Electronic Supplementary Material (ESM) Content Page

Electronic supplementary material (ESM) content Page

1.  ESM 1: Search strategy……………………………………………………. 2

2.  ESM 2: Study selection form……………………………………………… 5

3.  ESM 2: Data extraction form…………………………..………………….. 7

4.  ESM 4: Study details….…………………………………………………… 10

5.  ESM 5: Funnel plots……………………………………………………….. 18

6.  ESM 6: Subgroup analyses………………………………………………… 23

7.  ESM 7: Trial sequential analyses of all trials……………………………… 26

8.  ESM 8: Trial sequential analyses of trials with overall low risk of bias…... 31

ESM 1: Search strategy

Detailed method

An experienced librarian performed the literature search supervised by a consultant intensive care clinician (SB). Papers published up to and including 3 December 2014 were searched in Ovid Medline, Embase, Cochrane Library, UpToDate and Guidelines International Network (GIN). An additional search was carried out in PubMed in order to retrieve papers that had not yet been entered into Ovid Medline. We identified ongoing studies by searching PROSPERO (International database of prospectively registered systematic reviews in health and social care) and the metaRegister of Controlled Trials (mRCT). In Ovid Medline, Medical Subject Headings (MeSH) and terms in title or abstract were searched alone or in combination, including pulmonary embolism, thrombosis, intensive care, anticoagulants and thrombosis prophylaxis. This search was then adapted for use in the other databases. Forward citation searching using Google Schoolar and Web of Science through 4 February 2015, and hand searching of reference lists were also conducted. Pharmacological prophylaxis against VTE with LMWH versus UFH was considered, irrespective of whether it was combined with a mechanical prophylaxis or not. The literature search was not limited regarding date of publication or study design, however the population was limited to adult humans above 18 years, and the language to English, Swedish, Danish or Norwegian. The librarian also made an additional search in relevant medical books and journals not indexed in the databases mentioned above.

PROSPERO - International database of prospectively registered systematic reviews in health and social care

Record Title:

Thromboprophylaxis or Thromboprophylactic

(thrombosis or embolism or embolic or thromboembolism or thromboembolic) and (prophylactic or prophylaxis or anticoagulant or anticoagulants or antithrombin or antithrombins)

metaRegister of Controlled Trials

http://www.controlled-trials.com/mrct/

Thromboprophylaxis or Thromboprophylactic or ((thrombosis or embolism or thromboembolsism) and (prophylactic or prophylaxis or anticoagulant or anticoagulants or antithrombin or antithrombins))

Cochrane Library (Cochrane Reviews, Other Reviews, Technology Assessments , NHS Economic Evaluation)

