Low-Risk, Stable Chest Pain Patients and Calcium Score of Zero
Low-Risk, Stable Chest Pain Patients and Calcium Score of Zero
There is a sizeable body of evidence with respect to CACS and stenosis on CTCA in chest pain syndromes, and in asymptomatic patients, as a screening tool. There are, however, not much published UK data supporting the recent NICE guidelines for patients referred to secondary care with stable chest pain. In this observational study, CTCA was used as a measure of coronary artery stenosis in symptomatic low-risk, stable patients with a CACS of zero. It shows a negative predictive value of 99% for significant stenosis in low-risk patients with absent calcium in their coronary arteries. However, one must be cautious in interpreting such results as, although no significant stenoses were detected on either CTCA or coronary angiogram in this patient population, 16.5% did have non-calcified stenosis as measured by CTCA.
Meta-analyses have revealed that the sensitivity and specificity of CTCA to determine significant luminal narrowing compared with the gold standard of invasive angiography can be up to 97% and 90%, respectively. In a more specific context of CACS of zero, an Italian study of 279 patients quoted sensitivity, specificity, and positive and negative predictive values of CTCA versus coronary angiography as high as 100%, 95%, 76% and 100%, respectively. The use of CACS to determine the absence of coronary artery stenosis as compared with invasive coronary angiography has also been validated by numerous studies as highlighted by Sarwar et al.'s seminal meta-analysis. It shows a negative predictive value for significant CAD, as compared with invasive coronary angiography, of 93% in the pooled data of 10,335 patients. This highlights the fact that CTCA can be an alternative measureof luminal stenosis as compared toformal angiography.
In asymptomatic patients, an absence of coronary artery calcification confers an excellent prognosis. This patient population has been shown to have a cardiovascular event rate of as low as 0.5% over four years. Hence, in the USA, there is a great drive to use CACS as a prognostic tool in asymptomatic individuals. In the UK, however, under the National Health Service (NHS), investigations are reserved for symptomatic individuals and CACShas found a niche in excluding significant CAD in low-risk, stable individuals thathave been referred to secondary care for further assessment.
The current position in Europe is that absence of calcium cannot be used to rule out coronary artery stenoses in symptomatic individuals, especially when young and with acute symptoms. However, this statement is mostly based on a study that identified 21 consecutive patients from a patient population of 2,300 over a period of two years. These are very small numbers in a single retrospective study and more research is required in this emerging field.
In the Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography Using 64 Detectors (CORE 64) substudy, Gottlieb et al. discuss that CACS of zero "does not exclude obstructive stenosis or the need for revascularisation among patients with high enough suspicion of coronary artery disease". The CORE 64 substudy does not fit in the UK context of assessing low-risk, stable patients. The patients selected for the trial were eligible for invasive coronary angiography within a month after a clinical assessment in the acute setting.
They were, hence, at an inherently intermediate-to-high risk of adverse cardiac events, regardless of their calcium scores. Although the CORE 64 study is against associating a CACS of zero with low risk of adverse events, it did also show that in the eight patients with CACS zero and low clinical probability of CAD, no obstructive CAD was detected. Moreover, in patients with CACS zero and intermediate (n=57) to high (n=7) CAD probability, 21% and 29%, respectively, had at least one significant coronary lesion. These numbers are too small to draw any meaningful conclusions but they do indicate that there is more value in having a CACS of zero in low-risk patients rather than high-risk ones, even in the presence of symptoms.
From the Coronary CT Angiography Evaluation For Clinical Outcomes International Multicenter (CONFIRM) registry, a recent study has shown that "the absence of measurable CAC significantly reduced, but did not fully exclude, the presence of obstructive CAD on current generation CCTA". Again, in contrast to the UK approach, this study applies to stable all-comers who were referred by physicians with chest pain syndromes without a detailed risk assessment to identify the true low-risk patients. The authors do quote that absent calcium confers negative predictive values of 96% and 99% for stenoses of ≥50% and ≥70%, respectively. In terms of prognosis, Sarwar et al. found a 1.8% adverse cardiovascular event rate in a pooled sample of 921 symptomatic patients with no detectable calcium on CTCA, compared with an almost 9% event rate if coronary calcium was present. This does support the argument that detection of calcification by CTCA does predict significant stenosis and adverse cardiac events.
These two studies further emphasise the importance of a careful assessment of symptoms coupled with risk profiles in a clinical setting, as is alluded to by Greenland and Bonow. We cannot depart from the fact that a test is only rendered useful if specialist clinical judgement and evaluation is applied to the suitability and interpretation of the test in the right framework to answer the right questions.
This is a small, observational, prospective study, which does not assess prognostic significance of calcium scores in a clinical setting. Long-term morbidity and mortality data are needed in this evolving area of cardiac imaging. The level of stenosis was not assessed by the gold standard, which is invasive coronary angiography, and, ultimately, CACS and CTCA are anatomical tests with no functional elements.
