Prognostic value of the Oxygen uptake efficiency slope and other exercise

variables in patients with Coronary Artery Disease.

Short title: Prognostic value of the OUES in CAD

Selected as best moderated poster presentation in a session on cardiac rehabilitation at the

ESC Congress 2014

Presented as a poster at Europrevent 2014

Ellen Coeckelberghs* 

Roselien Buys* 

Kaatje Goetschalckx

Véronique A Cornelissen

Luc Vanhees

Department of Rehabilitation Sciences, KU Leuven and Department of Cardiovascular Diseases,

University Hospitals of Leuven, Leuven, Belgium

* Authors contributed equally

Corresponding author and contact details

Prof. Luc Vanhees

Department of Rehabilitation Sciences

Tervuursevest 101, B 1501, 3001 Leuven, Belgium

Tel: +32-16-329158

Fax: +32-16-329179

E-mail address: luc.vanhees@faber.kuleuven.be

Other e-mail addresses: ellen.coeckelberghs@faber.kuleuven.be

roselien.buys@faber.kuleuven.be

kaatje.goetschalckx@uzleuven.be

véronique.cornelissen@faber.kuleuven.be

Word Count:5013

Potential conflicts of interest: There are no conflicts of interest to declare.

1

Abstract

Background: Peak exercise capacity (VO2 peak) is an independent predictor for mortality in

patients with coronary artery disease (CAD). However, sometimes cardiopulmonary exercise tests

(CPET) are stopped prematurely. Therefore, submaximal exercise measures such as the oxygen

uptake efficiency slope (OUES) have been introduced. The aim of this study was to assess the

prognostic value of the OUES, along with other exercise parameters, in patients with CAD.

Methods: We included 1409 patients with CAD (age 60.7 ± 9.9 years; 1205 males), who

underwent CPET between 2000 and 2011. One hundred and sixty one patients (11.5%) could not

perform a CPET until the maximum. The OUES was calculated and information on mortality was

obtained. Cox proportional hazards regression analyses were used to assess the relation of OUES,

VE/VCO2 slope, VO2/work-rate slope and the two ventilatory thresholds with all-cause and

cardiovascular (CV) mortality. Receiver operating characteristic (ROC) curve analyses was

performed to define optimal cut-off values.

Results: During an average follow-up of 7.45 ± 3.20 years (range 0.16-13.95 years), 158 patients

died, among which 68 patients for CV reasons. The OUES was related to all-cause (hazard ratio:

0.568, p<0.001) and CV (hazard ratio: 0.461, p<0.001) mortality. When significant covariates were

entered in the Cox regression analysis, OUES remained related with mortality (p<0.05). When

other submaximal exercise parameters were added to the model, OUES and VE/VCO2 slope also

remained significantly related to mortality.

Conclusion: In conclusion, the OUES is an independent predictor for all-cause and cardiovascular

mortality in patients with CAD, irrespective of a truly maximal effort during CPET. Furthermore,

the OUES provides prognostic information, complementary to the VE/VCO2 slope and VO2peak.

Abstract word count: 268

Keywords: Oxygen uptake efficiency slope; prognosis; coronary artery disease; exercise capacity

Introduction

2

Exercise capacity is an independent predictor of all-cause and cardiovascular mortality in patients

with coronary artery disease (CAD).1-4 Peak oxygen uptake (VO2 peak) is a highly reliable measure

of overall exercise performance and has been accepted as the golden clinical standard for aerobic

exercise capacity since many years.1,2,5,6 However, approximately 4 to 22% the patients with

cardiovascular diseases are incapable of reaching peak effort during a graded exercise test. 7 , 8

Exercise tests can be interrupted prematurely by the patient for a motivational or emotional

(anxiety) reason or by the supervisor for medical reasons. Therefore, submaximal exercise

variables have been introduced in order to better interpret exercise capacity in case of a non-

maximal test. Moreover, these submaximal exercise variables should provide prognostic

information. Baba and co-workers developed in 1996 the Oxygen Uptake Efficiency Slope (OUES)9,

which represents the relationship between minute ventilation (VE) and oxygen uptake during

graded exercise. Cardiovascular, musculoskeletal and respiratory fitness are, likewise to oxygen

consumption, incorporated into one single index.10, 11 The advantage of the OUES is that it can be

determined even when the exercise test is interrupted prematurely.11-13 Furthermore, it has been

shown to be a reliable and reproducible parameter that can be easily calculated. 10, 11, 14-16 The

OUES is highly correlated with other exercise parameters such as VO2 peak and the ventilatory

aerobic threshold (VAT). 10, 14, 15,12, 17-21 Hence, a higher OUES means a better aerobic exercise

capacity and might thus also be related to a lower incidence of cardiac events and a lower

mortality.21,22 Recently, a few studies reported on the OUES as a prognostic marker in congenital

heart disease23 congestive heart failure (CHF)18, 21, 24, 25 and in pulmonary arterial hypertension26 27.

