Incremental Prognostic Value of Exercise Stress Testing in Primary Prevention

In primary prevention, addition of C-reactive protein and family history to standard risk factor assessment (Reynolds Risk Score or RRS) provides superior risk stratification for future cardiovascular (CV) events. We sought to assess whether addition of functional capacity to RRS provided incremental prognostic value. This was a prospective observational cohort study of 3,964 consecutive asymptomatic adults without documented CV disease (mean age 51 years, 78% men) evaluated between 2005 and 2013, who underwent clinical and treadmill stress testing at baseline. RRS was calculated; % age-gender predicted metabolic equivalents (AGP-METs) achieved and heart rate recovery (HRR) were recorded. End point was death and myocardial infarction. Findings were tested in derivation (n = 1,982) and validation samples (n = 1,982). Mean RRS and C-reactive protein were 3.7 ± 4 and 2 ± 4 mg/dl. Nine percent had family history of premature CV disease. %AGP-METs achieved, and HRR were 113 ± 20 and 24 ± 8 beats/min. Forty-six percent achieved <110% AGP-METs, whereas 41% had RRS ≥3. At 7.3 ± 3 years, there were 83 (2%) events (39 in derivation and 44 in validation samples). In derivation group, on multivariable survival analysis, higher RRS (Hazard ratio or HR 1.27 [1.07 to 1.39]), lower % AGP METs (HR 1.21 [1.09 to 1.34]) achieved and abnormal (<12 beats/min) HRR (HR 1.15 [1.02 to 1.23]) were associated with increased longer-term events (all p <0.01). Findings were similar in validation group. Cutoffs of RRS >3 and %AGP-METs <110 were associated with increased longer-term events on spline analysis in the derivation group. The continuous net reclassification improvement for longer-term events, when %AGP-METs was added to RRS was 0.79 (95% confidence interval 0.52 to 1.05; p <0.01). Findings were confirmed in validation group. In conclusion, in primary prevention, addition of exercise capacity to RRS (incorporating traditional risk factors, family history, and inflammation) provides incremental prognostic value.