Correlation of the disease-specific Canadian Cardiovascular Society (CCS) classification and health-related quality of life (15D) in coronary artery disease patients.

BACKGROUND: Generic health-related quality of life (HRQoL) and disease-specific instruments measure HRQoL from different aspects, although generic instruments often contain dimensions that reflect common symptoms. We evaluated how the change in 15D HRQoL and Canadian Cardiovascular Society (CCS) grading of angina severity correlate among coronary artery disease patients during 12-month follow-up.
METHODS: Altogether 1 271 patients scheduled for coronary angiography between June 2015 and February 2017 returned the 15D HRQoL and CCS questionnaires before angiography and after one-year follow-up as a part of routine clinical practice. Spearman correlations between one-year changes in the CCS and the 15D and its dimensions were evaluated. Changes in 15D were classified into 5 categories based on the reported minimal important difference (MID) for the instrument.
RESULTS: Change in the CCS grade correlated moderately with the MID-based change in the 15D (r = 0.33, 95% confidence interval 0.27-0.39). Correlations between these instruments were similar in different age groups, between sexes and treatment modalities. Of the individual 15D dimensions, changes in breathing (r = 0.40) and vitality (r = 0.30) had the strongest correlations with CCS change.
CONCLUSION: The symptom-based evaluation of the change in the CCS grade may not catch the full benefit or harm of the treatment and vice versa, a generic instrument, such as 15D, likely does not fully capture change in disease-specific symptoms. Thus, generic and disease-specific instruments are complementary and should be used in conjunction.

Introduction

Patient reported outcomes (PROs), such as generic and disease-specific health-related quality of life (HRQoL) instruments or measures of symptom severity, are commonly used to evaluate the effectiveness of treatments. Generic and disease-specific instruments have different assets. Generic HRQoL instruments, such as the 15D [1, 2], provide a wider perspective of an individual’s quality of life and can be used for calculation of quality-adjusted life years (QALYs) [3-7]. Disease-specific instruments, such as the Canadian Cardiovascular Society (CCS) [8, 9] grading used to assess symptom severity in coronary artery disease (CAD), are usually more sensitive to changes in the specific symptoms of a disease. However, generic instruments typically contain dimensions, which can reflect disease-specific changes. For example, the 15D instrument includes breathing and discomfort and symptoms which can indicate the severity of CAD.

The CCS grading is the most commonly used tool to evaluate the symptoms of CAD in clinical practise, and it is usually rated by the treating physician [10]. The CCS is easy to assess and it provides a rapid assessment of a patient’s symptom severity whereas responses to a HRQoL questionnaire, such as the 15D, needs first to be converted, by using a set of utility or preference weights, to a single health index utility score [2, 11]. As disease-specific measures do not provide similar preference-based quality of life information as generic HRQoL instruments, there have been mapping studies between these two types of measurements [12]. It is important to understand how measured outcomes reflect the patient’s overall quality of life, regardless on whether the application area of the results is clinical practice or health economic analysis [13-15].

Previous studies have assessed the correlation between clinician measured CCS grading or New York Heart Association (NYHA) functional classification and patient-reported generic HRQoL, mainly in cross-sectional designs [16-18]. Therefore, it is unknown whether the change in symptom severity evaluated by the CCS is associated with the change in generic HRQoL. Further, the earlier studies have usually compared physician-evaluated CCS to a patient-reported generic HRQoL instrument. Therefore, it is unknow whether the change in self-reported CCS correlates with the change in self-reported generic HRQoL. To evaluate this, we investigated the correlation between the change in patient-reported CCS and the generic 15D HRQoL score among patients with coronary artery disease.

Material and methods

Study design and population

This observational cohort study was conducted as a part of routine clinical practice. Data were collected from the Kuopio University Hospital Heart Center. Patients scheduled for coronary angiography between June 2015 and February 2017, and subsequently treated by optimal medical therapy (OMT), coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) filled in the CCS and 15D HRQoL questionnaires pre-angiography at baseline and after a one-year of follow-up.

The NOMESCO Classification of Surgical Procedures codes [19] were used to identify angina patients. After excluding patients with more than one operation during the same treatment episode, the total population included 1271 patients. Of them, 603 were treated with OMT only, 240 with OMT plus CABG and 428 with OMT plus PCI.

