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Statins and intermittent claudication

 

Clinical bottom line


Results from one large and one small randomised controlled trial suggest that 40 mg/day of simvastatin can reduce symptoms of intermittent claudication. Most patients with intermittent claudication should be taking a statin to reduce risk of CHD or stroke anyway.


Intermittent claudication is caused by peripheral arterial disease in the lower limbs. It limits walking distance, causes pain, reduces quality of life, and has a mortality rate of 3 to 5% per year. Patients are at high risk of coronary heart disease and cerebrovascular disease, and most will fall within current guidelines for treatment with statins to reduce this risk. Bandolier wondered if statins might also alleviate the symptoms of intermittent claudication.

In the Scandinavian Simvastatin Survival Study (4S), patients with a history of myocardial infarction or angina, with raised total cholesterol levels, were treated with simvastatin (20 to 40 mg/day) or placebo for five years [1]. Analysis of adverse experiences likely to be caused by atherosclerotic disease shows a reduction in the risk of new or worsening intermittent claudication from 3.6% on placebo to 2.3% on simvastatin (relative risk reduction of 38%) [2]. The study was randomised and double-blinded, but this outcome was based on patients' reports of symptoms (subjective) and clinical examination (possible interobserver bias), with no systematically applied objective measurement of atherosclerosis. It does, however, strongly suggest that simvastatin has effects on the arterial vasculature beyond the coronary and cerebral circulations, with clinically significant/demonstrable effects on ischaemic symptoms.

In another double-blind, placebo-controlled study, 86 patients with peripheral arterial disease (Fontaine stage II), intermittent claudication, and total cholesterol greater than 220 mg/dL (5.7 mmol/L) were randomised to treatment with simvastatin (40 mg/day) or placebo for six months [3]. Pain-free and total walking distance, resting and postexercise ankle-brachial indexes, self-assessment questionnaire scores and lipid profiles were determined at 0, 3 and 6 months.

Table 1 Effect of simvastatin (40 mg/day) on walking distance and ankle-brachial index (mean ± SD)

Baseline
6 Months
Measurement

simvastatin (n=43)

placebo (n=43)
simvastatin (n=43)
placebo (n=43)
Pain-free walking (metres)
72 ± 13
74 ± 15
190 ± 38
100 ± 34
Total walking (metres)
96 ± 18
93 ± 13
230 ± 45
104 ± 29
Ankle-brachial index - rest
0.53 ± 0.06
0.55 ± 0.06
0.65 ± 0.08
0.56 ± 0.10
-postexercise
0.35 ± 0.11
0.39 ± 0.07
0.55 ± 0.12
0.36 ± 0.13
Results are expressed as Mean ± SD

Measures of walking distance and ankle-brachial index improved significantly more in the simvastatin group than the placebo group. Intermediate values were recorded at three months.

The self-assessment questionnaire asked patients to estimate on a 10-step scale:

All parameters improved in the simvastatin group compared to placebo at three months, and improvement was maintained or increased at six months.

Expected reductions were seen in the simvastatin group for total and LDL cholesterol. There were no significant changes in HDL cholesterol, triglycerides, aminotransferases or creatinine kinase in either group.

The authors suggest that these observed improvements with simvastatin are not due primarily to reduction in size of peripheral atherosclerotic plaques, since the change in ankle-brachial index is small compared to increase in walking distance. It is more likely that functional effects such as plaque stabilisation and improved endothelial function are responsible.

Another randomised, double-blinded study compared lovastatin (20 mg/day) with policosanol (10 mg/day) for 20 weeks in patients with moderately severe intermittent claudication [4]. There was no placebo group. Measurements of walking distance, ankle-brachial index and quality of life improved with policosanol, but not lovastatin. It may be that lovastatin is not effective, at least at this dose, but since there were only 14 patients in each group, the results are not robust.

Comment


It seems reasonable to expect that statins will affect the entire vascular system, not just the coronary and cerebral circulations, and not unreasonable to hope that that they might bring about clinical improvement in symptoms of peripheral ischaemic disease. Results from one large and one small randomised controlled trial suggest that 40 mg/day of simvastatin can reduce symptoms of intermittent claudication. Larger randomised controlled trials with blinded objective outcome assessments are needed to confirm this, compare simvastatin with other statins/therapies, and understand the mechanisms involved. One trial involving 350 patients with symptomatic intermittent claudication treated with atorvastatin or placebo is underway. Meanwhile most patients with intermittent claudication should be taking a statin to reduce risk of CHD or stroke anyway.

References


  1. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994 344: 1383-1389.
  2. TR Pedersen et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998 81: 333-335.
  3. S Mondillo 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: 359-364.
  4. G Castano et al. Effects of policosanol and lovastatin in patients with intermittent claudication: a double-blind comparative pilot study. Angiology 2003 54: 25-38.