USA 2 Division of Cardiology Atlanta VA Medical Center Decatur GA USA 3 Division of Cardiology Morehouse School of Medicine Atlanta GA USA 4 AMC MET Medical College L.G Hospital Ahmedabad Gujarat India 5 Division of Cardiology Emory University School of Medicine Atlanta GA USA 6 Division of Cardiology Medical College of Georgia Augusta GA USA * Correspondence Upenkumar Patel, MBBS, MPH, Department of Internal Medicine, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, NY, USA. Emails: drupenpatel1989@gmail.com; upatel@numc.edu 08 8 2020 12 2020 36 6 10.1002/joa3.v36.61068 1073 24 4 2020 01 7 2020 21 7 2020 © 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm SocietyThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract Background The frequency and temporal trend in the prevalence of arrhythmias and associated in‐hospital outcomes in patients with sickle cell disease (SCD) have never been quantified. Methods Our study cohort of SCD patients and sub‐types of arrhythmias were derived from the 2010‐2014 National Inpatient Sample using relevant diagnostic codes. The frequency and trends of arrhythmia and odds of inpatient mortality were measured. Results A total of 891 450 hospitalized SCD patients were identified, of which, 55 616 (6.2%) patients experienced arrhythmias. The SCD cohort with arrhythmia demonstrated higher all‐cause mortality (2.7% vs 0.4%; adjusted OR 2.53, 95% CI 2.15‐2.97, P < .001), prolonged hospital stays (6.9 vs 5.0 days) and higher hospital charges ($53 871 vs $30 905) relative to those without arrhythmias (P < .001).The frequency of supraventricular arrhythmia (AFib, SVT, and AF) and ventricular arrhythmia (VFib and VT) were 1893 and 362 per 100 000 SCD‐related admissions, respectively. Unspecified arrhythmias (4126) were seen most frequently followed by AFib (1622) per 100 000 SCD‐related admissions. From 2010 to 2014, the frequency of any arrhythmias and atrial fibrillation in hospitalized SCD patients relatively increased by 29.6% and 38.5%, respectively. There was nearly a twofold (2.4% in 2010 to 5.0% in 2014) increase in the frequency of arrhythmia among patients aged <18 years. The frequency of arrhythmias in hospitalized male and female SCD patients relatively increased by 28.8% and 31.4%, respectively (P trend < .001). Conclusions The frequency of arrhythmias among SCD patients is on the rise with worse hospitalization outcomes, including higher in‐hospital mortality and higher resource utilization as compared to those without arrhythmias. Nearly 6% of all SCD‐related admissions revealed concomitant arrhythmias. Rising trends in arrhythmia were seen in SCD‐related admissions from 2010‐2014. Unspecified arrhythmias were most prevalent followed by AFib. Arrhythmia events raised the odds (OR 2.53) of inpatient mortality in SCD. Length of stay and charges were higher in the SCD cohort with arrhythmia. arrhythmiaatrial fibrillationmortalityprevalencesickle cell anemiasickle cell disease source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.5 mode:remove_FC converted:12.12.2020 Patel U , Desai R , Hanna B , et al. Sickle cell disease-associated arrhythmias and in-hospital outcomes: Insights from the National Inpatient Sample . J Arrhythmia . 2020 ;36 :1068 –1073 . 10.1002/joa3.12418 ==== Body 1 INTRODUCTION Sickle cell disease (SCD) is one of the most common structural genetic disorders of hemoglobin, affecting around 100 000 patients in the United States (US), 1 most often African Americans. 2 Patients with SCD suffer from chronic hemolytic anemia and recurrent episodes of ischemia‐reperfusion injury. Among the most common clinical manifestations of SCD are vaso‐occlusive crises, which often result in recurrent hospitalizations and are an indicator of poor prognosis. 