Clinical significance of diabetes on symptom and patient delay among patients with acute myocardial infarction—an analysis from China Acute Myocardial Infarction (CAMI) registry

Rui FU, Si-Dong LI, Chen-Xi SONG, Jing-Ang YANG, Hai-Yan XU, Xiao-Jin GAO, Yi XU, Jian-Ping ZENG, Jun-Nong LI, Ke-Fei DOU,#, Yue-Jin YANG,#, on behalf of the CAMI Registry study group Beijing, China

?

Clinical significance of diabetes on symptom and patient delay among patients with acute myocardial infarction—an analysis from China Acute Myocardial Infarction (CAMI) registry

Rui FU1,*, Si-Dong LI1,*, Chen-Xi SONG1, Jing-Ang YANG1, Hai-Yan XU1, Xiao-Jin GAO1, Yi XU1, Jian-Ping ZENG2, Jun-Nong LI3, Ke-Fei DOU1,#, Yue-Jin YANG1,#, on behalf of the CAMI Registry study group Beijing, China

1Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China2XiangTan Center Hospital, Xiangtan, Hunan, China3Department of Cardiology, Weinan Central Hospital,Weinan, Shanxi, China

Diabetes is frequently associated with poor prognosis among acute myocardial infarction (AMI) patients. Patients with these comorbidities often have atypical symptoms and subsequent delay in treatment. Few studies have reported detailed AMI symptoms in patients with diabetes. This study compared AMI symptoms and presentation characteristics between diabetics and non-diabetics.We included patients from the China AMI registry diagnosed with AMI between January 2013 and September 2014. Baseline characteristics, symptomology, and delay in treatment were compared between diabetics and non-diabetics. Multivariable logistic regression analysis was used to explore independent predictors of atypical symptoms.A total of 4450 (20.2%) patients had diabetes. They were older, more often women, higher in body mass index, and more likely to have non-ST segment elevation myocardial infarction. Fewer diabetic patients presented with persistent precordial chest pain (63.1%. 68%,< 0.0001), diaphoresis (60.1%. 65.6%,< 0.0001), fatigue (16.7%. 18.3%,= 0.0123), and incontinence (0.4%. 0.7%,= 0.0093). Time to hospital presentation was longer among patients with diabetes than those without. In multivariable analysis, diabetes was identified as an independent predictor of atypical symptoms (OR: 1.112, 95% CI: 1.034-1.196).Our study is the first large-scale study providing evidence that diabetics are less likely to present with typical chest pain and more likely to experience treatment delay when suffering from an AMI. Our results may increase clinician awareness of recognizing AMI patients rapidly to reduce diagnosis and treatment delay, particularly in the context of diabetes.

2019; 16: 395?400. doi:10.11909/j.issn.1671-5411.2019.05.002

Acute myocardial infarction; Diabetes; Symptoms; Patient delay

1 Introduction

Diabetes has become an increasing burden all over the world. In 2014, the global prevalence of diabetes among adults was 8.5% with 422 million suffering from the disease.[1]Diabetes is associated with poor prognosis among patients with acute myocardial infarction (AMI).[2]Patients with diabetes are more likely to present with atypical symptoms[3]and are slower to receive treatment[4]when they have an AMI.

It is important for patients with diabetes to recognize possible symptoms of AMI and minimize their delay in seeking care. There are few large-scale studies of sympto-mology in patients with AMI complicated by diabetes. In the studies that have been performed, patients were simply classified into “chest pain” and “no chest pain” groups with-out detailed description of symptoms. These studies enrolled patients from Europe, the United States,[5,6]Japan[7]and Korea,[8]but there is limited data regarding the impact of diabetes on symptoms of AMI among Chinese patients.

The aim of this study was to describe symptoms and admission characteristics of AMI patients complicated by diabetes.