((thromboprophyl* or ((thrombosis or thromboemboli* or ((pulmonary OR lung or thrombo*) and emboli*)) and (anticoag* or antithrombin* or prophyla*))) and (critical* or intensive or icu or trauma* or emergen*)):ti,ab,kw
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present
1 / pulmonary embolism/ or pulmonary infarction/ or thrombosis/ or thromboembolism/ or "intracranial embolism and thrombosis"/ or intracranial embolism/ or intracranial thrombosis/ or sinus thrombosis, intracranial/ or cavernous sinus thrombosis/ or lateral sinus thrombosis/ or sagittal sinus thrombosis/ or embolism, paradoxical/ or venous thromboembolism/ or venous thrombosis/ or budd-chiari syndrome/ or upper extremity deep vein thrombosis/ / 131032
2 / exp "Chemicals and Drugs (non mesh)"/ / 11401865
3 / intensive care units/ or burn units/ or coronary care units/ or recovery room/ or respiratory care units/ / 40428
4 / Critical care/ or intensive care/ / 38306
5 / Critical Illness/ / 15719
6 / exp Emergency Medical Services/ or Emergency Service, Hospital/ or Trauma Centers/ / 90705
7 / (intensive or icu or critical* or trauma* or emergen*).ti. / 279828
8 / 3 or 4 or 5 or 6 or 7 / 369394
9 / exp Anticoagulants/ / 182322
10 / exp Thrombosis/pc [Prevention & Control] / 23939
11 / exp Pulmonary Embolism/pc [Prevention & Control] / 4164
12 / (thromboprophyla* or prophyla* or anticoag* or antithromb*).ti,ab. / 193236
13 / Thrombin/ai [Antagonists & Inhibitors] / 3375
14 / 9 or 10 or 11 or 12 or 13 / 337111
15 / 1 and 2 and 8 and 14 / 1041
16 / limit 15 to (danish or english or norwegian or swedish) / 854
17 / limit 16 to "all child (0 to 18 years)" / 115
18 / limit 17 to "all adult (19 plus years)" / 71
19 / 17 not 18 / 44
20 / 16 not 19 / 810
PubMed
(((thromboprophyl* or (thrombosis[ti] or thromboemboli*[ti] or ((pulmonary[ti] OR lung[ti] OR thrombo*[ti]) and emboli*[ti]) and (anticoag* or antithrombin* or prophyla* or prevent or prevents or prevention))) and (critical*[ti] or icu[ti] or intensive[ti] or trauma[ti] or traumas[ti] or traumatic[ti] or traumatized[ti] or emergen*[ti] OR (intensive care unit*))) AND (english[lang] OR danish[lang] OR norwegian[lang] OR swedish[lang])) not medline[sb]
Embase 1980 to 2013
1 / intensive care unit/ / 75390
2 / intensive care/ / 78679
3 / critically ill patient/ / 14963
4 / Critical illness/ / 20864
5 / (intensive or icu or critical* or trauma* or emergen*).ti. / 345059
6 / 1 or 2 or 3 or 4 or 5 / 424736
7 / embolism prevention/ / 580
8 / thrombosis prevention/ / 6209
9 / 7 or 8 / 6620
10 / exp anticoagulant agent/ / 445424
11 / anticoagulant therapy/ / 23868
12 / 10 or 11 / 448406
13 / 6 and 9 and 12 / 294
14 / limit 13 to (danish or english or norwegian or swedish) / 263
15 / limit 14 to (embryo <first trimester> or infant <to one year> or child <unspecified age> or preschool child <1 to 6 years> or school child <7 to 12 years> or adolescent <13 to 17 years>) / 23
16 / limit 15 to (adult <18 to 64 years> or aged <65+ years>) / 11
17 / 15 not 16 / 12
18 / 14 not 17 / 251
Cochrane Central Register of Controlled Trials May 2013
1 / thromboprophyl*.mp. / 408
2 / (thrombosis or thromboemboli* or ((pulmonary or lung or thrombo*) and emboli*)).ti. / 3927
3 / (anticoag* or antithrombin* or prophyla*).mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] / 22391
4 / 1 or (2 and 3) / 1974
5 / (critical* or intensive or trauma* or emergen*).mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] / 33082
6 / 4 and 5 / 138

ESM 2: Study selection form

Reviewer, date:______

Number, first author, year:______

Review summary:

Decision made by one reviewer (after fulfilling this study selection form)

Include Ο (all questions below answered “yes”)

Discuss Ο (some question below answered “unknown”)

Exclude Ο (some question below answered “no”)

Final decision made by the reviewers (after discussion with other reviewer(s))

Include Ο (all questions below answered “yes”)

