Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC 5pLJWRWfK4zWPJHbvzdbFtf S0066-782X2019000900367 S0066-782X2019005015102 10.5935/abc.20190150 Original Article Clinical Characteristics and Adverse Events in Acute Coronary Syndrome Patients with a History of Peripheral Arterial Disease Kang Yun-Peng Chen Li-Ying Kang Tie-Duo 0000-0002-6910-1278 Liu Wen-Xian Capital Medical University Beijing An Zhen Hospital affiliated Beijing China Beijing An Zhen Hospital affiliated to Capital Medical University, Beijing - China Mailing Address: Wen-Xian Liu, Beijing An Zhen Hospital affiliated to Capital Medical University - No. 2, Anzhen road, Chaoyang district Beijing 100029 - China. E-mail: lwx_lwxas88@163.com

Author contributions

Conception and design of the research: Yun-Peng K, Li-Ying C, Wen-Xian L; Acquisition of data and Analysis and interpretation of the data: Yun-Peng K, Li-Ying C, Tie-Duo K; Statistical analysis: Tie-Duo K, Wen-Xian L; Writing of the manuscript: Yun-Peng K, Li-Ying C; Critical revision of the manuscript for intellectual content: Yun-Peng K, Tie-Duo K, Wen-Xian L.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 29 08 2019 09 2019 113 3 367 372 19 09 2018 10 12 2018 16 01 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Abstract Background:

In clinical observation, patients with acute coronary syndrome complicated with peripheral artery disease have poor prognosis, so the relationship between the diseases and clinical characteristics need to be further explored.

 Objective:

This study aims to investigate clinical characteristics and independent risk factors for in-hospital adverse events in acute coronary syndrome patients with a history of peripheral arterial disease (PAD).

 Methods:

A total of 5,682 patients with acute coronary syndrome were included into this study. These patients were divided into two groups according to the presence or absence of a history of PAD: PAD group (n = 188), and non-PAD (control) group (n = 5,494). Then, the clinical characteristics and incidence of in-hospital adverse events were analyzed; p < 0.05 was considered statistically significant.

 Results:

The age of PAD patients was higher than that in the control group (65.5 ± 10.3 years vs. 58.6 ± 11 years, p < 0.001), and the proportion of PAD patients with diabetes history and stroke history was higher than that in the control group (73 [39%] vs. 1472 [26.8%], p = 0.018; 36 [19.3%] vs. 396 [7.2%], p < 0.001). The multivariate logistic regression analysis between groups based on in-hospital adverse events revealed that a history of PAD (OR = 1.791, p = 0.01), a history of diabetes (OR = 1.223, p = 0.001), and age of > 65 years old (OR = 4.670, p < 0.001) were independent risk factors for in-hospital adverse events.

 Conclusion:

A history of PAD, advanced age, and a history of diabetes are independent risk factors for in-hospital adverse events in patients with acute coronary syndrome.

 Keywords Acute Coronary Syndrome Atherosclerosis Mortality Peripheral Arterial Disease Hospitalization/complications Diabetes Mellitus Risk Factors Introduction

Atherosclerosis is a systemic vascular disease and one of the main causes of death and disability among Chinese residents. It mainly occurs in the coronary and cerebral arteries and affects the peripheral arteries (upper extremity, lower extremity, mesenteric and carotid arteries).

Peripheral artery disease (PAD) is a general name that refers to vascular diseases, except for cardio-cerebrovascular diseases. The narrow concept of PAD mainly refers to atherosclerotic stenosis or occlusion of the lower extremities, which causes symptoms of chronic or acute ischemia in the lower extremities.1 PAD patients have a high risk of cardiovascular disease. A study2 revealed that the risk of myocardial infarction in patients with PAD increased by 20-60%, and the risk of death caused by coronary artery disease (CAD) increased by 2-6 times. Therefore, similar to CAD), PAD can be a powerful predictor of death induced by myocardial infarction, stroke and other vascular diseases,3 and is closely correlated with the occurrence of death for cardiovascular events.4 Since the proportion of patients with lower extremity arterial disease is high in patients with PAD, in the present study, the lower extremity arterial disease was included into the concept of PAD and was investigated and discussed.

 Methods

Subjects: A total of 5,682 patients with acute coronary syndrome (ACS), who were admitted to the Department of Cardiology, Beijing Anzhen Hospital from April 2002 to August 2016, were included into the present study. Among these patients, 188 patients had a history of PAD. The age of the patients ranged from 36 to 84 years, with a median age of 64 years old; 143 patients were male (76.1%) and 45 patients were female (23.9%). The remaining 5,494 ACS patients without PAD were assigned as the control group. The age of these patients ranged from 25 to 90 years old, with a median age of 59 years old; 3,972 patients were male (72.3%) and 1,522 patients were female (27.7%).

Inclusion and exclusion criteria: Patients diagnosed and treated for ACS, with history of PAD were included into the study. The diagnostic criteria for ACS were based on the 2015 European Society of Cardiology diagnostic criteria.5

Exclusion criteria: patients with previous admissions for myocardial infarction, patients with acute myocardial infarction caused by embolus shedding, intravascular operation, or other diseases; patients who presented with cardiogenic shock, cardiac arrest and gastrointestinal bleeding upon admission; patients with acute infectious disease, malignant tumors and autoimmune diseases; pregnant women.

