Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 https://doi.org/10.1186/s12955-020-01312-4 RESEARCH Open Access Health-related qualify of life, angina type and coronary artery disease in patients with stable chest pain Nina Rieckmann1*, Konrad Neumann1,2, Sarah Feger3, Paolo Ibes3, Adriane Napp3, Daniel Preuß3, Henryk Dreger4, Gudrun Feuchtner5, Fabian Plank6, Vojtěch Suchánek7, Josef Veselka8, Thomas Engstrøm9, Klaus F. Kofoed9, Stephen Schröder10, Thomas Zelesny11, Matthias Gutberlet12, Michael Woinke13, Pál Maurovich-Horvat14, Béla Merkely14, Patrick Donnelly15, Peter Ball16, Jonathan D. Dodd17, Mark Hensey18, Bruno Loi19, Luca Saba20, Marco Francone21, Massimo Mancone22, Marina Berzina23, Andrejs Erglis23, Audrone Vaitiekiene24, Laura Zajanckauskiene24, Tomasz Harań25, Malgorzata Ilnicka Suckiel26, Rita Faria27, Vasco Gama-Ribeiro27, Imre Benedek28,29, Ioana Rodean28, Filip Adjić30,31, Nada Čemerlić Adjić30,31, José Rodriguez-Palomares32, Bruno Garcia del Blanco32, Katriona Brooksbank33, Damien Collison34,35, Gershan Davis36,37, Erica Thwaite38, Juhani Knuuti39, Antti Saraste40, Cezary Kępka41, Mariusz Kruk41, Theodora Benedek29,42, Mihaela Ratiu42,43, Aleksandar N. Neskovic44,45, Radosav Vidakovic45,46, Ignacio Diez47, Iñigo Lecumberri48, Michael Fisher49,50, Balasz Ruzsics49, William Hollingworth51, Iñaki Gutiérrez-Ibarluzea52, Marc Dewey3† and Jacqueline Müller-Nordhorn1† Abstract Background: Health-related quality of life (HRQoL) is impaired in patients with stable angina but patients often present with other forms of chest pain. The aim of this study was to compare the pre-diagnostic HRQoL in patients with suspected coronary artery disease (CAD) according to angina type, gender, and presence of obstructive CAD. Methods: From the pilot study for the European DISCHARGE trial, we analysed data from 24 sites including 1263 patients (45.9% women, 61.1 ± 11.3 years) who were clinically referred for invasive coronary angiography (ICA; 617 patients) or coronary computed tomography angiography (CTA; 646 patients). Prior to the procedures, patients completed HRQoL questionnaires: the Short Form (SF)-12v2, the EuroQoL (EQ-5D-3 L) and the Hospital Anxiety and Depression Scale. (Continued on next page) * Correspondence: nina.rieckmann@charite.de † Marc Dewey and Jacqueline Müller-Nordhorn contributed equally to this work. 1 Institute of Public Health, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 2 of 10 (Continued from previous page) Results: Fifty-five percent of ICA and 35% of CTA patients had typical angina, 23 and 33% had atypical angina, 18 and 28% had non-anginal chest discomfort and 5 and 5% had other chest discomfort, respectively. Patients with typical angina had the poorest physical functioning compared to the other angina groups (SF-12 physical component score; 41.2 ± 8.8, 43.3 ± 9.1, 46.2 ± 9.0, 46.4 ± 11.4, respectively, all age and gender-adjusted p < 0.01), and highest anxiety levels (8.3 ± 4.1, 7.5 ± 4.1, 6.5 ± 4.0, 4.7 ± 4.5, respectively, all adjusted p < 0.01). On all other measures, patients with typical or atypical angina had lower HRQoL compared to the two other groups (all adjusted p < 0.05). HRQoL did not differ between patients with and without obstructive CAD while women had worse HRQoL compared with men, irrespective of age and angina type. Conclusions: Prior to a diagnostic procedure for stable chest pain, HRQoL is associated with chest pain characteristics, but not with obstructive CAD, and is significantly lower in women. Trial registration: Clinicaltrials.gov, NCT02400229. Keywords: Chest pain, Angina, Coronary artery disease, Computed tomography angiography, Invasive coronary angiography, Health-related quality of life Background Methods About 20 million patients present annually in Europe Design, participants and procedure with recent onset stable chest pain [1]. Patients with This study is part of the pilot study of the multicenter stable chest pain are frequently referred for diagnostic DISCHARGE trial (www.dischargetrial.eu; EC-GA evaluation for coronary artery disease (CAD). A high 603266), a pragmatic randomized controlled trial at 25 percentage of patients referred for invasive coronary European clinical sites in 16 countries which assesses angiography (ICA) have no obstructive CAD, [2, 3] but the comparative effectiveness of ICA and CTA in chest even with mild CAD or normal coronary arteries, pa- pain patients with a low-to-intermediate likelihood for