Treatment of Venous Thrombosis and Pulmonary Embolism.ppt

OBJECTIVES

Treatment of Venous Thrombosis and Treatment of Venous Thrombosis and Pulmonary Embolism Pulmonary Embolism

• Prevent death from PE

• Prevent post-thrombotic syndrome

• Prevent recurrent venous thromboembolism (VTE)

• Achieve these objectives with minimal side effects and inconvenience

Treatment of VTETreatment of VTE

• Anticoagulants

• Thrombolytic therapy

• Caval interruption

• Surgical removal

AnticoagulantsAnticoagulants• Initial treatment with heparin is necessary.• Induction period with heparin therapy can be

reduced to 5 days.• Treatment following hospital discharge is necessary.• LMWH is a major advance.• Optimal therapeutic range with warfarin established.• Optimal duration of warfarin therapy still to be established.• New oral small-molecule direct thrombin inhibitor.*

* Does not have FDA approval for any indication.

Thrombolytic TherapyThrombolytic Therapy

• Not often indicated in venous thrombosis

• Useful in major PE

• Possible new indication in PE

Caval FilterCaval Filter

• A single randomized trial has defined advantages and drawbacks of caval filters. The results indicate that inferior venacaval filters:

a) Prevent recurrent PE in short term

b) Increase the risk of recurrent deep venousthrombosis (DVT) in the long term

SurgerySurgery

• Endarterectomy for chronic thromboembolic pulmonary hypertension can be life saving.

• Venous surgery is rarely indicated.

• Venous stenting combined with catheter-directed thrombolytic therapy is being used in some centers to treat patients with iliofemoral venous thrombosis and severe obstruction.

AnticoagulantsAnticoagulants

• Heparin

• Vitamin K antagonists (warfarin)

• LMWH

• Danaparoid*

• Hirudin*

• Pentasaccharide*

• Oral small-molecule direct thrombin inhibitor**Danaparoid is not approved by the FDA for use in the treatment of thrombosis or HIT. Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.

Oral: Multiple clinical trials Small molecule DTI†*

Injection: Phase 3Pentasaccharide*

InjectionHirudin*

InjectionDanaparoid*

OralWarfarin

InjectionLMWH

Injection Heparin

*Danaparoid is not approved by the FDA for use in the treatment of thrombosis or HIT. Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.

†DTI=direct thrombin inhibitor

AnticoagulantsAnticoagulants

TF VII

IX

XaX

IXa

a

II Va

IIa

VIIIa

FIBRINOGEN FIBRIN

Coagulation CascadeCoagulation Cascade

TF VII

IX

XaX

IXa

a

II Va

IIa

VIIIa

FIBRINOGEN FIBRIN

WARF

WARF

WARF

WARF

UFH, LMWHUFH, LMWH

UFH, LMWH

Established AnticoagulantsEstablished Anticoagulants

TF VIIa

IX

XaX

IXa

II Va

IIa

VIIIa

FIBRINOGEN FIBRIN

New AnticoagulantsNew Anticoagulants

PENTASAC*HIRUDIN*

ORAL SMALL- MOLECULE DTI †*

†

* Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT. Pentasaccharide and the new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.

† DTI=direct thrombin inhibitor

New Anticoagulants for Treatment of DVTNew Anticoagulants for Treatment of DVT

• Hirudin* (recombinant; lepirudin) is effective for treating thrombosis associated with HIT.

• The new oral small-molecule direct thrombin inhibitor* appears promising in multiple clinical trials.

• Pentasaccharide* has been evaluated in phase 2 studies and is being tested in phase 3 studies.

* Natural hirudin is not approved by the FDA for any indication; recombinant hirudin (lepirudin) is approved for the treatment of thrombosis associated with HIT.The new oral small-molecule direct thrombin inhibitor do not have FDA approval for any indication.

• Initial treatment with heparin is necessary.• Induction period with heparin therapy can be

reduced to 5 days. • LMWH can replace heparin and is now treatment

of choice.• Continued treatment following hospital discharge

is necessary.• Optimal therapeutic range with warfarin is an INR

of 2.0 to 3.0.• Optimal duration of warfarin therapy still to

be established.