2 Methods

2.1 Study population

Details of the China Acute Myocardial Infarction (CAMI) Registry have been previously described.[9]Briefly, the CAMI registry included 108 participating hospitals in 27 provinces and 4 municipalities in Mainland China, assuring a comprehensive representation of hospitals in China. From January 2013 to September 2014, a total of 26,082 patients were included in the CAMI registry. Patients diagnosed with AMI as defined by the third universal definition of myocardial infarction[10]were eligible. According to this definition, AMI is diagnosed by clinical evidence of myocardial necrosis consistent with myocardial ischemia, detection of a rise and/or fall of cardiac biomarkers with at least one value above the 99thpercentile upper reference limit (URL), and at least one of the following symptoms of ischemia: new or presumed-new significant ST-segment or T-wave (ST-T) changes or left bundle branch block (LBBB), development of pathological Q waves on ECG, imaging evidence of new loss of viable myocardium or new regional wall abnormality, or identification of intracoronary thrombus by angiography or autopsy.

Subjects with missing or invalid data for admission dia-gnosis, age, body mass index (BMI), and symptomology were excluded from the analysis. In the end, a total of 21,994 patients were included. They were divided into a diabetes group and a non-diabetes group according to the presence of diabetes (Figure 1).

This study was registered on www.clinicaltrials.gov (NCT01874691). Written informed consent was obtained from eligible patients before registration.

Figure 1. Study flow chart. From January 2013 to September 2014, a total number of 26,082 AMI patients were registered in CAMI registry. We excluded 4088 patients due to missing or invalid data on age, BMI, on admission diagnosis and symptomology and finally included 21,994 patients. Among these patients, 4450 patients had diabetes and 17544 patients were non-diabetes. CAMI: China acute myocardial infarction.

2.2 Data collection and definition

The CAMI registry adopted multiple measures to assure data quality. The investigators at each participating site re-ceived detailed training on the protocol and standardized data collection. The data entry system also had a real-time automatic logic and range algorithm to ensure the com-ple-teness, validity, and accuracy of the data quality. In addition, the data management team performed data checks regularly and sent queries for participating hospitals to review and revise the missing or invalid data. We extracted data on patient demographics, medical history, clinical presentation, time to hospital, and admission diagnosis. Symptom as-sessment included persistent chest pain (≥ 20 min), diapho-resis, nausea, vomiting, syncope, fatigue, and incontinence. Silent MI was defined as a heart attack with few symptoms. Atypical MI was defined as presentation without typical chest pain. The key point that differentiates atypical from typical AMI is typical precordial chest pain symptoms con-sistent with myocardial necrosis. The diabetes group in-cluded patients who used oral medication or insulin or those with known medical history of diabetes prior to hospital presentation, but did not include those with new-onset dia-betes during hospitalization.

2.3 Statistical analysis

Continuous variables were presented as mean ± SD or median (25thand 75thpercentiles) and compared using Stu-dent t tests or rank tests, as appropriate. Categorical vari-ables were described using frequencies and compared using chi-square tests. A multivariable logistic regression model was introduced to explore independent predictors of atypical symptoms. The following factors were initially fitted in the model: age; sex; heart rate; blood pressure; BMI; prior history of primary percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, angina, stroke, diabetes, hypertension, hyperlipidemia, or heart failure (HF); type of MI; anterior wall MI; Killip classification; prodro--mal symptoms; smoking status; and family history of coro-nary artery disease (CAD). After stepwise selection, those variables with< 0.05 were retained in the model. All analyses were performed using SAS 9.4 software (SAS In-stitute, Cary, North Carolina).

3 Results

3.1 Baseline characteristics

Among the 21,994 patients eligible for our analysis, 4,450 (20.2%) patients had diabetes. Table 1 compares baseline characteristics between patients with and without diabetes. Patient age ranged from 16 to 100 years, with a mean age of 62.9 ± 12.5 years. Compared with those without diabetes, patients with diabetes were older (mean age 64.4. 62.6 years), more often women (33.2%. 23.8%), had higher BMI (24.6. 24.0 kg/m2), and were more likely to present with non-ST segment elevation myocardial infarction (NSTEMI) (31.6%. 24.4%). Patients in the diabetes group also had higher prevalence of prior MI, heart failure, and CABG. Regarding traditional CAD risk factors, patients with diabetes were more likely to have hypertension and hyperlipidemia, but less likely to be a smoker (all< 0.0001).

Table 1. Baseline characteristics of patients with vs. without diabetes.

Values are presented as mean ± SD and(%) unless otherwise indicated. BMI: body mass index; CABG: coronary artery bypass graft; CAD: coronary artery disease; MI: myocardial infarction; NSTEMI: non- ST-segment elevation myocardial infarction; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction.