Exclude Ο (some question below answered “no”), reason number:______

______

Detailed review

1. Is it an empirical study?

Yes: Ο No: Ο Unknown: Ο

2. Is the study aimed to assess the effect of pharmacological thromboprophylaxis in intensive care unit (ICU) patients?

Yes: Ο No: Ο Unknown: Ο

3. Is the study design one of the below mentioned?

Randomized controlled trial Yes: Ο No: Ο Unknown: Ο

Controlled trial without randomization Yes: Ο No: Ο Unknown: Ο

Interrupted time series Yes: Ο No: Ο Unknown: Ο

Cohort study Yes: Ο No: Ο Unknown: Ο

Case-control study Yes: Ο No: Ο Unknown: Ο

Other: ______Yes: Ο No: Ο Unknown: Ο

4. Is the population human adult patients (above 18 years)?

Yes: Ο No: Ο Unknown: Ο

5. Is the intervention pharmacological thromboprophylaxis with any low molecular weight heparin (LMWH) in any dose?

Yes: Ο No: Ο Unknown: Ο

6. Is the comparator pharmacological thromboprophylaxis with any unfractionated heparin (UFH) in any dose?

Yes: Ο No: Ο Unknown: Ο

7. Is the study design to assess effects of pharmacological thrombosis prophylaxis?

Yes: Ο No: Ο Unknown: Ο

8. Is the intervention and the comparator one of the following?

Heparin, Low-Molecular-Weight

- bemiparin Yes: Ο No: Ο Unknown: Ο
- certoparin Yes: Ο No: Ο Unknown: Ο
- dalteparin Yes: Ο No: Ο Unknown: Ο
- enoxaparin Yes: Ο No: Ο Unknown: Ο
- fondaparinux Yes: Ο No: Ο Unknown: Ο