A more established exercise parameter to predict prognosis is the VE/VCO2 slope, which

represents the linear regression relation of the minute ventilation (VE) and the carbon dioxide

production (VCO2).28 It is a measure of ventilatory efficiency that has been shown to be related to

morbidity and mortality in diverse groups of patients such as patients with CHF, congenital heart

disease, in patients with chest pain suspected of CAD and respiratory disease.12, 21, 29-32

3

A third submaximal parameter derived from gas exchange data is the oxygen uptake versus

exercise intensity slope (VO2/work-rate slope) which represents the adequacy of the oxygen

transport.33

Finally, two ventilatory thresholds can be determined using gas exchange data during graded

exercise 34 : the first ventilatory threshold or VAT and the second ventilatory threshold or

respiratory compensation point (RCP). In patient with CHF, the VAT has been shown to be a

reliable parameter the for cardiovascular mortality prognostication.35, 36

However, to the best of our knowledge, the prognostic value of the OUES and other submaximal

gas exchange variables in patients with CAD has not been investigated yet, and therefore, the aim

of the present study is to assess the prognostic value of the OUES in CAD, irrespective of the

maximal character of the exercise test.

Methods

Study population

All patients with CAD, referred to the outpatient cardiac rehabilitation program at the University

Hospitals Leuven (Belgium) between January 2000 and December 2010, were included in the

study. CAD was defined by a recent history of acute myocardial infarction (AMI), percutaneous

coronary intervention (PCI) or coronary artery bypass surgery (CABG). Patients were not included

if they presented with exercise-induced myocardial ischemia and/or malignant ventricular

arrhythmias. Moreover, CAD patients with congenital heart disease, pacemaker or implantable

cardioverter defibrillator implantation were excluded. The study was approved by the Local

Ethical Committee. General and demographic information, exercise testing data, drug treatment

and the presence of cardiovascular risk factors were collected at the time of enrolment in the

program.

4

Cardiopulmonary exercise testing (CPET)

Graded exercise tests were performed on a cycle ergometer (Siemens-Elema 380B; Ergometrics

800S, Ergometrics, Bitz, Germany), in an air-conditioned laboratory where the room temperature

was regulated at 18-22°C. Patients were asked to cycle at a constant rate of 60 rates per minute.

The initial workload of 20W was increased by 20W every minute. Blood pressure was measured at

rest, with the patient sitting on the bicycle, and every 2 minutes during graded exercise. Heart

rate and a 12-lead electrocardiogram (Max Personal Exercise Testing®, Marquette, WI, USA) were

registered continuously. In- and expired gasses were analyzed breath-by-breath by means of the

Oxyxon Pro (Jaeger, Mijnhardt, The Netherlands). All patients were asked to perform a symptom-

limited graded exercise test until exhaustion. Exhaustion was defined by the patients based on

feelings of exhaustion, dyspnea, pain, or tiredness in the legs. Peak values were defined as the 30

seconds average at the highest workload achieved. Peak oxygen uptake (VO2 peak) was compared

to predicted normal values.28 In addition, the capability of performing an exercise test until

maximum was defined by the criteria described by Mezzani et al.33 A maximal effort was assumed

if the CPET was terminated by the patient due to exhaustion, dyspnea, pain or tiredness in the

legs and if 1) peak RER ≥ 1.10 and/or 2) rating of perceived exertion (RPE) ≥ 16 on the Borg scale. 33

Otherwise, the test was coded as submaximal. The OUES was determined from the relation VO2=a

log10 VE + b, in which ‘a’ is the OUES and ‘b’ is the intercept.9 The VE/VCO2 slope was calculated

from the equation: VE = m (VCO2) + b, in which ‘m’ = VE/VCO2 slope. The non-linear part of this

slope after the respiratory compensation point was not used in the regression analysis by

excluding the last 10% of the exercise test.33 The VAT was determined by the nadir in the

ventilatory equivalent for oxygen or, when necessary, also by the V-slope method. 34 The RCP was

defined as ‘the nadir or non-linear increase in the VE/VCO2 ratio according to external workload. 34

Both thresholds were expressed in ml/min oxygen uptake. Respiratory data were averaged every

15 seconds. The first minute of exercise was excluded because of the often very irregular

breathing pattern at the onset of exercise. PROC ROBUSTREG (SAS Institute Inc, Cary, NC, USA)

5

was used in order to account for possible outliers. Results for the OUES were compared to the

predicted normal values based on the equations proposed by our group37, for patients under 60

years of age and by Hollenberg et al.11, for patients of 60 years and older. Equations adjusted for

BSA were used in all patients and percentages of predicted values were also calculated.

