Prevention of venous thromboembolism in immobilized neurological patients: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)

Thrombosis Research 124 (2009) e26–e31

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Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s

Regular Article

Prevention of venous thromboembolism in immobilized neurological patients: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET) Walter Ageno a,⁎, Giancarlo Agnelli b, Giovanni Checchia c, Claudio Cimminiello d, Maurizio Paciaroni b, Gualtiero Palareti e, Mario Pini f, Franco Piovella g, Enrico Pogliani h, Sophie Testa i a

Dipartimento di Medicina Clinica, Università dell'Insubria, Varese, Italy Dipartimento di Medicina Interna, Università di Perugia, Perugia, Italy U.O. Fisiatria, Ospedale Santa Corona, Pietra Ligure, Italy d Unità Operativa di Medicina 2°, Ospedale Civile di Vimercate, Vimercate, Italy e U.O. Angiologia e Malattie della Coagulazione, Università di Bologna, Bologna, Italy f U.O. Medicina Interna, Ospedale di Fidenza, Fidenza, Italy g U.O. Malattie Tromboemboliche, Policlinico S. Matteo, Pavia, Italy h Dipartimento di Ematologia, Università Milano Bicocca, Monza, Italy i UO Laboratorio Analisi Chimico Cliniche e Microbiologia- Centro, Emostasi e Trombosi, AO Istituti Ospitalieri, Cremona, Italy b c

a r t i c l e

i n f o

Article history: Received 27 March 2009 Received in revised form 21 June 2009 Accepted 30 June 2009 Available online 30 July 2009

a b s t r a c t Neurological disorders are often associated with immobilization, thus placing patients at increased risk for venous thromboembolism (VTE). This risk is very high in patients with acute ischemic stroke and spinal cord injuries, and it remains poorly defined in patients with peripheral nervous disorders or degenerative disorders of the central nervous system. The benefit of prophylactic strategies remains often unclear. The Italian Society for Studies on Haemostasis and Thrombosis promoted the development of evidence- and consensus-based guidelines to help physicians involved in the management of neurological patients. After a comprehensive and systematic review of the literature, a panel of experts formulated recommendations for the prevention of VTE in adolescent or adult patients presenting with different neurological disorders. Patients with acute ischemic stroke should routinely receive pharmacological prophylaxis to be started within 48 hours and continued for approximately 14 days; patients with acute hemorrhagic stroke should routinely receive mechanical prophylaxis, pharmacological prophylaxis should be considered once the patient is stable; patients with neuro-muscular degenerative diseases and with other major risk factors for venous thrombosis should be considered for the administration of pharmacological or mechanical prophylaxis; patients with peripheral nerve diseases should receive mechanical prophylaxis while immobilized and in the presence of additional risk factors for VTE, patients with Guillain Barrè should be considered for pharmacological prophylaxis with low molecular weight heparin; patients with spinal cord injury should receive combined mechanical and pharmacological prophylaxis; patients with non traumatic spinal cord diseases should be considered for pharmacological prophylaxis. © 2009 Elsevier Ltd. All rights reserved.

Introduction Patients affected by acute or chronic neurological disorders associated with immobilization are at increased risk for venous thromboembolism (VTE). This risk has been defined in patients with acute ischemic stroke or spinal cord injury, but it is less established in other settings such as in patients with peripheral nervous disorders or degenerative disorders of the central nervous system. Furthermore, the accuracy and clinical utility of screening diagnostic tests in asymptomatic, immobilized patients are poorly defined and the efficacy and safety of different methods of antithrombotic prophylaxis ⁎ Corresponding author. U.O. Medicina I, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy. E-mail address: [email protected] (W. Ageno). 0049-3848/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2009.06.032

are often not supported by adequate evidence. Such lack of evidence may translate into variations in clinical practice patterns regarding the identification of high risk patients requiring pharmacological prophylaxis and the selection of adequate therapeutic strategies. For instance, there are uncertainties on the risk to benefit ratio of pharmacological prophylaxis in some patients with acute ischemic stroke, on the optimal prophylactic strategies in patients with acute hemorrhagic stroke, on the optimal duration of prophylaxis in patients with spinal cord injury, and on the use of prophylactic strategies in patients with Guillaine Barrè syndrome or other acute peripheral nervous diseases provoking immobilization. In order to assist clinicians in their decision approach to patients with acute or chronic neurological disorders causing immobilization, the Italian Society for Studies on Haemostasis and Thrombosis (Società Italiana per lo Studio dell'Emostasi e della Trombosi, SISET)

