Appendix D Evidence Tables - National Health and Medical ...

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IPC vs. GCS. 9. 3. Foot Pump plus UFH vs. UFH. 13. 4. Foot pump vs. no foot pump. 16 .... Hospitalised medical myocardial infarction patients ...... Cont: 11/660 .
Clinical Practice Guideline FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM IN PATIENTS ADMITTED TO AUSTRALIAN HOSPITALS

APPENDIX D • Evidence Tables

Contents How to read the evidence tables, evidence summaries and forest plots vii Abbreviations used in the evidence tables

x

Total hip replacement tables 1 – 30

1

1. GCS vs. no GCS 2. IPC vs. GCS 3. Foot Pump plus UFH vs. UFH 4. Foot pump vs. no foot pump 5. Foot pump vs. LMWH 6. IPC vs. LMWH 7. IPC vs. warfarin 8. UFH vs. no UFH 9. UFH vs. aspirin 10. Warfarin vs. UFH 11. LMWH vs. no LMWH 12. LMWH vs. UFH 13. Fondaparinux vs. LMWH 14. LMWH vs. warfarin 15. LMWH timing 16. LMWH dose 17. Extended duration LMWH vs. extended duration placebo 18. Extended duration UFH vs. extended duration placebo 19. Warfarin vs. no warfarin 20. Warfarin vs. aspirin 21. IPC vs. no treatment 22. Warfarin timing 23. Warfarin duration 24. Warfarin dose (adjusted vs. fixed) 25. GCS plus fondaparinux vs. fondaparinux 26. Foot pump vs. UFH plus aspirin 27. IPC vs. UFH 28. Danaparoid vs. UFH 29. Danaparoid vs. warfarin 30. Danaparoid vs. no treatment

Hip fracture surgery tables 31 – 49 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.

IPC vs. LMWH LMWH timing LMWH delivery LMWH vs. no treatment LMWH vs. UFH LMWH plus DHE vs. placebo UFH vs. no treatment UFH dose (adjusted vs. fixed) IPC or foot pump vs. no treatment IPC (thigh vs. calf) Warfarin vs. aspirin Warfarin vs. placebo/no treatment GCS plus fondaparinux vs. fondaparinux

2 9 13 16 18 26 29 37 41 45 49 56 69 76 83 87 95 99 101 104 110 113 115 117 121 123 126 128 130 132 135 136 142 146 148 154 160 162 168 170 176 178 180 187

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44. 45. 46. 47. 48. 49.

Fondaparinux vs. LMWH Extended duration fondaparinux Danaparoid vs. LMWH Danaparoid vs. aspirin Danaparoid vs. warfarin Aspirin vs. no aspirin

Total knee replacement tables 50 – 60 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.

Foot pump vs. no treatment IPC vs. no IPC Foot pump vs. LMWH LMWH vs. IPC IPC vs. aspirin LMWH vs. no LMWH LMWH vs. UFH IPC plus LMWH vs. IPC plus aspirin Warfarin vs. LMWH Warfarin timing Fondaparinux vs. LMWH

Rivaroxaban tables 61 – 64

189 192 194 196 198 200 203 204 206 208 213 215 220 224 229 232 238 240 243

61 and 62: Rivaroxaban vs. LMWH in total hip replacement 244 63 and 64: Rivaroxaban vs. LMWH (varying durations) in total knee replacement 269

Dabigatran etexilate tables 65 – 67 65. Dabigatran etexilate vs. LMWH in total hip replacement 66 and 67.Dabigatran etexilate vs. LMWH in total knee replacement

Knee arthroscopy table 68 68. Knee arthroscopy: LMWH vs. no treatment or GCS

Lower leg fractures and injuries with immobilisation table 69 69. LMWH vs. no treatment

Mixed orthopaedic surgery tables 70 – 80 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

LMWH vs. UFH Extended duration UFH vs. no treatment GCS vs. no treatment Foot pump vs. IPC IPC vs. no treatment IPC vs. warfarin Warfarin vs. aspirin Warfarin vs. no treatment Warfarin vs. UFH Aspirin vs. placebo

291 292 304 325 326

335 336 343 344 346 352 354 356 358 364 366 368 370 372

General surgery tables 81 – 88

379

81. UFH vs. no treatment 82. LMWH vs. no treatment/placebo

380 382

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83. 84. 85. 86. 87. 88.

LMWH vs. UFH GCS vs. no GCS IPC vs. no treatment Foot pump vs. no treatment GCS vs. UFH IPC vs. UFH

Urological surgery tables 89 – 95 89. 90. 91. 92. 93. 94. 95.

UFH vs. no UFH LMWH vs. no treatment IPC vs. no treatment IPC vs. GCS IPC thigh length vs. calf length IPC vs. UFH IPC vs. low dose warfarin

Gynaecological surgery tables 96 – 101 96. 97. 98. 99. 100. 101.

UFH vs. no treatment LMWH vs. UFH GCS vs. no treatment IPC vs. no treatment IPC vs. LMWH Warfarin vs. no treatment

Abdominal surgery tables 102 – 113 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113.

LMWH vs. no treatment or placebo LMWH vs. UFH LMWH dose (5000 IU vs. 2500 IU) LMWH dose (3500 IU vs. 2500 IU) Extended duration heparin Fondaparinux vs. no fondaparinux (IPC background) Fondaparinux vs. LMWH Aspirin vs. UFH GCS vs. no treatment IPC plus UFH vs. no treatment plus UFH GCS vs. UFH IPC vs. UFH

Cardiac, thoracic and vascular surgery tables 114 – 116 114. IPC vs. no IPC 115. UFH dose 116. LMWH vs. UFH

Neurosurgery tables 117 – 123 117. 118. 119. 120. 121. 122. 123.

UFH vs. no treatment LMWH vs. no LMWH LMWH vs. UFH LMWH vs. IPC GCS vs. no treatment IPC vs. no treatment IPC vs. GCS

387 400 409 415 417 419 421 422 426 428 430 432 434 439 441 442 446 454 456 460 462 465 466 472 497 499 501 504 507 510 513 516 518 520

523 524 528 530 535 536 538 546 550 552 554 561

v

Trauma and spinal surgery tables 124 – 130 124. 125. 126. 127. 128. 129. 130.

LMWH vs. foot pump plus LMWH IPC vs. warfarin Low-dose warfarin vs. no treatment IPC vs. no treatment Foot pump vs. IPC Foot wrap vs. thigh wrap IPC Thigh IPC vs. calf IPC

Hospitalised medical stroke patients tables 131 – 138 131. 132. 133. 134. 135. 136. 137. 138.

UFH vs. no treatment Adjusted dose UFH vs. no treatment LMWH vs. no treatment/placebo LMWH vs. UFH Danaparoid vs. placebo Danaparoid vs. UFH GCS vs. no treatment IPC vs. no treatment

Hospitalised medical myocardial infarction patients tables 139 – 140 139. UFH vs. no treatment 140. LMWH vs. UFH

Hospitalised medical cancer patients (with a central venous catheter) tables 141 – 143 141. LMWH vs. no treatment/placebo 142. LMWH vs. warfarin 143. Warfarin vs. no treatment

Hospitalised general medical patients tables 144 – 147 144. 145. 146. 147.

UFH vs. no treatment LMWH vs. placebo LMWH vs. UFH Fondaparinux vs. placebo

Anaesthesia tables 148 – 149 148. Regional anaesthesia vs. general anaesthesia 149. Regional anaesthesia plus general anaesthesia vs. general anaesthesia

563 564 567 569 571 573 575 577

579 580 590 592 603 609 615 621 624

627 628 635

637 638 645 647

651 652 659 670 680 683 684 691

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How to read the evidence summaries, evidence tables and forest plots Evidence tables For each comparison, individual study data was tabulated into evidence tables. As discussed in Appendix A of the guideline, these were obtained from a number of sources: •

• •

The 2007 NICE VTE Prevention Guidelines “Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery” Other systematic reviews of VTE prevention Original study reports.

Evidence summaries For each comparison, an evidence summary has been created which list the studies included in the meta-analysis and the results of each outcome. When results were statistically significant, numbers needed to treat for benefit (NNTB) or harm (NNTH) were also calculated. These provide an estimate of the number of people that would need to be treated with the intervention for one person to experience a beneficial outcome (usually avoidance of a VTE event) (NNTB) or a harmful outcome (NNTH). In cases where relative risk has been pooled, an estimate of the event rate in the control arm was also included (based on the average of the event rates in the control arms of the included studies). This was needed to calculate the numbers needed to treat. The evidence summaries are accompanied by forest plots and evidence tables for each included study. Occasionally, the evidence table contains evidence derived from a systematic review. As explained in the methodology section of the guideline (Appendix B), if an existing systematic review included studies of the same indication (for example total hip replacement surgery) then it was possible to include the systematic review as the included study. However, unless this was a very large systematic review, the results of the component studies from these systematic reviews were entered into the meta-analysis separately to ensure that risks ratios recorded in this guideline were derived from the same meta-analysis program (and used the same underlying assumptions). In using systematic reviews as source documents (alongside the NICE VTE prevention guidelines), we were restricted in the descriptive information available to that reported in the systematic review. This may have resulted in a lack of information in some cases, particularly about patient characteristics such as age, weight or pre-existing risk factors. Where this information is not listed in the evidence tables, this means it was not available in the systematic review.

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Occasionally, there are no forest plots for a particular comparison because there was only one study for that comparison. In these cases, no meta-analysis was undertaken. Relative risks for these studies were calculated using RevMan for consistency and listed in the evidence table. Meta-analysis Where possible, data from the included studies have been combined statistically to produce summary estimates of effect using the statistical meta-analysis program RevMan 5.0. The results are summarised as risk ratios (or relative risks), that is, the ratio of the risk of experiencing an outcome in the intervention group to risk of that same outcome in the control group. A risk ratio of one indicates no difference between comparison groups. In VTE prophylaxis studies risk ratios of less than one indicate that the intervention was effective in reducing the risk of that outcome (for example deep vein thrombosis). Each risk ratio is also accompanied by a 95% confidence interval which indicates the range of values around a point estimate in which the true value is thought to lie 95% of the time. Narrow confidence intervals indicate a precise estimate of the effect, whereas wide confidence intervals indicate a lack of precision in the effect estimate. Through statistically pooling (meta-analysing), more precise estimates of the effect of the intervention on the important outcomes can be obtained compared with individual studies considered in isolation. Meta-analysis increases the statistical power of the analysis and may find a statistically significant result where none of the individual studies included in the analysis were statistically significant when considered in isolation. Forest plots The results of each meta-analysis are displayed graphically in forest plots which show the individual results of each study together with the combined meta-analysis result. Forest plots also include the overall risk ratio for that outcome. The results of individual studies are shown as squares centred on each study’s point estimate. A horizontal line runs through each square to show each study’s 95% confidence interval. The overall estimate from the metaanalysis and its confidence interval are shown at the bottom, represented as a diamond. The centre of the diamond represents the pooled point estimate, and its horizontal tips represent the confidence interval. Forest plots usually include a “line of 1” (for dichotomous outcomes) and are labelled at the bottom with ‘favours the intervention’ or ‘favours the comparator’ which assist users to interpret the findings. If the lines showing 95% confidence intervals for individual studies, or the diamond showing the confidence intervals of the pooled relative risk, cross the “line of 1” then the result is not statistically significant. Statistical heterogeneity refers to the variation in the effect estimates from a set of studies. It is indicated by the I2 value shown at the bottom of each forest plot. Very broadly, the higher this value, the more statistical heterogeneity is present. Typically values above I2 = 50% indicate excessive heterogeneity. If heterogeneity is high, it may indicate that the studies are not suitable for statistical pooling using meta-analysis. In cases where the I2 was greater than

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50%, a random effects meta-analysis was used (which is more stringent in assessing the statistical significance of the overall estimate of effect). The forest plot also allows readers to see the heterogeneity among the results of the studies. This can be assessed informally by considering the spread of results and the direction of outcomes for the included studies (i.e. by looking at the square box and line plots). The results or estimates of effects of treatment from separate studies may seem to be very different – in terms of the size of treatment effects or even to the extent that some indicate beneficial and others suggest adverse treatment effects. Such results may occur because of differences between studies (e.g. the patient populations, outcome measures, definition of variables or duration of follow-up).

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Abbreviations used in the evidence tables aPPT

Activated partial thromboplastin time

BMI

Body mass index

CECT

Continuous enhanced circulation therapy

CER

Control event rate

CI

Confidence interval

CONT

Control

COPD

Chronic obstructive pulmonary disease

CPM

Continuous passive motion

CR

Cochrane review

CVCs

Central venous catheters

DHE

Dihydroergotamine

DVT

Deep vein thrombosis

FID

Foot impulse device

FIT

Foot impulse technology

FUT

125

GCS

Graduated compression stockings

GP

General practitioner

HIT

Heparin-induced thrombocytopenia

IBS

Inflammatory bowel syndrome

INR

International normalised ratio

INT

Intervention

IPC

Intermittent pneumatic compression

IPG

Impedance plethysmography

ITT

Intention to treat

IV

Intravenous

LMWH

Low molecular weight heparin

LoS

Length of stay

M/F

Ratio of the number of males to females in the study

MD

Mean difference

MI

Myocardial infarction

MR

Magnetic Resonance

I-Fibrinogen uptake test

x

MRI

Magnetic Resonance Imaging

NA

Not applicable

NHMRC

National Health and Medical Research Council

NICE

National Institute for Health and Clinical Excellence, United Kingdom

NICS

National Institute of Clinical Studies

NNTB

Number needed to treat to benefit

NNTH

Number needed to treat to harm

NR

Not reported

NS

Not specified

OAC

Oral anticoagulant

OR

Odds ratio

p value

The probability that an observed difference could have occurred by chance

pDVT

Proximal deep vein thrombosis

PE

Pulmonary embolism

PNS

p value not significant

PTS

Post-thrombotic limb syndrome

PTT

Partial thromboplastin time

QoL

Quality of life

RCT

Randomised controlled trial

RD

Risk difference

RR

Risk ratio

RRR

Relative risk reduction

SC

Subcutaneous

SR

Systematic review

TED stockings

A brand of graduated compression stockings

Tx

Treatment

UFH

Unfractionated heparin

US

Ultrasound

V/Q scan

A ventilation/perfusion lung scan

VAS

Visual analogue scale

VFP

Venous foot pump

VTE

Venous thromboembolism

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TOTAL HIP REPLACEMENT TABLES 1 - 30

1

Evidence summary 1. Total hip replacement: GCS vs. no GCS Asymptomatic DVT Significantly fewer asymptomatic DVT were detected in the GCS group compared with no GCS in 7 studies: RR 0.60 (95% CI 0.45 to 0.79) NNTB 7 (95% CI 5 to 14)

Proximal DVT Significantly fewer proximal DVT were detected in the IPC group compared with no GCS in 5 studies: RR 0.68 (95% CI 0.41 to 1.14)

PE No significant difference in PE was detected in six studies: RR 0.35 (95% CI 0.01 to 1.25) No fatal PE reported in any studies

I Barnes 1978 Fredin 1989 Gallus 1983 Kalodiki 1996b Lieberman 1994 Ohlund 1983 Siragusa 1994 I Barnes 1978 Gallus 1983 Kalodiki 1996b Lieberman 1994 Siragusa 1994 I Barnes 1978 Fredin 1989 Kalodiki 1996b Lieberman 1994 Ohlund 1983 Siragusa 1994

2

Evidence table 1. Total hip replacement: GCS vs. no GCS Reference Gallus 1983

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 95 Int: n= NR Cont: n= NR

Patient groups Type of surgery: Total hip replacement.

Intervention Type: GCS

Comparison No treatment

Length of follow-up

Dose: knee length single Timing: intraoperatively to day 7 post-op

Barnes 1978

RCT

II ROB: low

Total: 18 Int: n=8 Cont: n=10

Type of surgery: Total hip replacement. Age: >50 Sex: male and female Pre-existing risk factors: Some patients had aspirin during the study, some had previous DVT, some had previous leg injuries, some had varicose veins, some with venous skin changes.

Additional noncomparative prophylaxis: none Type: GCS

Additional noncomparative prophylaxis: none No treatment

Dose: thigh length Timing: duration of hospitalisation Additional noncomparative prophylaxis: none

Additional noncomparative prophylaxis: none

Outcome measures DVT: confirmed by FUT daily postoperative, IPG day 7, venography day 7 post-op

Effect size Int: 15/43 Cont: 25/47

Proximal DVT

Int: 10/43 Cont: 12/47

Comments Sequentially sealed opaque envelopes. DVT assessment blinded

Source: Roderick 2005

Both groups: No losses to follow-up

DVT: confirmed by Doppler US pre-op to discharge on alternate days

Int: 0/8 Cont: 5/10 p value:0.029

Proximal DVT

Int: 0/8 Cont: 4/10

Randomisation by sequentially numbered sealed opaque envelopes

Non-fatal PE

Int: 0/8 Cont: 3/10

Allocation concealment adequate

Fatal PE

Int: 0/8 Cont: 0/10 p value: Int: 0/8 Cont: 3/10

Source: Amaragiri 2002, Roderick 2005

All PE: assessed by scan

DVT and PE assessment unblinded.

3

Reference Lieberman 1994

Siragusa 1994

Study type RCT

RCT

Evidence Level II ROB: mod

II ROB: low

No. of patients Total: 260 Int: n=130 Cont: n=130

Total: 70 Int: n=35 Cont: n=35

Patient groups Type of surgery: Total hip replacement.

Type of surgery: Total hip replacement.

Intervention Type: GCS (Thigh length sequential applied on post-op day 6-8)

Comparison No treatment

Length of follow-up

Outcome measures DVT: confirmed by venography on day 6-8 post-op (not confirmed) Proximal DVT

Effect size Int: 7/113 Cont: 9/118

Comments DVT assessment blinded.

Int: 0/113 Cont: 1/118

Method of randomisation not known

Fatal PE

Int: 0/130 Cont: 0/130

Source: Roderick 2005

Additional noncomparative prophylaxis: aspirin

Additional noncomparative prophylaxis: aspirin

Type: ?GCS (not stated)

No treatment

DVT: confirmed by venography

Int: 6/35 Cont: 10/35

DVT assessment blinded.

Additional noncomparative prophylaxis: heparin

Additional noncomparative prophylaxis: heparin

Proximal DVT

Int: 5/35 Cont: 4/35 Int: 0/35 Cont: 0/35 Int: 0/35 Cont: 0/35 Int: 0/35 Cont: 0/35

Method of randomisation: on site computer

Source: Roderick 2005

DVT: confirmed by FUT pre-op then day 1, 3, 5, 7. Venography day 10. Non-fatal PE

Int: 13/49 Cont: 21/48

DVT and PE assessment blinded.

Int: 0/49?50 Cont: 2/48?50

Randomisation using sequentially numbered sealed opaque envelopes

Fatal PE

Int: 0/49?50 Cont: 0/48?50

All PE: assessed by scan or post-mortem

Int: 0/49?50 Cont: 2/48?50

Non-fatal PE Fatal PE All PE

Fredin 1989

RCT

II ROB: low

Total: 150 Int: n=50? Cont: n=50? 3 arms Total available for analysis 144. Results for patients operated leg were not included Exclusion criteria: Swelling of legs, leg

Type of surgery: Total hip replacement.

Type: GCS

No treatment

Dose: Thighlength Timing: 1 day pre-op to day 14 post-op Additional noncomparative prophylaxis: dextran

Additional noncomparative prophylaxis: dextran

4

Reference

Kalodiki 1996

Study type

Evidence Level

RCT

II ROB: low

No. of patients ulcers, eczema, malignancy, varicose veins, previous DVT, previous PE, cardiovascular disease Total: 76 Int: n=38 Cont: n=38

Patient groups

Intervention

Comparison

Type of surgery: Total hip replacement.

Type: GCS Dose: Thighlength

No treatment

Timing: pre-op to discharge (8-12 days)

Outcome measures

Effect size

Comments Source: Roderick 2005

DVT: confirmed by venography on day 8-12 post-op. Proximal DVT

Int: 8/32 Cont: 12/32

Non-fatal PE

Int: 2/39 Cont: 3/38

DVT and PE assessment blinded. Randomisation using pharmacy coded container administered sequentially

Fatal PE

Int: 0/39 Cont: 0/38

All PE: assessed by scan

Int: 2/39 Cont: 3/38

No treatment

DVT: confirmed by FUT on day 1-10 post-op (4-5 times per patient)

Int: 7/31 Cont: 15/31 p value:0.05

Additional noncomparative prophylaxis: dextran

Fatal PE

Int: 0/31* Cont 0/31*

Additional noncomparative prophylaxis: LMWH

Additional noncomparative prophylaxis: LMWH Ohlund 1983

RCT

II ROB: low

Total: 63 Int: n=31 Cont: n=31

Type of surgery: Total hip replacement.

Exclusion criteria: none mentioned.

Age: all >50 Sex: male and female

* number of patients who were DVT assessed Note: the study did not provide the specific number of patients randomised to each group, only the total number randomised, which was 63.

Type: GCS Dose: Knee length Additional noncomparative prophylaxis: dextran

Length of follow-up

Int: 4/32 Cont: 9/32

Source: Roderick 2005 DVT assessment not blinded. Randomisation by closed list of random numbers Allocation concealment adequate Source: Roderick 2005

5

Forest plot 1a: Asymptomatic DVT Comparison of GCS vs. no GCS in total hip replacement GCS no treatment Study or Subgroup Events Total Events Total Weight 1.1.1 venography: blinded Fredin 1989 Gallus 1983 Kalodiki 1996b Lieberman 1994 Siragusa 1994 Subtotal (95% CI)

13 15 8 7 6

49 43 32 113 35 272

21 25 12 9 10

Risk Ratio M-H, Fixed, 95% CI

48 47 32 118 35 280

22.1% 24.9% 12.5% 9.2% 10.4% 79.2%

0.61 [0.34, 1.07] 0.66 [0.40, 1.07] 0.67 [0.32, 1.41] 0.81 [0.31, 2.11] 0.60 [0.24, 1.47] 0.65 [0.49, 0.88]

10 10

5.2% 5.2%

0.11 [0.01, 1.75] 0.11 [0.01, 1.75]

31 31

15.6% 15.6%

0.47 [0.22, 0.98] 0.47 [0.22, 0.98]

321 100.0%

0.60 [0.45, 0.79]

Risk Ratio M-H, Fixed, 95% CI

77 49 Total events Heterogeneity: Chi² = 0.31, df = 4 (P = 0.99); I² = 0% Test for overall effect: Z = 2.78 (P = 0.005) 1.1.2 US: not blinded Barnes 1978 Subtotal (95% CI)

0

8 8

0 Total events Heterogeneity: Not applicable Test for overall effect: Z = 1.56 (P = 0.12)

5 5

1.1.3 FUT: not blinded Ohlund 1983 Subtotal (95% CI)

7

31 31

7 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.00 (P = 0.05) Total (95% CI)

15 15

311

97 56 Total events Heterogeneity: Chi² = 2.48, df = 6 (P = 0.87); I² = 0% Test for overall effect: Z = 3.67 (P = 0.0002) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours GCS Favours no treatmen

6

Forest plot 1b: Proximal DVT Comparison of GCS vs. no GCS in total hip replacement GCS no treatment Study or Subgroup Events Total Events Total Weight 1.2.1 venography: blinded Gallus 1983 Kalodiki 1996b Lieberman 1994 Siragusa 1994 Subtotal (95% CI)

10 4 0 5

43 32 113 35 223

12 9 1 4

Risk Ratio M-H, Fixed, 95% CI

47 32 118 35 232

38.2% 30.0% 4.9% 13.3% 86.5%

0.91 [0.44, 1.89] 0.44 [0.15, 1.30] 0.35 [0.01, 8.45] 1.25 [0.37, 4.27] 0.77 [0.45, 1.30]

10 10

13.5% 13.5%

0.14 [0.01, 2.20] 0.14 [0.01, 2.20]

242 100.0%

0.68 [0.41, 1.14]

Risk Ratio M-H, Fixed, 95% CI

26 19 Total events Heterogeneity: Chi² = 2.05, df = 3 (P = 0.56); I² = 0% Test for overall effect: Z = 0.98 (P = 0.33) 1.2.3 US: not blinded Barnes 1978 Subtotal (95% CI)

0

8 8

0 Total events Heterogeneity: Not applicable Test for overall effect: Z = 1.40 (P = 0.16) Total (95% CI)

4 4

231

30 19 Total events Heterogeneity: Chi² = 3.61, df = 4 (P = 0.46); I² = 0% Test for overall effect: Z = 1.46 (P = 0.14) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

7

Forest plot 1c: PE Comparison of GCS vs. no GCS in total hip replacement Study or Subgroup 1.1.1 Fatal PE Barnes 1978 Fredin 1989 Kalodiki 1996b Lieberman 1994 Ohlund 1983 Siragusa 1994 Subtotal (95% CI)

GCS No treatment Events Total Events Total Weight 0 0 0 0 0 0

8 50 39 130 31 35 293

Total events 0 Heterogeneity: Not applicable Test for overall effect: Not applicable

0 0 0 0 0 0

10 50 38 130 31 35 294

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

Not estimable Not estimable Not estimable Not estimable Not estimable Not estimable Not estimable

0

1.1.2 Non-fatal PE Barnes 1978 Fredin 1989 Kalodiki 1996b Siragusa 1994 Subtotal (95% CI)

0 0 2 0

8 50 39 35 132

3 2 3 0

10 36.3% 50 28.8% 38 35.0% 35 133 100.0%

0.17 [0.01, 2.96] 0.20 [0.01, 4.06] 0.65 [0.11, 3.67] Not estimable 0.35 [0.10, 1.25]

