Diagnostic Cardiac CT for the Improvement of Cardiovascular Event Prediction

Twenty-Year Results of the Heinz Nixdorf Recall Study

Background: The aim of the long-term Heinz Nixdorf Recall Study (observation period 20 years) was to establish the extent to which computed tomography (CT) improves the predictability of cardiovascular events relative to determination of risk factors alone.

Methods: In the period 2000–2003, study staff examined 4355 probands (53% of them female) aged 45–75 years with no signs of cardiovascular disease. The Atherosclerotic Cardiovascular Disease (ASCVD) score was calculated on the basis of demographic data and cardiovascular risk factors. Cardiac CT was carried out over the same period and coronary artery calcification (CAC) was graded according to the Agatston score.

Results: The median duration of follow-up was 18.2 years for men and 17.8 years for women. Myocardial infarction or stroke occurred in 458 (11%) of the 4154 participants with complete data. Overall, estimation of risk using a combination of ASCVD score and CAC grade was superior to the ASCVD score alone—even after 10 and 20 years. Classification into established risk categories improved by 12.2% (95% confidence interval: [5.3%; 18.1%]). In the highest ASCVD risk category, we observed occurrence of a cardiovascular event over 20 years for 14% [5.0%; 23.1%] of probands with a CAC score = 0 but for 34.2% [27.5%; 41.4%] of those with a CAC score ≥ 400. In the lowest ASCVD risk category, an event occurred in 2.4% [1.4%; 3.7%] of probands with a CAC score = 0 and in 23.5% [2.3%; 35.8%] of those with a CAC score ≥ 400.

Conclusion: Even after 20 years, individual risk prediction is improved by addition of CT-based determination of coronary artery calcification to the ASCVD score. Therefore, assessment of ASCVD risk factors should be complemented more widely by cardiac CT in the primary prevention of cardiovascular disease.

Most cardiovascular deaths are due to myocardial infarction (1, 2). People who die from myocardial infarction often do not reach the hospital, dying suddenly and unexpectedly (3). An event of this nature occurs in 60% to 80% of all patients who die within 28 days of a myocardial infarction; among those over the age of 75 it is more than 90% (4, e1, e2). Stroke mortality, like that of myocardial infarction, is declining, but among older people it is still high (2).

Coronary atherosclerosis remains asymptomatic for decades, because vascular remodeling compensates for impending narrowing of the vessel lumen until the area of atheromatous plaque attains 40% to 50% of the cross-sectional area of the vessel, at which point the lumen does progressively start to narrow (5). Atheromas and fibroatheromas give rise to ruptures and erosions of plaque or to intramural hematomas – the causes of acute coronary syndrome (6). Thrombi and washed-out <atheromas lead to microembolisms and microinfarcts, causing acute malignant arrhythmias (6, e3, e4). Other causes are rare (e5).

Even in the early stages of atherosclerosis, coronary artery calcifications occur. These can be detected, localized, and quantified as signs of subclinical atherosclerosis by means of cardiac computed tomography (CT) (7, 8, 9, e6-e9); the radiation exposure involved is now very low (<1 mSv) (e10).

The Heinz Nixdorf Recall (Risk Factors, Evaluation of Coronary Calcification, and Lifestyle) Study (HNR Study) (10) and the US Multi-Ethnic Study of Atherosclerosis (MESA) (11) were initiated in 2000 with the aim of demonstrating prospectively that diagnostic cardiac CT is superior to even the most recently developed risk scores. Over the first short observation period of up to 5 years, both studies identified an additional benefit from cardiac CT in individual cardiac risk assessment compared with general risk scores (12, 13, e11, e12). To date, there have been no long-term studies beyond a period of 15 years. The HNR study has enabled the longitudinal observation of participants in good cardiac health over a period of >20 years in relation to cardiac and cardiovascular events, making it possible to estimate the extent to which cardiac imaging may improve the prediction of individual cardiovascular events.

