Abstract
Background
We evaluate sex-based differences in the effectiveness of early cardiac computed tomographic angiography (CCTA) versus standard emergency department (ED) evaluation in patients with acute chest pain.
Methods and Results
In the ROMICAT II multicenter controlled trial, we randomized 1000 patients (47% women) 40-74 years old with symptoms suggestive of acute coronary syndrome (ACS) to an early CCTA or standard ED evaluation. In this pre-specified analysis, women in the CCTA arm had greater reduction in length of stay (LOS), lower hospital admission rates, and lesser increased cumulative radiation dose than men when comparing ED strategies (p-interactions≤0.02). While women had lower ACS rates than men (3% vs 12%, p<0.0001), sex differences in LOS persisted after adjustment for baseline differences including ACS rate (p-interaction<0.03). LOS was similar between sexes with normal CCTA findings (p=0.11). There was no missed ACS for either sex. No difference was observed in major adverse cardiac events between sex and ED strategies (p-interaction=0.39). Women had more normal CCTA examinations than men (58% vs 37%, p<0.0001), less obstructive coronary disease by CCTA (5% vs 17%, p=0.0001), but similar normalcy rates for functional testing (p=1.0). Men in the CCTA arm had the highest rate of invasive coronary angiography (18%), while women had comparable low 5% rates irrespective of ED strategies.
Conclusions
This trial provides data supporting an early CCTA strategy as an attractive option in women presenting to the ED with symptoms suggestive of ACS. The findings may be explained by lower CAD prevalence and severity in women than men.
Keywords: sex, chest pain, acute coronary syndrome, emergency department, cardiac computed tomography
INTRODUCTION
Coronary artery disease (CAD) is a leading cause of mortality for women in the United States, with poorer prognosis than for men.1 Contrast enhanced cardiac computed angiography (CCTA) is an advanced non-invasive imaging modality with excellent diagnostic accuracy for the detection of CAD.2-4 Recently, three large multicenter trials showed that CCTA implemented early in the Emergency Department (ED) evaluation of chest pain was a safe alternative as compared to standard ED evaluation and was associated with reduced length of stay (LOS).5-7 Controversy remains regarding whether patients subgroups at relatively low risk for CAD merit non-invasive testing, especially involving cardiac imaging, when presenting to the ED with chest pain.8 Women in particular are known to be at lower risk for having CAD as compared to age-matched men.1, 9 Moreover, women have higher rates of false positive or indeterminate exercise testing, due to nonspecific ST-T wave abnormalities and breast attenuation on nuclear imaging that may simulate anterior segment myocardial ischemia.9 Because CCTA directly visualizes CAD, it may be particularly beneficial in women, especially in those less than 65 years of age.10 However, societal concerns exist regarding the potential increase risk of breast cancer from radiation exposure of a CCTA and other imaging tests, particularly in younger women.8, 11
In this pre-specified analysis from the recently reported Rule-Out Myocardial Infarction with Computer-Assisted Tomography (ROMICAT)-II trial, we aimed to determine whether sex is associated with differences in effectiveness and safety, including radiation exposure, of an early CCTA versus standard ED evaluation in patients presenting to the ED with chest pain suggestive of acute coronary syndrome (ACS). We also examined whether results of diagnostic testing could explain any such observed differences.
METHODS
Study Population and Protocol
ROMICAT-II was a randomized multicenter controlled trial consisting of 1000 patients at 9 US sites who presented to the ED during weekday daytime hours with symptoms suggestive of ACS but without ischemic ECG changes or initial positive troponin. The study design, inclusion and exclusion criteria, and primary results have been reported previously.5, 12 The study was approved by the institutional review board at each participating site and all participants provided informed consent. Briefly, eligible patients were between the age of 40 to 74 years, had chest pain or anginal equivalent of at least five minutes duration within 24 hours of ED presentation, were in sinus rhythm and warranted further risk stratification to rule out ACS. Major exclusion criteria were history of known CAD, new diagnostic ischemic changes on the initial ECG, initial troponin in excess of the 99th percentile of the local assay, impaired renal function (creatinine >1.5 mg/dL), hemodynamic or clinical instability, known allergy to iodinated contrast agent, body mass index >40 kg/m2, or currently symptomatic asthma.