tients are still at increased risk for future major adverse CAD [13]. One of the purposes of the pilot study was to cardiovascular events and all-cause mortality [4, 5]. After test the logistic feasibility of a pre-diagnostic assessment the exclusion of obstructive CAD, many patients con- of several validated HRQoL measures. The DISCHARGE tinue to experience cardiac symptoms such as palpita- pilot study was non-randomised and the protocol re- tions, dyspnoea and chest pain, which negatively impact quested that each site include at least 60 patients with their health-related quality of life (HRQoL) [6]. HRQoL suspected CAD who were routinely referred for diagnos- refers to how people perceive the impact of health con- tic evaluation (30 CTA and 30 ICA). Referred patients ditions or symptoms on their quality of life, in the do- had to have stable chest pain and be at least 30 years of mains of physical, emotional and social well-being as age. Exclusion criteria were not having a sinus rhythm, well as functional capacities in everyday life. being pregnant or depending on haemodialysis. Compared to the general population of adults without Patients were approached for study participation in CAD, HRQoL is decreased in adults with CAD, with the the clinics upon their scheduled visit for ICA or CTA. most pronounced differences in self-rated physical func- Dependent on local requirements for data acquisition, tioning and self-rated overall health [7]. Patients with written and/or oral informed consent was given by all stable angina pectoris also have lower HRQoL in com- patients participating in the DISCHARGE pilot study. A parison to the general population [8, 9]. study nurse interviewed patients to assess the criteria for However, not all patients referred for a cardiac angina classification. Patients then completed the diagnostic procedure have typical angina pectoris; HRQoL measures on paper. After that, they underwent atypical angina as well as non-anginal chest discom- their scheduled diagnostic procedure in routine care. fort may also prompt a referral for diagnostic evalu- All data was stored anonymously. The study was ap- ation of CAD [3, 10–12]. To our knowledge, no study proved by the ethics committee of the Charité- Universi- to date has assessed how these different presentations tätsmedizin Berlin (EA1/294/13) and by the German of chest pain or discomfort relate to HRQoL. Federal Office for Radiation Protection (Z5–2246/2– In the present study, we analyse whether there is a re- 2014-001). lationship between different presentations of chest dis- comfort and HRQoL in patients referred for diagnostic Measures ICA or computed tomography (CTA). We further test Health-related quality of life whether pre-diagnostic HRQoL differs between patients Short form (SF)-12v2 The SF-12v2 is a generic measure with and without obstructive CAD, and male and female of health status which encompasses an eight-scale profile patients. of functional health and well-being (physical functioning, Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 3 of 10 physical health-related role limitations, bodily pain, gen- Obstructive CAD was defined as the presence of at eral health, vitality, social functioning, emotional health- least one coronary artery > 50% diameter stenosis diag- related role limitations and mental health) [14]. The eight nosed by either CTA or ICA. For cases in whom an ICA domains are aggregated in a physical component sum- was performed after CTA, the ICA result was selected mary score (PCS) and mental component summary score for final diagnosis. (MCS). Scores were transformed to t-scores [14]. We ap- plied the standard scoring algorithm (based on the SF- Statistical analyses 12v2 2009 U.S. general population normative sample) be- Two-level analyses were performed with angina classifica- cause country-specific algorithms are only available for tion, diagnostic outcome (positive versus negative for CAD) some, but not all countries in DISCHARGE. and gender as independent factors and age as covariate. The upper level of the analysis consisted of the participating sites, EuroQoL (EQ-5D-3 L) The EQ-5D-3 L [15] assesses the lower level of the individual patients. Linear random current HRQoL in five dimensions: mobility, self-care, intercept models were used to account for possible correla- usual activities, pain/discomfort, and anxiety/depression, tions arising from the two-level structure. Missing values each of