3.2 Clinical presentation

Symptoms for all patients are shown in Table 2. A total of 71 (1.6%) patients in the diabetes group and 237 (1.3%) patients in the non-diabetes group experienced no symptoms (= 0.2223).

The most common symptoms in both groups were persistent precordial chest pain, diaphoresis, chest distress, and radiation pain. Patients in the diabetes group were less likely to present with persistent precordial chest pain (63.1%. 68%,< 0.0001), diaphoresis (60.1%. 65.6%,< 0.0001), fatigue (16.7%. 18.3%,= 0.0123), and incontinence (0.4%. 0.7%,= 0.0093). Prevalence of other symptoms was similar between the two groups.

Table 2. Symptom presentation of patients with vs. without diabetes.

Values are presented as mean ± SD and(%) unless otherwise indicated.

3.3 Time to hospital presentation

Table 3 shows time to hospital presentation for patients in both the diabetes and the non-diabetes groups. Patients with diabetes were more likely to have a delay in presenting to a hospital than patients without diabetes. Compared with the non-diabetes group, patients with diabetes were less likely to present to a hospital in the timeframes: (1) less than 3 h, (2) 3–6 h, or (3) 6–12 h after symptom presentation. However, they were more likely to present to the hospital more than 12 h after symptom onset than patients without diabetes (= 0.0003).

Table 3. Time to hospital of patients with. without diabetes.

Time to hospitalDiabetes group(n = 4450)Non-diabetes group(n = 17544)P value < 3 h898 (20.2%)3758 (21.4%)0.0003 3-6 h1013 (22.8%)4210 (24.0%) 6-12 h650 (14.6%)2767 (15.8%) 12-24 h512 (11.5%)1951 (11.1%) 1-7 days1377 (30.9%)4858 (27.7%)

3.4 Independent predictors of atypical symptoms

Independent predictors of symptoms without chest pain are shown in Table 4. After adjusting for confounders including age, sex, diabetes, type of MI, anterior wall MI, Killip classification, heart rate, blood pressure, predromal symptoms, BMI, hypertension, smoking status, PCI, prior CABG, renal failure, prior angina, hyperlipidemia, family history of CAD, prior stroke, and prior HF, diabetes remained an independent predictor of atypical symptoms (those without chest pain) (odds ratio [OR]: 1.112, 95% confidence interval (CI): 1.034–1.196).

Table 4. Independent predictors of atypical symptoms.

Adjusted for age, sex, diabetes, type of MI, anterior wall MI, Killip classification, heart rate, blood pressure, prodromal symptoms, BMI, hypertension, smoking status, PCI, prior CABG, renal failure, prior angina, hyperlipidemia, family history of CAD, prior stroke, prior HF. BMI: body mass index; CABG: coronary artery bypass graft; CAD: coronary artery disease; MI: myocardial infarction; NSTEMI: non-ST segment elevation myocardial infarction; STEMI: ST segment elevation myocardial infarction; PCI: percutaneous coronary intervention.

4 Discussion

In this analysis of a nationwide prospective multicenter registry, we found that AMI patients with diabetes were less likely to present with persistent precordial chest pain, diaphoresis, fatigue, and incontinence when compared with those without diabetes. Patients in the diabetes group also had longer times to hospital presentation compared with those in the non-diabetes group. Multivariable analysis showed diabetes to be an independent predictor of atypical symptoms.

In this study, 4,450 out of 21,994 patients had diabetes. The prevalence of diabetes among AMI patients was 20.5%, which was lower than previously reported: 30% in the OASIS study,[11]27% for NSTEMI patients and 21% for STEMI patients in the GRACE study,[5]and 29% in the NRMI study.[12]This finding may be explained the low awareness rate of diabetes in China, which was reported to be 30.1% in previous studies.[13]

The AMI patients in our study with diabetes were older, more often women, had higher BMI, and had more comorbidities. We also found that AMI patients with diabetes were more likely to present without typical symptoms, including persistent chest pain, diaphoresis, and radiation pain. History of diabetes was found to be an independent predictor of atypical presentation. These findings were in accordance with previously published studies.[5-7,14-17]However, our study further described and compared the specific components of typical symptoms (i.e., chest pain, chest distress, diaphoresis, and radiation pain) in patients with and without diabetes, demonstrating that diabetics were less likely to present with chest pain, diaphoresis, and radiation pain.