All patients were randomized to either CCTA as part of the initial evaluation or to the standard ED evaluation strategy, as dictated by local caregivers. CCTA was performed with at least 64- slice CT technology and both retrospectively ECG-gated and prospectively ECG-triggered CCTA protocols were allowed. The standard ED evaluation strategy was performed at the discretion of the local caregivers and included no diagnostic testing, functional testing (exercise treadmill test [ETT], exercise or pharmacological nuclear imaging, stress echocardiography), or invasive coronary angiography. Patients discharged within 24 hours of ED presentation were contacted by phone within 72 hours to evaluate for potential missed ACS. Patients were followed for 28 days after discharge from the ED or hospital by phone interview and queried regarding repeat ED visits or hospitalizations for recurrent chest pain, diagnostic testing/interventions, and major adverse cardiac events (MACE) with verification of medical records. This pre-specified analysis focused on comparing differences between women and men on the effectiveness and safety endpoints of implementing an early CCTA strategy versus standard ED evaluation.
End Points
The primary endpoint was the length of stay (LOS), defined as the time from ED presentation to the time of the discharge order. Secondary effectiveness endpoints included rates of direct ED discharge (defined as the proportion of patients discharged from the ED without admission to an observation unit or hospital), hospital admission, and downstream testing (defined as ≥ 2 diagnostic tests, which included CCTA, ETT, nuclear stress test, stress echocardiography, transthoracic echocardiography, and invasive coronary angiography). Additional secondary endpoints included rates of invasive coronary angiography, revascularization (percutaneous coronary intervention [PCI] and/or coronary arterial bypass surgery [CABG]), and repeat ED or hospitalization for recurrent chest pain at 28 days. Safety endpoints included missed ACS (defined as an unexpected cardiovascular event within 72 hours after hospital discharge in patients with a hospital stay of less than 24 hours), and MACE (defined as death, myocardial infarction [MI], unstable angina, or urgent coronary revascularization that occurred within 28 days). Radiation exposure from testing was calculated in mSv for CCTA, nuclear perfusion imaging, and invasive coronary angiography using standard methods13 including a conversion coefficient of 0.014 for the chest for CCTA scans. Cumulative radiation dose was defined as the mean radiation dose during the index evaluation and follow-up period.
Statistical analysis
Descriptive statistics were expressed as mean ± standard deviation (SD) or median with interquartile range [IQR] for continuous variables and as frequency and percentages for nominal variables. To compare differences between groups, we used Fisher’s exact test for categorical variables and Student t test for continuous variables, as appropriate. We used logistic regression or exact logistic regression to test the interaction between sex and randomized evaluation strategies for binary outcomes and analysis of variance or quantile regression for continuous outcomes, as appropriate. For adjusted analyses of the sex interaction and randomized ED strategies on mean and median LOS, we controlled for age, cardiac risk factors (hypertension, diabetes, dyslipidemia, smoking, family history of premature CAD), as well as other covariates that were different between men and women (race, beta-blocker medication, diastolic blood pressure, and ACS prevalence). We used Student t test to compare the mean effective radiation dose between groups and analysis of variance to test the interaction between sex and randomized evaluation strategies. A 2-tailed p- and p-interaction value of <0.05 were considered to indicate statistical significance. All analyses were performed using SAS (Version 9.2, North Carolina).
RESULTS
Study Population
Out of the 1000 patients, there were 468 (47%) women and 532 (53%) men. Of the 501 patients in the CCTA arm, 239 were women and 262 were men. Of the 499 patients in the standard evaluation arm, 229 were women and 270 were men. Table 1 depicts the baseline characteristics of the ROMICAT II trial participants as stratified by sex and randomized ED strategies. There were no differences in baseline characteristics by randomized evaluation strategies in men or in women (all p>0.05). Overall, women were older, more frequently African American, more often had diabetes mellitus and were more often on beta-blocker medication as compared to men (all p≤0.03). Conversely, fewer women were Caucasian and smokers as compared to men (both p<0.01). Initial ED presentations were similar between sexes (all p≥0.37) except that women had lower diastolic blood pressure (p<0.0001). Women had higher rates of non-cardiac chest pain than men (p<0.0001). Importantly, women had a lower rate of ACS as a final diagnosis than men (3% vs 12%, p<0.0001), though there was no difference in ACS rate by randomization strategies of CCTA versus standard ED evaluation in women (3% vs 3%, p=1.0) or men (14% vs 10%, p=0.14; p-interaction=0.46).
Table 1.
