Prognosis of undiagnosed chest pain: linked electronic health record cohort studyBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1194 (Published 03 April 2017) Cite this as: BMJ 2017;357:j1194
All rapid responses
Dr Jordan and colleagues reported increased risk of cardiovascular events in patients with unattributed chest pain for at least five years.1 As most of the patients explored for new chest pain did not have a specific diagnosis recorded, it gave rise to a large number of cardiovascular events in subsequent years. Accordingly, those patients should be targeted for better assessment and prevention. I would like to emphasize ways for better 1/ cardiovascular risk prediction, 2/ prevention based on algorithms and 3/ accuracy in diagnosing chest pain.
1/ As a matter of fact, cardiovascular risk prediction may be better assessed by clinically available established algorithms.2 Accuracy may even be improved when using artificial intelligence (machine-learning with 30 variables) compared to above-mentioned algorithms (8 variables).3 Clearly, machines do help clinicians embrace the complexity of cardiovascular risk prediction, and subsequent explorations and preventive strategy (which should be adapted from risk-adjusted algorithms). However, some new variables emerge as new powerful markers/factors of cardiovascular risk, including trimethylamin-N-oxid (TMAO) levels.4
2/ Definitely, continued research on cardiovascular risk prediction with a major role of TMAO is eagerly needed for improving algorithms that will more correctly identify subjects who could benefit from preventive measures, while avoiding unnecessary treatments in others. Mediterranean diet and physical exercise should be universally embraced, such as fighting against tobacco, stress, sleep deprivation, inactivity and so on. However, other measures have narrow therapeutic index and/or higher costs and should be restricted to subjects with particular cardiovascular risk5,6. These algorithms of preventive interventions are not yet commonplace otherwise not yet universally accepted, and their utility should be explored in future studies7.
3/ Finally, positive and negative diagnosis of chest pain should be improved; accordingly, patients that may have had patent coronary disease would have been correctly classified. At follow-up, once patients have been delineate to be at risk, they may be subject to investigations, adapted on their pretest probability. Cardiac imaging techniques add diagnostic and prognostic value in higher-risk populations over exercise ECG8. If pre-test probability is high but with unexpected “negative” stress test, calcium scoring by computed tomography should follow8. As for clinical risk prediction, noninvasive testing may improve their accuracy by combining information: adding post-exercise troponin dosage, or carotid ultrasound to exercise testing may improve sensibility9.
As a conclusion, the overall population and particularly those with new chest pain should be targeted for better cardiovascular risk prediction, assessment and prevention.
1. Jordan KP, Timmis A, Croft P, et al. Prognosis of undiagnosed chest pain: linked electronic health record cohort study. BMJ 2017;j1194.
2. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 suppl 2):S49–73.
3. Weng SF, Reps J, Kai J, Garibaldi JM, Qureshi N. Can machine-learning improve cardiovascular risk prediction using routine clinical data? PLOS ONE 2017;12(4):e0174944.
4. Tang WHW, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368(17):1575–84.
5. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195–207.
6. Bibbins-Domingo K, on behalf of the U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016;164(12):836.
7. Lloyd-Jones DM, Huffman MD, Karmali KN, et al. Estimating Longitudinal Risks and Benefits From Cardiovascular Preventive Therapies Among Medicare Patients. J Am Coll Cardiol 2017;69(12):1617–36.
8. Bourque JM, Beller GA. Value of Exercise ECG for Risk Stratification in Suspected or Known CAD in the Era of Advanced Imaging Technologies. JACC Cardiovasc Imaging 2015;8(11):1309–21.
9. Ahmadvazir S, Shah BN, Zacharias K, Senior R. Incremental Prognostic Value of Stress Echocardiography With Carotid Ultrasound for Suspected CAD. JACC Cardiovasc Imaging [Internet] 2017 [cited 2017 Apr 23];Available from: http://linkinghub.elsevier.com/retrieve/pii/S1936878X17302395
Competing interests: No competing interests
Thank you for the interest in our paper. In response to Dr Yeolekar, we fully agree that cardiac conditions may present with other symptoms than chest pain which need further attention and may require immediate investigation. Our study was about an initial recorded presentation of chest pain and future studies could usefully assess the long term prognosis of these other symptoms for cardiovascular events.
Dr Moss and colleagues raise the important issue that studies to date do not provide clear evidence about the overall costs and benefits of referral and investigation of all patients who consult their general practitioner and our study was certainly not designed to provide the answer to that question. The SCOT HEART study provided important evidence about the usefulness of CTCA in clarifying diagnosis in patients referred to hospital for assessment of suspected angina and about its potential effectiveness in reducing subsequent cardiac mortality and morbidity. However the SCOT HEART study was unable to answer the question of the overall costs and benefits of offering CTCA to all patients presenting with chest pain in primary care since it was investigating a selective group of referred patients, and the proportion of all patients in primary care consulting with chest pain which this group represented was not given. Our study suggests that such a referred group are at higher risk of CVD than non-referred patients, whilst the SCOT HEART study found that even in the referred group most patients had normal coronary arteries or mild coronary heart disease.
