- Email: [email protected]
Controversies in the antiphospholipid syndrome and stroke
Thrombosis Research (2004) 114, 483 — 488
intl.elsevierhealth.com/journals/thre
Controversies in the antiphospholipid syndrome and stroke Paul A. Gatenby* Medical School, Australian National University and The Canberra Hospital, Frank Fenner Building 42, Canberra, ACT 0200, Australia Received 1 June 2004; received in revised form 15 June 2004; accepted 23 June 2004 Available online 28 July 2004
KEYWORDS Antiphospholipid syndrome; Autoimmune disease; Stroke; Cerebral embolism
Abstract Many clinicians providing care and advice to patients with antiphospholipid syndrome (APS), where the principal clinical manifestation is stroke, do so in the setting of an evidence base of mixed quality. Indeed, systematic studies have not particularly helped the practising clinician as they have been characterised by variable criteria used to select subjects, making it impossible to extrapolate to typical clinic patients. This has left us with a number of key questions, each of which attracts controversy in terms of patient management. In this review, these are posed as a series of questions with the answer, or lack of one, considered after each question. The review draws attention to the important questions that require answers for current primary and secondary prevention, as well as treatment of APS and stroke, and suggests a series of studies that are needed to clarify these issues. D 2004 Elsevier Ltd. All rights reserved.
Introduction There are a substantial number of gaps in our knowledge about stroke and antiphospholipid (aPL) antibodies. Many of these were reviewed in a consensus meeting at the last Antiphospholipid Abbreviations: aCL, anticardiolipin; APASS, Antiphospholipid Antibody in Stroke Study Group; aPL, antiphospholipid; APS, antiphospholipid syndrome; h2GP1, beta 2 glycoprotein-1; LA, lupus anticoagulant; TIA, transient ischaemic attack; WARSS, Warfarin versus Aspirin Recurrent Stroke Study. * Tel.: +61 2 6125 2622; fax: +61 2 6125 4814. E-mail address: [email protected].
Congress in Taormina, Sicily, 2002 [1]. The purpose of this paper is not to review in detail the evidence, or lack of it, in regard to the relationship between, and management of, stroke and antiphospholipid antibodies, but to pose a series of questions that, as physicians caring for patients, we need answers to. In each case, whether or not we have all or part of the answer will be assessed. Cerebrovascular disease, stroke and transient ischaemic attacks (TIAs) are some of the most common causes of morbidity and mortality in developed nations and are rapidly growing in importance in developing countries as they adopt
0049-3848/$ - see front matter D 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2004.06.033
484 the worst aspects of a western lifestyle [2,3,4]. There are many causes of stroke, with the vast bulk being accounted for by degenerative vascular disease associated with age, hypertension, smoking, elevated serum lipids, cardiac disease and diabetes [5]. Quite frankly, this huge burden of disease may drown out the impact of uncommon potential associations with stroke—such as aPL antibodies—and makes good clinical studies difficult to perform. Furthermore, with the exception of the very young, many of the subjects that will enter any studies endeavouring to answer questions about aPL and stroke will almost certainly have one or more of these other, generally more common, risk factors. The questions, and this is not an exhaustive list, that a physician responsible for the care of patients requires answers to include: ! ! !
! ! ! !
Is aPL a risk factor in a primary sense for cerebrovascular disease? If so, is there evidence to support primary preventative measures? How should an acute cerebrovascular event be managed in the context of aPL? Does it differ from management of a dconventionalT cerebrovascular event? That is, is urgent specific diagnosis required? Is aPL associated with a risk of recurrent stroke? If so, how should they optimally be prevented? What is the relative role of embolic strokes in patients with aPL? What should we advise if aPL becomes persistently negative in the course of patient follow-up?
Each of these will be dealt with in turn. As has been elegantly pointed out before, there are a number of ways of addressing most of these issues, each with the potential to give different answers because the different methods are asking slightly different questions. Firstly, patients who have already had a formal diagnosis of antiphospholipid syndrome (APS) made can be compared, according to Sapporo criteria [6], with a control population over time. Whether they have already had a stroke or not is clearly an important variable which immediately divides the group into primary and secondary risk. Secondly, a group of stroke patients can be compared with a group without stroke for the presence of aPL–anticardiolipin (aCL), lupus anticoagulant (LA) and anti-beta 2 glycoprotein-1 (h2GP1). Finally, a group without stroke can be tested for aPL and followed prospectively, potentially for a long period to determine the incidence of stroke when compared to controls. To each of these studies could be added more specific ques-
P.A. Gatenby tions about whether strokes are embolic, thrombotic or both, and all could potentially act as a platform for studies on management decisions [1]. Most large series of patients exemplified by the Euro Phospholipid Project have a substantial proportion of patients presenting with stroke, generally at a young age (b55 years), indeed, stroke appears to be the most common arterial thromboembolic disorder in APS [7].