Baseline Characteristics of Patients by Sex
| Women | Men | |||
|---|---|---|---|---|
| CCTA Arm | Standard ED Evaluation |
CCTA Arm | Standard ED Evaluation |
|
| n (%) | 239 (48) | 229 (46) | 262 (52) | 270 (54) |
| Demographics | ||||
| Age (mean ± SD) | 55.5±7.8 | 55.8±8.1 | 52.7±8.1 | 53.2±7.9 |
| Race | ||||
| African American (%) | 77 (32) | 73 (32) | 64 (24) | 68 (25) |
| Caucasian (%) | 143 (60) | 144 (63) | 187 (71) | 186 (69) |
| Asians (%) | 14 (6) | 6 (3) | 4 (2) | 7 (3) |
| Others (%) | 5 (2) | 6 (3) | 7 (3) | 12 (4) |
| Ethnicity, Hispanic or Latino (%) | 32 (13) | 29 (13) | 27 (10) | 39 (14) |
| Cardiovascular Risk Factors | ||||
| Hypertension (%) | 124 (52) | 139 (61) | 145 (55) | 133 (49) |
| Diabetes mellitus (%) | 46 (19) | 50 (22) | 40 (15) | 37 (14) |
| Dyslipidemia (%) | 98 (41) | 105 (46) | 132 (50) | 119 (44) |
| Former or current smoking (%) | 108 (45) | 93 (41) | 141 (54) | 150 (56) |
| Family history of premature CAD | 72 (30) | 66 (29) | 63 (24) | 70 (26) |
| (%) | ||||
| No. risk factors (% of 0-1 / 2-3 / ≥4) | ||||
| 0-1% (%) | 88 (37) | 89 (39) | 94 (36) | 102 (38) |
| 2-3 (%) | 134 (56) | 115 (50) | 137 (52) | 142 (53) |
| ≥4 (%) | 17 (7) | 25 (11) | 31 (12) | 26 (10) |
| Relevant Prior Medication | ||||
| Aspirin (n, %) | 56 (23) | 54 (24) | 59 (23) | 59 (22) |
| Beta Blocker (n, %) | 47 (20) | 46 (20) | 41 (16) | 36 (13) |
| Statins (n, %) | 72 (30) | 72 (31) | 71 (27) | 79 (29) |
| Initial ED Presentation | ||||
| Chief complaint | ||||
| Chest pain with or without | 212 (89) | 205 (90) | 232 (89) | 247 (91) |
| radiation (%) | ||||
| Pain arm/jaw/shoulder/epigastric | 11 (5) | 8 (3) | 10 (4) | 8 (3) |
| (%) | ||||
| Shortness of breath (%) | 3 (1) | 7 (3) | 4 (2) | 3 (1) |
| Other (%) | 13 (5) | 9 (4) | 16 (6) | 12 (4) |
| Heart Rate (bpm) | 78±14 | 77±14 | 77±15 | 77±15 |
| Systolic blood pressure (mmHg) | 143±23 | 144±24 | 145±23 | 144±22 |
| Diastolic blood pressure (mmHg) | 80±13 | 80±14 | 86±13 | 85±13 |
| Body mass index (kg/m2) | 29.3±5.7 | 29.5±5.3 | 29.4±4.9 | 28.7±4.4 |
| Discharge Diagnosis during Index | ||||
| Non-cardiac CP (%) | 220 (92) | 215 (94) | 206 (79) | 30 (85) |
| Non-coronary CP (%) | 5 (2) | 3 (1) | 2 (1) | 5 (2) |
| Coronary CP, not ACS(%) | 8 (3) | 5 (2) | 17 (6) | 9 (3) |
| ACS (%) | 6 (3) | 6 (3) | 37 (14) | 26 (10) |
| Unstable angina pectoris (%) | 6 (3) | 3 (1) | 29 (11) | 14 (5) |
| Myocardial infarction (%) | 0 (0) | 3 (1) | 8 (3) | 12 (4) |
CAD denotes coronary artery disease; CP, chest pain; ACS, acute coronary syndrome.
All p-values between randomized ED strategies within sex are <0.05.
Primary and Secondary Effectiveness Endpoints
Table 2 shows sex differences in endpoints between evaluation strategies. For either mean or median LOS (Figure 1), women had a greater reduction in LOS than men when CCTA was used as compared to standard evaluation. Compared to the standard ED evaluation, an early CCTA strategy resulted in 13.6 hours shorter mean LOS in women versus a 2.2 hour difference in men (p-interaction=0.006). Using median LOS, implementing an early CCTA strategy resulted in a 19.4 hour shorter median LOS for women and 16.6 hours reduction for men (p-interaction=0.0005). The sex difference in the effects of evaluation strategy on mean and median LOS persisted after adjustments for baseline sex differences including age, cardiac risk factors, and ACS rate (all p-interactions<0.03). A similar sex difference was seen with log-transformed LOS.
Table 2.
