Thromb Haemost 2008; 99(01): 182-189
DOI: 10.1160/TH07-04-0265
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

High-dose atorvastatin in peripheral arterial disease (PAD): Effect on endothelial function, intima-media-thickness and local progression of PAD

An open randomized controlled pilot trial
Silviana Spring
1   Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland
,
Roger Simon
1   Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland
,
Bernd van der Loo
1   Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland
,
Tamara Kovacevic
1   Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland
,
Christiane Brockes
1   Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland
,
Valentin Rousson
2   Department of Biostatistics, ISPM, University Zurich, Zurich, Switzerland
,
Beatrice Amann-Vesti
1   Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland
,
Renate Koppensteiner
1   Clinic of Angiology, Department of Medicine, University Hospital Zurich, Switzerland
› Author Affiliations
Financial support: The study was an investigator-initiated trial and was supported by a research grant from Pfizer AG.
Further Information

Correspondence to:

Renate Koppensteiner, MD
Professor of Medicine
Head, Division of Angiology
Department of Internal Medicine II
Vienna General Hospital, Medical School
Währinger Gürtel 18 – 20, A – 1090 Vienna, Austria
Phone: +43 40 400 / 4670   
Fax: +43 40 400 / 4665   

Publication History

Received: 12 April 2007

Accepted after major revision: 02 November 2007

Publication Date:
24 November 2017 (online)

 

Summary

Beneficial effects of aggressive lipid-lowering with high-dose atorvastatin (80 mg/day) have been demonstrated in patients with coronary and cerebrovascular disease. The impact of such a therapy in patients with peripheral arterial disease (PAD) is less known so far. Here we studied the effects of high-dose atorvastatin on brachial artery endothelial function, common carotid intima-media thickness (IMT) and local progression of PAD in these patients. One hundred of 500 patients screened with documented PAD were randomly assigned to receive 80 mg of atorvastatin daily for six months or to continue on conventional medical treatment. Ninety-six percent of patients in the control group were on standard statin treatment. High resolution B-mode ultrasonography was used to study brachial artery flowmediated dilation (FMD), IMT and ankle-brachial index (ABI) at baseline and at six months. FMD and IMT at baseline and at six months were 4.1 (0.06–8.6) versus 5.0 (0.76 vs. 8.1) %, p=0.96, and 0.76 (0.66–0.82) versus 0.73 (0.63–0.81) mm, p=0.41, respectively, in the atorvastatin group, and 2.66 (-1.9 – 6.9) versus 3.65 (0.0–8.6)%, p=0.02, and 0.78 (0.71–0.90) versus 0.77 (0.70–0.90) mm, p=0.48,in the control group. ABI at baseline and at six months was not different in either group. LDL cholesterol was reduced from 2.53 (2.21–3.28) to 1.86 (1.38–2.29) mM (p<0.0001) in the atorvastatin group, whereas levels remained stable in the control group [2.38 (1.94–3.16) vs.2.33 (1.82–2.84) mM, p=0.61]. Major adverse cardiovascular events occurred in 2.1% in the atorvastatin group and 1.9% in the control group (p= 0.61). In conclusion, in this pilot trial aggressive lipid-lowering with 80 mg of atorvastatin daily for six months had no effect on brachial artery FMD in patients with PAD. IMT andABI were also similar in patients with and without high-dose atorvastatin at six months.


