1 European Heart Journal Quality of Care and Clinical Outcomes (2015) 1, doi: /ehjqcco/qcv003 CLINICAL RESEARCH Atypical chest pain in diabetic patients with suspected stable angina: impact on diagnosis and coronary outcomes Cornelia Junghans 1, Neha Sekhri 2, M. Justin Zaman 3, Harry Hemingway 1,4, Gene S. Feder 5, and Adam Timmis 6 * 1 Department of Epidemiology and Public Health, University College London, London, UK; 2 Barts Health, London Chest Hospital, London, UK; 3 James Paget University Hospital, Norfolk NR31 6LA, UK; 4 FarrInstitute of Health Informatics Researchat London, London, UK; 5 Centrefor Academic Primary Care,School of Social and Community Medicine, Universityof Bristol, Bristol, UK; and 6 Dept Cardiology, Barts Heart Centre, Queen Mary University London, West Smithfield, London EC1A 7BE, UK Received 30 March 2015; accepted 1 April 2015; online publish-ahead-of-print 12 June 2015 Aims Silent myocardial ischaemia occurs commonly in diabetes. Whether altered perception of ischaemia also predisposes to atypical presentations with under-diagnosis of coronary disease is not known. To determine whether (i) patients with diabetes diagnosed with angina are more likely to report atypical symptoms compared with patients without diabetes, and (ii) atypical symptoms in patients with diabetes cause angina to go unrecognized, increasing the risk of coronary events.... Methods Prospective, multicentre cohort study of 8662 ambulatory patients with suspected angina, of whom 906 had diabetes. and results We recorded detailed chest pain descriptors and fatal and non-fatal coronary events over a median of 3.08 years of follow-up. Proportionately more patients with than without diabetes received a diagnosis of angina (42.7 vs. 25.1%). Among patients with diabetes diagnosed with angina, a greater proportion had atypical chest pain compared with patients without diabetes (21.0 vs. 11.3%), but the hazard of fatal and non-fatal coronary events was similar. However, among patients diagnosed with non-cardiac chest pain, those with diabetes most of whom had atypical symptoms remained at greater risk of coronary events [2.29 (95% CI 1.54, 3.41)] and all-cause mortality [1.67 (95% confidence interval, CI 1.04, 2.69)] compared with non-diabetic patients.... Conclusion Patients with diabetes and atypical symptoms are nearly twice as likely to be diagnosed with angina compared with nondiabetic patients. Those diagnosed with non-cardiac pain are at increased risk of coronary events. Our study emphasizes the need for more intensive investigation of diabetic patients with chest pain, particularly those presenting with atypical symptoms Keywords Diabetes Angina Silent ischaemia Prognosis Introduction The clinical history is the cornerstone of diagnosis in patients presenting with stable chest pain, symptoms that are typical in terms of character, location, and relation to exertion permitting a reliable diagnosis of stable angina in the majority of cases. 1 3 In patients with diabetes, however, there is evidence that ischaemia may be painless, or experienced atypically due to autonomic neuropathy affecting the sensory innervation of the heart. 