Frequency of Vascular Events With Short-term Thromboprophylaxis in Fast-track Hip and Knee-arthroplasty
Conditions: Thromboembolic Events, Post-operative Bleeding
Sponsor: Rigshospitalet, Denmark

 
Frequency of vascular events using “short 
treatment”thrombosis prophylaxis after fast-
track hip and knee arthroplasty 
FETA-study 
Version 3, 23/03-2012 
Christoffer Calov Jørgensen, MD. 
 
 
 

2 
 
1. 
Intention of study ...................................................................................................................................... 5 
1.1 
Primary outcome ............................................................................................................................... 5 
1.2 
Hypothesis ......................................................................................................................................... 5 
2. 
Participants and methods .......................................................................................................................... 5 
2.1 
Design ................................................................................................................................................ 5 
3. 
Patient selection ........................................................................................................................................ 6 
3.1 
Inclusion criteria ................................................................................................................................ 6 
3.2 
Plan: ................................................................................................................................................... 6 
3.3 
Discharge criteria ............................................................................................................................... 7 
4. 
Statistics ..................................................................................................................................................... 7 
5. 
Budget ....................................................................................................................................................... 7 
6. 
Safety analysis ........................................................................................................................................... 8 
7. 
Duration of study ....................................................................................................................................... 8 
8. 
Interimanalysis .......................................................................................................................................... 8 
9. 
Data collection ........................................................................................................................................... 8 
10. 
Authors .................................................................................................................................................. 8 
11. 
Study committees .................................................................................................................................. 9 
11.1 
Steering committee ........................................................................................................................... 9 
11.2 
Clinical events committee ................................................................................................................. 9 
12. 
Ethics and Legal aspects ........................................................................................................................ 9 
12.1 
Ethic Committee (EC) ......................................................................................................................... 9 
13. 
Ethical aspects and perspectives of the study ..................................................................................... 10 
14. 
Reference List ...................................................................................................................................... 11 
15. 
Appendix 1 ........................................................................................................................................... 13 
16. 
Appendix 2 ........................................................................................................................................... 14 
17. 
Appendix 3 ........................................................................................................................................... 15 
17.1 
DVT .................................................................................................................................................. 15 
17.2 
Pulmonary embolism ....................................................................................................................... 15 
17.3 
Myocardial infarction ...................................................................................................................... 15 
17.4 
Stroke ............................................................................................................................................... 16 
17.5 
Other thromboembolic events ........................................................................................................ 16 
18. 
Appendix 4 ........................................................................................................................................... 17 
19. 
Protocol editing and changes after study initiation ............................................................................ 18 

3 
 
Frequency of vascular events using “short treatment” 
thrombosis prophylaxis in fast-track hip and knee 
arthroplasty (FETA-study) 
A prospective descriptive cohort study using prophylaxis for 3±2 days in patients receiving fast-track 
elective hip or knee arthroplasty 
In cooperation with the Lundbeck Foundation Centre for Fast-track Hip and Knee Replacement(LCFHK). 
Project leader and coordinating investigator: 
Christoffer C. Jørgensen, MD/Research Fellow,  Section for Surgical Pathophysiology 4074, The Juliane 
Marie Centre, Rigshospitalet, Blegdamsvej 9,2200 CPH  Phone:+45 35454616 
Clinical responsibility: 
Kjeld Søballe, MD, Professor, DMSci, Department of Orthopedics, Århus University Hospital, Tage Hansens 
Gade 
Henrik Kehlet, MD, Professor, Phd. Section for Surgical Pathophysiology 4074, The Juliane Marie Centre, 
Rigshospitalet, Copenhagen 
Other investigators: 
Per Kjærsgaard-Andersen MD, Sygehus Lillebælt 
Torben Bæk Hansen MD, Professor, Regionshospitalet Holstebro 
Henrik Husted, MD, Hvidovre Hospital 
Lars-Peter Jorn, MD, Regionshospitalet Viborg 
Mogens Berg Laursen, MD, Ortopædkirurgien Nordjylland 
Lars Tambour Hansen, MD, Sydvestjysk Hospital Grindsted/Esbjerg 
Statistics: 
Christoffer C. Jørgensen, external statistical assistance can be requested if necessary. 
Study sites: 
Orthopedic departments: Århus University Hospital THG, Hvidovre Hospital, Ortopædkirurgien Nordjylland 
(Farsø), Regionshospitalet Holstebro, Sygehus Lillebælt, Regionshospitalet Viborg and Sydvestjysk Sygehus 
Grindsted/Esbjerg.  

