Abstract
Background
Whether measuring and reporting of coronary artery calcium scores (CACS) might lead to changes in cardiovascular risk management is not established. In this observational study we examined whether high baseline CACS were associated with the initiation as well continuation of new lipid lowering medication (LLM), blood pressure lowering medication (BPLM) and regular aspirin (ASA) use in a multi-ethnic population-based cohort.
Methods and Results
MESA is a prospective cohort study of 6814 participants free of clinical cardiovascular disease at entry who underwent CAC testing at baseline examination (exam 1). Information on LLM, BPLM and regular ASA usage was also obtained at baseline, and at exams 2 and 3 (average of 1.6 and 3.2 years after baseline respectively). In this study we examined: 1) initiation of these medications at exam 2 among participants not taking these medications at baseline; and 2) continuation of medication use to exam 3 among participants already on medication at baseline. Among MESA participants, initiation of LLM, BPLM and ASA was greater in those with higher CACS After taking into account age, gender, race, MESA site, LDL cholesterol, diabetes mellitus, BMI, smoking status, hypertension, systolic blood pressure, and SES (income, education and health insurance), the risk ratios for medication initiation comparing those with CACS>400 vs. CACS=0 were 1.53 (95% CI: 1.08, 2.15) for LLM, 1.55 (1.10-- 2.17) for BPLM, and 1.32 (1.03–1.69) for ASA initiation, respectively. The risk ratios for medication continuation among those with CAC>400 vs. CACS=0 were 1.10 (95% CI: 1.01–1.20) for LLM, 1.05 (1.02–1.08) for BPLM, and 1.14 (1.04- 1.25) for ASA initiation, respectively.
Conclusion
CACS>400 was associated with a higher likelihood of initiation and continuation of LLM, BPLM and ASA. The association was weaker for continuation than for initiation of these preventive therapies.
Keywords: Coronary artery calcification, Computed tomography, Medications, Adherence, Prevention
INTRODUCTION
Extensive data exists demonstrating the benefits of lipid lowering medications (LLM), blood pressure lowering medications (BPLM), and aspirin (ASA) for primary prevention of coronary events1–3.However only 50–57% of those at increased cardiovascular risk appear to be on statins and aspirin indicating that these agents remain underused by high-risk patients and health-care providers 4–7. Thus, effective interventions that improve their utilization are needed to reduce the burden of cardiovascular diseases (CVD) in high risk asymptomatic individuals.
Large prospective studies have consistently demonstrated that assessment of coronary artery calcium scores (CACS) adds incremental cardiovascular risk predictive information8,9. However to date there are conflicting data whether a higher baseline CACS is associated with increased subsequent utilization of cardiovascular preventive medications10–15. In this study we evaluated the relationship between baseline CACS and rate of initiation and adherence to preventive therapies, specifically, LLM, BPLM and regular ASA, in men and women aged 45–84, from four racial/ethnic groups, (White, African-American, Hispanic, and Chinese) in the prospective Multi-Ethnic Study of Atherosclerosis (MESA)16.
METHODS
The Multi-Ethnic Study of Atherosclerosis (MESA) was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease in individuals without known cardiovascular disease16. This prospective cohort study included 6,814 women and men ages 45–84 years old recruited from 6 U.S. communities (Baltimore, MD; Chicago, IL; Forsyth County, NC; Los Angeles County, CA; northern Manhattan, NY; and St. Paul, MN). The cohort includes 38% White (N=2,624), 28% African-American (N=1,895), 22% Hispanic (N=1492), and 12% Chinese (N=803) participants. The institutional review boards at participating institutions approved the study and that all participants gave written informed consent at each exam.
Baseline medical history, anthropometric measurements, and laboratory data for the present study were taken from the first examination of the MESA cohort (July 2000 to August 2002). These self-administered questionnaires were available in English, Spanish, and Chinese. Information about age; gender, ethnicity, and medical history were obtained by questionnaires. Resting blood pressure was measured three times in the seated position, and the average of the 2nd and 3rd readings was recorded. Hypertension was defined as a systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or use of baseline BPLM. Body mass index was calculated from the equation weight (kg)/ height (m2). Total and HDL-C were measured from blood samples obtained after a 12-hour fast. LDL-C was estimated by the Friedewald equation17. Current smoking was defined as having smoked a cigarette in the last 30 days. Diabetes mellitus was defined as a fasting glucose ≥126 mg/dL or use of hypoglycemic medications.
Information on socioeconomic factors including highest degree or level of school completed, employment status, total household income, residential status, health insurance coverage, and source of usual medical care was collected from the MESA participants by questionnaires. Education was classified as less than high school, completed high school, bachelor’s degree, and graduate or professional school. The total household income was classified as <$25,000; $25,000 to $49,999; $50,000 to $94,999; and ≥$100 000. Health insurance status was considered as yes (HMO, Medicaid, Medicare, veteran’s healthcare) or none.
For medication use, the participant was asked to bring to the clinic containers for all medications used during the two weeks prior to the visit. The interviewer then recorded the name of each medication, the prescribed dose, and frequency of administration from the containers. Regular ASA use was defined as self-reported use more than 3 times a week. At baseline (n= 6,814) information of LLM and BPLM was noted in almost all (n=6,811, 99.9%) individuals, whereas that of regular ASA use was recorded in 6,528 (96%) participants.
National Cholesterol Education Program (NCEP) ATP III guidelines were used to assess appropriateness for LLM utilization18. The LDL cholesterol cutoffs recommended by the NCEP III guidelines for initiation of LLM are as follows: 0–1 risk factors (≥190 mg/dl), ≥2 risk factors and 10 year CHD risk ≤20% (≥160 mg/dl), CHD or CHD equivalents with 10 year CHD risk ≥20% (≥130 mg/dl)18. JNC VII was used to assess eligibility for BPLM (≥140/90 mm of Hg and ≥130/80 mm of Hg for those with diabetes or chronic kidney disease)19. Individuals with 10-year CHD risk ≥10% were considered eligible for regular ASA use as per American Heart Association guidelines for primary prevention of cardiovascular disease and stroke20.
Computed tomography scanning of the chest was performed either with an ECG-triggered (at 80% of the RR interval) electron-beam computed tomography scanner (Chicago, Los Angeles, and New York field centers; Imatron C-150, Imatron) or with prospectively ECG-triggered scan acquisition at 50% of the RR interval with a multidetector computed tomography system at acquired 4 simultaneous 2.5-mm slices for each cardiac cycle in a sequential or axial scan mode (Baltimore, Forsyth County, and St. Paul field centers; Lightspeed, General Electric or Siemens, Volume Zoom). Each participant was scanned twice. Scans were read centrally at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center to identify and quantify coronary calcification. The CAC measurements among scanning centers and between participants were adjusted with a standard calcium phantom scanned simultaneously with each participant. The mean Agatston score was used in all analyses. Agreement with regard to presence of CAC was high (κ-statistic 0.90 to 0.93 between and within readers), and the intraclass correlation coefficient for the Agatston score between readers was 0.99. We standardized results into 4 CAC score categories (0, 1–100, 101–400, and >400). These categories have been provided in recent guidelines and represent a simple categorization of the range of CAC scores encountered in clinical practice8,9. Coronary artery calcium scores results were reported back to the participant, and if they consented, to their physician also. In our study, 76% of participants authorized release of the results to their physicians. The letter included a statement that the score was average, below average, or above average for participants of the same age and sex; and that the letters did not make specific recommendations regarding medication use or clinical management.
Information on LLM, BPLM and ASA usage were also assessed at exams 2 and 3 (average of 1.6 and 3.2 years after baseline respectively). Of the 6814 individuals in the original cohort at baseline, 6,233 (91%) and 5,947 (87%) participated in exam 2 and 3. In exam 2 (n= 6,233) information of both lipid lowering and blood pressure lowering medication was present in 5,972 (96%) individuals, whereas that of regular ASA use was recorded in 6,231 (99.9%) participants. Finally, in exam 3 (n= 5,947) information of both lipid lowering and blood pressure lowering medication was present in 5,845 (98%) individuals, whereas that of regular ASA use was recorded in all (100%) participants, respectively.
Overall 5,492/6814 (81%) participants had complete information for LLM as well BPLM in all exams (baseline, exam 2 and exam 3). The respective proportion was 82% (n=5566/6814) for regular ASA use. The proportions of complete medication assessment from exam 1 through exam 3 were similar according to lipid levels, hypertension status and/or CHD risk level.
In this study we examined initiation of LLM/BPLM/ASA at exam 2 among participants not taking these medications at baseline, and continuation of medication use to exam 3 among participants already on medication at baseline.
Statistical Analysis
In our study mean ±SD and proportions were used to summarize the characteristics of the study sample. Continuous variables were compared by ANOVA, and categorical variables were compared by the Chi square statistics. The initiation and continuation of medications were fairly common (greater than 10%) in our cohort, hence odds ratios (ORs) would overestimate the relative risk (RR)21. Relative risk regression was used to model the probability of medication initiation (or continuation) as a function of CACS. The exponentiated parameters β are interpreted as relative risks. Relative risk estimates are presented from the regression model y=exp(XTβ). We assumed Gaussian error and used robust standard error estimates. Four sets of models were examined in a hierarchical fashion: Model 1 (unadjusted); Model 2 (adjusted for age, gender, race/ethnicity and MESA site) and Model 3 (adjusted for age, gender, race/ethnicity, MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, and smoking status) & Model 4 (adjusted for age, gender, race/ethnicity, MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status, income, education, and health insurance). All statistical analyses were performed with STATA version 10.0 (Stata Corp., Austin, Texas, http://www.stata.com). The level of significance was set at p < 0.05 (two-tailed).