4 6 The clinical implications of altered pain perception in diabetic coronary disease remain uncertain and while some investigators have reported that atypical or silent presentations are more frequent in diabetic patients with acute myocardial infarction, 7 15 others have found no differences compared with non-diabetic patients Studies in stable coronary disease have been more consistent in showing that patients with diabetes have a higher prevalence of silent ischaemia compared with those without, 10,22,23 but it is not known whether atypical angina presentations are also more common as there have been no large cohort studies comparing chest pain descriptors in patients with and without diabetes. The question is important for two reasons, * Corresponding author. Tel: , Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please
2 38 C. Junghans et al. first because misinterpretation of atypical chest pain may cause angina to go unrecognized with adverse prognostic consequences and second because recent guidelines on stable chest pain and coronary disease cite no evidence on typicality of symptoms in patients with diabetes and present no guidance for physicians as to whether this should influence investigational or diagnostic strategy. In the present study, we have examined the symptomatic presentation of a large cohort of patients with incident chest pain referred for cardiological assessment to test (i) whether patients with diabetes diagnosed with angina are more likely to report atypical symptoms compared with patients without diabetes, and (ii) whether atypical symptoms in patients with diabetes that cause angina to go unrecognized are associated with an increased risk of non-fatal and fatal coronary events. Methods Population Ten thousand five hundred and eighty six consecutive patients were recruited in six rapid access chest pain clinics from January 1996 to December 2002, mostly within 48 h after referral from primary care with new-onset chest pain. Details of the cohort have been reported previously. 28 We included only appropriate referrals (patients with no previous history of chest pain or documented IHD) (n ¼ ), those with a presentation of stable chest pain with a recorded diagnosis and follow-up data and complete clinical or demographic details (see Figure 1 for selection criteria), leaving 8662 patients for analysis. Baseline characteristics Diabetes was recorded in patients on insulin or oral hypoglycaemic drugs and included both type I and type II diabetes. The clinician assessing the patient in the clinic ascribed ethnicity as Asian, White, Black, or Other during the consultation. Asian included patients of Indian, Pakistani, Sri Lankan, and Bangladeshi origin, usually referred to as South Asian. Data on smoking status, history of hypertension, diabetes, and ECG results were recorded by the treating physician. Classification of chest pain The physician made an overall assessment of symptoms as typical or atypical, and entered a diagnosis of angina or non-cardiac chest pain at the end of the consultation. We used the physician assessment of chest pain typicality in our primary analysis but in a separate analysis, to exclude the possibility of selection bias, we made an objective assessment of chest pain typicality using modified Diamond Forrester criteria 29 where features of typical cardiac chest pain, recorded during the consultation from a dropdown menu (see Table 2), were defined as (i) constricting quality, (ii) central or left-side location, (iii) 15 min duration, and (iv) provocation by exercise. Atypical pain was defined as 2 of these features. Figure 1 Flowchart of patients included in the analysis.
