Methods

The FIT Project is a retrospective cohort study investigating the implications of physical fitness and/or exercise capacity on CVD outcomes and mortality. Patients were excluded from the registry if they were <18 years old at the time of stress testing or if they were evaluated by pharmacologic stress testing. The FIT Project is comprised of the following: (1) directly measured exercise data (exercise duration, METS); (2) retrospective collection of medical history and medication treatment data taken at the time of the stress test; (3) retrospective verification and supplementation of supporting clinical data using the electronic medical record (EMR) and administrative databases; and (4) epidemiologic follow-up for total mortality and select nonfatal outcomes by the way of linkage with the death registry and medical claims files. FIT project was approved by the Institutional Review Board committee at Henry Ford Hospital.

We analyzed data from 69,885 consecutive patients who underwent physician-referred treadmill stress testing from 1991 to 2009 at Henry Ford Hospital in Detroit, Michigan, which is part of a large, vertically integrated (both health care insurer and health care provider) health system. Patients without a recorded RHR (n = 570), with known coronary artery disease ([CAD]; n = 10,106), previous congestive heart failure (n = 864), previous atrial fibrillation or flutter (n = 1,160), or those referred for arrhythmia (n = 551) were excluded from this study. Known CAD was defined as previous myocardial infarction (MI), percutaneous coronary intervention, coronary artery bypass surgery, or previous documented obstructive CAD on an angiogram. Previous congestive heart failure was defined as a clinical diagnosis of heart failure with reduced ejection fraction or with preserved ejection fraction at baseline. Previous atrial fibrillation was defined as a clinical diagnosis of at least paroxysmal atrial fibrillation at baseline. Those with missing data on METS (n = 774) were excluded from analyses that adjusted for exercise capacity. This left a total of 56,634 patients available for overall analyses and 55,860 for analyses adjusted for METS.

All patients underwent routine clinical treadmill stress testing using the standard Bruce protocol. Treadmill stress tests completed using a protocol other than the standard Bruce protocol were not eligible for this study. The treadmill test was symptom-limited and was terminated if the patient had exercise-limiting chest pain, shortness of breath, or other limiting symptoms as assessed by the supervising clinician independent of the achieved heart rate. In addition, testing could be terminated early at the discretion of the supervising clinician for significant arrhythmias, abnormal hemodynamic responses, diagnostic ST-segment changes, or if the participant was unwilling or unable to continue.

RHR and blood pressure (BP) were taken in the seated position before stress testing by a trained clinical personnel. Target heart rate (HR) was calculated as 85% of the age-predicted maximal HR determined by the formula: 220 − age. An “adequate” test was defined as achieving ≥85% age-predicted maximal HR. Exercise capacity, expressed in estimated METS, was calculated by the Quinton treadmill controller based on achieved speed and elevation. Maximum METS achieved was recorded from the total treadmill time and was categorized into 4 groups (<6, 6 to 9, 10 to 11, ≥12). Other potential stress test information including perfusion imaging or echocardiographic results and HR recovery were not available in this data set.

A medical history data including age, gender, race (self-report), indication for stress test, anthropomorphic data, risk factor burden, past medical history, and active medication use was obtained by a nurses and/or exercise physiologists immediately before the stress test. Indication for stress test referral was provided by the referring physician and subsequently categorized into common indications (e.g., chest pain, shortness of breath, pre-operative evaluation, and so forth). Risk factors were defined and gathered prospectively by self-report and then augmented by a retrospective search of the EMR. Smoking status was defined as listed per EMR; current smoking was defined as self-reported active smoking at the time of the stress test. Diabetes mellitus was defined as a previous diagnosis of diabetes, use of hypoglycemic medications including insulin, or EMR problem list-based diagnosis of diabetes. Hypertension was defined as a previous diagnosis of hypertension, use of antihypertensive medications (including β blocker or calcium channel blocker), or EMR problem list-based diagnosis of hypertension. Dyslipidemia was defined by previous diagnosis of any major lipid abnormality, use of lipid-lowering medications, or EMR problem list-based diagnosis of hypercholesterolemia or dyslipidemia. Obesity was defined by EMR problem list or self-report. Family history of CAD was defined as compatible history in a first degree relative. The 2013 American Heart Association/American College of Cardiology atherosclerotic CVD 10-year risk score was also estimated.

