Lipid-Lowering Therapy in Peripheral Artery Disease: Stepping in the Right Direction

Peripheral artery disease (PAD) is a common manifestation of systemic atherosclerosis affecting 20% of Americans over the age of 80¹ and over 200 million people worldwide.² As well as being common, it also carries high mortality and morbidity; and yet, patients with PAD are overlooked on multiple levels. Many go unrecognized in clinical practice. The PARTNERS study observed that only half of PAD patients were recognized to have the disease by their physicians.³ Even when diagnosed, the risk of a future cardiovascular (CV) event may be underappreciated. In the Reduction of Atherothrombosis for Continued Health (REACH) registry, an international cohort of patients with coronary artery disease (CAD), stroke, PAD or multiple atherosclerotic risk factors who were followed prospectively, PAD patients had the highest annual rate of mortality and total CV event rates among all risk groups.⁴ Although risk factors for PAD are similar to those of CAD and stroke, preventive therapy is underutilized in this high-risk population. The National Health and Nutrition Examination Survey (NHANES, 1999 to 2004) demonstrated significantly lower use of antiplatelet therapy (27.4% vs 65.8%), statins (18.3% vs 57.5%) and renin-angiotensin system inhibition (20.8% vs 34.3%) in PAD patients with no other cardiovascular disease (CVD) compared to those with PAD and concomitant CVD.⁵ The majority of clinical cardiovascular trials evaluate outcomes in PAD patients only as a subgroup or a post-hoc analysis or simply neglect to describe this population in general.

Lipid-lowering therapy for CVD and PAD
Statins are the cornerstone of lipid-lowering therapy and are paramount to the goal of reducing the risk of a major cardiovascular event including death, myocardial infarction (MI) and stroke. Many large, randomized controlled trials (RCT) have been performed to show the benefit of statins in both primary and secondary cardiovascular prevention but these trials were mostly designed with a focus on CAD.

The first major statin clinical trial was the Scandinavian Simvastatin Survival Study (4S) where adults with coronary heart disease and who were treated with simvastatin experienced a 30% reduction in mortality compared to placebo.⁶ The West of Scotland Coronary Prevention Study (WOSCOPS) which evaluated statin use for primary prevention⁷ also showed a significant reduction in CV events, establishing a new indication for statin use for primary prevention. However, these trials, and many others that followed, did not specifically enroll patients with PAD, nor did they assess PAD-related outcomes.

The Heart Protection Study (HPS) was an important clinical trial in the evolution of statin therapy⁸ because of its inclusion of PAD patients. Investigators enrolled over 20,000 people, including high-risk primary prevention and secondary prevention statin candidates. In addition to CAD, patients with other atherosclerotic diseases including stroke, PAD and carotid artery disease, were enrolled for secondary prevention. The intervention group received simvastatin and experienced a 13% reduction in all-cause mortality compared to the placebo group.⁸ A subgroup analysis of study participants with previous cerebrovascular disease showed a significant 20% reduction in subsequent major vascular events.⁹ The HPS also had a large subgroup of patients with PAD (6,748) as well. Subgroup analysis of this PAD population again showed a significant, 22% reduction in major CV events in the intervention group.¹¹ The absolute reduction in a first major vascular event was 63 per 1,000 patients with PAD and 50 per 1,000 without pre-existing PAD. Among all participants, there was a 16% relative reduction in the rate of first peripheral vascular event following randomization, largely irrespective of baseline low-density lipoprotein (LDL) cholesterol and other factors. This effect reflected a 20% relative risk reduction in non-coronary revascularization procedures. Following HPS, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial enrolled patients with a prior stroke or transient ischemic attack (TIA) and randomized them to high-dose atorvastatin or placebo.¹⁰ The statin arm demonstrated a significant reduction in both strokes (hazard ratio [HR], 0.84) and major coronary events (HR 0.65).

However, no dedicated, placebo-controlled randomized clinic trial was done to primarily evaluate the efficacy of statin therapy in PAD patients. A 2007 Cochrane review of lipid-lowering therapy in PAD patients concluded that there is a beneficial treatment effect for total cardiovascular events and the most evidence of benefit was with statin therapy.¹² Here again the authors note that only 2 RCTs involving a statin were included in the review and 95% of those patients were from the HPS. The major emphasis was on the impact of statin use on hard cardiovascular endpoints. Pooling of the results from several small trials on a range of different lipid-lowering agents, the authors reported a significant decrease in revascularization rate, pain-free walking distance and total walking distance with lipid-lowering therapy compared to placebo.¹² Notable trials involving statin use included an evaluation of walking time with atorvastatin compared to placebo which demonstrated a significant improvement in pain-free walking time (78±10 sec) in the atorvastatin group compared to placebo (39±8 seconds, p=0.047) at 12 months.¹³ Another study comparing a high dose simvastatin versus placebo in PAD trial participants showed an increase in pain-free walking distance of 90 meters (95% CI: 64-116 meters; p<0.005) in the statin arm compared to placebo.¹⁴ The mean total walking distance also was significantly greater in the simvastatin group.¹⁴ The most robust data for adverse limb events and statin use comes from the REACH registry, which reported an 18% reduction in a composite endpoint of worsening claudication, critical limb ischemia and lower extremity revascularization or ischemic amputation.¹⁵ 

