研究背景
氣喘在很多文獻顯示與心血管疾病有著關聯性。氣喘會引發慢性呼吸道發炎，進而引發全身性發炎反應。在急性惡化期，病人不僅因為支氣管收縮，導致窒息，如無及時救援，則將面臨生命危險。 吸入性類固醇 (ICS) 在氣喘控制與治療中是主流療法，原因在於ICS能夠抑制氣道發炎反應，不僅能降低病人面臨急性惡化的風險，在過去的研究，同時也能降低死亡率。過去有氣喘控制狀況與心血管疾病相關研究，不過ICS劑量與心血管疾病的相關性研究尚未有定論。

研究目的
本研究的目的如下
1. 確立氣喘控制狀態與控制不良氣喘組中的ICS控制劑量，對各種心血管疾病 (CVD) 的發生風險的機會.
2. 確認氣喘控制與藥物使用對CVD的發生的關聯性.

研究方法
本研究使用台灣健保資料庫做全人口觀察型研究，以回溯性資料收集來收集氣喘組以及非氣喘組，並且依照NAEPP指引將氣喘組分為控制良好氣喘組，部份控制氣喘組以及控制不良氣喘組。我們使用KM曲線 (Kaplan-Meier curve)，利用累積發生率計算出各個組別與各種CVD的預後，並使用log-rank test進行組間比較。本研究也使用單變量與多變量Cox比例風險模式(univariate and multivariable Cox proportional hazards models)。我們使用此推論性統計，確立各個氣喘控制組與各種心血管疾病之間的風險比。另外，我們從控制不佳氣喘組，依照GINA指引中的藥物濃度，進一步將這組分成無ICS使用，輕ICS使用，中ICS使用，以及高ICS，使用同樣進行Cox比例風險模式進行分析。

結果
本研究顯示，控制不佳氣喘組對比非氣喘組，任何一項CVD風險比呈現顯著性增加，即便用慢性阻塞性肺病 (COPD)做調整，結果依舊不變。本研究同樣顯示，無ICS使用之控制不佳氣喘組使用控制良好氣喘組做比較，發現對全CVD發生具顯著風險，除了肺栓塞，結果不顯著，而上述結果調整了COPD，結果不變。在控制不佳氣喘組之不同ICS 劑量發現，無ICS 使用組對缺血性腦中風，冠狀動脈疾病，肺栓塞，以及任何心血管疾病，都具顯著風險，唯獨ICH的結果是無顯著風險，這些結果調整COPD後顯示無差別。

結論
控制不良氣喘組比較非氣喘組，在各種CVD的預後是最差的，且調整COPD後，結果沒有差異，唯獨出血性腦中風，調整COPD後顯示顯著風險。無ICS使用之控制不良氣喘組比較控制良好氣喘組，對於各種CVD的風險比則是增加的，除了肺栓塞。控制不良氣喘組之ICS 劑量，對缺血性腦中風，CAD，肺栓塞，任何心血 疾病都有影響，除了ICH，而當中對肺栓塞的影響最顯著，隨著ICS劑量上升風險比越高。

Background
Asthma is found to have correlation with cardiovascular disease (CVD) in many previous studies. The probable mechanism between asthma and CVD including chronic systemic inflammation through persistent airway inflammation. During asthma exacerbation period, patients not only suffered from suffocation caused by bronchospasm, people will also face death if not been adequately treated in time. Inhaled corticosteroid (ICS) is the mainstay treatment in controlling asthma by inhibited airway inflammation. ICS is not only found to decrease the incidence of exacerbation, previous studies also revealed ICS can also decrease mortality. Through literately review, the study of correlation between controlling status in asthma with cardiovascular disease remain scarce. Moreover, the effect of ICS dose on disease progression in cardiovascular disease still indetermined.

Aims
We aimed to clarify
1. The correlation between asthma controlling status and the dose of ICS within poorly controlled asthma on risk of developing cardiovascular disease.
2. The effect of asthma control and ICS use on CVD incidence.

Methods
This was a retrospective, observational study using Taiwan nationwide cohort database. We separated asthma cohort into well controlled group, partial controlled group and poorly controlled group according to NAEPP guideline on acute exacerbation grading after matching for age, sex and calendar year. We used Kaplan-Meier model on cumulative incidence of the two cohorts and comparing difference between the two cohorts using log-rank test. We used univariate and multivariable Cox proportional hazards models to determine the HR between asthma controlling group with cardiovascular disease, including stroke, intracranial hemorrhage (ICH), coronary artery disease (CAD), pulmonary embolism and any of cardiovascular disease (CVD). We also separated ICS in poorly controlled asthma group according to dose suggested in GINA guideline, to determine the effect of ICS among poorly controlled asthma group. We used multivariable Cox proportional hazards models to determine the HR between different dose of ICS in poorly controlled asthma group with cardiovascular disease.

