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1.  Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients 
European heart journal  2013;35(13):844-852.
Aims
The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD.
Methods and results
Models were developed in a linked electronic health records cohort of 102 023 SCAD patients from the CALIBER programme, with mean follow-up of 4.4 (SD 2.8) years during which 20 817 deaths and 8856 coronary outcomes were observed. The Kaplan–Meier 5-year risk was 20.6% (95% CI, 20.3, 20.9) for mortality and 9.7% (95% CI, 9.4, 9.9) for non-fatal MI or coronary death. The predictors in the models were age, sex, CAD diagnosis, deprivation, smoking, hypertension, diabetes, lipids, heart failure, peripheral arterial disease, atrial fibrillation, stroke, chronic kidney disease, chronic pulmonary disease, liver disease, cancer, depression, anxiety, heart rate, creatinine, white cell count, and haemoglobin. The models had good calibration and discrimination in internal (external) validation with C-index 0.811 (0.735) for all-cause mortality and 0.778 (0.718) for non-fatal MI or coronary death. Using these models to identify patients at high risk (defined by guidelines as 3% annual mortality) and support a management decision associated with hazard ratio 0.8 could save an additional 13-16 life years or 15-18 coronary event-free years per 1000 patients screened, compared with models with just age, sex, and deprivation.
Conclusion
These validated prognostic models could be used in clinical practice to support risk stratification as recommended in clinical guidelines.
doi:10.1093/eurheartj/eht533
PMCID: PMC3971383  PMID: 24353280
Stable coronary artery disease; Stable angina; Prognosis; Myocardial infarction; Electronic health records; CALIBER
2.  Comparison of Random Forest and Parametric Imputation Models for Imputing Missing Data Using MICE: A CALIBER Study 
American journal of epidemiology  2014;179(6):764-774.
Multivariate imputation by chained equations (MICE) is commonly used for imputing missing data in epidemiologic research. The “true” imputation model may contain nonlinearities which are not included in default imputation models. Random forest imputation is a machine learning technique which can accommodate nonlinearities and interactions and does not require a particular regression model to be specified. We compared parametric MICE with a random forest-based MICE algorithm in 2 simulation studies. The first study used 1,000 random samples of 2,000 persons drawn from the 10,128 stable angina patients in the CALIBER database (Cardiovascular Disease Research using Linked Bespoke Studies and Electronic Records; 2001–2010) with complete data on all covariates. Variables were artificially made “missing at random,” and the bias and efficiency of parameter estimates obtained using different imputation methods were compared. Both MICE methods produced unbiased estimates of (log) hazard ratios, but random forest was more efficient and produced narrower confidence intervals. The second study used simulated data in which the partially observed variable depended on the fully observed variables in a nonlinear way. Parameter estimates were less biased using random forest MICE, and confidence interval coverage was better. This suggests that random forest imputation may be useful for imputing complex epidemiologic data sets in which some patients have missing data.
doi:10.1093/aje/kwt312
PMCID: PMC3939843  PMID: 24589914
angina, stable; imputation; missing data; missingness at random; regression trees; simulation; survival
3.  Comparison of Random Forest and Parametric Imputation Models for Imputing Missing Data Using MICE: A CALIBER Study 
American Journal of Epidemiology  2014;179(6):764-774.
Multivariate imputation by chained equations (MICE) is commonly used for imputing missing data in epidemiologic research. The “true” imputation model may contain nonlinearities which are not included in default imputation models. Random forest imputation is a machine learning technique which can accommodate nonlinearities and interactions and does not require a particular regression model to be specified. We compared parametric MICE with a random forest-based MICE algorithm in 2 simulation studies. The first study used 1,000 random samples of 2,000 persons drawn from the 10,128 stable angina patients in the CALIBER database (Cardiovascular Disease Research using Linked Bespoke Studies and Electronic Records; 2001–2010) with complete data on all covariates. Variables were artificially made “missing at random,” and the bias and efficiency of parameter estimates obtained using different imputation methods were compared. Both MICE methods produced unbiased estimates of (log) hazard ratios, but random forest was more efficient and produced narrower confidence intervals. The second study used simulated data in which the partially observed variable depended on the fully observed variables in a nonlinear way. Parameter estimates were less biased using random forest MICE, and confidence interval coverage was better. This suggests that random forest imputation may be useful for imputing complex epidemiologic data sets in which some patients have missing data.
doi:10.1093/aje/kwt312
PMCID: PMC3939843  PMID: 24589914
angina, stable; imputation; missing data; missingness at random; regression trees; simulation; survival
4.  Type and timing of heralding in ST-elevation and non-ST-elevation myocardial infarction: an analysis of prospectively collected electronic healthcare records linked to the national registry of acute coronary syndromes 
Aims:
It is widely thought that ST-elevation myocardial infarction (STEMI) is more likely to occur without warning (i.e. an unanticipated event in a previously healthy person) than non-ST-elevation myocardial infarction (NSTEMI), but no large study has evaluated this using prospectively collected data. The aim of this study was to compare the evolution of atherosclerotic disease and cardiovascular risk between people going on to experience STEMI and NSTEMI.
