Methods

HF-ACTION was a trial of exercise training versus usual care in 2,331 patients with EF ≤35% and New York Heart Association (NYHA) class II to IV symptoms despite optimal HF therapy for at least 6 weeks. Patients with major co-morbidities that could interfere with exercise training, including exercise-limiting AP, were excluded from HF-ACTION. In patients randomized to exercise training, the protocol included 36 supervised exercise sessions followed by home-based training for an additional 2 years. Median follow-up was 2.5 years. An independent Clinical Events Committee adjudicated deaths and cardiovascular (CV) hospitalizations until the first HF hospitalization. Angina is characterized in this cohort by patient report and Canadian classification score (CCS) at baseline and follow-up visits. For the present analysis, we defined a priori the following angina subgroups:

• (1)
  

  Baseline angina: angina reported at baseline during 6 minutes walk testing and/or by patient report with a CCS grade >0.

  
  
  
  
  • (a)
    

    Resolved angina (at 3 months and 12 months): angina reported at baseline, but no angina reported at postbaseline visit (3 and 12 months).

    
    
  • (b)
    

    Persistent angina (at 3 months and 12 months): angina reported at baseline and at a postbaseline visit.

  
  
  
  
• (2)
  

  No baseline angina: angina not reported at baseline on 6-minute walk testing and no angina reported by the patient at baseline (or CCS grade of 0).

  
  
  
  
  • (a)
    

    Incident angina (at 3 months and 12 months): angina reported on postbaseline assessment by medical history or 6-minute walk testing.

    
    
  • (b)
    

    No angina (at 3 months and 12 months): no angina reported at baseline or postbaseline visits.

  
  

All-cause mortality or all-cause hospitalization was the primary clinical end point of HF-ACTION. Secondary clinical end points included CV mortality/CV hospitalization and CV mortality/HF hospitalization. Changes in exercise capacity, depression, and HFQoL from baseline to 3 months were assessed by peak oxygen uptake (VO ₂ ) on cardiopulmonary exercise test, 6-minute walk distance (6MWD), beck depression score, Kansas City Cardiomyopathy Questionnaire overall summary score and EuroQol 5-dimension score. After the trial started, full adherence was defined as ≥90 minutes weekly of exercise during months 1 to 3 and ≥120 minutes weekly during subsequent months.

For the descriptive analysis of patient characteristics and parameters of interest, continuous variables were reported as median (25, 75%) and categorical variables as proportion, percentage. The primary baseline angina cohorts (angina vs no angina) were analyzed for differences with the analysis of variance F-test (or Kruskal–Wallis nonparametric test if data were nonnormally distributed) and the chi-square test (or Fisher’s exact test) for continuous and categorical variables, respectively.

Covariate-adjusted Cox proportional hazards models were created to determine the association between baseline angina group and clinical outcomes. All models included adjustment for predictors associated with worse outcomes for mortality, hospitalization, and composite end points, developed for HF-ACTION. In brief, variables were predefined using a stepwise variable selection based on a bootstrapped backward selection process. Kaplan–Meier survival curves as a function of angina status were plotted and compared by log-rank analysis.

Exercise capacity and HRQoL at 3 and 12 months were missing in many patients known to be alive. Thus, the relation between angina group and change in exercise capacity and HRQoL was assessed by creating linear regression models inversely weighted for missing data. In brief, we estimated each patient’s probability of nonmissing 3 (12) months of follow-up HRQoL using baseline characteristics in a logistic regression. Among patients with an observed follow-up response, the regression of the change in HRQoL was weighted by the inverse of that probability to account for missing data. Unadjusted linear models included baseline values of the corresponding end point. Models were also adjusted for baseline predictors that are listed in relevant figure and table footnotes.

We also performed 2 landmark analyses assessing the association between each angina subclassification (e.g., developed, resolved, nonangina) for all patients who were alive and had not experienced the clinical event by the 3- and 12-month visit. The reference group for these analyses was the “nonangina” group.

We assessed for an interaction between AP status and exercise training with respect to outcomes and the change in HRQoL and exercise capacity from baseline to 3 months. We focused on the 3-month follow-up visit for the exercise capacity and HRQoL variables because data were less complete at 12 months. The p value was reported for the interaction of AP status and exercise therapy for clinical outcomes and the change in exercise and health status variables. For all analyses, a 2-tailed p value <0.05 was required for significance. Where interactions were significant, the risk (and 95% CI) of experiencing the clinical end point associated with exercise training compared with usual care was also reported for each AP status. Similarly, the treatment effect (and 95% CI) is reported for change in health status and exercise capacity outcomes.

Results

From the HF-ACTION cohort, 406 of 2,331 patients (17%) had AP at baseline and worse NYHA class and depression but similar proBNP level compared with those without baseline AP ( Table 1 ). Baseline exercise parameters were similar by AP status, but patients with AP had worse HRQoL scores ( Table 2 ). Adherence rates to the exercise intervention at 3 months in patients with and without baseline AP were 51 of 186 (27%) versus 205 of 828 (25%), respectively (p = 0.45).

Baseline AP was associated with a 22% increased risk for all-cause mortality or hospitalization (unadjusted p = 0.002; adjusted p = 0.007; Figure 1 ), and 24% increased risk for all-cause hospitalization (unadjusted p = 0.001; adjusted p = 0.003; Table 3 ). Hospitalization cause was CV in 247 of 406 (61%) and 975 of 1,925 patients (51%) with and without baseline AP, respectively. Further breakdown of CV hospitalizations showed similar HF hospitalization rates (p >0.2 for both unadjusted and adjusted HR). There was no evidence of a differential association between exercise training and clinical outcomes by AP status ( Table 4 ).

Unadjusted and adjusted ^∗ event curves by baseline angina group for all-cause mortality or all-cause hospitalization. Log-rank test adjusted p value = 0.007. ^∗ Adjusted for Weber class, Kansas City Cardiomyopathy Questionnaire symptom stability score, blood urea nitrogen, country, left ventricular EF, gender, beta-blocker dosage, mitral regurgitation grade, and ventricular conduction before baseline cardiopulmonary exercise test.

Table 3

Association between baseline angina and clinical outcomes in patients with chronic heart failure patients

Clinical Outcome/Model	Event Count and (%)		Hazard Ratio for Baseline AP (95% CI)	P-Value
	No Baseline AP	Baseline AP
All-Cause Mortality or All-Cause Hospitalization	1255/1925 (65.2%)	300/406 (73.9%)
Unadjusted			1.22 (1.08 – 1.39)	0.002
Adjusted ∗			1.22 (1.06 – 1.41)	0.01
All-Cause Mortality	321/1925 (16.7%)	66/406 (16.3%)
Unadjusted			0.91 (0.70 – 1.19)	0.48
Adjusted †			0.88 (0.67 – 1.17)	0.39
All-Cause Hospitalization	1200/1925 (62.3%)	289/406 (71.2%)
Unadjusted			1.24 (1.09 – 1.41)	0.001
Adjusted ∗			1.25 (1.08 – 1.45)	0.003
CV Mortality or HF Hospitalization	572/1925 (29.7%)	134/406 (33.0%)
Unadjusted			1.09 (0.90 – 1.31)	0.39
Adjusted ‡			1.06 (0.86 – 1.32)	0.57

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