Method

From 2000 to 2003, the HNR study recruited in the cities of Bochum, Essen, and Mülheim a total of 4355 participants (Figure 1) aged 45–75 years and with no signs in their past history of coronary artery disease or stroke. The study center was in Essen, and the cardiac CT studies were carried out in Bochum and Mülheim (10, 14, 15, e13). Two complete follow-up examinations were carried out after 5 years (with CT) and 10 years (without CT). Annual follow-up interviews by mail or telephone have been ongoing for more than 20 years now. The present article is based on data from 4154 of the 4355 participants (53% of them women) (Figure 1), all of whom underwent cardiac CT and determination of risk factors in 2000–2003 after their enrollment in the study (eMethod).

Figure 1

Flow diagram for the Heinz Nixdorf Recall Study

The Ethics Board of the Medical Faculty of the University of Essen reviewed and approved the study (AT: 99–69–1200, 12 May 1999), which was subsequently also approved by the Federal Office for Radiation Protection (10, 15, e6, e7).

Cardiovascular risk factors

All three examinations (see eMethod) included a medical history, computer-assisted interview, anthropometric data collection, blood pressure measurements, and the taking of blood samples; at the first two, cardiac CT was performed (10, 15, e13-e24).

The findings were used for calculation of the ASCVD (atherosclerotic cardiovascular disease) score, which is based on identical endpoints to our study over a 10-year observation period (16, e25) and is internationally accepted (17, e26). In a German study, cardiovascular risk estimation using the ASCVD score was considered appropriate for primary prevention (e27) and was recommended for use in the German population (e27, e28). The estimated 10-year risk was divided into the following categories:

• <5% (low)
• 5% to <7.5% (borderline)
• 7.5% to <20% (intermediate)
• ≥20% (high) (e25)

Cardiac CT was performed as part of the study in 4154 of the 4355 participants between 2000 and 2003, as already stated, using electron-beam CT and without knowledge of participants’ baseline data (10, 15). An image acquisition time of 100 ms, a slice thickness of 3 mm, and prospective ECG triggering were used. The Agatston score, also called the coronary artery calcium (CAC) score, was calculated from the density grades and area (e31, e32) and scores were assigned to the following categories based on event rates:

• CAC = 0 (low)
• CAC >0 to <100 (borderline)
• CAC 100 to <400 (intermediate)
• CAC ≥400 (high) (12, 15, eMethod)

The cardiac CT results were not reported to either the physicians at the study center or the study participants.

End points

In accordance with the study protocol (10,12), only hard primary and secondary end points were included in the analysis. For this article, fatal and nonfatal myocardial infarctions (primary end points) and strokes (secondary end points) were listed and taken together as cardiovascular events, which since 2004 have been continuously validated by an external, independent panel of experts (chaired by Prof. Bode, Freiburg, Germany). For fatal and nonfatal strokes, an additional expert panel of neurologists was set up (chaired by Prof. Berger, Münster, Germany).

Statistics

Continuous data were represented as the mean ± standard deviation or median (25^th and 75^th percentiles), depending on their distribution characteristics. Categorical variables were shown as frequency (N) and percentage (%). Differences between study participants with and those without cardiovascular events were presented as statistical differences with 95% confidence intervals (95% CI), with confidence intervals being derived from the observed distribution. In accordance with the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk (16), the ASCVD risk score for cardiovascular events was determined from the measurement values in a participant’s baseline examination (2000–2003) and recalibrated according to the observed event frequency in our 20-year study data (eMethods).

Calibration and discrimination are the relevant quality criteria for risk scores. The improvement in the discrimination of the ASCVD score brought about by adding to it the CAC score is demonstrated as the improvement in discriminative ability (Harrell’s C), the net improvement in classification into established risk categories (net reclassification improvement, NRI), and the improvement in discriminatory power (integrated discrimination improvement, IDI) (for details see Box 1 and eMethods).

