Evidence Table 32LMWH vs UFH

Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Avikainen et al 199526RCT1+Total: 167
Intervention : n = 83 (DVT assessed in 79)
Control: n = 84 (DVT assessed in 79)
Type of surgery: Hip replacement (& Duration of surgery)Type: LMWH (Enoxaparin)
Dose: 40mg/0.4 ml
Type: UFH
Dose: 5000 IU
Both groups: Until discharge (10th post- op - ).DVT Confirmed by: US on 10–14th post-op day.US results for 158 patients
Int: 1/79
Control: 4/79
p value: >0.05
Also reported: perioperative and postoperative blood loss, transfusion requirements

Not reported: PTS, QoL, survival, LoS, funding
Intervention: Mean age: 65 (range 27–86) yrs
M/F:30/53
Timing: Begun 12hrs pre-op and repeated daily for 10 days

Additional non- comparative prophylaxis: Not reported
Timing: Begun 2hrs pre-op and repeated twice daily for 10 daysPVT Confirmed by: US on 10–14th post-op day.Int: 1/79
Control: 4/79
p value: >0.05
Control: Mean age: 66 (range 34–86)
M/F:25/59
PE Confirmed by: Not routinely assessed. Symptomatic confirmed by V/Q scanAll patients:
Int: 0/84
Control: 1/83
p value: 0.4970
Pre-existing risk factors: varicose veins
Beghi et al 199338RCT1+Total: 39
Intervention : n = 20
Control: n = 19
Type of surgery:
Open heart surgery
Type: LMWH (Fluxum)
Dose: 3200 IU
Type: LDUH
Dose: 5000 IU
Both groups: 11 daysDVT
Confirmed by: Doppler US (on 7th post-op day?)
Int: 0/20
Control: 0/19
p value: N/A
Comments: Patients with cardiac disease requiring post- operative oral anticoagulation were not included in the study.

Not reported: Proximal DVT, PE, PTS, QoL, survival, LoS

Also reported: units of transfused blood per patient; volume of bleeding; haemoglobin g/100cc; platelets n/mm3
Duration of surgery:
Intervention:
209 ± 11.82 min
Control:
224 ± 13.37 min

Age & Gender:
Intervention: Mean age: 60.2 ± 1.94 yrs
M/F:15/5

Control: Mean age: 60.5 ± 2.39 yrs
M/F: 16/3
Timing: Begun 1st day post-op and repeated three times daily until 4th post-op day

Additional non- comparative prophylaxis: Not reported
Timing: Begun 1st day post-op and repeated daily until 4th post-op day
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Bergmann & Neuhart, 199645

Country of study:
France

Study design:
RCT, double blind, multicentre, equivalence study.

List who was masked to interventions:
Physicians, nurses, patients and the independent expert reading the fibrinogen scans.

Evidence level:
1+

Duration of follow-up:
10 days
Patient group: Elderly in patients bedridden due to an acute illness

Setting:
In-patients, multicentre

Inclusion criteria:
  • Age ≥65 years
  • Acute medical illness which led to a recent reduction of autonomous mobility (<4 days), unable to walk 10m unassisted.
Exclusion criteria:
  • Contraindication to anticoagulant treatment (uncontrolled hypertension, recent haemorrhagic stroke, any other haemorrhagic diseases)
  • Any ongoing venous, arterial or cardiac disease requiring “curative” anticoagulant treatment
  • History of allergy or thrombocytopenia induced by UFH or LMWH
  • Haemostasis abnormality (in particular platelet count <100 × 109/l)
  • Weight>80kg
  • Use of heparin or anticoagulants, aspirin or NSAIDS, for more than 24 hours before inclusion
  • Any contraindication to isotopic and/or venographic investigations
  • Renal failure (creatinine >150microM)
  • Local disorders of the lower limbs likely to interfere with the fibrinogen uptake test
All patients
N: 442
Age (mean): 83.2 ± 0.34
M/F: 123/316
Additional risk factors* [*calculated by NCC-AC team from numbers in Tablle 2 of paper, in the results section. Both groups were described as “similar”, although results not shown]

Group 1
No. randomised: 225
No. of dropouts: 2
Age (years ±sem): 82.6±0.46
M/F: 60/163
Weight (kg ± sem): 57.0±0.78
Reasons for hospitalisation (at baseline): Group 2
No. randomised: 217
No. of dropouts: 1
Age (years ±sem): 83.8±0.51
M/F: 63/153
Weight (kg ± sem): 57.8±0.79
Reasons for hospitalisation (at baseline):
Group 1
UFH
Heparin calcium, 5000U (in 0.2 ml pre-filled syringe), every 12 hours

Start time:
Duration: 10 days

Group 2
Enoxaparin
(Lovenox®) 20mg (in 0.2ml pre filled syringe), alternated with identical appearance placebo (mannitol), every 12 hours
Duration: 10 days

Mean duration of treatment for 439 patients was 9.5 ± 0.1 days.

Additional non- comparative prophylaxis:
All cause mortalityGroup 1: 8/223
Group 2: 7/216
P value: 1.00
calculated by NCC-AC team from numbers randomised using Fishers exact test]
Funding:
Rhone Poulence Rorer

Limitations:
  • This was an equivalence study, maximum difference of 7% in incidence of venous thrombosis between 2 groups. Powered at 80%, n required was 244 per group. Total number was less than calculated sample size because study stopped when I fibrinogen stopped being marketed in 1991.
  • 37 patients in enoxaparin group and 34 patient sin UFH group had asymptomatic decrease in Hb ≥20g/L, and was not counted as major bleeding. Hemodilution was cited as reason, but it was not reported whether these patients were the ones with hemoconcentration upon inclusion.
Outcomes not reported:
Fatal PE, PE asymptomatic or symptomatic, Fatal bleeding, Neurological bleeding, Upper GI bleeding, PTS, Pulmonary hypertension, QoL, LOS

Additional outcomes reported:
  • Symptomatic VTE- 7/20 of patients with VTE were symptomatic: 1 PE6 lower extremities.
  • 18% presented with hemoconcentration upon inclusion. 37 patients in the enoxaparin group and 34 patients in the UFH group had asymptomatic decrease of ≥ 20g/L in Hb levels. The investigators considered that these were due to hemodilution.
Notes:
Symptomatic pulmonary embolism (confirmed by: perfusion lung scan)Group 1: 0/216
Group 2: 1/207
P value: 0.49
calculated by NCC-AC team from numbers randomised using Fishers exact test
DVT, asymptomatic or symptomatic (Fibrinogen scan, conducted within 24 hours of enrolment, and everyday, thereafter in both legs)Group 1: 10/216
Group 2: 9/207
P value: 1.00
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Thigh DVT(confirmed by: as in DVT)Group 1: 2/216
Group 2: 4/207
P value: 0.44
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Calf DVT (confirmed by: as in DVT)Group 1: 8/216
Group 2: 5/207
P value: 0.49
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Major bleeding (description: clinical, associated with either a fall of haemoglobin 20g/l, need for transfusion of ≥2 blood units, bleeding was retroperitoneal or intracranial)Group 1: 2/223
Group 2: 1/216
P value: 1.00
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Minor bleeding (description: haematuria in the LMWH group, 1 epistaxis, 1 haematemesis in the UFH group)Group 1: 2/223
Group 2: 1/216
P value: 1.00
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Heparin induced thrombocytopenia (patient had normal platelet count upon inclusion, asymptomatic thrombocytopenia on Day 9 which resolved spontaneously on 15 days after discontinuation of heparin )Group 1: 1/223
Group 2: 0/216
P value: 1.0
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Cohn et al., 1999124

Country of study: United states

Study design: RCT

List who was masked to interventions: Double blinded

Evidence level: 1+

Duration of follow-up: Up to 30 days
Patient group:
Trauma patients-moderate injuries (predominantly blunt trauma)

Setting:
Level 1 trauma centre (Yale, New Haven)

Inclusion criteria:
Trauma patients with at least one of the following risk factors:
  • Age >45
  • Expectation of >2 days bed rest
  • History of DVT or PE
  • Coma (Glasgow coma score (GCS)<7)
  • Pelvis fracture
  • Lower extremity facture
  • Repair of major lower extremity vein
  • Complex wound of lower extremity
  • Femoral catheter
Exclusion criteria:
Patient meet any of the following criteria All patients
N: 104
Age (mean): not stated
M/F: not stated
Additional risk factors: ISS (injury severity score= 12)

Group 1: UFH
No. randomised: 53
No. of dropouts: 21
Penetrative injury: 0
Orthopaedic injuries:29
ISS: 13±14
Penetrating injury: 0

Group 2: LMWH
No. randomised: 51
No. of dropouts: 17
Penetrative injury: 2
Orthopaedic injuries:32
ISS: 10±5
Penetrating injury: 2
Group 1
Unfractionated heparin (UFH)
Dose: 5000IU subcutaneously
Frequency: twice a day
Group 2
LMWH (which one?)
Dose: 30mg subcutaneously
Frequency: twice a day

Start: within 24 hours of trauma
End time: until patients were fully ambulatory or discharged, or 30 consecutive 24-hour period, which ever was longer,
Duration: up to 30 days

Additional non- comparative prophylaxis:
None.
Patients were not allowed any elastic stocking, calf compression boots or anti-platelet drugs while under evaluation

Received vena cava filters:
UFH: 3
LMWH:2
DVT, asymptomatic or symptomatic (confirmed by: Doppler ultrasound, weekly)Group1: 2/32 (6.25%)
Group 2: 0/34
P value: 0.23
[#values calculated by NCC-AC staff, using Fisher’s exact test]
Funding:
Not stated
Limitations:
  • High drop out rate-36.5%, power diminished. Not ITT analysis
  • Which LMWH was used?
Outcomes not reported:
All cause mortality, Symptomatic PE, Symptomatic or asymptomatic PE, Symptomatic DVT, Thigh DVT, Calf DVT
Fatal bleeding, Neurological
Bleeding Upper GI bleeding, HIT, Post thrombotic syndrome, Pulmonary hypertension, QoL

Additional outcomes reported:
  • 5 patients of each arm had “bleeding complications”. It was not clear whether these were major bleeding, as major bleeding had been defined. It was decided that the bleeding data not to be included after discussion among reviewers.
  • Not stated from which treatment arm: (removed from evaluable group)Thrombocytopenia, n=2, excessive bleeding, n=1
Notes:
Regular weekly ultrasound scan for DVT
Symptomatic pulmonary embolism (Confirmed by: patients with clinical signs of PE(hypoxia, tachypnea, chest pain, tachycardia) would be evaluated by ventilation and perfusion scan and/or angiogramGroup1: 0/53
Group 2: 0/51
P value: 1.0
Length of stayGroup1: 12±9 days
Group 2: 12± 0 days
P value: NS
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Colwell et al., 1995130Multicentre RCT involving 25 centres.1+Total:
453

Intervention :
n = 228
Control:
n = 225
Type of surgery: Elective knee arthroplastyType:
Enoxaparin 30mg every 12 hours
Type:
Unfractionated heparin 5000 units every 8 hours
Treatment period up to 14 days, follow up approx 3 weeks after last doseDVT Confirmed by: US or venographyInt: 54/145
Control: 74/143
p value: 0.02
Comments:
Only 63.6% of patients evaluated. Multicentre 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.
Also reported: incidence of DVTs diagnosed from all means including symptomatic, broken down into distal and proximal.
Intervention: Mean age: 67.5± 9.5 yrs
M/F:107/121
Timing:
started day of surgery (within 8hours of surgical closure) and continued for a minimum of 4 days and maximum of 14 days.
Timing:
started day of surgery (within 8hours of surgical closure) and continued for a minimum of 4 days and maximum of 14 days.
PE Confirmed by: ventilation perfusion scan or pulmonary angiographyInt: 0/145
Control: 1/143
p value: 0.4965
Control: Mean age: 68.6± 8.8 yrs
M/F:91/134
Total haemorrhage episodesInt: 46/228
Control: 52/225
p value: 0.2470
Major haemorrhage episodes (major not defined)Int: 3/228
Control: 3/225
p value: 1.000
Additional non- comparative prophylaxis:
none reported
Additional non- comparative prophylaxis:
none reported
Minor haemorrhage episodes (minor not defined)Int: 43/228
Control: 49/225
p value: 0.4840
Length of Hospital Stay (Mean±SD, range)Int: 7±2 days
range: 1–14 days
Control: 7.1±2 days
range: 2–15 days
p value: not significant
Not reported:
PTS, QoL, length of hospital stay, survival.
Funding:
not reported
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Diener et al., 2006165 (PROTECT trial)

Country of study: EU

Study design: RCT, double blinded, multicentre

List who was masked to interventions: Investigators and patients. End point committee

Evidence level: 1+

Duration of follow-up: 3 months
Patient group: Acute ischaemic stroke

Setting: 37 centres in EU, most patients treated in stroke units

Inclusion criteria:
  • Age 18 to 85 years with clinical diagnosis of ischaemic stroke
  • NIHSS score of 4 to 30, with mild to severe paresis of a leg.
Exclusion criteria:
  • Indication of thrombolysis
  • No availability of CT scan
  • Ct documented signs of intracerebral or subarachnoid bleeding
  • Current bleeding or thrombosis
  • History of bleeding or thrombosis within the past 12 months
  • Recurrent gastrointestinal ulcerations
  • Post thrombotic syndrome
  • Acute or unstable cardiovascular disease
  • Major infection
  • Currently active, recurrent or metastatic cancer within the last 5 years
  • Platelet count <75000/microL
  • Severe diabetic retinopathy
  • Estimated body weight <55jg
  • Pregnant or breast feeding
All patients
N: 545

Group 1
No. randomised: 273
Per protocol: 248
M/F: 164/109
Age (mean ±SD): 67.3 ±10.6
Additional characteristics: Group 2
No. randomised: 272
Age (mean ±SD): 66.3 ±10.9
Per protocol: 242
M/F: 149/123
Additional characteristics:
Group 1
UFH 5000IU, 3 times daily, subcutaneously
Start: 15.4±6.2