aPL as a primary risk factor There are reports of patients in many series of APS who have developed a stroke as a further manifestation of their APS in the course of follow-up, when the original presentation may have been some other problem, such as a venous thrombosis. There are no studies that enable in a systematic way to put a quantitative risk on this event. Moreover, now that most people in the latter setting are treated, it is unlikely that this study will ever be done [8– 11]. The setting in which a clinician needs answers is more likely to be the patient in whom antibodies are discovered almost by accident—a patient with SLE being exhaustively screened, a patient with an obstetric presentation of APS or a biological false positive test for syphilis at a blood bank. Population risk studies only tangentially address these issues. Case control studies using the second approach above produce conflicting results. Thus, some have shown an association with stroke and different combinations of aPL [12–15], others have not [16– 19]. Studies of this type are particularly vulnerable to the impact of aPL being swamped by other more common risk factors for stroke, particularly if they include an older population in their cohort. Indeed, the studies that tend to favour an association generally have younger subjects, with notable exceptions [13,14]. Negative studies tend to be unselected and consequently involve older subjects, again, there are exceptions [19]. One study produces mixed results depending upon the aPL combination examined[20]. Long-term population studies are uncommon, the most important performed as part of the Honolulu Heart Study by Brey et al. [21] demonstrated significant association with IgG-aCL (h2GP1 dependent). The risk appeared to be a threshold rather than a dose-related effect and fell away with time, perhaps as further co-morbidities were acquired by the population under study [21]. LA was not measured in this study. Ginsberg et al. [22] in a large study involving American physicians were unable to show a relationship between aCL and
Controversies in the antiphospholipid syndrome and stroke stroke. It is unclear from their study whether or not the aCL was h2GP1 dependent and LA was not measured. A large WHO study did not find aCL to be an independent risk factor when examining multiple risk factors in a general population with stroke as an outcome [23]. These studies do not really address the intersection of aPL with other risk factors, indeed, this could be a complex issue to dissect. The author’s expectation at this stage is that further studies, particularly if confined to younger (b55 years) subjects with better selection of aPL tests, will probably confirm aPL as a primary low level risk factor. There are no studies that address the issue of primary prevention, although low dose of aspirin is recommended for primary prevention of stroke in high risk subjects in general. High risk includes multiple conventional risk factors [24]. Groups report using aspirin to beneficial effect in this setting [25].
Management of acute disease The management of acute cerebrovascular disease is subject to ongoing study in a broad sense, let alone the subset associated with aPL. Following the success of thrombolytic therapy and myocardial infarction, a number of studies have examined the role of this therapy in acute stroke. To date, the outcome has only been significantly better than alternative therapy at an acceptable cost in side effects when thrombolytic therapy has been instituted very early, within 3 h [26]. If indeed the early institution of thrombolytic therapy, where possible, becomes the standard modality of treatment of thromboembolic stroke, then there will be no necessity to urgently diagnose an antiphospholipid antibody-related stroke, as those patients will be treated in the same way as all of the patients presenting promptly for therapy. However, it will still be important to ask the question in this small subset of patients about the value of delayed institution of thrombolytic therapy, something that appears ineffective in the vast bulk of patients with stroke. Our own experience of such patients has, like others, been rewarding [27] and clearly large, nested studies need to be done. Thus, we have treated a 52-year-old woman who presented to the Emergency Department within 2 h of onset of a right hemiplegia and aphasia. Cerebral CT perfusion scan with contrast revealed acute ischemia in the region of the left middle cerebral artery with increased blood flow indicative of acute cerebral
485
hypoxia. She received intravenous tissue plasminogen activator and soon afterwards commenced a rapid recovery. A subsequent MRI brain scan indicated an acute infarct in the same territory. We concluded that the damage had been limited but not completely prevented (Tuck, R., personal communication, 2003). The patient had a past history of two miscarriages and was found to be, and remains, positive to LA, aCL and anti-h2GP1. If there was a greater benefit shown in patients with aPL, then assessing aPL status could become an urgent procedure. At this stage, we do not know what the optimum management of an acute stroke in an aPL-positive patient should be. This is true whether it is a primary or secondary event.
Recurrent stroke A substantial number of studies using the first method described above have provided evidence in support of aPL being a risk factor for recurrence [8– 11,28,29]. There are exceptions to this, and again, the differences appear to be due to different patient populations and the nature and range of aPL assays used in the various studies. The magnitude of the risk shows wide variation and may decline with time [11]. Not surprisingly, the magnitude appears to vary with the type of study. Followup of patients who unequivocally meet the criteria for APS, with or without lupus, generally discloses a significant risk, certainly significant enough that physicians who look after such patients are concerned to prevent the recurrence [11,28,29]. However, in stroke patients in general, of all ages, selected on the basis of a positive aPL, the risk appears a little greater than the general stroke population. The Antiphospholipid Antibody in Stroke Study Group (APASS) subset of the Warfarin versus Aspirin Recurrent Stroke Study (WARSS) study is the most influential here [20]. This study did exclude patients with embolic disease and was a cohort with many differences from the typical APS patients described by others [10,11,28,29]. The author’s conclusion at this stage is that there is an increased risk of recurrent stroke. The risk is greater in subjects who unequivocally meet the diagnostic criteria for APS. The relative predictive value of aCL, LA and anti-h2GP1 and other tests needs further study, as does the question of whether the risk is dose-related or a threshold effect. There is a desperate need for a risk profile to guide what is done is relation to the next issue, secondary prevention.