Follow-up

The primary endpoint of the study was all-cause mortality; cardiovascular mortality was the

secondary endpoint. Information about the vital status, date and cause of death of the patients

was gathered by consulting the patients’ medical files. If no patient contact was registered in

these files during the last 6 months, the patients’ general practitioners were contacted by post.

The follow-up period ended on December 31, 2013. The overall response rate was 89%. Deaths

were coded according the International Classification of Diseases (ICD-code), ninth revision.38

Statistical analysis

We used SAS statistical software version 9.3 for Windows (Sas Institute Inc, Cary, NC, USA) to

analyze the data and Graphpad Prism 6.0 (Graphpad Software, San Diego, California, USA) to plot

the figures and to perform receiver operator characteristic (ROC) curve analyses. Data are

reported as mean value ± standard deviation or number (percentage). Comparisons between

groups were performed by unpaired t-test and chi square contingency analysis. Distributions were

checked for normality with the Shapiro-Wilk statistic. The Cox proportional hazards regression

model39 was used for survival analysis. Relative hazard-rates with 95% confidence limits are

reported for single and multiple regression analysis. Variables included in the multivariate analysis

were OUES, age, gender, CABG, systolic blood pressure, history of diabetes as well as the maximal

character of the graded exercise test. Dichotomous variables were coded 0 when the condition

was absent and 1 when it was present. Furthermore, (ROC) curve analysis was performed to

define cut-off values of several gas exchange variables. . These values were chosen according to

6

the highest sum of sensitivity and specificity. Statistical results were considered significant if

p<0.05.

Results

Patients’ characteristics and exercise parameters

Between January 2000 and December 2010, 1590 Caucasian CAD patients enrolled in the

ambulatory cardiac rehabilitation program of which 181 patients were lost to follow-up. The

patients who were lost to follow-up, were younger than the included patients (p < 0.05). The

general and exercise testing variables of the remaining 1409 patients (86% male) at baseline are

described in table 1. Overall, mean age was 60.7 ± 9.9 years. Mean OUES was 1739 ± 593,

corresponding to 70 ± 20% of predicted and VO2 peak was 19.5 ± 5.6 ml/kg/min or 73 ± 17% of

predicted. The distribution of the OUES is shown in figure 1.

Baseline characteristics for the total group, survivors and non-survivors, together with the relative

hazard rates for all-cause mortality, are provided in table 1. At the entry of the study, survivors

and non-survivors differed significantly for age, resting systolic blood pressure, history of diabetes,

drug intake, recent history of CABG, and most exercise testing variables (p<0.05). Following the

criteria mentioned above, 1248 patients could perform a graded exercise test until maximum and

161 patients (11.5%) did not. Exercise tests were interrupted prematurely by the patient because

of angina (n=2), subjective complaints (n=153 ) or fear (n=4 ) and by the supervision (n=2) because

of arrhythmias. At the entry of the study, both groups differed significantly for age, gender, peak

heart rate, peak RER an OUES (p<0.05). The group that was not able to perform a graded exercise

test until the maximum, was older and had a higher percentage of women. They also had a higher

BMI and a lower exercise capacity. The RCP was reached in 1119 patients (81,1%) and not reached

in 261 (18,9%) patients. In another 29 patients, the RCP could not be determined.

Follow-up

7

Vital status at the end of the follow-up period could be tracked in 1409 patients, 181 patients

were lost to follow-up for the following reasons: physician (general practitioner-GP) retired (n=21)

or died (n=12) or refused to cooperate (n=8); patients changed from GP (n=11); patient moved

abroad (5) or no response from GP was received (n=124). The total follow-up period was 58.6

patient-years with an average follow-up of 7.45 years (range 0.16 to 13.95). One hundred fifty

eight (11.2%) patients died at an average of 5.47 ± 3.09 years after their start in the cardiac

rehabilitation program. The cause of death was cardiovascular in 68 patients, non-cardiovascular

in 80 patients (of which 71 died of cancer) and unknown in 10 patients (official death certificates

could not be checked). Moreover, patients who were included in the study after an AMI had a

significantly higher risk for cardiovascular mortality compared to revascularisated patients

(p<0.001). For all-cause mortality, no significant differences were found.