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promoted the development of evidence- and consensus-based guidelines. The aim of these guidelines was to provide updated evidence on the risk of VTE and on the most beneficial prophylactic strategies in the different patient categories, and also to provide consensus-based suggestions to drive physicians activity in the presence of major evidence gaps. Final goals of this project are to improve patients survival and functional outcome by reducing the incidence of both thromboembolic and hemorrhagic events and to reduce management costs of these patients. The guidelines elaborated during this project are presented here. Methods The executive committee of the SISET charged one chairman (WA) with the development of the present guidelines, and invited an expert panel made of 7 members of the society selected for their expertise in research and clinical practice in the prevention of VTE (GA, CC, GP, MP, EP, FP, ST), 1 expert neurologist (MP) and 1 expert in rehabilitation medicine (GC). The present guidelines focus on adolescent (13 to 18 years of age) and adult patients affected by neurological disorders associated with immobilization or reduced mobility. These disorders have been separately covered in the following chapters: acute ischemic stroke; acute hemorrhagic stroke; neuro-muscular degenerative diseases such as demyelinizing diseases, parkinsonian syndromes, dementia, and muscular dystrophies; peripheral nervous system diseases such as Guillain Barrè syndrome; spinal cord injuries; and non-traumatic spinal-cord diseases. In each chapter, information on the efficacy and safety of mechanical prophylaxis of VTE with graduated compression stockings (GCS) or intermittent pneumatic compression (IPC); of pharmacological prophylaxis of VTE with unfractionated heparin (UFH), low molecular weight heparin (LMWH), or aspirin (ASA); and of routine screening methods with d-dimer or ultrasonography were evaluated. Literature search was performed using the MEDLINE (1966 to February Week 2 2009) and EMBASE (1980 to February Week 2 2009) electronic databases. For each topic, two reviewers performed study selection independently, with disagreements resolved through discussion and by the opinion of a third reviewer, if necessary. Detailed information on search strategies and results are available upon request. Selected articles were ranked according to a hierarchy of evidence levels, including systematic reviews, controlled clinical trials, uncontrolled clinical trials and case series. In the absence of evidence, a formal consensus method was applied. A detailed description of the organization and methodology of the SISET guidelines is reported elsewhere [1]. Results Acute ischemic stroke Brief appraisal of the evidence VTE is one of the most frequent complications occurring in patients with acute ischemic stroke. Asymptomatic deep vein thrombosis (DVT), as detected by routine screening with diagnostic tests, can occur in about 50% of patients [2]. The incidence of symptomatic DVT in these patients is about 5%, and objectively confirmed pulmonary embolism (PE) can be detected in approximately 2% of patients in the absence of thromboprophylaxis [3]. It has been estimated that about 5% of all deaths occurring early after acute ischemic stroke are attributable to PE [4]. Evidence on GCS is currently limited. The results of a Cochrane review including only two studies failed to prove a clear benefit for GCS when they are used as the only prophylactic method [5] (Level 1+). The optimal timing of application of GCS and their optimal duration are currently unknown. Ongoing clinical studies may add important