Diagnostic criteria for related diseases: diabetes mellitus was diagnosed based on the Guidelines for the Prevention and Treatment of Diabetes in China (2013 Edition).6 The criteria for diabetes diagnosis were based on the typical symptoms of diabetes in addition to random blood glucose ≥ 200 mg/dL and/or fasting blood glucose ≥ 126 mg/dL and/or blood glucose level at two hours after glucose load ≥ 200 mg/dL. Hypertension was diagnosed according to the Chinese Guidelines for the Management of Hypertension in China (2015 revised edition).7 The patient was diagnosed with hypertension when systolic blood pressure (SBP) was ≥ 140 mmHg (1 mmHg = 0.133 kPa) or diastolic blood pressure (SBP) was ≥ 90 mmHg. Dyslipidemia was diagnosed according to the Guidelines for Prevention and Treatment of Dyslipidemia in Chinese Adults (2016 revised edition):8 triglyceride (TG) ≥ 150 mg/dL, total cholesterol (TC) ≥ 201 mg/dL, low-density lipoprotein cholesterol (LDL-C) ≥ 131 mg/dL, high-density lipoprotein cholesterol (HDL-C) < 38 mg/dL, and smoking ≥ 10 cigarettes per day for more than one year.

Clinical data acquisition: (1) baseline clinical and demographical data of patients were recorded, including gender, age, body mass index, smoking history, alcohol consumption, family history of CAD, and past history of diabetes, hypertension, and dyslipidemia; (2) clinical indicators were recorded within 24 hours after admission, including heart rate, SBP and DBP. Fasting blood samples were collected in the morning of the next day after admission for the laboratory tests - blood routine test (complete blood count and platelet count) was performed using an automatic blood cell analyzer; blood lipid profile (triglyceride triacylglycerol, TC, LDL-C, and HDL-C) was determined using an automatic biochemical analyzer; brain (B-type) natriuretic peptide concentration was determined by radioimmunoassay, and troponin I was determined by mass spectrometry. The echocardiographic indexes included left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter. The coronary angiography results were recorded after admission. In-hospital adverse events included acute left heart failure, cardiogenic shock, cardiac arrest and death.

Statistical analysis

Statistical analysis was conducted using the statistical software SPSS 22.0. Normally distributed data were expressed as mean ± standard deviation, and non-normally distributed measurement data were expressed as median and interquartile range (P25, P75), and counts expressed as percentage. Data with normal distribution were compared using independent sample t-test, non-normally distributed continuous variables were evaluated using Mann-Whitney U-test, and discrete variables were compared using Chi-square (X2) test. The multivariate logistic regression analysis between groups for in-hospital adverse events was performed. A two-sided test was used in the present study, and a p < 0.05 was considered statistically significant.

 Results

Comparison of baseline data: mean age of PAD patients was 65.5 ± 10.3 years old and mean age of patients in control group was 58.6 ± 11 years old, with a statistically significant difference (p<0.05). The proportion of patients with diabetes mellitus in the PAD group was 39%, while that in the non-PAD group was 26.8%, and the difference was statistically significant. The analysis of clinical data after admission revealed that the levels of creatinine, TC and LDL-C were significantly higher in the PAD group than in the non-PAD (p < 0.05, for all; Table 1).

Baseline data of acute coronary syndrome patients with and without a history of peripheral arterial disease admitted to hospital
Items ACS with a history of PAD (n = 188) ACS without a history of PAD (n = 5,494) p
Age (years) 65.5 ± 10.3 58.6 ± 11.0 < 0.001
Male (%) 143(76.1) 3972(72.3) 0.472
History of hypertension (%) 123(65.9) 3175(57.8) 0.129
History of diabetes mellitus (%) 73(39) 1472(26.8) 0.018
Dyslipidemia (%) 24(12.5) 890(16.2) 0.464
History of smoking (%) 104(55.7) 3044(55.4) 0.987
History of alcohol intake (%) 30(15.9) 1170(21.3) 0.464
History of stroke (%) 36(19.3) 396(7.2) < 0.001
SBP (mmHg) 126.36 ± 20.25 124.47 ± 26.67 0.389
DBP (mmHg) 72.47 ± 12.01 74.02 ± 13.03 0.233
HR (bpm) 76.09 ± 14.03 74.44 ± 19.37 0.280
WBC (109/L) 7.3(5.9,9.7) 7.3(5.9,9.6) 0.801
RBC (1012/L) 4.3(3.9,4.6) 4.5(4.1,4.8) 0.001
PLT (109/L) 205.04 ± 69.76 206.88 ± 66.03 0.795
ALT(U/L) 26.0(17.0,41.0) 26.0(17.0,44.0) 0.510
Creatinine (mg/dL) 0.97(0.75,1.24) 0.87(0.75,1.02) 0.021
AU (mg/dL) 5.91 ± 1.89 5.78 ± 2.13 0.545
Fasting plasma glucose (mg/dL) 106.3(93.7,147.7) 108.1(93.7,136.9) 0.381
TG (mmol/L) 123.9(79.7,159.4) 132.8(88.5,185.9) 0.079
TC (mg/dL) 166.3(139.2,189.5) 154.6(127.6,170.1) 0.002
LDL-C (mg/dL) 100.62(81.3,123.8) 89.0(73.5,108.4) 0.004
HDL-C (mg/dL) 34.8(27.1,46.4) 34.8(30.9,46.4) 0.586
D-dimer (umol/L) 99.0(50.0,196.2) 105.0(50.0,188.0) 0.832

Data expressed as mean ± standard deviation or median (interquartile range). ACS: acute coronary syndrome; PAD: peripheral arterial disease; SBC: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; WBC: white blood count; RBC: red blood count; PLT: platelet count; ALT: alanine aminotransferase; AU: albumin in urine; TG: triglycerides; TC: total cholesterol; LDL-C: low density lipoprotein; HDL-C: high density lipoprotein.

