This study used complementary MRI techniques and exercise studies to comprehensively evaluate functional changes in patients with PAD who were treated with lipid-lowering therapy for 2 years. Statin-naïve patients randomized to simvastatin or simvastatin + ezetimibe demonstrated no change in calf muscle perfusion or metabolism, and there was no difference between groups in these MRI parameters despite greater initial LDL lowering in the S + E group. Similar findings were seen in the parallel study of patients previously on a statin with ezetimibe added at study enrollment and when looking at the study population as a whole. Thus, effective LDL lowering did not improve lower extremity functional capacity in PAD. However, resting ABI did improve in the E group and in the patients as a whole, whereas exercise ABI did not.
There is an increasing evidence base underlying the benefits of statins on morbidity and mortality in PAD. In a study of 1,374 patients with PAD, higher doses of statins were associated with lower incidence of all-cause mortality and cardiac death (4
). Statin therapy reduced coronary events in elderly patients with PAD and LDL ≥125 mg/dl (21
). Analysis of data from the Scandinavian Simvastatin Survival Study demonstrated a 38% reduction in the risk of the development of new or worsening claudication symptoms over a follow-up period of 5.4 years (22
). In more than 6,700 patients in the Heart Protection Study, first major vascular events were reduced from 32.7% with placebo to 26.4% with simvastatin. There also was a 16% relative reduction in the rate of first peripheral vascular event, independent of baseline LDL, primarily due to a 20% relative reduction in noncoronary revascularization procedures (23
). The latter study suggests that it may be the pleiotropic effects of statins that are responsible for benefit in PAD (24
). In general, the mechanisms of benefit remain incompletely understood (25
). Despite guideline-recommended use, statins are underused in the PAD population (26
Several studies suggest benefits of statins on walking performance, although there is some lack of consensus in the literature. A nonrandomized retrospective study demonstrated that, when adjusted for comorbidities, patients with PAD and an ABI <0.9 who were taking statins demonstrated better 6-min walk performance, walking velocity, and overall performance score. A similar patient group studied by the same investigators showed less of a decline in annual walking performance when taking statins (27
). Mohler et al. (6
) studied 354 patients with symptomatic PAD randomized to either placebo or atorvastatin 10 mg or atorvastatin 80 mg and found an increase in pain-free walking time, a secondary endpoint, after 12 months in the atorvastatin 80-mg group (p = 0.025). However, the primary endpoints were negative. A recent multicenter double-blind trial found no increase in treadmill walking time compared with dietary intervention alone after 28 weeks of lipid lowering with either high- or low-dose niacin + lovastatin (28
). In addition, a randomized study of atorvastatin 80 mg for 6 months in PAD demonstrated no effect on brachial artery flow-mediated dilation, carotid intimal-medial thickness, or ABI (29
Despite achieving significant LDL and total cholesterol lowering, no improvement in functional performance was found in the present study. There are several potential explanations for this. For one, nearly one-half of the study population were already taking statins at the time of entry into the study and may have already received maximal benefit. However, even the group of statin-naïve patients did not show an improvement in exercise parameters. This may reflect a difference in power between studies, although Mohler et al (6
). likewise did not find an increase in treadmill walking time. Another potential explanation is that a decline in walking performance over time is expected in PAD. A prospective cohort of PAD patients demonstrated a decrease in 6-min walk distance over 2 years of follow-up (2
). Thus, the absence of a functional decline or decrease in perfusion or energetics in the present study may represent a positive finding. Thus, a limitation of the present study is the absence of a placebo group without active treatment to better understand the natural history. Due to the known morbidity and mortality benefits with statins in PAD, a placebo group was not included in the statin-naïve patients.
An improvement in resting ABI was noted in the E group and the patient group as a whole. Although this is encouraging and underscores the simplicity and importance of ABI as a measure, it is less clear as to why this benefit did not translate into any improvement in calf muscle physiology or exercise capacity. In our baseline study of this patient population, we found a correlation between ABI and per-fusion index of r = 0.33, p < 0.01 (12
). More subtle measures of physiological changes are needed in this patient population to test the potential benefits of novel therapies.
In the same patient population, we showed plaque regression in the superficial femoral artery in statin-naïve patients treated with either simvastatin or simvastatin/ezetimibe (14
). It may be that this effect of the initiation of statin therapy is responsible for much of the therapeutic benefit in PAD. Despite the plaque regression in the statin-naïve patients begun on statins, no improvement in tissue perfusion, cellular metabolism, or functional status was seen. This suggests that the vascular benefits of statins in PAD may primarily be at the level of macrovascular atherosclerotic plaque and not at the microvascular or cellular level. It may be that improvement in tissue perfusion and cellular metabolism is necessary for improvement in functional performance. This speaks against the benefit of lipid lowering in PAD being pleiotropic. This also points out the need for therapies focused on improving skeletal muscle perfusion and metabolism in PAD.
In coronary artery disease, high-dose statin therapy has been shown to reduce atherosclerotic plaque progression by intravascular ultrasound (30
) and also to have an impact on angina and time to ischemic events (31
). The mechanisms of skeletal muscle dysfunction and claudication in PAD may be quite different from those of myocardial dysfunction and angina in CAD.
The study was primarily powered to measure atherosclerotic plaque progression and not to detect changes in calf muscle perfusion or metabolism. As a result, it was not powered to detect differences in perfusion or metabolism among the groups. Given the relatively large SDs for PCr recovery time, an improvement in calf muscle energetics over time with LDL reduction may have been shown with a larger study population. It is possible that more than 2 years of statin therapy is needed to observe a difference in calf muscle perfusion or metabolism. Alternatively, a more potent statin or higher dose of simvastatin may have resulted in an improvement in calf muscle metabolism or perfusion. For example, an improvement in pain-free walking time was found in PAD patients treated with atorvastatin 80 mg.
We studied only the more symptomatic leg for calf muscle perfusion and energetics; however, the MRA and exercise parameters are certainly influenced by disease in both legs. We did not measure the extent of collateral blood vessels seen on MRI because the development of a signifi-cant collateral blood supply could alter the relationship between discrete stenosis seen on MRA and calf muscle measures of perfusion or metabolism.
A significant number of patients (n = 17) had to be excluded from study analysis due to interval revascularization of their study leg, which reduced overall power of the study. Due to the coexistence of renal disease in patients with PAD, additional patients were excluded from the gadolinium-based calf muscle perfusion and MRA due to concerns for nephrogenic systemic fibrosis. Nongadolinium-based techniques for measuring calf muscle perfusion and oxygenation are being developed. Arterial spin labeling (32
) and blood oxygen level–dependent imaging are 2 such promising techniques (33
Despite randomization of the statin-naïve patients, there remained a significant difference in the MRA index at each time point between S and S + E groups. Despite this difference in macrovascular disease, no differences in baseline physiological parameters were found. The relatively low LDL cholesterol at baseline for the study population as a whole may have contributed to the negative findings seen in this study. There was no placebo control in the statin-naïve patients for reasons stated previously. Without statins on board, many of these parameters may have worsened over the 2-year time period as has been demonstrated by others. The study would have been strengthened by the use of a placebo control in the E group.