Whether lower heart rate thresholds (defined as the percentage of age-predicted maximal heart rate achieved, or ppMHR) should be used to determine chronotropic incompetence in patients on beta-blocker therapy (BBT) remains unclear. In this retrospective cohort study, we analyzed 64,549 adults without congestive heart failure or atrial fibrillation (54 ± 13 years old, 46% women, 29% black) who underwent clinician-referred exercise stress testing at a single health care system in Detroit, Michigan from 1991 to 2009, with median follow-up of 10.6 years for all-cause mortality (interquartile range 7.7 to 14.7 years). Using Cox regression models, we assessed the effect of BBT, ppMHR, and estimated exercise capacity on mortality, with adjustment for demographic data, medical history, pertinent medications, and propensity to be on BBT. There were 9,259 deaths during follow-up. BBT was associated with an 8% lower adjusted achieved ppMHR (91% in no BBT vs 83% in BBT). ppMHR was inversely associated with all-cause mortality but with significant attenuation by BBT (per 10% ppMHR HR: no BBT: 0.80 [0.78 to 0.82] vs BBT: 0.89 [0.87 to 0.92]). Patients on BBT who achieved 65% ppMHR had a similar adjusted mortality rate as those not on BBT who achieved 85% ppMHR (p >0.05). Estimated exercise capacity further attenuated the prognostic value of ppMHR (per-10%-ppMHR HR: no BBT: 0.88 [0.86 to 0.90] vs BBT: 0.95 [0.93 to 0.98]). In conclusion, the prognostic value of ppMHR was significantly attenuated by BBT. For patients on BBT, a lower threshold of 65% ppMHR may be considered for determining worsened prognosis. Estimated exercise capacity further diminished the prognostic value of ppMHR particularly in patients on BBT.
Chronotropic incompetence—the inability to appropriately increase heart rate to accommodate increased physiologic demands—is a powerful and independent predictor of mortality in both healthy subjects and in those with chronic medical conditions. Nevertheless, despite its prognostic utility, chronotropic incompetence remains underappreciated in clinical practice, in part from the potential confounding effects of beta-blocker therapy (BBT), and the multitude of heart rate thresholds and equations derived for this patient population. Notably, exercise capacity is also a powerful predictor of survival ; however, the combined effect of exercise capacity and BBT on the prognostic value of peak exertional heart rate remains unexplored. Whether lower heart rate thresholds should be used in patients on BBT represents an important area of uncertainty. Therefore, in this study, we aimed to describe the interaction between peak exertional heart rate (defined as the percentage of age-predicted maximal heart rate achieved, or ppMHR), BBT, and estimated exercise capacity on the risk for all-cause mortality in a large cohort of men and women without heart failure who were clinically referred for exercise stress testing. We hypothesized that lower ppMHR would be associated with greater mortality risk and that this association would be attenuated by both BBT and higher exercise capacity.
Methods
This study is based on data from the Henry Ford Exercise Testing Project (The FIT Project), a retrospective cohort study aimed at investigating the long-term implications of estimated exercise capacity on all-cause mortality. The FIT Project is unique in its combined use of (1) directly measured exercise data; (2) retrospective collection of medical history and medication treatment data taken at the time of the stress test; and (3) retrospective supplementation of supporting clinical data using the electronic medical record (EMR) and administrative databases.
The FIT Project cohort represents a registry of 69,885 consecutive patients who underwent clinician-referred treadmill stress testing at Henry Ford Health System in metropolitan Detroit, Michigan from 1991 to 2009. These medical centers are part of a large, vertically integrated organization that provides health care and offers a managed care insurance plan. Treadmill, medical history, and medication data were collected by exercise physiologists and nurses and entered at the time of testing into a common clinical reporting tool that directly populated the EMR. Supporting clinical data were derived from the EMR and administrative databases shared across the Henry Ford Health System. Data from the FIT Project were gathered retrospectively, deidentified in the data set, and approved by the Henry Ford Health System Institutional Review Board.
We considered patients from the FIT Project cohort excluding those with a baseline history of heart failure (n = 1,579) and atrial fibrillation (n = 1,975). Patients were further excluded if any covariates of interest were missing (n = 1,967), leaving a study cohort of 64,549 subjects. Patients were categorized according to baseline BBT, with 13,608 (21%) patients on BBT and 50,941 (79%) patients not on BBT at the time of stress testing.