4 
 
Background: 
Surgery is recognized as being related to the development of thrombosis, especially after major orthopedic 
surgery (1;2). These complications are defined as venous thromboembolic events (VTE), including deep 
venous thrombosis (DVT) and pulmonary embolism (PE).  
Pharmacological prophylaxis reduces the risk of thrombosis and recommendations (grade 1a)from the 
American College of Chest Physicians (ACCP) are one of three following anticoagulantia: 
1: Low molecular weight heparin (LMWH)  
2: Faktor Xa-inhibitors 
3: Vitamin-K-antagonists 
Recommended duration of thrombosis prophylaxis is 10 days after total knee arthroplasty (TKA) and 35 
days after total hip arthroplasty (THA) (3).  
 
In the United States of America most surgeons follow ACCP guidelines. Studies have shown that about 90 % 
of surgeons adhere to guidelines, however, many use additional prophylaxis such as compressive 
stockings(4). More recent investigations find a lower compliance amongst surgeons world wide of about 
50% (5). There are disagreements about the validity of the before mentioned guidelines due tothe many 
exclusion and inclusion criteria in the analyzed studies and due to the fact that it is the thoracic surgeons 
who dictate the orthopedic surgeons guidelines(6), therefore the American Academy of Orthopedic 
Surgeons (AAOS has developed their own guidelines. The main difference between ACCP and AAOS 
guidelines is the use of compressive stocking and acetylsalicylic acid as only prophylaxis in patients at risk of 
bleeding and a general disagreement on the relationship of DVT and PE(7).  
In Denmark, the Danish Society of Orthopedic Surgeons (DSOS) has their own guidelines of 7 days of 
postoperative thrombosis prophylaxis which illustrates the controversies in this area.  
 
The few studies who do not comply with ACCP guidelines, using acetylsalicylic acid (and early mobilization) 
as only prophylaxis show very low frequencies of vascular events (8-11), raising doubts about the best 
choice of treatment, especially considering increased mortality with LMWH compared to acetylsalicylic 
acid(12). 
 
Preliminary uncontrolled studies in TKA have shown that early mobilization (<24 hours after surgery) 
reduces risk of postoperative VTE in patients treated with LMWH(13),  and as frequency of DVT following 
TKA is decreasing over time using warfarin (VKA) as prophylaxis(14), interest in postoperative mobilization 
is increasing. 
 
The trend towards enhanced recovery protocols (fast-track surgery) where optimized pain treatment, early 
mobilization (<24 hours), preoperative patient information etc. aims to decrease length of hospital stay. 
Data on THA and TKA patients from Hvidovre Hospital proves that 92 % of patients were discharged within 
5 days and 41 % within 3days(15).  
 
An un-published preliminary study from Hvidovre Hospital in about 2000 patients shows very low 
frequency of symptomatic VTE in 90-days follow-up, with mortality of 0.15%, DVT/PE/death in TKA of 0.66% 

5 
 
and 0.52% in THA when using a fast-track setup (16).  This is lower than comparable literature with 
thrombosis prophylaxis for 35 days postoperatively. 
 
 
A group of experts has suggested that pharmacological thrombosis prophylaxis in patients with early 
mobilization is non-obligatory, this would result in decreased side-effects such as bleedings, less 
inconvenience in the patients and economical advantages(17). This has resulted in short prophylaxis 
treatment being standard of care in several departments in Denmark (i.e. Hørsholm, Hvidovre and Farsø 
hospitals). 
 
No previous study has been published with a detailed description on the risk of vascular events, including 
arterial complications, using short-treatment thrombosis prophylaxis in a fast-track setup after THA/TKA or 
commented on identification of risk factors(2;18;19). 
 
It must be mentioned that Asian patients (Korea, China etc.) do not have a tradition for thrombosis 
prophylaxis after THA due to the low frequencies of VTE without prophylaxis. In this context, differences in 
genetics and dietary habits etc. must be considered (20;21).  
 
