Home treatment of DVT with long Home treatment of DVT with long

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Home treatment of DVT with long Home treatment of DVT with long

Home-LITE:

Home treatment of DVT with longterm

LMWH vs. a vitamin K antagonist

Efficacy, safety, patient satisfaction and

post-thrombotic thrombotic syndrome

Russell D. Hull

Professor of Medicine,Thrombosis Research Unit

University of Calgary


Coalition’s 2010 Venous Disease Research Award

Member organizations of Venous Disease Coalition:

American Academy of Physician Assistants

American Academy of Nurse Practitioners

American College of Cardiology

American College of Chest Physicians

American College of Phlebology

American Osteopathic Association

American Radiological Nurses Association

American Society of Health-System Pharmacists

American Society of Hematology

American Society for Clinical Oncology

American Thrombosis Hemostasis Network

American Venous Forum

Anticoagulation Forum

APS Foundation of America

Canadian Chapter Society for Vascular Nursing

Canadian Society for Vascular Surgery

Canadian Cardiovascular Society

Case Management Society

Hemophilia & Thrombosis Research Society

Institute for Safe Medication Practices

Medical Compression Garment Assoc. of North America

National Alliance of Thrombosis & Thrombophilia

National Gerontological Nursing Association

North American Thrombosis Forum

Preventive Cardiovascular Nursing Association

Society for Cardiovascular Angiography & Interventions

Society for Clinical Vascular Surgery

Society of Critical Care Medicine

Society of Interventional Radiology

Society for Vascular Medicine

Society for Vascular Nursing

Society for Vascular Surgery

Society of Vascular Ultrasound

Spirit of Women

Thrombosis Interest Group of Canada


Home-LITE: key messages

• In patients with DVT, how does long-term home

treatment with tinzaparin compare with usual

care?

• Patients in the two treatment groups had

similar rates of recurrent VTE, death, and

bleeding

• With tinzaparin there was a significantly lower

incidence of PTS and leg ulcers

• Patients treated with tinzaparin expressed

greater treatment satisfaction

DVT: deep vein thrombosis; VTE: venous thromboembolism; PTS: post-thrombotic syndrome


Treatment of VTE: ACCP 2008

Initial treatment

• Use subcutaneous (s.c.) LMWH rather than UFH, for ≥5

days (until INR ≥2.0 for 24 h)

• Treat as outpatient if possible

Long-term treatment

• Treat with a vitamin K antagonist (VKA) for ≥3 months

• Duration affected by risk factors and bleeding risk

ACCP: American College of Chest Physicians; LMWH: low molecular weight heparin;

UFH: unfractionated heparin; INR: international normalized ratio

Kearon C, et al. Chest 2008;133:454–545.


Long-term treatment of VTE

Long-term treatment of DVT (3 to 6 months)

• LMWH is as effective as oral anticoagulation

• With LMWH, bleeding rates are similar or lower than

with oral anticoagulation

• LMWH is recommended for long-term treatment of

DVT (and PE) in patients with cancer

• In trials of long-term treatment, most patients were

treated in hospital initially

PE: pulmonary embolism

Kearon C, et al. Chest 2008;133:454–545.


1. Main LITE

The LITE studies

Broad spectrum of patients

All hospitalized initially

2. Main LITE Cancer

A priori analysis in cancer patients

3. Home-LITE

Outpatients

ti t


Main LITE: long-term LMWH vs. VKA in

patients with DVT

• Similar rates of recurrent VTE (3 and 12 months)

• ‘All bleeding’ and ‘minor bleeding’ significantly lower with

tinzaparin at 3 months

• No new major bleeding events with tinzaparin after day 23

Ble eeding events

(n)

*

13.0%

19.8%

**

3.3% 4.6% 9.8%

15.2%

Tinzaparin

Heparin/warfarin

All Major Minor

*p = 0.011, 011 diff. –6.8%; 95% CI (-12.4 to -15); -1.5); **p p = 0.022, 022 diff. -5.5%; 5%; 95% CI (-10.4 to -06) -0.6)

CI: confidence interval

Hull RD, et al. Am J Med 2007;120:72–82.


