The additive prognostic value of coronary flow reserve (CFR) over regional wall motion has been established, but there is more than a binary (normal–abnormal) response in CFR, which can be continuously titrated. We assessed the prognostic value of quartiles of CFR, evaluated by transthoracic Doppler of the left anterior descending coronary artery (LAD), in patients with known or suspected coronary artery disease (CAD). One thousand six hundred twenty patients (1,006 men, 64 ± 11 years of age) underwent dipyridamole (up to 0.84 mg/kg over 6 minutes) stress echocardiography with CFR evaluation of LAD by Doppler and coronary angiography. Patients were followed up for a median of 19 months. Mean CFR in the entire population was 2.25 ± 0.65. Stress echocardiogram was positive for ischemia in 480 patients (30%). Obstructive (≥70% vessel stenosis) CAD at angiography was present in 650 patients (40%). During follow-up, there were 298 events (42 deaths, 73 ST-elevation myocardial infarctions, and 183 non–ST-elevation myocardial infarctions). Patients (n = 399) undergoing revascularization were censored. With the Kaplan-Meier method, the first quartile of CFR (≤1.80) was associated with a worse (p <0.0001) event rate than other quartiles in the entire population and in patients with no ischemia at stress echocardiography. Furthermore, the second quartile of CFR (1.81 to 2.16) was predictive of increased (p <0.0001) risk compared to the higher quartiles. In conclusion, Doppler echocardiographically derived CFR in LAD is a strong and independent prognostic predictor in patients with known or suspected CAD, but the spectrum of prognostic stratifications is expanded if the response is titrated according to a continuous scale rather than artificially dichotomized.
Dual imaging of wall motion and coronary flow reserve (CFR) in the left anterior descending coronary artery (LAD) is the current state-of-the art technique for vasodilator stress echocardiography, providing superior diagnostic and prognostic contributions compared to standard stress testing. In particular, a CFR ≤2.0 in the LAD added prognostic information over wall motion analysis in patients with known or suspected coronary artery disease (CAD) and allowed effective risk assessment in diabetics with negative stress echocardiographic results by wall motion criteria, in subjects with intermediate LAD stenosis and in those with normal or near normal coronary arteries. Interestingly enough, the prognostic capability of CFR was not affected by ongoing anti-ischemic therapy. Nevertheless, there is more than a binary (normal–abnormal) response in CFR, which can be continuously titrated. Accordingly, in this prospective, multicenter, observational study, we sought to investigate the prognostic information derived by analysis of quartiles of CFR assessed with transthoracic Doppler of the LAD during dipyridamole stress echocardiography in patients with known or suspected CAD.
Methods
We prospectively initially considered 1655 in-hospital patients with chest pain syndrome. They were prospectively enrolled in the study from August 2003 to March 2008 from 4 Italian cardiology institutions (Lucca, Mestre, Cesena, Pisa). All patients met the following inclusion criteria: (1) stable chest pain syndrome; (2) eligibility for dipyridamole stress echocardiography by standard wall motion criteria; (3) enrollment in a follow-up program; and (4) coronary angiography performed within 15 days from index test. Exclusion criteria were (1) a technically poor acoustic window precluding satisfactory imaging of the left ventricle (for 2-dimensional echocardiography) or of LAD flow Doppler (for CFR assessment); (2) severe valvular heart disease; and (3) unwillingness to give informed consent. No patient had previous bypass surgery, congenital heart disease, or significant co-morbidity decreasing life expectancy to <1 year. Of the 1,655 patients initially selected for the study, 15 (1%) were excluded for inadequate echocardiographic image quality during stress precluding satisfactory imaging of LAD flow and 20 (1.2%) were excluded for inadequate wall motion analysis. No patient was lost to follow-up.
Thus, 1,620 patients (1,006 men, 64 ± 11 years of age) represented the final study group. Follow-up data were available for all subjects. Indications for stress echocardiography were suspected CAD in 937 patients (58%) and risk stratification of known CAD (i.e., history of myocardial infarction and/or angiographic evidence of ≥70% diameter coronary stenosis) in 683 (42%). Diabetes mellitus, arterial hypertension, and hypercholesterolemia were defined according to standard definitions. According to individual needs and physicians’ choices, 781 patients (48%) were evaluated after antianginal drugs had been discontinued, and 839 (52%) patients 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.
