Author + information
- Received May 8, 2018
- Revision received July 10, 2018
- Accepted July 23, 2018
- Published online July 1, 2019.
- Tom Finck, MDa,
- Julius Hardenberg, MDa,
- Albrecht Will, MDa,
- Eva Hendrich, MDa,
- Bernhard Haller, PhDb,
- Stefan Martinoff, MDa,
- Jörg Hausleiter, MDc and
- Martin Hadamitzky, MDa,∗ ()
- aInstitut für Radiologie und Nuklearmedizin, Deutsches Herzzentrum München, Klinik an der Technische Universität München, Munich, Germany
- bInstitut für Medizinische Informatik, Statistik und Epidemiologie, Klinikum rechts der Isar der Technische Universität München, Munich, Germany
- cMedizinische Klinik und Poliklinik I, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
- ↵∗Address for correspondence:
Priv.-Doz. Dr. med. Martin Hadamitzky, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 München, Germany.
Objectives The aim of this study was to determine the long-term prognostic power of coronary computed tomography angiography (CTA) to predict cardiac death and nonfatal myocardial infarction.
Background Prognostic usefulness of coronary CTA has been confirmed for short- and intermediate-term follow-up. However, long-term data for prognostic usefulness is still lacking, but is paramount because of the slowly progressing nature of coronary artery disease (CAD).
Methods A total of 2,011 patients with suspected but not previously diagnosed CAD were examined by coronary CTA. Mean follow-up was 10.0 years (interquartile range [IQR]: 8.1 to 11.2 years). Cox proportional hazards analysis was used for the composite endpoint of cardiac death and nonfatal myocardial infarction. Event-free survival, which was defined as the years it took to reach a cumulative 1% risk for the composite endpoint and reclassification from clinical risk, was calculated.
Results The study endpoint was reached in 58 patients (42 cardiac deaths, 16 nonfatal myocardial infarctions). Coronary CTA-assessed CAD severity (normal, nonobstructive, or obstructive) showed the best correlation with the endpoint, with an adjusted c-index of 0.704, compared with a univariate c-index of 0.622 for the clinical risk model (Morise score) alone. The annual event rate for patients with normal coronary arteries on baseline coronary CTA was 0.04%, which translated to an event-free survival period of 10 years. The highest annual event rate of 1.33% was found in patients with 3-vessel obstructive CAD. Reclassification from clinical risk (Morise score) was possible in approximately two-thirds of all patients (68%; p < 0.0001), which led to a substantial reduction of the intermediate-risk group (reduction from 74% to 15%) in favor of the low-risk group (increase from 20% to 83%).
Conclusions Patients with normal coronary CTA results benefitted from an event-free survival period of 10 years against cardiac death and nonfatal myocardial infarction. Risk stratification according to coronary CTA results allowed for the delineation of clearly diverging prognostic groups and reclassified approximately two-thirds of all patients from clinical risk groups.
- coronary artery disease
- coronary computed tomographic angiography
- event-free survival
Coronary computed tomography angiography (CTA) is an established noninvasive imaging modality to assess CAD. The high diagnostic accuracy of coronary CTA has put it in the spotlight as a low-risk alternative to invasive angiography in clinical workflow (1).
Coronary CTA has the ability to detect both calcified and noncalcified plaques as a sign of early CAD, and therefore, it can be used as a prognostic tool to assess cardiovascular risk.
The prognostic value of coronary CTA in the short-to-intermediate term has been demonstrated by multiple single-center and multicenter studies. To date, the largest follow-up studies have evaluated the prognostic implications of coronary CTA in >25,000 patients, with a mean follow-up of 5.6 years, whereas the longest follow-up was 7.8 years in a cohort of 1,469 patients (2–8).
However, CAD is a slowly developing disease in which adverse clinical events often occur with a long latency to morphological vessel changes. Because the maximum follow-up of previously mentioned studies was approximately 5 to 6 years, longer observation periods will be of great importance to establish coronary CTA as a useful prognostic tool to assess cardiovascular risk.
We therefore extended our follow-up of previously published studies and adjudicated outcomes to 10 years (9). The objective of this study was to validate the negative predictive value of coronary CTA and to investigate the incremental predictive value of different coronary CTA parameters in risk prediction compared with standard clinical risk assessment. We investigated if an event-free survival period against cardiac events could be defined and if risk reclassification could be achieved based on coronary CTA results.
