Author + information
- Received July 15, 2004
- Revision received September 14, 2004
- Accepted September 16, 2004
- Published online January 4, 2005.
- Elena Biagini, MD*,†,
- Abdou Elhendy, MD, FACC‡,
- Jeroen J. Bax, MD§,
- Vittoria Rizzello, MD*,
- Arend F.L. Schinkel, MD*,
- Ron T. van Domburg, PhD*,
- Miklos D. Kertai, MD*,
- Boudewijn J. Krenning, MD*,
- Manolis Bountioukos, MD*,
- Claudio Rapezzi, MD†,
- Angelo Branzi, MD†,
- Maarten L. Simoons, MD, FACC* and
- Don Poldermans, MD*,* ()
- ↵*Reprint requests and correspondence:
Dr. Don Poldermans, Department of Cardiology, Thoraxcenter Room Ba 300, Erasmus MC, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
Objectives The aim of this study was to investigate the effects of gender on long-term prognosis of patients undergoing dobutamine stress echocardiography (DSE).
Background Gender differences in the predictors of outcome among patients with known or suspected coronary artery disease undergoing DSE have not been adequately studied.
Methods We studied 2,276 men and 1,105 women with known or suspected coronary artery disease who underwent DSE. Follow-up events were cardiac death and nonfatal myocardial infarction (MI).
Results Dobutamine stress echocardiography was normal in 687 men (30%) and 483 women (44%) (p < 0.0001). Ischemia on DSE was present in 1,194 men (52%) and 416 women (38%) (p < 0.001). During a mean follow-up of 7 ± 3.4 years, there were 894 (26%) deaths (442 attributed to cardiac causes) and 145 (4%) nonfatal MIs. The annual cardiac event rate was 2.5% in men and 1.2% in women with normal DSE. Independent predictors of cardiac events in patients with normal DSE using a Cox proportional hazards regression analysis were male gender (hazard ratio [HR]: 1.7 [range 1.1 to 2.8]), age (HR: 1.02 [range 1.01 to 1.04]), history of heart failure (HR: 3.4 [range 1.5 to 7.9]), previous MI (HR: 1.7 [range 1.1 to 2.8]), and diabetes (HR: 2.4 [range 1.3 to 4.5]). Independent predictors of cardiac events in patients with an abnormal DSE were age (HR: 1.03 [range 1.02 to 1.04]), history of heart failure (HR: 1.7 [range 1.3 to 2.1]), diabetes (HR: 1.4 [range 1.1 to 1.8]), heart rate at rest (HR: 2.8 [range 1.4 to 5.8]), wall motion abnormalities at rest (HR: 1.06 [range 1.04 to 1.09]), and ischemia on DSE (HR: 1.04 [range 1.02 to 1.07]). Myocardial ischemia was an independent predictor of cardiac events in both men and women.
Conclusions Dobutamine stress echocardiography provides independent prognostic information in both men and women. In patients with normal DSE, gender is independently associated with cardiac events. The outcome of patients with abnormal DSE is not related to gender, after adjusting for stress echocardiographic abnormalities.
Coronary artery disease (CAD) is a leading cause of mortality and morbidity in industrialized countries, in men as well as in women (1). Previous studies of the effect of gender on long-term survival of patients with known or suspected CAD have yielded conflicting results (2,3). Clinical evaluation of CAD has traditionally been more challenging in women compared with men because of the lower prevalence of the disease, the higher incidence of referral bias, and the intrinsic performance of various modalities of stress testing. Dobutamine stress echocardiography (DSE) has been reported as an effective noninvasive tool in detecting CAD and assessing prognosis in women (4,5). There is a controversy regarding the presence of a gender-based difference in the accuracy of DSE in detecting CAD (5–7). However, gender differences in the predictors of outcome among patients with known or suspected CAD undergoing DSE have not been adequately studied. The aims of this study were: 1) to assess the predictors of cardiac death and nonfatal myocardial infarction (MI) during a long-term follow-up in men and women referred for DSE for evaluation of MI on DSE; and 2) to find whether gender has an impact on outcome after controlling for clinical variables and stress echocardiographic data.
Materials and methods
The study population consisted of 3,875 consecutive patients with limited exercise capacity and known or suspected CAD, referred for DSE between January 1990 and January 2003 at the Thoraxcenter, Rotterdam, the Netherlands. Follow-up was successful in 3,836 patients (99%). A total of 455 patients (12%) underwent early coronary revascularization in the first 60 days after DSE and were excluded from the analysis. The final population consisted of 3,381 patients. The protocol was approved by the Hospital Ethics Committee. All patients gave informed consent before the test. Clinical characteristics and indications for testing were entered into a computerized database before DSE. Known CAD was defined as documentation of previous MI or myocardial revascularization or angiographic documentation of significant coronary artery stenosis. Suspected CAD was defined as the presence of symptoms related to CAD or the evidence of an abnormal baseline electrocardiogram associated with the presence of cardiac risk factors for CAD.
