Training intensity and improvements in exercise capacity in elderly patients undergoing European cardiac rehabilitation - the EU-CaRE multicenter cohort study.

OBJECTIVES: Guidelines for exercise intensity prescription in Cardiac Rehabilitation (CR) are inconsistent and have recently been discussed controversially. We aimed (1) to compare training intensities between European CR centres and (2) to assess associations between training intensity and improvement in peak oxygen consumption ([Formula: see text]O2) in elderly CR patients.
METHODS: Peak [Formula: see text]O2, heart rate and work rate (WR) at the first and second ventilatory thresholds were measured at start of CR. Training heart rate was measured during three sessions spread over the CR. Multivariate models were used to compare training characteristics between centres and to assess the effect of training intensity on change in peak [Formula: see text]O2.
RESULTS: Training intensity was measured in 1011 out of 1633 EU-CaRE patients in 7 of 8 centers and the first and secondary ventilatory threshold were identified in 1166 and 817 patients, respectively. The first and second ventilatory threshold were found at 44% (SD 16%) and 78% (SD 9%) of peak WR and 78% (SD 9%) and 89% (SD 5%) of peak heart rate, respectively. Training intensity and session duration varied significantly between centres but change in peak [Formula: see text]O2 over CR did not. Training above the first individual threshold (β 0.62, 95% confidence interval [0.25-1.02]) and increase in training volume per hour (β 0.06, 95%CI [0.01-0.12]) were associated with a higher change in peak [Formula: see text]O2.
CONCLUSION: While training intensity and volume varied greatly amongst current European CR programs, changes in peak [Formula: see text]O2 were similar and the effect of training characteristics on these changes were small.

Introduction

Structured exercise training serving the purpose to improve exercise capacity and prognosis [1, 2] is a cornerstone of current comprehensive cardiac rehabilitation (CR). However, quantification of frequency, duration and especially intensity of exercise training varies between national and international CR guidelines [3].

The gold standard to prescribe exercise intensity is the determination of individual training domains (light-moderate, moderate-high, high-severe) defined by the first and secondary ventilatory thresholds (VT1, VT2) derived from cardiopulmonary exercise testing (CPET) [4]. However, these physiological thresholds are not readily detectable in all patients, and the determination thereof requires the conductance of CPET, which is not always available or feasible. Current guidelines suggest intensity prescription in percent of peak effort, ranging from 40% to 80% of peak oxygen consumption (O2), 50–90% of peak heart rate (HR), or 40–70% of HR reserve [3]. Significant inconsistencies between different guidelines and discrepancies in threshold-based intensities were found in a recent study on patients undergoing CR [5], upon which the need of reconsidering the current guidelines for exercise prescription in the CR setting has been discussed [6]. The need for clearer guidelines, however, may only be indicated if training intensity plays an important role for the improvement in exercise capacity. A recent meta-analysis found significantly greater, though not clinically meaningful, improvements in peak O2 with vigorous exercise interventions compared to interventions with lower intensities in a general CR population [7]. Despite the fact that guidelines recommend exercise above the VT1, low intensities may also have a beneficial effect on exercise capacity, especially in cardiac patients with a significantly reduced pre-training exercise capacity [4] and patients with chronic heart failure [8]. The importance of training intensity in elderly cardiac patients has not been investigated thoroughly so far.

The aim of this study was (1) to compare training intensity domains derived from ventilatory thresholds with relative intensities of current guidelines in a large population of elderly cardiac patients and (2) to compare the training intensities utilized in different European CR centers and its influence on changes in peak O2.

Methods

The EU-CaRE study was a prospective cohort study, that assessed the (cost) effectiveness, sustainability and participation levels in current CR programs of eight cardiac rehabilitation centres in seven European countries (Denmark, France, Germany, the Netherlands, Italy, Spain and Switzerland). The study was approved by all relevant medical ethics committees: Landesärztekammer Rheinland Pfalz, Germany (Nr. 837.341.15, (10109)); Comission Nationale de l'Informatique et de Libertés, France (DR-2016-021); medisch-ethische toetsingscomissie METC Isala Zwolle, The Netherlands (15.0350); Secretario do Comité de Ética da Investigación de Santiago-Lugo, Spain (2015/486); Comitato Ethico per Parma, Italy (34360); Videnskabsetiske Komite C for Region Hovedstaden, Denmark (593); Kantonale Ethikkomission Bern, Switzerland (290/15). The study was registered at trialregister.nl (NL5166). All participants gave written informed consent before they were included in the study.

