Original Articles. Value of Exercise Treadmill Testing in the Risk Stratification of Patients With Pulmonary Hypertension

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1 Original Articles Value of Exercise Treadmill Testing in the Risk Stratification of Patients With Pulmonary Hypertension Sanjiv J. Shah, MD; Thenappan Thenappan, MD; Stuart Rich, MD; James Sur, MD; Stephen L. Archer, MD; Mardi Gomberg-Maitland, MD, MSc Background The ability of the Naughton-Balke exercise treadmill test, an objective indicator of exercise capacity, to predict abnormal hemodynamics and mortality in pulmonary hypertension is unknown. Methods and Results We performed a cohort study of 603 patients with pulmonary hypertension from 1982 to 2006, and studied the utility of exercise treadmill test as a predictor of abnormal hemodynamics and death. We used multivariable linear regression to determine whether exercise capacity, measured in metabolic equivalents, was associated with abnormal hemodynamics, and we used a Cox proportional hazards model to determine whether decreased exercise capacity predicted death. Mean age was years, 76% were women, 63% had World Health Organization category I pulmonary arterial hypertension, and 23% were World Health Organization functional classes I and II. Mean exercise capacity was metabolic equivalents. Decreased exercise capacity was independently associated with elevated right atrial and mean pulmonary artery pressure, decreased cardiac index, and increased pulmonary vascular resistance. During median follow-up of 4.6 years, 36% of the patients died. Decreased exercise capacity was associated with mortality (multivariable hazard ratio, 1.18; 95% CI, 1.01 to 1.37 for each 1-metabolic equivalent decrease in exercise capacity; P 0.031; P after adjusting for invasive hemodynamic variables). Decreased exercise capacity also predicted mortality in functional classes I II patients, 24% of whom died (hazard ratio, 1.53; 95% CI, 1.04 to 2.26 for each 1-metabolic equivalent decrease in exercise capacity; P 0.032), although this association did not persist after adjusting for invasive hemodynamic variables (P 0.63). Conclusions Reduced exercise capacity on exercise treadmill test is associated with worse hemodynamics and is a predictor of mortality in patients with pulmonary hypertension. (Circ Heart Fail. 2009;2: ) Key Words: pulmonary hypertension exercise hemodynamics mortality In the evaluation of patients with cardiorespiratory illness, assessment of functional capacity is extremely valuable. Reduced functional capacity in patients with heart failure, whether evaluated subjectively by New York Heart Association class, or objectively by 6-minute walk test (MWT) or cardiopulmonary exercise testing with determination of peak oxygen consumption (VO 2 ), is associated with a worse hemodynamic profile and adverse outcomes. 1 In patients with pulmonary hypertension (PH), World Health Organization (WHO) functional class 2 (analogous to New York Heart Association functional class) and 6-MWT are tools that are used to define clinical severity. Functional class determination is low cost and offers prognostic assessment in a variety of diseases but is a subjective measure on behalf of both patient and physician. Although 6-MWT is thought to be a more objective measure of exercise capacity, it is too dependent on patient and physician factors and is susceptible to motivational factors, especially in patients with WHO functional classes I II symptoms, who have the ability to respond to motivation with increased exercise. 3 7 Cardiopulmonary exercise testing is considered the reference standard for the assessment of functional capacity and VO 2, but it is not available in many centers, is complex, is more expensive than determination of functional class and 6-MWT, and (compared with 6-MWT) may only add marginally to risk prediction in PH. 7,8 Clinical Perspective on p 286 We have shown that exercise treadmill testing (ETT) may offer a more objective alternative to 6-MWT. 9 Using the Naughton-Balke exercise protocol, 10 we determined that ETT was a reliable measure of exercise capacity in pulmonary arterial hypertension and correlated with 6-MWT. In addition, ETT seemed to be more sensitive than 6-MWT in detecting changes in exercise capacity in less sick patients. Furthermore, a recent meta-analysis of pulmonary arterial hypertension clinical trials 11 found no association between Received July 16, 2008; accepted March 30, From the Division of Cardiology (S.J.S.), Department of Medicine, Northwestern University Feinberg School of Medicine; and the Section of Cardiology (T.T., S.R., J.S., S.L.A., M.G.), Department of Medicine, University of Chicago, Chicago, Ill. The online-only Data Supplement is available at Correspondence to Mardi Gomberg-Maitland, MD, MSc, Director of Pulmonary Hypertension, University of Chicago Medical Center, 5841 S Maryland Ave, MC 2016, Chicago, IL mgomberg@medicine.bsd.uchicago.edu 2009 American Heart Association, Inc. Circ Heart Fail is available at DOI: /CIRCHEARTFAILURE

