23-03-2016 V 1.4

PROTOCOL

Intermediate dose low-molecular-weight heparin for thromboprophylaxis.

A systematic review with meta-analysis and trial sequential analysis

Ruben J. Eck, Jørn Wetterslev, Wouter Bult, Iwan C.C. van der Horst, Frederik Keus

Correspondence

R.J. Eck, M.D.

University of Groningen

University Medical Center Groningen

Department of Critical Care

P.O. Box 30.001

9700 RB Groningen

The Netherlands

Phone: +31 6 42514894

Fax: +31-503619986

Email: r.j.eck@umcg.nl

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Ruben J. Eck, Wouter Bult, Iwan C.C. van der Horst, Frederik Keus

Department of Critical Care, University of Groningen, University Medical Center Groningen,

The Netherlands

Wouter Bult

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen,

Groningen, The Netherlands

Jørn Wetterslev

The Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Department

7812, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.

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INTRODUCTION

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary

embolism (PE), is a frequent cause of increased morbidity and mortality among hospitalized

patients (1). VTE may either be clinically obvious and diagnosed, or may remain undetected

(2). Commonly recognized risk factors for VTE are active cancer, previous VTE, reduced

mobility, known thrombophilic condition, recent trauma and/or surgery, elderly age (>70),

heart and/or respiratory failure, acute myocardial infarction or stroke, acute infection, obesity

and ongoing hormonal treatment (3).

Several pharmacological agents for thromboprophylaxis are available, of which

unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are most

commonly used. Two recent reviews with meta-analysis suggested benefit of LMWH over

UFH in acutely ill medical patients and critically ill ICU patients based on decreased risk of

DVT (4). No such beneficial effect was shown in a Cochrane review on LMWH versus UFH

in oncologic surgery patients (5).

Many systematic reviews with meta-analyses have been conducted on LMWH

thromboprophylaxis in specific patient groups such as cardiac and thoracic surgery patients

(6), non-surgical medically ill patients (4,7-9), patients with cancer (10-13), patients having

non-major orthopaedic surgery (14), pregnant and postnatal woman at risk of VTE (15) and

bariatric surgery patients (16,17). None of these reviews evaluated the efficacy of LMWH in

all patient categories. Only few reviews compared different doses of LMWH in selected

populations (orthopaedic and bariatric surgery) (16,17). The American College of Chest

Physicians (ACCP) guidelines provide no recommendations regarding the dose of LMWH in

patients at high risk of VTE (18-20). No systematic review has been conducted specifically

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addressing the research question of intermediate dose LMWH versus placebo for

thromboprophylaxis including all patient populations.

Objective

The objective is to perform a systematic review with meta-analyses and trial sequential

analyses (TSA) of randomized clinical trials (RCT´s) according to the Cochrane Handbook

for Systematic Reviews of Interventions comparing the benefits and harms of intermediate

dose LMWH versus placebo or no treatment in patients at risk of VTE (21). Available

evidence will be evaluated in the perspective of the three dimensions of possible risks of

errors: the systematic error (bias), the random error (`the play of chance´), and the design

error (the outcome measure chosen) (22).

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METHODS

This protocol will be online available at PROSPERO.

Criteria for considering trials for this review

We will consider all randomized clinical trials for inclusion irrespective of language, blinding,

publication status, or sample size. Quasi-randomized trials and observational studies will be

excluded.

Patients

Only randomized trials with adult patients at risk for VTE allocated to receive either

intermediate dose LMWH, a placebo, or no treatment will be eligible for inclusion, regardless

their underlying disease and whether they were admitted to the hospital or visited the

outpatients clinic.

Alternative intervention

The alternative intervention is intermediate dose LMWH. All trials will be considered that

evaluate LMWH in an intermediate dose, independent of the type of LMWH or duration of

treatment. Trials investigating ultra-low-molecular-weight heparin will also be included in

this review. As the process of depolymerization of native heparin is different for each product,

the U.S. Food and Drug Administration (FDA) and World Health Organization (WHO) have

classified each LMWH as a separate drug (23). Different types of LMWH can therefore not

be used interchangeably and each type may be registered for different clinical applications in

different doses. In Europe, several LMWH preparations (e.g., enoxaparin, tinzaparin,

dalteparin, nadroparin, reviparin, etc) are licensed for the prevention and treatment of VTE. In

the United States three different preparations (e.g., enoxaparin, tinzaparin and dalteparin) are

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currently approved for a range of clinical applications. Table 1 summarizes the recommended

low and intermediate prophylactic and therapeutic LMWH doses according to the ‘Summary

of Product Characteristics’ (SPC) as approved by different medicine evaluation boards across

a variety of nations (24-29).

