Objective Evaluation of the effectiveness and safety of long-term low molecular weight heparin (LMWH) in patients with antiphospholipid syndrome (APS) that had not previously responded to or tolerated oral vitamin K antagonists.
Methods 23 patients with confirmed diagnosis of APS were retrospectively recruited. All patients were receiving LMWH as a result of intolerance and/or lack of response to warfarin therapy. The type of LMWH, the duration of treatment, the reason for switching to LMWH and the adverse effects were recorded. Outcomes were classified as no improvement, partial improvement or total improvement after at least 1 year of using LMWH.
Results The average duration of LMWH treatment was 36 months. Most of the patients were on treatment with enoxaparin (n=16, 69%) and were switched to LMWH from warfarin mainly because of thrombosis despite therapeutic international normalised ratio (n=9, 39%). Good quality of life with no evidence of recurrent thrombotic events was noted in nine patients (39%), whereas 11 (48%) showed partial clinical improvement but no evidence of recurrent thrombotic episodes. Osteoporosis was reported in five patients (23%), all of whom were also receiving treatment with corticosteroids.
Conclusions Long-term LMWH may be a safe and effective alternative to warfarin for APS patients.
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The antiphospholipid antibody syndrome (APS) is a prothrombotic disorder characterised by the predisposition to venous and/or arterial thrombosis and pregnancy morbidity due to the presence of autoantibodies directed against phospholipid binding proteins.1
Vitamin K antagonists are the most common drugs used in patients with APS and thrombosis. However, thrombotic events in APS patients on apparently correct therapeutic oral anticoagulation have been observed. The optimal management of these patients is controversial and several treatment strategies have been proposed. Low molecular weight heparin (LMWH) represents one of the alternatives for those patients with resistance or contraindications to oral anticoagulants.2
Several side effects have been described following long-term administration of heparin. Haemorrhage at any body site is the chief complication. On the other hand, osteoporosis has been reported in up to 5% of cases when using unfractionated heparin,3 although the exact incidence of LMWH-induced osteoporosis remains controversial.4 Heparin-induced thrombocytopaenia (HIT), hypersensitivity side effects, alopecia, elevation of liver enzymes and suppression of aldosterone synthesis have also been reported, mostly in pregnant women.
Therefore, little is known about the safety and efficacy of LMWH beyond a 9-month period in non-pregnant patients. Consequently, the aim of this study was to evaluate both the safety and efficacy of long-term treatment with LMWH in patients with APS.
Patients and methods
We retrospectively recruited 23 patients with both primary APS and APS associated with other autoimmune disorders. Patients fulfilling the following criteria were included in the study: a confirmed diagnosis of APS according to Sapporo criteria and at least 1-year treatment with LMWH at anticoagulant doses.
Patient notes were reviewed to identify the main features in terms of efficacy and safety relating to the long-term use of LMWH. Data collected included age, sex, race, type of APS (primary or secondary) and its clinical manifestations, categorised as only arterial thrombosis, only venous thrombosis, both arterial and venous thrombosis, pregnancy morbidity or neurological symptoms (headache, seizures, numbness/weakness in extremities…) with high intensity lesions on MRI. Previous treatment with warfarin and the reason for switching to LMWH were recorded. Information regarding the length of time on LMWH and the type of LMWH were also collected.
Aspects relating to the safety of the long-term use of LMWH such as bleeding, HIT and osteoporosis were recorded. Bleeding was considered as major if it resulted in death, in the need for a transfusion of at least two units of blood or if it led to a drop in haemoglobin of at least 2 g/dl or when occurring at a critical site (intracranial, intraspinal, pericardial, or retroperitoneal). HIT was defined as a fall in the platelet count on commencing treatment with heparin.5 Finally, osteoporosis was diagnosed when dual-energy x-ray absorptiometry (DEXA) detected a bone mineral density 2.5 SD or more below the young adult mean (T score at or below −2.5).6
All data were presented as the median (IQR) for continuous variables and as a percentage for categorical variables. Statistical analyses were carried out using SPSS software for Windows (version 15.0).
The median duration of LMWH therapy was 36 months (25–44), with a minimum of 14 months and a maximum of 216 months. The type of LMWH most commonly used was enoxaparin in 16 patients (69%), whereas seven (31%) were receiving other types of LMWH (dalteparin and tinzaparin).
Total improvement was observed in nine patients (39%), so thrombosis did not recur in this group of patients. Moreover, in those patients with central nervous system manifestations (n=2, 9%), resolution of neurological symptoms along with an improvement in more than 50% of the MRI lesions were observed. Partial improvement was present in 11 patients (48%), ie, despite no recurrent thrombosis occurring in any of them, only mild relief of neurological symptoms (n=8, 35%) or an improvement in less than 50% of the MRI lesions were achieved (n=3, 13%). Finally, no improvement was observed in three patients (13%) in whom no thrombosis recurrence (n=3, 13%) and no improvement in neurological symptoms nor in MRI lesions (n=2, 9%) were observed.
Osteoporosis (confirmed by DEXA) was the only important side effect reported (in five patients; 23%, all of them on long-term treatment with corticosteroids).
Four patients (17%) were receiving calcium and vitamin D supplements and six patients (26%) were taking calcium, vitamin D and bisphosphonates.