10 36.3% 50 28.8% 38 35.0% 35 133 100.0%

0.17 [0.01, 2.96] 0.20 [0.01, 4.06] 0.65 [0.11, 3.67] Not estimable 0.35 [0.10, 1.25]

Total events 2 8 Heterogeneity: Chi² = 0.86, df = 2 (P = 0.65); I² = 0% Test for overall effect: Z = 1.61 (P = 0.11) 1.1.3 Any PE Barnes 1978 Fredin 1989 Kalodiki 1996b Siragusa 1994 Subtotal (95% CI)

0 0 2 0

8 50 39 35 132

3 2 3 0

Total events 2 8 Heterogeneity: Chi² = 0.86, df = 2 (P = 0.65); I² = 0% Test for overall effect: Z = 1.61 (P = 0.11) 0.01 0.1 1 10 100 Favours GCS Favours no GCS

8

Evidence summary 2. Total hip replacement: IPC vs. GCS Asymptomatic DVT In one RCT, there were significantly fewer DVT with IPC compared with GCS: RR 0.03 (95% CI 0.00 to 0.41) In another RCT no differences were seen between IPC and GCS for proximal DVT: RR 0.36 (95% CI 0.12 to 1.07) PE No PE in either of the two RCTs

I Silbersack 2004 Ryan 2002

I Silbersack 2004 Ryan 2002

9

Evidence table 2. Total hip replacement: IPC vs. GCS Reference Ryan et al. 2002

Study type RCT

Evidence level II

No. of patients Total: 100 Int: n=50 Cont: n=50

Patient groups Patients who were to undergo total hip arthroplasty Int: n=50 Mean age: 70.1 Gender ratio (M:F): 19:31 (38%:62%) Cont: n=50 Mean age: 67.5 Gender ratio (M:F): 19:31 (38%:62%)

Silbersack et al. 2004

RCT

II

Total: 131 Int: n= 68 Cont: n=63

Type of surgery: patients >18 yrs, awaiting primary unilateral THR or TKR Int: No of patients with THR: 33 No of pts with TKR: 35 Mean Age: 63(29-90) Gender ratio(M:F):28:40 Cont: No of pts with THR: 28 No of pts with TKR:35 Mean Age: 65 (36-87)

Intervention Vena Flow pneumatic compression device applied to both lower extremities Duration: Started immediately after surgery and continued for duration of post-operative hospital stay Additional background prophylaxis: Aspirin (325mg 2x/day) Epidural anaesthesia LMW Heparins plus calf intermittent pneumatic compression devices Dose and Duration: Patients were given 40mg of anti-Xa enoxaparin-

Comparison Elastic stockings

Length of follow-up Until discharge (4-5 days on average)

Outcome measures Proximal DVT: confirmed by magnetic resonance venography

Effect size Int: 4/50 Cont: 11/50

Additional background prophylaxis: Aspirin (325mg 2x/day) Epidural anaesthesia

Comments Detailed findings of the magnetic resonance venogram reported e.g.: size and location of clot etc No clinically symptomatic DVT or PE developed in any patient Not reported: DVT, PTS, QoL

Symptomatic PE

Int: 0/50 Cont: 0/50 p value: N/A

Source: NICE LMW Heparins plus GCS Patients were also given 40mg of anti-Xa enoxaparinnatrium daily beginning on the eve prior to surgery Additional non-

First follow-up: between 6th & 12th postoperative day Second followup: between 6th and 12th postoperative weeks

DVT: confirmed by colour duplex US

First follow-up: Int: 0/68 Cont: 18/63 Second followup: Only of 105 of 113 pts (93%) who received prolonged prophylaxis with LMWH and GCS. One

Unrestricted grant from Aircast Europa GmbH, Neubeuren, Germany which made the VenaFlow system during the study period. - IPC was often used incorrectly

10

Reference

Study type

Evidence level

No. of patients

Patient groups Gender ratio(M:F): 19:44 Risk factors: Int: Previous VTE: 5/68 Varicose veins:45/68 Previous cancer: 4/68 Oestrogen users: 4/68 Cont: Previous VTE: 3/63 Varicose veins: 39/63 Previous cancer: 2/63 Oestrogen users: 2/63

Intervention natrium daily beginning on the eve prior to surgery until post-operative day 30 (self administration)

Comparison comparative prophylaxis: Regional anaesthesia: 46/63

Additional noncomparative prophylaxis: Regional anaesthesia: 49/68

Non-steroidal antiinflammatory drugs: 26/63

Aspirin users: 8/63

Length of follow-up

Outcome measures

PE: confirmed by spiral CT of lungs

Effect size fresh thrombosis case detected No cases of symptomatic PE

Comments at the beginning of the study - 27% of pts stopped using IPC prematurely - Night-time use of IPC was refused - In comparison with GCS, the IPC requires more supervision

Aspirin users: 11/68 Nonsteroidal antiinflammatory drugs: 25/68

11

Forest plot 2a: Asymptomatic DVT Comparison of IPC vs. GCS in total hip replacement

Forest plot 2b: Proximal DVT Comparison of IPC vs. GCS in total hip replacement

Forest plot 2c: PE Comparison of IPC vs. GCS in total hip replacement

12

Evidence summary 3. Total hip replacement: Foot Pump plus UFH vs. UFH Asymptomatic DVT One RCT did not show a significant difference between foot pump (with or without UFH plus aspirin) compared with UFH plus aspirin alone: RR 0.09 (95% 0.01 to 1.56) PE In one RCT there were no PE reported in the foot pump arms and one PE (non-fatal) was reported in the UFH plus aspirin arm

I Stannard 1996

I Stannard 1996

13

Evidence table 3. Total hip replacement: Foot Pump plus UFH vs. UFH Reference Stannard et al. 1996

Study type RCT

Evidence Level II

No. of patients Total: 75 Int 1: 25 Int 2: 25 Cont: 25

Patient groups Type of surgery: uncemented total hip arthroplasty Duration of surgery: Int 1: mean 106 (85-128 mins); Int2: mean 113 (15135) mins; Cont: mean 111 (87-140) mins; Int1: Mean age: 68.7 (range 48-86) yrs M/F: not reported Int2: Mean age: 65(range 51-79) yrs M/F: not reported Cont: Mean age: 69.7 (range 28-86) yrs M/F: not reported

Intervention Int 1: Type: Bilateral foot pump (PlexiPulse) plus LDUH plus aspirin Dose: Foot pump 16 hrs/day for first 3 days, then 12 hrs/day; LDUH 5000U; Aspirin 325mg Int 2: Type: Bilateral foot pump 16hrs/day for first 3 days, then 12hrs/day Timing: Foot pump begun immediately post-surgery and continued until end of study; LDUH begun 12hrs pre surgery and every 12hrs for first 3 days post-surgery, the aspirin 3x daily until end of study Additional prophylaxis: Spinal anaesthesia: 22/25

Comparison Type: LDUH plus aspirin Dose: LDUH 5000U; Aspirin 325 mg

Length of follow-up 2 weeks post-op

Outcome measures DVT: confirmed by Doppler US, positive scans confirmed by venography

Effect size Int1: 0/25 Int2: 0/25 Cont: 5/25 p value = 0.10 (not significant)

Comments 3/5 DVT were symptomatic. 1 PE was symptomatic. 4/5 patients who developed DVT had spinal anaesthesia. Two patients reported as excluded from study due to abnormal pre-op US findings. Does not report to which group(s) they belonged

PE: not routinely screened for. No confirmatory tests reported

Int1: 0/25 Int2: 0/25 Cont: 1/25 p value: not provided

Not reported: LoS, QoL, PTS, proximal DVT

Bleeding related complications: surgical wound drainage - time taken for wound to seal (no. days post op) Survival: specify

Int1: 5.9 days Int2: 3.8 days Cont: 6.2 days p value = 0.05 (significant)

Timing: LDUH begun 12hrs for first 3 days postsurgery, then aspirin 3x daily until end of study Additional prophylaxis: Spinal anaesthesia 21/25

Funding: Not reported

Int1: 25/25 Int2: 25/25 Cont: 25/25 p value: not significant

14

Forest plot 3a: Asymptomatic DVT Comparison of foot pump plus UFH vs. UFH in total hip replacement

Forest plot 3b: PE Comparison of foot pump plus UFH vs. UFH in total hip replacement

Forest plot 3c: Mortality Comparison of foot pump plus UFH vs. UFH in total hip replacement

15

Evidence summary 4. Total hip replacement: Foot pump vs. no foot pump DVT DVT was significantly decreased with the use of a foot pump compared with not using a foot pump: RR 0.26 (95% CI 0.09 to 0.70) NNTB 6 (95% CI to 1 to 11) Proximal DVT Proximal DVT was significantly decreased with the use of a foot pump compared with not using a foot pump: RR 0.16 (95% CI 0.04 to 0.65) NNTB 6 (95% CI 2 to 25)

I Fordyce 1992

I Fordyce 1992

16

Evidence table 4. Total hip replacement: Foot pump vs. no foot pump Reference Fordyce 1992

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 84 Int: n=42 Cont: n=42

Patient groups Type of surgery: Total hip replacement.

Intervention Type: Foot pump

Comparison Type: Foot pump

Dose: on operated leg during sitting and bed rest post-op

Dose: bilateral

Additional noncomparative prophylaxis: GCS

Additional noncomparative prophylaxis: GCS

Timing: post-op (not stated)

Length of follow-up

Outcome measures DVT: confirmed by venography on day 6-9 post-op Proximal DVT

Effect size Int: 4/39 Cont: 16/40

Int: 2/39 Cont: 13/40

Comments DVT assessment blinded. Randomisation by sealed envelopes Five patients were excluded – Two (one in each group) refused to have a venogram and in two (one from each group) it was not possible to perform venography. One patient in the Foot pump group died of MI on post-op day 1. Source: Roderick 2005

17

Evidence summary 5. Total hip replacement: Foot pump vs. LMWH Asymptomatic DVT Two RCTs showed no significant differences between foot pump and LMWH: RR 0.98 (95% CI 0.38 to 2.50) Symptomatic DVT In one of the RCTs, there was one symptomatic DVT in the foot pump group and one in the LMWH group PE There was one non-fatal PE reported in the foot pump group in one RCT Bleeding No instances of major bleeding were reported in one RCT Other adverse events In one RCT, a case of heparin-induced thrombocytopenia was reported in the LMWH group and in the other RCT, there were two re-admissions to hospital due to DVT (one in each group)

I Pitto 2004, Warwick 1998 I Pitto 2004 I Pitto 2004 Warwick 1998 I Pitto 2004 I Pitto 2004 Warwick 1998

18

Evidence table 5. Total hip replacement: Foot pump vs. LMWH Reference Pitto 2004

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 216 Int: n = 100 Cont: n = 100

Patient groups Type of surgery: Total hip replacement in patients with osteoarthritis

Intervention Type: A-V Impulse System foot pump (slippers) and patient in Trendelenburg position (head-high, feet-low)

Comparison Type: Low molecular weight heparin (Fraxiparin) continued after surgery

Patient groups and duration of surgery:

Cycle: 130 mmHg for one second every 20 seconds

Dose: adjusted to body weight, 0.2 to 0.6ml; 0.1ml = 950IU of anti Xa

Int: Mean age: 57.3±12 yrs M/F:30/70 Mean duration of surgery: 69 ± 10 minutes Cont: Mean age: 58.1±11 M/F:32/68 Mean duration of surgery: 65 ±11 minutes

Timing: (duration) started after surgery, not stated when stopped – could be used until discharge Additional noncomparative prophylaxis: Bilateral thigh-high antithromboembolic stockings. Physiotherapy and mobilisation with partial weight bearing usually started on post-op day 2. Low molecular weight heparin (Fraxiparin) administered subcutaneously 12 hours pre-operatively (dose adjusted to body weight, 0.2 to 0.6ml; 0.1ml = 950IU of anti Xa).

Timing: started post-op, not stated when stopped but could be until discharge Additional noncomparative prophylaxis: Bilateral thigh-high anti-thromboembolic stockings. Physiotherapy and mobilisation with partial weight bearing usually started on post-op day 2. Low molecular weight heparin (Fraxiparin) administered subcutaneously 12 hours pre-operatively (dose adjusted to body weight, 0.2 to

Length of follow-up Cont: 45 days Int: 45 days

Outcome measures DVT: confirmed by serial bilateral duplex ultrasound Proximal DVT: confirmed by serial bilateral duplex ultrasound Distal DVT: confirmed by serial bilateral duplex ultrasound Symptomatic DVT: confirmed by serial bilateral duplex ultrasound PE Fatal PE Major bleeding from wound Major bleeding not related to wound Heparin-induced thrombocytopenia Survival

Effect size Int: 3/97 Cont: 6/94 p value: 0.3 Int: 0/97 Cont: 2/94 p value: 0.29 Int: 3/97 Cont: 4/94 p value: 0.67 Not significant Int: 1/100 Cont: 1/100 p value: Not significant Int: 0/100 Cont: 0/100 Int: 0/100 Cont: 0/100 Int: 0/100 Cont: 0/100 Int: 0/100 Cont: 0/100 Int: 0/100 Cont: 1/100 Int: 100/100 Cont: 100/100

Comments Comments: Discrepancy with randomisation: computer generated numbers lead to 100 in each group but 216 were randomised. 16 dropped out of mechanical group because did not tolerate foot pump. Drop-outs occurred between post-operative days 3 and 10. Not reported: PE, LoS, post-thrombotic leg Also reported: Distal DVT, minor bleeding from wound; no. of hips without bruising at days 3 & 10, no. of hips without oozing at days 3 & 10 Funding: stated

19

Reference

Warwick 1998 (553)

Study type

RCT

Evidence Level

II ROB: low

No. of patients

Total: n =290 Int: n = 147 Cont: n = 143

Patient groups

Type of surgery: Patients undergoing total hip replacement Int: Mean Age: 68±11 M/F:94/53 Pre-existing risk factors: Previous thromboembolism: Int: n = 2, Cont: n = 3

Intervention

Foot pump for 7days

Comparison 0.6ml; 0.1ml = 950IU of anti Xa).

Enoxaparin Dose: 40mg/dly for 7 days

Length of follow-up

Cont: 3mths Int: 3mths

Outcome measures

DVT (overall): confirmed by venography on 6th, 7th & 8th day

Timing: 7days Additional prophylaxis: Not reported

Proximal vein thrombosis

Distal vein thrombosis

Symptomatic PE: confirmed by ventilation perfusion scanning Fatal PE

Effect size

Int: 24/136 Cont: 18/138 (95%CI, -3.9 to +13.0%) p value: Not significant Int: 17/136 Cont: 12/138 (95%CI, -3.5 to +11.1%) p value: Not significant Int: 7/136 Cont: 6/138 (95%CI, -4.2 to +5.8%) p value: Not significant Int: 1/136 Cont: 0/138 p value: Not significant Int: 0/136

Comments that authors have or will receive benefits from a commercial party directly related to the subject of this study. Does not state who the commercial party is or what the benefits are. Source: NICE Comments: 136 patients in the intervention and 138 in the comparison group completed both venography and the 3 month follow-up. No patient died during follow-up Not reported: PTS, Bleeding related complications, QoL, Survival Also reported: Intraoperative blood loss, post-op drainage, median no. of units

20

Reference

Study type

Evidence Level

No. of patients

Patient groups

Intervention

Comparison

Length of follow-up

Outcome measures

Readmission to hospital because of DVT

Effect size Cont: 0/138 p value: Not significant Int: 1/136 Cont: 1/138 p value: Not significant

Comments transfused, oozing and bruising of thigh Source: NICE

21

Forest plot 5a: Asymptomatic DVT Comparison of foot pump vs. LMWH in total hip replacement

Forest plot 5b: Proximal DVT Comparison of foot pump vs. LMWH in total hip replacement

22

Forest plot 5c: Distal DVT Comparison of foot pump vs. LMWH in total hip replacement

Forest plot 5d: Symptomatic DVT Comparison of foot pump vs. LMWH in total hip replacement

Forest plot 5e: PE Comparison of foot pump vs. LMWH in total hip replacement

23

Forest plot 5f: Mortality Comparison of foot pump vs. LMWH in total hip replacement

24

Forest plot 5g: Adverse events Comparison of foot pump vs. LMWH in total hip replacement

25

Evidence summary 6. Total hip replacement: IPC vs. LMWH Proximal DVT In one RCT there was no significant difference in asymptomatic DVT between IPC and LMWH groups.

I Stone 1996

26

Evidence table 6. Total hip replacement: IPC vs. LMWH Reference Stone 1996

Study type RCT

Evidence Level II

No. of patients Total: 50 Int: n= 25 Cont: n= 25

Patient groups Type of surgery: Total hip replacement Int: Mean age: 64 (range 42 – 83) yrs M/F:10/15 Cont: Mean age: 64 (range 37-82) yrs. M/F:8/15 Pre-existing risk factors: Not reported. Patients with known cancer were excluded.

Intervention Type: Calf length IPC device. Worn on contralateral leg only during operation, and then bilaterally from the end of the procedure. Timing: Duration of device use not reported. Additional noncomparative prophylaxis: None

Comparison Type: LMWH Dose: 40 mg once daily Timing: Begun on the evening before surgery and continued until discharge (usually after 10 days). Additional noncomparative prophylaxis: None

Length of follow-up Both groups: 6 weeks post-op

Outcome measures Proximal DVT: confirmed by Colour duplex ultrasound, one week and six weeks post-op.

Effect size At one week: Int: 0/50 Cont: 0/50 At six weeks: Int: 1/50 Cont: 1/50 p value: Not significant

Comments Comments: Method of randomisation not reported. No mention of whether all included pts were assessed again at 6 weeks. Not reported: DVT (only proximal reported), PE, Postthrombotic leg, major bleeding, QoL, survival, LoS. Also reported: Blood loss into drains, blood transfusion during and post-op, wound infection and haematoma. Source: NICE

27

Forest plot 6a: Proximal DVT Comparison of IPC vs. LMWH in total hip replacement IPC LMWH Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI 53.3.2 IPC v LMWH: ultrasound: not blinded Stone 1996 Subtotal (95% CI)

1

50 50

1 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) Total (95% CI)

1

50 100.0% 50 100.0%

1.00 [0.06, 15.55] 1.00 [0.06, 15.55]

50 100.0%

1.00 [0.06, 15.55]

Risk Ratio M-H, Fixed, 95% CI

1

50

1 1 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.00 (P = 1.00) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours IPC Favours LMWH

28

Evidence summary 7. Total hip replacement: IPC vs. warfarin Asymptomatic DVT No significant differences across 4 RCTs were seen between IPC and warfarin for numbers of asymptomatic DVT, although there were significantly fewer proximal DVT for warfarin compared with IPC: RR 2.48 (95% CI 1.35 to 4.58) Assuming a control rate of 5% (note control group here is warfarin), NNTB = 14 (95% CI 6 to 67) Therefore, for every 14 patients treated with IPC, an additional proximal DVT can be expected, compared with warfarin PE PE not reported in 2 RCTs Death One death in the IPC group was reported (2 RCTs) Bleeding No instances of major or clinically important bleeding were reported in 3 RCTs

I Bailey 1991 Francis 1992 Kaempffe 1991 Paiement 1987

I Bailey 1991 Paiement 1987 I Bailey 1991 Kaempffe 1991 I Bailey 1991 Francis 1992 Paiement 1987

29

Evidence table 7. Total hip replacement: IPC vs. warfarin Reference Bailey 1991

Study type RCT

Evidence Level II ROB: low

No. of patients Total 95 Int: 50 Cont: 45

Patient groups Type of surgery: total hip replacement Duration of Surgery: Mean operating time Int: 184.5 min Cont: 208.5 min Mean age: Int: 65.3 years (range: 41- 88) Cont: 64.4 years (range: 45-50) M/F: Int: 24/26 Cont: 22/23

Intervention Sequential pneumatic compression device covering legs and thighs (IPC) Timing: Applied after surgery in the recovery ward and worn continuously for the remainder of the study (except during bathing and physical therapy). Additional noncomparative prophylaxis: graded elastic compression stockings applied on admission and continued until after discharge.

Comparison Low dose warfarin Dose: 10mg before surgery (7.5mg for women over 70 and patients with minor abnormalities of liver function tests). Timing: Evening before surgery and doses given after surgery adjusted to maintain a prothrombin time at 14-16 seconds. Prothrombin times routinely obtained by post-operative day 2 or 3. Additional noncomparative prophylaxis: graded elastic compression stockings applied before and after surgery

Length of follow-up Cont: 5 to 7 days (also day diagnostic test done for DVT) Int: 5 to 7 days (also day diagnostic test done for DVT)

Outcome measures DVT: confirmed by venography (see comments) Major bleeding: defined in the paper as "clinically important bleeding" Proximal DVT

Effect size Int: 3/50 Cont: 12/45 p value: 1500 mL of whole blood; serosanguinous secretion at the wound after day 6; haemorrhage requiring reintervention and any retroperineal or intracranial haemorrhage and haemorrhage warranting permanent treatment

Int: 68/494 Cont: 50/495

Int: 9/1012 Cont: 12/1003

Comments period (knee or hip not specified) Missing data: overall (knee and hip) 2018 patients were randomised with 3 losses (1 LMWH and 2 UFH); 20% of the LMWH group and 19% of the UFH group were not evaluated for efficacy (mostly due to inadequate venography) Safety data: was not presented separately for hip and knee patients. However it was reported that 15 hip patients (1.2%) and 6 knee patients (0.8%) had major bleeding.

58

Reference

Study type

Evidence Level

No of participants; and characteristics

Intervention

Comparison

Length of follow-up

Outcome measures cessation

Effect size

Surgical reintervention

Int: 1/1012 Cont: 5/1003

Discontinuation due to bleeding

Int: 3/1012 Cont: 2/1003

Transfusion > 1500 ml

Int: 0/1012 Cont: 1/1003

Minor bleeding

Int: 38/1012 Cont: 29/1003 Int: 70/1012 Cont: 68/1003

Serious adverse events Horbach 1996

RCT

II

Type of surgery: elective hip replacement 305 Int: n=152 Cont: n=153 Int: mean age 64.2 ±10.0 years M/F: 72/80 Cont: 64.9 ± 9.8 years M/F: 70/83

Kakkar 2000

RCT

II

Pre-existing risk factors: Previous thrombosis: Int 13: Cont 16 Previous PE: Int 3: Cont 6 Varices: Int 69: Cont 79 Diabetes: Int 10: Cont 8 Obesity: Int 5: Cont 26 Obstructive pulmonary disease: Int 3: Cont 2 Cardiac insufficiency: Int 0: Cont 1 Malignancy: Int 1: Cont 1 Type of surgery: patients scheduled for elective hip replacement surgery

Type: LMWH (certoparin) Dose: 3000 IU plus 0.5 mg DHE injections Timing: started 2 hours before surgery and continued for at least 14 post-op days or longer if patient was still institutionalised Additional noncomparative prophylaxis: Not reported

Type: LMWH

Type: UFH

14 days

Dose: starting dose of 15000 IU/day was increased to a plateau value of 28,800 ± 7150 IU/day to maintain the activated partial thromboplastin time in the prescribed range injected subcutaneously daily.