Characteristics of the coronary artery: coronary angiography was performed for all included patients. Multi-vessel disease was defined as the presence of two or more main branches of the coronary artery or its major branches with ≥70% stenosis.8,9 According to these features, the disease was divided into three types: left main coronary artery disease (≥50% stenosis in the left main trunk), total occlusion (100% vascular stenosis), and calcification. The proportion of patients with multi-vessel stenosis was 12.1% in the PAD group, significantly higher than the non-PAD group (p < 0.05). In terms of left main CAD, occlusion, calcification and bifurcation lesions, the proportion of patients with these diseases was higher in patients with ACS combined with stroke, than in patients without stroke; but the difference was not statistically significant (Table 2).

Characteristics of coronary artery lesions in acute coronary syndrome patients with and without a history of peripheral arterial disease [case(%)]
Items ACS with a history of PAD (n = 188) ACS without a history of PAD (n = 5494) p
Left main coronary artery disease 9(4.8) 206(3.7) 0.777
Multivessel stenosis 22(12.1) 478(8.7) 0.015
Bifurcation lesion 27(14.4) 917(16.7) 0.782
Occlusion lesion 18(4.3) 191(3.6) 0.511
History of diabetes Calcified lesions 3(0.7) 15(0.2) 0.656

ACS: acute coronary syndrome; PAD: peripheral arterial disease.

Comparison of in-hospital adverse events: adverse events during in-hospital treatment included death, cardiogenic shock, acute left heart failure and cardiac rupture. In-hospital mortality rate was statistically significantly higher in ACS patients in the PAD group (1.1%), compared with patients in the control group (0.4%) (p < 0.05, Table 3).

The incidence of adverse events in acute coronary syndrome patients with and without a history of peripheral arterial disease [case(%)]
Items ACS merged with PAD history (n = 188) ACS not merged with PAD history (n = 5,494) p
Death 5(2.6) 23(0.4) 0.035
Cardiogenic shock 6(3.1) 203(3.7) 0.435
Acute left heart failure 7(3.7) 174(3.2) 0.355
Cardiac rupture 0(0) 2(0.03) 0.707

ACS: acute coronary syndrome. PAD: peripheral arterial disease.

After the patients were grouped according to the presence of the above events, the variables were selected for multivariate logistic regression analysis. The results revealed that history of PAD (OR = 1.791, p = 0.01), history of diabetes (OR = 1.223, p = 0.001), and age of >65 years old (OR = 4.670, p < 0.001) were independent risk factors for in-hospital adverse events (Table 4).

Multivariate Logistic regression analysis based on in-hospital adverse events
Items SE OR 95%CI p
History of PAD 0.220 1.791 1.05-2.88 0.010
History of hypertension 0.169 1.112 0.79-1.55 0.529
History of diabetes mellitus 0.082 1.223 1.01-1.41 < 0.001
Age > 65 years old 0.181 4.670 3.21-6.44 < 0.001
Multivessel disease 1.015 0.625 0.08-4.57 0.643

PAD: peripheral arterial disease.

Discussion

There is a close correlation between atherosclerotic heart disease and PAD.10 Patients with PAD have more extensive atherosclerosis, and the lesions are often more serious. Therefore, the risk of atherosclerotic events in this group is further increased. In the GRACE trial, approximately 9.7% of 41,108 ACS patients had PAD.11 In the present study, 5,682 ACS patients were included; 188 of them (3.3%) had a history of PAD, and this proportion was lower than the proportion reported in the GRACE trial.

The occurrence and development of atherosclerosis are closely correlated to age. A study revealed that PAD patients were older and had higher risk of cardiovascular disease.12 Furthermore, the present study revealed that patients with ACS complicated with PAD was older than patients in the control group. The multivariate logistic regression analysis of in-hospital adverse events between the groups revealed that an age of ≥65 years old is an independent risk factor for in-hospital adverse events (OR = 4.670, p < 0.001). The older the age, the higher the incidence of the adverse events, which is consistent with existing literature. Therefore, for elderly ACS patients with a history of PAD, more attention should be given to changes in patient condition. In the present study, although the incidence of stroke in ACS patients with a history of PAD was higher (19.3%) than in controls, further analysis revealed that it did not affect in-hospital adverse events.

