Abstract
Background:
Coronary artery calcium (CAC) scoring can identify individuals who may benefit from aggressive prevention therapies. However, there is a paucity of contemporary data on the impact of CAC testing on patient management.
Methods:
Retrospective cohort study of adults who underwent CAC testing at Brigham and Women’s Hospital between 2015 and 2019. Information on baseline medications, follow-up medications, lifestyle modification, and downstream cardiovascular testing within one-year post-CAC were obtained from electronic health records.
Results:
Of the 839 patients with available baseline and follow-up data, 376 (45%) had a CAC = 0, 289 (34%) had CAC = 1–99, and 174 (21%) had CAC≥100. The mean age at time of CAC testing was 59 ± 9.7 years. Patients with higher CAC scores were more likely to be male, have diabetes and hypertension, and have higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol. A non-zero CAC score was associated with initiation of aspirin (41% increase, p < 0.001), anti-hypertensives (9% increase, p = 0.031), and lipid-lowering therapies (114% increase, p < 0.001), whereas CAC = 0 was not. Among individuals with CAC≥100, 75% were started on new or more intense lipid-lowering therapy. Higher calcium scores correlated with increased physician recommendations for diet (p = 0.008) and exercise (p = 0.004). The proportion of cardiovascular downstream testing following CAC was 9.1%, and the majority of patients who underwent additional testing post-CAC had CAC scores ≥100.
Conclusion:
Approximately half of individuals referred for CAC testing had evidence of calcified coronary plaque, and of those who had significant calcifications (CAC≥100), nearly 90% were prescribed lipid-lowering therapies post-CAC. Rates of downstream non-invasive testing were low and such testing was mostly performed in patients who had at least moderate CAC.
Keywords: Cardiovascular, Calcium, Prevention, Statin, Lifestyle
1. Introduction
Coronary artery calcium (CAC) scoring, as endorsed by the 2018 Cholesterol and 2019 American College of Cardiology/American Heart Association prevention guidelines, is commonly used in primary care and preventive cardiology to further risk stratify individuals who are at borderline or intermediate 10-year atherosclerotic cardiovascular disease (ASCVD) risk when indication for statin is unclear.1,2 Several studies have shown that calcium scoring can identify patients at higher risk who would benefit from more preventive therapies including pharmacotherapy, lifestyle interventions, and need for downstream testing.3–7 Specifically, patients with higher calcium scores were more likely to initiate aspirin, intensify lipid-lowering medications, and implement lifestyle modifications independent of risk factors, demographics, and baseline characteristics.8–15 The impacts of calcium scoring on downstream cardiovascular (CV) testing were less clear, with studies reporting mixed results.13,16,17
Although prior studies have shown that calcium scoring can influence patient management, many of them represent trends from over a decade ago when CAC testing was not yet endorsed by national guidelines. Moreover, intensive preventive pharmacotherapies, including newer lipid-lowering alternatives such as PCSK9 inhibitors, were less commonly used or unavailable.9–12,14,15
Given the increased use of CAC testing for CV risk stratification18,19 and the availability of newer lipid-lowering agents, we sought to examine the impact of CAC testing on subsequent preventive therapies and downstream testing in a contemporary cohort of patients from a large academic referral center.
2. Methods
2.1. Study population
This is a retrospective cohort study of 839 consecutive patients ≥18 years of age who underwent CAC scoring at Brigham and Women’s Hospital between 2015 and 2019 who had available pre-CAC and post-CAC follow-up data. Scans were acquired using a third-generation dual source CT (Siemens Force), as per standard guidelines. Patients with known coronary artery disease (CAD) were excluded. Tests performed for pre-operative testing were also excluded. This study was approved by the Mass General Brigham Institutional Review Board.
2.2. Baseline cardiovascular risk factors
Electronic medical records were reviewed to determine the presence of baseline CV risk factors. Hypertension was defined as diagnosis of hypertension or use of anti-hypertensive medication. Diabetes was defined as a hemoglobin A1C ≥ 6.5%, or diagnosis or treatment of diabetes. Family history of premature CAD was defined as fatal myocardial infarction (MI), non-fatal MI, coronary revascularization, or diagnosis of CAD occurring before 55 years of age in first-degree male family members and before 65 years of age in first-degree female family members. Current smoking was defined as using tobacco products within one year prior to CAC testing.