Methods:
We identified patients experiencing STEMI and NSTEMI in the national registry of myocardial infarction for England and Wales (Myocardial Ischaemia National Audit Project), for whom linked primary care records were available in the General Practice Research Database (as part of the CALIBER collaboration). We compared the prevalence and timing of atherosclerotic disease and major cardiovascular risk factors including smoking, hypertension, diabetes, and dyslipidaemia, between patients later experiencing STEMI to those experiencing NSTEMI.
Results:
A total of 8174 myocardial infarction patients were included (3780 STEMI, 4394 NSTEMI). Myocardial infarction without heralding by previously diagnosed atherosclerotic disease occurred in 71% STEMI (95% CI 69–72%) and 50% NSTEMI patients (95% CI 48–51%). The proportions of myocardial infarctions with no prior atherosclerotic disease, major risk factors, or chest pain was 14% (95% CI 13–16%) in STEMI and 9% (95% CI 9–10%) in NSTEMI. The rate of heralding coronary diagnoses was particularly high in the 12 months before infarct; 4.1-times higher (95% CI 3.3–5.0) in STEMI and 3.6-times higher (95% CI 3.1–4.2) in NSTEMI compared to the rate in earlier years.
Conclusions:
Acute myocardial infarction occurring without prior diagnosed coronary, cerebrovascular, or peripheral arterial disease was common, especially for STEMI. However, there was a high prevalence of risk factors or symptoms in patients without previously diagnosed disease. Better understanding of the antecedents in the year before myocardial infarction is required.
doi:10.1177/2048872613487495
PMCID: PMC3821819  PMID: 24222835
Cardiovascular diseases; epidemiology; myocardial infarction; risk factors
5.  Prognosis Research Strategy (PROGRESS) 3: Prognostic Model Research 
PLoS Medicine  2013;10(2):e1001381.
In this article, the third in the PROGRESS series on prognostic factor research, Sara Schroter and colleagues review how prognostic models are developed and validated, and then address how prognostic models are assessed for their impact on practice and patient outcomes, illustrating these ideas with examples.
doi:10.1371/journal.pmed.1001381
PMCID: PMC3564751  PMID: 23393430
6.  Prognosis Research Strategy (PROGRESS) 2: Prognostic Factor Research 
PLoS Medicine  2013;10(2):e1001380.
In the second article in the PROGRESS series on prognostic factor research, Sara Schroter and colleagues discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.
doi:10.1371/journal.pmed.1001380
PMCID: PMC3564757  PMID: 23393429
7.  Data Resource Profile: Cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER) 
The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼105 patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail s.denaxas@ucl.ac.uk
doi:10.1093/ije/dys188
PMCID: PMC3535749  PMID: 23220717
electronic heath records; linkages; cardiovascular
8.  Influenza Infection and Risk of Acute Myocardial Infarction in England and Wales: A CALIBER Self-Controlled Case Series Study 
The Journal of Infectious Diseases  2012;206(11):1652-1659.
Background. An association between infections and vascular events has been observed, but the specific effect of influenza and influenza-like illnesses on triggering acute myocardial infarction (AMI) is unclear.
Methods. Episodes of first AMI from 1 January 2003 through 31 July 2009 were identified using linked anonymized electronic medical records from the Myocardial Ischaemia National Audit Project and the General Practice Research Database. Self-controlled case series analysis was used to investigate AMI risks after consultation for acute respiratory infection. Infections were stratified by influenza virus circulation, diagnostic code, and vaccination status to assess whether influenza was more likely than other infections to trigger AMI.
Results. Of 22 024 patients with acute coronary syndrome, 11 208 met the criterion of having had their first AMI at the age of ≥40 years, and 3927 had also consulted for acute respiratory infection. AMI risks were significantly raised during days 1–3 after acute respiratory infection (incidence ratio, 4.19 [95% confidence interval, 3.18–5.53], with the effect tapering over time. The effect was greatest in those aged ≥80 years (P = .023). Infections occurring when influenza was circulating and those coded as influenza-like illness were associated with consistently higher incidence ratios for AMI (P = .012).
Conclusions. Influenza and other acute respiratory infections can act as a trigger for AMI. This effect may be stronger for influenza than for other infections.
Clinical trials registration. NCT01106196.
doi:10.1093/infdis/jis597
PMCID: PMC3488196  PMID: 23048170
9.  The freetext matching algorithm: a computer program to extract diagnoses and causes of death from unstructured text in electronic health records 
Background
Electronic health records are invaluable for medical research, but much information is stored as free text rather than in a coded form. For example, in the UK General Practice Research Database (GPRD), causes of death and test results are sometimes recorded only in free text. Free text can be difficult to use for research if it requires time-consuming manual review. Our aim was to develop an automated method for extracting coded information from free text in electronic patient records.