Study population

CR patients with an age of ≥65 after an acute coronary syndrome, percutaneous intervention (PCI), CABG, surgical or percutaneous heart valve replacement (HVR) or documented coronary artery disease (CAD) were consecutively included from January 2016 –January 2018.

Patients with a contraindication to CR [9], mental impairment leading to inability to cooperate, severe impaired ability to exercise, signs of severe cardiac ischemia and/or a positive exercise testing on severe cardiac ischemia, insufficient knowledge of the native language and an implanted cardiac device were excluded.

Data collection and processing

CPETs were performed on a cycle ergometer before and after CR using an individualised ramp protocol to achieve patient’s voluntary exhaustion within 8 to 12 min of ramp duration. CPET raw data was processed in the core laboratory (Uni Bern) using MATLAB software (R2017, The MathWorks®, United States). To reduce a potential systematic bias for centres, all ventilatory thresholds (VT1 and VT2) were visually determined by one single investigator (TM), a sports scientist with extensive experience in setting ventilatory thresholds in healthy people as well as cardiac patients. The investigator was blinded to patient characteristics and centre. Interrater reliability was determined in a random subset of 200 CPETs, in which thresholds were determined by a second experienced investigator (MW) blinded also to patients and centres as well as to thresholds set by the other investigator. VT1 was set at the beginning of a continuing increase of the ventilatory equivalent for oxygen (E/O2) without an increase in the ventilatory equivalent for carbon dioxide (E/ CO2) or beginning of a continuing increase in the end-tidal pressure of oxygen (PETO2) without a decrease in the end-tidal pressure of carbon dioxide (PETCO2), whichever was more discernible. VT2 was set when there was a steeper E/ CO2CO2 increase or PETCO2 decrease due to the exercise-induced lactic acidosis [10]. A centred moving average over 30 s for O2, HR and WR was recorded at VT1, VT2 and peak exercise.

In each patient, we aimed to record HR during three training sessions, namely in a session during the first third of CR, during the middle of CR and towards the end of CR. The mean training HRs of a patient’s monitored training sessions were averaged to one single mean training HR. In Copenhagen, Paris and Zwolle, training heart rate was measured with a mobile device and chest strap from MobiHealth B.V (Zwolle, The Netherlands). Ludwigshafen and Bern used stationary 3 channel electrocardiogram systems (Schiller Medizintechnik GmbH, München, Germany and ergoline GmbH, Bitz, Germany). Raw data of all monitored trainings except those from Parma and Nijmegen were processed in Bern using a MATLAB algorithm to smooth the HR signal and to filter noisy signals by robust local regression. Due to technical limitations, Parma provided HR (measured with ApexPro FH Telemetry system, GEHealthcare, U.S.) and training duration already averaged for each training and there were no monitored training sessions available for the small group of patients from Nijmegen (32 patients).

Statistical analysis

All statistics were performed with R (Version 3.5.1, R Core Team, 2017).

Descriptive statistics included mean and standard deviation (SD) of O2, HR, HR reserve and WR in percent of peak values at VT1 and VT2. Threshold values were given for a subgroup of patients reaching formal exertion during CPET at start of CR, defined by peak respiratory exchange ratio (RER = CO2/O2) >1.1. Level of agreement in VT setting within the random subset of 200 tests were assessed by Bland Altman plots. Training characteristics for each centre were reported by median and interquartile ranges for intensity in percent of HR peak and HR reserve at baseline CPET, average duration per session, total volume (duration × number of performed endurance sessions) and weekly volume. Proportion of patients with mean training intensity below their individual VT1 was calculated for each centre.

Centre differences in training HR, duration, training volume and change in peak O2 were tested using robust multivariate linear models (robustbase package) with centre as fixed factor and adjusted for the following potential confounders: age, sex, index intervention (PCI, CABG, surgical HVR, percutaneous HVR, documented CAD), HR at VT1, beta-blocker, diabetes mellitus, days between index intervention and baseline CPET, and time between baseline CPET and recorded training in days. The effect of training intensity domain (training HR below vs. above individual VT1) on change in peak O2 was assessed by group comparison using Wilcoxon-rank sum test and with a multivariate linear mixed model (lmer package) with centre as random factor and additionally adjusted for the following fixed factors: age, sex, duration of CR, training volume per CR [h], peak O2 at start of CR, index intervention and beta-blocker. Diagnostic plots were used to assess model assumptions. Alpha level was set at 0.05 for all analyses (two-tailed for Wilcoxon-rank sum test).

