Clinical Practice Guideline
The Prophylaxis of Venous Thromboembolism
Background: Venous thromboembolism (VTE) is the third most common cardiovascular condition, after myocardial infarction and stroke. Prophylactic measures in accordance with current guidelines can significantly reduce the risk of VTE and the associated morbidity and mortality. Until now, the German interdisciplinary, evidence- and consensus-based (S3) clinical practice guideline on VTE prophylaxis was based on a complete review of all pertinent literature available in MEDLINE up to January 2008. More recent publications and drug approvals have made a thorough revision necessary.
Methods: A systematic search was carried out in the MEDLINE and Embase databases for publications that appeared from 1 January 2008 to 7 August 2013. Updates of 5 national and international reference guidelines and 2 new Health Technology Assessment (HTA) reports were considered as well. A structured consensus-finding process was carried out with delegates from 27 scientific medical societies and from the Union of Medical Specialist Associations.
Results: 46 randomized controlled trials (RCTs) were included for critical appraisal. New findings led to re-evaluation of the value of compression stockings in combination with pharmacological prophylaxis (open recommendation), and suggest equal value of non-vitamin K antagonist oral anticoagulants (NOACs) and low molecular weight heparins (LMWH) or fondaparinux in elective hip and knee replacement (strong recommendation). For patients undergoing hip fracture surgery, we recommend LMWH or fondaparinux.
Conclusion: Further research is needed to assess the value of NOACs for pharmacological prophylaxis in orthopedic/trauma patients undergoing surgical procedures other than the ones mentioned above, and into the benefit and harm of new devices available for mechanical prophylaxis. The stringent implementation of basic measures such as early mobilization, movement exercises, and patient instruction is a key point to prevent venous thromboembolism.
Venous thromboembolism (VTE) is the third most common cardiovascular condition, after stroke and myocardial infarction (1). In the general population, the annual incidence of VTE is approximately 1/1000 on average, showing a linear increase with age (1, 2). It can be assumed that in the age group 60–69 years the VTE incidence rate (IR) has already doubled (IR 2.57/1000; 95% confidence interval [CI]: 2.54; 2.61) (1). Hospitalized patients are at a significantly increased risk of VTE, with wide variations depending on the cause of the hospitalization (1, 2). Older autopsy studies attributed 5 to 10% of in-hospital deaths to pulmonary embolism (3, 4). Since risk-adapted primary prophylaxis of venous thromboembolism can significantly reduce VTE events (5–7), the implementation of adequate strategies for risk assessment and prophylaxis based on high-quality guidelines is internationally viewed as a key indicator for patient safety (8, 9). In Germany, a set of rules for high-quality guidelines established by the Association of Scientific Medical Societies in Germany (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften) (10) was first used in 2009 to develop a clinical practice guideline (11) which was based on a systematic search and critical appraisal (12) of the literature available in the MEDLINE database (via PubMed), published until 9 January 2008, as well as on 12 international guidelines. The approval of novel anticoagulants and new evidence, especially related to mechanical methods and to patients with medical/neurological conditions, necessitated a complete revision of the 2009 guideline.
27 medical specialty societies and the Union of Medical Specialist Associations (Gemeinschaft Fachärztlicher Berufsverbände) were involved in the update process and approved the guideline (eTable 1) (13). A systematic literature search was conducted in the MEDLINE (via PubMed) and EMBASE databases for the period from 1 January 2008 to 7 August 2013 (eTables 2 and 3). Forty-six randomized controlled trials (RCTs) met the inclusion criteria (eFigure). These were assessed for methodological quality (14). In addition, updates of 5 of the guidelines used as references (15–19) and two new Health Technology Assessment (HTA) reports (20, 21) were taken into account. Three grades of recommendation are distinguished. The differences in the strength of recommendation are expressed by the use of the wording “we recommend” (strong recommendation), “we suggest” (recommendation) and “may” (open recommendation) in combination with corresponding arrow symbols (↑↑, ↑ and ↔, respectively) (eTable 4). Besides the quality of evidence, factors taken into account for determining the grade of recommendation included the balance of benefits and harms, the clinical relevance of outcomes and effect sizes, the consistency and external validity of the study results, as well as ethical and legal considerations. For questions left unanswered by the literature search, recommendations were adopted by means of expert consensus. The guideline was funded by the AWMF’s guideline fund and the participating medical societies, without any financial support from the industry. For detailed information about the methodology and rationale for the recommendations, including 87 evidence tables, please refer to the long version of this guideline and pertinent report on the AWMF website (13).