Methods
We reviewed the electronic patient records in GPRD of a random sample of 3310 patients who died in 2001, to identify the cause of death. We developed a computer program called the Freetext Matching Algorithm (FMA) to map diagnoses in text to the Read Clinical Terminology. The program uses lookup tables of synonyms and phrase patterns to identify diagnoses, dates and selected test results. We tested it on two random samples of free text from GPRD (1000 texts associated with death in 2001, and 1000 general texts from cases and controls in a coronary artery disease study), comparing the output to the U.S. National Library of Medicine’s MetaMap program and the gold standard of manual review.
Results
Among 3310 patients registered in the GPRD who died in 2001, the cause of death was recorded in coded form in 38.1% of patients, and in the free text alone in 19.4%. On the 1000 texts associated with death, FMA coded 683 of the 735 positive diagnoses, with precision (positive predictive value) 98.4% (95% confidence interval (CI) 97.2, 99.2) and recall (sensitivity) 92.9% (95% CI 90.8, 94.7). On the general sample, FMA detected 346 of the 447 positive diagnoses, with precision 91.5% (95% CI 88.3, 94.1) and recall 77.4% (95% CI 73.2, 81.2), which was similar to MetaMap.
Conclusions
We have developed an algorithm to extract coded information from free text in GP records with good precision. It may facilitate research using free text in electronic patient records, particularly for extracting the cause of death.
doi:10.1186/1472-6947-12-88
PMCID: PMC3483188  PMID: 22870911
10.  Is access to specialist assessment of chest pain equitable by age, gender, ethnicity and socioeconomic status? An enhanced ecological analysis 
BMJ Open  2012;2(3):e001025.
Objectives
To determine whether access to rapid access chest pain clinics of people with recent onset symptoms is equitable by age, socioeconomic status, ethnicity and gender, according to need.
Design
Retrospective cohort study with ecological analysis.
Setting
Patients referred from primary care to five rapid access chest pain clinics in secondary care, across England.
Participants
Of 8647 patients aged ≥35 years referred to chest pain clinics with new-onset stable chest pain but no known cardiac history, 7570 with documented census ward codes, age, gender and ethnicity comprised the study group. Patients excluded were those with missing date of birth, gender or ethnicity (n=782) and those with missing census ward codes (n=295).
Outcome measures
Effects of age, gender, ethnicity and socioeconomic status on clinic attendance were calculated as attendance rate ratios, with number of attendances as the outcome and resident population-years as the exposure in each stratum, using Poisson regression. Attendance rate ratios were then compared with coronary heart disease (CHD) mortality ratios to determine whether attendance was equitable according to need.
Results
Adjusted attendance rate ratios for patients aged >65 years were similar to younger patients (1.1, 95% CI 1.05 to 1.16), despite population CHD mortality rate ratios nearly 15 times higher in the older age group. Women had lower attendance rate ratios (0.81, 95% CI 0.77 to 0.84) and also lower population CHD mortality rate ratios compared with men. South Asians had higher attendance rates (1.67, 95% CI 1.57 to 1.77) compared with whites and had a higher standardised CHD mortality ratio of 1.46 (95% CI 1.41 to 1.51). Although univariable analysis showed that the most deprived patients (quintile 5) had an attendance rate twice that of less deprived quintiles, the adjusted analysis showed their attendance to be 13% lower (0.87, 95% CI 0.81 to 0.94) despite a higher population CHD mortality rate.
Conclusion
There is evidence of underutilisation of chest pain clinics by older people and those from lower socioeconomic status. More robust and patient focused administrative pathways need to be developed to detect inequity, correction of which has the potential to substantially reduce coronary mortality.
Article summary
Article focus
Is access to chest pain clinics of people with recent onset symptoms equitable according to local need and consistent with national policy.
Key messages
Need for evaluation in chest pain clinics will vary according to the variable incidence of heart disease in different age, gender, socioeconomic and ethnic groups.
There is evidence of underutilisation of chest pain clinics by older people and those from lower socioeconomic status.
Strengths and limitations of this study
Large, diverse and unselected patient population with uniformly collected patient-level data, allowing robust comparisons between demographic and clinical groups.
Ecological fallacy with respect to age and sex has been avoided by applying an enhanced ecological analysis.
Need to use census wards, not postcodes, as the smallest geographical areas for which mortality and demographic data were available.
Ethnicity was not based on self-ascription.
doi:10.1136/bmjopen-2012-001025
PMCID: PMC3378943  PMID: 22700834
11.  Treading carefully: a qualitative ethnographic study of the clinical, social and educational uses of exercise ECG in evaluating stable chest pain 
BMJ Open  2012;2(1):e000508.
Objective
To examine functions of the exercise ECG in the light of the recent National Institute for Health and Clinical Excellence guidelines recommending that it should not be used for the diagnosis or exclusion of stable angina.
Design
Qualitative ethnographic study based on interviews and observations of clinical practice.
Setting
3 rapid access chest pain clinics in England.
Participants
Observation of 89 consultations in chest pain clinics, 18 patient interviews and 12 clinician interviews.
Main outcome measure
Accounts and observations of consultations in chest pain clinics.