Results

Overall, 1633 patients (mean age 72±5.4, 77% male) were included in the EU-CaRE study. Baseline characteristics were reported in detail elsewhere [11]. Fig 1 shows the flow chart of the available number of measured training intensities, ventilatory thresholds derived from the CPET at start of CR and outcome measures in change in peak O2. Level of agreement of the ventilatory thresholds assessed by two investigators in a subset of CPETs is shown in S1 Fig and considered as acceptable.

Fig 1

Flow-chart of available cases.

N’s represent number of patients having data on training intensity and/or ventilatory thresholds and/or change in peak O2. a Number of patients with available training intensity and identified VT1; bNumber of patients with available training intensity and identified VT2; c Number of patients with available training intensity and identified VT1 and VT2. CPET, cardiopulmonary exercise testing; O2, oxygen consumption; T0, CPET at CR start; VT, ventilatory threshold.

Ventilatory thresholds reported in percent of different measures of peak effort are given in Table 1.

Table 1

First and second individual ventilatory thresholds at start and end of CR relative to peak exercise.

	CPET start of CR all		CPET end of CR all		CPET start of CR subset RER≥1.1
	VT1	VT2	VT1	VT2	VT1	VT2
	(n = 1166)	(n = 817)	(n = 1280)	(n = 893)	(n = 546)	(n = 490)
%V˙O2 peak	63 ± 11	84 ± 7	64 ± 12	88 ± 8	59±10	83±8
%WR peak	44 ± 16	78 ± 9	50 ± 14	85 ± 6	43±14	77±8
%HR peak	78 ± 9	89 ± 7	77 ± 9	91 ± 5	75±9	89±6
%HR reserve	45 ± 37	75 ± 22	50 ± 54	82 ± 40	42±19	74±19

CPET, cardiopulmonary exercise testing; CR, cardiac rehabilitation; VT, ventilatory threshold; O2, oxygen consumption; HR, heart rate; WR, workrate; RER, respiratory exchange ratio

There were no large differences in thresholds relative to peak effort found between CPET at start and end of CR. The ventilatory thresholds relative to peak effort were slightly lower in the subgroup of patients who reached full exertion (RER ≥1.1). Fig 2 illustrates the training intensities measured at the first third, middle and last third of the CR duration as well as the ventilatory thresholds by centre.

Fig 2

Training heart rate (green) at beginning (Tr1), middle (Tr2) and end (Tr3) of CR compared to heart rate at first and second ventilatory threshold (VT1, VT2) at CR start for each centre.

In most centres, training intensity increased over the course of CR and in all centres except one, the majority of patients trained at an intensity between VT1 and VT2.(Table 2).

Table 2

Training characteristics and differences between centres.

Training characteristics:	Overall	Bern	Copenhagen	Ludwigshafen	Paris	Parma	Santiago	Zwolle
(frequencies)
Patients with measured training HR	72% (1150 of 1601)	81% (165 of 203)	47% (111 of 237)	24% (55 of 228)	89% (196 of 219)	90% (222 of 247)	81% (199 of 247)	92% (202 of 220)
Patients with identified VT1	68% (1095 of 1601)	84% (170 of 203)	68% (162 of 237)	50% (115 of 228)	74% (161 of 219)	56% (139 of 247)	60% (149 of 247)	90% (199 of 220)
Patients with training HR below VT1	36% (304 of 848)	29% (41 of 139)	17% (15 of 88)	46% (12 of 26)	26% (38 of 144)	42% (58 of 137)	61% (79 of 130)	33% (61 of 184)
(median and interquartile ranges)
Training intensity [% of HR peak†]	80 [73; 87]	78 [73; 84]	83 [75; 89]	81 [72; 85]	84 [78; 91]	85 [80; 90]	73 [68; 79]	79 [74; 86]
Training intensity [% of HR reserve†]	52 [39; 65]	54 [45; 62]	64 [50; 76]	47 [39;61]	55 [42; 73]	52 [33; 69]	41 [32; 50]	53 [46; 66]
Training Duration [min]	29 [25; 35]	33 [31; 35]	30 [26; 34]	22 [22; 23]	29 [27; 31]	20 [20; 27]	54 [48; 59]	26 [25; 27]
Total training volume [h]a	6.6 [4.6; 15.5]	18.3 [15.5; 20.0]	7.0 [5.8; 8.1]	5.6 [5.1; 5.8]	6.1 [5.3; 6.9]	5.9 [4.4; 8.4]	19.3 [16.8; 21.9]	4.2 [3.8; 4.5]
Weekly training volume [min]	61 [40; 124]	55 [49; 68]	30 [23; 34]	120 [107; 133]	126 [109; 139]	182 [96; 215]	56 [46; 68]	36 [32; 40]
Training dose	548 [381; 1236]	1448 [1271; 1614]	586 [470: 690]	453 [392; 519]	507 [443; 581]	476 [375; 653]	1404 [1263; 1593]	330 [302; 361]
(volume [h] * intensity [% of HR peak])
Change in peak V˙O2 [ml/kg/min]	1.83 [0.35; 3.54]	1.91 [-0.14; 4.66]	1.63 [0.24; 3.65]	2.03 [0.57; 3.53]	2.82 [0.89; 4.34]	1.69 [0.57; 3.17]	1.52 [0.23; 2.93]	1.50 [-0.20; 3.09]
Centre differences b in:
(ref: grand mean)
Training HR [bpm]		3.5**	9.7***	-6.8***	2.3*	-3.3**	-9.7***	4.4***
Training Duration [min]		1.8**	-2.0**	-8.2***	-2.1***	-8.6***	24.7***	-5.5***
Total training volume [h]		8.8***	-3.1***	-3.3***	-3.3***	-3.2***	9.9***	-5.7***
Change in peak V˙O2 [ml/kg/min]		0.5	0.1	0.1	0.4	-0.1	-0.4	-0.5*