Mechanisms underlying atypical symptoms among diabetes have previously been proposed. The type and severity of AMI symptoms were dependent on activation of afferent neurons. Nerve impulses were then transmitted to autonomic nervous system and induce symptoms. Patients with diabetes had high prevalence of neuropathy, which led to atypical symptoms.[18]Multi-vessel disease and complex le-sions were more common among diabetes, leading to more frequent angina pectoris and preconditioning.[19]In addition, patients with diabetes often have symptoms associated with hypoglycemia or comorbidities. Therefore, when patients with diabetes suffer a heart attack, it is hard for them to rapidly recognize whether these symptoms are cardiac in origin.

Other studies have shown contradictory results that fre-quency or intensity of chest pain or other symptoms did not differ between two groups.[20,21]However, these studies were conducted over a decade ago with a much smaller sample size (fewer than 2000), thereby limiting their power. It is reasonable to believe that patients with diabetes have different symptoms from non-diabetics.

Another major finding of our study is that among AMI patients, those with diabetes had a longer time to hospital presentation than those without diabetes. Similar results were also shown in other studies. Sheiferet analyzed 102,399 patients with AMI and discovered that diabetes was an in-dependent predictor of delayed treatment (OR: 1.11, 95% CI: 1.07-1.14).[4]Another large-scale study with sample size of 482,377 also showed that delayed time to treatment ranged from 45-63 minutes.[22]Diabetes has also been iden-tified as a predictor of longer door-to-balloon time.[23]There-fore, clinicians should put more efforts into educating the public about MI symptoms, particularly in diabetic pa-tients. This may help patients recognize early symptoms of AMI more rapidly, reduce delay in seeking treatment, and im-prove patients’ prognosis.

4.1 Limitations

Differences in the prevalences of AMI and diabetes may be potential bias for the association and should be investigated in future studies. AMI symptoms may be different between type 1 and type 2 diabetic patients. However, the CAMI registry did not collect data regarding type of diabetes. All patients were divided by history of diabetes before presentation to a hospital. Some patients with newly diagnosed diabetes after AMI onset were classified into the non-diabetes group. Our study was an observational study that did not include follow-up data. Future studies should be conducted to explore the prognostic value of diabetes on short or long-term mortality among AMI patients.

4.2 Conclusions:

Our study is the first large-scale study to provide evidence that AMI patients with diabetes were more likely to have atypical symptoms and take a longer time to present to a hospital. The results of our study are of mechanistic insight and may make clinicians more aware of recognizing AMI patients rapidly and reducing delay in diagnosis and treatment, particularly in the context of diabetes. Our data provide solid scientific support to initiate large-scale follow-up studies on the prognostic contribution of diabetes to cardiovascular disease risk in AMI patients.

Acknowledgements

This project was approved by the institutional review board central committee at Fuwai Hospital, National Center for Cardiovascular Diseases, China. Written informed consent was obtained from eligible patients before registration. The data used in our study was from CAMI registry dataset and is not publicly available but is available from corresponding author on reasonable request. The authors declare that they have no competing interests. This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009), the Twelfth Five-Year Plan-ning Project of the Scientific and Technological Department of China (2011BAI11B02), and 2014 Special fund for scientific research in the public interest by National Health and Family Planning Commission of the People’s Republic of China (No. 201402001). We are very grateful to the TIMI Study Group and the Duke Clinical Research Institute for their contributions in the design, conduct, and data analyses of CAMI registry. We also want to thank all the investigators and coordinators for their great work and active participation. We thank Sara Connell, OD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

1 Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030.2006; 3: e442.

2 Eliasson M, Jansson JH, Lundblad D, Naslund U. The disparity between long-term survival in patients with and without diabetes following a first myocardial infarction did not change between 1989 and 2006: an analysis of 6,776 patients in the Northern Sweden MONICA Study.2011; 54: 2538–2543.

3 El-Menyar A, Zubaid M, Sulaiman K,. Atypical presen-tation of acute coronary syndrome: a significant independent predictor of in-hospital mortality.2011; 57: 165– 171.

4 Sheifer SE, Rathore SS, Gersh BJ,. Time to presentation with acute myocardial infarction in the elderly: associations with race, sex, and socioeconomic characteristics.2000; 102: 1651–1656.

5 Franklin K, Goldberg RJ, Spencer F,. Implications of diabetes in patients with acute coronary syndromes. The Global Registry of Acute Coronary Events.2004; 164: 1457–1463.

6 Canto AJ, Kiefe CI, Goldberg RJ,. Differences in symptom presentation and hospital mortality according to type of acute myocardial infarction.2012; 163: 572– 579.

7 Fujino M, Ishihara M, Ogawa H,. Impact of symptom presentation on in-hospital outcomes in patients with acute myocardial infarction.2017; 70: 29–34.

8 Cho JY, Jeong MH, Ahn YK,. Comparison of outcomes of patients with painless versus painful ST-segment elevation myocardial infarction undergoing percutaneous coronary inter-vention.2012; 109: 337–343.

9 Xu H, Li W, Yang J,. The China Acute Myocardial Infarction (CAMI) Registry: A national long-term registry-re--search-education integrated platform for exploring acute myo-cardial infarction in China.2016; 175: 193– 201.e3.

10 Thygesen K, Alpert JS, Jaffe AS,. Third universal defi-nition of myocardial infarction.2012; 60: 1581–1598.

11 Malmberg K, Yusuf S, Gerstein HC,. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Orga-nization to Assess Strategies for Ischemic Syndromes) Re-gistry.2000; 102: 1014–1019.

12 Gore MO, Patel MJ, Kosiborod M,. Diabetes mellitus and trends in hospital survival after myocardial infarction, 1994 to 2006: data from the national registry of myocardial infarction.2012; 5: 791–797.

13 Xu Y, Wang L, He J,. Prevalence and control of diabetes in Chinese adults.2013; 310: 948–959.

14 Pek PP, Loy EY, Wah W,. Reperfusion treatment delays amongst patients with painless ST segment elevation myo-cardial infarction.2017; 19: 355–363.

15 ?uli? V, Eterovi? D, Miri? D, Sili? N. Symptom presentation of acute myocardial infarction: influence of sex, age, and risk factors.2002; 144: 1012–1017.

16 Cho JY, Jeong MH, Ahn YK,. Comparison of outcomes of patients with painless versus painful st-segment elevation myocardial infarction undergoing percutaneous coronary inter-vention.2012; 109: 337–343.

17 Canto JG, Shlipak MG, Rogers WJ,. Prevalence, clinical characteristics, and mortality among patients with myocardial infarction presenting without chest pain.2000; 283: 3223.

18 Arslanian-Engoren C, Engoren M. Physiological and anato-mical bases for sex differences in pain and nausea as pre-senting symptoms of acute coronary syndromes.2010; 39: 386–393.

19 Jax TW, Peters AJ, Plehn G, Schoebel FC. Relevance of hemostatic risk factors on coronary morphology in patients with diabetes mellitus type 2.2009; 8: 24.

20 Paim CP, Azzolin Kde O, de Moraes MA. [Chest pain in acute myocardial infarction among diabetic and non-diabetic patients].2012; 65: 77–82. [Article in Portuguese].

21 Thuresson M, Jarlov MB, Lindahl B,Symptoms and type of symptom onset in acute coronary syndrome in relation to ST elevation, sex, age, and a history of diabetes.2005; 150: 234–242.

22 Ting HH, Bradley EH, Wang Y,. Factors associated with longer time from symptom onset to hospital presentation for patients with ST-elevation myocardial infarction.2008; 168: 959–968.

23 Blankenship JC, Skelding KA, Scott TD,. Predictors of reperfusion delay in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention from the HORIZONS-AMI trial.2010; 106: 1527– 1533.

Correspondence to:Yue-Jin YANG & Ke-Fei DOU, Department of Car-diology, Fuwai Hospital, 167 Beilishi Road, Beijing 100037, China. E-mails: yangyjfw@126.com (YANG YJ) & drdoukefei@126.com (DOU KF)

January 2, 2019

April 17, 2019

May 9, 2019

May 28, 2019

*The first two authors contributed equally to this article.