Effect of cloricromene on intermittent claudication. A randomized,double-blind,placebo-controlled trial in patients treated with aspirin: effect on claudication distance and quality of life

Abstract

The main aim of medical treatment for intermittent claudication (IC) is the reduction of mortality and morbidity from ischemic cardiovascular disease. However, symptomatic treatment with the aim of improving exercise performance and the overall quality of life may also be an important target of the clinical management of patients with intermittent claudication. Cloricromene, a drug with antithrombotic and anti-ischemic activities, has previously shown some promising results in patients with claudication. We have carried out a clinical trial to assess the effect of cloricromene on the claudication distance and on the quality of life of patients with IC chronically treated with aspirin. A total of 159 patients with IC, Stage II (Fontaine), were enrolled in a double-blind, randomized, prospective, multicenter study comparing cloricromene (100 mg orally b.i.d.) or an identical placebo for 6 months. All patients received 160 mg/day aspirin. The primary end-point was the improvement of initial claudication distance (ICD) at 6 months as measured by a standardized treadmill test. The secondary end-points were the absolute claudication distance (ACD) at 6 months, the percentage of patients defined as responders to treatment (improvement of ICD of at least 40%), changes in the ischemic window (IW), quality of life as assessed by the SF-36 questionnaire, and the occurrence of major cardiovascular events. The ICD increased in both treatment groups, with a non-significant difference at 6 months in favor of cloricromene of +12.3 m. The ACD, percentage of responders to treatment and ischemic window also improved in both groups with a slight, non-significant trend in favor of cloricromene. Pretreatment quality of life scores showed only a slight worsening compared with an age-matched, healthy population and did not change upon treatment. A post hoc subgroup analysis showed a significant benefit from cloricromene in patients with an ICD at enrollment higher than the median of the patient population. In conclusion, treatment with cloricromene for 6 months does not significantly improve claudication in patients with Stage II Fontaine peripheral arteriopathy chronically treated with aspirin. An improvement of 40-60 m in the ICD on a standardized treadmill test does not translate into a self-perceived improvement in the quality of life as assessed by the SF-36 questionnaire.

Keywords

intermittent claudication ischemic window peripheral vascular disease quality of life treadmill test

References

Hiatt WR , Hirsch AT , Regensteiner JG , Brass EP and the Vascular Clinical Trialists . Clinical trials for claudication. Circulation 1995; 92: 614-621.

Criqui MH , Fronek A , Barrett-Connor E , Klauber MR , Gabriel S , Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation 1985; 71: 510-515.

Fowkes FGR. Targeting subclinical atherosclerosis. Br Med J 1998; 316: 1764-1764.

Criqui MH , Langer RD , Fronek A et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: 381-386.

Leng GC , Fowkes FGR. The epidemiology of peripheral arterial disease. Vasc Med Rev 1993; 4: 5-18.

Antiplatelet Trialists’ Collaboration . Collaborative overview of randomized trials of antiplatelet therapy. I. Prevention of death, myocar-dial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994; 308: 81-106.

Weitz JI , Byrne J , Clagett P et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation 1996; 94: 3026-3049.

CAPRIE Steering Committee . A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-1339.

Gardner AW , Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA 1995; 274: 975-980.

10.

Hiatt WR. Current and future drug therapies for claudication. Vasc Med 1997; 2: 257-262.

11.

Hood SC , Moher D , Barber CG. Management of intermittent claudication with pentoxifilline: meta-analysis of randomized controlled trials. Can Med Assoc J 1996; 155: 1053-1059.

12.

Money SR , Herd JA , Isaacsohn JL et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg 1998; 27: 267-275.

13.

Beebe HG , Dawson DL , Cutler BS et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med 1999; 153: 2041-2050.

14.

Lowe GDO , Fowkes FGR , Dawes J , Donan PT , Lennie SE , Housley E. Blood viscosity, fibrinogen, and activation of coagulation and leukocytes in peripheral arterial disease and the normal population in the Edinburgh artery study. Circulation 1993; 87: 1915-1920.

15.

Woodburn KR , Rumley A , Hurtagh A , Lowe GDO. Acute exercise and markers of endothelial injury in peripheral arterial disease. Eur J Vasc Endovasc Surg 1997; 14: 140-142.

16.

Squadrito F , Prosdocimi M , Altavilla D , Zingarelli B , Caputi AP. Cloricromene. Cardiovasc Drug Rev 1991; 4: 357-371.

17.

Gresele P , Ribaldi E , Mezzasoma AM et al. Cloricromene inhibits leukotriene formation by human polymorphonuclear leukocytes by suppressing arachidonate release from membrane phospholipids. Biochem Pharmacol 1993; 45: 123-130.

18.

Stasi M , Gresele P , Prosdocimi M et al. Cloricromene inhibits G-protein-mediated activation of phospholipase A2 in human platelets. J Lipid Mediat Cell Signal 1993; 7: 253-267.

19.

Ribaldi E , Mezzasoma AM , Francescangeli E et al. Inhibition of PAF synthesis by stimulated human polymorphonuclear leucocytes with cloricromene, an inhibitor of phospholipase A2 activation. Br J Pharmacol 1996; 118: 1351-1358.

20.

Andreozzi GM , Allegra C , Borgatti E et al. The beneficial effect of orally administered cloricromene on the treadmill walking distance of patients with intermittent claudication. Eur Bull Drug Res 1994; 2: 1-9.

21.

Gresele P , Migliacci R. Extrapolation of trial results suggests that aspirin is useful in intermittent claudication. Br Med J 1998; 317: 1587-1588.

22.

Dav1` G , Giammaresi C , Catalano I et al. Platelet aggregation, ATP release and cytoplasmic Ca2+ movement: the effects of cloricromene. Thromb Res 1994; 76: 121-131.

23.

Newman AB , Siscovick DS , Manolio TA et al. Ankle-Arm Index as a marker of atherosclerosis in the cardiovascular health study. Circulation 1993; 88: 837-845.

24.

Feinberg RL , Gregory RT , Wheeler JR et al. The ischemic window: a method for the objective quantitation of the training effect in exercise therapy for intermittent claudication. J Vasc Surg 1992; 16: 224-250.

25.

Dickson CS , Gregory RT. Calculating the ischemic window: a simple method. J Vasc Technol 1995; 19: 147-148.

26.

Steawart AL , Hays RD , Ware JE. The MOS short-form general health survey. Med Care 1988; 26: 724-735.

27.

Apolone G , Mosconi P. The Italian SF-36 health survey: translation, validation and norming. J Clin Epidemiol 1998; 51: 1025-1036.

28.

Beattie DK , Golledge J , Greenhalgh RM , Davies AH. Quality of life assessment in vascular disease: toward a consensus. Eur J Vasc Endovasc Surg 1997; 13: 9-13.

29.

The European Agency for the Evaluation of Medicinal Products. Note for guidance on the clinical investigation in the treatment of chronic peripheral arterial occlusive disease. CMP/EWP/233/1995 final.

30.

Creutzig A , Bullinger M , Cachovan M et al. Improvement in the quality of life after i.v. PGE1 therapy for intermittent claudication. Vasa 1997; 26: 122-127.

31.

Apolone G , Cifani S , Liberati MC , Mosconi P. Questionario sullo stato di salute SF-36. Traduzione e validazione in italiano (progetto IQOLA). Medic 1997; 5: 86-94.

32.

Regensteiner JG , Steiner JF , Hiatt WR. Exercise training improves functional status in patients with peripheral arterial disease. J Vasc Surg 1996; 23: 104-115.