Endpoints Stratified by Sex
| CCTA Arm (n=501) Women: n=239 Men: n=262 |
Standard ED Evaluation (n=499) Women: n=229 Men: n=270 |
p-value | p-interaction | |
|---|---|---|---|---|
| Primary Endpoint | ||||
| Length of Stay (hours) | ||||
| Women, mean±SD | 17.0±24.5 | 30.7±24.1 | <0.0001 | 0.006 / 0.0005* |
| median* [25th, 75th %ile] | 8.0 [6.3, 24.5] | 27.4 [22.1, 30.8] | <0.0001 | |
| Men, mean±SD | 28.8±44.7 | 31.0±30.9 | 0.44 | |
| median* [25th, 75th %ile] | 9.5 [6.5, 29.7] | 26.2 [21.2, 29.9] | <0.0001 | |
| Secondary Endpoints | ||||
| Direct ED Discharge | ||||
| Women, n (%) | 132 (55) | 33 (14) | <0.0001 | 0.22 |
| Men, n (%) | 107 (41) | 33 (12) | <0.0001 | |
| Hospital Admission | ||||
| Women, n (%) | 33 (14) | 57 (25) | 0.003 | 0.005 |
| Men, n (%) | 75 (29) | 69 (26) | 0.44 | |
| Downstream Testing | ||||
| Index Visit | ||||
| Women, n (%) | 37 (16) | 22 (10) | 0.07 | 0.08 |
| Men, n (%) | 79 (30) | 31 (12) | <0.0001 | |
| At 28-days Follow-up | ||||
| Women, n (%) | 47 (20) | 24 (11) | 0.007 | 0.23 |
| Men, n (%) | 86 (33) | 36 (13) | <0.0001 | |
| Invasive Coronary Angiography | ||||
| Index Visit | ||||
| Women, n (%) | 12 (5) | 12 (5) | 1.0 | 0.15 |
| Men, n (%) | 42 (16) | 24 (9) | 0.02 | |
| At 28-days Follow-up | ||||
| Women, n (%) | 13 (5) | 12 (5) | 1.0 | 0.24 |
| Men, n (%) | 46 (18) | 28 (10) | 0.02 | |
| PCI | ||||
| Index Visit | ||||
| Women, n (%) | 5 (2) | 2 (1) | 0.45 | 0.69 |
| Men, n (%) | 19 (7) | 12 (4) | 0.20 | |
| At 28-days Follow-up | ||||
| Women, n (%) | 6 (3) | 2 (1) | 0.29 | 0.45 |
| Men, n (%) | 21 (8) | 15 (6) | 0.30 | |
| PCI/CABG at 28-day | ||||
| Women, n (%) | 7 (3) | 2 (1) | 0.18 | 0.33 |
| Men, n (%) | 25 (10) | 18 (7) | 0.27 | |
| Repeat ED/Hospitalizations for CP | ||||
| Women, n (%) | 6 (3) | 2 (1) | 0.50 | 0.11 |
| Men, n (%) | 9 (3) | 17 (6) | 0.77 | |
| Safety Endpoints | ||||
| Missed ACS | ||||
| Women, n (%) | 0 (0) | 0 (0) | - | - |
| Men, n (%) | 0 (0) | 0 (0) | - | |
| 28-day MACE | ||||
| Women, n (%) | 1 (0.4) | 1 (0.4) | 1.0 | 0.48 |
| Men, n (%) | 1 (0.4) | 5 (1.9) | 0.22 |
Abbreviations as in Table 1. CCTA denotes cardiac computed tomography angiography; ED, emergency department; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; MACE, major adverse cardiovascular event.
p-interaction for median LOS.
Figure 1.
Length of stay (LOS) as stratified by randomized ED evaluation strategy and by sex. Women had shorter LOS as compared to men when implementing an early CCTA strategy as compared to standard ED evaluation (mean Δ11.5 hours, p-interaction=0.006; median Δ2.8 hours, p-interaction=0.0005).
Direct ED discharge was over 3 times as high with early CCTA as with standard evaluation in both sexes. In contrast, hospital admission rates in women were reduced by nearly half in the CCTA arm versus standard evaluation but did not differ by arm in men (p-interaction 0.005).
Downstream testing at both the index visit and at 28-day follow-up was more common in the CCTA arm in both men and women, with no significant interactions by sex. There was also no interaction by sex in evaluation strategies for invasive coronary angiography, PCI, or recurrent chest pain hospitalizations (all p-interactions≥0.08). Invasive coronary angiography was nearly twice as common in men with the early CCTA strategy (18%) versus standard evaluation, but was comparably low at 5% in women, irrespective of randomized evaluation strategy, both during the index visit and at 28-day follow-up. It is noteworthy that men in the CCTA arm had the highest prevalence of downstream testing, including invasive coronary angiography and PCI.
Safety Endpoints
There was no missed ACS for either sex. There was no difference between sex and randomized ED strategies for 28-day MACE (p-interaction=0.39), though the number of events was very low in each of the groups.