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
RESULTS
A total of 6,814 men and women (47% male, mean age 62±10 years) completed the first MESA examination. Half of the study population had no detectable CAC (50%), whereas CACS of 1–100, 101–400 and >400 was seen in 26%, 14% and 10% individuals respectively. Table 1 demonstrates the baseline characteristics of study participants according to baseline CACS. Study participants with high CACS were more likely to be men, older, diabetic and hypertensive. In addition, a high CACS was also associated with low income and high likelihood of presence of health insurance. The prevalence at baseline of reported LLM, BPLM as well ASA increased linearly according to CACS (p<0.0001).
Table 1.
Baseline Characteristics According to Coronary Artery Calcium Score at MESA Exam 1
| CACS=0 | CACS 1–100 | CACS 101–400 | CACS>400 | P value | |
|---|---|---|---|---|---|
| Age (years) | 58±9 | 64±10 | 68±9 | 70±8 | <0.0001 |
| Male Gender (%) | 37% | 52% | 60% | 70% | <0.0001 |
| Race (%) | |||||
| Caucasians | 33% | 39% | 48% | 52% | |
| Chinese American | 12% | 13% | 12% | 8% | <0.0001 |
| African American | 31% | 26% | 22% | 22% | |
| Hispanic | 24% | 22% | 18% | 18% | |
| LDL-C (mg/dl) | 116±31 | 119±32 | 119±31 | 115±32 | 0.17 |
| Diabetes Mellitus (%) | 11% | 15% | 18% | 25% | <0.0001 |
| Hypertension (%) | 35% | 49% | 57% | 66% | <0.0001 |
| Education (< high school) | 17% | 20% | 17% | 18% | 0.53 |
| Income (<$ 50,000) | 57% | 63% | 63% | 65% | <0.0001 |
| Health Insurance (No) | 11% | 9% | 5% | 4% | <0.0001 |
| Lipid Lowering Medication | 11% | 19% | 21% | 29% | <0.0001 |
| Blood Pressure Lowering Medication | 29% | 40% | 47% | 58% | <0.0001 |
| Regular Aspirin Use | 20% | 25% | 34% | 40% | <0.0001 |
Initiation of Cardiovascular Preventive Medications
Lipid Lowering Medications
There were 5,969 participants with information on LLM at both exams 1 and 2. Of these, 4,994 (84%) did not report use of LLM at baseline, of whom 15% were appropriate candidates for LLM according NCEP guidelines Overall, 517 (10%) of these individuals reported initiation of LLM between exam 1 and exam 2. Almost all of this new use was due to statin initiation (89%). We observed a significantly higher initiation of LLM among individuals who qualified for treatment according to NCEP guidelines versus those not considered appropriate for LLM treatment by NCEP guidelines (24% vs. 8%, p<0.0001).
The incidence of new LLM initiation was lowest among those with no CAC (7%), with increasing rates across higher CACS (table 2). A higher incidence of LLM initiation across CAC scores was observed whether appropriate (p=0.01) or not (p<0.001) according to NCEP ATP III guidelines, respectively.
Table 2.
Initiation (%) of Lipid Lowering Medication, Blood pressure Lowering Medication & Regular Aspirin in Exam 2 According to Exam 1 CAC Scores
| CAC=0 | CAC 1–100 | CAC 101–400 | CAC>400 | P Value | |
|---|---|---|---|---|---|
| Lipid Lowering Medication Initiation | |||||
| Total population | 7% | 11% | 15% | 21% | <0.001 |
| Appropriate Candidate According to NCEP guidelines: Yes | 21% | 22% | 25% | 36% | 0.01 |
| No | 6% | 8% | 13% | 16% | <0.001 |
| Blood Pressure Lowering Medication Initiation | |||||
| Total population | 9% | 14% | 17% | 24% | <0.001 |
| Appropriate Candidate According to JNC VII Criteria : Yes | 19% | 24% | 27% | 34% | 0.001 |
| No | 5% | 7% | 9% | 12% | 0.001 |
| Regular Aspirin Initiation | |||||
| Total population | 14% | 19% | 26% | 32% | <0.001 |
| Appropriate Candidate According to AHA guidelines : Yes | 20% | 22% | 29% | 33% | <0.001 |
| No | 12% | 16% | 21% | 29% | <0.001 |
Table 3 demonstrates the unadjusted and adjusted relative risk of LLM initiation according to baseline CACS. In the unadjusted model (model 1), as compared with those with absent CAC, the likelihood of LLM initiation was 2.86 fold higher with CACS>400. However, the relative risk for LLM initiation was reduced to 1.53 (95% CI: 1.08, 2.15) among those with CACS>400 compared to those with no detectable CAC in model 4. The interaction between LLM indicated per NCEP and CACS was not statistically significant (p=0.19).