 
1. Intention of study 
1.1 
Primary outcome 
To conduct a high quality cohort study to investigate the frequency of symptomatic DVT, PE, acute 
myocardial infarction (AMI, stroke and other vascular events and/or death of other causes in patients 
having elective uni and bilateral THA/TKA, revision THA/TKA and uni-KA in a fast-track setup including short 
treatment thrombosis prophylaxis(3 ± 2 days). Additionally, identification of risk factors for such events will 
be attempted (Appendix 4). 
 
1.2 
Hypothesis 
No increased frequency of symptomatic thromboembolic events in THA/TKA in a fast-track setup with short 
treatment thrombosis prophylaxis. 
 
2. Participants and methods 
2.1 
Design 
A detailed prospective multicenter high quality cohort study of about 5000 patients > 18 years old, having  
elective uni- or bilateral THA/TKA, revision and uni-KA with thrombosis prophylaxis only during 
hospitalization (3 ± 2 days/ 72 ± 48 hours). Follow-up is 90 days. Patients with postoperative clinical 

6 
 
symptoms of vascular events are encouraged to seek a physician in order to receive relevant examination 
and treatment (se appendix 3). 
 
3. Patient selection 
Patients will be included from the Orthopedic departments of: Århus Sygehus, Tage Hansens Gade, 
Regionshospitalet Holstebro, Hvidovre Hospital, Sydvestjysk sygehus Grindsted, Vejle Hospital and 
Ortopædkirurgien Nordjylland (Farsø), starting ultimo December ´09 til December ´11, 5000 patients need 
to be included. In all centers mean length of hospital stay (LOS) is short, with discharge before day 3 ± 2. 
LOS is defined as number of nights spent in hospital after surgery. 
 
3.1 
Inclusion criteria 
 
Males and females> 18 years old 
 
Primary uni/bilateral THA/TKA, revision THA/TKA and uni-KA in fast-track setup 
 
Discharge on day 3 ± 2/72 ± 48 hours 
 
 
Observations and tests 
3.2 
Plan: 
 
 
 
 
Day -7 til -1: 
The patient goes through physical examination and demographics are registered (appendix 4).  
Dag 0: defined as day of surgery 
Patient has surgery 
Thrombosis prophylaxis according to local guidelines (appendix 1). 
Admission 
Interview 
Surgery 
Discharge 
End 
follow-up 
Day 0 
Day 3±2 
Day 90±5 

7 
 
Dag 3 ± 2: Patient is discharged (4.3) and ceases thrombosis prophylaxis.  
Dag 90 ± 5:End follow-up 
3.3 
Discharge criteria 
 
Independent in daily activities 
 
In/out of bed 
 
In/out of chair 
 
Independent walk with mobility aid 
If the patient is not discharged on day 3 ± 2,the patient should follow Danish Society of Orthopedic 
Surgeons (DSOS) guidelines (7 days). This group will be followed separately. 
In case of regular treatment with acetylsalicylic acid or other thrombocyte inhibitor, this should be 
continued after surgery and with addition of thrombosisprophylaxis during hospitalization.  
If the patient is in regular potent anticoagulative therapy (PACT), the patient will need bridging, 
with cessation of PACT 4 days preoperatively, and postoperative thrombosis prophylaxis until the 
patient’s INR reaches therapeutic values (INR 2-3). This is done by the patients’ general 
practitioner. 
 
 
4. Statistics 
A pre-study power-calculation showed that at least 3000 patients were needed (power(β) 82 % with a 
significance level (α) of 0,05) with expected event-rates of 3% (22-25)and a maximum event rate of 4 %. We 
expect to include about 5000 patients which would increase power and the statistic possibility of 
identifying risk-factors (preoperative variables). In addition isolated analysis on the primary procedures will 
be performed.  
5. Budget 
The study is partly financed by Århus University (1.100.000dkr)and the Lundbeck Foundation Centre for 
Fast-track Hip and Knee Replacement(LCFHK) (550.000dkr). This has already been agreed upon. 
Further project nurses/secretaries will be hired by LCFHK, therefore no further administrative assistance in 
relation to the project is expected.  
There will be no pharmacological expenses. 

