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Thromb Haemost 2000; 83(05): 672-677
DOI: 10.1055/s-0037-1613890
Review Article
Schattauer GmbH

Improvement of Walking Distance by Defibrotide in Patients with Intermittent Claudication

Results of a Randomized, Placebo-controlled Study (the DICLIS Study)
F. Violi
1   From the Istituto di Ia Clinica Medica, Università “La Sapienza” Roma
,
E. Marubini
2   Istituto di Statistica Medica e Biometria, Università degli Studi di Milano
,
S. Coccheri
3   Cattedra e Divisione di Angiologia, Università degli Studi di Bologna
,
G. G. Nenci
4   Istituto di Medicina Interna e Vascolare, Università degli Studi di Perugia, Italy
› Author AffiliationsThe DICLIS Study was funded by Crinos – Villaguardia (CO), Italy. We are especially indebted to Drs M. Iacobelli, P. Ferrari and G. Clerici for their support.
Further Information

Publication History

Received 01 October 1999

Accepted after resubmission 14 January 2000

Publication Date:
08 December 2017 (online)

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Summary

Defibrotide is an antithrombotic drug which enhances prostacyclin production and activates fibrinolytic system. The aim of this study was to investigate the improvement of walking distance in patients with intermittent claudication treated with defibrotide.

DICLIS was a double blind, placebo-controlled study which included patients with walking distance autonomy at a standardized treadmill test ≤350 ≥100 meters. A total of 310 patients were randomly allocated to placebo (n = 101), defibrotide 800 mg/day (n = 104) or defibrotide 1200 mg/day (n = 105).

During a one year follow-up, the Absolute Walking Distance (AWD) was measured six times (0, 30, 60, 90, 180, 360 days).

Similar improvement in walking distance was found in the three groups until the 90th day; thereafter placebo group showed no further increase, while AWD continued to increase in the defibrotide groups. Between the 180th and 360th day visits, AWD was significantly higher (P <0.01) in patients given defibrotide than in patients given placebo. No difference in efficacy was observed between the two dosages of defibrotide. No differences in side effects were observed among the three groups.

The results of the present trial suggest that long-term administration of defibrotide improves walking distance in patients with intermittent claudication.

Abbreviations: DICLIS = Defibrotide Intermittent CLaudication Italian Study, AWD = Absolute Walking Distance, IC = Intermittent Claudication, PVD = Peripheral Vascular Disease, LVOCF = Last Valid Observation Carried Forward, ITT = Intention-To-Treat

Appendix, please see p. 676.