486
Secondary prevention of stroke The optimal prevention of recurrence is the question that has received most attention. While primary prevention in a very broad sense is very important for the health of the populations we serve, physicians are largely concerned with the management of disease once declared, that is, secondary prevention. Relatively small studies, taking patients who unequivocally had APS, showed that the prevention of recurrent events, including stroke, was possible and appeared to be best achieved with high-intensity warfarin [28,30]. More recently, in the prevention of recurrent venous thrombosis, the need for high-intensity warfarin has been challenged [31]. However, the appropriate dose and duration of warfarin in arterial disease, including stroke, remains undefined. Indeed, the APASS study challenges the use of warfarin at all. In that study of stroke patients of unselected age, embolic disease excluded, there was no difference between low dose of aspirin and low-intensity warfarin in preventing recurrent stroke [20]. Not surprisingly, the subcommittee at the last Antiphospholipid Conference in Taormina, 2002, charged with preparing recommendations on the management of stroke, concluded that there was insufficient evidence on which to base any recommendations about prevention of stroke recurrence [1]. Many of us who look after patients with APS felt that the subjects in the APASS study bore little resemblance to our patients and have not altered our practice of warfarin prophylaxis [11]. The study does, however, appear to have influenced the broader neurological community, and more definitive prospective studies, stratified for variables like age, gender, embolic risk and the presence of APS or not, are needed. The current impasse is a reflection of the fact that how you ask the question will determine the answer obtained. This is important because in the general stroke literature there is growing evidence that warfarin is not more effective than aspirin in preventing recurrent strokes, even at high intensity [32,33]. This mandates that studies supporting a potential exception for APS, just as for embolic strokes, be carried out.
The role of embolic disease A number of reports in the early 1990s, including our own group, concluded that most patients appear to have embolic disease [34,35]. Subse-
P.A. Gatenby quent larger studies show that while a significant proportion of patients continue to have embolic disease, there are clearly many who do not. Our own updated experience shows up to 30% of patients may be embolic (Hawkins, C., et al., submitted, 2004). Any future studies of secondary prevention must stratify patients into embolic versus non-embolic stroke. In other settings where embolism is a high risk, such as atrial fibrillation or prosthetic cardiac valves, warfarin is clearly indicated [4,36,37], and this begs the question of whether or not it would be ethical to conduct a trial of APS patients with clear-cut embolic disease.
Disappearing aPL Our group and others have observed patients in whom, after a variable period of time, the aPL tests become persistently negative. This is hardly a surprise as the observation has been made with a number of autoantibodies [38]. It is a minority of patients in our series, but at presentation, the patients were indistinguishable from other patients with stroke and aPL (Hawkins, C., et al., submitted, 2004). Thus, we have experienced eight patients who presented with clinical evidence of cerebrovascular events, four with definite abnormalities on CT or MRI brain scan, all of whom were initially positive for one or more aPL and all of whom became persistently negative at some stage during follow-up. Apart from less frequent brain imaging abnormalities, as a group, these patients demonstrated a similar profile to our Sapporo criteria positive patients. There are no studies that address the issue of long-term therapy in this group, but their existence is an indication of the need to repeat the tests in any studies that are done to ensure that they be stratified as a subgroup for separate analysis.
Concluding remarks While physicians are trained to be able to make decisions in the face of uncertainty, we are increasingly challenged to make our decisions based on evidence. In this paper, both the evidence and the lack of evidence to support decisions that we make all the time has been highlighted. I believe the Conference should encourage and facilitate the design and performance of large, appropriately stratified studies that will have to be multi-centre to produce answers to the questions
Controversies in the antiphospholipid syndrome and stroke posed here. Most of these will have to be done as nested studies in larger stroke studies, but should be cognisant of the age of the subjects, whether a formal diagnosis of APS has been made, the aPL profile and persistence and whether embolic disease is to be included or not.