Results
The exercise ECG was observed to have functions that extended beyond diagnosis. It was used to clarify a patient's story and revise the initial account. The act of walking on the treadmill created an additional opportunity for dialogue between clinician and patient and engagement of the patient in the diagnostic process through precipitation of symptoms and further elaboration of symptoms. The exercise ECG facilitated reassurance in relation to exercise capacity and tolerance, providing a platform for behavioural advice particularly when exercise was promoted by the clinician.
Conclusions
Many of the practices that have been built up around the use of the exercise ECG are potentially beneficial to patients and need to be considered in the re-design of services without that test. Through its contribution to the patient's history and to subsequent advice to the patient, the exercise ECG continues to inform the specialist assessment and management of patients with new onset stable chest pain, beyond its now marginalised role in diagnosis.
Article summary
Article focus
Given the widespread use of the exercise ECG in assessments of patients with stable chest pain, this paper seeks to understand its role in the light of emerging evidence about its poor performance as a diagnostic test.
This paper reports on the functions of the exercise ECG in UK chest pain clinics, highlighting those uses that go beyond its diagnostic function.
This paper is part of an international debate about the appropriate initial tests for patients with new onset stable chest pain.
Key messages
The exercise ECG has additional functions that transcend its technical contribution to diagnosis: it can help clarify symptoms and other aspects of the clinical history, engage the patient in the diagnostic process, provide a context for guidance on reversible cardiovascular risk factors, be used to better involve and reassure patients and has the potential use for tailored lifestyle advice.
Through its contribution to the patient's history and to subsequent advice to the patient, the exercise ECG continues to inform the specialist assessment and management of patients with new onset stable chest pain, beyond its now marginalised role in diagnosis.
Many of the practices that have been built up around the use of the exercise ECG are potentially beneficial to patients. As chest pain clinic services are re-configured without the test, in line with UK national (National Institute for Health and Clinical Excellence (NICE)) guidance, these practices need to be integrated into new diagnostic pathways.
Strengths and limitations of this study
A strength of our study is its ethnographic design incorporating the observation of patient–clinician consultations and combining these data with interviews: we knew what participants did as well as said.
The fieldwork was undertaken at a key time just before the introduction of the UK's 2010 NICE guidelines and therefore provides an understanding of current practice that can inform their implementation.
A limitation of our study is that data were collected largely from two chest pain clinics, potentially limiting the transferability of the findings, although the clinicians in the research team thought that the clinics were not atypical compared to others they had experienced.
doi:10.1136/bmjopen-2011-000508
PMCID: PMC3277903  PMID: 22318662
12.  Extracting Diagnoses and Investigation Results from Unstructured Text in Electronic Health Records by Semi-Supervised Machine Learning 
PLoS ONE  2012;7(1):e30412.
Background
Electronic health records are invaluable for medical research, but much of the information is recorded as unstructured free text which is time-consuming to review manually.
Aim
To develop an algorithm to identify relevant free texts automatically based on labelled examples.
Methods
We developed a novel machine learning algorithm, the ‘Semi-supervised Set Covering Machine’ (S3CM), and tested its ability to detect the presence of coronary angiogram results and ovarian cancer diagnoses in free text in the General Practice Research Database. For training the algorithm, we used texts classified as positive and negative according to their associated Read diagnostic codes, rather than by manual annotation. We evaluated the precision (positive predictive value) and recall (sensitivity) of S3CM in classifying unlabelled texts against the gold standard of manual review. We compared the performance of S3CM with the Transductive Vector Support Machine (TVSM), the original fully-supervised Set Covering Machine (SCM) and our ‘Freetext Matching Algorithm’ natural language processor.
Results
Only 60% of texts with Read codes for angiogram actually contained angiogram results. However, the S3CM algorithm achieved 87% recall with 64% precision on detecting coronary angiogram results, outperforming the fully-supervised SCM (recall 78%, precision 60%) and TSVM (recall 2%, precision 3%). For ovarian cancer diagnoses, S3CM had higher recall than the other algorithms tested (86%). The Freetext Matching Algorithm had better precision than S3CM (85% versus 74%) but lower recall (62%).
Conclusions
Our novel S3CM machine learning algorithm effectively detected free texts in primary care records associated with angiogram results and ovarian cancer diagnoses, after training on pre-classified test sets. It should be easy to adapt to other disease areas as it does not rely on linguistic rules, but needs further testing in other electronic health record datasets.
doi:10.1371/journal.pone.0030412
PMCID: PMC3261909  PMID: 22276193
13.  Clopidogrel discontinuation after acute coronary syndromes: frequency, predictors and associations with death and myocardial infarction—a hospital registry-primary care linked cohort (MINAP–GPRD) 
European Heart Journal  2011;32(19):2376-2386.
Aims
Adherence to evidence-based treatments and its consequences after acute myocardial infarction (MI) are poorly defined. We examined the extent to which clopidogrel treatment initiated in hospital is continued in primary care; the factors predictive of clopidogrel discontinuation and the hazard of death or recurrent MI.