Results
We found poorly controlled asthma group had significant HR on all cardiovascular disease (CVD) outcome, comparing with non-asthma group, even after adjusting with COPD, except ICH, showing significant change after adjusting COPD. We also found no ICS use in poorly controlled asthma group had significant hazard on all CVD outcome except pulmonary embolism, comparing with well controlled asthma group. After adjusting for COPD, the significant HR remains the same in no ICS use in poorly controlled asthma group, except for pulmonary embolism. ICS dose in poorly controlled asthma group has significant HR on stroke, CAD, pulmonary embolism and any CVD, however not in ICH, where pulmonary embolism had positive correlation with ICS dose. The result persisted even after adjusting with COPD.

Conclusion
In our study, poorly controlled asthma group had the poorest outcome on all cardiovascular disease (CVD), comparing with non-asthma group, even after adjusting with COPD. No ICS use in poorly controlled asthma group had significant HR on all CVD outcome except pulmonary embolism, and the worst outcome in all CVD. The effect of ICS dose in poorly controlled asthma group is prominent in stroke, CAD, pulmonary embolism and any CVD, especially pulmonary embolism. ICH seemed less likely to have ICS effect. Pulmonary embolism had positive correlation with ICS dose.

1. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59(5):469-478.
2. Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. European Respiratory Journal. 2008;31(1):143.
3. Global Health Estimates 2020: Disease burden by Cause, Age, Sex, by Country and by Region, 2000-2019. Geneva, World Health Organization. 2020.
4. Pelkonen MK, Notkola I-LK, Laatikainen TK, Jousilahti P. 30-year trends in asthma and the trends in relation to hospitalization and mortality. Respiratory medicine. 2018;142:29-35.
5. Ernst P, Spitzer WO, Suissa S, et al. Risk of Fatal and Near-Fatal Asthma in Relation to Inhaled Corticosteroid Use. JAMA. 1992;268(24):3462-3464.
6. Graudenz GS, Carneiro DP, Vieira RdP. Trends in asthma mortality in the 0- to 4-year and 5- to 34-year age groups in Brazil. J Bras Pneumol. 2017;43(1):24-31.
7. Tursynbek Nurmagambetov RK, and Paul Garbe. The Economic Burden of Asthma in the United States, 2008–2013. Ann Am Thorac Soc. 2018;15(3):348-356.
8. Bethesda. National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. . National Heart, Lung, and Blood Institute (US);2007.
9. Asthma GIf. Global Strategy for Asthma Management and Prevention. 2021.
10. Ichinose M ea. Japanese guidelines for adult asthma 2017. Allergology International. 2016.
11. Novelli F, Bacci E, Latorre M, et al. Comorbidities are associated with different features of severe asthma. Clinical and Molecular Allergy. 2018;16(1):25.
12. Tay TR, Radhakrishna N, Hore-Lacy F, et al. Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life. Respirology. 2016;21(8):1384-1390.
13. Wardzyńska A, Kubsik B, Kowalski ML. Comorbidities in elderly patients with asthma: Association with control of the disease and concomitant treatment. Geriatrics & Gerontology International. 2015;15(7):902-909.
14. Nakamura Y, Tamaoki J, Nagase H, et al. Japanese guidelines for adult asthma 2020. Allergology International. 2020;69(4):519-548.
15. KF; C, SE; W, JL; B, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-373.
16. Selroos O, Kupczyk M, Kuna P, et al. National and regional asthma programmes in Europe. European Respiratory Review. 2015;24(137):474-483.
17. Bourdin A, Bjermer L, Brightling C, et al. ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions. European Respiratory Journal. 2019;54(3):1900900.
18. Daugherty J, Lin X, Baxter R, Suruki R, Bradford E. The impact of long-term systemic glucocorticoid use in severe asthma: A UK retrospective cohort analysis. Journal of Asthma. 2018;55(6):651-658.
19. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with systemic corticosteroids. The Cochrane database of systematic reviews. 2001(1):Cd002178.
20. Knoflach M, Kiechl S, Mayr A, Willeit J, Poewe W, Wick G. Allergic Rhinitis, Asthma, and Atherosclerosis in the Bruneck and ARMY Studies. Archives of Internal Medicine. 2005;165(21):2521-2526.