DVT: confirmed by bilateral ascending venography Proximal DVT

Timing: started 2 hours before surgery and continued for at least 14 post-op or longer if the patient was still institutionalised Type: UFH

VTE total

4 weeks

Int: 17/142 Cont: 14/147 Int: 17/142 Cont: 13/147 Int: 0/142 Cont: 0/147

Distal DVT

Int: 15/142 Cont: 8/147

Proximal and distal DVT PE: confirmed by pulmonary scintigraphy

Int: 2/142 Cont: 5/147 Int: 0/142 Cont: 1/147 (non-fatal)

Bleeding wound

Int: 8/142 Cont: 6/147

Surgical reintervention (due to bleeding) VTE total

Int: 0/142 Cont: 1/147 Int: 9/125 Cont: 25/134

Comments

Open trial 305 patients randomised; 289 evaluated Also reported: intraoperative and post-operative blood loss, post-operative transfusions, revision of wound, haematoma at injection site, petechia

Financially supported by laboratories

59

Reference

Study type

Evidence Level

No of participants; and characteristics 298 patients Int: 149 Cont: 149

Perhoniemi 1996

RCT

II

Duration of surgery: Int: 110±55.1 Cont: 100±58.7 Age and gender: Int: Mean age 70.4±10.9 years: M/F 49/100 Cont: Mean age 70.5±9.2 years: M/F 45/104 Pre-existing risk factors: Previous DVT: Int: n = 4 Cont: n = 12; Previous PE: Int: n = 1 Cont: n = 3; Varicose veins: Int: n = 44 Cont: n = 46; Varicose ulcer: Int: n = 3 Cont: n = 6; Obesity: Int: n = 23 Cont: n = 27 165 patients Int: 80 Cont: 80 Type of surgery: patients over 40 requiring hip or knee (endoprosthesis or fracture) surgery Excluded patients: If trauma happened < 24 hours before admission Age and gender: Int: Mean age 72±8.6 years: M/F 22/58 Cont: Mean age 73.8±7.6 years: M/F 21/60

Intervention Dose and timing: one dose daily of subcutaneous LMWH (3500 IU bemiparin) plus placebo injection of 0.9% saline. Prophylaxis started 2 hours before surgery and continued for at least 8 post-operative days or longer if patient was still institutionalised

Comparison Dose and timing: 5000 units of calcium heparin injected subcutaneously twice daily. Prophylaxis started 2 hours before surgery and continued to at least 8 post-operative days or longer if patient was still institutionalised

Length of follow-up

Type: UFH plus DHE

Dose: 40 mg once per day

Dose: 5000 IU UFH and 0.5 mg DHE 2 times per day

Timing: Begun 12 hours before surgery and continued for 7 consecutive days

Timing: Begun 2 hours before surgery and continued for 7 consecutive days

Additional noncomparative prophylaxis: Spinal anaesthesia: 78/80

Additional noncomparative prophylaxis: Spinal anaesthesia: 72/80

Effect size

DVT: confirmed by bilateral elective venography Proximal DVT

Int: 9/101 Cont: 24/116

Distal DVT Proximal and distal DVT PE: confirmed by ventilation perfusion scan Patients transfused

Additional noncomparative prophylaxis: not reported Type: LMWH (enoxoparin)

Outcome measures

7 days

Int: 3/101 Cont: 5/116 Int: 4/101 Cont: 13/116 Int: 2/101 Cont: 6/116 Int: 1/125 Cont: 2/134

Wound haematomas

Int: 74/149 Cont: 66/149 Int: 8/149 Cont: 7/149

DVT: confirmed by Doppler US

Int: 1/80 Cont: 0/80

Comments Farmaceuticos Rovi S.A. (Madrid, Spain) who also supplied LMWH and UFH Also reported: operative blood loss, post-operative drain loss

165 patients randomised; 160 evaluated Not reported: Proximal DVT, PTS, QoL, LOS, major bleeds

PE (symptomatic): confirmed by isotope scintigraphy

Int: 0/80 Cont: 2/80

Also reported: duration of operation, volume of blood loss, volume of blood transfusion, haemoglobin values, number of haematomas (did not distinguish between major and minor)

60

Reference Senaran 2006

Study type RCT

Evidence Level II

No of participants; and characteristics Type of surgery: Hip arthroplasty 100 patients Int: 50 Cont: 50 Excluded patients: any history precluding anticoagulant therapy (i.e. blood dyscrasia, heparin induced thrombocytopenia, allergy to heparin) Age and gender: Int: Mean age 55.2±8.5 years: M/F 12/38 Cont: Mean age 52.4±11.2 years: M/F 17/33

Intervention Type: LMWH (enoxaparin) Dose: 40 mg once per day Timing: begun 12 hours before surgery and continued for 7-10 days Additional noncomparative prophylaxis: none reported

Comparison Type: UFH Dose: (5000 IU) 3 times per day Timing: begun 8 hours before surgery and continued for 7-10 days Additional noncomparative prophylaxis: none reported

Length of follow-up 6 weeks

Outcome measures DVT: confirmed by Doppler US

Effect size Int: 0/50 Cont: 2/50

Late DVT (symptomatic) at 6 weeks: confirmed by Doppler US PE (symptomatic): confirmed by ventilation perfusion scan or pulmonary angiography

Int: 2/50 Cont: 0/50

Major bleeding

Int: 2/50 Cont: 0/50

Comments

Int: 0/50 Cont: 0/50

61

Forest plot 12a: Major VTE Comparison of LMWH vs. UFH in total hip replacement

Forest plot 12b: All VTE Comparison of LMWH vs. UFH in total hip replacement

62

Forest plot 12c: Asymptomatic DVT Comparison of LMWH vs. UFH in total hip replacement LMWH UFH Study or Subgroup Events Total Events Total Weight 11.3.1 venography: blinded Haas 2006 Subtotal (95% CI)

87

494 494

Total events 87 Heterogeneity: Not applicable Test for overall effect: Z = 0.44 (P = 0.66)

82

Risk Ratio M-H, Fixed, 95% CI

495 495

66.0% 66.0%

1.06 [0.81, 1.40] 1.06 [0.81, 1.40]

147 147

10.3% 10.3%

1.35 [0.68, 2.68] 1.35 [0.68, 2.68]

116 116

18.0% 18.0%

0.43 [0.21, 0.88] 0.43 [0.21, 0.88]

79 80 50 209

3.2% 0.4% 2.0% 5.6%

0.25 [0.03, 2.19] 3.00 [0.12, 72.56] 0.20 [0.01, 4.06] 0.43 [0.11, 1.64]

967 100.0%

0.94 [0.75, 1.19]

Risk Ratio M-H, Fixed, 95% CI

82

11.3.2 venography: not blinded Horbach 1996 Subtotal (95% CI)

17

142 142

Total events 17 Heterogeneity: Not applicable Test for overall effect: Z = 0.87 (P = 0.39)

13 13

11.3.3 venography: blinding not known Kakkar 2000 Subtotal (95% CI)

9

101 101

Total events 9 Heterogeneity: Not applicable Test for overall effect: Z = 2.30 (P = 0.02)

24 24

11.3.4 ultrasound: blinding not known Avikainen 1995 Perhoniemi 1996 Senaran 2006 Subtotal (95% CI)

1 1 0

79 80 50 209

4 0 2

Total events 2 6 Heterogeneity: Chi² = 1.92, df = 2 (P = 0.38); I² = 0% Test for overall effect: Z = 1.24 (P = 0.22) Total (95% CI)

946

Total events 115 125 Heterogeneity: Chi² = 9.34, df = 5 (P = 0.10); I² = 46% Test for overall effect: Z = 0.49 (P = 0.62)

0.01 0.1 1 10 100 Favours LMWH Favours UFH

Forest plot 12d: Late DVT (symptomatic) Comparison of LMWH vs. UFH in total hip replacement

63

Forest plot 12e: Proximal DVT Comparison of LMWH vs. UFH in total hip replacement

64

Forest plot 12f: Distal DVT Comparison of LMWH vs. UFH in total hip replacement

Forest plot 12g: Proximal and distal DVT Comparison of LMWH vs. UFH in total hip replacement

65

Forest plot 12h: PE Comparison of LMWH vs. UFH in total hip replacement

Forest plot 12i: Death Comparison of LMWH vs. UFH in total hip replacement

66

Forest plot 12j: Adverse events hip & Knee Comparison of LMWH vs. UFH in total hip replacement

67

Forest plot 12k: Adverse events Comparison of LMWH vs. UFH in total hip replacement

68

Evidence summary 13. Total hip replacement: Fondaparinux vs. LMWH VTE There were significantly fewer VTE in the fondaparinux group compared with the LMWH group in 2 RCTs: RR 0.57 (95% CI 0.35 to 0.95) NNTB 25 (95% CI 14 to 100) DVT There were significantly fewer incidences of DVT in the fondaparinux group compared with the LMWH group in 2 RCTs: RR 0.55 (95% CI 0.35 to 0.85) NNTB 25 (95% CI 14 to 50) The reverse was true for symptomatic DVT: RR 5.66 (95% CI 1.00 to 32.03) (NNTB unable to be calculated); and no significant difference was seen for proximal DVT: RR 0.62 (95% CI 0.12 to3.27) PE No significant differences between fondaparinux and LMWH were seen for PE in 2 RCTs: RR 2.33 (95% CI 0.60 to 8.99) Death No significant differences between fondaparinux and LMWH were seen for death in 2 RCTs: RR 1.1 (95% CI 0.41 to 3.14) Adverse events There were significantly more instances of major bleeding in fondaparinux group compared with the LMWH group in 2 RCTs: RR 1.55 (95% CI 1.06 to 2.26) NNTH 100 (lower 95% CI 50); but none of the other adverse events reported showed significant differences in the 2 RCTs

I Lassen 2002 Turpie 2002

I Lassen 2002 Turpie 2002

I Lassen 2002 Turpie 2002

I Lassen 2002 Turpie 2002 I Lassen 2002 Turpie 2002

69

Evidence table 13. Total hip replacement: Fondaparinux vs. LMWH Reference Lassen 2002

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 2309 Int: n: 1154 (918) Cont: n: 1155 (908) Drop-outs (not treated): Int: 21 Comp: 15 Drop-outs (not available for analysis): Int: 214 Comp: 232

Patient groups Type of surgery: Patients scheduled for primary elective total hip-replacement surgery or revision of at least one component of a previously implanted total hip prosthesis. Duration of surgery: 2.4 hours, SD: ±0.83 Int: Mean age: 67, range: 24-97; M/F:402/517 Cont: Mean age: 67, range: 30-90; M/F:396/512 Pre-existing risk factors: History of VTE: Int: 40 (4%). Cont: 35 (4%) Orthopaedic surgery within the previous 12 months: Int: 84 (9%) Cont: 85 (9%)

Intervention LMWH: 40 mg of Enoxaparin 1x/day and placebo. The first active dose was given 12±2 hrs pre-operatively and the second 12 to 24 hours post-op. Treatment was scheduled to continue until day 5 to 9. Day of surgery is day 1. Additional noncomparative prophylaxis: The use of graduated compression stockings and physiotherapy was recommended No. patients receiving/using: GCS = 654/919 Anticoagulant or antiplatelet therapy (not aspirin) = 30/919 NSAIDs or aspirin: 493/919

Comparison 2.5 mg of Fondaparinux sodium and a placebo. The first active dose was given 6±2 hrs post-op and the second 12 or more after the first. Treatment was scheduled to continue until day 5 to 9. Day of surgery is day 1. Additional noncomparative prophylaxis: The use of graduated compression stockings and physiotherapy was recommended No. patients receiving/using: GCS = 649/908 Anticoagulant/antipl atelet therapy (not aspirin = 29/908 NSAIDs or aspirin: 483/908

Length of follow-up 49 days study period 11 days

Outcome measures DVT: confirmed by systematic bilateral ascending venography (number of events/ total number) VTE

Symptomatic DVT Proximal DVT*: confirmed by systematic bilateral ascending venography Non fatal PE: confirmed by lung scan, pulmonary angiography or helical computed tomography or at autopsy Fatal PE Major bleeding** Fatal bleeding

Effect size Int: 83/918 Cont: 36/908 p value: 30=48/111 (43.2%) BMI≤30=63/111 (56.8%) No of VTE out of total no. of BMI group BMI>30=48/837 (5.73%) BMI≤30 = 63/1959 (3.22%) Also reported: minor bleeding Not reported: PTS, LoS, QoL, fatal PE Funding: No direct funding for this study. Indirect funding (i.e. authors’ institution funding) Rhone Poulenc Rorer Pharmaceuticals

77

Reference

Study type

Evidence Level

No. of patients

Patient groups >30kg/m2 (32.3%) (BMI reported for 93.7% of this group) P=0.0055

Intervention how many patients received these

Comparison

Length of follow-up

Outcome measures Adverse events: Most commonly reported were fever, anaemia, nausea Serious adverse events Survival (specify)

Hull 2000

RCT

II ROB:

Total: 1501 Int: n=489 Cont: n=983

Type of surgery: Total hip replacement.

Type: warfarin Dose: INR 2-3 placebo heparin

Type: LMWH Dose: 2500-5000 IU subcutaneously placebo warfarin

Timing: night of surgery?

Timing:2500 IU + 2 hrs pre-op, 4h post-op, 5000 once daily

Additional noncomparative prophylaxis: none

Francis 1997

RCT

II ROB:

Total: 580 Int: n=292 Cont: n=288

Type of surgery: Total hip replacement.

Type: warfarin Dose: PT 1.41.5 Timing: pre-op night then once daily post-op to discharge Additional

Both groups: day 6+2

Clinical PE Death Major haemorrhage

Additional noncomparative prophylaxis: none Type: LMWH Dose: 5000 IU subcutaneously once daily Timing: two preop then once daily to discharge

Asymptomatic DVT: confirmed by bilateral venography on day 6+2 Proximal DVT

Wound haematoma Both groups: to discharge? DVT assessed mean day 7[2] post-op

Effect size Int: 934/1495 Cont: 987/1506 p value: 0.0870 Int: 134/1495 Cont: 167/1506 p value: 0.0128 Int: 1485/1495 Cont: 1497/1506 p value: 0.8226 Int: 81/338 Cont: 80/673

Comments

Int:11/363 Cont: 6/712 Int: 0/489 Cont: 0/983 Int: 2/489 Cont: 2/983 Int: 22/489 Cont: 76/983 p value Int: 62/489 Cont: 119/983

Method of randomisation: not known if list of random numbers closed or open

DVT: confirmed by venography

Int: 49/190 Cont: 28/192

Proximal DVT: confirmed by venography

Int: 16/190 Cont: 10/192

Major bleeds

Int: 4/190 Cont: 6/192

Source: NICE Patients, clinicians and DVT assessors blinded

DVT assessment blinded? Yes

Source: Mismetti 2004, Roderick 2005 Method of randomisation: not stated. DVT assessment blinded? Yes

Additional non-

78

Reference

Study type

Evidence Level

No. of patients

Patient groups

Intervention noncomparative prophylaxis: none

Comparison comparative prophylaxis: none

Length of follow-up

Outcome measures

Effect size

Comments Source: Mismetti 2004, Roderick 2005

79

Forest plot 14a: Asymptomatic DVT Comparison of LMWH vs. warfarin in total hip replacement LMWH warfarin Study or Subgroup Events Total Events Total Weight 55.1.1 venography: blinded Francis 1997 Hull 2000 Subtotal (95% CI)

28 80

192 673 865

49 81

190 31.4% 338 68.6% 528 100.0%

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

0.57 [0.37, 0.86] 0.50 [0.37, 0.66] 0.52 [0.41, 0.65]

108 130 Total events Heterogeneity: Chi² = 0.26, df = 1 (P = 0.61); I² = 0% Test for overall effect: Z = 5.54 (P < 0.00001) 528 100.0%

865

Total (95% CI)

0.52 [0.41, 0.65]

108 130 Total events Heterogeneity: Chi² = 0.26, df = 1 (P = 0.61); I² = 0% Test for overall effect: Z = 5.54 (P < 0.00001) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours LMWH Favours warfarin

Forest plot 14b: Proximal DVT Comparison of LMWH vs. warfarin in total hip replacement LMWH warfarin Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI 55.2.1 venography: blinded Francis 1997 Hull 2000 Subtotal (95% CI)

10 6

192 712 904

16 11

190 52.5% 363 47.5% 553 100.0%

Risk Ratio M-H, Fixed, 95% CI

0.62 [0.29, 1.33] 0.28 [0.10, 0.75] 0.46 [0.25, 0.83]

Total events 16 27 Heterogeneity: Chi² = 1.58, df = 1 (P = 0.21); I² = 37% Test for overall effect: Z = 2.59 (P = 0.010) Total (95% CI)

904

553 100.0%

0.46 [0.25, 0.83]

Total events 16 27 Heterogeneity: Chi² = 1.58, df = 1 (P = 0.21); I² = 37% Test for overall effect: Z = 2.59 (P = 0.010) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours LMWH Favours warfarin

Forest plot 14c: Symptomatic DVT Comparison of LMWH vs. warfarin in total hip replacement LMWH warfarin Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI 55.3.1 US or venography: blinding not known Colwell 1999 Subtotal (95% CI)

40 1506 1506

Total events 40 Heterogeneity: Not applicable Test for overall effect: Z = 0.48 (P = 0.63) Total (95% CI)

44 1495 100.0% 1495 100.0%

Risk Ratio M-H, Fixed, 95% CI

0.90 [0.59, 1.38] 0.90 [0.59, 1.38]

44

1506

Total events 40 44 Heterogeneity: Not applicable Test for overall effect: Z = 0.48 (P = 0.63) Test for subgroup differences: Not applicable

1495 100.0%

0.90 [0.59, 1.38]

0.01 0.1 1 10 100 Favours LMWH Favours warfarin

80

Forest plot 14d: Both DVT and PE Comparison of LMWH vs. warfarin in total hip replacement LMWH warfarin Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI 55.4.1 US or venography: blinding not known Colwell 1999 Subtotal (95% CI)

9 1506 1506

Total events 9 Heterogeneity: Not applicable Test for overall effect: Z = 1.64 (P = 0.10) Total (95% CI)

3 1495 100.0% 1495 100.0%

Risk Ratio M-H, Fixed, 95% CI

2.98 [0.81, 10.98] 2.98 [0.81, 10.98]

3

1506

1495 100.0%

2.98 [0.81, 10.98]

9 3 Total events Heterogeneity: Not applicable Test for overall effect: Z = 1.64 (P = 0.10) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours LMWH Favours warfarin

Forest plot 14e: PE Comparison of LMWH vs. warfarin in total hip replacement Study or Subgroup Colwell 1999 Hull 2000 Total (95% CI)

LMWH warfarin Events Total Events Total Weight 6 1506 0 983

9 1495 100.0% 0 489

0.66 [0.24, 1.85] Not estimable

1984 100.0%

0.66 [0.24, 1.85]

2489

6 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.79 (P = 0.43)

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

9 0.01 0.1 1 10 100 Favours LMWH Favours warfarin

81

Forest plot 14f: Adverse events Comparison of LMWH vs. warfarin in total hip replacement LMWH warfarin Study or Subgroup Events Total Events Total Weight 55.6.1 major bleeding Colwell 1999 Francis 1997 Hull 2000 Subtotal (95% CI)

9 1506 6 192 76 983 2681

4 1495 10.7% 4 190 10.7% 22 489 78.5% 2174 100.0%

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

2.23 [0.69, 7.24] 1.48 [0.43, 5.18] 1.72 [1.08, 2.73] 1.75 [1.16, 2.62]

Total events 91 30 Heterogeneity: Chi² = 0.24, df = 2 (P = 0.89); I² = 0% Test for overall effect: Z = 2.70 (P = 0.007) 55.6.2 wound haematoma Hull 2000 Subtotal (95% CI)

119

983 983

Total events 119 Heterogeneity: Not applicable Test for overall effect: Z = 0.32 (P = 0.75)

62

489 100.0% 489 100.0%

0.95 [0.72, 1.27] 0.95 [0.72, 1.27]

134 1495 100.0% 1495 100.0%

1.24 [1.00, 1.54] 1.24 [1.00, 1.54]

62

55.6.3 serious adverse events Colwell 1999 Subtotal (95% CI)

167 1506 1506

Total events 167 Heterogeneity: Not applicable Test for overall effect: Z = 1.93 (P = 0.05)

134

55.6.4 adverse events (e.g. fever, anaemia, nausea) Colwell 1999 Subtotal (95% CI)

987 1506 1506

Total events 987 Heterogeneity: Not applicable Test for overall effect: Z = 1.75 (P = 0.08)

934 1495 100.0% 1495 100.0%

1.05 [0.99, 1.11] 1.05 [0.99, 1.11]

934

0.01 0.1 1 10 100 Favours LMWH Favours warfarin

Forest plot 14g: Death Comparison of LMWH vs. warfarin in total hip replacement Study or Subgroup Colwell 1999 Hull 2000 Total (95% CI)

LMWH warfarin Events Total Events Total Weight 9 1506 2 983 2489

10 1495 2 489

Risk Ratio M-H, Fixed, 95% CI

79.0% 21.0%

0.89 [0.36, 2.19] 0.50 [0.07, 3.52]

1984 100.0%

0.81 [0.36, 1.82]

Total events 11 12 Heterogeneity: Chi² = 0.28, df = 1 (P = 0.59); I² = 0% Test for overall effect: Z = 0.51 (P = 0.61)

Risk Ratio M-H, Fixed, 95% CI

0.01 0.1 1 10 100 Favours LMWH Favours warfarin

82

Evidence summary 15. Total hip replacement: LMWH timing Asymptomatic DVT No significant difference between pre-operative and post-operative administration of LMWH was seen for asymptomatic DVT in one RCT: RR 1.14 (95% CI 0.74 to 1.76) PE No PE recorded (in one RCT) Bleeding No significant differences in major or minor bleeding were seen between pre-operative and post-operative administration of LMWH were seen (in one RCT): Major bleeding RR 1.87 (95% CI 0.88 to 3.97) Minor bleeding RR 1.26 (95% CI 0.60 to 2.62)

I Palareti 1996

I Palareti 1996 I Palareti 1996

83

Evidence table 15. Total hip replacement: LMWH timing Reference Palareti 1996

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 180 randomised (outcome for 131)

Patient groups Type of surgery: Elective hip replacement

Intervention Type: LMWH (nadroparin) begun pre-op

Int: n = 91 (65 assessed for VTE)

Duration of surgery: Int: 84.6±29.4 min Cont: 80.0±28.4 min

Dose: 7500 IU, 10000 IU

Cont: n = 89 (66 assessed for VTE)

Int: Mean age: 62.3±6.8 yrs M/F:26/65 Cont: Mean age: 61.3±7.6 yrs M/F:29/60 Pre-existing risk factors: age, obesity, varicose veins, previous VTE (no significant differences between groups).

Timing: 7500 units begun 12hrs pre-op and repeated daily until 3rd day post-op. Then 10000 units daily until for 14 days or until discharge. Additional noncomparative prophylaxis: Early mobilisation, graduated compression stockings, physical exercise

Comparison Type: LMWH (nadroparin) begun post-operatively Dose: 7500 IU, 10000 IU Timing: Placebo 12hrs pre-op, and then LMWH 7500 units begun eve post-op and repeated daily until 3rd day postop. Then 10000 units daily until discharge or for 14 days. Additional noncomparative prophylaxis: Early mobilisation, graduated compression stockings, physical exercise

Length of follow-up Both groups: 4-6 weeks post-op

Outcome measures DVT: confirmed by bilateral ascending venography on 10th15th post-op day, or earlier if symptomatic Proximal DVT: confirmed by bilateral ascending venography on 10th- 15th post-op day, or earlier if symptomatic PE: Not routinely assessed. Clinical suspicion investigated with V/Q scan Bleeding related complications

Effect size Int: 27/65 Cont: 24/66 p value: not significant

Major haemorrhage

Int: 2/90 Cont: 3/89 p value: not significant Int: 14/90 Cont: 11/89 p value: not significant

Minor haemorrhage: clinically evident but without *

Int: 7/65 Cont: 4/66 p value: Not significant Int: 0/90 Cont: 0/89 p value: N/A Safety analysis (179 patients. 1 patient excluded - wrong intervention)

Comments Comments: Multicentre study involving 7 orthopaedic departments. Across the whole study group, age was a significant risk factor for developing DVT. * intracranial, ocular (with reduction of viscous), articular, retroperitoneal, and/or associated with reduction of haemoglobin ≥ 2g/dl or a need to transfuse ≥ 2 U of blood Not reported: PTS, QoL, LoS, survival, Funding

84

Forest plot 15a: Asymptomatic DVT Comparison of LMWH timing in total hip replacement

Forest plot 15b: Proximal DVT Comparison of LMWH timing in total hip replacement

Forest plot 15c: PE Comparison of LMWH timing in total hip replacement

85

Forest plot 15d: Adverse events Comparison of LMWH timing in total hip replacement

86

Evidence summary 16. Total hip replacement: LMWH dose Asymptomatic DVT Significantly fewer DVT were seen for 60 mg/day versus 40 mg/day LMWH (Enoxaparin) in 2 RCTs: RR 0.50 (95% CI 0.32 to 0.79) Assuming a control rate of 20% NNTB 13 (95% CI 9 to 50) But no significant difference was seen for LMWH (Certoparin) 5000 v 3000 IU in one RCT Symptomatic DVT In one RCT, there were 2 symptomatic DVT in each group (Certoparin): RR 1.01 (95% CI 0.14 to 7.10) PE No significant difference between higher and lower doses was seen in the 2 Enoxaparin RCTs: RR 0.35 (95% CI 0.01 to 8.47) Death No significant difference between higher and lower doses was seen in the 2 Enoxaparin RCTs: RR 0.65 (95% CI 0.11 to 3.84) Adverse events No significant differences in major bleeding were seen between higher and lower doses of Enoxaparin in 2 RCTs: RR 1.87 (95% CI 0.88 to 3.97) major bleeding

I Colwell 1994 Spiro 1994 Adolf 1999

I Adolf 1999

I Colwell 1994 Spiro 1994 I Colwell 1994 Spiro 1994 I Colwell 1994 Spiro 1994

87

Evidence table 16. Total hip replacement: LMWH dose Reference Adolf 1999

Study type RCT

Evidence Level II

No. of patients Total: 341 Randomised

ROB: low Int: n = 169 Cont: n = 172 (81 exclusions, 34 intervention, 47 control).

Patient groups Type of surgery: Total hip replacement Randomised patients Int: Mean age: 67±11.7 yrs M/F:70/99 Randomised patients Cont: Mean age: 69±9.5 M/F:64/108 Pre-existing risk factors: Smoking 44/341 Previous DVT 29/341 Previous PE 5/341 Varicose veins 133/341 (no significant difference between groups).

