Methods

We evaluated 1,023 participants from the Heart and Soul Study, a prospective cohort study originally designed to investigate the effects of psychosocial factors on health outcomes in patients with stable CHD. Detailed methods of this study have been previously described. In brief, participants were eligible if they had at least one of the following: history of myocardial infarction (MI), angiographic evidence of ≥50% stenosis in ≥1 coronary vessels, evidence of exercise-induced ischemia by treadmill electrocardiogram or stress nuclear perfusion imaging, or a history of coronary revascularization. Participants were excluded if they were unable to walk 1 block, had an acute coronary syndrome within the previous 6 months, or were likely to move out of the area within 3 years.

Between September 11, 2000, and December 20, 2002, 1,024 participants were enrolled from 12 outpatient clinics in the San Francisco Bay Area, including 549 (54%) with a history of MI, 237 (23%) with a history of revascularization but not MI, and 238 (23%) with a diagnosis of coronary disease that was documented by their physician, based on a positive angiogram or treadmill test in >98% of cases. All study participants completed a full-day evaluation including medical history, extensive questionnaires, blood tests, and an exercise treadmill test with echocardiograms at baseline and after stress. The analytic cohort for this investigation included the 1,023 participants who completed the AP frequency domain of the Seattle Angina Questionnaire (SAQ). All participants provided informed consent. This study was approved by the institutional committee on human research.

The primary predictor was AP frequency measured with the SAQ. The SAQ is a 19-item, self-administered questionnaire that has been validated for use in patients with CHD. The questionnaire is divided into several domains, including AP frequency, quality of life, treatment satisfaction, and physical limitation. The AP frequency domain includes 2 questions with Likert scale responses. The questions are “Over the past 4 weeks, on average, how many times have you had chest pain, chest tightness, or AP?” and “How many times have you had to take nitroglycerin for your chest pain, chest tightness, or AP?” Scores for AP frequency are translated into a score on a 100-point scale, with 100 representing no AP and 0 representing AP occurring ≥4 times/day. Scores for the physical limitation domain of the SAQ were also calculated on a 100-point scale, with 100 representing no limitation and 0 representing severe physical limitations because of AP.

Participants were divided into categories of AP frequency based on SAQ scores, defined as absent (score 100), monthly (score 61 to 99), weekly (score 31 to 60), and daily (score 0 to 30). Because only 10 participants reported daily AP, those with daily or weekly AP were combined into a single category for analysis.

Annual telephone interviews were conducted with participants or their proxy to inquire about interval hospitalization or death. For any reported event, medical records, electrocardiograms, death certificates, autopsy, and coroner’s reports were obtained. Each event was adjudicated by 2 independent and blinded reviewers. In the event of disagreement, the adjudicators conferred, reconsidered their classification, and requested consultation from a third, blinded adjudicator, if needed.

Hospitalization for AP was strictly defined as hospitalization for definite or probable AP on the basis of symptoms, physician diagnosis, medical treatment, documented CHD, revascularization during admission, stenosis >70% documented during admission, ischemia by electrocardiogram, or ischemia by stress testing. Hospitalization for chest pain was not considered AP without objective evidence of cardiac ischemia. Revascularization was defined as percutaneous coronary intervention or coronary artery bypass graft surgery. MI was defined using standard diagnostic criteria. Heart failure was defined as hospitalization for signs and symptoms of heart failure. Death was verified by death certificates.

Demographic characteristics, medical history, and smoking status were collected by self-report questionnaire. Depressive symptoms were assessed using the 9-item Patient Health Questionnaire, a self-report instrument that measures the frequency of depressive symptoms, with a score of 10 or higher being classified as having depressive symptoms. We measured weight and height to calculate body mass index (kg/m ² ). Supine blood pressure at rest was measured with a standard sphygmomanometer. Participants were asked to bring their medications to the study appointment, and research personnel recorded all current medications and categorized using Epocrates Rx (Epocrates, Inc., San Mateo, California). Total and high-density lipoprotein cholesterol were determined from 12-hour fasting serum samples.

Participants underwent symptom-limited treadmill exercise testing according to a standard Bruce protocol (those unable to complete the standard protocol underwent operator-modified grade and speed adjustments) with continuous 12-lead electrocardiogram monitoring. Exercise capacity was estimated as the total METs achieved at peak exercise. Before exercise, participants underwent complete 2-dimensional echocardiograms at rest with all standard views using an Acuson Sequoia Ultrasound System (Siemens Medical Solutions, Mountain View, California) with a 3.5-MHz transducer. Standard 2-dimensional parasternal short-axis and apical 2- and 4-chamber views were used to calculate chamber sizes (indexed to body surface area) and left ventricular ejection fraction. At peak exercise, precordial long- and short-axis and apical 2- and 4-chamber views were obtained to ascertain wall motion abnormalities. We defined exercise-induced ischemia as the presence of 1 or more new wall motion abnormalities at peak exercise that were not present at rest. A single experienced cardiologist, who was blinded to the results of questionnaires and clinical histories, interpreted all echocardiograms.

Baseline characteristics were compared across categories of AP frequency using the chi-square test for categorical variables and 1-way analysis of variance for continuous variables. Fisher’s exact test was performed for categorical variables with fewer than 5 participants in a cell. Event rates per 100 person-years were calculated by category of AP frequency. Cox proportional hazards models were used to compare event rates between participants without AP with participants with daily or weekly AP. We adjusted models for all investigated baseline characteristics (demographics, co-morbidities, medications, and treadmill exercise capacity) associated with AP frequency with p <0.10 and EF and inducible ischemia. We constructed Cox proportional hazards models representing AP frequency as a continuous variable by numerical SAQ AP frequency score and for the association of SAQ physical limitation scale with outcomes. We tested the proportional hazards assumption by evaluating Schoenfeld residuals and found no violations of the proportional hazards assumption (all p >0.05 for association between residuals and time). Multiple imputation was performed using iterative chained equations for covariates with missing data, including smoking (n = 3), hypertension (n = 3), history of heart failure (n = 6), diastolic blood pressure (n = 10), β-blocker use (n = 13), exercise capacity (n = 80), EF (n = 27), and inducible ischemia (n = 86). All analyses were performed using Stata, version 12 (StataCorp LP, College Station, TX).