|dc.contributor.author||Chapman, Andrew R.||
|dc.description.abstract||Myocardial infarction is a leading cause of morbidity and mortality worldwide. The
purpose of this thesis was to develop strategies for the assessment of patients with
suspected myocardial infarction using a high-sensitivity cardiac troponin I assay, and
to evaluate the relationship between the aetiology of myocardial infarction and long
term clinical outcomes to identify opportunities to modify outcomes.
In the United Kingdom, approximately 1 million patients present to hospital with chest
pain each year and are assessed for suspected myocardial infarction, yet fewer than
20% of patients receive this diagnosis. Prior clinical standards mandated the admission
of patients for serial cardiac troponin testing to identify myocardial necrosis and
determine if myocardial infarction had occurred. However, new high-sensitivity
assays offer a magnitude improvement in diagnostic precision, and as such provide a
novel approach to diagnose or exclude myocardial infarction at an earlier stage.
In our first study, I evaluate the performance of a high-sensitivity cardiac troponin I
assay as a risk stratification tool in patients with suspected acute coronary syndrome.
A systematic review and individual patient-level data meta-analysis was performed,
including prospective studies measuring high-sensitivity cardiac troponin I in patients
with suspected acute coronary syndrome, where the diagnosis was adjudicated
according to the universal definition of myocardial infarction. The primary outcome
was myocardial infarction or cardiac death during the index hospitalization or at 30
days. Meta-estimates for primary and secondary outcomes were derived using a
binomial-normal random effects model. Performance was evaluated in subgroups and
across a range of troponin concentrations (2-16 ng/L) using individual patient data.
A total of 22,457 patients were included in the meta-analysis (age 62 [15.5] years;
n=9,329 (41.5%) women), of whom 2,786 (12.4%) experienced myocardial infarction
or cardiac death at 30 days. Cardiac troponin I concentrations were <5 ng/L at
presentation in 11,012 (49%) patients, with a negative predictive value of 99.5% (95%
confidence interval [CI] 99.3-99.6) for myocardial infarction or cardiac death at 30
days. Lower thresholds did not improve safety, but did significantly reduce the
proportion identified as low risk.
This threshold of 5 ng/L formed the basis for the development of a diagnostic pathway
for patients with suspected acute coronary syndrome. In a cohort study of 1,218
patients with suspected acute coronary syndrome who underwent high-sensitivity
cardiac troponin I measurement at presentation, 3 and 6 or 12 hours, I derived and
validated a novel pathway (rule out myocardial infarction if <5 ng/L at presentation,
or change <3 ng/L and <99th centile at 3 hours), and compared this with the established
European Society of Cardiology 3-hour pathway (rule out myocardial infarction if
<99th centile at presentation, or at 3 hours if symptoms <6 hours). The primary
outcome was a comparison of the negative predictive value (NPV) of both pathways
for myocardial infarction or cardiac death at 30 days. The primary outcome was
evaluated in pre-specified subgroups stratified by age, gender, time of symptom onset
and known ischaemic heart disease.
In those <99th centile at presentation, the ESC pathway ruled out myocardial infarction
in 28.1% (342/1,218) and 78.9% (961/1,218) at presentation and 3 hours respectively,
missing 18 index and two 30-day events (NPV 97.9%, 95% confidence intervals [CI]
96.9-98.7%). The novel pathway ruled out 40.7% (496/1,218) and 74.2% (904/1,218)
at presentation and 3 hours, missing two index and two 30-day events (NPV 99.5%,
95% CI 99.0-99.9%; P<0.001 for comparison). The NPV of the novel pathway was
greater than the ESC pathway overall (P<0.001), and in all subgroups including those
presenting early or known to have ischaemic heart disease.
There are a number of additional approaches for the rule out of myocardial infarction.
Clinical risk scores apply conventional risk factors to estimate the probability of
myocardial infarction. The most widely implemented scores, HEART, EDACS,
GRACE and TIMI, have been extensively validated when used alongside
contemporary troponin assays, however, their impact on pathways applying high-sensitivity
cardiac troponin testing is less clear.