The next step is, as Dr Moss and colleagues suggest, to understand more about the epidemiology of referral, and to investigate whether clinical characteristics can appropriately allocate patients to prognostically low risk groups to help support GP decisions about referral, and about the long-term costs and benefits of wider use of cardiac investigations in practice. Reassurance may not alleviate symptoms, and the reassured may still be at higher risk of future heart disease than those not referred. In response to Dr Moss and colleagues’ query about whether we included exercise ECG. We apologise that it is not clear in the paper, but we did include it.
In response to Dr Selmonosky, thoracic outlet syndrome may be a cause of presented chest pain but it rarely appears in the GP coded records. We accept this might be because it is under-recognised in primary care. Such patients would be included in our chest pain unattributed to a cause group if they were simply recorded as chest pain with no underlying reason. As we state in the paper, and as Dr Selmonosky suggests, further work now needs to determine prognostic factors for cardiovascular events in this unattributed chest pain group.
1. Jordan KP, Timmis A, Croft P, et al. Prognosis of undiagnosed chest pain: linked electronic health record cohort study. BMJ 2017;357;j1194.
2. SCOT-HEART investigators. CT coronary angiography in patients with suspected angina due to coronary artery disease (SCOT-HEART): an open-label, parallel group multicentre trial. Lancet 2015;285:2383-2391.
Professor of Biostatistics, Keele University
Professor of Primary Care Epidemiology, Keele University
Professor of Clinical Cardiology, Barts Heart Centre
Competing interests: No competing interests
"It isn’t that they can’t see the solution. It is that they cannot see the problem.”
Gilbert Keith Chesterton (1874-1936)
"If your experiment needs statistics, you ought to have done a better experiment.”
Lord Ernest Rutherford (1871-1937)
I ask you for forgiveness if I have misinterpreted your statistical study about chest pain published in the British Medical Journal, PMID 28373260. My knowledge of statistics is not profound, like most Primary Care Physicians.
The conclusion of your study is that patients with unexplained (unattributed, undiagnosed, misdiagnosed) chest pain, have a higher incidence of cardiovascular disease when compared to other groups of patients, the so-called non-coronary chest pain patients.The problem as you stated is that you cannot predict who, in your group of unexplained chest pain patients, will develop cardiovascular disease.
The corollary is that everybody should follow the usual measures to prevent coronary artery disease, diet, weight exercise, et cetera.
The result of your studies are similar in a way to the studies of so-called syndrome X, microvascular angina, endothelial dysfunction, et cetera, the corollary is that they did not find any special pharmacological therapy that may help. In none of the articles about this so called disorder was TOS ruled out. The only measure will be to continue the usual medical therapy and follow the guidelines to prevent coronary artery disease. Obviously, the genetic component has not been discussed extensively.
Another problem with this study is that when you describe the etiology of non-coronary chest pain, only these entities are considered to be the etiological factor in your group of patients with non-coronary chest pain.
Obviously, a common cause of chest pain was ignored, therefore the conclusions are flawed. Thoracic Outlet Syndrome (TOS) is a common cause of chest pain, the diagnosis can be made by the Primary Care Physician by means of a Diagnostic Triad. This Diagnostic Triad includes the relative weakness of the fifth finger maneuver (RWFF), and can be associated with the White Hand Sign (WHS).
The relative weakness of the fifth finger (RWFF) has a surprisingly incidence in the general population. It has a high incidence in secretaries and physicians, they are hunched over computers and patients many hours of the working day. It is present in all patients with TOS with the other two components of the Diagnostic Triad.
Also the association among coronary artery disease, reflux esophagitis, and thoracic outlet syndrome is practically unknown and could be high. Therefore, when one of the diseases is diagnosed, the other two should be ruled out. Any study that relies only on symptoms of chest pain without a physical examination to rule out TOS by principle is flawed.
It is well-known that patients with proper therapy for reflux esophagitis associated with chest pain, continue to have chest pain. The same fact occurs in patients who have coronary stents to prevent the result of coronary stenosis and myocardial ischemia. Many of them continue to have non-ischemic chest pain.
The so-called musculoskeletal causes of chest pain don’t have any scientific basis, many of these patients have undiagnosed TOS.
Regarding the third, anxiety, the medical literature is full of psychiatric diagnosis in those patients who have unexplained chest pains. It looks like the index of a psychiatric book. they were told to have anxiety, depression, panic attacks, catastrophic thinking, central pain, et cetera. In none of these articles has TOS been ruled out. The presence of the WHS in these patients has never been reported.
A similar situation occurs in patients with lumbar back pain, associated or not with pain and paresthesias of the lower extremities, the incidence of undiagnosed Piriformis Syndrome (PS) may reach a figure of 36%, but the FAIR test is not consistently performed in those patients, to rule out PS as the sole cause of the patient's symptoms, or to be associated with spinal root pain.