3 The improved survival of patients with SCD owing to recent advances in treatments has resulted in a rise in the incidence of the more chronic cardiopulmonary manifestations of the disease, such as myocardial infarction (MI), pulmonary hypertension (PH), left ventricular diastolic dysfunction and cardiac arrhythmias. 4 The frequency of sudden death in the aging SCD patient population is also on the rise. 4 , 5 , 6 An investigation of an autopsy series uncovered that cardiopulmonary etiologies such as MI, PH, heart failure, and cardiac arrhythmias were the most common causes of death. 5 , 7 Electrocardiographic abnormalities, for example, QT prolongation and ventricular arrhythmias are not inconsistent in SCD patients. 8 , 9 The cumulative frequency and temporal trends of cardiac arrhythmias in patients with SCD have not been explored in the SCD population through large‐scale, cross‐sectional studies. We aimed to quantify the frequency and characterize the temporal trends of fatal and non‐fatal in‐hospital arrhythmias and consequent in‐hospital outcomes in patients primarily admitted for SCD using a nationally representative US cohort. 2 METHODS 2.1 Data source The study cohort was acquired from 2010 to 2014 National Inpatient Sample (NIS) database, a part of Healthcare Cost and Utilization Project (HCUP), funded by the Agency for Healthcare Research and Quality (AHRQ), to evaluate the frequency and hospitalization outcomes of arrhythmias in hospitalized SCD patients. The NIS is the largest all‐payer publicly accessible inpatient healthcare database in the United States. It includes more than 7 million unweighted and more than 35 million weighted hospitalizations (national estimates) each year. Institutional review board (IRB) approval was not required as the NIS is a de‐identified database. 10 2.2 Study population International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) codes were used as reported earlier to identify hospitalized SCD patients as primary diagnosis (282.41, 282.42, 282.6, 282.60‐282.64, 282.68, and 282.69) and arrhythmias as secondary diagnosis (ICD‐9‐CM codes for atrial fibrillation [AFib] 427.31, atrial flutter [AF] 427.32, supraventricular tachycardia [SVT] 427.0, ventricular fibrillation [VFib] 427.41, ventricular tachycardia [VT] 427.1, atrioventricular [AV] block 426.0, 426.10, 426.11, 426.12, 426.13 and unspecified arrhythmias 427.2, 427.9, 427.89, 785.0). 3 , 11 , 12 , 13 , 14 . Discharges related to sickle cell trait (282.5) or thalassemia (282.49) were omitted from the study cohort. 2.3 Statistical analyses The Pearson chi‐square test and Student's t test were used to assessing categorical and continuous variables, respectively. The trends in the frequency of arrhythmias in hospitalized SCD patients were measured by the linear‐by‐linear association test. After adjusting for baseline characteristics and comorbidities, a two‐step hierarchical multivariate regression model was utilized to estimate the risk of in‐patient mortality due to any arrhythmias. A multivariate regression model was adjusted for baseline demographics including age, gender, and race, payer status, admission day (weekend or weekdays), hospital bed size, location/teaching status and region, all baseline comorbidities. SPSS version 22 (IBM Corp) was used for all statistical analyses. 