2.3. Laboratory values
Baseline lipids values were extracted from the Mass General Brigham electronic health record and included any values obtained prior to CAC scan. If multiple values were available, the maximum value was used. If no lipid values were available prior to CAC scan, values obtained up to 6 months post-CAC were included.
2.4. Changes in medical therapy, downstream testing, and lifestyle recommendations
Baseline prescriptions of lipid-lowering therapy, aspirin, and anti-hypertensives were ascertained for each individual through a comprehensive review of electronic medical records. Medical records were reviewed from 2 years pre-CAC to up to one-year post-CAC for changes in prescription of medical therapies or intensification of lipid-lowering therapies. Lipid-lowering therapies included statins, ezetimibe, PCSK9 inhibitors, and other lipid-lowering therapies (fibrates, niacin, prescription omega-3 fatty acids, and bile-acid-binding resins). Intensification was defined as an increase in dose of existing lipid-lowering therapy, change from less intense lipid-lowering regimen to more intense lipid-lowering regimen, or addition of adjunctive lipid-lowering therapy (such as ezetimibe, fibrates, PCSK9 inhibitors, prescription omega-3 fatty acids) to an existing lipid-lowering regimen.
Downstream testing was defined as any invasive or non-invasive cardiovascular testing within one year post-CAC including exercise stress testing, single photon emission computed tomography myocardial perfusion imaging (SPECT MPI), positron emission tomography myocardial perfusion imaging (PET MPI), stress cardiac magnetic resonance imaging, stress echocardiography, coronary computed tomography angiography, and invasive angiography.
Physician recommendation for lifestyle modification was ascertained from comprehensive chart review and defined as physician documentation of recommendations for lifestyle modifications within 6-month post-CAC or at the following visit. Lifestyle modifications ascertained included exercise, weight loss, diet, and smoking cessation.
2.5. Interpretation of CAC scores
All CAC scans were conducted in accordance with existing hospital protocol. Results of CAC scans were stratified according to Agatston score, which reflects the overall extent of coronary calcifications, as: 1) no calcifications (CAC = 0); 2) presence of calcifications (CAC>0); the latter was further divided into: mild (1–99) or at least moderate (≥100) amount of coronary calcifications.
2.6. Statistical analysis
All analyses were performed using Stata Version 15.1 (StataCorp, College Station, TX). Categorical variables are reported as frequencies and proportions and were compared with χ2 or Fisher’s exact tests, as appropriate. Continuous variables are reported as means or medians and compared with t-tests or Mann-Whitney tests, as appropriate. Differences in the proportions of patients receiving changes in medical therapies before and after undergoing CAC testing was assessed using McNemar’s test.
3. Results
3.1. Baseline characteristics
Of the 970 individuals who underwent CAC scoring, 839 (86%) had available baseline and follow-up medication data within the prespecified time period, met inclusion and exclusion criteria, and were included in the final analysis. Among this group, 376 (45%) had CAC = 0, 289 (34%) had CAC = 1–99, and 174 (21%) had CAC≥100 (Fig. 1). Baseline lipid values were not available in 311 (37%) patients. The presence and severity of calcified coronary artery plaque was associated with increasing age, male sex, diabetes, hypertension, higher low-density lipoprotein cholesterol and total cholesterol levels, and lower high-density lipoprotein cholesterol levels. A comparison of the baseline characteristics between these groups is shown in Table 1.
Fig. 1. Distribution of Coronary Artery Calcium Scores Among Study Population –
no calcification (CAC = 0) (green), mild calcifications (CAC = 1–99) (orange), and at least moderate calcifications (CAC≥100) (red).
Table 1.