Informed consent and ethical considerations

The study was approved by the Research Ethics Committee of the Northern Savo Hospital District (number 3/2014). Written informed consent was obtained from all individual participants included in this study.

Instruments

The CCS was used to define symptom severity [8]. The CCS grading system employs four grades from I (without limitation of physical activity) to IV (inability to carry out any physical activity without discomfort) [8, 9, 20, 21]. The CCS is a widely used instrument and its correlation with mortality has been established previously [22, 23].

The 15D instrument is a generic, patient-reported questionnaire for measuring HRQoL [2]. It consists of 15 dimensions (mobility, vision, hearing, breathing, sleeping, eating, speech, excretion, usual activities, mental function, discomfort and symptoms, depression, distress, vitality, and sexual activity) with five ordinal levels. Based on the dimension scores, a single index score ranging from 0 (being dead) to 1 (being in full health) can be calculated. Missing values in 3 or less dimensions were imputed as described previously [1] and the index score was calculated from the health state descriptive system by utilizing the Finnish utility weights [2].

The change in the CCS grades between the baseline and 12-month follow-up was reported on a scale of 1 to 5, with “1” indicating marked deterioration (12-month grade minus baseline grade ≥2), “2” moderate deterioration (12-month grade minus baseline grade 1), “3” no change, “4” moderate improvement (12-month grade minus baseline grade -1) and “5” marked improvement (12-month grade minus baseline grade ≤-2). For the 15D total score, the change, i.e. the difference in scores between the baseline and 12-month follow-up, was classified into 5 categories based on the reported minimal important difference (MID) for the instrument [24]. MID represents the smallest change in the HRQoL score that can be considered to be important from a clinical perspective [25]. The change in each 15D dimension was scaled with a similar scale as used for the CCS grades. The used scales of changes are presented in Table 1.

Table 1

Categorisation of changes in CCS and 15D.

	Change in the CCS grade	Change in the 15Da	Change in 15D dimensions
Definition	12-month grade minus baseline grade	12-month index score minus baseline index score	12-month level minus baseline level
Scaled Change
1 = much worse	≥2, deterioration	<-0.035	≥2, deterioration
2 = slightly worse	1	-0.035 − -0.015	1
3 = no change	0, no change	-0.015< − <0.015	0, no change
4 = slightly better	-1	0.015 − 0.035	-1
5 = much better	≤-2, improvement	>0.035	≤-2, improvement

aBased on the reported minimal important difference (MID) for the instrument [24].

Statistical analysis

Differences in baseline CCS distributions between treatment groups (OMT, CABG and PCI) were tested with Chi Square test. Correlations between changes in the CCS with changes in the 15D and its dimensions from baseline to one year after entering the treatment were studied using Spearman correlation coefficient, as it is suitable for re-ranked values of processed data [26]. Correlations were examined in the total study population and within treatment subgroups, and age and gender groups. The population was divided into two groups based on baseline age (<70 or ≥70 years). Patients who had missing values in more than three 15D dimensions were included in dimension-specific analyses, but excluded from the main analyses as the 15D total score cannot be derived in these cases. All statistical analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and R 3.6.3 (The R Foundation for Statistical Computing, Vienna, Austria).

Results

Population characteristics

Population characteristics by the treatment groups are presented in Table 2. The proportion of women differed between the treatment groups (48.1% of the OMT, 16.3% of the CABG and 24.8% of the PCI patients). The mean age was similar in all three treatment groups.

Table 2

Participant characteristics.