Methods and results
We linked the Myocardial Ischaemia National Audit Project registry and the General Practice Research Database to examine adherence to clopidogrel in primary care among patients discharged from hospital after MI (2003–2009). Hospital Episode Statistics and national mortality data were linked, documenting all-cause mortality and non-fatal MI. Of the 7543 linked patients, 4650 were prescribed clopidogrel in primary care within 3 months of discharge. The adjusted odds of still being prescribed clopidogrel at 12 months were similar following non-ST-elevation myocardial infarction (NSTEMI) 53% (95% CI, 51–55) and ST-elevation myocardial infarction (STEMI) 54% (95% CI, 52–56), but contrast with statins: NSTEMI 84% (95% CI, 82–85) and STEMI 89% (95% CI, 87–90). Discontinuation within 12 months was more frequent in older patients [>80 vs. 40–49 years, adjusted hazard ratio (HR) 1.50 (95% CI, 1.15–1.94)] and with bleeding events [HR 1.34 (95% CI, 1.03–1.73)]. 18.15 patients per 100 person-years (95% CI, 16.83–19.58) died or experienced non-fatal MI in the first year following discharge. In patients who discontinued clopidogrel within 12 months, the adjusted HR for death or non-fatal MI was 1.45 (95% CI, 1.22–1.73) compared with untreated patients, and 2.62 (95% CI, 2.17–3.17) compared with patients persisting with clopidogrel treatment.
Conclusion
This is the first study to use linked registries to determine persistence of clopidogrel treatment after MI in primary care. It demonstrates that discontinuation is common and associated with adverse outcomes.
doi:10.1093/eurheartj/ehr340
PMCID: PMC3184230  PMID: 21875855
ACS; Myocardial infarction; Clopidogrel; Anti-platelet; Observational
14.  NICE clinical guideline: chest pain of recent onset 
doi:10.3399/bjgp10X515124
PMCID: PMC2913741  PMID: 20822694
15.  Threshold Haemoglobin Levels and the Prognosis of Stable Coronary Disease: Two New Cohorts and a Systematic Review and Meta-Analysis 
PLoS Medicine  2011;8(5):e1000439.
Anoop Shah and colleagues performed a retrospective cohort study and a systematic review, and show evidence that in people with stable coronary disease there were threshold hemoglobin values below which mortality increased in a graded, continuous fashion.
Background
Low haemoglobin concentration has been associated with adverse prognosis in patients with angina and myocardial infarction (MI), but the strength and shape of the association and the presence of any threshold has not been precisely evaluated.
Methods and findings
A retrospective cohort study was carried out using the UK General Practice Research Database. 20,131 people with a new diagnosis of stable angina and no previous acute coronary syndrome, and 14,171 people with first MI who survived for at least 7 days were followed up for a mean of 3.2 years. Using semi-parametric Cox regression and multiple adjustment, there was evidence of threshold haemoglobin values below which mortality increased in a graded continuous fashion. For men with MI, the threshold value was 13.5 g/dl (95% confidence interval [CI] 13.2–13.9); the 29.5% of patients with haemoglobin below this threshold had an associated hazard ratio for mortality of 2.00 (95% CI 1.76–2.29) compared to those with haemoglobin values in the lowest risk range. Women tended to have lower threshold haemoglobin values (e.g, for MI 12.8 g/dl; 95% CI 12.1–13.5) but the shape and strength of association did not differ between the genders, nor between patients with angina and MI. We did a systematic review and meta-analysis that identified ten previously published studies, reporting a total of only 1,127 endpoints, but none evaluated thresholds of risk.
Conclusions
There is an association between low haemoglobin concentration and increased mortality. A large proportion of patients with coronary disease have haemoglobin concentrations below the thresholds of risk defined here. Intervention trials would clarify whether increasing the haemoglobin concentration reduces mortality.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary artery disease is the main cause of death in high-income countries and the second most common cause of death in middle- and low-income countries, accounting for 16.3%, 13.9%, and 9.4% of all deaths, respectively, in 2004. Many risks factors, such as high blood pressure and high blood cholesterol level, are known to be associated with coronary artery disease, and prevention and treatment of such factors remains one of the key strategies in the management of coronary artery disease. Recent studies have suggested that low hemoglobin may be associated with mortality in patients with coronary artery disease. Therefore, using blood hemoglobin level as a prognostic biomarker for patients with stable coronary artery disease may be of potential benefit especially as measurement of hemoglobin is almost universal in such patients and there are available interventions that effectively increase hemoglobin concentration.
Why was This Study Done?
Much more needs to be understood about the relationship between low hemoglobin and coronary artery disease before hemoglobin levels can potentially be used as a clinical prognostic biomarker. Previous studies have been limited in their ability to describe the shape of this relationship—which means that it is uncertain whether there is a “best” hemoglobin threshold or a continuous graded relationship from “good” to “bad”—to assess gender differences, and to compare patients with angina or who have experienced previous myocardial infarction. In order to inform these knowledge gaps, the researchers conducted a retrospective analysis of patients from a prospective observational cohort as well as a systematic review and meta-analysis (statistical analysis) of previous studies.