Box 1

Glossary for the statistical methods used

Results

Cardiovascular events

The demographic data for participants with and those without a cardiovascular event (20-year incidence 11.0%) are shown in eTable 1. There were 267 myocardial infarctions and 191 strokes; of these, 105 myocardial infarctions and 9 strokes were fatal (eTables 2 and 3 give the demographic data separately for men and for women). Participants with events were on average approximately 5 years older and showed higher values for all cardiovascular risk factors except for total cholesterol and LDL cholesterol. Their mean ASCVD score was more than doubled, and the CAC score more than tenfold higher. A CAC score ≥400 was determined in 25.8% of participants with a cardiovascular event and 8% of those without a cardiovascular event; in men these figures were, respectively, 31.6% and 13.5%, and in women, 14.9% and 3.5%.

eTable 1

Demographic data for all participants included in the study, divided into those with and those without a fatal or nonfatal cardiovascular event (myocardial infarction and/or stroke) over the course of 20 years

eTable 2

Demographic data for men

eTable 3

Demographic data for women

We observed a cardiovascular event within the 20 years in 8 of 57 subjects (14.0%; 95% confidence interval: [5.0; 23.1]) with the highest ASCVD score associated with a CAC score = 0. However, for the same ASCVD risk group but associated with a CAC score ≥400, a cardiovascular event was recorded in 66 of 193 participants (34.2% [27.5; 41.4]) (eTable 4). In the lowest ASCVD risk group, the corresponding figures were 2.4% [1.4; 3.7] for a CAC score = 0 and 23.5% [2.3; 35.8] for a CAC score ≥400.

eTable 4

Hazard ratio with 95% confidence interval for a cardiovascular event (CVE) within 20 years, including competing events (COE), for categories of 10-year ASCVD risk and CAC score, all 4154 participants

Among 644 participants who died (53.1% men, age 63.8 ± 7.3 years, survival 11.9 [7.5; 15.3] years), there was definitely no cardiovascular event. Their ASCVD score was 17.6% ± 12.9%. A CAC score ≥400 was found in 106 (16.5%) participants. These 644 deaths were considered as “competing events” (see eMethod).

Survival without a cardiovascular event

The survival curves (Figures 2 and 3, eFigures 1 and 2) make clear the additional information gained from the CAC score when added to the ASCVD score and divided into the four risk groups. The dependence on the value of the CAC score is visible, especially for women (Figure 3, eFigure 2).

eFigure 1

In men, survival without a cardiovascular event falls as coronary artery calcification rises for every category of calculated ASCVD risk

Figure 2

In men, survival without a cardiovascular event falls as coronary artery calcification rises for every category of calculated ASCVD risk

Figure 3

In women, survival without a cardiovascular event falls as coronary artery calcification rises for every category of calculated ASCVD risk

eFigure 2

In women, survival without a cardiovascular event falls as coronary artery calcification rises for every category of calculated ASCVD risk

Looking at the time to onset of a cardiovascular event within 20 years (Figure 4, eTable 4), the additional gain by determining the CAC score compared with the ASCVD score becomes clear and shows up particularly strongly in the lower groups. Where the ASCVD risk is high (≥20%), a CAC score ≥400 results in a hazard ratio (HR) for the occurrence of a cardiovascular event of 18.66 [11.20; 31.09] (reference: low ASCVD risk, CAC score = 0). If, on the other hand, the ASCVD score is high but the CAC score = 0, the HR drops to 6.59 [2.88; 15.05]. Because of the low number of events in the women’s reference group, the values for men are lower (5.37 and 2.06, respectively) than those for women (35.74 and 10.52, respectively) (eTable 5, eTable 6).

Figure 4

Hazard ratio (HR) with 95% confidence interval (CI) for an ASCVD event over the course of 20 years, men and women

eTable 5

Hazard ratio with 95% confidence interval* for a cardiovascular event (CVE) within 20 years, including competing events (COE), for categories of 10-year ASCVD risk and CAC score, all 1954 men

eTable 6

Hazard ratio with 95% confidence interval for a cardiovascular event (CVE) within 20 years, including competing events (COE), for categories of 10-year ASCVD risk and CAC score, all 12 200 Frauen

