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Prof. Denis Clement ,
Intermittent claudication of the lower limbs is the most common symptomatic manifestation of peripheral arterial disease (PAD). Besides disturbing the daily lives of patients, intermittent claudication carries a very high risk of cardiovascular morbidity and mortality. Also, hypertension is a risk factor for vascular disorders including PAD. There is no consensus yet on the specific treatment of hypertension in PAD patients because of the limited number of controlled studies on antihypertensive therapy in such a specific PAD population.
The prevalence of PAD in males is approximately 1.5% in those under the age of 50 and reaches 4 to 5% in the above 50 years age group. In females the prevalence is lower in the under age 50 but, contrary to common belief, it is as high as it is in males in those who are over the age of 60 (1). The prevalence of asymptomatic PAD is approximately twice that of claudication. At least half to two-thirds of individuals with PAD are asymptomatic or have atypical limb exertional symptoms.
The clinical syndrome of intermittent claudication has reached a new dimension because it has become clear that on top of symptoms of aching pain in the legs during exercise, patients carry an increased risk of cardiovascular morbidity and mortality. Therefore, PAD has become an important marker of systemic atherosclerosis (2). Furthermore, there is a striking association between diabetes mellitus and atherosclerotic vascular disease.
The most potent risk factors for PAD include age, smoking and obesity. Additional risk factors are hyperlipidemia, elevated plasma homocysteine and hypertension (3-4).
Hypertension is associated with the development of atherosclerosis - particularly in the coronary and cerebral circulation - as well as with a two-to-threefold increased risk of claudication (3-4). Conversely, there is a significantly increased prevalence of hypertension in PAD patients. These data show that PAD and hypertension are very often linked to each other. This largely increases the total CV risk in these patients and the new challenge is to treat both conditions in the same patient.
The treatment of patients with hypertension and PAD should focus both on improving the local symptoms in the legs and on decreasing blood pressure and total CV risk. For local symptoms, the general rules are the ones for all claudication patients: regular training and stop smoking programs(5). The two most accepted drugs to help increase claudication distance are Naftidrofuryl (6) which also improves the quality of life, and Cilostazol, a phosphodiesterase inhibitor, more often used in USA and Japan (7). There is no convincing evidence that any one antihypertensive drug is superior to the other when it comes to improving claudication distance. Slightly better results are obtained with ACE inhibitors though. The newer centrally acting antihypertensive drugs combined with Imidazoline receptors like Moxonidine or Rimenidine, could play a particular role. It has been shown that Moxonidine can increase insulin sensitivity (8) which is appealing since many PAD patients have an increased resistance to insulin.
It has not been fully clarified, however, onto which level blood pressure should be decreased. In patients with diabetes associated to hypertension, values of 130/85 mm Hg. or lower should be obtained instead of the regular 140/90 mm Hg. And because risk in PAD is almost as high as in diabetes, one wonders whether goal values of 130/80 mm Hg. should be proposed as well but this has not been sufficiently addressed in the literature. Careful measurement of blood pressure is essential in this respect - 24-hour ambulatory recordings can improve measurement (9).
Other than blood pressure control, all efforts should made to decrease total cardiovascular risk. Antiplatelets drugs (5,7) like aspirin or clopidogrel should be administered in all PAD patients; ACE inhibitors have been shown to improve blood pressure control, claudication distance (see above) as well as the risk for cardiovascular morbidity and mortality (10). Recent information has been convincing in showing that statins are capable of decreasing such risks in similar ways (11).
All efforts should be made to improve patient compliance to these treatment regimes; cost calculations also should be made to see whether drug treatment costs would outweigh the costs necessary to treat cardiovascular events.
Thus, in PAD patients with hypertension (table 1), the total CV risk is substantially increased. Blood pressure should be brought down to at least 140/90 mm Hg. and if possible to pressures as low as 130/80 just like in diabetic patients. This can be done with all antihypertensive drugs, yet ACE inhibitors seem to have a slightly more favourable effect on claudication distance. Nevertheless, the most important measure will be to decrease total CV risk. This can be done by adding antiplatelet drugs, ACE inhibitors and statins to the treatment.
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2. Clement D.L.; H.Boccalon et al. A clinical approach to the management of the patient with coronary (Co) and/or carotid (Ca) artery disease who presents with leg ischaemia (Lis). International Angiology: 2000: 19: 97-125. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10905794
3. Kannel WB, D’Agostino RB, Wilson PW, et al. Diabetes, fibrinogen and risk of cardiovascular disease: the Framingham experience. Am Heart J 1990; 120:672-676. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2389702
4. Fowkes FG, Hously E, Riemersma RA, et al. Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am J Epidemiol 1992; 135:331-340. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1550087
5. Duprez D, Clement DL. Medical treatment of peripheral vascular disease: good or bad? Eur Heart J 1992;13:149-151. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1555609
6. Boccalon H; Lehert P; Mosnier M. Effect of naftidrofuryl on physiological walking distance in patients with intermittent claudication. Ann Cardiol Angéiol 2001: 50: 175-82 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12555510
7. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med 2001; 344: 1608-1621. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11372014
8. Haenni A. and Lithell H. Moxonidine improves insulin sensitivity in insulin-resistant hypertensives. J.Hypertension: 1999: 17: suppl 3: S29-S35 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10489096
9. Clement D.L.; ML De Buyzere; D.A. De Bacquer et al. Prognostic value of Ambulatory blood Pressure Recordings in patients with treated hypertension. New England Journal of Medicine: 2003: 348: 2407-2415 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12802026
10. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342: 145-153. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10639539
11. Heart Protection Study Collaborative Group (HPSCG), MRC/BHF Heart protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7–22. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
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