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information. Evidence on IPC originates from the same Cochrane review [5] (Level 1+). Although there are no sufficient proofs to support the efficacy of IPC in this setting, we have taken into consideration that IPC was proven effective in other high risk settings such as in patients undergoing major orthopaedic surgery. Several studies, as well as one Cochrane review [6] and one meta-analysis [7], have assessed UFH and LMWH in patients with acute ischemic stroke (Level 1++). Clinical studies had heterogeneous designs and have assessed different regimens of both UFH and LMWH, including both prophylactic and therapeutic doses. The quality of the systematic reviews is high, but their results lack consistency and their conclusions are different. This is in particular due to the different definitions used for clinically relevant outcomes. Our conclusions are based on our pre-defined end-points: VTE for the evaluation of efficacy and intracerebral bleeding for the evaluation of safety. UFH is effective to prevent DVT, prophylactic doses of 5000 IU bid or tid do not appear to increase the risk of intracerebral bleeding [7]. LMWH is effective in the prevention of both DVT and PE and no increased bleeding rates are observed when prophylactic doses (i.e. ≤6000 IU/qd or ≤86 IU/kg/qd) are administered. Recent studies and a meta-analysis suggest that LMWH may be more effective than UFH, in particular when LMWH is compared with UFH administered at the dose of 5000 IU bid [8–10]. No evidence on the efficacy and safety of either UFH or LWMH when administered for more than 14 days from the acute event is currently available. No data are also available on the safety of either UFH or LMWH in patients with large ischemic lesions. The concomitant administration of UFH and ASA (less than 300 mg qd) should not increase the risk of bleeding; no conclusive data are available for LMWH. Based on the results of a Cochrane review, ASA alone is clearly less effective than UFH or LMWH in the prevention of symptomatic DVT [11] (Level 1++).

Recommendations We suggest that GCS should not be used as the only prophylactic strategy in patients with acute ischemic stroke (Grade B). We suggest the use of GCS as the only prophylactic strategy in patients with contraindications to pharmacological prophylaxis (Grade B). GCS should be applied as soon as possible and maintained while the patient is bedridden (Good Practice Point [GPP]). The optimal type of GCS is unknown (GPP). We suggest that IPC should not be used as the only prophylactic strategy in patients with acute ischemic stroke (Grade B). We suggest that IPC should be applied in combination with GCS in patients with contraindications to pharmacological prophylaxis (Grade B). We are aware that the availability of IPC is insufficient in many Italian hospitals; this suggestion is made with the purpose of promoting a greater utilization of these prophylactic tools (GPP). The optimal type of compression and the optimal duration of application are unknown. We recommend the routine use of prophylactic doses of either LMWH or UFH (5000 IU tid) for the prevention of VTE in patients with acute ischemic stroke (Grade A). LMWH should be preferred over UFH (Grade B). Treatment should be started within 48 hours from the acute event and should continue for approximately 14 days (Grade A). Treatment should not be administered in patients with evidence of hemorrhagic transformation (Grade D). The use of pharmacological prophylaxis should not be a contraindication for the concomitant administration of ASA (Grade B). The first dose should be postponed in the presence of a large ischemic lesion (GPP). Treatment duration should be assessed on an individual basis according to the degree of immobilization (GPP). We recommend the monitoring of platelet count during prophylactic treatment with either UFH or LMWH (GPP). ASA is not recommended for the prevention of DVT and PE in patients with acute ischemic stroke (Grade A). ASA cannot be considered an effective alternative to UFH or LMWH in patients with contraindications to anticoagulant prophylaxis (GPP).

