Finn Wisløff

A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).

Summary.  Background: The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high‐intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0–4.0) vs. moderate (INR 2.0–3.0) intensities of anticoagulation failed to confirm this assumption. Methods: We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high‐intensity warfarin (INR range 3.0–4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0–3.0 in 52 patients or aspirin alone, 100 mg day−1 in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk. Results: The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow‐up was 3.2 (SD 0.6) in the high‐intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high‐intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49–7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high‐intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92–5.15). Conclusions: High‐intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life

Summary. We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S‐Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony‐stimulating factor (G‐CSF) + Epo. S‐Epo ≤ 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S‐Epo > 500 U/l and ≥ 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G‐CSF + Epo. The overall response rate was 42% with 28·3% achieving a complete and 13·2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0·001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0·01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48–74%) to treatment with G‐CSF + Epo. The majority of these patients have shown complete and durable responses.

Guidelines on the diagnosis and management of multiple myeloma 2005

In 2001, guidelines for the diagnosis and management of myeloma were published by the Guidelines Working Group of the UK Myeloma Forum (UKMF) on behalf of the British Committee for Standards in Haematology (BCSH) (UK Myeloma Forum; British Committee for Standards in Haematology, 2001). That same year, the second edition of guidelines prepared by the Nordic Myeloma Study Group (NMSG) in 1995 was issued (in the Scandinavian languages; http:// www.myeloma-nordic.org). As both sets of guidelines were intended to be evidence based, it was reassuring to note that the recommendations were similar. Subsequently, informal contact between members of the two groups led to the decision to prepare these common, updated guidelines. These revised and updated guidelines include new sections on imaging and the management of skeletal disease, cover new developments in disease classification and staging and the use of new therapeutic approaches, such as thalidomide, bortezomib and reduced-intensity allogeneic transplantation. The guidelines are presented in specific sections as follows:

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Health‐related quality of life assessed before and during chemotherapy predicts for survival in multiple myeloma

Measurement of health‐related quality of life was integrated into a randomized trial (NMSG 4/90) comparing melphalan/prednisone to melphalan/prednisone + interferon α‐2b in newly diagnosed multiple myeloma. One of the aims of the study was to assess the prognostic significance of quality‐of‐life scores, using the EORTC QLQ‐C30 questionnaire. Univariate analysis showed a highly significant association with survival from the start of therapy for physical functioning as well as role and cognitive functioning, global quality of life, fatigue and pain. In multivariate analysis, physical functioning and W.H.O. performance status were independent prognostic factors (P values=0.001 for both) when analysed in a Cox regression model with the somatic variables β‐2 microglobulin, skeletal disease and age. The best prediction for survival from the start of therapy was obtained by combining the β‐2 microglobulin and physical functioning scores in a variable consisting of three risk factor levels with an estimated median survival of 17, 29 and 49 months, respectively. At a 12 months landmark analysis, the relative risk for patients with physical functioning score 0–20 v 80–100 was 5.63 (99% CI 2.76–11.49), whereas the relative risk for patients without an objective response to chemotherapy compared to those with at least a minor response was 2.32 (99% CI 1.44–3.74). Quality‐of‐life assessment may be an independent and valuable addition to the known prognostic factors in multiple myeloma.

Measurement of health-related quality of life in multiple myeloma

When a randomized trial (NMSG 4/90) comparing treatment with melphalan/prednisone to melphalan/prednisone + interferon α‐2b in newly diagnosed multiple myeloma was inititated in 1990, a quality‐of‐life assessment was integrated into the study. We used the questionnaire (QLQ‐C30) developed by the European Organization of Research and Treatment of Cancer (EORTC) Study Group on Quality of Life. The QLQ‐C30 incorporates five functional scales, three symptom scales, a global health and quality‐of‐life scale and some single symptom measures. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 524 (90.2%) of 581 patients enrolled in the NMSG 4/90 completed the first questionnaire, and 484 (83.3%) completed all questionnaires given to them. All but one of the scales met the minimum criteria of reliability (Cronbach’s alpha ≥0.70). Validity was shown by (1) the ability of the scales to discriminate clearly between patients differing in clinical status as defined by pre‐treatment W.H.O. performance index and Durie & Salmon stage, and (2) the sensitivity to changes in objective disease status (response and relapse). This is the first report of the measurement of health‐related quality of life in a prospective clinical trial in multiple myeloma. The results demonstrate that the QLQ‐C30 is a reliable and valid instrument for the measurement of quality of life in these patients. The data will be used for a cost–utility analysis of the results of the NMSG 4/90 trial.

Interpretation of quality of life scores in multiple myeloma by comparison with a reference population and assessment of the clinical importance of score differences

Objectives:  Without clear guidelines, clinicians and health care providers are often uncertain how to interpret (quality of life) QOL scores. To facilitate the interpretation, QOL scores of multiple myeloma patients at diagnosis were compared with the scores of a reference population, and the clinical significance of QOL score differences and of changes in scores over time was assessed.