Randomized clinical trials may occasionally use custom doses of LMWH that are not covered

by Table 1. We have therefore classified LMWH doses to be either in the low prophylactic

range or in the intermediate prophylactic range (Table 2). This classification between low and

intermediate dose ranges is based on the recommended SPC doses as summarized in Table 1.

This systematic review seeks to answer the question whether intermediate dose LMWH is

preferred over placebo or no treatment for the prevention of VTE, therefore, we will only

include randomized trials in which LMWH was used in the intermediate dose range as

indicated according to Table 2. There will be no restrictions on durations of interventions.

In case different types or doses (or weight adjusted doses) were used in one trial or even in

one patient, we will classify the trial according to what was used most of the time.

Randomized trials will be included based on the intention for LMWH use, i.e., prophylactic or

therapeutic use. We will classify other unforeseen types of (infrequently used) LMWH not

listed in table 1 and 2 following the dosage regimens applied in the identified trials.

Control intervention

The control intervention will be placebo or no treatment. There will be no restrictions on

durations of interventions.

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Table 1. Dose recommendation of commonly used LMWHs according to Summary of

Product Characteristics in national registries

Product Prophylactic Therapeutic dose

Low dose Intermediate dose

Nadroparin

(Fraxiparine®)

2850 IU (=0,3 ml) 5700 IU (=0,6 ml)* 171 IU /kg once daily

or 86 IU /kg twice

daily

Dalteparin (Fragmin®) 2500 IU (=0,2 ml) 5000 IU (=0,2 ml) 200 IU /kg once daily

or 100 IU /kg twice

daily

Enoxaparin (Clexane®) 20 or 30 mg (=0,2 –

0,3 ml)

40 mg (=0,4 ml)

once, or 30 mg

(=0,3 ml) twice

daily

1,5 mg /kg once daily

or 1 mg /kg twice

daily

Tinzaparin (Innohep®) 3500 IU (=0,35 ml) 4500 IU (=0,45 ml) 175 IU /kg once daily

Parnaparin (Fluxum®) 3200 IU (= 0,3 ml) 4250 IU (= 0,4 ml) 6400 IU twice daily

Bemiparin (Zibor®) 2500 IU (=0,2 ml) 3500 IU (=0,2 ml) 115 IU /kg once daily

Reviparin (Clivarin®) 1432 IU (=0,25 ml) 3436 IU (=0,6 ml) 143 IU /kg over two

gifts

IU: International Units; ml: milliliters; kg: kilograms; mg: milligrams. All doses are administered once daily

unless specified otherwise. *Not in SPC; based on Dutch thromboprophylaxis guidelines (30).

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Table 2. Classification of low and intermediate dose prophylactic ranges, based on Table 1

Product Prophylactic

Low dose range Intermediate dose

range

Nadroparin

(Fraxiparine®)

< 5700 IU ≥ 5700 IU

Dalteparin (Fragmin®) < 5000 IU ≥ 5000 IU

Enoxaparin (Clexane®) < 40 mg ≥ 40 mg

Tinzaparin (Innohep®) < 4500 IU ≥ 4500 IU

Parnaparin (Fluxum®) < 4250 IU ≥ 4250 IU

Bemiparin (Zibor®) < 3500 IU ≥ 3500 IU

Reviparin (Clivarin®) < 3436 IU ≥ 3436 IU

IU: International Units; mg: milligrams.

Outcomes

Primary outcomes

The primary outcome will be all-cause mortality at maximal follow-up.

Secondary outcomes

Our secondary outcomes will be the number of patients with at least one serious adverse event

(SAE), symptomatic VTE, major bleeding, VTE diagnosed through screening of all patients

in the trial (including both symptomatic and asymptomatic events), and heparin-induced

thrombocytopenia (HIT).

