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Abstract

General Considerations

Timing of Prophylaxis

Venous thromboembolism (VTE) prophylaxis involves a balance of risks and benefits. Chemical prophylaxis poses a dilemma, as the closer it is administrated to surgery for a given dose, the better the thromboprophylaxis but the greater is the risk of bleeding complications.¹ In Europe, low-molecular-weight heparin (LMWH) is given at a lower dose prior to operation providing an anticoagulant effect to counteract the intraoperative activation of coagulation factors and venous stasis. However, if a given dose of the drug is administered too long before surgery, then, intraoperative blood levels would be inadequate for effective prophylaxis, whereas if given too close to surgery then surgical bleeding is a threat. In North America, LMWH is given after surgery at a higher dose and more frequently. This should reduce the risk of surgical bleeding, yet intraoperative thrombogenesis is not prevented and thrombi may have already begun forming. The drug is now expected to be therapeutic as well as prophylactic. Therefore, prophylaxis needs to be given close but not too close to surgery.^2,3

Intermittent pneumatic compression (IPC) and foot impulse technology (FIT) sleeves are available in sterile packages that allow for intraoperative use, reducing both the risk of bleeding and the duration that the patient is not under LMWH prophylaxis.^4–6

Spinal and Epidural Anesthesia

Meta-analyses show that spinal and epidural anesthesia reduce both thromboembolism and perhaps mortality in hip fractures surgery^7,8 and total knee replacement (TKR).^9–11 This method does not reduce risk sufficiently on its own but should be regarded as a useful adjunct. Initial European experience suggested that neuraxial anesthesia could be safely used in the presence of LMWH.¹² However, more recently there have been concerns that a spinal hematoma may develop on rare occasions.^13,14 Guidelines have been suggested.^15,16 The LMWH (or pentasaccharide) can be given safely 4 hours after removal of the epidural catheter (see section on Pregnancy). However, LMWH or pentasaccharide should be avoided while a continuous postoperative neuraxial block is in place. The catheter should not be inserted until serum levels of the chemical agent used are at their lowest. This means that postoperative administration of the agent is generally safer and more predictable than preoperative administration when epidural analgesia is needed.

Duration of Prophylaxis in Elective Orthopedic Surgery

Studies in patients having total hip replacement (THR)^1,17–25 demonstrate that there is prolonged risk, with 45% to 80% of all symptomatic events occurring after discharge from the hospital.^19,26–28 Randomized controlled trials (RCTs) in patients having THR indicate that prolonged thromboprophylaxis with LMWH for up to 35 days is safe and effective irrespective of whether inhospital prophylaxis was with LMWH or warfarin. It decreases the frequency of venographically detected total deep vein thrombosis (DVT), proximal DVT, and symptomatic VTE after the seventh day by more than 50%.^25,29–33 One RCT compared warfarin prophylaxis (international normalized ratio [INR] 2-3) for 9 days with warfarin extended for 1 month after hospital discharge. The VTE occurred in 5.1% of inhospital prophylaxis patients and 0.5% in those having extended prophylaxis (relative risk [RR] 9.4; 95% confidence interval [CI] 1.2-73.5).³⁴ This study was prematurely terminated because of the superiority of prolonged prophylaxis. As indicated above, it has been subsequently demonstrated that extended prophylaxis with warfarin is associated with more hemorrhagic complications than with LMWH.³⁵ The RECORD2 study³⁶ that compared extended thrombophylaxis (35 days) using rivaroxaban with short-term enoxaparin (10-14 days) followed by placebo further confirmed the benefits of extended prophylaxis after THR suggested by the RECORD1 study.³⁷

Further studies are needed before recommendations can be made for prophylaxis beyond 35 days. The optimal duration of prophylaxis is unknown. Epidemiological data on postoperative death rates indicate a much longer duration of risk in subgroups such as emergency patients (eg, hip fracture) and patients with comorbidity (eg, rheumatoid arthritis) in which vascular deaths dominate.^38,39

Elective Hip Replacement

The Risk

In the absence of prophylaxis, patients undergoing elective major joint replacement and those with hip fracture have a DVT risk of approximately 50% as shown in studies performed in the 1970s, 1980s, and 1990s^19,40,41 (Table 6.1).^{42–91,67,92–109} Similar high rates of VTE were found in the placebo groups of 2 recent dose-ranging studies for enoxaparin and fondaparinux performed in Japan.^110,111 The frequencies of proximal DVT (Table 6.2)^{63–65,67–69,112,113} and pulmonary embolism (PE; Tables 6.3^112,114 and 6.4 115,116) are also high, and symptomatic events range from 2% to 5%.¹¹⁷ In a population-based study in Scotland, the incidence of VTE including fatal PE for the years 1999 to 2001 was 2.27% for primary hip arthroplasty and 1.79% for total knee arthroplasty.¹¹⁸ The risk of clinical DVT and PE continues after hospitalization over a period of approximately 3 months^{19,20,117,119} (Table 6.5).^18,120–123 Mortality studies have confirmed a reduced survival for 2 to 3 months following elective surgery with the highest death rate initially early after operation.^38,124

Table 6.1.

The Frequency of all DVT in Orthopedic Surgery and Trauma, in the Absence of Prophylaxis (Diagnosed by Surveillance With Objective Methods: Phlebography, FUT, or DUS).^a