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Acute hemorrhagic stroke Brief appraisal of the evidence Although the incidence of VTE in patients with acute hemorrhagic stroke is less defined than it is in patients with acute ischemic stroke, the risk appears to be potentially similar. In a recent prospective cohort study carried out in 988 patients with primary intracerebral hemorrhage, the incidence of symptomatic VTE at a 90-day follow up was 2.9% (symptomatic DVT 1.1%, symptomatic PE 1.8%) [12]. We have identified only one randomized controlled study that evaluated the efficacy of mechanical prophylaxis in this setting [13] (Level 2). In this study, GCS alone were compared with GCS combined with IPC in 151 patients with hemorrhagic stroke. The results of the study suggest that IPC plus GCS is superior to GCS alone in the prevention of asymptomatic DVT. Because available evidence is limited, because GCS alone have been shown to be effective in other settings, and because GCS are more commonly available than IPC in many Italian hospitals, we have suggested the use of GCS as a first line prophylactic strategy despite the results of the above mentioned study. Five studies evaluating the efficacy and safety of UFH or LMWH have been identified [14–18] (Level 2). Only one of these studies was a randomised controlled study, but the sample size was too small to allow any meaningful conclusion [14].Although none of the published studies have reported an increased rate of bleeding complications, we have concluded that available evidence is insufficient to support the safety of pharmacological prophylaxis. No clinical studies on the use of ASA were identified. Thus, recommendations are based on formal consensus among experts. Recommendations We suggest the routine use of GCS in patients with acute hemorrhagic stroke (Grade D). GCS should be applied as soon as possible and maintained while the patient is bedridden (GPP). The optimal type of GCS is unknown (GPP). When available, we suggest the use of IPC in combination with GCS in patients with acute hemorrhagic stroke (GPP). We are aware that the availability of IPC is insufficient in many Italian hospitals; this suggestion is made with the purpose of promoting a greater utilization of these prophylactic tools (GPP). The optimal type of compression and the optimal duration of application are unknown. The routine use of either LMWH or UFH is not suggested for the prevention of VTE in patients with acute hemorrhagic stroke (Grade D). In patients at particularly high risk of VTE because of previous VTE, known cancer, known thrombophilia, recent surgery or trauma, the subsequent introduction of pharmacological prophylaxis should be considered (D). The optimal timing to start pharmacological prophylaxis depends on when the bleeding lesion is stabilized and must be assessed on an individual basis (GPP). We suggest that ASA alone or in combination with either LMWH or UFH should not be used for the prevention of VTE in patients with acute hemorrhagic stroke (Grade D). Neuro-muscular degenerative diseases Brief appraisal of the evidence Neuro-muscular degenerative diseases, including demyelinating diseases, parkinsonian syndromes, dementia, and muscular dystrophies, are commonly associated with immobilization. Long term immobilization may place these patients at increased risk for VTE. However, very little information is available on the incidence of VTE in these patients. In a study on 81 patients with Parkinson disease, the incidence of ultrasonographic detected asymptomatic DVT was 4.9% [19]. We have found no clinical studies that have assessed the efficacy and safety of either mechanical or pharmacological prophylaxis of VTE in this setting. Thus, the following recommendations are based on formal consensus among experts.

Recommendations We suggest the use of GCS in patients with neuro-muscular degenerative diseases, concomitant immobilization and with additional risk factors for VTE (previous VTE, known cancer, known thrombophilia, recent surgery or trauma) (Grade D). GCS should be maintained while immobilization persists (GPP). The need to combine the use of GCS with IPC is uncertain (Grade D). We also suggest to consider the use of LMWH in immobilized patients defined at particularly high risk for VTE (Grade D). The benefit of UFH as an alternative to LMWH is uncertain (Grade D). Doses and duration of thromboprophylaxis with LMWH should be determined on an individual basis (GPP). We recommend the monitoring of platelet count during treatment with LMWH (GPP). We suggest not using ASA for the prevention of VTE (Grade D). Peripheral nerve diseases Brief appraisal of the evidence Immobilisation is a consequence of peripheral nerve diseases such as Guillain-Barrè syndrome and other polyneuropathies. Prolonged immobilization places these patients at increased thromboembolic risk, although the real incidence of VTE has been poorly studied. In the only one available study, a retrospective study on 73 patients with Guillain-Barré syndrome, the incidence of symptomatic VTE was 7% (5 patients with DVT, 3 with concomitant PE), despite 50 patients having received pharmacological prophylaxis [20]. We have found no clinical studies that have assessed the efficacy and safety of mechanical prophylaxis with GCS or IPC in this setting. Recommendations are thus based on formal consensus among experts. Evidence on the benefits of UFH or LMWH is limited (Level 3). To date, three studies reporting small case series have been published [20–22]. Only the first of these three studies has evaluated the incidence of VTE in Guillain-Barré syndrome patients, most of whom treated with anticoagulant drugs (50 patients treated with warfarin, UFH, LMWH, or not treated) [20]. The results of this study show a high incidence of VTE and do not suggest any benefit from the administration of UFH, whereas the evidence on the potential benefits of LMWH is limited. Recommendations We suggest the routine use of GCS in patients with peripheral nerve diseases, concomitant immobilization and with additional risk factors for VTE (previous VTE, known cancer, known thrombophilia, recent surgery or trauma) (Grade D). GCS should be maintained while immobilization persists (GPP). We do not suggest the routine use of IPC in these patients (Grade D). The need to combine the use of GCS with IPC in high risk patients is uncertain (Grade D). We suggest the use of either LMWH or UFH in immobilized patients with Guillain Barrè syndrome (Grade D). Doses and duration of thromboprophylaxis should be determined on an individual basis (GPP). We recommend the monitoring of platelet count during treatment with either UFH or LMWH (GPP). We suggest not to use ASA for the prevention of VTE (Grade D). Spinal cord injuries Brief appraisal of the evidence Spinal cord injury exposes patients to a high risk of VTE. The incidence of DVT in the absence of prophylaxis ranges between 50 and 80% [23]. Evidence on the benefit of GCS derives from four clinical studies, none of which was randomised or controlled [24–27] (Level 3). The study designs of these studies do not allow for an appraisal of the effectiveness of GCS as the only method of prevention. Based on the high risk for VTE in these patients, GCS alone appears to be inadequate for the prevention of VTE.

