Persistent elevation of inflammatory markers such as C-reactive protein (CRP) has been associated with an increased risk of recurrent cardiac events after acute coronary syndromes (ACS). Conflicting evidence is available regarding whether aspirin can reduce CRP after ACS. We investigated whether the dosage and adherence to aspirin was associated with the CRP level 3 months after ACS. Adherence to aspirin was monitored for 3 months in a cohort of 105 patients enrolled within 1 week of an ACS using an electronic chip stored in the pill bottle cap. The CRP level was measured at baseline and 3 months. Logistic regression analysis was used to test whether poor adherence to aspirin and a lower aspirin dosage were associated with increased CRP levels, controlling for age, ACS type, disease co-morbidity, baseline CRP level, use of clopidogrel and statins, depressive symptoms, smoking, and adherence to other medications. Aspirin adherence was inversely correlated with the CRP level at 3 months (Spearman’s r = −0.36, p <0.001). In the adjusted model, every 10% decrease in aspirin adherence was associated with a 1.7 increased risk (95% confidence interval 1.2 to 2.4) of a CRP level of ≥3.0 mg/L at 3 months. Low-dose aspirin was associated with a 7.1 increased risk (95% confidence interval 1.5 to 33.3) of a CRP level of ≥3.0 mg/L. The Charlson co-morbidity index, depressive symptoms, and baseline CRP level were also predictive of a CRP level of ≥3.0 mg/L at 3 months. The association between aspirin adherence and CRP level was not attenuated by controlling for other risk-reducing behaviors. In conclusion, a strong association was found between aspirin adherence and the CRP level after an ACS.
The amount of exposure to aspirin might be associated with C-reactive protein (CRP) levels after an acute coronary syndromes (ACS). Thus, we tested whether lower adherence to aspirin and/or a lower prescribed aspirin dosage in the 3 months after hospitalization for an ACS were associated with higher CRP levels at 3 months. Aspirin adherence was assessed using an electronic medication monitor. Because the adherence to aspirin might be a proxy for adherence to other medications that are more definitively linked with anti-inflammatory effects, we also explored the association between aspirin adherence and CRP level after controlling for self-reported adherence to medications in general.
Methods
The present study was performed as a part of the Coronary Psychosocial Evaluation Study (COPES), a series of multisite observational cohort studies that examined the relation between depression and prognosis after ACS. In brief, from May 1, 2003 to April 15, 2005, a cohort of patients was recruited from 3 academic hospitals (Yale-New Haven Hospital and the Hospital of St. Raphael in New Haven, Connecticut, and the Mount Sinai Medical Center, New York, New York) within 1 week of hospitalization for an ACS. The study defined an ACS as either acute myocardial infarction (MI) or unstable angina using standard criteria. The study protocol required patients to have symptoms consistent with acute myocardial ischemia and ≥1 of the following: ischemic electrocardiographic changes, angiographic findings indicative of coronary artery disease at the current admission, a documented history of coronary artery disease, or an acute increase in serum troponin levels greater than the laboratory cutoff of each hospital. A study cardiologist confirmed ACS eligibility for all patients. An additional eligibility criterion was a score on the Beck Depression Inventory (BDI) of ≤4 or ≥10, ranges selected in the parent study to delineate patients without and with depression at baseline. The patients were excluded if they lived in a nursing home, exhibited cognitive impairment, or engaged in alcohol or substance abuse. All patients gave informed consent before enrollment. The institutional review boards at each hospital approved the study.
On hospital discharge, the patients who were prescribed a daily dose of aspirin (81, 162, or 325 mg) and who were willing to have their aspirin adherence monitored by an electronic chip in the cap of their pill bottle were provided with a 90-day supply of their prescribed aspirin in a Medication Event Monitoring System (MEMS, Aprex, Fremont, California) bottle. The MEMS device records the date and time whenever the bottle cap is opened. MEMS data were collected continuously for the next 3 months. The percentage of days the bottle cap was opened the correct number of times (once a day) was calculated.