8 
 
Expenses in relation to transportation, travelling and course activities are expected to amount to about 
50.000 dkr. 
Data from the Danish National Patient Registry (NPR) about 15.000 dkr. 
Other materials 5.000 dkr. 
6. Safety analysis 
To evaluate the risk of bleeding-complications in patients having THA or TKA in a fast-track setup (Appendix 
2). 
7. Duration of study 
The expected duration of the study, assuming the aforementioned number of participants, is 24 months. All 
included patients will after 90 ±5 days be investigated by NPR. Duration of enrollment is estimated to be 
about 20 months. The study is expected to run from ultimo December ´09 until December ´11. 
8. Interimanalysis 
An interim analysis will be done after 1500 and 3000 patients. 
Intention: To evaluate whether the true risk of complications is higher (worse treatment) or lower (better 
treatment) 4%. Three analyses will be done. In each analysis, the risk of complication including CI will be 
calculated. In the 1st analysis (1500 patients),the exact 99.5% CI will be calculated, in the 2nd analysis an 
exact 99 % CI and in the 3rd analysis (5000 pt) an exact 95.2% CI. 
In simulation, it has been calculated that if the true risk is 3%, the total power is 97.6%. If the true risk of 
events is 6%, total power is 99.9%.  
 
In case of an unacceptable safety profile and/or a very high number of primary events, the Clinical event 
committee can recommend an early termination of the study to the Steering committee, who will decide 
hereafter.   
9. Data collection 
After follow-up, data will be extracted from NPR with regards to diagnosis codes of vascular events, 
bleeding episodes, LOS and death. In case of events, the patient’s medical charts will be requested and 
evaluated. The study is approved by the Danish Data Protection Agency. 
10. Authors 
According to alphabetical order, however, with writer as primary author and Henrik Kehlet as senior 
author. (13.1) 
 

9 
 
11. Study committees 
The LCFHK will lead the logistic coordination of the different study committees. 
11.1 
Steering committee 
The steering committee will ensure that all aspects of the study, such as safety and efficiency are 
maintained and that information from other committees can lead to timely changes.  
Members: 
Per Kjærsgaard-Andersen, Vejle Hospital 
Torben Bæk Hansen, Regionshospitalet Holstebro 
Henrik Husted, Hvidovre Hospital 
Henrik Kehlet, Rigshospitalet, København 
Mogens Berg Laursen, Ortopædkirurgien Nordjylland 
Kjeld Søballe, Århus Universitetshospital 
11.2 
Clinical events committee 
A clinical events committee will be founded, consisting of the writer and Steen Husted, where 
uncertainties regarding verification of diagnosis will be discussed. (Appendices 2+3) 
 
12. Ethics and Legal aspects 
12.1 
Ethic Committee (EC) 
The study will be presented to the Scientific Ethics Committee (SEC) and receive approval from here. It has 
been preliminarily approved as a quality-control study, as Hvidovre, Hørsholm and Farsø amongst others 
presently use this treatment as standard of care. 
 

10 
 
13. Ethical aspects and perspectives of the study 
The duration of thrombosis prophylaxis after THA and TKA is subject to debate, both nationally and 
internationally. The degree of thrombo prophylactic effect vs. discomfort for the patient, bleeding-related 
side effects and, not the least, health related expenses need to be investigated in the “real life” setup in 
which the patients are operated. I Denmark the Danish Society of Orthopedic Surgeons recommend 7 days 
of treatment as a compromise (international recommendations up to 35 days), but also allow prolonged 
treatment on indication (unspecified). Studies suggest that with early mobilization and an uncomplicated 
postoperative phase the risk of VTE is significantly decreased. Thus there is no indication of prolonged 
thrombosis prophylaxis with related increased risk of bleeding-related side effects in this group(16). This 
study with short treatment thrombosis prophylaxis in patients having THA/TKA in a fast-track setup is in 
accordance with highest international expertise(17). Additionally there is disagreement regarding the 
American guidelines, where patients receive treatment with acetylsalicylic acid only(9). 
We believe that this is a very important study, as it can influence, not only orthopedic recommendations, 
men generally on major surgery, such as abdominal surgery, gynecology, and other major surgical 
specialties using a fast-track setup(26;27). We believe that literature and, not in the least clinical 
experience, provide the background for a study of this character. Empirically, more and more surgeons do 
not follow the international recommendations and create their own. The Danish Society of Orthopedic 
Surgeons recommend 7 days of postoperative thrombosis prophylaxis (different from international 
recommendations), proving the lack of agreement in this area. 
The design of the study will ensure that all data and the analysis of data will be in accordance with the 
Helsinki Declaration as well as local laws and regulations. The investigators will at any point allow the 
Steering committee or representatives of the Steering committee to review documents in order to ensure 
this. 
 