Intervention Type: Increased dose LWMH (Certoparin) Dose: 5000 IU

Comparison Type: standard dose LMWH (Certoparin) Dose: 3000 IU

Timing: Begun at least 2 hours pre-op, then repeated daily until 12th- 14th day post-op

Timing: Begun at least 2 hours preop, then repeated daily until 12th14th day post-op

Additional noncomparative prophylaxis: none reported

Additional noncomparative prophylaxis: none reported

Length of follow-up Both groups: 1214 days post-op

Outcome measures DVT: confirmed by bilateral ascending venography on 12- 14th post-op day (earlier if symptomatic) Proximal DVT: confirmed by venography Symptomatic PE: Supposed to have been confirmed by V/Q scan but appears not to be case. Bleeding related complications: Transfusion Volumes (mean)

Multicentre RCT

II ROB: low

Total: 610 Multi-centre

Type of surgery: Hip replacement surgery, including

Int A: LMWH (Enoxaparin) Dose: 30mg

Int B: LMWH (Enoxaparin) Dose: 40mg once

Study period: 7 days

Int: 475±186 ml Cont: 770±136 p value: 0.2 Int A: 1/208 Int B: 2/199 Int C: 1/161 p value: A to B not given; A to C >0.2; B to C >0.2 Int A: 0/208 Int B: 2/199 Int C: 0/161 p value: not reported Int A: 10/208 Int B: 16/199 Int C: 13/161 p value: not reported Int A: 2/208 Int B: 2/199 Int C: 2/161 p value: not reported

patients evaluated for DVT. Multi-centre study, not all centres used a valid diagnostic technique (same numbers in each group). An intention to treat analysis was followed. Results are available for patients diagnosed by valid test alone as well as all patients. Other outcomes reported: Total proximal and distal DVT (i.e. confirmed by venography, supportive noninvasive vascular examinations or other clinical evidence of treatment failure.) thrombocytosis, haemoglobin levels, alanine aminiotransferase, minor bleeding Not reported: PTS, QoL Funding: Rhone Poulenc Pharmaceuticals

Source: NICE

90

Forest plot 16a: Asymptomatic DVT Comparison of LMWH dose in total hip replacement

Forest plot 16b: Proximal DVT Comparison of LMWH dose in total hip replacement

91

Forest plot 16c: Distal DVT Comparison of LMWH dose in total hip replacement

Forest plot 16d: Symptomatic DVT Comparison of LMWH dose in total hip replacement

92

Forest plot 16e: PE Comparison of LMWH dose in total hip replacement

Forest plot 16f: Death Comparison of LMWH dose in total hip replacement

93

Forest plot 16g: Adverse events Comparison of LMWH dose in total hip replacement

94

Evidence summary 17. Total hip replacement: extended duration LMWH vs. extended duration placebo DVT In a systematic review of six RCTs, there were significantly fewer DVT in the extended LMWH group compared with the extended duration placebo group: RR 0.41 (95% CI 0.32 to 0.54) NNTB 7 (95% CI 6 to 9) Proximal DVT There were also significantly fewer proximal DVT in these six RCTs: RR 0.31 (95% CI 0.20 to 0.47) NNTB 31 (95% CI 25 to 61) Symptomatic DVT There were also significantly fewer symptomatic DVT in these six RCTs: RR 0.36 (95% CI 0.20 to 0.67) NNTB 13 (95% CI 11 to 17) PE No cases of PE reported in the extended LMWH group compared with eight PE in the extended placebo group (two of these PE were fatal). Adverse events No differences were seen between extended LMWH and extended placebo for thrombocytopenia, major bleeding, minor bleeding or wound haematoma

I Hull 2001

I Hull 2001

I Hull 2001

I Hull 2001 I Hull 2001

95

Evidence table 17. Total hip replacement: Extended duration LMWH vs. extended duration placebo Reference Hull 2001

Study type SR of 6 RCTs (Bergqvist 1996, Planes 1996, Dahl 1997, Lassen 1998, Hull 2000b, Comp 2001)

Evidence Level I ROB: low

No. of patients Total: 1953 Int: 1091 Cont: 862

Patient groups Type of surgery: Elective hip replacement

Intervention Extended posthospital LMWH

Comparison Out of hospital Placebo

Enoxaparin (3 studies) Dalteparin (3 studies)

Five studies had LMWH prophylaxis in hospital followed by out of hospital placebo. The remaining study had a comparator group that received in hospital warfarin followed by out of hospital placebo.

Timing: pre-operatively in four studies and post-op in one study. The remaining study included separate randomly assigned groups for pre-operative and post-operative initiation of therapy. Additional noncomparative prophylaxis: GCS – some patients used in four studies.

Additional noncomparative prophylaxis: GCS – some patients used in four studies

Length of follow-up In hospital prophylaxis ranged from 6-14 days. Extended out of hospital duration ranged from 18-29 days.

Outcome measures DVT: confirmed by venography

Effect size 6 trials RR 0.41 95% CI 0.32 to 0.54)

PE

Int: 0/899 Cont: 8/884 (2 were fatal)

Symptomatic VTE (outside hospital)

6 trials RR 0.36 95% CI 0.20 to 0.67 6 trials RR 0.31 95% CI 0.20 to 0.47 Int: 5/1091 [0.46%(CI, 0.15% to 1.07%)] Cont: 3/862 [0.34% (CI, 0.07% - 1.01%)] p value: 1.000

Proximal DVT Thrombocytopenia

Major bleeding

Int: 0 Cont: 1

Minor bleeding

Int: 29 Cont: 21

Death

Int: 1 Cont: 3 Int: 12 Cont: 8

Wound haematoma (4 trials)

Comments Not reported: QoL, funding, PTS or LoS.

96

Forest plot 17a: DVT Comparison of extended duration LMWH vs. extended duration placebo in total hip replacement

Forest plot 17b: Proximal DVT Comparison of extended duration LMWH vs. extended duration placebo in total hip replacement

97

Forest plot 17c: Symptomatic DVT Comparison of extended duration LMWH vs. extended duration placebo in total hip replacement

98

Evidence summary 18. Total hip replacement: Extended duration UFH vs. extended duration placebo DVT In one small RCT, no significant difference was seen in the number of DVT between extended UFH and extended for: RR 0.57 (95% CI 0.18 to 1.81) Proximal DVT There was also no significant difference for proximal DVT: RR 0.17 (95% CI 0.02 to 1.37) Major bleeding No instances of major bleeding were reported in either the extended UFH or extended placebo group

I Manganelli 1998

I Manganelli 1998 I Manganelli 1998

99

Evidence table 18. Total hip replacement: Extended duration UFH vs. extended duration placebo Reference Manganelli 1998

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 79 randomised Int: n = 33 Cont: n = 28 18 withdrawals (8 intervention, 10 control).

Patient groups Type of surgery: Elective total hip replacement Mean age: Int: 65±8.2 years Cont: 66.2±11.5 years M/F: Int: 10/23 Cont:15/23 Pre-existing risk factors: Obesity (no significant differences between groups)

Intervention Type: Extended duration unfractionated heparin Dose: 5000 IU

Comparison Type: unfractionated heparin

Timing: 5000 IU from 1 day pre-op, every 8hrs for 30 days

Timing: 5000 IU from 1 day pre-op, every 8hrs until discharge

Additional noncomparative prophylaxis: Not reported

Dose: 5000 IU

Length of follow-up Both groups: 45 days post-op

Outcome measures DVT: confirmed by unilateral ascending venography on 45th day post-op (earlier if symptomatic) Proximal DVT: confirmed by unilateral ascending venography on 45th day post-op (earlier if symptomatic) Major haemorrhage: clinically overt and associated with a decrease in haemoglobin values of 2g/dl or more, compared with the last post-op value, or a need for blood transfusion, or if it was retroperitoneal or intracranial Length of hospital stay

Effect size Int: 4/33 Cont: 6/28 p value: 0.48

Comments Comments: Patients randomised at discharge. 2 patients had objectively confirmed PE, but the paper does not report the study group these patients were in.

Int: 1/33 Cont: 5/28 p value: 0.08 Int: 0/33 Cont: 0/33 p value: N/A

Not reported: PE, PTS, QoL, Survival, funding

Int: 12±2 days Cont: 12±3 days p value: not significant

100

Source: NICE

Evidence summary 19. Total hip replacement: Warfarin vs. no warfarin Asymptomatic DVT No significant difference was seen between warfarin and no warfarin in 2 RCTs Adverse events No significant difference in number of wound haematomas was seen between warfarin and no warfarin in one RCT

I Fordyce 1991 Hume 1973b I Hume 1973b

101

Evidence table 19. Total hip replacement: Warfarin vs. no warfarin Reference Hume 1973

Study type RCT

Evidence Level II ROB: mod

No. of patients Total: 36 Int: n=17 Cont: n=19

Patient groups Type of surgery: Total hip replacement.

Intervention Type: warfarin Dose: adjusted 1.5 PTT

Comparison No treatment

Timing: recovery room to time not stated.

Fordyce 1991

RCT

II ROB: low

Total: 148 Int: n=74 Cont: n=74

Type of surgery: Total hip replacement.

Outcome measures DVT: confirmed by FUT

Wound haematoma

Additional noncomparative prophylaxis: GCS

Additional noncomparative prophylaxis: GCS

Type: warfarin Dose: fixed low dose

No treatment

Timing: 1 week pre-op and 3 weeks post-op Additional noncomparative prophylaxis: none

Length of follow-up Both groups: to discharge

Additional noncomparative prophylaxis: none

Effect size Int: 10/17 Cont: 8/19

Int: 6/17 Cont: 1/19

Comments DVT assessment blinded? not stated Method of randomisation: not stated PE not reported.

Source: Mismetti 2004 Asymptomatic DVT: confirmed by FUT on day 1-14 postop/discharge

Int: 25/74 Cont: 19/74

Symptomatic DVT

Int: 6/74 Cont: 5/74

DVT assessment blinding not stated. Randomisation by pharmacy coded container administered sequentially

Source: Roderick 2005

102

Forest plot 19a: Asymptomatic DVT Comparison of warfarin vs. no warfarin in total hip replacement

Forest plot 19b: Adverse events Comparison of warfarin vs. no warfarin in total hip replacement

103

Evidence summary 20. Total hip replacement: Warfarin vs. aspirin Asymptomatic DVT No significant difference was seen between warfarin and aspirin in 2 RCTs PE No significant difference was seen between warfarin and aspirin in 2 RCTs Bleeding No significant difference in bleeding related comparisons was seen between warfarin and aspirin in one RCT

I Harris 1974 Lotke 1996 I Lotke 1996 Woolson 1991 I Lotke 1996

104

Evidence table 20. Total hip replacement: Warfarin vs. aspirin Reference Harris 1974

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 187 randomised. Results for 168 Int 1: n=55 Int 2: n=62 Cont: n=51

Patient groups Type of surgery Total hip replacement. Int 1: Mean age 58.4 yrs [SD – NR] M/F 35/26 Int 2: Mean age 55.5 yrs [SD – NR] M/F 21/29 Pre-existing risk factors: Obesity (no significant difference between groups)

Lotke 1996

RCT

II ROB: low

Total: 388 (76 exclusions) Int: n=146 Cont: n=166

Type of surgery: Total hip or knee arthroplasty Int: Mean age: 67.1

Intervention Int 1: Type: adjusted dose Warfarin Dose: 5mg pre-op then adjusted PTT 1.5x control (or for 18 secs) Int 2: Type: LMW Dextran 10% w/v Dose: 500mL Duration all interventions: Continued until the patient was fully ambulatory and ready for discharge Additional noncomparative prophylaxis: All patients wore stockings during and post-surgery, leg elevation, foot and ankle exercises. Type: adjusted dose Warfarin Dose: 10mg pre-op then PTT 1.2 – 1.5 x control

Comparison Type: Aspirin Dose: 1200mg Duration: continued until the patient was fully ambulatory and ready for discharge

Length of follow-up All groups: until discharge

Proximal DVT confirmed by venography, 125Ifibrinogen uptake test

Additional noncomparative prophylaxis: All patients wore stockings during and postsurgery, leg elevation, foot and ankle exercises.

Type: Aspirin Dose: 325mg twice daily

Outcome measures DVT: confirmed by venography, 125I-fibrinogen uptake test

Length of hospital stay

Both groups: 910 days post-op. All patients observed for

DVT: confirmed by venography (ipsilateral) on 7th – 9th day post-op

Effect size Int 1: 10/55 Int 2: 14/62 Cont: 18/51 p value: no sig diff between groups Int 1: 3/55 Int 2: 8/62 Cont: 10/51 p value: no sig diff between groups Mean (all groups) 21 days (no significant difference between groups)

Int: 78/146 Cont: 100/166 p value: Not significant

Comments Fourth group of patients received LDUH. This arm excluded due to a change in dose after 12 patients and then discontinued after 20 patients. 2 patients in the dextran group received a clinical diagnosis of PE. Multiple thrombi were significantly more common in patients receiving aspirin than either warfarin or dextran. Funding: Not reported. Source: NICE

Comments: No difference in size or location of clots between study groups. Patients with TKR had 2.6 x incidence of calf DVT

105

Reference

Study type

Evidence Level

No. of patients

Patient groups yrs (SD not reported) M/F: 121/91 across both groups Cont: Mean age: 66.4yrs (SD not reported) M/F: 121/91 across both groups

Intervention Timing: 10mg eve before operation. Then adjusted dose from 2nd day postop

Comparison Timing: Begun on day of admission

Additional noncomparative prophylaxis: not reported

Additional noncomparative prophylaxis: Not reported

Length of follow-up 6 months

Outcome measures Proximal DVT: confirmed by venography (ipsilateral) on 7th – 9th day post-op

Effect size Int: 18/146 Cont: 16/166 p value: not significant

Distal DVT: confirmed by venography (ipsilateral) on 7th-9th day postop

Small: 42/146 Cont: 45/166 p value: Not significant

PE: confirmed by V/Q scan on 8th-10th day postop

High probability V/Q scan Int: 12/146 Cont: 16/166 p value: not significant Int: 7/146 Cont: 6/166 p value: not significant

Bleeding related complications: prolonged wound drainage (requiring immobilisation, attention in rehabilitation for wound problems, or surgical evacuation)

Comments than THR. Larger no of TKRs in aspirin group, but subgroup analyses showed no difference in DVT. Not reported: Fatal PE, PTS, QoL, Survival, LoS

Large: 18/146 Cont: 39/146 p value: not significant

Source: NICE

106

Reference Woolson 1991

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 196 patients 217 operations

Patient groups Type of surgery: THR (primary or revision)

Int 1: 69 pts and operations

Int 1: ave age: 67.9 M/F 31/38

Int 2: 73 pts and 76 operations

Int 2: ave age: 66.3 M/F 27/66

Cont: 70 pts and 72 operations (see comments)

Cont: ave age: 62.3 M/F 35/35 Pre-existing risk factors: Intervention: history of DVT 10/69, varicose veins 9/69 Cont: history of DVT 4/72, varicose veins 5/72

Intervention Int 1: Type: Warfarin plus IPCD plus GCS Dose: 7.5 or 10mg on evening before surgery, then adjusted to maintain prothrombin time between 14 and 16 seconds Int 2: Type: Thigh-length Intermittent pneumatic compression and graduated elastic stockings Timing: Warfarin started evening before surgery, IPCD and stockings started at surgery, both continued until discharge

Comparison Type: Aspirin plus IPCD plus GCS Dose: 650mg twice per day

Timing: started evening before surgery and until discharge Additional noncomparative prophylaxis: Not reported

Length of follow-up Intervention until discharge, followed up for 3 months

Outcome measures Proximal DVT : confirmed by venography or ultrasonography

Effect size Int1: 6/69 Int2: 9/76 Cont: 7/72 p value: not significant

Symptomatic PE: confirmed by ventilation or perfusion scan*

Int1: 0/69 Int2: 0/76 Cont: 1/72 p value: not significant

Total blood loss (ml)

Int1:1564(n=69) Int2:1539(n=76) Cont: 1595(n=72) p value: not significant

Total blood replacement (units)

Int1: 2.8 (n=69) Int2: 2.7 (n=76) Cont: 2.9 (n=72) p value: not significant

LoS (days)

Int1: 9 (n=69) Int2: 10 (n=76) Cont: 9 (n=72) p value: not significant

Comments Out of 196 patients, 20 had bilateral hip replacement, 1 had both procedures in the same operation, 18 had at least one week between procedures, 1 had bilateral procedure and a revision at a later date. All of these are included in the total to make 217 operations. *DVT screened whilst in hospital, symptomatic PE followed for 3 months. Not reported: all DVT, QoL, PTS, survival Also reported: Symptomatic DVT by operation, prothrombin time Funding: reports: no commercial funding

107

Forest plot 20a: Asymptomatic DVT Comparison of warfarin vs. aspirin in total hip replacement

Forest plot 20b: Proximal DVT Comparison of warfarin vs. aspirin in total hip replacement

Forest plot 20c: Distal DVT Comparison of warfarin vs. aspirin in total hip replacement

108

Forest plot 20d: PE Comparison of warfarin vs. aspirin in total hip replacement

Forest plot 20e: Adverse events Comparison of warfarin vs. aspirin in total hip replacement

109

Evidence summary 21. Total hip replacement: IPC vs. no treatment Asymptomatic DVT Significantly fewer asymptomatic DVT were detected in the IPC group compared with no treatment in one study: RR 0.51 (95% CI 0.37 to 0.69) NNTB 4 (95% CI 3 to 6) Proximal DVT Significantly fewer proximal DVT were detected in the IPC group compared with no treatment in one study: RR 0.57 (95% CI 0.36 to 0.90) NNTB 7 (95% CI 4 to 33) PE No significant difference in PE (either fatal or non fatal) detected in one study: RR 1.04 (95% CI 0.07 to 16.47)

I Hull 1990

I Hull 1990

I Hull 1990

110

Evidence table 21. Total knee replacement: IPC vs. no treatment Reference Hull 1990

Study type RCT

Evidence Level II ROB:

No. of patients Total: 310 Int: n=152 Cont: n=158

Patient groups Type of surgery: Total hip replacement.

Intervention Type: IPC

Comparison No treatment

Dose: Thighlength sequentially

Additional noncomparative prophylaxis: none

Timing: post-op to discharge/day 14 Additional noncomparative prophylaxis: none

Length of follow-up

Outcome measures DVT Proximal DVT Non-fatal PE Fatal PE All PE

Effect size Int: 36/124 Cont: 77/136 Int: 22/124 Cont: 42/135 Int: 0/152 Cont: 1/158 Int: 1/152 Cont: 0/158 Int: 1/152 Cont: 1/158

Comments

Source: Roderick 2005

111

Forest plot 21a: Asymptomatic DVT Comparison of IPC vs. no treatment in total hip replacement Study or Subgroup Hull 1990

IPC No treatment Events Total Events Total Weight 36

124

77

124

Total (95% CI)

Risk Ratio M-H, Fixed, 95% CI

134 100.0%

0.51 [0.37, 0.69]

134 100.0%

0.51 [0.37, 0.69]

36 77 Total events Heterogeneity: Not applicable Test for overall effect: Z = 4.30 (P < 0.0001)

Risk Ratio M-H, Fixed, 95% CI

0.01

0.1 1 10 100 Favours IPC Favours no treatme

Forest plot 21b: Proximal DVT Comparison of IPC vs. no treatment in total hip replacement Study or Subgroup Hull 1990

IPC No treatment Events Total Events Total Weight 22

124

42

124

Total (95% CI)

22 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.42 (P = 0.02)

Risk Ratio M-H, Fixed, 95% CI

135 100.0%

0.57 [0.36, 0.90]

135 100.0%

0.57 [0.36, 0.90]

Risk Ratio M-H, Fixed, 95% CI

42 0.01

0.1 1 10 100 Favours IPC Favours no treatme

Forest plot 21c: PE Comparison of IPC vs. no treatment in total hip replacement Study or Subgroup 46.4.1 any PE Hull 1990 Subtotal (95% CI)

IPC No treatment Events Total Events Total Weight 1

152 152

1 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.03 (P = 0.98)

1

Risk Ratio M-H, Fixed, 95% CI

158 100.0% 158 100.0%

1.04 [0.07, 16.47] 1.04 [0.07, 16.47]

158 100.0% 158 100.0%

0.35 [0.01, 8.44] 0.35 [0.01, 8.44]

158 100.0% 158 100.0%

3.12 [0.13, 75.94] 3.12 [0.13, 75.94]

Risk Ratio M-H, Fixed, 95% CI

1

46.4.2 non-fatal PE Hull 1990 Subtotal (95% CI)

0

152 152

0 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.65 (P = 0.52)

1 1

46.4.3 fatal PE Hull 1990 Subtotal (95% CI)

1

152 152

Total events 1 Heterogeneity: Not applicable Test for overall effect: Z = 0.70 (P = 0.49)

0 0

0.01 0.1 1 10 100 Favours GCS Favours no treatmen

112

Evidence summary 22. Total hip replacement: Warfarin timing Proximal DVT No significant differences in proximal DVT were seen for warfarin started four days pre-operatively compared with one day pre-operatively Bleeding No significant differences in blood loss were seen for warfarin started four days pre-operatively compared with one day preoperatively

I Swiestra 1988

I Swiestra 1988

113

Evidence table 22. Total hip replacement: Warfarin timing Reference Swierstra et al. 1988

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 101 Int: n=50 Cont: n=51

patient groups Type of surgery: THR Mean duration of surgery: (mins) Int: 178±34 Cont: 175±27 Mean age: Int: 66±11 years Cont: 66±10 years M/F: Int: 13/37 Cont: 7/44 Pre-existing risk factors: previous history of VTE, varicosis

Intervention Type: Acenocoumarol starting 4 days preop

Comparison Type: Acenocoumarol Dose: 3mg preop then INR 2.1

Dose: 3mg pre-op then INR 2.1

Timing: 3mg 1 day pre-op and day of op, then adjusted dose INR 2.1 until discharge

Timing: Begun 4 days pre-op. 3mg daily on 4th & 3rd day pre-op then adjusted dose aiming for INR of 1.5-1.6 during surgery. Post-op adjusted dose, INR 2.1 until discharge Additional noncomparative prophylaxis: None reported

Additional noncomparative prophylaxis: none reported

Length of follow-up Both groups: to discharge

Outcome measures Proximal DVT: confirmed by venography (99mTc plasmin), 10 days post-op Bleeding related complications Peri-operative blood lossamount of blood in suction apparatus, weight of gauzes. Post operative blood loss – contents of drain bottles. No of blood transfusions

Effect size Int: 12/50 Cont: 11/51 p value: Not significant

Peri-operative blood loss: Int: 1.11±0.52 L Cont: 1.2±0.62 L p value: Not significant Postoperative blood loss: Int: 0.6±0.41 L Cont: 0.58±0.33L p value: Not significant

Comments Comments: Unclear how many patients were randomised and how many of these were excluded. 17 intervention and 22 control patients used NSAIDs. Analysis showed no relationship between NSAID use and development of Proximal DVT Not reported: calf vein thrombi, PE, PTS, QoL, LoS, survival, funding Source: NICE

114

Evidence summary 23. Total hip replacement: Warfarin duration DVT There were significantly fewer DVT in the warfarin extended 4 weeks post discharge compared with the warfarin until discharge group: RR 0.12 (95% CI 0.02 to 0.95) NNTB 25 (95% CI 14 to 100) PE No PE were reported in the extended warfarin group with one PE (non-fatal) reported in the non-extended group Major bleeding One case of major bleeding was reported in the extended warfarin group with no cases in the non-extended group

I Prandoni 2002

I Prandoni 2002 I Prandoni 2002

115

Evidence table 23. Total hip replacement: Warfarin duration Reference Prandoni et al. 2002

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 360 Int: n=184 Cont: n=176

Patient groups Type of surgery: Total hip arthroplasty. Median age: Int: 68 years (range: 48-82 years) Cont: 69 years (range: 44-87 years) M/F: Int: 83/101 Cont: 79/97

Intervention Type: Extended warfarin Dose: 5mg pre-op then adjusted dose INR 2.0 - 3.0 Timing: 5mg 2nd day pre-op then adjusted dose INR 2.0 – 3.0 continued for 4 weeks Additional noncomparative prophylaxis: not reported

Comparison Type: Warfarin Dose: 5mg pre-op then adjusted dose INR 2.0 – 3.0 Timing: 5mg 2nd day preop then adjusted dose INR 2.0 – 3.0 until discharge (mean 9 days) Additional noncomparative prophylaxis: not reported

Length of follow-up Both groups: 4 weeks. Patients observed for further 2 months

Outcome measures Proximal DVT: confirmed by bilateral Doppler US of proximal venous system at 1, 2 & 4 weeks post op

Effect size Int: 1/184 Cont: 8/176 (3 symptomatic)

PE: not routinely assessed. Symptomatic PE confirmed by V/Q, spiral CT or angiography

Int: 0/184 Cont: 1/176

Fatal PE: confirmed by autopsy or where PE could not be ruled out

Int: 0/184 Cont: 0/176 p value: not reported Int: 1/184 Cont: 0/176

Major bleeding Defined as 1. clinically overt & associated with either a decrease in haemoglobin of at least 2.0g/dL or requiring transfusion of 2 or more units red blood cells 2. Intracranial or retroperitoneal 3. resulted in permanent discontinuation of anticoagulation

Comments Comments: Study prematurely terminated after 360 patients because of statistically significant and clinically relevant superiority of extended over short-term prophylaxis observed. 3 patients from each group violated protocol, but ITT analysis performed. In the following 2 months 2 symptomatic VTE events occurred in intervention group. Not reported: Distal DVT, PTS, QoS, LoS, funding

Source: NICE

116

Evidence summary 24. Total hip replacement: Warfarin dose (adjusted vs. fixed) DVT There were significantly fewer DVT with adjusted dose warfarin compared with fixed dose warfarin: RR 0.53 (95% CI 0.31 to 0.90) NNTB 14 (95% CI 10 to 67), assuming a control event rate of 15% Proximal DVT No significant differences were seen between adjusted and fixed dose warfarin for proximal DVT in one RCT: RR 0.36 (95% CI 0.12 to 1.09) PE No PE reported in one trial and one fatal PE reported in the adjusted dose group of the other RCT Major bleeds In one RCT there were no major bleeds in the adjusted dose group and two in the fixed dose group

I Bern 2002 Feller 1992

I Feller 1992

I Bern 2002 Feller 1992 I Feller 1992

117

Evidence table 24. Total hip replacement: Warfarin dose (adjusted vs. fixed) Reference Bern et al. 2002

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 98 (20 excluded) Int: n=43 Cont: n=35

patient groups Type of surgery: unilateral THR (for degenerative disease) Int: (49 patients randomised) Mean age: 61.9 Range: 31-91 yrs M/F: 25/24 Cont: (49 patients randomised) mean age: 65.3 Range: 29-84yrs M/F: 30/19

Intervention Type: adjusted dose warfarin Dose: 5mg preop, the PT 1.3-1.5 x normal Timing: 5 mg eve pre-op, then adjusted dose until 6th week Additional noncomparative prophylaxis: stockings. 23/49 originally randomised received dextran intra-operatively

Comparison Type: fixed low-dose warfarin Dose: 1 mg Timing: begun 7 days pre-op and continued until 6th week Additional noncomparative prophylaxis: stockings. 29/49 originally randomised received dextran intraoperatively

Length of follow-up Both groups: 6 weeks postop

Outcome measures DVT: confirmed by Doppler duplex US at discharge or 7 days post-op and repeated at 6 wks FU

Effect size Int: 0/43 Cont: 0/35

PE: not routinely assessed. Clinical suspicion investigated with V/Q and angiogram

Int: 0/43 Cont: 0/35

Bleeding related complications

Peri-operative blood loss mean (range) Int: 625 (200 – 2,250) Cont: 557 (200 – 1400) p value: not significant Transfusions given mean (range) Int; 2.4 (0-5) Cont: 2.3 (0-5) p value: not significant

Comments Comments: 6 patients excluded from adjusted dose and 14 from fixed dose group. Difference in withdrawals due to 8 patients. 1 withdrawal from each group developed DVT Not reported: Proximal DVT, PTS, QoL, Survival, LoS Funding: Study supported by donations to the Foundation for Haematology Research, and residual funds from previous grant from Dupont Pharmaceuticals Company (Wilmington, DE)

Source: NICE

118

Reference Feller 1992

Study type RCT

Evidence Level II ROB: mod

No. of patients Total: 200 Int: n=100 Cont: n=100

patient groups Type of surgery: Total hip replacement.

