Daniela Tormene MALATTIE TROMBOEMBOLICHE Anatomic theatre, Padua University.
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Daniela Tormene MALATTIE TROMBOEMBOLICHE MALATTIE TROMBOEMBOLICHE Anatomic theatre, Padua Univers Anatomic theatre, Padua Universi
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Transcript of Daniela Tormene MALATTIE TROMBOEMBOLICHE Anatomic theatre, Padua University.
Daniela Tormene
MALATTIE TROMBOEMBOLICHEMALATTIE TROMBOEMBOLICHE
Anatomic theatre, Padua UniversityAnatomic theatre, Padua University
Brandjes DPM, Heijboer H, Büller HR, et al.
Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment
of proximal-vein thrombosis (A.T.H.O.S.)
N Engl J Med 1992
A.T.H.O.S. STUDYA.T.H.O.S. STUDYResultsResults
_______________________________________________ Sintrom Hep. + Sintrom (N=60) (N=60)_______________________________________________
Symptomatic VTE 20% 6.7%
Asympt. DVT extens. 39.6% 8.2%
Major bleeding 5.0% 3.0%_______________________________________________
Different heparin dosage Different heparin dosage regimens in venous thrombosisregimens in venous thrombosis
___________________________________________________ Starting U/24 h Recurrent VTE (%) High Low High Low___________________________________________________
Brandjes, 1992 30,000 0 6.7 20.0
Hull, 1986 30,000 iv 30,000 sc 5.2 19.8
Raschke, 1993 30,240 24,000 5.0 25.0___________________________________________________
Heparin nomogramHeparin nomogram(Cruikshank et al., 1991) (Cruikshank et al., 1991)
Bolus: 5000 U followed by 1280 U/h. First APTT after 6h___________________________________________________APTT Bolus Hold Rate change Rep. APTT(sec) (U) (min) (U/h)< 50 5,000 0 + 120 6 h50-59 0 0 + 120 6 h 60-85 0 0 0 next morning 89-95 0 0 - 80 6 h96-1200 30 - 80 6 h> 120 0 60 - 160 6 h
Current Treatments for Patients Current Treatments for Patients with Acute VTE with Acute VTE
• Unfractionated or low-molecular-weight heparin followed by 3–6 months of oral anticoagulant therapy
• Thrombolytic treatment in selected patients with critical PE
• Intracaval filter in selected patients with contraindications to antithrombotic drugs
Buller HR et al. Chest 2004
Efficacy and safety of LMWH in Efficacy and safety of LMWH in comparison to UFHcomparison to UFH
Thrombus reduction
Recurrent VTE
Major bleeding
OR=0.69 (0.59-0.81)
OR=0.68 (0.55–0.84)
OR=0.57 (0.39–0.83)
Favours LMWHFavours LMWH RRRR Favours Favours UFHUFH
0.0 0.5 1.0 1.5 2.0
Effects of LMWH vs Unfractionated Heparin (UFH) in Effects of LMWH vs Unfractionated Heparin (UFH) in the Treatment of Acute VTEthe Treatment of Acute VTE
(22 studies, 8867 symptomatic patients)(22 studies, 8867 symptomatic patients)
Total mortality OR=0.76 (0.62–0.92)
CochraneReview System
2004
New Therapeutic OpportunitiesNew Therapeutic Opportunities
• Home treatment of DVT• Treatment of PE• HIT and Osteoporosis• Treatment of DVT in cancer patients• Treatment of SVT• The potential of new drugs
Home treatment of suitable patients with Home treatment of suitable patients with DVTDVT
Outpatient DVT treatment with LMWH Outpatient DVT treatment with LMWH TASMAN and North-American studiesTASMAN and North-American studies
Outpatient DVT treatment with LMWH Outpatient DVT treatment with LMWH TASMAN and North-American studiesTASMAN and North-American studies
TASMANTASMAN North-American North-American
LMWHLMWH UFHUFH LMWHLMWH UFH UFH
(n=202) (n=198) (n=247) (n=253)
Recurrent VTERecurrent VTE 14 (6.9%) 17 (8.6%) 13 (5.3%) 17 (6.7%)
Major bleedingMajor bleeding 1 (0.5%) 4 (2.0%) 5 (2.0%) 3 (1.2%)
MortalityMortality 14 (6.9%) 16 (8.1%) 11 (4.4%) 17 (6.7%)
Ambulatory treatment with LMWHAmbulatory treatment with LMWH
Author LMWH Setting Pts
Grau ‘98 Nadroparin DVT 39
Harrison ‘98 Dalt/Tinzap DVT 89
Mattiasson ‘98 Dalteparin DVT 240
Wells ‘98 Dalteparin DVT/PE 184
Kovacs ‘00 Dalteparin PE 108
Labas ‘01 Enoxaparin DVT 96
Lapidus ‘02 Tinzaparin DVT 332
Beer ’03 Nadroparin PE 104
Wells ’05 Daltep/Tinzap DVT/PE 505
Wells PS, Kovacs MJ, Bormanis J, Wells PS, Kovacs MJ, Bormanis J, Forgie MA, Goudie D, Morrow B, Forgie MA, Goudie D, Morrow B,
Kovacs JKovacs J