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  • References

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  • 2 Amarenco P, Labreuche J, Lavallée P. et al. Statins in stroke prevention and carotid atherosclerosis: systematic review and meta-analysis. Stroke 2004; 35: 2902-2909.
  • 3 Amarenco P, Bogousslavsky J, Callahan A. for the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549-559.
  • 4 Bainton D, Sweetnam P, Baker I. et al. Peripheral vascular disease: Consequence for survival and association with risk factors in the Speedwell prospective heart disease study. Br Heart J 1994; 72: 128-132.
  • 5 Dormandy JA, Murray GD. The fate of the claudicant- a prospective study of 1969 claudicants. Eur J Vasc Surg 1991; 5: 131-133.
  • 6 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy- 3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21: 1712-1719.
  • 7 Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 2003; 23: 729-736.
  • 8 Ridker PM, Rifai N, Pfeffer MA. et al. Long-term effects of pravastatin on plasma concentrations of C-reactive protein. The Cholesterol and Recurrent Events (CARE) investigators. Circulation 1999; 100: 230-235.
  • 9 Davis M, Atwal AS, Nair DR. et al. The effect of short-term lipid-lowering with atorvastatin on carotid artery intima media thickness in patients with peripheral vascular disease: a pilot study. Curr Med Res Opin 2000; 16: 198-204.
  • 10 Ejiri J, Inoue N, Tsukube T. et al. Oxidative Stress in the pathogenesis of thoracic aortic aneurysm : protective role of statin and angiotensin II type 1 receptor blocker. Cardiovasc Res 2003; 59: 988-996.
  • 11 Celermajer DS, Adams MR, Clarkson P. et al. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med 1996; 334: 150-154.
  • 12 Balletshofer BM, Rittig K, Enderle MD. et al. Endothelial dysfunction is detectable in young normotensive degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 2000; 101: 1780-1784.
  • 13 Neunteufl TH, Katzenschlager R, Hassan A. et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 1997; 129: 111-118.
  • 14 Yataco AR, Corretti MC, Gardner AW. et al. Endothelial reactivity and cardiac risk factors in older patients with peripheral arterial disease. Am J Cardiol 1999; 83: 754-758.
  • 15 Brevetti G, Silvestro A, Schiano V. et al. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: Additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation 2003; 108: 2093-2098.
  • 16 Gokce N, Keaney Jr JF, Hunter LM. et al. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003; 41: 1769-1775.
  • 17 Bots ML, Hofman A, Grobbee DE. Increased common carotid intima media thickness. Adaptive response or a reflection of atherosclerosis? Findings from the Rotterdam Study. Stroke 1997; 28: 2442-2447.
  • 18 Ebrahim S, Papacosta O, Whincup P. et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999; 30: 841-850.
  • 19 Bots ML, Hoes AW, Hofman A. et al DE. Cross-sectionally assessed carotid intima-media thickness relates to long-term risk of stroke, coronary heart disease and death as estimated by available risk functions. Intern Med 1999; 245: 269-276.
  • 20 O'Leary DH, Polak JF, Kronmal RA. et al. Carotidartery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group (see comments). N Engl J Med 1999; 340: 14-22.
  • 21 Kastelein JJP, de Groot E, Sankatsing R. Atherosclerosis measured by B-mode ultrasonography: effect of statin therapy on disease progression. Am J Med 2004; 116: 31S-36S.
  • 22 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486-2497.
  • 23 Kanters SDJM, Algra A, van Leeuwen MS. et al. Reproducibility of In Vivo Carotid Intima-Media Thickness Measurements: A Review. Stroke 1997; 28: 665-671.
  • 24 Dogra GK, Watts GF, Chan DC. et al. Statin therapy improves brachial artery vasodilator function in patients with type 1 diabetes and microalbuminuria. Diabet Med 2005; 22: 239-242.
  • 25 Alonso R, Mata P, de Andres R. et al. Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin. Atherosclerosis 2001; 157: 423-429.
  • 26 Agewall S, Hernberg A. Atorvastatin normalizes endothelial function in healthy smokers. Cli Sci 2006; 111: 87-91.
  • 27 Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007; 45: 645-654.
  • 28 Smilde TJ, Wissen S, Wollersheim H. et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, doubleblind trial. Lancet 2001; 357: 577-581.
  • 29 van Etten RW, de Koning EJP, Honing ML. et al. Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2002; 22: 799-804.
  • 30 Laufs U, La Fata V, Plutzky J. et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 1129-1135.
  • 31 Kalinowski L, Dobrucki LW, Brovkovych V. et al. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation 2002; 105: 933-938.
  • 32 Wassmann S, Laufs U, Baumer AT. et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 2001; 59: 646-654.
  • 33 Taylor AJ, Kent SM, Flaherty PJ. et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002; 106: 2055-2060.
  • 34 Schmermund A, Achenbach S, Budde T. et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months. Circulation 2006; 113: 427-437.
  • 35 Feringa HHH, Karagiannis SE, van Waning VH. et al. The effect of intensified lipid-lowering therapy on long-term prognosis in patients with peripheral arterial disease. J Vasc Surg 2007; 45: 936-943.
  • 36 Ridker PM, Cannon CP, Morrow D. et al. Pravastatin or atorvastatin evaluation and infection therapy – thrombolysis in myocardial infarction 22 (Prove it – TIMI 22) investigators. N Engl J Med 2005; 352: 20-28.
  • 37 Nissen SE, Tuzcu EM, Schoenhagen P. et al. Reversal of atherosclerosis with aggressive lipid lowering (Reversal) investigators. N Engl J Med 2005; 352: 29-38.
  • 38 Tekin A, Tekin G, Güzelsoy D. et al. Effects of atorvastatin (10 mg) on hemostatic and inflammatory parameters in hyperlipidemic patients with angiographically proven coronary artery disease. Am J Cardiol 2004; 93: 206-209.
  • 39 Blanco-Colio LM, Martin-Ventura JL, de Teresa E. et al. on behalf of the ACTFAST investigators. Increased soluble Fas plasma levels in subjects at high cardiovascular risk. Atorvastatin on inflammatory markers (AIM) study, a substudy of ACTFAST. Arterioscler Thromb Vasc Biol 2007; 27: 168-174.

