05 Wirzba Pharmacomechanical Tx

Rocky Mountain ACP Internal Medicine Conference
November 22, 2012
Brian Wirzba, MD, FRCPC, FACP
No financial disclosures or conflicts of interest
for this presentation
I have received honoraria for presentations and
advisory panel work in the area of osteoporosis
from Amgen, Eli Lilly and Norvartis in the last 2
By the end of this short snapper the audience will have:
 Have a better understanding of the current
pharmomechanical therapies (PMT) available for treatment
of large proximal DVTs.
 Be aware of the published data to support PMT for large
proximal DVTs (and the limitations of this data).
68 y.o. presented to the GNH ER with a 10d Hx of L leg
swelling and 2d of pain in the upper thigh.
 She had traveled to Portugal 1 month ago (12hr flight) followed by
transient bilateral leg swelling for 2d (resolved)
 No history of malignancy or symptoms of occult malignancy
 No family Hx of VTE, no other immobility or risks
 HRT age 55-57
 PHx – generally healthy, remote hysterectomy, normal yearly labs
Venous Doppler – extensive DVT in L Leg from calf to
pelvis in the L iliac vein
Patient started on LMWH and given 5mg Warfarin
Given clot into the pelvis a CT Abdomen/Pelvis was
 “Extensive thrombosis involving the entire L common and external
and internal iliac veins, associated edema and enlargment of the L
iliopsoas and piriformis muscles related to the obstruction. The
thrombus superiorly extends to the level of the aortic bifurcation
and May-Thurner syndrome is suspected. No neoplasm evident.”
Proximal DVT’s have generally been treated with
anticoagulation alone:
 Unfractionated or Low Molecular Weight Heparin (UFH/LMWH)
 Warfarin with a target INR 2-3 for 3-12 months
Early trials with systemic thrombolysis (primarily
Streptokinase) showed reduced thrombus but had a 3x
increase in bleed risk
Am J Med 1984;76:393-397
Trials have generally focused on Mortality, Hospitalization
and Bleeding, but what about Post-Phlebitic Syndrome?
PTS is thought to occur to some degree in 20-50% of
patients within 2 years of a DVT
Chest 2012;141:308-320
J Thromb Haemost. 2005;3:939-942
Ann Intern Med. 2008;149:698-707
In general after any lower extremity DVT:
  30-60% of patients have no residual symptoms
  30-50% will have some degree of PTS
  5-10% will have severe PTS
PTS usually develops within 6 months but can up to 2
years after the acute DVT.
15% of patients with upper extremity DVT develop PTS
Thrombosis Research 2006; 117:609-614
387 patients (347 seen at 4mo) with acute symptomatic
QOL Scores for patients with severe PTS are similar to
DVT in 8 Canadian hospitals treated with routine care
patients with Chronic Angina, Cancer and Severe CHF
Ann Intern Med 2008;149:698-707
Previous DVT (especially if ipsilateral 5-10x)
Signs of Post-Thrombotic Syndrome at 1 month (4x)
Extensive or More Proximal DVT (2x)
Obese (2x)
“may” be increased if inadequate initial
Older Age – not consistent
Female – not consistent
NOT influenced by cause of DVT, intensity or duration
of anticoagulation
 “Iliofemoral DVT patients have the largest thrombus burden
and up to 75% have chronic painful edema with 40% having
venous claudication when treated with anticoagulation
therapy alone.”
Eur J Vasc Surg 1990;4:43-48
Ann Surg 204;239:118-126
J Surg Res 1977;22:483-488
JAMA 1983;250:1289
Systemic Thrombolysis
Flow Directed Thrombolysis (Pedal IV infusion)
Surgical Interventions:
 Vein Dilatation and Stenting, Venous Bypass Grafting,
Endophlebectomy with reconstruction, Valve reconstruction &
transplant, interruption of perforating veins.
CDT – Catheter-directed Intrathrombus Thrombolysis
PMT – Percutaneous Mechanical Thrombectomy
PCDT – Pharmomechanical Catheter Directed
Anticoag alone is inadequate
Big clots lead to worse Sx
Early clot dissolution is good
CDT can remove clot
CDT provides fast relief of Sx
CDT uses less thrombolytic
CDT has fewer bleeding SE
Society of Interventional Radiology Position Statement:
 “The published literature suggests that adjunctive CDT plus
anticoagulant therapy is an acceptable initial treatment strategy for
many patients with acute iliofemoral DVT”
J Vasc Interv Radiol 2006;17:613-616
Hydrodynamic or Rheolytic thrombectomy catheter
Based on industrial technology
Multiple generations since 1992 introduction
Adjunctive CDT has been shown effective in:
 90% thrombolysis rate in patients with iliofemoral DVT
Vasc Interv Radiol 2006;17:435-448
Radiology 1999;211:39-49
 Reducing anaesthesia, incision issues, and prolonged recovery
(compared to surgical thrombectomy)
Eur J Vasc Surg 1990;4:483-489
Semin Vasc Surg 1996;9:34-45
In the National Venous Registry:
 Patients treated with short term thrombosis (<10 days) had better
outcomes than those with older clot
 Correction of underlying venous lesions after successful
thrombolysis (usually with intravascular stenting) appeared to be
Radiology 1999;211:39
Open label, RCT from Norway with 209 patients looking at
CDT vs. Anticoagulation alone over 2 years
Mean duration of CDT was 2.4 days (max 6d) with 43/90
having complete lysis, 37 having partial, and 10
unsuccessful lysis including 2 technical failures.