Group 2
Certoparin 3000U anti Xa once daily, subcutaneously, plus 2 placebo injections
Start: 15.4±6.2

All treatment started within 24 hours of stroke symptom onset
Duration: 12–16 days

Additional non- comparative prophylaxis:
Ticlopidine, clopidogrel, or aspirin alone (≤325mg daily) or in combination with dipyramidole allowed

Aspirin
Group 1:78.4%
Group 2:77.2%
Aspirin + dipyramidole
Group 1:11.7%
Group 2:17.6%
Clopidogrel
Group 1: 17.6%
Group 2: 16.9%
Ticlopidine
Group 1: 4.4%
Group 2: 2.9%

No mention of mechanical prophylaxis methods
All cause mortality (confirmed by: Autopsy whenever allowed. Stroke progression as cause of death: n=4 in certoparin, n=3 in UFH during treatment period. At 3 month follow up, n=3 in certoparin, n=1 in UFH)Treatment period
Group1: 7/273
Group 2: 7/272
P value: 1.0

Between treatment period and 3 month follow up:
Group1: 8/273
Group 2: 14/272
P value: 0.2

Total: up to 3 month follow up:
Group1: 15/273
Group 2: 21/272
P value: 0.31
[p values calculated by team at NCCAC suing Fisher’s exact test]
Funding:
Novartis

Limitations:
  • Percentages of patients with concurrent antiplatelet agents were not reported
  • Seemed to have involved both stroke unit centres and non-stroke unit centres- outcomes not compared
Outcomes not reported:
Calf DVT, PTS, Pulmonary hypertension, QoL, LOS

Additional outcomes reported:
Causes of death

NOTES:
  • Patients screened for DVT at baseline with duplex and compression ultrasonography.
Fatal pulmonary embolism (confirmed by: Not autopsy performed. Suspected, because D-dimer positive but no signs of cardiac aetiology found)Group1: 1/273
Group 2: 0/272
P value: 1.0
[p values calculated by team at NCCAC suing Fisher’s exact test]
Symptomatic pulmonary embolism (confirmed by: no clinically suspected PE)Group1: 1/273
Group 2: 0/272
P value: 1.0
[p values calculated by team at NCCAC suing Fisher’s exact test]
Proximal DVT, asymptomatic or symptomatic (confirmed by: Duplex and compression ultrasonography. Routinely scanned at Days 3–4, 7–8, 12–16 and when clinical symptoms occurred )Group1: 23/273
Group 2: 18/272
P value: 0.52
[p values calculated by team at NCCAC suing Fisher’s exact test]
Note: all were reported as proximal DVT
Fatal bleeding (description: 1 intracranial bleeding was confirmed by autopsy-during treatment period. At 3 month follow up, 1 severe bleeding in the UFH group was confirmed by autopsy. The bleeding type of the LMWH group was not reported )During treatment period
Group1: 1/273
Group 2: 0/272
P value:

Between treatment period and 3 month follow up:
Group1: 1/273
Group 2: 1/272
P value:
[p values calculated by team at NCCAC suing Fisher’s exact test]
Major bleeding at 16 days
(description: intracranial (only if parenchymal), retroperitoneal, gastrointestinal resulted in death, clinically overt and led to transfusion of ≥ U of packed RBC/whole blood, or Hb fall of ≥ 2g/dL)
Group1: 5/273
Group 2: 3/272
P value: 0.73
[p values calculated by team at NCCAC suing Fisher’s exact test]
Neurological bleeding
CT scan performed at baseline, Days 7 to 8 routinely and anytime in the case of clinical suspicion of intracranial haemorrhage
Group1: 3/273
Group 2: 2/272
P value: 1.0
[p values calculated by team at NCCAC suing Fisher’s exact test]
Upper GI bleedingGroup1: 2/273
Group 2: 0/272
P value: 0.5
Minor bleeding (description: bleedings which did not meet classification of major bleeding )Group1: 5/273
Group 2: 7/272
P value: 0.58
[p values calculated by team at NCCAC suing Fisher’s exact test]
Heparin induced thrombocytopaenia(suspecte d cases, not measurement of antibodies performed to confirm)Group1: 2/273
Group 2: 1/272
P value: 1.0
[p values calculated by team at NCCAC suing Fisher’s exact test]
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Farkas et al 1993181RCT1+Total: 233
Intervention : n = 122
Control: n = 111

269 patients randomised, 36 excluded
Type of surgery: Vascular surgery – aortic or aortoiliac and aneurysmectomy; aorto- femoral bypass for atherosclerotic disease; and femoropopliteal or femorodistal bypass.Type: LMWH (Enoxaparin)
Dose: 2100 IU pre-op, then 4200 IU
Type:
Unfractionated heparin Dose: 5000 units pre- op, 7500 units post-op
1 monthDVT Confirmed by: Duplex US, confirmed by venography on 7th–10th day post- op. Earlier if clinical suspicionInt: 10/122
Control: 4/111
p value: Not significant)
Comments: Numbers in each group for baseline data do not tally with text. Arterial patency also assessed by duplex US scanning. No significant differences observed between groups in terms of development of post-op arterial thrombosis.

Thrombocytopenia (which resolved spontaneously within 3 days) reported in 2 LMWH patients.

Not reported: PVT, PTS, QoL, LoS,

Funding: Trial supported by grant from Labaratoires Pharmuka, France.
Mean duration of surgery:
Intervention: 4.2±1.4 h
Control: 4.2±1.5h
Timing: Begun day pre-op and repeatedly daily until 7th day post- opTiming: Begun day pre-op and repeated twice daily until 7th day post-opPE Confirmed by: Clinical suspicion investigated by angiogramInt: 0/122
Control: 0/111
p value: N/A
Intervention: Mean age: 65±11 yrs
M/F:101/25
Additional non- comparative prophylaxis: Intraoperative use of UFH (94.4%) or protamine (7.9%) was authorised in both groupsAdditional non- comparative prophylaxis: Intraoperative use of UFH (97.4%) or protamine (9.4%) was authorised in both groupsPreoperative red blood cell unitsInt: 3.91±2.79 units
Control: 3.61±1.91
p value: Not significant
Control: Mean age: 64±11 yrs M/F:99/18Post-operative suction drain volumeInt: 423±438ml
Control: 408±455ml
p value: Not significant
Pre-existing risk factors: Past history of VTE, age, obesity, varicose veins, COPD (no significant diffs between groups apart from COPD – more in LMWH group, p=0.02).SurvivalInt: 120/122
Control: 111/111
p value: not reported
Faunø et al 1994183RCT1+Total: 185
Intervention : n = 92
Control: n = 93

224 patients randomised . 39 excluded (16 LMWH, 23 UH)
Type of surgery: Unilateral knee replacement

Duration of operation:
Intervention: 102±24 min
Control: 104±20

Intervention: Mean age: 70±10 yrs
M/F:38/55

Control: Mean age: 71±11
M/F:35/57

Pre-existing risk factors: Not reported
Type: LMWH (Enoxaparin) Dose: 40 mg

Timing: Begun evening pre-op and repeated daily until 7–10th day post-op.

Additional non- comparative prophylaxis: Short compression stocking on involved limb and long compression stocking on uninvolved limb.
Type: UH Dose: 5000 IU

Timing: Begun evening pre-op and repeated 3 times daily until 7–9th day post-op.

Additional non- comparative prophylaxis:
Short compression stocking on involved limb and long compression stocking on uninvolved limb.
2 monthsDVT Confirmed by: bilateral ascending venography on 7–9th day post-opInt: 21/92
Control: 25/93
p value: 0.6 Not significant
Also reported: total blood loss, decrease in haemoglobin levels, transfusion requirements
PVT Confirmed by:
bilateral ascending venography on 7–9th day post-op
Int: 3/92
Control: 5/93
p value: Not reported
PE Confirmed by: Not routinely assessed. Clinical suspicion investigated with V/Q scanInt: 0/92
Control: 0/93
Wound haematomaInt: 8/92
Control: 12/93
p value: 0.5
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Geerts et al., 1996218

Country of study: Canada

Study design: RCT, double blinded, patients stratified according to the presence or absence of lower extremity fractured

List who was masked to interventions: Patients and investigators

Evidence level: 1++

Duration of follow-up: Up to 14 days
Patient group:
Major trauma patients, adult

Setting:
Level I trauma facility in Canada

Inclusion criteria:
Consecutive adult trauma patients admitted to the trauma centre, who did not have any of the exclusion criteria

Exclusion criteria:
Any of the following
-

Injury severity score (ISS) <9

-

Likely to survive or remain in hospital for <7 days

-

Frank intracranial bleeding on computed tomographic scans (cerebral contusion, localized petechial haemorrhages, or diffuse axogonal damage were not excluded)

-

Bleeding that remained uncontrolled 36 hours after the injury

-

Systemic coagulopathy; prothrombin time (PTT) >3s above control value

-

Platelet count <50,000/mm3

-

Needed therapeutic anticoagulation

-

Cannot undergo venography (allergy to contrast material)

-

renal failure (defined as a serum creatinine level higher than 3.4 mg per deciliter [300 μmol per liter])

-

pregnant

-

venous access could not be achieved because of amputation or a major foot injury

All patients
N: 344
No of dropouts: 13
No of patients with sufficient venography: 265 (77%)
M/F: 192/265*
99/136 group 1, 93/129 Group2

Group 1
No. randomised: 173
No. of dropouts: 7
Additional risk factors*:
-

Age (year): 37.0±16.5

-

ISS: 22.7±9.0

-

Predicted risk of DVT: 54.7±26.3

-

Surgery performed: 119/136,

-

Blood transfusion in the first 24 hours: 48/136,

-

Maximal mobility (mean of daily corrected score): 2.4±1.0

-

Hospital stay (days): 23.5±13.8

-

Site of major injury:

  • Head: 6/136
  • Face, chest, abdomen: 53/136 Spine: 24/136
  • Lower limb (orthopaedic injury): 75/136
Group 2
No. randomised: 171
No. of dropouts: 6
Additional risk factors*:
-

Age (year): 39.1±16.8

-

ISS: 23.1±8.3

-

Predicted risk of DVT: 53.5±25.4

-

Surgery performed: 107/129

-

Blood transfusion in the first 24 hours: 55/129

-

Maximal mobility (mean of daily corrected score): 22.4±1.0

-

Hospital stay (days): 26.0± 15.4

-

Site of major injury:

  • Head: 7/129
  • Face, chest, abdomen: 47/129
  • Spine: 16/129
  • Lower limb (orthopaedic injury): 69/129
* Information based on patients with adequate venography (n=265)

Predicted risk of thrombosis was calculated using this formula:
ex1+ex
Group 1
heparin calcium, 5000u, 12hourly.

Group 2
Enoxaparin (Clexane), 30 mg

For both groups: Given as 0.3-ml subcutaneous injections every 12 hours in a blinded fashion with preloaded syringes.

Start: within 36 hours of the injury
Duration: up to 14 days.

Additional non- comparative prophylaxis:
No mechanical or other pharmacologic methods of antithrombotic prophylaxis were allowed by the protocol The study drug was generally not withheld in the event of a surgical procedure, although in exceptional circumstances such as spinal fixation, a single preoperative dose was permitted to be withheld. Treatment with the study medication was then resumed at the first dosing time after the operation.
All cause mortalityGroup1: 0/173
Group 2: 2/171
P value: 0.25
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Funding:
Ontario Ministry of Health, Rhone Poulenc Rorer provided study medications, Mallinckrodt Medical Inc provided contrast agent for venography

Limitations:
-

Single site study

-

Method of randomisation concealment not well described

Outcomes not reported:
Upper GI bleeding QoL, Pulmonary hypertension

Additional outcomes reported:
Blood transfusions:
Heparin: 99/173, 3.8±2.6 units
Enoxaparin: 101/171, 4.2±3.1 units

Marder Scores:
Heparin (n=136): 2.3±5.0
Enoxaparin (n=129): 1.0±2.8
(P value: 0.012 by Wilcoxan rank sum test provided by report)

Notes:
Out of 1076 admissions into the unit, 698 (64.9%) were not eligible

The neurological bleeding cases were included in major bleeding.
Fatal pulmonary embolism (confirmed by: autopsy)Group1: 0/173
Group 2: 0/171
P value: 1.00
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Symptomatic pulmonary embolism (Confirmed by: ventilation perfusion scan in patients with clinical presentation. Patients with nondiagnostic scans underwent pulmonary angiography, venous ultrasonography, contrast venography, or a combination of these, if necessary, within 24 hours after the scanning)Group1: 0/136
Group 2: 1/129
P value: 0.49
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
DVT, asymptomatic or symptomatic (confirmed by: venography of both legs with ioversol, a non-ionic contrast agent between Day 10 and 14, or just before discharged if it occurred earlier. DVT was defined as a constant intraluminal filling defect in a deep leg vein that was seen on ≥ 2. See above for symptomatic DVT) )Group1: 60/136
Group 2: 40/129
P value: 0.014 (reported)
[P=0.03, calculated by NCC-AC team from numbers randomised using Fishers exact test]
Thigh DVT(confirmed by: Proximal-vein thrombosis was defined as thrombosis involving the popliteal or more proximal veins.)Group1: 20/136
Group 2: 8/129
P value: 0.012
[P=0.03, calculated by NCC-AC team from numbers randomised using Fishers exact test]
Calf DVT (confirmed by: see DVT )Group1: 40/136
Group 2: 32/129
P value: 0.27
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Fatal bleeding (description: confirmed by autopsy)Group1: 0/173
Group 2: 0/171
P value: 1.0
Major bleeding (description: Sites: chest tube, 1000ml of epistaxis, intraoperative, subdural haematoma, facial soft tissues, retroperitoneum )Group1: 1/173
Group 2: 5/171
P value: 0.12
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Neurological bleeding (Subdural haematoma with hemiparesis 4 days after craniotomy for severe skull fracture)Group1: 0/173
Group 2: 1/171
P value: 0.50
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Heparin induced thrombocytopenia (confirmed by heparin- dependent IgG antibodies)Group1: 2/173
Group 2: 0/171
P value: 0.50
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Length of stayGroup1: 23.5±13.8
Group 2: 26.0± 15.4
P value:
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Goldhaber et al., 2002225RCT1+Total: 150

Intervention : n = 75 (DVT assessed in)

Control: n = 75 (DVT assessed in)
Type of surgery: Patients undergoing craniotomy with suspected or metastatic brain tumour

Excluded people with a history of overt bleeding, heparin allergy or VTE within the prior 6 months

Intervention: Mean age: 48.33 (±15.07) yrs
M/F:39/36

Control: Mean age: 48.87 (±12.52) yrs
M/F:40/35

Pre-existing risk factors: not reported
Type: LMWH (Enoxaparin)
Dose: 40mg/in the morning, placebo in the evening

Timing: Begun morning of 1st postoperative day and continued until discharge or VTE diagnosed.