What Did the Researchers Do and Find?
The researchers conducted a systematic review and meta-analysis of previous studies and found ten relevant studies, but none evaluated thresholds of risk, only linear relationships.
The researchers carried out a new study using the UK's General Practice Research Database—a national research tool that uses anonymized electronic clinical records of a representative sample of the UK population, with details of consultations, diagnoses, referrals, prescriptions, and test results—as the basis for their analysis. They identified and collected information from two cohorts of patients: those with new onset stable angina and no previous acute coronary syndrome; and those with a first myocardial infarction (heart attack). For these patients, the researchers also looked at all values of routinely recorded blood parameters (including hemoglobin) and information on established cardiovascular risk factors, such as smoking. The researchers followed up patients using death of any cause as a primary endpoint and put this data into a statistical model to identify upper and lower thresholds of an optimal hemoglobin range beyond which mortality risk increased.
The researchers found that there was a threshold hemoglobin value below which mortality continuously increased in a graded manner. For men with myocardial infarction, the threshold value was 13.5 g/dl: 29.5% of patients had hemoglobin below this threshold and had a hazard ratio for mortality of 2.00 compared to those with hemoglobin values in the lowest risk range. Women had a lower threshold hemoglobin value than men: 12.8 g/dl for women with myocardial infarction, but the shape and strength of association did not differ between the genders, or between patients with angina and myocardial infarction.
What Do These Findings Mean?
These findings suggest that there are thresholds of hemoglobin that are associated with increased risk of mortality in patients with angina or myocardial infarction. A substantial proportion of patients (15%–30%) have a hemoglobin level that places them at markedly higher risk of death compared to patients with lowest risk hemoglobin levels and importantly, these thresholds are higher than clinicians might anticipate—and are remarkably similar to World Health Organization anemia thresholds of 12 g/dl for women and 13 g/dl for men. Despite the limitations of these observational findings, this study supports the rationale for conducting future randomized controlled trials to assess whether hemoglobin levels are causal and whether clinicians should intervene to increase hemoglobin levels, for example by oral iron supplementation.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000439.
Wikipedia provides information about hemoglobin (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Health Organization provides an overview of the global prevalence of coronary artery disease, a factsheet on the top ten causes of death, as well as information on anemia
doi:10.1371/journal.pmed.1000439
PMCID: PMC3104976  PMID: 21655315
16.  Prognosis of stable angina pectoris: why we need larger population studies with higher endpoint resolution 
Heart  2006;93(7):786-791.
The prognosis of angina was described as “"unhappy” by the Framingham investigators and as little different from that of 1‐year survivors of acute myocardial infarction. Yet recent clinical trials now report that angina has a good prognosis with adverse outcomes reduced to “normal levels”. These disparate prognostic assessments may not be incompatible, applying as they do to population cohorts (Framingham) and selected participants in clinical trials. Comparisons between studies are further complicated by the absence of agreed case definitions for stable angina (contrast this with acute coronary syndromes). Our recent data show that for patients with recent onset symptoms attending chest pain clinics, angina remains a high‐risk diagnosis and although many patients receive symptomatic benefit from revascularisation, prognosis is usually unaffected. This leaves little room for complacency and, with angina the commonest initial manifestation of coronary artery disease, there is the opportunity for early detection, risk stratification and treatment to modify outcomes. Meanwhile, larger population‐based studies are needed to define the patient journey from earliest presentation through the various syndrome transitions to coronary or noncardiac death in order to increase understanding of the aetiological and prognostic differences between the different coronary disease phenotypes.
doi:10.1136/hrt.2006.103119
PMCID: PMC1994448  PMID: 16952966
17.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Background
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Conclusion
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000286.
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
doi:10.1371/journal.pmed.1000286
PMCID: PMC2879408  PMID: 20532236
18.  Cardiothoracic ratio within the “normal” range independently predicts mortality in patients undergoing coronary angiography 
Heart  2006;93(4):491-494.
Objective
To determine whether cardiothoracic ratio (CTR), within the range conventionally considered normal, predicted prognosis in patients undergoing coronary angiography.
Design
Cohort study with a median of 7‐years follow‐up.
Setting
Consecutive patients undergoing coronary angiography at Barts and The London National Health Service (NHS) Trust.
Subjects
1005 patients with CTRs measured by chest radiography, and who subsequently underwent coronary angiography. Of these patients, 7.3% had a CTR ⩾0.5 and were excluded from the analyses.
Outcomes
All‐cause mortality and coronary event (non‐fatal myocardial infarction or coronary death). Adjustments were made for age, left ventricular dysfunction, ACE inhibitor treatment, body mass index, number of diseased coronary vessels and past coronary artery bypass graft.