- nadroparin Yes: Ο No: Ο Unknown: Ο
- parnaparin Yes: Ο No: Ο Unknown: Ο

- reviparin Yes: Ο No: Ο Unknown: Ο

- tinzaparin Yes: Ο No: Ο Unknown: Ο

Heparin, unfractionated Yes: Ο No: Ο Unknown: Ο

Other, specify______Yes: Ο No: Ο Unknown: Ο

9. Is the outcome one of the following?

- Incidence of deep venous thrombosis Yes: Ο No: Ο Unknown: Ο

- Incidence of pulmonary embolism Yes: Ο No: Ο Unknown: Ο

- Incidence of bleeding Yes: Ο No: Ο Unknown: Ο

- Patient mortality Yes: Ο No: Ο Unknown: Ο

- Length of stay (ICU or hospital) Yes: Ο No: Ο Unknown: Ο

- Heparin induced thrombocytopenia Yes: Ο No: Ο Unknown: Ο

10. Additional comments

______

______

______

______

______

ESM 3: Data extraction form

Reviewer (name, date):______

First author, year:______

1. Study identification

Study identifier (first author, year): ______

Study location (country, city):______

2. Study method

Study design:______

Risk of bias (from checklist):______

3. Study participants

Number of patients: Total:______Intervention: ______Comparison :______

Male gender (%): Total:______Intervention: ______Comparison:______

Age (average): Total:______Intervention: ______Comparison:______

ISS score (median): Total:______Intervention: ______Comparison:______

Setting (ICU type): Mixed:______Surgical:_____ Medical:______Trauma:______

4. Interventions

Intervention drug and dose:______

Comparison drug and dose:______

Co intervention, mechanical:______

Co intervention, medical:______

Subgroups of different drugs and/or doses: Yes: Ο No: Ο

5. Outcomes reported

Deep venous thrombosis, any Yes: Ο No: Ο Time points:______

Diagnostic method: ______Yes: Ο No: Ο Time points:______

Screening: ______Yes: Ο No: Ο Time points:______

Deep venous thrombosis, symptomatic Yes: Ο No: Ο Time points:______

Diagnostic method: ______Yes: Ο No: Ο Time points:______

Screening: ______Yes: Ο No: Ο Time points:______

Deep venous thrombosis, proximal Yes: Ο No: Ο Time points:______

Diagnostic method: ______Yes: Ο No: Ο Time points:______

Screening: ______Yes: Ο No: Ο Time points:______

Pulmonary embolism, any Yes: Ο No: Ο Time points:______

Diagnostic method: ______Yes: Ο No: Ο Time points:______

Screening: ______Yes: Ο No: Ο Time points:______

Pulmonary embolism, symptomatic Yes: Ο No: Ο Time points:______

Diagnostic method: ______Yes: Ο No: Ο Time points:______

Screening: ______Yes: Ο No: Ο Time points:______

Bleeding, any Yes: Ο No: Ο Time points:______

Definition: ______Yes: Ο No: Ο Time points:______

Site: ______Yes: Ο No: Ο Time points:______

Cause______Yes: Ο No: Ο Time points:______

Consequence______Yes: Ο No: Ο Time points:______

Bleeding, major Yes: Ο No: Ο Time points:______

Definition: ______Yes: Ο No: Ο Time points:______

Site: ______Yes: Ο No: Ο Time points:______

Cause______Yes: Ο No: Ο Time points:______

Consequence______Yes: Ο No: Ο Time points:______

Mortality Yes: Ο No: Ο Time points:______

ICU Yes: Ο No: Ο Time points:______

Hospital Yes: Ο No: Ο Time points:______

Other time point: ______Yes: Ο No: Ο Time points:______

Cause of death:______Yes: Ο No: Ο Time points:______

Length of stay (LOS) Yes: Ο No: Ο Time points:______

ICU LOS:______Yes: Ο No: Ο Time points:______

Hospital LOS:______Yes: Ο No: Ο Time points:______

Heparin induced thrombocytopenia (HIT) Yes: Ο No: Ο Time points:______

Definition: ______Yes: Ο No: Ο Time points:______

6. Results

Outcome reported / Dichotomous data / Continuous data
Specify data / Intervention
N sick /
N exposed (%) / Comparison
N sick /
N exposed (%) / Intervention Median / IQR
Mean / SD / Comparison
Median / IQR
Mean / SD
Any DVT
Symptomatic DVT
Proximal DVT
Any PE
Symptomatic PE
Any bleeding
Major bleeding
ICU mortality
Hospital mortality
Mortality other time point
ICU LOS
Hospital LOS
HIT

7. Additional comments

______

______

______

______

______

______

ESM 4: Study details

Geerts WH, 1996

Study data

Participants / Number
Randomisation
Inclusion criteria
Exclusion criteria / 265
UFH (136) or LMWH (129)
Adult trauma patients
ISS<9. Survival<7 days. Hospital LOS<7 days. Intracranial bleeding on CT. Uncontrolled bleeding 36 hours after injury. Systemic coagulopathy (PT>3 seconds above control value or platelets<50.000/mm3. Therapeutic anticoagulation. Allergy against contrast medications for venography. Renal failure (serum creatinin>300 mmol/l. Pregnant. Unable to achieve venous access for venography
Interventions / Intervention 1
Intervention 2
Co-intervention / UFH 5000 U SC x 2
LMWH (enoxaparin) 30 mg SC x2
No co-intervention was allowed
Outcomes / DVT
PE
Bleeding
Length of stay
HIT / Clinical surveillance, if suspected ultrasound confirmed by venography. Control venography day 10 and 14 after injury. DVTs sub classified in four categories, whereof two proximal and two distal groups
Clinical surveillance, if suspected ventilation-perfusion scanning supplemented by pulmonary angiography, venous ultrasonography, contrasts venography or combinations
Major bleeding was defined as associated with a decrease in Hb>2 G/dl, transfusion of ≥2 units PRBC, intracranial or retroperitoneal bleeding or need for surgery
Hospital
Number
Follow-up time
Notes / 14 days
Lower extremity veins were screened

Risk of bias

/ Authors’ judgment
of risk / Support of judgment
Random sequence generation / Low / Randomized by a computer-derived protocol
Allocation concealment / Unclear / Describes randomization, insufficient information to permit judgement
Blinding of participants, personnel and outcome assessors / Low / Study drugs were administrated in a blinded fashion and outcome assessor was blinded
Incomplete outcome data / Unclear / 21 % and 25 % drop-outs in the two compared groups
Selective outcome reporting / Unclear / The outcomes reported in the study is not clearly predefined
Other sources of bias / Unclear / Intention to treat strategy not described
A priori power estimation not described Funded by Health Research Grants from the Ontario Ministry of Health

