Ongoing randomized clinical trials for the treatment of thrombosis in the antiphospholipid syndrome

Summary

Thrombotic events are a major clinical problem for patients with antiphospholipid antibodies (APA). However, current recommendations for their prevention and treatment are still based on retrospective studies. Data from large scale, prospective clinical trials are required to ultimately identify the optimal management of these patients. To date, at least four randomized studies are underway. The WAPS and PAPRE clinical trials are aimed to establish the correct duration and intensity of oral anticoagulation in APA patients with major arterial or venous thrombosis. The WARSS-APASS is a collaborative study to evaluate the efficacy and safety of aspirin or low-dose oral anticoagulants in preventing the recurrence of ischemic stroke. The recently announced UK Trial compares low-dose aspirin with or without low-intensity anticoagulation for the primary prevention of vascular events in APA-positive patients with SLE or adverse pregnancy history, but still thrombosis-free. It is hoped that the results of these trials will be available soon since clinicians urgently need more powerful data to treat their patients with the APA syndrome.

Zusammenfassung

Thrombotische Ereignisse sind ein großes klinisches Problem für Patienten mit Antiphospholipid-Antikörpern (APA). Aktuelle Empfehlungen zur Prävention und Therapie stützen sich jedoch nach wie vor auf retrospektive Studien. Daten aus groß angelegten, prospektiven klinischen Studien sind erforderlich, um die optimale Behandlung dieser Patienten letztendlich festzulegen. Bisher laufen mindestens vier randomisierte Studien. In den klinischen Studien WAPS und PAPRE sollen die korrekte Dauer und Intensität einer oralen Antikoagulation bei APA-Patienten mit schwerer arterieller oder venöser Thrombose ermittelt werden. WARSS-APASS ist eine Gemeinschaftsstudie, in der Wirksamkeit und Sicherheit von Azetylsalizylsäure oder niedrig dosierten oralen Antikoagulanzien zur Verhütung von Rezidiven eines ischämischen Schlaganfalls untersucht werden sollen. Die vor kurzem angekündigte UK-Studie vergleicht niedrig dosierte Azetylsalizylsäure mit oder ohne Antikoagulation geringer Intensität zur Primärprävention von vaskulären Ereignissen bei APA-positiven Patienten mit SLE oder ungünstiger Schwangerschaftsanamnese, die jedoch noch thrombosefrei sind. Die Ergebnisse dieser Studien werden hoffentlich bald vorliegen, da Ärzte dringend aussagekräftigere Daten zur Behandlung ihrer Patienten mit dem APA-Syndrom benötigen.

Keywords

Antiphospholipid antibodies - lupus anticoagulants - randomized clinical trials

Schlüsselwörter

Antiphospholipidantikörper - Lupus-Antikoagulanz - randomisierte klinische Studien

• References

• 1 Greaves M, Cohen H, Machin SJ, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome. Br J Haematol 2000; 109: 704-15.
• 2 Finazzi G, Brancaccio V, Moia M. et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies. A four-year prospective study from the Italian Registry. Am J Med 1996; 100: 530-6.
• 3 Italian Registry of Antiphospholipid Antibodies. Thrombosis and thrombocytopenia in antiphospholipid syndrome (idiopathic and secondary to SLE). Haematologica 1993; 78: 313-8.
• 4 Vianna JL, Khamashta MA, Ordi-Ros J. et al. Comparison of the primary and secondary antiphospholipid syndrome: a European multicenter study of 114 patients. Am J Med 1994; 96: 3-9.
• 5 Ginsburg KS, Liang MH, Newcomer L. et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992; 117: 997-1002.
• 6 Nencini P, Baruffi MC, Abbate R. et al. Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischemia. Stroke 1991; 189-93.
• 7 Sletnes KE, Smith P, Abelnoor M, Arnesen H, Wisloff F. Antiphospholipid antibodies after myocardial infarction and their relation to mortality, reinfarction and non-haemorrhagic stroke. Lancet 1992; 339: 451-3.
• 8 Muir KW, Squire IB, Alwan W, Lees KR. Anticardiolipin antibodies in an unselected stroke population. Lancet 1994; 344: 452-6.
• 9 Levine SR, Brey RL, Joseph CLM. et al. Risk of recurrent thromboembolic events in patients with focal cerebral ischemia and antiphospholipid antibodies. Stroke 1992; 23 (Suppl. 01) I 29-32.
• 10 Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GRV. The management of thrombosis in the antiphospholipid syndrome. N Engl J Med 1995; 332: 993-7.
• 11 Galli M, Finazzi G, Bevers EM, Barbui T. Kaolin clotting time and dilute Russell’s viper venom time distinguish between prothrombindependendent and β2-glycoprotein I-dependent antiphospholipid antibodies. Blood 1995; 86: 617-23.
• 12 Derksen RHWM, de Groot PG, Kater L. et al. Patients with antiphospholipid antibodies and venous thrombosis should receive long term anticoagulant treatment. Ann Rheum Dis 1993; 52: 689-92.
• 13 Rosove MH, Brewer PMC. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Int Med 1992; 117: 303-8.
• 14 Lockshin MD. Answers to the antiphospholipid-antibody syndrome?. N Engl J Med 332: 1025-7.
• 15 Nasr SZ, Parke AL. Thrombosis in the antiphospholipid syndrome. N Engl J Med 1995; 333: 666 (letter).
• 16 Slivka A, Walz E. Thrombosis in the antiphospholipid syndrome. N Engl J Med 1995; 333: 665-6 (letter).
• 17 Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-91.
• 18 Krnic-Barrie S, O’Connor CR, Looney SW. et al. A retrospective review of 61 patients with antiphospholipid syndrome. Analysis of factors influencing thrombosis. Arch Intern Med 1997; 157: 2101-8.
• 19 Schulman S, Svenungsson E. Granqvists. et al. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998; 104: 332-8.
• 20 Gonzales-Trujillo JL, Villegas-Jimenez A, Rios-Luna N. et al. Conventional intensity may be as effective as high intensity oral anticoagulation in the antiphospholipid syndrome. J Autoimmunity 2000; 15: A22 (abstr.).
• 21 Khamashta MA. Management of thrombosis in the antiphospholipid syndrome. In: Hughes Syndrome. Khamashta MA. ed. London: Springer; 2000: 391-6.
• 22 Finazzi G, Barbui T. et al. Feasibility of a randomized clinical trial for the prevention of recurrent thrombosis in the antiphospholipid syndrome: the WAPS project. Ann Med Interne (Paris) 1996; 147 (Suppl. 01) 38-41.
• 23 Finazzi G, Marchioli R. The WAPS (Warfarin in AntiPhospholipid Syndrome) study. Update and preliminary results. The Hematology Journal 2000; 1: 135 (abstr.).
• 24 Kjell Benson BA, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000; 342: 1878-86.
• 25 Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies and the hierarchy of research design. N Engl J Med 2000; 342: 1887-92.
• 26 Pocock SJ, Elbourne DR. Randomized trials or observational tribulations?. N Engl J Med 2000; 342: 1907-9.
• 27 The WARSS APASS, PICCS and HAS Study Groups. The feasibility of a collaborative double-blind study using an anticoagulant. J of Stroke and Cerebrovasc Dis 1997; 7: 100-12.
• 28 Levine S, Brey RL, Tilley BC. et al. The WARSS-APASS collaborative study: baseline aPL prevalence. J Autoimmunity 2000; 15: A8 (abstr.).
• 29 Khamashta MA. Primary prevention of thrombosis in subjects with positive antiphospholipid antibodies. Autoimmunity 2000; 15: 249-53.