ISCHEMIA trial: do the new stable chest pain guidelines need updating?

Br J Cardiol 2021;28(1)doi:10.5937/bjc.2021.004 Leave a comment
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The European Society of Cardiology (ESC) updated their guidelines on stable chest pain in 2019,1 and recommended the use of either imaging stress tests or computed tomography (CT) coronary angiography (CTCA). They emphasised the importance of imaging stress tests or CT fractional flow reserve (CT-FFR) as a second test, to assess any coronary stenoses found on CTCA. The National Institute for Health and Care Excellence (NICE) 2016 guidelines, on stable chest pain,2 recommend CTCA for all patients with new-onset chest pain and, in a separate guideline in 2017,3 recommended CT-FFR to assess coronary stenoses. This need for a second test for the assessment of the significance of coronary stenoses is to reduce the need for invasive coronary angiography (ICA), because CTCA can be associated with false-positive results, as it can overestimate the degree of coronary stenosis, compared with ICA.4


For UK healthcare professionals only

The recently published ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial is likely to change this practice.5 The ISCHEMIA trial compared medical therapy with invasive management in patients with proven ischaemia, after excluding patients with left main stem (LMS) stenosis with CTCA, and found no difference in outcome. We suggest that the ISCHEMIA trial results are likely to shift clinical practice towards CTCA as the primary diagnostic test for new chest pain.

Current guidelines

The updated ESC guidelines1 on new stable chest pain, published in 2019, recommended investigation based on the likelihood of a patient having coronary artery disease (CAD). They provided a risk score, based on gender, age and typicality of chest pain, to assess the likelihood of having CAD, and recommended investigation for those with a risk score above 15%. They allowed for the use of both CTCA or imaging stress tests, as first-line tests, but they emphasised that CTCA is more effective in those with low-to-intermediate likelihood of having CAD, because of the excellent negative-predictive value, and that imaging stress tests are more effective in those with intermediate-to-high likelihood of having CAD, because they have a high positive-predictive value in high-prevalence populations. Furthermore, they emphasised that when CTCA is used, and significant coronary stenoses are found (50–90% stenosis), imaging stress tests or CT-FFR are needed to confirm the presence of ischaemia. Naturally, if CTCA is used in patients with high likelihood, this need for second-line testing to assess the functional significance of coronary stenoses would increase, thus leading to a higher proportion of patients requiring two tests, with the additive cost.

The NICE guidelines,2 on new stable chest pain, published in 2016, took a much simpler approach where they recommended that risk scores should not be used and that all patients with new stable chest pain, whether typical or atypical, should be investigated with CTCA and that imaging stress tests should only be used in those where the CTCA is ‘inconclusive’. A subsequent NICE guideline in 2017,3 recommended the use of CT-FFR when a stenosis is identified on CTCA, to assess its functional significance and act as a gatekeeper to ICA, to avoid large numbers of patients going on to have ICA as a result of a significant coronary stenosis on CTCA, which is often found to be less significant on ICA. This is because CTCA can overestimate the degree of stenosis because of its lower spatial resolution.4

Impact of the ISCHEMIA trial

The recent publication of the ISCHEMIA trial (n=5,179)5 will mean that both these guidelines will need updating, sooner than planned. ISCHEMIA was the largest clinical trial randomising patients to optimal medical therapy (OMT) versus invasive management, with the aim of full revascularisation, in patients with moderate-to-severe ischaemia on stress testing (75% with imaging stress tests and 25% with exercise electrocardiogram [ECG]), followed by CTCA, to exclude patients with >50% LMS stenosis and exclude patients with non-obstructive CAD. The rationale for the ISCHEMIA trial was to build on COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation)6 and BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes)7 trials, which demonstrated that in patients with stable ischaemic heart disease (SIHD), an initial management strategy of revascularisation plus OMT did not reduce the risk of death or myocardial infarction (MI) compared with OMT alone. Both trials randomised patients after ICA. The ISCHEMIA trial randomised patients with SIHD after CTCA instead.

ISCHEMIA found no difference in a combined primary outcome of death, MI, resuscitated cardiac arrest, unstable angina or heart failure between the two strategies. However, there was a reduction in angina in the invasive strategy and 26% of patients in the OMT strategy crossed over to invasive management, over the four-year follow-up, and 21% of patients in the OMT strategy were revascularised. If we accept the findings of ISCHEMIA, that there is no clinical advantage in early revascularisation and that OMT should be tried first, which would be consistent with most guidelines, then we will need to exclude significant LMS disease, and CTCA should become the first-line test for all new stable chest pain patients. However, there will be no need to investigate patients with a second-line test to assess for the significance of a coronary stenosis.

Hence, the, once controversial, NICE 2016 guideline has gained further credibility following the publication of ISCHEMIA, albeit with some caveats. The NICE 2017 recommendation to use CT-FFR to act as a gatekeeper to ICA may no longer be needed. For patients with ongoing symptoms despite a period of OMT, there will be two options, which will be guided by the symptoms and the initial CTCA findings. One option, will be to proceed directly to ICA and possible revascularisation. The other, would be to undertake an imaging stress test to confirm the presence of ischaemia and guide appropriate revascularisation. Cardiac magnetic resonance (CMR) stress perfusion can be used to assess for the presence of inducible ischaemia and ischaemic territory, without radiation. In the MR-INFORM (MR Perfusion Imaging to Guide Management of Patients With Stable Coronary Artery Disease) trial,8 patients with stable angina were randomised to ICA with invasive-FFR-guided revascularisation versus CMR-stress-perfusion-guided revascularisation. The CMR approach led to fewer revascularisations, but with similar outcome to the invasive-FFR approach. There are similar data for stress echocardiography,9 demonstrating good correlation and prediction of outcome compared with invasive-FFR, with the advantage of significantly lower cost. Thus, initial CTCA followed by OMT and interval imaging stress test, for some of those with ongoing symptoms, as a gatekeeper to ICA, may be the most clinically effective strategy. This approach would be supported by the SCOT-Heart (Scottish COmputed Tomography of the HEART)10 five-year outcome study results, which demonstrated a reduction in death and MI in patients investigated with CTCA plus exercise ECG, compared with those investigated with exercise ECG alone. The superior outcome in the CTCA arm was ascribed to higher use of secondary prevention once atherosclerotic CAD was demonstrated on CTCA. The NICE guideline simple approach to the investigation of stable chest pain, with a single fast test, that requires minimal social contact, will be particularly helpful during the COVID-19 epidemic.

Conflicts of interest

None declared.




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