Evaluation of ASCVD risk score and CAC score

Calibration

The 10-year ASCVD risk—extrapolated to 20 years—noticeably overestimates the event rate (eFigure 3). Possible causes could be a difference in baseline risk between the United States and Germany or differences between the data collection periods. For this reason, the ASCVD score for 20 years was calibrated with the event rate observed in our study, with very good results (ASCVD score, recalibrated, eFigure 3). The newly calculated ASCVD score plus CAC score shows excellent calibration.

eFigure 3

Calibration plot

Discrimination

When the ASCVD score is compared with the ASCVD score plus CAC score for the entire 20-year period, increased discrimination is shown for all three metrics considered (eTable 7). The improved ability to discriminate (Harrell’s C) persisted in the long term over 5, 10, and 20 years, but showed a slight tendency to decline overall (Box 1, eTable 7) – this was more clearly so for men (eFigure 4), whereas for women, even after 20 years, the improved discrimination with the ASCVD score plus CAC score versus the ASCVD score alone remained constant (eFigure 5).

eFigure 4

Harrell’s C, men

eFigure 5

Harrell’s C, women

eTable 7

Measures of discrimination by ASCVD score with 95% confidence intervals [95% CI] and improvement achieved by addition of the CAC score

Net improvement in classification

For 20-year risk, compared with ASCVD score alone, ASCVD score plus CAC score achieved a 12.2% [5.3; 18.1] improvement in classification (NRI) (Table 1a/b): 16.7% [7.1; 24.1] in men, and 9.6% [−0.3; 21.3] in women (eTables 8 and 9). In relation to borderline and intermediate risk we saw an 18.6% improvement, and a 16.9% improvement intermediate risk alone (eTables 10a/b and 11a/b).

Table 1

Reclassification table for participants with/without a cardiovascular event who were enrolled in the study 20 years ago, all four risk groups

eTable 8

Reclassification table for men with/without a cardiovascular event who were enrolled in the study 20 years ago

eTable 9

Reclassification table for women with/without a cardiovascular event who were enrolled in the study 20 years ago

eTable 10

Reclassification table for participants with/without a cardiovascular event who were enrolled in the study 20 years ago, „borderline“ and „intermediate“ ASCVD risk groups

eTable 11

Reclassification table for participants with/without a cardiovascular event who were enrolled in the study 20 years ago, „intermediate“ ASCVD risk group

Improvement in discriminatory power

Improved discriminatory power of the ASCVD score plus CAC score compared with ASCVD score alone was evidenced by the IDI (integrated discrimination improvement) values, which were 0.027 [0.016; 0.043] for all participants, 0.030 [0.014; 0.050] for men, and 0.026 [0.008; 0.050] for women.

Usefulness of ASCVD score alone versus ASCVD score plus CAC score

The number of persons who need to be examined in order for one event to be correctly predicted (“number needed to diagnose,” NND) is calculated as NND = 1/(sensitivity + specificity −1). Sensitivity (from Table 1a) and specificity (from Table 1b) of the scores with respect to intermediate or high risk (≥14.4%) can be obtained from the table, as detailed in the table footnote. The calculation gives NND = 2.92 for the ASCVD score and NND = 2.60 (that is, an 11% reduction) for the ASCVD score plus CAC score, thus underlining the greater accuracy of prediction obtained from ASCVD score plus CAC score.

Discussion

The Heinz Nixdorf Recall Cohort Study shows that even after 20 years the degree of coronary artery calcification still has predictive significance for cardiovascular events. Adding the CAC score to the ASCVD score improves identification of increased individual cardiovascular risk not only in the short term but also in the long run. The difference in the incidence of cardiovascular events in participants with and without coronary artery calcification continues to increase throughout the observation period. Cardiovascular event-free survival for 45- to 75-year-old participants without coronary artery calcification is 82% after 20 years even in those with a very high 10-year ASCVD score, but falls to 62% in those with a CAC score ≥400. The improvement in risk classification from including coronary artery calcification is 18.6% among participants with a 10-year ASCVD risk of 5% to 20%. This value is higher than those of other risk factors, such as hs-CRP, HbA_1c, or HDL cholesterol, which show much smaller effects (12). Therefore, determining CAC score in addition to registering risk factors allows optimally individualized decision-making for therapy in persons with an elevated ASCVD score plus CAC score versus merely lifestyle modification for those at low risk. Especially in persons at intermediate risk level, the CAC score helps in therapeutic decision-making depending on the up- or down-grading of risk.