Established AnticoagulantsEstablished Anticoagulants

Initial Treatment With Heparin Necessary Initial Treatment With Heparin Necessary in Treating Proximal Vein Thrombosisin Treating Proximal Vein Thrombosis

ConfirmedSymptomaticRecurrence

Positive

Negative

Total

Placebo and Acenocoumarol

12

48

60

Heparin and Acenocoumarol

4

56

60

Group Total

16

104

120

P = 0.058

Data from Brandjes et al, 1992

Confirmed Symptomatic Recurrence and/or Confirmed Symptomatic Recurrence and/or Venographic Evidence of Significant Extension Venographic Evidence of Significant Extension

and/or New High-Probability V/Q Scanand/or New High-Probability V/Q Scan

Positive

Negative

Total

Placebo and Acenocoumarol

28

25

53

Heparin and Acenocoumarol

7

42

49

Group Total

35

67

102

P < 0.001

Data from Brandjes et al, 1992

Event

Induction Period With Heparin Induction Period With Heparin Can Be Reduced to 5 DaysCan Be Reduced to 5 Days

Recurrent VTE

During heparin

During warfarin

Total duringtreatment

Short(4 days)

3.6%

3.3%

6.9%

Long(9.5 days)

4.7%

1.6%

6.3%

Short(5 days)

0%

7.1%

7.1%

Long(10 days)

0%

7.0%

7.0%

Gallus 1986 (266 pts) Hull 1990 (199 pts)

Treatment Following Hospital Treatment Following Hospital Discharge NecessaryDischarge Necessary

Author RecurrentVTE (%)

Lagerstedt 0

29

VTE = venous thromboembolism; SC = subcutaneous

Initial Courseof Heparin

5 days

Long-TermTreatment

Hull 0

47

14 days Warfarinvs

SC heparin 5000twice daily

Warfarinvs

no treatment

Hull et al, 1979; Lagerstedt et al, 1985

LMWH: A Major AdvanceLMWH: A Major Advance• Weight-adjusted subcutaneous dosing predictable

(Handeland et al,1990; Bratt et al, 1990)• Mechanism of more predictable dose response

(Young et al, 1993, 1994)• Less osteopenia than UFH (Shaughnessy et al, 1995; Monreal et al,

1994)• Less HIT than UFH (Warkentin et al, 1995)• Once-daily subcutaneous dosing effective in DVT (Hull et al, 1992)• Outpatient treatment effective and safe (Levine et al, 1996; Koopman

et al, 1996)• Treatment of PE effective and safe (Columbus Investigators, 1997;

Simonneau et al, 1997)

Meta-AnalysisMeta-AnalysisLMWH vs Heparin for Treatment of DVTLMWH vs Heparin for Treatment of DVT

Primary Studies:

Duroux, 1991Hull, 1992Prandoni, 1992Lopaciuk, 1992

Levine, 1996Koopman, 1996Fiessinger, 1996Luomanmaki, 1996Columbus, 1997

All studies (fixed-effect model)

Simonneau, 1993Lindmarker, 1994

Gould et al, 1999

Recurrent Thromboembolism(n=3566)

OR 0.85(P=0.28)

0.01 0.1 1 10 100FavorsLMWH

FavorsUFHOdds Ratio (OR)

Efficacy and Safety of Two Trials Using Efficacy and Safety of Two Trials Using Outpatient LMWHOutpatient LMWH

Study

Levine

Koopman

Treatment

UFH

UFH

LMWH

LMWH

Number

253

198

247

202

RecurrentVTE

6.7%

8.6%

5.3%

6.9%

MajorBleeding

1.2%

2.0%

2.0%

0.5%

Hospital

6.5

Days in

1.1

8.12.7

Levine et al, 1996; Koopman et al, 1996

A Comparison of LMWH (Tinzaparin) A Comparison of LMWH (Tinzaparin) With UFH for the Treatment of Acute PEWith UFH for the Treatment of Acute PE

Outcome Event IV Heparin SC LMWH 175 U/kg QD

Simonneau et al, 1997

Days 1–8 3 414 (4.5%) 12 (3.9%)

Death

Days 1–90

Days 1– 8 2 36 (1.9%) 5 (1.6%)

Recurrent TE

Days 1–90

Days 1–8 5 38 (2.6%) 6 (2.0%)

Major bleeding

Days 1–90

Days 1–8 9 (2.8%) 9 (3.0%)22 (7.1%) 18 (5.9%)

Composite

Days 1–90

n = 308 n = 304

IV=intravenous; SC=subcutaneous; QD=once daily; TE=thrombotic events

Harrison et al, 1998

Treatment of DVT in PracticeTreatment of DVT in Practice• Two hospitals, 1 year• 113 consecutive patients referred to thrombosis units• 13 excluded (no local treatment [5], outpatient UFH [8])• 11 hospitalized

– Comorbid disease (4)– High risk of bleeding (3)– Pain control (1)– Inadequate home support (1)– Weekend admission (2)

• 89 received outpatient LMWH– 75% self-injected or had family member perform injections.

