We determined whether statin use was associated with lower all-cause and cardiovascular disease (CVD) mortality in 579 participants with lower extremity peripheral arterial disease (PAD) according to the presence and absence of elevated C-reactive protein (CRP) and D-dimer levels. Statin use was determined at baseline and at each annual visit. The CRP and D-dimer levels were measured at baseline. The mean follow-up was 3.7 years. The analyses were adjusted for age, gender, race, co-morbidities, ankle brachial index, cholesterol, and other confounders. Of the 579 participants, 242 (42%) were taking a statin at baseline and 129 (22%) died during follow-up. Statin use was associated with lower all-cause mortality (hazard ratio 0.51, 95% confidence interval [CI] 0.30 to 0.86, p = 0.012) and CVD mortality (hazard ratio 0.36, 95% CI 0.14 to 0.89, p = 0.027) compared to statin nonuse. No statistically significant interaction was found for the baseline CRP or D-dimer level with the association of statin use and mortality. However, statin therapy was associated with significantly lower all-cause and total mortality only among participants with baseline CRP values greater than the median and not among those with CRP values less than the median (hazard ratio 0.44, 95% CI 0.23 to 0.88 vs hazard ratio 0.73, 95% CI 0.31 to 1.75 for all-cause mortality and hazard ratio 0.20, 95% CI 0.063 to 0.65 vs hazard ratio 0.59, 95% CI 0.093 to 3.79 for CVD mortality). In conclusion, among those with PAD, statin use was associated with lower all-cause and CVD mortality compared to no statin use. The favorable association of statin use with mortality was not influenced significantly by the baseline CRP or D-dimer level.
We studied the associations between statin use and all-cause and cardiovascular disease (CVD) mortality among patients with peripheral arterial disease (PAD) with high versus low levels of C-reactive protein (CRP) and D-dimer. Men and women with PAD have increased levels of circulating inflammatory biomarkers and D-dimer compared to those without PAD. Thus, patients with PAD are a potentially ideal cohort in which to study the associations between biomarker levels, statin therapy, and mortality. We hypothesized that favorable associations of statin use with mortality would be stronger in those with PAD and high levels of CRP and D-dimer than among those with low levels of CRP and D-dimer.
Methods
The present study was an observational, prospective study of participants with PAD in the Walking and Leg Circulation Study (WALCS) and WALCS II cohort studies. The WALCS cohort was assembled from October 1998 to March 2000. The WALCS II cohort was assembled from November 2002 to April 2004. The data from ≤6 years of follow-up for the WALCS cohort and ≤2 years of follow-up for the WALCS II cohort were used in the present report. The institutional review boards of Northwestern University Feinberg School of Medicine and Catholic Health Partners Hospitals (Chicago, Illinois) approved the protocol. All participants gave written informed consent.
In WALCS and WALCS II, the participants with PAD were identified consecutively from among patients diagnosed with PAD in 3 Chicago-area noninvasive vascular laboratories. A small number of participants were identified from among consecutive patients in a large general internal medicine practice who were screened using the ankle brachial index (ABI) and found to have an ABI <0.90. The participants were age ≥55 years at baseline.
We defined PAD as an ABI of <0.90. Exclusion criteria have been reported and are summarized here. Patients with dementia were excluded because of their inability to answer questions accurately. Nursing home residents, wheelchair-bound patients, patients with foot or leg amputations, and patients with recent major surgery were excluded, because they have uniquely impaired functioning, and because WALCS and WALCS II were designed to study the natural history of lower extremity functioning over time. Non-English–speaking patients were excluded, because investigators were not fluent in non-English languages.
After the participants had rested supine for 5 minutes, we used a hand-held Doppler probe (Nicolet Vascular Pocket Dop II, Golden, Colorado) to measure the systolic pressures in the right brachial, dorsalis pedis, and posterior tibial arteries and left dorsalis pedis, posterior tibial, and brachial arteries. Each pressure was measured twice. We calculated the ABI in each leg by dividing the average pressures in each leg by the average of the 4 brachial pressures. We used the average brachial pressures in the arm with the greatest pressure when one brachial pressure was greater than the opposite brachial pressure in both measurement sets, and the 2 brachial pressures differed by ≥10 mm Hg in at least one measurement set. In these cases, subclavian stenosis was possible. The lowest leg ABI was used in analyses.