which can take one of three responses (no prob- were imputed using Rubin’s method of multiple imputation lems/some or moderate problems/extreme problems). with m = 20 samples (imputation method: predictive mean We calculated the percentages of patient groups with matching). Since only between 1.1 and 3.3% of the values some/moderate or extreme problems in each domain. were missing we calculated means, standard deviations and Further, health states can be presented along the five di- errors from the original sample and used multiple imput- mensions, e.g. health state 11212 represents a patient who ation only for the confirmatory part (P-values) of the analysis. indicates some problems (=2) on the usual activities and Intra class correlation coefficients for all measures ranged be- anxiety/depression dimensions and no problems (=1) on tween 0.05 and 0.08 indicating that site effects are small. The the other dimensions. These health states can be con- two-sided level of significance was α = 0.05. Since no primary verted to a single index value using available EQ-5D-3 L and secondary endpoints were defined for the pilot study, we value sets. We used the value set appropriate for all Euro- did not adjust the level of significance for multiple testing. pean countries (study type VAS) [15]. For graphic display of all measures in one diagram, Additionally, the EuroQol includes a visual analogue measures were standardized such that the minimum ob- scale (VAS) on which participants rate how good or bad servation of all measures corresponds to 0 and the max- their own health is today, on a scale from 0 (worst imagin- imum observation to 100. able health state) to 100 (best imaginable health state). All statistical analyses were performed using the statis- tical programming language R version 3.3.1. For the Hospital anxiety and depression scale The HADS as- two-level and multiple imputation analyses the functions sesses the presence and severity of symptoms of anxiety lme and mice from the R packages nlme version 3.1–131 and depression and was originally developed as a screen- and mice version 2.46.0, respectively, were used. ing tool for affective disorders in medical patients [16]. The depression and anxiety subscales each contain seven questions with scores from 0 to 3. Total scores for each Results subscale thus range from 0 to 21, with higher scores in- Characteristics of the study sample dicating worse anxiety / depression. Between April 2014 and July 2017, 25 sites included a total of 1523 patients. Of these, 60 patients were ex- Angina classification and diagnosis of obstructive coronary cluded post-hoc and 200 patients had to be excluded artery disease from the present analyses due to insufficient or missing A study nurse interviewed patients to assess the spe- HRQoL data or inconclusive / invalid diagnostic result cific nature of their angina. They were then classified (Fig. 1). Characteristics of the remaining analysis sample according to one of four angina categories [11]: 1) from 24 sites (n = 1263) are displayed in Table 1. Of typical angina pectoris (fulfilling the three criteria a) these, 617 underwent ICA, 570 had a CT only and 76 retrosternal chest discomfort, b) chest discomfort pre- had a CT and a subsequent ICA. About 45% of patients cipitated by exertion, and c) prompt relief [30s – 10 had typical angina pectoris, 28% atypical angina pectoris, min] of chest discomfort by rest or nitroglycerin) 2) 23% non-anginal chest discomfort, and 5% other chest atypical angina pectoris (two out of three criteria for discomfort. Overall, 69% of patients were found to not typical angina pectoris), 3) non-anginal chest discom- have obstructive CAD (no obstructive CAD was found fort (one out of three criteria for typical angina pec- in 56%, 77% 82% and 83% among patients with typical toris) and 4) other chest discomfort (none of the angina pectoris, atypical angina pectoris, non-anginal criteria for typical angina pectoris). and other chest pain, respectively). Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 4 of 10 Fig. 1 Patient flow-chart Health-related quality of life, angina classification and Fourty-eight % of the entire sample (55%, 50%, 38%, diagnostic outcome 18% among typical angina, atypical angina, non-anginal Figure 2 shows (standardized) differences in HRQoL mea- chest discomfort and other chest discomfort patients) sures by angina group and by CAD group. For the Figure, had a HADS anxiety score of > = 8, commonly used as a scores for the EurQol and the HADS were recoded so that cut-off for clinical anxiety. Because the anxiety levels higher values indicate higher HRQoL on all measures. were overall very high, we further tested whether pa- The mean scores and results of pairwise comparisons (ad- tients differed in their anxiety according to the original justed for age and gender) are displayed in the respective diagnostic procedure they had been scheduled for. Mean Table 2. Patients with typical angina had lower SF-12 (SD) anxiety scores were slightly higher in patients physical functioning scores and higher HADS anxiety scheduled for ICA (7.7 ± 4.2) in comparison to those levels compared to the three other angina groups. On all of patients scheduled for CT (7.4 ± 4.3; age and gen- other measures, patients with typical or atypical angina der- adjusted p < 0.01). Importantly, controlling for were similar and had lower scores compared to the two the scheduled diagnostic procedure did not attenuate other groups. Patients with non-anginal and other chest the anxiety differences between the chest pain groups discomfort did not differ in their HRQoL on any measure. which all remained significant. Table 1 Characteristics of the Study Sample Total Sample (n = 1263) Age, years 61.1 ± 11.3 Men 683 (54.1%) Angina Classification Typical Angina Pectoris 569 (45.1%) Atypical Angina Pectoris 352 (27.9%) Non-anginal chest discomfort 284 (22.5%) Other chest discomfort 58 (4.6%) Obstructive CAD based upon results of diagnostic procedure 389 (30.8%) Values are presented as mean ± SD or n (%) CAD coronary artery disease Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 5 of 10 Fig. 2 Health-related quality of life in (a) angina groups and (b) patients with and without CAD. For graphic display, measures were standardized such that the minimum observation of all measures corresponds to 0 and the maximum observation to 100. CAD, Coronary artery disease; HADS, Hospital anxiety and depression scale; VAS, visual analogue scale With and without adjustment for age and gender, there according to the EQ-5D-3 L. Again, patients with and were no significant HRQoL differences between patients without a diagnosis of CAD did not differ on any of with and without obstructive CAD. Only a non-significant these dimensions. trend towards a lower SF-12 physical functioning score was observed for patients with CAD (Table 2). Gender differences in health-related quality of life Figure 3 depicts the percentage of patients with some All measures indicate significantly poorer HRQoL for or moderate / extreme problems in mobility, self-care, women (see Fig. 4). Mean (SD) values for the SF-12 usual activities, pain/discomfort, and anxiety/depression physical component summary score and the SF-12 Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 6 of 10 Table 2 Health-related quality of life measures Total Gender Angina Classification Diagnostic Outcome sample Men Women p Typical Atypical Non-anginal Other p* ObstructiveCAD No p Angina Angina chest chest obstructive Pectoris Pectoris discomfort discomfort CAD SF-12 Physical 43.1 44.2 41.8 0.001 41.2 43.3 (9.1)ade 46.2 (9.0)bd 46.4 < 41.9 (8.9) 43.7 (9.4) 0.072 Health (9.3) (9.2) (9.3) (8.8)abc (11.4)ce 0.001 SF-12 Mental 45.7 47.0 44.1 < 44.5 (9.5)ab 45.1 (9.9)cd 47.6 (10.1)ace 51.4 < 45.6 (10.0) 45.7 (9.8) 0.117 Health (9.8) (9.8) (9.7) 0.001 (8.7)bde 0.001 EQ-5D-3 L 66.3 67.7 64.5 0.010 64.0 65.6 69.6 (18.8)ace 76.6 < 64.1 (18.3) 67.2 (19.0) 0.111 Visual (18.8) (18.3) (19.3) (18.1)ab (19.4)cd (16.8)bde 0.001 Analogue Scale EQ-5D-3 L 0.69 0.71 0.66 < 0.65 0.68 0.74 (0.20)ac 0.79 < 0.67 (0.20) 0.69 (0.21) 0.230 Utility Score (0.21) (0.20) (0.21) 0.001 (0.21)ab (0.20)cd (0.22)bd 0.001 HADS 5.9 5.5 6.4 (4.1) < 6.5 (4.0)ab 6.1 (3.7)cd 4.8 (3.8)ac 4.6 (4.5)bd < 6.0 (4.0) 5.8 (4.0) 0.380 Depression (3.95) (3.8) 0.001 0.001 HADS Anxiety 7.5 6.9 8.2 (4.3) < 8.3 (4.1)a 7.5 (4.1)a 6.5 (4.0)a 4.6 (4.5)a < 7.3 (4.1) 7.6 (4.2) 0.861 (4.21) (4.0) 0.001 0.001 Unadjusted values are presented as mean ± SD. p-values are based upon multiple imputation analyses and adjusted for age and gender where appropriate. Possible site effects were accounted for by mixed model analysis * Pairwise comparisons: angina classification groups with a common superscript differ significantly (p < 0.05). After applying a Bonferroni correction, some of the comparisons between patients with other or non-anginal chest