*p <0.05,

**<0.01,

***<0.001

† at CR start

a Total training volume is the mean duration of the endurance training session × attended number of endurance sessions over the course of CR

b Multivariate robust linear model adjusted for age, sex, index intervention, HR at VT1, Beta-blocker, Diabetes Mellitus, days between index intervention and start of CR, days between start of CR and training

We found no significant centre differences with regard to change in peak O2, as reported previously [12], despite significant differences in training intensity as well as training volume. Only one centre differed significantly from the average change in peak O2, having also the lowest total training volume compared to all other centres.

Overall, from the subset of 808 patients in whom the training intensity domain could be determined, 519 (64%) exercised with an intensity above their individual VT1 and improved their peak O2 significantly more (+2.26 ml/kg/min in average) than patients who exercised with an intensity below the VT1 (+1.63 ml/kg/min, Table 3).

Table 3

Patient characteristics according to training intensity domains.

	Training Intensity Domains
	Light-moderate	Moderate-high	p-value2	Missing3
	(below VT1)	(above VT1)
	N = 2891	N = 5191		N = 8251
Age [years]	72.7 (5.2)	72.1 (5.0)	0.17	73.4 (5.7)
Male sex	231 (80%)	436 (84%)	0.17	592 (72%)
Index Intervention			0.53
CABG	84 (29%)	170 (33%)		227 (28%)
Chronic CAD no intervention)	22 (7.6%)	34 (6.6%)		40 (4.8%)
PCI	157 (54%)	274 (53%)		459 (56%)
Percutaneous treated VHD	2 (0.7%)	8 (1.5%)		23 (2.8%)
Surgical treated VHD	24 (8.3%)	33 (6.4%)		76 (9.2%)
Betablocker	241 (83%)	422 (81%)	0.52	664 (80%)
CR duration [days]	79 (57)	71 (52)	0.094	63 (52)
Total aerobic training hours per CR [hours]	10.9 (7.4)	9.2 (6.2)	0.027	9.0 (6.1)
Peak V˙O2 at start of CR [ml/kg/min]	16.9 (4.4)	17.6 (4.7)	0.025	14.5 (4.6)
Peak V˙O2 at end of CR [ml/kg/min[	18.5 (4.7)	19.9 (5.2)	<0.001	16.4 (4.8)
Change in peak V˙O2 [ml/kg/min]	1.63 (2.48)	2.26 (2.84)	0.003	2.00 (2.80)
Change in peak V˙O2 [% of baseline]	11 (16)	14 (18)	0.008	17 (26)

Statistics presented: mean (SD); n (%)

Statistical tests performed for training intensity group differences: Wilcoxon rank-sum test; chi-square test of independence; Fisher's exact test

3 Patients with missing data for training heart rate (n = 613), VT1 (n = 508) or change in peak O2 (n = 51)

VT1, first ventilatory threshold; CABG, coronary artery bypass grafting; CAD, coronary artery disease; PCI, percutaneous coronary intervention; VHD, valvular heart disease; CR, cardiac rehabilitation; O2, oxygen consumption

In the multivariate mixed model, training above the individual VT1 remained significantly associated with a higher improvement in peak O2 [ml/kg/min] (β 0.62, 95% confidence interval 0.25–1.02). In addition, total training volume in hours per CR (β 0.06, 95%CI 0.01–0.12) was associated with a higher change in peak O2. The interaction between intensity and volume was not significant and therefore removed from the model. The full output of the multivariate model is shown in S1 Table.