3 Table 1 Baseline characteristics in diabetics and non-diabetics Demographic and clinical Non-diabetic patients Diabetic patients characteristics Atypical Typical P for Total Atypical Typical P for Total (n ) (n ) difference (n ) (n 5 582) (n 5 324) difference (n 5 906)... Median age in years (IQR) 51 (42 51) 59 (50 68) 53 (44 63) 56 (47 56) 61 (63 59) 58 (49 67) Female gender 2780 (48.2%) 918 (46.2%) (47.7%) 272 (46.9%) 154 (47.5%) (47.1%) South Asian ethnicity 1441 (25.0%) 343 (17.2%) 1784 (23.0%) 296 (50.9%) 137 (42.3%) (47.8%) Risk factors Current smoker 1397 (24.2%) 534 (26.9%) (24.9%) 99 (17.0%) 45 (14.9%) (15.9%) Hypertension 1706 (29.9%) 792 (38.8%) 2498 (32.2%) 312 (53.6%) 191 (58.9%) (55.5%) Hypercholesterolaemia 935 (16.2%) 491 (24.7%) 1426 (18.4%) 183 (31.4%) 116 (35.8%) (33.0%)... Clinical characteristics Mean pulse rate (+SD) 76.5 (+0.15) 76.2 (+0.27) (+11.7) 79.5 (+0.52) 77.4 (+0.65) (+12.2) Mean SBP (+SD) 138 (+0.26) 145 (+0.48) 140 (+20.6) 143 (+0.89) 147 (+1.12) (+21.1) Mean DBP (+SD) 85 (+0.15) 87 (+0.26) 85 (+11.5) 86 (+0.48) 85 (+0.65) (+11.6)... Exercise ECG Test done 3014 (52.3%) 1452 (73.0%) 4466 (57.6%) 333 (57.2%) 216 (66.6%) (60.6%) Test +ve for ischaemia 274 (9.1%) 471 (32.4%) 745 (16.8%) 47 (14.1%) 92 (42.6%) 139 (25.3%)... Diagnosis Non-cardiac chest pain 5117 (88.7%) 689 (34.6%) 5806 (74.9%) 460 (79.0%) 59 (18.2%) 519 (57.3%) Angina 650 (11.3%) 1300 (65.4%) 1950 (25.1%) 122 (21.0%) 265 (81.8%) 387 (42.7%) Atypical chest pain in diabetes 39
4 40 C. Junghans et al. Table 2 Chest pain characteristics in diabetics and non-diabetics Non-diabetics (n ) Diabetics (n 5 906) P for difference History of chest pain weeks 3690 (47.6%) 463 (51.1%).1 month and, 6 months 3050 (39.9%) 345 (38.0%).6 months and,12 months 1016 (13.1%) 98 (10.8%) Location of chest pain 0.26 Central 4078 (52.6%) 495 (54.6%) Left sided 2366 (30.5%) 277 (30.6%) Right sided 234 (3.0%) 33 (3.6%) Sub-mammary 556 (7.2%) 49 (5.4%) Epigastric 509 (6.6%) 51 (5.6%) Other 13 (0%) 1 (0%) Radiation of chest pain None 4849 (62.5%) 504 (55.6%) Left arm/shoulder 1856 (23.9%) 244 (26.9%) Right arm/shoulder 161 (2.1%) 25 (2.8%) Throat/jaw 462 (6.0%) 65 (7.2%) Back 405 (5.2%) 62 (6.8%) Other 23 (0.3%) 6 (0.7%) Chest pain trigger Nothing 4417 (57.0%) 433 (47.8%) Exercise 1948 (25.1%) 312 (34.4%) Exercise and rest 898 (11.6%) 127 (14.0%) Stress 283 (3.7%) 14 (1.6%) Eating 196 (2.5%) 20 (2.2%) Other 14 (0.2%) 0 (0%) Quality of chest pain Aching 2906 (37.5%) 293 (32.3%) Stabbing 1801 (23.2%) 166 (18.3%) Constricting 2054 (26.5%) 319 (35.2%) Nondescript 995 (12.8%) 128 (14.1%) CP duration Seconds 504 (6.5%) 47 (5.2%),5 min 1484 (19.1%) 181 (20.0%) 5 15 min 1844 (23.8%) 276 (30.5%) min 787 (10.2%) 104 (11.5%) Hours/variable 3137 (40.5%) 298 (32.9%) Associated symptoms None 5177 (66.8%) 556 (61.4%) SOB 2002 (25.8%) 287 (31.7%) Dizziness 111 (1.4%) 15 (1.7%) Palpitations 287 (3.7%) 26 (2.9%) Other 159 (2.0%) 21 (2.3%).1 Symptom 20 (0.3%) 1 (0.1%) Follow-up and outcomes Patients were flaggedfor mortalitywiththeofficefornational Statistics and for hospital admissions and procedures with the Secondary User Service. Successful matching was achieved in 99.5% of the cohort. The coronary outcome was a composite endpoint of death due to coronary heart disease (International Classification of Diseases-10 codes I20 I25) or nonfatal acute coronary syndrome [non-fatal myocardial infarction (I21 I23), unstable angina (I24)], with mean follow-up of 3.12 years (SD 1.62).
5 Atypical chest pain in diabetes 41 Statistical analysis Forthe comparison of baseline characteristics, continuous variables were presented as a median with inter-quartile range or mean with standard deviation and compared using Student s t-test. Proportions were compared using the c-statistic. To examine the probability of receiving a diagnosis of angina according to physician assessment, odds ratios with 95% confidence intervals by diabetic status were calculated. To examine the prognostic validity of physician assessment on coronary outcome, we used Cox proportional hazards regression, adjusting for age, sex, ethnicity, hypertension, and hypercholesterolemia. We used the computer-generated classification of typicality based on the Diamond Forrester algorithm in sensitivity analyses. Stata 8 (version 8.2, StataCorp, College Station, TX, USA) was used for all analyses in this study. We compared physician-defined and algorithm-defined chest pain classification using the kappa statistic. Results Demographic and clinical characteristics Of the 8662 patients with suspected angina, 906 (10.5%) had diabetes. Patients with diabetes were older and a higher proportion had prior hypertension and hypercholesterolaemia, but fewer were current smokers (Table 1). The frequency of exercise stress testing was comparable in patients with and without diabetes (60.6 vs. 57.6%), but positive test results were more common in patients with diabetes whether chest pain was recorded as typical (42.6 vs. 32.4%) or atypical (14.1 vs. 9.1%). Proportionately more patients with than without diabetes received a diagnosis of angina (42.7 vs. 25.1%). Chest pain characteristics and diabetes Across the whole cohort of 8662 patients, there was 86.4% agreement (kappa 0.64) between chest pain typicality recorded by the clinic physician and chest pain typicality derived by applying the Diamond Forrester criteria. Using the assessment of the clinic physician, chest pain was recorded as typical in a greater proportion of patients with than without diabetes (34.3 vs. 21.5%). This was reflected in the chest pain descriptors recorded at the consultation, patients with diabetes being more likely to report chest pain as constricting and occurring in response to exertion with radiation to arms, neck, throat, or jaw (Table 2). However, among patients with diabetes diagnosed with angina, a greater proportion had atypical symptoms, compared with patients without diabetes (21.0 vs. 11.3%) (Table 1). Prognosis Mean follow-up was years. The cumulative probability of coronary events (Figure 2) was higher in patients with typical symptoms, with little difference in the hazard of coronary events between patients with [hazards ratio, HR 3.89 (95% confidence interval, CI 2.92, 5.18)] and without [HR 2.78 (95% CI 2.31, 3.35)] diabetes (Table 3). Among patients diagnosed with angina, diabetic status and typicality of symptoms had no significant effect on the hazard of coronary events or all-cause mortality (Table 3). However, among patients diagnosed with non-cardiac chest pain, those with diabetes most of whom had atypical symptoms remained at significantly greater risk of coronary events [2.29 (95% CI 1.54, 3.41)] Figure 2 Kaplan Meier survival curves showing the effect of symptom typicality and diabetic status on cumulative probability of non-fatal acute coronary syndromes and coronary death. and all-cause mortality [1.67 (95% CI 1.04, 2.69)] compared with non-diabetic patients. Discussion Main findings This is the first large cohort comparison of the relation between diabetes, chest pain characteristics, and clinical outcomes in patients presenting for cardiological assessment of suspected angina. Atypical presenting symptoms were recorded twice as frequently in diabetic patients diagnosed with angina compared with non-diabetic patients but were associated with a risk of coronary events similar to patients with typical symptoms. Atypical symptoms that caused angina to go unrecognized in patients with diabetes, leading to a diagnosis of noncardiac chest pain, were associated with an increased risk of non-fatal and fatal coronary events. Context Evidence for altered perception of ischaemic cardiac pain in people with diabetes is based largely on reports that symptoms of myocardial ischaemia and infarction are more commonly not experienced or not recognized compared with people without diabetes. 6 14,21,22 In some studies, this has been related to diabetic autonomic neuropathy affecting the sensory innervation of the heart, and there is further evidence that neuropathy might influence pain thresholds. 4 6 However, there is no evidence that autonomic neuropathy affects the quality of chest pain and its relation to exertion in other respects. The belief that atypical presentations are common in patients with diabetes with suspected angina is largely based on collective clinical experience now enshrined in medical textbooks and websites. 30,31 Clinical implications Our study validates the perception that atypical presentations of angina are more common in diabetes and merit more aggressive investigation than in patients with atypical symptoms who do not have diabetes. Patients with diabetes and atypical symptoms had a somewhat higher frequency of exercise electrocardiography and