Additional non- comparative prophylaxis: graduated compression stockings (73/75 participants) intermittent pneumatic compression devices (72/75 participants)
Type: UFH
Dose: 5000 IU twice per day

Timing: Begun morning of 1st postoperative day and continued until discharge or VTE diagnosed.

Additional non- comparative prophylaxis: graduated compression stockings (72/75 participants) intermittent pneumatic compression devices (71/75 participants)
30 daysDVT Confirmed by duplex ultrasonographyInt: 9/75
Control: 5/75
p value: 0.401
Patients scanned one day prior to, or on day of discharge

Funding
Research grant from Aventis

Not reported: PTS, QoL
Symptomatic DVT Confirmed by duplex ultrasonographyInt: 0/75
Control: 0/75
p value: not sig
Proximal DVT Confirmed by duplex ultrasonographyInt: 2/75
Control: 2/75
p value: 1
Unilateral calf DVT Confirmed by duplex ultrasonographyInt: 6/75
Control: 2/75
p value: 0.276
Bilateral calf DVT Confirmed by duplex ultrasonographyInt: 1/75
Control: 1/75
p value: 1
Major postoperative bleeding complicationsInt: 2/75
Control: 1/75
p value: 0.57
Length of stayInt: 6.07 ±3.56 days
Control: 5.75 ±3.24 days
p value: 0.566
MortalityInt: 0/75
Control: 0/75
p value: not sig
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Green et al., 1990233

Country of study:
USA

Study design:
RCT

List who was masked to interventions:
unclear

Evidence level:
1+

Duration of follow-up:
8 weeks
Patient group: Trauma, complete motor paralysis after spinal cord injury

Setting:
A regional spinal cord injury care centre in US

Inclusion criteria:
  • Complete motor and spinal surgery sustained within the preceding 72 hours
Exclusion criteria:
  • Bleeding injuries not accessible to haemostatic control
  • Severe trauma to the head or lower extremities as well as spinal column
  • Coagulopathy or evidence of thrombosis at baseline examination
  • Cardiovascular instability
  • Refusal by patient or next of kin to give informed, written consent
All patients
N: 41 2 patients in each group failed to complete the planned 8 week trial, because they were transferred 4–29 days after initiation of therapy to other institutions. None of these patients experienced bleeding or thrombosis

Group 1
No. randomised: 21
No. of dropouts: 2
Age (mean): 31.4±15.5
M/F: 17/4
Additional risk factors:
 Spinal injury location:
  • Cervical:13
  • Thoracic:6
  • Lumbar:2
Baseline activate thromboplastin time, aPTT (s): 28.0±2.5

Group 2
No. randomised: 20
No. of dropouts: 4
Age (mean): 28.3±11.8
M/F: 17/3
Additional risk factors:
 Spinal injury location:
  • Cervical: 10
  • Thoracic: 9
  • Lumbar: 1
Baseline activate thromboplastin time, aPTT(s): 27.7±3.3
Group 1 Heparin 5000unit, 8 hourly, subcutaneous.

Group 2
logiparin (tinzaparin) 3500anti-Xa, subcutaneously, once daily

Start time: at least 24 hours after injury. If patient require surgery, morning dose of either heparin or LMWH was withheld, and treatment resumed the following morning

End time not explicitly stated.

Patients on heparin received drugs for and average of 40±19 days (total of 843 days for 21 patients).
Patients on LMWH received drugs for and average of 47±16 days (total of 945 days for 20 patients).

Additional non- comparative prophylaxis:
Other prophylactic measures such as calf- compression boots, elastic stockings and aspirin were withheld.
All cause mortality (confirmed by: )Group1: 2/21
Group 2: 0/20
P value: 0.49
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Funding:
National Institute of Disability and Rehabilitation Research, Department of Education.
Novo Lab supplied logiparin.

Limitations:
  • Unmasked: different dosing regimen
  • Duration of prophylaxis not stated a priori, criteria for discontinuation not stated.
  • Haematoma, melaena and haematuria were considered bleeding events if they necessitated the discontinuation of prophylactic therapy and decisions made by ward physicians not participating in the study. Unclear if they were blinded to the study.
  • 2 patients from each arm transferred out not stated whether analysis based on randomised patient.
Outcomes not reported:
Symptomatic PE, PE asymptomatic or symptomatic, Calf DVT, Heparin induced thrombocytopaenia, PTS, Pulmonary hypertension, QoL

Additional outcomes reported:
  • aPTT for bleeding and thrombotic events
  • Patients on LMWH had more venous studies completed, and more days on prophylaxis.
Notes:
  • Study did not report exclusion criteria based on age. Uncertain whether children/teenagers were included
  • 2 patients in LMWH temporarily switched to heparin at Day 22 and Day 23 because LMWH was temporarily not available
Fatal pulmonary embolism (confirmed by: autopsy)Group1: 2/21
Group 2: 0/20
P value: 0.49
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Symptomatic DVT (confirmed by: abnormal flow study)Group1: 1/21
Group 2: 0/20
P value: 1.0
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
DVT, asymptomatic or symptomatic (confirmed by: 2 patients confirmed by venography, 3rd patients confirmed by symptom and abnormal flow study. Patients screened with impedence plethysomography, Doppler flow measurement and DUS twice weekly in the first 2 weeks, once weekly for the next two weeks, and biweekly for the next 4 weeks )Group1: 3/21
Group 2: 0/20
P value reported: 0.02 (Kaplan Meier Log rank test.)
P value: 0.23 [calculated by NCC-AC team from numbers randomised using Fishers exact test]
Thigh DVT (confirmed by: see DVT. 1 patient; superficial femoral vein, 1 patient popliteal vein, patient had both femoral and popliteal vein)Group1: 3/21
Group 2: 0/20
P value: 0.23
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Fatal bleeding (description: )Group1: 0/21
Group 2: 0/20
P value: 1.0
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Upper GI bleedingGroup1: 1/21
Group 2: 0/0
P value: NS
Minor bleeding (description: “ 2 patients had bleeding severe enough to require discontinuation of heparin therapy; in both the aPTT was considerably prolonged”
Patient 1: neck hematoma, aPTT: 44.5s
Patient 2: gastrointestinal and genitourinary bleeding, aPTT: 38.0
Group1: 2/21
Group 2: 0/20
P value: 0.49
[calculated by NCC-AC team from numbers randomised using Fishers exact test]
Length of stayGroup1: 40±19 days
Group 2: 47±16 days
P value: not reported
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Haas et al., 2005244RCT1+Total: 23,078

Intervention : n = 11,542 60 did not undergo surgery but were included in the analysis as part of an intention to treat analysis

Control: n = 11,536 44 did not undergo surgery but were included in the analysis as part of an intention to treat analysis
Type of surgery: Mixed: patients over 40 undergoing surgery not less than 30 minutes between 1991 and 1996 at 67 centres in Germany, Austria and the Czech Republic

Procedure:
General: 17,057
Gynaecology: 2351
Traumatology: 1580
Orthopaedics: 1425
Urology: 402
Other: 159
No surgery: 104

Exclusion criteria: severe hypertension imparied renal or hepatic function; any haemostatic or bleeding disorder; previous inclusion in a trial within the preceding 4 weeks; pregnancy; lactation or known contraindication to heparin.

Age & Gender: Intervention: Median age: 58 yrs M/F: 5021/6521

Control:
Median age: 58 yrs
M/F: 4995/6541
Type: LMWH (Centoparin)
Dose: 3000 anti Xa IU subcutaneously once per day plus placebo injections

Timing: Begun not less than 2 hours prior to surgery and continued for a minimum of 5 days and maximum of 20 days.

Additional non- comparative prophylaxis: Other drugs known to alter blood coagulation were restricted and only prescribed if unavoidable. Treatments such as GCS and other types of physiotherapy were used according to normal practice at those centres.

Spinal anaesthesia: 1153/11542
Epidural anaesthesia: 65/11542
Type: LDUH
Dose: 5000 IU subcutaneously 3 times per day

Timing: Begun not less than 2 hours prior to surgery and continued for a minimum of 5 days and maximum of 20 days.

Additional non- comparative prophylaxis: Other drugs known to alter blood coagulation were restricted and only prescribed if unavoidable. Treatments such as GCS and other types of physiotherapy were used according to normal practice at those centres.

Spinal anaesthesia: 1086/11536
Epidural anaesthesia: 63/11536
14 daysFatal pulmonary embolism* confirmed by autopsy.Int: 17/11,542
Control: 18/11,536
p value: 1.0
Comments:
* PE regarded as primary cause of death if autopsy revealed obstruction of the pulmonary trunk or fesh emboli in either two pulmonary arteries or two lobar arteries.

Not reported: DVT, Proximal DVT, symptomatic PE, PTS, QoL, LoS

Also reported: incidence of fatal PE and death by surgical procedure; blood loss in drainage tubes; no. of patients requiring and volume of blood transfusion,
MortalityInt: 166/11,542
Control: 146/11,536
p value: 0.28
No. of deaths having an autopsyInt: 114/166 (68.7%)
Control: 105/146 (71.9%)
Thrombocytopeni a (not stated how confirmed)Int: 21/11,542
Control: 16/11,536
p value: not sig
Bleeding complicationsIntervention group:
Postop wound bleeding: 34
Haemorrhagic stroke: 10
Gastric bleeding: 2
Intestinal bleeding: 4
Abnormal uterine bleeding: 1

Comparison group:
Postop wound bleeding: 35
Haemorrhagic stroke: 7
Gastric bleeding: 7
Intestinal bleeding: 3
Abnormal uterine bleeding: 2
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Haas et al., 2006242 (ECHOS trial)

Country of study:
Multicentre study: Europe

Study design:
RCT

List who was masked to interventions:
Double-blind study

Evidence level:
1+

Duration of follow-up:
6–8 weeks after discharge (9–10 weeks in a proportion of cases).
Patient group:
Patients undergoing elective total hip (THR)- 68.3% or knee replacement (TKR)-31.7%

Setting:
Multinational study

Inclusion criteria:
Patients ≥40 years undergoing THR or TKR, whose projected hospital stay was al least 11 days.

Exclusion criteria:
  • Previous history of VTE ≥ 6 months
  • a positive D-dimer bedside test (SimpliRed) or any signs of acute thrombosis
  • body weight of < 45 kg or > 100 kg
  • known contraindications to heparin
  • allergy to contrast media
  • congenital or acquired hemorrhagic diathesis
  • thrombocytopenia (platelets < 100000 per cubic milimiter)
  • macroscopic haematuria
  • cerebrovascular stroke
  • intracranial or intraocular bleeding within past 6 months
  • active peptic ulcer, other gastro-duodenal bleeding within past 6 months
  • active advanced malignant disease
  • impaired liver or renal function; nephritic syndrome
  • uncontrolled hypertension
  • Taking anticoagulants, platelet aggregation inhibitors (except for aspirin < 300 mg per day) up to 8 days before surgery
  • Pregnant, breastfeeding, <6 months postpartum
  • Childbearing potential, not taking contraceptive precautions
  • Drugs or alcohol abuse
  • Participated in investigational drug studies within 4 weeks prior to study entry.
All patients
N: 2018
THR: 1233
TKR: 782

Group 1; LMWH
No. randomised: 1013
No. of dropouts: n=1 not included in safety outcomes
n=200 not evaluated for efficacy outcomes
THR (n): 620 (61.3 %)
TKR (n): 392 (38.7%)
General anesthesia (%):61.3%
Cement prosthesis (n): 678 (67%)
Duration of surgery (min)- median (range): 85 (30–320)
Age mean (+/SD): 66.1 +/− 9.3
Weight (kg): 76.6 +/− 12.1
Height (cm): 165.8 +/− 8.3
Female (n): 676 (66.8%)
BMI (kg/m2):27.8 +/− 3.8

Group 2: UFH up
No. randomised: 1005
No. of dropouts: n=2 not included in safety outcomes
n= 190 not evaluated for efficacy outcomes
THR (n): 613 (61.1%)
TKR (n): 390 (38.9%)
Duration of surgery (min)- median (range): 85 (28–260)
General anaesthesia (%): 60.9%
Cement prosthesis (n): 692 (69%)
Age mean (+/SD): 66.9 +/− 9.8
Weight (kg):77 +/− 12.4
Height (cm):166.3 +/− 8.45
Female (n):655 (65.3%)
BMI (kg/m2): 27.8 +/− 3.9
Group1:
LMWH
Reviparin
4200 IU once daily + one placebo injection

Group 2:
UFH
7500 IU subcutaneous bd

Start: Evening before surgery, administered the following day 6–8 h after surgery and given at 6–8 a.m. and 6–8 p.m. on subsequent days. Duration: 11 to 14 days, until venography was performed.