Wells PS, Kovacs MJ, Bormanis J, Wells PS, Kovacs MJ, Bormanis J, Forgie MA, Goudie D, Morrow B, Forgie MA, Goudie D, Morrow B,
Kovacs JKovacs J
Expanding eligibility for outpatient treatment of deep venous thrombosis
and pulmonary embolism with low-molecular-weight heparin
Arch Intern Med 1998
Study designStudy designStudy designStudy design
Prospective long-term evaluation of a wide series of patients with a broad spectrum of venous thromboembolic presentations treated at home with dalteparin (200 U/Kg every 24 hours) for a minimum of 5 days
Patients treated at homePatients treated at homePatients treated at homePatients treated at home
Patients consideredPatients considered 233233 Patients excluded 3939 - concomitant med. problems: 20 - massive pulmonary embolism 6 - cost considerations 6 - active bleeding 4 - phlegmasia coerulea dolens 3 Patients treated on a home basisPatients treated on a home basis 194194
Features of home treated patients Features of home treated patients Features of home treated patients Features of home treated patients
Characteristics Homecare Self-injection (N=95) (N=99)
Mean age 63.5 + 16 63.1 + 17Proximal DVT 77 77Pulmonary embolism 16 18Arm DVT 2 4Idiopathic 28 32Cancer 32 29Previous DVT 14 15DVT due to risk factors 21 23
Prospective 3-month evaluationProspective 3-month evaluationof clinical outcomes of clinical outcomes
Prospective 3-month evaluationProspective 3-month evaluationof clinical outcomes of clinical outcomes
EventsEvents Homecare Homecare Self-injection Self-injection (N=95) (N=99)
Recurrent VTERecurrent VTE 3 (3.2%) 4 (4.0%)
Major bleedingMajor bleeding 2 (2.1%) 2 (2.0%)
MortalityMortality* 6 (6.3%) 8 (8.0%)
* * due to cancer in 11 patientsdue to cancer in 11 patients
ConclusionsConclusionsConclusionsConclusions
More than 80% of patients with acute venous thromboembolism can be treated at home with a low-molecular-weight heparin
Patients can safely and effectively perform self-injection of the anticoagulant drug
Treatment of Pulmonary
Embolism
NEJM 1997: COLUMBUS and NEJM 1997: COLUMBUS and THESEE studies. Main resultsTHESEE studies. Main resultsNEJM 1997: COLUMBUS and NEJM 1997: COLUMBUS and THESEE studies. Main resultsTHESEE studies. Main results
COLUMBUS THESEE
LMWH UFH LMWH UFH
(n=510) (n=511) (n=304) (n=308)
Recurrent VTERecurrent VTE 27 (5.3%) 25 (4.9%) 5 (1.6%) 6 (1.9%)
Major bleedingMajor bleeding 16 (3.1%) 12 (2.3%) 6 (2.0%) 8 (2.6%)
MortalityMortality 36 (7.1%) 39 (7.6%) 12 (3.9%) 14 (4.5%)
Ann Intern Med 2004; 140: 175-83
Low-molecular-weight heparin compared Low-molecular-weight heparin compared with intravenous unfractionated heparin for with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-treatment of pulmonary embolism: a meta-analysis of randomized, controlled trialsanalysis of randomized, controlled trials
Quinlan DJ, McQuillan A, Eikelboom JW
Recurrent VTE in patients with symptomatic PE
Short- and Long-term Outcome of Short- and Long-term Outcome of Patients with PEPatients with PE
Konstantinides S et al. Circulation 1997;96:882–8Goldhaber SZ et al. Lancet 1999;353:1386–9Ribeiro A et al. Circulation 1999;10:1325–30
Grifoni S et al. Circulation 2000;101:2817–22Pengo V et al. N Engl J Med 2004; 350: 2257-64
Konstantinides S et al. N Engl J Med 2002;347:1143–50
Heparin Plus Alteplase Heparin Plus Alteplase Compared with Heparin Alone Compared with Heparin Alone in Patients with Submassive in Patients with Submassive
Pulmonary EmbolismPulmonary Embolism
• Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W
UFH plus alteplase (nUFH plus alteplase (n==118)118)
UFH alone (nUFH alone (n==137)137)
Event = in-hospital death or clinical deterioration
requiring an escalation of treatment
70
80
90
100
5 10 15 20 25 30
Pro
bab
ilit
y o
f even
t-fr
ee s
urv
ival
(%)
Days
Cumulative ProbabilityCumulative Probabilityof Event-free Survivalof Event-free Survival
Konstantidines S et al. N Engl J Med 2002;347:1143–50
HIT and Osteoporosis HIT and Osteoporosis
Reduction of HIT and osteoporosis?Reduction of HIT and osteoporosis?Reduction of HIT and osteoporosis?Reduction of HIT and osteoporosis?
