Sex, CAD Risk and Treadmill Testing: New Scoring System Improves Mortality Estimates

A new sex-specific score for estimating mortality risk among patients undergoing exercise treadmill testing is superior to traditional risk stratification tools, a large cohort study has shown. The sex-specific risk score, developed at Cleveland Clinic, offers particular advantages in identifying patients who are at highest risk of death.

“Our data support considering a sex-specific approach when assessing the prognosis of patients who undergo exercise testing,” says Leslie Cho, MD, principal investigator of the study, published online by JAMA Cardiology on Oct. 26, 2016.

An accompanying editorial in that journal commends the study for its “meticulous” design, arguing that it “notably advances the field in three important areas of cardiovascular medicine” — namely, the use of clinical prediction models, sex-specific research and treadmill testing.

Where existing risk scores fall short

The study was prompted by the fact that the standard for assessing prognosis in patients with coronary artery disease, the Duke Treadmill Score, was developed and validated in men nearly three decades ago. “The Duke score has never been well validated in women, and its validity in a contemporary population is unclear, given how therapeutic advances have substantially reduced cardiovascular mortality over the past 30 years,” notes Dr. Cho, Director of Cleveland Clinic’s Women’s Cardiovascular Center.

Even the subsequent Lauer nomogram, while superior to the Duke score in predicting all-cause mortality, excluded certain populations and failed to account for sex-related differences.

“Our aim was to develop comprehensive sex-specific risk scores to estimate all-cause mortality in a more inclusive and contemporary population,” Dr. Cho explains.

Study design: Derivation plus internal and external validation

So she and colleagues conducted a retrospective cohort analysis of 59,877 consecutive patients undergoing symptom-limited treadmill testing at Cleveland Clinic over an 11-year period ending in December 2010. They randomized the cohort into two samples — one for deriving the risk score, the other for validating it — and developed separate risk scores for men and women.

The researchers then used 49,278 consecutive patients who underwent treadmill testing at Henry Ford Hospital from 1991 through 2009 as an external validation cohort. “This Henry Ford cohort gives further credibility to our stress test findings,” Dr. Cho observes.

Across all cohorts, standard discrimination and calibration statistics were used to compare the sex-specific risk scores against the Duke Treadmill Score and Lauer nomogram for predicting the primary end point of all-cause mortality.

The Cleveland Clinic cohort was 59.4 percent male and 40.6 percent female; the Henry Ford Hospital cohort was 52.5 percent male and 47.5 percent female. Median patient age in both cohorts was 54 years. Mortality rates were 4.2 percent over 7 years of follow-up (median) in the Cleveland Clinic cohort and 13.5 percent over 10.2 years of follow-up (median) in the Henry Ford cohort.

Key findings: Sex matters in risk profile

Results from the derivation cohort produced a risk score reflecting differences in the weight of risk assigned to men and women across a range of factors, including peak treadmill METs, weight, age, heart rate recovery, smoking status, and the presence or absence of end-stage renal failure, diabetes, hypertension, heart failure and other comorbidities.

In the Cleveland Clinic validation sample, C statistics were higher for the sex-specific risk score than for the other tools, as follows:

• Sex-specific risk score, 0.79 in women and 0.81 in men
• Duke Treadmill Score, 0.70 in women and 0.72 in men
• Lauer nomogram, 0.74 in women and 0.75 in men

The new risk score’s discrimination by sex was similarly strong in the Henry Ford Hospital cohort, with C statistics of 0.78 for women and 0.79 for men, and good tracking of observed versus predicted mortality was demonstrated.

Overall results from the combined cohorts showed that exercise capacity had the greatest impact on prognosis in both sexes and all risk factors had a differential impact on prognosis in women relative to men.

Available for immediate clinical adoption

The researchers found that most of the superiority of the sex-specific risk score derived from correct reclassification of high-risk patients — i.e., those who died.

“The major advantage of our risk score is the identification of patients who are likely to have a fatal event,” says Dr. Cho. “As cardiovascular mortality continues to fall, pinpointing patients with the highest residual risk becomes increasingly important.”

To that end, she notes that Cleveland Clinic has developed a freely accessible online calculator that uses the new sex-specific risk score to estimate 10-year mortality in patients undergoing exercise treadmill testing. “This is an easy-to-use tool that can be used today by physicians to assess prognosis and tailor risk factor modification,” Dr. Cho observes. “Since exercise capacity remains the predominant risk factor in both men and women with coronary artery disease, this tool can be used to underscore the importance of exercise as well.”