Additional non- comparative prophylaxis:
  • All thromboprophylactic medication was withdrawn before treatment initiation. Aspirin <300mg/day allowed
  • Postopreative NSAIDS allowed
  • Mechanical methods e.g. GCS, physiotherapy, early mobilization, were routinely provided.
  • Additional thrombophrophylaxis (e.g. sequential intermittent pneumatic compression) was excluded.
All cause mortality:Until Day 11–14
Group 1; 2/813
Group 2: 2/815
P value: 1.00*
(Two patients died of acute myocardial infarction (one in each group), one due to a fatal PE (UFH) and one due to sudden cardiac arrest (LMWH) Information from text (page 338)
Funding:
Supported by Abbott GmbH & Co. KG, Ludwigshafen, Germany.

Limitations:
  • Reporting quality - discrepancy in numbers of deaths in table vs text
Outcomes not reported:
Symptomatic DVT
Length of stay
Quality of life
Pulmonary hypertension
Post thrombotic syndrome

Additional outcomes reported:
  • % of patients using general vs regional anasthesia
  • Serious adverse events
  • Mean changes between baseline and discharge values for liver enzymes/
Notes:
% of patients not evaluated for efficacy =19.2%
Fatal pulmonary embolism (confirmed by: autopsy)Group 1; 0/813
Group 2: 1/815
P value: 1.00*
Symptomatic pulmonary embolism (confirmed by: Possible PE was assessed by ventilation- perfusion lung scan, pulmonary angiography, or by autopsy))Events until day 11–14
Group1:1/813 (0.1%)
Group 2: 1/815 (0.1%)
P value: 1.00*
“Three patients were confirmed to have PE between days 15 and 68 including two patients who had previously experienced a DVT”- treatment arm not stated
DVT, asymptomatic or symptomatic. Screened by systematic bilateral ascending contrast venography between days 11–14 after surgery or earlier if clinical signs of DVT occurred.
VTE during follow-up was determined by clinical symptoms and confirmatory venography.
All patients
Group1:200/813 (24.6%)
Group 2: 204/815 (25%)
P value: 0.86*
THR patients
Group1:87/494
Group2: 81/495
P value: 0.61*

TKA patients
Group 1: 113/319
Group 2: 124/320
P value: 0.41*
Thigh DVT(screened for by: Proximal DVT was defined as an intraluminal defect proximal to the knee joint space on venograms)Group1:25/813 (3.1%)
Group 2: 42/815 (5.2%)
P value: 0.045*

THR patients
Group1:19/494
Group2: 31/495
P value: 0.11*

TKA patients
Group 1: 6/319
Group 2: 114/320
P value: 0.33*
Calf DVT (screened for by: systematic bilateral ascending contrast venography between days 11–14 after surgery or earlier if clinical signs of DVT occurred)Distal DVT:
Group1:175/813 (21.5%)
Group 2: 162/815 (19.9%)
P value: 0.43*

THR patients
Group1: 68/494
Group2: 50/495
P value: 0.08*

TKA patients
Group 1: 107/319
Group 2: 112/320
P value: 0.08*
Fatal bleeding (description: Bleedings and death reported but no mention of fatal bleeding)Group1: 0/1012
Group 2: 0/1003
P value: 1.0*
Major bleeding (description: any severe overt bleeding; associated with a Hb drop ≥2g/dL within 24 h of the 1st postoperative day, transfusion of > 1500 mL of whole blood (except autologus transfusion); sero-sanguinous secretion at the wound site after day 6; hemorrhage requiring re-intervention and any retroperitoneal or intracranial haemorrhage or warranting permanent treatment cessation)Major bleeding (during treatment period day 1–14)
Group1:9/1012 (0.9%)
Group 2: 12/1003 (1.2%)
P value: 0.52*
Minor bleeding (description: small wound hematoma, wound oozing or hematoma not at the operation area, decreases of postoperative Hb concentration in the expected range and transfusion requirements within the normal range)Group1:38/1012 (3.8%)
Group 2: 29/1003 (2.9%)
P value: 0.32*
Heparin induced thrombocytopaeniaGroup1:0/1012 (0%)
Group 2: 0/1003 (0%)
P value: 1.00*
Harenberg et al., 1990256

Country of study:
Germany

Study design:
RCT, double blinded

List who was masked to interventions:
Investigators, patients

Evidence level:
1+

Duration of follow-up:
10 days
Patient group:
Mixed, inpatients

Setting:
Inpatients, single centre(?)

Inclusion criteria:
  • Aged 40–80 years
  • Confined bed rest for ≥1 week due to general medical illness after admission
Exclusion criteria: All patients
N: 200
No. of dropouts: 34 (completed less than ≥ 7 days of treatment)
Group 1
UFH 5000IU subcutaneously, 3x daily

Group 2
LMWH 1.50 aPTT units subcutaneously, plus 2 placebo injections, 8 hourly

Start time: not stated: Duration: 10days, range 7–12 days

Additional non- comparative prophylaxis:
No compression elastic compression stocking used.

Injections discontinued if patients spend less than 20/24 hours in bed.
All cause mortality [Not certain whether these mortality figures referred to all patients recruited (n=200) or just the 166 patients who finished the protocol]Group1: 1/83
Group 2: 3/89
P value: 0.62
[Calculated by NCCAC staff using Fishers exact test]
Funding: Not reported. Substances provided by Sandoz AG
Limitations:
  • Name of LMWH not stated- 3.8D 86 IU/mg and supplied by Sandoz
  • Clarity of report- dated outcomes measures?
Outcomes not reported:
All cause mortality, DVT, asymptomatic or symptomatic, Fatal bleeding, Major bleeding, Upper GI bleeding, Minor bleeding, Heparin induced

Additional outcomes reported:
aPTT values

Notes:
Only patients who completed ≥ 7 days of treatment were included in the analysis
DVT, asymptomatic or symptomatic (confirmed by: Doppler ultrasonography )Group1: 1/83
Group 2: 1/89
P value: 1.0
4 on each group was suspected based on impedance plethysmography

In table 5 of report, 4 patients in heparin group and 2 patients in LMWH group was reported as “suspicion of thrombosis”, 1 patient in LMWH group was reported as “thrombosis”.
Fatal bleeding (description: “1 patient treated with heparin developed gastrointestinal bleeding on day 8 and dies of cardiac failure)Group1: 1/83
Group 2: 0/89
P value: NS
Major bleeding (description: (description: “ 1 patient treated with heparin developed gastrointestinal bleeding on day 8 and dies of cardiac failure))Group1: 1/83
Group 2: 0/89
P value: NS
Main diagnosisGp1Gp2Upper GI bleeding (description: (description: “ 1 patient treated with heparin developed gastrointestinal bleeding on day 8 and dies of cardiac failure)Group1: 1/83
Malignancy1723Group 2: 0/89
Heart insufficiency1112P value: NS:
Coronary Heart Disease1112Minor bleeding (description: hematomas at injection site )Group1: 57%
Atrial Fibrillation34Group 2: 24%
Cerebral Ischaemia44P value:
Infections53Not certain whether percentages based on randomised group or efficacy group
Asthma Bronchiale22
Others1617
Risk FactorsGp1Gp2
Varicose veins5658
Cardiac Arrhythmias4231
Hypertension3628
Diabetes3219
Coronary heart disease2111
Stenosis A carotis189
Renal insufficiency178
Peripheral arterial disease114
Smoking1017
Cerebral Sclerosis64
Cardiomyopathy37
Hyperthyrodism34
Group 1
No. randomised: (not stated) 82 completed trial
No. of dropouts:
Age (mean): 65.8±9.9
M/F: 35/47

Group 2
No. randomised: (not stated) 84 completed trial
No. of dropouts:
Age (mean): 66.2±8.8
M/F: 39/45
Harenberg et al., 1996257

Country of study: Germany

Study design: Multicentre double blind study

List who was masked to interventions: Investigator and patients, critical event committee

Evidence level: 1+

Duration of follow-up: 10 days
Patient group:
Hospitalised, bed ridden patients with increased risk of thrombosis

Setting:
Inpatient, 10 centres in Germany

Inclusion criteria:
  • Aged 50–80 years
  • Expected duration of bedrest >10 days
  • ≥1 of the following risk factors present:
Exclusion criteria: The post operative phase is not an exclusion criteria

All patients
N: 1968 randomised, 378 excluded from efficacy analysis
Group 1
UFH 5000IU, 3 times daily, subcutaneously, at 8 hour intervals

Group 2
Fraxiparine 36mg (3100IU of antiXa), plus 2 placebo injections, 3 times daily, at 8 hour intervals

Start time: within 12 hours of admission to hospital
End time: day 11
Duration: 10 days

Additional non-comparative prophylaxis: (list or write not reported or not applicable)
All cause mortalityGroup1: 9/780
Group 2: 23/810
P value: 0.02
In group1, causes of death were carcinoma (4), pneumonia (1), chronic obstructive pulmonary disease (1), cardiac insufficiency (1), atrial fibrillation (1) and renal insufficiency (1) respectively.

In Group 2 causes of death were carcinoma (3), pneumonia (4), stroke (4), cardiac insufficiency (9), myocardial infarction (1) and PE (1) and diabetes (1) respectively.
Funding:
Not stated

Limitations:
  • Reporting focused on safety outcomes (blood test results), DVT and PE reporting not clear
  • Incidences of death and primary endpoints were not equally distributed between centres. In centres where no primary end points were observed, incidence of death the in LMWH group was 3.5x higher
Outcomes not reported:
PE asymptomatic or symptomatic DVT, asymptomatic or symptomatic, Thigh DVT, Calf DVT Fatal bleeding Neurological bleeding Upper GI bleeding Heparin induced thrombocytopaenia PTS, Pulmonary hypertension, QoL, LOS

Additional outcomes reported: 4 cases of thrombocytopenia in UFH group, 0 in fraxiparine.

Various clinical chemistry results

Notes:
DVT and PE events were combined and reported as “primary end points”.

Study was designed as an equivalence study. Emphasis of report was on “safety”-clinical chemistry.
Fatal pulmonary embolism (confirmed by: perfusion scintigraphy, additional angiography or ventilation scintiscan performed if results were low probability defects)Definite PE
Group1: 0/780
Group 2: 1/810
P value:
Probable PE
Group1: 3/780
Group 2: 3/810
P value:
16 patients death was classified as “possible” PE, but it was not stated which group they belonged to.
Symptomatic pulmonary embolism (confirmed by: perfusion scintigraphy, additional angiography or ventilation scintiscan performed if results were low probability defects))Probable PE
Group1: 3/780
Group 2: 3/810
P value:
DVT, asymptomatic or symptomatic

Or

Symptomatic DVT?? (screening at Day 1 and Day 11 and upon presentation of clinical signs)
Group1: 1/780
Group 2: 3/810
P value:

Not described whether symptomatic or asymptomatic. Likely to be all symptomatic cases, as none of them occurred on the day of planned scans.
Major bleeding no description of criteriaGroup1: 4/780
Group 2: 5/810
P value: 1.0
Minor bleeding no description of criteriaGroup1: 7/780
Group 2: 3/810
P value: 0.34
Main DiagnosisGp1Gp2
Cardiac insufficiency143150
Cerebrovascular diseases134149
Coronary heart disease131139
Cancer6357
Diabetes5747
Gastro. Or neph. Disease4538
Chronic obstructive lung disease4641
Pneumonia or infections1626
Other diseases144166
Group 1
No. randomised: 985
No. of dropouts: 205( 140 dropped out, 65 not eligible)
Age (mean): 70.4±7.9
M/F: 372/408
Additional risk factors: Group 2
No. randomised: 983
No. of dropouts: 173 (119 dropped out, 54 not eligible)
Age (mean): 70.5±8.3
M/F: 344/466
Additional risk factors: *p=0.02
Hillbom et al., 2002278

Country of study: Finland

Study design: Multicentre, double blinded, randomised study

List who was masked to interventions: Double blinded study

Evidence level: 1+

Duration of follow-up: 3 months
Patient group:
Acute ischaemic stroke

Setting:
7 centres in Finland. Inpatient

Inclusion criteria:
  • Acute ischaemic stroke, defined as acute onset of paralysis lasting at least 24 hours and necessitating bed rest
  • Confirmed by CT scan
Exclusion criteria:
  • Unconscious-Glasgow Coma Scale <9
  • Immobilised before onset of stroke
  • Evidence of haemorrhagic stroke
  • Stroke thought to be cardioembolic in origin
  • History of DVT, PE myocardial infraction, recent neurosurgery (within the last 3 months)
  • History of subarachnoid haemorrhage, gastrointestitinal bleeding or active peptic ulceration
  • Hypersensitivity to heparin, LMWH or radio opaque contrast media
  • Severe heart failure, uncontrolled hypertension, hepatic or renal impairment, malignant disease, endocarditis or haemorrhagic diathesis
  • Current drug abuse
  • Requiring anticoagulant or antiplatelet therapy
  • Pregnant or lactating
  • Abnormal blood clotting tests
  • Treatment would not be started with 48 hours of stroke onset
All patients
N: 212

Group 1
No. randomised: 106
Efficacy population: 72
No. of dropouts: 0
M/F: 59/47
Age: 69±10
Weight (kg): 77±16

Risk factors for DVT:
Elderly (>70 years):48/106
Immobilised: 104/106
*Obesity: 28/106
*Alcoholism: 4/106
Varicose veins: 10/106
History of DVT: 3/106
Risk factors for Stroke:
Hypertension: 48/106
Current smoking: 25/106
*Diabetes mellitus: 21/106
History of myocardial infarction: 5/106
History of stroke or TIA: 5/106
Group 2
No. randomised: 106
Efficacy population: 76
No. of dropouts: 0
M/F: 68/38
Age: 68±12
Weight (kg):73±13

Risk factors for DVT:
Elderly (>70 years):53/106
Immobilised: 101/106
*Obesity: 10/106
*Alcoholism: 12/106
Varicose veins: 10/106
History of DVT:3/106

Risk factors for Stroke:
Hypertension: 45/106
Current smoking: 28/106
*Diabetes mellitus: 12/106
History of myocardial infarction: 7/106
History of stroke or TIA: 8/106

* Obesity (p=0.002), diabetes (p=0.13), alcoholism (p=0.066)
[ Values calculated by NCCAC staff using Fisher’s exact test]
Group 1
Unfractionated heparin, 5000IU, subcutaneously, 8 hourly.