Demographics and risk factors of study population stratified by coronary artery calcium severity.
| Factor | Agatston Score | |||
|---|---|---|---|---|
| 0 (n = 376, 45%) | 1–99 (n = 289, 34%) | ≥100 (n = 174, 21%) | p-value | |
| Demographics | ||||
| Age, median (IQR) | 56 (49, 62) | 59 (54, 66) | 64 (58, 70) | <0.001 |
| Female Sex | 194 (51.6%) | 109 (37.7%) | 44 (25.3%) | <0.001 |
| White | 316 (84.0%) | 249 (86.2%) | 151 (86.8%) | 0.58 |
| Risk Factors | ||||
| Diabetes | 8 (2.1%) | 19 (6.6%) | 9 (5.2%) | 0.016 |
| Hypertension | 115 (30.6%) | 112 (38.8%) | 93 (53.4%) | <0.001 |
| Current Smoking | 13 (3.5%) | 14 (4.8%) | 10 (5.7%) | 0.43 |
| Family History of any CAD in 1st degree relative | 204 (54.3%) | 160 (55.4%) | 106 (60.9%) | 0.29 |
| Lipids a | ||||
| TG, median (IQR) | 96 (69, 135) | 100 (76, 147) | 110 (75, 159) | 0.12 |
| TC, median (IQR) | 207 (181, 238) | 199 (163, 231) | 169 (145, 223) | <0.001 |
| HDL, mean (SD) | 64.9 (23.7) | 59.2 (19.0) | 54.4 (16.5) | <0.001 |
| LDL, mean (SD) | 125.2 (37.1) | 119.4 (43.9) | 103.7 (45.0) | <0.001 |
Available among 528 (63%) out of 839 patients.
3.2. Preventive lipid-lowering therapies pre- and Post-CAC
Baseline prescriptions for lipid-lowering therapy were higher among patients with evidence of coronary calcifications than those without (31.3% vs 22.3%, p = 0.005). Post-CAC, 80 (21%) patients with no calcifications were on lipid-lowering therapy (2% reduced intensity, 12% remained on the same dose, 4% initiated therapy, and 3% intensified therapy); 158 (55%) patients with CAC = 1–99 were on lipid-lowering therapy post-CAC (1% reduced intensity, 17% remained on same dose, 29% initiated therapy, and 8% intensified therapy); and 151 (87%) of patients with CAC≥100 were on lipid-lowering therapy post-CAC (11% remained on the same dose, 56% initiated therapy, and 19% intensified therapy) (Fig. 2). There were 8 (2.1%) patients with CAC=0, 27 (9.3%) patients with CAC = 1–99, and 8 (4.6%) patients with CAC≥100 who were recommended lipid-lowering therapy post-CAC but declined.
Fig. 2. Changes in lipid-lowering therapy –
initiation (blue), intensification (dark green), no change (light green), or reduction (orange) of lipid-lowering therapy post-coronary artery calcium (CAC) scoring. Patients with higher calcium scores were more likely to be prescribed lipid-lowering therapies post-CAC. (Rx = prescription).
Among patients with CAC = 0, there was no significant difference in prescriptions for any lipid-lowering therapy pre- versus post-CAC (22.3% vs 21.3%, p = 0.47). When stratified by lipid-lowering therapy subtype, there was no significant difference in prescriptions for statins, ezetimibe, and PCSK9 inhibitors pre- versus post-CAC (Table 2), but post-CAC, such individuals were less likely to be prescribed other types of lipid-lowering therapy (e.g. niacin and fibrates) (1.3% vs 2.4%, p = 0.046).
Table 2. Medical Therapy at Baseline and Post-Coronary Artery Calcium (CAC) Scan Stratified by Agatston Score –
The table compares the prevalence of medical therapy in patients pre- versus post- CAC.
