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).