The mean (SD) change in peak O2 in this subgroup of 808 patients included in the multivariate model was 2.04 (SD 2.74) ml/kg/min. The model explained 15.6% of the variance of change in peak O2, with training intensity and training volume adding 0.8% and 0.5%, respectively, to the explained variance.

Discussion

The present study provides data from a large cohort of elderly cardiac patients to compare current guidelines on exercise intensity with intensities derived from individual ventilatory threshold and compares training characteristics between seven European CR programs. Training characteristics varied widely between centres with total training volume ranging from 4.2 h to 19.3 h, training intensity from 73% to 85% of peak heart rate, and number of weeks from 2 to 21. In contrast, improvements in peak O2 from start to end of CR varied little between centres. While training above the individual VT1 and higher training volume were significantly associated with greater improvement in peak O2, both variables explained less than one percent of the variance of the change in peak O2.

Ventilatory thresholds

According to the joint position statement of the European Association for Cardiovascular Prevention and Rehabilitation, the American Association of Cardiovascular and Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation, the VT1 is reached at around 50–60% of peak O2 and 60–70% of peak HR whereas the VT2 is reached at around 70–80% of peak O2 and 80–90% of peak HR [4]. On average, the thresholds identified in this study are slightly higher than these ranges, probably due to a lesser degree of exertion reached in these elderly patients. However, the thresholds were only slightly lower relative to peak in a subgroup of patients who reached maximal exertion (RER≥1.1) and still relatively high when compared to the thresholds in the guidelines. This means that if training intensity was prescribed relative to peak O2 or peak HR, the resulting training intensities tended to be below the target intensity. Our findings are in accordance to a previous study in patients with coronary artery disease, which found a large inter-individual variation, ranging from 47–91% of peak O2 and 55–96% of peak HR [13]. Correspondingly, for 30% of our patients the target training HR was below the VT1. There is consensus in the CR community that threshold-based exercise intensity prescription is superior to intensities derived from peak values [4, 13, 14]. However, if CPETs cannot be performed or thresholds not identified, relative intensities are recommended [4]. This applied to approximately 25% of the patients in this study in whom VT1 could not be identified, and approximately 50% of patients in whom VT2 was not reached or could not be detected. On the other hand, around half of the patients did not reach an RER ≥1.1 and therefore probably did not reach full exertion. However, a maximal or near-maximal effort is crucial for correct intensity prescription when using relative intensity domains [4]. Hence, prescription of optimal training intensities with current established methods may be difficult in elderly cardiac patients.

Training intensity

Training HR was between HR at VT1 and VT2 in the majority (64%) of patients and consequently in the range of the moderate to high-intensity domain [4]. Nevertheless, a considerable proportion of patients exercised at a HR below their individual VT1, ranging from 17% to 61% in different centres, despite the widely endorsed recommendation for progression from moderate to vigorous intensity exercise over the duration of CR [3]. However, evidence exists that also low exercise intensity may be effective in cardiac patients with reduced exercise capacity [4]. In this study, changes in peak O2 did not differ greatly between centres, despite differences in training volume and training intensity.

On a patient level on the other hand, a higher training intensity and greater training volume were significantly associated with increased changes in peak O2 over the course of CR. Patients who trained at an intensity above their individual VT1 increased their peak O2 on average by 0.63 ml/kg/min more than patients who trained below their individual VT1. This relation remained stable in the multivariate model adjusted for potentially confounding factors (such as centres) with a 0.62 ml/kg/min significantly greater change in peak O2 in patients who exercised above VT1. Whether this difference was clinically meaningful is questionable, while it corresponded to little more than a quarter of the mean change in peak O2, both, a 14% and 11% improvement are relatively small. In comparison, a recent meta-analysis on 13’220 patients of 128 studies (mean age 58.4) found an additional improvement of 1.5 ml/kg/min over the course of CR through prescription of higher intensities, which the authors did not consider as clinically relevant [7]. In addition, a higher total training volume achieved during CR was associated with a greater change in peak O2, corresponding to 0.07 ml/kg/min increase in peak O2 for every one-hour increase in total training volume during CR. Each metabolic equivalent (MET, 3.5 ml/kg/min of O2) increase in exercise capacity during CR has previously been found to be associated with 13% lower mortality [15]. Accordingly, exercise training for 50 hours may increase peak O2 by one MET. Patients exercising above the VT1 may achieve one MET improvement with fewer training hours, although this relation is not supported by our data (no significant interaction between training volume and intensity).