Initial Diagnostic Testing Results
Table 3 shows the test results as stratified by sex. Of note, women had more normal CCTA examinations than men (58% vs 37%, p<0.0001) but had similar normalcy rates for functional testing (81% vs. 81%, p=1.0). There was no difference in mean LOS between sexes when the CCTA findings were normal (p=0.11) (Figure 2). Of the patients in the CCTA arm, the proportion of women with no CAD or non-obstructive CAD was higher than men (90% vs 80%, p=0.005), while women had a lower rate of obstructive epicardial coronary disease than men (5% vs 17%, p=0.0001),
Table 3.
Initial Diagnostic Testing Results as stratified by Sex within the treatment groups
| Women | Men | p | |
|---|---|---|---|
| CCTA Arm | |||
| Cardiac CT Angiography (n=473) | n=224 | n=249 | <0.0001 |
| No CAD (%) | 130 (58) | 93 (37) | |
| Non-obstructive CAD (%) | 71 (32) | 107 (43) | |
| Obstructive CAD (%) | 11 (5) | 41 (17) | |
| Indeterminate (%) | 12 (5) | 8 (3) | |
|
| |||
| Standard Evaluation Arm | |||
| Standard Evaluation with diagnostic testing (n=346)* | n=171 | n=175 | |
| Normal (%) | 138 (81) | 142 (81) | 1.0 |
| ETT (n=138) | n=62 | n=76 | |
| Normal (%) | 59 (95) | 70 (92) | 0.51 |
| Nuclear (n=108) | n=56 | n=52 | |
| Normal (%) | 44 (79) | 38 (73) | 0.65 |
| Stress Echo (n=100) | n=53 | n=47 | |
| Normal (%) | 35 (66) | 34 (72) | 0.52 |
Figure 2.
Length of stay (LOS) in patients with no coronary artery disease by CCTA as stratified by sex. There were no difference in mean LOS between sex when the CCTA findings were normal (p=0.11).
Radiation Exposure
Figure 3 shows the effective cumulative radiation dose by randomized ED strategies and its corresponding cumulative 28-day dose as stratified by sex. As might be predicted, in both men and women, the early CCTA strategy resulted in higher cumulative radiation exposure at the index visit and at 28-day follow-up (all p<0.0001). However, cumulative radiation dose was higher in men than women in the CCTA arm at both time points (both p-interactions≤0.02). Notably, in the standard ED arm, 347 (70%) patients had either an initial diagnostic test with no radiation exposure (138 patients had ETT and 100 patients with stress echocardiography) or no testing at all (n=109, 22%). Additionally, there were more patients who did not undergo a diagnostic test in the standard ED evaluation than in the CCTA arm (women: 19% with no diagnostic test in standard evaluation vs 2% in the CCTA arm; men: 24% in the standard evaluation vs 2% in the CCTA arm; both p<0.0001; p-interaction=0.39).
Figure 3.
Cumulative radiation dose by randomized ED strategy as stratified by sex at index visit and 28-day follow-up.
Table 4 summarizes the effective radiation dose by initial diagnostic testing modality and the subsequent cumulative radiation dose at index visit and 28-day follow-up as stratified by sex. In general, women undergoing CCTA receive lower radiation dose than men. Interestingly, in women who were scanned with the newest 128-slice dual-source CT scanner technology (which was available at 3 out of the 9 clinical sites), the mean cumulative radiation dose was low and similar between CCTA and standard ED strategies (5.8 mSv vs 5.0 mSv, p=0.69). In men, however, the mean cumulative radiation dose at 28-day follow-up remained higher in the CCTA arm compared to standard evaluation (12.9 mSv vs. 5.6 mSv, p<0.0001; p-interaction=0.01) despite utilization of newer CT scanner technology.
Table 4.
Effective radiation dose (mSv) of initial diagnostic testing modality and cumulative radiation dose during the index visit and 28-day follow-up stratified by sex.