Results
The risk of death was increased among patients with a CTR in the upper part of the normal range. In total, 94 (18.9%) of those with a CTR below the median of 0.42 died compared with 120 (27.8%) of those with a CTR between 0.42 and 0.49 (log rank test p<0.001). After adjusting for potential confounders, this increased risk remained (adjusted HR 1.45, 95% CI 1.03 to 2.05). CTR, at values below 0.5, was linearly related to the risk of coronary event (test for trend p = 0.024).
Conclusion
: In patients undergoing coronary angiography, CTR between 0.42 and 0.49 was associated with higher mortality than in patients with smaller hearts. There was evidence of a continuous increase in risk with higher CTR. These findings, along with those in healthy populations, question the conventional textbook cut‐off point of ⩾0.5 being an abnormal CTR.
doi:10.1136/hrt.2006.101238
PMCID: PMC1861494  PMID: 17164481
19.  Assessing the cost effectiveness of using prognostic biomarkers with decision models: case study in prioritising patients waiting for coronary artery surgery 
Objective To determine the effectiveness and cost effectiveness of using information from circulating biomarkers to inform the prioritisation process of patients with stable angina awaiting coronary artery bypass graft surgery.
Design Decision analytical model comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgency scores, and a risk score) and three strategies based on a risk score using biomarkers: a routinely assessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), or both. The order in which to perform coronary artery bypass grafting in a cohort of patients was determined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years (QALYs) were compared.
Data sources Swedish Coronary Angiography and Angioplasty Registry (9935 patients with stable angina awaiting coronary artery bypass grafting and then followed up for cardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects (relative risks) of biomarkers.
Results The observed risk of cardiovascular events while on the waiting list for coronary artery bypass grafting was 3 per 10 000 patients per day within the first 90 days (184 events in 9935 patients). Using a cost effectiveness threshold of £20 000-£30 000 (€22 000-€33 000; $32 000-$48 000) per additional QALY, a prioritisation strategy using a risk score with estimated glomerular filtration rate was the most cost effective strategy (cost per additional QALY was <£410 compared with the Ontario urgency score). The impact on population health of implementing this strategy was 800 QALYs per 100 000 patients at an additional cost of £245 000 to the National Health Service. The prioritisation strategy using a risk score with C reactive protein was associated with lower QALYs and higher costs compared with a risk score using estimated glomerular filtration rate.
Conclusion Evaluating the cost effectiveness of prognostic biomarkers is important even when effects at an individual level are small. Formal prioritisation of patients awaiting coronary artery bypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along with simple, routinely collected clinical information was cost effective. Prioritisation strategies based on the prognostic information conferred by C reactive protein, which is not currently measured in this context, or a combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be cost effective. The widespread practice of using only implicit or informal means of clinically ordering the waiting list may be harmful and should be replaced with formal prioritisation approaches.
doi:10.1136/bmj.b5606
PMCID: PMC2808469  PMID: 20085988
21.  Evaluating the causal relevance of diverse risk markers: horizontal systematic review 
Objectives To develop a new methodology to systematically compare evidence across diverse risk markers for coronary heart disease and to compare this evidence with guideline recommendations.
Design “Horizontal” systematic review incorporating different sources of evidence.
Data sources Electronic search of Medline and hand search of guidelines.
Study selection Two reviewers independently determined eligibility of studies across three sources of evidence (observational studies, genetic association studies, and randomised controlled trials) related to four risk markers: depression, exercise, C reactive protein, and type 2 diabetes.
Data extraction For each risk marker, the largest meta-analyses of observational studies and genetic association studies, and meta-analyses or individual randomised controlled trials were analysed.
Results Meta-analyses of observational studies reported adjusted relative risks of coronary heart disease for depression of 1.9 (95% confidence interval 1.5 to 2.4), for top compared with bottom fourths of exercise 0.7 (0.5 to 1.0), for top compared with bottom thirds of C reactive protein 1.6 (1.5 to 1.7), and for diabetes in women 3.0 (2.4 to 3.7) and in men 2.0 (1.8 to 2.3). Prespecified study limitations were more common for depression and exercise. Meta-analyses of studies that allowed formal Mendelian randomisation were identified for C reactive protein (and did not support a causal effect), and were lacking for exercise, diabetes, and depression. Randomised controlled trials were not available for depression, exercise, or C reactive protein in relation to incidence of coronary heart disease, but trials in patients with diabetes showed some preventive effect of glucose control on risk of coronary heart disease. None of the four randomised controlled trials of treating depression in patients with coronary heart disease reduced the risk of further coronary events. Comparisons of this horizontal evidence review with two guidelines published in 2007 showed inconsistencies, with depression prioritised more in the guidelines than in our review.
Conclusions This horizontal systematic review pinpoints deficiencies and strengths in the evidence for depression, exercise, C reactive protein, and diabetes as unconfounded and unbiased causes of coronary heart disease. This new method could be used to develop a field synopsis and prioritise future development of guidelines and research.
doi:10.1136/bmj.b4265
PMCID: PMC2773829  PMID: 19892791
22.  Quality of acute coronary care in emerging economies 
doi:10.1503/cmaj.090503
PMCID: PMC2691429  PMID: 19506274
23.  Incremental prognostic value of the exercise electrocardiogram in the initial assessment of patients with suspected angina: cohort study 
Objective To determine whether resting and exercise electrocardiograms (ECGs) provide prognostic value that is incremental to that obtained from the clinical history in ambulatory patients with suspected angina attending chest pain clinics.