Patient Groups	Number of Studies	Patients DVT, n	95% CI Incidence
Elective hip replacement
Belch et al⁴²		36	20
Bergqvist et al⁴³		71	45
Dechavanne et al⁴⁴		27	13
Dechavanne et al⁴⁵		20	8
Evarts et al⁴⁶		56	30
Gallus et al⁴⁷		47	28
Harris et al⁴⁹		51	23
Hoek et al⁵⁰		99	56
Hull et al⁵¹		158	77
Ishak and Morley⁵²		41	22
Kalodiki et al⁵³		14	13
Mannucci et al⁵⁴		51	22
Morris et al⁵⁵		32	16
Turpie et al⁵⁶		50	21
VTCSG⁵⁷		30	11
Welin-Berger et al⁵⁸		16	5
Total	17	851	435 (51%) 48%-54%
Multiple trauma
Freeark et al⁵⁹		124	4
Geerts et al⁶⁰		349	201
Kudsk et al⁶¹		38	24
Shackford et al⁶²		25	1
Total	4	536	270 (50%) 46%-55%
Total knee replacement
Hull et al⁶³		29	19
Kim⁶⁴		244	80
Leclerc et al⁶⁵		57	31
Lynch et al⁶⁶		75	28
Stringer et al⁶⁷		55	31
Stulberg et al⁶⁸		49	41
Wilson et al⁶⁹		32	22
Total	7	541	252 (47%) 42%-51%
Hip fracture
Ahlberg et al⁷⁰		45	16
Checketts and Bradley⁷¹		26	13
Darke⁷²		66	11
Galasko et al⁷³		50	23
Gallus et al⁷⁴		23	11
Kakkar et al⁷⁵		50	20
Lahnborg⁷⁶		69	28
Montrey et al⁷⁷		81	22
Morris and Mitchell⁷⁸		74	50
Morris and Mitchell⁷⁹		76	49
Myhre and Holen⁸⁰		55	22
Powers et al⁸¹		63	29
Rogers et al⁸²		37	19
Svend-Hansen et al⁸³		65	28
Xabregas et al⁸⁴		25	12
Total	15	805	353 (44%) 40%-47%
Spinal cord injury
Bors et al⁸⁵		99	58
Brach et al⁸⁶		10	9
Rossi et al⁸⁷		18	13
Silver⁸⁸		32	8
Watson⁸⁹		234	42
Frisbie and Sasahara⁹⁰		17	1
Merli et al⁹¹		17	8
Myllynen et al⁹²		9	9
Yelnik et al⁹³		22	12
Total	9	458	160 (35%) 31%-39%
Isolated lower limb injuries
Hjelmstedt and Bergwall⁹⁴		76	34
Abelseth et al⁹⁵		82	18
Kujath et al⁹⁶		127	21
Kock et al⁹⁷		163	7
Lassen et al²¹⁵		159	29
Jorgensen et al⁹⁹		77	10
Lapidus et al¹⁰⁰		96	27
Goel et al¹⁰¹		111	14
Total	8	891	160 (18%) 16%-21%
Elective spinal surgery
West et al¹⁰²		41	6
Oda et al¹⁰³		110	17
Total	2	151	23 (15%) 10%-22%
Knee arthroscopy
Stringer et al⁶⁷		48	2
Demers et al¹⁰⁴		184	33
Williams et al¹⁰⁵		85	3
Jaureguito et al¹⁰⁶		239	5
Delis et al¹⁰⁷		102	8
Wirth et al¹⁰⁸		111	5
Michot et al¹⁰⁹		63	10
Total	7	832	66 (8%) 6-10%

Abbreviations: CI, confidence interval; DVT, deep venous thrombosis.

^aThe listed frequency is true for the total groups of patients. The presence of additional risk factors indicated in the text is likely to increase the risk of thromboembolism for individual patients.

Table 6.2.

The Frequency of Proximal DVT in the Absence of Prophylaxis Diagnosed by Surveillance With Objective Methods (Fibrinogen Uptake Test or Venography).

Patient Group	Number of Studies	Number of Patients	Incidence of DVT	95% CI
Elective hip replacement (Imperiale and Speroff)¹¹²	25	1436	330^a (23%)	20.8%-25.2%
Total knee replacement (Hull et al,⁶³ Kim,⁶⁴ Leclerc et al,⁶⁵ Mckenna et al,¹¹³ Stringer et al,⁶⁷ Stulberg et al, ⁶⁸ Wilson et al⁶⁹)	7	536	41 (7.6%)	5.5%-10.1%

Abbreviations: CI, confidence interval; DVT, deep vein thrombosis.

^aThis number is an estimate from the percentage given in the article.

Table 6.3.

The Frequency of Clinical Pulmonary Embolism^a in the Absence of Prophylaxis.

Patient Group	Number of Studies	Number of Patients	Clinical PE	95% CI
Elective hip replacement (Imperiale and Speroff)¹¹²	25	1436	57^b (4%)	3.0%-5.1%
Traumatic orthopedic surgery) (APTC)¹¹⁴	11	494	34 (6.9%)	4.8%-9.5%

Abbreviations: CI, confidence interval; PE, pulmonary embolism.

^aIn most of the studies using an objective method of screening for DVT, patients found to have proximal thrombosis were treated with anticoagulants; the true incidence of clinical pulmonary embolism in series without such screening and intervention is unknown.

^b this number is an estimate from the percentage given in the article.

Table 6.4.

The Frequency of Fatal Pulmonary Embolism Without Prophylaxis. ^a

Patient Group	Number of Studies	Patients n	Incidence of Fatal PE	95% CI
Elective hip replacement (Collins et al)¹¹⁵	12	485	8 (1.65%)	0.38%-2.7%
Fractured neck of femur (Lassen and Borris)¹¹⁶	23	1195	48 (4.0%)	3.0%-5.3%

Abbreviations: CI, confidence interval; PE, pulmonary embolism.

^a In most of the studies using an objective method of screening for DVT, patients found to have proximal thrombosis were treated with anticoagulants; the true incidence of fatal pulmonary embolism in the absence of intervention is unknown.

Table 6.5.

Mortality After Elective Hip Replacement in the Absence of Routine Pharmacological Prophylaxis.^a

Author	Number of Patients	Follow-Up	Total Deaths	95% CI	Fatal PE	95% CI	Anticoagulant Use
Seagroatt et al¹²⁰	11 600	90 days	93 (1.10%)	0.87%-1.31%	–	–	Very low
Sheppeard et al¹²¹	3016	Inpatient	19 (0.63%)	0.38%-0.98%	12 (0.40%)	0.20%-0.70%	20%^b
Warwick et al¹⁸	1162^c	90 days	15 (1.30%)	0.73%-2.10%	4 (0.34%)	0.09%-0.90%	11%^b
Wroblewski et al¹²²	18 104	1 year	362 (2.0%)	1.80%-2.20%	1.27 (0.70%)	0.58%-0.82%	–
Fender et al¹²³	2111	42 days	19 (0.91%)	0.05%-1.42%	4 (0.19%)	0.05%-0.49	65%

Abbreviations: CI, confidence interval; PE, pulmonary embolism.

^a Indicates information not available.

^b High-risk patients received anticoagulation.

^cAll patients wore thigh-length elastic stockings.

There is a high incidence of proximal DVT (18%-36%) in patients having THR^{47,50,51,53,56,125–128} in contrast to patients having TKR in whom the preponderance of thrombosis is distal.^{66–68,129,130}

Modern THR surgery is performed with a continuing reduction in hospital stay (3-6 days) so that patients are discharged while still at risk. Thus, the majority of clinical events appear after hospital discharge, giving a false impression of a decreasing problem.^20,131,119

A recent meta-analysis of 10 RCTs that used venography in patients having THR treated by LMWH found that for every 5 patients with asymptomatic DVT in a screening program, 1 patient experienced symptomatic VTE within 3 months of the operation.¹³² The consistency of this finding with previous reports strengthens the belief that asymptomatic DVT is a surrogate for symptomatic DVT.

Prophylactic Methods and Recommendations

General Considerations

Prophylactic methods that have been investigated in patients having THR include aspirin, fixed low-dose unfractionated heparin (LDUH), LMWH, heparinoid, recombinant hirudin, oral direct-Xa inhibitors, oral direct thrombin inhibitors, fixed mini-dose and adjusted doses of vitamin K agonists (VKA), graduated elastic compression (GEC) stockings, IPC, and FIT. To determine the risk reduction for each prophylactic method, only randomized studies with systematic screening tests for DVT have been used for the purposes of this analysis (Tables 6.6–6.8^{4,69,114,130,133–139} and Figures 6.1–6.3^{1,47,51,63,65,140–145}).