Dyslipidemia has been considered an important risk factor for atherosclerosis.13 Existing studies have shown that cholesterol is closely related to the occurrence and development of PAD. In the formation and development of atherosclerosis, LDL-C plays an important role. Furthermore, evidence supporting the relationship between LDL-C and PAD has been found.14 The present study also revealed that the level of LDL-C was higher in the PAD group than in the control group. Therefore, lipid-lowering therapy should be strengthened for patients with PAD complicated with ACS. Among the common risk factors for atherosclerosis, diabetes has been well-recognized as an independent risk factor for atherosclerosis. The ARIC study15 revealed that, as compared with patients with a 0-5-year course of diabetes, the risk for PAD in patients with a course of diabetes of ≥ 6 years significantly increased, and the relative risk was 1.24. The present study also revealed that a history of diabetes was an independent risk factor for in-hospital adverse events (OR = 1.223, p < 0.001). Long-term hyperglycemia affects the elasticity and stiffness of the blood vessel walls, which leads to endothelial dysfunction and microcirculatory dysfunction. Therefore, controlling blood sugar is a necessary measure to reduce the incidence of ACS and PAD.16

Analysis of the characteristics of coronary arterial lesions revealed that compared with left main coronary artery disease, bifurcation lesions and calcification, and other serious CADs, ACS patients with PAD are more frequently affected by multivessel disease in coronary arteries. Also, atherosclerosis was characterized by extensive vascular involvement in coronary arteries. Therefore, multivessel lesions tend to indicate extensive wall motion abnormalities, leading to poor prognosis. This study has also confirmed this.

In the present study, analysis of in-hospital adverse events revealed that in-hospital mortality in ACS patients with PAD was 1.1% (p = 0.035), and the difference was statistically significant when compared with the control group. A meta-analysis revealed that after 2.7 years of follow-up for patients with acute myocardial infarction complicated with a PAD history, cardiovascular deaths occurred in 17.8% of patients, and 52.3% of these patients, and only 28% of patients without PAD experienced re-hospitalization caused by nonfatal myocardial infarction, nonfatal stroke and heart failure. Therefore, PAD is an independent risk factor for predicting poor outcomes.17

Thus, it can be concluded that patients with a history of PAD are more likely to experience many adverse events. In the present study, mortality due to adverse events was lower than that reported in the literature. The reasons for these differences may be that the subjects included in the present study were ACS patients, including low-risk patients such as patients with unstable angina. Furthermore, patients were not followed-up, and only in-hospital cardiovascular deaths were counted.

The limitation of the present study was that it had a single-center, retrospective design, and a single-center study may have bias in case selection. Furthermore, our sample (ACS population) included patients with unstable angina, non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction. The difference in severity between these conditions may have led to observation bias.

 Conclusion

Patients with ACS complicated with a history of PAD have extensive coronary disease and high in-hospital mortality. A history of PAD is an independent risk factor for in-hospital adverse events.

Sources of Funding

This study was funded by China Cardiovascular Disease Drug Research Foundation.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

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Implications of the 2013 ACC/AHA cholesterol guidelines on contemporary clinical practice for patients with atherosclerotic coronary and peripheral arterial disease. Indian Heart J. 2017;69(4):464-8. Gunasekaran P Jeevanantham V Sharma S Thapa R Gupta K Implications of the 2013 ACC/AHA cholesterol guidelines on contemporary clinical practice for patients with atherosclerotic coronary and peripheral arterial disease Indian Heart J 2017 69 4 464 468 14 Amrock SM, Abraham CZ, Jung E, Morris PB, Shapiro MD. Risk Factors for Mortality Among Individuals With Peripheral Arterial Disease. Am J Cardiol. 2017;120(5):862-7. Amrock SM Abraham CZ Jung E Morris PB Shapiro MD Risk Factors for Mortality Among Individuals With Peripheral Arterial Disease Am J Cardiol 2017 120 5 862 867 15 Wattanakit K, Folosm AR, Selvin E, Weatherley BD, Pankow JS, Brancati FL, et al. Risk factors for peripheral arterial disease incidence in person with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 2005;180(2):389-97. Wattanakit K Folosm AR Selvin E Weatherley BD Pankow JS Brancati FL Risk factors for peripheral arterial disease incidence in person with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study Atherosclerosis 2005 180 2 389 397 16 Signorelli SS, Katsiki N. Oxidative stress and inflammation: their role in the pathogenesis of peripheral artery disease with or without type 2 diabetes mellitus. Curr Vasc Pharmacol. 2018;16(6):547-54. Signorelli SS Katsiki N Oxidative stress and inflammation: their role in the pathogenesis of peripheral artery disease with or without type 2 diabetes mellitus Curr Vasc Pharmacol 2018 16 6 547 554 17 Inglis SC, Bebchuk J, Al-Suhaim SA, Case J, Pfeffer MA, Solomon SD, et al. Peripheral artery disease and outcomes after myocardial infarction: an individual-patient meta-analysis of 28,771 patients in CAPRICORN, EPEHESUS, OPTIMAAL and VALIANT. Int J Cardiol. 2013;168(2):1094-101. Inglis SC Bebchuk J Al-Suhaim SA Case J Pfeffer MA Solomon SD Peripheral artery disease and outcomes after myocardial infarction: an individual-patient meta-analysis of 28,771 patients in CAPRICORN, EPEHESUS, OPTIMAAL and VALIANT Int J Cardiol 2013 168 2 1094 1101 Artigo Original Características Clínicas e Eventos Adversos em Pacientes com Síndrome Coronariana Aguda e História de Doença Arterial Periférica Kang Yun-Peng Chen Li-Ying Kang Tie-Duo 0000-0002-6910-1278 Liu Wen-Xian Beijing An Zhen Hospital affiliated to Capital Medical University, Beijing - China Correspondência: Wen-Xian Liu, Beijing An Zhen Hospital affiliated to Capital Medical University - No. 2, Anzhen road, Chaoyang district Beijing 100029 - China. E-mail: lwx_lwxas88@163.com