Our study shows that long-term LMWH may be a safe and effective alternative to warfarin for APS patients with no response, poor tolerance, or for those who refuse to take vitamin K antagonists.
Vitamin K antagonists are the mainstay treatment in patients with APS and thrombosis.7 Despite the effectiveness of oral anticoagulation for the prevention of thromboembolic episodes, thrombotic complications in the setting of apparently therapeutic oral anticoagulation have been observed. There is currently no consensus on the optimal management of patients with recurrent thrombotic events despite proper anticoagulation with oral vitamin K antagonist therapy, and several treatment strategies have been proposed. One option includes increasing the therapeutic international normalised ratio range above 3.0, although current evidence seems to show the ineffectiveness and difficulty of implementing this option.8 9 Other therapy strategies suggested are the addition of acetylsalicylic acid to warfarin, the use of other anticoagulants (such as lepirudin) or hydroxychloroquine. Finally, long-term treatment with therapeutic doses of LMWH represents an alternative for those patients with a bad response or contraindications to oral anticoagulants.2 Some of the advantages of LMWH over warfarin include a predictable anticoagulant response due to a good bioavailability, dose-independent clearance and decreased affinity for heparin-binding protein. Furthermore, recent studies suggest that LMWH, via the inhibition of complement system and the enhancement of β-2-glycoprotein-I binding to tissues, might have an added beneficial effect in preventing the hypercoagulability state of APS patients.10
The efficacy and safety of long-term treatment with LMWH have previously been assessed in some specific populations. In oncological patients, in whom a higher incidence of bleeding and recurrent venous thromboembolism have been reported, emerging evidence has shown LMWH to be more effective and safe than warfarin in the treatment of cancer-related venous thromboembolism.11 On the other hand, in thrombophilic pregnant women, absolute and RR of thrombosis are significantly decreased following prophylaxis with LMWH, which is associated with a low rate of adverse effects.12
With regard to the APS population, Bick and Rice13 in 1999 published the first study in which long-term dalteparin was used in APS patients due to warfarin resistance or intolerance. During an average time of 309 days of therapy none of the 24 individuals included in the study experienced any episode of re-thrombosis or major side effects. Ahmed et al14 reported the case of a patient with APS who was changed to enoxaparin 1.5 mg/kg per day because of problems in achieving a therapeutic international normalised ratio, and 2 months later after being on LMWH developed an extensive pulmonary embolism. On the other hand, Dentali et al2 reported a very good response to long-term LMWH in two patients with APS and warfarin resistance followed for 2 and 6 years, respectively.
To the best of our knowledge, our report and that of Bick and Rice13 are the only studies that describe the efficacy and safety of the long-term use of LMWH in a cohort of patients with a diagnosis of APS. The median duration of LMWH therapy in our cohort was 36 months (25–44), with a maximum of 216 months (18 years), the largest reported in the medical literature up to now. In our study, LMWH therapy resulted in total or partial clinical improvement without recurrent thrombosis in 20 patients (87%). Osteoporosis was the only important side effect reported (23%), although it is important to note that all the patients affected were receiving long-term treatment with corticosteroids.
Long-term heparin treatment has been reported to cause osteoporosis in both laboratory animals and humans. Osteoporosis caused by long-term heparin therapy is thought to be reversible and is uncommonly associated with symptomatic fractures, but the real incidence of osteoporosis in patients receiving LMWH is difficult to assess because DEXA is not usually performed before starting therapy.15
Bleeding is one of the most fearsome side effects of heparin. Recently, the aggregate data from the Cochrane Database of Systematic Reviews reported that long-term LMWH is as effective as vitamin K antagonists but significantly safer as a result of less risk of bleeding.16 Similarly, Hull et al17 found that all types of bleeding were significantly less frequent in patients receiving 3 months LMWH for deep vein thrombosis compared with those receiving oral anticoagulants. All these previous favourable results are in agreement with those found in the present study, in which no patient showed any major bleeding event.
HIT is a potentially life-threatening adverse effect of heparin. It represents a hypercoagulable state related to endothelium damage as well as platelet-activating antibodies.18 Its real prevalence is thought to range from 0% to 2.8% for LMWH and from 0% to 3.5% for unfractionated heparin.19 The rarity of this side effect was confirmed in our cohort, in which no patients developed HIT.
The favourable pharmacokinetics of LMWH result in a predictable dose–response anticoagulant effect, and monitoring its activity is generally thought not to be necessary in clinically stable patients. However, anti-Xa activity monitoring could improve the safety of LMWH according to available data and expert recommendations, especially in selected populations with high haemorrhagic risk. Monitoring of anti-Xa activity should thus be mainly considered in older patients, patients with renal impairment, or obesity.20
In conclusion, there are several scenarios in which recurrent thrombosis may occur despite optimal oral anticoagulation therapy, such as APS. Until the availability of newer anticoagulant agents, long-term LMWH therapy may be a safe and effective alternative to warfarin for APS patients. However, despite these encouraging results, the low number of patients and the relatively short follow-up period (median 36 months) considered in this study, makes further controlled clinical trials necessary to confirm LMWH as a valid alternative to oral anticoagulants.
Competing interests None.
Ethics approval This study was conducted with the approval of St Thomas’ Hospital, London SE1 7EH, UK.
Provenance and peer review Not commissioned; externally peer reviewed.
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