Harrison et al, 1998

OutcomesOutcomesRecurrent VTE 7% (6/89)• Fatal PE and bleed (1)• DVT (5); all had cancer

Major Bleeding 2% (2/89)• Fatal bleed and PE (1)• Arm bleed: hospitalized

Patient Satisfaction Very: 91% (75/82)

• Dosing in obese patients and in renal insufficiency

• Dosing in pregnancy

• Protamine reversal

• Interchangeability of different preparations

LMWH: Outstanding QuestionsLMWH: Outstanding Questions

Trial of Intensive versus Less Intensive Trial of Intensive versus Less Intensive Warfarin Therapy (3 Months)Warfarin Therapy (3 Months)

Regimen

INR 3.0–4.0

INR 2.0–3.0

Frequency ofRecurrent VTE

2%

2%

Frequency ofBleeding

Complications

22%

4%

Hull et al, 1982

Warfarin

StudyNo. of

Patients

%AnnualizedRecurrence

No. ofPatients


Prandoni et al, 1996 145 19 105 4

BTS, 1992 596 13 116 3

Hirsh, 1995 117 15 70 1

Levine et al, 1995 212 16 89 0

Schulman et al, 1995 553 9 344 3.5

IDIOPATHIC DVT* POSTOP DVT

* Idiopathic and continuing risk factorsBTS = British Thoracic Society

Risk Factors for RecurrenceRisk Factors for Recurrence

Study

Schulman et al, 1995

Rate of Recurrence After DiscontinuingRate of Recurrence After DiscontinuingAnticoagulants in PatientsAnticoagulants in Patients

With Idiopathic ThrombosisWith Idiopathic Thrombosis

Kearon et al, 1999

Months ofObservation

24

10

No. ofPatients

553

83


9

27

Recurrent VTE

Major bleeding

Warfarin versus Placebo After Initial Warfarin versus Placebo After Initial 3 Months of Warfarin Therapy for 3 Months of Warfarin Therapy for

First Idiopathic VTEFirst Idiopathic VTE

Placebo(n=83)

17 (27%/patient-year)

0 (0%/patient-year)

Warfarin(n=79)

1 (1.3%/patient-year)

3 (3.8%/patient-year)

Prespecified interim efficacy analysis led to termination afteran average of 10 months.

Kearon et al, 1999

Risk Factors for Recurrence in Patients Risk Factors for Recurrence in Patients With Idiopathic VTE Treated With With Idiopathic VTE Treated With

Warfarin for 3 MonthsWarfarin for 3 Months

All patients

Antiphospholipidantibody

Factor V Leiden

Prothrombinmutation

Hazard Ratio

4.0(1.2–13)

0.5

2.2

Kearon et al, 1999

No Recurrence

49/66 (74)

2/61 (3)

17/59 (29)

2/59 (3)

No./Total No. (%)Recurrent VTE

17/66 (26)

4/16 (25)

3/16 (19)

1/16 (6)

No./Total No. (%)

Major and Fatal Bleeding DuringMajor and Fatal Bleeding DuringOral AnticoagulationOral Anticoagulation

• Finn et al, 1993

• 1% cumulative incidence of fatal bleeding at 1 year and 2% at 3 years

• Palareti et al, 1996

• 1.1% major bleeds/100 patient-years

• 0.25% fatal bleeds/100 patient-years

• Schulman et al, 1997

• 2.7% major hemorrhage in 6-month group compared with 8.6% in the indefinite treatment group

• Kearon et al, 1999

• 3.8% per patient-year incidence of major bleed in patients on therapy for 3 months

Low RiskModerate RiskHigh Risk

MI = myocardial infarction; DM = diabetes mellitus

Risk of BleedingRisk of Bleeding

Major Bleeding

2%5%

23%

3%12%48%

3 Months 12 Months(0)

(1 or 2)(3 or 4)

