G. Finazzi Division of Hematology, Ospedali Riuniti, Bergamo, Italy (head: Prof. T. Barbui)

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1 77/ Schattauer GmbH Ongoing randomized clinical trials for the treatment of thrombosis in the antiphospholipid syndrome G. Finazzi Division of Hematology, Ospedali Riuniti, Bergamo, Italy (head: Prof. T. Barbui) Keywords Antiphospholipid antibodies, lupus anticoagulants, randomized clinical trials 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 lowintensity 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. The optimal management of thrombosis in patients with antiphospholipid antibodies (APA) is still uncertain since only retrospective studies are available. Current prophylaxis and therapy are chosen on the basis of the patient s Schlüsselwörter Antiphospholipidantikörper, Lupus-Antikoagulanz, randomisierte klinische Studien 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. Aktuelle klinische Studien zum Thrombosemanagement beim Antiphospholipid-Syndrom Hämostaseologie 2001; 21: clinical picture and predicted risk of vascular complications. No treatment is generally suggested in asymptomatic low-risk individuals, whereas oral anticoagulation is recommended in patients affected with major thrombotic complications (1). However, these recommendations remain to be confirmed in randomized clinical trials (RCTs), now in progress. In this chapter, the incidence and risk factors for thrombosis, current management recommendations and ongoing RCTs for prophylaxis and treatment of vascular complications in patients with APA will be reviewed. Natural history and risk factor for thrombosis The incidence and major predictors of thrombotic events have been analyzed in a large, prospective cohort study (2). 360 consecutive patients (M/F 118/242, median age 39, range 2-78 yrs), fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC, n = 326) and/or raised IgG anticardiolipin (ACA, n = 185), were collected from 16 Institutions referring to the Italian Registry of APA (3). After a median follow-up of 3.9 yrs (range 0.5-5), 34 patients developed a thrombotic complication, with a total incidence of 2.5% pt-yr. Multivariate logistic regression analysis identified a previous thrombosis and IgG ACA titer above 40 units as independent risk factors for thrombotic events. Patients with a history of vascular events showed a 5.4% pt-yr incidence of further complications as compared with 0.95% pt-yr in asymptomatic subjects. Another prospective investigation in symptomatic patients showed a 4.5% pt-yr rate of thrombosis, in good agreement with these data (4). The second major factor influencing the risk of vascular complications was IgG

2 78/47 Ongoing trials in antiphospholipid syndrome ACA above 40 GPL units. Elevated ACA levels were a significant predictor of thrombosis in other prospective investigations. In a case-control study in healthy adult men, the relative risk for venous thromboembolism was significantly associated with IgG ACA levels above 33 U and rose steeply above 38 GPL units (5). Patients with ACA exceeding 20 GPL or MPL units had a higher probability of cerebral ischemic or systemic thrombotic events during followup than patients without (6). Conversely, low positive ACA levels were not identified as independent risk factors for stroke (7, 8). Age, previous miscarriages, underlying SLE (systemic lupus erythematosus) or related diseases and smoking were not independent risk factors for thrombosis. In the multicentric European study of APA syndrome there was also no difference in the rate of thrombosis between patients with or without overt SLE (4). Hypertension, hyperlipidemia, diabetes and cigarette smoking were not significantly associated with thrombotic complications in other investigations in APS patients (9, 10). Different diagnostic tests for LAC were not associated with a different rate of thrombosis. We have previously reported that drvvt and KCT are preferentially sensitive to 2-glycoprotein I-dependent or prothrombin-dependent antiphospholipid antibodies respectively, and that the former type of antibody is more frequently associated with retrospective thrombosis than the latter (11). However, the simple positivity of either of two test is not sufficient to distinguish between the two antibodies. Therefore, their role in predicting thrombosis remains to be further assessed. Summing up, patients with APA at presentation might be divided into two groups: the first asymptomatic subjects has a low risk of vascular complications and needs only careful observation; the second patients with previous thrombosis and high ACA titer requires active therapy. Current management strategies The clinical course of APA patients after the first thrombotic event was retrospectively evaluated by different groups of investigators. Derksen et al. (12) showed that the probability of having no recurrence of thrombosis over an eight-year period was 100% among patients receiving oral anticoagulation with INR between 2.5 and 4.0, as compared with 22% among patients who stopped warfarin. Rosove et al. (13) reported in 70 patients that high-intensity warfarin therapy (INR 3) conferred better antithrombotic protection (0 events per year) than intermediate- (INR 2-2.9; 7% events per year), low-intensity warfarin (INR <1.9; 57% events per year), aspirin (32% events per year) or no treatment (19% events per year), but five patients had significant bleeding events at high warfarin dosage (3.1% events per year). These findings were confirmed in another study of 147 patients (10). Treatment with