Baseline differences in the HF-ACTION trial by sex

Abstract

Background: In patients with heart failure (HF), assessment of functional capacity plays an important prognostic role. Both 6-minute walk and cardiopulmonary exercise testing have been used to determine physical function and to determine prognosis and even listing for transplantation. However, as in HF trials, the number of women reported has been small, and the cutoffs for transplantation have been representative of male populations and extrapolated to women. It is also well known that peak VO(2) as a determinant of fitness is inherently lower in women than in men and potentially much lower in the presence of HF. Values for a female population from which to draw for this important determination are lacking.

Methods: The HF-ACTION trial randomized 2,331 patients (28% women) with New York Heart Association class II-IV HF due to systolic dysfunction to either a formal exercise program in addition to optimal medical therapy or to optimal medical therapy alone without any formal exercise training. To characterize differences between men and women in the interpretation of final cardiopulmonary exercise testing models, the interaction of individual covariates with sex was investigated in the models of (1) VE/VCO(2), (2) VO(2) at ventilatory threshold (VT), (3) distance on the 6-minute walk, and (4) peak VO(2).

Results: The women were younger than the men and more likely to have a nonischemic etiology and a higher ejection fraction. Dose of angiotensin converting enzyme inhibitor (ACEI) was lower in the women, on average. The lower ACEI dose may reflect the higher use of angiotensin II receptor blocker (ARB) in women. Both the peak VO(2) and the 6-minute walk distance were significantly lower in the women than in the men. Perhaps the most significant finding in this dataset of baseline characteristics is that the peak VO(2) for women was significantly lower than that for men with similar ventricular function and health status.

Conclusion: Therefore, in a well-medicated, stable, class II-IV HF cohort of patients who are able to exercise, women have statistically significantly lower peak VO(2) and 6-minute walk distance than men with similar health status and ventricular function. These data should prompt careful thought when considering prognostic markers for women and listing for cardiac transplant.

Trial registration: ClinicalTrials.gov NCT00047437.

Figure 1

Figure 1a. Peak VO₂ is higher in men regardless of NYHA Class, p<0.001. Note the quantitative interaction (p=0.002) between gender and NHYA Class in the peak VO₂ model with the gender difference, although subtle, greater in the NYHA Class II patients. Figure 1b. The interaction of sex and ECG ventricular conduction (QRS conduction) classification by predicted values of Peak VO₂ across the range of possible Sex/ECG VCD combinations while holding the value of other covariates constant. While predicted values are higher among males in all groups, they are not clearly distinguishable in the paced and RBBB groups.

Figure 2

The interaction of sex and BMI vs. predicted values of VO₂ at VT across the range of possible Sex/BMI combinations while holding the value of other covariates constant. The predicted rate of decrease with increasing BMI is stronger among females.

Figure 3

Figure 3a. The interaction of sex and age vs. predicted values of VE/VCO2 across the range of possible sex/age combinations while holding the value of other covariates constant. While a positive relationship between VE/VCO2 and age is predicted by the model among both males and females, the predicted increase with age is stronger among males. Figure 3b The interaction of Sex and BMI. While a negative relationship between VE/VCO2 and BMI is predicted by the model among both males and females, the predicted rate of decrease with increasing BMI is stronger among males.

Figure 3

Figure 3a. The interaction of sex and age vs. predicted values of VE/VCO2 across the range of possible sex/age combinations while holding the value of other covariates constant. While a positive relationship between VE/VCO2 and age is predicted by the model among both males and females, the predicted increase with age is stronger among males. Figure 3b The interaction of Sex and BMI. While a negative relationship between VE/VCO2 and BMI is predicted by the model among both males and females, the predicted rate of decrease with increasing BMI is stronger among males.

Figure 4

The interaction of sex and race for values of 6 min walk in each race/sex combination. While predicted 6-minute walk distance is higher for white patients than for black patients, and higher for males than for females in both racial groups, the disparity between predicted values among males and females is greater among white patients.