Contribuição dos autores

Concepção e desenho da pesquisa: Yun-Peng K, Li-Ying C, Wen-Xian L; Obtenção de dados e Análise e interpretação dos dados: Yun-Peng K, Li-Ying C, Tie-Duo K; Análise estatística: Tie-Duo K, Wen-Xian L; Redação do manuscrito: Yun-Peng K, Li-Ying C; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Yun-Peng K, Tie-Duo K, Wen-Xian L.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

Na observação clínica, os pacientes com síndrome coronariana aguda com doença arterial periférica têm prognóstico ruim, portanto, a relação entre as doenças e as características clínicas precisa ser mais explorada.

 Objetivos:

Este estudo tem o objetivo de investigar características clínicas e fatores de risco independentes para eventos adversos hospitalares em pacientes com síndrome coronariana aguda e história de doença arterial periférica (DAP).

 Métodos:

Foram incluídos no estudo 5682 pacientes com síndrome coronariana aguda. Os pacientes foram divididos em dois grupos de acordo com a presença ou ausência de DAP prévia: grupo DAP (n = 188) e grupo sem DAP (n = 5494, grupo controle). Em seguida, foram analisadas características clínicas e a incidência de eventos adversos hospitalares nesses grupos; um p < 0,05 foi considerado estatisticamente significativo.

 Resultados:

A idade dos pacientes com DAP foi maior que a idade do grupo controle (65,5 ± 10,3 anos vs. 58,6 ± 11 anos, p < 0,001), e a proporção de pacientes com história de diabetes ou acidente vascular cerebral foi maior no grupo DAP que no grupo controle [73 (39%) vs. 1472 (26,8%), p = 0,018; 36 (19,3%) vs. 396 (7,2%), p < 0,001). A análise de regressão logística multivariada para eventos adversos hospitalares mostrou que história de DAP (OR = 1,791, p = 0,01), história de diabetes (OR = 1,223, p = 0,001), e idade >65 anos de idade (OR = 4,670, p < 0,001) foram fatores de risco independentes para eventos adversos hospitalares.

 Conclusão:

DAP prévia, idade avançada, e história de diabetes são fatores de risco independentes para eventos adversos hospitalares em pacientes com síndrome coronariana aguda.

 Palavras-chave Síndrome Coronariana Aguda Aterosclerose Mortalidade Doença Arterial Periférica Hospitalização/complicações Diabetes Mellitus Fatores de Risco Introdução

A aterosclerose é uma doença vascular sistêmica e uma das principais causas de morte e invalidez na população chinesa. Ocorre principalmente nas artérias coronárias e cerebrais, e afeta também as artérias periféricas (artérias das extremidades superiores e inferiores, artéria mesentérica e artéria carótida).

A doença arterial periférica (DAP) é um nome genérico que se refere a doenças vasculares, com exceção das doenças cerebrovasculares. O conceito restrito de DAP refere-se à estenose aterosclerótica ou oclusão das extremidades inferiores, que causa sintomas de isquemia crônica ou aguda nas extremidades inferiores.1 Os pacientes com DAP têm alto risco de desenvolverem doença cardiovascular. Um estudo2 mostrou que o risco de infarto de miocárdio aumentou em 20-60%, e o risco de morte causada por DAC aumentou em 2-6 vezes em pacientes com DAP. Assim, semelhante à DAC, a DAP pode atuar como um forte preditor de morte induzida por infarto do miocárdio, acidente vascular cerebral e outras doenças vasculares,3 e está intimamente correlacionada com a ocorrência de morte por eventos cardiovasculares.4 Uma vez que a proporção de pacientes com doença arterial nas extremidades inferiores é mais alta em pacientes com DAP, no presente estudo, a doença arterial de extremidades inferiores foi incluída no conceito de DAP, investigada e discutida.

 Métodos

Participantes: foram incluídos no estudo 5.682 pacientes com síndrome coronariana aguda (SCA) admitidos no Departamento de Cardiologia do Hospital Anzhen de Beijing no período entre abril de 2002 e agosto de 2016. Entre esses pacientes, 188 tinham história de DAP. A idade dos pacientes variou entre 36 e 84 anos, com mediana de 64 anos; 143 (76,1%) eram homens e 45 (23,9%) mulheres. Os demais 5.494 pacientes com SCA sem DAP constituíram o grupo controle. A idade desses pacientes variou de 25 a 90 anos, com mediana de 59 anos; 3.972 (72,3%) pacientes eram do sexo masculino e 1.522 (27,7%) do sexo feminino.