3 RESULTS 3.1 Study population and baseline characteristics A total of 891 450 weighted SCD‐related hospitalizations were identified from 2010 to 2014. Of these, 55 616 (6.2%) encounters (mean age 39.55 (±20.41) yrs, 59.7% females) were associated with arrhythmias. Among hospitalized patients with SCD, the frequency of arrhythmias was highest in those aged 18‐44 years. The SCD‐arrhythmia cohort consisted more often of African Americans (88.3%) and Medicaid enrollees (36.4%) with weekday (76.1%) admissions. The SCD cohort with arrhythmia was more likely managed at large (65.6%), nonprofit private (74.2%), urban‐teaching hospital (74.5%) in the southern (49.6%) part of the US. The SCD cohort with arrhythmia had a higher prevalence of major comorbidities as compared to those without arrhythmia. The SCD cohort with arrhythmia had worse hospitalization outcomes including increased mortality (2.7% vs 0.4%), a longer length of stay (6.9 (±8.2) vs 5.0 (±6.8) days) and higher total hospital charges ($53 871 vs $30 905) as compared to hospitalized SCD patients without arrhythmias (P < .001) (Table 1). TABLE 1 Baseline characteristics and outcomes of sickle cell disease (SCD) inpatient encounters with vs without arrhythmia(s) Variable SCD + no arrhythmia SCD + any arrhythmia P‐value* Weighted N 835 834 55 616 Age (y) at admission Mean age ± SD 29.0 ± 15.8 39.6 ± 20.4 <.001 <18 19.1% 11.0% 18‐44 65.1% 49.4% 45‐64 13.3% 27.2% ≥65 2.5% 12.3% Gender <.001 Male 37.7% 40.3% Female 62.3% 59.7% Race <.001 White 2.4% 4.5% African American 90.3% 88.3% Hispanic 4.2% 4.0% Asian or Pacific Islander 0.4% 0.5% Native American 0.1% 0.1% Other 2.5% 2.6% Primary expected payer <.001 Medicare 21.8% 34.8% Medicaid 49.3% 36.4% Private including HMO 21.3% 21.1% Self‐pay 4.4% 4.8% No charge 0.4% 0.3% Others 2.7% 2.6% Admission day Weekday 76.6% 76.1% Weekend 23.4% 23.9% Bed size of hospital <.001 Small 10.4% 10.7% Medium 25.2% 23.6% Large 64.4% 65.6% Location/teaching status of hospital <.001 Rural 4.3% 3.9% Urban—non‐teaching 21.7% 21.6% Urban—teaching 74.0% 74.5% Region of hospital <.001 Northeast 22.4% 20.3% Midwest 19.2% 21.4% South 50.3% 49.6% West 8.1% 8.8% Control/ownership of hospital <.001 Government, non‐federal 16.7% 16.2% Private, not‐profit 73.1% 74.2% Private, invest‐own 10.2% 9.6% Comorbidities Alcohol abuse 1.4% 2.5% <.001 Deficiency anemias 8.5% 17.6% <.001 Congestive heart failure 3.1% 12.5% <.001 Chronic pulmonary disease 17.2% 20.8% <.001 Coagulopathy 3.8% 8.1% <.001 Depression 6.8% 8.6% <.001 Diabetes, uncomplicated 4.9% 11.0% <.001 Diabetes, chronic complications 1.3% 3.0% <.001 Drug abuse 7.3% 7.6% .053 Hypertension 18.5% 39.0% <.001 Hypothyroidism 2.1% 5.0% <.001 Liver disease 2.0% 4.2% <.001 Fluid and electrolytes disorders 16.7% 32.4% <.001 Obesity 6.3% 9.6% <.001 Paralysis 1.4% 2.8% <.001 Peripheral vascular disorders 0.8% 3.1% <.001 Psychoses 3.1% 4.3% <.001 Pulmonary circulation disorders 4.1% 10.5% <.001 Renal failure 5.6% 17.0% <.001 Valvular disease 1.4% 6.1% <.001 Weight loss 1.6% 4.7% <.001 Sepsis 4.1% 8.6% <.001 Acute myocardial infarction 0.3% 1.5% <.001 Pneumonia 8.6% 15.0% <.001 Acute chest syndrome 5.1% 7.9% <.001 SCD with crisis 56.5% 47.9% <.001 Splenic sequestration 0.8% 1.4% <.001 Outcomes All‐cause in‐hospital mortality 0.4% 2.7% <.001 Total hospital charges (mean) $30 905 $53 871 <.001 Length of stay (d) (mean ± SD) 5.0 ± 6.8 6.9 ± 8.2 <.001 Abbreviation: SCD, sickle cell disease. * Significant P‐values ≤ .05 at 95% confidence interval. John Wiley & Sons, Ltd3.2 Frequency and trends in arrhythmias among SCD‐related hospitalizations The frequencies of arrhythmias documented per 100 000 hospitalized SCD patients were as follows: any arrhythmias (6256 per 100 000), unspecified arrhythmias (4126 per 100 000), AFib (1622 per 100 000), AF (141 per 100 000), SVT (130 per 100 000), atrioventricular (AV) block (255 per 100 000), VFib (40 per 100 000) and VT (322 per 100 000) (Figure 1A). The frequency of supraventricular arrhythmia (AFib, SVT, and AF) and ventricular arrhythmia (VFib and VT) were 1893 and 362 per 100 000 SCD‐related admissions, respectively. The frequency of any arrhythmia in hospitalized SCD patients increased from 5.4% in 2010 to 7.0% in 2014 (29.6% relative increase, P trend < .001). The frequency of AFib increased from 1.3% in 2010 to 1.8% in 2014 (38.5% relative increase, P trend < .001) among hospitalized SCD patients (Figure 1B). From 2010 to 2014, the frequency of arrhythmias in hospitalized male and female SCD patients relatively increased by 28.8% and 31.4%, respectively (Figure 1C) (P trend < .001). Among hospitalized SCD patients, the frequency of arrhythmia increased nearly two‐fold (108% relative increase, 2.4% in 2010 to 5.0% in 2014) in <18 years old age group (P trend < .001). The frequency of arrhythmias among hospitalized SCD patients increased by 13.0% in those aged 18‐44, 26.2% in those aged 45‐64 and 15.7% in those aged ≥65 during the study period (Figure 1D). FIGURE 1 (A) Frequency of any arrhythmias and subtype of arrhythmias per 100 000 SCD‐related hospitalizations. (B) Percent distribution of any arrhythmias and atrial fibrillation among SCD‐related hospitalizations. (C) Percent distribution of arrhythmias among SCD‐related hospitalizations stratified by gender. (D) Percent distribution of arrhythmias among SCD‐related hospitalizations stratified by age 3.3 Odds of in‐hospital mortality in SCD‐related hospitalizations with arrhythmias The SCD cohort with arrhythmia demonstrated a higher odd of in‐patient mortality (unadjusted OR 6.81, 95% CI 5.95‐7.80, P < .001; adjusted OR 2.53, 95% CI 2.15‐2.97, P < .001) as compared to SCD patients without arrhythmia. 4 DISCUSSION This study reveals a significant increase in the frequency of arrhythmias in hospitalized SCD patients over the study period. Unspecified arrhythmias (65.9%) were seen most frequently, followed by AFib (25.9%) among SCD‐related admissions. The frequency of arrhythmias among hospitalized SCD patients increased in all age and gender groups. However, the relative increase in the frequency of arrhythmias in hospitalized SCD patients was most pronounced in females and patients younger than 18 years. Another notable finding of the study was that the arrhythmia incidence during hospitalizations for SCD was a significant predictor for worse outcomes, including a higher prevalence and odds of all‐cause mortality, prolonged length of stay and higher total hospital charges as compared to the cohort without arrhythmias. Nearly three decades ago, Maisel et al reported that nearly 80% of SCD patients experienced cardiac arrhythmias during vaso‐occlusive pain crises. 8 The reason for the increased frequency of arrhythmias in SCD patients remains largely unclear, but a predilection to cardiac autonomic dysfunction, QT prolongation, and myocardial fibrosis have been posited as possible explanations. 15 , 16 Indik and colleagues studied two cohorts of SCD and established that a prolonged QT interval and ventricular tachyarrhythmias were significant predictors of mortality in this population. 