By Van Selby, MD
Assistant Professor of Medicine, University of California San Francisco Advanced Heart Failure Section
Dr. Selby reports no financial relationships relevant to this field of study.
SYNOPSIS: A large study of patients with chronic systolic heart failure undergoing cardiopulmonary exercise testing found peak oxygen uptake (VO2), exercise duration, and percent predicted peak VO2 were the strongest predictors of survival. The association between peak VO2 and survival varied substantially by sex.
SOURCE: Keteyian SJ, et al. Variables measured during cardiopulmonary exercise testing as predictors of mortality in chronic systolic heart failure. J Am Coll Cardiol 2016;67:780-789.
Cardiopulmonary exercise (CPX) testing is commonly used to measure functional capacity and determine prognosis in heart failure with reduced ejection fraction (HFrEF). Although several individual CPX-derived variables have been shown to correlate with survival, no study has compared the relative predictive strengths of many CPX-derived variables and the effect of patient sex on these associations.
In a post-hoc analysis of the HF-A Controlled Trial Investigating Outcomes of exercise traiNing (HF-ACTION) trial, Keteyian et al compared the ability of 10 different CPX-derived parameters to predict clinical outcomes. Two thousand one hundred patients with chronic HFrEF and New York Heart Association (NYHA) functional class II-IV symptoms underwent CPX using a modified Naughton treadmill protocol. The primary outcome was all-cause survival.
During a median follow-up of 32 months, 357 subjects died. Nearly all 10 of the measured variables were predictive of mortality; only the respiratory exchange ratio (RER) was not significantly associated with survival. After adjusting for age and sex, the strongest predictors were peak oxygen uptake (VO2), percent predicted peak VO2 (%pp VO2), and exercise duration. In men, peak VO2 was the single strongest predictor of mortality (P < 0.0001), with a peak VO2 cutpoint of 10.9 mL/kg/min identifying those with a 10% 1-year mortality rate. In women, exercise duration was the strongest predictor (P < 0.0001). Peak VO2 was a strong predictor as well, though with a cutpoint of 5.3 mL/kg/min identifying those with 10% 1-year mortality. When the analysis was stratified according to the RER (the ratio between CO2 production and O2 uptake), the peak VO2 predicted survival in patients with RER > 0.95.
The authors concluded peak VO2, exercise duration, and %pp VO2 are the strongest predictors of outcomes in patients with HFrEF, peak VO2 cutpoints vary by gender, and RER has little effect on the ability of peak VO2 to predict mortality.
COMMENTARY
CPX testing has been used for decades in the evaluation of chronic heart failure (HF). Using either a treadmill or cycle, CPX identifies impairments in aerobic capacity, providing valuable information regarding functional capacity and severity of HF. CPX testing is particularly important in the evaluation of candidates for heart transplantation. A landmark study found a peak VO2 < 14 mL/kg/min identified HF patients with increased mortality compared to heart transplantation, and this cutpoint is now commonly used to identify transplant candidates (although a cutpoint of 12 mL/kg/min is often used in patients on beta-blockers). The Keteyian et al study contributes substantially to the understanding of CPX by confirming the utility of CPX-derived variables in a large, contemporary HF cohort.
These findings refine the ability to apply CPX results when making clinical decisions, and tailor interpretations of the results to a particular patient. One of the most important findings from this study is the sex-related differences. Exercise capacity appears to be a particularly important predictor in women. Peak VO2 is a strong predictor as well; however, the cutpoint used to identify women at increased risk of mortality appears to be much lower than current values. A peak VO2 of approximately 5 mL/kg/min identified women with 1-year expected mortality of 10% (the approximate cutoff at which transplant is indicated). The exact reason for the observed male-female discrepancy is unknown, but others have hypothesized that it may be due to higher body fat in women. Currently, a peak VO2 of 14 mL/kg/min is generally used regardless of sex.
Another important issue is the utility of peak VO2 regardless of the RER. An RER ≥ 1.1 is generally recommended to confirm maximal exercise effort, with variables such as peak VO2 losing their prognostic ability at RER < 1.1. As a result, clinicians dismiss many CPX results due to inadequate effort. In the Keteyian et al study, peak VO2 discriminated mortality in all patients with RER > 0.95, and a peak VO2 < 12 was associated with poor survival regardless of RER. Clinicians should not dismiss the significance of a low peak VO2 just because a patient did not meet traditional criteria for maximal exercise effort.
There are limitations worth noting. The cohort studied only included HFrEF, and the findings cannot be extrapolated to HF with preserved ejection fraction. All patients exercised according to a modified Naughton protocol. While this is the most commonly used protocol in the United States, the data may not be generalizable to CPX performed using alternative protocols. Despite these limitations, the Keteyian et al study confirms the prognostic utility of CPX in the evaluation of HFrEF, and demonstrates that a lower peak VO2 cutpoint may be necessary in female patients.
