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When to use CT Angiography - Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data
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BMJ 12 June 2019
In this pooled analysis of patient level data, we show that coronary CTA is most appropriately implemented for clinical decision making in patients with suspected obstructive CAD and a pretest probability ranging from 7% to 67%. In this low-to-intermediate clinical probability range, coronary CTA was able to accurately stratify patients into those with a disease post-test probability of below 15%, in whom other reasons for the chest pain should be considered, and those with a probability above 50%, in whom further testing is recommended.3
What is already known on this topic
• Coronary computed tomography angiography (CTA) is an accurate non-invasive alternative to invasive coronary angiography, and can rule out coronary artery disease (CAD) with high certainty
• By contrast with recent guidelines from the National Institute for Health and Care Excellence, the European Society of Cardiology recommends not considering CTA in all patients with typical and atypical angina, but only in patients with a 15-50% pretest probability of CAD, estimated by clinical information such as sex, age, and chest pain type
What this study adds
• According to a no-treat/treat threshold model, patients with a pretest probability of CAD ranging from 7% to 67% could benefit most from coronary CTA to rule out or confirm CAD
• CTA using more than 64 detector rows was empirically more sensitive and specific than CTA using up to 64 detector rows
Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients
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When Coronary CTA Is Most Appropriate for Suspected Heart Disease
Reuters
https://www.medscape.com/viewarticle/914696?src=wnl_edit_tpal&uac=27194HK&impID=2004721&faf=1
By Megan Brooks
June 22, 2019
NEW YORK (Reuters Health) - New research helps zero in on which patients with suspected coronary artery disease (CAD) will derive the most benefit from coronary computed tomography angiography (CTA).
"Our results indicate that the accuracy of coronary CTA is highest for clinical decision making if probability of coronary disease is between 7% and 67%," lead authors Dr. Robert Haase and Dr Marc Dewey from Charite - University Medicine Berlin in Germany, told Reuters Health by email.
"Until now, guidelines recommend to consider CTA in stable chest pain either in all patients with angina pectoris (National Institute for Health and Care Excellence) or only those with 15-50% probability of coronary disease (European Society of Cardiology)," they explained.
Coronary CTA is an accurate non-invasive alternative to invasive coronary angiography and can rule out CAD with high certainty. But it remains unclear which patients might benefit the most from the procedure, the authors note in a report online June 12 in the BMJ.
They designed their study to see whether coronary CTA should be performed in patients with any clinical probability of CAD and whether the diagnostic performance differs by patient subgroup. The study was a meta-analysis of individual patient data (n=5332) from 65 prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard.
According the results, at a pretest probability of 7%, the positive predictive value of coronary CTA was 50.9% and the negative predictive value was 97.8%. The corresponding values at a pretest probability of 67% were 82.7% and 85.0%. The overall sensitivity and specificity of coronary CTA were 95.2% and 79.2%, respectively.
"In this low-to-intermediate clinical probability range, coronary CTA was able to accurately stratify patients into those with a disease post-test probability of below 15%, in whom other reasons for the chest pain should be considered, and those with a probability above 50%, in whom further testing is recommended," write the researchers.
Coronary CTA using more than 64 detector rows was empirically more sensitive and specific than CCTA using up to 64 detector rows, "indicating that recent CTA technology with more than 64 rows should be used," they note.
The diagnostic performance of CCTA was not significantly influenced by type of angina pectoris, but it was slightly higher in men and lower in older patients.
This meta-analysis using individual patient data can "help physicians in better identifying the patients for whom coronary CTA is the most appropriate diagnostic test," they conclude in their article.
The study was funded by the joint program of the German Research Foundation (DFG) and the German Federal Ministry of Education and Research. Several authors disclosed relationships with various pharmaceutical companies.
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Abstract
Objective To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients.
Design Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies.
Data sources Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators.
Eligibility criteria for selecting studies Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups.
Results Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)).
Conclusions In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients.