discomfort and atypical angina pectoris do not reach statistical significance Measures (possible range in parenthesis): SF-12 Physical and Mental Health (0–100), EQ-5D-3 L Visual Analogue Scale (0–100), EQ-5D-3 L Utility Score (−0.0734–1) and HADS Depression and Anxiety (0–21) mental component summary score were 41.8 (9.3) and (19.3) for men (p = 0.010). Mean HADS depression 44.1 (9.7) for women and 44.2 (9.2) and 47.0 (9.8) for and anxiety scores were 6.39 (4.06) and 8.23 (4.32) men (p = 0.001 and p < 0.001). For EQ-5D utilities, the for women and 5.47 (3.81) and 6.91 (4.03) for men mean (SD) score was 0.66 (0.21) for women and (both p < 0.001). After adjusting for age and angina 0.71 (0.20) for men (p < 0.001). On the VAS, the classification, all gender differences remained sig- mean score was 64.5 (19.3) for women and 67.7 nificant (all p < 0.01). Fig. 3 Percentage of patients with some or moderate / extreme problems in EuroQol problem dimensions. Problem dimensions from the EuroQol (EQ-5D-3 L). Groups refer to: 1 = Typical angina pectoris, 2 = Atypical angina pectoris, 3 = Non-anginal chest discomfort and 4 = Other chest discomfort Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 7 of 10 Fig. 4 Summary of health-related quality of life differences between women and men. For graphic display, measures were standardized such that the minimum observation of all measures corresponds to 0 and the maximum observation to 100. HADS, Hospital anxiety and depression scale; VAS, visual analogue scale Sensitivity analysis utility score, which is a multidimensional conglomerate Analyses comparing patients with and without obstruct- of several physical and emotional states. ive CAD were repeated in the subsample of patients who Minimal clinically important differences (MCID) in had typical angina pectoris. In this subsample, there these measures have not been assessed for patients with were also no differences in HRQoL between patients chest discomfort. Conventionally, for the SF-12, a 2-point with and without an eventual diagnosis of CAD (all p- difference is often assumed a MCID, and differences be- values > 0.3, data not shown). tween typical angina patients and the other chest pain groups exceeded this difference in both the mental and physical health component score of the SF-12. Discussion Comparisons of the HRQoL scores in the present sam- This study included 1263 patients from 24 European ple with other patient samples should be made with cau- sites which were referred for elective ICA or CTA. tion due to sample differences in age, gender and clinical There were significant differences in pre-diagnostic characteristics. HRQoL according to patients’ chest pain characteristics. Patients in our sample had similar (<= 1 point differ- Adjusting for age and gender, patients with typical and ence) pre-diagnostic physical functioning and mental atypical angina pectoris had worse quality of life in com- health component scores on the SF-12 compared to a parison to patients with non-anginal chest pain and sample of 4146 patients with stable angina from the Scot- other chest discomfort. These differences were observed tish COmputed Tomography of the HEART (SCOT- across the different functional and emotional aspects of HEART) trial, which compared standard care for angina HRQoL and also across the different measures we patients with standard care plus CTA [17]. However, employed here, confirming their good discriminative val- SCOT-HEART did not differentiate between different idity for different presentations of chest pain. chest pain presentations and also included angina patients In comparison to patients with atypical angina, typical with known CAD. In the Cresent trial, [18] which com- angina patients had worse self-rated physical functioning pared the effectiveness and safety of cardiac CTA and and higher levels of anxiety, but no HRQoL differences functional testing in 350 patients (> 50% with typical chest between these two angina groups were observed on the pain), overall health ratings with the EuroQol VAS were other measures. Thus, the SF-12 physical functioning comparable to the ones in our sample. In the recent Pro- and the HADS anxiety score appear to have a somewhat spective Multicenter Imaging Study for Evaluation of greater discriminatory power compared to the EuroQol Chest Pain (PROMISE) trial, [19] which randomized Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 8 of 10 patients to either