All consecutive inpatients and outpatients with suspected, but not previously diagnosed, CAD who underwent coronary CTA at our institution from October 10, 2004 to October 31, 2008 were eligible for analysis. Patients were excluded if they were in an acute life-threatening situation, including patients with acute coronary syndromes and patients who did not have stable sinus rhythm during the examination. Written informed consent was obtained before the investigation. Information about age, weight, and height of the patient, symptoms, cardiac history, and current medication was collected. The following cardiac risk factors were recorded: 1) presence and degree of hypertension (for binary analysis, hypertension was defined as a systolic blood pressure of >140 mm Hg or administration of antihypertensive therapy); 2) diabetes mellitus (defined as fasting blood glucose level >7 mmol/l or use of oral antidiabetic therapy); 3) smoking (defined as current smoker or previous smoker within the last year); and 4) positive family history (defined as presence of cardiac death or myocardial infarction in first-degree relatives younger than 55 years in men or younger than 65 years in women). In addition, laboratory results for total cholesterol, low-density lipoprotein and the high-density lipoprotein fraction, and triglycerides were collected. The Morise score was calculated from these data. This score evaluates both risk factors and clinical symptoms, and was best suited to evaluate cardiac risk in our study population (10). The study design was approved by the local ethics committee.
The detailed scan protocol has been described elsewhere (9). Different CT hardware was used during the study period: a 64-slice, single-source CT scanner was used from October 2004 to September 2006, and a 64-slice, dual-source CT scanner was used from October 2006 to October 2008 (both Siemens Healthineers, Erlangen, Germany). A recently proposed cardiac-specific conversion factor of 0.026 mSv/(mGy × cm) was used to estimate the radiation effective dose (11).
Coronary artery segmentation was performed according to the simplified American Heart Association classification, using the first 15 segments of the original 18 segments. Vessel segments >1.5 mm diameter were evaluated by 2 physicians who had read >400 cardiac CTs at the time the scan was performed. Disagreements were settled by consensus.
Each stenosis was rated visually according to the following groups: no stenosis (0%); minimal stenosis (1% to 24%); and mild (25% to 49%), moderate (50% to 69%), and severe (≥70%) stenosis. Segments with artifacts were assigned to the most appropriate group. From the primary analysis, the following coronary CTA scores were calculated, with CAD severity assessed as proposed by Ostrom et al. (12): normal, nonobstructive, and obstructive (which was itself divided into 1-, 2-, and 3- vessel obstructive). The segment involvement score (SIS) was the number of segments with any stenosis ≥25% or any calcified, mixed, or noncalcified plaque irrespective of the degree of stenosis. Addition of affected segments resulted in a score ranging from 0 to 15.
The CADRADS (Coronary Artery Disease Reporting and Data System) was used as proposed by Cury et al. (13).
Follow-up information was obtained by clinical visits if available, by detailed questionnaires sent by mail, or if the questionnaires were not returned, by phone contact. All reported events were verified by hospital records or phone contact with the attending physician, if possible, and adjudicated by 2 physicians in consensus. The primary endpoint of this study was a composite of cardiac death or nonfatal myocardial infarction.
Definition of event-free survival
In an analogy to established practice, low patient risk was defined as a cumulative event rate for cardiac death and nonfatal myocardial infarction as <1% (14). In the setting of our study, event-free survival was defined as the duration that a patient remained in the low-risk category, calculated by the number of years it took a patient to cumulatively reach 1% probability of cardiac death or nonfatal myocardial infarction.
Categorical variables were expressed as frequencies and percentages; continuous variables were described as mean ± SD or as median (interquartile range [IQR]) for time intervals. All statistical evaluations were based on the event-free survival for the study endpoint using the Kaplan-Meier method. Hazard ratios and multivariable analyses were calculated and performed using the Cox proportional hazards method. Concordance c-indexes were evaluated from time-to-event data as proposed by Harrell et al. (15). In the multivariable model, the incremental c-index for adding the coronary CTA variable to clinical risk scores was calculated. Non-categorical net reclassification improvement, as proposed by Pencina et al. (16), was calculated. Reclassification was derived from the observed annual event rate (AER) for the composite endpoint in the 6 subgroups defined by the Morise score risk and the presence of obstructive CAD, with low-risk patients defined as having an annual risk of <0.5% and high-risk patients defined as having an annual risk of >1%. All statistical tests were performed 2-sided, and a significance level of 5% was used. The statistical package R version 2.10.1, including the package rms (R Foundation, Vienna, Austria), was used for statistical analysis (17,18).
