Prof. Pavel Poredos,
The efficacy of preventive measures and medication used in secondary prevention has mostly been studied in coronary patients and data regarding PAD patients are scanty. Yet, as atherosclerosis is a generalised disease with similar ethiopathogenesis in different locations, systemic effects (including PAD) of treatment of risk factors are expected. Subgroup analysis of large trials and some small studies indicated that treatment of PAD patients with antiplatelet drugs, statins and ACE inhibitors prevent progression of local disease, reduce cardiovascular events and improve prognosis much to the same extent as with coronary patients. Therefore, therapeutic measures used in secondary prevention of atherosclerosis in PAD patients are as important as those used in coronary or cerebrovascular patients.
Peripheral vascular disease is just one manifestation of the general disease process of atherosclerosis. Therefore, patients with a clinical manifestation of peripheral arterial disease (PAD) are likely to have similar atherosclerotic lesions in other vascular beds, including in cerebral and coronary arteries. Even in the absence of a history of myocardial infarction or stroke, the relative risk of death from cardiovascular causes in patients with PAD is roughly the same as in patients with coronary or cerebrovascular disease. Consequently, atherosclerosis in the peripheral circulation should be considered in the same manner as atherosclerosis in the coronary circulation (1).
While great emphasis has been placed on the aggressive pharmacological management of coronary artery disease, less attention has been devoted to the pharmacological management of peripheral vascular disease, despite its significant morbidity and mortality. There is little evidence – based data on the efficacy of preventive measures on peripheral arterial occlusive disease. Nevertheless, as the ethiopathogenesis of atherosclerotic lesions in the peripheral arteries is similar or identical to that in other parts of the circulatory system, a comparable effect of preventive measures is expected in the full arterial system, including arteries of the legs.
For patients with symptomatic PAD, the focus must be mainly on prevention of ischemic complications and prevention of progression of the atherosclerotic process. In addition to risk factor management, designated interventions include administration of a platelet inhibitor, statins and in selected patients and the use of an angiotensin- converting enzyme inhibitor as well.
The benefit of aspirin for patients with known coronary and cerebrovascular disease is well established, but there are no trials which precisely estimate the preventive effect of aspirin in PAD patients. Nevertheless, some subgroup analyses of large trials have shown a positive effect of aspirin in PAD patients. The Physician health study confirmed that a low dose of aspirin reduces the progression of intermittent claudication and the risk of PAD surgery by 54% (2). The Antithrombotic Trialists collaboration concluded that the patency of an above knee bypass could be improved using aspirin. A similar effect was observed at dosages ranging from 75 to 350 mg/d. In addition, different studies confirmed the efficacy of aspirin in prevention of cardiovascular events in PAD patients. Metaanalysis of results of aspirin treatment in PAD patients showed a 23% reduction in serious vascular events, and similar benefit was observed among patients with intermittent claudication, bypass surgery or angioplasty (3). Favorable results were also obtained in studies using other antiplatelet drugs. Data from the CAPRIE study (enrolling also patients with PAD) showed that clopidogrel was at least as effective in prevention of cardiovascular complications in PAD patients as was aspirin (4).
Different studies have shown that hyperlipoproteinemia is also a relevant risk factor for PAD. Hypercholesterolemia was found in 45-59% of symptomatic PAD patients. Studies showing a benefit in cardiovascular and cerebrovascular outcome in patients with PAD treated with statins are available. However, studies specifying the outcome of the PAD itself are sparse.
In a 5-year follow-up study in which hypercholesterolemia was treated by a partial ileal bypass (POSCH study), the incidence of claudication was reduced to 19% in the surgically treated group vs. 33.6% in the control group and was related to the decrease in cholesterol concentration (23.3%) (5). Similarly, a 2-year follow-up study of 153 patients with femoral atherosclerosis treated with colestipol – niacin demonstrated a decreased progression of femoral atherosclerosis (6). Subgroup analysis of the Scandinavian Simvastatin Survival Study (4S) showed a risk reduction of almost 38% in new or worsening intermittent claudication (7). Some studies also indicated that besides their lipolytic effect, statins may directly influence peripheral haemodynamics. Statins, by preventing accompanying coronary or cerebrovascular incidents, also improve prognosis and survival of PAD patients. In the Heart Protection Study (HPS) PAD patients treated with simvastatin had a significant reduction in vascular events and revascularization. Five years of statin treatment prevented 70 major cardiovascular events in 1000 patients with PAD (8).
