Take-aways While prior studies have only documented improvements in walking distance and coronary revascularization in patients with PAD on statin therapy, a large study now suggests that statin therapy positively impacts limb outcomes. A decreased need for ischemic amputation is an important finding given the high morbidity and mortality associated with advanced PAD. Future research should focus on identifying barriers to improving patient and physician compliance with statin use across the entire spectrum of patients with PAD.

ACCEL | Peripheral artery disease (PAD) is common in the United States, often seriously impairing mobility, function, and quality of life. We know from the Heart Protection Study that statin use is associated with a 20-25% reduction in the risk of coronary events, stroke, or coronary revascularization compared with placebo. Statin therapy carries a class I indication for use in PAD. Does it similarly reduce events in patients with PAD?

Certainly, PAD patients have a high rate of adverse limb events as well as a 25% annual risk of amputation in patients with advanced PAD. Statins have been shown to increase pain-free walking distance in patients with PAD but the effects on maximal walking time were incongruent.^1,2 Another observational study reported that statins were associated with improved walking velocity and 6-minute walking distance.³

However, use of statins turned out to be disappointing in a recent small study of 68 patients with mild-to-moderate symptomatic PAD. They were studied at baseline and annually for 2 years after beginning simvastatin 40 mg, simvastatin 40 mg/ezetimibe 10 mg if statin-naïve, or ezetimibe 10 mg if already on a statin.⁴ Phosphocreatine recovery time, calf perfusion, and 6-minute walk distance were measured.

Despite effective low-density lipoprotein (LDL) reduction, tissue perfusion, metabolism, and exercise parameters did not improve, although rest ankle-brachial index improved. This small, non-placebo–controlled trial suggests that LDL-lowering does not improve calf muscle physiology or functional capacity in PAD. Thus, the authors concluded that the primary indication for lipid-lowering therapy in PAD remains the reduction of cardiovascular events and not specifically the improvement of calf muscle physiology, energetics, or walking performance.

In an accompanying editorial in JACC, Mitchell Krucoff, MD, and colleagues noted that the study's largely negative endpoints leave several unanswered questions about both the role of medical therapies affecting lipid metabolism and the mechanistic assumptions underlying the role of such therapies in PAD patients.⁵ The evidence suggests that PAD represents a complex and heterogeneous disease with multiple vascular beds and physiological mechanisms for symptomatic progression and adverse outcomes. The new data, they wrote, suggest that plaque regression is only one endpoint within a myriad of potential responses to the medical, or overall, treatment of patients with atherosclerosis.

The authors emphasized that this complexity itself must be considered in study designs—especially in the selection of surrogate/mechanistic endpoint measures—and in how clinicians make therapeutic decisions to treat PAD patients most effectively.

A Light at the End of the Peripheral Artery

Now we have more information, albeit from data yet to be published. Investigators evaluated the impact of statin use on 4-year adverse systemic and limb outcomes in patients with established PAD enrolled in the REACH registry. A total of 5,861 patients with established symptomatic PAD were included.

Despite having a Class I indication for use in patients with PAD, data from this large international registry suggest that statin use remains suboptimal—used in fewer than two-thirds of eligible patients. However, when looking at individuals with PAD but without ischemic heart disease, the use of statins was even lower—roughly half of these patients.

Unlike the earlier small study, the REACH registry shows that, at 4 years, statin use was associated with a significant reduction in adverse systemic outcomes (cardiovascular death/MI/stroke) and adverse limb outcomes. Moreover, each of the three individual component of the combined endpoint of adverse limb outcomes was significantly reduced with statin therapy (TABLE), including cutting the incidence of new amputation nearly by half.

Although prior studies have documented improvements in walking distance and coronary revascularization in patients with PAD, this is one of the first and largest studies to demonstrate an impact on adverse limb outcomes. Reduction in need for ischemic amputations with statin use is an especially important finding.

The authors suggested that future research should focus on identifying barriers to improving patient and physician compliance with statin use across the entire spectrum of patients with PAD.

References

1. Mohler ER 3rd, et al. Circulation. 2003;108:1481-6.
2. Mondillo S, et al. Am J Med. 2003;114:359-64.
3. McDermott MM, et al. Circulation. 2003;107:757-61.
4. West AM, et al. J Am Coll Cardiol. 2011;58:1068-76. http://content.onlinejacc.org/cgi/content/abstract/58/10/1068
5. Krucoff MW, et al. J Am Coll Cardiol. 2011;58:1077-9. http://content.onlinejacc.org/cgi/content/full/58/10/1077

TABLE. REACH Registry: Statin Therapy and Long-Term Adverse Limb Outcomes in Patients with PAD
	Multivariate Modeling Statin Use (Y/N) (n = 5,861)	Multivariate Modeling Time-varying Statin Use (n = 5,006)	Multivariate Modeling Propensity Analysis (n = 5,642)
Primary systemic outcome (CV death/MI/stroke)	0.83 (0.73 - 0.96) p = 0.0094	0.79 (0.67 - 0.93) p = 0.0038	0.85 (0.75 - 0.96) p = 0.0083
Primary limb outcome (worsening PAD)*	0.82 (0.72 - 0.92) p = 0.0013	0.85 (0.75 - 0.97) p = 0.018	0.79 (0.71 - 0.89) p < 0.0001
New amputation	0.64 (0.48 - 0.86) p = 0.0027	0.60 (0.44 - 0.82) p = 0.0014	0.57 (0.43 - 0.74) p < 0.0001

Y/N = yes/no; CV = cardiovascular; PAD = peripheral artery disease; MI = myocardial infarction.
*Worsening claudication/new episode of critical limb ischemia, new lower extremity percutaneous or surgical revascularization, or amputation

Keywords: Incidence, Registries, Myocardial Ischemia, Quality of Life, Ankle Brachial Index, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peripheral Arterial Disease, Simvastatin

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