Intervention Type: warfarin Dose: adjusted INR 2-4

Comparison Type: warfarin Dose: fixed dose 1mg

Timing: night preop to day 3 postop (fixed) then adjusted

Timing: night pre-op to day 14 post-op

Additional noncomparative prophylaxis: calf stimulation

Additional noncomparative prophylaxis: calf stimulation

Length of follow-up Both groups:

Outcome measures DVT: confirmed by: venography on day 11-13 post-op (once) Proximal DVT Non-fatal PE

Effect size Int: 16/98 Cont: 30/97 Int: 4/98 Cont: 11/97 Int: 0/100 Cont: 0/100

Fatal PE

Int: 1/100 Cont: 0/100

All PE: assessed by scan

Int: 1/100 Cont: 0/100

Major bleeds

Int: 0/100 Cont: 2/100

Comments DVT assessment not blinded and PE assessment blinding not stated. Randomisation by sealed not opaque envelopes

Source: Roderick 2005

119

Forest plot 24a: DVT Comparison of warfarin dose (adjusted vs. fixed) in total hip replacement adjusted dose fixed dose Study or Subgroup Events Total Events Total Weight 19.1.1 US: blinding not reported Bern 2002 Subtotal (95% CI)

0

43 43

Total events 0 Heterogeneity: Not applicable Test for overall effect: Not applicable

0

35 35

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

Not estimable Not estimable

0

19.1.2 venography: blinded Feller 1992 Subtotal (95% CI)

98 98

30

Total events 16 Heterogeneity: Not applicable Test for overall effect: Z = 2.33 (P = 0.02)

30

Total (95% CI)

16

141

16 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.33 (P = 0.02) Test for subgroup differences: Not applicable

97 100.0% 97 100.0%

0.53 [0.31, 0.90] 0.53 [0.31, 0.90]

132 100.0%

0.53 [0.31, 0.90]

30 0.5 0.7 1 1.5 2 Favours adjusted dose Favours fixed dose

120

Evidence summary 25. Total hip replacement: GCS plus fondaparinux vs. fondaparinux DVT No significant differences were seen between the GCS plus fondaparinux group and the fondaparinux group: RR 0.87 (95% CI 0.48 to 1.896) VTE No significant difference was seen between GCS plus fondaparinux compared with fondaparinux alone for combined VTE and sudden death, any VTE or any DVT in one RCT: RR 0.51 (95% CI 0.24 to 1.07) Adverse events In the same RCT, no differences were seen between the groups for major or minor bleeding: RR 0.34 (95% CI 0.01 to 8.35) major bleeding

I Cohen 2007

I Cohen 2007

I Cohen 2007

121

Evidence table 25. Total hip replacement: GCS plus fondaparinux vs. fondaparinux Reference Cohen 2007

Study type RCT

Evidence level II

No. of patients 856 randomised (795 evaluated) Int: (n=395) Cont: (n=400)

Patient groups Surgery: primary or revision total hip replacement (n=721); or fracture of the proximal third of the femur (n=74) 18 years or older Exclusions: bilateral joint surgery, multiple trauma, delay > 24 hours between trauma and admission, conditions precluding use of GCS, leg oedema, PVD, peripheral neuropathy, marked leg deformity, conditions increasing bleeding risk, pregnant/lactating women, women of reproductive age taking inadequate contraceptive precautions

Intervention GCS plus Fondaparinux GCS applied preoperatively and worn for a mean 42 days (range 35 to 49) – usually long-leg; Fondaparinux 2.5 mg daily, given postoperatively for 5-9 days; first dose given 6 hours after wound closure

Comparison Fondaparinux 2.5 mg daily, given postoperatively for 59 days; first dose given 6 hours after wound closure

Length of follow-up Mean 42 days (range 35 to 49)

Outcome measures VTE or sudden death (by day 42) – THR patients only

Effect size Int:10/358 Cont: 20/363

VTE* (symptomatic and asymptomatic together)

Int:1/395 Cont: 1/400

Death (VTE related)

Int: 0/395 Cont:0/400

DVT

Int:19/395 Cont: 22/400

Bleeding (major)

Int:0/391 Cont: 1/404

Bleeding (minor)

Int: 25/391 Cont: 29/404

Comments Randomised by sealed envelope *VTE defined as at least one of: objectively verified, symptomatic TE (proximal or distal DVT or fatal or nonfatal PE), or asymptomatic proximal DVT demonstrated by bilateral proximal ultrasound or venography.

122

Evidence summary 26. Total hip replacement: Foot pump vs. UFH plus aspirin Asymptomatic DVT No significant difference between foot pump (with or without UFH plus aspirin) compared with UFH plus aspirin alone (in one RCT): RR 0.09 (95% CI 0.01 to 1.56) PE In one RCT there were no PE reported in the foot pump arms and one PE (nonfatal) was reported in the UFH plus aspirin arm

I Stannard 1996

I Stannard 1996

123

Evidence table 26. Total hip replacement: Foot pump vs. UFH plus aspirin Reference Stannard et al. 1996

Study type RCT

Evidence Level II

No. of patients Total: 75 Int 1: 25 Int 2: 25 Cont: 25

Patient groups Type of surgery: uncemented total hip arthroplasty Duration of surgery: Int 1: mean 106 (85-128 mins); Int2: mean 113 (15135) mins; Cont: mean 111 (87-140) mins; Intervention1: Mean age: 68.7 (range 4886) yrs M/F: not reported Intervention2: Mean age: 65(range 51-79) yrs M/F: not reported Cont: Mean age: 69.7 (range 28-86) yrs M/F: not reported

Intervention Intervention 1: Type: Bilateral foot pump (PlexiPulse) plus LDUH plus aspirin Dose: FOOT PUMP 16 hrs/day for first 3 days, then 12 hrs/day; LDUH 5000U; Aspirin 325mg Intervention 2: Type: Bilateral foot pump 16hrs/day for first 3 days, then 12hrs/day Timing: FOOT PUMP begun immediately postsurgery and continued until end of study; LDUH begun 12hrs pre surgery and every 12hrs for first 3 days post-surgery, the aspirin 3x daily until end of study

Comparison Type: LDUH plus aspirin Dose: LDUH 5000U; Aspirin 325 mg Timing: LDUH begun 12hrs for first 3 days postsurgery, then aspirin 3x daily until end of study Additional prophylaxis: Spinal anaesthesia 21/25

Length of follow-up 2 weeks post-op

Outcome measures DVT: confirmed by Doppler US, positive scans confirmed by venography

Effect size Int1: 0/25 Int2: 0/25 Cont: 5/25 p value = 0.10 (not significant)

PE: not routinely screened for. No confirmatory tests reported

Int1: 0/25 Int2: 0/25 Cont: 1/25 p value: not reported

Bleeding related complications surgical wound drainage - time taken for wound to seal (no. days post op)

Int1: 5.9 days Int2: 3.8 days Cont: 6.2 days p value = 0.05 (significant)

Survival

Int1: 25/25 Int2: 25/25 Cont: 25/25 p value: not significant

Comments 3/5 DVT were symptomatic. 1 PE was symptomatic. 4/5 patients who developed DVT had spinal anaesthesia. Two patients reported as excluded from study due to abnormal pre-op US findings. Does not report to which group(s) they belonged Not reported: LoS, QoL, PTS, proximal DVT Funding: Not reported

Additional prophylaxis: Spinal anaesthesia: 22/25

124

Forest plot 26a: Asymptomatic DVT Comparison of foot pump vs. UFH plus aspirin in total hip replacement

Forest plot 26b: PE Comparison of foot pump vs. UFH plus aspirin in total hip replacement

Forest plot 26c: Mortality Comparison of foot pump vs. UFH plus aspirin in total hip replacement

125

Evidence summary 27. Total hip replacement: IPC vs. UFH DVT Compared with UFH, there were significantly fewer DVT for IPC: RR 0.38 (95% CI 0.19 to 0.76) NNTB 5 (95% CI 3 to 13) ‘Major’ proximal DVT Compared with UFH, there were significantly fewer DVT for IPC: RR 0.18 (95% CI 0.04 to 0.77) NNTB 7 (95% CI 4 to 25)

I Santori 1994

I Santori 1994

126

Evidence table 27. Total hip replacement: IPC vs. UFH Reference Santori 1994

Study type RCT

Evidence Level II ROB: low

No. of patients Total: 132 Int: n = 67 Cont: n = 65

patient groups Type of surgery: Patients undergoing total hip replacement. All patients had compression stockings after operation Excluded: history of VTE, varicose veins, venous insufficiency in the legs, malignant neoplasm Int: Mean age: 72.4±6.65 M/F:19/48 Control Mean age: 69.8±6.22 M/F:15/50 Pre-existing risk factors: Not reported

Intervention Type: Intermittent plantar foot pump (aka impulse group) on both feet immediately after the operation and used for 7 to 10 days. When patients started walking at postoperative day 4 or 5 the foot pump was only used when the patient was in bed. Additional prophylaxis: GCS on both legs after operation. Neither the length nor for how long they were worn was stated. Physiotherapy with mobilisation started on 2nd postoperative day. Walking began on 4th or 5th postoperative day

Comparison Type: Calcium heparin. 5000 Units 3x per day for 10 days starting on the day before the operation Additional prophylaxis: GCS on both legs after operation. Neither the length nor for how long they were worn was stated. Physiotherapy with mobilisation started on 2nd post-operative day. Walking began on 4th or 5th postoperative day

Length of follow-up Intervention for 8 to 10 days, followup 6 weeks

Outcome measures DVT (overall): confirmed by thermography & Doppler US followed by phlebography “Major” proximal DVT “Major” proximal & distal DVT

Blood loss Mean ±SD total blood loss (ml) Blood transfused Mean ±SD volume of blood transfused (ml)

Effect size Int: 9/67 Cont: 23/65 p value: 75% in 1 study Age: mean age 79 in 1 study

Patient groups Type of surgery: Surgery for fracture of hip or femoral neck

Intervention Type: LMWH

Comparison Type: LMWH

Timing: pre-op commencement

Timing: post-op commencement

Additional noncomparative prophylaxis: early mobilisation – 1 study

1 study used a placebo control Additional noncomparative prophylaxis: early mobilisation – 1 study

Length of follow-up 7-10 days or until ambulatory

Outcome measures Any DVT: confirmed by phlebography or US Proximal DVT: confirmed by phlebography or US

Effect size Int: 9/115 Cont: 24/115 RR: 0.38 (95% CI 0.19 to 0.78) (n=2 studies) Int: 6/115 Cont: 15/115 RR: 0.30 95% CI 0.01 to 6.49; random effects (n=2 studies)

Any PE

Int: 0/80 Cont: 0/74 RR: not estimable (n=1 study)

Mortality

Int: 9/121 Cont: 11/119 RR: 0.95 (95% CI 0.13 to 6.91); random effects (n=2 studies)

Wound haematoma

Int: 3/115 Cont: 6/115 RR: 0.49 (95% CI 0.13 to 1.87) (n=2 studies) Int: 3/115 Cont: 2/115 RR: 1.40 (95% CI 0.28 to 7.08) (n=2 studies)

Wound infection

Comments 1 study had a large loss to follow-up (32/239) due to unavailability of confirmation of DVT

143

Forest plot 32a: DVT Comparison of LMWH timing in hip fracture surgery preop start postop start Study or Subgroup Events Total Events Total Weight 35.1.1 phlebography: not blinded Jorgensen 1998 Subtotal (95% CI)

9

74 74

9 Total events Heterogeneity: Not applicable Test for overall effect: Z = 1.39 (P = 0.17)

15

Risk Ratio M-H, Random, 95% CI

72 72

64.4% 64.4%

0.58 [0.27, 1.25] 0.58 [0.27, 1.25]

43 43

35.6% 35.6%

0.06 [0.00, 0.92] 0.06 [0.00, 0.92]

115 100.0%

0.25 [0.02, 2.82]

Risk Ratio M-H, Random, 95% CI

15

35.1.2 US: blinding not reported Williams 1994 Subtotal (95% CI)

0

41 41

0 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.02 (P = 0.04)

9 9

115

Total (95% CI)

24 9 Total events Heterogeneity: Tau² = 2.21; Chi² = 3.00, df = 1 (P = 0.08); I² = 67% Test for overall effect: Z = 1.12 (P = 0.26)

0.01 0.1 1 10 100 Favours preop start Favours postop start

Forest plot 32b: Proximal DVT Comparison of LMWH timing in hip fracture surgery preop start postop start Study or Subgroup Events Total Events Total Weight 35.2.1 phlebograhy: not blinded Jorgensen 1998 Subtotal (95% CI)

6

74 74

6 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.05 (P = 0.96)

6

Risk Ratio M-H, Random, 95% CI

72 72

58.6% 58.6%

0.97 [0.33, 2.88] 0.97 [0.33, 2.88]

43 43

41.4% 41.4%

0.06 [0.00, 0.92] 0.06 [0.00, 0.92]

115 100.0%

0.30 [0.01, 6.49]

Risk Ratio M-H, Random, 95% CI

6

35.2.2 US: blinding not reported Williams 1994 Subtotal (95% CI)

0

41 41

0 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.02 (P = 0.04) Total (95% CI)

115

9 9

6 15 Total events Heterogeneity: Tau² = 3.93; Chi² = 4.32, df = 1 (P = 0.04); I² = 77% Test for overall effect: Z = 0.77 (P = 0.44)

0.01 0.1 1 10 100 Favours preop start Favours postop start

144

Forest plot 32c: Death Comparison of LMWH timing in hip fracture surgery Study or Subgroup

preop start postop start Events Total Events Total Weight

Jorgensen 1998 Williams 1994

6 3

Total (95% CI)

80 41

2 9

121

74 45

Risk Ratio M-H, Random, 95% CI

47.1% 52.9%

2.77 [0.58, 13.32] 0.37 [0.11, 1.26]

119 100.0%

0.95 [0.13, 6.91]

Total events 9 11 Heterogeneity: Tau² = 1.54; Chi² = 3.96, df = 1 (P = 0.05); I² = 75% Test for overall effect: Z = 0.05 (P = 0.96)

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours preop start Favours postop start

Forest plot 32d: Adverse events Comparison of LMWH timing in hip fracture surgery preop start postop start Study or Subgroup Events Total Events Total Weight 35.5.1 wound haematoma Jorgensen 1998 Williams 1994 Subtotal (95% CI)

3 0

74 41 115

3 Total events Heterogeneity: Not applicable Test for overall effect: Z = 1.05 (P = 0.29)

6 0

Risk Ratio M-H, Fixed, 95% CI

72 100.0% 43 115 100.0%

0.49 [0.13, 1.87] Not estimable 0.49 [0.13, 1.87]

72 40.9% 43 59.1% 115 100.0%

2.92 [0.31, 27.41] 0.35 [0.01, 8.34] 1.40 [0.28, 7.08]

Risk Ratio M-H, Fixed, 95% CI

6

35.5.2 wound infection Jorgensen 1998 Williams 1994 Subtotal (95% CI)

3 0

74 41 115

1 1

2 3 Total events Heterogeneity: Chi² = 1.15, df = 1 (P = 0.28); I² = 13% Test for overall effect: Z = 0.41 (P = 0.68) 0.01 0.1 1 10 100 Favours preop start Favours postop start

145

Evidence summary 33. Hip fracture surgery: LMWH delivery DVT No significant differences were seen for DVT between the twice vs. once daily delivery of LMWH: RR 1.76 (95% CI 0.46 to 6.72) Proximal DVT No significant differences were seen for proximal DVT between the twice vs. once daily delivery of LMWH: RR 2.94 (95% CI 0.38 to 22.53) Distal DVT No significant differences were seen for DVT between the twice vs. once daily delivery of LMWH: RR 0.98 (95% CI 0.13 to 7.51) PE No cases of PE were reported Death No deaths were reported Wound haematoma No significant differences were seen for wound haematomas between the twice vs. once daily delivery of LMWH (2 in each group): RR 0.91 (95% CI 0.07 to 11.34)

I Barsotti 1990

I Barsotti 1990

I Barsotti 1990

I Barsotti 1990 I Barsotti 1990 I Barsotti 1990

146

Evidence table 33. Hip fracture surgery: LMWH delivery Reference Barsotti 1990

Study type RCT

Evidence Level II RoB: mod

No. of patients Total: 103 Int: n=54 Cont: n=59 Female: 82 female 21 male Age: mean age 82 yrs

Patient groups Type of surgery: Patients with recent (within 24h) femoral neck fractures Hip screw fixation – 13 Moore prosthesis – 44 Ender nails – 46 Excluded: obesity, previous VTE, abnormal plethysmograp hy, renal failure, treatment within previous 8 days with VKA, antiplatelet or heparin, thrombocytope nia, coagulation abnormalities, allergy to iodine or radio opaque dyes

Intervention Type: LMWH Type: Enoxaparin Dose: 20mg 2x daily Timing: evening of operation Additional noncomparative prophylaxis: 40mg LMWH 8 hours pre-op

Comparison Type: LMWH Type: Enoxaparin Dose: 40mg 1x daily Timing: evening of operation Additional noncomparative prophylaxis: 40mg LMWH 8hrs pre-op

Length of follow-up 10-15 days until discharge

Outcome measures Any DVT: confirmed by venography Proximal DVT: confirmed by venography

Effect size Int: 9/49 Cont: 5/48 RR: 1.76 (95% CI 0.46 to 6.72) Int: 6/49 Cont: 2/48 RR: 2.94 (95% CI 0.38 to 22.53)

Distal DVT: confirmed by venography

Int: 3/49 Cont: 3/48 RR: 0.98 (95% CI 0.13 to 7.51)

Any PE

Int: 0/54 Cont: 0/49 RR: not estimable

Mortality

Int: 0/54 Cont: 0/49 RR: not estimable

Wound haematoma

Int: 2/54 Cont: 2/49 RR: 0.91 (95% CI 0.07 to 11.34)

Comments Allocation concealment unclear

147

Evidence summary 34. Hip fracture surgery: LMWH vs. no treatment DVT There were significantly fewer DVT in the LMWH groups compared with the no treatment groups: RR 0.63 (95% CI 0.42 to 0.94) NNTB 5 (95% CI 3 to 33) assuming a control event rate of 0.5 Proximal DVT There were significantly fewer DVT in the LMWH groups compared with the no treatment groups: RR 0.16 (95% CI 0.05 to 0.45) NNTB 6 (95% CI 5 to 9) assuming a control event rate of 0.2 Distal DVT No significant differences were seen between LMWH and no treatment for distal DVT: RR 0.75 (95% CI 0.54 to 1.05) PE No significant differences were seen between LMWH and no treatment for PE: RR 0.48 (95% CI 0.08 to 2.90) All of the PE recorded were fatal (1 in the LMWH and 4 in the no treatment groups) Death No significant differences were seen between LMWH and no treatment for death: RR 0.78 (95% CI 0.28 to 2.18) Adverse events No significant differences between LMWH and no treatment were seen for wound haematomas, wound infections or numbers of patients requiring blood transfusions

I Handoll 2002 Cochrane Review (3 RCTs)

I Handoll 2002 Cochrane Review (4 RCTs)

I Handoll 2002 Cochrane Review (4 RCTs) I Handoll 2002 Cochrane Review (3 RCTs)

I Handoll 2002 Cochrane Review (2 RCTs) I Handoll 2002 Cochrane Review (2 RCTs)

148

Evidence table 34. Hip fracture surgery: LMWH vs. no treatment Reference Handoll 2002 5 included studies Figuerido 1994: venography, not blinded Jorgensen 1992: FUT, blinded Kew 1999: US, not likely to be blinded Sourmelis 1995a: venography, blinding not stated Sourmelis 1995b: venography, blinding not stated

Study type Cochrane Review

Evidence Level I ROB: low

No. of patients Total: 373 Female: >75% Age: mainly elderly in 2 studies

Patient groups Type of surgery: Surgery for fracture of hip or femoral neck % of cervical or intracapsular hip fracture in 3 studies range 47% to 57%

Intervention Type: LMWH Timing: pre-op commencement Additional noncomparative prophylaxis: early mobilisation – 1 study

Comparison Type: No treatment 2 studies had no treatment and in 3 studies there was a placebo Additional noncomparative prophylaxis: early mobilisation – 1 study

Length of follow-up 7-10 days or until ambulatory

Outcome measures Any DVT: confirmed by FUT and venography

Effect size Int: 21/67 Cont: 53/110 RR: 0.63 (95% CI 0.42 to 0.94) (n=3 studies)

Proximal DVT: confirmed by FUT and venography

Int: 2/109 Cont: 28/150 RR: 0.16 (95% CI 0.05 to 0.45) (n=4 studies)

Distal DVT: confirmed by FUT and venography

Int: 34/109 Cont: 60/150 RR: 0.75 (95% CI 0.54 to 1.05) (n=4 studies)

Any PE

Int: 1/69 Cont: 4/118 RR: 0.48 (95% CI 0.08 to 2.90) (n=3 studies) Int: 0/53 Cont: 0/93 RR: not estimable (n=2 studies) Int: 1/46 Cont: 4/63 RR: 0.48 (95% CI 0.08 to 2.90) (n=2 studies)

Non-fatal PE

Fatal PE

Mortality

Death – other causes (not confirmed PE)

Comments

Int: 5/46 Cont: 9/63 RR: 0.78 (95% CI 0.28 to 2.18) (n=2 studies) Int: 4/46 Cont: 5/63 RR: 1.09 (95% CI 0.31 to 3.86) (n=2 studies)

149

Reference

Study type

Evidence Level

No. of patients

Patient groups

Intervention

Comparison

Length of follow-up

Outcome measures Wound haematoma

Effect size Int: 1/14 Cont: 2/17 RR: 0.61 (95% CI 0.06 to 6.02) (n=1 study)

Wound infection

Int: 2/30 Cont: 2/38 RR: 1.27 (95% CI 0.19 to 8.47) (n=1 study)

Transfusion (mean units)

MD: 83.82 units (95% CI 182.33 to 349.97) (n=1 study)

Transfusion (no. patients)

Int: 29/44 Cont: 34/55 RR: 1.12 (95% CI 0.68 to 1.85) (n=2 studies)

Comments

150

Forest Plot 34a: DVT Comparison of LMWH vs. no treatment in hip fracture surgery

Forest Plot 34b: Proximal DVT Comparison of LMWH vs. no treatment in hip fracture surgery

Forest Plot 34c: Distal DVT Comparison of LMWH vs. no treatment in hip fracture surgery

151

Forest plot 34d: PE Comparison of LMWH vs. no treatment in hip fracture surgery

Forest plot 34e: Death Comparison of LMWH vs. no treatment in hip fracture surgery

152

Forest plot 34f: Adverse events Comparison of LMWH vs. no treatment in hip fracture surgery

153

Evidence summary 35. Hip fracture surgery: LMWH vs. UFH DVT No significant difference was seen between LMWH and UFH for DVT: RR 0.68 (95% CI 0.38 to 1.23) overall (random effects) This effect was significant in the two RCTs of LMWH plus DHE vs. UFH: RR 0.49 (95% CI 0.25 to 0.95) Proximal DVT No significant difference was seen between LMWH and UFH for proximal DVT: RR 1.01 (95% CI 0.22 to 4.70) using a random effects model Distal DVT No significant difference was seen between LMWH and UFH for distal DVT: RR 0.68 (95% CI 0.23 to 2.00) PE None of the reported PE reported to be fatal: RR 3.29 (95% CI 0.82 to 13.32) Wound haematoma No significant difference was seen between LMWH and UFH for wound haematomas: RR 0.60 (95% CI 0.19 to 1.88)

I Handoll 2002 Cochrane Review (5 RCTs)

I Handoll 2002 Cochrane Review (3 RCTs) I Handoll 2002 Cochrane Review (2 RCTs) I Handoll 2002 Cochrane Review (4 RCTs) I Handoll 2002 Cochrane Review (3 RCTs)

154

Evidence table 35. Hip fracture surgery: LMWH vs. UFH Reference Handoll 2002 5 included studies: Hoffman 1996: venography, some blinding? Monreal 1989: venography (some patients only), blinded Pini 1989: FUT, blinded Dulic 1996: US, blinding not reported Lassen 1989: plasmin scanning, blinding not reported

Study type Cochrane Review

Evidence Level I

No. of patients Total: 644

ROB: mod

306 LMWH vs. UFH 338 LMWH plus DHE vs. UFH plus DHE Female: > 75% in 2 studies < 22% in1 study

Patient groups Type of surgery: Surgery for fracture of hip or femoral neck

Intervention Type: LMWH various doses and timing

% of cervical or intracapsular hip fracture in 3 studies range 47% to 57%

Additional noncomparative prophylaxis: DHE – 2 studies

Comparison Type: UFH 5000IU x3 daily pre-op and 5000IU x2 daily post-op

Length of follow-up 7-10 days or until ambulatory

Outcome measures Any DVT: confirmed by venography in 4 studies and US in 1 study

Effect size Int: 47/252 Cont: 64/227 RR: 0.68(95% CI 0.38 to 1.23) random effects (n=5 studies) 3 studies without DHE Int: 28/136 Cont: 25/111 RR: 0.91 (95% CI 0.36 to 2.31)

Additional noncomparative prophylaxis: DHE – 2 studies

Age: NR Proximal DVT: confirmed by FUT or venography

Comments 2 studies had significant losses to follow-up. DVT results should be viewed with caution

2 studies with DHE Int: 19/116 Cont: 39/116 RR: 0.49 (95% CI 0.25 to 0.95) Int: 19/132 Cont: 22/128 RR: 1.01(95% CI 0.22 to 4.70) random effects (n=3 studies) 2 studies without DHE Int: 14/69 Cont: 6/66 RR: 2.23 (95% CI 0.92 to 5.40) 1 study with DHE Int: 5/63 Cont: 16/62 RR: 0.31 (95% CI 0.12 to 0.79)

155

Reference

Study type

Evidence Level

No. of patients

Patient groups

Intervention

Comparison

Length of follow-up

Outcome measures Distal DVT: confirmed by FUT or venography Any PE

Non-fatal PE

Fatal PE

Mortality

Wound haematoma

Effect size Int: 5/69 Cont: 7/66 RR: 0.68 (95% CI 0.23 to 2.00) (n=2 studies without DHE) Int: 7/189 Cont: 1/165 RR: 3.29 (95% CI 0.82 to 13.32) (n=4 studies) Int: 6/136 Cont: 0/111 RR: 12.42 (95% CI 0.72 to 213.88) (n=3 studies without DHE) Int: 0/122 Cont: 0/120 RR: not estimable (n=3 studies)

Comments

Int: 6/122 Cont: 7/120 RR: 0.85 (95% CI 0.31 to 2.36) (n=3 studies) Int: 4/136 Cont: 6/113 RR: 0.60 95% CI 0.19 to 1.88 (n=3 studies)

156

Forest plot 35a: DVT Comparison of LMWH vs. UFH in hip fracture surgery

Forest plot 35b: Proximal DVT Comparison of LMWH vs. UFH in hip fracture surgery

157

Forest plot 35c: Distal DVT Comparison of LMWH vs. UFH in hip fracture surgery

Forest plot 35d: PE Comparison of LMWH vs. UFH in hip fracture surgery

158

Forest plot 35e: Death Comparison of LMWH vs. UFH in hip fracture surgery

Forest plot 35f: Adverse events Comparison of LMWH vs. UFH in hip fracture surgery

.