Group 2
Enoxaparin (Clexane), 40mg, subcutaneously, once daily. 2 placebo injections to maintain 8 hourly interval blinding.

In both arms
Start time: within 48 hours of stroke onset End time: 10±2 days later, or until discharge

Additional non-comparative prophylaxis:
Concomitant treatment with anticoagulant or antithrombotic therapy, NSAIDS, aspirin or other antiplatelet therapy, or any other treatment which could influence interpretation of study data was prohibited.

No mention about mechanical prophylaxis methods
All cause mortality
16/17 patients died of stroke within treatment period, 22/32 during the follow up period
Within treatment period (10±2 days)
Group1: 8/106
Group 2: 9/106
P value: 1.00
[Calculated by NCC-AC team using Fisher’s Exact test]

At 3 month follow up
Group1: 28/106
Group 2: 21/106
P value: 0.33
[Calculated by NCC-AC team using Fisher’s Exact test]
Funding:
Aventis Pharma

Limitations:
  • Sample size of 400 was planned, but oly 212 recruited and 165 patients (81 in enoxaparin and 84 in UFH) group completed study
  • NO mention about mechanical prophylaxis methods
  • Significantly more obese patients in UFH group and higher percentages of diabetic patients
Outcomes not reported:
Upper GI bleeding
Additional outcomes reported:
Haemorrhagic transformation of the brain infarction

Notes:
# The number of DVT cases reported was 26/106 in the UFH group and 17/106 in the LMWH group respectively. However, 2 cases in the UFH group and 3 in the LMWH group were detected after the study period. This cases were excluded.

Patients were analysed using both randomised number, and the efficacy subgroup
Fatal pulmonary embolism (confirmed by: autopsy) Of all the patients who died, 14 had autopsy. 4 in UFH and 2 in enoxaparin group had PEGroup1: 2/106
Group 2: 1/106
P value: 0.62
[Calculated by NCC-AC team using Fisher’s Exact test]
Symptomatic pulmonary embolism (ventilation perfusion scan and pO2 when clinically indicated)Group1: 4/106
Group 2: 2/106
P value: 0.68
[Calculated by NCC-AC team using Fisher’s Exact test]
Symptomatic DVT (confirmed by: unilateral phlebography within 24h of clinical indication)Group1: 3/72
Group 2: 1/76
P value: 0.36
[Calculated by NCC-AC team using Fisher’s Exact test]
DVT, asymptomatic or symptomatic (confirmed by: as in symptomatic DVT, and bilateral ascending phlebography at day 10±2 or the last assessment, and autopsy )Group1: 24/106
Group 2: 14/106
P value: 0.17 (# see notes)
[Calculated by NCC-AC team using Fisher’s Exact test]
Thigh (Proximal)
DVT(confirmed by: as in DVT)
Group1: 4/72
Group 2: 2/76
P value: 0.43
[Calculated by NCC-AC team using Fisher’s Exact test]
Calf (Distal)DVT (confirmed by: As in DVT)Group1: 3/72
Group 2: 1/76
P value: 0.36
[Calculated by NCC-AC team using Fisher’s Exact test]
Fatal bleeding (description: autopsy)Of the patients who died, 14 had autopsy. 1 in enoxaparin group had cerebral haemorrhage
Major bleeding (description: intracranial haemorrhage)Group1: 0/106
Group 2: 1/106
P value:
Neurological bleeding (intracerebral haemorrhage) confirmed by cerebral CT scan, within 24 hours of clinical indication and within 24 hours of the final administrationGroup1: 0/106
Group 2: 1/106
P value: 1.0
[Calculated by NCC-AC team using Fisher’s Exact test]
Neurological bleeding (Haemorrhagic transformation of the brain infarction) Confirmed by CT scan within 24 hours of final administrationGroup1: 20/86
Group 2: 14/81
P value: 0.44
[Calculated by NCC-AC team using Fisher’s Exact test]
Minor bleeding (description: included 3 in enoxaparin and 4 in UFH with hematomas>5cm in diameter at injection site)Group1: 6/106
Group 2: 5/106
P value: 1.00
[Calculated by NCC-AC team using Fisher’s Exact test]
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Horbach et al., 1996285RCT1+Total: 305 Intervention n: 152 Control n: 153Type of surgery: Patients undergoing elective hip replacement surgery.

Intervention: Mean age: 64.2 ± 10.0 years M/F:72/80

Control: Mean age: 64.9 ± 9.8 years M/F:70/83

Pre-existing risk factors: Previous thrombosis: Int: n = 13 Cont: n = 16; Previous PE: Int: n = 3 Cont: n = 6; Varices: Int: n = 69 Cont: n = 79; Diabetes mellitus: Int: n = 10 Cont: n = 8; p=0.498; obesity: Int: n = 5 Cont: n = 26; obstructive pulmonary disease: Int: n = 3 Cont: n = 2; Cardiac insufficiency: Int: n = 0 Cont: n = 1; Malignancy: Int: n = 1 Cont: n = 1
Type, dose and timing: One dose daily of subcutaneous LMWH (3000 IU of Certoparin) plus 0.5mg DHE injections. Prophylaxis started 2 hours before surgery and continued for at least 14 post operative days or longer if patient was still institutionalised.

Additional non-comparative prophylaxis: Not reported
Type, dose and timing: 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. Prophylaxis started 2 hours before surgery and continued for at least 14 post operative days or longer if patient was still institutionalised.14 daysVTE totalInt:17/142 (12.0%)
Cont: 14/147 (9.5%)
p=0.50
Study on fixed dose combination of LMWH with Dihyroergotamine vs adjusted dose UFH (starting with 15,000 IU/day and increased to 28,800 IU/day ±7,150 IU/day) in prevention of DVT after total hip replacement.

Also reported: intraoperative and postoperative blood loss, postoperative transfusions, revieion of vound, reoperation due to bleed ing complications, hematoma at injection site, patechlal,
DVT confirmed by bilateral ascending venography.Int:17/142
Cont: 13/147; p=0.76
Proximal DVT:Int:0/142
Cont: 0/147
Distal DVT:Int:15/142
Cont: 8/147; p=2.59
Proximal and Distal DVT:Int:2/142
Cont: 5/147; p=1.21
PE Confirmed by pulmonal szintigraphy.Int:0/142
Cont: 1/147; p=0.87
Kakkar et al., 2000327RCT1+Total: 298 Intervention n: 149 Control n: 149Type of surgery: Patients scheduled for elective hip replacement surgery.

Duration of surgery:
Int: 110±55.1
Control: 100±58.7; p=0.207

Age and gender:
Intervention: Mean age: 70.4 ± 10.9
years M/F:49/100

Control: Mean age:
70.5 ± 9.2 years
M/F:45/104

Pre-existing risk factors:
Previous DVT: Int: n = 4 Control: n = 12; Previous PE: Int: n = 1 Control: n = 3; Varicose veins: Int: n = 44 Control: n = 46; Varicose ulcer: Int: n = 3 Control: n = 6; obesity: Int: n = 23 Control: n = 27;
Type, dose and timing: One dose daily of subcutaneous LMWH (3500 IU of Bemiparin) plus a placebo injections 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.

Additional non-comparative prophylaxis: Not reported
Type, dose and timing: 5000 units of Calcium heparin injected subcutaneously twice daily. Prophylaxis started 2 hours before surgery and continued for at least 8 post operative days or longer if patient was still institutionalised.4 weeksVTE totalInt: 9/125 (7.2%)
Cont: 25/134 (18.7%)
p=0.01
Financially supported by Laboratories Farmaceuticos Rovi S.A.; (Madrid, Spain) Who also provided supply of LMWH and std UFH sodium

Also reported: Operative blood loss, postoperative drain loss
DVT confirmed by bilateral elective venography.Int: 9/101 (8.9%)
Cont: 24/116 (20.7%)
p=0.03
Proximal DVT:Int: 3/101 (3.0%)
Cont: 5/116 (4.3%)
p=0.73
Distal DVT:Int: 4/101 (4.0%)
Cont: 13/116 (11.2%)
p=0.08
Proximal and Distal DVT:Int: 2/101 (2.0%)
Cont: 6/116 (5.2%)
p=0.23
PE Confirmed by ventilation perfusion scan.Int: 1/125 (0.8%)
Cont: 2/134 (1.5%)
p=1.00
Patient transfusedInt: n = 74/149
Control: n = 66/149; p=0.42
Wound hematomasInt: n = 8/149
Control: n = 7/149; p=1.00
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Kleber et al., 2003350 (The PRINCE study)

Country of study: Germany

Study design: Multicentre RCT, open label study

List who was masked to interventions: Open label study. Central reviewers of efficacy end points (interpreting the screening tests and assessment of venous thromboembolic events) were masked.

Evidence level: 1+

Duration of follow-up: 10±2 days
Patient group:
Heart failure (n=333)and respiratory disease(n=332) patients

Setting:
inpatient

Inclusion criteria:
  • Aged ≥18
  • Hospitalised for severe respiratory disease (based on lung function test or blood gas analyses outside normal range and at ≥1 of these: severe functional loss ≥2 lung segments, severe secondary pulmonary hypertension, pneumonia, interstitial lung disease, lung cancer and/or metatstases with life expectancy > 2 months, or exacerbation of COPD )or heart failure (class III or IV according to New York Heart Association classification)
  • Confined to bed >2/3 of the time
Exclusion criteria: All patients
No randomised: 668 (3 withdrawn before receiving any study medication)
No. of dropouts: 214/665
Age (mean): 70±14
Group 1
UFH 5000IU 3 times daily, subcutaneously

Group 2
Enoxaparin 40mg once daily, subcutaneously

Start time: Day 1(on enrolment day)
Duration: 10±2 days

Additional non-comparative prophylaxis:
All cause mortality (confirmed by: )Group1: 15/333
Group 2: 9/332
P value:
Funding:
Aventis Pharma

Limitations: Outcomes not reported:
Symptomatic DVT
Calf DVT
Fatal bleeding
Neurological bleeding
Upper GI bleeding
Heparin induced thrombocytopaenia PTS,
Pulmonary hypertension QoL,
LOS

Additional outcomes reported:
Notes:
Fatal pulmonary embolism (confirmed by: Autopsy. 1 heart failure patient in UFH group had both PE and DVT)Group1: 1/212
Group 2: 0/239
P value:
Symptomatic pulmonary embolism (confirmed by: perfusion scintigram)Group1: 0/212
Group 2: 1/239
P value:
DVT, asymptomatic or symptomatic (confirmed by: patients with positive D dimmer or fibrin monomer test underwent bilateral venography. Autopsy)
1 heart failure patient in UFH group had both PE and DVT
By D-dimer test
Group1: 86/212
Group 2: 84/236
P value

: By Venography/autopsy, including venogram conducted >24 hours after last dose
Group1: 28/235
Group 2: 26/264
P value:

By Venography/autopsy, in primary efficacy population
Group1: 22/212
Group 2: 19/239
P value:

In heart failure patients:
By Venography/autopsy
Group1: 15/93
Group 2: 11/113
P value:

In respiratory failure patients
By Venography/autopsy
Group1: 7/119
Group 2: 8/126
P value
Thigh (Proximal)DVT(confirmed by: )Group1: 4/212
Group 2: 9/239
P value:
Risk FactorsGp1Gp2Major bleeding (description: 1 urogenital – enoxaparin and 1 haemorrhoidal-UFH. Defined as retroperitoneal or intracranial bleeding, overt bleeding with Hb )Group1: 1/333
Group 2: 1/332
P value:
Immobilisation332333Minor bleeding (description:)Group1: 11/333
Group 2: 4/332
P value:
Congestive heart failure186186
Age >70yr185187
COPD134142
Venous Disease137129
Overweight10498
Diabetes Mellitus101104
Severe infection6156
Pervious myocardial infarction4141
Pre-existing malignancy2516
Dehydration1523
History of DVT2019
Group 1
No. randomised: 333
M/F:183/150
No evaluated: 212
Severe respiratory disease:164
Heart failure:169

Group 2
No. randomised: 332
M/F:160/172
No evaluated: 239
Severe respiratory disease:168
Heart failure:164
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Koch 1997 (11 studies) 72,174,198,243,380,381,400,458,527,549,635

All of these studies were included in the guideline review.
Systematic Review1+Total: 3608
Int: 1800
Cont: 1808
Type of surgery:
11 orthopaedic studies
LMWH

Dose: Ranged between 3100–5000 Anti X-a units

Timing: Initiated preoperatively at diagnosis to postoperatively 12–24 hours.

Duration: Ranged from greater than 6 to 14 days.

Additional non-comparative prophylaxis:
GCS (1 study) Leg bandages (1 study)
UFH

Dose: 5000–7500 IU

Timing: Initiated preoperatively at diagnosis to postoperatively 12–24 hours.

Duration: Ranged from greater than 6 to 14 days

Additional non-comparative prophylaxis:
GCS (1 study) Leg bandages (1 study
NRDVT confirmed by radiofibrinogen update test or phlebography.Int: 250/1761
Cont: 284/1765
p value: 0.1212
Funding: grant from Deutsche Forschungsgemeinschaft.

Not reported: QoL, LoS, PTS.
Proximal DVTInt: 84/1430
Cont: 120/1432
p value: 0.0017
PE (observed)Int: 18/1570
Cont: 33/1570
p value: 0.0471
Major bleeding:Int: 69/1604
Cont: 79/1619
p value: 0.4497
Lastoria et al., 2006383RCT1+Total: 75
M/F: 59/16
Int: 41
Cont: 34
Type of surgery:
Vascular: Major lower extremity amputation (30 above-knee and 45 below-knee)

Inclusion criteria:
Patients over 18 years, undergoing elective or emergency lower-limb amputation for critical-limb ischemia.
Excluded if had previous venous thrombo-embolism, and patients with contra-indication for anticoagulant prophylaxis.
LMWH (enoxaparin)

Dose: 40mg/day

Timing: 12 hours before surgery or in emergency cases in the first postoperative day.