23 had angioplasty, 15 had venous stents, 1 had thrombus
aspiration and IVC filter (Angiojet)
20 had bleeding complications in CDT but only 3 major
and 5 clinically relevant. 4 had non-bleeding SE.
There was no difference in recurrent DVT, PE, Death
No direct comparisons b/w old and new
technologies but the rates of bleeding have
dropped by ½ (to about 4.8%) perhaps due to
better patient selection.
Only 22% of patients with PCDT need only 1 treatment
 Most need 2 or more treatments and infusion time
There is a reduced treatment time and tPA dose
 No decrease in LOS or ICU LOS
J Vasc Surg 2008;48:1532
Systemic Thrombolysis
Flow Directed ThrombolysisNOT
IV infusion)
Surgical Interventions: routine Anticoagulation in
 Vein Dilatation and Stenting, Venous Bypass
Endophlebectomy with reconstruction,
transplant, interruption of perforating veins.
CDT – Catheter-directed Intrathrombus Thrombolysis
Compression Stockings
PMT – Percutaneous Mechanical Thrombectomy
ARE recommended for all
PCDT – Pharmomechanical Catheter Directed
Acute Symptomatic Leg
DVT’s (Grade 2B)
ACCP 2012 Guidelines Section 2.9
 2.9 – In patients with Acute Proximal DVT of the leg, we
suggest anticoagulation therapy alone over catheter
directed thrombolysis (CDT) [Grade 2c]
 Remarks – Patients who are most likely to benefit from CDT,
who attach a high value to prevention of postthrombotic
syndrome (PTS), and a lower value to the initial complexity,
cost, and risk of bleeding with CDT, are likely to choose CDT
over anticoagulation alone.
Chest. 2012, 141(2), Supp p21
2-4d ICU
bleed risk
Moving an outpatient condition into
the inpatient world (again)
Phlegmasia cerulea dolens
Acute IVC thrombosis
Acute Iliofemoral DVT
Low bleeding risk
> 1 year life expectancy
 <70 year old age
Good Functional Status & Ambulatory
Does not have PTS already
Can tolerate procedure
Not pregnant
No Contraindication to tPA
Given clot into the pelvis a CT Abdomen/Pelvis was
 “Extensive thrombosis involving the entire L common and external
and internal iliac veins, associated edema and enlargment of the L
iliopsoas and piriformis muscles related to the obstruction. The
thrombus superiorly extends to the level of the aortic bifurcation
and May-Thurner syndrome is suspected. No neoplasm evident.”
NIH funded, multicenter, randomized, open-label,
assessor-blinded controlled clinical trial
692 patients in 28 centers
Patients followed for 2 years
Does PCDT prevent PTS?
Does PCDT improve QOL?
Is PCDT safe enough?
Is PCDT cost effective?
What is the mechanism by which PCDT prevents PTS?
 What about femoropopliteal DVT?
 Smaller margin for potential benefit
 What about subacute/chronic DVT
 Doesn’t work as well
 Valvular damage already done
 Need for IVC Filter?
 No good data. Manufacturers have recommended it.
 Balloon Angioplasty/Stents
 Iliocaval venous stenosis – eg. May-Thurner Syndrome
 ASA long term, Clopidegril for 8 weeks
 True Cost
 359 consecutive DVTs in 7 Canadian hospitals
 Over 4 months there was generally an improvement in QOL
scores however:
 1/3 patients had worsening QOL during followup
 This worsening correlated with worsening PTS scoring
Arch Intern Med 2005;165:1173-1178
 Venous Ulcers lead to >2 million work days lost and $300M in
the US annually
J Vasc Surg 2001;33:1022-1027
J Am Acad Dermatol 1994;31:49-53
Thrombosis Interest Group of Canada PTS Guideline, 2009
Br J Haematol. 2009;145:286-295
After looking up May-Thurner Syndrome – called vascular
surgery for opinion – in OR
Finally at 5pm on a Friday what else is there to do but to
call the next vascular surgeon on call.
