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DVT PROPHYLAXIS IN ICU
Dr Gagan Brar
INTRODUCTION• Venous thromboembolism (VTE) includes the spectrum of deep vein
thrombosis (DVT) and pulmonary embolism (PE).• Extraordinarily common in hospitalized patients.• Estimating the frequency of DVT is problematic.• Nonspecific clinical findings and high rate of undiagnosed events
underestimate the true incidence of disease.• Autopsy data may overestimate meaningful events by detecting
Incidence And Natural History
• The incidence of VTE is thought to be in excess of 600,000 cases per year in the united states
• In a study of critically ill patients,10% to 30% of medical/surgical intensive care unit (ICU) patients experienced DVT within the first week of admission.
• Approximately 60% of trauma patients had DVT within the first 2 weeks, most of which were clinically silent .
• The prevalence of VTE as a cause of critical illness is also uncertain.
Attia J, Ray JG,Cook DJ, et al: Deep vein thrombosis and its prevention in critically illadults. Arch Intern Med161:1268,2001
Risk Factors• Every risk factor for VTE can be derived from virchow's triad.
Increasing Evidence: DVT risk factors reflect these underlying pathophysiologic processes VTE does not usually develop in their absence.
Convincing evidence that risk increases in proportion to the number of predisposing factors
• Strong risk factors (odds ratio> 10)
• Hip or leg fracture• Hip or knee replacement• Major general surgery• Major trauma, including spinal
• Moderate risk factors (odds ratio2–9)
• Arthroscopic knee surgery• Central venous catheterization• Congestive heart or respiratory failure• Hormone replacement and oral
contraceptive therapy• Malignancy (active or recently treated)• Pregnancy• Paralytic stroke• Prior VTE• Thrombophilia (inherited or acquired
• Weak risk factors (odds ratio <2)• Bed rest > 3d• Prolonged immobility due to sitting (e.g.,car or air travel)• Increasing age• Laparoscopic surgery• Obesity• Pregnancy• Varicose veins
• Anderson FA Jr,Spencer FA: Risk factors for venous thromboembolism Circulation107[23, Suppl 1]:I9,2003.
• Critically ill patients may be at especially high risk for VTE due to • Severe underlying disease• Immobility• Veno invasive catheters
• Incidence of VTE increases correspondingly with the number of risk
• Thrombosis may occur in up to 67%of patients with invasive catheters .
• The frequency of clinically meaningful complications due to cvc-related thrombosis remains unclear.
Venous Thromboembolism Risk Assessment
• The Padua Prediction Score was used • to determine VTE risk in 1180 consecutive medical patients. Patients were
followed for up to 90 days following admission to assess the occurrence of symptomatic VTE . The percent of subjects developing VTE was as follows:
• •“Low risk” patients (711): 0.3 percent• •“High risk” patients receiving adequate in-hospital thromboprophylaxis
(186): 2.2 percent• •“High risk” patients not receiving adequate in-hospital
thromboprophylaxis (283): 11.0 percent
A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score.Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, De Bon E, Tormene D, Pagnan A, Prandoni PJ Thromb Haemost. 2010;8(11):2450.
• ●The IMPROVE risk score was used to determine VTE risk in 15,156 medical patients enrolled in the observational International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) study .
• The observed rate of VTE within 92 days of admission was 0.4 to 0.5 percent if none of these risk factors was present, and was in the range of 8 to 11 percent in those with the highest risk score.
• The GENEVA risk score was subject to a• multicentre validation study , 1478 hospitalized medical patients,• 43% did not receive thromboprophylaxis.
• Over three percent of high-risk score subjects developed symptomatic VTE or VTE-related death at 90 days, compared to 0.6 percent of low-risk score patients.
• When only patients who did not receive prophylaxis were considered, these risks were 3.5 and 1.1 percent respectively
Prediction scores • Require validation from independent, prospective studies before they
can be used in routine practice. • Despite the absence of a prospectively validated risk model, the
following conclusions can be reached:• In general, VTE prophylaxis should be considered in medical patients
older than age 40 who have limited mobility for ≥3 days, and have at least one thrombotic risk factor .
• All patients admitted to intensive care units are considered high risk for VTE , even after routine prophylactic anticoagulation .
Bleeding risk assessment• Validated models are lacking• Makes it difficult for the clinician to fully assess the risks and benefits
of prophylactic anticoagulation • Retrospective analysis of data from (IMPROVE) has been used
• to assess in-hospital bleeding incidence• to identify risk factors at the time of admission associated with in-hospital
bleeding risk in acutely ill medical patients
• The cumulative incidence of major and non-major in-hospital bleeding within 14 days of admission was 3.2 percent.
• Active gastroduodenal ulcer (OR 4.15; 95% ci 2.21-7.77)• Bleeding within the three months prior to admission (OR 3.64; 95%
ci 2.21-5.99), and a • Platelet count <50,000/microl (OR 3.37; 95% ci 1.84-6.18) Strongest independent risk factors for bleeding at the time of admission.• Other bleeding risk factors included increased age,
hepatic and/or renal failure, intensive care unit stay, presence of a central venous catheter, rheumatic disease, cancer, and male sex
• If this model is validated in other patient populations, it may assist clinicians in estimating the risks of prophylactic anticoagulation in patients at risk for VTE
PREVENTION OF VTE
Overall Approaches• Primary prophylaxis —carried out using either drugs or physical
methods that are effective for preventing deep vein thrombosis (DVT).
• Secondary prevention — Secondary prevention involves the early detection and treatment of subclinical venous thrombosis by screening medical patients with objective tests that are sensitive for the presence of DVT.
• Primary prophylaxis :• preferred in most clinical circumstances• more cost effective than treatment of complications once they occur
Secondary prevention with screening is reserved for patients in whom primary prophylaxis is either contraindicated or shown to be ineffective
• The characteristics of an ideal primary prophylactic method includes ease of administration, effectiveness, safety (particularly with respect to bleeding), and cost-effectiveness or at least cost-neutrality when compared with current standards.
Mechanical Methods Of Thromboprophylaxis• Intermittent pneumatic compression (IPC), • Graduated compression stockings (GCS), and• Venous foot pumps (VFP).
Indicated in patients :At high risk of bleeding or in whom anticoagulation is contraindicated (eg, gastrointestinal or intracranial hemorrhage) .
Transition to a pharmacologic agent should be considered as soon as the bleeding risk becomes acceptably low or has been reversed
Intermittent Pneumatic Compression (IPC) Devices
• Prevents deep vein thrombosis (DVT) by enhancing blood flow in the deep veins of the legs, thereby preventing venous stasis .
• IPC also reduces plasminogen activator inhibitor-1 (PAI-1), thereby increasing endogenous fibrinolytic activity.
• Roberts VC, Sabri S, Beeley AH, Cotton LT. The effect of intermittently applied external pressure on the haemodynamics of the lower limb in man. Br J Surg 1972; 59:223.
• Comerota AJ, Chouhan V, Harada RN, et al. The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis. Ann Surg 1997; 226:306.
• Alternative for VTE prevention in medical patients with a high risk of bleeding .
• Complications:• Skin breakdown is a known complication, especially in the frail older
adult population.• No data available on skin complications
• Contraindication Patients with evidence of leg ischemia due to peripheral vascular disease. Attention must be paid to optimal compliance, as well as proper fit of the ipc device.
• Data on the efficacy and safety of IPCs are limited. • one large randomized trial in patients with stroke suggested that IPCs reduce the
incidence of VTE .
Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial.CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration, Dennis M, Sandercock P, Reid J, Graham C, Forbes J, Murray G.
A multicenter, randomized trial of 2876 immobile patients with acute stroke (CLOTS 3) reported that, compared to no device, IPC use was associated with a lower rate of VTE at 30 days (12 versus 8.5 percent; absolute risk reduction 3.6 percent; 95% CI 1.4 to 5.8) without altering mortality (13 versus 11 percent).
Graduated compression stockings and venous foot pump • There is less convincing evidence regarding the efficacy of graduated
compression stockings (GCS) and venous foot pump (VFP) in randomized clinical trials.
• In a meta-analysis, GCS was found to be ineffective in the prevention of VTE in patients with ischemic stroke.
• Amaragiri SV, Lees TA. Elastic compression stockings for prevention of deep vein thrombosis. Cochrane Database Syst Rev 2000; :CD001484.
• André C, de Freitas GR, Fukujima MM. Prevention of deep venous thrombosis and pulmonary embolism following stroke: a systematic review of published articles. Eur J Neurol 2007; 14:21
• One randomized trial showed that thigh-length GCS was associated with no benefit with respect to reduction of VTE, along with a fourfold increase in skin ulcers and necrosis .
• Similarly, there are few convincing studies showing the efficacy of VFP devices.
1.CLOTS Trials Collaboration, Dennis M, Sandercock PA, et al. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet 2009; 373:1958
• The 2012 ACCP Guidelines suggest the use of either IPC or GCS rather than no mechanical prophylaxis in acutely ill hospitalized medical patients at increased risk for thrombosis who are bleeding or are at high risk for major bleeding .
Mechanical Compression and Pharmacologic Prophylaxis:• No studies that have compared mechanical compression vs
anticoagulants to prevent VTE in hospitalized medical patients
• Indirect evidence from various orthopedic and non orthopedic surgical populations.
• Meta-analysis by Eppsteiner of 16 trials (3,887 patients) of various compression modalities tested against LDUH or LMWH
Mechanical Compression and Pharmacologic Prophylaxis• Trials in postsurgical patients that compared the combination of
intermittent pneumatic compression devices with a pharmacologic method to pharmacologic therapy used alone showed a strong trend toward fewer dvts with combination therapy
• Indirect data derived primarily from surgical populations suggest that GCS may be modestly effective at preventing asymptomatic DVT and possibly PE in hospitalized medical patients
Mechanical Thromboprophylaxis• May be preferable to no prophylaxis in patients at
appreciable risk for VTE who are also at high risk for bleeding
• Costs related to purchase and maintenance and the time and vigilance required to ensure optimal compliance
• Must ensure that the correct size is used, that they are properly applied, and that they are worn at all times
• Devices are often not functioning when patients are out of bed or being transported, either due to
• Improperly applied sleeves or nonfunctioning compression pump
• Devices were properly functioning in ,50% of postoperative patients in one study and only 19% of trauma patients in another.
• Newer battery-powered portable devices are available, and a recent study reported better compliance with these devices than with traditional plug-in devices
PHARMACOLOGIC AGENTS FOR VTE PREVENTION
Selection of agent• In hospitalized and immobilized medical patients, especially those at
high risk for VTE (eg, stroke, myocardial infarction, and critically ill), pharmacologic prophylaxis with unfractionated heparin (UFH), low molecular weight (LMW) heparin, or fondaparinux have all been shown to be superior to placebo or mechanical devices in preventing deep venous thrombosis (DVT) and pulmonary embolism (PE)
formularies).• UNFRACTIONATED HEPARIN• LOW MOLECULAR WEIGHT HEPARINS
UNFRACTIONATED HEPARIN • Heparin is an Indirect Thrombin Inhibitor that complexes with
Antithrombin (AT, formerly known as AT III), converting this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and Ixa
• The usual dose is 5000 units subcutaneously every 8 or 12 hours.• Bleeding, heparin-induced thrombocytopenia (HIT), and osteoporosis• Relatively low side effect profile, relatively inexpensive and easily
administered.• Anticoagulant monitoring is also not required, the platelet count
should be monitored regularly.
In a meta-analysis of 12 randomized studies of UFH given either two (BID) or three (TID) times daily for the prevention of VTE in medical patients, the following findings were noted :
• No significant difference in the overall rate of VTE between BID (5.4/1000 patient-days) and TID (3.5/1000 patient-days) UFH heparin dosing.
• TID heparin showed a trend toward a decrease in PE (bid 1.5/1000 patient-days, TID 0.5/100 patient-days) and in proximal DVT plus PE (BID 2.3/1000 patient-days, TID 0.9/1000 patient-days).
• The risk for major bleeding was significantly greater with TID than with BID UFH dosing (BID 0.35/1000 patient-days, TID 0.96/1000 patient-days).
A second meta-analysis involving 16 studies found no difference between BID and TID UFH dosing in the relative risks for DVT, PE, death, or major bleeding .
LOW MOLECULAR WEIGHT HEPARINS• Three LMW heparins have been approved for clinical use in the
United States : ENOXAPARIN, DALTEPARIN,TINZAPARIN.• Additional LMW heparin products are either commercially available in
Europe and other countries or are in phase III clinical trials .• These include REVIPARIN, NADROPARIN, BEMIPARIN, AND
Advantages• They have greater bioavailability• The duration of the anticoagulant effect is greater because of reduced
binding to macrophages and endothelial cells, permitting administration only once or twice daily.
• The anticoagulant response (anti-Xa activity) is highly correlated with body weight, permitting administration of a fixed dose.
• However, the dose may have to be adjusted for patients who are extremely obese or have renal insufficiency
• Laboratory monitoring is not necessary• Much less likely to induce immune-mediated thrombocytopenia (ie,
heparin-induced thrombocytopenia) than UFH• They do not increase osteoclast number and activity as much as UFH,
and may therefore produce less bone loss .
• Medical patients with severely-restricted mobility during acute illness: 40 mg once daily; continue until risk of DVT has diminished (usually 6 to 11 days).
• Obesity: In morbidly-obese patients (BMI ≥40 kg/m2), increasing the prophylactic dose by 30% may be appropriate for some indications.
• Abdominal surgery: 40 mg once daily, with initial dose given 2 hours prior to surgery; continue until risk of DVT has diminished (usually 7 to 10 days).
• Knee replacement surgery: 30 mg every 12 hours, with initial dose within 12 to 24 hours after surgery, and every 12 hours for at least 10 days or until risk of DVT has diminished. The ACCP recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested
• Bariatric surgery : Roux-en-Y gastric bypass: Appropriate dosing strategies have not been clearly defined (Borkgren-Okonek, 2008; Scholten, 2002):
• BMI ≤50 kg/m2: 40 mg every 12 hours• BMI >50 kg/m2: 60 mg every 12 hours
• Hip replacement surgery:• Twice-daily dosing: 30 mg every 12 hours, with initial dose within 12 to 24
hours after surgery, and every 12 hours for at least 10 days or until risk of DVT has. The ACCP recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested
• Once-daily dosing: 40 mg OD, with initial dose within 9 to 15 hours before surgery, and daily for at least 10 days (or up to 35 days postoperatively) or until risk of DVT has diminished. The ACCP recommends initiation ≥12 hours preoperatively or ≥12 hours postoperatively; extended duration of up to 35 days suggested .
• Crcl ≥30 ml/minute: No dose change .Monitor closely for bleeding.• Crcl <30 ml/minute:clcr 20 to 29 ml/min: dvt prophylaxis in abdominal
surgery, hip replacement, knee replacement, or in medical patients during acute illness:
• Subq: 30 mg once daily. ( The canadian labeling recommends 20 to 30 mg once daily (based on risk/benefit assessment) for prophylaxis in abdominal or colorectal surgery or in medical patients during acute illness).
RCTs – unfractionated heparin Vs Control
Unfractionated Vs LMW heparin
Incidence of DVT – UFH Vs Placebo
Symptomatic DVT – UFH Vs placebo
Pulmonary Embolism – UFH Vs placebo
Major bleeding UFH Vs Placebo
ICU mortality – UFH Vs placebo
DVT incidence – LMWH Vs UFH
Symptomatic DVT – LMWH Vs UFH
Pulmonary embolism – LMWH Vs UFH
Symptomatic pulmonary embolism – LMWH Vs UFH
Major bleeding – LMWH Vs UFH
ICU mortality – LMWH Vs UFH
Fondaparinux (Arixtra)Adult DVT prophylaxis: SubQ: Adults ≥50 kg: 2.5 mg OD. • Prophylactic use contraindicated in patients <50 kg. • DVT prophylaxis with history of HIT (off-label use): SubQ: 2.5 mg OD• Fondaparinux is a highly sulfated pentasaccharide. • Indirect factor xa inhibitor • Acts indirectly on factor xa by binding to antithrombin (at), inducing a
conformational change in at that increases the ability of at to inactivate factor xa.• Binds to at with a higher affinity than the native pentasaccharide of unfractionated
heparin or low molecular weight heparin• 100 percent bioavailable after subcutaneous injection, • Half-maximal and peak serum concentrations reached in 25 minutes and 1.7 hours
following subcutaneous injection, respectively .• Longer half-life (15 to 17 hours) allowing it to be given once daily
Using the composite end point of asymptomatic or symptomatic DVT and non-fatal or fatal PE, fondaparinux was compared with placebo for 6 to 14 days in 644 hospitalized medical patients.