• Likely but not conclusively demonstratedLikely but not conclusively demonstrated
• At least in medical patients, the rate of LMWH-related HIT is At least in medical patients, the rate of LMWH-related HIT is
not negligible not negligible (0.80%, Prandoni et al, Blood 2005) (0.80%, Prandoni et al, Blood 2005)
• In patients requiring the long-term administration of heparin, In patients requiring the long-term administration of heparin,
the use of UFH is associated with a higher rate of bone the use of UFH is associated with a higher rate of bone
fractures than LMWHfractures than LMWH (Monreal et al, Thromb Haemost 1994) (Monreal et al, Thromb Haemost 1994)
Potential benefit of LMWHs on Potential benefit of LMWHs on survival in cancer patientssurvival in cancer patients
LMWH UFH
(n=85) (n=85)
Generation of the hypothesisGeneration of the hypothesis(Prandoni et al, Lancet 1992)(Prandoni et al, Lancet 1992)
6-month mortality 5 (5.9%)9 (10.6%)
Cancer-related mortality1/15 (6.7%)8/18 (44.4%)
… although this is a post-hoc finding, it is interesting that 44% of the cancer patients in the standard heparin group died, compared with only 7% of cancer patients in the LMWH group. This difference is statistically unusual (p=0.021) if these treatments had no effect on the likelihood of succumbing to cancer …
Prandoni et al, Lancet 1992
Author Year No. of studies
Cancer mortality OR
UFH LMWH
Green 1992 2 7/62 (11%) 21/67 (31%) 0.28
Siragusa 1995 13 10/74 (14%) 23/81 (28%) 0.39
Hettiarachchi 1999 9 47/306 (15%) 71/323 (22%) 0.61
Gould 1999 11 22/132 (17%) 38/147 (26%) 0.57
Meta-analyses of DVT treatment studiesMeta-analyses of DVT treatment studiesMeta-analyses of DVT treatment studiesMeta-analyses of DVT treatment studies
Clinical trials addressing the value of Clinical trials addressing the value of LMWH on cancer survivalLMWH on cancer survival
• FAMOUS (J Clin Oncol 2004)
• MALT (J Clin Oncol 2005)
• CLOT 2 (J Clin Oncol 2005)
• TURKISH STUDY (J Thromb Haemost 2004)
Persisting indications for UFH in the Persisting indications for UFH in the treatment of patients with VTEtreatment of patients with VTE
• Renal insufficiency
• Relative contraindications to heparin
• Suspicion of PE in patients with critical
presentation
The Potential of New Drugs
Factor Xa
AT
ArgArgLys
PentasaccharidePentasaccharide
Factor Xa, Factor Xa, the only the only targettarget
Pentasaccharides Pentasaccharides
AT
I SS
E
M .
... . .
.
Fondaparinux in Comparison Fondaparinux in Comparison to (Low Molecular Weight) to (Low Molecular Weight)
Heparin for the Initial Heparin for the Initial Treatment of Patients with Treatment of Patients with Symptomatic Deep Venous Symptomatic Deep Venous Thrombosis or Pulmonary Thrombosis or Pulmonary
EmbolismEmbolism
• The Matisse studies
The Matisse Investigators. Blood 2002;100:A302
Fondaparinux (n=1098) LMWH (n=1107)Matisse DVT
Fatal PE 5 (0.5%) 5 (0.5%)
Non-fatal PE or DVT 38 (3.5%) 40 (3.6%)
Total symptomatic recurrent VTE 43 (3.9%) 45 (4.1%)
-0.15 %
= 3.5%0 1.5% -1.8%
Fondaparinux - LMWH (95% CI )
Fondaparinux (n=1103) UFH (n=1110)
Fondaparinux - UFH (95% CI )
Matisse PE
-1.2%
= 3.5%0 0.5% -3.0%
Fatal PE 16 (1.5%) 15 (1.4%)
Non-fatal PE or DVT 26 (2.4%) 41 (3.6%)
Total symptomatic recurrent VTE 42 (3.8%) 56 (5.0%)
AT
I S SE
M ... .
. .. Matisse: Primary EfficacyMatisse: Primary Efficacy
Outcome at 3 MonthsOutcome at 3 Months
The Matisse Investigators. Blood 2002;100:A302
Matisse DVT
3.7%
4.2%
Matisse PE4.5%
6.3%
AT
I S SE
M ... .