17 We observed a nearly threefold higher odds of in‐hospital mortality among SCD hospitalized patients with arrhythmias as compared to those without arrhythmias on multivariate analysis. In keeping with this finding was a study that suggested that a prolonged QT was an independent predictor of increased sudden deaths in patients with SCD. 18 Moreover, Gacon et al revealed that AV block during the vaso‐occlusive crisis due to an ischemic event at AV node and bundle of hiss could be contributory to abnormal cardiac rhythms in SCD. 19 As increasing utilization of telemetry services during hospitalizations, overall rising trends of arrhythmia irrespective of underlying medical conditions were observed throughout time. 20 Our study also showed rising trends in arrhythmias among SCD cohort between 2010 and 2014. It is well‐established that traditional risk factors such as hypertension, diabetes mellitus, congestive heart failure, chronic pulmonary disease and behavioral issues such as drug/alcohol abuse are major risk factors for developing cardiac arrhythmias in the general population and our cohort also showed higher burden of all these comorbidities among SCD cohort with arrhythmia which could be the confounding factors in hospitalization outcomes. 12 , 21 However, our study showed that SCD cohort with arrhythmia raised the odd of in‐patient mortality in the adjusted multivariate regression model. Arrhythmias in SCD patients may lead to a greater number of in‐hospital complications and necessitate increased diagnostic workup, factors which may account for the observed increase in hospital length of stay in this cohort. This result suggests that early recognition and prompt treatment of cardiac arrhythmias using telemetry services for hospitalized SCD may be helpful in lowering the burden of sudden cardiac death in SCD patients; further research is warranted to explore this possibility. It is also possible that the association between arrhythmias and increased mortality in this population is not causative; the presence of arrhythmias may simply serve as a marker of advanced disease in patients with SCD. 5 LIMITATIONS Limitations of this retrospective analysis are largely related to the limitations of NIS data interpretation. Diagnoses may have been coded incorrectly during patient encounters due to human error. Due to the anonymized nature of NIS data, the frequency of arrhythmias in hospitalized SCD patients may have been overestimated if individual patients presented for multiple inpatient encounters (eg, an individual patient cannot be followed longitudinally in NIS data). The cause of death cannot be adjudicated from NIS data. Propensity‐matched analysis was not performed in this study which could be another limitation in assessing the outcomes between two cohorts. Nevertheless, this is the largest nationally representative study exploring the burden of arrhythmias and their role as predictors of worse outcomes in hospitalized SCD patients. 6 CONCLUSIONS The frequency of arrhythmias among hospitalized SCD patients is on the rise, unspecified arrhythmias were seen most frequently followed by AFib among SCD‐related admissions. The presence of arrhythmia in SCD was associated with worse in‐hospital outcomes and increased healthcare resource utilization. Further research is required to explore whether or not early recognition and management of arrhythmias in the SCD population will lead to improved clinical outcomes. CONFLICT OF INTEREST None. Supporting information Table S1 Click here for additional data file. ==== Refs REFERENCES 1 Brousseau DC , Panepinto JA , Nimmer M , Hoffmann RG . The number of people with sickle‐cell disease in the United States: national and state estimates . Am J Hematol . 2010 ;85 (1 ):77 –8 .20029951 2 Hassell KL . Population estimates of sickle cell disease in the U.S . Am J Prev Med . 2010 ;38 (4 Suppl ):S512 –S521 .20331952 3 Okam MM , Shaykevich S , Ebert BL , Zaslavsky AM , Ayanian JZ . National trends in hospitalizations for sickle cell disease in the United States following the FDA approval of hydroxyurea, 1998–2008 . Med Care . 