Duration: During hospitalisation

Additional non-comparative prophylaxis:
Not reported
UFH

Dose: 5000 IU (subcutaneously)

Timing: 12 hours before surgery or in emergency cases in the first postoperative day.

Duration: During hospitalisation

Additional non-comparative prophylaxis: Not reported
NRDVT confirmed by duplex scanning (5–8 days after surgery)Int: 4 (9.7%)
Cont: 4 (11.7%)
P=0.92
Funding: Paulista State University.

Not reported: Proximal DVT s, PEs, duration of hospital stay, QoL or post-thrombotic syndrome.

Notes:
DVT: 1 bilateral thrombosis in each group.

No significant difference between interventions in DVTs in level of amputation or sex of patient.
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Lechler et al., 1996387

Country of study:
Austria and Germany

Study design:
RCT, double blinded, multi centre

List who was masked to interventions:
Patients and investigators

Evidence level:
1+

Duration of follow-up:
7 days
Patient group:
Immobilised medical patients

Setting: 26 medical centres

Inclusion criteria:
  • ≥ 18 years old
  • expected immobilisation of >1/2 of the time for the whole study period of 7 days, and at least one of additional risk factors such as:
Exclusion criteria:
  • Anticoagulation and/or treatment with aggregation inhibitors or NSAIDS for the preceding 7 days
  • Regional anaesthesia
  • Pregnancy or lactation
  • Bleeding disorder
  • Thrombocytopenia (<100,000/μL)
  • Head trauma in the past 6 months
  • Haemorrhagic stroke in the preceding 4 weeks
  • Suspicion for internal bleeding
  • Severe liver disease/renal insufficiency
  • Thromboembolism on admission and participation in a clinical trial in the preceding 6 weeks
All patients
N: 959
Age (mean): 74±13
Group 1
UFH 5000IU 3 times daily, subcutaneously

Group 2
Enoxaparin 40mg, daily and 2 placebo injection( isotonic mannitol solution) (total of 3 injections daily)

All injections were 0.2 ml
Start time: within 24 hours of admission
Duration: 7 days

Additional non-comparative prophylaxis:
Patients on anticoagulants, aggregation inhibitors and NSAIDs were excluded from study

Mechanical prophylaxis unknown
All cause mortality (confirmed by: )Group1: 11/482
Group 2: 7/477
P value: 0.47
[calculated by NCCAC team using Fisher’s exact test]
Funding:

Limitations:
  • Not reported:
    • Method of randomisation/concealment
    • Results across centres
    • Mortality causes
    • Mechanical prophylactic methods, or ambulation policies
Outcomes not reported:
Fatal PE, Symptomatic PE, Symptomatic DVT, Major bleeding, Minor bleeding, Heparin induced thrombocytopaenia PTS, Pulmonary hypertension, QoL, LOS

Additional outcomes reported:
8 urogenital bleedings reported-not stated which group.
Haematomas >5 cm in diameter: 52 events in UFH and 22 in enoxaparin

Notes:
All patients were screened for DVT at study entry using B-mode scan or duplex sonography.
Symptomatic pulmonary embolism (confirmed by: perfusion scan, angiography and autopsy in cases of death if permitted)Group1: 4/443
Group 2: 0/442
P value: 0.12
[calculated by NCCAC team using Fisher’s exact test]
DVT, asymptomatic or symptomatic (confirmed by: duplex sonography at end of study period, or when clinically suspected. Positive cases were confirmed with phlebography)Group1: 4/443
Group 2: 1/442
P value: 0.38
[calculated by NCCAC team using Fisher’s exact test]
Major bleeding (description: decrease in Hb≥2g/dl, transfusion of >2 units of blood and/or retroperitoneal or intracranial bleeding)Group1: 7/482
Group 2: 2/477
P value: 0.18
[calculated by NCCAC team using Fisher’s exact test]
2 patients in heparin group were reported to have “severe bleeding”. However, the definition was not provided.
Upper GI bleeding9 gastrointestinal bleeding cases. Not stated which group it was from.
Main Diagnoses (%):Gp1Gp2
Cardiovascular diseases67.570.5
Endocrinologic diseases27.930.1
Respiratory diseases24.323.4
Gastrointestinal and urogenital diseases22.621.8
Central nervous diseases15.817.8
Cancer14.712.9
Bone diseases10.812.2
Skin diseases3.53.1
Others8.28.9
Group 1
No. randomised: 482
Stipulated efficacy evaluation conducted: 443
Per protocol population:377
M/F: 178/304
Age (mean): 74±13
Risk factors (%)
  • Immobilisation: 100
  • Age >60 years: 88.8
  • Overweight: 32.8
  • Severe infection: 19.1
  • Malignant disease: 14.7
  • Paresis hemiplegia, paraplegia: 7.5
  • Previous VTE: 7.7
Group 2
No. randomised: 477
Stipulated efficacy evaluation conducted: 442
Per protocol population:393
M/F: 183/294
Age (mean): 74±13
Risk factors (%)
  • Immobilisation: 100
  • Age >60 years: 87.2
  • Overweight: 28.7
  • Severe infection: 20.1
  • Malignant disease: 20.1
  • Paresis hemiplegia, paraplegia: 7.5
  • Previous VTE: 6.1
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Legnani et al., 1990393RCT1+Total: 50

Intervention : n = 24
Control: n = 26
Type of surgery:
Gynaecological laparotomy patients (& Duration of surgery)
Type:
4000iu LMWH (Alfa LMW1-OP 2123) subcutaneously once per day

Patients with malignancy (11/24 patients) and/or undergoing Wertheim-Meigs laparotomy (2/24 patients) received 4000iu LMWH subcutaneously twice daily
Type:
5000iu calcium heparin (Italfarmaco) subcutaneously twice daily

Patients with malignancy (12/26 patients) and/or undergoing Wertheim-Meigs laparotomy (2/26 patients) received 5000iu calcium heparin subcutaneously three times daily
8 days post- operativelyDVT Confirmed by:
125I FUT
Int: 5/24
Contol: 5/26
p value: 1.0000
Comments:
PE and survival not reported but it appears all patients completed the study as none lost to follow-up prior to discharge.

Not reported:
PE
PTS
bleeding
QoL

Funding:
not reported
Intervention: Mean age: 55.6±7.6 yrs
M/F: not reported
Fatal PE (see comments):Int: 0/24
Control: 0/26
p value: N/A
Control: Mean age: 55.7±10.5
M/F: not reported
Survival (see comments)Int: 24/24
Control: 26/26
p value: N/A
Pre-existing risk factors:
No previous history of DVT
Timing:
started 2 hours preoperatively and continued until postoperative day 7
Timing:
started 2 hours preoperatively and continued until postoperative day 7
Additional non-comparative prophylaxis:
none reported
Additional non-comparative prophylaxis:
none reported
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Levi et al., 2007397

Country of study:
multicentre-US, Uk, Netherlands etc (20 countries)

Study design:
RCT, equivalence 1:1:2 randomisation of UFH, LMWH, placebo

List who was masked to interventions:
Patients, investigators and all study personnel

Evidence level:
1+

Duration of follow-up:
28 days
Patient group:
Patient with severe sepsis on drotrecogin alfa (Activated) (Drot AA)

Setting:
Multicentre, inpatient

Inclusion criteria:
7. Aged ≥18 years old
8. Receiving inpatient treatment for severe sepsis
9. Indicated for DrotAA under an approved label in the country in which the patient enrolled, defined as one or both of the following:
-

Multiple organ dysfunction (MOD); EMEA label

-

Patients at higher risk of death (as defined by Acute Physiology Age and Chronic Health Evaluation [APACHE] II scores ≥ 25; US label)

Exclusion criteria:
11. Contraindicated for treatment with prophylactic LMWH or UFH
12. Required a higher dose of heparin than specified in protocol or concurrent need for other anticoagulant medication
13. Acute or chronic renal failure with estimates creatinine clearance less than 30ml/min
14. Moribund or not expected to survive 28 days
15. Patient or family not committed to aggressive management of severe sepsis

All patients
N: 1935 (ITT population. 2002 enrolled, 2 had consent issues, 59 did not receive study drugs)

Group 1 and Group 2
No. randomised: 976
Age (mean): 59.6±16.1
No. of dropouts:

Additional risk factors:
Age ≥ 65 years: 411/976
Patient history:
-

Hypertension:378/976

-

Recent surgery: 330/976

-

COPD: 171/976

-

Malignancy: 134/976

-

Chronic liver disease: 55/976

-

Congestive myopathy 49/976

-

Deep vein thrombosis: 32/976

-

Pulmonary thromboembolism: 12/976

-

APACHE II score: 23.8±7.6

-

APACHE≥25: 462/976

Group 3
No. randomised: 959
Age (mean): 58.4±16.0
No. of dropouts:
Additional risk factors:
Age ≥65 years: 367/959
Patient history:
-

Hypertension: 356/959

-

Recent surgery: 331/959

-

COPD: 160/959

-

Malignancy: 112/959

-

Chronic liver disease: 52/959

-

Congestive myopathy: 46/959

-

Deep vein thrombosis: 19/959

-

Pulmonary thromboembolism: 13/959

-

APACHE II score: 24.0±7.4

-

APACHE≥25: 431/959

Group 1
UFH
5000 U, subcutaneous, every 12 hours

Group 2
LMWH (enoxaparin) 40 mg, subcutaneous, one daily, ( a second injection of placebo was administered after 12 hours to maintain blinding of 12 hourly injections.

Group 1 and 2 were combined in many section of the analysis as “heparin

Group 3
Placebo
Administered twice daily

Start: as soon as possible after initiating Drot AA, no more than 12 hours later
Stop: Until completion of Drot AA infusion.
Duration: 96 hours, during administration of Drot AA. If Drot AA infusion continued beyond Day 4 because of interruptions, study drug injections were continued every 12 hours until the infusion was completed. If the 12-hour time point for study drug administration occurred within 2 hours after completion of Drot AA infusion, the final study drug injection was administered then.

Other drugs:
Both groups received Drot AA at 24 microgram/kg/hour for 96 hours, according to local hospital guidelines

Additional non-comparative prophylaxis: “all other patient care was at the discretion of the investigator, including the use of commercial heparin (commercial use of heparin use during Days 0–6 refers to use in the 1–2 d after Drot AA and study drug administration)”. Commercial use of heparin was not statistically significant between treatment arms(data not shown)

“The use of prophylactic heparin and mechanical methods between Study Days 7–28 were very similar in both groups”- details not reported
All cause mortality (for 28 days, cause of death determined by investigator opinion). This was the primary objective of study.

8 patients had unknown 28- day survival status
Heparin (Group 1 and 2): 275/972 (28.3)
Group1:145/495 (29.3%)
Group2:130/477 (27.3%)
Group3:305/955 (31.9%)

P value: (reported) heparin vs placebo=0.08
Funding:
Eli Lilly (designed and sponsored the study1)

Limitations:
The protocol only covered administration of Drot AA and placebo/heparin in Days 0–6. Any other aspects of care, use of heparin &/or mechanical methods, including the use of heparin after the completion of Drot AA Days 4–6 were at the discretion of the investigators.

Subgroup analysis of the study had shown that: among the group of patients who were exposed to heparin at baseline, those randomised to placebo had higher mortality rate than those receiving heparin.

Outcomes not reported:
Fatal PE, Symptomatic PE, PE asymptomatic or symptomatic, symptomatic DVT
DVT, asymptomatic or symptomatic
Thigh DVT, Calf DVT, Upper GI bleeding, Minor bleeding, post thrombotic syndrome, pulmonary hypertension, Quality of life, Length of stay

Additional outcomes reported:

Venous thrombotic events:
Days 0–6:
Heparin: 45/976
Placebo: 49/959
P value: 0.60
Days 0–28:
Heparin: 56/976
Placebo: 67/959
P value: 0.26
(defined as objectively confirmed non fatal or fatal pulmonary embolism (PE), asymptomatic lower extremity DVT, detected by bilateral compression ultrasonography performed at the end of study drug administration (Study Days 4–6), symptomatic lower extremity DVT confirmed by objective means (ultrasound or other accepted diagnostic modalities) an symptomatic central vein thrombosis, confirmed by objective means)

Ischaemic stroke:
Days 0–6
Heparin: 3/976
Placebo: 12/959
P value: 0.02
Days 0–28
Heparin: 5/976
Placebo: 17/959
P value: 0.01
Any bleeding event:
Days 0–6
Heparin: 105/976
Placebo: 78/959
P value: 0.049
Days 0–28
Heparin: 121/976
Placebo: 105/959
P value: 0.32

Notes:
The study was designed to evaluate whether heparin interfered with the efficacy of Drot AA in adult patients with severe sepsis at high risk of death.

Heparin may have direct therapeutic effects in severe sepsis and disseminated intravascular coagualation independent of their anti thrombotic properties.

High doses of heparin lead to higher clearance of DrotAA through increasing the rate of inhibition of activated protein C by protein C inhibitors
Fatal bleeding
(overt bleeds considered the primary cause of death)
Days 0–6
Heparin: 1/976
Placebo: 3/959
P value: 0.31

Days 0–28
Heparin: 4/976
Placebo: 11/959
P value: 0.06
Major bleeding (described as “serious bleeding events” and included: fatal bleeding &/or non fatal serious bleeding defined as intracranial brain haemorrhage confirmed by brain imaging or autopsy, or bleeding at a critical location [e.g. retinal haemorrhage, major haemorrhage, or spinal haemorrhage] and/or an otherwise life threatening event bleed that did not meet other criteria)Days 0–6
Heparin: 22/976
Placebo: 24/959
P value: 0.72

Days 0–28
Heparin: 38/976
Placebo: 50/959
P value: 0.16

Note: Bleeding events which were reported as non serious adverse events that occurred during infusion (Days 0–6) and led to or contributed to the need for transfusion of packed red blood cells were classified as “non serious bleeding events”.
Neurological bleeding (central nervous system bleeding events)Days 0–6
Heparin: 3/976
Placebo: 3/959
P value: 0.98
Days 0–28
Heparin: 10/976
Placebo: 7/959
P value: 0.49
Heparin induced thrombocytopaeniaDays 0–6
Heparin: 10/976
Placebo: 6/959
P value: 0.33
Days 0–28
Heparin: 12/976
Placebo: 11/959
P value: 0.87
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Macdonald et al., 2003415RCT1+Total: 100

Intervention : n = 51
Control: n = 49
Type of surgery:
Patients undergoing craniotomy for brain neoplasm, including trans-sphenoidal surgery, intracranial aneurysm, vascular malformation, infection, spontaneous intracranial hematoma, closed head injury or cortical resection for epilepsy.