[15]
[16]
[17]
References [1] Brey RL, Chapman J, Levine SR, Ruiz-Irastorza G, Derksen RHWM, Khamashta M, et al. Stroke and the antiphospholipid syndrome: consensus meeting Taormina 2002. Lupus 2003;12:508 — 13. [2] Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ, Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet 2002;360:1347 — 60. [3] Ebrahim S. Cost-effectiveness of stroke prevention. Brit Med Bull 2000;56:557 — 70. [4] Reddy KS. Cardiovascular diseases in the developing countries: dimensions, determinants, dynamics and directions for public health action. Pub Health Nutr 2002;5:231 — 7. [5] Wolf PA, Clagett GP, Easton JD, Goldstein LB, Gorelick PB, Kelly-Hayes M, et al. Preventing ischaemic stroke in patients with prior stroke and transient ischaemic attack. Stroke 1999;30:1991 — 4. [6] Wilson WA, Gharavi AE, Koike T, Locksin MD, Branch DW, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum 1999;42:1309 — 11. [7] For the Euro Phospholipid Project Group, Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 2002;46:1019 — 27. [8] The Antiphospholipid Antibodies in Stroke Study GroupBabikian VL, Brey RL, Coull BM, Dewitt LD, Feinberg WM, et al. Clinical and laboratory findings in patients with antiphospholipid antibodies and cerebral ischaemia. Stroke 1990;21:1268 — 73. [9] Levine S.R, Brey RL, Sawaya KL, Salowich-Palm L, Kokkinos J, et al. Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Ann Neurol 1995;38:119 — 24. [10] Finazzi G, Brancaccio V, Moia M, Ciavarella N, Mazzucconi MG, 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. [11] Ruiz-Irastorza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrada MJ, Hughes GRV. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome. Arch Intern Med 2002;162:1164 — 9. [12] Nencini P, Baruffi MC, Abbate R, Massai G, Amaducci L, Inzitari D. Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischaemia. Stroke 1992;23:189 — 93. [13] The Antiphospholipid Antibodies in Stroke Study (APASS) Group. Anticardiolipin antibodies are an independent risk factor for first ischaemic stroke. Neurology 1993;43: 2069 — 73. [14] Tuhrim S, Rand JH, Wu XX, Weinberger J, Horowitz DR, Goldman ME, et al. Elevated anticardiolipin antibody titre
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
487 is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 1999; 30:1561 — 5. Brey RL, Stallworth CL, McGlasson DL, Wozniak MA, Wityk RJ, et al. Antiphospholipid antibodies and stroke in young women. Stroke 2002;33:2396 — 401. Muir KW, Squire IB, Alwan W, Lees KR. Anticardiolipin antibodies in an unselected stroke population. Lancet 1994;344:452 — 6. The Antiphospholipid Antibodies and Stroke Study (APASS) Group. Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. Neurology 1997; 48:91 — 4. Tanne D, D’Olhaberriague L, Trivedi AM, Salowich-Palm L, Schultz LR, Levine SR. Anticardiolipin antibodies and mortality in patients with ischaemic stroke: a prospective follow-up study. Neuroepidem 2002;21:93 — 9. Van Goor MPJ, Alblas CL, Leebeek FWG, Koudstaal PJ, Dippel DWJ. Do antiphospholipid antibodies increase the long-term risk of thrombotic complications in young patients with a recent TIA or ischaemic stroke? Acta Neurol Scand 2004;109:410 — 5. The APASS Writing Committee. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischaemic stroke. JAMA 2004;291:576 — 84. Brey RL, Abbott RD, Curb JD, Sharp DS, Ross GW, Stallworth CL, Kittner SJ. h2-Glycoprotein 1-dependent anticardiolipin antibodies and risk of ischaemic stroke and myocardial infarction. Stroke 2001;32:1701 — 6. Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, et al. Anticardiolipin antibodies and the risk for ischaemic stroke and venous thrombosis. Ann Intern Med 1992;117:997 — 1002. Ahmed EA, Stegmayr B, Trifunovic J, Weinehall L, et al. Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Vasterbotten Cohort Project. Stroke 2000;31:1289 — 93. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update. Consensus Panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation 2002;106:388 — 91. Cuadrado J.M, Khamashta MA. The antiphospholipid antibody syndrome (Hughes syndrome): therapeutic aspects. Baillie `re’s Clin Rheumatol 2000;14:151 — 63. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. The Cochrane Database of Systematic Reviews 2004;1. Julkunen H, Hedman C, Kauppi M. Thrombolysis for acute ischaemic stroke in the primary antiphospholipid syndrome. J Rheumatol 1997;24:181 — 3. Rosove MH, Brewer PMC. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992;117:303 — 8. Feldmann E, Levine SR. Cerebrovascular disease with antiphospholipid antibodies: immune mechanisms, significance and therapeutic options. Ann Neurol 1995; 37:S114 — 30. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughesz GRV. The management of thrombosis in the antiphospholipid antibody syndrome. N Engl J Med 1995; 332:993 — 7. Crowther M.A, Ginsberg JS, Julian J, Denburg J, Hirsh J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the
488 antiphospholipid antibody syndrome. N Engl J Med 2003; 349:1133 — 8. [32] Pullicino P for the Warfarin–Aspirin Recurrent Stroke Study Group, Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischaemic stroke. N Engl J Med 2001;345:1444 — 51. [33] The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) Study Group. Oral anticoagulation in patients after cerebral ischaemia of arterial origin and risk of intracranial haemorrhage. Stroke 2003;34:45 — 7. [34] Pope JM, Canny CL, Bell DA. Cerebral ischaemic events associated with endocarditis, retinal vascular disease and lupus anticoagulant. Am J Med 1991;90:299 — 309.