6 42 C. Junghans et al. Table 3 Hazard ratios (95% CI) for typical versus non-typical symptoms in prediction of coronary events (coronary heart disease death or non-fatal acute coronary syndrome) and all-cause mortality All patients (n ) Patients diagnosed with Patients diagnosed with angina (n ) non-cardiac chest pain (n )... n/n HR a (95% CI) P HR a (95% CI) P HR a (95% CI) P Coronary events (n ¼ 598) Atypical non-diabetics 222/ (reference) 1 (reference) (reference) Typical diabetics 66/ (2.92, 5.18) 1.38 (0.99, 1.92) 2.26 (0.92, 5.60) Typical non-diabetics 256/ (2.31, 3.35) 1.11 (0.88, 1.40) 1.52 (1.02, 2.27) Atypical diabetics 53/ (1.42, 2.63) 0.91 (0.54, 1.53) 2.29 (1.54, 3.41) Death all causes (n ¼ 350) Atypical non-diabetics 180/ (reference) 1 (reference) (reference) Typical diabetics 28/ (1.16, 2.62) 1.22 (0.73, 2.02) 2.35 (0.86, 6.42) Typical non-diabetics 111/ (0.87, 1.41) 0.98 (0.69, 1.39) 0.47 (0.25, 0.90) Atypical diabetics 31/ (1.03, 2.27) 1.19 (0.58, 2.45) 1.67 (1.04, 2.69) a Adjusted for age, sex, ethnicity, hypertension, and hypercholesterolemia. positive tests compared with patients without diabetes, and this may have contributed to their over-representation among patients diagnosed with angina. However, differences in non-invasive testing were small and other factors must also have contributed, notably awareness by physicians of the increased risk of coronary disease in patients with diabetes and an intuitive lowering of diagnostic thresholds to include more with atypical symptoms among those diagnosed with angina. The outcome data provide evidence that the diagnostic decisions made by physicians were appropriate by showing similar hazards of non-fatal and fatal coronary events for diabetic and non-diabetic patients diagnosed with angina, regardless of the typicality of symptoms. However, the outcome data also showed that among patients diagnosed with non-cardiac chest pain, hazards were significantly higher in patients with diabetes, and the opportunity to treat this high-risk group when they present with atypical symptoms should not be missed. There may be a need, therefore, for further lowering of diagnostic thresholds and for more intensive investigation of patients with diabetes presenting with atypical symptoms, recent studies confirming the value of non-invasive testing for identifying high-risk patients who present in this way. 32,33 Implications for guidelines and future research Quantitative analysis of the probability of coronary disease in patients presenting with chest pain is recommended in guidelines for decisions about non-invasive investigation, but some widely used algorithms take no account of diabetes in their probability estimates. Our data illustrate the importance of modifying these estimates to take account of the heightened risk in patients with diabetes and other risk factors. Our data also indicate a need for further research into the extended cardiovascular risks associated with diabetes, recent work using linked primary care and disease registries showing considerable heterogeneity, the heightened risk of coronary disease contrasting with the protection against aneurysmal disease. 34 Strengths and limitations Strengths of this study were the contemporaneous recording of detailed chest pain descriptors in a large cohort of patients with recent onset symptoms and the linked coronary outcomes. The baseline data collection and follow-up for this analysis were completed 7 years ago, but this is unlikely to have affected our main findings relating to typicality of symptoms, diagnosis of angina, and coronary outcomes in patients with diabetes. Angina is a clinical diagnosis and in our study was validated by the coronary outcome data, not always by anatomical or functional testing. Diabetes was defined only by treatment being received at the time of the consultation without additional tests. Although south Asian ethnicity was more common among patients with diabetes, we have previously reported that angina does not present atypically in this group, and in the present study, there is no interaction of ethnicity with diabetes status in its relation with atypical presentations. 35 Conclusions In a large cohort of patients with undifferentiated chest pain, atypical symptoms were more likely to be a manifestation of angina in patients with diabetes. Clinicians lowered diagnostic thresholds in these patients, but this was not sufficient to capture all those at risk, as reflected by the adverse outcomes in diabetic patients diagnosed with non-cardiac chest pain. Our study emphasizes the need for more intensive investigation of diabetic patients with chest pain, particularly those presenting with atypical symptoms. Funding A.T. acknowledges support of Barts Cardiovascular Biomedical Research Unit, funded by the National Institute for Health Research. The study was funded by the National Health Service s Service Delivery and Organisation research and development programme. Conflict of interest: none declared.
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