Low-density lipoprotein lowering does not improve calf muscle perfusion, energetics, or exercise performance in peripheral arterial disease.

J Am Coll Cardiol. 2011 Aug 30;58(10):1068-76.

West AM, Anderson JD, Epstein FH, Meyer CH, Wang H, Hagspiel KD, Berr SS, Harthun NL, Weltman AL, Dimaria JM, Hunter JR, Christopher JM, Kramer CM.

Source

Department of Medicine, University of Virginia Health System, University of Virginia, Charlottesville, Virginia.

Abstract

OBJECTIVES:

We hypothesized that low-density lipoprotein (LDL) reduction regardless of mechanism would improve calf muscle perfusion, energetics, or walking performance in peripheral arterial disease (PAD) as measured by magnetic resonance imaging and magnetic resonance spectroscopy.

BACKGROUND:

Statins improve cardiovascular outcome in PAD, and some studies suggest improved walking performance.

METHODS:

Sixty-eight patients with mild to moderate symptomatic PAD (age 65 ± 11 years; ankle-brachial index [ABI] 0.69 ± 0.14) were studied at baseline and annually for 2 years after beginning simvastatin 40 mg (n = 20) or simvastatin 40 mg/ezetimibe 10 mg (n = 18) if statin naïve, or ezetimibe 10 mg (n = 30) if taking a statin. Phosphocreatine recovery time was measured by (31)P magnetic resonance spectroscopy immediately after symptom-limited calf exercise on a 1.5-T scanner. Calf perfusion was measured using first-pass contrast-enhanced magnetic resonance imaging with 0.1 mM/kg gadolinium at peak exercise. Gadolinium-enhanced magnetic resonance angiography was graded. A 6-min walk and a standardized graded Skinner-Gardner exercise treadmill test with peak Vo(2) were performed. A repeated-measures model compared changes over time.

RESULTS:

LDL reduction from baseline to year 2 was greater in the simvastatin 40 mg/ezetimibe 10 mg group (116 ± 42 mg/dl to 56 ± 21 mg/dl) than in the simvastatin 40 mg group (129 ± 40 mg/dl to 90 ± 30 mg/dl, p < 0.01). LDL also decreased in the ezetimibe 10 mg group (102 ± 28 mg/dl to 79 ± 27 mg/dl, p < 0.01). Despite this, there was no difference in perfusion, metabolism, or exercise parameters between groups or over time. Resting ABI did improve over time in the ezetimibe 10 mg group and the entire study group of patients.

CONCLUSIONS:

Despite effective LDL reduction in PAD, neither tissue perfusion, metabolism, nor exercise parameters improved, although rest ABI did. Thus, LDL lowering does not improve calf muscle physiology or functional capacity in PAD. (Comprehensive Magnetic Resonance of Peripheral Arterial Disease; NCT00587678).

Statins and Peripheral Arterial Disease

Based on the Heart Protection Study, persons with PAD should be treated with statins regardless of age, gender, or initial serum lipids levels. 

In addition to that  - Three double-blind, randomized, placebo-controlled studies have also demonstrated that statins improve walking performance in persons with PAD.

In a study of 69 persons, mean age 75 years, with intermittent claudication, a mean ABI of 0.63, and a serum LDL cholesterol of 125 mg/dl or higher, 3 of 34 persons (9%) treated with simvastatin and 6 of 35 persons (17%) treated with placebo died before the 1-year study was completed . Compared with placebo, simvastatin significantly increased treadmill exercise time until the onset of intermittent claudication by 24% at 6 months and by 42% at 1 year after therapy. 

In a study of 354 persons, mean age 68 years, with intermittent claudication and hypercholesterolemia, at 1-year follow-up, compared with placebo, atorvastatin 80 mg daily significantly improved pain-free treadmill walking distance by 40% and significantly improved community-based physical activity. 

In a study of 86 persons, mean age 67 years, with intermittent claudication and hypercholesterolemia, at 6-month follow-up, compared with placebo, simvastatin 40 mg daily significantly improved pain-free walking distance and total walking distance on a treadmill, significantly improved the mean ABI at rest and after exercise, and significantly improved symptoms of claudication.

It is also interesting to note that Statin use is also associated with superior leg functioning independent of cholesterol levels and other potential confounders. The data suggest that non-cholesterol-lowering properties of statins may influence functioning in persons with and without PAD.

1. Aronow WS, Nayak D, Woodworth S, Ahn C. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at 6 months and at 1 year after treatment. Am J Cardiol. 2003;92:711–2. 

2. Mohler ER, III, Hiatt WR, Creager MA., the Study Investigators Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation. 2003;108:1481–6.

3. Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med. 2003;114:359–64.

Lancet. 2002 Jul 6;360(9326):7-22. 

MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.

Heart Protection Study Collaborative Group.

Abstract  : Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations.

METHODS: 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.

FINDINGS: All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4).  

The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause.

 

INTERPRETATION: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.