We used algorithms developed for the Women’s Health and Aging Study to document baseline co-morbidities. These algorithms combine data from patient report, physical examination, medical record review, medications, relevant laboratory values, and a primary care physician questionnaire. Baseline co-morbidities were stroke, myocardial infarction, angina, heart failure, diabetes, history of hypertension, pulmonary disease, and cancer. The history of hypertension was derived from self-report and physician questionnaires.
The principal study investigator (MMM) reviewed the lists of medication for each study visit, unaware of all other patient data and identified the presence versus absence of statin use for each participant.
The blood was collected into ethylenediamine-tetra-acetic acid and sodium citrate vacutainer tubes and immediately iced. The tubes were spun at 3,000 revolutions per minute for 20 minutes at 4°C in a refrigerated centrifuge. The blood was stored at −70°C until analyses were completed ≤3 years after blood collection.
We measured the CRP using an immunotechnique on the Behring, BN II analyzer (Dade Behring, Wilmington, Delaware. This method can detect CRP concentrations as low as 0.15 mg/L. The coefficient of variability was 4.26% for CRP. We used an Asserachrom D-Di kit (Diagnostica Stago, Asnières-sur-Seine, France) to measure D-dimer using an enzyme-linked immunosorbent assay procedure. The coefficient of variability was 9.4%.
The total cholesterol was measured using enzymatic reaction with peroxidase/phenol-4-aminoiphenazone indicator reaction. High-density lipoprotein cholesterol was measured with direct enzymatic colorimetric assay.
We determined cigarette smoking history by patient report using a structured interview. The pack-years of smoking were calculated according to the number of years smoked and the average number of packs daily. The physical activity was measured using patient-reported number of blocks walked during the past week. Height and weight were measured at the baseline study visit. Body mass index was calculated as kilograms per meter squared.
The deaths were ascertained from the Social Security Death index. The survival status for all participants was available. The death certificates were obtained from the state of Illinois or medical records. The cause of death was determined by a certified nosologist. Cardiovascular deaths were those with International Classification of Disease, version 10, codes ranging from I01.0 to I99.9, including deaths from coronary heart disease, stroke, peripheral vascular disease, and other CVD. Decedents without certificates were excluded from the CVD mortality analyses but not the all-cause mortality analyses.
We compared the baseline characteristics between the statin users and nonusers with PAD using general linear models for continuous variables and chi-square tests for categorical variables. The time-dependent Cox regression analyses were used to evaluate the associations of statin use and mortality. The time-dependent analyses allowed us to incorporate the onset of statin therapy during follow-up in our analyses. To determine whether baseline CRP value or D-dimer modified associations of statin use and mortality, analyses were repeated separately in participants with baseline CRP or D-dimer values greater than versus less than the median. We tested for the presence of an interaction between high versus low CRP levels and statin use in the association of statin use and mortality. Similar analyses were performed for high versus low D-dimer levels. The analyses were adjusted for age, gender, race, ABI, BMI, pack-years of smoking, stroke, myocardial infarction, angina, heart failure, diabetes, hypertension, pulmonary disease, cancer, total cholesterol, high-density lipoprotein, blocks walked in the past week, and WALCS I versus WALCS II cohort. We analyzed data, and the funding agency played no role in analyses.
Results
Of the 679 participants with PAD from WALCS and WALCS II, 579 (85%) had blood drawn at baseline and were included in these analyses. The mean age was 73 ± 8.5 years, the mean ABI was 0.65 ± 0.15, and 58% were men. Four participants had blood analyzed only for D-dimer, and 10 had blood analyzed only for CRP. The median baseline CRP and D-dimer values were 2.6 mg/L and 0.65 μg/ml, respectively. Of the 287 participants with a baseline CRP value greater than the median (ie, CRP >2.6 mg/L), 155 (54%) also had an elevated D-dimer level greater than the median (ie, D-dimer >0.65 μg/ml). During a mean follow-up of 3.7 years, 129 participants (22%) died; 43 deaths (33%) were from CVD. Death certificates were located for 77% of the decedents.