Figure 6.1.

Effect of intermittent pneumatic compression (IPC) in the prevention of deep vein thrombosis (DVT) diagnosed by surveillance with phlebography or duplex ultrasound* (Fisher et al)¹⁹⁷ in randomized controlled studies of patients having hip replacement.^47,51,140

Figure 6.2.

Figure 6.3.

Effect of warfarin versus low-molecular-weight heparin (LMWH) in the prevention of deep vein thrombosis (DVT) diagnosed by surveillance with phlebography in patients having knee surgery.^{1,65,142–145}

Table 6.6.

Effect of Antiplatelet Therapy (eg, Aspirin) in the Prevention of DVT Diagnosed by Surveillance With Objective Methods (Fibrinogen Uptake in General Surgery and Phlebography in Orthopedic Surgery) in Randomized Controlled Studies (Antiplatelet Trialists' Collaboration).¹¹⁴

	Control Groups^a			Antiplatelet Groups
Type of Patient	Number of Trials With Data	Patients, n	DVT (%)	Patients, n	DVT (%)	RR	95%CI
Orthopedic traumatic	10	444	186 (42)	454	163 (36)	0.86	0.73-1.0
Orthopedic elective	13	436	232 (53)	427	160 (37)	0.70	0.61-0.82
High risk medical	8	266	61 (23)	261	39 (15)	0.65	0.45-0.94

Abbreviations: CI, confidence interval; DVT, deep venous thrombosis; RR, relative risk.

^a In most trials patients were allocated evenly to antiplatelet therapy or control, but in some more were deliberately allocated to active treatment. To allow direct comparison between percentages adjusted control totals were calculated, (actual DVT incidence in 700 of 2050surgical controls; all medical trials evenly balanced).

Table 6.7.

Effect of Antiplatelet Therapy (eg, Aspirin) in the Prevention of PE in Randomized Controlled Studies (Antiplatelet Trialists' Collaboration).¹¹⁴

	Control Groups			Antiplatelet Groups
Type of Patient	Number of Trials With Data	Number of Patients	PE	Number of Patients	PE	RR	95%CI
Orthopedic Traumatic	11	494	34 (6.9%)	504	14 (2.8%)	0.40	0.22-0.71
Orthopedic Elective	16	537	29 (5.4%)	529	14 (2.6%)	0.49	0.26-0.92

Abbreviations: CI, confidence interval; PE, pulmonary embolism; RR, relative risk.

Table 6.8.

Effect of Prophylaxis Using the Combination of Foot Impulse Technology (FIT) With Graduated Elastic Compression (GEC) on Proximal DVT, in Orthopedic Patients.

			Control			Foot Impulse Technology plus Additional Method of Prophylaxis
			Method of Prophylaxis
Author	Diagnostic Method	n	Proximal DVT		n	Proximal DVT
Hip surgery
Bradley et al⁴	GEC	44	11 (25%)	FIT + GEC	30	2 (6.7%)
Fordyce and Ling¹³³	GEC	40	13 (32%)	FIT + GEC	39	2 (5%)
Santori et al¹³⁴	LDUH	65	13 (20%)	FIT + GEC	67	2 (3.0%)
Warwick et al¹³⁵	LMWH + GEC	138	27 (17.4%)	FIT + GEC	136	12 (9%)
Pitto et al¹³⁶ US	LMWH	100	2 + 4* (6%)	FIT + GEC	100	0 + 3* (3%)
Knee surgery
Blanchard et al¹³⁷	LMWH	60	2 (3.3%)	FIT only	48	4 (8.3%)
Wilson et al⁶⁹	Nil	32	6 (19%)	FIT only	28	0
Westrich et al¹³⁰	Aspirin	83	49 (59%)	FIT + aspirin	81	22 (27%)
Warwick et al¹³⁸	LMWH	99	57 (58%)	FIT	98	48 (54%)
Hip fracture
Stranks et al¹³⁹	GEC	39	9 (32%)	FIT + GEC	41	0

Abbreviations: DVT, deep vein thrombosis; LDUH, low-dose unfractionated heparin; LMWH, low-molecular-weight heparin.

The LDUH (5000 IU 8 or 12 hours) was found to be effective in reducing DVT from 46.8% to 23.3% (RR 0.50; 95% CI 0.43-0.58; meta-analysis of 20 randomized controlled studies in patients having elective THR)¹¹⁵ and was the method of choice in the 1980s.

The LMWH has been subsequently demonstrated to be superior to LDUH for elective THR surgery, reducing DVT from 21.2% to 13.8% (RR 0.66; 95% CI 0.52-0.84) and PE from 4.1% to 1.7% (RR 0.4; 95% CI 0.19-0.84).^{32,128,146–153} Thus, LDUH is no longer recommended.

As indicated in the section on “General, Vascular, Bariatric and Plastic Surgical patients,” regulatory bodies in Europe and North America now consider the various LMWHs to be distinct drug products. They require clinical validation for specific indications of each drug. Therapeutic interchange among these products is not appropriate.

The RCTs have shown that recombinant hirudin (desirudin) is more effective than LDUH^154–156 or LMWH.¹⁵⁵ Of 2079 patients studied, 1587 were included in the primary efficacy analysis. Overall, DVT was reduced with hirudin 15 mg twice daily (bid) compared to 40 mg enoxaparin from 25.5% to 18.45% (P = .001; relative risk reduction [RRR] 28.0%). The safety profile was the same in both the groups.¹⁵⁵

Several RCTs have compared VKA with LMWH. The LMWH was found to be more effective ^{1,142,157,158} or at least as effective¹⁴³ for preventing asymptomatic DVT. However, this was at the expense of a slight increase in hemorrhagic complications. When LMWH was started before or immediately after surgery, there was a marked reduction of proximal DVT from 3% to 0.8% (RR 0.28; 95% CI 0.1-0.74).³ Symptomatic DVT was also reduced from 4.4% in the warfarin group to 1.5% in the LMWH group (RR 0.32; 95% CI 0.12-0.88). A meta-analysis of VKA in orthopedic surgery¹⁵⁹ showed a RR of 0.56 (95% CI 0.37-0.84) for DVT and 0.23 for PE (95% CI 0.09-0.59) compared to placebo. The VKAs were less effective than LMWH in preventing total DVT (RR 1.51; 95% CI 1.27-1.79) and proximal DVT (RR 1.51; 95% CI 1.04-2.17) although the risk of wound hematoma was increased from 3.3% in the VKA recipients to 5.3% in LMWH recipients (RR 2.29; 95% CI 1.09-7.75).