Study population and patient characteristics
During the study period, 2,176 patients with suspected, but not previously diagnosed, CAD underwent coronary CTA. A total of 77 patients were excluded; 5 patients with acute aortic dissection who underwent coronary CTA as a pre-operative assessment, 1 patient because of life-threatening conditions, and 71 patients who did not have stable sinus rhythm during the scan. Of the remaining 2,099 patients, 2011 patients were contacted for follow-up at a median of 10.0 years (IQR: 8.1 to 11.2 years) and were included in the study. This translated to a follow-up rate of 96%.
Mean patient age was 59 ± 11 years; 1,328 patients (66%) were men. The pre-test risk assessed by the Morise risk score was low in 399 patients (20%), moderate in 1,498 patients (74%), and high in 114 patients (6%). Detailed patient baseline characteristics are provided in Table 1.
Endpoints and clinical correlation
With a total of 42 cardiac deaths and 16 nonfatal myocardial infarctions, the study endpoint occurred in a total of 58 patients (3% of study population). Fifty-three patients died from noncardiac causes, which resulted in a total of 111 deaths.
The Morise score had a decent discriminatory ability for composite endpoints, with a c-index of 0.622. Hazard ratios for the clinical risk model are shown in Table 2.
The CT scan was performed on a 64-slice, single-source scanner in 1,166 patients and on a 64-slice dual-source scanner in 845 patients. Median radiation exposure for coronary CTA was 13.9 mSv (IQR: 10.4 to 17.8 mSv).
Analysis for CAD severity showed that 570 patients had normal coronary arteries, 897 patients had nonobstructive coronary stenosis, and 544 patients had obstructive CAD. Of these patients, 274 had 1-vessel obstructive CAD, 174 patients had 2-vessel obstructive CAD, and 96 patients had 3-vessel obstructive CAD.
Investigation for CADRADS resulted in 570 patients (28%) being classified as CADRADS 0, 310 patients (15%) as CADRADS 1, 587 patients (29%) as CADRADS 2, 415 patients (21%) as CADRADS 3, 87 patients (5%) as CADRADS 4a, 29 patients (1%) as CADRADS 4b, and 13 patients (1%) as CADRADS 5.
The mean SIS was 1.9 ± 2.5 segments.
Discriminatory ability of coronary CTA parameters
For primary endpoint analysis, CAD severity and CADRADS classification correlated best with outcome. For CAD severity, the c for improvement over clinical risk was 0.704 (p < 0.001). The predictive power of the CADRADS classification was slightly lower, with a c for improvement of 0.673 (p < 0.001). SIS had a comparable predictive power, with a c for improvement over clinical risk of 0.666 (p < 0.001). Hazard ratio analysis for the different coronary CTA parameter groups is shown in Table 3.
Receiver-operator curves for the Morise score as a pre-test clinical parameter and a stepwise model after addition of coronary CTA parameters (CADRADS, CAD severity, SIS) are given in Figure 1. Kaplan-Meier curves for patients with normal, nonobstructive, and obstructive coronary segments, CADRADS groups, and different degrees of SIS are shown in Figure 2. No significant time dependency on survival analysis was noted (data not shown).
Annual event rates for endpoints ranged from 0.04% (95% confidence intervals: 0.01% to 0.16%) in patients with normal coronary arteries to 1.33% (95% confidence intervals: 0.74% to 2.41%) for patients with 3-vessel obstructive CAD.
Figure 3 shows the average event-free survival period of all study participants as a function of coronary CTA findings and clinical parameters. Within the complete cohort, but also when we analyzed independently of the Morise scores, sex, age, or presence of diabetes, we noticed a strikingly lower AER for patients with normal coronary arteries on baseline coronary CTA in comparison to patients with obstructive or nonobstructive vessel changes. Event-free survival for all investigated patients aged younger than 60 years with normal coronary arteries reached the full observation length of 10 years, independent of clinical risk, age, sex, or presence of diabetes. In contrast, the overall event-free survival for patients with obstructive or nonobstructive stenoses fell to 2.2 years, and fell further to 1.4 years in patients with diabetes.
Reclassification from clinical risk
By clinical risk assessment (Morise score), 399 (20%) patients were classified as low risk, 1,498 (74%) as intermediate risk, and 114 (6%) as high risk. Further classification by CAD severity led to 1,674 (83%) patients being classified as low risk, 308 (15%) as intermediate risk, and 29 (2%) as high risk. As such, coronary CTA allowed risk reclassification for approximately two-thirds of all patients for the composite endpoint (Figure 4). Non-categorical net reclassification improvement for the composite endpoint was 68% (p < 0.001).
For patients with suspected but not previously diagnosed CAD, we demonstrated that 1) the lack of CAD on baseline coronary CTA translated into an excellent long-term prognosis and conferred an event-free survival of 10 years against hard cardiac events; 2) quantitative assessment of both coronary vessel obstruction and the generalized plaque burden, irrespective of luminal obstruction, identified patients at higher long-term cardiac risk; and 3) approximately two-thirds of all patients were reclassified regarding their long-term cardiac risk.
Analysis of 10-year follow-up data within our patient cohort revealed AERs of <0.05% for patients with no CAD on baseline coronary CTA. Although similar observations were made at 2- and 5- year follow-up, long-term prognostic data were paramount because these data better reflect the slowly evolving process of CAD (9,19). Similar to our findings, Ostrom et al. (12) analyzed electron-beam CT angiography data from 2,538 consecutive patients over a mean follow-up of 6.5 years and noted a survival rate of 98.3% in patients with normal coronary arteries. After follow-up of >6 years, Clerc et al. (20) reported comparable results, with 0% incidence of cardiac death, myocardial infarction, and elective revascularization in 153 patients with no CAD at baseline coronary CTA.
Illustrated as event-free survival, all patients (except older adults) with normal coronary arteries on baseline coronary CTA had a cumulative event rate of <1% during the whole observation length of 10 years, irrespective of clinical risk, whereas patients with obstructive or nonobstructive stenoses had an event-free survival period of only 2.1 years.
The concept of a “warranty period” for coronary artery calcium was investigated previously by Valenti et al. (21), who showed an event-free survival of 15 years against all-cause mortality in patients with a coronary calcium score of 0 Agatston units.
Normal findings during dobutamine echocardiography, N13-ammonia positron emission tomography, and magnetic resonance stress imaging had shorter event-free survival periods of 1, 3, and 2 years in men (4 years in women), respectively (22–24).
The longest event-free survival for stress−rest single-photon emission computed tomography (SPECT) was described by Romero-Farina et al. (25) in nearly 3,000 patients with normal stress and rest SPECT using a composite endpoint of cardiac death and nonfatal myocardial infarction. For patients aged younger than 65 years, they calculated an event-free survival period of 5 years (25). The shorter event-free survival periods for functional image testing was easily explained by the fact that it relied on hemodynamically relevant coronary stenoses typical for a more progressive stage of CAD. By not only assessing obstructive coronary stenosis but also subtle coronary changes in earlier stages of CAD, coronary CTA can assess the whole range of coronary artery changes. This, and the high negative predictive value during a 10-year follow-up period as shown in this study, emphasized the particular usefulness of this modality in the low to intermediate pre-test risk population. This agrees with a recent meta-analysis of noninvasive cardiac investigations (coronary CTA, cardiovascular magnetic resonance, exercise electrocardiographic testing, positron emission tomography, stress echocardiography, and SPECT). Pooled AERs for >12,000 patients were significantly different among modalities, but the lowest event rate of cardiac death or myocardial infarction occurred in patients with normal findings on coronary CTA (26).
The event-free survival period in our patient cohort was, by method, limited by the follow-up period of 10 years. Extrapolating the AER of 0.04% for patients with normal findings on baseline coronary CTA would logically translate into a substantially longer period of low cardiac risk.
