Candesartan treatment for peripheral occlusive arterial disease
Candesartan treatment for peripheral occlusive arterial disease
Objectives: In this prospective, double-blind, placebo-controlled study we observed the influence of treatment with candesartan 8mg on restenosis rates after stent implantation into the femoral artery 6 months after percutaneous transluminal angioplasty (PTA). We hypothesised that angiotensin II type 1 (AT1)-receptor blockade with candesartan would reduce restenosis rates by reducing angiotensin II-mediated intima hyperproliferation within the stented vessel segment in patients with peripheral occlusive disease.
Patients and Methods: Eighty-seven patients with peripheral occlusive arterial disease stage IIb who had been successfully treated with PTA and stent implantation were randomised to receive orally either candesartan 8mg (n = 44) or placebo (n = 43). Follow-up included evaluation of the degree of stenosis and thickness of the intima-media complex (primary endpoint). In addition, thickness of the interventricular septum, crurobrachial pressure ratios, and pain-free walking distance were determined (secondary endpoints).
Results: The degree of stenosis after 6 months was not significantly different between the groups studied (35.9 ± 39.6% for candesartan vs 36.0 ± 38.4% for placebo). Relevant restenosis including stent occlusions was found in nine patients (20.5%) in the candesartan group and in ten patients (23.3%) in the placebo group. The thickness of the intima-media complex 6 months after stent implantation was 1.60 ± 0.32mm in the candesartan group and 1.64 ± 0.32mm in the placebo group (not significant). There were no differences in secondary endpoints between the treatment groups. Controls after 3 months (20.9 ± 33.6% for candesartan vs 27.6 ± 38.3% for placebo; p = 0.39) and 9 months (44.1 ± 40.8% for candesartan vs 47.7 ± 37.2% for placebo; p = 0.67) of therapy revealed a lower degree of stenosis in patients treated with candesartan.
Conclusions: Although not significant, candesartan treatment tended to improve the prognostic benefits after stent implantation, suggesting that an antiproliferative effect after stenting may need higher doses than an antihypertensive effect of the drug. This hypothesis requires confirmation in further prospective studies with higher daily doses of candesartan, which are already in progress.
Femoropopliteal percutaneous transluminal an-gioplasty (PTA) is currently the preferred approach for the treatment of arteriosclerotically altered vascular segments. The procedure is minimally invasive to the patient and has almost reached technical perfection. However, the further fate of patients after PTA will be determined by the subsequent development of restenosis, which is still the `Achilles heel' of the procedure. Three distinct processes contribute to late lumen loss after PTA: early elastic recoil, late vessel remodelling, and neointimal hyperplasia. Stent implantation is able to prevent remodelling and to abolish recoil. However, neo-intimal hyperplasia is a complication after stenting and the main cause of in-stent restenosis. Several pharmacological approaches to reduce in-stent re-stenosis and progression of atherosclerosis have recently been investigated. There is evidence from in vitro and in vivo experiments that the renin-angiotensin-aldosterone system (RAAS) might be involved in the pathophysiology of restenosis. Whereas most clinical studies performed with ACE inhibitors were unable to detect a significant difference in the frequency of angiographic restenosis, several experimental studies have demonstrated that angiotensin II type 1 (AT1)-receptor antagonists may be effective in reducing intima thickening and progression of atherosclerosis. The first clinical study evaluating the effectiveness of valsartan in preventing coronary restenosis demonstrated a positive effect of valsartan treatment on neointimal proliferation after stenting. Wakeyama et al. recently failed to demonstrate a significant beneficial effect of candesartan treatment on neointimal hyperplasia in coronary arteries. Intimal hyperplasia, the major reason for in-stent re-stenosis, is much more frequent and more extensively expressed in arteries below the inguinal ligament, which leads - compared with coronary arteries - more often to the development of haemodynamically relevant restenoses. Therefore, the results obtained in coronary arteries may not be easily transferred to the situation in peripheral femoral arteries. The present study was designed to investigate the influence of AT1-receptor blockade with candesartan on restenosis and thickness of the intima-media complex within the stented vessel segment 6 months after the intervention. To the best of our knowledge this is the first clinical study investigating the effect of candesartan on restenosis after stenting of peripheral arteries.
