Major Orthopedic Surgery

Major Orthopedic Surgery (MOS)

1. MOS background
THR, TKR, HFS

4. Fondaparinux in MOS
Dosing Clinical trials
PENTATHLON PENTAMAKS EPHESUS PENTHIFRA PENTHIFRA Plus FLEXTRA EXPERT

2. Epidemiology
VTE prevalence and incidence

3. Clinical practice
ACCP guidelines and changes

5. Conclusions

MOS background
MOS encompasses:
Elective total hip replacement (THR/arthroplasty) Elective total knee replacement (TKR/arthroplasty) Hip fracture surgery (HFS)

Why is this population at an increased risk of VTE?

Advanced age Lower extremity trauma Reduced mobility for prolonged periods post-surgery

As VTE is frequently asymptomatic, routine thromboprophylaxis remains the most appropriate strategy

 How many patients undergo MOS each year?

Hip fracture incidence in Europe

1,200
Thousands of patients

1,000
800 600 400

Men Women

200 0 2000 2010 2020 2030 2040 2050

Hip fracture Europe

WHO Report 2000

Hip fracture surgery:

A common condition worldwide
By 2050 numbers will increase three-fold from 1.7 million to 6.3 million worldwide

Life-time risk of fracture will rise to an incredible 35% for women, 17% for men
Unprecedented increases will occur in developing countries over next 50 years A global health problem
WHO Press release 1999 American Academy of Orthopedic Surgeons Bulletin June 2001

 What is the prevalence of VTE postMOS without prophylaxis?

VTE prevalence post-MOS in absence of prophylaxis

Procedure1
Total
Hip arthroplasty 4257

DVT %
Proximal
1836

PE %
Total
0.928

Proximal
0.12.0

Knee arthroplasty
HFS

4185

522

1.510

0.11.7

4660

2330

311

2.57.5

Even with prophylaxis, symptomatic VTE was seen in 2.4% hip arthroplasty and 1.7% hip arthroplasty patients 1992962
1Geerts 2White

WH, et al. Chest 2004;126:338S400S. RH, et al. Arch Intern Med 1998;158:15251531.

Consequences of post-operative VTE

Mortality
Due to fatal PE

Morbidity
Hypercoagulation Symptomatic DVT Non-fatal PE Post-thrombotic syndrome
chronic leg swelling, discomfort, dermatitis, leg ulcers and reduced quality of life1
Geerts WH, et al. Chest 2004;126:338S400S.

Fatal PE and hip fracture (1)

Post-traumatic sub-clinical DVT following hip fracture is the source of fatal PE PEs arise equally from silent distal or proximal DVT Patients with post-traumatic clinical DVT (~2%) are treated, which virtually eliminates the risk of fatal PE1

1 Frostick

SP. Haemostasis 2000;30 Suppl:8487.

Fatal PE and hip fracture (2)

Despite current prophylaxis methods, approximately 12% patients suffer fatal PE within 3(6) months after surgery1-3 1,700,000 hip fractures per annum in the western world 17,00034,000 cases of fatal PE per year4 Post-traumatic sub-clinical DVT is an emerging problem in Asia5

1Haas

S, et al. Thromb Haem 2003; . 2Lubinus P, Klauser W. SICOT/SIROT 2001. 3 Frostick SP. Haemostasis 2000;30 Suppl:8487. 4 WHO Press Release 1999. 5 El-Nour S. SICOT 2002.

Post-operative deaths in THR surgery

Cause of death Vascular deaths PE Stroke Cardiac Gastrointestinal bleed Percentage (%) 74 19 11 44 11

Perforated peptic ulcer

Other causes
Cohort study of 7000 THR patients

4
10.5

Gregg PJ, Devlin HB. National Total Hip Replacement Outcome Study 2000

Increased PE and mortality in HFS

5.0 4.5 4.0 3.5

Mortality (%) % Deaths

0.9 0.8

Fatal PE
(%)

0.7
0.6

% Deaths

3.0 2.5 2.0 1.5 1.0 0.5

0.5
0.4 0.3 0.2 0.1 0

Primary Re-do THR THR

Hip fracture

Primary Re-do THR THR

Hip fracture

Lubinus P, Klauser W. SICOT 2001

Mortality differences:
Emergency versus selected patients
16 14 12 10 8 6 4 2 0 Mortality rate %

Total Hip Replacement Hip Fracture Surgery (THR) (HFS)

The incidence of fatal PE in the hip fracture group was 2.2%

Frostick SP. Haemostasis 2000;30 Suppl:847

Reasons for mortality discrepancy

Elective major joint
Young: ~6570 years Healthy Medically optimized (if moderate systemic comorbidity)

Emergency hip fracture

Old: ~80 years Thin Marginal CRV capacity Concomitant systemic disease(s) Medically not optimized Non-selected

Selected (avoid severe systemic comorbidity)

Does prolonged prophylaxis following hip fracture reduce overall mortality?