high-intensity warfarin (INR 3) with or without lowdose aspirin was significantly more effective than treatment with low-intensity warfarin (INR <3) with or without low-dose aspirin or treatment with aspirin alone in preventing further thrombotic events (recurrence rates 1.3%, 23% and 18% per year respectively). Significant bleeding occurred in 29 patients during warfarin-treatment (7.1% per year). These studies would indicate that APA patients who have had a documented major thrombotic event should receive life-long warfarin to achieve an INR of 3.0 or higher (14). However, there is concern about the implications of recommending such therapy on the basis of retrospective and nonrandomized data (15, 16). Fatal, cerebral or uncontrollable bleeding was reported during anticoagulation and the cumulative risk of hemorrhage is expected to increase with duration and intensity of treatment. Other studies questioned the need for high-intensity anticoagulation in all APA patients with thrombosis, suggesting to maintain an INR of for those with venous thromboembolism and to reserve intensive anticoagulation for those with recurrent or arterial vascular events (17-20). Thus, the benefit/risk of long-term highdose warfarin in the treatment of patients with APA syndrome is still uncertain and more compelling evidence is required before this therapy becomes acceptable as the standard of care (21). The WAPS project General design Fig. 1 General design of the WAPS study The WAPS study (Warfarin in AntiPhospholipid antibody Syndrome) is aimed to

3 79/48 Finazzi assess the benefit/risk of long-term highdose warfarin in the prevention of recurrences in patients with the antiphospholipid syndrome (APS) (22, 23). The trial was set up taking into account that the current treatment of APS patients is highly heterogenous (21). Thus, the general design was based on the uncertainty principle, that reflects the common sense adopted in the routine clinical practice. In other words, on the basis of clinical judgement, physicians categorize patients with APA and thrombosis as follows: 1. patients for whom clinicians are substantially uncertain as to the benefit/risk of high-dose warfarin. This group is expected to include most APA patients with thrombosis and will be randomized to high-dose warfarin (INR ) versus conventional treatment (that is the antithrombotic therapy currently recommended in patients without APA); 2. patients for whom clinicians are substantially certain that the benefit of high-dose warfarin overcomes the risks of treatment (for example patients with recurrent thrombosis despite conventional antithrombotic prophylaxis); 3. patients for whom clinicians are substantially certain that the risks of highdose warfarin overcomes the benefit (for example patients with uncertain thrombotic history or those with excessive bleeding risk). Patients in group 2 and 3 are not randomized, since their recruitment would be unethical, but they are registered and followed-up in an observational arm of the study together with asymptomatic patients with antiphospholipid antibodies. Patients included in the observational arm can be switched to the randomized study whenever the condition of uncertain benefit/risk does occur (for example asymptomatic patients who develop a thrombotic event). Both randomized patients and those included in the observational arm are followed up until an endpoint is reached or the study is concluded. Main end points will be major thrombosis, major bleeding and overall mortality. The observational arm is an essential part of the study to know how many patients are excluded from randomization Table 1 Baseline clinical and laboratory characteristics of 426 APA patients enrolled in the WAPS study and to obtain information on their clinical features and natural history. The importance of observational studies in evaluating the effects of treatments has been recently emphasized. In two excellent analysis, the results obtained in well-designed observational studies were similar to those registered in randomized, controlled trials (24, 25). In particular, two issues have been raised: first, observational data bases can be useful adjuncts to randomized cohorts to see whether efficacy under controlled conditions translates into effective treatments in routine practice; second, making the studies as much as like routine practice may help to make clinical trials more feasible and their results more widely generalizable (26). All these concepts have been borne in mind in the planning of the WAPS study. A scheme of the general study design is shown in Figure 1. Update and characteristics of enrolled patients Up to September 2000, 426 patients from 39 Hospitals in 5 actively participating countries (Italy, Norway, Poland, Czech Republic and Argentina) have been included. 315 patients have been enrolled in the observational and 111 in the randomized arms of the study, respectively. Their main clinical and laboratory features are summarized in Table 1. Reasons for excluding patients from the trial and including in the observational arm were as follows: asymptomatic in 128 cases; excessive bleeding risk in 51; absolute indication to high-dose warfarin in 48; refusal in 77; not specified in 11. Median follow-up is now 27 months (range 3-37) for the observational and 29 months (range 3-37) for the randomized cohorts of patients, respectively. A crucial issue for the outcome of the study is a correct adherence of randomized patients to the prescribed therapeutic range.to check this point, actual PT INR of the randomized patients was assessed at 3, 6, 12 and 24 months of follow-up. Median (and range) values of patients randomized in the high-dose group (assigned range ) was 3.1 ( ); 3.4 ( ), 3.1 ( ) and 3.1 ( ), whereas in the conventional group (assigned range 2.0 to 3.0) was 2.3 ( ), 2.4 ( ) and 2.7 ( ) and 2.5 ( ) respectively. The end of the enrolment phase for both arms of the study is foreseen after three years from starting in December At that point, an interim analysis of data will