Suggested calling Hematology at UAH “as there is a study
going on using thrombolytics”
Called the Hematologist (not on call) – “This is the
standard of care!! No need to do it at the UAH. Call the
radiologist on call for interventional at the UAH.
“Absolutely this is the standard of care!! We will do it this
weekend at the GNH. Have you ever done them?”
“By the way you need to arrange an ICU bed.”
Saturday am – radiologist from UAH on call for IR
BASE + 30 MIN INFUSION (aka Trellis)
Saturday pm – repeat venogram – residual thrombus so
given tPA overnight at and infusion of 0.5mg/hr
Sunday am – tPA discontinued due to low fibrinogen level
Radiologist from UAH on call for IR performed:
 ANGIOPLASTY PERIPHERAL – of common iliac stenosis
remove IVC filter
Tuesday am – failed attempt at IVC
filter removal from the R side
Wednesday – patient had IVC filter removed with a
bilateral catheter (double IR) approach through the R IJ
and the R CFV
Rx with IV UFH  LMWH
Transitioned to Warfarin x 6mo
Indefinite ASA
OT saw patient for compression
(-) Hypercoaguable workup
Patient stable at 1 and 4mo f/u
Short term treatment with SC LMWH, IV UFH, monitored
SC UFH, Fixed dose SC UFH, SC Fondaparinux [all Grade 1a]
Treat with short term agent for at least 5 days and until
INR >2.0 for 24hrs [Grade 1c]
Initiate Warfarin on the first day of treatment [Grade 1a]
Standard anticoagulation prevents thrombus extension
and embolization to the pulmonary arteries but does not
directly lyse the acute thrombus
Thrombosis Interest Group of Canada PTS Guideline, 2009
66% RRR in recanalization of thrombosed veins
Am J Med 2011;124:756-765
81% RRR in venous ulceration at 3 mo (0.5 vs. 4.1%)
Am J Med 2009;122:762-769
Prolonged LMWH (3mo.) has been shown to reduce PTS
vs. Warfarin
Chest. 2008;133:454S-545S
ACCP 2008 Guidelines Section 3.1
 3.1.1 – For a patient who has had a symptomatic proximal DVT, we
recommend the use of an elastic compression stocking with an
ankle pressure gradient of 30-40mmHg if feasible. Compression
therapy, which may include use of bandages acutely, should be
started as soon as feasible after starting anticoagulation therapy
and should be continued for a minimum of 2 years, and longer if
patients have symptoms of PTS. [Grade 1c]
Ann Intern Med. 2004;141:249-256
Chest. 2008;133:454S-545S
54% RRR with the use of ECS for 2 years
Cochrane Database of Systematic Reviews 2004;1:2004
ACCP 2008 Guidelines Section 3.2
 3.2.1 – For a patients with severe edema of the leg due to PTS, we
suggest a course of intermittent pneumatic compression.[Grade 2b]
 3.2.2 – For a patients with mild edema of the leg due to PTS, we
suggest the use of elastic compression stockings. [Grade 2c]
 3.3.1 – In patients with venous ulcers resistant to healing with
wound care and compression we suggest the addition of
intermittent pneumatic compression. [Grade 2b]
Chest. 2008;133:454S-545S
Thrombosis Interest Group of Canada PTS Guideline, 2009
 No strong evidence to support surgical interventions (valvuloplasty)
 EVLT (Endovenous Laser Treatment) can be used for superficial
varicosities – primarily cosmetic, not useful in the most severe cases
Femoropopliteal veins with DVT:
 Are recanalized in 50% of patients at 3mo
 Are recanalized in 90% of patients at 12mo
 Have valvular reflux evident on Doppler at 1mo in 40% of patients
J Vasc Surg 1992;15:377-384
J Vasc Surg 1993;18:596-608
Iliofemoral veins with DVT:
 Are recanalized in only 5% of patients with anticoagulation alone
Ann Surg 2004;239:118-126
Ann Intern Med 2008;149:698-707
Cochrane Review (2004 & 2007):
 12 studies reviewed
 Significant reduction of clot lysis (RR 24% early, 37% late)
 Similar effects seen in the degree of improvement of patency
 Reduced Post Thrombotic Syndrome (RR 66%)
 Reduced leg ulceration (RR 53%) – hindered by low numbers
 No mortality benefit
 No clear effect on PE or recurrent DVT
 Increased bleeding (RR 173%)
 Increased Stroke Risk (RR 170%)
 This did seem to improve with more recent trials
• 19 studies – heterogeneous designs
• Significant lysis observed in 79% of the 945 limbs treated
• Of 98 patients with iliofemoral DVT treated with CDT (n 68) vs.
anticoagulation alone (n=30) the QOL was better and correlated
with the degree of lysis

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