Introduction
It is currently unclear in which subgroups of patients with suspected coronary artery disease (CAD) computed tomography angiography (CTA) has highest diagnostic clinical performance. Current guidelines recommend choosing the type of first line imaging test by taking the pretest probability of CAD into account, because it substantially affects diagnostic accuracy.123 According to the most recent recommendation of the National Institute for Health and Care Excellence,4 coronary CTA should be the primary imaging test in patients with suspected CAD and possible angina, while the guidelines of the European Society of Cardiology on the management of CAD recommend considering CTA only in patients with a CAD pretest probability of 15-50%.34 Moreover, little is known about CTA’s diagnostic performance in clinically important patient subgroups such as sex, age, and angina pectoris type and its association with the estimated clinical pretest probability of CAD.
Optimising the use of diagnostic imaging tests in patients with suspected CAD is crucial, given that about two thirds of invasive coronary angiograms performed in Europe and the United States show no evidence of obstructive CAD and increasing use of cardiac imaging tests poses a burden on healthcare costs.56 CTA has the potential to reliably exclude obstructive CAD,78 while halving the events of coronary heart disease after five years of follow-up9 and improving the diagnostic yield of coronary angiography.810 Its implementation as a first line diagnostic imaging test in patients with suspected CAD remains controversial. Since available diagnostic accuracy studies of CTA are moderate in size, data pooling can provide a more accurate assessment of its diagnostic performance. Individual patient data allow researchers to evaluate clinically important subgroups and individually estimate the pretest probability and to determine its effect on the diagnostic test performance of CTA. With the rationale to define the clinical context and clinical probability in which CTA has highest discriminative ability to diagnose or rule out CAD, we formed the COME-CCT (Collaborative Meta-Analysis of Cardiac CT) Consortium to pool patient level data from diagnostic accuracy studies of CTA enrolling patients with a clinical indication for coronary angiography as the reference standard for angiographic CAD.11 This work will help clinicians identify those patients with stable chest pain for whom CTA is most suitable.
Discussion
In this pooled analysis of patient level data, we show that coronary CTA is most appropriately implemented for clinical decision making in patients with suspected obstructive CAD and a pretest probability ranging from 7% to 67%. In this low-to-intermediate clinical probability range, coronary CTA was able to accurately stratify patients into those with a disease post-test probability of below 15%, in whom other reasons for the chest pain should be considered, and those with a probability above 50%, in whom further testing is recommended.3
Our study also showed that the diagnostic performance of CTA was not significantly influenced by the angina pectoris type, but it was higher in men and lower in older patients. After we excluded non-diagnostic examinations from the analysis, the accuracy of CTA improved and the difference in diagnostic performance between female and male patients became non-significant. Moreover, diagnostic examinations are now more commonly conducted by computed tomography scanners with more than 64 detector rows, which had lower rates of non-diagnostic examinations.
Clinical context and guidelines
Current European and US guidelines recommend calculating patients’ pretest probability of CAD to guide diagnostic decisions.338 The European Society of Cardiology specifically recommends considering CTA in patients with 15-50% pretest probability of obstructive CAD,3 whereas the NICE guideline recommends coronary CTA as the primary imaging test for all patients with possible angina and suspected obstructive CAD.4 Our results show that using the no-treat/treat threshold approach, CTA offers good to excellent results in pretest probability range of 7% to 67%. The procedure yields a post-test probability below 15%, where other reasons for the chest pain should be considered, in case of negative CTA (that is, NPV ≥85%); and above 50%, where ischaemia testing is recommended, in case of positive CTA (that is, PPV ≥50%). Since no IPD meta-analysis has so far investigated in which patients CTA has the highest diagnostic performance, the results presented here might have important implications for current guidelines. The results of the diagnostic performance model can also be used to define the appropriate pretest probability range depending on the NPV and PPV deemed to be acceptable for the specific diagnostic purpose.
The main clinical strength of coronary CTA is its high NPV, and this is supported by our findings, which show that CTA can also detect both obstructive and non-obstructive CAD and therefore is a suitable imaging modality to guide subsequent management.39 This may make patient management more efficient and can also lower costs, not least by reducing the high rate of negative coronary angiographies performed annually. Recently published randomised clinical trials support these assumptions. Although the PROMISE trial—which compared CTA with an initial functional testing strategy in the evaluation of chest pain—did not show a reduction in major adverse cardiovascular events (defined as death, myocardial infarction, and unstable angina needing hospital admissions, or a major procedural complication), subsequent invasive coronary angiography was more effective in the CTA group.40
The SCOT-HEART trial prospectively compared standard care with standard care plus CTA for the diagnosis of CAD in patients with recent onset chest pain.41 In the trial, CTA was found to increase diagnostic certainty, increase the identification of obstructive and non-obstructive CAD, and eliminate the need for further downstream stress imaging tests.41 Furthermore, the five year clinical outcome analysis of SCOT-HEART showed that standard care plus CTA resulted in a halving of fatal and non-fatal myocardial infarction without increasing the five year rate of coronary revascularisations but initiating more targeted preventive and anti-anginal treatments.9 However, some controversy remains about the use of coronary CTA as the first line diagnostic test in patients with stable chest pain and suspected CAD,42 and our IPD meta-analysis provides insights about in which patients CTA has highest predictive values.
Our IPD meta-analysis data can thus help physicians in better identifying the patients for whom coronary CTA is the most appropriate diagnostic test. Whether CTA can further improve clinical effectiveness in patients with a clinical indication for coronary angiography is an important question. The CAD-Man study showed that coronary CTA can reduce the need for invasive coronary angiography by up to 80% and can reduce procedural complications.8 A similar safety profile with non-inferiority of CTA versus invasive coronary angiography in terms of major cardiovascular events at one year was found in the CONSERVE trial.43 However, coronary CTA still has to be analysed in a multicentre study of patients with a clinical indication for invasive coronary angiography, and the randomised DISCHARGE trial will provide more data in this regard.44
Comparison with other studies
Meta-analyses using aggregated data from studies that mostly excluded patients with non-diagnostic CTA examinations or considered them positive have reported a mean sensitivity for CTA per patient of 97.2% to 100% and a specificity of 87.4% to 89%.2145 We found lower sensitivities and specificities when including non-diagnostic tests as false positives or negatives in our IPD analysis in a worst case scenario, confirming that the performance of diagnostic tests is lower when non-diagnostic test results are considered and not merely excluded from the analysis.16 Our data also confirm the findings of a study level meta-regression analysis suggesting a hyperbolic decrease and increase of the NPVs and PPVs with increasing pretest probability, respectively.7 We also showed that pretest probability overestimated true CAD prevalence by about 10 percentage points up to a pretest probability of 40%; while above a pretest probability of 50%, true CAD prevalence was underestimated by about 10 percentage points. Future trials should address how to improve the accuracy of pretest probability estimation in patients with suspected CAD. Also, CTA using more than 64 detector rows led to significantly higher empirical sensitivity and specificity, indicating that recent CTA technology with more than 64 rows should be used.
Criteria have been proposed to ensure a reasonable use of coronary CTA.4647 Our study can help refine these criteria by allowing to individually define the appropriateness of coronary CTA based on the patient’s clinical pretest probability. Moreover, according to our findings, one should be cautious to use CTA in patients with a clinical pretest probability exceeding 67% since the NPV drops below 85%. In addition, the odds to find obstructive CAD on CTA (and thus also the likelihood to require another invasive test after non-invasive CTA) increases with the pretest probability. On the other hand, the PPV of coronary CTA becomes rather low in patients with a pretest probability of less than 7%, so that, in this situation, about half of the positive CTA examinations would result in unnecessary further testing. For ease of understanding, we visualised the predictive values of coronary CTA depending on pretest probability in figure 2. The European Society of Cardiology guidelines suggest a pretest probability range of 15-50% for diagnostic testing with coronary CTA. In this narrower range of pretest probability, CTA had an NPV and PPV of at least 90.9% and 55.8%, respectively.