Table 3.
Unadjusted and Adjusted Relative Risks for Initiation of Lipid-Lowering Medications between MESA Exam 1 and Exam 2, According to NCEP Appropriateness Criteria
| Overall | NCEP Recommends LLM | ||||
|---|---|---|---|---|---|
| RR (95% CI) | No RR (95% CI) |
Yes RR (95% CI) |
|||
| Model 1: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.43 (1.16, 1.76) | 1.31 (1.00, 1.71) | 1.04 (0.75, 1.44) | ||
| 101–400 | 2.05 (1.64, 2.58) | 2.20 (1.67, 2.91) | 1.18 (0.81, 1.72) | ||
| >400 | 2.86 (2.27, 3.59) | 2.78 (2.06, 3.75) | 1.70 (1.21, 2.39) | ||
| Model 2: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.29 (1.01, 1.64) | 1.12 (0.84, 1.50) | 1.26 (0.83, 1.90) | ||
| 101–400 | 1.77 (1.30, 2.41) | 1.76 (1.23, 2.53) | 1.58 (0.90, 2.77) | ||
| >400 | 2.40 (1.78, 3.22) | 2.15 (1.52, 3.05) | 2.32 (1.41, 3.83) | ||
| Model 3: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.07 (0.83, 1.38) | 1.04 (0.74, 1.46) | 1.32 (0.87, 1.99) | ||
| 101–400 | 1.24 (0.87, 1.76) | 1.36 (0.79, 2.32) | 1.51 (0.84, 2.71) | ||
| >400 | 1.49 (1.07, 2.08) | 1.57 (1.00, 2.48) | 2.01 (1.12, 3.62) | ||
| Model 4: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.06 (0.81, 1.38) | 0.80 (0.53, 1.20) | 1.30 (0.85, 1.98) | ||
| 101–400 | 1.26 (0.86, 1.84) | 1.40 (0.91, 2.13) | 1.48 (0.81, 2.71) | ||
| >400 | 1.53 (1.08, 2.15) | 1.59 (1.06, 2.39) | 2.18 (1.25, 3.79) | ||
Model 1: unadjusted
Model 2: adjusted for age, gender, race and MESA site
Model 3: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status
Model 4: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status, income, education, and health insurance.
Blood Pressure Lowering Medications
There were 5,969 participants with information on BPLM at both exams 1 and 2. At exam 1, 3766 (63%) individuals were not on any BPLM at exam 1 ; 87% (n=3311) of these were not on any BPLM at exam 2. Overall 31% of those with no BPLM at exam 1 were considered candidates for drug therapy according to JNC criteria. The use of new BPLM in exam 2 was nearly three fold higher among those with CAC>400 (24%) compared to those without any detectable CAC (9%) (table2). The rate of BPLM initiation increased linearly with CAC scores, whether considered hypertensive (p=0.001) or not (p=0.001) according to JNC VII criteria, respectively.
The relationship of BPLM initiation based on CAC scores in multivariate analyses is shown in table 4. Compared with those with any CAC, the initiation of BPLM was 2.75 (95% CI: 2.1–3.6) fold higher among MESA participants with CAC>400; the relative risk attenuated to 1.55 (95% CI: 1.10–2.17) in adjusted model 4. No significant interaction between BPLM indicated per JNC VII and high CACS was observed (p=0.22)
Table 4.