Age & Gender:
Intervention:
Mean age: 51 ±15 yrs
M/F:23/28

Control:
Mean age: 49 ±15 yrs
M/F: 23/26
Type: LMWH (Dalteparin)
Dose: 2500 IU once per day

Timing: Begun at time of surgery and continued for 1 week

Additional non-comparative prophylaxis:
Thigh length intermittent pneumatic compression devices worn from time of admission until discharge or the patient was ambulatory for more than 3 hours per day.
Type: LDUH
Dose: 5000 IU twice per day

Timing: Begun at time of surgery and continued for 1 week

Additional non-comparative prophylaxis: Thigh length intermittent pneumatic compression devices worn from time of admission until discharge or the patient was ambulatory for more than 3 hours per day.
1 monthDVT Confirmed by: Doppler US (on 7th post-op day?)Int: 2/51
Control: 0/49
p value: 0.30
Comments:
Excluded patients with VTE, thrombocytopenia, abnormal prothrombin time, abnormal partial thromboplastin time, abnormal bleeding time, history of hypersensitivity to heparin or pork products, penetrating head injury or pregnancy.

Not reported: Proximal DVT, PTS, QoL, LoS

Also reported:
anaesthesia time; blood loss; no. of patients requiring intraoperative transfusion, surgeon’s impression of haemostasis, no. of patients requiring erythrocyte transfusion
Symptomatic pulmonary embolism
confirmed by ventilation perfusion scan or spiral CT.
Int: 0/51
Control: 0/49
p value: not sig
Intracranial haemorrhage
confirmed by CT scan and MRI
Int: 2/51
Control: 1/49
p value: 0.59
ThrombocytopeniaInt: 2/51
Control: 0/49
p value: 0.30
MortalityInt: 0/51
Control: 1/49
p value: 0.48
McLeod et al., 2001439RCT1+Total: 936
Intervention n: 468
Control n: 468
Type of surgery: Patients undergoing colorectal surgery.Type, dose and timing: One dose daily of subcutaneous LMWH (40 mg of Enoxaparin) plus 2 placebo injections of 0.9% saline every 8 hours for up to 10 days after surgery. Prophylaxis started 2 hours before surgery.

Additional non-comparative prophylaxis: Not reported
Type, dose and timing: 5000 units of Calcium heparin injected subcutaneously every 8 hours for 10 days. Prophylaxis started 2 hours before surgery.10 daysVTE rate was the same in both groups

DVT confirmed by bilateral duplex compression US or venography.
PE Confirmed by lung scan or pulmonary angiogram
44/468 (9.4%) (95% CI of the difference, 0 ±3.7%)

Proximal DVT:

Int: 2.8%
Control: 2.6%

Int: n = 1
Control: 0
Screening tests used are not consistent through out study.
Intervention: Mean age: 52 ± 18 years
M/F:376/298
Bleeding complications:
Major bleeding


Minor bleeding


Int: n = 18/653
Control: n = 10/643
Int: n = 52/653
Control: n = 32/643
Control: Mean age: 50 ± 17 years
M/F:355/320
Pre-existing risk factors: History of prior thromboembolism: Int: n = 14 Control: n = 19

Malignancy: Int: n = 164
Control: n = 160

Inflammatory bowel disease: Int: n = 202
Control: n = 211

Rectal procedure: Int: n = 241 Control: n = 246
Mismetti 2001450

48 studies 9,32,37,49,50,52,62, 75,76,82,92,100,131,138,140,171,179, 199,210,216,224,227,246,262,269271,282,283,321,323325,328,329,358,359,361,396,403,496, 503,570,575578,586,588,589,660,667,685

45 of these studies were included in the guideline review 9,32,37,50,52,75,76, 82,92,100,138,140, 171,179,199,210,216,224,227,246,262, 269271,282,283,321,324,328,329,358,359, 361,396,403,496,503,570,575,586,588, 589,660,667,685
Systematic review1+Total: 15349Type of surgery: General (36 studies)

Gynaecology (5 studies)

T (thoracic? 1 study)

Mixed (6 studies)
Type: LMWH

Timing:
Postoperative (1 study)
Preoperative (47 studies)

Duration:
3–10 days

Additional non-comparative prophylaxis:
Not reported
UFH

Additional non-comparative prophylaxis: none
7 days – 3 monthsDVT FUT, FUT + veno, Thermography, IPG, Doppler.Int: 310/8100
Cont: 350/7319
p value: 0.0036
Not reported: LoS, QoL, PTS

Funding: Sanofi-Synthelabo grant

Event rates reported here are for all studies as published in the systematic review.
PEInt: 13/3895
Cont: 20/3857
p value: 0.2264
Major bleedingInt: 219/7473
Cont: 245/6986
p value: 0.0528
Proximal DVTInt: 6/1466
Cont: 20/1437
p value: 0.0053
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Osman et al., 2007504

Country of study: Egypt

Study design: Prospective randomised open label study

List who was masked to interventions: Open label?

Evidence level: 1−

Duration of follow-up: 2 weeks? Not clearly stated
Patient group:
Non “high risk”, isolated, live-donor renal transplantation.

Setting:
Dec 2003 to March 2005.
Urology and Nephrology Centre, Mansoura University

Inclusion criteria:
Consecutive, isolated, live-donor renal transplantation operated by the same surgical team

Exclusion criteria:
Categorised as “risky “ because
-

<16 years old

-

grafts with multiple arteries

-

a history of thromboembolic disease

-

artheromatous arteries

-

collagen vascular disease

-

intraoperative technical difficulties

All patients
N: 75
M/F: 52/23

Group 1 (LMWH)
No. randomised: 25
No. of dropouts:
M/F:14/11
Age (year): 28.3±8
Pre-transplant Hb level: 8.8±2
Ischaemia time (min): 44.7±11
Delayed diuresis: 1/25
Donor gender, M/F:11/14
Donor age (year): 35.9±11
Harvested kidney (right): 10/25

Group 2 (UFH)
No. randomised: 25
No. of dropouts:
M/F:19/6
Age (year): 29.4±8
Pre-transplant Hb level: 9.7±1.6
Ischaemia time (min): 46.3±12
Delayed diuresis: 1/25
Donor gender, M/F: 15/25
Donor age (year): 35.3±10
Harvested kidney (right): 10/25

Group 3 (Control)
No. randomised: 25
No. of dropouts:
M/F:19/6
Age (year): 26±6
Pre-transplant Hb level: 8.6±1.7
Ischaemia time (min): 42.5±8
Delayed diuresis: 2/25
Donor gender, M/F:14/9
Donor age (year): 33±9
Harvested kidney (right): 11/25

Note: The groups were comparable, in all the above variables. However, there was a trend to significance for pretransplant haemoglobin levels, p=0.07
Group 1
LMWH
Dose: 3500anti-Xa IU in 0.35 ml once daily
Duration: 1 week

Group 2
UFH
Dose: 5000IU, twice daily
Duration: 1 week

Group 3
Control
Did not receive heparinisation

Additional non-comparative prophylaxis:
Not reported

Note: All patients discharged 2 weeks post operatively if no post-operative complications were found
All cause mortality (confirmed by: no mortality reported )Group 1: 0/25
Group 2: 0/25
Group 3: 0/25
P value: 1.0
Funding:
None stated

Limitations:
-

Open label study

-

No indication that patients or investigators were blinded – very likely open label study

-

Method of DVT screening not clearly specified, and frequency of screening not reported.

-

Duration of follow up not clearly stated

Outcomes not reported: PE asymptomatic or symptomatic, DVT, asymptomatic or symptomatic, Thigh DVT, Calf DVT, Fatal bleeding, Neurological bleeding, Upper GI bleeding, Minor bleeding, Heparin induced thrombocytopaenia, Post thrombotic syndrome, Pulmonary hypertension, Quality of life, Length of stay

Additional outcomes reported:
-

Graft thrombosis

-

Number receiving transfusion

-

Mean transfused units

-

Haemoglobin drop in non transfused patients

-

Other transplant related parameters

Notes:
Fatal pulmonary embolism (confirmed by: screening method and frequency not specified)Group 1: 0/25
Group 2: 0/25
Group 3: 0/25
P value: 1.0
Symptomatic pulmonary embolism (confirmed by: screening method and frequency not specified)Group 1: 0/25
Group 2: 0/25
Group 3: 0/25
P value: 1.0
Symptomatic DVT (confirmed by: screening method and frequency not specified)Group 1: 0/25
Group 2: 0/25
Group 3: 0/25
P value: 1.0
Major bleeding (description: Reoperated. Found to be due to slipped ligature)Group 1: 1/25
Group 2: 0/25
Group 3: 0/25
P value: 0.37
Bibliographic referenceStudyTypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Perhoniemi et al., 1996515RCT1+Total: 165

Intervention : n = 80
Control: n = 81*

Not reported to which group the other 4 patients were allocated nor what happened to them
Type of surgery: Patients over 40 requiring hip or knee (endoprosthesis or fracture) surgery.

Excluded patients: if trauma happened >24 hours before admission.

Age & Gender: Intervention:
Mean age: 72 ±8.6 yrs
M/F:22/58

Control:
Mean age: 73.8 ±7.6 yrs
M/F: 21/60
Type: LMWH (Enoxoparin)
Dose: 40mg once per day

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

Additional non-comparative prophylaxis: Spinal anaesthesia: 78/80
Type:
Dihydroergotamin (0.5mg) + LDUH (5000 IU) 2 times per day

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

Additional non-comparative prophylaxis: Spinal anaesthesia: 72/80
7 daysDVT Confirmed by: Doppler USInt: 1/80
Control: 0/80
p value: not sig
* reports 81 patients in UFH group but lists results for that group as 80.

Not reported: Proximal DVT, PTS, QoL, LoS, major bleeds

Also reported: duration of operation; volume of blood loss; volume of blood transfusion, haemaglobin values; no. of haematomas (did not distinguish between major and minor).
Symptomatic pulmonary embolism confirmed by isotope scintigraphy.Int: 0/80
Control: 2/80
p value: not sig
Senaran et al., 2006597RCT1+Total: 100

Intervention : n = 50
Control: n =50
Type of surgery: Hip arthroplasty.

Excluded patients: any history precluding anticoagulant therapy (i.e. blood dyscrasia, heparin induced thrombocytopenia, allergery to heparin).

Age & Gender: Intervention:
Mean age: 55.2 ±8.5 yrs
M/F:12/38

Control:
Mean age: 52.4 ±11.2 yrs
M/F: 17/33
Type: LMWH (Enoxoparin)
Dose: 40mg once per day

Timing: Begun 12 hours before surgery and continued for 7 to 10 days

Additional non-comparative prophylaxis: none reported
Type: UFH (5000 IU) 3 times per day

Timing: Begun 8 hours before surgery and continued for 7 to 10 days

Additional non-comparative prophylaxis: none reported
6 weeksDVT Confirmed by: Doppler USInt: 0/50
Control: 2/50
p value: not sig
~ defined as overt bleeding associated with at least one of the following: death or life-threatening event, bleeding confimed to be retroperineal, intracranial, or intraocular, postoperative transfusion of >2 units of packed red blood cells or whole blood, a decrease in haemoglobin level by more than 20g/l compared with relevant postoperative level.