21. Bautista LE, Vera LM, Arenas IA, Gamarra G. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. Journal of human hypertension. 2005;19(2):149-154.
22. Strand LB, Tsai MK, Wen CP, Chang SS, Brumpton BM. Is having asthma associated with an increased risk of dying from cardiovascular disease? A prospective cohort study of 446 346 Taiwanese adults. BMJ open. 2018;8(5):e019992.
23. Popa C, Netea MG, van Riel PL, van der Meer JW, Stalenhoef AF. The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. Journal of lipid research. 2007;48(4):751-762.
24. Torén K, Lindholm NB. Do patients with severe asthma run an increased risk from ischaemic heart disease? International journal of epidemiology. 1996;25(3):617-620.
25. Iribarren C, Tolstykh IV, Eisner MD. Are patients with asthma at increased risk of coronary heart disease? International journal of epidemiology. 2004;33(4):743-748.
26. Schanen JG, Iribarren C, Shahar E, et al. Asthma and incident cardiovascular disease: the Atherosclerosis Risk in Communities Study. Thorax. 2005;60(8):633.
27. Cazzola M, Calzetta L, Bettoncelli G, et al. Cardiovascular disease in asthma and COPD: a population-based retrospective cross-sectional study. Respiratory medicine. 2012;106(2):249-256.
28. Iribarren C, Tolstykh IV, Miller MK, Sobel E, Eisner MD. Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts. American journal of epidemiology. 2012;176(11):1014-1024.
29. Chung WS, Lin CL, Ho FM, et al. Asthma increases pulmonary thromboembolism risk: a nationwide population cohort study. The European respiratory journal. 2014;43(3):801-807.
30. Bang DW, Wi C-I, Kim EN, et al. Asthma Status and Risk of Incident Myocardial Infarction: A Population-Based Case-Control Study. The Journal of Allergy and Clinical Immunology: In Practice. 2016;4(5):917-923.
31. Mayor S. Adult onset asthma may increase risk of heart disease and stroke. BMJ. 2016;354:i4685.
32. Cepelis A, Brumpton BM, Laugsand LE, et al. Asthma, asthma control and risk of acute myocardial infarction: HUNT study. European Journal of Epidemiology. 2019;34(10):967-977.
33. Kim SY, Lim H, Lim JS, Choi HG. Analysis of the Relationship between Adult Asthma and Stroke: A Longitudinal Follow-Up Study Using the Korean National Sample Cohort. BioMed research international. 2019;2019:8919230.
34. Cepelis A, Brumpton BM, Laugsand LE, Langhammer A, Janszky I, Strand LB. Asthma, asthma control and risk of ischemic stroke: The HUNT study. Respiratory Medicine: X. 2020;2:100013.
35. Pollevick ME, Xu KY, Mhango G, et al. The Relationship Between Asthma and Cardiovascular Disease: An Examination of the Framingham Offspring Study. Chest. 2021;159(4):1338-1345.
36. Wee JH, Park MW, Min C, Byun SH, Park B, Choi HG. Association between asthma and cardiovascular disease. European journal of clinical investigation. 2021;51(3):e13396.
37. Guo J, Zhang Y, Liu T, Levy BD, Libby P, Shi G-P. Allergic asthma is a risk factor for human cardiovascular diseases. Nature Cardiovascular Research. 2022;1(5):417-430.
38. Lee CJ, Hwang J, Kang CY, et al. Asthma and increased risk of myocardial infarction and mortality among hypertensive Korean patients. Hypertension Research. 2023;46:1694–1704
39. Tattersall MC, Guo M, Korcarz CE, et al. Asthma predicts cardiovascular disease events: the multi-ethnic study of atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2015;35(6):1520-1525.
40. Appleton SL, Ruffin RE, Wilson DH, Taylor AW, Adams RJ. Cardiovascular disease risk associated with asthma and respiratory morbidity might be mediated by short-acting beta2-agonists. The Journal of allergy and clinical immunology. 2009;123(1):124-130.
41. Tomisa G, Horváth A, Sánta B, Keglevich A, Tamási L. Epidemiology of comorbidities and their association with asthma control. Allergy, Asthma & Clinical Immunology. 2021;17(1):95.
42. Tattersall MC, Barnet JH, Korcarz CE, Hagen EW, Peppard PE, Stein JH. Late-Onset Asthma Predicts Cardiovascular Disease Events: The Wisconsin Sleep Cohort. Journal of the American Heart Association. 2016;5(9):e003448
43. Çelebi Sözener Z, Aydın Ö, Mungan D, Mısırlıgil Z. Obesity-asthma phenotype: Effect of weight gain on asthma control in adults. Allergy and asthma proceedings. 2016;37(4):311-317.