	OMT (n = 603, 47.4%)	CABG (n = 240, 18.9%)	PCI (n = 428, 33.7%)	Total (N = 1271, 100%)
Mean age at baseline (SD)	67.4 (10.0)	67.4 (8.8)	68.8 (9.0)	67.9 (9.5)
Age <70 years, n (%)	334 (55.4%)	136 (56.7%)	223 (52.1%)	693 (54.5%)
Men, n (%)	313 (51.9%)	201 (83.8%)	322 (75.2%)	836 (65.8%)
CCS at baseline
I	64 (10.6%)	36 (15.0%)	29 (6.8%)	129 (10.1%)
II	332 (55.1%)	148 (61.7%)	282 (65.9%)	762 (60.0%)
III	115 (19.1%)	48 (20.0%)	76 (17.8%)	239 (18.8%)
IV	59 (9.8%)	6 (2.5%)	23 (5.4%)	88 (6.9%)
Missing data	33 (5.5%)	2 (0.8%)	18 (4.2%)	53 (4.2%)
Mean change in CCSa (95% CI)	-0.39 (-0.48 –-0.30) (n = 365)	-0.64 (-0.75– -0.53) (n = 169)	-0.43 (-0.52 –-0.33) (n = 280)	-0.45 (-0.51 –-0.39) (n = 814)
Missing data	236 (39.5%)	71 (29.6%)	148 (34.6%)	457 (36.0%)
Mean 15D at baseline (95% CI)	0.820 (0.101) (n = 593)	0.857 (0.085) (n = 238)	0.832 (0.098) (n = 423)	0.831 (0.098) (n = 1254)
Missing data	10 (1.7%)	2 (0.8%)	5 (1.2%)	17 (1.3%)
Mean change in 15Da (95% CI)	-0.004 (-0.010–0.003) (n = 387)	0.034 (0.020–0.047) (n = 173)	0.016 (0.009–0.024) (n = 292)	0.011 (0.006–0.016) (n = 852)
Missing data	216 (35.8%)	67 (27.9%)	136 (31.8%)	419 (33.0%)

a12-months score minus baseline.

Distributions of baseline CCS grades differed between the treatment groups (p<0.001). Of all the participants, 60.0% reported CCS grade II at the baseline. The mean 15D score was 0.831 (standard deviation [SD] 0.098) at the baseline. The CABG group had a higher baseline score (0.857; SD 0.085) compared to the PCI group (0.832; SD 0.098) and the OMT group (0.820; SD 0.101).

Changes in the individual HRQoL instruments

A total of 814 (64.0%) patients reported both baseline and 12-month follow-up CCS grade. Of them, 350 (43.0%) patients reported an improvement in the CCS grade (Table 3). This was observed most often among the CABG treated patients of whom 59.2% experienced relief of their symptoms. Only 56 (6.9%) patients reported worsening of CCS grade. However, 408 (50.1%) of patients did not experience any change in their symptoms.

Table 3

Changes in the CCS and 15D from baseline to 12 months follow-up by subgroups.

The values are n (%).

	Treatment group			Age group		Gender		Total
	OMT	CABG	PCI	<70	≥70	male	female
Change in CCS	n = 365	n = 169	n = 280	n = 425	n = 389	n = 534	n = 280	n = 814 (100%)
(≥2, deterioration) 1	5 (1.4%)	0 (0.0%)	6 (2.1%)	6 (1.4%)	5 (1.3%)	6 (1.1%)	5 (1.8%)	11 (1.4%)
(1) 2	22 (6.0%)	8 (4.8%)	15 (5.4%)	25 (5.9%)	20 (5.1%)	30 (5.6%)	15 (5.4%)	45 (5.5%)
(0, no change) 3	208 (57.0%)	61 (36.1%)	139 (49.6%)	200 (47.1%)	208 (53.5%)	255 (47.8%)	153 (54.6%)	408 (50.1%)
(-1) 4	95 (26.0%)	87 (51.5%)	99 (35.4%)	150 (35.3%)	131 (33.7%)	199 (37.3%)	82 (29.3%)	281 (34.5%)
(≤-2, improvement) 5	35 (9.6%)	13 (7.7%)	21 (7.5%)	44 (10.4%)	25 (6.4%)	44 (8.2%)	25 (8.9%)	69 (8.5%)
Missing values								n = 457
Change in 15D a	n = 387	n = 173	n = 292	n = 441	n = 411	n = 554	n = 298	n = 852 (100%)
(much worse) 1	107 (27.6%)	27 (15.6%)	58 (19.9%)	93 (21.1%)	99 (24.1%)	128 (23.1%)	64 (21.5%)	192 (22.5%)
(slightly worse) 2	45 (11.6%)	13 (7.5%)	31 (10.6%)	42 (9.5%)	47 (11.4%)	55 (9.9%)	34 (11.4%)	89 (10.4%)
(no change) 3	87 (22.5%)	27 (15.6%)	55 (18.8%)	94 (21.3%)	75 (18.2%)	100 (18.1%)	69 (23.2%)	169 (19.8%)
(slightly better) 4	54 (14.0%)	16 (9.2%)	44 (15.1%)	48 (10.9%)	66 (16.1%)	76 (13.7%)	38 (12.7%)	114 (13.4%)
(much better) 5	94 (24.3%)	90 (52.0%)	104 (35.6%)	164 (37.2%)	124 (30.2%)	195 (35.2%)	93 (31.2%)	288 (33.8%)
Missing values								n = 419

aBased on the reported minimal important difference (MID) for the instrument [24].