In 1,935 patients with suspected acute coronary syndrome, I evaluated the safety and
efficacy of our novel pathway or the European Society of Cardiology 3-hour pathway
alone, or in conjunction with low-risk TIMI (0 or 1), GRACE (≤108), EDACS (<16)
or HEART (≤3) scores. Myocardial infarction or cardiac death at 30-days occurred in
14.3% (276/1,935). The ESC pathway ruled out 70% with 27 missed events giving a
negative predictive value (NPV) of 97.9% (95% confidence interval [CI], 97.1 to
98.6%). Addition of a HEART score ≤3 reduced the proportion ruled out by the ESC
pathway to 25%, but improved the NPV to 99.7% (95%CI 99.0 to 100%, P<0.001).
The novel pathway ruled out 65% with three missed events for a NPV of 99.7%
(95%CI 99.4 to 99.9%). No risk score improved the NPV, but all reduced the
proportion ruled out (24-47%, P<0.001 for all).
Whilst myocardial infarction due to atherosclerotic plaque rupture and thrombosis
(type 1) is well described, the natural disease course of myocardial infarction due to
oxygen supply-demand imbalance without atherothrombosis (type 2) is poorly
understood. I aimed to define long-term outcomes and explore risk stratification in
patients with type 2 myocardial infarction and myocardial injury. Consecutive patients
(n=2,122) with elevated cardiac troponin I concentrations (≥0.05 μg/L) were identified
at a tertiary cardiac centre. All diagnoses were adjudicated as per the Universal
Definition of Myocardial Infarction. The primary outcome was all-cause death.
Secondary outcomes included major adverse cardiovascular events (MACE; non-fatal
myocardial infarction or cardiovascular death) and non-cardiovascular death. To
explore competing risks, cause-specific hazard ratios were obtained using Cox
The adjudicated index diagnosis was type 1 or type 2 myocardial infarction or
myocardial injury in 1,171 (55.2%), 429 (20.2%) and 522 (24.6%) patients,
respectively. At five years, all-cause death rates were higher in those with type 2
myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1
myocardial infarction (36.7%). The majority of excess deaths in those with type 2
myocardial infarction or myocardial injury were due to non-cardiovascular causes (HR
2.32, 95%CI 1.92-2.81, versus type 1 myocardial infarction). Despite this, the
observed crude MACE rates were similar between groups (30.6% versus 32.6%), with
differences apparent after adjustment for co-variates (HR 0.82, 95%CI 0.69-0.96).
Coronary heart disease was an independent predictor of MACE in those with type 2
myocardial infarction or myocardial injury (HR 1.71, 95%CI 1.31-2.24). Patients with
type 2 myocardial infarction were less likely to receive secondary prevention therapy,
suggesting a treatment gap may exist and there may be potential to modify clinical
A risk stratification threshold has been defined using high-sensitivity cardiac troponin
I which identifies patients at very low risk of myocardial infarction or cardiac death.
A diagnostic pathway incorporating this risk stratification threshold appears safer than
established guidelines which apply the 99th centile alone. The use of clinical risk
scores does not appear to improve the safety of this approach, however, does
significantly reduce efficacy. Overall, these findings demonstrate the potential of high-sensitivity
cardiac troponin testing to improve the efficiency of the assessment of
patients with suspected acute coronary syndrome without compromising patient safety.