P.A. Gatenby [35] Fulham M.J, Gatenby PA, Tuck RR. Focal cerebral ischaemia and antiphospholipid antibodies: a case for cardiac embolism. Acta Neurol Scand 1994;90:417 — 23. [36] Kennedy J, Buchan AM. Eer decreasing circles: advances in antiplatelet therapy and anticoagulation. Stroke 2003; 34:348 — 50. [37] Gerraty RP. Stroke prevention: what’s new? Intern Med J 2003;33:177 — 81. [38] Amital H, Schoenfeld Y. Autoimmunity and autoimmune diseases such as systemic lupus erythematosus. In: Lahita RG, editor. Systemic Lupus Erythematosus. Elsevier, London7 Academic Press; 2004. p. 3 — 27. Chap. 1.
intl.elsevierhealth.com/journals/thre
Controversies in the antiphospholipid syndrome and stroke Paul A. Gatenby* Medical School, Australian National University and The Canberra Hospital, Frank Fenner Building 42, Canberra, ACT 0200, Australia Received 1 June 2004; received in revised form 15 June 2004; accepted 23 June 2004 Available online 28 July 2004
KEYWORDS Antiphospholipid syndrome; Autoimmune disease; Stroke; Cerebral embolism
Abstract Many clinicians providing care and advice to patients with antiphospholipid syndrome (APS), where the principal clinical manifestation is stroke, do so in the setting of an evidence base of mixed quality. Indeed, systematic studies have not particularly helped the practising clinician as they have been characterised by variable criteria used to select subjects, making it impossible to extrapolate to typical clinic patients. This has left us with a number of key questions, each of which attracts controversy in terms of patient management. In this review, these are posed as a series of questions with the answer, or lack of one, considered after each question. The review draws attention to the important questions that require answers for current primary and secondary prevention, as well as treatment of APS and stroke, and suggests a series of studies that are needed to clarify these issues. D 2004 Elsevier Ltd. All rights reserved.
Introduction There are a substantial number of gaps in our knowledge about stroke and antiphospholipid (aPL) antibodies. Many of these were reviewed in a consensus meeting at the last Antiphospholipid Abbreviations: aCL, anticardiolipin; APASS, Antiphospholipid Antibody in Stroke Study Group; aPL, antiphospholipid; APS, antiphospholipid syndrome; h2GP1, beta 2 glycoprotein-1; LA, lupus anticoagulant; TIA, transient ischaemic attack; WARSS, Warfarin versus Aspirin Recurrent Stroke Study. * Tel.: +61 2 6125 2622; fax: +61 2 6125 4814. E-mail address: [email protected].
Congress in Taormina, Sicily, 2002 [1]. The purpose of this paper is not to review in detail the evidence, or lack of it, in regard to the relationship between, and management of, stroke and antiphospholipid antibodies, but to pose a series of questions that, as physicians caring for patients, we need answers to. In each case, whether or not we have all or part of the answer will be assessed. Cerebrovascular disease, stroke and transient ischaemic attacks (TIAs) are some of the most common causes of morbidity and mortality in developed nations and are rapidly growing in importance in developing countries as they adopt
0049-3848/$ - see front matter D 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2004.06.033
484 the worst aspects of a western lifestyle [2,3,4]. There are many causes of stroke, with the vast bulk being accounted for by degenerative vascular disease associated with age, hypertension, smoking, elevated serum lipids, cardiac disease and diabetes [5]. Quite frankly, this huge burden of disease may drown out the impact of uncommon potential associations with stroke—such as aPL antibodies—and makes good clinical studies difficult to perform. Furthermore, with the exception of the very young, many of the subjects that will enter any studies endeavouring to answer questions about aPL and stroke will almost certainly have one or more of these other, generally more common, risk factors. The questions, and this is not an exhaustive list, that a physician responsible for the care of patients requires answers to include: ! ! !
! ! ! !
Is aPL a risk factor in a primary sense for cerebrovascular disease? If so, is there evidence to support primary preventative measures? How should an acute cerebrovascular event be managed in the context of aPL? Does it differ from management of a dconventionalT cerebrovascular event? That is, is urgent specific diagnosis required? Is aPL associated with a risk of recurrent stroke? If so, how should they optimally be prevented? What is the relative role of embolic strokes in patients with aPL? What should we advise if aPL becomes persistently negative in the course of patient follow-up?
Each of these will be dealt with in turn. As has been elegantly pointed out before, there are a number of ways of addressing most of these issues, each with the potential to give different answers because the different methods are asking slightly different questions. Firstly, patients who have already had a formal diagnosis of antiphospholipid syndrome (APS) made can be compared, according to Sapporo criteria [6], with a control population over time. Whether they have already had a stroke or not is clearly an important variable which immediately divides the group into primary and secondary risk. Secondly, a group of stroke patients can be compared with a group without stroke for the presence of aPL–anticardiolipin (aCL), lupus anticoagulant (LA) and anti-beta 2 glycoprotein-1 (h2GP1). Finally, a group without stroke can be tested for aPL and followed prospectively, potentially for a long period to determine the incidence of stroke when compared to controls. To each of these studies could be added more specific ques-
P.A. Gatenby tions about whether strokes are embolic, thrombotic or both, and all could potentially act as a platform for studies on management decisions [1]. Most large series of patients exemplified by the Euro Phospholipid Project have a substantial proportion of patients presenting with stroke, generally at a young age (b55 years), indeed, stroke appears to be the most common arterial thromboembolic disorder in APS [7].