 
 
 
 
 
 
 
 
 

11 
 
 
14. Reference List 
 
 
(1)  Kakkar VV. Deep vein thrombosis. Detection and prevention. Circulation 1975; 51(1):8-19. 
 
(2)  Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J ThrombHaemost 2009; 7 Suppl 1:301-304. 
 
(3)  Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR et al. Prevention of venous 
thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th 
Edition). Chest 2008; 133(6 Suppl):381S-453S. 
 
(4)  Anderson FA, Jr., Hirsh J, White K, Fitzgerald RH, Jr. Temporal trends in prevention of venous 
thromboembolism following primary total hip or knee arthroplasty 1996-2001: findings from the Hip and 
Knee Registry. Chest 2003; 124(6 Suppl):349S-356S. 
 
(5)  Friedman RJ, Gallus AS, Cushner FD, Fitzgerald G, Anderson FA, Jr. Physician compliance with guidelines for 
deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin 2008; 24(1):87-97. 
 
(6)  Callaghan JJ, Dorr LD, Engh GA, Hanssen AD, Healy WL, Lachiewicz PF et al. Prophylaxis for thromboembolic 
disease: recommendations from the American College of Chest Physicians--are they appropriate for 
orthopaedic surgery? J Arthroplasty 2005; 20(3):273-274. 
 
(7)  Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American 
College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty 
differ: what are the implications for clinicians and patients? Chest 2009; 135(2):513-520. 
 
(8)  Callaghan JJ, Warth LC, Hoballah JJ, Liu SS, Wells CW. Evaluation of deep venous thrombosis prophylaxis in 
low-risk patients undergoing total knee arthroplasty. J Arthroplasty 2008; 23(6 Suppl 1):20-24. 
 
(9)  Cusick LA, Beverland DE. The incidence of fatal pulmonary embolism after primary hip and knee replacement 
in a consecutive series of 4253 patients. J Bone Joint Surg Br 2009; 91(5):645-648. 
 
(10)  Lachiewicz PF, Soileau ES. Mechanical calf compression and aspirin prophylaxis for total knee arthroplasty. 
ClinOrthopRelat Res 2007; 464:61-64. 
 
(11)  Tian H, Song F, Zhang K, Liu Y. [Efficacy and safety of aspirin in prevention of venous thromboembolism after 
total joint arthroplasty]. Zhonghua Yi XueZaZhi 2007; 87(47):3349-3352. 
 
(12)  Sharrock NE, Gonzalez D, V, Go G, Lyman S, Salvati EA. Potent anticoagulants are associated with a higher all-
cause mortality rate after hip and knee arthroplasty. ClinOrthopRelat Res 2008; 466(3):714-721. 
 
(13)  Pearse EO, Caldwell BF, Lockwood RJ, Hollard J. Early mobilisation after conventional knee replacement may 
reduce the risk of postoperative venous thromboembolism. J Bone Joint Surg Br 2007; 89(3):316-322. 
 
(14)  Xing KH, Morrison G, Lim W, Douketis J, Odueyungbo A, Crowther M. Has the incidence of deep vein 
thrombosis in patients undergoing total hip/knee arthroplasty changed over time? A systematic review of 
randomized controlled trials.Thromb Res 2008; 123(1):24-34. 
 
(15)  Husted H, Holm G, Jacobsen S. Predictors of length of stay and patient satisfaction after hip and knee 
replacement surgery: fast-track experience in 712 patients. ActaOrthop 2008; 79(2):168-173. 

12 
 
 
(16)  Husted, Otte K, Kristensen B, Ørsnes T, Wong C, Kehlet H. Incidens of tromboembolic complications with fast-
track hip and knee arthroplasty.  1-20. 2009. 
Ref Type: Unpublished Work 
 
(17)  Salvati EA, Sharrock NE, Westrich G, Potter HG, Valle AG, Sculco TP. The 2007 ABJS Nicolas Andry Award: 
three decades of clinical, basic, and applied research on thromboembolic disease after THA: rationale and 
clinical results of a multimodal prophylaxis protocol. ClinOrthopRelat Res 2007; 459:246-254. 
 