Key words

Polydeoxyribonucleotides - fibrinolytic agents - intermittent claudication
 

  • References

  • 1 Coffman JD. Intermittent claudication: Be conservative. N Engl J Med 1991; 325: 577-8.
    CrossrefPubMedGoogle Scholar
  • 2 Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: 381-6.
    CrossrefPubMedGoogle Scholar
  • 3 Weitz JI, Byrne J, Clagett P, Farkouh ME, Porter JM, Sackett DL, Strandness E, Taylor LM. Diagnosis and Treatment of Chronic Arterial Insufficiency of the Lower Extremities: A Critical Review. Circulation 1996; 94: 3026-49.
    CrossrefPubMedGoogle Scholar
  • 4 Berti F, Rossoni G, Niada R, Omini C, Pretolani M, Mandelli C. Beneficial Effects of Defibrotide against Myocardial Ischemia and Decline of BAdrenoceptor Function in the Rabbit. Haemostasis 1986; 16 (Suppl. 01) 13-7.
    PubMedGoogle Scholar
  • 5 Niada R, Mantovani M, Prino G, Pescador R, Berti F, Omini C, Folco GC. Antithrombotic activity of a polydeoxyribonucleotidic substance extracted from mammalian organs: a possible link with prostacyclin. Thromb Res 1981; 23: 233-46.
    CrossrefPubMedGoogle Scholar
  • 6 Loebel P, Schroer K. Selective stimulation of coronary vascular PGI2 but not of platelet thromboxane formation by defibrotide in the platelet perfused heart. Naunyn Schmiedebergs Arch Pharmacol 1985; 331: 125-30.
    CrossrefPubMedGoogle Scholar
  • 7 Coccheri S, Biagi G, Legnani C, Bianchini B, Grauso F. Acute effects of Defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man. A placebo controlled study. Eur J Clin Pharmacol 1988; 35: 151-6.
    CrossrefPubMedGoogle Scholar
  • 8 Biagi G, Legnani C, Rodorigo G, Coccheri S. Modulation of arachidonate metabolite generation in human blood by oral defibrotide. Arzneimittelforschung 1991; 41: 511-5.
    PubMedGoogle Scholar
  • 9 Costantini V, Luzi P, Boselli C, Bastiano ML, Bisacci R, Nenci GG. Effects of defibrotide on prostanoid synthesis and fibrinolytic activity in human veins. Eur J Intern Med 1989; 01: 115-20.
    PubMedGoogle Scholar
  • 10 Mussoni L, Evolvi C, Donati MB. Activation of plasma and vascular fibrinolytic activity by a polydeoxyribonucleotidic substance, fraction P, in rats and rabbits. Thromb Haemost 1979; 42: 388.
    PubMedGoogle Scholar
  • 11 Violi F, Ferro D, Alessandri C, Quintarelli C, Saliola M, Balsano F. Inhibition of tissue plasminogen activator inhibitor by defibrotide in atherosclerotic patients. Semin Thromb Hemost 1989; 15: 226-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Violi F, Ferro D, Saliola M, Quintarelli C, Basili S, Balsano F. Effect of oral defibrotide on tissue-plasminogen activator inhibitor balance. Eur J Clin Pharmacol 1992; 42: 379-83.
    PubMedGoogle Scholar
  • 13 Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, Hoppensteadt D, Kinchla NM, Neuberg D, Waller EK, Antin JH, Soiffer R, Vredenburgh J, Lill M, Woolfrey AE, Bearman SI, Iacobelli M, Fareed J, Guinan EC. Treatment of Severe Veno-Occlusive Disease With Defibrotide: Compassionate Use Results in Response Without Significant Toxicity in a High-Risk Population. Blood 1998; 92: 737-44.
    PubMedGoogle Scholar
  • 14 Strano A, Fareed J, Sabbà C, Albano O, Allegra C, Carlizza A, Binaghi F, Fronteddu F, Del Guercio R, Arpaia MR, Pinto A, Alletto G, Walenga JM, Hoppensteadt D, Nazzari M, Ferrari PA. A double-blind, multicenter, placebo controlled, dose comparison study of orally administered defibrotide: preliminary results in patients with peripheral arterial disease. Semin Thromb Hemost 1991; 17 (Suppl. 02) 228-34.
    PubMedGoogle Scholar
  • 15 Fleiss JL. The parallel Group Design. In: Fleiss JL. editors. The design and analysis of clinical experiments. New York: John Wiley and Sons; 1986: 46-51.
    Google Scholar
  • 16 Diggle PJ, Liang KY, Zeger SL. editors. The analysis of longitudinal data. Oxford University Press; 1994
    Google Scholar
  • 17 Walter SD, Feinstein AR, Wells CK. Coding ordinal independent variables in multiple regression analyses. Am J Epidemiol 1987; 125: 319-23.
    CrossrefPubMedGoogle Scholar
  • 18 SAS Institute. SAS’s user guidelines: basic version. 5th edition. Cary NC: SAS Institute; 1985
    Google Scholar
  • 19 Bagger JP, Helligsoe P, Randsbaek F, Kimose HH, Jensen BS. Effect of Verapamil in Intermittent Claudication. A Randomized, Double-Blind, Placebo-Controlled, Cross-over Study after Individual Dose-Response Assessment. Circulation 1997; 95: 411-5.
    CrossrefPubMedGoogle Scholar
  • 20 Brevetti G, Chiariello M, Ferulano G, Policicchio A, Nevola E, Rossini A, Attisano T, Ambrosio G, Siliprandi N, Angelini C. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation 1988; 77: 767-73.
    CrossrefPubMedGoogle Scholar
  • 21 Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease: A prospective double-blind arteriographically controlled trial. Lancet 1985; 01: 415-9.
    PubMedGoogle Scholar
  • 22 Goldhaber SZ, Manson JE, Stampfer MJ, LaMotte F, Rosner B, Buring JE, Hennekens CH. Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians’ Health Study. Lancet 1992; 340: 153-5.
    PubMedGoogle Scholar
  • 23 Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, Grasselli S, Violi F, Hellemans H, Vanhove P. Ticlopidine in the treatment of intermittent claudication: a 21-months double-blind trial. J Lab Clin Med 1989; 115: 84-91.
    PubMedGoogle Scholar
  • 24 Smith FB, Rumley A, Lee AJ, Leng GC, Fowkes FGR, Lowe GDO. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758-63.
    CrossrefPubMedGoogle Scholar