Clinical assessment of low molecular weight heparin effects in peripheral vascular disease. A new low molecular weight heparin in the treatment of peripheral arterial disease. Randomized trial of the effects of low-dose calcium-heparin in patients with peripheral arterial disease and claudication. Italian CAP Study Group. Acenocoumarol and pentoxifylline in intermittent claudication. A controlled clinical study. The APIC Study Group. Efficacy of low-molecular-weight heparin in the management of intermittent claudication.
This study was carried out, using the double-blind method vs placebo, on 36 patients suffering from stage II peripheral vascular disease (PVD) according to Leriche, to check the clinical and hemorrheologic effects of the administration of a new low molecular weight heparin (LMWH). After a one-month washout period, the patients were randomly assigned either to the group treated with the LMWH (15,000 aXaU/day sc) or to the group treated with indistinguishable placebo. At the start of the study and after three and six months of treatment, clinical, instrumental, and laboratory tests were performed to assess local and systemic efficacy and tolerance. The LMWH under study caused a statistically significant increase in claudication time, with a parallel increase in the absolute claudication distance and in the interval free of pain. The drug also led to a significant increase in activated partial thromboplastin time, the values of which, however, remained within the normal limits, and to a marked reduction in blood viscosity. No significant variation was observed in the tolerability parameters in the two treatment groups, and no local or systemic adverse reactions occurred. A double blind study was conducted on patients afflicted with obstructive arteriopathy of the lower limbs in order to verify the efficacy and tolerability, in long term treatment, of a new low molecular weight heparin (Alfa LMW1). Of the 55 patients studied, 28 were treated with Alfa LMW1 given subcutaneously in doses of 8,000 I.U. AXa daily for 6 months; the remainder 27 were treated with Placebo. Efficacy of Alfa LMW1 was evaluated by monitoring the lower limb segmental pressures and some pressure ratios (thigh/arm, ankle/arm). Moreover, by means of the treadmill test, also checked were: time of claudication; ankle/arm pressure ratio before and after exercise and time required to return to initial pressure. By means of the strain gauge plethysmography, basal flow and peak flow after ischemia were also evaluated. The results obtained indicated a significant difference in efficacy between the two therapies, most notable after the third month. While in the Alfa LMW1 group a significant (p less than 0.01) and progressive improvement by the third month of treatment was seen, in the Placebo group a slight improvement was registered only at the end of the study and this was significantly inferior with respect to the comparison group. We performed a long-term, multicenter, randomized, double-blind trial to evaluate the efficacy and tolerability of low-dose, subcutaneous calcium-heparin (12,500 IU/day) in comparison with placebo in patients with stable peripheral arterial disease of the lower extremities.
                At the end of a 2-week washout period, during which aspirin placebo was given, 201 patients were randomly assigned to receive either subcutaneous calcium-heparin or placebo for two 3-month treatment periods, each of which was followed by a 6-month period of observation. All of the patients were given low-dose aspirin (50 mg/day) throughout the 18-month study. The main efficacy variables were pain-free and maximum walking time (by standard treadmill test). Patients answered a questionnaire about pain and the limitation of daily activities. Results were analyzed by intention-to-treat.
                At the end of the study, the estimated increase in pain-free walking time was 39% in the heparin group and 23% in the placebo group (P = 0.09). The estimated increase in maximum walking time was 40% in the heparin group and 16% in the placebo group (P = 0.05). Patients treated with heparin also reported that they had to stop walking because of leg pain, or had daily activities limited by leg pain, less frequently than the placebo group (P <0.01).
                Treatment with low-dose subcutaneous calcium-heparin is safe and effective in improving walking performance and reducing physical disability in patients with stable peripheral arterial disease and claudication. The efficacy and safety of pentoxifylline (400 mg tid orally) and acenocoumarol, administered singly or in combination, in the treatment of intermittent claudication associated with chronic occlusive arterial disease were evaluated in a multi-center, randomized, factorial, blind clinical trial involving 146 patients. The response to treatment was assessed by measuring pain-free walking time on the treadmill and by Doppler ankle/arm systolic pressure ratio at rest and after treadmill. Both pentoxifylline and acenocoumarol were significantly more effective than placebo in increasing the proportion of patients who improved their performance on the treadmill after one year of treatment. Benefit from active treatment was also apparent from the results of Doppler examinations performed after physical exercise. No significant differences were observed in comparing the effect of one active drug versus the other or versus the combined treatment. Five major hemorrhagic complications were registered in anticoagulated patients, two fatal cerebral hemorrhages and one gastrointestinal bleeding occurring in the group treated with both active drugs. The investigators conclude that (1) pentoxifylline is effective and safe in the treatment of patients with intermittent claudication (2) the benefits of oral anticoagulant therapy are outweighed by the risk of serious bleeding, and (3) the risk of bleeding is probably increased by the combined treatment with pentoxifylline. Treating chronic arterial occlusive disease with heparin is controversial because of the risks associated with long-term anticoagulant therapy. Low molecular weight (LMW) heparin (mw about 5000 Dalton), which selectively inhibits the Xa factor with minimal risk of hemorrhage, seems to offer new possibilities in the prevention and treatment of both venous and acute arterial thromboembolism. Therefore, 44 patients with intermittent claudication were recruited to a randomized, double-blind, controlled study. Twenty-two were treated for six months with a single daily subcutaneous dose (15,000 UaXa) of LMW heparin and 22 with placebo administered in the same way over the same period of time. After six months, LMW heparin treatment not only improved walking capacity (by lengthening the pain-free walking time by 25%) but also significantly modified the hemorrheologic pattern (by reducing fibrinogen concentrations and whole blood viscosity at low shear rates). LMW heparin also exerted an antithrombotic and profibrinolytic effect by significantly increasing both the anti-Xa factor and plasminogen activity without markedly modifying activated partial thromboplastin time (+20%). No LMW heparin-treated patient hemorrhaged or reported other noteworthy side effects. These results suggest LMW heparin might be a useful drug in the long-term treatment of chronic arterial occlusive disease of the limbs.
No benefit of heparin, LMWHs or oral anticoagulants has been established for intermittent claudication. An increased risk of major bleeding events has been observed especially with oral anticoagulants. The use of anticoagulants for intermittent claudication cannot be recommended at this stage.