Not reported:
Proximal DVT, PTS, QoL, LoS

Also reported:
serious discharge, hepatic dysfunction, renal complications, dysfunction and major haematoma
Symptomatic DVT at 6 weeks Confirmed by: Doppler USInt: 2/50
Control: 0/50
p value: not sig
Symptomatic pulmonary embolism confirmed by ventilation perfusion scan or pulmonary angiography.Int: 0/50
Control: 0/50
p value: not sig
Major bleeding ~Int: 1/50
Control: 4/50
p value:
Study detailsPatientsInterventionsOutcome measuresEffect sizeComments
Sherman et al., 2007598

Country of study: International: US, Europe and Asia

Study design: RCT, non blinded

List who was masked to interventions: Nil-Open label

Evidence level: 1+

Duration of follow-up: Total of 90 days, 14 days for main outcomes, 48 hours for bleeding events
Patient group:
Acute Ischaemic Stroke

Setting:
200 centres in 15 countries

Inclusion criteria:
  • ≥ 18 years
  • Acute ischaemic stroke confirmed by computed tomography (CT) or magnetic resonance imaging (MRI)
  • Unable to walk unassisted because of motor impairment, indicated by National Institute of Health Stroke Scale (NIHSS) ≥2 for motor function of leg
  • Onset ≤ 48 hours of randomisation
Exclusion criteria:
  • Evidence of VTE at screening or active bleeding
  • Evidence of history of intracranial haemorrhage, heparin induced or enoxaparin induced thrombocytopenia or thrombosis or both
  • Hypersensitivity to iodinated contrast media or iodine
  • Spinal or epidural analgesia or lumbar puncture within the preceding 24 hours
  • Thrombolytic treatment within the preceding 24hours
  • Comatose at screening (NIHSS score ≥2 for level of consciousness)
  • Known or suspected cerebral aneurysm or arteriovenous malformation
  • Confirmed malignant disease that might have posed an increase risk of bleeding or compromise follow up or outcome assessment
  • Impair haemostasis, e.g. baseline platelet count <100000 per microL, aPTT 1.5 times the laboratory upper limit of normal, INR>1.5
  • Major surgery or trauma within the preceding 3 months
  • Expected need for full-dose treatment with therapeutic levels of an anticoagulant
  • Treatment with LMWH or UFH at prophylactic dose for > 48h before inclusion
  • Allergy or known hypersensitivity to heparin or enoxaparin
  • Bacterial endocarditis
  • Prosthetic heart valve
  • Known or suspected anaemia (Hb<100g/L)
  • Uncontrolled arterial hypertension (systolic blood pressure (BP) >180mmHg or diastolic BP>100mmHg) at randomisation or clinical hypertensive urgency
  • Life expectancy <3 months due to comorbid disorders
  • Participation in another clinical study within the preceding 30 days
  • Any clinically relevant serious diseases, including severe liver disease or renal failure (creatinine clearance <30mL/min on ≥ 2 occasions)
  • Female patients, if breast feeding, pregnant, or could become pregnant during the study
All patients
N: 1762
Characteristics:
Group 1
Unfractionated heparin (UFH), Dose/route: 5000U, subcutaneously, every 12h
Start: within 48 hours
Duration: 10±4days

Group 2
Enoxaparin (Clexane)
Dose/route: 40mg, subcutaneously, once daily
Start: within 48 hours
Duration: 10±4days

Additional non-comparative prophylaxis:
Mechanical prophylaxis not mentioned.
Concomitant antiplatelet therapy was allowed.
Number of patients receiving anti-platelet therapy:
In the randomised group:
At baseline:
Enoxaparin: 825/884 (92%)
UFH: 791/878 (90%)
Received for >6 days after randomisation
Enoxaparin: 82% 726/884
UFH group: 80% 698/878
All cause mortality (up to Day 14 and 90 respectively)Day 14
Group 1: 45/872
Group 2: 48/877
P value: 0.58
Day 90
Group 1: 103/872
Group 2: 100/877
P value:0.96
(P values were based on hazard ratio-log rank test)
Funding:
Sanofi Aventis-funded and provided editorial support

Limitations:
  • Open label trial
  • Safety (bleeding outcomes) not reported as stated in protocol-Minor extracranial haemorrhage (secondary safety outcome) not reported, “clinically important bleeding”- a post hoc definition was used
  • No routine scanning of intracranial haemorrhage, a primary outcome.
  • Use of mechanical prophylactic methods?
Outcomes not reported: All cause mortality at 48 hours, PE asymptomatic or symptomatic, Major bleeding, Neurological bleeding, Upper GI bleeding, Minor bleeding Heparin induced thrombocytopaenia, post thrombotic symdrome, pulmonary hypertension QoL, LOS

Additional outcomes reported:
Subgroup analysis by patient characteristics (forest plots)
Outcomes by NIHSS score (by Day 14?)
VTE

NIHSS<14
Grp 1: 14.0%(10.91–17.02)
Grp 2 : 8.3% (5.90–10.70)
P value: 0.004
NIHSS ≥14
Grp 1: 29.7%(22.94–36.49)
Grp 2 :16.3%(10.53–21.97)
P value: 0.004

DVT
NIHSS<14
Grp 1: 13.6%(10.54–16.58)
Grp 2 : 8.1%(5.73–10.48)
P value: 0.005

NIHSS ≥ 14
Grp 1: 29.1%(22.41–35.88)
Grp 2:16.3%(10.53–21.97)
P value: 0.005

Clinically significant intracranial bleeding
NIHSS<14
Grp 1: 0.3%(−0.12 to 0.77)
Grp 2: 0.3% (−0.12 to 0.74)
P value: 0.97
NIHSS ≥ 14

Grp 1: 1.6%(0.04 to 3.16 )
Grp 2:16.3%(−0.33 to 2.05)
P value: 0.47

Major extracranial
NIHSS<14
Grp 1: 0%
Grp 2 : 0.5%(−0.06 to 0.99)
P value: 0.09
NIHSS ≥ 14
Grp 1: 0
Grp 2: 1.7%(0.05–3.40)
P value: 0.04

Notes:
Methodological paper published in year 2005
Fatal pulmonary embolism (up to 14 days, confirmed by autopsy )Group 1: 2/669
Group 2: 1/666
P value: 1.00
[Calculated by NCC-AC team using Fisher’s Exact test]
Symptomatic pulmonary embolism (up to 14 days, confirmed by: )Group 1: 6/669
Group 2: 1/666
P value: 0.059
Symptomatic DVT (confirmed by: compression ultrasonography of the affected limb within 48 hours of symptom onset )Group 1: 4/669
Group 2: 1/666
P value: 0.18
Note this was on efficacy group (screened), rather than randomised group
DVT, asymptomatic or symptomatic (up to 14 day, confirmed by: Asymptomatic patients confirmed by bilateral contrast venography within 72 hours of last dose of study medication. Ultrasonography used for patients who were unable to do venography )Group 1: 118/669
Group 2: 67/666
P value:<0.0001
Note this was on efficacy group (screened), rather than randomised group
Proximal DVT( up to 14 days, confirmed by: see DVT)Group 1: 64/669
Group 2: 30/666
P value: 0.0003
Distal DVT (up to 14days confirmed by: see DVT )Group 1: 85/669
Group 2: 44/666
P value: 0.0002
Fatal bleeding (description: within 48 hours of stopping treatment )Group 1: 4/872
Group 2: 5/877
P value: 1.0
Major bleeding (intracranial and extracranial)Group 1: 6/872
Group 2: 11/877
P value:0.33
[value calculated by NCC-AC team using Fisher’s exact test]
Major (extracranial) bleeding (description: Within 48 hours of stopping treatment, overt bleeding resulting in either death, drop of Hb level of ≥ 30g/L, need for transfusion ≥2 units of blood, surgical intervention or decompression of closed space to s top or control event, bleeding in retroperitoneal or intraocular location )Group 1: 0/872
Group 2: 7/877
P value: 0.015
Group 1Group 2Neurological (Intracranial) bleeding ( within 48 hours of stopping treatment, symptomatic, confirmed by head CT or MRI scan, or autopsy)Group 1: 6/872
No randomised878884Group 2: 4/877
No. dropoutsP value: 0.55
For safety population:67Minor (extracranial ) bleeding (within 48 hours of stopping treatment. Description: any clinically overt bleeding not meeting the criteria for major extracranial bleeding, and associated with at least one of the following: epistaxis lasting more than 5 minute or needing intervention, ecchymosis or haematoma >5 cm at its widest point, haematuria not associated with urinary catheter trauma, gastrointestinal haemorrhage not related to intubation of nasogastric tube placement, wound haematoma or haemorrhagic wound complications not associated with features of over haemorrhage classified as major or subconjuctival haemorrhage needing end of study treatment )Group 1: 48/872
Group 2: 42/877
P value: 0.50
For efficacy population209218
Age (years)66.1±12.965.9±12.9
 <65372371
 65–75265312
 >75241201
M/F473/405521/363
BMI (kg/m3)27.0±5.327.0±5.3
 ≥30183179
Race
 White523523
 Black5568
 Asian193182
 Hispanic6873
 Others3938
NIHSS score
 <14626648
 ≥14252236
Motor leg function (NIHSS score):
 003
 11016
 2381356
 3293316
 4387193
Venous stasis syndrome113
Varicosis1619
Previous VTE1416
Previous thrombolytic therapy5850
Concomitant antiplatelet:791815
 Aspirin738767
 Aspirin with dipyramidole4536
 Clopidogrel174189
 Dipyramidole4740
 Ticlopidine2828
 other5652
Spinal Cord Injury Thromboprophylaxis Investigators, 2003617

Country of study: Multi-centre study in 27 sites across US & Canada

Study design: RCT

List who was masked to interventions: Investigators blinded

Evidence level: 1+

Duration of follow-up: Up to 6 weeks
Patient group: Spinal Cord Injury (SCI)-rehabilitative phase

Setting: Rehabilitative SCI services-ICU, acute care ward and rehabilitation facility

Inclusion criteria:
  • All patients who had completed the study on the effectiveness of hearpin + intermittent pneumatic compression (IPCD) vs LMWH in acute phase of SCI without objective evidence of DVT
  • Patients receiving UFH + IPCD received UFH in this study
  • Patients receiving LMWH 30mg bid received LMWH in this study
Inclusion criteria for the acute phase were:
  • Age 15 or older
  • Sustained traumatic SCI from spinal cord level C2 to T12 within previous 72 hours
  • American Spinal Injury Association (ASIA) classification of A (complete motor or sensory deficit) or B (complete motor and incomplete sensory deficit) or C (incomplete motor deficit and sensory deficit with > half muscles having strength grade <3)
Exclusion criteria for the acute phase were: All patients
N (randomised): 172
Only information on assessable patients (n=119) was provided:

Group 1 (UFH)
No. randomised: 86
No. of dropouts: 26
No assessable: 60
Age (mean): 34.0±16.5
M/F: 47/13
Additional risk factors:
BMI: 24.5±3.8
Surgery: 8

Group 2 (LMWH)
No. randomised: 86
No. of dropouts: 27
No assessable: 59
Age (mean): 30.5±13.2
M/F: 53/6
Additional risk factors:
BMI: 25.0 ± 5.5
Surgery: 7
Group 1: UFH
Low Dose Heparin 5000 U subcutaneous, 8 hourly
Start: End of acute phase (Day 14)
End: End of 8th week
Duration: 6 weeks

Group 2: LMWH
LMWH Enoxaparin
40 mg once daily
Start time: within 72 hours of injury
Start: End of acute phase (Day 14)
End: End of 8th week
Duration: 6 weeks

Additional non-comparative prophylaxis: Not Applicable
All cause mortality (confirmed by: NR )Group 1: 3/86
Group 2: 2/86
P value: 1.00#
[#values calculated by NCC-AC staff, using Fisher’s exact test]
Funding:
Not stated, however, acute phase was funded by Rhone-Poulenc Rorer/Aventis Pharmaceuticals manufacturers of enoxaparin
Limitations:
This phase included only patients without objective evidence of DVT. However, number of subjects which were classified as without objective evidence of VTE was 172 (86 in each treatment arm), which was more than the number of assessable patients reported in the acute phase study (n=107). Discrepancy not explained.

Only about 70% patients randomised were included in the efficacy analysis.

Baseline characteristics were only reported for patients with evaluable outcomes.

Outcomes not reported: Symptomatic PE Thigh DVT, Calf DVT Fatal bleeding, Neurological Bleeding Upper GI bleeding, HIT, Post thrombotic syndrome, Pulmonary hypertension
Quality of life, Length of Stay
Fatal pulmonary embolism (confirmed by: ventilation-perfusion lung scan, spiral CT or pulmonary angiography within 4 days of last dose)Group 1: 1/60
Group 2: 0/59
P value: 0.99#
[#values calculated by NCC-AC staff, using Fisher’s exact test]
Pulmonary embolism, asymptomatic or symptomatic (confirmed by: ventilation-perfusion lung scan, spiral CT or pulmonary angiography within 4 days of last dose)Group 1: 2/60 (3.3%)
Group 2: 1/59 (1.7%)
P value: 1.00#
Reported value: 0.576
[#values calculated by NCC-AC staff, using Fisher’s exact test]
DVT, asymptomatic or symptomatic (confirmed by: proximal and distal venography or proximal Doppler Ultrasound within 4 days of last dose)Group 1: 11/60
Group 2: 4/59
P value: 0.095#
(Reported value=0.067)
[#values calculated by NCC-AC staff, using Fisher’s exact test]
Major bleeding -based on prior definition of transfusion of 2 units of packed red blood cells. Patient had hematuria, and even though there were no significant change in haemoglobin level, 2 bags of packed RBC were transfusedGroup 1: 1/86*
Group 2: 0/86
P value: 1#
[#values calculated by NCC-AC staff, using Fisher’s exact test]
Bibliographic referenceStudy TypeEvidence levelNo. of patientsPatients characteristicsInterventionComparisonLength of follow upOutcome measuresEffect sizeComments
Ward & Pradhan, 1998670RCT+Total: 552
Intervention n:271
Control n: 281
Type of surgery:
Women undergoing major gynaecological surgery.
Type, dose and timing: One dose daily of subcutaneous 5000 LMWH Reviparin (Fragmin) injection at a site distant from the surgical site. Treatment was begun 12 hrs prior to surgery and continued for 5 days or until full activity was resumed whichever was longer.

Additional non- comparative prophylaxis: The use of compression stockings and intermittent calf compression devices used by small number of women with previous history of DVT or PE.
Type, dose and timing: Twice daily subcutaneous dose of 5000 U Sodium Heparin. Injection at a site distant from the surgical site. Treatment was begun 12 hrs prior to surgery and continued for 5 days or until full activity was resumed whichever was longer.

Additional non- comparative prophylaxis: The use of compression stockings and intermittent calf compression devices used by small number of women with previous history of DVT or PE.
6 WeeksDVT confirmed by Doppler US or VenographyInt: n = 0; Control: n = 1
Intervention: Mean age: 55 ± 17 yearsPE Confirmed by V/Q lung scan.Int: n = 5; Control: n = 1
Control: Mean age: 55 ± 16 yearsBlood transfusionInt: n = 57; Control: n = 39
Pre-existing risk factors:

Previous VTE: presence indicated but no figures are given

Malignant disease: Int: n = 222 Control: n = 239

Radical surgery: Int: n = 208 Control: n = 222

Non radical surgery: Int: n = 63 Control: n = 59

From: Appendix D, Evidence tables

Cover of Venous Thromboembolism
Venous Thromboembolism: Reducing the Risk of Venous Thromboembolism (Deep Vein Thrombosis and Pulmonary Embolism) in Patients Admitted to Hospital.
NICE Clinical Guidelines, No. 92.
National Clinical Guideline Centre – Acute and Chronic Conditions (UK).
Copyright © 2010, National Clinical Guideline Centre - Acute and Chronic Conditions.

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