Statin therapy in patients with peripheral artery disease

Studies of patients with atherosclerosis have shown that HMG-CoA reductase inhibitor (statin) therapy can be beneficial in these patients. These drugs have been reported to provide favorable pleiotropic effects by inhibiting vascular inflammation, stabilizing atherosclerotic plaques, reducing oxidative stress, and lowering cholesterol.1 In multiple clinical settings, statins have been shown to reduce the likelihood of cardiovascular events and mortality.2-7 Patients with peripheral artery disease (PAD) are at particularly high risk for poor cardiovascular outcome. Beyond improving survival rates and decreasing cardiovascular events,2,3 statins may also improve leg functioning in these patients.8

In several studies, improved outcome was observed after statin therapy in patients with high inflammatory activity.8-10 Thus, besides the lipid-lowering properties, the anti-inflammatory effects of statin therapy seem to play a major pathophysiologic role. We prospectively studied the effects of statin treatment on measurements of inflammatory activity and the cardiovascular outcome of patients with severe peripheral atherosclerosis. The end points were all-cause mortality and a composite of myocardial infarction (MI) and death.

Methods

A total of 515 consecutive inpatients (median age, 70 years; 296 men; median ankle—brachial index, 0.51) with angiographically proven, advanced PAD were enrolled in this cohort study. All patients were scheduled to have a peripheral percutaneous intervention. Statin therapy was initiated in a nonrandomized fashion in the outpatient clinic 1 to 2 months before the index hospital admission at the discretion of the treating physician. Demographic data, clinical characteristics, and various laboratory measurements, including the inflammatory markers high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), fibrinogen, leukocyte count, and serum albumin, were obtained on hospital admission. Patients were observed for a median of 21 months (interquartile range, 12 to 25 months) for all-cause mortality and the occurrence of MI. Multivariate statistical analysis was performed to assess the effects of statin treatment on mortality and MI, adjusting for inflammation and other potential confounders.

Results

Of the 515 patients, 269 (52%) were placed on statin therapy at least 4 weeks before being admitted to the hospital. Because of the nonrandomized design, patients receiving statins had more severe comorbidities, such as diabetes mellitus (and a higher median glycosylated hemoglobin level), higher body mass index, hypertension, and a history of coronary artery disease (CAD), MI, or stroke.

At the time of the index hospital admission at least 1 month after initiation of treatment, a lower cholesterol level was found in statin users. Statin users also exhibited markedly less inflammatory activity compared with nonusers, as shown by lower hs-CRP levels (P < .001), lower SAA levels (P = .001), lower fibrinogen levels (P = .007), higher albumin levels (P < .001), and lower neutrophil counts (P = .049; figure 1).

During follow-up, there were 61 cardiovascular deaths and four deaths from noncardiovascular causes; 19 patients had an MI, of which five were fatal and 14 were nonfatal. The adjusted survival rate and event-free survival rate (freedom from death and MI) were substantially improved for patients receiving statin therapy compared with patients who did not receive statin therapy (adjusted hazard ratio [HR], 0.52; P = .022, for survival; adjusted HR, 0.48; P = .004, for event-free survival, respectively). Particularly in patients with high inflammatory activity (hs-CRP levels > 0.42 mg/dL), statin therapy was associated with a substantially reduced risk of mortality (adjusted HR, 0.58; P = .046) or the composite of MI and death (adjusted HR, 0.46; P = .016), whereas patients with low inflammatory activity (hs-CRP ≤ 0.42 mg/dL) did not appear to have substantial improvement from statin therapy (figure 2). Similar findings were obtained by quantifying inflammation with SAA levels, fi-brinogen levels, neutrophil counts, or serum albumin levels.

Discussion

For patients with advanced PAD, particularly in the presence of high inflammatory activity, statin therapy seemed to reduce mortality and improve event-free survival, highlighting the importance of prescribing these drugs for patients with PAD. The current findings also support the hypothesis that, for patients with advanced atherosclerosis, the favorable results of statin therapy are mainly mediated through an anti-inflammatory pathway or, alternatively, that statins diminish the harmful effects of inflammation.

In patients with atherosclerotic disease, it has been shown that statins provide many favorable effects.1 By attenuating the vascular inflammatory process independently of their cholesterol-lowering effects,9,11,12 these drugs seem to substantially slow the harmful clinical effects of severe atherosclerosis. Inflamma-tion and the underlying cellular and molecular mechanisms have been recognized as cornerstones of atherosclerosis development and pro-

gression.13,14 In this context, plaque rupture and atherothrombosis, which may translate into the clinical complications of atherosclerotic disease, such as MI or stroke, are known to be closely associated with enhanced inflammatory activity. In line with these previous findings, we observed that the association between statin use and outcome was significantly affected by the patient’s inflammatory status. It appears that the most important mechanism of statin therapy is decreasing vascular inflammation or reducing the effects of inflammatory activity. This view is supported by reduced baseline inflammatory activity in statin users, which has been reported by others previously.1

Virtually identical findings to those in our present study were observed in the Cholesterol and Recurrent Events (CARE) trial, which evaluated patients with CAD.4 In that study, patients with high inflammatory activity received a significantly greater benefit from statins. In addition, the respective effect size of cardiovascular event reduction was similar to the findings in our study. Thus, it may be assumed that, for patients with severe atherosclerosis, the anti-inflammatory effects of statin drugs may be more important for the prevention of cardiovascular adverse events than for the lipid-lowering effects, which appear to be essential in preventing atherosclerosis from starting and progressing.

In published data on statins, the protective properties of the drugs have been shown predominantly in patients with cerebrovascular atherosclerosis and CAD.4-6,9 Patients with PAD are considered to have severe atherosclerotic disease, however, and it was uncertain whether statins would also show promise in these highest-risk patients. In two of the large randomized controlled trials, the Scandinavian Simvastatin Survival Study (4S)3 and the Heart Protection Study,2 statin therapy appeared to be beneficial with regard to cardiovascular outcome for patients with PAD. In our study, we investigated patients with even more advanced disease, as shown by a low ankle—brachial index, including a large proportion of patients with critical limb ischemia, all of whom required revascularization. Remarkably, even in these patients, statins performed well, even during the comparatively short follow-up phase.

Conclusion

In patients with widely advanced PAD, we found that treatment with statin drugs resulted in markedly improved intermediate-term cardiovascular outcome, particularly in

the presence of high inflammatory activity. However, in patients with low inflammatory activity, as indicated by hs-CRP levels below 0.42 mg/dL, no significant improvement of outcome was found with statin treatment. n