Critérios de inclusão e de exclusão: Pacientes com diagnóstico e tratamento para SCA, com história de DAP foram incluídos no estudo. Os critérios diagnósticos para SCA foram baseados nos critérios da Sociedade Europeia de Cardiologia de 2015.5

Critérios de exclusão: foram excluídos pacientes com internações prévias por infarto do miocárdio, infarto agudo do miocárdio causado por desprendimento de trombos, cirurgia intravascular, ou outras doenças; pacientes com choque cardiogênico, parada cardíaca e sangramento gastrointestinal na admissão; pacientes com doença infecciosa aguda, tumores malignos ou doenças autoimunes, e gestantes.

Critérios diagnósticos para doenças relacionadas: o diagnóstico de diabetes mellitus foi estabelecido com base nas diretrizes para a prevenção e tratamento de diabetes na China de 2013.6 Os critérios para diagnóstico de diabetes basearam-se na presença de sintomas típicos de diabetes além de glicemia aleatória ≥ 200mg/dL e/ou glicemia de jejum ≥ 126 mg/dL e/ou glicemia duas horas após ingestão de solução de glicose ≥ 200mg/dL. O diagnóstico de hipertensão foi estabelecido com base nas diretrizes para o manejo da hipertensão na China (edição revisada de 2015).7 O paciente foi diagnosticado com hipertensão se apresentasse pressão sistólica ≥140 mmHg (1 mmHg = 0,133 kPa) ou pressão diastólica ≥90 mmHg. O diagnóstico de dislipidemia foi feito com base nas diretrizes para a prevenção e tratamento de dislipidemia em adultos na China (edição revisada de 2016):8 triglicerídeos (TG) ≥ 150 mg/dL, colesterol total (CT) ≥ 201 mg/dL, lipoproteína de baixa densidade (LDL-C) ≥ 131 mg/dL, lipoproteína de alta densidade (HDL) < 38 mg/dL, e tabagismo ≥10 cigarros por dia por um ano ou mais.

Coleta dos dados clínicos: (1) foram coletados dados clínicos e demográficos basais dos pacientes, incluindo sexo, idade, índice de massa corporal, história de tabagismo, consumo de álcool, história familiar de DAC, e ocorrência de diabetes, hipertensão ou dislipidemia previamente; (2) foram registrados indicadores clínicos no período de 24 horas após internação, incluindo frequência cardíaca, pressão sistólica e diastólica. Amostras de sangue foram coletadas dos pacientes em jejum na manhã seguinte do dia da internação para as análises laboratoriais. Hemograma completo e contagem de plaquetas foram realizados usando um analisador automático e contagem de leucócitos; perfil lipídico (triglicerídeos, CT, LDL-C e HDL-C) foi determinado por um analisador bioquímico automático; a concentração de peptídeo natriurético tipo B foi determinada por radioimunoensaio, e os de troponina I foi determinada por espectrometria de massa. Os índices ecocardiográficos incluíram fração de ejeção do ventrículo esquerdo (FEVE) e diâmetro diastólico final do ventrículo esquerdo. Os resultados da angiografia coronária foram registrados após admissão. Eventos adversos na internação incluíram insuficiência cardíaca esquerda, choque cardiogênico, parada cardíaca e morte.

Análise estatística

A análise estatística foi realizada pelo programa SPSS versão 22.0. Os dados com distribuição normal foram expressos em média ± desvio padrão, os dados com distribuição não normal expressos em mediana e intervalo interquartil (P25, P75), e contagens expressas em porcentagens. Os dados com distribuição normal foram comparados usando o teste t para amostras independentes, e variáveis contínuas sem distribuição normal avaliadas pelo teste de Mann-Whitney. As variáveis discretas foram comparadas pelo teste do qui-quadrado (X2). Foi realizada uma análise de regressão logística multivariada entre os grupos quanto aos eventos adversos durante internação. Usou-se teste bicaudal, e um valor de p < 0,05 foi considerado estatisticamente significativo.

 Resultados

Comparação dos dados basais: a idade média dos pacientes com DAP foi 65,5 ± 10,3 anos, e a idade média do grupo controle foi 58 ± 11 anos, com diferença estatisticamente significativa (p < 0,05). A proporção de pacientes com diabetes mellitus no grupo com DAP foi 39%, enquanto no grupo sem DAP foi 26,8%, e a diferença foi estatisticamente significativa. A análise dos dados clínicos após readmissão revelou que os níveis de creatinina, CT e LDL-C foram significativamente maiores no grupo com DAP que no grupo sem DAP (p < 0,05 para todos; Tabela 1).