Of the 679 participants with PAD, 242 (42%) included in the present analyses were taking a statin at baseline. Table 1 lists the baseline characteristics of statin users versus nonusers. Statin users included a greater prevalence of whites and a greater prevalence of cardiac or cerebrovascular disease compared to nonusers. Statin users had greater BMI values, lower total cholesterol, and lower CRP levels.
| Variable | Statin Use | p Value ⁎ | |
|---|---|---|---|
| No (n = 337) | Yes (n = 242) | ||
| Age (years) | 73.0 ± 8.9 | 72.1 ± 7.9 | 0.21 |
| Men | 56.3% | 59.5% | 0.44 |
| Black race | 18.1% | 12.0% | 0.045 |
| Ankle brachial index | 0.64 ± 0.15 | 0.65 ± 0.15 | 0.91 |
| Body mass index (kg/m 2 ) | 27.2 ± 5.3 | 28.2 ± 4.8 | 0.02 |
| Cigarette smoking (pack years) | 37.0 ± 36.7 | 37.6 ± 34.5 | 0.86 |
| Total cholesterol (mg/dl) | 185.3 ± 40.4 | 169.8 ± 35.7 | <0.001 |
| High-density lipoprotein cholesterol (mg/dl) | 45.3 ± 19.1 | 43.6 ± 15.4 | 0.27 |
| Blocks walked during past week | 36.9 ± 69.1 | 29.9 ± 52.7 | 0.18 |
| Diabetes mellitus | 34.1% | 31.4% | 0.49 |
| Pulmonary disease | 38.0% | 34.7% | 0.42 |
| Cancer | 17.8% | 18.6% | 0.81 |
| Hypertension (by history) | 88.0% | 91.2% | 0.23 |
| Cardiac or cerebrovascular disease † | 47.8% | 64.0% | <0.001 |
| Baseline C-reactive protein level (mg/L) | 6.1 ± 10.5 | 3.8 ± 4.0 | 0.002 |
| Baseline D-dimer level ‡ (μg/ml) | 1.1 ± 1.4 | 0.97 ± 1.4 | 0.50 |
⁎ Derived from comparisons between statin users and statin nonusers.
† Cardiac or cerebrovascular disease was defined as ≥1 of the following: history of myocardial infarction, heart failure, angina, and stroke.
Compared to statin nonusers, statin users had lower all-cause mortality (hazard ratio 0.51, 95% confidence 0.30 to 0.86, p = 0.012) and CVD mortality (hazard ratio 0.36, 95% confidence interval 0.14 to 0.89, p = 0.027), adjusting for age, gender, race, ABI, BMI, cigarette smoking, stroke, myocardial infarction, angina, heart failure, diabetes, hypertension, pulmonary disease, cancer, total cholesterol, high-density lipoprotein, physical activity, and WALCS I versus WALCS II cohort.
Table 2 lists the associations of statin use with all-cause and CVD mortality, according to the baseline CRP levels. In participants with baseline CRP levels greater than the median (CRP >2.6 mg/L), statin use was associated with a significantly lower risk of all-cause mortality and CVD mortality compared to statin nonuse, adjusting for known and potential confounders ( Table 2 ). For participants with low baseline CRP levels, no significant associations were found of statin use with lower all-cause or CVD mortality ( Table 2 ). No significant interactions were found between the high versus low CRP level and statin use in the association of statin use with all-cause mortality (p for interaction term = 0.67) or CVD mortality (p for interaction term = 0.39).
| CRP (mg/L) | All-Cause Mortality | Cardiovascular Mortality | ||||||
|---|---|---|---|---|---|---|---|---|
| Participants | Death | HR (95% CI) | p Value | Participants | Death | HR (95% CI) | p Value | |
| <2.6 | ||||||||
| Statin nonuser | 160 | 32 | 1.0 (Referent) | NA | 160 | 8 | 1.0 (Referent) | NA |
| Statin user | 128 | 21 | 0.73 (0.31–1.75) | 0.48 | 128 | 4 | 0.59 (0.093−3.79) | 0.58 |
| >2.6 | ||||||||
| Statin nonuser | 175 | 50 | 1.0 (Referent) | NA | 175 | 21 | 1.0 (Referent) | NA |
| Statin user | 112 | 26 | 0.44 (0.23–0.88) | 0.019 | 112 | 10 | 0.20 (0.063–0.65) | 0.0075 |
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