Dobutamine stress protocol
Low- to high-dose DSE (up to 40 μg/kg/min plus 2 mg atropine, if necessary) was performed according to a standard protocol as previously reported (6). Test end points were achievement of target heart rate (85% of maximal age- and gender-predicted heart rate), maximal dose of dobutamine and atropine, extensive new wall motion abnormalities, >2 mV downsloping ST-segment depression measured 80 ms after the J point compared with baseline, hypertension (blood pressure >240/120 mm Hg), a decrease in systolic blood pressure of >40 mm Hg compared with at rest, significant arrhythmias, or any intolerable adverse effect considered to be the result of dobutamine or atropine.
Echocardiographic imaging and interpretation
Two-dimensional echocardiographic images were acquired at rest, during dobutamine stress, and during recovery using standard views. Regional wall motion and systolic wall thickening were scored on a five-point scale using a standard 16-segment left ventricular model. Ischemia was defined as new or worsened wall motion abnormalities during stress indicated by an increase of wall motion score ≥1 grade in ≥1 segment. A biphasic response in an akinetic or severely hypokinetic segment was considered as an ischemic response. Ischemia was not considered present when akinetic segments at rest became dyskinetic during stress. For each patient, a wall motion score index was calculated by dividing the sum of segment scores by the total number of interpreted segments.
Follow-up data collection was performed by contacting the patient's general practitioner and by review of hospital records. The date of the last review or consultation was used to calculate follow-up time. Follow-up events noted were overall mortality and hard cardiac events (nonfatal MI and cardiac death). Myocardial revascularization procedures were also noted.
Continuous data were expressed as mean values ± SD. The Student ttest was used to analyze continuous data and the chi-square test was used for differences between proportions. Univariate and multivariate Cox proportional hazard regression models (BMDP Statistical Software Inc., Los Angeles, California) were used to identify independent predictors of follow-up events (8). Variables were selected in a stepwise forward selection manner with entry and retention set at a significance level of 0.05. The probability of survival was calculated using the Kaplan-Meier method, and survival curves were compared using the log-rank test. A p value <0.05 was considered statistically significant.
Patient characteristics and hemodynamic response
Mean age was 61 ± 10 years. There were 2,276 men (67%) and 1,105 women (33%). Clinical and hemodynamic data are presented in Tables 1 and 2,⇓respectively. Arrhythmias were non-sustained ventricular tachycardia in 124 patients (4%), atrial fibrillation in 43 patients (1%), severe hypotension (decrease in systolic blood pressure >40 mm Hg compared with baseline) in 33 patients (1%), and ventricular fibrillation in four patients (0.1%). Defibrillation was successful and no electrocardiographic or cardiac enzymatic changes suggestive of MI were observed in these four patients. The test was terminated for achievement of the target heart rate in 3,009 patients (89%), maximal dobutamine/atropine dose in 101 patients (3%), ST-segment changes in 99 patients (3%), arrhythmias in 30 patients (1%), angina in 40 patients (1%), abnormal blood pressure in 38 patients (1%), and other symptoms in 64 patients (2%).
Echocardiographic data and outcome
Dobutamine stress echocardiography was normal in 687 men (30%) and 483 women (44%) (p < 0.0001). Ischemia on DSE was detected in 1,194 men (52%) and 416 women (38%) (p < 0.0001); of these patients 1,077 men (47%) and 364 women (33%) had resting wall motion abnormalities as well (p < 0.0001).
During a mean follow-up of 7 ± 3.4 years, there were 894 deaths (26%), of which 442 (13%) were attributed to cardiac causes (Table 3).Men had a higher annual total mortality rate (5.7% vs. 3.9%) and cardiac event rate (4.2% vs. 2.6%) compared with women (both p < 0.0001). Of the 372 patients (11%) who did not reach the target heart rate during DSE, 93 (25%) had normal DSE, 19 (5%) had ischemia, 74 (20%) had fixed wall motion abnormalities, and 186 (50%) had both ischemia and fixed wall motion abnormalities.
Predictive value of clinical data and test results
There were 1,170 patients (35%) with normal DSE. Independent clinical predictors of hard cardiac events in these patients were male gender (hazard ratio [HR]: 1.7 [range 1.1 to 2.8]), age (HR: 1.02 [range 1.01 to 1.04]), history of heart failure (HR: 3.4 [range 1.5 to 7.9]), previous MI (HR: 1.7 [range 1.1 to 2.8]), and diabetes (HR: 2.4 [range 1.3 to 4.5]). Independent predictors of cardiac events in patients with abnormal DSE were age (HR: 1.03 [range 1.02 to 1.04]), history of heart failure (HR: 1.7 [range 1.3 to 2.1]), diabetes (HR: 1.4 [range 1.1 to 1.8]), heart rate at rest (HR: 2.8 [range 1.4 to 5.8]), wall motion abnormalities at rest (HR: 1.06 [range 1.04 to 1.09]), and ischemia on DSE (HR: 1.04 [range 1.02 to 1.07]).
Univariate and multivariate predictors of hard cardiac events evaluated separately in men and women are shown in Tables 4 and 5,⇓respectively. Resting wall motion score index and ischemia on DSE were predictive of cardiac events in both genders. Kaplan-Meier survival curves for the end point of cardiac death/nonfatal infarction are presented in Figure 1.In patients with normal DSE, the annual hard cardiac event rate during seven years of follow-up was 2.5% in men and 1.2% in women (p < 0.0001). There was no difference in annual hard cardiac event rate between men and women with wall motion abnormalities at rest (2.9% vs. 2.1%, p = 0.1) or men and women with both rest and new wall motion abnormalities (5.9% vs. 4.6%, p = 0.3). Survival curves according to the results of DSE are shown in Figure 2(men) and Figure 3(women).
This study demonstrated an independent prognostic value of DSE for the prediction of cardiac events in both men and women during a long-term mean follow-up of seven years.
In patients with normal DSE, male gender remained an independent predictor of cardiac death and nonfatal MI after adjustment for other clinical variables. In patients with abnormal DSE the outcome was related to the severity of left ventricular dysfunction and inducible ischemia on DSE, but not to the gender. These data indicate that women with abnormal DSE should be treated as aggressively as men considering the clinical and echocardiographic risk profiles, as the risk imposed by these parameters was not gender related.
The underlying cause for the association of male gender with a higher cardiac event rate among patients with normal DSE is not clear. One explanation could be a gender-related difference in the prevalence and/or progression of non-obstructive coronary arterial lesions that were not severe enough to induce ischemia on DSE in the group with normal DSE. Another explanation could be a gender difference in the diagnostic accuracy of DSE, with some studies showing a better accuracy of DSE in women than in men (6). However, there is controversy among published reports regarding this issue, with some studies reporting better accuracy in men (7) and others reporting similar accuracy in both genders (5).
The association of higher heart rate at rest with adverse outcome may be related to onset of autonomic dysfunction as an early compensatory mechanism with incipient heart failure (9). Some investigators suggested that sympathetic overactivity could be the common factor acting on cholesterol, heart rate, pulse pressure, and arterial stiffness with subsequent increase in cardiac workload (10,11).
Comparison with previous studies
Data in published reports regarding the impact of gender on long-term prognosis of patients with CAD are inconsistent. Few studies have specifically focused on gender differences in the predictors of outcome after noninvasive stress testing. Although some of these studies showed incremental prognostic value of stress imaging techniques in both genders, most of these studies did not specifically address the impact of gender on survival after adjusting for other clinical and stress imaging parameters (12–14).
Patients with chronic non-cardiac diseases such as end-stage renal disease or chronic obstructive pulmonary disease were not excluded from the study. These patients may be at a higher risk for cardiac death despite a negative stress test for ischemia. Patients enrolled in January 2003 had a short follow-up period. Finally, the study enrolled patients over 13 years with implementation of new changes in imaging such as second harmonic imaging and myocardial contrast overtime. Differences in accuracy related to the use of these methods may have had an impact on the results.
Clinical implications and conclusions
Dobutamine stress echocardiography provides independent prognostic information for the prediction of cardiac events during long-term follow-up in both genders. The prognosis after a normal DSE is more favorable in women than in men, after correction for clinical variables. The outcome of patients with abnormal DSE is related to severity of left ventricular dysfunction and ischemia on DSE, but not related to gender after adjusting for other variables. Therefore, women with abnormal DSE should be treated as aggressively as men, because the risk imposed by echocardiographic abnormalities is not gender related.
- Abbreviations and acronyms
- coronary artery disease
- dobutamine stress echocardiography
- hazard ratio
- myocardial infarction
- Received July 15, 2004.
- Revision received September 14, 2004.
- Accepted September 16, 2004.
- American College of Cardiology Foundation
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