Main LITE Cancer: long-term LMWH vs.

VKA in patients with DVT and cancer

• LMWH was more effective than VKA for preventing recurrent VTE 1

• Bleeding rates were similar in the two groups

• Similar results were seen in the CLOT study with dalteparin 2

VTE occurre nce

(cumulative

incidence [% %])

20

15

10

5

Heparin/warfarin

Tinzaparin

0

0 100 200 300

Days

At risk (n)

Heparin/warfarin 100 78 65 56 51 46 44

Tinzaparin 100 80 68 65 57 54 47

Reduced

risk of

recurrent

VTE with

LMWH

p = 0.044

1. Hull RD, et al. Am J Med 2006;119:1062-1072.

2. Lee AY, et al., N Engl J Med 2003;349:146–153.


Home-LITE: study design

• Purpose: compare outcomes for 3 months of treatment with

tinzaparin vs. ‘usual care’ at home

• 12-week multicenter, open-label, randomized controlled trial

Randomization

n s.c. tinzaparin OD, 175 IU/kg/day

/d

D1

Warfarin for

recurrent DVT

or at doctor’s

discretion

OD: once daily

s.c. tinzaparin OD, 175 IU/kg/day for ≥5 days until

INR 2.0–3.0 for 2 consecutive days. Warfarin from

day 1 (D1), for 3 months

12 weeks


Home-LITE: endpoints

• Primary efficacy outcome measure:

• Symptomatic, recurrent VTE at 12 weeks and 1 year

• Primary safety outcome measure:

• Bleeding events (all, major or minor) during the 12-week

treatment period

• Other efficacy measures:

• Death rates at 12 weeks and 1 year

• Self-reported treatment satisfaction

• Symptoms of PTS

• Incidence of venous leg ulcers

• Other safety measures:

• Incidence of thrombocytopenia

• Bone fractures


Home-LITE: participant p flow

797 patients assessed for

eligibility

480

randomized

317 excluded:

104 received heparin, LMWH or oral

anticoagulant therapy for >2 days at

time of referral

213 unable/declined to give written

consent

240 assigned to tinzaparin

0 lost to follow-up at 3 months

(+2 at 12 months)

2 withdrew consent at 3 months

(+1 at 12 months)

240 assigned to usual care with

tinzaparin and warfarin

0 lost to follow-up at 3 months

(+4 at 12 months)

1 withdrew consent at 3 months

(+2 at 12 months)

240 included in analysis 240 included in analysis


Baseline characteristics of participants

p

Characteristic

Tinzaparin Usual care

n = 240 n = 240

Age, years (number


Recurrent VTE with tinzaparin vs. . usual care

Tinzaparin

n = 240

n (%)

Usual care

n = 240

n (%)

Absolute

difference a

(95% Cl) (%)

p-value

At 84 days b 8 (3.3) 8 (3.3) 0.0 (–3.2, 3.2) 1.00

Cumulative incidence

25 (10.4) 20 (8.3) 21 2.1 (–31 3.1, 73) 7.3) 043 0.43

at 365 days

a

Tinzaparin minus usual care

b

Recurrent venous thromboembolism at 84 days: of 8 patients in each group,

4 had pulmonary embolism and 4 had recurrent DVT


Recurrent VTE with tinzaparin vs. . usual care

p = 0.43

10.4%

2.1

Tinzaparin

Usual care

p = 0.34

Epi isodes of VTE

3.3%3.3%

33%33%

8.3%

p = 0.002

5.0%

4.6

-2.5

p = 0.20

4.6%

7.1%

2.1

21

5.0%

2.1%

0.4%


Incidence of recurrent VTE

• Between days 85–112, recurrent VTE was significantly

higher h with tinzaparin

i

• Between days 112-365, recurrent VTE was higher with

usual care

• Cumulative incidence of VTE did not differ between the

two groups at 1 year

• Imbalance likely to result from an ongoing prothrombotic

state evidenced when therapy is discontinued 1

• Of note: patients did not receive identical treatment

after 12 weeks

• Among the 12 tinzaparin patients with VTE between days 84-112,

8 did not receive ongoing anticoagulation therapy after 84 days

1. Rodger MA, et al. CMAJ 2008;179:417–426.


Death rates with tinzaparin

vs. . usual care

Tinzaparin

N = 240

n (%)

