Acute Iliofemoral DVT

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Acute Iliofemoral DVT

Medical Management of

Acute Iliofemoral DVT

Thomas L. Ortel, M.D., Ph.D.

Duke University Medical Center

10 December 2010


Disclosures

• Grant support: NIH, CDC, Eisai, Pfizer,

GlaxoSmithKline, Trinity, IL.

• Consulting positions: Sanofi, PhytoChem,

Thoratec.

• No other disclosures.

• Off-label medication use: none.


Great Debates


Great Debates


Great Debates


Great (Debacles) Debates


Great Debates


Medical vs. endovascular

management of iliofemoral thrombosis


Audience Response


Medical Management of

Acute Iliofemoral DVT

• Anticoagulant therapy: Heparin/LMWH with

warfarin.


Anticoagulation vs. No

Anticoagulation for Acute PE

• Patients with clinical diagnosis of PE

randomized to receive either IV heparin with

nicoumalone to prolong PT to 2-3 times normal

for 14 days vs. „routine care‟.

• 35 patients enrolled between March 1957 and

April 1958, at which time it “…became

necessary to review the further conduct of the

trial”.

Barrett & Jordan, Lancet, 1960; 1: 1309-12.


Anticoagulants vs. No Anticoagulants

Group Total

Deaths from

recurrent PE

Non-fatal

recurrences

Other

deaths

Untreated 19 5 5 0

Treated 16 0 0 1

Barrett & Jordan, Lancet, 1960; 1: 1309-12.


ACCP Guidelines: Initial DVT Therapy

1.1.1 For patients with objectively confirmed DVT,

we recommend short-term treatment with

SC LMWH (Grade 1A), IV UFH (Grade 1A),

monitored SC UFH (Grade 1A), fixed-dose

SC UFH (Grade 1A), or SC fondaparinux

(Grade 1A) rather than no such short-term

treatment.

Kearon, et al., Chest, 2008; 133: 454S-545S.


ACCP Guidelines: Initial DVT Therapy

1.1.3 In patients with acute DVT, we recommend

initial treatment with LMWH, UFH, or

fondaparinux for at least 5 days and until

the INR is ≥ 2.0 for 24 h (Grade 1C).

1.4.1 In patients with acute DVT, we recommend

initial treatment with LMWH SC once or

twice daily, as an outpatient if possible

(Grade 1C), or as an inpatient if necessary

(Grade 1A), rather than treatment with UFH.

Kearon, et al., Chest, 2008; 133: 454S-545S.


ACCP Guidelines: Warfarin Therapy

1.1.4 In patients with acute DVT, we recommend

initiation of VKA together with LMWH, UFH,

or fondaparinux on the first treatment day

rather than delayed initiation of VKA (Grade

1A).

2.2.1 In patients with DVT, we recommend that

the dose of VKA be adjusted to maintain a

target INR of 2.5 (range, 2.0-3.0) for all

treatment durations (Grade 1A).

Kearon, et al., Chest, 2008; 133: 454S-545S.


Poor Management of Heparin

and Recurrent VTE

Frequency of Recurrent VTE

Treatment Group Subtherapeutic aPTT Therapeutic aPTT P-value

Subcutaneous

heparin

10/36 (27.8%) 1/21 (4.8%) 0.041

Intravenous heparin 3/17 (17.6%) 0/41 (0%) 0.022

All patients 13/53 (24.5%) 1/62 (1.6%)


Poor Management of Warfarin

and Recurrent VTE

• 297 patients with

unprovoked VTE monitored

during VKA therapy and 21

months after VKA stopped.

• Relative risk of recurrence

was higher for those

patients who spent the

most time with INR‟s < 1.5

(RR 2.77, 95% CI 1.49-

5.18; p=0.001).

Palareti G, et al. J Thromb Haemost, 2005; 3: 955-61.


Poor Management of Warfarin

and Postthrombotic Syndrome

• 244 patients with a first episode of DVT (location

not defined) treated with VKA for at least 3

months and with up to 4.9 yrs of follow-up.

• 81 patients (33%) developed postthrombotic

syndrome using Villalta scoring system.

• Those patients who had an INR < 2.0 for more

than 50% of the time had an increased risk to

develop PTS compared to patients with

therapeutic INR‟s (OR, 2.71; 95% CI, 1.44-5.10).

Van Dongen CJJ, et al. J Thromb Haemost, 2005; 3: 939-942.


Medical Management of

Acute Iliofemoral DVT

• Anticoagulant therapy: Heparin/LMWH with

warfarin.

• New anticoagulants: Dabigatran and

rivaroxaban.


Therapeutic Targets of

New Oral Anticoagulants

Gross PL & Weitz JI. Clin Pharm Therap 2009;86:139-146.


New Anticoagulants: Dabigatran

• 2564 patients randomized to

either warfarin or dabigatran.

• TTR for warfarin group: 60%

Schulman S, et al. N Engl J Med, 2009; 361: 2342-52.


New Anticoagulants: Rivaroxaban

• 3449 patients with DVT treated with rivaroxaban (n=1731)

or enoxaparin with a VKA (n=1718) for 3, 6, or 12 months.

• TTR for warfarin patients: 57.7%.

• Bleeding complications comparable for the two therapies.

Einstein Investigators. N Engl J Med, 2010; e-pub ahead of print.


Limitations of the New Anticoagulants

• Dabigatran and rivaroxaban are both primarily

cleared by the kidney.

• Medication compliance issues related to taking a

non-monitored drug.

• Inability to therapeutically reverse the

anticoagulant effect.

• Lack of laboratory tests to assess anticoagulant

effect.

• Cost.