Correspondence to:

Renate Koppensteiner, MD
Professor of Medicine
Head, Division of Angiology
Department of Internal Medicine II
Vienna General Hospital, Medical School
Währinger Gürtel 18 – 20, A – 1090 Vienna, Austria
Phone: +43 40 400 / 4670   
Fax: +43 40 400 / 4665   

  • References

  • 1 Schwarz GG, Anders GO, Ezekowitz MD. et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACLE Study: A Randomized Controlled Trial. J Am Med Assoc 2001; 285: 1711-1718.
  • 2 Amarenco P, Labreuche J, Lavallée P. et al. Statins in stroke prevention and carotid atherosclerosis: systematic review and meta-analysis. Stroke 2004; 35: 2902-2909.
  • 3 Amarenco P, Bogousslavsky J, Callahan A. for the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549-559.
  • 4 Bainton D, Sweetnam P, Baker I. et al. Peripheral vascular disease: Consequence for survival and association with risk factors in the Speedwell prospective heart disease study. Br Heart J 1994; 72: 128-132.
  • 5 Dormandy JA, Murray GD. The fate of the claudicant- a prospective study of 1969 claudicants. Eur J Vasc Surg 1991; 5: 131-133.
  • 6 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy- 3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21: 1712-1719.
  • 7 Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 2003; 23: 729-736.
  • 8 Ridker PM, Rifai N, Pfeffer MA. et al. Long-term effects of pravastatin on plasma concentrations of C-reactive protein. The Cholesterol and Recurrent Events (CARE) investigators. Circulation 1999; 100: 230-235.
  • 9 Davis M, Atwal AS, Nair DR. et al. The effect of short-term lipid-lowering with atorvastatin on carotid artery intima media thickness in patients with peripheral vascular disease: a pilot study. Curr Med Res Opin 2000; 16: 198-204.
  • 10 Ejiri J, Inoue N, Tsukube T. et al. Oxidative Stress in the pathogenesis of thoracic aortic aneurysm : protective role of statin and angiotensin II type 1 receptor blocker. Cardiovasc Res 2003; 59: 988-996.
  • 11 Celermajer DS, Adams MR, Clarkson P. et al. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med 1996; 334: 150-154.
  • 12 Balletshofer BM, Rittig K, Enderle MD. et al. Endothelial dysfunction is detectable in young normotensive degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 2000; 101: 1780-1784.
  • 13 Neunteufl TH, Katzenschlager R, Hassan A. et al. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 1997; 129: 111-118.
  • 14 Yataco AR, Corretti MC, Gardner AW. et al. Endothelial reactivity and cardiac risk factors in older patients with peripheral arterial disease. Am J Cardiol 1999; 83: 754-758.
  • 15 Brevetti G, Silvestro A, Schiano V. et al. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: Additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation 2003; 108: 2093-2098.
  • 16 Gokce N, Keaney Jr JF, Hunter LM. et al. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003; 41: 1769-1775.
  • 17 Bots ML, Hofman A, Grobbee DE. Increased common carotid intima media thickness. Adaptive response or a reflection of atherosclerosis? Findings from the Rotterdam Study. Stroke 1997; 28: 2442-2447.
  • 18 Ebrahim S, Papacosta O, Whincup P. et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999; 30: 841-850.