Of the 852 (67.0%) patients who filled in the 15D questionnaires at both time-points, almost half (47.2%) experienced a clinically important improvement (>0.015) in their 15D score according to the MID of the instrument (Table 3). Compared to the changes in the CCS, where only 6.9% reported deterioration of symptoms during the follow-up, 281 (33.0%) of the patients had a worse (<-0.015) 15D score and only 169 (19.8%) reported no change in their 15D score. Compared to other subgroups, a majority of CABG treated patients (61.3%) reported improved (>0.015) 15D score at the end of the follow-up.

Correlation between changes in CCS and 15D

Altogether 805 (63.3%) patients had both CCS and 15D index scores reported at both timepoints and were included in these analyses. In all subgroups, correlations between the changes in the CCS grade and the MID-based changes in the 15D ranged from weak to only moderate. Among all patients, the Spearman correlation coefficient of the change in the two instruments was 0.33 (95% confidence interval [CI] 0.27–0.39) (Fig 1, S1 Table).

Fig 1

Spearman correlation coefficients (95% confidence intervals) between one-year changes in the CCS and the 15D and its dimensions.

The correlation coefficients between the changes in the CCS grade and the MID-based changes in the 15D were stronger in those treated with PCI (r = 0.39; 95% CI 0.28–0.48) than in CABG (r = 0.29; 95% CI 0.15–0.43) or OMT (r = 0.27; 95% CI 0.18–0.37) treatment groups (Fig 2A, S1 Table). Similarly, correlation coefficients were stronger in men than in women and in younger patients (age <70 years) than in older patients (Fig 2B and 2C, S1 Table).

Fig 2

Spearman correlation coefficients (95% confidence intervals) between one-year changes in the CCS and the 15D and its dimensions in subgroups.

(a) Correlations by treatment groups; (b) Correlations by age groups, <70 and ≥70; (c) Correlations by gender.

Of the individual 15D dimensions, the change in the breathing dimension (r = 0.40; 95% CI 0.34–0.45) followed by the vitality (r = 0.30; 95% CI 0.24–0.36) had the strongest correlation with the change in the CCS grade in the total study population (S2 Table). Changes in other dimensions were only weakly correlated with the CCS change (S2 Table). The correlations were similar across subgroups (Fig 2). The strongest individual correlation was observed in the PCI treatment group between the changes in the breathing dimension and the CCS grade (r = 0.46; 95% CI 0.36–0.55), but it did not differ statistically significantly from the other treatment groups (Fig 2A).

Discussion

Our study shows that the patient-reported change in severity of CAD symptoms measured with CCS correlated moderately (r = 0.33) with the change in the generic HRQoL measured with the 15D. Strongest, although only moderate, correlations were observed between the change in the CCS grade and the changes in the 15D dimensions of breathing and vitality. The moderate correlation between the changes in the CCS grade and 15D index reflect that the CCS grade represents the severity of cardiac symptoms whereas the 15D is influenced, not only by cardiac health, but also by other dimensions of life, such as concomitant diseases [27]. These findings imply that symptom-based evaluation of the change in the CCS grade may not reflect the full benefit or harm of angina treatment, and thus, also other outcome measures are needed.

Although the correlation between CCS grade and 15D was only moderate, the proportion of patients with clinically meaningful improvement of symptoms was almost the same with both instruments; 47.2% of patients reported a clinically meaningful improvement in HRQoL measured with the 15D and 43.0% with the CCS. The correlation between CCS and 15D was weakened by the discrepancy in patients reporting worsening of symptoms or no benefit. Less than 10% of the patients reported increasing symptom severity (CCS grade), while every third patient reported worsening of generic HRQoL (15D). Correspondingly, using the CCS instrument, half of the patients did not experience any benefit, whereas this was the case on in only one fifth of patients when 15D was applied. This difference between CCS and 15D suggests that not only the severity of angina pectoris symptoms, but also other dimensions of health captured by the generic instrument are important aspects of quality of life. The proportion of CAD patients with deterioration of overall HRQoL was comparable with that reported in a previous study [28] demonstrating the external validity of our results.

