Status for behandling af dyb venøs trombose og lungeemboli Status for behandling af dyb venøs trombose og lungeemboli Steen Husted Aarhus Universitetshospital Steen Husted Steen Husted Aarhus Universitetshospital Aarhus Universitetshospital
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