159

Evidence summary 36. Hip fracture surgery: LMWH plus DHE vs. placebo DVT No significant difference was seen between the LMWH plus DHE group and the placebo group for DVT: RR 0.62 (95% CI 0.36 to 1.07) Major haemorrhage One major haemorrhage was reported in each group

I Lassen 1989

I Lassen 1989

160

Evidence table 36. Hip fracture surgery: LMWH plus DHE vs. placebo Reference Lassen 1989

Study type RCT

Evidence Level II

No. of patients Total: 142 Int: n= 68 Cont: n= 74

Patient groups Type of surgery: Hip fracture surgery

Intervention Type: LMWH (Certoparin) Dose: 3000 antiXa units plus 0.5mg DHE once daily Timing: Commenced preop at diagnosis of fracture and continued until post-op day 7

Comparison Type: Placebo Additional noncomparative prophylaxis: none

Length of follow-up Both groups: 6 days

Outcome measures Asymptomatic DVT: confirmed by venography if FUT positive Major haemorrhage

Effect size Int: 14/53 Cont: 23/54

Comments Blind

Int: 1/68 Cont: 1/74

Source: Zuffrey 2003

Additional noncomparative prophylaxis: none

161

Evidence summary 37. Hip fracture surgery: UFH vs. no treatment DVT Significantly fewer DVT were seen in the UFH groups compared with the no treatment groups: RR 0.61 (95% CI 0.45 to 0.83) NNTB 6 (95% CI 4 to 8) assuming a control event rate of 0.45 Proximal DVT No significant differences were seen between UFH and no treatment for proximal DVT: RR 0.86 (95% CI 0.50 to 1.48) Distal DVT No significant differences were seen between UFH and no treatment for distal DVT: RR 0.31 (95% CI 0.05 to 1.83) PE No significant differences were seen between UFH and no treatment for any PE: RR 1.16 (95% CI 0.53 to 2.54); or for fatal PE (6 studies): RR 0.47 (95% CI 0.17 to 1.29) Death No significant differences were seen between UFH and no treatment for any PE: RR 1.25 95% CI 0.81 to 1.95 However for causes of death other than PE, this just reached statistical significance in favour of no treatment: RR 1.68 (95% CI 1.00 to 2.82) Adverse events In one RCT there were 2 wound haematomas and 2 wound infections in the UFH group compared with 1 wound haematoma and 2 wound infections in the no treatment group.

I Handoll 2002 Cochrane Review (10 RCTs)

I Handoll 2002 Cochrane Review (3 RCTs) I Handoll 2002 Cochrane Review (2 RCTs) I Handoll 2002 Cochrane Review (7 RCTs)

I Handoll 2002 Cochrane Review (6 RCTs)

I Handoll 2002 Cochrane Review (2 RCTs)

In another RCT, no difference between groups was seen, with 26/68 patients in the UFH group requiring transfusions compared with 39/82 in the no treatment group.

162

Evidence table 37. Hip fracture surgery: UFH vs. no treatment Reference Handoll 2002 10 included studies Bergqvist 1979: FUT, probably not blinded Checketts 1974: FUT, blinding unlikely Galasko 1979: venography: blinding unlikely Gallus 1973: FUT, blinding for confirmatory venogram but not for FUT Kiviluoto 1980: clinical, probably not blinded Lahnborg 1980: FUT, blinding not reported Morris 1977: FUT, blinding unlikely Moskovitz 1978: FUT, almost

Study type Cochrane Review

Evidence Level I

No. of patients Total: 826

ROB: low

Female: between 66 and 100% of randomised Age: mean age range (where given) 73 to 79 years

Patient groups Type of surgery: surgery for fracture of hip or femoral neck

Intervention Type: UFH 5000IU x3 daily pre-op and 5000IU x2 daily post-op

% of cervical or intracapsular hip fracture in 3 studies range 47% to 57%

Timing: pre-op commencement Additional noncomparative prophylaxis: early mobilisation: 1 study GCS: 1 study

Comparison Type: No treatment 6 studies had no treatment and in 4 studies there was a placebo Additional noncomparative prophylaxis: early mobilisation: 1 study GCS: 1 study

Length of follow-up 7-10 days or until ambulatory

Outcome measures Any DVT: confirmed by FUT or venography Proximal DVT: confirmed by FUT or venography Distal DVT: confirmed by FUT or venography Any PE

Non-fatal PE

Fatal PE

Mortality

Effect size Int: 103/407 Cont: 166/409 RR: 0.61 (95% CI 0.45 to 0.83) – random effects (n=10 studies) Int: 18/80 Cont: 17/68 RR: 0.86 (95% CI 0.50 to 1.48) (n=3 studies)

Comments

Int: 5/52 Cont: 14/46 RR: 0.31 (95% CI 0.05 to 1.83) – random effects (n=2 studies) Int: 12/335 Cont: 10/336 RR: 1.16 (95% CI 0.53 to 2.54) (n=7 studies) Int: 8/192 Cont: 0/199 RR: 4.94 (95% CI 1.10 to 22.07) (n=4 studies) Int: 4/310 Cont: 10/311 RR: 0.47 (95% CI 0.17 to 1.29) (n=6 studies) Int: 37/310 Cont: 29/311 RR: 1.25 (95% CI 0.81 to 1.95)

163

Reference certainly blinded Sven-Hansen 1981: FUT, blinded Xabregas 1978: FUT, blinded

Study type

Evidence Level

No. of patients

Patient groups

Intervention

Comparison

Length of follow-up

Outcome measures

Death – other causes (not confirmed PE)

Wound haematoma

Wound infection

Blood loss (ml)

Effect size (n=6 studies)

Comments

Int: 33/310 Cont: 19/311 RR: 1.68 (95% CI 1.00 to 2.82) (n=6 studies) Int: 2/25 Cont: 1/25 RR: 2.00 (95% CI 0.19 to 20.67) (n=1 study) Int: 2/25 Cont: 2/25 RR: 1.00 (95% CI 0.15 to 6.55) (n=1 study) MD: 47.21mL (95% CI 32.74 to 127.16) (n=2 studies)

Transfusion (mean units)

WMD: 0.23 units (95% CI 0.73 to 0.27) (1 study)

Transfusion (no. patients)

Int: 26/68 Cont: 39/82 RR: 0.80 (95% CI 0.55 to 1.17) (n=1 study)

164

Forest plot 37a: DVT Comparison of UFH vs. no treatment in hip fracture surgery

Forest plot 37b: Proximal DVT Comparison of UFH vs. no treatment in hip fracture surgery

Forest plot 37c: Distal DVT Comparison of UFH vs. no treatment in hip fracture surgery

165

Forest plot 37d: PE Comparison of UFH vs. no treatment in hip fracture surgery

166

Forest plot 37e: Death Comparison of UFH vs. no treatment in hip fracture surgery

Forest plot 37f: Adverse events Comparison of UFH vs. no treatment in hip fracture surgery

167

Evidence summary 38. Hip fracture surgery: UFH dose (adjusted vs. fixed) DVT No differences were seen between adjusted and fixed doses of UFH for any DVT, proximal or distal DVT

I Tabener 1989

168

Evidence table 38. Hip fracture surgery: UFH dose (adjusted vs. fixed) Reference Taberner 1989

Study type RCT

Evidence Level II RoB: moderate

No. of patients Total: 28 Int n=14 Cont n=14 M/F: 24/4 Age: (range 43-91) mean age Int 79 yrs Cont 74 yrs No losses to FU but 2 withdrawals from DVT screening

Patient groups Type of surgery: Patients with fractured neck of femur Excluded: underlying bleeding tendency, hepatic disease, uncontrolled hypertension, active peptic ulceration, previous history thromboembolism, cerebrovascular accident, oral anticoagulation treatment, aspirin in previous week, allergy to iodide, pathological fracture, malignant disease

Intervention Type: UFH adjusted dose Dose: 5000IU 8hrs post admission then adjusted according to clotting response (activated partial thromboplastin time target 5055s) Timing: commenced 8 hours post admission

Comparison Type: UFH fixed dose Dose: 5000IU Timing: commenced 8 hours post admission then every 8 hours until 14th post-op day if mobile or until ambulatory Additional noncomparative prophylaxis: 40mg LMWH 8hrs pre-op

Length of follow-up At least 14 days

Outcome measures Any DVT: FUT, US, plethysmography, venography

Effect size Int: 1/14 Cont: 2/14 RR: 0.50 (95% CI 0.02 to 10.05)

Comments Allocation concealment unclear.

Proximal DVT: confirmed by venography

Int: 0/14 Cont: 1/14 RR: 0.33 (95% CI 0.01 to 20.11)

Randomisation by random tables.

Distal DVT: confirmed by venography

Int: 1/14 Cont: 1/14 RR: 1.00 (95% CI 0.03 to 33.46)

Blinding unlikely.

Additional noncomparative prophylaxis: 40mg LMWH 8 hours pre-op

169

Evidence summary 39. Hip fracture surgery: IPC or foot pump vs. no treatment DVT There were significantly fewer DVT in the IPC or foot pump groups compared with no treatment: RR 0.31 (95% CI 0.19 to 0.50) NNTB 3 (95% CI 3 to 4) assuming event rate of 50% for no treatment There was moderate heterogeneity between the 2 foot pump RCTs for this outcome, but changing to a random effects model made very little difference Proximal DVT There were significantly fewer proximal DVT in the IPC or foot pump groups compared with no treatment: RR 0.22 (95% CI 0.10 to 0.53) NNTB 9 (95% CI 7 to 14) assuming a 15% event rate for no treatment PE There were significantly fewer PE (fatal or nonfatal) in the IPC or foot pump groups compared with no treatment: RR 0.40 (95% CI 0.17 to 0.96) NNTB 17 (95% CI 12 to 250) assuming a 10% event rate for no treatment Death In four RCTs, there was no significant difference in death rates between IPC or foot pump and no treatment: RR 0.50 (95% CI 0.22 to 1.14) Adverse events In one RCT there were 2 instances of haematoma in each of the IPC and the no treatment groups; and 1 instance in each group for haematuria

I Handoll 2002 Cochrane Review (5 RCTs)

I Handoll 2002 Cochrane Review (4 RCTs)

I Handoll 2002 Cochrane Review (5 RCTs)

I Handoll 2002 Cochrane Review (4 RCTs) I Handoll 2002 Cochrane Review (1 RCT)

170

Evidence table 39. Hip fracture surgery: IPC or foot pump vs. no treatment Reference Handoll 2002 5 included studies: Figuerido 1994 (venography) Fisher 1995 (venography) Gargan 1993 (venography) Hartman 1982 (FUT) Stranks 1992 (US)

Study type Cochrane Review

Evidence Level I

No. of patients Total: 669

ROB: low

Female: >60% female Age: >45yrs

Patient groups Type of surgery: Hip fracture surgery

Intervention Type: IPC (3 studies) Foot pump (2 studies)

Comparison Type: No treatment

Additional noncomparative prophylaxis: none

Additional noncomparative prophylaxis: none

Length of follow-up 7-10 days or until ambulatory

Outcome measures Any DVT: confirmed by FUT and venography

Effect size Overall Int: 16/222 Cont: 52/229 RR: 0.31 (95% CI 0.19 to 0.50) (n=5 studies) IPC Int: 8/147 Cont: 25/157 RR: 0.32(95% CI 0.15 to 0.66) (n=3 studies) Foot Pump Int: 8/75 Cont: 27/72 RR: 0.30(95% CI 0.15 to 0.58) (n=2 studies)

Proximal DVT: confirmed by FUT and venography

Int: 5/204 Cont: 26/210 RR: 0.22 (95% CI 0.10 to 0.53) (n=4 studies) Int: 10/53 Cont: 21/50 RR: 0.45 (95% CI 0.23 to 0.85) (n=2 studies) Int: 5/238 Cont: 16/249 RR: 0.40 (95% CI 0.17 to 0.96) (n=5 studies)

Distal DVT: confirmed by FUT and venography Any PE

Fatal PE

Int: 1/128 Cont: 8/128

171

Reference

Study type

Evidence Level

No. of patients

Patient groups

Intervention

Comparison

Length of follow-up

Outcome measures

Mortality

Haematoma

Haematuria

Fatal stroke

Transfusion (mean volume of transfusion in mLs)

Effect size RR: 0.27 (95% CI 0.07 to 1.08) (n=4 studies) Int: 7/128 Cont: 15/128 RR: 0.50 (95% CI 0.22 to 1.14) (n=4 studies) Int: 2/19 Cont: 2/17 RR: 0.89 (95% CI 0.14 to 5.68) (n=1 study) Int: 1/19 Cont: 1/17 RR: 0.89 (95% CI 0.06 to 13.23) (n=1 study) Int: 0/19 Cont: 1/17 (n=1 study) Int 713.89 [345.53] mL Cont 641.18 [355.31]mL WMD: 72.71mL (95% CI -159.68 to 305.10) (1 study)

172

Forest plot 39a: DVT Comparison of IPC or foot pump vs. no treatment in hip fracture

Forest plot 39b: Proximal DVT Comparison of IPC or foot pump vs. no treatment in hip fracture

Forest plot 39c: Distal DVT Comparison of IPC or foot pump vs. no treatment in hip fracture

173

Forest plot 39d: PE Comparison of IPC or foot pump vs. no treatment in hip fracture

Forest plot 39e: Death Comparison of IPC or foot pump vs. no treatment in hip fracture

174

Forest plot 39f: Adverse events Comparison of IPC or foot pump vs. no treatment in hip fracture

175

Evidence summary 40. Hip fracture surgery: IPC (thigh vs. calf) DVT No significant difference between the thigh IPC and the calf IPC was seen for number of DVT PE There were no fatal PE in either group

I Stannard 2001 I Stannard 2001

176

Evidence table 40. Hip fracture surgery: IPC type (thigh vs. calf) Reference Stannard 2001

Study type RCT

Evidence level II RoB: mod

No. of patients Total: 140 Int: n = 54 Cont: n = 53

Patient groups Type of surgery: Orthopaedic (hip fracture)

Intervention Type: bilateral thighcalf low pressure compression device (IPC)

Age and gender: NR

Dose: 45mm Hg

Pre-existing risk factors: all patients had sustained a pelvic or acetabular fracture due to blunt trauma requiring surgery. Injury severity scores recorded.

Timing: (duration) mean 20.8hrs/day (range 424hrs/day)(time started) as soon as possible following admission to trauma service (time finished) discharge

Comparison Type: Bilateral combination calffoot high pressure compression device (IPC) Dose: 160mm Hg Timing: (duration) mean 21.3hrs/day (range 724hrs/day)(time started) as soon as possible following admission to trauma service (time finished) discharge

Length of follow-up Follow-up to discharge Cont: mean 6 days postsurgery Int: mean 6.5 days postsurgery

Outcome measures DVT: confirmed by duplex US, MRI

Effect size Int: 10/54 Cont: 5/53 p value: 0.265 (not significant)

Fatal PE:

Int: 0 Cont: 0

Survival

134/140 (No deaths due to PE, unclear which groups these patients belonged to)

Comments 33 patients dropped out. Paper doesn’t state how many were lost from each group. Also reported whether DVT were occlusive or nonocclusive and > or < 2cm in size. Increased patient age and time elapsed from injury to surgery were associated with higher rates of thrombosis Not reported: PE, QoL, LoS, PTS, Bleeding Source: NICE 21

177

Evidence summary 41. Hip fracture surgery: Warfarin vs. aspirin DVT There were significantly fewer DVT with warfarin compared with aspirin: RR 0.49 (95% CI 0.28 to 0.86) NNTB 5 (95% CI 3 to 17) Proximal DVT There were no significant differences between warfarin and aspirin for proximal DVT: RR 0.87 (95% CI 0.31 to 2.45) PE One PE was reported; this occurred in the aspirin group and was fatal: RR 0.34 (95% CI 0.01 to 8.16) Death There were no significant differences between warfarin and aspirin for death: RR 0.85 (95% CI 2.64 to [unable to calculate]) Major bleeding There were no significant differences between warfarin and aspirin for major bleeding: RR 5.08 (95% CI 0.61 to 42.28)

I Powers 1989

I Powers 1989

I Powers 1989 I Powers 1989

I Powers 1989

178

Evidence table 41. Hip fracture surgery: Warfarin vs. aspirin Reference Powers 1989

Study type RCT

Evidence Level II

No. of patients Total: 131 Int: n= 65 Cont: n= 66

Patient groups Type of surgery: Hip fracture surgery

Intervention Type: Warfarin Dose: NR Timing: commenced postop & continued until discharge, or 3 weeks.

Comparison Type: Aspirin Dose: 650mg twice daily

Length of follow-up Both groups: 3 months

Outcome measures DVT: confirmed by venography on day 21

Effect size Int: 13/65 Cont: 27/66

DVT assessment blinded

Proximal DVT

Int: 6/65 Cont: 7/66

Clinical PE

Int: 0/65 Cont: 1/66 (fatal) Int: 5/65 Cont: 5/66

Death Major haemorrhage

Comments Open trial

Source: Mismetti 2004

Int: 5/65 Cont: 1/66

179

Evidence summary 42. Hip fracture surgery: Warfarin vs. placebo/no treatment DVT There were significantly fewer DVT with warfarin compared with no treatment: RR 0.42 (95% CI 0.32 to 0.55) NNTB 4 (95% CI 3 to 5) assuming a control event rate of 0.5 Proximal DVT There were significantly fewer proximal DVT with warfarin compared with no treatment: RR 0.28 (95% CI 0.13 to 0.60) NNTB 10 (95% CI 8 to 18) assuming a control event rate of 0.14 PE There were significantly fewer PE (any and fatal) in the warfarin group compared with no treatment: RR (any PE): 0.12 (95% CI 0.03 to 0.49) NNTB 11 (95% CI 10 to 20) assuming a control event rate of 0.1 In addition, one fatal PE was reported in the no treatment group of Korvald 1973 Major bleeding In two RCTs, no significant differences were seen between warfarin and no treatment: RR 1.95 (95% CI 0.43 to 8.88)

I Myrhe 1969 Morris 1976 Powers 1989 Korvald 1973 I Morris 1976 Powers 1989 Korvald 1973 I Myrhe 1969 Morris 1976 Powers 1989 Korvald 1973

I Morris 1976 Powers 1989

180

Evidence table 42. Hip fracture surgery: Warfarin vs. placebo/no treatment Reference Myrhe 1969

Study type RCT

Evidence Level II

No. of patients Total: 105 Int: n= 50 Cont: n= 55

Patient groups Type of surgery: Hip fracture surgery

Intervention Type: Warfarin Dose: NR

Comparison Type: Placebo

Timing: commenced postop, duration not indicated.

Length of follow-up Both groups: 3 weeks

Outcome measures DVT: confirmed by venography during week 3 Clinical PE

Death Morris 1976

RCT

II

Total: 160 Int: n= 80 Cont: n= 80

Type of surgery: Hip fracture surgery

Type: Warfarin Dose: target TT 10%

Type: no treatment

Timing: within 24 hours of admission, until patient mobile/3 months. Additional noncomparative prophylaxis: none

Powers 1989

RCT

II

Total: 128 Int: n= 65 Cont: n= 63

Type of surgery: Hip fracture surgery

Type: Warfarin Dose: target INR 2 – 2.7 Timing: from post-op to 21 days post-op/discharge

Type: no treatment

Int: 1/50 (1 fatal) Cont: 7/55 (2 fatal) Int: 4/50 Cont: 6/55

Comments Double-blinded trial DVT assessment not blinded

Source: Mismetti 2004

DVT: confirmed by FUT on days 110 post-op (daily) Proximal DVT

Int: 23/75 Cont: 50/74

DVT/PE assessment – not stated if blinded.

Int: 0/75 Cont: 5/74

Non-fatal PE

Int: 0/80 Cont: 2/80 Int: 0/80 Cont: 6/80

Randomisation using sequentially numbered sealed opaque envelope.

Fatal PE Additional noncomparative prophylaxis: none

Effect size Int: 9/44 Cont: 22/41

All PE: assessed by x-ray Major bleeds

Int: 0/80 Cont: 8/80 Int: 9/80 Cont: 2/80

Fatal PE

Int: 0/25 Cont: 0/25 Int: 13/65 Cont: 29/63

DVT: confirmed by FUT on days 1 to 3 post-op, once daily on alternate days. IPG on days 4 to 5 post-op (alternate days).

Source: Roderick 2005 Unit of randomisation – placebo. DVT assessment blinded. PE assessment – not stated if blinded.

181

Reference

Study type

Evidence Level

No. of patients

Patient groups

Intervention

Comparison

Additional noncomparative prophylaxis: none

Additional noncomparative prophylaxis: none

Length of follow-up

Outcome measures Venography 21 days postop/discharge Proximal DVT Non-fatal PE Fatal PE All PE: assessed by scan Major bleeds

Korvald 1973

RCT

II

Total: 99 Int: n= ? Cont: n= ?

Type of surgery: Hip fracture surgery

Type: Warfarin Dose: target TT 8 – 15%

Type: no treatment

Timing: commenced upon admission, duration not specified. Additional noncomparative prophylaxis: Dextran

DVT: confirmed by venography or FUT, 2 – 3 weeks post-op. 25 patients had FUT on alternate days until day 710 post-op. Proximal DVT

Additional noncomparative prophylaxis: Dextran

Fatal PE: Assessed post mortem.

Effect size

Int 6/65 Cont: 19/63 Int 0/65 Cont: 2/63 Int 0/65 Cont: 0/63 Int 0/65 Cont: 2/63 Int: 5/65 Cont: 5/63 Int: 4/39 Cont: 15/43

Comments Randomisation using sequentially numbered sealed opaque envelope.

Source: Roderick 2005

DVT assessment – not specified if blinded. Randomisation method not specified.