In a clinical trial for THR,³⁵ 1279 patients were randomized on the third postoperative day to LMWH or to warfarin for the subsequent 6 weeks. The primary end point was the overall clinical failure rate that is symptomatic VTE (radiologically confirmed), major hemorrhage, or deaths. The failure rate was 3.7% in the LMWH group and 8.3% in the warfarin group (P = .01). Major bleeding occurred in 1.4% in the LMWH group and in 5.5% in the warfarin group. It appears that reduced bleeding seen initially after surgery due to the slow onset of action for warfarin is offset by long-term increased bleeding. Furthermore, national drug registries have shown warfarin to be a major cause of readmission and fatal bleeding.^160,161 With these data, and because of the need for monitoring, the small therapeutic window and the risk of drug interactions, some surgeons find it difficult to see an advantage for VKA over LMWH.

In contrast to LMWH, the pentasaccharide fondaparinux is a pure synthetic chemical compound. It is a potent indirect inhibitor of factor Xa acting by a catalytic effect facilitating antithrombin binding to activated factor X and represents one of the many attributes of heparins. The drug is administered by subcutaneous injection once daily (qd). It has been registered internationally for major orthopedic surgery. Two large RCTs compared fondaparinux to enoxaparin.^98,162 Reduction of asymptomatic DVT was 26% (RR 0.74; 95% CI 0.47-0.89) and symptomatic PE was 56% (RR 0.44; 95% CI 0.27-0.66) with fondaparinux. For the 2 studies combined, the incidence of major bleeding was 3% in the fondaparinux and 2.1% in the enoxaparin patients (P >.05). Fondaparinux may accumulate and increase bleeding in patients with impaired renal function.

A meta-analysis in the early 1990s¹¹⁴ demonstrated that antiplatelet therapy in elective hip surgery is only moderately effective for protection against DVT (RR 0.7; 95% CI 0.61-0.82; Table 6.6), but the observed reduction in the risk of PE was substantial (RR 0.49; 95% CI 0.26-0.92; Table 6.7). However, the subsequent PEP study^163,164 showed that aspirin is not as valuable as the meta-analysis suggested. Over 13 000 patients with hip fracture were randomized to have either aspirin or placebo. The overall death rate was identical in each group. Risk reduction for symptomatic VTE was from 2.5% to 1.6% and this was only one-half of that expected from LMWH and one-third from pentasaccharide. The reduced risk of VTE was matched by an increased risk of blood transfusion, gastrointestinal bleeding, and wound bleeding. In a supplementary group of 4000 patients with elective hip and knee replacement, there was an insignificant difference in symptomatic VTE.¹⁶⁴ The relative weak thromboprophylactic effect of aspirin therefore carries an alternative complication rate and its use might deprive patients of safer or more effective prophylaxis.

The Cochrane database ¹⁶⁵ and an earlier meta-analysis¹⁶⁶ show that GEC is effective in reducing DVT in hospitalized patients, but there are few robust studies specific to orthopedic surgery.^52,167 Because other methods of prevention are more effective, GEC stockings on their own are not recommended.

The IPC is effective in patients having THR^47,51,140 (Figure 6.1) reducing DVT from 43.6% in the control groups to 21% in the compression groups (RR 0.48; 95% CI 0.36-0.64). Modern technology has made IPC devices light, silent, more portable, and more effective in preventing stasis by sensing venous volume so that the compression period follows immediately after venous refilling. In addition, different sleeve designs and materials have been used to improve patient compliance.¹⁶⁸ In a recent study involving 392 evaluable patients having THR in which IPC was compared to LMWH, the incidence of postoperative DVT was found to be 3% in both the groups.¹⁶⁹

Three subsequent RCTs have compared combined modalities with LMWH. In the first study¹⁷⁰ in 131 patients having THR and TKR, the combination of LMWH plus IPC was more effective than LMWH plus GEC stockings (DVT incidence 0% vs 28%). In the second study involving 277 patients, the combination of LMWH plus IPC was more effective than LMWH (DVT incidence 6.6% vs 19.5%).¹⁷¹ In the third study involving 1803 patients having various orthopedic operations, the combination of LMWH plus IPC was also more effective than LMWH (DVT incidence 0.4% vs 1.7%). In the subgroup of 306 patients having THR, the incidence of DVT was 0% in the combined modalities group and 5.2% in the LMWH group (P <0.001¹⁷²; see section on combined modalities). In another study involving 121 evaluable patients having THR or TKR, in which IPC plus aspirin 100 mg daily was also compared to LMWH, the incidence of postoperative venographic DVT was found to be 6.6% in the IPC group and 28.3% in the LMWH group (RR 0.23; 95% CI 0.08-0.65).¹⁷³

The FIT combined with GEC is effective in reducing the incidence of proximal DVT in patients having THR or TKR (Table 6.8) with less bleeding and swelling. Direct comparisons with chemical prophylaxis are sparse; there is probably superiority to LDUH¹³⁴ and equivalence with LMWH for THR^136,174 but not for TKR.¹³⁷

The IPC and FIT offer an alternative for patients with contraindications to chemical prophylaxis (Figure 6.1 and Table 6.9).

Table 6.9.

	Control Groups^a			Antiplatelet Groups
Type of Patient	Number of Trials With Data	Patients, n	DVT (%)	Patients, n	DVT (%)	RR	95%CI
Orthopedic traumatic	10	444	186 (42)	454	163 (36)	0.86	0.73-1.0
Orthopedic elective	13	436	232 (53)	427	160 (37)	0.70	0.61-0.82

Abbreviations: CI, confidence interval; DVT, deep venous thrombosis; RR, relative risk.

Rivaroxaban is a new oral direct Xa inhibitor. Two studies (RECORD1 and RECORD2) have compared rivaroxaban with enoxaparin in patients having THR. In RECORD1 study that involved 3153 evaluable patients, both prophylactic regimens were given for 31 to 39 days. Superior efficacy of rivaroxaban was demonstrated, with an incidence of venographic VTE of 3.7% in the enoxaparin group and 1.1% in the rivaroxaban group (P < .001). The incidence of major and nonmajor clinically relevant bleeding was 2.5% in the enoxaparin group and 3.2% in the rivaroxaban group (not significant [NS]).³⁷ The RECORD2 study investigated the efficacy of extended thrombophylaxis (35 days) with rivaroxaban compared to short-term enoxaparin (10-14 days) followed by placebo.³⁶ The incidence of venographic VTE was 9.3% in the enoxaparin group and 2.0% in the rivaroxaban group (P < .0001). The incidence of major and nonmajor clinically relevant bleeding was 2.8% in the enoxaparin group and 3.3% in the rivaroxaban group (NS).