Guidelines for statin use in PAD
National guidelines and consensus statements began advocating for lipid lowering therapy for the treatment and prevention of coronary heart disease as early as the early 1990s, nearly 10 years before recommendations for treatment in PAD. These delays highlight the historical focus on CAD without acknowledging the high risk of CV events in PAD patients. This includes not only the traditional outcomes of MI, stroke and death, but also adverse limb events such as acute limb ischemia, amputation and need for limb revascularization.

In regard to treatment recommendations in PAD, statin dosing and LDL targets remain an area of complexity without consensus. The 2005 American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines for PAD give a Class I recommendation for an LDL-cholesterol (LDL-C) below 100 mg/dl¹⁶ but this target is not specified in the 2016 update.¹⁷ However, the LDL-C goals remain in the recently updated European Society of Cardiology PAD guidelines.¹⁸ The National Lipid Association (NLA) published recommendations for patient-centered management of dyslipidemia with the focus on reducing atherosclerotic cardiovascular disease events with the emphasis on LDL-C threshold rather than on statin dosage.^19,20

Recent lipid-lowering clinical trials are giving more attention to PAD
In contrast to the statin trials, recent CVD studies have enrolled a subset of PAD patients with prespecified subgroup analyses including evaluation for adverse limb outcomes.^21,22 The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial is one example.²³ The investigators demonstrated a similar relative risk reduction in major adverse cardiovascular events in the treatment arm for PAD and non-PAD patients (HR of 0.79 vs 0.81; p for interaction=0.41). There also was a reduction in major adverse limb events in the treatment arm (HR 0.58 95% CI, 0.38-0.88; p=0.0093) which was also not statistically different in the PAD vs non-PAD population (p-interaction=0.29). However, due to the much higher prevalence of limb events in PAD patients, the absolute risk reduction was much greater in that population (absolute risk reduction 2.4% vs 1.9% in PAD vs non-PAD populations respectively). Despite these advances, it should be noted that most PAD patients included in these clinical and observation trials were symptomatic. There remains a gap in data for patients with asymptomatic PAD.

Personal thoughts on therapeutic inertia
How does this history and our experiences with statin use relate to how patients are treated in offices? As the PARTNERS study suggested, those of us who evaluate and treat patients are much better at tuning in to signs and symptoms of coronary disease than peripheral artery disease.³ Granted, most healthcare providers encounter CAD much more frequently than PAD but if you don’t seek, you won’t find. One can imagine a situation where a “low risk” individual has a CVD risk score that doesn’t meet the threshold for statin or antiplatelet therapy but has unrecognized PAD. Maybe they are too sedentary to be bothered by leg pain or the pain gets written off as joint pain, a sign of aging. Or an individual may fall into the gray area of asymptomatic PAD where data on treatment efficacy is lacking. Regardless, this hypothetical patient may miss out on years of potential risk lowering therapy or even worse, may experience a CV or limb event that could have been prevented. Consider another situation where an asymptomatic individual with undiagnosed PAD has been treated with statin for primary prevention but comes in to the office complaining of leg pain. Medical providers who are accustomed to treating patients with intolerance to statins may jump to this diagnosis without fully considering the possibility of PAD leading to interruption or undertreatment with statin in a patient with markedly elevated CV risk. We must stay vigilant to avoid this type of inertia in our practice.

Conclusions
Patients with peripheral artery disease have a high risk of future adverse cardiovascular and limb events. Despite this elevated risk, they receive incomplete preventive therapy. Historically these patients have been under-represented in clinical trials, but this is beginning to change as several recent major clinical trials have included prespecified PAD subgroup analyses as well as adjudicated limb efficacy endpoints. One important therapeutic step that needs to be addressed in patients with PAD is addressing their cardiovascular risk in a way similar to that of CAD patients and fully addressing PAD patients’ need for statin therapy. It also is vital to address the presence or absence of PAD in primary and secondary CV prevention patients on statin therapy who are complaining about muscle pain in the legs. With a little effort and patient-centered statin dose adaptation, we have the potential to reach a major impact on morbidity and mortality in the PAD population.

Disclosure statement: All authors of this article have no financial disclosures to report.

References available here.