As expected, CAD severity or CADRADS, which are both parameters that directly quantify the degree of luminal obstruction, but also the SIS, which takes into account nonobstructive coronary lesions, all had comparable, good predictive power for the composite endpoint. The levels of CADRADS and/or CAD severity and SIS certainly overlapped to a certain degree because coronary stenoses are associated with a more advanced stage of CAD. However, the decision for post-coronary CTA revascularization was mainly based on the presence or lack of obstructive CAD. Therefore, the similar outcome of patients with obstructive disease and those with a high SIS showed that even if a coronary stenosis, which is the hallmark of CAD, can be alleviated by revascularization, the long-term cardiovascular risk in such patients remains substantially elevated. This can be partly explained by previous observations that most myocardial infarctions occur after acute rupture of nonstenotic plaques and should further underline the strength of coronary CTA in assessing the generalized coronary plaque burden (27). In accordance with our observations, Dougoud et al. (28) identified the number of segments with plaques of >25% stenosis, as given by SIS, as an independent predictor of cardiac death, myocardial infarction, or urgent revascularization on follow-up of <7 years. Min et al. (29) found an absolute difference in all-cause mortality of 5.9% between patients with a SIS of >5 and a SIS of ≤5 after a 15-month follow-up of 1,127 patients.
Although prognostic groups could be delineated during the entire follow-up period, the survival curves of patient subgroups with a high SIS or obstructive stenoses dipped after approximately 5 years, whereas the lower risk groups followed a more linear decrease. This is of interest because it would be expected that events in high-risk subgroups would occur earlier and underlined the need for longer follow-up durations after coronary CTA.
A valid diagnostic test should be able to clearly detect low- and high-risk groups. Assessment of clinical risk by the Morise score led to most patients being classified as intermediate risk, which might be unsatisfactory when it comes to clinical decision making. After coronary CTA, reclassification could be done for approximately two-thirds of all patients. Although an additional prognostic benefit in patients with low clinical risk could not be demonstrated, the 85% of intermediate-risk patients without obstructive CAD had a particularly low event rate and could be reclassified into the low-risk group. Thus, coronary CTA might be useful for this patient population by guiding further preventive medication, at least in cases in which decisions based on clinical risk alone are difficult.
The results from this study underlined the role of coronary CTA as a powerful noninvasive tool to assess cardiovascular risk. The excellent long-term predictive value of coronary CTA might ultimately guide pharmacological or invasive treatment strategies for patients with clinically suspected CAD. However, before broad implementation, such strategies will need to be validated in prospective outcome studies.
This was a single-center observational study. Results might be influenced by the geographical patient characteristics and by the local investigation algorithm. Results from the index coronary CTA probably guided referring physicians toward pharmacological treatment, which arguably led to more patients with preventive cardiovascular treatment in our study cohort than in the general population. However, information about patient compliance with medical treatment was not available. Overall, the study cohort consisted mainly of patients at low to intermediate risk of obstructive CAD because patients with an intermediate to high pre-test risk referred to our institution were predominantly investigated by SPECT or invasive coronary angiography during the study period. Finally, the low number of events (n = 58) might have reduced the statistical power of our analysis. However, we are convinced that restrictive endpoint analysis for hard cardiac events best reflects the usefulness of coronary CTA in cardiovascular risk prediction and clinical decision-making. The differences of the reported event rates (Morise score) are at least partially explained by the more cardiac-specific endpoints in the underlying study.
With a median follow-up of 10 years, this study provided the longest prognostic data set of coronary CTA parameters so far investigated. The absence of CAD on baseline coronary CTA had an excellent negative predictive value and allowed for the definition of a 10-year event-free survival period against hard cardiac events. Quantification of coronary vessel obstruction, but also generalized vessel alterations visualized by coronary CTA improved risk prediction over clinical risk scores. After coronary CTA, reclassification from clinical risk can be done for approximately two-thirds of all patients.
COMPETENCY IN MEDICAL KNOWLEDGE: Coronary CTA is a reliable tool to assess long-term cardiovascular risk and can attribute a 10-year event-free survival against hard cardiac events. A substantial number of patients can be reclassified from clinical risk after coronary CTA.
TRANSLATIONAL OUTLOOK: The role of future studies will be to evaluate if primary preventive treatment guidance based on coronary CTA results will be able to improve patient outcome or reduce costs.
Dr. Hausleiter has received speaker honoraria and research support from Abbott Vascular and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- annual event rate
- coronary artery disease
- Coronary Artery Disease Reporting and Data System
- coronary computed tomography angiography
- segment involvement score
- single-photon emission computed tomography
- Received May 8, 2018.
- Revision received July 10, 2018.
- Accepted July 23, 2018.
- 2019 American College of Cardiology Foundation
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