44. Tomisa G, Horváth A, Szalai Z, Müller V, Tamási L. Prevalence and impact of risk factors for poor asthma outcomes in a large, specialist-managed patient cohort: a real-life study. Journal of asthma and allergy. 2019;12:297-307.
45. Wang C-Y, Lai C-C, Wang Y-H, Wang H-C. The prevalence and outcome of short-acting β2-agonists overuse in asthma patients in Taiwan. npj Primary Care Respiratory Medicine. 2021;31(1):19.
46. Guerra S, Sherrill DL, Bobadilla A, Martinez FD, Barbee RA. The relation of body mass index to asthma, chronic bronchitis, and emphysema. Chest. 2002;122(4):1256-1263.
47. Dogra S, Ardern CI, Baker J. The relationship between age of asthma onset and cardiovascular disease in Canadians. The Journal of asthma : official journal of the Association for the Care of Asthma. 2007;44(10):849-854.
48. Guite HF, Dundas R, Burney PG. Risk factors for death from asthma, chronic obstructive pulmonary disease, and cardiovascular disease after a hospital admission for asthma. Thorax. 1999;54(4):301-307.
49. Bazan-Socha S, Mastalerz L, Cybulska A, et al. Impaired fibrinolysis and lower levels of plasma α(2)-macroglobulin are associated with an increased risk of severe asthma exacerbations. Sci Rep. 2017;7(1):11014.
50. To WS, Midwood KS. Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis & tissue repair. 2011;4:21.
51. Bazan-Socha S, Kuczia P, Potaczek DP, et al. Increased blood levels of cellular fibronectin in asthma: Relation to the asthma severity, inflammation, and prothrombotic blood alterations. Respiratory medicine. 2018;141:64-71.
52. Tripodi A. Thrombin Generation Assay and Its Application in the Clinical Laboratory. Clinical Chemistry. 2016;62(5):699-707.
53. Bazan-Socha S, Mastalerz L, Cybulska A, et al. Asthma is associated with enhanced thrombin formation and impaired fibrinolysis. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2016;46(7):932-944.
54. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286(3):327-334.
55. Bard RL, Rubenfire M, Eagle K, Clarke NS, Brook RD. Utility of C-reactive protein measurement in risk stratification during primary cardiovascular disease prevention. Am J Cardiol. 2005;95(11):1378-1379.
56. Takemura M, Matsumoto H, Niimi A, et al. High sensitivity C-reactive protein in asthma. European Respiratory Journal. 2006;27(5):908-912.
57. Kasayama S, Tanemura M, Koga M, Fujita K, Yamamoto H, Miyatake A. Asthma is an independent risk for elevation of plasma C-reactive protein levels. Clinica chimica acta; international journal of clinical chemistry. 2009;399(1-2):79-82.
58. Zietkowski Z, Tomasiak-Lozowska MM, Skiepko R, Mroczko B, Szmitkowski M, Bodzenta-Lukaszyk A. High-sensitivity C-reactive protein in the exhaled breath condensate and serum in stable and unstable asthma. Respiratory medicine. 2009;103(3):379-385.
59. Kadakal F, Aras G, Kanmaz D, et al. The assessment of high sensitivity C-reactive protein as a systemic marker in moderate asthma patients and changing levels by inhaled corticosteroids. JPMA The Journal of the Pakistan Medical Association. 2013;63(7):893-898.
60. Wee JH, Park MW, Min C, Byun SH, Park B, Choi HG. Association between asthma and cardiovascular disease. European journal of clinical investigation. 2021;51(3):e13396.
61. Iribarren C, Tolstykh IV, Eisner MD. Are patients with asthma at increased risk of coronary heart disease? International journal of epidemiology. 2004;33(4):743-748.
62. Sneeboer MMS, Majoor CJ, de Kievit A, et al. Prothrombotic state in patients with severe and prednisolone-dependent asthma. The Journal of allergy and clinical immunology. 2016;137(6):1727-1732.
63. Sneeboer MMS, Hutten BA, Majoor CJ, Bel EHD, Kamphuisen PW. Oral and inhaled corticosteroid use and risk of recurrent pulmonary embolism. Thrombosis Research. 2016;140:46-50.
64. Otsuki M, Miyatake A, Fujita K, Hamasaki T, Kasayama S. Reduced carotid atherosclerosis in asthmatic patients treated with inhaled corticosteroids. The European respiratory journal. 2010;36(3):503-508.
65. Kurashima K, Kanauchi T, Hoshi T, et al. Effect of early versus late intervention with inhaled corticosteroids on airway wall thickness in patients with asthma. Respirology. 2008;13(7):1008-1013.