. ..
Major bleed Clinically relevant non-major bleed
Matisse: Principal SafetyMatisse: Principal SafetyOutcome: Initial TreatmentOutcome: Initial Treatment
Fondaparinux
LMWH
Fondaparinux
UFH
The Matisse Investigators. Blood 2002;100:A302
O O
O O
O O
O
OH
OH
COO-
O
OSO3-
OH
HNSO3-
HO O
O
OSO3-
OSO3-
HNSO3-
O
O
OH
OSO3-
COO-
O
OSO3-
OSO3-
HNSO3-
O
O
OH
OSO3-
COO-
OOSO3
-
OSO3-
OCH3
HNSO3-
O
OH
OH
COO-
O
OSO3-
OH
HNSO3-
HO O
O
OCH3
OCH3
COO-
O
OSO3-
OCH3
OSO3-
H3CO O
O
OSO3-
OSO3-
OSO3-
O
O
OCH3
OSO3-
COO-
OOSO3
-
OSO3-
OCH3
OSO3-
OOSO3
-
OHOCH3
HNSO3-
Fondaparinux (Fondaparinux (ArixtraArixtra® ® ))MOST LIKE NATURALMOST LIKE NATURALOnce-a-dayOnce-a-day
Org31550Org31550MORE POTENTMORE POTENTA new binding site discoveredA new binding site discovered
Idraparinux,Idraparinux, SanOrg34006 SanOrg34006 SIMPLIFIEDSIMPLIFIEDOnce-a-weekOnce-a-week
PentasaccharidesPentasaccharidestailor madetailor made
OCH3OCH3
0
5
10
15
2.5 mg 5 mg 7.5 mg 10 mg Warfarin
Idraparinux
Inci
den
ce (
%)
Asymptomatic + symptomatic VTE + unexplained death
Overall dose trend P=0.062
2/128
3/119
2/124
PERSIST: Thrombotic Burden: PERSIST: Thrombotic Burden: Deterioration (ITT Population)Deterioration (ITT Population)
7.3
12.6
6.86.34.8
Persist Investigators. Blood 2002;100:A301ITT = intent to treat
0
24
6
8
1012
14
16
2.5
mg
5 m
g
7.5
mg
10 m
g
War
farin
2.5
mg
5 m
g
7.5
mg
10 m
g
War
farin
Inci
dence
(%
)
Major bleeding Any bleeding
Idraparinux Idraparinux
PERSIST: Bleeding Events PERSIST: Bleeding Events
Persist Investigators. Blood 2002;100:A301
0.0
3.01.5
6.9
0.82.3
11.9
13.8
15.3
8.3
VAN GOGH DVT VAN GOGH PE
IDR VS ENOXAPARIN OR UFH FOLLOWED BY VKAIDR VS ENOXAPARIN OR UFH FOLLOWED BY VKA
IDRAPARINUX IN THE TREATMENT OF VTE
Phase III studies
ConclusionsConclusions• Home treatment of DVT with LMWH is feasible, safe and
cost-effective for selected patients• Patients with acute PE and right-ventricular dysfunction
might benefit from a combination of heparin and thrombolytic drugs to a greater extent than from heparin alone
• LMWH is more effective than oral anticoagulants for prevention of recurrent VTE in cancer patients
• Among the categories of emerging new compounds, for the time being only fondaparinux is an alternative to conventional anticoagulation, but can only be used for the initial VTE treatment
RE-COVER I1
RE-COVER II2
EINSTEIN-DVT3
EINSTEIN-PE4
AMPLIFY5 Hokusai-VTE6
Study drug Dabigatran Rivaroxaban Apixaban Edoxaban
Study design* Double-blind Open-label Double-blind Double-blind
Pre-randomization heparin
NR <48 hrs <36 hrs <48 hrs
Heparin lead-in At least 5 days None None At least 5 days
Dose 150 mg BID 15 mg BID x 3 wk then 20 mg
QD
10 mg BID x 7 d then 5 mg BID
60 mg QD30 mg QD†
Dose reduction NONE NONE NONE 18%
Randomized population
2,5641
2,5682
3,4493
4,8334
5,400 8,292
Treatment duration
6 months Pre-specified 3, 6, 12 months
6 months Flexible 3 to 12 months
1. Schulman et al. N Engl J Med 2009;361:2342–2352; 2. Schulman et al. Blood 2011;118:Abstract 2053. EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 4. EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–1297
5. Agnelli et al. N Engl J Med 2013. doi:10.1056/NEJMoa.1302507; 6. The Hokusai-VTE Investigators. N Engl J Med 2013
VTE treatment: study designs
*Comparator was warfarin in each case†Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding by predefined criteriaNR=not reported