Int: 1/39 Cont: 2/43 Int: 0/? Cont: 1/? Source: Roderick 2005

182

Forest plot 42a: DVT Comparison of warfarin vs. placebo/no treatment in hip fracture surgery warfarin no treatment Events Total Events Total Weight Study or Subgroup 36.1.1 venography: not blinded 41 19.5% 22 44 9 Myrhe 1969 41 19.5% 44 Subtotal (95% CI) 9 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.92 (P = 0.004)

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

0.38 [0.20, 0.73] 0.38 [0.20, 0.73]

22

36.1.2 FUT: blinding not reported Morris 1976 Subtotal (95% CI)

23

75 75

50

74 74

43.1% 43.1%

0.45 [0.31, 0.66] 0.45 [0.31, 0.66]

63 63

25.2% 25.2%

0.43 [0.25, 0.76] 0.43 [0.25, 0.76]

43 43

12.2% 12.2%

0.29 [0.11, 0.81] 0.29 [0.11, 0.81]

221 100.0%

0.42 [0.32, 0.55]

50 23 Total events Heterogeneity: Not applicable Test for overall effect: Z = 4.13 (P < 0.0001) 36.1.3 FUT/IPG/venography: blinded Powers 1989 Subtotal (95% CI)

13

65 65

13 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.94 (P = 0.003)

29 29

36.1.4 venography/FUT: blinding not reported 15 39 4 Korvald 1973 39 Subtotal (95% CI) 4 Total events Heterogeneity: Not applicable Test for overall effect: Z = 2.37 (P = 0.02) Total (95% CI)

15

223

116 49 Total events Heterogeneity: Chi² = 0.75, df = 3 (P = 0.86); I² = 0% Test for overall effect: Z = 6.31 (P < 0.00001) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours warfarin Favours no treatment

183

Forest plot 42b: Proximal DVT Comparison of warfarin vs. placebo/no treatment in hip fracture surgery warfarin no treatment Study or Subgroup Events Total Events Total Weight 36.2.1 Venography: not blinded Subtotal (95% CI) 0 0 Total events 0 Heterogeneity: Not applicable Test for overall effect: Not applicable

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

Not estimable

0

36.2.2 FUT: blinding not reported Morris 1976 Subtotal (95% CI)

0

75 75

Total events 0 Heterogeneity: Not applicable Test for overall effect: Z = 1.64 (P = 0.10)

5

74 74

20.7% 20.7%

0.09 [0.01, 1.59] 0.09 [0.01, 1.59]

63 63

72.2% 72.2%

0.31 [0.13, 0.72] 0.31 [0.13, 0.72]

43 43

7.1% 7.1%

0.55 [0.05, 5.84] 0.55 [0.05, 5.84]

180 100.0%

0.28 [0.13, 0.60]

5

36.2.3 FUT/IPG/venography: blinded Powers 1989 Subtotal (95% CI)

6

65 65

Total events 6 Heterogeneity: Not applicable Test for overall effect: Z = 2.73 (P = 0.006)

19 19

36.2.4 venography: not blinded Korvald 1973 Subtotal (95% CI)

1

39 39

Total events 1 Heterogeneity: Not applicable Test for overall effect: Z = 0.49 (P = 0.62) Total (95% CI)

2 2

179

Total events 7 26 Heterogeneity: Chi² = 0.96, df = 2 (P = 0.62); I² = 0% Test for overall effect: Z = 3.28 (P = 0.001) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours warfarin Favours no treatment

184

Forest plot 42c: PE Comparison of warfarin vs. placebo/no treatment in hip fracture surgery Study or Subgroup 36.3.1 any PE Morris 1976 Myrhe 1969 Powers 1989 Subtotal (95% CI)

warfarin no treatment Events Total Events Total Weight 0 1 0

80 50 65 195

8 7 2

Risk Ratio M-H, Fixed, 95% CI

80 48.0% 55 37.7% 63 14.3% 198 100.0%

0.06 [0.00, 1.00] 0.16 [0.02, 1.23] 0.19 [0.01, 3.96] 0.12 [0.03, 0.49]

80 49.4% 55 50.6% 63 198 100.0%

0.08 [0.00, 1.34] 0.16 [0.02, 1.23] Not estimable 0.12 [0.02, 0.62]

80 49.6% 63 50.4% 143 100.0%

0.20 [0.01, 4.10] 0.19 [0.01, 3.96] 0.20 [0.02, 1.66]

Risk Ratio M-H, Fixed, 95% CI

17 1 Total events Heterogeneity: Chi² = 0.42, df = 2 (P = 0.81); I² = 0% Test for overall effect: Z = 2.94 (P = 0.003) 36.3.2 fatal PE Morris 1976 Myrhe 1969 Powers 1989 Subtotal (95% CI)

0 1 0

80 50 65 195

6 7 0

13 1 Total events Heterogeneity: Chi² = 0.16, df = 1 (P = 0.69); I² = 0% Test for overall effect: Z = 2.53 (P = 0.01) 36.3.3 nonfatal PE Morris 1976 Powers 1989 Subtotal (95% CI)

0 0

80 65 145

2 2

4 0 Total events Heterogeneity: Chi² = 0.00, df = 1 (P = 0.99); I² = 0% Test for overall effect: Z = 1.49 (P = 0.14) 0.01 0.1 1 10 100 Favours warfarin Favours no treatment

185

Forest plot 42d: Major Bleeding Comparison of warfarin vs. placebo/no treatment in hip fracture surgery Study or Subgroup Morris 1976 Powers 1989 Total (95% CI)

warfarin no treatment Risk Ratio Events Total Events Total Weight M-H, Random, 95% CI 9 5

80 65 145

2 5

80 45.5% 63 54.5%

4.50 [1.00, 20.18] 0.97 [0.29, 3.19]

143 100.0%

1.95 [0.43, 8.88]

14 7 Total events Heterogeneity: Tau² = 0.73; Chi² = 2.53, df = 1 (P = 0.11); I² = 60% Test for overall effect: Z = 0.86 (P = 0.39)

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours warfarin Favours no treatment

186

Evidence summary 43. Hip fracture surgery: GCS plus fondaparinux vs. fondaparinux VTE or sudden death There were significantly more cases of VTE or sudden death in the GCS plus fondaparinux group compared with the fondaparinux alone group: RR: 6.47 (95% CI 1.61 to 26.05) NNTB (with fondaparinux alone): 2 (95% CI 1 to 5)

I Cohen 2007

NOTE: This is a subgroup analysis only, so results need to be interpreted with caution VTE-related deaths No VTE-related deaths were reported

I Cohen 2007

187

Evidence table 43. Hip fracture surgery: GCS plus fondaparinux vs. fondaparinux Reference Cohen 2007

Study type RCT

Evidence level II

No. of patients Total: 39 randomised Int: n=23 Cont: n=16 Note: part of a larger RCT mostly of THR

Patient groups Type of surgery: Fracture of the proximal third of the femur ) Age: 18 years or older Exclusions: bilateral joint surgery, multiple trauma, delay > 24 hours between trauma and admission, conditions precluding use of GCS, leg oedema, PVD, peripheral neuropathy, marked leg deformity, conditions increasing bleeding risk, pregnant/lactating women, women of reproductive age taking inadequate contraceptive precautions

Intervention Type: GCS plus fondaparinux

Comparison Type: Fondaparinux

GCS applied preop and worn for a mean 42 days (range 35 to 49) – usually long-leg; Fondaparinux 2.5 mg daily, given post-op for 5-9 days; first dose given 6 hours after wound closure

Dose: 2.5 mg daily, given post-op for 5-9 days; first dose given 6 hours after wound closure

Length of follow-up Mean 42 days (range 35 to 49)

Outcome measures VTE or sudden death (by day 42) VTE-related deaths

Effect size Int: 9/16 Cont: 2/23 RR: 6.47 (95% CI 1.61 to 26.05) Int: 0/23 Cont: 0/16

Comments Randomised by sealed envelope *VTE defined as at least one of: objectively verified, symptomatic TE (proximal or distal DVT or fatal or nonfatal PE), or asymptomatic proximal DVT demonstrated by bilateral proximal ultrasound or venography. Need to interpret VTE result with caution as it is a subgroup analysis only (as part of larger RCT)

188

Evidence summary 44. Hip fracture surgery: Fondaparinux vs. LMWH VTE Significantly fewer VTE were seen for fondaparinux compared with LMWH: RR 0.44 (95% CI 0.32 to 0.59) NNTB 9 (95% CI 7 to 20) DVT Significantly fewer DVT were seen for fondaparinux compared with LMWH: RR 0.42 (95% CI 0.31 to 0.57) NNTB 9 (95% CI 7 to 20) Symptomatic DVT One symptomatic DVT was recorded in the fondaparinux group, and in the LMWH group Proximal DVT Significantly fewer proximal DVT were seen for fondaparinux compared with LMWH: RR 0.21 (95% CI 0.09 to 0.51) NNTB 33 (95% CI 20 to 50) PE One non-fatal and two fatal PE were recorded in the fondaparinux group, and in the LMWH group Bleeding No significant differences between fondaparinux and LMWH were seen for major bleeding (with one fatal bleed reported in the LMWH group)

I Eriksson 2001

I Eriksson 2001

I Eriksson 2001 I Eriksson 2001

I Eriksson 2001 I Eriksson 2001

189

Evidence table 44. Hip fracture surgery: Fondaparinux vs. LMWH Reference Eriksson 2001

Study type RCT

Evidence Level II RoB: low

No. of patients Total: 1711 Int: n: 849 Cont: n:862 Dropouts (not treated): Int: 18 Cont: 20 Dropouts (not available for analysis): Int: 205 Cont: 218

Patient groups Type of surgery: Patients scheduled to undergo standard surgery for fracture of the upper third of femur, including femoral head and neck within 48 hours of admission. Duration of surgery: 104 mins, SD: ±44 Age (mean ± SD): Int: 76.8 ±12.3 Cont: 77.3 ±12.6 M/F: Int: 187/644 Cont:224/698 Pre-existing risk factors: History of VTE: Int: 29 (3.5%) Cont: 32 (3.8%). Orthopaedic surgery within the previous 12 months: Int: 33 (4.0%) Cont: 26 (3.1%)

Intervention Type: 2.5 mg of Fondaparinux sodium and a placebo. The first active dose was given 6±2 hrs post-op and the second 12 or more after the first. Treatment was scheduled to continue until day 5 to 9. Day of surgery is day 1.

Comparison Type: 40 mg of Enoxaparin 1x/day and placebo. The first active dose was given 12±2 hrs pre-op and the second 12 to 24 hours post-op.

Additional noncomparative prophylaxis: The use of graduated compression stockings and physiotherapy was recommended

Additional noncomparative prophylaxis: The use of graduated compression stockings and physiotherapy was recommended

No. patients receiving/using: GCS: 312/626

No. patients receiving/using: GCS: 295/624

Anticoagulant or anti-platelet therapy (not aspirin): 23/626

Anticoagulant or anti-platelet therapy (not aspirin): 21/624

NSAIDs or aspirin: 141/626

NSAIDs or aspirin: 126/624

Treatment was scheduled to continue until day 5 to 9. Day of surgery is day 1.

Length of follow-up 49 days

Outcome measures DVT: confirmed by systematic bilateral ascending venography VTE

Symptomatic DVT Proximal DVT: confirmed by venography as above Non fatal PE: confirmed by lung scan, pulmonary angiography or helical CT or at autopsy Fatal PE Major bleeding* Fatal bleeding Bleeding leading to re-operation Minor bleeding – number Post-operative transfusions

Effect size Int: 49/624 Cont: 117/623 RR: 0.42 (95% CI 0.31 to 0.57) Int: 52/626 Cont: 119/624 RR 0.44 (95% CI 0.32 to 0.59) Int: 1/831 Cont: 1/840 Int: 6/650 Cont: 28/646 p value: 200 µmol/L)

Intervention

Comparison

Length of follow-up

Outcome measures Clinically relevant non-major bleeding

Effect size Int: 2/56 Cont: 2/57

Minor bleeding:

Int: 5/56 Cont: 2/57

Comments catheter (CVC) was placed or a contiguous vein (patients with clinically suspected catheterrelated CVT prior to venography were investigated by duplex US first). Positive US counted as CVT

641

Forest plot 141a: Symptomatic DVT Comparison of LMWH vs. no treatment/placebo in hospitalised medical cancer patients with a central venous catheter Study or Subgroup Karthaus 2006 Monreal 1996 Niers 2007 Verso 2005

LMWH no treatment Events Total Events Total Weight 10 1 0 2

294 16 56 155

5 5 1 6

521

Total (95% CI)

Risk Ratio M-H, Fixed, 95% CI

34.0% 28.0% 7.5% 30.5%

0.99 [0.34, 2.83] 0.16 [0.02, 1.22] 0.34 [0.01, 8.15] 0.33 [0.07, 1.63]

370 100.0%

0.51 [0.24, 1.06]

145 13 57 155

17 13 Total events Heterogeneity: Chi² = 3.08, df = 3 (P = 0.38); I² = 3% Test for overall effect: Z = 1.80 (P = 0.07)

Risk Ratio M-H, Fixed, 95% CI

0.01 0.1 1 10 100 Favours LMWH Favours no treatmen

Forest plot 141b: Asymptomatic DVT Comparison of LMWH vs. no treatment/placebo in hospitalised medical cancer patients with a central venous catheter LMWH no treatment Study or Subgroup Events Total Events Total Weight 51.1.1 venography: blinded Karthaus 2006 Monreal 1996 Niers 2007 Verso 2005 Subtotal (95% CI)

10 0 7 20

294 16 56 155 521

6 3 4 22

Risk Ratio M-H, Fixed, 95% CI

145 21.2% 13 10.1% 57 10.5% 155 58.1% 370 100.0%

0.82 [0.30, 2.22] 0.12 [0.01, 2.09] 1.78 [0.55, 5.75] 0.91 [0.52, 1.60] 0.90 [0.58, 1.39]

370 100.0%

0.90 [0.58, 1.39]

Risk Ratio M-H, Fixed, 95% CI

37 35 Total events Heterogeneity: Chi² = 3.26, df = 3 (P = 0.35); I² = 8% Test for overall effect: Z = 0.47 (P = 0.64) Total (95% CI)

521

37 35 Total events Heterogeneity: Chi² = 3.26, df = 3 (P = 0.35); I² = 8% Test for overall effect: Z = 0.47 (P = 0.64) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours LMWH Favours no treatmen

642

Forest plot 141c: Death Comparison of LMWH vs. no treatment/placebo in hospitalised medical cancer patients with a central venous catheter Study or Subgroup Karthaus 2006 Monreal 1996 Verso 2005 Total (95% CI)

LMWH no treatment Events Total Events Total Weight 6.0% 140 1 4 285 5.0% 13 1 16 1 194 89.0% 20 13 191 492

22 18 Total events Heterogeneity: Chi² = 0.89, df = 2 (P = 0.64); I² = 0% Test for overall effect: Z = 0.93 (P = 0.35)

347 100.0%

Risk Ratio M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

1.96 [0.22, 17.42] 0.81 [0.06, 11.77] 0.66 [0.34, 1.29] 0.75 [0.40, 1.38]

0.01 0.1 1 10 100 Favours LMWH Favours no treatmen

643

Forest plot 141d: Bleeding Comparison of LMWH vs. no treatment/placebo in hospitalised medical cancer patients with a central venous catheter LMWH no treatment Study or Subgroup Events Total Events Total Weight 51.4.1 Major bleeding Karthaus 2006 Niers 2007 Verso 2005 Subtotal (95% CI)

1 0 0

285 56 155 496

1 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.50 (P = 0.61)

1 0 0

Risk Ratio M-H, Fixed, 95% CI

140 100.0% 57 155 352 100.0%

0.49 [0.03, 7.80] Not estimable Not estimable 0.49 [0.03, 7.80]

57 100.0% 57 100.0%

1.02 [0.15, 6.98] 1.02 [0.15, 6.98]

57 100.0% 57 100.0%

2.54 [0.51, 12.58] 2.54 [0.51, 12.58]

Risk Ratio M-H, Fixed, 95% CI

1

51.4.2 Clinically relevant non-major bleeding Niers 2007 Subtotal (95% CI)

2

56 56

2 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.02 (P = 0.99)

2 2

51.4.3 Minor bleeding Niers 2007 Subtotal (95% CI)

5

56 56

5 Total events Heterogeneity: Not applicable Test for overall effect: Z = 1.15 (P = 0.25)

2 2

0.01 0.1 1 10 100 Favours LMWH Favours no treatment

644

Evidence summary 142. Hospitalised medical cancer patients with a central venous catheter: LMWH vs. warfarin Asymptomatic DVT No significant difference in asymptomatic DVT was detected in one study: RR: 2.86 (95% CI 0.62 to 13.22)

I Mismetti 2003

Symptomatic DVT No significant difference in symptomatic DVT was detected in one study: RR: 2.29 (95% CI 0.22 to 23.44) Catheter Related Thrombosis No significant difference catheter related thrombosis (CRT) was detected in one study (total thromboembolic events): RR 2.00 (95% CI 0.68 to 5.89)

I Mismetti 2003 I Mismetti 2003

645

Evidence table 142. Hospitalised medical cancer patients with a central venous catheter: LMWH vs. warfarin Reference Mismetti 2003

Study type RCT

Evidence Level II

No. of patients Total: 60 Int: 30 Cont: 30 Available for primary efficacy analysis: Int: 21 Cont: 24

Patient groups Medical indication: cancer patients with a central venous catheter (CVC)

Intervention Type: LMWH (Nadroparin) Dose: 2850 IU qd Timing: continued for 90 days

Comparison Type: warfarin Dose: 1 mg/day

Length of follow-up

Outcome measures Asymptomatic DVT

Effect size Int: 5/21 (3 in catheter) Cont: 2/24 (1 in catheter) RR: 2.86 (95% CI 0.62 to 13.22)

Symptomatic DVT

Int: 2/21 (0 in catheter) Cont: 1/24 (0 in catheter) RR: 2.29 (95% CI 0.22 to 23.44)

Total thromboembolic events PE

Int: 7/21 Cont: 4/24 RR: 2.00 (95% CI 0.68 to 5.89) Int: 0 Cont: 0

Comments Pilot study. Unblinded interventions

Source: ACCP 2008, Mismetti 2003

646

Evidence summary 143. Hospitalised medical cancer patients with a central venous catheter: Warfarin vs. no treatment DVT No significant difference were seen in three studies: RR 0.75 (95% CI 0.24 to 2.35) Adverse events No deaths were detected in one study and no significant difference in major bleeding was detected in another study: Deaths: RR not estimable Major bleeding: RR 0.14 (95% CI 0.01 to 2.63)

I Bern 1990 Heaton 2002 Couban 2005 I Heaton 2002 Couban 2005

647

Evidence table 143. Hospitalised medical cancer patients with a central venous catheter: Warfarin vs. no treatment Reference Bern 1990

Heaton 2002

Couban 2005

Study type RCT

RCT

RCT

Evidence Level II

II

II

No. of patients Total: 82 Int: 42 Cont: 40

Total: 88 Int: 45 Cont: 43

Total: 255 Int: 130 Cont: 125

Patient groups Medical indication: cancer patients with central venous catheter (CVC)

Medical indication: cancer (haematological malignancies) patients with central venous catheters (CVCs)

Medical indication: cancer patients with central venous catheters (CVCs) Solid tumours: 65% Leukaemia: 35%

Intervention Type: warfarin Dose: fixed dose 1mg/day

Comparison Type: no treatment

Length of follow-up Both groups: 90 days

Outcome measures DVT: confirmed by venography at 90 days

Effect size Int: 4/42 Cont: 15/40

34% of randomised patients did not complete the trial.

Timing: continued for 90 days

Type: warfarin Dose: 1mg/day

Type: no treatment

DVT

Deaths

Type: warfarin Dose: 1mg/day Timing: during central venous catheter (CVC) lifespan (approx 73 days)

Comments Unblinded interventions.

Type: placebo

Int: 8/45 (6 catheterrelated) Cont: 5/43 (4 catheter-related) Int: 0/45 Cont: 0/43 RR: not estimable

DVT: not specified how confirmed

Int 6/130 Cont 5/125

Major bleeding

Int 0/130 Cont 3/125

Source: ACCP 2008 Unblinded interventions. No difference in clot-free catheter survival.

Source: ACCP 2008, Heaton 2002 No difference in central venous catheter (CVC) life span

Source: ACCP 2008, Couban 2005

648

Forest plot 143a: DVT Comparison of warfarin vs. no treatment in hospitalised medical cancer patients with a central venous catheter Study or Subgroup Bern 1990 Couban 2005 Heaton 2002 Total (95% CI)

warfarin no treatment Events Total Events Total Weight 4 6 8

42 130 45 217

15 5 5

40 125 43

Risk Ratio M-H, Random, 95% CI

34.4% 31.7% 34.0%

0.25 [0.09, 0.70] 1.15 [0.36, 3.68] 1.53 [0.54, 4.31]

208 100.0%

0.75 [0.24, 2.35]

Total events 18 25 Heterogeneity: Tau² = 0.71; Chi² = 6.75, df = 2 (P = 0.03); I² = 70% Test for overall effect: Z = 0.49 (P = 0.63)

Risk Ratio M-H, Random, 95% CI

0.01 0.1 1 10 100 Favours WARFARIN Favours control

649

650

HOSPITALISED GENERAL MEDICAL PATIENTS TABLE 144 - 147

651

Evidence summary 144. Hospitalised general medical patients: UFH vs. no treatment DVT No significant difference in DVT was detected in 4 studies: RR 0.50 (95% CI 0.24 to 1.03) (A random effects model was used due to heterogeneity of I2=63%)

I Belch 1981 Cade 1982a Cade 1982b Gardlund 1996

However, when one study using autopsy to assess DVT in patients with infection was excluded, significantly fewer DVT were detected in the UFH group compared with no treatment in 3 studies: RR 0.39 (95% CI 0.23 to 0.44) NNTB 8 (95% CI 6 to 9), assuming a CER of 0.21 (Heterogeneity was reduced to I2=18%) PE Significantly fewer PE were detected in the UFH group compared with no treatment in two studies: RR 0.60 (95% CI 0.41 to 0.86) NNTB 83 (95% CI 56 to 238), assuming a CER of 0.03

Belch 1981 Cade 1982a Cade 1982b

Non-fatal PE There were significantly fewer non-fatal PE in the UFH group compared with no treatment in one study: RR 0.51 (95% CI 0.33 to 0.80) Fatal PE No significant difference in fatal PE was detected in two studies: RR 0.86 (95% CI 0.44 to 1.68) Bleeding No significant difference in serious fatal bleeding was detected in one study: RR 2.39 (95% CI 0.92 to 6.22) No significant bleeding complications were reported in another study Death No significant difference in death was detected in one study: RR 0.94 (95% CI 0.80 to 1.09)

I Belch 1981 Gardlund 1996

Gardlund 1996

Belch 1981 Gardlund 1996 I Gardlund 1996

Belch 1981 I Gardlund 1996

652

Evidence table 144. Hospitalised general medical patients: UFH vs. no treatment Reference Belch 1981

Cade 1982a

Study type RCT

RCT

Evidence Level II

II

No. of patients Total: 100 Int: 50 Cont: 50

Patient groups Medical indication: heart failure or chest infection

Exclusion criteria: Age 80, iodine allergy, high risk for bleeding, DVT or PE on admission, bed rest for more than 2 days before admission.

Age range: 40-80 years

Total: 250 Int: 125 Cont: 125

Medical indication: age >40, complete bed rest, cardiac failure, obesity, previous VTE, cancer or recent surgery

119 critically ill Int: 60 Cont: 59 131 medical Int: 65 Cont: 66

Mean age: Int: 66.6 years 70% male

Intervention Type: UFH (heparin calcium) Dose: 5000U 3 times daily

Comparison Type: no treatment

Length of follow-up Both groups: 14 days

Timing: continued until fully mobile

Pre-existing risk factors: King rates risk as moderate

Int: mean age 60 years; Male 72% Pre-existing risk factors: King rates risk as high

Type: UFH Dose: 5000U twice daily Timing: continued until mobilised or within 10 days

Type: no treatment

Both groups: 10 days

Outcome measures DVT: confirmed by FUT every other day (asymptomatic) PE: confirmed by not specified

Effect size Int: 2/50 Cont: 13/50 RR: 0.15 (95% CI 0.04 to 0.65) Int: 0/50 Cont: 2/50 RR: 0.20 (95% CI 0.01 to 4.06)

Minor bleeding: epistaxis (nosebleed), haematoma >5cm

1 episode of epistaxis (nosebleed)

Major bleeding: not defined

No significant bleeding complications

DVT: confirmed by FUT once daily

Critically ill Int: 8/60 Cont: 17/59 RR: 0.46 (95% CI 0.22 to 0.99)

Comments Allocation not concealed. Not double blind. No description of withdrawals.

Source: Dentali 2007, Wein 2007, King 2007, Sjalander 2007 Randomisation by coded ampoules. Double blind.