SAE will be defined as the composite outcome measure summarizing all serious events

necessitating an intervention, operation, or prolonged hospital stay according to the

International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) definitions

(31). Mortality will be excluded in our definition of SAE to avoid double counts. VTE,

symptomatic or asymptomatic, includes DVT and PE. A diagnosis of DVT will be accepted

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when objectified by either ultrasound, a fibrinogen uptake test, venography, or

plethysmography. A diagnosis of PE will be accepted when objectified by a ventilation-

perfusion scan, computed tomography, pulmonary angiography or autopsy. Major bleeding

will be defined according to the criteria used in the individual trials. In case the author’s

definitions are unclear, we will attempt to define major bleeding according to the definitions

of the Scientific and Standardization Committee of the International Society on Thrombosis

and Haemostasis (Appendix 2) (32,33). HIT will be defined according to trial criteria, as long

as objectified by a mandatory laboratory test. All outcomes will be graded from the patients’

perspective according to GRADE (Table 3) (34).

Table 3. Outcomes graded from patients’ perspective (34)

The importance of outcomes

All-cause mortality 9 Critical for decision making

Serious adverse events 8 Important, but not critical for decision making

Symptomatic VTE 7

Major bleeding 6

All VTE diagnosed through

screening

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Heparin-induced thrombocytopenia 4

3

2 Not important for decision making - of lower

importance to patients 1

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Search methods for identification of studies:

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) in The

Cochrane Library, PubMed/MEDLINE, Web of Science and EMBASE. The search will be

conducted using the search strategy in Appendix 1. The references of the identified trials will

be screened to identify further relevant trials. We will check the trial registers at

www.clinicaltrials.gov, https://www.clinicaltrialsregister.eu, and www.centerwatch.com for

any ongoing randomized trials.

Data collection and analysis

Trial selection and extraction of data

Two authors will independently identify the trials for inclusion. We will also list the excluded

studies with the reasons for exclusion. Two authors will independently extract the following

data: study characteristics (lead author, publication year, country or region, number of

participating sites, number of patients enrolled), participant characteristics (age, sex and other

baseline characteristics, inclusion and exclusion criteria), intervention characteristics (dose

and duration of thromboprophylaxis of both the alternative and control intervention, co-

interventions), evaluated outcomes, and risks of bias according to the domains of bias in the

Cochrane Handbook for Systematic Reviews of Interventions as described below (21).

Any unclear or missing information will be sought by contacting the authors of the individual

trials. If there is any doubt whether the trial reports shared the same participants - completely

or partially (by identifying common authors and centres) - the authors of the trials will be

contacted to clarify whether the trial report had been duplicated. We will resolve any

differences in opinion through discussion.

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Assessment of bias risk

Two authors will assess the risk of bias of the trials independently, without masking of trial

names. We will follow the instructions given in the Cochrane Handbook for Systematic

Reviews of Interventions (21). According to empirical evidence, the following risk of bias

components will be extracted from each trial.

Sequence generation

• Low risk of bias (the method used is either adequate (e.g., computer generated random

numbers, table of random numbers) or unlikely to introduce confounding).

• Uncertain risk of bias (there is insufficient information to assess whether the method used is

likely to introduce confounding).

• High risk of bias (the method used is improper and likely to introduce confounding).

Allocation concealment

• Low risk of bias (the method used (e.g., central allocation) is unlikely to induce bias on the

final observed effect).

• Uncertain risk of bias (there is insufficient information to assess whether the method used is

likely to induce bias on the estimate of effect).

• High risk of bias (the method used (e.g., open random allocation schedule) is likely to

induce bias on the final observed effect).

Blinding of participants and personnel

• Low risk of bias (blinding was performed adequately, or the outcome measurement is not

likely to be influenced by lack of blinding).

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• Uncertain risk of bias (there is insufficient information to assess whether the type of

blinding used is likely to induce bias on the estimate of effect).

• High risk of bias (no blinding or incomplete blinding, and the outcome is likely to be

influenced by lack of blinding).

Blinding of outcome assessors

• Low risk of bias (blinding was performed adequately, or the outcome measurement is not

likely to be influenced by lack of blinding).

• Uncertain risk of bias (there is insufficient information to assess whether the type of

blinding used is likely to induce bias on the estimate of effect).

• High risk of bias (no blinding or incomplete blinding, and the outcome measurement is

likely to be influenced by lack of blinding).

Incomplete outcome data

• Low risk of bias (the underlying reasons for missingness are unlikely to make treatment

effects depart from plausible values, or proper methods have been employed to handle

missing data).

• Uncertain risk of bias (there is insufficient information to assess whether the missing data

mechanism in combination with the method used to handle missing data is likely to induce

bias on the estimate of effect).

• High risk of bias (the crude estimate of effects (e.g., complete case estimate) will clearly be

biased due to the underlying reasons for missingness, and the methods used to handle missing

data are unsatisfactory).

Selective outcome reporting

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• Low risk of bias (the trial protocol is available and all of the trial’s pre-specified outcomes

that are of interest in the review have been reported or similar or all of the primary outcomes

in this review have been reported).

• Uncertain risk of bias (there is insufficient information to assess whether the magnitude and

direction of the observed effect is related to selective outcome reporting).

• High risk of bias (not all of the primary outcomes in this review have been reported and not

all of the trial’s pre-specified outcomes that are of interest in the review have been reported).

We will consider trials classified as low risk of bias in all the domains of sequence generation,

allocation concealment, blinding of participants and personnel, blinding of outcome assessors,

incomplete outcome data, and selective outcome reporting as trials with low risk of bias.

Trials with one or more of these risk of bias domains scored as unclear or high risk of bias

will be considered high risk of bias trials (21). Furthermore, we will register and describe

other characteristics of the trials, e.g., risk of vested interests bias, baseline imbalance, early

stopping, and other than intention-to-treat analysis.

We will base our conclusions mainly on results from trials with low risk of bias and construct

a summary of findings table based primarily on the low risk of bias estimates and only

secondarily on all trials.

Statistical methods

We will perform the meta-analyses according to the Cochrane Handbook for Systematic

Reviews of Interventions (21). We will use the software package Review Manager 5.3.5 (35).

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For dichotomous variables, we will calculate the risk ratio (RR) with Trial Sequential

Analysis (TSA)-adjusted confidence interval (CI), adjusting for sparse data and repetitive

testing, if there are two or more trials for an outcome. For rare events (<5% in the control

group) we will calculate odds ratios (OR) or Peto’s OR in case of very rare events (<2% in the

control group) with TSA-adjusted CI. We will report the proportion of patients with the

outcome in each group. A p-value of less than 0.05 will be considered statistically significant.

We will use a fixed-effect and a random-effects model for meta-analysis in the presence of

two or more trials included under the outcomes. In case of discrepancy between the two

models, we will report the results of both models. Considering the anticipated abundant

clinical heterogeneity (in populations, alternative and control interventions, and settings) we

will emphasise the random-effects model except if one or two trials dominate the available

evidence.

Heterogeneity as I-square will be explored by the chi-squared test with significance set at p-

value of 0.10. The quantity of heterogeneity will be measured by D2 as well (36).

The analysis will be performed on an intention-to-treat basis whenever possible, otherwise,

we will adopt the ’available-case analysis´. We will also report the results of risk difference

(RD) if conclusions are different from the results of risk ratio. In case of statistical significant

RR we will calculate the number needed to treat (NNT) or number needed to harm (NNH)

with TSA-adjusted confidence limits.

Sensitivity analyses

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For dichotomous outcomes we will perform best-worst and worst-best scenarios as sensitivity

analyses for participants lost to follow-up.

Subgroup analysis

We intend to perform the following subgroup analyses:

Trials with low risk of bias (adequate in all domains) compared to trials with high risk

of bias (one or more of the domains of bias assessed as inadequate or unclear).

The intervention effect varying with the types of patients included (e.g., patients

having orthopaedic surgery, patients having non-orthopaedic surgery, medical

patients, or critically ill patients).

The intervention effect varying with the type of medication (e.g., nadroparin,

enoxaparin)

The intervention effect varying with length of follow-up: trials with any follow-up

smaller than or equal to 30 days versus trials with follow-up more than 30 days.

The intervention effect varying with length of the intervention period: trials with

length of the intervention period smaller than or equal to 30 days versus trials with

length of the intervention period more than 30 days.

Only subgroup analyses showing statistical subgroup differences (significant test of

interactions; p<0.05) will provide evidence of an intervention effect pending the subgroup.

Bias exploration

We plan to use a funnel plot to explore small trial bias and to use asymmetry in funnel plot of

trial size against treatment effect to assess this bias if more than 10 trials are available (21).

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Trial sequential analysis (TSA)

Meta-analyses may result in type-I errors due to an increased risk of random error when few

data are collected and due to repeated significance testing when a cumulative meta-analysis is

updated with new trials (37-42). To assess the risk of type-I errors, we will use TSA. TSA

combines information size estimation for meta-analysis (cumulated sample size of included

trials) with an adjusted threshold for statistical significance in the cumulative meta-analysis

(37,38). The latter, called trial sequential monitoring boundaries, reduce type-I errors. In TSA

the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis

and helps to clarify whether additional trials are needed or not. The idea in TSA is that if the

cumulative Z-curve crosses the trial sequential monitoring boundary, a sufficient level of

evidence has been reached and no further trials are needed. If the Z-curve doesn’t cross the

boundary and the required information size has not been reached, there is insufficient

evidence to reach a conclusion (37-41). We will apply TSA since it reduces the risk of type-I

error in a cumulative meta-analysis and may provide important information on how many

more patients need to be included in further trials. Information size will be calculated using

the variance according to the meta-analytic model corresponding to the diversity adjusted

information size (DIS), suggested by a relative risk reduction (RRR) of 10%. We will

calculate the model variance based (diversity (D²) adjusted) required information size since

the heterogeneity adjustment with I2 tends to underestimate the required information size (36).

However, if D-square equals zero we will also perform a TSA using a D-square of 25%. We

will perform TSA on all outcomes. The required information size will as a sensitivity analysis

also be calculated based on a RRR suggested by the meta-analysis of the included trials and

using the model based variance (appropriately adjusted for diversity) according to an overall

type-I error of 5% and a power of 90% considering early and repetitive testing. The TSA will

be conducted using the unweighted control event proportion calculated from the actual meta-

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analyses. We shall provide the CI adjusted for sparse data and repetitive testing, which we

describe as the TSA-adjusted CI.

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(41) Thorlund K, Imberger G, Walsh M, Chu R, Gluud C, Wetterslev J, et al. The number of

patients and events required to limit the risk of overestimation of intervention effects in meta-

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firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 2008 Jan;61(1):64-75.

21

Appendix 1: search strategy

PubMed/MEDLINE

1. "Heparin, Low-Molecular-Weight"[Mesh] OR low-molecular-weight heparin*[tiab] OR

lmwh[tiab]

2. "Nadroparin"[Mesh] OR nadroparin*[tiab] OR fraxiparin*[tiab] OR cy 216[tiab] OR cy216[tiab]

OR lmf cy216[tiab] OR seleparin*[tiab]

3. "Enoxaparin"[Mesh] OR enoxaparin*[tiab] OR clexane[tiab] OR klexane[tiab] OR lovenox[tiab]

OR emt 966[tiab] OR emt 967[tiab] OR pk-10,169[tiab] OR pk 10169[tiab] OR pk10169[tiab]

4. "Dalteparin"[Mesh] OR dalteparin*[tiab] OR fragmin*[tiab] OR tedelparin[tiab] OR kabi

2165[tiab] OR fr 860[tiab]

5. "tinzaparin"[Supplementary Concept] OR tinzaparin*[tiab] OR innohep[tiab] OR logiparin[tiab]

OR lhn-1[tiab]

6. ardeparin*[tiab] OR normiflo[tiab]

7. "bemiparin"[Supplementary Concept] OR bemiparin*[tiab] OR zibor*[tiab]

8. "certoparin"[Supplementary Concept] OR certoparin*[tiab] OR mono-embolex[tiab] OR

embolex[tiab] OR sandoparin[tiab]

9. cy222 OR cy 222

10. OR "reviparin"[Supplementary Concept] OR reviparin*[tiab] OR clivarin[tiab] OR lu

47311[tiab]