aPL as a primary risk factor There are reports of patients in many series of APS who have developed a stroke as a further manifestation of their APS in the course of follow-up, when the original presentation may have been some other problem, such as a venous thrombosis. There are no studies that enable in a systematic way to put a quantitative risk on this event. Moreover, now that most people in the latter setting are treated, it is unlikely that this study will ever be done [8– 11]. The setting in which a clinician needs answers is more likely to be the patient in whom antibodies are discovered almost by accident—a patient with SLE being exhaustively screened, a patient with an obstetric presentation of APS or a biological false positive test for syphilis at a blood bank. Population risk studies only tangentially address these issues. Case control studies using the second approach above produce conflicting results. Thus, some have shown an association with stroke and different combinations of aPL [12–15], others have not [16– 19]. Studies of this type are particularly vulnerable to the impact of aPL being swamped by other more common risk factors for stroke, particularly if they include an older population in their cohort. Indeed, the studies that tend to favour an association generally have younger subjects, with notable exceptions [13,14]. Negative studies tend to be unselected and consequently involve older subjects, again, there are exceptions [19]. One study produces mixed results depending upon the aPL combination examined[20]. Long-term population studies are uncommon, the most important performed as part of the Honolulu Heart Study by Brey et al. [21] demonstrated significant association with IgG-aCL (h2GP1 dependent). The risk appeared to be a threshold rather than a dose-related effect and fell away with time, perhaps as further co-morbidities were acquired by the population under study [21]. LA was not measured in this study. Ginsberg et al. [22] in a large study involving American physicians were unable to show a relationship between aCL and
Controversies in the antiphospholipid syndrome and stroke stroke. It is unclear from their study whether or not the aCL was h2GP1 dependent and LA was not measured. A large WHO study did not find aCL to be an independent risk factor when examining multiple risk factors in a general population with stroke as an outcome [23]. These studies do not really address the intersection of aPL with other risk factors, indeed, this could be a complex issue to dissect. The author’s expectation at this stage is that further studies, particularly if confined to younger (b55 years) subjects with better selection of aPL tests, will probably confirm aPL as a primary low level risk factor. There are no studies that address the issue of primary prevention, although low dose of aspirin is recommended for primary prevention of stroke in high risk subjects in general. High risk includes multiple conventional risk factors [24]. Groups report using aspirin to beneficial effect in this setting [25].
Management of acute disease The management of acute cerebrovascular disease is subject to ongoing study in a broad sense, let alone the subset associated with aPL. Following the success of thrombolytic therapy and myocardial infarction, a number of studies have examined the role of this therapy in acute stroke. To date, the outcome has only been significantly better than alternative therapy at an acceptable cost in side effects when thrombolytic therapy has been instituted very early, within 3 h [26]. If indeed the early institution of thrombolytic therapy, where possible, becomes the standard modality of treatment of thromboembolic stroke, then there will be no necessity to urgently diagnose an antiphospholipid antibody-related stroke, as those patients will be treated in the same way as all of the patients presenting promptly for therapy. However, it will still be important to ask the question in this small subset of patients about the value of delayed institution of thrombolytic therapy, something that appears ineffective in the vast bulk of patients with stroke. Our own experience of such patients has, like others, been rewarding [27] and clearly large, nested studies need to be done. Thus, we have treated a 52-year-old woman who presented to the Emergency Department within 2 h of onset of a right hemiplegia and aphasia. Cerebral CT perfusion scan with contrast revealed acute ischemia in the region of the left middle cerebral artery with increased blood flow indicative of acute cerebral
485
hypoxia. She received intravenous tissue plasminogen activator and soon afterwards commenced a rapid recovery. A subsequent MRI brain scan indicated an acute infarct in the same territory. We concluded that the damage had been limited but not completely prevented (Tuck, R., personal communication, 2003). The patient had a past history of two miscarriages and was found to be, and remains, positive to LA, aCL and anti-h2GP1. If there was a greater benefit shown in patients with aPL, then assessing aPL status could become an urgent procedure. At this stage, we do not know what the optimum management of an acute stroke in an aPL-positive patient should be. This is true whether it is a primary or secondary event.
Recurrent stroke A substantial number of studies using the first method described above have provided evidence in support of aPL being a risk factor for recurrence [8– 11,28,29]. There are exceptions to this, and again, the differences appear to be due to different patient populations and the nature and range of aPL assays used in the various studies. The magnitude of the risk shows wide variation and may decline with time [11]. Not surprisingly, the magnitude appears to vary with the type of study. Followup of patients who unequivocally meet the criteria for APS, with or without lupus, generally discloses a significant risk, certainly significant enough that physicians who look after such patients are concerned to prevent the recurrence [11,28,29]. However, in stroke patients in general, of all ages, selected on the basis of a positive aPL, the risk appears a little greater than the general stroke population. The Antiphospholipid Antibody in Stroke Study Group (APASS) subset of the Warfarin versus Aspirin Recurrent Stroke Study (WARSS) study is the most influential here [20]. This study did exclude patients with embolic disease and was a cohort with many differences from the typical APS patients described by others [10,11,28,29]. The author’s conclusion at this stage is that there is an increased risk of recurrent stroke. The risk is greater in subjects who unequivocally meet the diagnostic criteria for APS. The relative predictive value of aCL, LA and anti-h2GP1 and other tests needs further study, as does the question of whether the risk is dose-related or a threshold effect. There is a desperate need for a risk profile to guide what is done is relation to the next issue, secondary prevention.