All patients underwent routine, clinically referred, symptom-limited treadmill stress testing following the standard Bruce protocol. For subjects with repeat stress testing, only the results from the first test were considered in the registry. Patients less than 18 years old at the time of stress testing and patients tested using non-Bruce protocol tests were not included in the registry. In accordance with clinical guidelines, symptom-limited treadmill testing was terminated at the discretion of the supervising clinician for reasons that included significant arrhythmias, abnormal hemodynamic responses, diagnostic ST-segment changes, exercise-limiting symptoms such as chest pain or shortness of breath, or if the patient was unwilling or unable to continue. Heart rate at rest and blood pressures were taken before stress testing by clinical personnel. Peak exertional heart rate during exercise testing was recorded. The maximal age-predicted heart rate used to calculate ppMHR was defined as 220-age in the main analyses, with alternative calculations provided by Brawner et al, and Tanaka et al, available in sensitivity analyses. Chronotropic incompetence was defined by a threshold of 85% ppMHR. Estimated exercise capacity, expressed as estimated metabolic equivalents of task (estMETs), was calculated by the treadmill controller system (Q-Stress; Quinton Instruments, Bothell, Washigton) using peak speed and grade based on equations reported by the American College of Sports Medicine.
A medical history including age, gender, race, indication for testing, risk factor burden, active medication use, and past medical history was obtained by trained nurses and/or exercise physiologists immediately before the stress test. Race was defined exclusively by self-report. Obesity was defined by clinician report at the time of stress testing or body mass index ≥30 kg/m 2 . Smoking history was defined as self-reported smoking at the time of testing. Family history of coronary artery disease (CAD) was defined as a self-reported history of CAD in a first-degree relative. Indication for stress testing was extracted from the stress test requisition provided by the referring clinician and subsequently categorized into common indications (chest pain, shortness of breath, preoperative evaluation, and so on). Information on medication use and past medical history were supplemented by a retrospective search of the EMR, administrative databases, and/or pharmacy claims files from enrollees in the integrated health plan. A database-verified diagnosis was considered present when the appropriate International Statistical Classification of Diseases and Related Health Problems Ninth code was present on ≥3 separate encounters within the health system. Diabetes mellitus, hyperlipidemia, and hypertension were defined as a self-reported before diagnosis, a database-verified diagnosis, and/or use of medications for each medical condition. Known CAD was defined as previous myocardial infarction(MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), or documented CAD on a previous angiogram.
Mortality was ascertained in April 2013, after federal law changes in 2011 limited reporting of certain deaths by state agencies. An algorithmic search of the Social Security Death Index Death Master File was completed using social security number, first name, last name, and date of birth data.
Baseline groups, stratified by use of BBT, were compared using the chi-square testing or analysis of variances techniques as appropriate. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) associated with decreasing strata of ppMHR. We considered the propensity for patients to be on BBT, and a propensity score was derived from logistic regression models adjusting for age, gender, race, history of CAD, MI, PCI, CABG, diabetes, obesity or smoking, use of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers and aspirin, and date of stress testing to account for secular trends in the prescription of β blockers. The propensity score models enable assessment of the survival benefits from the chronotropic effects and other pleotropic mechanisms associated with BBT.
We also sought to obtain adjusted mortality rates at the median follow-up time of 10.6 years (interquartile range 7.7 to 14.7 years) as a function of ppMHR using a margins of response logistic regression model, which similarly accounts for differences in co-morbidity burden and other baseline characteristics between those on and not on BBT. The advantage of this statistical model is that it provides absolute adjusted mortality rates (instead of only relative risk) that are potentially more intuitive and readily comparable (i.e., BBT vs no BBT) than results from traditional Cox regression models. Both Cox regression and margins of response models were adjusted for age, gender, race, systolic and diastolic blood pressure at rest, a history of diabetes, hyperlipidemia, hypertension, obesity, smoking, CAD, PCI, CABG, MI, family history of CAD, use of medications for chronic obstructive pulmonary disease and hypertension, use of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, aspirin and statins, and indication for stress testing. Additional adjustment for estMETs as a continuous variable was performed in augmented models as a mediation analysis.
In graphical analyses examining the association between ppMHR and adjusted mortality rate, a fractional polynomial trend line was generated and superimposed on the data to clearly display the relation between the 2 variables of interest. Statistical analyses were performed using Stata version 13.1, 2014 (StataCorp, College Station, Texas).
Results
Table 1 lists the baseline characteristics for the study cohort. Patients on BBT were older, more likely to have medical co-morbidities, and use cardiovascular medications including aspirin and statins (p <0.001 for all covariates). Table 2 lists the stress test results for the study cohort. Those on BBT had lower resting and peak exertional heart rates, lower estimated exercise capacity, and were less likely to achieve ≥85% ppMHR (p <0.001 for all covariates). In adjusted multivariate models, BBT was associated with a consistent 8% lower ppMHR compared with those not on BBT, even when stratified by gender and baseline CAD status ( Table 3 ).