11. "parnaparin"[Supplementary Concept] OR parnaparin[tiab] OR cb-01-05-mmx[tiab] OR

fluxum[tiab]

12. "semuloparin"[Supplementary Concept] OR semuloparin*[tiab] OR ave5026[tiab])

13. OR/ 1-12

14. "Mortality"[Mesh:noexp] OR mortality[tiab] OR "survival" [Mesh] OR survival[tiab]

15. Thrombosis"[Mesh] OR thrombos*[tiab] OR thrombot*[tiab] OR "Thromboembolism"[Mesh]

OR thromboembol*[tiab] OR "Pulmonary Embolism"[Mesh] OR vte[tiab] OR dvt[tiab]

16. OR/ 14-15

17. randomized controlled trial[pt] OR randomi* [tiab] OR randomly[tiab] OR placebo[tiab] OR

trial[ti]

18. animals[mh] NOT humans[mh]

19. 17 NOT 18

20. 13 AND 16 AND 19

22

EMBASE

1. low molecular weight heparin'/exp OR ('low molecular' NEXT/3 heparin*):ab,ti OR lmwh:ab,ti

2. (nadroparin* OR fraxiparin* OR cy216 OR 'cy 216' OR 'lmf cy216' OR seleparin* OR

tedegliparin*):ab,ti

3. (enoxaparin OR clexane OR klexane OR lovenox OR emt966 OR 'emt 966' OR 'emt 967' OR 'pk

10,169' OR 'pk 10169' OR pk10169):ab,ti

4. (dalteparin* OR fragmin* OR tedelparin OR 'kabi2165' OR 'kabi 2165' OR 'fr 860' OR

fr860):ab,ti

5. (tinzaparin* OR innohep OR logiparin OR 'lhn-1'):ab,ti

6. (ardeparin OR normiflo):ab,ti

7. (bemiparin OR zibor):ab,ti

8. (certoparin OR alphaparin OR 'mono-embolex' OR embolex OR sandoparin):ab,ti

9. ('cy 222' OR cy222):ab,ti

10. ('reviparin sodium' OR clivarin* OR 'lu 47311'):ab,ti

11. (parnaparin OR 'cb-01-05-mmx' OR fluxum):ab,ti

12. (semuloparin OR ave5026):ab,ti

13. OR/ 1-12

14. 'mortality'/de OR mortality:ab,ti OR 'survival'/de OR survival:ab,ti

15. 'thromboembolism'/exp OR thrombos*:ab,ti OR thrombot*:ab,ti OR thromboembol*:ab,ti OR

'pulmonary embolism' OR dvt:ab,ti OR vte:ab,ti

16. OR/ 14-15

17. 'randomized controlled trial'/exp OR (randomi*ed NEXT/3 controlled NEXT/3 (trial OR

study)):ab,ti

18. 'animal'/exp OR 'nonhuman'/exp NOT 'human'/exp

19. 17 NOT 18

20. 13 AND 16 AND 19

23

Cochrane Central Register of Controlled Trials (CENTRAL)

1. Low-molecular-weight heparin* OR lmwh

2. nadroparin* OR fraxiparin* OR cy216 OR ''cy 216'' OR ''lmf cy216'' OR seleparin* OR

tedegliparin*

3. enoxaparin* OR clexane OR klexane OR lovenox OR emt966 OR ''emt 966'' OR ''emt 967'' OR

''pk-10,169'' OR ''pk 10169'' OR pk10169

4. dalteparin* OR fragmin* OR tedelparin OR kabi2165 OR ''kabi 2165'' OR ''fr 860'' OR fr860

5. tinzaparin* OR innohep OR logiparin OR ''lhn-1''

6. ardeparin OR normiflo

7. bemiparin OR zibor

8. certoparin OR alphaparin OR ''mono-embolex'' OR embolex OR sandoparin

9. cy222 OR ''cy 222''

10. reviparin* OR clivarin OR ''lu 47311''

11. parnaparin OR ''cb-01-05-mmx'' OR fluxum

12. semuloparin OR ave5026

13. OR/ 1-12

14. Mortality OR survival

15. thrombos* OR thromboembol* OR thrombot* OR pulmonary embolism OR vte OR dvt OR pe