Dados basais de pacientes com síndrome coronariana aguda com e sem história de doença arterial periférica admitidos no hospital
Características SCA com história de DAP (n = 188) SCA sem história de DAP (n = 5494) p
Idade (anos) 65,5 ± 10,3 58,6 ± 11,0 < 0,001
Homens (%) 143(76,1) 3972(72,3) 0,472
História de hipertensão (%) 123(65,9) 3175(57,8) 0,129
História de diabetes mellitus (%) 73(39) 1472(26,8) 0,018
Dislipidemia (%) 24(12,5) 890(16,2) 0,464
História de tabagismo (%) 104(55,7) 3044(55,4) 0,987
História de etilismo (%) 30(15,9) 1170(21,3) 0,464
História de AVC (%) 36(19,3) 396(7,2) < 0,001
Pressão sistólica (mmHg) 126,36 ± 20,25 124,47 ± 26,67 0,389
Pressão diastólica (mmHg) 72,47 ± 12,01 74,02 ± 13,03 0,233
FC (times/min) 76,09 ± 14,03 74,44 ± 19,37 0,280
Leucócitos (109/L) 7,3(5,9,9,7) 7,3(5,9,9,6) 0,801
Hemácias (1012/L) 4,3(3,9,4,6) 4,5(4,1,4,8) 0,001
Plaquetas (109/L) 205,04 ± 69,76 206,88 ± 66,03 0,795
ALT (U/L) 26,0(17,0,41,0) 26,0(17,0,44,0) 0,510
Creatinina (mg/dL) 0,97(0,75,1,24) 0,87(0,75,1,02) 0,021
AU (mg/dL) 5,91 ± 1,89 5,78 ± 2,13 0,545
Glicemia jejum (mg/dL) 106,3(93,7,147,7) 108,1(93,7,136,9) 0,381
TG (mmol/L) 123,9(79,7,159,4) 132,8(88,5,185,9) 0,079
CT (mg/dL) 166,3(139,2,189,5) 154,6(127,6,170,1) 0,002
LDL-C (mg/dL) 100,62(81,3,123,8) 89,0(73,5,108,4) 0,004
HDL-C (mg/dL) 34,8(27,1,46,4) 34,8(30,9,46,4) 0,586
Dímero D (umol/L) 99,0(50,0,196,2) 105,0(50,0,188,0) 0,832

SCA: síndrome coronariana aguda; DAP: doença arterial periférica; AVC: acidente vascular cerebral; ALT: alanina aminotransferase; AU: albumina na urina; TG: triglicerídeos; CT: colesterol total; LDL-C: lipoproteína de baixa densidade; HDL-C: lipoproteína de alta densidade.

Características da artéria coronária: angiografia coronária foi realizada em todos os pacientes incluídos. A doença de múltiplos vasos foi definida como a presença de dois ou mais ramos da artéria coronária ou seus principais ramos com estenose ≥ 70%.8,9 De acordo com essas características, a doença foi dividida em três tipos: doença da artéria coronária principal esquerda (≥ 50% estenose no tronco principal esquerdo), oclusão total (100% de estenose vascular), e calcificação. A proporção de pacientes com estenose em múltiplos vasos foi de 12,1% no grupo com DAP, significativamente maior que no grupo sem DAP (p < 0,05). Em relação à DAC, oclusão, calcificação e lesões de bifurcação, a proporção de pacientes com essas doenças foi maior nos pacientes com SCA combinada com infarto que em pacientes sem infarto, mas a diferença não foi estatisticamente significativa (Tabela 2).

Características das lesões na artéria coronária em pacientes com síndrome coronariana aguda com e sem história de doença arterial periférica [caso (%)]
Características SCA com história de DAP (n = 188) SCA sem história de DAP (n = 5.494) p
Doença da artéria coronária esquerda 9(4,8) 206(3,7) 0,777
Estenose de múltiplos vasos 22(12,1) 478(8,7) 0,015
Lesão de bifurcação 27(14,4) 917(16,7) 0,782
Lesão obstrutiva 18(4,3) 191(3,6) 0,511
História de diabetes Lesões calcificadas 3(0,7) 15(0,2) 0,656

SCA: síndrome coronariana aguda; DAP: doença arterial periférica.

Comparação de eventos adversos na internação: os eventos adversos durante o tratamento hospitalar incluíram morte, choque cardiogênico, insuficiência cardíaca esquerda aguda, e ruptura cardíaca. A taxa de mortalidade hospitalar foi estatisticamente mais alta nos pacientes com SCA no grupo com DAP (1,1%) em comparação a pacientes do grupo controle (0,4%) (p < 0,05, Tabela 3).

Incidência de eventos adversos em pacientes com síndrome coronariana aguda com e sem história de doença arterial periférica [caso (%)]
Eventos SCA com história de DAP (n = 188) SCA sem história de DAP (n = 5494) p
Morte 5(2,6) 23(0,4) 0,035
Choque cardiogênico 6(3,1) 203(3,7) 0,435
Insuficiência cardíaca esquerda aguda 7(3,7) 174(3,2) 0,355
Ruptura cardíaca 0(0) 2(0,03) 0,707

SCA: síndrome coronariana aguda; DAP: doença arterial periférica.

Após os pacientes serem agrupados quanto à presença desses eventos, as variáveis foram selecionadas para a análise de regressão logística múltipla. Os resultados mostraram que história de DAP (OR = 1,791, p = 0,01), história de diabetes (OR = 1,223, p = 0,001), e idade maior que 65 anos de idade (OR = 4,670, p < 0,001) foram fatores de risco independentes para eventos adversos hospitalares (Tabela 4).

Análise de regressão logística multivariada de eventos adversos hospitalares
Itens Erro padrão OR IC95% p
História de DAP 0,220 1,791 1,05-2,88 0,010
História de hipertensão 0,169 1,112 0,79-1,55 0,529
História de diabetes mellitus 0,082 1,223 1,01-1,41 < 0,001
Idade > 65 anos 0,181 4,670 3,21-6,44 < 0,001
Doença de múltiplos vasos 1,015 0,625 0,08-4,57 0,643

DAP: doença arterial periférica.