2 Shah et al Exercise Treadmill Testing in PH 279 change in 6-MWT and survival, causing some to conclude that 6-MWT is not an adequate surrogate end point in PH. 11,12 Given the possible advantages of ETT in PH, we sought to understand the value of ETT as a marker of abnormal hemodynamics, and as a noninvasive predictor of survival in patients with PH. We hypothesized that poor exercise capacity on ETT would be highly associated with abnormal hemodynamics and would be a strong predictor of poor outcomes. Furthermore, we hypothesized that ETT would be a valuable test even in less sick patients (WHO functional classes I and II). We tested these hypotheses in the Pulmonary Hypertension Connection (PHC) registry. 13 Methods Study Sample We studied patients in the PHC registry, which was initiated in March 2004, and which has been described in detail previously. 13,14 All patients evaluated at a single United States practice over time at 3 different university hospitals (University of Illinois at Chicago, Rush University Medical Center, and University of Chicago Medical Center) between 1982 and 2006 were entered into the database. Over the study period, 4 physicians acquired all the clinical data. Data were collected by a chart review and entered using an internet-based electronic data capture system. Patients were entered retrospectively from 1982 to February 2004 and prospectively from March 2004 through Since the registry was initiated, only 2 investigators with expertise in data management and understanding of clinical care of patients with PH entered the data. Neither of these investigators participated in the care of the patients in the registry. Hemodynamics were entered separately without the knowledge of any of the other clinical data, and outcomes (mortality data) were collected by the investigators after all other data had already been entered. Therefore, clinical data entry was performed blinded to hemodynamics and eventual outcome. Informed consent for participation in the registry was obtained during initial evaluation for new patients, or during routine office visits for patients who were already being followed before initiation of the registry ( 1% refused entry into the study). Data entry occurred after the complete initial evaluation. For all variables, outliers were verified by a chart review to minimize data entry errors. The PHC registry was approved by the respective institutional review boards based on the location of the practice, and all actively seen patients gave informed consent to be entered into the registry. Greater than 95% of the patients in the registry were seen as outpatients during initial evaluation (the remaining were inpatients transferred from the referring institution). We collected baseline demographic, clinical, medication, exercise testing, and cardiac catheterization data on all patients seen by our practice. ETT Of the total PHC registry cohort (N 1360), we excluded patients who were 18 years at the time of referral (N 43) and also excluded patients if we could not determine whether or not they had undergone ETT by a chart review (N 114). Of the remaining 1203 patients, 309 with missing ETT data and 291 with missing ETT and functional class data were excluded. The remaining 603 patients comprised our study cohort. Supplementary table S1 demonstrates the differences between the study cohort and those in the PHC registry who had missing exercise capacity and functional class data. Of the 603 patients in our study, 458 (76%) were entered retrospectively and the remaining 145 (24%) were entered prospectively. Reasons for not undergoing ETT at baseline included the following: (1) the patient had already undergone evaluation of exercise capacity using another modality (6-MWT or cardiopulmonary exercise testing) or if the patient had undergone exercise testing at the referring facility; (2) the patient was hospitalized during initial evaluation (only outpatients underwent ETT); and (3) the patient could not walk on a treadmill because of orthopedic issues. WHO functional class IV was not an exclusion criterion for ETT if the patient could ambulate and was not hospitalized at the time of initial evaluation. All treadmill tests used the Naughton-Balke protocol, 10 and treadmill time (in seconds) was converted to exercise metabolic equivalents (METs) as described previously, 9 although it should be noted that the conversion formula for exercise time to METs has not been validated in PH. Sex-specific nomograms for METs have been published previously. 