Prognostic significance of the OUES and other exercise parameters

The Cox proportional hazard assumption was satisfied for all CPET variables, except for the Borg

score and the percentage predicted OUES. Table 2 gives an overview of the relative hazard rates

of the OUES for all-cause and cardiovascular mortality 1) unadjusted; 2) adjusted for age and

gender; 3) adjusted for age, gender and the maximal character of a graded exercise test; and 4)

adjusted for all previous and the other significant covariates, being history of diabetes, recent

history of CABG and resting systolic blood pressure. The relative hazard rate for the OUES, after

adjustment for all significant covariates is 0.63 (p<0.01) for all-cause and 0.56 (p<0.05) for

cardiovascular mortality. Hence, an increase of the OUES with 1000 units is associated with a

decreased risk for all-cause and cardiovascular mortality of 37% and 44%, respectively.

Concerning the exercise parameters, based on the single cox proportional hazard regression, VO 2

peak, OUES, VE/VCO2-slope, VAT, RCP and O2/WR-slope were are all significant predictors of

mortality (Table1).

8

Based on ROC curve analyses, optimal cut-off values for the submaximal and maximal parameters

were obtained, using their optimal sensitivity and specificity. The Kaplan Meier plots for OUES,

VE/VCO2-slope and VO2peak with their optimal cut-off values are shown in Figure 2. This figure

shows a significantly higher mortality for patients with an OUES≤1550, a VE/VCO2>31.5, and peak

VO2≤18.30 ml/kg/min).

Discussion

To the best of our knowledge, this is the first study that investigated the prognostic value of the

OUES in a large group of patients with CAD referred to cardiac rehabilitation. Our results show

that, in a sample of 1409 CAD patients (86% males), the OUES is a predictor for all-cause and

cardiovascular mortality, irrespective of the maximal character of the graded exercise test.

Cardiopulmonary exercise testing variables have been proven to be an important source for

prognostic information.40 A wealth of data has been published, showing the prognostic

significance of VO2 peak in different patient populations, including patients with CAD.1-3,31,41, 42 In

patients with heart failure, it has been shown that the traditional exercise parameters in this

population such as the VE/VCO2-slope and VO2 peak are less useful as a prognostic marker when

derived from a submaximal exercise test.43 In our study, 11,5% of the CAD patients did not reach a

true peak effort (peak RER ≥ 1.10 or a RPE ≥ 16) during the exercise test. We demonstrated that

the patients who were not able to perform a maximal exercise test, were significantly older and

reached lower exercise capacity compared to the remainder of the group. Some similarities with

the above mentioned heart failure study 43 is present. However, both the studied patient

population and the employed definition of a ‘maximal’ exercise test are different from ours.

Nevertheless, in this study, we demonstrated that the OUES is an independent prognosticator for

both all-cause and cardiovascular mortality, even after adjusting for significant covariates such as

age, elevated resting systolic blood pressure, diabetes, CABG and the maximal character of the

9

exercise test. This is consistent with the finding that the OUES calculated from the first 75% of gas

exchange data of an exercise test does not differ from the values obtained from a complete

exercise test.11-13 Therefore, it is recommended to use the OUES in order to predict mortality in

patients that are unable to perform a graded exercise test until their maximum. Nevertheless,

when we included VO2 peak and other submaximal exercise variables in our multivariate model,

the independent prognostic value of the OUES disappeared for all-cause mortality. So overall, VO2

peak seems to be the strongest predictor of all-cause mortality in this patient population

(p<0.001). However, we cannot neglect the fact that almost 12% of the patients were not able to

reach peak effort. Therefore, there is a strong need for submaximal predictors of mortality.