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Four studies have assessed the role of IPC [24–26,28], but only one was randomised and controlled [28] (Level 2). There are insufficient data to support the use of IPC as the only method of prevention, whereas IPC in combination with pharmacological prophylaxis, with or without GCS, appears to be effective. The methodological limitations of the only randomised, controlled study do not allow a definitive conclusion on the efficacy of IPC plus pharmacological prophylaxis versus pharmacological prophylaxis alone [28]. However, given the high risk of VTE in these patients, this combination should be considered if feasible. In the presence of contraindications to pharmacological prophylaxis, the combination of IPC and GCS appears potentially effective. A number of randomised, controlled trials have evaluated the efficacy and safety of UFH [25,26,28–40]. Unfortunately, the heterogeneity of study designs and the usually small sample size of the studies make the overall results rather inconsistent (Level 1-). UFH appears to be sufficiently effective in preventing DVT, and this efficacy appears to be increased when combined with IPC. The optimal dose of UFH can not be identified, but the efficacy appears to be higher with higher prophylactic doses (5000 IU tid). The safety profile appears to be acceptable, and a 6-week duration of prophylaxis shows a favourable efficacy to safety profile. Similar limitations in study designs and study samples apply to the randomized controlled studies that have assessed LMWH [24,28–31,34,41–46] (Level 1-). However, the results of these studies are certainly more consistent. LMWH appears to be effective in the prevention of VTE, and the results of a recent meta-analysis suggest LMWH may be superior to UFH [47]. The safety profile of LMWH appears acceptable and and a 6-week duration of prophylaxis shows a favourable efficacy to safety profile. Only one randomised, controlled study has compared IPC and the combination of IPC and ASA plus dipyridamole [48] (Level 1-). This study enrolled only 28 patients. The limited available evidence suggests that ASA does not add any benefit to IPC. Recommendations We suggest that GCS should not be used as the only prophylactic strategy in patients with spinal cord injury (Grade C). Also, in patients with contraindications to pharmacological prophylaxis, GCS should not be used alone (Grade C). We suggest the routine use of IPC in association to GCS and pharmacological prophylaxis for the prevention of VTE in patients with spinal cord injury (Grade B). In the presence of contraindications to pharmacological prophylaxis, we suggest the combination of IPC and GCS (Grade B). We are aware that the availability of IPC is insufficient in many Italian hospitals; this suggestion is made with the purpose of promoting a greater utilization of these prophylactic tools (GPP). The optimal type of compression and the optimal duration of application are unknown. We suggest the use of either prophylactic doses of LMWH or UFH (5000 IU tid) for the prevention of VTE in these patients (Grade B). Prophylaxis should be continued for at least 6 weeks (Grade C). LMWH is preferred over UFH (Grade C). We recommend the monitoring of platelet count during prophylactic treatment with either UFH or LMWH (GPP). We suggest not using ASA for the prevention of VTE (Grade C). Non-traumatic spinal cord diseases Brief appraisal of the evidence Immobilisation is a possible consequence of non-traumatic spinal cord disease. These patients remain bedridden for prolonged periods of time becoming at increased risk for VTE. However, the real incidence of VTE in patients with non-traumatic spinal cord diseases has been poorly studied. We have found no clinical studies that have assessed the efficacy and safety of mechanical prophylaxis with GCS or IPC in this setting. Thus, recommendations are based on formal consensus among experts. Evidence on UFH has been derived from the results of two studies: a cohort-study with an historical control with 13 patients

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and a series of 11 cases in which therapeutic doses of UFH were used [49,50] (Level 3). The results of these two studies did not produce any conclusion because of their inconsistency. Nonetheless, it is possible to hypothesize a benefit in the use of UFH in high risk patients. Dosage and duration of treatment are not available. Finally, evidence on LMWH has been derived from a single cohort-study with 13 enrolled patients and an historical control [49] (Level 3). This limited evidence does not allow for any definitive conclusion, however, it suggests a possible benefit with the use of LMWH in patients at high risk. Also for LMWH information on doses and duration are not available. Because no studies have assessed ASA, recommendations are based on formal consensus among experts. Recommendations We suggest the use of GCS in patients with non-traumatic spinal cord injury (Grade D). GCS should be applied as soon as possible and maintained while immobilization persists (GPP). The need to combine the use of GCS with IPC is uncertain (Grade D). We suggest considering the use of either LMWH or UFH in these patients (Grade D). Doses and duration of pharmacological thromboprophylaxis should be determined on an individual basis (GPP). We recommend monitoring platelet counts during treatment with UFH or LMWH (GPP). We suggest not using ASA for the prevention of VTE (Grade D). Screening for VTE in immobilized neurological patients Brief appraisal of the evidence Uncertainty exists regarding the utility of routine laboratory and instrumental diagnostic investigations in asymptomatic long-term bedridden patients for the early identification of DVT. A few studies have been carried out assessing the potential role of d-dimer in patients with acute ischemic stroke and spinal cord injury [51–55] (Level 1- for studies on patients with acute ischemic stroke and 2 for studies on patients with spinal cord injury). Although the volume of evidence is discreet, in particular for the studies in patients with acute ischemic stroke [51–53], the authors have used different types of ddimers and have employed arbitrarily selected cut-offs which were not subsequently validated. The sensitivity of the tests performed was not suitable for the early diagnosis of DVT in asymptomatic patients. Five studies have assessed the accuracy of the routine use of ultrasonography of the lower limbs in patients with spinal cord injury [56–60] (Level 3). The volume of evidence appears limited, due to the inadequate methodologies and sample sizes of the selected studies. Recommendations D-dimer testing is not recommended as a screening test for VTE in bedridden neurological patients (Grade B for patients with ischemic stroke and spinal cord injuries, Grade D for other patients categories). Routine ultrasonography is not recommended as a screening test for VTE in bedridden neurological patients (Grade B for patients with spinal cord injuries, Grade D for other patients categories). Conclusions Over the last years, research on the incidence and prevention of VTE in neurological patients has mainly focused on patients with acute ischemic stroke and patients with spinal cord injury. National and international guidelines have thus produced evidence based recommendations to drive prophylactic strategies in these two settings. However, many other neurological disorders are associated with immobilization, and may thus expose patients to a similar risk of VTE. One of the aims of these guidelines was therefore to provide clinicians with some practical suggestions for the management of patients at risk for VTE, in areas where evidence based recommendations are currently unavailable. These suggestions were in many cases based on formal consensus among experts in the field, and should

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therefore be interpreted with caution and applied on an individual basis after a careful evaluation of the risks and benefits associated with the suggested strategy. Another objective of these guidelines was to highlight areas of potential interest for future research projects, in order to fill some existing knowledge gaps. These gaps not only exist in areas where clinical studies are clearly lacking, but also in areas where the results of clinical trials are conflicting or non-conclusive because of their intrinsic limitations. In many neurological patients the balance between the risk of VTE associated with the clinical condition and the risk of bleeding associated with pharmacological prophylactic strategies remains extremely uncertain. Conflict of interest statement None of the authors had conflicts of interest to disclose. References [1] Iorio A, Ageno W, Cosmi B, Imberti D, Lussana F, Siragusa S, et al. 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