Grion AM, et al. Clin Appl Thromb Haem 2002;8:1436

Summary of epidemiology
Increasing need for MOS due to aging population MOS highly traumatic
Systemic hypercoagulation is long lasting

Clinical consequences of MOS:

Mortality dominated by vascular deaths Contribution of PE to mortality is substantial

Reduced survival, mostly in:

Non-selected patients Patients with systemic comorbidity

Extend thromboprophylaxis
Improved survival

Guidelines

Clinical practice
Europe: first dose of LMWH administered preoperatively
This optimizes the effectiveness of thromboprophylaxis12

US: postoperative initiation is preferred

Driven by bleeding concerns12

Delicate balance between dose and timing versus appropriate efficacy and safety
SZ. Chest 2000;117:15367 2 Raskob GE, Hirsh J. Chest 2003;124:379S385S
1Goldhaber

Implications of clinical practice

With LMWHs
Greater bleeding risk if started -2 to +4 hours relative to major surgery Pre-operative dose probably not critical for optimal benefit/risk ratio

With fondaparinux
Similar efficacy but greater bleeding risk (bleeding index >2) if started 36 hours after major joint surgery Therefore, start no sooner than 6 hours after surgery

Summary of ACCP guideline changes from 6th to 7th hip fracture surgery
6th ACCP Conference
For patients undergoing hip fracture surgery (HFS), we recommend either LMWH or adjusted-dose warfarin prophylaxis (grade 1B because the available data are limited)

7th ACCP Conference

For patients undergoing HFS, we recommend the routine use of fondaparinux (grade 1A), LMWH at the usual high-risk dose (grade 1C+), adjusted dose VKA (target INR 2.5; INR range 2.0 to 3.0) [grade 2B], or LDUH (grade 1B)

Geerts WH, et al. Chest 2004;126:338S400S.

Summary of ACCP guideline changes from 6th to 7th duration

6th ACCP Conference
The optimal duration of anticoagulant prophylaxis after THR or TKR surgery is uncertain, although at least 7 to 10 days of prophylaxis is recommended (grade 1A)

7th ACCP Conference

We recommend that patients undergoing THR, TKA, or HFS receive thromboprophylaxis with LMWH (using a high-risk dose), fondaparinux (2.5 mg daily), or a VKA (target INR 2.5; INR range 2.0 to 3.0) for at least 10 days (grade 1A)

Geerts WH, et al. Chest 2004;126:338S400S.

Summary of ACCP guideline changes from 6th to 7th extended prophylaxis

6th ACCP Conference
Extended out-of-hospital LMWH prophylaxis (beyond 7 to 10 days after surgery) may reduce the incidence of clinically important thromboembolic events, and we recommend this approach at least for high-risk patients (grade 2A because of uncertainty regarding costeffectiveness)

7th ACCP Conference

THR or HFS patients: extended prophylaxis for up to 28 to 35 days after surgery (grade 1A) Post-THR, recommended options include LMWH (grade 1A), a VKA (grade 1A), or fondaparinux (grade 1C+) Post-HFS, recommended options are fondaparinux (grade 1A), LMWH (grade1C+), or a VKA (grade 1C+)

Geerts WH, et al. Chest 2004;126:338S400S.

Clinical Trials

Phase III clinical trials

PENTAMAKS

EPHESUS

7,344 patients
PENTATHLON 2000
PENTHIFRA

Fondaparinux Phase III trials in MOS

Same design for all studies Same efficacy and safety endpoints Same blinded adjudicating committee

Total patient base of 7,344 patients

Study design
Randomized, double-blind Treatment 72 days start 62 hrs post-op

Fondaparinux 2.5 mg once daily

R
start pre-op or post-op Enoxaparin 40 mg once daily or 30 mg twice daily Follow up day 427

Venogram day 511

EPHESUS

ENT P A THLON

PENTAMAKS

2000

PENTHIFRA
[PENTasaccharide in HIp FRActure surgey]

PENTHIFRA hip surgery

Does fondaparinux reduce the risk of VTE in hip fracture patients post-surgery?
1,711 patients undergoing surgery for fracture to the upper third of the femur
Fondaparinux 2.5 mg SC once daily (n=831) post-operatively Enoxaparin sodium 40 mg once daily (n=840) pre-operatively Treatment for at least 5 days

Primary efficacy outcome:

VTE detection up to day 11 (detected by bilateral venography), documented symptomatic DVT or PE