Laboratory diagnosis of the antiphospholipid syndrome

Much has happened since Conley and Hartmann [1] described the lupus inhibitor in two SLE patients in 1952. These patients had prolonged coagulation tests and biologically false positive syphilis tests. Although the term ‘‘lupus anticoagulant’’ (LA) was coined for this inhibitor [2], it soon became clear that it is neither confined to patients with SLE nor a coagulation inhibitor in vivo. The paradoxical association with thrombosis was suspected in the early 1960s [3]. Thus, the laboratory diagnosis of LA became important. In 1980, it was reported that the LA activity of a plasma was caused by antibodies against negatively charged phospholipids (PL) [4]. In the early 1980s, several groups tried to simplify the laboratory diagnosis using solid phase PL as antigens [5]. As the main antigen in the serological tests for syphilis is cardiolipin (CL), CL was selected as an antigen in these assays [6], although this PL is associated with mitochondrial rather than cell membranes and does not play a part in coagulation in vivo. Further work demonstrated that the concordance between coagulation tests for LA and the anticardiolipin (aCL) assay was only about 60% [7]. However, since patients negative for LA, but positive for aCL, seemed to have similar clinical symptoms, aCL ELISA tests became established as a routine investigation in addition to coagulation tests for LA. Around 1990, two independent groups showed that the real antigen in the anti-cardiolipin test was a glycoprotein, h2-glycoprotein I (h2GPI), rather than CL itself [8,9]. When the protein binds to a negatively charged surface, antigenic sites are exposed. A similar surface may be provided by microtiter plates. Thus, some ‘‘antiphospholipid antibodies’’ (APA) bind directly to h2GPI in the absence of PL. Some LA antibodies react with proteins other than h2GPI; most frequently prothrombin [10]. Conversely, some antibodies to h2GPI may be devoid of LA activity [11]. In general, the requirement for a protein cofactor distinguishes patients with the antiphospholipid syndrome (APS) from patients with syphilis and other infections. It has now been shown that autoimmune APA may be directed against a variety of PL-binding proteins. The most important of these protein cofactors, next to h2GPI and prothrombin, are protein C, protein S, annexin V, HMW kininogen, and factor XI. Individual patients often have a mixture of antibodies with different specificities. At present, the laboratory aspects of the APS are rather complicated (Fig. 1). The ability of some APA to prolong coagulation in vitro seems to depend on the formation of bivalent complexes between antibodies and either h2GPI [12] or prothrombin [13]. These complexes have increased affinity for PL and compete with coagulation factors for the same catalytic surface. The pathogenic mechanisms of APA have been difficult to unravel. Some of the hypotheses that have been proposed are activation of endothelial cells, blood platelets or monocytes, acquired protein C resistance, and impaired fibrinolytic capacity (for a review, see Ref. [14]. Actually, there is so far no direct evidence in humans that these antibodies are pathogenic rather than just laboratory markers. However, in experimental animals, APA may cause at least some of the disease states associated with the APS [15]. The diverse antibody specificities found in patients with the APS indicate that different pathogenic mechanisms may be involved. In addition to venous and arterial thrombosis, thrombocytopenia and recurrent pregnancy loss, a large variety of clinical symptoms are found to be associated with APA. Classification criteria for the APS were recently redefined [16] and have been validated [17,18] (Table 1). The delineation of the APS is a challenge, because the clinical features are common in other settings and the laboratory tests are not specific for this syndrome. Regardless of whether APA are pathogenic or simply disease markers, mounting clinical evidence suggests that they are important risk factors. In SLE (secondary APS), aCL or LA positivity defines a group with a substantially increased risk of pregnancy complications and venous and arterial thrombosis [19–21]. In individuals with no underlying autoimmune disease, APA positivity implies an

Hemostatic variables as independent predictors for fetal growth retardation in preeclampsia

BACKGROUND Preeclampsia is a major contributor to perinatal disease and fetal growth retardation (FGR). It has been suggested that increased intravascular coagulation, fibrin deposition in spiral arteries and hypoperfusion of the placenta are involved in these pregnancy complications. METHODS Multiple variables of the hemostatic system and lipid metabolism, as well as clinical features, were entered into univariate and multivariate models in order to examine the association with preeclampsia and FGR. RESULTS Two hundred women with preeclampsia and 97 normotensive pregnant women were examined. Plasma levels of the thrombin-antithrombin complex (TAT), tissue factor pathway inhibitor free antigen (TFPI-Fag), protein S free antigen, plasminogen activator inhibitor type-1 (PAI-1) activity and serum levels of triglycerides were significantly increased, whereas plasma levels of antithrombin (AT), fibrinogen, C4b-binding protein (C4b-BP), PAI-2 antigen and serum HDL-cholesterol levels were decreased in the presence of preeclampsia. In the multivariate regression analysis, high TFPI-Fag plasma levels were associated with the presence of preeclampsia. The presence of FGR was in the univariate analysis associated with decreased PAI-1 activity and lower concentrations of fibrin, fibrinogen, factor VII antigen and PAI-2 antigen, as well as with evidence of macroscopic placental infarction. In a multivariate regression model, low maternal weight, placental infarction and low PAI-2 levels were predictors for low birth weight. In a logistic regression model, with the presence or absence of FGR as the dependent variable, male sex of the infant, placental infarction, low PAI-1 activity and factor VII antigen or PAI-2 antigen levels were independent predictors. CONCLUSIONS Our results are consistent with activated coagulation in the placental vessels in preeclampsia. A low concentration of PAI-2 antigen in plasma emerged as the most consistent risk factor for preeclampsia and FGR.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

BACKGROUND Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. METHODS This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883. FINDINGS From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. INTERPRETATION Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma. FUNDING Nordic Cancer Union and Novartis Healthcare.