Age 65 yearsStroke in pastGastrointestinal bleeding in pastMI, anemia (Hct <30%), renal failure (Cr >1.5 mg/dL), or DM

Beyth et al, 1998

No. Risk Factors

Risk of Major Bleeding During Warfarin Risk of Major Bleeding During Warfarin AnticoagulationAnticoagulation

• < 65 years of age with no other risk factors:3%

65 years of age with multiple risk factors:42%

820 Patients Followed for 1 Year 820 Patients Followed for 1 Year

Beyth et al, 1998

Fatality Rates With Recurrent VTE Fatality Rates With Recurrent VTE and With Bleedingand With Bleeding

• 5% to 7% of recurrent PE events are fatal (Douketis et al, 1998).

• 20% of major bleeding events are fatal (Schulman et al, 1997; Palareti et al, 1996).

• Nonfatal recurrent VTE more serious than nonfatal major bleeding.

Duration of AnticoagulationDuration of Anticoagulation• VTE recurrences occur at a rate of 10%–25% in the first year

anticoagulants are discontinued. (Schulman 1995, Kearon 1998)

• Risk of recurrent VTE decreases over time, but risk of bleeding increases.

8.6%2.7%Major hemorrhage

2.6%20.7%Rate of VTE recurrence

Indefinite Treatment

6 Months of Therapy

Schulman 1997

Optimal Duration of Anticoagulant Therapy Optimal Duration of Anticoagulant Therapy for Symptomatic Venous Thrombosis: for Symptomatic Venous Thrombosis:

RecommendationsRecommendations

Indication Duration

Proximal thrombosis: reversible cause

Idiopathic proximal vein thrombosis

Idiopathic calf-vein thrombosis

Calf-vein thrombosis: reversible cause

3 to 6 months

6 months to >1 year

6 months to 1 year

6 weeks to 3 months

Factors That May Influence Duration Factors That May Influence Duration of Oral Anticoagulationof Oral Anticoagulation

Shorter Course• Bleeding risk• Unstable anticoagulant

response• Inconvenient anticoagulation• Fear of recurrence or

bleeding

Longer Course• VTE presentation (eg,

massive PE)• Poor cardiopulmonary

reserve• Severe post-thrombotic

syndrome• Thrombophilia• Recurrent VTE

Potential Indications for Indefinite Potential Indications for Indefinite Anticoagulant TherapyAnticoagulant Therapy

• Inherited thrombophilia: AT, protein C and S deficiency not factor V Leiden or prothrombin mutation

• Antiphospholipid syndrome

• Recurrent idiopathic VTE

• Malignancy

• Thromboembolic pulmonary hypertensionAT = antithrombin

Oral Small-Molecule Oral Small-Molecule Direct Thrombin Inhibitor*Direct Thrombin Inhibitor*

• Direct comparison with warfarin currently in progress

• If oral small-molecule direct thrombin inhibitor is as effective as warfarin, the advantages will be as follows:

– No monitoring

– Fewer drug interactions

* The new oral small-molecule direct thrombin inhibitor does not have FDA approval for any indication.


DVT• Thrombolytic therapy achieves complete early lysis in

30% to 40% of cases (heparin 10%).

• Increases bleeding threefold.

• Probably reduces the incidence of post-thrombotic syndrome. However, risk of severe post-thrombotic syndrome about 10% with adequate anticoagulation.

• Catheter-directed thrombolysis with administration into thrombus claimed to be more effective, but further study is required.


PE• Two-hour high-dose t-PA or urokinase effective.

• Improves resolution at 24 hours but not at 7 days.

• Role in massive embolism accepted.

• Role in submassive, major embolism controversial.

Thrombolysis(n=188)

38%

Thrombolysis for DVTThrombolysis for DVT

45% 13%

No Change Marked LysisMajor

Bleeding

Hirsh et al, 1996

• Pooled analysis of eight randomized trials

Repeat Venography

Heparin(n=144)

78% 10% 3.5%

Thrombolysis 12%

Thrombolysis for PEThrombolysis for PE

30% 58%

2 hours 1 day 1 month

Dalen et al, 1997

Improvement of Perfusion

Heparin 0% 10% 60%

45%

1 week

40%

• Accelerates resolution• No effect on extent of resolution• No effect on frequency of recurrence