In earlier studies, the association between CCS and NYHA class and generic instruments, such as EQ-5D and SF-6D have been somewhat controversial. In line with us, in the study by Goldsmith et al. one class increase of CCS grade, i.e. worsening of symptoms, was associated with a decrease in HRQoL measured with the EQ-5D instrument among CAD and heart failure patients [17]. Similarly, in heart failure patients the EQ-5D and SF-6D instrument’s utility scores decreased with increasing disease severity [16]. On the other hand, positive changes in EQ-5D and SF-6D instruments have been reported without co-occurring changes in the NYHA functional status [16]. This demonstrates that when assessing the overall therapeutic effect of a treatment, not only disease specific symptoms but also wider perspective of the patient’s quality of life are needed.

With respect to the individual 15D dimensions, the CCS change correlated most strongly with changes in breathing (r = 0.40) and vitality (r = 0.30). The correlation between breathing and CCS was highest among the PCI patients (r = 0.46). This is expected based on the CCS grading definitions and is also in line with previous studies in CABG and PCI patients [28, 29]. Only weak correlations were observed between the change in the CCS grade and other dimensions of the 15D that would be expected to correlate with the CCS, including mobility and usual activities.

The prevalence of elderly patients with coronary artery disease is increasing. Elderly patients have greatest morbidity and mortality as well as high prevalence of comorbidities [30], which may influence the perceived effect of the treatment [31]. Indeed, in our study CCS class improved in 46% of patients in the younger age groups whereas only in 40% in the older age group. However, using the generic instrument (15D), the impact of age was less obvious; 15D improved in 48% and 46% in of the younger and the older population, respectively.

Routinely collected PRO data may not present the actual patient case-mix and may be biased towards younger and healthier patients [32]. A limitation of our study is that we did not have data on those patients who declined to answer the questionnaires at the baseline and, therefore, it is possible, that the studied patient population may not represent the actual case-mix of those treated. However, our study population is larger, and collected from a real-world setting which are strengths in comparison to previous smaller cross-sectional study [18] and randomized controlled trials [17].

Conclusion

In conclusion, our cohort study provides real-life insight on the correlation between the changes in the CCS grade and the changes in the 15D in clinical practice. The observed moderate correlation between the changes in the CCS grade and the 15D indicates that the symptom-based evaluation of the change in the CCS grade may not catch the full benefit or harm of the treatment and vice versa, a generic instrument, such as 15D, may not capture the effect of treatment on symptoms. Although generic instruments, such as 15D, contain dimensions that to some extent capture changes in specific symptoms, disease-specific instruments are complementary and both are needed as they may be more sensitive for these changes. Therefore, both generic HRQoL and disease specific measurements are needed to capture the full effect of the treatment in future studies.

Spearman correlation coefficients (95% confidence limits) between change in the CCS and the 15D in different subgroups.

(PDF)

Click here for additional data file.

Spearman correlation coefficients (95% confidence limits) between change in the CCS and the 15D’s dimensions.

(PDF)

Click here for additional data file.

2 Nov 2021

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Reviewer #1: The manuscript aims to investigate the correlation between the change in patient-reported CCS and the generic 15D HRQoL score. The manuscript is structured but is regular written. The results present new and useful data for researchers and clinicians. The reviewer appreciates the effort of the authors. However, some parts need to be corrected. My specific comments are appended below.

Keywords:

-Rewrite “angina pectoris” as “Angina Pectoris” and “health-related quality of life” as “Health-Related Quality Of Life”. This is a MeSH term, and the first letter must be capitalized

-CCS and 15D are not a MeSH terms. I suggest you to change these terms as MeSH terms.

- I suggest you to keep keywords in alphabetical order

Introduction:

-In the first three paragraphs, the authors mention the importance of specific assessment of symptoms and HRQOL for economic analysis in health, but this is not the focus of the article, and there is no need to mention it repeatedly.

-I suggest the authors cite the study hypothesis.