| Women | Men | p | |||
|---|---|---|---|---|---|
|
| |||||
| n | mean±SD | n | mean±SD | ||
| ETT, n=140 | 63 | 77 | |||
| Initial ETT Test | 0 | 0 | - | ||
| Index Visit | 1.3±4.2 | 1.6±5.2 | 0.68 | ||
| 28-day follow-up | 1.9±5.3 | 2.7±8.1 | 0.48 | ||
| Nuclear Stress Test, n=116 | 60 | 56 | |||
| Initial Nuclear Test | 14.9±4.9 | 13.5±4.3 | 0.11 | ||
| Index Visit | 15.3±5.0 | 14.5±7.0 | 0.48 | ||
| 28-day follow-up | 15.3±5.0 | 14.5±7.0 | 0.49 | ||
| Stress Echo, n=106 | 58 | 48 | |||
| Initial Stress Echo Test | 0 | 0 | - | ||
| Index Visit | 0.3±1.2 | 0.1±0.9 | 0.57 | ||
| 28-day follow-up | 0.3±1.2 | 0.1±0.9 | 0.56 | ||
| CCTA, n=474*,† | 224 | 250 | |||
| Initial CCTA Test | 9.3±4.3 | 10.4±5.4 | 0.009 | ||
| Index Visit | 11.1±8.6 | 14.3±11.0 | 0.0005 | ||
| 28-day follow-up | 11.4±8.7 | 14.7±11.8 | 0.0005 | ||
| 128-slice DSCT, n=78† | 29 | 49 | |||
| Initial DSCT Test | 4.9±3.6 | 6.2±3.8 | 0.14 | ||
| Index Visit | 5.3±4.0 | 12.2±13.0 | 0.001 | ||
| 28-day follow-up | 5.8±4.4 | 12.9±14.4 | 0.002 | ||
DISCUSSION
In this pre-specified analysis of the ROMICAT-II trial, women had a greater reduction in LOS than men when early CCTA was used in the ED evaluation of chest pain suggestive of ACS. Women in the CCTA arm also had lower hospital admission rate and lesser increase in cumulative radiation dose than men. We also observed that men in the CCTA arm had the highest rate of invasive coronary angiography (18%), while women had comparable low 5% rates irrespective of ED strategies. Given that both sexes had similar LOS if CCTA results were normal, these findings may be explained largely by a lower burden of CAD in women, in whom there was a higher normal CCTA rate as compared to men (58% vs 37%) and lower rate of obstructive coronary disease by CCTA (5% vs 17%). This difference in CAD prevalence and severity in women observed in the CCTA arm allowed for their earlier discharge from the hospital and resulted in fewer downstream tests and procedures than men, including invasive coronary angiography and PCI, which contributed to the finding of lower increased radiation dose in women.
It is important to note that awareness of heart disease risk remains under-recognized amongst women, with only 54% recognizing cardiac disease as their leading cause of mortality in the US.14 Because CCTA is able to visualize non-obstructive CAD, which is typically not detectable during stress testing, it could be argued that both women and men could benefit from more aggressive primary prevention regimen, such as statin therapy. Moreover, CCTA in this symptomatic ED cohort detected coronary atherosclerosis in over 1/3 of women (32% non-obstructive and 5% obstructive CAD) which is associated with long-term adverse outcomes compared to individuals free of CAD,15-16 providing greater motivation to treat modifiable coronary risk factors. Conversely, a normal CCTA examination, which was found in 58% of women in our study who underwent CCTA, has a MACE-free “warranty period” for at least two years with a very favorable prognosis and hence provides useful information if patients present again to the ED within this time frame.15-16
These potential benefits of CCTA need to be evaluated in the context of its risks, particularly radiation exposure. Overall, 70% of patients in the standard evaluation arm received no diagnostic testing (22%) or initial tests without radiation exposure (ETT or stress echocardiography). Not surprisingly, the cumulative radiation dose was lowest for those whose initial diagnostic test did not require ionizing radiation. Although cumulative radiation exposure was higher for both sexes in the CCTA arm as compared to standard evaluation, women had less increased radiation exposure than men. Our data also shows that use of newer CCTA technology results in significant lowering of radiation exposure in the CCTA arm to doses comparable to those with the standard evaluation, especially for women (~5 mSv). By comparison, the effective radiation dose from a nuclear stress test was ~15 mSv. While radiation dose concern from estimating lifetime attributable risk of cancer suggest a linkage between CCTA and increased risk for breast cancer in women,11 the validity and conclusions of such model-based report has been questioned by the American Association of Physicists in Medicine17 and may be inconsequential with doses approaching the annual background radiation dose of ~3 mSv. 13
Further efforts in employing dose-saving algorithms utilized in conjunction with newest CT scanner technology could reduce the radiation dose to 3 mSv or less.18-19
Limitations
The study has several notable limitations. While the adjusted analyses provide additional support to strengthen our findings that there are sex-specific treatment effects on LOS, potential confounders may still exist. We were limited by the small number of patients who underwent coronary revascularization to show statistically significant differences by sex. The small number of major adverse events in this low-intermediate risk sample precludes definitive conclusions as to whether there is a greater benefit for women than men undergoing CCTA. The lack of follow-up beyond 28 days in this trial limits the ability to examine potential longer-term benefits of a CCTA strategy in the ED. The newest CT scanners may not be commonly available in practice. Because the sample size for assessment of radiation exposure using the newest CT scanner technology is relatively small, this interaction should be interpreted with caution. However, in addition to the 128-slice dual-source CT scanner, other CT platforms have the capability of radiation dose reduction.20-22
CONCLUSION
In the ED evaluation of low-intermediate risk patients with chest pain suggestive of ACS, women undergoing CCTA as compared to a standard evaluation strategy have a greater reduction in LOS and hospital admissions as compared to men, comparable low invasive coronary angiography rates between ED strategies, and hence lower increased cumulative radiation dose compared to men. These findings may be explained by lower CAD prevalence and severity in women than men and provide support that an early CCTA strategy is an attractive alternative in women with such symptoms.