Classification of Acute PEClassification of Acute PE

• Massive PE with shock or syncope

• Major PE with right-ventricular dysfunction

• Major PE with normal right-ventricular function

• Minor PE

Goldhaber, 1999Nass et al, 1999

Recommended Treatment of Acute PERecommended Treatment of Acute PE

• Massive PE with shock or syncope– Thrombolysis or surgery

• Major PE with right-ventricular dysfunction– Anticoagulants (Dalen)– Thrombolysis (Goldhaber)

• Major PE without right-ventricular dysfunction– Anticoagulants

• Minor PE– Anticoagulants

Hyers et al, 1998Goldhaber, 1999Goldhaber, 1998

Dalen et al, 1997Nass et al, 1999

Thrombolysis for Massive PEThrombolysis for Massive PE

Heparin (10,000 U bolus + 1000 U/hr IV) versus streptokinase (1.5 million U IV over 60 min) + heparin

Patients (8)• Cardiogenic shock; HR 124; Pa02 46 (4/4 heparin patients had already deteriorated on heparin)

Heparin Streptokinase + HeparinMortality 4/4 0/4

Jerjes-Sanchez et al, 1995

Randomized Trial of Alteplase versus Randomized Trial of Alteplase versus Heparin in Normotensive Patients Heparin in Normotensive Patients

With Acute PEWith Acute PE

Recurrent PE

Death

Heparin(n=55)

5 (9%)

Alteplase(n=46)

0

P

0.06

All events occurred in patients with right-ventricular dysfunction.

2 (3.6%) 0

Goldhaber et al, 1993

Management Strategy and Prognosis Management Strategy and Prognosis for Pulmonary Embolism (MAPPET)for Pulmonary Embolism (MAPPET)

Konstantinides et al, 1997

• 719 patients without cardiogenic shock

• 169 received thrombolytic therapy:30-day mortality 4.7%; recurrent PE 7.7%; major bleeding 21.9%

• 550 received heparin:30-day mortality 11.1%; recurrent PE 18.7%; major bleeding 7.8%

Heparin or Thrombolysis in Heparin or Thrombolysis in Hemodynamically Stable Major Acute Hemodynamically Stable Major Acute PE With Right-Ventricular DysfunctionPE With Right-Ventricular Dysfunction

PE recurrence %

Bleeding %SevereIntracranial

Death %

Thrombolysis(n=64)

15.6

4.7

Heparin(n=64)

0

0

P

0.001

0.24

128 consecutive patients (matched but not randomized) between 1992 and 1997

Hamel et al, 1998

9.4 0 0.028

6.25 0 0.12

4.7 4.7 1.0

Pulmonary EmbolectomyPulmonary Embolectomy

• Can be life saving in patients with massive PE.

• In consecutive series of 96 patients, mortality was 37% (Meyer et al, 1991).

• Cardiac arrest and associated cardiopulmonary disease were independent predictors of death.

• Elective pulmonary embolectomy was life saving in selected patients with chronic thromboembolic pulmonary hypertension (Moser et al, 1990).

Randomized Trial of Caval InterruptionRandomized Trial of Caval Interruption

• Initial benefit in preventing PE offset by excess of recurrent DVT in the longer term in the absence of anticoagulant.

• Therefore, caval filter not recommended for this patient population in the long term.

Decousus et al, 1998

Evaluation of Inferior Venacaval Filter in Evaluation of Inferior Venacaval Filter in Patients With Proximal Venous ThrombosisPatients With Proximal Venous Thrombosis

Symptomatic PE at day 12Total PE at day 12

Recurrent DVT at 2 years

IVC Filter

2

37 (20.8%)

No Filter

5

21 (11.6%)†

2 (1.1%)

9 (4.8%)*

All patients received 3 months of anticoagulants; primary end-point data unavailable for 28 patients.

*P=0.03 †P=0.02

Decousus et al, 1998

Treatment of VTETreatment of VTE

• Anticoagulants

• Thrombolytic Therapy

• Caval Interruption

• Surgical Removal

Issues for Future ResearchIssues for Future Research

• Optimal duration of anticoagulant therapy

• Lower therapeutic range for warfarin

• Relative efficacy and safety of new oral small-molecule direct thrombin inhibitor* versus warfarin

• Role of thrombolytic therapy for treatment of DVT and PE

* The new oral small-molecule direct thrombin inhibitor does not have FDA approval for any indication.

Documents

Treatment of Venous Thrombosis and Pulmonary Embolism.ppt