Unadjusted and Adjusted Relative Risks for Initiation of Blood Pressure-Lowering Medications between MESA Exam 1 and Exam 2, According to JNC VII Criteria
| Overall | JNC VII Criteria Recommends BPLM | ||||
|---|---|---|---|---|---|
| RR (95% CI) | No RR (95% CI) |
Yes RR (95% CI) |
|||
| Model 1: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.63 (1.32, 2.01) | 1.62 (1.11, 2.34) | 1.28 (1.01, 1.63) | ||
| 101–400 | 1.95 (1.52, 2.50) | 1.86 (1.15, 2.99) | 1.41 (1.07, 1.86) | ||
| >400 | 2.75 (2.12, 3.57) | 2.53 (1.44, 4.43) | 1.81 (1.36, 2.41) | ||
| Model 2: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.34 (1.04, 1.72) | 1.07 (0.54, 2.10) | 1.32 (0.78, 1.37) | ||
| 101–400 | 1.60 (1.18, 2.16) | 1.29(0.69, 2.43) | 1.05 (0.88, 2.07) | ||
| >400 | 2.02 (1.44, 2.82) | 1.48 (0.63, 3.48) | 1.88 (1.35, 2.61) | ||
| Model 3: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.23 (0.99, 1.45) | 1.21 (0.51, 2.87) | 1.23 (0.96, 1.57) | ||
| 101–400 | 1.26 (0.94, 1.68) | 0.92 (0.32, 2.61) | 1.27 (0.92, 1.74) | ||
| >400 | 1.52 (1.10, 2.10) | 1.58 (0.56, 4.47) | 1.57 (1.14, 2.17) | ||
| Model 4: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.26 (1.00, 1.59) | 1.45 (0.41, 5.45) | 1.30 (0.99, 1.52) | ||
| 101–400 | 1.27 (0.95, 1.70) | 0.79 (0.12, 2.91) | 1.33 (0.97, 1.81) | ||
| >400 | 1.55 (1.10, 2.17) | 2.00 (0.41, 9.84) | 1.61 (1.14, 2.26) | ||
Model 1: unadjusted
Model 2: adjusted for age, gender, race and MESA site
Model 3: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status
Model 4: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status, income, education, and health insurance.
Regular Aspirin Use
There were 5,957 participants with information on ASA use at both exams 1 and 2. Of these, 4,759 (84%) did not report use of ASA at baseline, with 31% of these meeting eligbility criteria for ASA use. New regular ASA use was reported in 862/4759 (18%) of these individuals at the follow-up exam 2. In a similar fashion to LLM and BPLM initiation rates, ASA initiation was lowest among those with no detectable CACS (14%), with increasing rates across higher CACS categories (table 2). The rate of ASA initiation at MESA exam 2 was higher across with higher CAC scores, whether considered appropriate (p<0.001) or not (p<0.001) according to AHA recommendations, respectively.
As shown in table 5, the relative risks for initiation in unadjusted model with CAC>400 vs. CAC=0 was 2.24 (95% CI: 1.88–2.68); this relationship was attenuated to 1.32 (1.03–1.69) after taking into account, demographics, MESA site, traditional risk factors and SES (model 4). The interaction term for regular ASA indicated per AHA guidelines and CACS did not achieve statistical significance (p=0.14).Overall there was no interaction between CACS and gender as well as race/ethnicity in initiation of LLM, BPLM as well regular ASA use.
Table 5.
Unadjusted and Adjusted Relative Risks for Initiation of Regular Aspirin between MESA Exam 1 and Exam 2, According to AHA Prevention Guidelines Criteria
| Overall | AHA Prevention Guidelines R ecommend Regular ASA Use | ||||
|---|---|---|---|---|---|
| RR (95% CI) | No RR (95% CI) |
Yes RR (95% CI) |
|||
| Model 1: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.22 (1.15, 1.55) | 1.31 (1.05, 1.63) | 1.10 (0.90, 1.36) | ||
| 101–400 | 1.87 (1.59, 2.21) | 1.76 (1.31, 2.37) | 1.48 (1.19, 1.84) | ||
| >400 | 2.24 (1.88, 2.68) | 2.45 (1.69, 3.56) | 1.64 (1.31, 2.05) | ||
| Model 2: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.12 (0.94, 1.32) | 1.01 (0.77, 1.32) | 1.10 (0.88, 1.36) | ||
| 101–400 | 1.42 (1.16, 1.74) | 1.10 (0.76, 1.61) | 1.43 (1.13, 1.82) | ||
| >400 | 1.56 (1.24, 1.96) | 1.45 (0.92, 2.29) | 1.57 (1.22, 2.02) | ||
| Model 3: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.07 (0.90, 1.26) | 0.91 (0.68, 1.24) | 1.08 (0.86, 1.34) | ||
| 101–400 | 1.31 (1.06, 1.61) | 0.93 (0.58, 1.49) | 1.37 (1.07, 1.75) | ||
| >400 | 1.34 (1.07, 1.68) | 1.19 (0.72, 1.96) | 1.39 (1.07, 1.81) | ||
| Model 4: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.10 (0.92, 1.32) | 0.92 (0.67, 1.26) | 1.09 (0.86, 1.38) | ||
| 101–400 | 1.30 (1.04, 1.63) | 0.94 (0.56, 1.55) | 1.34 (1.05, 1.74) | ||
| >400 | 1.32 (1.03, 1.69) | 1.21 (0.70, 2.09) | 1.34 (1.01, 1.78) | ||
Model 1: unadjusted
Model 2: adjusted for age, gender, race and MESA site
Model 3: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status
Model 4: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status, income, education, and health insurance.