Medical patients Int: 1/65 Cont: 7/66 RR: 0.15 (95% CI 0.02 to 1.15) All patients Int: 9/125 Cont: 24/125 RR: 0.38 (95% CI 0.18 to 0.77)

Source: King 2007, Sjalander 2007

653

Reference Cade 1982b

Gardlund 1996

Study type RCT

RCT

Evidence Level II

II

No. of patients Total: 234 Int: 140 Cont: 94 Imputed data from reported percentages in abstract. King reported that Int was n=140 therefore have assumed control was n=94 Total: 11693 Int: 5776 Cont: 5917 Exclusion criteria: age 60 years

Intervention Type: LMWH (Enoxaparin) Dose: 4000U once daily

Comparison Type: placebo

Length of follow-up Both groups: 90 days

Timing: continued until hospital discharge

Samama 1999

RCT

II

Total: 1102 Int: 367 Cont: 371 Exclusion criteria: Age 150µmol/L, intubation, HIV, uncontrolled hypertension (>200/100 mm Hg), active peptic ulcer disease, bacterial endocarditis, conditions associated with an increased risk of bleeding, hypersensitivity to heparin or HIT, platelets 100 x 109/L prolonged aPPT, INR >1.2, ongoing (>48hrs) or required anticoagulant therapy

Patient groups

Total: 2472 Int: 1230 Cont: 1244

Medical indication: congestive heart failure, acute or respiratory disease, non-pulmonary sepsis, cancer

Intervention

Comparison

Length of follow-up

Outcome measures Distal DVT

Effect size Int: 11/291 Cont: 27/288 RR: 0.40 (95% CI 0.20 to 0.80)

Symptomatic PE: Confirmed by scintigraphy, angiography, CT

Int: 0/291 Cont: 3/288 RR: 0.14(95% CI 0.01 to 2.73)

Major bleeding: Haemoglobin drop ≥ 2g dL-1, transfusion of 2 or more units of blood, retroperitoneal or intracranial or fatal All cause mortality

Int: 12/272 Cont: 7/263 RR: 1.66 (95% CI 0.66 to 4.15)

Comments

Int: 41/272 Cont: 50/263 RR: 0.79 (95% CI 0.54 to 1.16)

Source: Dentali 2007, Sjalander 2007, Wein 2007, Lloyd 2008

Age: >40 years

Type: LMWH (Nadroparin) Dose: 7500U once daily Timing: continued until hospital discharge, or 21 days

Type: placebo

Both groups: 21 days

Symptomatic PE: confirmed by angiography, autopsy Major bleeding

All cause mortality

Int: 10/1230 Cont 17/1244 RR: 0.59 (95% CI 0.27 to 1.29) (according to Dentali – all fatal) Int: 1/1230 Cont: 3/1244 RR: 0.34 (95% CI 0.04 to 3.24) Int: 124/1230 Cont: 128/1244 RR: 0.98 (95% CI 0.78 to 1.24)

Allocation concealed. Double blind. Withdrawals described.

Source: Dentali 2007, Sjalander 2007

661

Reference Leizorovicz 2004

Study type RCT

Evidence Level II

No. of patients Total: 3706 Int: 1856 Cont: 1850 Exclusion criteria: Age 3days of immobility, acute coronary syndrome within 1 month, major surgical or invasive procedure in previous month or planned in next 2 weeks, bacterial endocarditis, immobilised lower limb, stroke within 3 months, high risk for bleeding, platelets 48h before randomisation, contraindication to heparin, serum creatinine level >177 µmol/L, hepatic insufficiency or active hepatitis, pregnancy or breast-feeding, life expectancy 65 years

3 patients did not receive the randomised treatment (Int: 1, Cont: 2)

Mean age Int: 82.6 years, 27% male Cont: details not provided

Safety analysis: 439 Int: 216 Cont: 223

Pre-existing risk factors: King rates risk as high

Effect size Int: 3/89 (all proximal) Cont: 4/83 RR: 0.70 (95% CI 0.16 to 3.03) Int: 0/82 Cont: 0/84 RR: not estimable Int: 3/82 Cont: 1/84 RR: 3.07 (95% CI 0.33 to 28.94)

Type: LMWH (Enoxaparin) Dose: 20mg subcutaneously once daily

Type: UFH (heparin calcium) Dose: 5000IU subcutaneously twice daily

DVT: confirmed by FUT once daily and positives assessed with phlebography or Doppler US

Int: 7/207 Cont: 8/216 RR: 0.91 (95% CI 0.34 to 2.47)

Timing: continued for 10 days

Timing: continued for 10 days

Proximal DVT

Int: 4/207 Cont: 2/216 RR: 2.09 (95% CI 0.39 to 11.27) Int: 1/207 Cont: 0/216 RR: 3.13 (95% CI 0.13 to 76.40) Int: 7/216 Cont: 8/223

PE: confirmed by pulmonary angiography Mortality

Comments Problems with randomisation. Double blind.

Source: Wein 2007, King 2007, Harenberg 1990 Double blind. No other methodological problems noted. Adverse events: Related to study treatments: Urticaria, hypereosinophilia, cutaneous

671

Reference

Study type

Evidence Level

No. of patients Efficacy analysis: 423 Int: 207 Cont: 216

Patient groups

Intervention

Comparison

Length of follow-up

Outcome measures

Major bleeding complication: haematemesis due to gastric ulcer and bulbitis, proctorrhagia due to sigmoid polyp, haematemesis plus melena) Minor bleeding: haematuria, epistaxis, minor haematemesis Thrombocytopenia

Effect size RR: 0.90 (95% CI 0.33 to 2.45) Int: 1/216 Cont: 2/223 RR: 0.52 (95% CI 0.05 to 5.65)

Comments erythema, vascular purpura, rise in (aPTT) Unrelated to treatments but related to study: intolerance of FUT

Int: 1/216 Cont: 2/223 RR: 0.52 (95% CI 0.05 to 5.65) Int: 0/216 Cont: 1/223 RR: 0.34 (95% CI 0.01 to 8.40)

672

Reference

Study type

Evidence Level

No. of patients

Patient groups

Intervention

Comparison

Length of follow-up

Outcome measures Adverse events

Effect size Total Int: 18/216 Cont: 19/223 RR: 0.98 (95% CI 0.53 to 1.81)

Comments

Related to study treatments Int: 2/216 Cont: 4/223 Related to study but not treatments Int: 2/216 Cont: 1/223

Harenberg 1996

RCT

II

Total: 1968 Int: 1004 Cont: 726

Medical indication: medical patients, aged 50-80 Mean age and gender: Int: 70.4 years, 48% male Cont: details not provided

Type: LMWH (Nadroparin) Dose: 36mg subcutaneously once daily

Type: UFH (heparin calcium) Dose: 5000IU subcutaneously 3 times daily

Timing: continued for 8-11 days

Timing: continued for 8-11 days

DVT: confirmed by US on days 1, 7, 8-11, or when clinically suspected.

PE:

Unrelated to study or treatments Int: 14/216 Cont: 14/223 RR: 2.89 (95% CI 0.30 to 27.71)

Source: Wein 2007, King 2007, Bergmann 1996

Double blind. Problems with randomisation.

RR: 0.96 (0.19 to 4.76)

673

Reference

Study type

Evidence Level

Lechler 1996

RCT

II

No. of patients

Patient groups Pre-existing risk factors: King rates risk as moderate

Intervention

Comparison

Total: 959 Cont: 482

Medical indication: medical patients, ≥18 years

Type: LMWH (Enoxaparin) Dose: 40mg subcutaneously once daily

Type: UFH (heparin calcium) Dose: 5000IU subcutaneously 3 times daily

Timing: continued for 7 days

Timing: continued for 7 days

Mean age and gender: Int: 74.0 years, 37% male Cont: details not provided Pre-existing risk factors: King rates risk as high

Length of follow-up

Outcome measures Mortality

Effect size RR: 2.46 (95% CI 1.15 to 5.28)

Comments Source: Wein 2007, King 2007

DVT: confirmed by US on days 1, 7, 8-11, or when clinically suspected.

RR: 0.25 (95% CI 0.03 to 2.23)

Double blind.

PE

RR: 0.11 (95% CI 0.01 to 2.06)

Mortality

RR: 0.64 (95% CI 0.25 to 1.64)

Problems with randomisation and patient withdrawals.

Source: Wein 2007, King 2007

674

Reference Kleber 2003

Study type RCT

Evidence Level II

No. of patients Total: 668 Int: 332 Cont: 333 3 randomised patients withdrawn before receiving study meds and excluded from analysis Excluded from efficacy analysis: Int: 93/332 Cont: 121/333

Patient groups Medical indication: severe respiratory disease or heart failure, aged over 18 Mean age: Int: 70 years Cont: details not provided Pre-existing risk factors: heart failure patients – mean of 5 respiratory disease – mean of 4

Intervention Type: LMWH (Enoxaparin) Dose: 40mg subcutaneously once daily

Comparison Type: UFH (heparin calcium) Dose: 5000IU subcutaneously 3 times daily.

Timing: continued for 8-12 days

Timing: continued for 8-12 days

Additional noncomparative prophylaxis: 20% GCS

Additional noncomparative prophylaxis: 20% GCS

Length of follow-up

Outcome measures DVT: confirmed by D-dimer on days 2, 5 and at end of study; venography done when positive

Effect size Int: 19/239 Cont: 22/212 RR: 0.77 (95% CI 0.43 to 1.38)

Comments Problems with blinding

Heart failure Int 11/113 Cont: 14/93

Proximal DVT

PE

Mortality

Minor bleeding: haematoma >5cm and minor bleeding Major bleeding: intracranial, retroperitoneal bleeding, decrease in haemoglobin of ≥ 2g/dL, or transfusion of ≥ 2U of blood.

Respiratory disease Int: 8/126 Cont: 7/119 Int: 5/239 Cont: 4/212 RR: 1.11 (95% CI 0.30 to 4.08) Int: 1/239 (non-fatal) Cont 1/212 (fatal) RR: 0.89 (95% CI 0.06 to 14.09) Int: 9/239 Cont 15/212 RR: 0.53 (95% CI 0.24 to 1.19) Int: 4/332 Cont 11/333 RR: 0.36 (95% CI 0.12 to 1.13)

Source: Wein 2007, King 2007, Kleber 2003

Int: 1/332 Cont 1/333 RR: 1.00 (95% CI 0.06 to 15.97)

675

Forest plot 146a: DVT Comparison of LMWH vs. UFH in hospitalised general medical patients log[Risk Ratio] Study or Subgroup 50.1.1 US + venography: blinded Harenberg 1990 Harenberg 1996 Subtotal (95% CI)

-0.35667 1.0613

SE Weight 0.75 1.15

Risk Ratio IV, Fixed, 95% CI

Risk Ratio IV, Fixed, 95% CI

9.7% 0.70 [0.16, 3.04] 4.1% 2.89 [0.30, 27.53] 13.9% 1.07 [0.31, 3.66]

Heterogeneity: Chi² = 1.07, df = 1 (P = 0.30); I² = 6% Test for overall effect: Z = 0.11 (P = 0.92) 50.1.2 FUT: blinded Bergmann 1996 Subtotal (95% CI)

-0.09431

0.51

21.0% 21.0%

0.91 [0.33, 2.47] 0.91 [0.33, 2.47]

-1.3863 1.125

4.3% 4.3%

0.25 [0.03, 2.27] 0.25 [0.03, 2.27]

60.8% 60.8%

0.77 [0.43, 1.39] 0.77 [0.43, 1.39]

100.0%

0.80 [0.50, 1.26]

Heterogeneity: Not applicable Test for overall effect: Z = 0.18 (P = 0.85) 50.1.3 US: blinded Lechler 1996 Subtotal (95% CI)

Heterogeneity: Not applicable Test for overall effect: Z = 1.23 (P = 0.22) 50.1.4 D-dimer: blinded? Kleber 2003 Subtotal (95% CI)

-0.26136

0.3

Heterogeneity: Not applicable Test for overall effect: Z = 0.87 (P = 0.38) Total (95% CI)

Heterogeneity: Chi² = 2.43, df = 4 (P = 0.66); I² = 0% Test for overall effect: Z = 0.98 (P = 0.33) Test for subgroup differences: Chi² = 1.36, df = 3 (P = 0.71), I² = 0%

0.01 0.1 1 10 100 Favours LMWH Favours UFH

676

Forest plot 146b: Proximal DVT Comparison of LMWH vs. UFH in hospitalised general medical patients Study or Subgroup

LMWH UFH Events Total Events Total Weight

Bergmann 1996 Kleber 2003

4 5

207 239

Total (95% CI)

446

2 4

216 212

Risk Ratio M-H, Fixed, 95% CI

31.6% 68.4%

2.09 [0.39, 11.27] 1.11 [0.30, 4.08]

428 100.0%

1.42 [0.51, 3.93]

Total events 9 6 Heterogeneity: Chi² = 0.34, df = 1 (P = 0.56); I² = 0% Test for overall effect: Z = 0.67 (P = 0.50)

Risk Ratio M-H, Fixed, 95% CI

0.01 0.1 1 10 100 Favours LMWH Favours UFH

Forest plot 146c: PE Comparison of LMWH vs. UFH in hospitalised general medical patients Study or Subgroup Bergmann 1996 Harenberg 1990 Harenberg 1996 Kleber 2003 Lechler 1996 Total (95% CI)

log[Risk Ratio]

SE Weight

0 0 1.141 1.629 -0.04082 0.82 -0.1165 1.41 1.5 -2.2073

Risk Ratio IV, Fixed, 95% CI

Risk Ratio IV, Fixed, 95% CI

Not estimable 13.4% 3.13 [0.13, 76.23] 52.9% 0.96 [0.19, 4.79] 17.9% 0.89 [0.06, 14.11] 15.8% 0.11 [0.01, 2.08] 100.0%

Heterogeneity: Chi² = 2.51, df = 3 (P = 0.47); I² = 0% Test for overall effect: Z = 0.40 (P = 0.69)

0.79 [0.24, 2.54] 0.01 0.1 1 10 100 Favours LMWH Favours UFH

677

Forest plot 146d: Deaths Comparison of LMWH vs. UFH in hospitalised general medical patients Study or Subgroup Bergmann 1996 Harenberg 1990 Harenberg 1996 Kleber 2003 Lechler 1996 Total (95% CI)

log[Risk Ratio]

SE Weight

-0.1054 0.51 1.1217 1.144 0.9002 0.39 -0.6349 0.41 -0.4463 0.48

Risk Ratio IV, Random, 95% CI

20.8% 7.6% 25.3% 24.5% 21.8%

0.90 [0.33, 2.45] 3.07 [0.33, 28.90] 2.46 [1.15, 5.28] 0.53 [0.24, 1.18] 0.64 [0.25, 1.64]

100.0%

1.04 [0.52, 2.08]

Heterogeneity: Tau² = 0.34; Chi² = 9.57, df = 4 (P = 0.05); I² = 58% Test for overall effect: Z = 0.11 (P = 0.91)

Risk Ratio IV, Random, 95% CI

0.01 0.1 1 10 100 Favours LMWH Favours UFH

678

Forest plot 146e: Major bleeding Comparison of LMWH vs. UFH in hospitalised general medical patients Study or Subgroup Bergmann 1996 Kleber 2003

LMWH UFH Events Total Events Total Weight 1 1

Total (95% CI)

216 332

2 1

548

223 333

Risk Ratio M-H, Fixed, 95% CI

66.3% 33.7%

0.52 [0.05, 5.65] 1.00 [0.06, 15.97]

556 100.0%

0.68 [0.11, 4.06]

Total events 2 3 Heterogeneity: Chi² = 0.13, df = 1 (P = 0.72); I² = 0% Test for overall effect: Z = 0.42 (P = 0.67)

Risk Ratio M-H, Fixed, 95% CI

0.01 0.1 1 10 100 Favours LMWH Favours UFH

Forest plot 146f: Minor bleeding Comparison of LMWH vs. UFH in hospitalised general medical patients Study or Subgroup Bergmann 1996 Kleber 2003 Total (95% CI)

LMWH UFH Events Total Events Total Weight 1 4

216 332 548

2 11

223 333

Risk Ratio M-H, Fixed, 95% CI

15.2% 84.8%

0.52 [0.05, 5.65] 0.36 [0.12, 1.13]

556 100.0%

0.39 [0.14, 1.08]

Total events 5 13 Heterogeneity: Chi² = 0.07, df = 1 (P = 0.80); I² = 0% Test for overall effect: Z = 1.82 (P = 0.07)

Risk Ratio M-H, Fixed, 95% CI

0.01 0.1 1 10 100 Favours LMWH Favours UFH

679

Evidence summary 147. Hospitalised general medical patients: Fondaparinux vs. placebo DVT No significant difference in DVT (all asymptomatic) was detected between fondaparinux and placebo in one study: RR 0.62 (95% CI 0.35 to 1.10) Asymptomatic proximal DVT No significant difference in proximal DVT was detected between fondaparinux and placebo in one study: RR 0.39 (95% CI 0.14 to 1.07) Asymptomatic distal DVT Significantly fewer distal DVT were detected in the fondaparinux group compared with no treatment in one study: RR 0.32 (95% CI 0.14 to 0.74) NNTB 20 (95% CI 13 to 100) Fatal PE No significant difference in fatal PE was detected in one study: RR 0.09 (95% CI 0.01 to 1.65) Deaths No significant difference in deaths was detected in one study: RR 0.55 (95% CI 0.29 to 1.03) Major bleeding No significant difference in major bleeding was detected in one study: RR 0.97 (0.06 to 15.52)

I Cohen 2006

I Cohen 2006

I Cohen 2006

I Cohen 2006 I Cohen 2006 I Cohen 2006

680

Evidence table 147. Hospitalised general medical patients: Fondaparinux vs. placebo Reference Cohen 2006

Study type RCT

Evidence Level II

No. of patients Total: 849 Int: 429 Cont: 420 Exclusion criteria: Age 180 μmol/L; hypersensitivity to contrast dye; anticipated intubation for >24hrs; antithrombotic use within 48hrs before randomization; indication for anticoagulant prophylaxis or therapy; life expectancy 60 years

Intervention Type: fondaparinux Dose: 2.5mg subcutaneously once daily Timing: continued for 6-14 days

Comparison Type: placebo

Length of follow-up Both groups: 32 days

Outcome measures Asymptomatic DVT: confirmed by bilateral venography days 1-15

Effect size Int: 18/321 Cont: 29/323 RR: 0.62 (95% CI 0.35 to 1.10)

Comments Double blind

Symptomatic DVT

Int: 0/321 Cont: 0/323 RR: not estimable

Withdrawals not described.

Asymptomatic Proximal DVT

Int: 5/321 Cont: 13/323 RR: 0.39 (95% CI 0.14 to 1.07) Int: 7/321 Cont: 22/323 RR: 0.32 (95% CI 0.14 to 0.74) During prophylactic treatment Int: 0/321 Cont: 5/323 RR: 0.09 (95% CI 0.01 to 1.65)

Asymptomatic distal DVT Fatal PE: confirmed by scintigraphy, angiography, CT, autopsy

All cause mortality

Major bleeding: haemoglobin drop > 2 g/dL, transfusion of 2 or more units of blood, critical location, need for surgical intervention, fatal

Sjalander says symptomatic PE during follow-up: Int 0/321 Cont 2/323 (RR 0.20, 95% CI 0.01 to 4.18) Int: 14/425 Cont: 25/414 RR: 0.55 (95% CI 0.29 to 1.03) Sjalander says all cause mortality during follow-up: Int 0/321 Cont 5/323 (RR0.09, 95% CI 0.01 to1.65) Int: 1/425 Cont: 1/414 RR: 0.97 (95% CI 0.06 to 15.52)

Allocation concealed.

Source: Dentali 2007, Lloyd 2008, Sjalander 2007

681

682

ANAESTHESIA TABLES 148 - 149

683

Evidence summary 148. Anaesthesia: Regional anaesthesia vs. general anaesthesia DVT Significantly fewer DVT were detected in the regional anaesthesia group compared with the general anaesthesia group (15 studies): RR 0.62 (95% CI 0.53 to 0.73) NNTB 6 (95% CI 5 to 8), assuming a CER of 0.45 Significantly fewer DVT were detected in the regional anaesthesia group compared with the general anaesthesia group whether the regional anaesthesia was epidural (11 studies): RR 0.62 (95% CI 0.51 to 0.75) NNTB 5 (95% CI 4 to 8), assuming a CER 0.52 or spinal (4 studies): RR 0.63 (95% CI 0.48 to 0.83) NNTB 5 (95% CI 4 to 11), assuming a CER 0.53 Proximal DVT Significantly fewer proximal DVT were detected in the regional anaesthesia group compared with general anaesthesia group (8 studies): RR 0.30 (95% CI 0.19 to 0.47) NNTB 5 (95% CI 4 to 8), assuming a CER 0.28

PE Significantly fewer PE were detected in the regional anaesthesia group compared with general anaesthesia group(7 studies): RR 0.56 (95% CI 0.38 to 0.84) NNTB 15 (95% CI 10 to 69) , assuming a CER of 0.16 Significantly fewer PE were detected in the regional anaesthesia group compared with general anaesthesia group whether the regional anaesthesia was epidural (6 studies): RR 0.61 (95% CI 0.38 to 0.99) NNTB 16 (95% CI 10 to 625), assuming a CER 0.16 or spinal (1 study): RR 0.47 (95% CI 0.23 to 0.96) Major bleeding No significant difference was detected in major bleeding between regional and general anaesthesia (7 studies): RR 0.10 (95% CI 0.01 to 1.71)

I Brichant 1995 Davis 1981 Davis 1989 Fredin 1986 Hendolin 1981 Hendolin 1982 Jorgensen 1991 McKenzie 1985 Mitchell 1991 Modig 1981 Modig 1985 Neilsen 1990 Poikolainen 1983 Rodrigo 1984 Williams-Russo 1996 I Davis 1989 Fredin 1986 Jorgensen 1991 Modig 1981 Modig 1985 Neilsen 1990 Rodrigo 1984 Williams-Russo 1996 I Davis 1989 Fredin 1986 Jorgensen 1991 Modig 1981 Modig 1985 Rodrigo 1984 Williams-Russo 1996

I Brichant 1995 Davis 1981 Fredin 1986 Hendolin 1982 Jorgensen 1991 McKenzie 1985 Williams-Russo 1996

684

Evidence table 148. Anaesthesia: Regional anaesthesia vs. general anaesthesia Reference Roderick et al, 2005 11 RCTs

Study type Systematic review

Evidence Level I RoB: low

No. of patients Total: 939 Int:367 Cont: 384 Misc: 188 (not reported number in each arm)

Patient groups Type of surgery: General (1 study) Urological (1 study) Orthopaedic (9 studies)

Intervention Regional Anaesthesia Timing: ranged from 73 mins to 3 days Not addressed in 4 studies Additional noncomparative prophylaxis: LMWH plus GCS (one study); GCS (two studies); Dextran 70 (one study); Dextran 40 plus 7500 IU H (one study); ASA, GCS on no-op limb (one study).

Mitchell et al, 1991

RCT

II RoB: low

Total: 72 Int: n = 34 Cont: n =38

Type of surgery: total knee arthroplasty Duration of surgery: Int: mean122 min Cont: mean 121 min Both study groups: Mean age: 64 years (range38-84) M/F: 45/27 No between-group differences for age or sex

Type: Epidural anaesthesia Timing: Operative period Additional noncomparative prophylaxis: Males received 650mg aspirin beginning eve pre surgery, females received adjusted dose warfarin partial

Comparison General Anaesthesia Timing: ranged from 79 – 150 mins. Not addressed in 6 studies. Additional noncomparative prophylaxis: LMWH plus GCS (one study); GCS (two studies); Dextran 70 (one study); Dextran 40 plus 7500 IU H (one study); ASA, GCS on noop limb (one study). Type: General anaesthesia Dose: sodium theopental Timing: Operative period Additional noncomparative prophylaxis: Males received 650mg aspirin beginning eve pre-surgery, females received adjusted dose

Length of follow-up Between 4 to 14 days post-operatively

Outcome measures DVT: confirmed by venography or fibrinogen uptake PE: confirmed by scan

Major bleeds

Scan performed up to day 8 after surgery

Effect size Int: 130/417 Cont: 198/416 p value: 0.0000 Int: 21/281 Cont: 32/264 (reported in 6 studies) p value: 0.0672 Int: 0/317 Cont: 5/315 (reported in 7 studies) p value: 0.0243

Proximal DVT

Int: 14/268 Cont: 47/253 (reported in 6 studies) p value: 0.0000

DVT: confirmed by bilateral venography 6th, 7th and 8th post-op days PE: confirmed by V/Q scan on 6th, 7th and 8th post-op days

Int: 12/34 Cont: 10/38 p value: Not significant All asymptomatic 10% of patients reported as having positive V/Q scan, all asymptomatic. No information on group.

Comments Not reported: LoS, QoL and PTS.

Source: NICE 60

Comments: Male patients received aspirin, female patients received warfarin. No differences in sex between study groups, and incidence and distribution of DVT not affected by pharmacological prophylaxis. Not reported:

685

Reference

Modig et al., 1981

Study type

RCT

Evidence Level

II RoB: low

No. of patients

Total: 30 Int: n = 15 Cont: n =15

Patient groups

Type of surgery: Total hip replacement (for severe osteoarthritis) Duration of surgery: Int: 147±27.9 min Cont: 161.3±34.5 min Mean age: Int: 66.5±5.5 years M/F:7/8 Cont: 65.4±6.3 M/F:8/7

Intervention thromboplastin time (PTT) 15-16 secs. All patients CPM machine daily and physical therapy.

Comparison warfarin partial thromboplastin time (PTT) 15-16 secs. All patients CPM machine daily and physical therapy.

Type: Continuous lumbar epidural block

Type: General anaesthesia

Dose: 0.5% bupivacaine with epinephrine (5μg/ml)

Dose: thiopentone

Post op: 4-6 ml of 0.5% bupivacaine with epinephrine ever 4 hours for 16 hours Timing: Prolonged into post-op period

Post-op: Parenteral analgesics on demand Timing: Intraoperatively.

Length of follow-up

Scanning was performed 14 days before surgery and 14 days post-operatively

Outcome measures

Effect size

Length of Hospital Stay

Int: Mean 10.4 days Cont: Mean 11.0 days p value: not reported

Proximal DVT

Incidence of proximal DVT reported to be 46% in epidural and 63% in general anaesthesia groups. (actual numbers can’t be reliably calculated from these figures) Int: 5/15 Cont: 11/15 p value: 0.0281

DVT: confirmed by bilateral venography on 14th post-op day Proximal DVT:

Comments PTS, bleeding, QoL, survival, funding Source: NICE 60

Not reported: PTS, QoL, survival, LoS, funding

Int: 3/15 Cont: 11/15 p value: