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J Am Coll Cardiol, 2003; 41:1125-1133, doi:10.1016/S0735-1097(03)00085-8 © 2003 by the American College of Cardiology Foundation |
* Departments of Imaging (Division of Nuclear Medicine), Department of Medicine (Division of Cardiology), and CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, and the Department of Medicine, University of California Los Angeles, School of Medicine, Los Angeles, California, USA
Atlanta Cardiovascular Research Institute, Atlanta, Georgia, USA
Manuscript received July 2, 2002; revised manuscript received August 30, 2002, accepted September 6, 2002.
* Reprint requests and correspondence: Dr. Daniel S. Berman, Department of Imaging, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room A042, Los Angeles, California 90048, USA.
bermand{at}cshs.org
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Abstract |
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BACKGROUND: Limited data are available regarding the incremental value of adenosine stress MPS for the prediction of cardiac death in women versus men and the impact of diabetes mellitus on post-adenosine MPS outcomes.
METHODS: Of 6,173 consecutive patients who underwent rest thallium-201/adenosine technetium-99m sestamibi MPS, 254 (4.1%) were lost to follow-up, and 586 with early revascularization 
60 days after MPS were censored, leaving 2,656 women and 2,677 men.
RESULTS: Women had significantly smaller adenosine stress, rest, and reversible defects than men. During 27.0 ± 8.8 month follow-up, cardiac death rates were lower in women than men (2.0%/year vs. 2.7%/year, respectively, p < 0.05). Before and after risk adjustment, cardiac death risk increased significantly in both men and women as a function of MPS results. Multivariable models revealed that MPS results provided incremental prognostic value over pre-scan data for the prediction of cardiac death in both genders. Also, while comparative unadjusted rates of early (60 days post-test) coronary angiography (17% vs. 23%) and revascularization (8% vs. 12%) were significantly lower in women (p < 0.05), after adjusting for MPS, these rates were similar in men and women. Importantly, diabetic women had a significantly greater risk of cardiac death compared with other patients. Also, after risk adjustment, patients with insulin-dependent diabetes mellitus (IDDM) had higher risk of cardiac death for any MPS result than patients with non–insulin-dependent diabetes mellitus.
CONCLUSIONS: The findings suggest that adenosine MPS has comparable incremental value for prediction of cardiac death in women and men and that MPS is appropriately influencing subsequent invasive management decisions in both genders. Diabetic women and patients with IDDM appear to have greater risk of cardiac death than other patients for any MPS result.
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Methods |
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60 days after index MPS) were censored as previously described (15). The final population consisted of 5,333 patients (2,656 women and 2,677 men). Rest Tl imaging. Patients were requested to be free of the effects of nitrates, calcium blockers, and beta-blockers at the time of MPS. Thallium-201 (3.0 to 4.5 mCi) was injected intravenously at rest, and MPS acquisition was started 10 min later (16). Patients with resting defects usually returned for 24-h Tl-201 MPS to assess reversibility (17).
Adenosine MPS protocol. Adenosine MPS was performed as previously described (18). All patients were instructed not to consume caffeine-containing products for 24 h before testing. Adenosine was infused at 140 µg/kg/min for 5 to 6 min. At the end of the second or third minute of infusion (of the 5- and 6-min protocols, respectively), Tc-99m sestamibi (25 to 40 mCi) was injected, and MPS acquisition was started approximately 60 min later. During adenosine infusion, 1,138 of 5,919 patients (44% women) performed low-level treadmill exercise, walking at 0% to 10% grade and 1 to 1.7 mph.
MPS acquisition protocol. The MPS acquisitions were performed as previously described with a circular or elliptical 180° acquisition for 64 projections at 25 s/projection for Tc-99m or 35 s/projection for Tl-201 (16). All images were subject to quality-control measures. No attenuation or scatter correction was used. After filtered back projection, short-axis, vertical long-axis, and horizontal long-axis tomograms were generated.
Stress ECG.
During adenosine infusion, 12-lead ECG was recorded each minute, with continuous monitoring of aVF, V1, and V5. Significant ST-segment depression during the adenosine stress test was defined as 
1 mm of horizontal or downsloping or 1.5 mm of upsloping (slope of >0.25 mV per 0.04 s) occurring 80 ms after the J point.
Image interpretation. Semiquantitative visual interpretation of MPS images used short-axis and vertical long-axis tomograms divided into 20 segments for each patient (16). Each segment was scored by consensus of two expert observers using a five-point scoring system (0 = normal, 4 = absence of segmental uptake). Three global perfusion indexes previously defined by our group were employed to combine assessments of defect extent and severity (6). By adding the 20 segment scores, summed stress scores (SSS) and summed rest scores (SRS) were calculated, using the 24-h Tl-201 for SRS when available. The sum of the differences between the SSS and SRS was defined as the summed difference score (SDS), assessing defect reversibility. The SSS <4 was defined as a normal scan; SSS 4 to 8, 9 to 13, and >13 were defined as mildly, moderately, and severely abnormal scans, respectively (19). The SDS <2 was considered no ischemia, 2 to 7 mild to moderate, and >7 severe ischemia (20). The SRS <2 was considered normal, 2 to 7 mild to moderate, and >7 extensive resting defects.
Follow-up data.
Follow-up was performed at 27.0 ± 8.8 months (all >1 year) by trained research personnel. The sole end point examined was cardiac death, confirmed by death certificate or medical records. Early revascularization was defined as performance of PCI or CABG 60 days after MPS.
Statistical analysis. All continuous variables are expressed as mean ± 1 standard deviation. Univariate analyses of continuous variables used unpaired t test. Univariate analyses of categorical variables were compared by chi-square. A threshold <0.05 was considered significant. The pre-scan likelihood of CAD was calculated by CADENZA (Advanced Heuristics Inc., Bainbridge Island, Washington) (21), which was based on clinical and historic information. For patients with known CAD, this likelihood is considered to represent the likelihood of ischemia.
The Kaplan-Meier method was used to depict survival curves. Cox proportional hazards model (S-PLUS 2000, MathSoft, Inc., Seattle, Washington) identified univariable and multivariable predictors of cardiac events. Selection of variables for consideration for entry was based on both univariate statistical significance and clinical judgment. A stepwise multivariable Cox regression analysis was performed using: 1) pre-MPS data (clinical and historical information), and 2) the increment in prognostic value after "forcing in" the significant clinical variables and then adding the most predictive nuclear variable(s). A significant increase in the global chi-square of a model after addition of the nuclear variables indicated incremental prognostic value. Based upon these models, we derived risk-adjusted cumulative survival curves to compare women and men with normal and varying degrees of abnormal MPS. These models were performed in the overall cohort as well as in men and women separately.
Receiver operating characteristic (ROC) curve analysis was performed to compare the value of combined clinical and MPS results for predicting cardiac events in men versus women using the final Cox model. The differences between ROC curve areas (area ± SE) were compared (22).
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Results |
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Comparison of prognostic value in women and men. The ROC curves showed excellent discrimination for predicting cardiac events in women and men using SSS (after adjusting for clinical variables). No gender-related differences in ROC areas were present (0.78 ± 0.02 vs. 0.83 ± 0.02, p = NS). These findings demonstrate that adenosine MPS is equally effective in identifying both men and women at high risk of cardiac mortality.
Comparison of insulin-dependent diabetes mellitus (IDDM) versus non–insulin-dependent diabetes mellitus (NIDDM). Subgroup analysis was performed in 2,826 patients from the overall cohort in whom information was available regarding the presence of IDDM or NIDDM. The characteristics of nondiabetics and two types of diabetics are shown in Table 5. The IDDM group was younger, more frequently had prior MI, PCI and CABG, hypertension, shortness of breath, and greater stress, rest, and reversible defects on MPS among the three groups (p < 0.05). However, they less frequently had angina, ischemic stress ECG, and had lower pre-scan likelihood of CAD (p < 0.05). There was no difference in use of low-level exercise during adenosine stress (p = NS).
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Discussion |
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Comparison with previous vasodilator MPS studies. While several studies have evaluated the incremental prognostic value of exercise MPS in women (6,8–10,23), only a few considered the prognostic implications of vasodilator stress MPS. Amanullah et al. (24) have shown that adenosine stress MPS added significant incremental prognostic value to clinical variables in women; however, there were no comparable data regarding men. In another study by Travin et al. (9), men and women with abnormal dipyridamole Tc-99m sestamibi MPS had similar event rates.
Our group previously reported the incremental value, role in risk stratification and post-MPS resource utilization of stress adenosine studies in a more limited cohort of 1,159 patients (25). We described that risk stratification was achieved by this test in men and women, and demonstrated the incremental prognostic value of this test in the overall cohort. Due to the limited size of the cohort, the detailed comparison of men and women contained in the present manuscript was not performed. Further, the impact of DM on the prognostic relationships was not addressed.
Comparison with previous exercise MPS studies. To our knowledge, this is the first study in a large population to compare the prognostic significance of adenosine stress MPS in women and men. Women less frequently had abnormal scan results, and only 21% of women but 42% of men had moderately to severely abnormal results on adenosine MPS. However, adenosine stress MPS provided comparable prognostic value for women and men in each category of perfusion defect abnormality. In the stepwise multivariable model, a similar increase in chi-square was seen in men and women by addition of adenosine MPS results to clinical data.
These findings are similar to what has been reported with exercise MPS; however, our findings revealed a greater mortality risk after adenosine stress than previously reported with exercise MPS in every category of scan abnormality. Pancholy et al. (23) examined 212 women who underwent coronary angiography and showed that exercise Tl201-MPS had independent and incremental prognostic value. Subsequently, Hachamovitch et al. (8) reported that exercise Tc-99m sestamibi MPS yielded incremental prognostic value in both women and men. In this study from our laboratory comprising 2,742 men and 1,934 women, we demonstrated that exercise MPS identifies low-risk women and men equally well, but relatively high-risk women more accurately than relatively high-risk men. Exercise MPS, therefore, was able to stratify women more effectively than men (8).
It has been generally appreciated that patients who undergo pharmacologic stress are "sicker" than patients who undergo exercise testing. In 1998, Hachamovitch et al. (19) reported that patients who underwent pharmacologic stress were older, more frequently had previous cardiac events or procedure, had a higher likelihood of CAD, more severe and extensive scan abnormalities, and greater subsequent rates of adverse outcomes. Others have found similar results (26,27). The use of pharmacologic stress rather than exercise has been shown to be an incremental predictor of poor prognosis over clinical, historical, and single-photon emission computed tomography data (19,20,27).
Relationship between adenosine MPS findings and referral to catheterization. Overall, a larger proportion of men were referred to early catheterization and revascularization than women in the current study. However, after adjusting for the extent and severity of inducible ischemia or scan abnormality, catheterization and revascularization rates were similar in men and women. In 1995, Hachamovitch et al. (6) reported on apparent gender-related differences in clinical management in patients undergoing exercise sestamibi MPS. Although men were referred to catheterization more frequently than women early after nuclear testing, there were no differences in the rate of referral to catheterization or revascularization after stratification by the amount of abnormally perfused myocardium as determined by the SSS. In fact, in this previous study, women with extensive inducible ischemia had greater referral rates to catheterization than men. Despite generally similar referral rates to catheterization, the cardiac event rates were observed to be higher in women than in men. In the current study, despite the greater overall risk and associated catheterization and revascularization rates in men compared with women, gender-related differences were not generally present with respect to risk or resource utilization after adjusting for confounding factors, such as the MPS results.
Impact of DM on cardiovascular risk in women undergoing MPS. The current study shows that diabetic women have a significantly greater risk of cardiac death for any degree of scan abnormality compared with diabetic men or nondiabetic men or women. In studies not using MPS, younger women have been shown to be at a much lower risk of coronary disease mortality than men; however, multiple studies have shown that diabetes "erases" this female advantage, increasing the risk of heart disease much more in women than in men. Barrett-Connor et al. (14), in a 14-year follow-up of 207 men and 127 women with NIDDM compared with 2,137 adult controls, first showed the excess risk associated with DM in women compared with men. In their study, Cox proportional hazards modeling revealed the relative hazard of CAD in diabetics versus nondiabetics, after adjusting for age, was 3.3 in women and 1.8 in men, and remained the same even after adjusting for age, systolic blood pressure, cholesterol, body mass index, and cigarette smoking. Further, a recent meta-analysis of 16 prospective cohort studies containing both men and women with and without diabetes found that, after adjusting for other cardiac risk factors, the relative risk of coronary death from diabetes was 2.58 (95% confidence interval, 2.05 to 3.26) for women and 1.85 (1.47 to 2.33) for men (difference, p < 0.05) (28). Although the precise physiological mechanisms for the greater risk of diabetic women compared with men has not been elucidated, it is believed that they are at least partially related to greater lipid abnormalities as well as more insulin resistance resulting in premature, accelerated vascular disease (29).
Regarding diabetes and MPS, in a cohort of 1,271 patients with and 5,862 patients without diabetes undergoing either exercise or adenosine MPS, Kang et al. (13) previously demonstrated that risk-adjusted event rates were higher in patients with diabetes than in those without diabetes in all SSS categories. These results were supported by a subsequent multisite data registry reporting a smaller group of diabetics (30). Our results are consistent with previous studies examining the impact of DM on cardiovascular risk in women and extend them to the extrapolation of risk in diabetic women from MPS results.
IDDM versus NIDDM. In the overall cohort, men and women combined, we found that there was an increased risk in the IDDM beyond that observed in NIDDM. After risk adjustment we found that the increased risk extended across the entire spectrum of MPS results. To our knowledge this increased risk for any MPS finding in patients with IDDM has not been previously reported.
Study limitations. This is a retrospective study in nature, although all data were collected and entered prospectively. The patients in this study were referred to a university-affiliated community hospital in a major urban area limiting the generalizability of the findings. Assessments of global and regional ventricular function with gated MPS were not performed in this study, as gated MPS was not routinely performed in our laboratory until 1995.
In this study, patients were not formally tested for the presence of DM. Hence, the "nondiabetic" group may have contained undiagnosed diabetics that may have diluted the study results. Although all patients were questioned regarding the type of diabetes they had, insulin use was not routinely recorded in the database until 1995.
Conclusions. The results of this study indicate that adenosine stress MPS has comparable strong incremental prognostic value over clinical variables and has a similar effect on catheterization and revascularization referrals in both men and women. Women with DM are at greater risk of adverse outcomes for any level of stress perfusion defects compared with nondiabetic women or diabetic men. Patients with IDDM have a greater risk than patients with NIDDM.
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Footnotes |
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