In summary, our results suggest that even patients who exercise at an intensity below their individual VT1 improved their peak O2, although somewhat less than those exercising above. This suggests that the focus on specific training intensities may be overrated in elderly cardiac patients.

Self-paced intensity instead of redefining prescription

Given the difficulties of determining ventilatory thresholds or using relative intensity domains in elderly patients, as well as the potentially low impact of training intensity on change in exercise capacity, a self-paced approach seems warranted in elderly cardiac patients.

Already widely established in clinical routine is the exercise intensity prescription according to self-rated perceived exertion using the BORG scale [4]. This method, while providing scope for patient autonomy, allows clinicians to direct patients towards different intensity ranges.

A recent meta-analysis found better affective response after self-selected exercise intensities [16]. However, the differences between self-paced and prescribed training intensities were mainly driven by studies that prescribed training intensity above the VT1, while studies with training intensities below the VT1 did not find differences with regard to affective response. Intensities above the VT1 were found to evoke greater negative affective response than self-selected exercise performed at lower intensities [17]. However, cardiac patients, and in particular, elderly cardiac patients were underrepresented in these studies. Nevertheless, it seems plausible that elderly cardiac patients would prefer self-selected or lower intensities. Patients’ preference for cardiac rehabilitation delivery has recently gained attention and home-based cardiac rehabilitation was discussed as valid alternative to centre-based CR [18, 19]. In view of the growing interest in personalised therapy, it would be more appropriate to direct the focus on patients’ preferences instead of redefining exercise intensity prescriptions. The beneficial effect of exercise is likely to be abolished when patients discontinue exercising after CR. Larger studies are warranted to assess if self-paced training intensities are feasible, safe and equally (sustainably) effective to prescribed intensities in elderly cardiac rehabilitation patients.

Limitations

We did not differentiate between training modalities, despite the fact that two centres (Copenhagen, Zwolle) performed high intensity interval trainings while the other centres mostly performed moderate continuous training. However, it seems unlikely that modality had a major impact on changes in exercise capacity as patients from Copenhagen and Zwolle did not differ largely from other centers with regard to changes in peak O2. Also, we did not assess habitual physical activity outside of the CR program which may have influenced changes in peak O2. Additionally, results of the present study do not reflect the whole population of the EU-CaRE study as only patients with monitored training sessions, and only those with good quality CPET (that allowed the determination of VT1) could be included in the multivariate models. Baseline peak O2 of the patients included in the model was 17.36 ml/kg/min, while the mean baseline peak O2 overall EU-CaRE patients was 15.94 ml/kg/min. Therefore, we do not know whether weaker patients could also increase their exercise capacity by one MET if they exercised for 50 hours. Nevertheless, this is, to the best of our knowledge, the first analysis relating accurately monitored exercise intensity to change in peak O2 in such a large data set of elderly CR patients.

Conclusion

Overall, training intensities of our elderly CR population followed current guidelines. While training intensities above the individual VT1 were associated with greater improvement in peak O2, the association was weak. Despite large differences in training intensities between current European CR programmes, improvements in exercise capacity were very similar. Therefore, the superiority of certain training prescription over others needs to be questioned and the focus on specific training intensities may be overrated in elderly patients.

In a quarter of our elderly CR cohort, the ventilatory thresholds could not be determined and full exertion (RER > 1.1) was not reached in about half of our cohort. Accurate prescription of exercise intensity may therefore often not be possible. Future studies on safety and efficacy of self-paced exercise intensity in elderly cardiac rehabilitation patients are warranted.

Reproducibility of ventilatory threshold setting in a subset of 200 randomly chosen cardiopulmonary exercise tests.

(DOCX)

Click here for additional data file.

Linear mixed model on change in peak O2 [ml/kg/min] with centre as random factor.

(DOCX)

Click here for additional data file.

10 Sep 2020

PONE-D-20-24527

Training intensity and improvements in exercise capacity in elderly patients undergoing European cardiac rehabilitation – The EU-CaRE multicenter cohort study

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Reviewers' comments:

Reviewer's Responses to Questions

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: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: Yes

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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

Reviewer #3: Yes

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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: Yes

Reviewer #3: Yes

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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 subject of this study is very relevant at this moment: I therefor thank the authors for performing this analysis: the percentage of (elderly) patients attending and completing CR remains too low worldwide.

The following items I think is missing/unanswered:

Was there a difference in results between pts LVEF above vs below 40% or between ACS vs stable AP vs valvereplacement pts?