Material and methods:

-I Suggest to separate ethical issues from the “Study design and population”. I suggest placing an item “Informed consent and ethical considerations” with the phrase of lines 89-91.

Results:

-It was not clear how the population was divided among those who completed each questionnaire. Since two instruments are being correlated, it is necessary for the studied population to complete the two questionnaires at both times.

-It would be important for the authors to explain the variation in participants, since 1,271 were included in the study, but different amounts filled each instrument (CCS and 15D).

-It would also be important to explain how many completed each instrument only at the first moment and why there were missing values and whether this would be a limitation for the study. Maybe na algorithm explain the included population would be helpfull.

-Suggestion line 148: put the percentage next to the number of patients

-S2 Table: Hearing dimension in the colun “95%” the autors wrote “0.00” I suggest change to “<0.01”

-The authors correlate HRQOL with procedures performed for angina (OMT, PCI, CABG), but sociodemographic characteristics (ie years of education, income) and clinical features (ie comorbidities, treatments for other diseases) affect HRQOL. It would be important to include this information in the results.

-Table 2: describe age ≥70 years, but they are a minority (45.5%) I suggest putting the majority

Discussion

-Line 195-196: The autors wrote 15D is influenced not only by heart health but also by other dimensions of life, such as concomitant illnesses. I suggest that in the results the authors describe whether the participants in this study had comorbidities i.e hypertension, diabetes.

-I suggest that the authors explain the criteria for selecting the age groups ≥70 / ≥ 70 years.

-I suggest discussing the results based on group age differences (≥70 / ≥ 70 years).

Reviewer #2: Methodology should be more clear.. and explained-well.

Under statistical analysis, only statistical methodology should be discussed/explained NOT the overall/general scoring etc etc.

Discussion should be re-written/revised appropriately matching with the objectives and the findings obtained, not just like expanding the intro part.

all the obtained results must be discussed in detail and by referring to/with earlier studies using same/similar research tools.

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Reviewer #1: Yes: Priscila Moreno Sperling Cannavan

Reviewer #2: No

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17 Dec 2021

Response to Reviewers

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: No

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript aims to investigate the correlation between the change in patient-reported CCS and the generic 15D HRQoL score. The manuscript is structured but is regular written. The results present new and useful data for researchers and clinicians. The reviewer appreciates the effort of the authors. However, some parts need to be corrected. My specific comments are appended below.

Keywords:

-Rewrite “angina pectoris” as “Angina Pectoris” and “health-related quality of life” as “Health-Related Quality Of Life”. This is a MeSH term, and the first letter must be capitalized

-CCS and 15D are not a MeSH terms. I suggest you to change these terms as MeSH terms.

- I suggest you to keep keywords in alphabetical order

Our response: We thank the Reviewer for commenting on this. We have rewritten the terms according to MeSH terms. We would prefer to include also 15D and CCS as key words although they are not MeSH terms but leave the final decision on this to the Editor. We have also sorted the keywords to alphabetical order.

Introduction:

-In the first three paragraphs, the authors mention the importance of specific assessment of symptoms and HRQOL for economic analysis in health, but this is not the focus of the article, and there is no need to mention it repeatedly.

Our response: We agree with the Reviewer and have modified the introduction so that health economics analyses are emphasized less.

-I suggest the authors cite the study hypothesis.

Our response: We would rather refrain from stating an exact hypothesis, because we did not have an a priori hypothesis for what we expected to find. Our aim was to assess whether the change measured by these two patient-reported instruments is correlated. However, we have revised the last paragraph of the introduction so that the rationale for our study is stated more clearly. The revised paragraph reads as follows: “Previous studies have assessed the correlation between clinician measured CCS grading or New York Heart Association (NYHA) functional classification and patient-reported generic HRQoL, mainly in cross-sectional designs [16-18]. Therefore, it is unknown whether the change in symptom severity evaluated by the CCS is associated with the change in generic HRQoL. Further, the earlier studies have usually compared physician-evaluated CCS to a patient-reported generic HRQoL instrument. Therefore, it is unknow whether the change in self-reported CCS correlates with the change in self-reported generic HRQoL. To evaluate this, we investigated the correlation between the change in patient-reported CCS and the generic 15D HRQoL score among patients with coronary artery disease.”