Apixaban is another new oral direct Xa inhibitor. In a double-blind placebo controlled study involving 5407 patients having THR, apixaban at a dose of 2.5 mg orally bid was compared with enoxaparin at a dose of 40 mg subcutaneously every 24 hours. Apixaban therapy was initiated 12 to 24 hours after closure of the surgical wound; enoxaparin therapy was initiated 12 hours before surgery. Prophylaxis was continued for 35 days after surgery, followed by bilateral venographic studies. The incidence of the primary efficacy outcome (asymptomatic or symptomatic DVT, nonfatal PE, or death from any cause during the treatment period) was 1.4% in the apixaban group and in 3.9% in the enoxaparin group (RR 0.36; 95% CI 0.22-0.54; P < .001) for both noninferiority and superiority. The incidence of major and clinically relevant nonmajor bleeding was 4.8% in the apixaban group and 5.0% in the enoxaparin group (P > 0.05).¹⁷⁵

Edoxaban is a new oral direct FXa inhibitor that is 10 000-fold more selective for FXa than thrombin.¹⁷⁶ In the randomized, double-blind, double-dummy STARS J-V trial (N = 503), edoxaban (30 mg qd) resulted in significantly fewer VTEs than enoxaparin (2000 IU bid; 2.4% vs 6.9%; P = .0157 for superiority). The difference between the incidence of major and clinically relevant nonmajor bleeding events between edoxaban (2.6%) and enoxaparin (3.7%) was not statistically significant (P = .475).

Dabigatran is a new oral direct inhibitor of thrombin. Two double-blind noninferiority trials evaluated the efficacy and safety of dabigatran in patients having elective THR. In the first study (RE-NOVATE), there were 3 groups of patients receiving dabigatran 150 mg, 220 mg, or enoxaparin 40 mg for 25 to 35 days (median 33 days) when bilateral venography was performed. The primary endpoint of total VTE and all-cause mortality occurred in 8.6%, 6.0%, and 6.7% of the groups, respectively (P < .0001 for noninferiority of each group versus enoxaparin).¹⁷⁷ In the second study (RE-NOVATE II) 220 mg of dabigatran was compared with 40 mg enoxaparin administered for the same period.¹⁷⁸ The primary end point of total VTE and all-cause mortality occurred in 7.7% in the dabigatran and 8.8% in the enoxaparin group (P < 0001 for noninferiority of dabigatran vs enoxaparin). There was no significant difference in major bleeding events between the various groups in either study.

Recommendations

The LMWH initiated and dosed according to the manufacturer’s recommendations (level of evidence: high), fondaparinux (level of evidence: high), VKAs (level of evidence: high), rivaroxaban (level of evidence: high), apixaban (level of evidence: high), dabigatran (level of evidence: high). IPC or FIT combined with GEC stockings are an equivalent alternative to LMWH (level of evidence: high) for those surgeons or anesthetists concerned about bleeding either in all or in certain patients. These devices can be used as long as tolerated and then replaced with chemical prophylaxis starting as soon as it is safe and continued for the rest of the 5-week period of risk. Desirudin is approved for short-term prophylaxis in approximately 20 European countries and the United States and can be used in patients with heparin-induced thrombocytopenia (level of evidence: high).

The LMWH combined with IPC is more effective than either prophylactic modality used alone and should be considered in all cases (level of evidence: high).

Prophylaxis with LMWH should be initiated either before or after operation depending on the adopted regimen (level of evidence: high). Fondaparinux should be started at least 6 to 8 hours after surgery. Prophylaxis should be continued for 4 to 6 weeks with LMWH (level of evidence: high) or fondaparinux (level of evidence: low; extrapolation from a hip fracture trial).

Elective Knee Replacement

The Risk

Data from THR should not be extrapolated to TKR. The incidence of asymptomatic DVT detected by venography is higher in patients having TKR than THR. However, the incidence of above-knee DVT is lower than in patients having THR (see section on THR above).

Prophylactic Methods and Recommendations

General considerations

The IPC is effective in patients having TKR (RR 0.27; 95% CI 0.14-0.49; Table 6.8). One small study demonstrated that IPC reduced the incidence of asymptomatic DVT from 65% to 6%.⁶³ A subsequent study found IPC to be more effective than aspirin.¹⁴¹ The IPC was found to be less effective than coumadin for preventing venographically detected DVT (32% vs 19%).¹⁷⁹ The FIT was also effective in 2 studies^69,130 but showed inferiority when compared to LMWH in 2 other studies^137,138 (Table 6.8).¹⁸⁰ In a recent study involving 136 patients having THR or TKR, in which a mobile IPC device was also compared to LMWH, the incidence of postoperative venographic DVT was found to be 6.6% in the IPC group and 28.3% in the LMWH group. Proximal DVT was detected in 1.6% in the IPC group and 10% in the LMWH group.¹⁷³

A RCT performed in 1992 demonstrated that LMWH was more effective than placebo. It reduced venographically detected DVT from 65% in the placebo group to 19% in the LMWH group (RR 0.30; 95% CI 0.16-0.58).¹⁸¹ Subsequent studies demonstrated that LMWH was more effective than LDUH (RR 0.75; 95% CI 0.58-0.92)^182,183 or warfarin (RR 0.68; 95% CI 0.62-0.76; Figure 6.3).

Fondaparinux (2.5 mg qd starting 6 hours after surgery) was more effective than enoxaparin (30 mg bid starting 12-24 hours after surgery) in 1 study.¹⁸⁴ The VTE (defined as venographically detected DVT, symptomatic DVT or symptomatic PE) was reduced from 27.8% in the enoxaparin group to 12.5% in the fondaparinux group (RR 0.45; 95% CI 0.32-0.62). However, major bleeding was more common with fondaparinux (2.1% vs 0.2%, P = .006). This increased rate of bleeding with fondaparinux was driven by a minority of patients given fondaparinux within 6 hours of surgery. The efficacy of fondaparinux was confirmed in a meta-analysis¹⁸⁵ that included the above study and 3 other RCTs comparing fondaparinux with enoxaparin in patients having orthopedic surgery other than TKR.

Rivaroxaban is a new oral direct anti-Xa inhibitor. Two studies (RECORD3 and RECORD4) have compared rivaroxaban with enoxaparin in patients having TKR. In RECORD3 study that involved 2531 evaluable patients, both prophylactic regimens were given for 10 to 14 days. The primary end point of total VTE was 18.9% enoxaparin and 9.6% for rivaroxaban (P < .001). The incidence of venographic DVT was 2.6% in the enoxaparin group and 1.0% in the rivaroxaban group (absolute risk reduction, 1.6%; 95% CI, 0.4-2.8; P < .01 for noninferiority). There was no significant difference in the incidence of major and nonmajor clinically relevant bleeding in the 2 groups.¹⁸⁶ The RECORD4 study¹⁸⁷ compared the efficacy and safety of rivaroxaban with the commonly used North American regimen of enoxaparin 30 mg bid until day 11 to 15 when bilateral venography was performed. The incidence of venographic VTE, PE, or death was reduced from 10.1% in the enoxaparin group to 6.9% in the rivaroxaban group (RR 0.69; 95% CI 0.51-0.92). There was no significant difference in the incidence of major and nonmajor clinically relevant bleeding in the 2 groups.