Usual care

N = 240

n (%)

Absolute

difference a

(95% Cl) (%)

p-value

At 84 days 9 (3.8) 9 (3.8) 0.0 (–3.4, 3.4) 1.00

Cumulative incidence

At 365 days 22 (9.2) 21 (8.8) 8) 04 0.4 (–47 4.7, 55) 5.5) 087 0.87

85 to 112 days 2 (0.8) 1 (0.4) 0.4 (–1.0, 1.8) 0.56

113 to 365 days 11 (4.6) 11 (4.6) 0.0 (–3.7, 3.7) 1.00

a

Tinzaparin minus usual care


Prevalence of bleeding with tinzaparin vs.

usual care

Tinzaparin

Usual care

0.9

Bleeding ev vents (n)

92% 9.2% 92% 9.2% 88% 8.8%

-0.8

12% 1.2%

0.4%

7.9%

All

Major bleeding

Minor bleeding

All comparisons were non-significant


Post-thrombotic thrombotic syndrome (PTS)

• PTS occurs in 20–60% of patients after a DVT 1

• Burdensome to patients and costly to society

• Pathophysiology possibly related to persistent

venous obstruction bt ti and/or reflux

• Recurrent VTE predicts the development of PTS 2

• A recent study showed PTS was present in >40% of

patients at 1, 4, 8, 12 and 24 months post-DVT 3

• PTS can be assessed reliably using the Villalta scale

and combinations of physical examination findings 4

1. Kearon C, et al. Chest 2008;133;454–545.

2. Kahn SR, et al. J Thromb Haemost 2005;3:718–723.

3. Kahn SR, et al. Ann Intern Med 2008;149:698–707.

4. Rodger MA, et al. Thromb Haemost 2008;100:164–166.


Symptoms and signs of PTS following 12 weeks

of therapy in Home-LITE

Symptom

Odds ratio (95% CI)

Swelling 0.83 (0.56, 1.24)

Difficulty walking

0.66 (0.43, 1.04)

Discoloration

0.71 (0.47, 1.07)

Heavy sensation

Veins enlarged

Skin warm and red

Swelling worse end of day

Compression stocking

0.81 (0.51, 1.27)

0.72 (0.47, 1.10)

0.87 (0.55, 1.38)

0.91 (0.62, 1.35)

0.69 (0.44, 1.07)

Overall OR

favored

tinzaparin

p = 0.001001

Overall 0.77 (0.67, 0.90)

OR: odds ratio

0 0.5 1.0 1.5 2.0

Favors LMWH

Favors usual care


Incidence of leg ulcers with tinzaparin vs.

usual care

During the 12-week study yp period, leg ulcers occurred in:

• 1 patient (0.5%) in the tinzaparin group (n = 198)

vs.

• 8 patients (4.1%) in the usual care group (n = 197)

• p = 0.02, OR 0.12 (95% CI: 0.01, 0.97)

• Daskalopoulos l reported that t patients t treated t with

tinzaparin for 6 months have a reduced risk of PTS and

leg ulcers at 42 months vs. usual care 1

1. Daskalopoulos M, et al. Eur J Vasc Endovasc Surg 2007;34:353-354.


LMWHs beyond anticoagulation

Heparin/LMWHs


Possible mechanism for reduction in PTS?