15,16 Patient Characteristics and Laboratory Measurements We analyzed the following baseline variables at the time of referral for characterization of clinical phenotype: demographic data including age and sex, comorbidities, WHO functional class, medications, albumin, creatinine, antinuclear antibody, and pulmonary function testing, including diffusing capacity of carbon monoxide. Invasive Hemodynamics Of the 603 subjects included in our analysis, 521 (86%) underwent baseline hemodynamic testing by right heart catheterization, the majority ( 95%) of which were performed at our institution by PH specialists. All hemodynamic testing performed at our institution was completed within 1 month of initial referral, and all patients were hemodynamically stable at the time of catheterization. Pulmonary vascular resistance (PVR) was calculated as follows: PVR (mean pulmonary artery pressure pulmonary capillary wedge pressure)/cardiac output. Mortality Vital statistics were collected for all patients by a chart review and by a query of the Social Security Death Index. For each death, the date of death was documented. Social Security Death Index data were available on all patients. In all patients who were not identified as deceased by the Social Security Death Index, we were able to confirm vital status by a chart review. Statistical Analysis All continuous variables are expressed as means SD unless otherwise noted, and P values 0.05 were considered statistically significant. We first compared groups of patients depending on baseline WHO functional class, dividing the cohort into 3 groups for descriptive purposes: WHO functional classes I II, class III, and class IV. Among the WHO functional class groups, we compared demographics, clinical characteristics, laboratory tests, and hemodynamics with analysis of variance and Kruskal-Wallis tests for continuous variables, and 2 and Fisher exact tests for categorical variables. To better understand the relationship between ETT exercise capacity and the various demographic, clinical, and laboratory variables, we performed univariate linear regression with ETT exercise capacity (METs) as the dependent variable. We then used univariate and backward-selection multivariable linear regression to determine whether ETT exercise capacity was associated with abnormal hemodynamics after adjusting for other baseline risk factors (linear regression assumptions were checked for all models). We studied the effect of each 1-MET decrease in exercise capacity on 4 hemodynamic variables, which have been shown to be important prognostic parameters in patients with PH 17 : right atrial pressure, mean pulmonary artery pressure, cardiac index, and PVR. We repeated these analyses in the subset of patients with WHO functional classes I II PH and in the subset of patients with WHO category I PH, studying the effect of each 1-MET decrease in exercise capacity on hemodynamics. Next, we used a locally weighted smoothed scatterplot curve to graphically depict the relationship between observed METs and mortality. We used the Kaplan-Meier method to estimate survival rates for patients with exercise capacity 3,3to6,and 6 METs, and Kaplan-Meier survival curves were compared by log-rank test. To determine the univariate and multivariable risk of death by

3 280 Circ Heart Fail July 2009 Table 1. Baseline Demographic, Clinical, Laboratory, Echocardiographic, and Hemodynamic Characteristics by Functional Class WHO Functional Class Characteristics I II (N 138) III (N 286) IV (N 179) P Age, y Female, n (%) 103 (75) 214 (76) 137 (77) 0.89 Etiology of pulmonary hypertension, n (%) 0.13 WHO category I (pulmonary arterial hypertension) 86 (62) 178 (62) 116 (65) WHO category II (pulmonary venous hypertension) 14 (10) 44 (15) 23 (13) WHO category III (pulmonary hypertension associated with hypoxemia) 2 (2) 13 (5) 10 (5) WHO category IV (pulmonary hypertension due to chronic 10 (7) 16 (6) 14 (8) thromboembolic disease) WHO category V (miscellaneous) 26 (19) 35 (12) 16 (9) Medications, n (%) Diuretics 42 (31) 137 (49) 113 (64) Calcium channel blockers 44 (32) 89 (32) 60 (34) 0.87 Digoxin 20 (15) 49 (17) 31 (18) 0.73 Warfarin 50 (37) 99 (35) 55 (31) 0.58 Prostacyclins 4 (3) 5 (2) 2 (1) 0.45 Endothelin blockers 3 (2) 11 (4) 7 (4) 0.68 Phosphodiesterase inhibitors 3 (2) 6 (2) 1 (0.5) 0.42 Comorbidities, n (%) Systemic hypertension 36 (26) 101 (36) 66 (37) Diabetes mellitus 10 (7) 20 (7) 19 (11) 0.36 Obesity 17 (12) 51 (18) 34 (19) 0.23 Coronary artery disease 4 (3) 22 (8) 12 (7) 0.15 Interstitial lung disease 11 (8) 37 (13) 25 (14) 0.23 Pulmonary embolism 34 (25) 60 (21) 41 (23) 0.69 Laboratory tests Serum creatinine, mg/dl (N 553) Albumin, g/dl (N 528) Positive antinuclear antibody test, n (%) (N 429) 42 (42) 105 (51) 67 (54) 0.18 Pulmonary function tests FEV 1, % predicted (N 504) Forced vital capacity, % predicted (N 503) FEV 1 /FVC, % (N 365) Total lung capacity, % predicted (N 460) DLCO, % predicted (N 442) Treadmill exercise capacity, METs Hemodynamics (N 521) Mean right atrial pressure, mm Hg* 7 (4 10) 9 (5 14) 12 (8 16) Mean pulmonary artery pressure, mm Hg Cardiac index, L/min/m Pulmonary vascular resistance, WU Pulmonary capillary wedge pressure, mm Hg Mean aortic pressure, mm Hg Pulmonary artery oxygen saturation, % Acute vasodilator response, % (N 409) 9 (11) 8 (4) 2 (1.4) *Values represent median (interquartile range) and P value was calculated using the Kruskal-Wallis statistic because right atrial pressure was right skewed. METs, we used a Cox proportional hazards analysis (with backward selection of covariates), and the proportionality assumption was tested and confirmed for all models. From our univariate analysis of variables associated with METs at P 0.10 and from the National Institutes of Health study of mortality in pulmonary arterial hypertension, 18 we determined that the following covariates should be entered into our multivariable models: age, etiology of PH, systemic hypertension, diabetes mellitus, obesity, interstitial lung disease,

4 Shah et al Exercise Treadmill Testing in PH 281 Figure 1. Differences in exercise capacity among various etiologies of pulmonary hypertension. PAH indicates pulmonary arterial hypertension; PVH, pulmonary venous hypertension; Hypoxemia, pulmonary hypertension due to hypoxemia; CTEPH, pulmonary hypertension due to chronic thromboembolic disease; Miscellaneous, pulmonary hypertension due to miscellaneous causes. diuretic and phosphodiesterase inhibitor use, WHO functional class, albumin, creatinine, antinuclear antibody test, forced vital capacity, diffusing capacity of carbon monoxide, and hemodynamic variables (right atrial pressure, mean pulmonary artery pressure, and cardiac index). To avoid multicollinearity, forced expiratory volume in 1 second and total lung capacity were not included in our multivariable analyses, because they were highly correlated with forced vital capacity (r 0.89, P and r 0.63, P , respectively). Transformation of hemodynamic variables for normality did not alter the results of any of our multivariable analyses. Finally, we repeated our Cox regression analyses in the subset of WHO functional classes I II patients and in the subset of patients who had WHO category I PH (pulmonary arterial hypertension). All statistical analyses were performed using Stata (version 9, StataCorp LP, College Station, Tex). The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written. Results Mean age on entry into the study was years and 76% were women. Of the total cohort, 63% had pulmonary arterial hypertension (WHO category I), 3.5% were taking endothelin antagonists, 1.8% were taking prostacyclins, 1.7% were on phosphodiesterase inhibitors, and 13% were on calcium channel blockers for PH (19% of the cohort were on calcium channel blockers for other reasons ie, systemic hypertension or Raynaud s phenomenon). As is characteristic of PH, the study patients had significantly reduced exercise capacity. Mean exercise time was minutes, and mean exercise capacity was METs (median, 3.1 METs; range, 1.1 to 11.1 METs). Even patients with WHO functional classes I II symptoms had decreased exercise capacity (mean, METs; median, 6.1 METs; 29% with poor exercise capacity 5 METs). Importantly, no patients had adverse complications or died during or shortly after the Naughton- Balke ETT protocol. Table 1 lists the demographic, clinical, laboratory, pulmonary function test, treadmill exercise capacity, and hemodynamic data stratified by WHO functional class. Functional classes I II patients were younger, less Table 2. Variables Associated With Exercise Capacity (Metabolic Equivalents) on Univariate Analysis Metabolic Equivalents Variables -Coefficient (95% CI) P Age* 0.36 ( 0.47 to 0.24) Etiology of pulmonary hypertension WHO category III (pulmonary 1.0 ( 1.9 to 0.15) hypertension associated with hypoxemia) WHO category 0.9 (0.4 to 1.5) V (miscellaneous) Comorbidities Systemic hypertension 0.82 ( 1.18 to 0.45) Diabetes mellitus 0.75 ( 1.38 to 0.11) Obesity 0.42 ( 0.88 to 0.04) Interstitial lung disease 0.73 ( 1.26 to 0.20) Medications Diuretics 1.15 ( 1.15 to 0.81) Phosphodiesterase inhibitors 1.66 (0.30 to 3.02) WHO functional class 1.78 ( 1.92 to 1.64) Pulmonary function tests Forced expiratory volume in (0.020 to 0.039) second Forced vital capacity (0.021 to 0.041) Total lung capacity (0.018 to 0.039) Diffusing capacity of carbon (0.026 to 0.043) monoxide Laboratory data Serum creatinine ( 0.60 to 0.08) Serum albumin 0.85 (0.46 to 1.23) Positive anti-nuclear antibody 0.67 ( 1.09 to 0.25) test *Per decade increase. Referent group WHO category I (pulmonary arterial hypertension). Per 1-unit increase in WHO functional class. Per 1-unit increase in % predicted value. Per 0.1 mg/dl increase in serum creatinine. Per 1 g/dl increase. likely to be on diuretic therapy, and had lower serum creatinine, higher serum albumin, and better results on pulmonary function testing. There was a graded decrease in exercise capacity and worsening hemodynamics with increasing functional class. In addition, functional classes I II patients were more likely to have a positive vasodilator response. Figure 1 displays the variability in exercise capacity by etiology of PH. WHO category III patients (PH associated with hypoxemia) had the worst exercise capacity, and WHO category V patients (PH due to miscellaneous causes) had the best exercise capacity. Table 2 lists the clinical variables that were associated with exercise capacity on univariate linear regression analysis at a significance of P Advanced age, systemic hypertension, diabetes mellitus, and diuretic use were all associated with decreased exercise capacity. Lung disease, as indicated

5 282 Circ Heart Fail July 2009 by a diagnosis of WHO category III PH, presence of interstitial lung disease, or low lung volumes on pulmonary function testing, was strongly associated with decreased exercise capacity. Table 3 summarizes the association of exercise capacity and abnormal hemodynamics. On univariate and multivariable analyses, reduced exercise capacity was associated with increased right atrial and mean pulmonary artery pressure, decreased cardiac index, and increased PVR. These associations persisted in the subgroup of patients who were WHO functional classes I II and in the subgroup of patients with pulmonary arterial hypertension. Figure 2 graphically depicts the differences in hemodynamic variables in subjects with exercise capacity 3,3to6,and 6 METs. Mean follow-up time was years (minimum follow-up time 1 day, maximum follow-up time 14.6 years). Of the total cohort, 217 (36%) died during the follow-up. Figure 3 shows the relationship between exercise capacity and mortality over the range of observed METs. Figure 4 displays the Kaplan-Meier survival curves for patients with exercise capacity 3, 3 to 6, and 6 METs. Table 4 summarizes the results of our Cox proportional hazards analysis. On univariate analysis, each 1-MET decrease in exercise capacity was associated with a 1.24-fold increased hazard ratio (HR) of death (95% CI, 1.14 to 1.35; P ). On multivariable analysis, each 1-MET decrease in exercise capacity continued to independently predict death (HR, 1.18; 95% CI, 1.01 to 1.37; P 0.031). Similar results were obtained in the subset of patients with WHO functional classes I II PH (Table 4). When invasive hemodynamic data were taken into consideration, reduced exercise capacity was associated with increased death, although at borderline significance (P 0.052) in the total cohort, but not in the functional classes I II patients (P 0.63). In the subgroup of patients with pulmonary arterial hypertension (N 380), decreased exercise capacity was an independent predictor of death on univariate and multivariable analyses, even when adjusted for hemodynamic variables (Table 4). We performed the following additional statistical analyses to further explore the association between ETT and death: (1) the effect of adding PVR to our multivariable models; (2) analysis of the subgroup of patients who did not have WHO category I pulmonary arterial hypertension (ie, WHO categories II to V PH); and (3) analysis of the subgroup of patients who were not on pulmonary arterial hypertension therapies (calcium channel blocker, endothelin antagonist, phosphodiesterase inhibitor, or prostacyclin) at the time of referral. Although PVR was highly associated with exercise capacity, we did not include it in our original multivariable Model 2 (Table 4) because PVR is a direct function of other variables in the multivariable model (namely mean PA pressure and cardiac output). Including PVR with these other variables in our multivariable models, would have resulted in multicollinearity. However, we did analyze the effect of replacing mean pulmonary artery pressure and cardiac output with PVR in our Model 2, and the results of our multivariable models did not change. Although WHO category I patients comprised the majority (63%) of our cohort, we found that the association between Table 3. Association of Treadmill Exercise Capacity and Abnormal Hemodynamics on Univariate and Multivariable Analysis Total Cohort, N 603 WHO Functional Classes I II, N 138 Pulmonary Arterial Hypertension, N 380 -Coefficient* (95% CI) P -Coefficient (95% CI) P -Coefficient* (95% CI) P -Coefficient (95% CI) P -Coefficient* (95% CI) P -Coefficient (95% CI) P Hemodynamic Parameter RAP, mm Hg 1.1 (0.9 to 1.3) (0.3 to 1.0) (0.3 to 1.0) (0.4 to 1.4) (0.8 to 1.4) (0.2 to 1.4) MPAP, mm Hg 2.1 (1.5 to 2.7) (1.1 to 2.6) (0.8 to 3.2) (1.3 to 4.5) (0.6 to 1.9) (0.5 to 3.1) CI, L min 1 m ( 0.16 to 0.09) ( 0.15 to 0.05) ( 0.13 to 0.007) ( 0.21 to 0.02) ( 0.20 to 0.02) ( 0.20 to 0.02) PVR, WU 0.9 (0.6 to 1.1) (0.6 to 1.2) (0.2 to 1.0) (0.3 to 1.6) (0.6 to 1.2) (0.5 to 1.7) WHO indicates World Health Organization; RAP, right atrial pressure; MPAP, mean pulmonary artery pressure; CI, cardiac index; PVR, pulmonary vascular resistance. *Per 1-MET decrease in exercise capacity on univariate analysis. Per 1-MET decrease in exercise capacity on multivariable analysis using backward selection with the following covariates: age, etiology of pulmonary hypertension, systemic hypertension, diabetes mellitus, obesity, interstitial lung disease, diuretic and phosphodiesterase inhibitor use, WHO functional class, albumin, creatinine, antinuclear antibody test, forced vital capacity, and diffusing capacity of carbon monoxide.

6 Shah et al Exercise Treadmill Testing in PH 283 Figure 2. Differences in hemodynamic parameters in patients with exercise capacity 3,3to6,and 6 metabolic equivalents. exercise capacity applied to the other categories of PH (WHO categories II to V). In this group of patients, each 1-MET decrease in exercise capacity resulted in a univariate HR 1.51 (95% CI, 1.12 to 2.04; P 0.007) and multivariable HR 1.86 (95% CI, 1.07 to 3.24; P 0.027). However, this association did not persist after adjusting for invasive hemodynamic variables (P 0.12) due to the decreased number of patients in this subgroup who had full hemodynamic data (N 156). When we repeated our Cox proportional hazards analyzes after excluding patients who were on treatment for PH at the Figure 3. Locally weighted smoothed scatterplot of the relationship between exercise capacity and mortality rate. time of referral, exercise capacity continued to predict mortality. On univariate analysis, each 1-MET decrease in exercise capacity was associated with HR 1.23 (95% CI, 1.11 to 1.35; P ) of death. On multivariable analysis, this association persisted (HR, 1.24; 95% CI, 1.08 to 1.44; P 0.003). Adding invasive hemodynamic variables to the multivariable model did not erase the association between exercise capacity and mortality in this subgroup (HR, 1.18; 95% CI, 1.01 to 1.38; P 0.04). Discussion In our large series of patients diagnosed with PH due to a variety of etiologies, we found that reduced exercise capacity, determined objectively by ETT, is associated with abnormal hemodynamics and is a predictor death. These results applied to our overall cohort and those with less severe symptoms who were WHO functional classes I II. Reduced exercise capacity was also an independent predictor of death in the more homogenous subgroup of patients with pulmonary arterial hypertension (WHO category I PH) who are often studied in clinical trials of PH-specific therapies. Excluding patients on treatment for PH with calcium channel blockers, endothelin antagonists, prostacyclins, or phosphodiesterase inhibitors did not remove the association between exercise capacity and death. Importantly, adding invasive hemodynamic variables to our multivariable models attenuated the association between ETT exercise capacity and death in most of our analyses

7 284 Circ Heart Fail July 2009 Figure 4. Kaplan-Meier survival curves for patients with exercise capacity 3,3to6,and 6 metabolic equivalents. except in the subgroup of patients with WHO category I PH (pulmonary arterial hypertension). These results show that ETT exercise capacity is an especially powerful predictor in WHO category I patients who have a more homogenous underlying pathophysiology. We hypothesize that in the other subgroups, including functional classes I II patients and non-who category I patients, adding invasive hemodynamics to the multivariable models most likely attenuated the association between exercise capacity and death because of the decreased statistical power of these subgroups (due to smaller sample size), and because both ETT exercise capacity and invasive hemodynamic testing evaluate the same underlying phenomenon: pulmonary vascular disease and its effect on right ventricular function. Regardless of the effect of adding invasive hemodynamics to our multivariable models, it is clear that ETT exercise capacity is a strong noninvasive predictor of abnormal hemodynamics and mortality. Table 4. Hazard Ratios for Treadmill Exercise Capacity as a Predictor of Mortality Total Cohort (N 603) The Naughton-Balke ETT protocol has several advantages. It is well-tolerated (no patients had adverse events during or shortly after testing in our study, indicating that the Naughton-Balke protocol is safe, even in WHO functional class IV patients), is more standardized than the 6-MWT, and less expensive and more widely available than cardiopulmonary exercise testing. In one of the original descriptions of the Naughton-Balke protocol, investigators found that exercise capacity determined by this test held prognostic significance regardless of functional class in patients with cardiac disease. 10 We have extended this finding to patients with PH by showing that ETT exercise capacity predicted abnormal hemodynamics and death even in the subgroup of PH patients who were less sick (WHO functional classes I II). Although reproducible, inexpensive, and easily performed, the 6-MWT has several limitations in that it is effort-dependent and susceptible to motivational factors. The use of the 6-MWT as WHO Functional Classes I II* (N 138) WHO Category I PAH* (N 380) Predictor Hazard Ratio (95% CI) P Hazard Ratio (95% CI) P Hazard Ratio (95% CI) P Treadmill exercise capacity (per each 1-MET decrease) Unadjusted 1.24 (1.14 to 1.35) (1.04 to 1.44) (1.12 to 1.34) Multivariable Model (1.01 to 1.37) (1.04 to 2.26) (1.01 to 1.38) Multivariable Model (1.00 to 1.37) (0.71 to 1.75) (1.02 to 1.41) WHO indicates World Health Organization; MET, metabolic equivalent; PAH, pulmonary arterial hypertension. *In the WHO functional classes I II subgroup, 33 deaths occurred during the follow-up; in the WHO category I PAH subgroup, 182 deaths occurred during the follow-up. Model 1: backward selection multivariable analysis using the following covariates: age, etiology of pulmonary hypertension, systemic hypertension, diabetes mellitus, obesity, interstitial lung disease, diuretic and phosphodiesterase inhibitor use, WHO functional class, albumin, creatinine, antinuclear antibody test, forced vital capacity, and diffusing capacity of carbon monoxide. Model 2: backward selection multivariable analysis using all covariates listed for Model 1 plus hemodynamic variables (right atrial pressure, mean pulmonary artery pressure, and cardiac index). For Model 2, N 566 for the total cohort, N 122 for WHO functional classes I II, and N 366 for WHO category I PAH because hemodynamic data was not available in all study patients.

