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
iii
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
iv
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
vi
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.
vii
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
viii
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).
ix
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
xi
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)
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I Handoll 2002 Cochrane Review (4 RCTs) I Handoll 2002 Cochrane Review (3 RCTs)
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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)
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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)
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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)
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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)
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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: