Status for behandling af dyb venøs trombose og lungeemboli

Status for behandling af dyb venøs trombose og lungeemboli

Steen HustedAarhus Universitetshospital

Steen HustedSteen Husted

Aarhus UniversitetshospitalAarhus Universitetshospital

VTE: A strong relationship between DVT and PE

About 50% of patients with proximal DVT of the leg have asymptomatic PE1

DVT (mainly asymptomatic) is found in around 80% of patients with PE2

Embolus

Migration

Thrombus

1. Pesavento R, et al. Minerva Cardioangiol 1997;45:369–3752. Girard P, et al. Chest 1999;116:903–908

VENOUS THROMBOEMBOLISMVENOUS THROMBOEMBOLISMVENOUS THROMBOEMBOLISM

Deep vein thrombosis and pulmonary embolism

•• Identical pathophysiology

•• Similar risk factors

•• Identical therapeutic goals

•• Similar treatment strategies

Venous thromboembolismVenous thromboembolismVenous thromboembolism

MAIN OBJECTIVES OF TREATMENT

•• Reduction of fatality

•• Prevention of recurrence

•• Prevention of late sequelae

PULMONARY EMBOLISMPULMONARY EMBOLISMPULMONARY EMBOLISM3 MONTHS MORTALITY RATE IN ACUTE PE 17.4%

•• 75% during initial hospitalisation

•• 45% caused by PE

ICOPER and Ann Int Med, 1996, 125

CumulativeIncidence

6

95 % confidenceRecurrent thrombatic events

50 %

40

30

20

10

00 1 2 3 4 5 7 8

Time (years)

RECURRENT VTE AFTER FIRST EPISODE OF DVTRECURRENT VTE AFTER FIRST EPISODE OF DVT

PULMONARY EMBOLISM and DVT TREATMENT

PULMONARY EMBOLISM and DVT PULMONARY EMBOLISM and DVT TREATMENTTREATMENT

INITIALINITIAL

Thrombolytic treatment

Heparin (UFH or LMWH)

Oral anticoagulant therapy (OAT) and new antithrombotics

LONG LONG --TERMTERM

OAT and new antithromboticsLMWH

HOMEHOME

OAT and new antithrombotics

LMWH

Indications for thrombolytic therapy

Thrombolytic therapy is indicated in patients with massive PE, as shown by shock and/or hypotension.

The use of thrombolytic therapy in patients with submassive PE (RV hypokinesia) is controversial.

Thrombolytic therapy is not indicated in patients without right ventricular overload.

Task Force Report, Eur Heart J 2000;21:1301

Troponins – a risk factor for poor outcome in acute pulmonary embolism

• Correlation between elevation of troponins and clinical course

• Elevation of TnT predicts recurrent pulmonary embolism• TnT >0.1 ng/mL related to more frequent prolonged

hypotension, cardiogenic shock, cardiopulmonary resuscitation and death

• Total mortality 44% in patients with TnT >0.1 ng/mL and 3% in those with TnT <0.1 ng/mL

• Measurement of TnT my help identifying high risk patients that are candidates for thrombolysis

Giannitis E et al, Circulation 2000;102:211-7 Gunkel O et al, Eur Heart J 2001;22(abstract suppl):317 Hruska N et al Circulation 2001;104(suppl II):II-467 Koralesky AE et al JACC 2002;212A Sallach JA et al JACC 2002;212A

Thrombolysis in submassive PEInclusion criterias:

- right ventricular dysfunction/strain (ECHO or electrocardiography)

- pulmonary-artery hypertension (ECHO or catheterization)

followed by confirmation of the PE diagnosis

Konstantinides et al, N Engl J Med 2002;347:1143-50

Exclusion criterias:- age >80 years, systolic BP <90 mmHG, symptoms

>4 days, other causes of an increased bleeding risk

Thrombolysis in submassive PE

• Double-blind, placebo-controlled study testing t-PA plus UFH vs UFH (n = 256)

• Primary endpoint: 30-day event-free* survival• Primary endpoint: 10.2 vs 24.6% (p=0.005)• Mortality: 3.4 vs 2.2% (p=0.71)• No fatal or ICH were seen* Catecholamine infusion, secondary thrombolysis, endotracheal

intubation, cardiopulmonary resuscitation, emergency surgical embolectomy or thrombus fragmentation by catheter

Konstantinides et al, N Engl J Med 2002;347:1143-50

INITIAL VTE TREATMENTINITIAL VTE TREATMENTINITIAL VTE TREATMENTUNFRACTIONATED HEPARIN

•• Symptomatic events •• Thrombotic extension •• Bleeding complications

Brandjes et al, N.Engl.J. Med. 1992; 327

•• Intravenous, weight adapted UFH

•• aPTT adjusted to 1.5-2.5 times control

•• Anti-Xa activity 0.3-0.6 IU

•• For at least 5 days with OAT and at least 2 days with INR in TI

Gallus et al. Lancet 1986; II. Hull et al. N.Engl.J.Med 1990; 322

Initiation of OATInitiation of OATInitiation of OAT

•• OAT starts at the same time as Heparin

Hull et al, N.Eng.J.Med. 1990; 332

•• OAT starts with expected daily maintenance dose of Warfarin

Episodes of excessive anticoagulation

No delay in achieving INR 2.0

Harrison et al, Ann Intern Med, 1997; 126Crowther et al, Ann Intern Med, 1999; 159

Early extreme decline in protein C and S

Initial treatment of VTE: LMWH vs UFH

*FEM = fixed effects model; †REM = random effects modelGould MK et al. Ann Intern Med 1999;130:800–9.

All studies (REM†)

All studies (FEM*)

0.01 0.1 1 10 100 0.01 0.1 1 10 100

OR=0.71 (p=0.25) OR=0.87 (p=0.40)OR=0.57 (p=0.047) OR=0.85 (p=0.28)

Favours

LMWH

Oddsratio

Favours

UFH

Favours

LMWH

Oddsratio

Favours

UFH

Columbus Investigators, 1997

Luomanmaki et al. 1996Fiessinger et al. 1996Koopman et al. 1996Levine et al. 1996Lindmarker et al. 1994Simonneau et al. 1993Lopaciuk et al. 1992Prandoni et al. 1992Hull et al. 1992Duroux, 1991Primary studies

Major bleeding(n=3674)

Recurrent thromboembolism

(n=3566)

LMWH or UFH in pulmonary embolismLMWH or UFH in pulmonary embolismLMWH or UFH in pulmonary embolism

COLUMBUS THÉSÉEVTE (1/3 PE) PE

REVIPARIN UFH TINZAPARIN UFH(n=510) (n=511) (n=304) (n=308)

RECURRENCES, % 5.3 4.9 1.6 1.9DEATHS, % 7.1 7.6 3.9 4.5MAJOR BLEEDINGS, % 3.1 2.3 1.0 1.6

Simmoneau et al, N.Eng.J.Med. 1997; 337The Columbus investigators, N.Eng.J.Med. 1997; 337

Home treatment in DVTHome treatment in Home treatment in DVTDVT

N Recurrence%

Major bleeding%

Levine, Enoxaparin 247 5.3 2.01996 UFH 253 6.7 1.1

Koopman, Nadroparin 202 6.9 0.51996 UFH 198 8.6 2.0

Home treatment in VTEHome treatment in VTEHome treatment in VTE

LMWH with early discharge

•• in about 80% of DVT patients

•• in patients with non-massive PE

Gould et al, Ann Intern Med. 1999; 130

Prolonged LMWH treatment

• LMWH once daily s.c. vs OAT has been studied in a number of small trials

• Cochrane review based on five studies:– non-significant reduced risk of VTE recurrence (OR

0.72; 95% CI 0.42-1.23).– non-significant reduced risk of bleeding (OR 0.63; 95%

CI 0.21-1.88)

Van der Heijden JF et al. Cochrane Database Syst Rev 2002;(1):CD002001

6 Month

Placebo ximelagatran +Warfarin/Enoxaparin

RR

Objective confirmation

of DVT

Ximelagatran + Placebo Warfarin/Enoxaparin

E

Until INR ≥ 2.0 at two consecutive measurements(5 - 20 days of Enoxaparin)

14 days follow up

max 14 days

onset of symptoms

24 h

ours

Enoxaparin

Ximelagatran or warfarin

Baseline exams – 72 h

Thrive: Study Design

End of Treatment

n=1240

n=1249

Oral anticoagulant therapy in cancer patients

Warfarin therapy is complicated – It is difficult to maintain tight therapeutic control

(anorexia, vomiting and drug interactions)

– There are frequent interruptions for thrombocytopenia and procedures

– Venous access is difficult

– There is increased risk of recurrence and bleeding

CLOT in cancer trial

Randomized Comparison of

Low-Molecular-Weight Heparin versus

Oral Anticoagulant Therapy for

Long Term Anticoagulation in

Cancer Patients with Venous Thromboembolism

Lee et al, N.Engl.J.Med. 2003;349:146

Study population

• Inclusion criteria– Objectively documented, symptomatic

proximal DVT and/or PE

– Active cancer• Cancer diagnosis within past 6 months• Recurrent or metastatic malignancy• Received cancer treatment within past 6 months

– 16 years or older

CLOT trial

Group Initial treatment Long-term therapy(5–7 days) (6 months)

OAC* Dalteparin 200 IU/kg Warfarin or acenocoumarolsc once-daily (target INR 2.5)

LMWH Dalteparin 200 IU/kg Month 1: Dalteparin 200 IU/kgsc once-daily Month 2–6: 75–80% of full-dose

*OAC = oral anticoagulant

0

5

10

15

20

25

Days post-randomization

0 30 60 90 120 150 180 210

Prob

abili

ty o

f rec

urre

nt V

TE (%

)

Risk reduction=52%

p=0.0017

Dalteparin

OAC

Recurrent VTE

Bleeding

LMWH OAC p*n=338 (%) n=335 (%)

Major bleed 19 (5.6) 12 (3.6) 0.27

Any bleed 46 (13.6) 62 (18.5) 0.093

*Fisher’s exact test

Long-term OAT treatmentin VTE

LongLong--term OAT treatmentterm OAT treatmentin VTEin VTE

UFH and nicoumalone reduce mortality in PE

UFH and Warfarin reduce recurrence in distal DVT

OAT vs. low-dose UFH reduces recurrence in DVT

OAT with INR 2.0-3.0 vs 3.0-4.5 equally effective but with less bleeding complications

Barrit and Jordan, Lancet 1960; I

Lagerstedt et al, Lancet 1985; II

Hull et al, N.Engl.J.Med. 1979; 301

Hull et al, N.Engl.J.Med. 1982,307

Duration of OAT in VTEDuration of OAT in VTEDuration of OAT in VTE

Factors influencing treatment duration:- presence or absence of major reversible risk factors- VTE localisation- thrombophilia- more than one episode of idiopathic VTE- active cancer- patient preference and clinical condition- bleeding risk (and quality of OAT

Duration of OAT in VTE• Risk of recurrence VTE 2-fold increased reducing OAT

duration from 3-6 months to 4-6 weeks with no difference in bleeding risk

• Recurrent VTE 4 times higher for idiopathic VTE

• Recurrent VTE after 3 or 6 months vs long-term OAT was increased after a second episode of VTE (6%/year) and in idiopathic VTE (25%/year) with an increase in major bleeding risk during long-term treatment

Brit. Thoracic Soc. Lancet 1992;340Schulman S et al. N Engl J med 1995; 332Levine MN et al. Thromb Haemost 1995;74

Schulman S et al N Engl J Med 1997;336Kearon C et al N Engl J Med 1999;340

Duration of OAT in VTE

• Recurrence after long-term observation similar in VTE patients treated for 3 vs 6 months (provoked and unprovoked; ref. 1) or 3 vs 12 months (unprovoked; ref. 2)

• Recurrence rates in PE patients treated with OAT for 3 vs 12 months (idiopathic) were similar and high (3.1% per patient year) during long-term follow-up (average 34.9 months). Major bleeding rate 1.8% during treatment extension

Ref. 1: Pinéde L et al. Circulation 2001;103Ref. 2: Agnelli G et al. N Engl J Med 2001;345

Agnelli G et al. Ann Int Med 2003;139

Long-term low-intensity OAT in VTE

• Long-term low-intensity OAT (mean 2.1 years; INR 1.5-2.0) in idiopathic VTE following a median of 6.5 months full-dose OAT reduced recurrence rate 64% (7.2 to 2.6 per 100 patient -years) without an increase in bleeding risk

• Conventional OAT (INR 2.0-3.0) vs low-dose OAT (INR 1.5-1.9) for a mean of 2.4 years following 12 months full-dose OATin ideopathic VTE patients reduced recurrence rate from 1.9 to 0.7 per 100 patient-years (HR 2.8; 95% CI 1.1-7.0). Bleeding risk was not increased (1.1 and 0.9 per 100 patient-years; HR 1.2; 95% CI 0.4-3,0).

Ridker PM et al. N Engl J Med 2003;348

Kearon C et al. N Engl J Med 2003;349

R

THRIVE III: Study Design

18 months

Placebo

E

6 ±1 months

Ximelagatran 24 mg, b.i.d.Initial VTEevent

2 weeks follow up

INR < 1.5

600 patients

600 patients

Stratification - malignancy

LPO April 2002FPI November 1999

VTE events, ITT population

0 90 180 270 360 450 540Days

Ximelagatran

Placebo

0

2

4

6

8

10

12

14

EstimatedCumulative risk (%)

12.6%

2.8%

P<0.0001 (HR 0.16;CI 0.09-0.30)

VTE - Duration of therapy ACCP Guidelines 2001

3-6 months– 1st event with time-limited risk factor

≥6 months– 1st idiopathic

12 months-lifetime– 1st event with*

• Cancer until resolved• ACA• AT deficiency

– Recurrent eventAll recommendations to be individualised

* Unclear for homozygous fVL, homocysteinemia, protein S or C deficiency