Methods

The initial population consisted of 3,691 patients evaluated at 5 Italian cardiology institutions (Lucca, Mestre, Cesena, Pisa, and Naples) from August 2003 to December 2008 for enrollment in a prospective study focused on assessing the prognostic value of CFR in the setting of known or suspected CAD. All patients underwent dipyridamole stress echocardiography with CFR assessment of LAD by transthoracic Doppler ultrasound. All had normal left ventricular function. All patients met the following inclusion criteria: (1) stable chest pain syndrome, (2) eligibility for dipyridamole stress echocardiography by standard wall motion criteria, and (3) enrollment in a follow-up program. Exclusion criteria were (1) technically poor acoustic window precluding satisfactory imaging of the left ventricle (for 2-dimensional echocardiography) or of LAD flow Doppler (for CFR assessment), (2) previous myocardial infarction, (3) previous revascularization by percutaneous coronary intervention or coronary artery bypass grafting, (4) global and regional left ventricular dysfunctions (ejection fraction <50%, wall motion score index >1), (5) dipyridamole test positivity for wall motion criteria, (6) significant valvular heart disease, (7) congenital heart disease, (8) unwillingness to give informed consent, and (9) significant co-morbidity decreasing life expectancy to <1 year. From the initial population, 1,660 patients (906 women, 754 men) with chest pain syndrome and normal stress echocardiographic results (i.e., no wall motion abnormality at rest and during stress) were selected and formed the study group. Mean left ventricular ejection fraction at rest was 60 ± 4%. Follow-up data were available for all subjects. Diabetes mellitus, arterial hypertension, and hypercholesterolemia were defined according to standard definitions. According to individual needs and physician’s choices, 1,039 patients (65%) were evaluated after antianginal drugs had been discontinued, and 561 patients (35%) were evaluated during antianginal treatment ( Table 1 ). All patients gave their written informed consent when they underwent stress echocardiography. When patients signed the written informed consent, they also authorized physicians to use their clinical data. Stress echocardiographic data were collected and analyzed by stress echocardiographers not involved in patient care.

Transthoracic stress echocardiographic studies were performed with commercially available ultrasound machine (Sonos 7500 or iE 33, Philips Ultrasound, Andover, Massachusetts; Sequoia C256 Acuson Siemens, Mountain View, California; Vivid System 7, GE/Vingmed, Milwaukee, Wisconsin) equipped with a multifrequency phased-array sector scan probe (S ₃ to S ₈ or leads V ₃ to V ₇ ) and with second harmonic technology. Two-dimensional echocardiography and 12-lead electrocardiographic monitoring were performed in combination with high-dose dipyridamole (up to 0.84 mg over 6 minutes). Echocardiographic images were semiquantitatively assessed using a 17-segment, 4-point scale model of the left ventricle. A wall motion score index was derived by dividing the sum of individual segment scores by the number of interpretable segments. CFR was assessed during the standard stress echocardiographic examination by intermittent imaging of wall motion and LAD flow. Coronary flow in the mid-distal portion of the LAD was searched in the low parasternal long-axis section under the guidance of color Doppler flow mapping. All studies were digitally stored to simplify off-line reviewing and measurements. Coronary flow parameters were analyzed off-line using the built-in calculation package of the ultrasound unit. Flow velocities were measured ≥2 times for each study, namely at baseline and at peak stress (before aminophylline injection). At each time point, 3 optimal profiles of peak diastolic Doppler flow velocities were measured, and the results were averaged. CFR was defined as the ratio between hyperemic peak and basal peak diastolic coronary flow velocities. A CFR value ≤2.0 was considered abnormal. Quality control of stress echocardiographic performance and reading in enrolled centers was assessed as follows: A reader from each recruiting center met the predefined criteria for stress echocardiographic reading. At that point, the center could start recruiting patients. The previously assessed intra- and interobserver variabilities for measurements of Doppler recordings and regional wall motion analysis assessment were <10%.