Cardiovascular risk from coronary artery calcification

The extent of coronary artery calcification is closely associated with cardiovascular risk (12, 13, e45, e46, e47, e48, e49, e50, e51). The CAC score classification chosen for this study has been used in previous studies (18, 19, 20). Data on the prevalence of coronary artery calcification are still relevant today (Box 2).

Box 2

Prevalence of coronary artery calcification

Other studies use CAC score >300 as the measure for the highest risk (13, 17, 21) or the limit CAC >0 or CAC >100 (22, 23, 24). A CAC score >100 is considered very high risk according to European Society of Cardiology / European Atherosclerosis Society guidelines if LDL-C in a patient on statin therapy is ≥158 mg/dL or ≥78 mg/dL with the aim of reducing the current target LDL-C values to below 55 mg/dL. This usually requires a combination of statins with other agents (25,26).

Participants with a CAC score = 0 or CAC score >0 to <100 also showed cardiovascular events in the long-term course, but these were less frequent than in participants with higher CAC scores. Over the course of 20 years, the progression and incidence of new coronary artery calcifications should be considered, which in our study were seen within 5 years in 31.3% of men and 22.9% of women (e46). The incidence of new coronary artery calcification appears to be dependent on a positive family history, smoking, high body mass index, hypertension, and diabetes mellitus (e45, e46, e47).

The significance of the degree of coronary vessel calcification is thus not completely independent of risk factors. This makes all the more surprising the increase it provides in the quality of prediction even compared with the bundling of risk factors in the current ASCVD score. It is for this reason that the ESC has now raised the CAC score for reclassification to recommendation class IIb with evidence level B in order to improve risk classification based on the European SCORE2 score (26). In contrast, the US guidelines raised the CAC score to recommendation class IIa for persons with an ASCVD score of 5% to 19.9% when there is uncertainty about the need for long-term statin therapy (27).

Improvement in risk estimation on the basis of CAC score

“Net reclassification improvement” (NRI) is commonly used as a measure to evaluate new risk markers (Box 1, eTable 7, eMethod). In our first 5-year analysis in 2010, the ASCVD score was not available, so we used the Framingham score, although this referred only to cardiac events (12). The improvement in classification based on coronary artery calcification was 21.7% for a 10-year risk of 6% to 20% and 30.6% for a 10-year risk of 10% to 20% (12). Compared with the Framingham score, the ASCVD score seems to markedly improve risk estimation, partly because it includes cardiovascular events as well as cardiac events (16). Despite this, including the degree of calcification still resulted in an 18.6% improvement in classification over the 20-year period, underscoring the value of cardiac CT.

Study limitations

The results of the CT studies, i.e., the calcium (CAC) scores, were initially not communicated to the study participants, primary care physicians, and researchers and staff involved in the study, but were only disclosed after 5 years. The study was not designed as a preventive intervention study, so the question of whether sharing their risk classification with participants would be effective in reducing cardiac events cannot be answered. However, it is anticipated that this will be answered in the future by the ROBINSCA study (18, 28). There are already indications that demonstrating the presence of coronary artery calcification to patients stimulates those patients to maintain a healthy lifestyle and take the medications they are prescribed (23, 24).

Intervention studies should now show whether this form of risk estimation used prospectively can also reduce event rates and thus become more widely utilized than before.