Thank you in advance for your time. I hope to receive your comments and criticism.
Competing interests: No competing interests
Providing patients with a timely and correct diagnosis poses significant challenges to frontline physicians, and this is no better exemplified than in those presenting with acute chest pain. As Jordan and colleagues have highlighted, a history of classical anginal symptoms remains an excellent discriminator for identifying individuals at high-risk of myocardial infarction, yet in primary care these account for only a minority of cases (<5%).  The main focus of acute chest pain management over the past decade has been to identify prognostically significant coronary artery disease (CAD) in those with less specific symptoms, and notably these cases accounted for over 70% of index presentations in the CALIBER study. However, an unresolved question is how to select out the high-risk individuals in these overall low-risk populations.
In this real-world registry, a referral for a specialist opinion or requesting a cardiac investigation was often considered unnecessary by generalists when faced with unattributed chest pain presentations, even at 6 months following presentation. Of note, we would be interested to know why exercise ECG was not considered as an investigation of chest pain, especially as this was the first line investigation of choice for stable chest pain during the time frame of this study. 
It would also be useful to know the composite breakdown of the different investigations in the current study to allow the results to be considered in relation to current practice where imaging has assumed a far more significant role in modern guidelines. Whilst cardiovascular computed tomography (CT) was rarely used prior to the NICE CG95 guidelines published in 2010,  contemporary trials in non-invasive cardiac imaging (such as SCOT-HEART ) have demonstrated that CT coronary angiography (CTCA) improves the diagnostic certainty of CAD in patients with less specific symptoms of angina. In CALIBER only 9.9% of unattributed cases underwent early investigation within 6-months, but similar to SCOT-HEART, prescription of statins increased when investigation results were available to frontline clinicians.
Importantly, the 2016 update of the NICE CG95 guidelines now recommend CTCA as the first line investigation in the assessment of undifferentiated chest pain. In addition, CTCA is the only testing strategy that has been shown to reduce ‘hard’ cardiovascular outcomes through more appropriate prescribing of preventive therapy.  Rapid confirmation or exclusion of CAD with CTCA allows appropriate reassurance or instigation of primary prevention therapy. Additionally, assessment of the wide-field-of-view dataset on CTCA studies may potentially allow for detection of other non-cardiac pathology mentioned in the CALIBER study, such as hiatus hernia, lung pathology and spinal abnormalities. With modern CT scanners, the average radiation dose from CTCA in the UK is now equivalent to a year or less of background radiation.  Its increased use in the assessment of chest pain in primary care may reduce morbidity and mortality as demonstrated already in secondary care based studies such as SCOT-HEART.
 Jordan KP, Timmis A, Croft P, et al. Prognosis of undiagnosed chest pain: linked electronic health record cohort study. BMJ 2017;357;j1194.
 de Bono D. Investigation and management of stable angina: revised guidelines 1998. Joint Working Party of the British Cardiac Society and Royal College of Physicians of London. Heart 1999;81:546-55.
 National Institute for Health and Clinical Excellence. Chest pain of recent onset: Assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin. CG95. London: National Institute for Health and Clinical Excellence, 2010.
 SCOT-HEART investigators. CT coronary angiography in patients with suspected angina due to coronary artery disease (SCOT-HEART): an open-label, parallel group multicentre trial. Lancet 2015;285:2383-2391.
 Williams MC, Hunter A, Shah AS, et al. Use of coronary computed tomographic angiography to guide management of patients with coronary disease. J Am Coll Cardiol 2016;67:1759-1768.
6. Nicol E, Castellano I, Harden S. A National survey of coronary CT angiography doses in the UK on behalf of the British Society of Cardiovascular CT (BSCCT). J Cardiovasc Comput Tomogr 2016;10:S60.
Alastair J Moss
Clinical research fellow, University of Edinburgh
Jonathan R Weir-McCall
Clinical lecturer and radiology registrar, University of Dundee
Michelle C Williams
Clinical lecturer and radiology registrar, University of Edinburgh
Edward D Nicol
Consultant cardiologist, Royal Brompton Hospital and Harefield NHS Trust, London
Competing interests: No competing interests
The study highlights long term follow up in a clinical symptom where long period assessment is generally less recorded and available. Patients with persistent or recurrent chest pain tend to be investigated to some logical clinical conclusion. Pleuritis, myalgia, acid peptic disease, reflux oesophagitis, trauma with or without rib fracture may be some non-cardiac conditions that cause initial confusion. However, every cardiac condition need not necessarily be accompanied by chest pain: fullness of the chest, feeling of constriction or tightness in the chest, shortness of breath are all symptoms that demand equal urgency and attention. Age above 30 in those with a family history of premature CAD and above 35 in others appears to be a fair cut off point to determine intensive IHD workup in our setup. However, the results of the study indicate th desirability of longer followup.
Dr ME Yeolekar, Mumbai
Competing interests: No competing interests