Continuation of Lipid Lowering, Blood Pressure Lowering & Aspirin
In this observational prospective study, 85%, 93% and 79% of individuals on LLM , BPLM and ASA at baseline reported that they continued these respective therapies at exam 3. The overall continued used of LLM was observed in 80% with CACS=0, compared to 86%, 88%, 91% with CACS 1–100, 101–400 and >400 (p=0.005). In a similar fashion continued use of BPLM (CACS 0: 91%, CACS 1–100: 93%, CACS 101–400: 94% and CAC>400: 96%, p=0.002) and regular ASA (CACS 0: 72%, CACS 1–100: 81%, CACS 101–400: 80% and CAC>400: 86%, p=0.001) was statistically significant with higher CAC scores.
The unadjusted and adjusted relative risk ratios of LLM, BPLM and ASA continuation according to baseline CACS are detailed in table 6. Among the MESA participants the likelihood of continuing these medications with higher CACS was marginally significant in all models. Study participants with CAC>400 compared to those with no detectable CAC were only 10% (p=0.023), 5% (p=0.002) and 14% (p=0.005) more likely to continue LLM, BPLM and ASA therapy respectively in the adjusted multivariable model 4. No interaction between CACS and gender as well as race/ethnicity in continuation of LLM, BPLM as well regular ASA use was observed.
Table 6.
Relative Risk Regression for Continuation of Lipid-Lowering Medications, Blood Pressure Lowering and Regular Aspirin between MESA Exam 1 and Exam 3
| Continuation of LLM | Continuation of BPLM | Continuation of ASA | |||
|---|---|---|---|---|---|
| RR (95% CI) | RR (95% CI) | RR (95% CI) | |||
| Model 1: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.07 (0.99, 1.15) | 1.03 (1.00, 1.06) | 1.12 (1.03, 1.21) | ||
| 101–400 | 1.11 (1.02, 1.20) | 1.03 (1.00, 1.07) | 1.11 (1.02, 1.22) | ||
| >400 | 1.14 (1.06, 1.23) | 1.05 (1.02, 1.09) | 1.19 (1.09, 1.29) | ||
| Model 2: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.06 (0.98, 1.14) | 1.04 (1.01, 1.07) | 1.10 (1.02, 1.19) | ||
| 101–400 | 1.08 (1.00, 1.17) | 1.05 (1.01, 1.08) | 1.07 (0.98, 1.17) | ||
| >400 | 1.11 (1.03, 1.21) | 1.07 (1.03, 1.10) | 1.14 (1.04, 1.24) | ||
| Model 3: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.05 (0.97, 1.13) | 1.03 (1.00, 1.06) | 1.09 (1.00, 1.17) | ||
| 101–400 | 1.08 (0.99, 1.17) | 1.03 (1.00, 1.07) | 1.06 (0.97, 1.16) | ||
| >400 | 1.10 (1.01, 1.20) | 1.05 (1.02, 1.09) | 1.13 (1.03, 1.23) | ||
| Model 4: | CACS Group: | 0 | Reference Group | Reference Group | Reference Group |
| 1–100 | 1.07 (1.00, 1.15) | 1.03 (1.00, 1.06) | 1.09 (1.01, 1.18) | ||
| 101–400 | 1.08 (1.00, 1.17) | 1.03 (1.00, 1.06) | 1.07 (0.97, 1.17) | ||
| >400 | 1.10 (1.01, 1.20) | 1.05 (1.02, 1.08) | 1.14 (1.04, 1.25) | ||
Model 1: unadjusted
Model 2: adjusted for age, gender, race and MESA site
Model 3: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status
Model 4: adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status, income, education, and health insurance.
Initiation/Continuation of Cardiovascular Preventive Medications Stratified by Race, Gender and Education
In a sub-analysis, we assessed the effect of high vs. low CAC scores (>100 vs. ≤100) on initiation and continuation of LLM, BPLM and ASA stratified by ethnicity, gender and educational status (≥ college vs. < college). As shown in table 7, in multivariable adjusted analyses, the relative risk ratios for initiation of these medications were similar across all ethnic groups, men and women, and according to educational attainment. No significant interactions with high vs. low CAC scores for initiation of these medication was noted across these stratifications (all p values>0.1). As far as continuation of LLM is concerned (table 8), African Americans with high CAC scores (>100) were more likely to continue LLM as compared to Caucasians and the interaction was statistically significant (p<0.0001). No such ethnic differences were noted for continuation of either BPLM or ASA. In addition, the relative risk ratio for continuation of LLM, BPLM as well as ASA were similar according to ethnicity, gender and education status (all p values>0.1).
Table 7.