Acknowledgments

The authors would like to thank all the study participants in the Heinz Nixdorf Recall (HNR) study, the staff of the HNR study center and the EBCT scanner facilities, the investigation team, and all former staff members of the HNR study. For the biometric design of the HNR study, our thanks go to H. Hirche, Institute of Medical Informatics, Biometry, and Epidemiology, University of Duisburg-Essen, Essen University Hospital. The authors also thank the advisory board of the HNR study: T. Meinertz, Hamburg, Germany (chair); C. Bode, Freiburg, Germany; P.J. de Feyter, Rotterdam, Netherlands; B. Güntert, Hall in Tirol, Austria; F. Gutzwiller, Bern, Switzerland; H. Heinen, Bonn, Germany; O. Hess (†), Bern, Switzerland; B. Klein (†), Essen, Germany; H. Löwel, Neuherberg, Germany; M. Reiser, Munich, Germany; G. Schmidt (†), Essen, Germany; M. Schwaiger, Munich, Germany; C. Steinmüller, Bonn, Germany; T. Theorell, Stockholm, Sweden; and S. N. Willich, Berlin, Germany.

The authors also thank the independent panel of experts for primary and secondary cardiovascular endpoints (fatal and nonfatal myocardial infarction and stroke): C. Bode, Freiburg (chair); H. R. Figulla, Jena; C. Hamm, Bad Nauheim; P. Hanrath, Aachen; H. Kälsch, Essen; W. Köpcke, Münster; A. Zeiher, Frankfurt. We are likewise indebted to the neurological endpoint panel: K. Berger, Münster (chair); B. Ringelstein, Münster; M. Dichgans, Munich; C. Weimar, Elzach; for the evaluation and characterization of fatal and nonfatal strokes.

Funding

The authors are grateful to the Heinz Nixdorf Foundation (Chairman: Martin Nixdorf; former Chairman: Dr. jur. Gerhard Schmidt [†]), for generously supporting this study. Parts of the study were also supported by the German Research Foundation (DFG) (DFG project: EI 969/2–3, ER 155/6–1;6–2, HO 3314/2–1;2–2;2–3;4–3, INST 58219/32–1, JO 170/8–1, KN 885/3–1, PE 2309/2–1, SI 236/8–1;9–1;10–1,) and by the Federal Ministry of Education and Science (BMBF project: 01EG0401, 01GI0856, 01GI0860, 01GS0820_WB2-C, 01ER1001D, 01GI0205), the Ministry of Innovation, Science, Research and Technology of the State of North Rhine-Westphalia (MIWFT-NRW), the Else Kröner-Fresenius Foundation (Project 2015_A119) and the German Social Accident Insurance (DGUV Project: FF-FP295). The study was also supported by the HIV/AIDS Competence Network, the Dean’s Office of the University Hospital and IFORES of the University of Duisburg–Essen, the European Union, the German Heart Failure Competence Network, the Essen Cultural Foundation, the Protein Research Unit within Europe (PURE), the Dr. Werner Jackstädt Foundation, and the following companies: Celgene GmbH Munich, Imatron/ GE-Imatron, Janssen, Merck KG, Philips, ResMed Foundation, Roche Diagnostics, Sarstedt AG&Co, Siemens HealthCare Diagnostics, Volkswagen Foundation.

Data sharing

The corresponding author has full access to all study data and bears final responsibility for submission of the article for publication. For privacy reasons (i.e., the data contain information that can potentially identify participants), it is not possible to share the HNR study data as a public-use file. Data requests can also be sent to: [e-mail].

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 20 April 2022, revised version accepted on 25 October 2022.

Corresponding author
Prof. Dr. med. Raimund Erbel, FESC, FAHA, FACC
Universitätsklinikum Essen (AöR)
Institut für Medizinische Informatik, Biometrie und Epidemiologie (IMIBE)
Hufelandstr. 55, 45147 Essen, Germany

Cite this as:
Erbel R, Lehmann N, Schramm S, Schmidt B, Hüsing A, Kowall B, Hermann DM, Gronewold J, Schmermund A, Möhlenkamp S, Moebus S, Grönemeyer D, Seibel R, Stang A, Jöckel KH on behalf of the Heinz Nixdorf Recall Study Group: Diagnostic cardiac CT for the improvement of cardiovascular event prediction—twenty-year results of the Heinz Nixdorf Recall Study. Dtsch Arztebl Int 2023; 120: 25–32. DOI: 10.3238/arztebl.m2022.0360

►Supplementary material

eMethod, eTables, eFigures:
www.aerzteblatt-international.de/m2022.0360

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