2014 ;52 (7 ):612 –8 .24926708 4 Gladwin MT , Sachdev V . Cardiovascular abnormalities in sickle cell disease . J Am Coll Cardiol . 2012 ;59 (13 ):1123 –33 .22440212 5 Darbari DS , Kple‐Faget P , Kwagyan J , Rana S , Gordeuk VR , Castro O . Circumstances of death in adult sickle cell disease patients . Am J Hematol . 2006 ;81 (11 ):858 –63 .16924640 6 Graham JK , Mosunjac M , Hanzlick RL , Mosunjac M . Sickle cell lung disease and sudden death: a retrospective/prospective study of 21 autopsy cases and literature review . Am J Forensic Med Pathol . 2007 ;28 (2 ):168 –72 .17525572 7 Fitzhugh CD , Lauder N , Jonassaint JC , Telen MJ , Zhao X , Wright EC , et al. Cardiopulmonary complications leading to premature deaths in adult patients with sickle cell disease . Am J Hematol . 2010 ;85 (1 ):36 –40 .20029950 8 Maisel A , Friedman H , Flint L , Koshy M , Prabhu R . Continuous electrocardiographic monitoring in patients with sickle‐cell anemia during pain crisis . Clin Cardiol . 1983 ;6 (7 ):339 –44 .6883828 9 Mueller BU , Martin KJ , Dreyer W , Bezold LI , Mahoney DH . Prolonged QT interval in pediatric sickle cell disease . Pediatr Blood Cancer . 2006 ;47 (6 ):831 –3 .16078213 10 HCUP Databases . Healthcare Cost and Utilization Project (HCUP) . Rockville, MD : Agency for Healthcare Research and Quality ; 2019 . 11 Desai R , Patel U , Deshmukh A , Sachdeva R , Kumar G . Burden of arrhythmia in recreational marijuana users . Int J Cardiol . 2018 ;264 :91 –2 .29642998 12 Desai R , Patel U , Singh S , Bhuva R , Fong HK , Nunna P , et al. The burden and impact of arrhythmia in chronic obstructive pulmonary disease: Insights from the National Inpatient Sample . Int J Cardiol . 2019 ;281 :49 –55 .30711267 13 Desai R , Kakumani K , Fong HK , Shah B , Zahid D , Zalavadia D , et al. The burden of cardiac arrhythmias in sarcoidosis: a population‐based inpatient analysis . Ann Transl Med . 2018 ;6 (17 ):330 .30306069 14 Desai R , Rupareliya C , Patel U , Naqvi S , Patel S , Lunagariya A , et al. Burden of arrhythmias in epilepsy patients: a nationwide inpatient analysis of 1.4 million hospitalizations in the United States . Cureus . 2017 ;9 (8 ):e1550.29018647 15 Kolo PM , Sanya EO , Olanrewaju TO , Fawibe AE , Soladoye A . Cardiac autonomic dysfunction in sickle cell anaemia and its correlation with QT parameters . Niger Med J . 2013 ;54 (6 ):382 –5 .24665151 16 Desai AA , Patel AR , Ahmad H , Groth JV , Thiruvoipati T , Turner K , et al. Mechanistic insights and characterization of sickle cell disease‐associated cardiomyopathy . Circ Cardiovasc Imaging . 2014 ;7 (3 ):430 –7 .24676783 17 Indik JH , Nair V , Rafikov R , Nyotowidjojo IS , Bisla J , Kansal M , et al. Associations of prolonged QTc in sickle cell disease . PLoS One . 2016 ;11 (10 ):e0164526.27736922 18 Upadhya B , Ntim W , Brandon Stacey R , Henderson R , Leedy D , O'Brien FX , et al. Prolongation of QTc intervals and risk of death among patients with sickle cell disease . Eur J Haematol . 2013 ;91 (2 ):170 –8 .23621844 19 Gacon PH , Jourdain P , Heba N , Amara W . Acute atrio‐ventricular block in sickle cell anemia . Ann Cardiol Angeiol (Paris) . 2014 ;63 (5 ):321 –6 .25266160 20 Tripathi B , Khan S , Arora S , Kumar V , Naraparaju V , Lahewala S , et al. Burden and trends of arrhythmias in hypertrophic cardiomyopathy and its impact of mortality and resource utilization . J Arrhythm . 2019 ;35 (4 ):612 –25 .31410232 21 deGoma EM , Knowles JW , Angeli F , Budoff MJ , Rader DJ . The evolution and refinement of traditional risk factors for cardiovascular disease . Cardiol Rev . 2012 ;20 (3 ):118 –29 .22183062