Data regarding the prognostic value of the OUES are scarce. In this study, we were able to

demonstrate for the first time that an increase of the OUES with 1000 is related with a 37% lower

risk for all-cause and 44% lower risk for cardiovascular mortality in patients with CAD. Our results

are in line with those from studies in patients with heart failure18, 24 or pulmonary hypertension26

and indicate that a lower OUES can predict a worse prognosis18, 21, 24, 26, 27. Davies et al. found that

the OUES is the strongest predictor in a CHF population18. On the contrary, Arena et al. found that

the VE/VCO2 slope is prognostically superior to the OUES in the same population. 24 For OUES, they

obtained a cut-off value of 1400, based on ROC curve analysis and found that in the group with an

OUES above 1400, there are 7% major cardiovascular events, versus 17.7% in the group with

OUES below 1400. Our cut-off values are slightly higher, probably because of the higher average

exercise capacity of our CAD population (VO2 peak: 17.9 mL/kg/min versus 19.5 mL/kg/min in our

study population), but the results are similar. We found that in the group with an OUES above

1550, 8.2 % of the patients died, and in the group with an OUES below 1550, 15.7% died. For the

VE/VCO2-slope our findings were similar. Our CAD patients have a slightly lower average VE/VCO2-

slope (29.8 versus 32.1 in Arena) and also the cut-off value where patient with CAD show a

significantly higher mortality rate, is lower than in Arena’s study (31.5 versus 34.0). Moreover,

10

since 88% of our patients are capable of reaching peak effort, it seemed warranted that we also

included the prognostic value of VO2 peak in our analysis. Based on ROC Curve analyses, we

calculated the optimal cut-off value which represented a higher risk for mortality and in our case

it was 18.3 ml/kg/min, which is much higher than the cut-off values of Davies and Arena

(14.7ml/kg/min and 14.3 ml/kg/min resp.). Again, it seems that CAD patients have, on average, a

higher exercise capacity than patients with CHF. Therefore, there is a need for developing cut-off

values specific for CAD patients. These specific cut-off values are shown in figure 2. Furthermore,

when combining the cut-off values of OUES, VE/VCO2-slope and VO2 peak,, it gives us additional

prognostic information as shown in figure 3. Patients who have an OUES<1550, a VE/VCO 2-

slope>31.5 and VO2 peak<18.3 ml/kg/min have a significant worse prognosis than patients who

have a bad performance on 1 or two exercise variables. Patients, who have a high exercise

capacity and perform good at all three parameters, have the best prognosis. Therefore, we

suggest using all three parameters complementary to each other when it comes to estimating

prognosis.

Study limitations

A first limitation of our study consists in the fact that all patients voluntary choose to participate

in the cardiac rehabilitation program and might as such constitute a selected population.

Secondly, patients who were lost to follow-up, were significantly younger than the studied group.

However, since the OUES remained significantly associated with mortality after adjustment for

age, it is reasonable to assume that this has not significantly influenced our study findings.

Thirdly, the female gender was under-represented in the present study.

Finally possible influencing co-factors like LVEF and habitual physical activity levels were not

available. .

11

Conclusion

Exercise capacity as expressed by the OUES is an independent predictor for all-cause and

cardiovascular mortality in patients with CAD, irrespective of the ability to reach a peak effort

during CPET. Furthermore, we developed specific cut-off values for CAD indicating a higher risk for

all-cause mortality. The OUES provides prognostic information, on top of the VE/VCO2-slope and

VO2 peak.

Funding

This work was supported by Research Foundation Flanders(FWO) (support to VAC as a

postdoctoral research fellow)

Acknowledgements

This work was presented during a poster presentations session at Europrevent 2014 and during a

moderated poster presentation session the the ESC Congress 2014. At the ESC Congress, it was

the winning poster presentation of a session on Cardiac Rehabilitation. The authors to thank, J.

Meertens, D. Schepers, F. Florequin and the department of management, information and

reporting of the UZ Leuven for their invaluable help in data collection and management.

Conflict of interest

No relationship with industry exists.

12

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Figure legends

17

Figure 1. Distribution of the OUES in our patient cohort, with indication of the cut-off we defined by ROC

curve analysis and the mean predicted normal value.

Figure 2: The Kaplan–Meier survival curves for

(A) the groups of patients with OUES above versus below the defined cut-off value of 1550,

(B) the groups of patients with VE/VCO2-slope above versus below the defined cut-off value of 31.5,

(C) the groups of patients with VAT above versus below the defined cut-off value of 11.2 ml/kg/min, and

(D) the groups of patients with Peak VO2 above versus below the defined cut-off value of 18.3 ml/kg/min.

Figure 3: The Kaplan–Meier survival curves with indication of the risk of early mortality based on the cut

off values of the OUES, Peak VO2 and VE/VCO2-slope. High risk: patients who have an OUES<1550, a

VE/VCO2 slope>31.5 and peak VO2<18.3. Moderate risk: low values for 1 or 2 exercise variables. Low

risk: good performance on all three parameters.

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