In all patients with surgical procedures, injuries or acute disease, we recommend that the risk of veno
- low risk (<10% / <1% / <0.1%)
- moderate risk (10%–40% / 1%–10% / 0.1%–1%)
- high risk (40%–80% / 10%–30% / >1%).
Examples for the classification of patients to these three risk categories are provided in Table 1.
Principles of VTE prophylaxis
As a principle, we suggest that all patients receive the basic measures including early mobilization, movement exercises and instructions for self-excercises (expert consensus) (↑). For patients with moderate or high VTE risk, we recommend pharmacological VTE prophylaxis (↑↑). In addition, mechanical measures (compression stockings, intermittent pneumatic compression [IPC]) may (↔) be applied.
In Germany, compression stockings have traditionally been used in addition to pharmacological prophylaxis. However, the evidence in support of this combination preventive treatment is dubious (22–24). Four RCTs evaluated the benefits of compression stockings as an adjunct to heparin prophylaxis (24). Pooled analysis of these studies as part of a network meta-analysis (25) showed an advantage for this combination treatment for the outcome deep vein thrombosis (DVT) (Odds Ratio [OR] 0.31, 95% confidence interval [CI] [0.16; 0.61]), but not for the outcome symptomatic DVT (number needed to treat [NNT]: 134–524), subject to VTE risk constellation). A recent non-interventional phase 4 study (XAMOS) found almost identical rates of symptomatic thromboembolism events with and without the use of additional mechanical measures (26). For pharmacological prophylaxis alone, it was 0.8% (45/5430) with rivaroxaban and 1.4% (71/5117) with other anticoagulants; in combination with additional mechanical measures, it was 1.0% (33/3348) and 1.3% (46/3528), respectively. Whether the length of compression stockings (knee-high versus thigh-high compression stockings) has an impact on VTE prevention has also been discussed. In line with an earlier meta-analysis (27), the recent network meta-analysis (25) found no significant difference for the endpoint DVT (OR 1.48, 95% CI [0.80; 2.73]). Among the mechanical measures, intermittent pneumatic compression (IPC) is superior to compression stockings with regard to DVT prevention (relative risk [RR] 0.6, 95% CI [0.39; 0.93]) (28).
For pharmacological prophylaxis, heparins, fondaparinux and (for approved indications) non-vitamin K antagonist oral anticoagulants (NOACs, previously referred to as new or novel oral anticoagulants) are recommended. When anticoagulants are used, we recommend the procedure-specific and patient-specific bleeding risk to always be taken into account (↑↑). In addition, we recommend that kidney and liver function be considered when choosing and administering an anticoagulant therapy (↑↑). We recommend that when using heparin, the risk of heparin-induced thrombocytopenia (HIT II) be taken into account (↑↑). When using unfractionated heparin (UFH), we suggest that platelet counts be regularly monitored (↑). We recommend that low-molecular-weight heparin (LMWH) be preferred over UFH (↑↑), while balancing efficacy with bleeding risk and HIT II risk. When using LMWH therapy, platelet monitoring may (↔) be omitted. We suggest that pharmacological VTE prophylaxis be initiated early after the risk-producing situation (↑). In surgical patients, LMWH prophylaxis may (↔) be started the evening before surgery, while prophylaxis with fondaparinux and the NOACs dabigatran etexilate, rivaroxaban and apixaban shall only be initiated postoperatively (↑↑). When administrating spinal or epidural anesthesia, special time intervals have to be observed because of the risk of spinal or epidural hematomas (19).
We recommend the duration of pharmacological VTE prophylaxis be guided by the persistence of relevant risk factors for VTE (↑↑). Where continuation of the prophylaxis is required after hospital discharge, we recommend that the physician responsible for the patient’s further treatment be informed about this (↑↑) and that patients be advised to immediately see their doctor to ensure the seamless continuation of VTE prophylaxis (↑↑). The guideline group considers successful communication at this interface as crucial (expert consensus).
After craniofacial and neck procedures, VTE prophylaxis may (↔) generally be omitted. However, in the presence of additional risks, e.g. extensive or large oncological procedures, we suggest that pharmacological prophylaxis be initiated (↑). In patients undergoing craniotomy/neurosurgical procedures or those with injuries to the central nervous system, we recommend that mechanical VTE prophylaxis be used (↑↑), given the special bleeding risk. With this approach, the risk of DVT can be significantly reduced (RR 0.41, 95% CI [0.21; 0.78]), accounting to approximately 3 (range, 1 to 4) prevented events/100 patients (29). Notwithstanding the information in manufacturers’ summaries of product characteristics, evidence suggesting potential additional benefits from pharmacological prophylaxis is available (29, 30). Further research is needed here, not least to determine the as yet unknown increase in bleeding risk associated with pharmacological prophylaxis. In patients undergoing moderate or major thoracic surgery we recommend pharmacological VTE prophylaxis with LMWH (↑↑). In patients not on anticoagulation therapy undergoing moderate or major cardiac surgery we recommend postoperative pharmacological VTE prophylaxis with UFH or LMWH (expert consensus) (↑↑). We suggest that patients undergoing leg vascular surgery receive VTE prophylaxis with UFH or LMWH, if they do not receive therapeutic anticoagulation treatment postoperatively (↑). In patients with no additional dispositional risk factors undergoing superficial-vein surgery (varicose vein surgery), pharmacological VTE prophylaxis may (↔) be omitted (expert consensus).
RCTs found no differences with regard to the VTE risk between patients undergoing visceral surgery, vascular surgery, gynecological and urological procedures in the abdomen and pelvic region. Therefore, the same recommendations apply to these subgroups (expert consensus, Table 2). We suggest that patients with low procedure-related expositional and absent or low dispositional VTE risk do not receive pharmacological prophylaxis (↑). We recommend that patients with moderate VTE risk (moderate surgery or minor surgery with additional dispositional risk factors) receive pharmacological prophylaxis with heparin (↑↑). In patients with high VTE risk (major surgery or moderate surgery with additional dispositional risk factors) we recommend prophylaxis with LMWH (↑↑). Alternatively, fondaparinux may be used (↔). For laparoscopic procedures and minimally invasive surgery (MIS), the same recommendations apply as for open procedures. Pharmacological prophylaxis is typically administered over a period of 7 days, regardless of whether the patient is still treated on an in-patient basis or already on an out-patient basis. In patients undergoing major oncological surgery we recommend VTE prophylaxis over a period of 4 weeks (↑↑). This regimen significantly reduces the VTE risk (13.6% vs. 5.9%; RR 0.44, 95% CI [0.28; 0.7]) without increasing the bleeding risk (31).
We recommend that patients undergoing major hip surgery receive pharmacological VTE prophylaxis in addition to the basic measures (↑↑). In patients undergoing elective total hip arthroplasty, we recommend that LMWH, fondaparinux or NOAK be used for pharmacological VTE prophylaxis; in case of fractures near joints and in patients undergoing near-joint osteotomy, we recommend LMWH or fondaparinux (↑↑). In patients with a history of heparin intolerance we recommend fondaparinux or a NOAC when undergoing elective hip surgery (↑↑), while in patients with fractures and those undergoing osteotomy we recommend fondaparinux (↑↑). In addition to pharmacological prophylaxis, mechanical measures (compression stockings, IPC) may (↔) be used. Where pharmacological prophylaxis is contraindicated, we recommend that IPC be applied (↑↑) (Table 3). We recommend that pharmacological prophylaxis be administered over a period of 28 to 35 days (↑↑). Prolonged prophylaxis with LMWH after discharge from hospital reduces the rates of venography-confirmed DVT (22.5% vs. 7.9%; RR 0.41, 95% CI [0.32; 0.54]) and symptomatic DVT (4.1% vs. 1.4%; RR 0.36, 95% CI [0.20; 0.47]) (32). The efficacy and safety of prophylaxis with dabigatran etexilate, rivaroxaban or apixaban, started postoperatively and continued over a period of approximately 5 weeks, was demonstrated in phase III studies (33–36). For fractures treated non-surgically with early functional therapy, no general recommendations can be issued due to a lack of pertinent data. In case of immobilization, we recommend that pharmacological prophylaxis be initiated (↑↑). For patients undergoing major knee surgery, corresponding recommendations apply (Table 3). Based on the evidence from available studies, we recommend pharmacological prophylaxis over a period of 11 to 14 days in patients undergoing knee surgery (↑↑). The recommendations for the NOACs dabigatran, rivaroxaban and apixaban in patients undergoing elective hip or knee preplacement surgery are supported by independently conducted HTA reports (20, 37, 38). However, the Institute for Quality and Efficiency in Health Care (IQWiG, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen) does not support the finding that there is evidence demonstrating an additional benefit provided by apixaban in patients undergoing elective knee replacement surgery compared with the LMWH enoxaparin (21). In patients undergoing non-surgical treatment of fractures with joint-spanning cast immobilization we recommend pharmacological prophylaxis (↑↑).
In patients with surgically treated bone injuries and/or immobilizing hard casts or below-knee orthoses we suggest pharmacological VTE prophylaxis in addition to the basic measures (↑). We recommend LMWH over other pharmacologic measures and that this be used until the removal of the fixating cast or until a defined partial weight bearing is achieved (expert consensus) (↑↑) (Table 3). Deviating from that, the German College of General Practitioners and Family Physicians (DEGAM, Deutsche Gesellschaft für Allgemein- und Familienmedizin) voted to decide the scope and duration of pharmacological prophylaxis in a primary care setting on a case-by-case basis in this patient group, owing to the lack of evidence.
Short arthroscopic procedures on the lower extremity do not generally require pharmacological VTE prophylaxis. We suggest that patients undergoing longer arthroscopic procedures receive pharmacological prophylaxis until normal mobility is restored, but not for less than 7 days (expert consensus) (↑). Deviating from that, the DEGAM voted for case-by-case decisions in a primary care setting. Here, again, data from studies are scarce.
We suggest that patients undergoing surgery on the upper extremity do not generally receive VTE prophylaxis other than the basic measures (expert consensus) (↑). For elective spinal surgery, the available data do not allow to make definite recommendations; thus, decisions have to be made on a case-by-case basis. We recommend that patients with spinal injuries receive pharmacological prophylaxis, while taking into account the bleeding risk; in patients with high bleeding risk we recommend IPC (expert consensus) (↑↑). For pelvic fractures, the same recommendations as for fractures near the hip apply (expert consensus). In polytrauma patients we recommend pharmacological prophylaxis with LMWH for the duration of intensive care (↑↑); in case of contraindications, we suggest that IPC be used (↑). We recommend that patients with burns and patients with immobilization receive pharmacological prophylaxis (↑↑).
Internal medicine and neurology
In hospital patients with acute medical illness and bed confinement we recommend pharmacological VTE prophylaxis, preferably LMWH in high-risk prophylaxis doses or fondaparinux (↑↑). We suggest that this be administered over a period of 6 to 14 days (↑). Heparins reduce the DVT risk by half compared with no prophylaxis or placebo (3.8% vs. 6.7%; OR 0.41, 95% CI [0.25; 0.67]) (39). In patients receiving in-patient treatment for malignancies we recommend pharmacological VTE prophylaxis, preferably with LMWH or fondaparinux (↑↑). We suggest that this be administered during the entire hospital stay (expert consensus) (↑). Patients with acute ischemic stroke and paretic leg have a high VTE risk and, therefore, we recommend they receive pharmacological prophylaxis (↑↑). We recommend that this preferably be based on LMWH or UFH in high-risk doses (↑↑) and suggest that this be continued for a period of 6 to 14 days, depending on the speed of mobilization (↑). We suggest that patients with acute hemorrhagic stroke and paretic leg receive pharmacological prophylaxis, as soon as there is no more risk of bleeding (↑). In patients where pharmacological prophylaxis is contraindicated, we suggest a mechanical prophylaxis be initiated, preferably IPC (Table 4) (↑).
Intensive care medicine
The vast majority of intensive care patients fall into the high-risk category. Only limited data from studies are available; a meta-analysis found that heparin thromboprophylaxis can reduce the DVT rate among critically ill intensive-care patients (14.7% vs. 7.5%; RR 0.51, 95% CI [0.41; 0.63]) (40). Thus, in these patients we recommend pharmacological VTE prophylaxis with heparin, preferably LMWH (expert consensus) (↑↑). In patients with bleeding diathesis, renal failure or uncertain absorption, low-dose intravenous UFH therapy may (↔) be initiated; where pharmacological prophylaxis is contraindicated, we suggest that mechanical measures (preferably, IPC) be used (↑).
Special considerations in pediatrics and neonatology
Data on the use of pharmacological and mechanical VTE prophylaxis in pediatric and neonatal patients are scarce. The special requirements resulting from the development of the hemostatic system and the pharmacokinetics in pediatric patients must be taken into account (e1).
Special considerations in outpatient care
We recommend that outpatient VTE prophylaxis be provided based on the same criteria as for in-patient prophylaxis (expert consensus) (↑↑). On discharge of a patient, it has to be decided whether the prophylaxis initiated in hospital is to be continued. In a special vote, the DEGAM recommends this indication be reviewed on a case-by-case basis in a consultation with the family physician, taking into account the patient’s individual VTE risk (↑↑). Immobility without acute illness is by itself not an indication for VTE prophylaxis other than the general basic measures.
Obligatory patient information
The outcome of the VTE risk assessment and the resulting measures for VTE prophylaxis must be discussed with the patient, including the benefits, risks and alternatives, during an informed consent discussion (section 630e, subsections 1 and 2, German Civil Code [BGB]). No specific formal requirements have to be fulfilled when conducting the informed consent discussion. However, written documentation of the key points discussed is compulsory (section 630f, subsection 2 BGB). If the patient refuses VTE prophylaxis and/or the physician refrains from initiating VTE prophylaxis, the physician should record this in the patient file.
With the aging of the population, the significance of VTE continues to grow. In a hospital setting, VTE is a common, but largely preventable complication. Thus, in all patients with surgical procedures, injuries or acute disease, the individual VTE risk has to be assessed and, where indicated, a risk-adapted prophylaxis is to be initiated. Implementation is required with regard to the basic measures, the communication at interfaces of care, the follow-up risk assessment by the physician responsible for the patient’s further care, and with regard to patient information. Detailed information is available in the long version of the guideline and in the guideline report (13).
Our sincere thanks go to all authors of the guideline and the contributing medical societies. Without their significant efforts, the creation of this guideline and the writing of this article would not have been possible (eTable 1). The guideline group would like to thank the Thrombosis Action Alliance (Aktionsbündnis Thrombose) which has set itself the task of implementing guidelines and promoting health services research. It fully supports the recommendations of this guideline.
Conflict of interest statement
Prof. Haas has received consultancy fees from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, and Sanofi. She has received reimbursement of travel expenses and lecture fees from Aspen, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, and Sanofi.
Prof. Kopp and Prof. Encke declare that no conflict of interest exists.
Manuscript received on 6 April 2016, revised version accepted on
13 June 2016.
Translated from the original German by Ralf Thoene, MD.
Prof. Dr. med. Ina Kopp
AWMF-Institut für Medizinisches Wissensmanagement
35043 Marburg, Germany
For eReferences please refer to:
Prof. Dr. med. Encke, Prof. Dr. med. Kopp, Prof. Dr. med. Haas
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