Hypertriglyceridemia is associated with an increased risk of peripheral arterial revascularization in high‐risk statin‐treated patients: A large administrative retrospective analysis

Abstract Background Peripheral artery disease (PAD) is common, and although it is associated with cardiovascular (CV) morbidity, mortality, reduced quality of life, and increased health care burden, PAD data are relatively scarce. Elevated triglycerides (TG) are associated with and are a risk factor for PAD. Hypothesis Large administrative retrospective data may provide further insight into the relationship between hypertriglyceridemia and peripheral arterial revascularization in high‐risk statin‐treated patients. Methods This retrospective administrative claims analysis of the Optum Research Database included statin‐treated patients aged ≥45 years with diabetes and/or atherosclerotic CV disease enrolled in 2010 and followed for ≥6 months. Patients with TG ≥150 mg/dL were propensity score‐matched to a comparator cohort with TG <150 mg/dL and high‐density lipoprotein cholesterol >40 mg/dL (n = 23 181 in each cohort). A sub‐analysis was conducted in patients with TG 200‐499 mg/dL and a matched comparator cohort (n = 10 990). Clustered P‐values were calculated using a Cox proportional hazard model with cohort as the independent variable (α, 0.05). Results Multivariate analysis showed a 37% higher rate of peripheral arterial revascularization in the elevated‐TG cohort vs the comparator cohort (hazard ratio [HR] 1.370, 95% confidence interval [CI] 1.263‐1.486; P < .001). Results in the high‐TG sub‐cohort were similar, with a 49% higher rate of revascularization vs the comparator cohort (HR 1.489; 95% CI, 1.348‐1.644; P < .001). Conclusions This large administrative retrospective analysis of high‐risk statin‐treated patients showed that elevated TG (≥150 mg/dL) and high TG (200‐499 mg/dL) were significant predictors of peripheral arterial revascularization; this warrants further study.


| INTRODUCTION
Epidemiologic, genetic, and clinical evidence show that elevated triglycerides (TG) and TG-rich lipoproteins are associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) and play a causal role in ASCVD development and progression. [1][2][3][4][5] Elevated TG are a risk factor for peripheral arterial disease (PAD). 6,7 PAD is common and is associated with cardiovascular (CV) morbidity, mortality, reduced quality of life, limb loss, and increased health care burden.
The prevalence of PAD is >200 million persons worldwide, with >40 million persons affected in Europe. 8 In the United States, the prevalence of PAD is ≥6.8 million individuals, with >13 000 deaths reported in 2015 and > 100 000 hospital discharges reported in 2014. 9 Data on PAD are relatively scarce compared with data on coronary artery disease. 10 Patients at high risk for CV disease, with controlled lowdensity lipoprotein cholesterol (LDL-C) but elevated TG and PAD, are increasingly encountered in clinical practice due, in part, to the increased prevalence of insulin resistance and diabetes mellitus. More information on the prevalence, health burden, health care costs, and resource utilization associated with this population is needed to optimize management and reduce associated morbidity and mortality.
The purpose of this retrospective analysis of a large medical claims database was to evaluate the impact of elevated TG on risk of peripheral arterial revascularization in high-risk statin-treated patients.

| METHODS
Details of the study design have been published previously. 11,12 This retrospective analysis used the Optum Research Database, which includes >160 million individuals. Patients were eligible if they were ≥ 45 years old, had documented diabetes and/or ASCVD, had ≥1 prescription(s) for statin therapy filled between January 1, 2010 and December 31, 2010, and had ≥6 months of baseline data prior to the first statin claim; patients were ineligible if they had niacin remaining on the index date from a recent prescription fill. Patients were followed for a period of ≥6 months beginning at the index date to the earliest of the following: end of the study (March 31, 2016), date of disenrollment from their insurance plan, or death.
Three study cohorts were assessed. Patients in the elevated-TG cohort were required to have TG ≥150 mg/dL at their most recent laboratory visit prior to the index date; the high-TG sub-cohort was required to have TG 200 to 499 mg/dL, and those in the comparator cohort were required to have TG <150 mg/dL and high-density lipoprotein cholesterol (HDL-C) >40 mg/dL. The primary endpoint was the frequency of major CV events (a composite of CV-related death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina) in the follow-up period. Secondary endpoints were direct health care costs (in US$) and resource utilization in the follow-up period. Other prespecified analyses included the effects of TG on the probability of freedom from peripheral arterial revascularization as reported here.
The primary and secondary endpoints were reported elsewhere. 11,12 Statistical analyses were carried out as follows: all study variables were analyzed descriptively and reported for the overall study sample, as well as stratified and statistically compared by cohort. A propensity score analysis was used to create a matched comparator study cohort similar to the analysis cohort, but without elevated or high TG, by controlling for confounding relationships. Propensity score matching was performed using a greedy match algorithm. 13 The procedure used attempts to match each case to a single control based on the first 8 digits of the propensity score, which was estimated using logistic regression, then 7 digits, etc., until a match was found.
The closest available match, known as the nearest neighbor, was used.
Ties were resolved randomly. A maximum allowed propensity score difference (ie, a caliper) of 0.01 between the matched case-control pairs was imposed a priori. Once a match was found, it was not reconsidered and the control was removed from the available pool for matches. The final sample of cases that were successfully matched to the controls was retained for analysis. The final list of variables included in the propensity score model was determined following review of the pre-matching descriptive analyses of patient characteristics and other pre-index measures and included age; gender; insurance type; region; baseline direct medical cost; LDL-C level relative to the median, if available; baseline use of statins, fibrates, or omega-3 fatty acids; and the following diagnoses: ASCVD, diabetes, stroke, hypertension, renal disease, and PAD. Patients in the elevated-TG cohort were matched in a 1:1 ratio to the comparator cohort. Those who were not matched were not included in the descriptive analyses.