486
Secondary prevention of stroke The optimal prevention of recurrence is the question that has received most attention. While primary prevention in a very broad sense is very important for the health of the populations we serve, physicians are largely concerned with the management of disease once declared, that is, secondary prevention. Relatively small studies, taking patients who unequivocally had APS, showed that the prevention of recurrent events, including stroke, was possible and appeared to be best achieved with high-intensity warfarin [28,30]. More recently, in the prevention of recurrent venous thrombosis, the need for high-intensity warfarin has been challenged [31]. However, the appropriate dose and duration of warfarin in arterial disease, including stroke, remains undefined. Indeed, the APASS study challenges the use of warfarin at all. In that study of stroke patients of unselected age, embolic disease excluded, there was no difference between low dose of aspirin and low-intensity warfarin in preventing recurrent stroke [20]. Not surprisingly, the subcommittee at the last Antiphospholipid Conference in Taormina, 2002, charged with preparing recommendations on the management of stroke, concluded that there was insufficient evidence on which to base any recommendations about prevention of stroke recurrence [1]. Many of us who look after patients with APS felt that the subjects in the APASS study bore little resemblance to our patients and have not altered our practice of warfarin prophylaxis [11]. The study does, however, appear to have influenced the broader neurological community, and more definitive prospective studies, stratified for variables like age, gender, embolic risk and the presence of APS or not, are needed. The current impasse is a reflection of the fact that how you ask the question will determine the answer obtained. This is important because in the general stroke literature there is growing evidence that warfarin is not more effective than aspirin in preventing recurrent strokes, even at high intensity [32,33]. This mandates that studies supporting a potential exception for APS, just as for embolic strokes, be carried out.
The role of embolic disease A number of reports in the early 1990s, including our own group, concluded that most patients appear to have embolic disease [34,35]. Subse-
P.A. Gatenby quent larger studies show that while a significant proportion of patients continue to have embolic disease, there are clearly many who do not. Our own updated experience shows up to 30% of patients may be embolic (Hawkins, C., et al., submitted, 2004). Any future studies of secondary prevention must stratify patients into embolic versus non-embolic stroke. In other settings where embolism is a high risk, such as atrial fibrillation or prosthetic cardiac valves, warfarin is clearly indicated [4,36,37], and this begs the question of whether or not it would be ethical to conduct a trial of APS patients with clear-cut embolic disease.
Disappearing aPL Our group and others have observed patients in whom, after a variable period of time, the aPL tests become persistently negative. This is hardly a surprise as the observation has been made with a number of autoantibodies [38]. It is a minority of patients in our series, but at presentation, the patients were indistinguishable from other patients with stroke and aPL (Hawkins, C., et al., submitted, 2004). Thus, we have experienced eight patients who presented with clinical evidence of cerebrovascular events, four with definite abnormalities on CT or MRI brain scan, all of whom were initially positive for one or more aPL and all of whom became persistently negative at some stage during follow-up. Apart from less frequent brain imaging abnormalities, as a group, these patients demonstrated a similar profile to our Sapporo criteria positive patients. There are no studies that address the issue of long-term therapy in this group, but their existence is an indication of the need to repeat the tests in any studies that are done to ensure that they be stratified as a subgroup for separate analysis.
Concluding remarks While physicians are trained to be able to make decisions in the face of uncertainty, we are increasingly challenged to make our decisions based on evidence. In this paper, both the evidence and the lack of evidence to support decisions that we make all the time has been highlighted. I believe the Conference should encourage and facilitate the design and performance of large, appropriately stratified studies that will have to be multi-centre to produce answers to the questions
Controversies in the antiphospholipid syndrome and stroke posed here. Most of these will have to be done as nested studies in larger stroke studies, but should be cognisant of the age of the subjects, whether a formal diagnosis of APS has been made, the aPL profile and persistence and whether embolic disease is to be included or not.