Discussion
There is a sizeable body of evidence with respect to CACS and stenosis on CTCA in chest pain syndromes, and in asymptomatic patients, as a screening tool. There are, however, not much published UK data supporting the recent NICE guidelines for patients referred to secondary care with stable chest pain. In this observational study, CTCA was used as a measure of coronary artery stenosis in symptomatic low-risk, stable patients with a CACS of zero. It shows a negative predictive value of 99% for significant stenosis in low-risk patients with absent calcium in their coronary arteries. However, one must be cautious in interpreting such results as, although no significant stenoses were detected on either CTCA or coronary angiogram in this patient population, 16.5% did have non-calcified stenosis as measured by CTCA.
Meta-analyses have revealed that the sensitivity and specificity of CTCA to determine significant luminal narrowing compared with the gold standard of invasive angiography can be up to 97% and 90%, respectively. In a more specific context of CACS of zero, an Italian study of 279 patients quoted sensitivity, specificity, and positive and negative predictive values of CTCA versus coronary angiography as high as 100%, 95%, 76% and 100%, respectively. The use of CACS to determine the absence of coronary artery stenosis as compared with invasive coronary angiography has also been validated by numerous studies as highlighted by Sarwar et al.'s seminal meta-analysis. It shows a negative predictive value for significant CAD, as compared with invasive coronary angiography, of 93% in the pooled data of 10,335 patients. This highlights the fact that CTCA can be an alternative measureof luminal stenosis as compared toformal angiography.
In asymptomatic patients, an absence of coronary artery calcification confers an excellent prognosis. This patient population has been shown to have a cardiovascular event rate of as low as 0.5% over four years. Hence, in the USA, there is a great drive to use CACS as a prognostic tool in asymptomatic individuals. In the UK, however, under the National Health Service (NHS), investigations are reserved for symptomatic individuals and CACShas found a niche in excluding significant CAD in low-risk, stable individuals thathave been referred to secondary care for further assessment.
The current position in Europe is that absence of calcium cannot be used to rule out coronary artery stenoses in symptomatic individuals, especially when young and with acute symptoms. However, this statement is mostly based on a study that identified 21 consecutive patients from a patient population of 2,300 over a period of two years. These are very small numbers in a single retrospective study and more research is required in this emerging field.
In the Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography Using 64 Detectors (CORE 64) substudy, Gottlieb et al. discuss that CACS of zero "does not exclude obstructive stenosis or the need for revascularisation among patients with high enough suspicion of coronary artery disease". The CORE 64 substudy does not fit in the UK context of assessing low-risk, stable patients. The patients selected for the trial were eligible for invasive coronary angiography within a month after a clinical assessment in the acute setting.
They were, hence, at an inherently intermediate-to-high risk of adverse cardiac events, regardless of their calcium scores. Although the CORE 64 study is against associating a CACS of zero with low risk of adverse events, it did also show that in the eight patients with CACS zero and low clinical probability of CAD, no obstructive CAD was detected. Moreover, in patients with CACS zero and intermediate (n=57) to high (n=7) CAD probability, 21% and 29%, respectively, had at least one significant coronary lesion. These numbers are too small to draw any meaningful conclusions but they do indicate that there is more value in having a CACS of zero in low-risk patients rather than high-risk ones, even in the presence of symptoms.
From the Coronary CT Angiography Evaluation For Clinical Outcomes International Multicenter (CONFIRM) registry, a recent study has shown that "the absence of measurable CAC significantly reduced, but did not fully exclude, the presence of obstructive CAD on current generation CCTA". Again, in contrast to the UK approach, this study applies to stable all-comers who were referred by physicians with chest pain syndromes without a detailed risk assessment to identify the true low-risk patients. The authors do quote that absent calcium confers negative predictive values of 96% and 99% for stenoses of ≥50% and ≥70%, respectively. In terms of prognosis, Sarwar et al. found a 1.8% adverse cardiovascular event rate in a pooled sample of 921 symptomatic patients with no detectable calcium on CTCA, compared with an almost 9% event rate if coronary calcium was present. This does support the argument that detection of calcification by CTCA does predict significant stenosis and adverse cardiac events.
These two studies further emphasise the importance of a careful assessment of symptoms coupled with risk profiles in a clinical setting, as is alluded to by Greenland and Bonow. We cannot depart from the fact that a test is only rendered useful if specialist clinical judgement and evaluation is applied to the suitability and interpretation of the test in the right framework to answer the right questions.
Study Limitations
This is a small, observational, prospective study, which does not assess prognostic significance of calcium scores in a clinical setting. Long-term morbidity and mortality data are needed in this evolving area of cardiac imaging. The level of stenosis was not assessed by the gold standard, which is invasive coronary angiography, and, ultimately, CACS and CTCA are anatomical tests with no functional elements.
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