standard functional testing or CTA, the are also prognostic factors for adverse cardiac outcomes pre-diagnostic EuroQol VAS scores were higher in com- and mortality in patients with established CAD [25, 26] parison to our sample. However, only 11% of patients in- and also in patients with stable angina [27, 28]. Whether cluded in the PROMISE trial had typical angina pectoris. patients’ HRQoL prior to or after receiving a diagnosis In comparison to the HRQoL of 8745 stable coronary of CAD has an impact on the subsequent treatment rec- heart disease patients with clinical events > 6 months ommendations by physicians (e.g., conservative treat- ago in the Euroaspire study, [20] the total sample of the ment vs. invasive procedures) remains to be studied. DISCHARGE pilot study patients had similar EuroQol utility and VAS scores, similar HADS depression scores, Strengths and limitations but substantially lower SF-12 mental health scores (4 In this multisite, multinational study, the range of patients point difference) and higher anxiety (1.6 point differ- with different presentation of chest pain reflects the clinical ence). In all these comparisons, HRQoL scores for the reality of diagnostic referrals. The pre-intervention assess- subgroups of patients with typical angina pectoris in our ments ensured that the HRQoL assessment was not influ- study fall substantially below the HRQoL of the other enced by patients’ knowledge of their actual diagnosis. One samples, indicating a high burden associated with this limitation was that only obstructive CAD was diagnosed. type of chest pain. There may well have been HRQoL differences between pa- Notably, almost half of our entire sample had a HADS tients with no CAD, mild (non-obstructive) CAD and ob- anxiety score > =8, the suggested cut-off [16] for prob- structive CAD. We did not assess severity and frequency of able clinical anxiety. Heightened anxiety prior to a diag- chest discomfort, which may account for some of the nostic procedure has been described before [21] and HRQoL differences between the chest pain groups. The could be attributed to the uncertainty of the origin of EuroQol utility values, for example, have been shown to co- the chest pain / discomfort and the fear associated with vary with clinically important differences in angina severity, heart disease. angina frequency and exertion [29, 30]. We did not include Patients with and those without obstructive CAD did healthy controls from each of the sites. However, the main not differ in their pre-diagnostic HRQoL, not even in pa- focus was to analyse whether different presentations of chest tients with typical angina pectoris. Thus, underlying ob- pain were associated with HRQoL and all measures were structive cardiac disease cannot explain the HRQoL able to discriminate between chest pain groups. differences between angina groups. This is in accordance with findings from a Canadian study with 1009 patients Conclusions referred for elective coronary angiography [22]. Com- More than half of the stable chest pain patients referred pared with population norms, patients with and without for diagnostic evaluation did not have typical angina CAD had high anxiety levels and lower HRQoL; the two pectoris. Our study showed that differences in chest pain groups did not differ on most HRQoL measures with presentation are associated with significant difference in the exception of lower self-rated physical functioning in HRQoL. Typical angina patients reported worse physical patients with CAD. However, no information on the ini- functioning and higher anxiety compared to patients tial chest pain characteristics were given in the Canadian with atypical, non-anginal or other chest discomfort, to sample and the CAD outcomes included mild CAD a clinically meaningful extent. Patients with typical or which we did not assess in our study. atypical angina significantly differed from the two other There were substantial gender differences in HRQoL: groups in anxiety and depression, overall physical func- women had consistently worse quality of life on all mea- tioning, mobility, overall pain and daily functioning. sures. Gender differences in HRQoL are well docu- Overall, anxiety levels were close to or above a clinical mented across a variety of chronic diseases. Women are cut-off. Women consistently reported substantially at greater risk for having clinical and subthreshold de- worse HRQoL compared to men. Notably, patients with pression and anxiety and perceive greater physical and versus those without obstructive CAD did not differ in social limitations in their daily lives. In a study with 123 their HRQoL, suggesting that the association between patients with stable CAD and angina pectoris, men and symptoms and HRQoL is driven by symptoms and not women described their chest pain in a similar manner, by cardiac disease. Further studies should assess how but women reported significantly higher physical limita- diagnostic evaluation for CAD impacts the HRQoL in tions due to angina pain [23]. patients with different presentations of chest pain, with It should be noted that HRQoL is also a prognostic and without confirmed CAD. factor in cardiac disease. In CAD patients, perceived physical limitations in everyday life were associated with Abbreviations CAD: Coronary artery disease; CTA: Computed tomography angiography; increased mortality and admission for acute coronary HADS: Hospital Anxiety and Depression Scale; HRQoL: Health- related quality syndrome across one year [24]. Depression and anxiety of life; ICA: Invasive coronary angiography; MCID: Minimal clinically important Rieckmann et al. Health and Quality of Life Outcomes (2020) 18:140 Page 9 of 10 difference; MCS: Mental component summary score; PCS: Physical Berlin, and Berlin Institute of Health, Berlin, Germany. 3Department of component summary score; PROMISE: Prospective Multicenter Imaging Study Radiology, Charité – Universitätsmedizin Berlin, corporate member of Freie for Evaluation of Chest Pain; SCOT-HEART: Scottish COmputed Tomography Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of of the HEART; VAS: Visual analogue scale Health, Berlin, Germany. 4Department of Cardiology and Angiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Acknowledgements Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Not applicable. Germany. 5Department of Radiology, Innsbruck Medical University, Innsbruck, Austria. 6Department of Internal Medicine III, Cardiology, Innsbruck Medical Patient consent University, Innsbruck, Austria. 7Department of Imaging Methods, Motol Obtained. University Hospital, Prague, Czech Republic. 8Department of Cardiology, Motol University Hospital, Prague, Czech Republic. 9Department of Authors’ contributions Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 10 NR, MD & JMN designed the study. NR drafted the manuscript. KN Department of Cardiology, ALB FILS KLINIKEN GmbH, Goeppingen, conducted the statistical analyses. All authors have contributed to the Germany. 11Department of Radiology, ALB FILS KLINIKEN GmbH, acquisition and interpretation of the data, critical revisions of the manuscript Goeppingen, Germany. 12Department of Radiology, University of Leipzig and all have approved the final version of the manuscript. Heart Centre, Leipzig, Germany. 13Department of Cardiology, University of Leipzig Heart Centre, Leipzig, Germany. 14Heart and Vascular Center, Funding Semmelweis University, Budapest, Hungary. 15Department of Cardiology, This work was supported by the 7th Framework Programme of the European Southeastern Health and Social Care Trust, Belfast, UK. 16Department of Union (EC-GA 603266). Radiology, Southeastern Health and Social Care Trust, Belfast, UK. 17 Department of Radiology, St. Vincent’s University Hospital, Dublin, Ireland. 18 Department of Cardiology, St. Vincent’s University Hospital, Dublin, Ireland. Availability of data and materials 19 Department of Cardiology, Azienda Ospedaliera Brotzu, Cagliari, CA, Italy. The datasets used and/or analysed during the current study are available 20 Department of Radiology, University of Cagliari, Cagliari, CA, Italy. from the corresponding author on reasonable request. 21 Department of Radiological, Pathological and Oncological Sciences, Sapienza University of Rome, Rome, Italy. 22Department of Cardiovascular, Ethics approval and consent to participate Respiratory, Nephrology, Anesthesiology and Geriatric Science, Sapienza This study was approved by the ethics committee of the Charité – University of Rome, Rome, Italy. 23Department of Cardiology, Paul Stradins Universitätsmedizin Berlin (EA1/294/13) and by the German Federal Office for Clinical University Hospital, Riga, Latvia. 24Department of Cardiology, Hospital Radiation Protection (Z5–2246/2–2014-001). of Lithuanian University of Health Sciences Kaunas Clinics, Kaunas, Lithuania. 