Greenfield LJ, 1997

Study data

Participants / Number
Randomisation
Inclusion criteria
Exclusion criteria / 18
UFH (7) or LMWH (11)
Adult trauma patients with age>18 years, an informed consent, a thromboembolic risk based on specified criteria, available for minimum one discharge follow-up and with an ISS≥9
Unable to achieve informed consent. Unable to receive anticoagulants or one of the mechanical methods for prophylaxis. Positive duplex scanning before initiation of prophylaxis. Anticoagulant treatment. Pregnant. Prisoners
Interventions / Intervention 1
Intervention 2
Co-intervention / UFH 5000 U SC x 2
LMWH (enoxaparin) 30 mg SC x 2
Half of the patients got vena cava inferior filters, unclear how many in each group
Outcomes / DVT
PE / Ultrasound surveillance at admission, day 3 and 6, thereafter weekly until four weeks
Locations of DVTs classified as proximal and distal, but data not presented for the two compared groups
Pulmonary angiography in cases of clinical signs and symptoms
Follow-up time
Notes / 4 weeks
Lower extremity veins were screened

Risk of bias

/ Authors’ judgment
of risk / Support of judgment
Random sequence generation / Unclear / Describes randomization, gives no description of method used to randomize
Allocation concealment / Unclear / Describes randomization, gives no description of concealment
Blinding of participants, personnel and outcome assessors / Unclear / Blinding of outcome assessor not described
Incomplete outcome data / Low / No drop-outs in the study
Selective outcome reporting / Unclear / The outcomes reported in the study is not clearly predefined
Other sources of bias / Unclear / Intention to treat and a priori power estimation not described
Unclear whether the two groups got the same mechanical prophylaxis
Stratification of patients according to their ability to recieve prophylaxis
Baseline characteristics of the compared groups not reported/described
Funded by Boston Scientific Corporation, Toshiba Corporation, Kendall Healthcare Products Company and Rhone-Poulenc Rorer
Cohn SM, 1999

Study data

Participants / Number
Randomisation
Inclusion criteria
Exclusion criteria / 66
UFH (32) or LMWH (34)
Adult trauma patients with at least one of the following risk factors: Age>45 years, expected>2 days bedrest, history of DVT or PE, coma (GCS<7), spinal cord injury, pelvis fracture, lower extremity fracture, repair of major lower extremity vein, complex wound of lower extremity or femoral venous catheter
Age<18 years, severe closed head injury, bleeding injuries without haemostatic control, active bleeding, cardiovascular instability, nursing mothers, heparin, warfarin or heparinoid compound within 7 days of injury, allergy to heparin, bisulfites or fish, history of protein C deficiency or HIT, malignant hypertension, hepatic encephalopathy, renal failure or failure to obtain informed consent
Interventions / Intervention 1
Intervention 2
Co-intervention / UFH 5000 U SC x 2
LMWH (enoxaparin) 30 mg SC x2
Compression devises were not used. 5 patients got IVC filter, 2 in the LMWH group and 3 in the UFH group
Outcomes / DVT
PE
Bleeding
Length of stay / Doppler ultrasonography screening weekly
Location of DVTs not specified
Ventilation-perfusion scanning, and pulmonary angiography on indication
Classified as any or major bleeding. Major was overt, decrease in Hb>2 g/dL, leading to 2 units of PRBC transfusion, retroperitoneal or intracranial
Hospital and ICU
Follow-up time
Notes / 30 days
Unclear which veins that were screened

Risk of bias

/ Authors’ judgment
of risk / Support of judgment
Random sequence generation / Low / Randomized via computer-generated schedule
Allocation concealment / Unclear / Describes randomization, unclear whether it was adequately concealed
Blinding of participants, personnel and outcome assessors / Unclear / Blinding of outcome assessor not described
Incomplete outcome data / High / High number of drop-outs, distribution in the two compared groups not described
Selective outcome reporting / Unclear / The outcomes reported in the study is not clearly predefined
Other sources of bias / High / A priori power estimation not followed
Intention to treat strategy not described
Baseline characteristics of the compared groups not reported/described
No funding source reported

Goldhaber SZ, 2000