Apixaban is another new oral direct Xa inhibitor. Two randomized double-blind control studies compared apixaban with enoxaparin. In the first study, the overall rate of primary events was much lower than anticipated (primary efficacy outcome 9.0% with apixaban and 8.8% with enoxaparin) and apixaban did not meet the noninferiority criteria compared with enoxaparin 30 mg bid in the prevention of VTE after TKR¹⁸⁸ However, in the second study it demonstrated superiority against enoxaparin 40 mg qd (primary efficacy outcome 15% with apixaban and 24% with enoxaparin; RR 0.62; 95% CI 0.51-0.74, P < .0001) without any significant difference in bleeding between the 2 groups.¹⁸⁹

Dabigatran is a new oral direct inhibitor of thrombin. Two double-blind noninferiority trials evaluated the efficacy and safety of dabigatran in patients having elective TKR. In the first study (RE-MODEL) there were 3 groups of patients receiving dabigatran 150 mg, 220 mg, or enoxaparin 40 mg for 6 to 10 days when bilateral venography was performed. The primary end point of total VTE and all-cause mortality occurred in 40.5%, 36.4%, and 37.7% of the groups, respectively (P = .0003 and .017 for noninferiority of each group vs enoxaparin).¹⁹⁰ In the second study (RE-MOBILIZE), there were also 3 groups of patients receiving dabigatran 150 mg, dabigatran 220, or enoxaparin 30 mg bid administered for 12 to 15 days (median 13 days).¹⁹¹ Noninferiority of either dabigatran dose was not confirmed. The primary end point of total VTE and all-cause mortality occurred in 33.7%, 31.1%, and 25.3% of the 3 groups, respectively. Among 1896 patients, dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin (P = .02 and P < .001, respectively). In all 3 treatment groups, the composite primary end point was driven primarily by the occurrence of distal DVT whereas no significant difference was observed in mortality rates. There was no significant difference in major bleeding events between the various groups in either study.

Combined Modalities

Three trials have compared combined modalities with LMWH. In the first study¹⁷⁰ in which 131 patients have THR and TKR, the combination of LMWH plus IPC was more effective than LMWH plus GEC stockings. In the subgroup of patients having TKR, the incidence of VTE was 0% in the combined modalities group and 40% in the LMWH group using compression ultrasonography. In the second study involving 277 patients, the combination of LMWH plus IPC was more effective than LMWH (DVT incidence 6.6% vs 19.5%; P = .018).¹⁷¹ In the third study involving 1803 patients having various orthopedic operations the combination of LMWH plus IPC was also more effective than LMWH (DVT incidence 0.4% vs 1.7%). In the subgroup of 133 patients having TKR, the incidence of DVT was 3.8% in the combined modalities group and 7.4% in the LMWH group (P < .038¹⁷²; see section on combined modalities).

Duration of Prophylaxis

The effect of extending prophylaxis using LMWH to 30 to 42 days beyond hospitalization on symptomatic DVT in patients having TKR is less (odds ratio [OR] 0.74; 95% CI 0.26-2.15; P > .05) than in patients having THR (OR 0.33; 95% CI 0.19-0.56; P < 0.05) as shown by a systematic review.¹⁹²

Recommendations

The LMWH (initiated and dosed according to the manufacturer’s recommendations; level of evidence: high), warfarin (although less effective; level of evidence: high), rivaroxaban (level of evidence: high), apixaban (level of evidence: high), dabigatran (level of evidence: high), and fondaparinux (level of evidence: high). The IPC is an alternative option (level of evidence: moderate due to small study size). The LMWH combined with IPC is more effective than LMWH prophylactic modality used alone and should be considered in all the cases (level of evidence: high).

Hip Fracture Surgery

The Risk

Patients having hip fracture surgery have the highest rates of DVT (46%-60%)^81,193,194 and fatal PE (2.5%-7.5%; Tables 6.1, 6.3, and 6.4). ^126,194,195 The VTE risk period lasts for 2 to 3 months after hip fracture surgery in spite of common short-term prophylaxis,^20,117 and the 90-day risk of overall death is 13%.¹⁹⁶ After hip fracture, the risk is greater than the standardized mortality, the majority dying of vascular events despite the fact that most patients receive some form of short-term prophylaxis.^38,124

Prophylactic Methods and Recommendations

General considerations

Because the risks of DVT and PE including fatal PE are high in patients with hip fracture (Tables 6.1, 6.3, and 6.4), prophylaxis should start as soon as possible after diagnosis and should be the same as that recommended for elective hip surgery.

Reduction in asymptomatic DVT has been demonstrated by IPC (RR 0.2; 95% CI 0.07-0.55)¹⁴⁰ and FIT in combination with GEC¹³⁹ (RR 0.32; 95% CI 0.32-0.67; Table 6.8). In the most recent study,¹⁹⁷ the combined end point of PE and proximal DVT using duplex ultrasound was reduced from 12% in the group without prophylaxis to 4% in the IPC group. More studies are needed.

A meta-analysis¹¹⁴ demonstrated that antiplatelet therapy in traumatic orthopedic surgery is only slightly effective for protection against DVT (RR 0.86; 95% CI 0.73-1; Table 6.6), but the observed reduction in the risk of PE is substantial (RR 0.4; 95% CI 0.22-0.71; Table 6.7). In a randomized, placebo-controlled trial of patients undergoing surgery for hip fracture (13 356 patients) or for elective hip or knee arthroplasty (4088 patients), aspirin in a dose of 160 mg daily started preoperatively was used as the primary prophylactic agent for 35 days. The primary end point of the study was total mortality, and the study failed to detect any difference between the placebo and the aspirin groups. However, in the subgroup analysis of the patients with hip fracture, aspirin reduced the incidence of symptomatic DVT by 29% (95% CI 3%-48%; P = .03) and PE by 43% (95% CI 18%-60%; P = .002). The PE or DVT was confirmed in 105 (1.6%) of 6679 patients assigned aspirin compared to 165 (2.5%) of 6677 patients assigned placebo, which represents an absolute reduction of 9 per 1000 and a proportional reduction of 36% (95% CI 19%-50%; P = .0003). However, the complication rate (transfusion requirements and bleeding) offsets much of the reduction in symptomatic VTE.¹⁶³ Since other methods are more effective, aspirin on its own is not recommended for routine thrombophylaxis.

Several studies performed in the 1970s demonstrated that LDUH was effective in reducing asymptomatic DVT, as reported in an overview ¹¹⁵ (RR 0.51; 95% CI 0.42-0.62). Although a significant reduction in total PE was not demonstrated, there was a significant reduction in fatal PE.¹¹⁵

The LMWH has been assessed against placebo,^53,198 LDUH,¹⁹⁹ danaparoid,²⁰⁰ high-dose (40 mg enoxaparin) LMWH,²⁰¹ and fondaparinux.²⁰² The LMWH has been found to be equally effective as LDUH without increase in hemorrhagic complications.²⁰³

Three RCTs have demonstrated that VKAs are effective in preventing asymptomatic DVT with a 61% RRR for DVT and 66% for proximal DVT, compared to no prophylaxis.^81,204,205 The increase in hemorrhagic complications reported varied from 0% to 47% without any increased bleeding in the most recent trial.⁸¹

Fondaparinux given for 11 days was more effective when compared to LMWH in reducing VTE from 19.1% to 8.3% (RR 0.46; 95% CI 0.32-0.59) and proximal DVT from 4.3% to 0.9% (RR 0.22; 95% CI 0.09-0.53).²⁰² There was no difference in major bleeding but minor bleeding was increased from 2.1% in the enoxaparin group to 4.1% in the fondaparinux group (P = .02). In a second study, patients who received fondaparinux for 7 days were randomized to continuation with fondaparinux or placebo for a further 3 weeks.²⁰⁶ The incidence of venographic DVT was 1.4% in the extended prophylaxis group and 35% in the placebo group (RR 0.04; 95% CI 0.01-0.13). Symptomatic VTE was 0.3% and 2.7%, respectively (RR 0.11; 95% CI 0.01-0.88). There was no difference in hemorrhagic complications.

Delayed admission to hospital or delayed surgery following hip fractures is associated with a high incidence of DVT developing prior to surgery.^207–210 The incidence of preoperative DVT as shown by venography can be as high as 62% for all DVT and 14% for proximal DVT when the delay is 48 hours or more.²¹⁰ Thus, it is strongly recommended that if surgical delay is anticipated, prophylaxis is commenced as close to the fracture as possible. Prophylaxis should be restarted once postoperative hemostasis has been achieved.

None of the new oral anticoagulant regimens shown to be effective in elective hip and knee replacement have been tested in the hip fracture population.

Recommendations

The LMWH (initiated and dosed according to the manufacturer’s recommendations; level of evidence: high), fondaparinux (level of evidence: high), adjusted dose VKA (INR range 2-3; level of evidence: high), or LDUH (level of evidence: high). The IPC or FIT combined with GEC should be used when there are contraindications for pharmacological prophylaxis (level of evidence: low). If surgery is likely to be delayed, prophylaxis should be initiated with LMWH or IPC or FIT plus GEC as close to the fracture as possible (level of evidence: low). Prophylaxis should be provided for 4 to 5 weeks after surgery (level of evidence: high).

Knee Arthroscopy

The Risk

Knee arthroscopy is a very common procedure that varies from a simple diagnostic technique to an extensive repair of injured soft tissues. The use of a tourniquet, manipulation of the leg, and distension of the joint with fluid may all associate this procedure with a risk of VTE. However, symptomatic VTE is very rare. This poses a dilemma, rare events in a common procedure will lead to quite a high number of events even though the proportional risk is very low. However, universal prophylaxis would be very expensive, with uncertain cost benefit and risk benefit ratios.

The frequency of DVT in patients undergoing arthroscopic procedures in the absence of prophylaxis varies greatly between studies; symptomatic DVT occurs in perhaps 0.6%.²⁰ Meta-analysis of 6 studies^{104,105,107–109,211} by Ilahi in 2005 shows that asymptomatic DVT occurs in approximately 9.9%; however, there is a very large range; ultrasound demonstrates rates from 6%²¹² to 16%¹⁰⁹ and venography from 3.1%²¹¹ to 17.9%¹⁰⁴

Prophylactic Methods and Recommendations

General considerations

In a meta-analysis of 4 randomized studies in which different LMWHs given for 5 to 7 days,²¹³ the RR of thrombotic events was 0.16 (95% CI 0.05-0.52) compared to placebo (0.76% vs 8.2%). All thrombotic events but 1 PE in the LMWH group were distal. Adverse effects were more frequent in the intervention group (RR 2.04; 95% CI 1.21-3.44; 9.5% vs 4.5%). The number needed to harm was 20 for adverse effects. A recent study involving 1317 patients compared LMWH with GEC.²¹⁴ The 3-month cumulative incidence of asymptomatic proximal DVT, symptomatic VTE, and all-cause mortality was 3.2% (21 of 660 patients) in the GEC group and 0.9% (6 of 657 patients) in the 7-day LMWH group (RR 0.29; 95% CI 0.12-0.71). The cumulative incidence of major or clinically relevant bleeding events was 0.3% in the stockings group, 0.9% in the 7-day LMWH group (NS).

Thus, although clinical VTE is uncommon and fatalities are rare, the huge number of patients undergoing knee arthroscopy surgery makes VTE complications potentially relatively frequent. There is a clear correlation between age and degree of trauma with VTE.⁶⁷ This justifies prophylaxis in patients with additional risk factors or when extensive surgery beyond a simple diagnostic procedure is performed.

Recommendations

Recommendation for simple diagnostic arthroscopy.

A careful risk assessment should be undertaken. Routine prophylaxis is not recommended unless other risk factors are present (level of evidence: low).

Recommendation for arthroscopic surgery (eg, ligament reconstructions).

The LMWH starting before or after surgery (level of evidence: moderate) or IPC in the presence of contraindications to LMWH are recommended (level of evidence: low) until full ambulation.

Isolated Below Knee Injuries and Plaster Casts

The Risk

Patients with below knee injuries and immobilization have a DVT incidence in the range of 10% to 35% depending on the type and severity of injury (Table 6.1)^{94–97,99,215} and carry a risk of clinical PE in the range of 0.4% to 2.1%.¹⁹⁶ A recent ultrasound study following Achilles tendon injury showed a 29% DVT prevalence and no PE in 49 patients treated surgically, but a 39% DVT prevalence and 3 PE in 46 treated nonoperatively²¹⁶. The frequency of symptomatic events is unknown.

Prophylactic Methods and Recommendations

General considerations

This group is so heterogeneous that studies and recommendations are difficult to devise. A clinical risk assessment is mandatory and for those with risk factors safe prophylaxis must be instituted. The risk of compartment syndrome, exacerbated by chemical thromboprophylaxis, must be considered in tibial fractures.

In one study of 253 patients with plaster casts of which the majority had soft tissue injuries, ultrasound incidence of DVT at cast removal was reduced from 17% in the control group to 5% in the LMWH group.⁹⁶ It was reduced from 4% in the control group to zero in the LMWH group in another study of 339 patients.⁹⁷ Considering both studies the RR was 0.21 (95% CI 0.09-0.49)

In patients with lower leg fractures, the 5-week incidence of venographic DVT was reduced from 18% in the control group to 10% in the LMWH group in one study (n = 293),²¹⁵ from 13% to 11% in another (n = 150),⁹⁹ and from 13% to 9% in a third study (n = 238).¹⁰¹ In none of the 3 studies was the effect of LMWH on DVT significant (P > .05). However, in the subgroups of patients having Achilles tendon repair, the incidence of DVT was reduced from 21% to 6% in the first study²¹⁵ and from 29% to 10% in the second⁹⁹ However, in a more recent study¹⁰⁰ involving 93 patients LMWH was ineffective (28% vs 21%). More effective methods are needed in well-defined groups of patients.