The observations in those with myocardial injury and infarction have identified a
phenotype of patients with type 2 myocardial infarction and coronary artery disease
who are at increased cardiovascular risk, and who may benefit from targeted secondary
prevention. The studies presented will inform the design of future clinical trials, and
may inform international guidelines for the assessment of patients with suspected acute
|dc.publisher||The University of Edinburgh||en
|dc.relation.hasversion||Chapman, AR, Adamson PA, Mills NL. Assessment and classification of patients with myocardial injury and infarction in clinical practice. Heart. 2017;103:10-18||en
|dc.relation.hasversion||Chapman AR, Mills NL. A single blood test to rule-out acute coronary syndrome. Heart. 2017;104:632-33||en
|dc.relation.hasversion||Chapman AR, Mills NL. Refining the diagnosis of Type 2 Myocardial Infarction. JAMA Cardiology. 2017;2:106.||en
|dc.relation.hasversion||Chapman AR, Lee KK, McAllister DA, Cullen L, Greenslade JH, Parsonage W, Worster A, Kavsak PA, Blankenberg S, Neumann J, Söerensen NA, Westermann D, Buijs MM, Verdel GJE, Pickering JW, Than MP, Twerenbold R, Badertscher P, Sabti Z, Mueller C, Anand A, Adamson P, Strachan FE, Ferry AV, Sandeman D, Gray A, Body R, Keevil B, Carlton E, Greaves K, Korley FK, Metkus TS, Sandoval Y, Apple FS, Newby DE, Shah AS, Mills NL. Association of High-Sensitivity Cardiac Troponin I Concentration With Cardiac Outcomes in Patients With Suspected Acute Coronary Syndrome. JAMA. 2017;318(19):1913-1924.||en
|dc.relation.hasversion||Chapman AR, Shah AS, Lee KK, Anand A, Francis O, Adamson P, McAllister D, Strachan FE, Newby DE, Mills NL. Long term outcomes in patients with type 2 myocardial infarction and myocardial injury. Circulation. 2017;318(19):1913-1924.||en
|dc.relation.hasversion||Chapman AR, Anand A, Boeddinghaus J, Ferry AV, Sandeman D, Adamson P, Andrews JPM, Tan S, Cheng S, D’Souza M, Orme K, Strachan FE, Nestelberger T, Twerenbold R, Badertscher P, Reichlin T, Gray AJ, Shah AS, Mueller C, Newby DE, Mills NL. Comparison of the efficacy and safety of novel rule-out pathways for acute myocardial infarction. Circulation. 135, 1586-1596.||en
|dc.relation.hasversion||MILLER-HODGES, E., ANAND, A., SHAH, A. S. V., CHAPMAN, A. R., GALLACHER, P., LEE, K. K., FARRAH, T., HALBESMA, N., BLACKMUR, J. P., NEWBY, D. E., MILLS, N. L. & DHAUN, N. 2018. High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients With Renal Impairment Presenting With Suspected Acute Coronary Syndrome. Circulation, 137, 425-435.||en
|dc.relation.hasversion||SHAH, A. S., ANAND, A., SANDOVAL, Y., LEE, K. K., SMITH, S. W., ADAMSON, P. D., CHAPMAN, A. R., LANGDON, T., SANDEMAN, D., VASWANI, A., STRACHAN, F. E., FERRY, A., STIRZAKER, A. G., REID, A., GRAY, A. J., COLLINSON, P. O., MCALLISTER, D. A., APPLE, F. S., NEWBY, D. E. & MILLS, N. L. 2015a. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet, 386, 2481-8.||en
|dc.relation.hasversion||SHAH, A. S. V., ANAND, A., CHAPMAN, A. R., NEWBY, D. E. & MILLS, N. L. 2016. Measurement of cardiac troponin for exclusion of myocardial infarction - Authors' reply. Lancet, 387, 2289-2291.||en
|dc.relation.hasversion||SHAH, A. S. V., SANDOVAL, Y., NOAMAN, A., SEXTER, A., VASWANI, A., SMITH, S. W., GIBBINS, M., GRIFFITHS, M., CHAPMAN, A. R., STRACHAN, F. E., ANAND, A., DENVIR, M. A., ADAMSON, P. D., D'SOUZA, M. S., GRAY, A. J., MCALLISTER, D. A., NEWBY, D. E., APPLE, F. S. & MILLS, N. L. 2017. Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study. Bmj, 359, j4788.||en
|dc.subject||high-sensitivity cardiac troponin I assay||en
|dc.subject||cardiac troponin testing||en
|dc.subject||risk stratification threshold||en
|dc.title||Improving the risk stratification, diagnosis and classification of patients with suspected myocardial infarction||en
|dc.type||Thesis or Dissertation||en
|dc.type.qualificationname||PhD Doctor of Philosophy||en