Safety outcomes:
Major bleeding and mortality from all causes

6 week follow-up
Eriksson BI, et al. N Engl J Med 2001;345:1298304

PENTHIFRA
Results

VTE All DVT

Fondaparinux n=831 (%) 8.3

7.9

Enoxaparin n=840 (%) 19.1*

18.8

Proximal DVT
Symptomatic PE

0.9
0.4

4.3
0.4
*P<0.001

Eriksson BI, et al. N Engl J Med 2001;345:1298304

PENTHIFRA
Results
The fondaparinux group had a significantly lower incidence of VTE by day 11 than the enoxaparin group (p<0.001; risk reduction 56.4%) There were no significant differences in the incidence of death or clinically relevant bleeding

Conclusions
2.5 mg fondaparinux was more effective than 30 mg enoxaparin in preventing VTE in this population and was equally safe Fondaparinux reduces the risk of VTE in hip fracture patients post-surgery
Eriksson BI, et al. N Engl J Med 2001;345:1298304

PENTHIFRA Plus
[PENTasaccharide in HIp FRActure surgery Plus Investigators]

PENTHIFRA Plus extended prophylaxis

To assess the benefit of extended prophylaxis (4 weeks) in the fondaparinux group
656 patients undergoing surgery for fracture to the upper third of the femur Patients given fondaparinux 68 days, then randomized to receive:
Fondaparinux 2.5 mg SC once daily post-operatively Placebo Treatment for at least 1923 days

Primary efficacy outcome:

VTE detection during the double-blind period (detected by bilateral venography), documented symptomatic DVT or PE

Safety outcomes:
Major bleeding

6 week follow-up
Eriksson BI, Lassen MR. Arch Int Med 2003;163:133742

Efficacy of extended prophylaxis

VTE risk reduction
40 All VTE up to Day 21 after randomization % Symptomatic VTE Symptomatic VTE up to Day 21 after randomization 3 2.5

35
% All VTE 30 25 20 15 10 5 0

RRR=96% p=4 x 10-22

35%

RRR=89% p=0.021

2.7%

2
1.5 1 0.5 0.3%

1.4%

Fondaparinux 3/208

Placebo 77/220

Fondaparinux Placebo 9/330 1/326

Eriksson BI, Lassen MR. Arch Int Med 2003;163:133742

VTE following hip fracture surgery

Persistence of risk for at least 4 weeks
Day after surgery
7 Placebo Fondaparinux 8 9 1 0 1 1 x 1 2 1 3 1 4 1 5 1 6 1 7 x 1 8 x x 1 9 x 2 0 x 2 1 x x 2 2 2 3 x 2 4 x 2 5

Nine symptomatic events (X) in the placebo group versus one in the fondaparinux group
Eriksson BI, Lassen MR. Arch Int Med 2003;163:133742

PENTHIFRA Plus
Results
Longer duration of prophylaxis results in improved efficacy A reduction of total VTE from 35% to 1.4%, with a relative risk reduction of 96% Symptomatic VTE was reduced from 2.7% to 0.3%, with a relative risk reduction of 89%

Conclusions
Extended prophylaxis with fondaparinux for 3 weeks after HFS decreased risk of VTE by 96% and was well tolerated

Significant patient benefit is achieved with the extended use of 2.5 mg fondaparinux
Eriksson BI, Lassen MR. Arch Int Med 2003;163:133742

Fondaparinux in MOS

Fondaparinux in MOS
Fondaparinux is indicated for the prophylaxis of DVT, which may lead to PE
In patients undergoing hip fracture surgery, including extended prophylaxis In patients undergoing hip replacement surgery In patients undergoing knee replacement surgery

Dosing:
2.5 mg administered by SC injection once daily

Fondaparinux is strongly recommended by the ACCP guidelines as the antithrombotic of choice in hip fracture surgery

Arixtra prescribing information

 Does fondaparinux improve the risk/benefit ratio set by enoxaparin in the prevention of VTE after MOS?

Superior efficacy of fondaparinux vs enoxaparin in all types of surgery

Fondaparinux better EPHESUS n=1,817 PENTATHLON 2000 n=1,584 PENTHIFRA n=1,250 PENTAMAKS n=724
61.6% 63.1% 55.2%
-80 -60 -40 -20 0 20

Enoxaparin better

Exact 95% CI
[72.9; 37.5] [52.2; 7.6]

58.5% 28.1%

[73.4; 45.0]
[75.5; 44.8]

Overall odds reduction

% odds reduction
-100

p=10 -17
40 60 80

[63.1; 45.8]
100 Homogeneity test: ns

Turpie AGG, et al. Arch Intern Med 2002;162:183340

Fondaparinux reduces the overall VTE rate compared to enoxaparin

p<0.001

Overall VTE rate (%)

16 14 12 10 8 6 4 2 0

13.7%

6.8%

Overall odds reduction = 55.2% [CI 45.8; -63.1]

Fondaparinux Enoxaparin n=2,703 n=2,682

Turpie AGG, et al. Arch Intern Med 2002;162:183340

Overall safety
All treated patients up to Day 11
Bleeding Fatal Non-fatal in critical organ Leading to re-operation Bleeding index 2 Other (minor)

Fondaparinux Enoxaparin p value (n=3,616) (n=3,621)

0 1 ns ns ns p<0.05 ns

0
12 (0.3%) [0.17; 0.58] 84 (2.3%) [1.9 ; 2.9]

1
8 (0.2%) [0.11; 0.47] 53 (1.5%) [1.1; 1.9]

109 (3.01%) [2.5; 3.6]

99 (2.73%) [2.2 ; 3.3]

Turpie AGG, et al. Arch Intern Med 2002;162:183340

Significant decrease of BI 2 when first injection is performed >6 hours post-op

% of overt bleeding (BI >2) with fondaparinux

Regression logistic model;p=0.008. Regression logistic model; p=0.008. CI denotes confidence interval and BI bleeding index CI denotes confidence interval and BI bleeding index.

Interval between surgery and first postoperative injection fondaparinux

Fondaparinux and analgesia

What is the problem? VTE prophylaxis drastically reduces the incidence of post-operative VTE Regional anesthesia improves patient outcome We have to deal with two paradoxical problems:
Avoid thrombosis and Avoid bleeding complications related to regional techniques

Guidelines for the use of epidural and spinal anesthesia in the multicenter fondaparinux MOS programme
Any indwelling intrathecal or epidural catheter to be removed at least 2 hours before the first postoperative injection Exclusion criteria:
Planned indwelling intrathecal or epidural catheter during the study treatment period Unusual difficulty in achieving epidural or spinal anesthesia (e.g. more than 2 attempts)

ESW Proceedings 2002

Pre-operative LMWH regimens are not optimal in case of regional anesthesia

In THR (EPHESUS) 20% of enoxaparin patients did not receive a pre-op dose due to regional anesthesia In hip fracture (PENTHIFRA) 75% of enoxaparin patients did not receive a pre-op dose due to emergency and use of regional anesthesia

Efficacy of fondaparinux vs enoxaparin: Impact of type of anesthesia

Fondaparinux better All patients (n = 5835) Regional anesthesia only (n=2496) General anesthesia1 (n=2889) Enoxaparin Odds 95% CI better reduction
55.2 57.3 [63.1; 45.8] [67.8; 43.7]

51.4

[62.8; 36.8]

% odds reduction - 0 20 40 60 80 100 100 80 60 40 20 1. General anesthesia was combined with regional anesthesia in 6.1% of cases Turpie AGG, et al. Arch Intern Med 2002;162:183340

Regional anesthesia does not affect safety and efficacy of fondaparinux

Almost half of the patients were given regional anesthesia1 The overall rate of VTE was not affected by regional anaesthesia: 10.5% and 10.0% for regional and general anaesthesia2 The rate of clinically important bleeding did not differ: 2.3% and 2.1% for regional and general anesthesia2 No case of neuraxial hematoma was reported with fondaparinux 2.5 mg

1. Turpie AGG, et al. Arch Intern Med 2002;162:183340 2. ESW Proceedings 2002

Fondaparinux summary
The efficacy of fondaparinux was superior to enoxaparin with a relative risk reduction >50%

Optimal timing of first dose is 68 hours after surgery

No difference in clinically relevant bleeding Extended prophylaxis provides additional clinical benefit Safety and efficacy unchanged by regional anesthesia

Current clinical trials

Is fondaparinux equally effective if administered the morning after the operation? (FLEXTRA) Is fondaparinux effective in extended thromboprophylaxis in patients with indwelling catheters for analgesia? (EXPERT)

FLEXTRA
Objective To compare fondaparinux 2.5 mg started 68 hours post-op with fondaparinux 2.5 mg started the first morning post-op

Methodology Multicenter, randomized, open label study 10 days prophylaxis in THR or TKR (n=2000) Assess efficacy (symptomatic VTE) and safety at 6 hrs Self-injection questionnaire US study completed Jan 2004

Kwong LM, et al. EFORT 2005

EXPERT
Objective To assess clinical efficacy and safety of extended prophylaxis with fondaparinux 2.5 mg (41 weeks) in all MOS patients and those with indwelling catheters for analgesia

Methodology Multicenter, multinational, prospective open label study (n=5539) In Europe mainly Completed in Jan 2005

Singelyn FJ, et al. EFORT 2005

Fondaparinux: the antithrombotic of choice in MOS

The data from the FLEXTRA and EXPERT trials support the flexible and extended use of fondaparinux in MOS These data reinforce the unquestionable efficacy and superiority fondaparinux has demonstrated in EPHESUS, PENTAMAKS, PENTATHLON 2000 and PENTHIFRA trials Fondaparinux is the antithrombotic of choice in MOS