[15]
[16]
[17]
References [1] Brey RL, Chapman J, Levine SR, Ruiz-Irastorza G, Derksen RHWM, Khamashta M, et al. Stroke and the antiphospholipid syndrome: consensus meeting Taormina 2002. Lupus 2003;12:508 — 13. [2] Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ, Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet 2002;360:1347 — 60. [3] Ebrahim S. Cost-effectiveness of stroke prevention. Brit Med Bull 2000;56:557 — 70. [4] Reddy KS. Cardiovascular diseases in the developing countries: dimensions, determinants, dynamics and directions for public health action. Pub Health Nutr 2002;5:231 — 7. [5] Wolf PA, Clagett GP, Easton JD, Goldstein LB, Gorelick PB, Kelly-Hayes M, et al. Preventing ischaemic stroke in patients with prior stroke and transient ischaemic attack. Stroke 1999;30:1991 — 4. [6] Wilson WA, Gharavi AE, Koike T, Locksin MD, Branch DW, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum 1999;42:1309 — 11. [7] For the Euro Phospholipid Project Group, Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 2002;46:1019 — 27. [8] The Antiphospholipid Antibodies in Stroke Study GroupBabikian VL, Brey RL, Coull BM, Dewitt LD, Feinberg WM, et al. Clinical and laboratory findings in patients with antiphospholipid antibodies and cerebral ischaemia. Stroke 1990;21:1268 — 73. [9] Levine S.R, Brey RL, Sawaya KL, Salowich-Palm L, Kokkinos J, et al. Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Ann Neurol 1995;38:119 — 24. [10] Finazzi G, Brancaccio V, Moia M, Ciavarella N, Mazzucconi MG, 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. [11] Ruiz-Irastorza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrada MJ, Hughes GRV. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome. Arch Intern Med 2002;162:1164 — 9. [12] Nencini P, Baruffi MC, Abbate R, Massai G, Amaducci L, Inzitari D. Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischaemia. Stroke 1992;23:189 — 93. [13] The Antiphospholipid Antibodies in Stroke Study (APASS) Group. Anticardiolipin antibodies are an independent risk factor for first ischaemic stroke. Neurology 1993;43: 2069 — 73. [14] Tuhrim S, Rand JH, Wu XX, Weinberger J, Horowitz DR, Goldman ME, et al. Elevated anticardiolipin antibody titre
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
487 is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 1999; 30:1561 — 5. Brey RL, Stallworth CL, McGlasson DL, Wozniak MA, Wityk RJ, et al. Antiphospholipid antibodies and stroke in young women. Stroke 2002;33:2396 — 401. Muir KW, Squire IB, Alwan W, Lees KR. Anticardiolipin antibodies in an unselected stroke population. Lancet 1994;344:452 — 6. The Antiphospholipid Antibodies and Stroke Study (APASS) Group. Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death. Neurology 1997; 48:91 — 4. Tanne D, D’Olhaberriague L, Trivedi AM, Salowich-Palm L, Schultz LR, Levine SR. Anticardiolipin antibodies and mortality in patients with ischaemic stroke: a prospective follow-up study. Neuroepidem 2002;21:93 — 9. Van Goor MPJ, Alblas CL, Leebeek FWG, Koudstaal PJ, Dippel DWJ. Do antiphospholipid antibodies increase the long-term risk of thrombotic complications in young patients with a recent TIA or ischaemic stroke? Acta Neurol Scand 2004;109:410 — 5. The APASS Writing Committee. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischaemic stroke. JAMA 2004;291:576 — 84. Brey RL, Abbott RD, Curb JD, Sharp DS, Ross GW, Stallworth CL, Kittner SJ. h2-Glycoprotein 1-dependent anticardiolipin antibodies and risk of ischaemic stroke and myocardial infarction. Stroke 2001;32:1701 — 6. Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, et al. Anticardiolipin antibodies and the risk for ischaemic stroke and venous thrombosis. Ann Intern Med 1992;117:997 — 1002. Ahmed EA, Stegmayr B, Trifunovic J, Weinehall L, et al. Anticardiolipin antibodies are not an independent risk factor for stroke: an incident case-referent study nested within the MONICA and Vasterbotten Cohort Project. Stroke 2000;31:1289 — 93. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update. Consensus Panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation 2002;106:388 — 91. Cuadrado J.M, Khamashta MA. The antiphospholipid antibody syndrome (Hughes syndrome): therapeutic aspects. Baillie `re’s Clin Rheumatol 2000;14:151 — 63. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. The Cochrane Database of Systematic Reviews 2004;1. Julkunen H, Hedman C, Kauppi M. Thrombolysis for acute ischaemic stroke in the primary antiphospholipid syndrome. J Rheumatol 1997;24:181 — 3. Rosove MH, Brewer PMC. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992;117:303 — 8. Feldmann E, Levine SR. Cerebrovascular disease with antiphospholipid antibodies: immune mechanisms, significance and therapeutic options. Ann Neurol 1995; 37:S114 — 30. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughesz GRV. The management of thrombosis in the antiphospholipid antibody syndrome. N Engl J Med 1995; 332:993 — 7. Crowther M.A, Ginsberg JS, Julian J, Denburg J, Hirsh J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the
488 antiphospholipid antibody syndrome. N Engl J Med 2003; 349:1133 — 8. [32] Pullicino P for the Warfarin–Aspirin Recurrent Stroke Study Group, Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischaemic stroke. N Engl J Med 2001;345:1444 — 51. [33] The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) Study Group. Oral anticoagulation in patients after cerebral ischaemia of arterial origin and risk of intracranial haemorrhage. Stroke 2003;34:45 — 7. [34] Pope JM, Canny CL, Bell DA. Cerebral ischaemic events associated with endocarditis, retinal vascular disease and lupus anticoagulant. Am J Med 1991;90:299 — 309.
P.A. Gatenby [35] Fulham M.J, Gatenby PA, Tuck RR. Focal cerebral ischaemia and antiphospholipid antibodies: a case for cardiac embolism. Acta Neurol Scand 1994;90:417 — 23. [36] Kennedy J, Buchan AM. Eer decreasing circles: advances in antiplatelet therapy and anticoagulation. Stroke 2003; 34:348 — 50. [37] Gerraty RP. Stroke prevention: what’s new? Intern Med J 2003;33:177 — 81. [38] Amital H, Schoenfeld Y. Autoimmunity and autoimmune diseases such as systemic lupus erythematosus. In: Lahita RG, editor. Systemic Lupus Erythematosus. Elsevier, London7 Academic Press; 2004. p. 3 — 27. Chap. 1.