The patients also provided blood samples in the hospital and after 3 months for measurement of CRP. After centrifugation, the serum samples were stored in aliquot portions at −70°C. The samples were shipped to a core laboratory (Specialty Laboratories, Valencia, California) for analysis of high-sensitivity CRP concentrations. The limit of detection of the CRP assay was 0.01 mg/L, the analytic measurable range was 0.2 to 160 mg/L, and the inter- and intra-assay coefficient of variation was <8%. Concentrations were determined by turbitometry (Bayer Diagnostics, Leverkusen, Germany).
A total of 172 patients agreed to have their adherence monitored using the MEMS. The details regarding enrollment into this substudy have been previously reported. Of the 172 patients, 105 (61%) had blood samples drawn at baseline and 3 months. The patients who refused the blood draw did not significantly differ (p >0.20) from those who agreed with respect to sociodemographics, depression score, or clinical factors. A CRP level of ≥3 mg/L was defined as elevated, because this identifies the increased risk of recurrent events and death.
The baseline demographics, discharge medications, and clinical variables, including the constituents of the Charlson co-morbidity index, a validated measure of risk of death for patients with chronic illness, were obtained by patient interview and chart abstraction at enrollment. Participants completed the BDI, a validated self-report instrument that has been used in previous studies of depression and ACS and that predicts post-ACS event-free survival.
At 3 months of follow-up, the patients returned the MEMS cap and were asked about their adherence to cardiovascular risk-lowering behaviors, including whether they had smoked tobacco products in the past 7 days; participated in a cardiac rehabilitation program; exercised regularly; and/or modified their diet to be heart healthy. In addition, patients were asked about their adherence to their medications using the Morisky scale; a self-report tool that has good agreement with objective measures of medication adherence. The scale included 4 items, each scored as either 0 (adherent) or 1 (nonadherent). The total score is calculated by summation to obtain a total score from 0 to 4. Patients with a score from 0 to 1 were categorized as having good medication adherence, and those with a score from 2 to 4 were categorized as having poor medication adherence.
CRP was log transformed so that it was normally distributed. Spearman’s correlation was used to assess the association between monitored aspirin adherence and CRP at 3 months. The chi-square and t tests were used to compare differences in patient characteristics between patients with and without elevated CRP, using a cutoff of 3 mg/L. Logistic regression analysis was then used to determine whether adherence to aspirin and aspirin dosage were independently associated with CRP level (≥3 vs <3 mg/L). Using linear regression analysis, we also tested whether the aspirin dosage and aspirin adherence were independently associated with a continuous measure of CRP. The models were adjusted for age, ACS type (unstable angina vs MI), Charlson co-morbidity index, baseline CRP level, statin and clopidogrel use, smoking status, and depressive symptom severity (BDI score) at baseline. The analyses were also adjusted for self-reported adherence to overall medications as measured using the Morisky scale. The a priori choice of predictors was determined from a review of the published data for important factors that might be associated with the CRP level after ACS. Finally, we used t tests to determine whether adherence to aspirin was associated with the aspirin dosage (81 mg vs 162 or 325 mg) and with self-reported exercise, consuming a heart healthy diet, and attending cardiac rehabilitation. All statistical analyses were performed using the Statistical Package for Social Sciences, version 13 (SPSS, Chicago, Illinois).
Results
The baseline and 3-month blood samples and MEMS-assessed aspirin adherence data were available for 105 patients. The mean age of this sample was 59 years (range 25 to 83), 47% were women, 87% were white, and 6% self-identified as Hispanic. The index ACS event was ST-segment elevation MI for 24% of patients, non–ST-segment elevation MI for 30% of patients, and unstable angina for 47% of patients. The mean adherence to aspirin (percentage of days aspirin was taken correctly) was 87% (range 23% to 100%), and 24% of patients took their aspirin on <80% of the days monitored.