What was the percentage of patients who completed the whole CR program offered per center? Why was the ventilator thresholds determined by 1 single investigator only?

Do you think there was a selection bias because only

patients with monitored training sessions, and only those with good quality CPET (that

allowed the determination of VT1) could be included in the multivariate models? Did this greatly influenced your results?

You advocate " self-paced-intensity", especially because this is an elderly population: I completely agree: do you know what the relation was between the achieved training intensities and improvement in Quality of Life in your study group? What are the reasons that Copenhagen and Zwolle chose for high intensity interval trainings?

Reviewer #2: This is an interesting paper with findings that could be clinically highly relevant. However, the reviewer did notice some issues in the methodology and results that require further (statistical) analysis, or at least significant reconsideration, to come to valid conclusions. Therefore, to increase the likelihood for publication, a major revision may be needed.

Introduction

It could be explained in greater detail to what extend VO2peak matters in older patients with CVD (e.g. prognosis, physical functioning, quality of life)?

Please include a study hypothesis?

Methods

What is ‘old’? For now, the cut-off of 65 years was used (which is arbitrary, but I understand the authors would select this age threshold), but in CR practice, 65 years is often the average age of the population (see for example reference 3). So I wonder whether similar results will be found if the authors would specifically focus on patients >75 years?

‘In each patient, we aimed to record HR during three trainings…’ should be ‘In each patient, we aimed to record HR during three training sessions…’?

Were changes in beta-blocker therapy allowed during CR? This could affect the training HR and consequently the statistical outcomes.

‘Alpha level was set at 0.05 for all analysis’: was this two-tailed?

Were the patients allowed to execute strength training (older patients are often in need of strength training...)? If so, was this corrected for during the statistical analysis?

Results

Please mention n/centre in Table 2.

In Table 2, total training volume should be expressed as peak effort training hours as well (sessions * duration/session * intensity). For now, the actual volume of exercise (expressed as hours) cannot be compared between the centres if the intensity also varied (to be determined by univariate correlations). In addition, would these peak effort training hours correlate with changes in VO2peak and thus affect the outcome from the regression analysis?

For now, the authors compared patients training below or above VT1. I’m not surprised that patients exercising above VT1 improve better when compared with patients exercising below VT1 (below VT1 is really low…). However, between VT1 and VT2 a large HR range can be prevalent in some patients. So the question arises whether the effects of exercise intensity would be seen if patients would be categorized according to a different % of VT2 (under the assumption that the patients did not exercise above VT2)?

Discussion

Habitual physical activity was not assessed during CR: this could have affected the change in VO2peak and should be acknowledged as a limitation.

The authors mention: ‘According to the joint position statement of the European Association for Cardiovascular Prevention and Rehabilitation, the American Association of Cardiovascular and Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation, the VT1 is reached at around 50-60% of peak VO2 and 60-70% of peak HR whereas the VT2 is reached at around 70-80% of peak VO2 and 80-90% of peak HR. [2] On average, the thresholds identified in this

study are slightly higher than these ranges, probably due to a lesser degree of exertion reached in these elderly patients.’ This actually is not an issue that should be considered as a study limitation: reference 3 reports similar thresholds…so they actually agree with literature. The reviewer believes rather the guidelines should change according to observations made in many CR centres.

Reviewer #3: This paper presents results from a prospective, multi-centre study investigating the cost effectiveness and sustainability of, and engagement in, cardiac rehabilitation (CR) programmes across several European countries. The analyses presented within this paper are a secondary analysis of the data, examining the intensity and volume of exercise completed during CR compared to current guidelines, and examine their association with improvements in directly measured V̇O2peak. A major strength of this study is the comparatively large sample size allowing for comprehensive multivariate modelling. The paper is novel in that it surveys exercise training variables within current CR programmes compared to international guidelines. Moreover, this paper is the first to examine the role of intensity and volume on cardiorespiratory fitness outcomes in a large cohort of older adults.

The paper is generally well written, though may benefit from minor edits as noted below.

General:

• Some inconsistencies in formatting of VO2 throughout.

• Incorrect formatting for abbreviations of physiological measures: VE requires subscript E, and VO2, VCO2 and VE all require an over-dot above the V to indicate values are per unit time (e.g. V̇O2 and V̇E).

• I strongly recommend referring to workload as work rate (abbreviated to WR in the results) as opposed to Watt – it is not common practice to refer to a variable by its units (e.g. the authors do not refer to heart rate as bpm)

Introduction:

• Formatting of list for aims should present numbers as (1) and (2).