16. OR/ 14-15

17. 13 AND 16

18. SEARCH IN: TRIALS

24

Web of Science

1. Low-molecular-weight heparin* OR lmwh

2. nadroparin* OR fraxiparin* OR cy216 OR ''cy 216'' OR ''lmf cy216'' OR seleparin* OR

tedegliparin*

3. enoxaparin* OR clexane OR klexane OR lovenox OR emt966 OR ''emt 966'' OR ''emt 967'' OR

''pk-10,169'' OR ''pk 10169'' OR pk10169

4. dalteparin* OR fragmin* OR tedelparin OR kabi2165 OR''kabi 2165'' OR fr 860 OR fr860

5. tinzaparin* OR innohep OR logiparin OR ''lhn-1''

6. ardeparin OR normiflo

7. bemiparin OR zibor

8. certoparin OR alphaparin OR ''mono-embolex'' OR embolex OR sandoparin

9. cy222 OR ''cy 222''

10. reviparin* OR clivarin OR ''lu-47311''

11. parnaparin OR ''cb-01-05-mmx'' OR fluxum

12. semuloparin OR ave5026

13. TS=(OR/ 1-12)

14. Mortality OR survival

15. thrombos* OR thromboembol* OR thrombot* OR pulmonary embolism OR vte OR dvt OR pe

16. TS=(OR/ 14-15)

17. (random* NEXT/3 trial*) OR (random* NEXT/3 stud*) OR (''randomized controlled'' OR

''randomised controlled'')

18. Trial*

19. (TS=17) OR (TI=18)

20. 13 AND 16 AND 19

25

Appendix 2: Major bleeding definitions according to the Scientific and Standardization

Committee of the International Society on Thrombosis and Haemostasis

Definition of major bleeding in clinical investigations of antihemostatic medicinal products in

non-surgical patients (33)

As general principles, a definition of major bleeding needs to be based on objective criteria,

and major bleeds are those that result in death, are life-threatening, cause chronic sequelae or

consume major health-care resources. With this in mind, the Control of Anticoagulation

Subcommittee recommends the following criteria for major bleeding in non-surgical patients:

1. Fatal bleeding, and/or

2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal,

intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with

compartment syndrome, and/or

3. Bleeding causing a fall in hemoglobin level of 20 g L−1

(1.24 mmol L−1

) or more, or

leading to transfusion of two or more units of whole blood or red cells.

Definition of major bleeding in clinical investigations of antihemostatic medicinal products in

surgical patients (32)

Taking into account historical criteria and additional consultations with European and North

American surgeons with experience from clinical trials and event adjudication the

Subcommittee on Control of Anticoagulation has approved the following recommendation for

definition of major bleeding in surgical studies.

1. Fatal bleeding, and/or

2. Bleeding that is symptomatic and occurs in a critical area or organ, such as

intracranial, intraspinal, intraocular, retroperitoneal, pericardial, in a non-operated

26

joint, or intramuscular with compartment syndrome, assessed in consultation with the

surgeon, and/or

3. Extrasurgical site bleeding causing a fall in hemoglobin level of 20 g L−1

(1.24 mmol L−1

) or more, or leading to transfusion of two or more units of whole

blood or red cells, with temporal association within 24–48 h to the bleeding, and/or

4. Surgical site bleeding that requires a second intervention– open, arthroscopic,

endovascular – or a hemarthrosis of sufficient size as to interfere with rehabilitation by

delaying mobilization or delayed wound healing, resulting in prolonged

hospitalization or a deep wound infection, and/or

5. Surgical site bleeding that is unexpected and prolonged and/or sufficiently large to

cause hemodynamic instability, as assessed by the surgeon. There should be an

associate fall in hemoglobin level of at least 20 g L−1

(1.24 mmol L−1

), or transfusion,

indicated by the bleeding, of at least two units of whole blood or red cells, with

temporal association within 24 h to the bleeding.

6. The period for collection of these data is from start of surgery until five half-lives after

the last dose of the drug with the longest half-life and with the longest treatment

period (in case of unequal active treatment durations).

7. The population is those who have received at least one dose of the study drug.