Compared to patients with a lower CRP level (<3 mg/L), patients with a higher CRP level (>3 mg/L) at 3 months were more likely (p <0.05) to have had greater baseline Charlson co-morbidity and BDI depressive symptom scores and to have higher baseline CRP levels ( Table 1 ). In contrast, patients with a higher CRP level at 3 months were less likely to have been discharged with clopidogrel or statins, although these differences were only statistically significant for statins.
| Characteristic | CRP Level (mg/L) | p Value | |
|---|---|---|---|
| ≤3 (n = 59) | >3 (n = 46) | ||
| Age (years) | 58.2 ± 11.4 | 60.8 (13.2) | 0.28 |
| Acute coronary syndrome type, myocardial infarction | 35 (59%) | 21 (46%) | 0.16 |
| Charlson co-morbidity index | 0.7 ± 0.9 | 1.7 ± 1.7 | <0.001 |
| Beck Depression Inventory, baseline | 5.6 ± 6.2 | 11.3 ± 8.7 | <0.001 |
| C-reactive protein, baseline | 13.8 ± 18.4 | 25.0 ± 23.3 | 0.01 |
| Smoking at 3 months | 8 (14%) | 7 (15%) | 0.81 |
| Discharge with statin | 55 (93%) | 36 (78%) | 0.03 |
| Discharge with clopidogrel | 52 (88%) | 35 (76%) | 0.10 |
| Good adherence to overall medications | 49 (83%) | 36 (78%) | 0.54 |
| Prescribed low-dose aspirin (81 mg) | 7 (12%) | 14 (30%) | 0.02 |
| Aspirin adherence 0–3 mo | 91.6 ± 13.3 | 80.8 ± 17.9 | 0.001 |
Of the 105 patients, 21 (20%) were discharged with low-dose aspirin (81 mg/day) and 83 (79%) with high-dose aspirin (325 mg/day). One patient was discharged with 162 mg/day and was included in the high-dose group. A greater proportion of patients hospitalized for MI were prescribed high-dose aspirin at discharge than patients hospitalized for unstable angina (92% vs 67%, respectively, p = 0.002). Patients discharged with low-dose aspirin had a significantly higher CRP level at 3 months than patients prescribed high-dose aspirin, even though the patients prescribed low-dose aspirin had had lower CRP levels at baseline ( Figure 1 ). In an adjusted analysis, low-dose aspirin was associated with a 7.1 increased risk (95% confidence interval 1.5 to 33.3) of a CRP level of ≥3.0 mg/L at 3 months ( Table 2 ). Aspirin adherence did not significantly differ between patients prescribed low- versus high-dose aspirin.
| Predictor | Unadjusted OR (95% CI) | Adjusted OR (95% CI) |
|---|---|---|
| Age | 1.02 (0.99–1.05) | 0.98 (0.93–1.04) |
| C-reactive protein concentration at baseline † | 1.03 (1.01–1.05) | 1.04 (1.01–1.07) |
| Acute coronary syndrome type, myocardial infarction | 0.58 (0.26–1.26) | 1.08 (0.29–4.01) |
| Charlson co-morbidity index † | 1.99 (1.32–2.99) | 1.96 (1.12–3.41) |
| Discharge with statin | 0.26 (0.08–0.90) | 0.32 (0.05–2.02) |
| Discharge with clopidogrel | 0.43 (0.15–1.21) | 0.99 (0.16–6.21) |
| Smoker at 3 months | 1.14 (0.38–3.43) | 0.68 (0.14–3.42) |
| Beck Depression Inventory score at baseline † | 1.11 (1.05–1.18) | 1.16 (1.07–1.26) |
| Poor adherence to medications overall (Morisky score) | 1.36 (0.51–3.61) | 0.97 (0.15–6.37) |
| Prescribed low-dose aspirin (81 mg) at discharge † | 3.22 (1.19–9.09) | 7.14 (1.54–33.33) |
| Poor adherence to aspirin † (continuous per 10% decrease) | 1.65 (1.20–2.27) | 1.65 (1.15–2.35) |
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