25 Department of Radiology, Wojewodzki Szpital Specjalistyczny We Competing interests Wroclawiu, Wroclaw, Poland. 26Department of Cardiology, Wojewodzki AN reports grants from Siemens Medical Solutions, grants from GE Szpital Specjalistyczny We Wroclawiu, Wroclaw, Poland. 27Department of Healthcare, grants from Toshiba Medical Systems, grants from Philips Medical Cardiology, Centro Hospitalar de Vila Nova de Gaia/ Espinho, Vila Nova de Systems, outside the submitted work. Gaia, Portugal. 28Center of Advanced Research in Multimodality Cardiac TE reports personal fees from Boston, personal fees from Bayer, personal fees Imaging, Cardio Med Medical Center, Tirgu Mures, Romania. 29Department of from Abbott, personal fees from Medtronic, personal fees from Novo, outside Internal Medicine, University of Medicine and Pharmacy, Tirgu Mures, the submitted work. Romania. 30Department of Cardiology, Institute for Cardiovascular Diseases of KFK reports grants from Canon Medical Corporation, grants from AP Møller Vojvodina, Novi Sad, Sremska Kamenica, Serbia. 31Faculty of medicine, og hustru Chastine McKinney Møllers Fond, grants from The Danish Heart University of Novi Sad, Novi Sad, Serbia. 32Department of Cardiology, Foundation, outside the submitted work. Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat JDD is an associate editor of Radiology, European Radiology, Quarterly Autònoma de Barcelona, Barcelona, Spain. 33BHF Centre of Research Journal of Medicine and Respirology. Excellence, Glasgow University, Glasgow, UK. 34Institute of Cardiovascular & JK reports personal fees from GE Healthcare, personal fees from AstraZeneca, Medical Sciences, University of Glasgow, Glasgow, UK. 35Golden Jubilee outside the submitted work. National Hospital, Clydebank, UK. 36Cardiovascular Medicine, University of AS reports grants from Academy of Finland, grants from Finnish Foundation Central Lancashire, Preston, UK. 37Department of Cardiology, Aintree for Heart Research, personal fees from Astra Zeneca, personal fees from University Hospital, Liverpool, UK. 38Department of Radiology, Aintree Bayer, personal fees from Abbott, personal fees from Novartis, outside the University Hospital, Liverpool, UK. 39Turku PET Centre, Turku University submitted work; . Hospital and University of Turku, Turku, Finland. 40Heart Center, Turku ANN reports grants from Ministry of Education, Science and Technological University Hospital and University of Turku, Turku, Finland. 41The National Development, Government of the Republic of Serbia, from null, during the Institute of Cardiology, Warsaw, Poland. 42County Clinical Emergency conduct of the study. Hospital, Tirgu Mures, Romania. 43Department of Radiology and Medical MD reports grant support from the FP7 Program of the European Imaging, University of Medicine and Pharmacy, Tirgu Mures, Romania. Commission for the randomized multicenter DISCHARGE trial (603266–2, 44 Clinic of Internal medicine/Interventional cardiology, Clinical Hospital HEALTH-2012.2.4.-2), from the Heisenberg Program of the DFG (DE 1361/14– Center Zemun-Belgrade, Belgrade, Serbia. 45Faculty of Medicine, University of 1), from the Digital Health Accelerator of the Berlin Institute of Health, and Belgrade, Belgrade, Serbia. 46Department of non-invasive diagnostics, the DFG graduate program on quantitative biomedical imaging (BIOQIC, GRK Cardiology Division, Clinical Hospital Center Zemun-Belgrade, Belgrade, 2260/1), personal fees from Canon Medical Systems, Guerbet, Cardiac MR Serbia. 47Department of Cardiology, Basurto Hospital, Bilbao, Spain. Academy Berlin, and Bayer. He is also the editor of Cardiac CT, published by 48 Department of Radiology, Basurto Hospital, Bilbao, Spain. 49Department of Springer, and offers hands-on workshops on CT imaging (www.ct-kurs.de). In- Cardiology, Royal Liverpool University Hospital, Liverpool, UK. 50Institute for stitutional master research agreements exist with Siemens Medical Solutions, Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital, General Electric, Philips Medical Systems, and Toshiba Medical Systems. The Liverpool, UK. 51Population Health Sciences, Bristol Medical School, University terms of these arrangements are managed by the legal department of Char- of Bristol, Bristol, UK. 52Osteba, Basque Office for Health Technology ité – Universitätsmedizin Berlin. Assessment, Ministry for Health, Basque Country, Spain. All other authors report no competing interests. 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