| RESULTS
Baseline demographic and clinical characteristics of the patient cohorts have been described previously. 11,12 Approximately, 1.6 million statin-treated patients with at least 1 prescription claim for a statin were identified from the database. After inclusion and exclusion criteria were applied and patients were propensity score matched, the elevated-TG cohort and the high-TG sub-cohort consisted of 23 181 patients and 10 990 patients, respectively, with matching numbers of patients in the respective comparator cohorts. Other than the expected difference in lipid levels due to cohort inclusion criteria in the elevated-TG and high-TG sub-cohorts, there were some baseline differences from their respective matched comparators that were statistically significant, but we do not consider these differences to be clinically important (Table 1). 11,12 Fibrate usage at baseline was similar between the elevated-TG cohort and its comparator (7.4% vs 7.2%, respectively, P = .131) and between the high-TG cohort and its comparator (9.1% vs 8.8%, respectively, P = .034; previously reported values of 13% and 8% for the two groups, respectively, 11 represented fibrate usage in the first 6 months).
Analysis of the impact of hypertriglyceridemia on the risk of peripheral revascularization showed that freedom from peripheral arterial revascularization was significantly higher in the comparator cohort than in the elevated-TG cohort ( Table 2). At 5 years, the probability of peripheral arterial revascularization was 6.9% in the elevated-TG cohort vs 4.9% in the comparator cohort. In a multivariate analysis controlled for patient characteristics and comorbidities, the rate of occurrence of peripheral arterial revascularization per unit time was 37% higher in the elevated-TG cohort vs the comparator cohort (HR 1.370, 95% confidence interval [CI] 1.263-1.486; P < .001; Figure 1). Similarly, in the high-TG sub-cohort, the comparator group had a higher rate of freedom from peripheral arterial revascularization than did the high-TG subcohort (P < .001) ( Table 3). At 5 years, the probability of peripheral arterial revascularization was 7.3% in the high-TG sub-cohort vs 4.8% in the comparator cohort. Based on a multivariate analysis that controlled for patient characteristics and comorbidities, the rate of occurrence of peripheral arterial revascularization per unit time was 49% higher in the high-TG cohort than in the comparator cohort (HR 1.489; 95% CI, 1.348-1.644; P < .001; Figure 1).

| DISCUSSION
This large administrative retrospective study, which analyzed claims data from more than 45 000 statin-treated patients in the Optum T A B L E 1 Patient demographics, characteristics, and baseline comorbidities 11,12 Elevated-TG a n = 23 181 Comparator a n = 23 181 P-value reporting an association between an atherogenic lipoprotein phenotype (elevated TG, reduced HDL-C, and decreased LDL size) and increased risk of PAD. [14][15][16] We previously showed that these elevated-and high-TG patient populations had worse CV outcomes and higher health care resource use and direct costs than patients with TG <150 and HDL-C > 40 mg/dL. 11,12 In patients with elevated TG and high TG, respectively, the overall risk of a major CV event was 26% and 35% higher than in the comparator cohorts after controlling for baseline characteristics and comorbidities (both P < .001). 11,12 Mean monthly direct health care costs were 11.8% higher in the elevated-TG cohort than in the comparator cohort ($1438 vs $1270) and 15% higher in the high-TG cohort than in the comparator cohort ($1462 vs $1279) (both P < .001). 11,12 The higher occurrence of an inpatient stay in patients with elevated TG (13% relative increase; 33.5% vs 30.5%) and high TG (17% relative increase; 34.0% vs 30.4%) (both P < .001) compared with matched controls would be expected to increase health care costs in these populations. 11,12 T A B L E 2 Freedom from peripheral arterial revascularization in statin-treated patients with high cardiovascular risk and elevated triglycerides vs comparators (Kaplan-Meier analysis)