VTE was detected in 5.6 percent of patients treated with fondaparinux versus 10.5 percent of patients given placebo, for a relative risk reduction of 47 percent (95% Cl 7.7-69)
In comparison studies
• Fondaparinux in recommended doses has shown lesser efficacy than enoxaparin 30 mg twice daily, (the enoxaparin regimen used in north america).
• Fondaparinux in recommended doses appears to have the same efficacy as enoxaparin 40 mg once daily (the enoxaparin regimen favored in europe).
• 50 percent reduction in the dose with reduced renal function (ie, creatinine clearances in the range of 30 to 50 ml/min) .
The safety and efficacy of reduced dosing was tested in a multicenter prospective cohort study in 206 acutely ill older medical patients (mean age 82 years; mean creatinine clearance 33 mL/minute [range 20 to 50]) at high risk for both bleeding and thrombosis. Subjects received 1.5 mg/day of fondaparinux for 6 to 15 days as thromboprophylaxis. Results included the following :
●Major bleeding occurred in one subject (0.49 percent)●Clinically relevant non-major bleeding occurred in eight subjects (3.88 percent)●Symptomatic VTE developed in three subjects (1.46 percent)
ASPIRIN• Highly effective in reducing major arterial thrombotic events . • Little evidence that aspirin has a significant effect on the prevention
of venous thromboembolic events in medical patients.
• An early meta-analysis and a later literature review indicated that aspirin reduced the incidence of VTE by approximately 20 percent compared with placebo or no treatment
• Collins R, Baigent C, Sandercock P, Peto R. Antiplatelet therapy for thromboprophylaxis: the need for careful consideration of the evidence from randomised trials. Antiplatelet Trialists' Collaboration. BMJ 1994; 309:1215
However, other studies have shown either no significant benefit or inferiority when compared with other modalities such as LMW heparin .
As a result, the 2012 ACCP Guidelines do not recommend the use of aspirin, either alone or in combination, as prophylaxis against VTE in any medical patient group
WARFARIN• Not appropriate for immediate and short-term prevention of VTE for
two reasons :• The ultimate anticoagulant effect of warfarin is delayed, does not
occur until 36 to 72 hours after drug administration.
• Achieving targeted levels of anticoagulation may be problematic due to comorbidities (eg, impaired liver function)
• Medications that interact with it (eg, antibiotics) that may lead to supratherapeutic anticoagulation.
Enoxaparin Vs Rivaroxaban – outcomes
Retrospective observational study of 175,665 critically ill adult patients .
The crude ICU and hospital mortality rates in those who received early thromboprophylaxis were 6.3 and 10.6 percent, respectively.
Rates were significantly lower than in those who did not receive thromboprophylaxis within 24 hours of icu admission (7.6 and 11.2 percent, respectively) .
• Pharmacological prophylaxis prevents deep vein thrombosis (strong evidence)
• It prevents pulmonary embolism (strong evidence)• Does it prevent ICU mortality? – Observational studies suggest it
may ; but these studies are not robust enough to address this question• Which agent to use? Fairly strong evidence to suggest that LMWH
may be more efficacious in preventing pulmonary embolism compared to UFH
• Fondaparinux may be more efficacious in selected subgroups of patients (post operative hip/knee surgery)
• Mechanical devices may not be effective when used in isolation
• However, while thromboprophylaxis has been shown to reduce the risk of VTE in hospitalized medical and surgical patients, and to reduce the risk of death in surgical patients [20,29], most studies and a meta-analysis have not been able to show a consistent beneficial effect of thromboprophylaxis on reducing overall mortality in hospitalized medical patients [30-37]. The reasons for this difference between medical and surgical patients are unclear but may be related to a greater number of comorbidities in medical patients that contribute to overall deaths.