8 Shah et al Exercise Treadmill Testing in PH 285 a measure of exercise capacity for left heart failure is no longer considered adequate. A recent systematic review of randomized controlled trials that used 6-MWT between 1988 and 2004 in heart failure demonstrated that the 6-MWT poorly discriminated pharmacological treatment effects, and had little prognostic and discriminative value in patients without advanced disease. 6 In addition, the most recent American Heart Association guidelines on exercise stress testing did not advocate time-based walk tests (such as the 6-MWT) and instead advocated ETT and cardiopulmonary exercise stress testing. 3 As more therapies become available for PH, and patients get treated earlier in their disease course, the ETT may be better at risk stratification in patients with higher functional capacity. Because one of the difficulties in managing patients with PH is the challenge in identifying at-risk patients early in the course of disease, it would be very helpful to have an objective test, such as low-intensity ETT, which could noninvasively predict abnormal hemodynamics and increased risk for death in patients with mild symptoms. Since its inception, the Naughton-Balke ETT protocol has served as a reliable, objective, noninvasive test, which has been validated in the cardiac catheterization laboratory as a predictor of oxygen consumption during exercise. In addition to a possible role in the evaluation of patients with PH, ETT could be used after the diagnosis of PH has been confirmed by invasive hemodynamic testing to evaluate response to therapies and for monitoring of disease progression and/or remission, although the use of ETT in this manner requires further study. With the continued development of PH-specific therapies, the need for a noninvasive objective assessment to follow an individual patient s response to therapy has become more critical, and the Naughton-Balke ETT may be just the right tool. There are several limitations to consider when interpreting our results. Our data collection started in early 2004, so most patients were studied retrospectively. Patients did not systematically undergo 6-MWT, so we are unable to directly compare 6-MWT to Naughton-Balke ETT. We do not have data on serial measurements of exercise capacity of ETT, so we cannot determine whether changes in ETT predict outcome. In addition, we did not have data on blood pressure, heart rate, and oxygen saturation response to exercise, and therefore cannot determine the prognostic implications of these variables. Other limitations include a study population comprised of patients cared for by a single tertiary referral practice, and the fact that ETT is not a direct measure of VO 2 and thus only an approximation of METs. However, the practical nature of ETT and its ability to closely correlate with direct measurement of VO 2 allows the test to be easily administered with good reliability and reproducibility. 9,10 Finally, the conversion formula for exercise time to METs used in our study has not been validated in PH. However, because METs in our study were derived directly from exercise time, we have effectively shown that decreased exercise time alone is an important clinical predictor of adverse outcomes. In summary, we found that reduced exercise capacity, determined objectively by Naughton-Balke ETT and measured in METs, is a powerful predictor of abnormal hemodynamics and death in PH. Importantly, ETT was able to noninvasively risk stratify patients with PH who are less sick (WHO functional classes I II), the very patients who are more likely to respond to vasodilator challenge, and in whom early treatment may be beneficial. Although 6-MWT has played an important role in the development of therapeutics for pulmonary arterial hypertension, alternative measures of therapeutic response (especially those already validated in other disease settings) appropriate to the study population should improve investigators ability to detect early signals of efficacy and better define the magnitude of benefit specific to cardiopulmonary function. ETT is a simple, widely available, and inexpensive modality for the objective determination of exercise capacity. Future clinical trials in PH should include the ETT as a surrogate end point to prospectively validate its use. Sources of Funding This work was supported by a Heart Failure Society of America Research Fellowship Award, an Actelion Entilligence Young Investigator Award, a Northwestern Memorial Foundation Dixon Translational Award, an American Heart Association Scientist Development grant N (all to S.J.S.), a Doris Duke Clinical Scientist Development Award (to M.G.M.), the Canadian Institutes for Health Research, and National Institutes of Health grant HL (to S.L.A.). Disclosures Dr Gomberg-Maitland has received research grant support from Actelion, Co-Therix, Encysive, Gilead, Lilly/Icos, Pfizer, and United Therapeutics and has served as a consultant and/or on advisory boards for Alkermes, Biomarin, Encysive, Gilead, Glaxo Smith- Kline, Medtronic, Pfizer, and United Therapeutics. She has a pending patent entitled, Compositions and Methods for Treating Pulmonary Hypertension, Gomberg-Maitland et al, WO/2007/ Dr Rich previously served as a part-time salaried employee at United Therapeutics, which concluded in January Dr Archer holds a provisional patent for the use of mitochondrial modulators for the treatment of cancer. References 1. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991;83: Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126: 7S 10S. 3. Arena R, Myers J, Williams MA, Gulati M, Kligfield P, Balady GJ, Collins E, Fletcher G. 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9 286 Circ Heart Fail July Oudiz RJ, Barst RJ, Hansen JE, Sun XG, Garofano R, Wu X, Wasserman K. Cardiopulmonary exercise testing and six-minute walk correlations in pulmonary arterial hypertension. Am J Cardiol. 2006;97: Groepenhoff H, Vonk-Noordegraaf A, Boonstra A, Spreeuwenberg MD, Postmus PE, Bogaard HJ. Exercise testing to estimate survival in pulmonary hypertension. Med Sci Sports Exerc. 2008;40: Gomberg-Maitland M, Huo D, Benza RL, McLaughlin VV, Tapson VF, Barst RJ. Creation of a model comparing 6-minute walk test to metabolic equivalent in evaluating treatment effects in pulmonary arterial hypertension. J Heart Lung Transplant. 2007;26: Patterson JA, Naughton J, Pietras RJ, Gunnar RM. Treadmill exercise in assessment of the functional capacity of patients with cardiac disease. Am J Cardiol. 1972;30: Macchia A, Marchioli R, Marfisi R, Scarano M, Levantesi G, Tavazzi L, Tognoni G. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J. 2007;153: Farber HW. The status of pulmonary arterial hypertension in Circulation. 2008;117: Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension: Eur Respir J. 2007;30: Shah SJ, Thenappan T, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Association of serum creatinine with abnormal hemodynamics and mortality in pulmonary arterial hypertension. Circulation. 2008;117: Gulati M, Black HR, Shaw LJ, Arnsdorf MF, Merz CN, Lauer MS, Marwick TH, Pandey DK, Wicklund RH, Thisted RA. The prognostic value of a nomogram for exercise capacity in women. N Engl J Med. 2005;353: Morris CK, Myers J, Froelicher VF, Kawaguchi T, Ueshima K, Hideg A. Nomogram based on metabolic equivalents and age for assessing aerobic exercise capacity in men. J Am Coll Cardiol. 1993;22: McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:78S 92S. 18. D Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115: CLINICAL PERSPECTIVE In patients with pulmonary hypertension (PH), World Health Organization functional class and the 6-minute walk test are noninvasive tools that are used to define clinical severity. However, these tests may suffer from their subjective nature, and the 6-minute walk test may not be able to discriminate functional capacity in World Health Organization classes I II patients. The ability of the Naughton-Balke exercise treadmill test (ETT), an objective indicator of exercise capacity, to predict abnormal hemodynamics and mortality in PH is unknown. In our cohort study of 603 patients with PH, we studied the use of ETT as a predictor of abnormal hemodynamics and death. Decreased exercise capacity was independently associated with elevated right atrial and mean pulmonary artery pressure, decreased cardiac index, and increased pulmonary vascular resistance. Decreased exercise capacity was associated with mortality in the study cohort overall, the subgroup of patients who were functional classes I II, and the subgroup of patients who had World Health Organization category I PH (pulmonary arterial hypertension). Although the 6-minute walk test has played an important role in the development of therapeutics for pulmonary arterial hypertension, ETT may improve the ability to detect early signals of efficacy and better define the magnitude of benefit specific to cardiopulmonary function. ETT is a simple, widely available, and inexpensive modality for the objective determination of exercise capacity. Future clinical trials in PH should include the ETT as a surrogate end point to prospectively validate its use.