  • 19 Bots ML, Hoes AW, Hofman A. et al DE. Cross-sectionally assessed carotid intima-media thickness relates to long-term risk of stroke, coronary heart disease and death as estimated by available risk functions. Intern Med 1999; 245: 269-276.
  • 20 O'Leary DH, Polak JF, Kronmal RA. et al. Carotidartery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group (see comments). N Engl J Med 1999; 340: 14-22.
  • 21 Kastelein JJP, de Groot E, Sankatsing R. Atherosclerosis measured by B-mode ultrasonography: effect of statin therapy on disease progression. Am J Med 2004; 116: 31S-36S.
  • 22 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486-2497.
  • 23 Kanters SDJM, Algra A, van Leeuwen MS. et al. Reproducibility of In Vivo Carotid Intima-Media Thickness Measurements: A Review. Stroke 1997; 28: 665-671.
  • 24 Dogra GK, Watts GF, Chan DC. et al. Statin therapy improves brachial artery vasodilator function in patients with type 1 diabetes and microalbuminuria. Diabet Med 2005; 22: 239-242.
  • 25 Alonso R, Mata P, de Andres R. et al. Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin. Atherosclerosis 2001; 157: 423-429.
  • 26 Agewall S, Hernberg A. Atorvastatin normalizes endothelial function in healthy smokers. Cli Sci 2006; 111: 87-91.
  • 27 Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007; 45: 645-654.
  • 28 Smilde TJ, Wissen S, Wollersheim H. et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, doubleblind trial. Lancet 2001; 357: 577-581.
  • 29 van Etten RW, de Koning EJP, Honing ML. et al. Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2002; 22: 799-804.
  • 30 Laufs U, La Fata V, Plutzky J. et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97: 1129-1135.
  • 31 Kalinowski L, Dobrucki LW, Brovkovych V. et al. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation 2002; 105: 933-938.
  • 32 Wassmann S, Laufs U, Baumer AT. et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 2001; 59: 646-654.
  • 33 Taylor AJ, Kent SM, Flaherty PJ. et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002; 106: 2055-2060.
  • 34 Schmermund A, Achenbach S, Budde T. et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months. Circulation 2006; 113: 427-437.
  • 35 Feringa HHH, Karagiannis SE, van Waning VH. et al. The effect of intensified lipid-lowering therapy on long-term prognosis in patients with peripheral arterial disease. J Vasc Surg 2007; 45: 936-943.
  • 36 Ridker PM, Cannon CP, Morrow D. et al. Pravastatin or atorvastatin evaluation and infection therapy – thrombolysis in myocardial infarction 22 (Prove it – TIMI 22) investigators. N Engl J Med 2005; 352: 20-28.
  • 37 Nissen SE, Tuzcu EM, Schoenhagen P. et al. Reversal of atherosclerosis with aggressive lipid lowering (Reversal) investigators. N Engl J Med 2005; 352: 29-38.
  • 38 Tekin A, Tekin G, Güzelsoy D. et al. Effects of atorvastatin (10 mg) on hemostatic and inflammatory parameters in hyperlipidemic patients with angiographically proven coronary artery disease. Am J Cardiol 2004; 93: 206-209.
  • 39 Blanco-Colio LM, Martin-Ventura JL, de Teresa E. et al. on behalf of the ACTFAST investigators. Increased soluble Fas plasma levels in subjects at high cardiovascular risk. Atorvastatin on inflammatory markers (AIM) study, a substudy of ACTFAST. Arterioscler Thromb Vasc Biol 2007; 27: 168-174.