Methods:

• The authors should elaborate on, or provide citation for, contraindications to cardiac rehabilitation as part of their exclusion criteria

• The methods state that thresholds were only analysed by a single author. The authors should provide a rationale for this and note the experience/expertise of the lead author to reliably identify ventilatory thresholds. Moreover, did the authors conduct any assessment of reliability for a random subset of CPET outputs? If not, I believe this should be undertaken and the agreement between authors presented within the results. As this is a major outcome for this study it is imperative the authors demonstrate the accuracy and reliability of their analyses.

• 30 s moving average for V̇O2, HR and Watts at VT1 and VT2 requires further clarification – was this taken as the 30 s prior or 30 s following, or 15 s either side?

• When determining whether a patient’s mean exercise intensity was above or below VT1, how was specifically determined? Did the authors calculate the mean HR for each session then compare the mean of these means to the HR at VT1? This requires further clarification.

Results:

• The authors should undertake secondary confirmation of thresholds identified using a second author. Given the large sample size this may be completed as a random subsample of 15-20% of participants. The authors should then report the level of agreement in identifying VT1 and VT2 in this subsample.

• Figure 1 is difficult to interpret. This could be made clearer by additional descriptions for the three lowest boxes describing what the n values represent (i.e. No. of pts with both VT1 and VT2, n = 768) [I am assuming that is what this box represents?]

• I believe a total cohort version of Figure 2 would be beneficial to include in the results. This could be included as an additional figure rather then adding further complexity to Figure 2.

• Legibility of Figure 2 could be improved by reducing line thickness of the boxplots and size of outlier symbols. Further, consider a different (lighter) colour scheme for the green and red boxes as these colours reduce the contrast with the box outline.

• There are abbreviation inconsistencies in caption for Figure 2.

• Can the authors include an additional column in Table 2 for the total cohort. This should be placed before the column for Bern. Naturally, present data for frequencies and median/IQR sections only.

• In Table 2, footnote markers for a and b should be swapped – currently b comes before a.

Discussion:

• Final statement in ‘Training intensity’ subsection could be elaborated on. The authors should clarify if they suggest that intensity is not an important consideration for exercise prescription in this population – if not, what should clinicians focus on?

• The self-paced exercise intensity subsection should be expanded to include discussion regarding perceptually-regulated exercise (i.e. RPE regulated). In practice, there is a continuum of self-regulated/self-paced exercise intensity. The authors have discussed affect-regulated exercise which encompasses exercising at an intensity that ‘feels good’ or elicits a positive affective response. In most circumstances, this is method of regulating exercise intensity introduces a high level of subjectivity; the clinician cannot effectively guide the patient to exercise at a low, moderate or high intensity. In contrast, with RPE-regulated exercise provides scope for patient subjectivity but still allows the clinician to direct the patient to different general intensities. This should be discussed in reference to the results of the present study that suggest that the intensity may not be important and that exercise at intensities that elicit a positive affective response may (only some emerging data is available) be associated with better attendance and compliance in CR programmes.

• The limitations section should not that thresholds used in analyses were identified by only 1 author. The authors should consider and discuss the impact of erroneous threshold values on their outcomes.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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30 Oct 2020

We would like to thank the reviewers for the very valuable comments, which we have gladly addressed and hopefully implemented to the editor’s and reviewers’ expectations. Many comments were very valid and we feel that the presented changes have greatly improved the clarity of the paper. Please find our point-to-point responses (red) in the uploaded file "response to the editor and reviewers".

Submitted filename: Response to the Editor and Reviewers.docx

Click here for additional data file.

4 Nov 2020

Training intensity and improvements in exercise capacity in elderly patients undergoing European cardiac rehabilitation – The EU-CaRE multicenter cohort study

PONE-D-20-24527R1

Dear Dr. Marcin,

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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Corstiaan den Uil

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 #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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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 #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: 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 #2: Yes

Reviewer #3: No

**********

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 #2: Yes

Reviewer #3: 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 #2: This is now a good and clinically relevant manuscript that can be published in its current form. There are no further suggestions.

Reviewer #3: Thank you for the opportunity to review the manuscript. I am satisfied with the edits performed and responses to reviewer comments. I believe the manuscript to be a valuable contribution to the cardiac rehabilitation field and recommend publication in its current state. I have no further comments for the revised manuscript.

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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 #2: No

Reviewer #3: No

6 Nov 2020

PONE-D-20-24527R1

Training intensity and improvements in exercise capacity in elderly patients undergoing European cardiac rehabilitation – The EU-CaRE multicenter cohort study

Dear Dr. Marcin:

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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