Discussão

Há uma forte correlação entre doença cardíaca aterosclerótica e DAP.10 Os pacientes com DAP apresentam doença aterosclerótica extensa, e com lesões geralmente mais graves. Assim, o risco de eventos ateroscleróticos nesse grupo é ainda maior. No estudo GRACE, aproximadamente 9,7% dos 41108 pacientes com SCA tiveram DAP.11 No presente estudo, foram incluídos 5682 pacientes com SCA e, desses, 188 (3,3%) tinham história de DAP; essa proporção foi inferior à apresentada no estudo GRACE.

A ocorrência e o desenvolvimento de aterosclerose estão fortemente correlacionados com a idade. Um estudo mostrou que pacientes com DAP têm idade mais avança e têm maior risco de doença cardiovascular.12 Além disso, o presente estudo mostrou que pacientes com SCA e com DAP como complicação eram mais velhos que os pacientes do grupo controle. A análise de regressão logística multivariada dos eventos adversos hospitalares entre os grupos mostrou que uma idade igual ou superior a 65 anos é um fator de risco independente para tais eventos (OR = 4,670, p < 0,001). Quanto maior a idade, maior a incidência de eventos adversos, o que é consistente com os dados existentes na literatura. Portanto, mudanças no estado de saúde de pacientes com SCA idosos e história de DAP merecem atenção. No presente estudo, a incidência de acidente vascular cerebral em pacientes com SCA e história de DAP foi mais alta (19,3%) que nos controles, mas tal dado não afetou os eventos adversos hospitalares.

A dislipidemia é considerada um importante fator de risco para aterosclerose.13 Estudos mostram que o colesterol está intimamente relacionado com a ocorrência e o desenvolvimento de DAP. O LDL-C exerce importante papel na formação e no desenvolvimento de aterosclerose. Ainda, existem evidências que corroboram a relação entre LDL-C e DAP.14 Nosso estudo revelou que o nível de LDL-C foi mais alto nos pacientes com DAP que no grupo controle. Portanto, deve-se enfatizar a terapia hipolipemiante para pacientes com SCA e DAP. Entre os fatores de risco comuns para aterosclerose, o diabetes tem sido bem reconhecido como um fator de risco independente para aterosclerose. O estudo ARIC15 mostrou que, em comparação a pacientes com diabetes há 0-5 anos, o risco de DAP em pacientes com diabetes há pelo menos 6 anos aumentou significativamente, e o risco relativo foi de 1,24. O presente estudo também mostrou que uma história de diabetes foi um fator de risco independente para eventos adversos hospitalares (OR = 1,223, p< 0,001). Em longo prazo, a hiperglicemia afeta a elasticidade e a rigidez das paredes dos vasos sanguíneos, o que leva à disfunção endotelial e à disfunção microcirculatória. Portanto, o controle da glicemia é uma medida necessária para reduzir a incidência de SCA e DAP.16

A análise das características das lesões arteriais coronárias revelou que, em comparação à doença da artéria coronária esquerda, lesões da bifurcação e calcificação, e outras DACs graves, os pacientes com DAP apresentam doença de múltiplos vasos nas artérias coronárias com mais frequência. Ainda, a aterosclerose afetou extensas áreas das artérias coronárias. Portanto, lesões de múltiplos vasos tendem a indicar alterações extensas de mobilidade da parede, levando a um pior prognóstico, fato que também foi confirmado pelo presente estudo.

Em nosso estudo, a análise dos eventos adversos durante internação revelou que a mortalidade hospitalar em pacientes com SCA e DAP foi 1,1% (p = 0,035), com diferença estatisticamente significativa em comparação ao grupo controle. Uma metanálise revelou que, após 2,7 anos de seguimento de pacientes com infarto agudo do miocárdio complicado e história de DAP, as mortes cardiovasculares ocorreram em 17,8% dos pacientes, 52,3% dos pacientes e somente 28% dos pacientes sem DAP relataram reinternação por infarto do miocárdio não fatal, acidente vascular cerebral não fatal e insuficiência cardíaca. Assim, a DAP é um fator de risco independente para predizer piores desfechos.17

Pode-se concluir, portanto, que pacientes com história de DAP estão mais propensos a eventos adversos. No presente estudo, a mortalidade por eventos adversos foi mais baixa que a relatada na literatura. Tais diferenças podem ser atribuídas ao fato de que os indivíduos incluídos no presente estudo eram pacientes com SCA, incluindo pacientes de baixo risco como pacientes com angina instável. Ainda, não houve acompanhamento dos pacientes, e somente mortes cardiovasculares ocorridas durante a internação foram contabilizadas.

A limitação do estudo foi seu delineamento unicêntrico e retrospectivo; estudos realizados em um único centro podem apresentar viés na seleção dos casos. Além disso, nossa amostra (população de pacientes com SCA) incluiu pacientes com angina instável, infarto do miocárdio sem elevação do segmento ST, e infarto do miocárdio com elevação do segmento ST. A diferença na gravidade entre essas doenças pode ter causado um viés de observação.

 Conclusão

Pacientes com SCA e história de DAP apresentam doença coronariana extensa e alta taxa de mortalidade hospitalar. História de DAP é fator de risco independente para eventos adversos hospitalares.

Fontes de financiamento

O presente estudo foi financiado pelo China Cardiovascular Disease Drug Research Foundation.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.