| Medical Therapy | CAC = 0 (n = 376, 45%) | CAC >0 (n = 463, 55%) | ||||
|---|---|---|---|---|---|---|
| Pre-CAC | Post-CAC | p-value | Pre-CAC | Post-CAC | p-value | |
| Any Lipid-Lowering | 84 (22.3%) | 80 (21.3%) | 0.47 | 144 (31.1%) | 309 (66.7%) | <0.001 |
| Statin | 74 (19.7%) | 69 (18.4%) | 0.34 | 126 (27.2%) | 293 (63.3%) | <0.001 |
| Ezetimibe | 8 (2.1%) | 13 (3.5%) | 0.096 | 15 (3.2%) | 32 (6.9%) | <0.001 |
| PCSK9 Inhibitor | 0 (0.0%) | 0 (0.0%) | 1.00 | 3 (0.65%) | 9 (1.9%) | 0.034 |
| Other Lipid-Lowering | 9 (2.4%) | 5 (1.3%) | 0.046 | 16 (3.5%) | 21 (4.5%) | 0.17 |
| Aspirin | 84 (22.3%) | 78 (20.7%) | 0.24 | 134 (28.9%) | 189 (40.8%) | <0.001 |
| Anti-Hypertensive | 92 (24.5%) | 97 (25.8%) | 0.25 | 165 (35.6%) | 179 (38.7%) | 0.031 |
Patients with coronary calcifications (CAC>0) were more than twice as likely to be prescribed any lipid-lowering therapy post-CAC compared with pre-CAC (66.7% vs 31.1%, p < 0.001). When stratified by lipid-lowering therapy subtype, there was a significant increase in prescriptions for statins, ezetimibe, and PCSK9 inhibitors. A full comparison between pre- and post-CAC prescriptions for each subtype of lipid-lowering therapy can be found in Table 2. As expected, the vast majority of lipid-lowering therapy prescriptions post-CAC were for statins.
3.3. Preventive aspirin therapy pre- and Post-CAC
Among the 463 patients with calcifications on CAC, 134 (28.9%) were on aspirin therapy pre-CAC, compared with 189 (40.8%) post-CAC (p < 0.001), representing a 41% increase from baseline. However, among patients with no calcifications, there was no difference in aspirin prescription pre-versus post-CAC (22.3% vs. 20.7%, p = 0.24). Among patients with at least moderate calcifications (CAC≥100), 63 (36.2%) were on aspirin therapy pre-CAC versus 108 (62.1%) post-CAC (p < 0.001), representing a 71% increase.
3.4. Anti-hypertensive therapy pre- and Post-CAC
Similar to aspirin therapy, patients found to have CAC>0 were more likely to be on anti-hypertensive medication post-CAC than pre-CAC (38.7% vs. 35.6%, p = 0.031). There was no significant difference in anti-hypertensive prescription pre- versus post-CAC in patients without calcifications.
3.5. Downstream testing
The rate of any downstream cardiovascular testing within one year post-CAC was 9.1%, and differed based on CAC score: 13 (3.5%), 16 (5.5%), 47 (27%) for CAC = 0, CAC = 1–99, and CAC≥100, respectively. Specifically, the rate of exercise stress testing, SPECT MPI, PET MPI, and stress echocardiography were higher in patients with CAC≥100 compared with those who had CAC<100 (p = 0.021 for PET MPI, p < 0.001 for all others) (Table 3a).
Table 3a. Downstream Invasive and Non-invasive Testing Within 12 months Post-Coronary Artery Calcium Scan Stratified by Agatston Score.
(MPI SPECT = single photon emission computed tomography myocardial perfusion imaging; MPI PET = positron emission tomography myocardial perfusion imaging; MRI = magnetic resonance imaging; CTA = computed tomography angiography).
| Downstream Testing | Agatston Score | |||
|---|---|---|---|---|
| 0 (n = 376, 45%) | 1–99 (n = 289, 34%) | ≥100 (n = 174, 21%) | p-value | |
| Any Testing | 13 (3.5%) | 16 (5.5%) | 47 (27.0%) | <0.001 |
| Exercise Stress Test | 4 (1.1%) | 6 (2.1%) | 14 (8.0%) | <0.001 |
| MPI SPECT | 0 (0.0%) | 4 (1.4%) | 18 (10.3%) | <0.001 |
| MPI PET | 0 (0.0%) | 0 (0.0%) | 2 (1.1%) | 0.021 |
| Cardiac MRI Stress | 0 (0.0%) | 0 (0.0%) | 1 (0.6%) | 0.15 |
| Coronary CTA | 1 (0.3%) | 3 (1.0%) | 2 (1.1%) | 0.38 |
| Invasive Angiography | 0 (0.0%) | 2 (0.7%) | 2 (1.1%) | 0.15 |
| Stress Echo | 9 (2.4%) | 3 (1.0%) | 12 (6.9%) | <0.001 |
When patients with CAC≥100 were further categorized into 3 groups (CAC = 100–299; CAC = 300–999; CAC≥1000), the distribution shows that the majority of downstream testing were performed in patients with CAC≥300 (Table 3b).