Relative Risk Regression for initiation of Lipid-Lowering Medications, Blood Pressure Lowering and Regular Aspirin between MESA Exam 1 and Exam 2 According to Race, Gender and Education Status
| LLM | BPLM | ASA | |
|---|---|---|---|
| Race | (CAC >100 vs. ≤100) | (CAC >100 vs. ≤100) | (CAC >100 vs. ≤100) |
| Caucasians | 1.27 (0.86–1.89) | 1.14 (0.77–1.68) | 1.16 (0.89–1.51) |
| African American | 1.73 (0.81–3.67) | 1.12 (0.60–2.07) | 1.14 (0.72–1.79) |
| Hispanic | 1.45 (0.78–2.70) | 1.26 (0.62–2.57) | 1.41 (1.02–1.95) |
| Gender | |||
| Females | 1.57 (1.02–2.42) | 1.37 (0.97–1.94) | 1.13 (0.87–1.45) |
| Males | 1.26 (0.94–1.68) | 1.12 (0.85–1.48) | 1.43 (1.15–1.77) |
| Education | |||
| Less than College | 1.42 (1.04–1.93) | 1.24 (0.91–1.68) | 1.25 (1.01–1.55) |
| ≥ College | 1.59 (0.95–2.68) | 1.17 (0.69–1.99) | 1.46 (1.10–1.95) |
Adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status, income, education, and health insurance
Table 8.
Relative Risk Regression for continuation of Lipid-Lowering Medications, Blood Pressure Lowering and Regular Aspirin between MESA Exam 1 and Exam 3 According to Race, Gender and Education Status
| LLM | BPLM | ASA | |
|---|---|---|---|
| Race | (CAC >100 vs. ≤100) | (CAC >100 vs. ≤100) | (CAC >100 vs. ≤100) |
| Caucasians | 1.03 (0.96–1.10) | 1.02 (0.98–1.06) | 1.14 (0.88–1.49) |
| African American | 1.27 (1.15–1.39) | 1.02 (0.99–1.06) | 1.17 (0.74–1.85) |
| Hispanic | 1.09 (0.94–1.27) | 1.00 (0.96–1.05) | 1.42 (1.02–1.96) |
| Gender | |||
| Females | 1.05 (0.97–1.13) | 1.00 (0.99–1.01) | 1.01 (0.90–1.14) |
| Males | 1.03 (0.96–1.12) | 1.04 (1.00–1.07) | 1.08 (1.00–1.17) |
| Education | |||
| Less than College | 1.08 (1.10–1.17) | 1.02 (0.99–1.05) | 1.02 (0.92–1.17) |
| ≥ College | 1.01 (0.94–1.09) | 1.03 (0.99–1.07) | 1.08 (0.99–1.18) |
Adjusted for age, gender, race MESA site, LDL cholesterol, diabetes mellitus, hypertension, systolic blood pressure, BMI, smoking status, income, education, and health insurance
DISCUSSION
In this prospective study of multi-ethnic asymptomatic individuals, elevated CACS was associated with nearly one and half fold increased likelihood of LLM, BPLM and regular ASA initiation in a mean follow-up of 1.6 years. In addition we found a marginal, albeit significant relationship between baseline CACS and medication continuation rates. The associations of higher baseline CACS with increased medication initiation and continuation rates remained significant, though attenuated, when adjusted for traditional risk factors, socioeconomic factors, and health insurance status.
Adequate control of risk factors with behavioral modification as well with appropriate use of LLM, BPLM and ASA in asymptomatic patients with a wide range of cardiac risk levels has been the cornerstone of preventive efforts to reduce the occurrence of cardiovascular events. The relationship of atherosclerosis imaging and subsequent utilization of preventive pharmacotherapy is not clear. To date, data from a few small-scale studies have suggested that presence and high burden of CACS results in increased utilization of preventive medications. Wong et al in a study of 703 self-referred adults aged 28–84 years reported that those with the highest CACS were more likely to begin ASA, LLM, or BPLM10. Taylor et al in a recent study compared statin and ASA usage in 1640 men, aged 40–50 years, following CAC testing15. At 6 year follow-up, statin use was 3-fold more likely among those with any CAC compared to CAC=0 (48% vs. 15%, P<.001) and aspirin use was nearly twice as likely (53% vs. 32% P < .01). The incidence of new statin use was more than 2 times greater among participants with CAC who were not at NCEP LDL goal at baseline and more than 4 times greater among participants with an LDL below the NCEP goal at baseline15. Similarly Orakzai et al have previously shown that those with elevated CACS were almost 3 times more likely to initiate aspirin therapy as compared to subjects with absent CACS22.The results of our study are consistent with these observations of increased downstream utilization of preventive medications among those with higher CACS. However, it is important to keep in mind that the initiation of these medications was still relatively low in exam 2 even in those with high CACS within the MESA cohort.