| Age (years) | 64 ± 11 |
| Men | 1006 (62%) |
| Previous myocardial infarction | 545 (34%) |
| Previous percutaneous coronary intervention | 500 (31%) |
| Known coronary artery disease (history of myocardial infarction or coronary artery disease assessed by angiography) | 683 (42%) |
| Left bundle branch block | 91 (6%) |
| Diabetes mellitus | 400 (25%) |
| Arterial hypertension (>140 mm Hg or >90 mm Hg) | 1,129 (70%) |
| Hypercholesterolemia (>180 mg/dl or on statin therapy) | 1,023 (63%) |
| Smoker | 565 (35%) |
| Anti-ischemic therapy at time of test | |
| β blockers | 619 (38%) |
| Calcium antagonists | 411 (25%) |
| Nitrates | 282 (17%) |
| ≥1 medication | 839 (52%) |
| Echocardiogram | |
| Wall motion score index at rest | 1.18 ± 0.30 |
| Left ventricular ejection fraction at rest (%) | 54 ± 9 |
| Wall motion abnormalities at rest | 646 (40%) |
| Ischemic test result | 480 (30%) |
| Peak wall motion score index | 1.23 ± 0.32 |
| Coronary flow reserve in left anterior descending coronary artery | 2.25 ± 0.65 |
| Angiographic findings | |
| No obstructive coronary artery disease | 970 (60%) |
| Obstructive coronary artery disease | 650 (40%) |
| 3-vessel disease or left main coronary artery disease | 84 (5%) |
| 2-vessel disease | 79 (11%) |
| 1-vessel disease | 387 (24%) |
| ≥70% left anterior descending coronary artery stenosis | 363 (22%) |
Transthoracic stress echocardiographic studies were performed with commercially available ultrasound machines (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 multifrequency phased-array sector scan probes (S3 to S8 or V3 to V7) 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. Ischemia was defined as stress-induced new and/or worsening of pre-existing wall motion abnormality. Wall motion abnormality at rest was akinetic or dyskinetic myocardium with no thickening during stress.
CFR was assessed during 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 by use of 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. All investigators were instructed to obtain all standard stress echocardiographic projections for wall motion assessment and CFR (see earlier); images were digitally stored at rest, at peak dipyridamole stress testing, and after aminophylline infusion. Quality control of stress echocardiographic performance and reading in enrolled centers was previously described in depth. Briefly, the reader from each recruiting center met the predefined criteria for stress echocardiographic reading. At that point, the center could start recruiting patients.
Previously assessed intra- and interobserver variabilities for measurements of Doppler recordings and regional wall motion analysis assessment were <10%.
Coronary angiography in multiple views was performed according to the standard Judkins or Sones technique. At least 5 views (including 2 orthogonal views) were acquired for the left and ≥2 orthogonal views for the right coronary arteries, respectively. Additional appropriate projections were obtained in case of superimposition of side branches or foreshortening of the segment of interest. All angiograms were visually evaluated by 2 independent observers who identified the stenotic segments and scored control arteries as smooth or irregular. All stenotic segments were evaluated by an automated edge detection system (GE Healthcare) providing percent stenosis diameter. Previously assessed intraobserver and interobserver variabilities of the method were 7% and 6%, respectively.
Outcome was determined from patient interviews at outpatient clinics, 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 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 of 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. The association of selected variables with outcome was assessed with the Cox proportional hazard model using univariate and stepwise multivariate procedures. A significance of 0.05 was required for a variable to be included in the multivariate model, and 0.1 was the cut-off value for exclusion. Hazard ratios with corresponding 95% confidence intervals were estimated. Statistical significance was set at p <0.05. Moreover, clinical findings, left ventricular ejection fraction at rest, ischemia at stress echocardiography, obstructive CAD at angiography, and CFR were sequentially included into the model. Global chi-square value of the model was calculated from the log-likelihood ratio; a significant increase after the addition of further variables indicated incremental prognostic value. SPSS 13.0 (SPSS, Inc., Chicago, Illinois) was used for analysis.
Results
No side effect that required premature interruption of the test was observed. Mean CFR in the entire study group was 2.25 ± 0.65 (first quartile ≤1.80, second quartile 1.81 to 2.16, third quartile 2.17 to 2.60, fourth quartile ≥2.60). Stress echocardiogram was positive for ischemia in 480 patients (30%). Coronary angiogram showed obstructive CAD in 650 patients (40%), 363 (22%) of whom had LAD stenosis. Of 970 patients with no obstructive CAD, 316 (33%) had a history of percutaneous coronary intervention (n = 66) or MI (n = 80) alone or in combination (n = 170). Main clinical, echocardiographic, and angiographic findings of the study population are listed in Table 1 .
During a median follow-up of 19 months (interquartile range 6 to 41), there were 298 events (42 deaths, 73 STEMIs, and 183 NSTEMIs). In addition, 399 patients underwent revascularization (97 with surgery, 302 with angioplasty). Patients without events had higher (p <0.0001) mean CFR (2.32 ± 0.66) than those with events (1.97 ± 0.54) and those undergoing subsequent revascularization (1.88 ± 0.51).
Using the Kaplan-Meier method, the first quartile of CFR (≤1.80) was predictive of a significantly (p <0.0001) worse event rate than other quartiles in the entire study population and in patients with no ischemia at stress echocardiography ( Figure 1 ). Moreover, the second quartile of CFR (1.81 to 2.16) was associated with a markedly (p <0.0001) increased risk compared to the higher quartiles ( Figure 1 ). The prognostic effect of quartiles of CFR was maintained when revascularization was the clinical end point ( Figure 2 ).