Acknowledgements
Drs. Truong, Hayden, and Hoffmann had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Sources: The study was supported by the NIH/NHLBI (U01HL092040 and U01HL092022). Dr. Truong was supported by the NIH (K23HL098370 and L30HL093896).
Footnotes
Conflict of Interest Disclosures: Dr. Truong receives grant support from Qi Imaging, St. Jude Medical, American College of Radiology Imaging Network, and Duke Clinical Research Institute.
Clinical Trial Registration Information: http://www.clinicaltrials.gov. Identifier: NCT01084239
Disclaimer: The manuscript and its contents are confidential, intended for journal review purposes only, and not to be further disclosed.
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References
- 1.Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Stafford R, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation. 2010;121:948–954. doi: 10.1161/CIRCULATIONAHA.109.192666. [DOI] [PubMed] [Google Scholar]
- 2.Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I, Paul N, Clouse ME, Shapiro EP, Hoe J, Lardo AC, Bush DE, Roos AD, Cox C, Brinker J, J.A. L. Diagnostic performance of coronary angiography by 64-Row CT. N Engl J Med. 2008;359:2324–2336. doi: 10.1056/NEJMoa0806576. [DOI] [PubMed] [Google Scholar]
- 3.Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, Scherer M, Bellinger R, Martin A, Benton R, Delago A, Min JK. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol. 2008;52:1724–1732. doi: 10.1016/j.jacc.2008.07.031. [DOI] [PubMed] [Google Scholar]
- 4.Meijboom WB, Meijs MF, Schuijf JD, Cramer MJ, Mollet NR, van Mieghem CA, Nieman K, van Werkhoven JM, Pundziute G, Weustink AC, de Vos AM, Pugliese F, Rensing B, Jukema JW, Bax JJ, Prokop M, Doevendans PA, Hunink MG, Krestin GP, de Feyter PJ. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol. 2008;52:2135–2144. doi: 10.1016/j.jacc.2008.08.058. [DOI] [PubMed] [Google Scholar]
- 5.Hoffmann U, Truong QA, Schoenfeld DA, Chou ET, Woodard PK, Nagurney JT, Pope JH, Hauser TH, White CS, Weiner SG, Kalanjian S, Mullins ME, Mikati I, Peacock WF, Zakroysky P, Hayden D, Goehler A, Lee H, Gazelle GS, Wiviott SD, Fleg JL, Udelson JE. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med. 2012;367:299–308. doi: 10.1056/NEJMoa1201161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Litt HI, Gatsonis C, Snyder B, Singh H, Miller CD, Entrikin DW, Leaming JM, Gavin LJ, Pacella CB, Hollander JE. CT angiography for safe discharge of patients with possible acute coronary syndromes. N Engl J Med. 2012;366:1393–1403. doi: 10.1056/NEJMoa1201163. [DOI] [PubMed] [Google Scholar]
- 7.Goldstein JA, Chinnaiyan KM, Abidov A, Achenbach S, Berman DS, Hayes SW, Hoffmann U, Lesser JR, Mikati IA, O’Neil BJ, Shaw LJ, Shen MY, Valeti US, Raff GL. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J Am Coll Cardiol. 2011;58:1414–1422. doi: 10.1016/j.jacc.2011.03.068. [DOI] [PubMed] [Google Scholar]
- 8.Redberg RF. Coronary CT angiography for acute chest pain. N Engl J Med. 2012;367:375–376. doi: 10.1056/NEJMe1206040. [DOI] [PubMed] [Google Scholar]
- 9.Mieres JH, Shaw LJ, Arai A, Budoff MJ, Flamm SD, Hundley WG, Marwick TH, Mosca L, Patel AR, Quinones MA, Redberg RF, Taubert KA, Taylor AJ, Thomas GS, Wenger NK. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: Consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation. 2005;111:682–696. doi: 10.1161/01.CIR.0000155233.67287.60. [DOI] [PubMed] [Google Scholar]
- 10.Bamberg F, Truong QA, Blankstein R, Nasir K, Lee H, Rogers IS, Achenbach S, Brady TJ, Nagurney JT, Reiser MF, Hoffmann U. Usefulness of age and gender in the early triage of patients with acute chest pain having cardiac computed tomographic angiography. Am J Cardiol. 2009;104:1165–1170. doi: 10.1016/j.amjcard.2009.06.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Einstein AJ, Henzlova MJ, Rajagopalan S. Estimating risk of cancer associated with radiation exposure from 64-slice computed tomography coronary angiography. JAMA. 2007;298:317–323. doi: 10.1001/jama.298.3.317. [DOI] [PubMed] [Google Scholar]