Ace inhibitors exert various beneficial actions on cardiac and vascular structure and function, beyond their blood pressure-lowering effects. Randomised, controlled clinical trials have shown that ACE inhibitors improve the endothelial function, cardiac and vascular remodeling, they retard the anatomic progression of atherosclerosis and reduce the risk of cardiovascular events and death. Therefore, these agents are recommended in the treatment of a wide range of patients at risk of adverse cardiovascular outcomes, including peripheral arterial disease. The antiatherogenic effect of the ACE inhibitor ramipril was confirmed in the HOPE study where it was shown that ramipril in PAD patients also prevents myocardial infarction, stroke and cardiovascular death (9).
As for other drugs used in secondary prevention of atherosclerosis, there are no relevant data on their efficacy in PAD patients. However, because of the similar ethiopathogenesis, the various therapeutic measures used in secondary prevention of atherosclerosis are expected to be effective in different forms of the atherosclerotic disease. One of the most important aspects of PAD treatment in fact is managing symptoms. Patients with symptomatic PAD often have a decreased quality of life because of pain walking and limitation of mobility. Positive treatment outcomes in intermittent claudication have been shown with treatment regimens that include: exercise, haemorheologic drugs (pentoxyfylline, cilostazol), risk factor modification, particularly smoking cessation, and also drugs used in secondary prevention of atherosclerosis (10, 11). Among antiplatelet drugs, only ticlopidine’s haemodynamic effects were found to relieve symptoms, increase walking distance and improve lower extremity ankle pressure indices (12). There are additional data on improvement of functional outcomes of PAD patients treated with statins. Subjects taking statins had a better 6-minute walk performance, faster walking capacity and a higher summary performance score (13). Mondillo and co-workers reported improvement of walking performance and symptoms of claudication in hypercholesterolemic patients with PAD during high dose therapy with simvastatin (14). Similarly, atorvastatin treatment (80mg/day for 12 months) improved the pain-free walking distance and community-based physical activity in patients with intermittent claudication (15). Therefore, patients with claudication may not only benefit from a reduction in vascular events from statin treatment but also have an improved lifestyle. However, these trials were rather small and their results need to be confirmed in larger trials.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Belch JF, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management. Arch Intern Med 2003; 163: 884-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12719196
2. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. preventive services task force. Ann Intern Med 2002; 136: 161-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11790072
3. Gerald F. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11786451
4. CAPRI Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1995; 348: 1329-39. 5. Buchwald H, Varco RL, Matts JP et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. N Engl J Med 1990; 323: 946-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2205799
6. Blankerhorn DH, Azen SP, Grawford DW et al. Effects of colestipol-niacin therapy on human femoral atherosclerosis. Circulation 1991; 83: 438-47. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1991366
7. Pedersen TR, Kjekshus J, Pyörälä K et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study. Am J Cardiol 1998; 81: 333-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9468077
8. Heart Protection Study Collaborative Group: MRC BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo controlled trial. Lancet 2002; 360: 7-22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12114036
9. Kim CK, Schmalfuss CM, Schofield RS, Sheps DS. Pharmacological treatment of patients with peripheral arterial disease. Drugs 2002; 65 637-47. 10. Beebe HG. Intermittent claudication: effective medical management of a common circulatory problem. Am J Cardiol 2001; 87: 14D-8D. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11434895
11. Tjon JA, Rieman LE. Treatment of intermittent claudication with pentoxifylline and cilostazol. Am J Health Syst Pharm 2001; 58: 485-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11286146
12. Arcan JC, Panak E. Ticlopidine in the treatment of peripheral occlusive arterial disease. Semin Thromb Hemost 1989; 15: 167-70. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2665087
13. McDermott MM, Guralnik JM, Greenland P et al. Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease. Circulation 2003; 107: 757-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12578881
14. Mondillo S, Ballo P, Barbati R, Guerrini, Ammaturo T, Agricola, E 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 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12714124
15. Mohler ER, Hiatt WR, Creager MA for the Study Investigators. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation 2003; 108: 1481-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12952839
Our mission: To reduce the burden of cardiovascular disease
© 2018 European Society of Cardiology. All rights reserved