As compared to a consistent relationship of high CACS with initiation of preventive therapies, data on whether atherosclerosis imaging improves medication adherence is conflicting. Kalia et al. reported that in a study of 505 asymptomatic individuals that LLM continuation was lowest (44%) among those with CAC score in the first quartile (0–30), whereas 91% of individuals with baseline CAC score in the fourth quartile (>526) adhered to LLM13. On the other hand, Taylor et al observed no significant differences according to presence or absence of CAC in either LLM (87% vs. 79%, p=0.06) or ASA (79% vs. 83%, P = 0.36) continuation respectively15.
In our study we found a modest, albeit significant relationship between baseline CAC score and medication continuation rates. The high overall medication continuation rate as seen in our study as well as by Taylor et al15 may have contributed to lack of a stronger association with baseline CACS. Adherence to preventive medication is a vital component for any success in preventing CHD. Although it has been reported that approximately 50% of patients receiving long-term treatment adequately adhere to their prescribed therapies irrespective of underlying disease severity23, 24 . However a higher adherence reported by Taylor et al as well seen in our study is encouraging. Whether these improvements are more related to physicians’ input or patient motivation need to be evaluated in further studies. In addition, it is important to keep in mind that the adherence reported in MESA may be higher than observed in the general population due to selection of a population that is health conscious.
This study has a variety of key methodological strengths overcoming the limitations of prior reports. Firstly, most of the studies published to date are of small sample size, retrospective in nature and include mainly non-Hispanic whites individuals who self referred for CAC testing10,13,15,22. The major advantage of our study is that it is a large, prospective, multi-ethnic population based cohort. Secondly, validated risk factors were measured rather than self reported, thus reducing the possibility of potential residual confounding. Thirdly the findings of our study appear to be more robust as we additionally took into account income, education, and health insurance which may affect the association of higher coronary atherosclerotic burden with medication use. Finally, an important strength is in regards to verification of medication use at follow-up exams. All MESA participants had to bring bottles of the medications in with them and report that they had taken these medications during the previous two weeks, which may reflect a more accurate assessment of medications use as compared to self reported medication in most of the prior reports10,13,22. Although Taylor et al15 in a study of nearly 1300 young men (40–52 years) confirmed medication use via the military electronic health record, it is important to note that the study population and health care system may not be representative of those observed in the community.
The results of our study should be interpreted in the context of several limitations. First, this study was observational without a control population that did not receive data on CACS. Secondly, we relied on self-reported medication use not verified through electronic pharmacy records. This may potentially contribute to the relatively high continuation rates reported in our study. If data on pharmacy refills were available in these participants this would have provided a more accurate assessment of the continued use of the respective medications. However assessing the bottles of the medications as well recording if the individuals have taken these medications during the previous two weeks, is likely to be more accurate that self reported medication use. In our study 24% of the participants did not authorize release of the results to their physicians, however further adjustment for this variable did not alter the association of medication adherence and or initiation with increasing CAC burden. In addition, data on all medications in exam 1-exam 3 was reported in 77% of the participants, with individuals missing having a higher probability of CAC compared to that with complete information (53% vs. 49%), which may potentially result in selection bias. However we believe that this would tend to bias findings toward the null.
In summary, in a large population based multi-ethnic cohort of men and women, high CACS was independently associated with increased likelihood of LLM, BPLM and ASA initiation and continuation. However whether this translates into a reduced rate of cardiovascular events is unknown. Only a randomized clinical trial can clarify whether CAC testing will eventually lead to improved CVD outcomes.
What is Known
To date there is extensive data that have consistently demonstrated that assessment of coronary artery calcium scores (CACS) adds incremental cardiovascular risk predictive information.
The relationship of atherosclerosis imaging and subsequent utilization of preventive pharmacotherapy is not clear.
To date, data from a few small-scale retrospective studies have suggested that presence and high burden of CACS results in increased utilization of preventive medications.
What this Article Adds
Our study is the first to demonstrate in a large, prospective, multi-ethnic population based cohort that elevated CACS is associated with nearly one and half fold increased likelihood of initiation of cardiovascular preventive pharmacotherapy as well as a marginal, albeit significant relationship between baseline CACS and continuation rates of these respective medications.
The additional key methodological strengths of our study overcoming the limitations of prior reports was presence of validated risk factors, taking into account socioeconomic factors which may affect this relationship, as well as verification of medication use at follow-up exams, thus reflecting a more accurate assessment at follow-up.
Acknowledgments
Funding Source
This research was supported by R01-HL-63963-01A1 and contracts N01-HC-95159 through N01-HC-95165 and N01 HC 95169 from the National Heart, Lung, and Blood Institute.
Footnotes
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DISCLOSURES
Matthew J Budoff is on the speaker bureau of GE Health Care. No other disclosures.
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