Medical Management of

Acute Iliofemoral DVT

• Anticoagulant therapy: Heparin/LMWH with

warfarin.

• New anticoagulants: Dabigatran and

rivaroxaban.

• Postthrombotic syndrome.


Iliofemoral DVT

• Patients with iliofemoral DVT are the subset of

patients with the largest thrombus burden and

highest risk for post thrombotic morbidity.

• With standard anticoagulant therapy, four

studies* reported that:

– Up to 75% of patients have chronic painful edema.

– 40% have symptoms of venous claudication.

However, none of these studies reported on

quality or duration of anticoagulation!

*O‟Donnell 1977; Strandness 1983; Akesson 1990; Delis 2004 (summarized in Kearon 2008).


Determinants of

Postthrombotic Syndrome

• 387 patients with acute symptomatic DVT

recruited from 2001 to 2004.

• Patients evaluated at 1, 4, 8, 12, and 24 months

after initial event.

• Standardized assessments with Villalta scale

used to determine the post-phlebitic syndrome.

• Compression stocking use varied, and

anticoagulation effectiveness was unavailable.

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


Post-thrombotic Syndrome

• Proximal extent of DVT:

– Iliac vein, 14 (4%);

– CFV, 77 (20%);

– SFV, 79 (20%);

– Popliteal vein, 63 (16%).

• Distal DVT only, 154

(40%).

• Previous ipsilateral DVT,

40 (55%).

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


Predictors of

Post-thrombotic Syndrome

Variable Impact on Villalta Score P value

CFV or iliac vein DVT: 2.23 increase in score vs. distal DVT


Compression Stockings and PTS

• 180 consecutive patients

with first episode of

symptomatic DVT.

• Randomized to wear or not

wear below-knee compression

stockings (30-40

mmHg at ankle) for 2 years.

• 5 of 90 patients stopped

wearing stockings due to

itching and redness.

Prandoni P, et al., Ann Intern Med 2004; 141: 249-256.


Medical Management of

Acute Iliofemoral DVT

• Anticoagulant therapy: Heparin/LMWH with

warfarin.

• Anticoagulant therapy: Dabigatran and

rivaroxaban.

• Postthrombotic syndrome.

• Systemic thrombolytic therapy.


Systemic Thrombolytic Therapy

Variable Patients Studied Relative Risk*

Early PE 382 patients in 5 trials 1.2 (95% CI, 0.3-4.4)

Late, recurrent DVT: 35 patients in 1 trial 1.4 (95% CI, 0.4-5.4)

Postthrombotic morbidity 101 patients in 2 trials 0.7 (95% CI, 0.5-0.9)

Leg ulceration 101 patients in 2 trials 0.5 (95% CI, 0.1-2.4)

Early major bleeding 668 patients in 10 trials 1.7 (95% CI, 1.04-2.29)

Intracranial bleeding 701 patients in 5 trials 1.7 (95% CI, 0.2-14)

* Compared to standard anticoagulation alone

Kearon, et al., Chest, 2008; 133: 454S-545S.


ACCP Guidelines

1.10.1 In selected patients with extensive

proximal DVT (e.g., symptoms for


Medical Management of

Acute Iliofemoral DVT

• Anticoagulant therapy: Heparin/LMWH with

warfarin.

• Anticoagulant therapy: Dabigatran and

rivaroxaban.

• Postthrombotic syndrome.

• Systemic thrombolytic therapy.

• Catheter-directed thrombolytic therapy.


CaVenT Study

• Open, multicenter, prospective, randomized

study comparing conventional treatment for DVT

with catheter-directed therapy in addition to

conventional treatment.

• Inclusion criteria: (a) age 18 – 75 years; (b)

onset of symptoms < 21 days; (c) objectively

verified iliofemoral or proximal femoral DVT; and

(d) informed consent.

Enden, et al., J Thromb Haemost, 2009; 7: 1268-75.


CaVenT Study: Efficacy

Catheter-directed

thrombolysis

(N=50)

Standard

therapy (N=53)

P-value

Iliofemoral patency* 32 (64%) 19 (35.8%) 0.004

Functional venous

obstruction*

Femoral venous

insufficiency*

* After six months of therapy.

10 (20%) 26 (49.1%) 0.004

30 (60%) 35 (66%) 0.53

Enden, et al., J Thromb Haemost, 2009; 7: 1268-75.


CaVenT Study: Safety Outcomes

• Ten overt bleeding complications occurred in

relation to the CDT procedures.

– Two sustained major complications (one required

surgery for compartment syndrome).

– Two suffered clinically relevant, non-major bleeding.

• No bleeding complications in patients receiving

standard therapy.

• None of the patients sustained recurrent VTE,

and no data reported on PTS.

Enden, et al., J Thromb Haemost, 2009; 7: 1268-75.


ACCP Guidelines

1.9.1 In selected patients with extensive acute

proximal DVT (e.g., iliofemoral DVT,

symptoms for


ACCP Guidelines

1.9.3 We suggest pharmacomechanical

thrombolysis (e.g., with inclusion of

thrombus fragmentation and/or aspiration) in

preference to CDT alone to shorten

treatment time if appropriate expertise and

resources are available (Grade 2C).

Kearon, et al., Chest, 2008; 133: 454S-545S.


Conclusions

• Anticoagulant therapy prevents recurrent VTE in

patients with DVT, but many of these patients,

particularly those with iliofemoral DVT, will

develop postthrombotic syndrome.

• New anticoagulants provide alternative options

for treatment of DVT, but may not improve longterm

outcomes compared to warfarin.

• Prospective, randomized trials of thrombolytic

therapy are needed (e.g., the ATTRACT trial).

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