• Long-term tinzaparin reduced the risk of developing

PTS and leg ulcers vs. usual care

• The mechanism for this reduction is unknown

• LMWHs have multiple effects, including

anti-inflammatory and anti-thrombotic effects

• Effects depend d on the chain length of LMWHs

• LMWHs are not clinically interchangeable

• Tinzaparin an LMWH with longer average chain length

• Tinzaparin, an LMWH with longer average chain length,

results in greater release of tissue factor pathway

inhibitor vs. other LMWHs 1 1. Mousa SA. Cardiovasc Drug Rev 2002;20:199–216.


Greater re-canalization of thrombi with

tinzaparin vs. usual care

• A recent study compared treatment of proximal DVT with OD fixed-

dose s.c. tinzaparin vs. usual care for 6 months 1

• Thrombus resolution/re-canalization was assessed using ultrasound

Outcomes at 1 year

(% of patients)

Tinzaparin

n = 119

VKA

n = 122

p-value

Recurrent VTE 5.0 10.7 0.11

Total re-canalization 91.5 69.2


Patient-reported satisfaction in Home-LITE

Home-LITE incorporated a treatment

satisfaction questionnaire

• Questions addressed practical aspects likely to

affect patient satisfaction

• Patients completed the questionnaires

independently at study-end (12 weeks)

• Responses were made on a 5-point Likert scale,

which h quantifies attitudes


Treatment satisfaction with tinzaparin vs.

usual care

OR (95% CI)

Convenient to go to lab for blood tests

Inconvenient due to visits to doctor’s office

Sometimes forgot to take treatment

Personal control of my care

Confident that health would be better in future

Treatment t interfered with lifestyle

l

Blood tests interfered with daily activities

Treatment did not interfere with work

Blood taken for testing causes discomfort

Confidence in treatment program

Discomfort because cannot take other medications

0.81 (0.57, 1.18)

0.87 (0.60, 1.25)

0.62 (0.43, 0.90)

0.79 (0.55, 1.14)

1.02 (0.71, 1.48)

0.81 (0.57, 1.15) 15)

0.59 (0.40, 0.85)

0.56 (0.39, 0.82)

1.26 (0.87, 1.81)

1.06 (0.72, 1.54)

0.86 (0.59, 1.24)

Wilcoxon rank sum

test p = 0.0024

0 1 2.0

Favors LMWH

Favors usual care


Pioneering aspects of Home-LITE

Home-LITE is the first reported trial

comparing long-term treatment of DVT with

LMWH or usual care in patients treated at

home from the outset

• Fewer exclusion criteria than previous trials

population mix closer to ‘real life’

• Large trial (n = 480)


Conclusions

• In patients with DVT, 12-week treatment with

tinzaparin offers similar efficacy and safety to

usual care

• Selected patients can successfully be treated

at home from the outset

• Tinzaparin is associated with a lower incidence

of PTS and leg ulcers potentially of great

clinical and economic benefit

• Patients expressed greater treatment

satisfaction with tinzaparin


Participating centers

Foothills Hospital, Calgary, AB

Peter Lougheed Centre, Calgary, AB

Rockyview General Hospital, Calgary, AB

Montreal General Hospital, Montreal, QC

St Joseph’s Health Centre, London, ON

University Hospital, London, ON

Jewish General Hospital, Montreal, QC

Sudbury General Hospital, Sudbury, ON

Sunnybrook Health Science Centre, Toronto, ON

University Hospital, Edmonton, AB

Kelowna General Hospital, Kelowna, BC

Group Health Centre, Sault Ste Marie, ON

Port Arthur General Hospital, Thunder Bay, ON

Vancouver General Hospital, Vancouver, BC

St Mary’s Hospital Centre, Montreal, QC

St Joseph’s General Hospital, Comox, BC

Burnaby Hospital, Burnaby, BC

Greater Niagara General Hospital, Niagara Falls, ON

St Boniface General Hospital, Winnipeg, MN Centre Universitaire de Santé, Fleurimont, QC

St Paul’s Hospital, Vancouver, BC

Red Deer Regional Hospital, Red Deer, AB

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