- 12.Hoffmann U, Truong QA, Fleg JL, Goehler A, Gazelle S, Wiviott S, Lee H, Udelson JE, Schoenfeld D. Design of the Rule Out Myocardial Ischemia/Infarction Using Computer Assisted Tomography: A multicenter randomized comparative effectiveness trial of cardiac computed tomography versus alternative triage strategies in patients with acute chest pain in the emergency department. Am Heart J. 2012;163:330–338. doi: 10.1016/j.ahj.2012.01.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Gerber TC, Carr JJ, Arai AE, Dixon RL, Ferrari VA, Gomes AS, Heller GV, McCollough CH, McNitt-Gray MF, Mettler FA, Mieres JH, Morin RL, Yester MV. Ionizing radiation in cardiac imaging: a science advisory from the American Heart Association Committee on Cardiac Imaging of the Council on Clinical Cardiology and Committee on Cardiovascular Imaging and Intervention of the Council on Cardiovascular Radiology and Intervention. Circulation. 2009;119:1056–1065. doi: 10.1161/CIRCULATIONAHA.108.191650. [DOI] [PubMed] [Google Scholar]
- 14.Mosca L, Mochari-Greenberger H, Dolor RJ, Newby LK, Robb KJ. Twelve-year follow-up of American women’s awareness of cardiovascular disease risk and barriers to heart health. Circ Cardiovasc Qual Outcomes. 2010;3:120–127. doi: 10.1161/CIRCOUTCOMES.109.915538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Schlett CL, Banerji D, Siegel E, Bamberg F, Lehman SJ, Ferencik M, Brady TJ, Nagurney JT, Hoffmann U, Truong QA. Prognostic value of CT angiography for major adverse cardiac events in patients with acute chest pain from the emergency department: 2-year outcomes of the ROMICAT trial. JACC Cardiovasc Imaging. 2011;4:481–491. doi: 10.1016/j.jcmg.2010.12.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011;58:849–860. doi: 10.1016/j.jacc.2011.02.074. [DOI] [PubMed] [Google Scholar]
- 17.AAPM Position Statement on Radiation Risks from Medical Imaging Procedures. 2012 http://www.aapm.org/org/policies/details.asp?id=318&type=PP¤t=true.
- 18.Achenbach S, Marwan M, Ropers D, Schepis T, Pflederer T, Anders K, Kuettner A, Daniel WG, Uder M, Lell MM. Coronary computed tomography angiography with a consistent dose below 1 mSv using prospectively electrocardiogram-triggered high-pitch spiral acquisition. Eur Heart J. 2010;31:340–346. doi: 10.1093/eurheartj/ehp470. [DOI] [PubMed] [Google Scholar]
- 19.Ghoshhajra BB, Engel LC, Major GP, Goehler A, Techasith T, Verdini D, Do S, Liu B, Li X, Sala M, Kim MS, Blankstein R, Prakash P, Sidhu MS, Corsini E, Banerji D, Wu D, Abbara S, Truong Q, Brady TJ, Hoffmann U, Kalra M. Evolution of coronary computed tomography radiation dose reduction at a tertiary referral center. Am J Med. 2012;125:764–772. doi: 10.1016/j.amjmed.2011.10.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Earls JP, Berman EL, Urban BA, Curry CA, Lane JL, Jennings RS, McCulloch CC, Hsieh J, Londt JH. Prospectively gated transverse coronary CT angiography versus retrospectively gated helical technique: improved image quality and reduced radiation dose. Radiology. 2008;246:742–753. doi: 10.1148/radiol.2463070989. [DOI] [PubMed] [Google Scholar]
- 21.Chen MY, Shanbhag SM, Arai AE. Submillisievert median radiation dose for coronary angiography with a second-generation 320-detector row CT scanner in 107 consecutive patients. Radiology. 2013;267:76–85. doi: 10.1148/radiol.13122621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Hou Y, Xu S, Guo W, Vembar M, Guo Q. The optimal dose reduction level using iterative reconstruction with prospective ECG-triggered coronary CTA using 256-slice MDCT. Eur J Radiol. 2012;81:3905–3911. doi: 10.1016/j.ejrad.2012.06.022. [DOI] [PubMed] [Google Scholar]