66. Camargo CA, Barr RG, Chen R, Speizer FE. Prospective Study of Inhaled Corticosteroid Use, Cardiovascular Mortality, and All-Cause Mortality in Asthmatic Women. Chest. 2008;134(3):546-551.
67. Lee C-H, Choi S, Jang EJ, et al. The effects of inhaled respiratory drugs on the risk of stroke: A nested case-control study. Pulmonary Pharmacology & Therapeutics. 2016;40:7-14.
68. Suissa S, Assimes T, Brassard P, Ernst P. Inhaled corticosteroid use in asthma and the prevention of myocardial infarction. The American Journal of Medicine. 2003;115(5):377-381.
69. Liang Y-R, Tzeng I, Hsieh P-C, et al. Transcriptome analysis in patients with asthma after inhaled combination therapy with long-acting β2-agonists and corticosteroids. International Journal of Medical Sciences. 2022;19(12):1770-1778.
70. Moore WC, Bleecker ER, Curran-Everett D, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. The Journal of allergy and clinical immunology. 2007;119(2):405-413.
71. Sneeboer MMS, Fens N, van de Pol MA, et al. Loss of asthma control and activation of coagulation and fibrinolysis. Clinical & Experimental Allergy. 2016;46(3):422-427.
72. Bang DW, Wi CI, Kim EN, et al. Asthma Status and Risk of Incident Myocardial Infarction: A Population-Based Case-Control Study. The journal of allergy and clinical immunology In practice. 2016;4(5):917-923.
73. Kumarathas I, Harsløf T, Andersen CU, et al. The risk of osteoporosis in patients with asthma. European clinical respiratory journal. 2020;7(1):1763612.
74. Gonzalez AV, Coulombe J, Ernst P, Suissa S. Long-term Use of Inhaled Corticosteroids in COPD and the Risk of Fracture. Chest. 2018;153(2):321-328.
75. Pujades-Rodríguez M, Smith CJP, Hubbard RB. Inhaled corticosteroids and the risk of fracture in chronic obstructive pulmonary disease. QJM: An International Journal of Medicine. 2007;100(8):509-517.
76. Saeed MI, Eklöf J, Achir I, et al. Use of inhaled corticosteroids and the risk of developing type 2 diabetes in patients with chronic obstructive pulmonary disease. Diabetes, Obesity and Metabolism. 2020;22(8):1348-1356.
77. Hua ML, Li L, Diao LL. Bronchial asthma and risk of 4 specific cardiovascular diseases and cardiovascular mortality: a meta-analysis of cohort studies. European review for medical and pharmacological sciences. 2022;26(14):5081-5091.
78. Chung WS, Lin CL, Chen YF, Ho FM, Hsu WH, Kao CH. Increased stroke risk among adult asthmatic patients. European journal of clinical investigation. 2014;44(11):1025-1033.
79. Portegies ML, Lahousse L, Joos GF, et al. Chronic Obstructive Pulmonary Disease and the Risk of Stroke. The Rotterdam Study. American journal of respiratory and critical care medicine. 2016;193(3):251-258.
80. Kim YR, Hwang IC, Lee YJ, Ham EB, Park DK, Kim S. Stroke risk among patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis. Clinics (Sao Paulo, Brazil). 2018;73:e177.
81. Carter P, Lagan J, Fortune C, et al. Association of Cardiovascular Disease With Respiratory Disease. Journal of the American College of Cardiology. 2019;73(17):2166-2177.
82. Majoor C, Kamphuisen P, Rijssenbeek-Nouwens L, et al. Increased incidence of pulmonary embolism in severe asthma. European Respiratory Journal. 2011;38(55):3969.
83. Alzghoul BN, Reddy R, Chizinga M, et al. Pulmonary Embolism in Acute Asthma Exacerbation: Clinical Characteristics, Prediction Model and Hospital Outcomes. Lung. 2020;198(4):661-669.
84. Zöller B, Pirouzifard M, Memon AA, Sundquist J, Sundquist K. Risk of pulmonary embolism and deep venous thrombosis in patients with asthma: a nationwide case-control study from Sweden. The European respiratory journal. 2017;49(2):1601014.
85. Yeh JJ, Lai MC, Yang YC, Hsu CY, Kao CH. Relationships Between Bronchodilators, Steroids, Antiarrhythmic Drugs, Antidepressants, and Benzodiazepines and Heart Disease and Ischemic Stroke in Patients With Predominant Bronchiectasis and Asthma. Frontiers in cardiovascular medicine. 2022;9:797623.
86. Zhang B, de Vries F, Setakis E, van Staa TP. The pattern of risk of myocardial infarction in patients taking asthma medication: a study with the General Practice Research Database. Journal of hypertension. 2009;27(7):1485-1492.