Objectives: In this prospective, double-blind, placebo-controlled study we observed the influence of treatment with candesartan 8mg on restenosis rates after stent implantation into the femoral artery 6 months after percutaneous transluminal angioplasty (PTA). We hypothesised that angiotensin II type 1 (AT1)-receptor blockade with candesartan would reduce restenosis rates by reducing angiotensin II-mediated intima hyperproliferation within the stented vessel segment in patients with peripheral occlusive disease.
Patients and Methods: Eighty-seven patients with peripheral occlusive arterial disease stage IIb who had been successfully treated with PTA and stent implantation were randomised to receive orally either candesartan 8mg (n = 44) or placebo (n = 43). Follow-up included evaluation of the degree of stenosis and thickness of the intima-media complex (primary endpoint). In addition, thickness of the interventricular septum, crurobrachial pressure ratios, and pain-free walking distance were determined (secondary endpoints).
Results: The degree of stenosis after 6 months was not significantly different between the groups studied (35.9 ± 39.6% for candesartan vs 36.0 ± 38.4% for placebo). Relevant restenosis including stent occlusions was found in nine patients (20.5%) in the candesartan group and in ten patients (23.3%) in the placebo group. The thickness of the intima-media complex 6 months after stent implantation was 1.60 ± 0.32mm in the candesartan group and 1.64 ± 0.32mm in the placebo group (not significant). There were no differences in secondary endpoints between the treatment groups. Controls after 3 months (20.9 ± 33.6% for candesartan vs 27.6 ± 38.3% for placebo; p = 0.39) and 9 months (44.1 ± 40.8% for candesartan vs 47.7 ± 37.2% for placebo; p = 0.67) of therapy revealed a lower degree of stenosis in patients treated with candesartan.
Conclusions: Although not significant, candesartan treatment tended to improve the prognostic benefits after stent implantation, suggesting that an antiproliferative effect after stenting may need higher doses than an antihypertensive effect of the drug. This hypothesis requires confirmation in further prospective studies with higher daily doses of candesartan, which are already in progress.
Femoropopliteal percutaneous transluminal an-gioplasty (PTA) is currently the preferred approach for the treatment of arteriosclerotically altered vascular segments. The procedure is minimally invasive to the patient and has almost reached technical perfection. However, the further fate of patients after PTA will be determined by the subsequent development of restenosis, which is still the `Achilles heel' of the procedure. Three distinct processes contribute to late lumen loss after PTA: early elastic recoil, late vessel remodelling, and neointimal hyperplasia. Stent implantation is able to prevent remodelling and to abolish recoil. However, neo-intimal hyperplasia is a complication after stenting and the main cause of in-stent restenosis. Several pharmacological approaches to reduce in-stent re-stenosis and progression of atherosclerosis have recently been investigated. There is evidence from in vitro and in vivo experiments that the renin-angiotensin-aldosterone system (RAAS) might be involved in the pathophysiology of restenosis. Whereas most clinical studies performed with ACE inhibitors were unable to detect a significant difference in the frequency of angiographic restenosis, several experimental studies have demonstrated that angiotensin II type 1 (AT1)-receptor antagonists may be effective in reducing intima thickening and progression of atherosclerosis. The first clinical study evaluating the effectiveness of valsartan in preventing coronary restenosis demonstrated a positive effect of valsartan treatment on neointimal proliferation after stenting. Wakeyama et al. recently failed to demonstrate a significant beneficial effect of candesartan treatment on neointimal hyperplasia in coronary arteries. Intimal hyperplasia, the major reason for in-stent re-stenosis, is much more frequent and more extensively expressed in arteries below the inguinal ligament, which leads - compared with coronary arteries - more often to the development of haemodynamically relevant restenoses. Therefore, the results obtained in coronary arteries may not be easily transferred to the situation in peripheral femoral arteries. The present study was designed to investigate the influence of AT1-receptor blockade with candesartan on restenosis and thickness of the intima-media complex within the stented vessel segment 6 months after the intervention. To the best of our knowledge this is the first clinical study investigating the effect of candesartan on restenosis after stenting of peripheral arteries.
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