Material and methods:

-I Suggest to separate ethical issues from the “Study design and population”. I suggest placing an item “Informed consent and ethical considerations” with the phrase of lines 89-91.

Our response: In accordance with the suggestion of the Reviewer, we have separated ethical issues to a new paragraph with a heading “Informed consent and ethical considerations”.

Results:

-It was not clear how the population was divided among those who completed each questionnaire. Since two instruments are being correlated, it is necessary for the studied population to complete the two questionnaires at both times.

Our response: We agree with the Reviewer and have clarified the number of people in the correlation analysis in the revised manuscript (lines183-184) as follows: “Altogether 805 (63.3%) patients had both CCS and 15D index scores reported at both timepoints and were included in these analyses.” We have also specified the number of patients included in the analyses assessing the changes in individual instruments on lines 167-168 and 174-175.

-It would be important for the authors to explain the variation in participants, since 1,271 were included in the study, but different amounts filled each instrument (CCS and 15D).

Our response: Please, see our answer to the previous comment.

-It would also be important to explain how many completed each instrument only at the first moment and why there were missing values and whether this would be a limitation for the study. Maybe na algorithm explain the included population would be helpfull.

Our response: We have reported the number (proportion) of missing data at baseline and after 12 months for both instruments in table 2. In addition, the number of patients with data available at both timepoints is reported in the table and Results section of the manuscript (lines 167-168, 174-175 and 183-184). Unfortunately, we have no data on the reasons for missing data.

-Suggestion line 148: put the percentage next to the number of patients

Our response: In line with the recommendation of the Reviewer, we have added the proportions next to the number of patients on lines 167, 174 and 183.

-S2 Table: Hearing dimension in the colun “95%” the autors wrote “0.00” I suggest change to “<0.01”

Our response: In accordance with the suggestion of the Reviewer, we have corrected the correlation coefficient as “<0.01”.

-The authors correlate HRQOL with procedures performed for angina (OMT, PCI, CABG), but sociodemographic characteristics (ie years of education, income) and clinical features (ie comorbidities, treatments for other diseases) affect HRQOL. It would be important to include this information in the results.

Our response: We thank the Reviewer for the comment. Unfortunately, we have no data on sociodemographic characteristics or clinical features.

-Table 2: describe age ≥70 years, but they are a minority (45.5%) I suggest putting the majority

Our response: In line with the recommendation of the Reviewer, we have changed the age to describe the majority, i.e., patients <70 years.

Discussion

-Line 195-196: The autors wrote 15D is influenced not only by heart health but also by other dimensions of life, such as concomitant illnesses. I suggest that in the results the authors describe whether the participants in this study had comorbidities i.e hypertension, diabetes.

Our response: We agree that describing the comorbidities would inform on the comorbidities of the study population, but we would prefer to keep the tables and manuscript in the current form. The main aim of our manuscript was to illustrate whether the changes in symptom-specific CCS and generic 15D instrument are consistently correlated (i.e., how much they measure the same phenomenon, can 15D capture the patient-reported change in CCS). As all participants had coronary artery disease, most of them had hypertension and/or diabetes and thus reporting the prevalence of these comorbidities would not result to a meaningful improvement in the manuscript.

-I suggest that the authors explain the criteria for selecting the age groups ≥70 / ≥ 70 years.

Our response: The aim was to study the treatment effect in two age groups (young and old) with approximately equal size (quantiles). As the median age in the study population (n=1271) was 69 years, rounding it to the nearest tenth resulted in two age groups (<70 and ≥70 years) with approximately same size (54.5 % and 45.5% of the study population).

-I suggest discussing the results based on group age differences (≥70 / ≥ 70 years).

Our response: In accordance with the suggestion of the Reviewer, we have added to the discussion section as follows (lines 267-272): ”The prevalence of elderly patients with coronary artery disease is increasing. Elderly patients have greatest morbidity and mortality as well as high prevalence of comorbidities [30], which may influence the perceived effect of treatment [31]. Indeed, in our study CCS class improved in 46% of patients in the younger age groups whereas only in 40% in the older age group. However, using the generic instrument (15D), the impact of age was less obvious; 15D improved in 48% and 46% in of the younger and the older population, respectively.“

Reviewer #2: Methodology should be more clear.. and explained-well.