A Cochrane review of the 1490 randomized patients concluded an OR of 0.49 for LMWH (95% CI 0.34-0.72) which supports a significant risk reduction for patients immobilized in plaster.²¹⁷ Furthermore, symptomatic VTE was also significantly reduced (OR 0.16; 95% CI 0.05-0.56). Complications were not increased in the LMWH group.

Recommendations

Currently available data based on a mixture of different types of injury suggest that routine LWMW prophylaxis should be considered for isolated limb trauma in the absence of contraindications (level of evidence: moderate). The drug will need to be administered in the outpatient setting until the patient is weight bearing.

Multiple Trauma

The Risk

The incidence of DVT in patients who have sustained major trauma is in excess of 50% ^{60,61,218–221} (Table 6.1) and PE is the third leading cause of death in those who survive beyond the first day.^60,222–224 The risk is particularly high in patients with spinal cord injury, pelvic fracture, and those needing surgery.^{60,61,225–227}

Prophylactic Methods and Recommendations

General considerations

Patients with multiple injuries have a particularly high risk for VTE. The tissue factor released by multiple injuries is potentiated by the likely surgical intervention and the subsequent prolonged immobility²²⁵ which produces marked venous stasis. Routine venography has shown a DVT frequency of 58% in these patients.⁶⁰

Well-designed studies in this area are few and thromboprophylaxis has to be assessed according to the risk of bleeding. However, in the absence of intracranial bleeding and when bleeding is under control, LMWH (enoxaparin 30 mg bid) started within 36 hours of injury has been shown to be more effective than LDUH (5 000 IU bid).²¹⁸ The LMWH reduced the incidence of venographic DVT from 44% in the LDUH to 31% in the LMWH group (RR 0.70; 95% CI 0.51-0.97). The superiority of LMWH to LDUH has been confirmed by a subsequent study and a meta-analysis.^220,228 A study comparing nadroparin fixed-daily dose versus a weight-adjusted dose did not demonstrate any significant difference (0% vs 3% DVT).²²⁹

Five randomized controlled trials have tested the efficacy of IPC. The first was in 304 patients with pelvic fractures but the study was small and underpowered so that the DVT reduction from 11% in the control group to 6% in the IPC group was not significant (P > .05).¹⁹⁷ In the second, which involved 149 patients, IPC was compared with FIT with an incidence of DVT of 6% and 21%, respectively (P < .02).²³⁰ The IPC or FIT were compared with enoxaparin 30 mg bid in the third study involving 372 patients with an incidence of DVT of 0.8% in the enoxaparin group, 2.5% in the IPC group, and 5.7% in the FIT.²³¹ The 2 most recent studies compared LMWH with IPC in 442 and 120 patients with trauma.^232,233 In these studies the incidence of DVT was 0.5% and 6.6% in the LMWH groups, with 2.7% and 3.3% in the IPC groups, respectively. Thus, mechanical methods are attractive if chemical prophylaxis is contraindicated.

The RCT of the use of inferior venacava (IVC) filters to prevent PE in patients with trauma in the absence of DVT have not been performed. A recent systematic review of 7 observational studies suggested a potential reduction in PE but an associated 2% to 6% incidence of complications (IVC occlusion, filter migration, and thrombosis at the insertion site).²³⁴

Recommendations

The LMWH started as soon as bleeding risk is acceptable (level of evidence: high) or IPC in the presence of contraindications to LMWH (level of evidence: high) and continued until full ambulation.

Electrical stimulation of the calf muscles may be considered in patients in whom pharmacological prophylaxis is contraindicated because of multiple injuries and IPC cannot be applied because of external fixation to a leg fracture. This is by extrapolation from studies in general surgery (level of evidence: low).

The use of IVC filter for primary prevention of PE when LMWH or IPC are contraindicated is not recommended (level of evidence: low).

Elective Spine Surgery

The Risk

Elective spine surgery consists of a mixture of types of surgical procedures ranging from simple laminectomy to complicated multilevel fusion. The procedures can be performed with a posterior, anterior, or combined approach. Data are very limited in elective spine surgery, both for efficacy and safety for different prophylactic methods. The incidence of DVT detected by routine venography in the absence of prophylaxis has been found to be 18% (Table 6.1).^103,235 A review of studies on complications in patients having spinal fusion reported a 3.7% incidence for symptomatic DVT and 2.2% for PE.²³⁶

Prophylactic Methods and Recommendations

General considerations

Two small randomized controlled studies, one comparing no prophylaxis with LDUH²³⁷ and the other with enoxaparin,²³⁸ demonstrated that prophylaxis reduces the incidence of asymptomatic DVT from 20% and 10%, respectively, to 0%.

Recommendations

Mechanical method

The IPC (level of evidence: low); drug: LMWH (level of evidence: low); initiation: before operation for IPC or after operation for LMWH; duration: during hospitalization (level of evidence: low).

Spinal Cord Injury

The Risk

In the absence of prophylaxis the incidence of silent DVT is of the order of 35% (Table 6.1). In this group of patients, PE is the third leading cause of death.^239,240 In a series of 1649 patients undergoing rehabilitation, symptomatic DVT occurred in 10% and PE in 3%.²⁴¹

Prophylactic Methods and Recommendations

General considerations

Three studies have compared LDUH with placebo.^90,91,242 Compared to controls, LDUH was associated with a nonstatistically significant reduction in the number of DVT (20.0% vs 29.4%; OR 0.55; 95% CI 0.11-2.64; P = .46).²⁴³ Five studies have compared LDUH with LMWH.^244–248 A meta-analysis comparing LDUH with LMWH has reported that although LMWH was associated with a nonstatistically significant reduction in the rate of all VTE (24.4% vs 22.7%; OR 0.78; 95% CI 0.24-2.53; P = .60, it was associated with a significant reduction in the rate of total PE (3.1% vs 9.2%; OR 0.29; 95% CI 0.090.95; P = .04).²⁴³ Also, compared to LDUH, LMWH was associated with a nearly significant reduction in major bleeding (2.4% vs 5.2%; OR 0.50; 95% CI 0.24-1.04; P = .07).

When a combination of LDUH with IPC was compared to LMWH in a randomized controlled study,²⁴⁷ results shown by routine venography were equally poor (63% vs 66%). It appears that patients with spinal cord injury are not only at high risk of VTE but also a highly resistant group to prophylactic measures. Further studies are needed.

Recommendations

The LMWH and/or LDUH (level of evidence: moderate) and LMWH plus IPC (level of evidence: low); initiation: IPC and GEC on admission and LMWH when bleeding risk is acceptable (level of evidence: low); duration: LMWH and IPC for 3 months and continuation with GEC indefinitely (level of evidence: low).

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