(18)  Seddighzadeh A, Zurawska U, Shetty R, Goldhaber SZ. Venous thromboembolism in patients undergoing 
surgery: low rates of prophylaxis and high rates of filter insertion. ThrombHaemost 2007; 98(6):1220-1225. 
 
(19)  Sharma OP, Oswanski MF, Joseph RJ, Tonui P, Westrick L, Raj SS et al. Venous thromboembolism in trauma 
patients. Am Surg 2007; 73(11):1173-1180. 
 
(20)  Kim YH, Kim JS. The 2007 John Charnley Award. Factors leading to low prevalence of DVT and pulmonary 
embolism after THA: analysis of genetic and prothrombotic factors. ClinOrthopRelat Res 2007; 465:33-39. 
 
(21)  Yoo MC, Cho YJ, Ghanem E, Ramteke A, Kim KI. Deep vein thrombosis after total hip arthroplasty in Korean 
patients and D-dimer as a screening tool. Arch Orthop Trauma Surg 2009; 129(7):887-894. 
 
(22)  Mahomed NN, Barrett JA, Katz JN, Phillips CB, Losina E, Lew RA et al. Rates and outcomes of primary and 
revision total hip replacement in the United States medicare population. J Bone Joint Surg Am 2003; 85-
A(1):27-32. 
 
(23)  Mantilla CB, Horlocker TT, Schroeder DR, Berry DJ, Brown DL. Frequency of myocardial infarction, pulmonary 
embolism, deep venous thrombosis, and death following primary hip or knee arthroplasty. Anesthesiology 
2002; 96(5):1140-1146. 
 
(24)  Ryge C. Epidemiology study in mayor orthopaedic surgery (ESMOS-study),København, faculty of health 
science, University of Copenhagen. 2008. 
 
(25)  Williams O, Fitzpatrick R, Hajat S, Reeves BC, Stimpson A, Morris RW et al. Mortality, morbidity, and 1-year 
outcomes of primary elective total hip arthroplasty. J Arthroplasty 2002; 17(2):165-171. 
 
(26)  Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg 2008; 
248(2):189-198. 
 
(27)  Schwenk W. Fast track rehabilitation in visceral surgery. Chirurg 2009; 80(8):690-701. 
 
(28)  Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK et al. Rivaroxaban versus enoxaparin for 
thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358(26):2765-2775. 
 
(29)  Bauer KA, Eriksson BI, Lassen MR, Turpie AG. Fondaparinux compared with enoxaparin for the prevention of 
venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345(18):1305-1310. 
 
(30)  Revideretaf DCS's arbejdsgruppevedr. AkutKoronartSyndrom,april 2009.  
http://cardio.dk/sw12185.asp#516_11345 . 29-10-2009.  
Ref Type: Electronic Citation 
 
(31)  Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T. Cerebrovascular disease in the 
community: results of a WHO collaborative study. Bull World Health Organ 1980; 58(1):113-130. 
 
 
 

13 
 
 
 
15. Appendix 1 
 
Local postoperative prophylaxis guidelines: 
ÅrhusSygehus: LMWH (Arixtra) for 7 daysin THA/ 5-7 daysFragminin TKA. 
Holstebro: LMWH (Fragmin) in 7 daysin THA/TKA. 
Hvidovre: X10a (Xarelto) 10 mg to discharge in THA/TKA. 
Ortopædkirurgien Nordjylland: LMWH (Fragmin) to discharge THA/TKA 
Vejle: LMWH (Klexane) for 7 days in THA/TKA 
Sydvestjysk Sygehus Grindsted: LMWH (Arixtra) 2.5mg x1 for 7 days in THA/TKA 
 
 
 
 
 
 
 
 
 
 
 
 