Under statistical analysis, only statistical methodology should be discussed/explained NOT the overall/general scoring etc etc.

Our response: We thank the Reviewer for the comment. We have restructured the section of statistical analyses according to the suggestion of the Reviewer.

Discussion should be re-written/revised appropriately matching with the objectives and the findings obtained, not just like expanding the intro part. all the obtained results must be discussed in detail and by referring to/with earlier studies using same/similar research tools.

Our response:

We thank the Reviewer for the suggestion and hope that the modification of the Introduction section as suggested by the Reviewer 1 above has removed some of the overlap.

We also agree that the Discussion to some extent “expands” the Introduction as the aim of the Introduction is to provide the context for performing the study, including a brief introduction to earlier studies related to the topic. We have rewritten and reorganized the Discussion in the revised manuscript. We hope that in the revised form the discussion of our results in the context of earlier studies on this topic is more evident. The following text has been added to the Discussion:

“Although the correlation between CCS grade and 15D was only moderate, the proportion of patients with clinically meaningful improvement of symptoms was almost the same with both instruments; 47.2% of patients reported a clinically meaningful improvement in HRQoL measured with the 15D and 43.0% with the CCS. The correlation between CCS and 15D was weakened by the discrepancy in patients reporting worsening of symptoms or no benefit. Less than 10% of the patients reported increasing symptom severity (CCS grade), while every third patient reported worsening of generic HRQoL (15D). Correspondingly, using the CCS instrument, half of the patients did not experience any benefit, whereas this was the case on in only one fifth of patients when 15D was applied. This difference between CCS and 15D suggests that not only the severity of angina pectoris symptoms, but also other dimensions of health captured by the generic instrument are important aspects of quality of life. The proportion of CAD patients with deterioration of overall HRQoL was comparable with that reported in a previous study [28] demonstrating the external validity of our results.

In earlier studies, the association between CCS and NYHA class and generic instruments, such as EQ-5D and SF-6D have been somewhat controversial. In line with us, in the study by Goldsmith et al. one class increase of CCS grade, i.e. worsening of symptoms, was associated with a decrease in HRQoL measured with the EQ-5D instrument among CAD and heart failure patients [17]. Similarly, in heart failure patients the EQ-5D and SF-6D instrument’s utility scores decreased with increasing disease severity [16]. On the other hand, positive changes in EQ-5D and SF-6D instruments have been reported without co-occurring changes in the NYHA functional status [16]. This demonstrates that when assessing the overall therapeutic effect of a treatment, not only disease specific symptoms but also wider perspective of the patient’s quality of life are needed.”

________________________________________

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Priscila Moreno Sperling Cannavan

Reviewer #2: No

Submitted filename: PONE_Point_by_point_response_161221.docx

Click here for additional data file.

9 Feb 2022

Submitted filename: PONE-D-21-19920R1_01.2022.docx

Click here for additional data file.

14 Feb 2022

Response to Reviewers:

1- The authors made several corrections and as the manuscript was sent for a new evaluation, there is no way to evaluate it, because the corrections and the first version of the manuscript are together in the same version, the correction with marking (ie: manuscript), leaving it confusing for the correction.

I suggest a new submission, only with the second version of the manuscript and that the authors highlight what was changed (i.e: manuscript).

Our response: We apologize for the inconvenience. However, the revised manuscript is submitted with tracked changes (utilizing “Track changes” tool in Microsoft Word) as suggested by the journal. In addition, the submission includes a clean version without tracked changes.

2- I also suggest that authors review the order of references in the introduction. The paragraphs were redacted, but the reference number did not change.

Our response: We are grateful for the Reviewer for noticing this. We have reviewed and corrected the order of the references.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

15 Mar 2022

Correlation of the disease-specific Canadian Cardiovascular Society (CCS) classification and health-related quality of life (15D) in coronary artery disease patients

PONE-D-21-19920R2

Dear Dr. Lavikainen,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Filipe Prazeres, MD, MSc, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have reviewed the manuscript and so it can be accepted and published.

Appreciated the revised version.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Priscila Moreno Sperling Cannavan

25 Mar 2022

PONE-D-21-19920R2

Correlation of the disease-specific Canadian Cardiovascular Society (CCS) classification and health-related quality of life (15D) in coronary artery disease patients

Dear Dr. Lavikainen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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