4 80/49 Ongoing trials in antiphospholipid syndrome be carried out and the duration of followup of enrolled patients established accordingly. Other ongoing RCTs in the APA syndrome The PAPRE study The PAPRE (Patients with Antiphospholipid antibodies: Prevent Recurrent Events) study was presented at the Lupus Anticoagulants/Phospholipid Dependent Antibodies SSC Subcommittee Meeting held in Washington, D.C. USA, 14 August 1999 by Dr. Mark A. Crowther, Mc Master University, Hamilton ON, Canada. The study is a randomized, double blind clinical trial in which patients are included with (a) a history of previous, objectively documented arterial or venous thrombosis, and (b) an antiphospholipid antibody (either lupus anticoagulant or anticardiolipin antibody) that is positive on two occasions at least three months apart. Patients are allocated to receive warfarin administered with a target intensity of or The a priori sample size of the study is 90 patients and the study requires that all patients be followed for a minimum of two years after enrollment for detecting objectively documented recurrent thrombosis. The study protocol also requires periodic audits of the achieved intensity of anticoagulation. These audits are being performed to ensure that there is a clear differentiation between the lowand high-intensity groups. As of June 30, 2000, 97 patients had been enrolled at 12 clinical centres in Canada and Australia (Dr. Crowther, personal communication). As the study is ongoing and is double-blind, no result is available at present. Closing recruitment is anticipated in 2001 and completing follow-up early in The study is currently funded by the CIHR (Canadian Institute of Health Research). The WARSS-APASS collaboration The WARSS (Warfarin-Aspirin Recurrent Stroke Study)-APASS (The AntiPhospholipid Antibodies and Stroke Study) Collaboration is a cost-effective strategy to study apl in ischemic stroke patients (27). The WARSS, a double-blind clinical trial, randomly assigns eligible patients with an ischemic stroke to receive either warfarin (adjusted to an INR between 1.4 to 2.8) or aspirin (325 mg daily). The APASS group is receiving serum for ACA and plasma for LA determinations on each enrolled patient at the time of enrollment, yearly if APA positive and at the time of end point event occurrence. Given the expected prevalence of APA in this population, a sufficient power to determine which treatment is superior in preventing recurrent stroke and other thrombo-occlusive events is not foreseen. However, the main goals of the Collaboration are as follows: 1. to estimate and compare the risk of recurrent thrombotic events in ischemic stroke patients with or without APA given warfarin or aspirin therapy; 2. to obtain and describe pilot treatment differences based on APA status for future sample size/feasibility determinations; 3. to obtain serial, yearly APA titers and to characterize the temporal evolution of titers in ischemic stroke patients. Other possible outcomes of the study include: to determine which ischemic stroke patients with APA are at particularly high or low risk of recurrent thrombo-occlusive events based on clinical, laboratory and radiological data within treatment groups; to determine the safety of warfarin in these patients and to develop a bank of APA positive sera and plasma for future ancillary studies into APA mechanisms. Enrollment began in 1993 and was completed on June 30, ,834 patients have been enrolled and baseline studies for APA have been recently reported (28). Further data from this study are expected to be available soon. The UK trial in primary prophylaxis A randomized, open trial involving rheumatology centres throughout the United Kingdom has been announced by Dr. Khamashta at the recent 9th International Symposium on APA held in Tours, September 2000 (29). The study is co-ordinated by the Lupus Research Unit at St. Thomas Hospital, London, and funded by the Arthritis Research Campaign. The trial is aimed to compare two therapeutic options (aspirin, 75 mg/day vs. aspirin, 75 mg/day plus warfarin adjusted to INR 1.5) for the primary prevention of thrombosis in APApositive subjects with SLE or adverse pregnancy history. The primary outcome will be time of first thrombotic event. Secondary outcomes will be: identification of clinical and serological markers for thrombosis, side-effects of treatments and death by any cause. The recruitment of a sample size of 1,000 patients over a 5-year period is foreseen. Conclusions At the dawn of the 21st century, several questions about pathophysiology and clinical aspects of APA syndrome have been answered. Still, numerous important issues remain open, mainly the optimal management of patients. Only prospective and controlled clinical trials can give an appropriate answer to this fundamental clinical problem. It is encouraging that these trials are currently in progress, so that adequate data will be available in the next few years to guide our treatment of patients with APS. 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: Finazzi G, Brancaccio V, Moia M, et al. 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