Design Multicentre cohort study.
Setting Rapid access chest pain clinics of six hospitals in England.
Participants 8176 consecutive patients with suspected angina and no previous diagnosis of coronary artery disease, all of whom had a resting ECG recorded. 4848 patients with a summary exercise ECG result recorded (positive, negative, equivocal for ischaemia) comprised the summary ECG subset of whom 1422 with more detailed exercise ECG data recorded comprised the detailed ECG subset.
Main outcome measure Composite of death due to coronary heart disease or non-fatal acute coronary syndrome during median follow-up of 2.46 years.
Results Receiver operating characteristics curves for the basic clinical assessment model alone and with the results of resting ECGs were superimposed with little difference in the C statistic. With the exercise ECGs the C statistic in the summary ECG subset increased from 0.70 (95% confidence interval 0.68 to 0.73) to 0.74 (0.71 to 0.76) and in the detailed ECG subset from 0.74 (0.70 to 0.79) to 0.78 (0.74 to 0.82). However, risk stratified cumulative probabilities of the primary end point at one year and six years for all three prognostic indices (clinical assessment only; clinical assessment plus resting ECG; clinical assessment plus resting ECG plus exercise ECG) showed only small differences at all time points and at all levels of risk.
Conclusion In ambulatory patients with suspected angina, basic clinical assessment encompasses nearly all the prognostic value of resting ECGs and most of the prognostic value of exercise ECGs. The limited incremental value of these widely applied tests emphasises the need for more effective methods of risk stratification in this group of patients.
doi:10.1136/bmj.a2240
PMCID: PMC2583389  PMID: 19008264
24.  Presentation of stable angina pectoris among women and South Asian people 
Background
There is speculation that women and South Asian people are more likely than men and white people to report atypical angina and that they are less likely to undergo invasive management of angina. We sought to determine whether atypical symptoms of angina pectoris in women and South Asians impacted clinically important outcomes and clinical management.
Methods
We prospectively identified 2189 South Asian people and 5605 white people with recent-onset chest pain at 6 chest-pain clinics in the United Kingdom. We documented hospital admissions for acute coronary syndromes, coronary deaths as well as coronary angiography and revascularization procedures.
Results
Atypical chest pain was reported by more women than men (56.5% vs 54.5%, p < 0.054) and by more South Asian patients than white patients (59.9% vs 52.5%, p < 0.001). Typical symptoms were associated with coronary death or acute coronary syndromes among women (hazard ratio [HR] 2.30, 95% CI 1.70–3.11, p < 0.001) but not among men (HR 1.23, 95% CI 0.96–1.57, p = 0.10). Typical symptoms were associated with coronary outcomes in both South Asian and white patients. Among those with typical symptoms, women (HR 0.76, 95% CI 0.63–0.92, p = 0.004) and South Asian patients (HR 0.52, 95% CI 0.41–0.67, p < 0.001) were less likely than men and white patients to receive angiography.
Interpretation
Compared to those with atypical chest pain, women and South Asian patients with typical pain had worse clinical outcomes. However, sex and ethnic background did not explain differences in the use of invasive procedures.
doi:10.1503/cmaj.071763
PMCID: PMC2535745  PMID: 18809897
25.  Inequity of access to investigation and effect on clinical outcomes: prognostic study of coronary angiography for suspected stable angina pectoris 
BMJ : British Medical Journal  2008;336(7652):1058-1061.
Objectives To determine whether coronary angiography for suspected stable angina pectoris is underused in older patients, women, south Asian patients, and those from socioeconomically deprived areas, and, if it is, whether this is associated with higher coronary event rates.
Design Multicentre cohort with five year follow-up.
Setting Six ambulatory care clinics in England.
Participants 1375 consecutive patients in whom coronary angiography was individually rated as appropriate with the Rand consensus method.
Main outcome measures Receipt of angiography (420 procedures); coronary mortality and acute coronary syndrome events.
Results In a multivariable analysis, angiography was less likely to be performed in patients aged over 64 compared with those aged under 50 (hazard ratio 0.60, 95% confidence interval 0.38 to 0.96), women compared with men (0.42, 0.35 to 0.50), south Asians compared with white people (0.48, 0.34 to 0.67), and patients in the most deprived fifth compared with the other four fifths (0.66, 0.40 to 1.08). Not undergoing angiography when it was deemed appropriate was associated with higher rates of coronary event.
Conclusions At an early stage after presentation with suspected angina, coronary angiography is underused in older people, women, south Asians, and people from deprived areas. Not receiving appropriate angiography was associated with a higher risk of coronary events in all groups. Interventions based on clinical guidance that supports individualised management decisions might improve access and outcomes.
doi:10.1136/bmj.39534.571042.BE
PMCID: PMC2376033  PMID: 18436918

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