Statins in PAD: What are we waiting for?

Atherosclerotic peripheral artery disease (PAD) is a growing yet underappreciated global health issue.¹ PAD affects more than 200 million individuals worldwide,² and atherosclerotic disease of the lower extremities confers a high risk of cardiovascular events and death.³ Patients with PAD have a 2.5-fold increased risk of myocardial infarction and a 3.1-fold increased risk of stroke compared to healthy individuals.³ Additionally, individuals with PAD are at heightened risk for lower extremity ulceration, acute limb ischemia, surgical and percutaneous revascularization, and amputation. Given the prevalence and morbidity of PAD, there is a clear need for therapies that improve PAD-specific outcomes, such as amputation, as well as reduce the risk of other major cardiovascular events that are common among patients with atherosclerosis.

Current professional society guidelines recommend statin therapy for all individuals with PAD.^{4, 5} Unfortunately, much of the data regarding lipid lowering therapy for PAD have been extrapolated from studies of coronary artery disease (CAD), and few studies have specifically examined limb outcomes. The Heart Protection Study randomized 20,536 subjects, 6,748 of whom carried a diagnosis of PAD, to either simvastatin 40mg daily or placebo with a mean follow up of 5 years.⁶ In the overall study population, simvastatin was associated with a 16% relative risk reduction in peripheral vascular events, which was driven primarily by a 20% reduction in non-coronary revascularization. Of note, this endpoint included not only lower extremity arterial procedures but also carotid interventions, and there were no differences in the rates of amputation between the two groups. Similarly, among 5,861 patients with symptomatic PAD in the REACH registry, statin therapy was associated with a 14% relative risk reduction in a composite endpoint that included worsening claudication, critical limb ischemia, peripheral revascularization, and amputation at 4 years.⁷ However, the existing studies have not been able to address whether statin intensity is related to limb outcomes, or whether statin therapy is associated with a mortality benefit in patients with PAD.

In this issue of Circulation, Arya et al. are able to address some of these key outstanding questions regarding the efficacy of statin therapy in this high risk population.⁸ The investigators used ICD-9 codes for PAD in addition to ankle-brachial indices, visits with vascular providers, or procedure codes for PAD to identify patients newly diagnosed with PAD in national Veterans Affairs data spanning the years of 2003 to 2014. They then categorized patients into three groups: those who were prescribed high-intensity statins, moderate- or low-intensity statins, or no statins within 1 year of their PAD diagnosis. The intensity of the prescribed statin was defined according to the current ACC/AHA guideline,⁹ and the authors used the highest intensity prescribed within 1 year of the PAD diagnosis date to categorize patients. The primary outcomes of interest were major amputation and death, and analyses compared both high-intensity and low-moderate intensity statin users to a comparator group who were not prescribed statins but who were prescribed an antiplatelet agent at the time of PAD diagnosis.

The authors identified 155,647 patients with incident PAD with an average follow up time of 5.9 years. The median age was 67.0 years, 86.7% were current/former smokers, 36.1% had diabetes, 31.2% had CAD, and 61.0% had carotid disease. Remarkably, despite their high risk, 45,503 patients (28%) were not prescribed statin therapy at the time of PAD diagnosis, although utilization rates were higher among those with pre-existing coronary artery disease or carotid artery stenosis at the time of PAD diagnosis. Unfortunately, these low utilization rates remained consistent over the course of the study (from 2006 to 2014). As might be anticipated, the group of patients included in the cohort were at high risk of the key clinical endpoints: 10,824 (7%) had an amputation and 63,287 (41%) died. The median time to amputation was 0.98 years, and the median time to death was 3.6 years, raising the possibility that earlier initiation of statin therapy may have delayed these outcomes, or slowed the progression of PAD. In multivariable adjusted Cox regression models comparing statin users to the active comparator group, low-moderate intensity statins were associated with a 17% reduction in mortality and a 19% reduction in amputation, while high-intensity statin therapy was associated with a 26% reduction in mortality and a 33% reduction in the risk of amputation.

Given the concern for residual confounding in this observational study, the investigators also performed a propensity score matched analysis. Compared to statin non-users, high-intensity and low-moderate intensity statin use were both associated with reductions in mortality (30% and 20%, respectively) and amputation (40% and 20%, respectively). In an important, novel finding, patients prescribed high-intensity statin therapy had a 15% lower risk of mortality and a 22% lower risk of amputation when compared to patients prescribed low-moderate intensity statins. These effects were consistent across a broad array of subgroups, although there were very few women enrolled in this cohort.

The investigators’ finding of a strong and intensity-dependent association between statin therapy and both amputation and mortality among individuals with incident PAD is of considerable clinical importance, both to patients and the physicians who care for them. However, the study was observational in nature, so a number of limitations are worth discussing. First, the patients who were prescribed an anti-platelet agent but not a statin have far higher rates of current and former smoking, while also having lower rates of diabetes, hypertension, and CAD. While the authors adjusted for these differences in their models, these differences raise the possibility of additional unidentified confounders that account for the differences in clinical outcome between these groups.

When assessing statin intensity and prescription rates, one would ideally perform a time-varying analysis to account for statin changes beyond the 1 year window used in the study. The analysis also does not account for the initiation of additional therapies, such as smoking cessation or angiotensin converting enzyme inhibitors, that could also explain some of the between-group differences. Finally, although rates of clopidogrel use were much lower than that of aspirin, data from the CAPRIE trial suggest clopidogrel 75mg daily is superior to aspirin 325mg daily in terms of secondary prevention of vascular death.¹⁰ Assuming an adequate sample size, it would be interesting to perform the analysis with two separate active comparator groups (aspirin alone versus clopidogrel alone).

The report by Arya and colleagues adds to a growing literature documenting the underutilization of statin therapy in PAD patients. They have also demonstrated a strong, intensity-dependent effect on amputation and mortality, two outcomes of clear import for both patients and physicians. Cardiologists, primary care physicians, insurers, and other care providers need to do a better job in helping both our colleagues and our patients understand the importance of these medications preserving both life and limb. By doing so, hopefully we can enhance rates of utilization and adherence to high-intensity statin therapy in this large and growing population of patients with peripheral artery disease.