From a clinical perspective, the diagnostic performance of CTA was not influenced by the angina pectoris type and was equally effective in ruling out angiographic CAD in patients with different angina pectoris types. Even though the reductions in diagnostic performance of CTA were small, decision makers should be aware that CTA has a slightly lower accuracy in patients older than 75, and in women compared with men, if non-diagnostic CTA results are included in the analysis. As mentioned above, non-diagnostic examinations are rarely seen when using computed tomography scanners with more than 64 detector rows; and when excluding non-diagnostic examinations, performance of CTA was similar in women and men. Similarly, our results showed that women had higher heart rates than men when examined by CTA and higher rates were the only factor associated with non-diagnostic examinations. Similar diagnostic accuracy of coronary CTA in men and women was reported by a multicentre study including 291 patients48 and by two single centre studies including 570 and 1372 patients.4950 In our IPD analysis of 3473 men and 1859 women including non-diagnostic examinations, we showed a small reduction in the area under the curve of CTA in women by 0.023 compared with men (fig 3). This difference might be explained by women being more likely to have high heart rates during CTA, which was the only factor significantly associated with non-diagnostic CTA results.
Strength and limitations of study
Our study had strengths and limitations. IPD meta-analyses are considered the gold standard of systematic reviews. Even though the individual diagnostic accuracy studies were similar in terms of inclusion criteria and reference standard definitions, they varied in geographical origin and composition. Although this study was done in 22 countries and has a multicentric and multicontinental design, participation was not equally distributed across the globe, and ethnicity was not collected in data analysis. Moreover, obstructive CAD was defined by invasive coronary angiography as angiographically significant CAD in all patients, quantitative analysis of invasive angiography was used in 69% of patients, and functional definitions of CAD (eg, including invasive fractional flow reserve) were not used in the original studies. Thus, findings might not be generalisable to real world practice, although additional invasive fractional flow reserve is used in less than 10% of examinations worldwide,51 making the findings relevant for current clinical practice.
To define no-treat and treat thresholds, we estimated pretest probabilities by using the updated Diamond and Forester model (also recommended by the current the European Society of Cardiology guidelines). This calculator is validated for patients with suspected CAD referred for invasive coronary angiography, which is also the setting of this analysis. Other prediction models for pretest probabilities do not focus on this cohort but on patients referred for non-invasive assessment, as in the CONFIRM study.52 Furthermore, although results of exercise tests can also be included in pretest calculation, they are not included in currently validated probability calculators and could thus not be considered in our review.53
As shown in table 1, the most frequently used computed tomography scanners had 64 detector rows (2438 of 5332 patients); thus, CTA performance in clinical practice using state-of-the-art technology with more than 64 detector rows could have been even better. An important limitation of our IPD analysis of the clinical performance of coronary CTA was that not all 154 studies that were identified through our search strategy could be included because the responsible corresponding authors did not provide IPD. However, we sought to systematically retrieve all IPD from the studies identified by the systematic review and, despite several reminders, a relevant proportion of authors did not reply at all (56/154, 36%) or indicated that they could not participate in the COME-CCT Consortium because they had no access to original data (7/154, 5%). According to a systematic review of data retrieval in IPD meta-analyses, 68% of meta-analyses retrieved IPD from at least 80% of a median of only 14 eligible studies.54 With 154 eligible studies, our study was relevantly larger, which has been shown to complicate retrieval.54
Diagnostic performance results were similar in studies for which IPD were available versus those for which no IPD were provided. To include unpublished grey literature, we systematically asked all corresponding authors of the identified published studies about further unpublished analyses and systematically searched clinicaltrials.gov for unpublished diagnostic accuracy studies of coronary CTA and invasive coronary angiography registered in this database. With this approach, we found two unpublished studies that could be included in the COME-CCT database. Our findings did not show evidence of publication bias, but we found heterogeneity between studies, pointing to potentially unknown site specific factors that might have influenced diagnostic accuracy. All studies included patients who had suspected CAD and were clinically indicated to undergo coronary angiography. This gave us the opportunity to compare results from research CTA with clinically indicated coronary angiography in all patients to avoid verification bias. But the results are representative for patients clinically referred for coronary angiography, and there was likely to be bias particularly at the extremes of pretest probability. For instance, individuals with low pretest probability were likely to have other unmeasured risk factors that increased their clinical probability, which could have overestimated PPVs of CTA.
Conclusions
In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type, was slightly higher in men, and was lower in older patients.
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