Outcome was determined from patient interviews at the outpatient clinic, hospital chart reviews, and telephone interviews with a patient, a patient’s close relative, or referring physician. Clinical events recorded during follow-up were death, nonfatal ST-elevation myocardial infarction (STEMI) or non–ST-elevation myocardial infarction (NSTEMI), and coronary revascularization (surgery or angioplasty). To avoid misclassification of cause of death, overall mortality was considered. STEMI was defined by typical symptoms, ST-segment elevation on electrocardiogram, and cardiac enzyme changes. NSTEMI was an acute coronary syndrome causing typical chest pain, cardiac enzyme increase, and/or electrocardiographic modifications consistent with acute ischemia requiring hospitalization. Data were analyzed for prediction of death, STEMI, and NSTEMI.

Continuous variables are expressed as mean ± SD. Continuous variables were compared using Student’s unpaired t test, and differences in categorical variables were assessed by chi-square test. Kaplan-Meier curves were used for estimation of event rate. Only the first event was taken into account. Patients undergoing coronary revascularization were censored at the time of the procedure. Annual event rates were obtained from Kaplan-Meier estimates to take censoring of data into account. Association of selected variables with outcome was assessed with Cox proportional hazard model using univariate and stepwise multivariate procedures. A significance of 0.05 was required for a variable to be included into the multivariate model, and 0.1 was the cut-off value for exclusion. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated. Statistical significance was set at a p value <0.05. SPSS 13.0 (SPSS, Inc., Chicago, Illinois) was used for analysis.

Results

The main clinical and echocardiographic characteristics of women and men are listed in Table 1 . No major complications occurred during stress echocardiography. A CFR ≤2.0 was assessed in 171 women (19%) and 147 men (19%, p = 0.80).

During a median follow-up of 19 months (interquartile range 10 to 34), 80 events (20 deaths, 13 STEMIs, and 47 NSTEMIs) were registered. According to the physician’s judgment, 128 patients underwent coronary revascularization (17 for surgery and 121 for angioplasty) after a median of 4 months (first quartile 1 month, third quartile 12 months) from the index stress echocardiogram. Incidence of cardiac events and revascularization procedures in women and men is presented in Table 2 . Univariate and multivariable prognostic indicators in women and men are listed in Table 3 . Independent predictors of unfavorable outcome were CFR ≤2.0 (HR 16.48, 95% CI 7.17 to 37.85, p <0.0001) in women and CFR ≤2.0 (HR 6.23%, 95% CI 3.42 to 11.33, p <0.0001) and antianginal therapy at time of testing (HR 2.11%, 95% CI 1.14 to 3.90, p = 0.02) in men ( Table 3 ). Four-year event rate associated with CFR values ≤2.0 and >2.0 were, respectively, 27% and 2% in women (p <0.0001) and 42% and 8% in men (p <0.0001; Figure 1 ). Rates of revascularization were also markedly higher (p <0.0001) in women and men with CFR ≤2.0 than in those with CFR >2.0 ( Figure 2 ).

Table 3

Univariate and multivariate prognostic indicators in women and men

	Women				Men
	Univariate Analysis		Multivariate Analysis		Univariate Analysis		Multivariate Analysis
	HR (95% CI)	p Value	HR (95% CI)	p Value	HR (95% CI)	p Value	HR (95% CI)	p Value
Age (years)	1.04 (1.01–1.08)	0.01			1.04 (1.01–1.07)	0.008
Family history of coronary artery disease	1.44 (0.67–3.10)	0.34			1.11 (0.56–2.20)	0.75
Arterial hypertension	1.54 (0.74–3.21)	0.25			3.66 (1.69–7.89)	0.001
Diabetes mellitus	1.28 (0.56–2.94)	0.55			1.92 (1.01–3.62)	0.05
Hypercholesterolemia	2.69 (1.26–5.75)	0.01			1.66 (0.92–2.99)	0.09
Smoking habit	0.77 (0.32–1.86)	0.56			1.13 (0.61–2.10)	0.70
≥2 risk factors	1.39 (0.69–2.79)	0.35			2.15 (1.12–4.11)	0.02
Left bundle branch block	1.50 (0.36–6.24)	0.58			1.95 (0.60–6.28)	0.26
Antianginal therapy at time of testing	1.86 (0.96–3.61)	0.07			2.62 (1.45–4.74)	0.001	2.11 (1.14–3.90)	0.02
Coronary flow reserve on left anterior descending coronary artery ≤2.0	17.99 (7.85–41.21)	<0.0001	16.48 (7.17–37.85)	<0.0001	7.16 (3.97–12.91)	<0.0001	6.23 (3.42–11.33)	<0.0001

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