Table 3b.
Any downstream testing within 12 months post-coronary artery calcium scan stratified by agatston score.
| Agatston Score | ||||||
|---|---|---|---|---|---|---|
| 0 (n = 376, 45%) | 1–99 (n = 289, 35%) | 100–299 (n = 99, 12%) | 300–999 (n = 58, 7%) | ≥1000 (n = 17, 2%) | p-value | |
| Downstream Testing (Any) | 13 (3.5%) | 16 (5.5%) | 12 (12.1%) | 23 (39.7%) | 12 (70.6%) | <0.001 |
Among the 839 individuals evaluated in our cohort, 4 (0.5%) underwent invasive angiography within the subsequent year. One case was a patient who had a CAC score of 3583 who was evaluated in another institution and subsequently underwent coronary artery bypass grafting surgery. Three patients were evaluated by invasive angiography following abnormal stress echocardiograms that were ordered for symptoms of dyspnea; in two such cases, coronary revascularization was subsequently performed and in a third case (where CAC score was 11), no significant epicardial CAD was identified.
3.6. Lifestyle recommendations
Among 376 patients with no calcifications on CAC, 119 (31.6%) had physician-documented recommendations to exercise, 41 (10.9%) to lose weight, and 124 (33.0%) to change diet. Of the 174 patients with CAC≥100, the recommendation rates were higher: 46%, 17.2%, and 46.6% respectively. Exercise and diet were more likely to be recommended to patients with higher CAC scores (p = 0.004 and p = 0.008, respectively), but weight loss and smoking cessation were not (p = 0.12 and p = 0.31, respectively) (Table 4).
Table 4.
Physician-recommended lifestyle modifications post-coronary artery calcium scan stratified by Agatston score.
| Lifestyle Recommendations | Agatston Score | |||
|---|---|---|---|---|
| 0 (n = 376, 45%) | 1–99 (n = 289, 34%) | ≥100 (n = 174, 21%) | p-value | |
| Exercise | 119 (31.6%) | 99 (34.3%) | 80 (46.0%) | 0.004 |
| Weight Loss | 41 (10.9%) | 40 (13.8%) | 30 (17.2%) | 0.12 |
| Diet | 124 (33.0%) | 103 (35.6%) | 81 (46.6%) | 0.008 |
| Smoking Cessation | 12 (3.2%) | 5 (1.7%) | 7 (4.0%) | 0.31 |
| Other | 29 (7.7%) | 12 (4.2%) | 16 (9.2%) | 0.072 |
3.7. Ordering physicians
Of the 839 CAC scans reviewed in the study, 487 (58%) were ordered by primary care physicians, 349 (42%) by cardiologists, and 3 (0.36%) by other specialty physicians (Fig. 3). When specifically examining the 349 scans ordered by cardiologists, 181 (52%) were ordered by general cardiologists and 168 (48%) by preventive cardiologists. Compared with non-cardiologists, cardiologists were more likely to either reduce or intensify lipid-lowering therapy in response to results of calcium scoring (p = 0.021). Furthermore, preventive cardiologists were more likely to intensify lipid-lowering medications post-CAC than general cardiologists (p = 0.033).
Fig. 3. Ordering Provider –
Ordering providers of coronary artery calcium scans stratified by specialty. PCPs (primary care providers) were the top ordering provider, followed by general cardiologists and preventive cardiologists.
4. Discussion
In this contemporary study examining the impact of CAC testing on downstream patient management, we found that almost half of individuals referred for testing did not have any calcified plaque (CAC = 0); however, the presence of any calcifications was associated with increased use of preventive therapies, both pharmacotherapies (lipid-lowering therapy, aspirin, and anti-hypertensives) and lifestyle modifications. Compared with older studies, our study shows a more robust intensification of lipid-lowering medications in patients with an elevated calcium score,10,12,15 with almost 90% of patients who have CAC≥100 being prescribed lipid-lowering therapy post-CAC, representing an absolute increase of 56% when compared with pre-CAC therapy. Additionally, these patients were more likely to be prescribed higher intensity statins or add-on non-statin agents,9–12,15 including PCSK9 inhibitors and prescription omega-3 fatty acids, and thus collectively, 75% of patients with CAC≥100 were started on new or more intense lipid-lowering therapy.
Our study shows that in some cases, CAC testing was performed in patients who were already on lipid-lowering therapies at baseline. While in the past CAC testing was mostly performed to decide on the role of starting statin therapy, in the current era, CAC testing can also be used to decide on the intensity of lipid lowering therapy,20 as well as the role of other agents such as aspirin.21,22 It is likely that in the future, CAC testing may provide an even greater role for selecting patients who may benefit from more aggressive therapies as there are several completed23 or ongoing24 cardiovascular prevention outcomes trials that have included patients with elevated CAC as part of the inclusion criteria.25
Prior studies have demonstrated mixed evidence regarding use of downstream testing, with some studies concluding that CAC testing was not associated with additional downstream testing and medical costs,13,17 while others found that CAC testing increased rates of invasive angiography in certain populations.16 Although our study found that 9.1% of patients underwent downstream testing following CAC, the tests that were performed were mostly among individuals with moderate or severe coronary calcifications – those who are the most likely to have future CV events.26 Notably, the rate of downstream invasive testing within one year following CAC testing was very low (0.5%), and mostly occurred in patients with abnormal non-invasive testing.
4.1. Limitations
Our study was limited by its retrospective design. We did not have consistent data on risk factors such as C-Reactive Protein and we were not able to calculate 10-year ASCVD scores for all our patients. In addition, data regarding physician-recommended lifestyle modifications were obtained through review of physician documentation. Since lifestyle recommendations are sometimes provided but not documented in the chart, it is likely that our rates represent an underestimation. Similarly, it is possible that downstream preventive therapies were performed in other institutions and thus our reported rates of initiation or intensification of preventive therapies may also be underestimated. Nevertheless, the rates we reported are higher than observed in prior studies. We did not have any outcomes data in our study, although the association of CAC with downstream cardiovascular events has been extensively documented in the past.26 Also, our results represent the experience of a single institution and may not be generalizable to other settings. For instance, the low rate of invasive angiography may be due to the fact that physicians in our hospital, relative to others, may be more likely to manage patients non-invasively. However, medical management of patients with stable CAD (while avoiding unnecessary invasive testing) is now well-advocated by guidelines and supported by recent clinical trials.27
Despite the aforementioned limitations, this is one of the few studies that investigated the impact of CAC scoring on downstream preventive therapies and testing in the contemporary era. We also explored changes in advanced therapies, such as PCSK9 inhibitors, and recommendations for lifestyle modification. In our study, risk factors and procedures were adjudicated by study investigators which is a more accurate method of adjudication than reliance on billing codes.
5. Conclusion
In summary, patients without known CAD who were referred for CAC testing and found to have coronary calcifications were more likely to have intensification of preventive pharmacologic therapy and receive recommendations for healthy lifestyle modification. Our findings suggest that CAC scoring is an effective tool to identify higher risk patients who would benefit from intensified preventive therapy in the contemporary era, without excessive use of downstream testing.
Sources of funding
Drs. Berman and Hsieh are supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32HL094301). Dr. Divakaran is supported by a joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679-10).
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Berman and Hsieh are supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32HL094301). Dr. Divakaran is supported by a joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679-10). Dr. Blankstein receives research support from Astellas Inc and Amgen Inc. The remaining authors have nothing to disclose.
Abbreviations
- ASCVD
Atherosclerotic Cardiovascular Disease
- CAC
Coronary Artery Calcium
- CAD
Coronary Artery Disease
- CV
Cardiovascular
- MI
Myocardial Infarction
- PET MPI
Positron Emission Tomography Myocardial Perfusion Imaging
- SPECT MPI
Single Photon Emission Computed Tomography Myocardial Perfusion Imaging
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