14 
 
 
16. Appendix 2 
Bleeding 
The safety endpoint is the frequency of bleeding(28)observe red no later than 2 days after last 
administration of thrombosis prophylaxis. Bleeding more than 2 days after last dose of thrombosis 
prophylaxis will not be considered as a side-effect. 
Diagnosis of bleeding 
In case of bleeding all information, ie. Anesthesia-charts, laboratory results, ultrasound findings, 
must be registered in the medical chart. All bleeding-episodes will be classified according to 
predefined criteria: 
Serious bleeding 
Minor bleedings 
Serious Bleedings are: 
- 
Fatal bleeding 
- 
Bleeding in a critical organ(retroperitoneal, intracraniel, intraocular, intraspinal, pericardiac 
bleeding with tamponade, intramuscular bleeding with compartment syndrome) 
- 
Bleeding needing surgical intervention (including joint puncture and aspiration) 
- 
Bleeding leading to infusion of >1 portion of  SAGM/full blood 
- 
Bleeding index ≥2 (defined as number of transfused portions of erythrocytes + diff between 
hemoglobin before and after bleeding measured in gram/dl).  
- 
Drop in hemoglobin of > 30g/L (=1,9mmol/L) 
- 
All bleedings not classified as serious bleedings will be classified as minor bleedings 
 

15 
 
 
17. Appendix 3 
Definition of clinical outcomes: 
 
17.1 
DVT 
Diagnosis done by ultrasound (if not possible venography). The main criteria for DVT is a negative 
compression test with ultrasound(9). 
17.2 
Pulmonary embolism 
Diagnosed by 
 Spiral CT-scan (29) 
 Perfusion-ventilation scintigrafia(9) 
 Pathologicalremoval of embolus(9) 
17.3 
Myocardial infarction 
 
Diagnosed in the following situations(30) 
 
Increase and/or fall in specific biomarkers (mainly troponin) with at least 1 value higher 
than the 99 percentile of upper reference threshold and 
Evidence for myocardial ischemia with at leastone of the following: 
- Symptoms of ischemia ( chest pain, dyspnoea, acute heart failure, arrhythmia)  
- ECG changes indicative of acute ischemia (new ST-T changes or new left side bundle 
branch block) 
- Development of pathological Q-waves on ECG  
- Radiological diagnostic evidence of new loss of viable myocardium or new regional 
dyskinesia. 
- Revasculisation by PCI or CABG. 
 
 
 

16 
 
17.4 
Stroke 
 
 
Defined as an acute neurological event with focal neurologic deficits and duration beyond 24 
hours (31), verified by CT/MR-scan. Strokes will be stratified according to type as ischemic, 
hemorrhagic or unknown. 
In case of progression of formerly known neurological symptoms, the progression must be present 
for more than 1 week or 24 hours if accompanied by new relevant CT or MR findings.  
Cardiovascular death 
Death of vascular causes include cardiovascular, cerebrovascular and death of other vascular 
causes or death with no clear documentation of non-vascular cause. Ex: 
Vascular death: Sudden death, MI, unstable angina pectoris, other CAD, stroke, arterial 
embolism, pulmonary embolism, dissecting aorta, heart insufficiency, cardiac arrhythmia, or 
death from bleeding (non-trauma related)   
Non-vascular death: Respiratory failure, pneumonia, cancer, trauma, suicide or other defined 
cause (i.e. liver or renal failure) 
Death of unknown /uncertain causes will be categorized as vascular death.  
TCI 
Definition is as for stroke, but are temporary and gone <24 hours. 
17.5 
Other thromboembolic events 
Need to be defined by a relevant specialist.  
 
 
 
 
 

17 
 
 
 
18. Appendix 4 
Date of surgery 
Social security number 
Joint (knee/hip) 
Height:    ______ cm 
Weight:    _______kg 
Hemoglobin level   ______ mmol/l 
(Taken no more than 1 week previously) 
Patients’ blood type? 
 
Living conditions (alone, with spouse/others, in institution (nursing home etc.) 
Smoking (yes/no) 
Alcohol >2 units a day (yes/no) 
Do you use walking aids prior to admission? 
Are you feeling well rested in the morning? 
Do you snore loudly? 
Do you use compressive stockings regularly? 
 
Do you receive treatment for high cholesterol (yes/no) 
Do you receive treatment for high blood pressure (yes/no) 
Do you have Type 1 diabetes (yes/no) 
Do you have Type 2 diabetes (yes/no) 
Have you had a previous cerebral attack? 
Have you had a previous venous thromboembolic event? 
Do you receive medication for any type of heart disease? 
Do you receive medication for any type of pulmonary disease? 
Do you receive medication for any type of psychiatric disease? 
Do you have a family member who has had a deep venous thrombosis or pulmonary embolus? 
Do you have a contraindication for antithrombotic medication? 
Do you use antithrombotic medication regularly (marevan, acetyl salicylic acid etc)?  
 