Medication use history was gathered by self-report at the time of the test and categorized into common indications (antihypertensive, lipid-lowering, and so forth). Atrioventricular (AV)-nodal blocker use was classified as β blockers, calcium channel blockers, amiodarone, and/or digitalis. In cases of missing data, medication use was supplemented and verified by a retrospective search of the EMR as well as pharmacy claims files from enrollees in the integrated health plan.

Ascertainment of mortality was conducted using an automated algorithm for searching the death master file of the Social Security Death Index. The death master file of the Social Security Death Index is a national registry of nearly all deaths that have occurred within the United States; death ascertainment was however conducted after the change in federal laws in 2011 limiting reporting of certain deaths by state agencies. Vital status was determined by April 2013.

MI and revascularization were ascertained by search of the EMR as well as through linkage with claims files from services delivered by the affiliated group practice and those services reimbursed by the health plan, including those occurring outside of the affiliated group. Linkage was performed using appropriate International Statistical Classification of Diseases and Related Health Problems, Ninth and Tenth Revision and Current Procedural Terminology codes for MI, percutaneous coronary intervention, and coronary artery bypass surgery. Incident MACE included fatal CAD, nonfatal MI, or revascularization (percutaneous coronary intervention or coronary artery bypass surgery). However, nonfatal events that occurred outside of the Henry Ford Health System would not have been captured. To limit bias associated with loss to follow-up, patients were censored at their last contact with the integrated Henry Ford Health System group practice.

Baseline RHR was divided into 5 groups (<60, 60 to 69, 70 to 79, 80 to 90, and ≥90 beats/min) with <60 beats/min as the reference. Although clinically “bradycardic”, other previous studies have also used <60 beats/min as reference. We tabulated the distribution of the clinical characteristics of the study participants by RHR groups and tested differences using chi-squared tests for categorical variables and t tests for normally distributed variables or log-transformed variables.

Cox proportional hazard models were performed to determine the association of RHR with all-cause mortality, MACE, MI, or revascularization. Model 1 adjusted for age, race, and gender. Model 2 was adjusted for Model 1 covariates plus systolic and diastolic BPs, hypertensive medication use, history of dyslipidemia, lipid-lowering medication, smoking, pulmonary disease medication, diabetes, family history of CAD, obesity, reason for stress test, and AV-nodal blocking medication. Model 3 was additionally adjusted for METS achieved (categories), as a marker of exercise capacity. Interactions by gender were tested using model 3 and the trend across RHR groups.

Results

Forty-nine percent (n = 27,596) of the study population were women. Fifty-two percent of patients were referred for exercise stress testing for evaluation of chest pain. Patients had a mean age of 53 ± 12 years and mean RHR of 73 ± 12 beats/min. On average, women had a higher RHR of 75 ± 12 beats/min compared with 72 ± 12 beats/min for men ( Table 1 ; p trend <0.001). The clinical characteristics by RHR groups are outlined in Table 1 . Participants with higher RHR tended to have higher BP, higher low-density lipoprotein cholesterol, higher triglycerides, lower high-density lipoprotein cholesterol, and more diabetes ( Table 1 ). Greater use of AV-nodal blockers and older age were present among those with a lower RHR. Eighty-one percent of participants achieved an exercise heart rate ≥85% predicted, with a mean METS of 9.2 ± 3. RHR was inversely correlated with METS achieved (r = −0.20, p <0.001 [unadjusted]).

After a mean follow-up time of 11.1 years (median 10.5 years), there were 6,255 deaths. The association of RHR groups with all-cause mortality is presented in Table 2 . Compared with the lowest RHR group, participants with RHR ≥90 beats/min had increased risk for all-cause mortality, which remained significant even after adjustment for exercise capacity. The association of RHR groups with all-cause mortality was also stratified by gender ( Table 2 ). In men, the highest RHR group (compared with the lowest) was still associated with mortality even after adjustment for fitness (hazard ratio 1.29, 95% confidence interval 1.12 to 1.47). This was not true with women; the association between fitness and mortality was nonsignificant after adjustment for fitness. The gender interaction was statistically significant (p interaction <0.001). However, when looking at the trend across RHR groups for women, there was a marginal nonsignificant trend for the association between higher RHR and mortality (p trend = 0.079).

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