 

18 
 
19. Protocol editing and changes after study initiation 
 
1) Project leader and coordinating  investigator: Changed from Michael Kjær Jacobsen to Christoffer 
C. Jørgensen 
2) Other investigators: The following investigators have been removed as the study was not initiated 
at their institutions: Steen Husted MD, Århus Universitety Hospital, THG Århus, Søren Mikkelsen 
MD, Regionshospitalet Silkeborg.  
The following investigators have been edited: Søren Solgaard MD, Gentofte Hospital Gentofte. 
The following investigators have been added: Lars Tambour Hansen MD, Sydvestjysk Sygehus 
Grindsted/Esbjerg  
3) Statistician: Niels Trolle Andersen is no longer responsible for statistics. Christoffer C. Jørgensen 
has been added and additional assistance will be acquired as needed. 
4) Study sites:The following study sites have not participated: Regionshospitalet Silkeborg, Hørsholm 
Hospital (due to closure). The following study sites have been added: Sydvestjysk Hospital 
Grindsted/Esbjerg April 2010, Gentofte Hospital, November 2012.  
5) Background: Hørsholm Hospital has been mentioned as having used short-treatment prophylaxis as 
standard of care. This is a mistake and should be omitted. 
6) 2.1 Design: Due to a large number of available patients, it has been decided to expand the study 
size. The intention is now to include 5000 PRIMARY operations in addition to a number of revisions 
and uni-KA. 3. 
7) 3. Patient selection: Changes according to 4) Study sites. 
8) 3.3 Discharge criteria: Thrombosis prophylaxis in patients with LOS >5 days: DOS guidelines are not 
7 days, but 5-10 days in TKA and 7-35 days after THA.  
9) 4. Statistics: The exact number of patients when using a Two-tailed one sample difference from 
constant test with the in the protocol mentioned specifications is 2838.  Using the same test, 2076 
patients will be needed to detect a 1% increase in frequency of symptomatic VTE, using α: 0.05, β: 
82 and a baseline risk of 1% with 35 days of treatment with LMWH. 
10) 7. Duration of study: As the database of this study forms the core of several independent studies 
on co-morbidity, duration of this study has been extended, and database registration is expected to 
last until ultimo 2016  
11) 9. Data collection: Collection of data has been changed from depending on ICD-10 diagnostic codes 
for vascular events only to include ALL readmissions in 90 days. These will be investigated using 
discharge papers and complete medical charts in order to increase quality of data. In addition 
further details on regular anti-coagulative therapy 6 months prior to surgery and 3 months after 
surgery be collected through a newly established cooperation with the Danish National Database of 
Reimbursed Prescriptions, in order to further improve data quality.1 
12) 10. Authors: Christoffer Calov Jørgensen is now primary author, Michael Kjær Jacobsen will figure 
as secondary author and Henrik Kehlet as senior author. The remaining investigators are co-authors 
in a random order when patients from their study sites are included in the specific studies.  
13) 11.1 Steering committee: The following persons are not part of the steering committee: Steen 
Husted, Lars-Peter Jorn, Søren Mikkelsen, Søren Solgaard. 
14) 11.2 Clinical event Committee: Consists of Christoffer Calov Jørgensen and Henrik Kehlet.  
15) 12.1 Ethic Committee: The study ended up being considered as a quality-control study on a 
standard of care. The Scientific Ethics Committee decided that the study needed no approval.  
16) Appendix 1: The local prophylaxis guidelines of the following departments are not relevant: 
Hørsholm and Silkeborg. Guidelines for the added departments are: Gentofte Hospital: X10a 
inhibitor (Xarelto) 10 mg x 1 in both THA/TKA until discharge. Sydvestjysk Sygehus Grindsted: 
LMWH (Arixtra) 2.5mg x 1 for 7 days. Treatment has been changed after study initiation in the 

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following departments: Hvidovre Hospital: X10a inhibitor (Xarelto) 10 mg to discharge THA/TKA. 
Viborg Hospital: LMWH (Fragmin) 5000 ie x 1 for 10 days.  
1Johannesdottir SA, Horváth-Puhó E, Schmidt M, Ehrenstein V, Pedersen L, Sørensen HT. Existing data sources for clinical 
epidemiology:The Danish National Database of Reimbursed Prescriptions. Clin Epidemiol 2012;4:1-11.