Rocky Mountain ACP Internal Medicine ConferenceNovember 22, 2012

Brian Wirzba, MD, FRCPC, FACP

Is the NKOTB a new Standard of Care?

Pharmomechanical Therapies for Large Proximal DVTs

Disclosures

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 years.

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).

Learning Objectives

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

Case Study

Given clot into the pelvis a CT Abdomen/Pelvis was ordered “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.”

Case Study

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?

What has been the “Standard”

PTS is thought to occur to some degree in 20-50% of patients within 2 years of a DVT

Chest 2012;141:308-320J Thromb Haemost. 2005;3:939-942Ann 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 PTSThrombosis Research 2006; 117:609-614

Why care about Post-Thrombotic Syndrome (PTS)?

387 patients (347 seen at 4mo) with acute symptomatic DVT in 8 Canadian hospitals treated with routine care

Ann Intern Med 2008;149:698-707

5.7%

56.8%

85.9% 14.1%

4.3%

4.9%

QOL Scores for patients with severe PTS are similar to patients with Chronic Angina, Cancer and Severe CHF

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

anticoagulationOlder Age – not consistentFemale – not consistent

NOT influenced by cause of DVT, intensity or duration of anticoagulation

Risks for PTS

“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;4:43-48Ann Surg 204;239:118-126

J Surg Res 1977;22:483-488JAMA 1983;250:1289

Iliofemoral DVTs are particularly problematic

Systemic ThrombolysisFlow 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 ThrombolysisPMT – Percutaneous Mechanical ThrombectomyPCDT – Pharmomechanical Catheter Directed

Thrombolysis

Types of “New” Interventions

Anticoag alone is inadequateBig clots lead to worse SxEarly clot dissolution is goodCDT can remove clot CDT provides fast relief of SxCDT uses less thrombolyticCDT 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

Hammer & Nail

Hydrodynamic or Rheolytic thrombectomy catheterBased on industrial technologyMultiple generations since 1992 introduction

AngioJet

AngioJet

Trellis

Trellis

Trellis

Adjunctive CDT has been shown effective in: 90% thrombolysis rate in patients with iliofemoral DVT

Vasc Interv Radiol 2006;17:435-448Radiology 1999;211:39-49

Reducing anaesthesia, incision issues, and prolonged recovery (compared to surgical thrombectomy)

Eur J Vasc Surg 1990;4:483-489Semin 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 beneficial

Radiology 1999;211:39

Evidence from the “other guys”

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)

ONE Modern Technology RCT Published

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

ONE Modern Technology RCT Published

NNT 7

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 ThrombolysisFlow 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 ThrombolysisPMT – Percutaneous Mechanical ThrombectomyPCDT – Pharmomechanical Catheter Directed

Thrombolysis

Types of “New” Interventions

NOT recommended over routine Anticoagulation in

most patients ACCP 2012 Guidelines

Compression Stockings ARE recommended for all Acute Symptomatic Leg

DVT’s (Grade 2B)

ACCP 2012 Guidelines Section 2.92.9 – 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

What about this new “Standard of Care”?

So should CDT or PCDT be the standard at your hospital?

A fine balance

Improved Patency

Improved QOL

Decreased PTS

2-4d ICU stay

10-20% bleed risk

Cost

Multiple programs involved

Moving an outpatient condition into the inpatient world (again)

Phlegmasia cerulea dolensAcute IVC thrombosisAcute Iliofemoral DVT

Low bleeding risk> 1 year life expectancy

<70 year old ageGood Functional Status & AmbulatoryDoes not have PTS alreadyCan tolerate procedureNot pregnantNo Contraindication to tPA

Indications

Given clot into the pelvis a CT Abdomen/Pelvis was ordered “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.”

Case Study

NIH funded, multicenter, randomized, open-label, assessor-blinded controlled clinical trial

692 patients in 28 centersPatients followed for 2 years

1. Does PCDT prevent PTS?2. Does PCDT improve QOL?3. Is PCDT safe enough?4. Is PCDT cost effective?5. What is the mechanism by which PCDT prevents PTS?

ATTRACT Study

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

Unknowns

Questions?

Additional Slides (NOT Presented)

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;33:1022-1027J Am Acad Dermatol 1994;31:49-53

QOL is affected post-DVT

Thrombosis Interest Group of Canada PTS Guideline, 2009Br J Haematol. 2009;145:286-295

Villalta PTS Scale – Helps in comparing outcomes

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.”

Case Study

Saturday am – radiologist from UAH on call for IR performed LIMITED US WITH INTERVENTIONAL IVC FILTER INSERTION, INCLUDES VENACAVAGRAM THROMBECTOMY USING A MECHANICAL DEVICE THROMBOLYSIS

BASE + 30 MIN INFUSION (aka Trellis)

Saturday pm – repeat venogram – residual thrombus so given tPA overnight at and infusion of 0.5mg/hr

Case Study

Sunday am – tPA discontinued due to low fibrinogen levelRadiologist from UAH on call for IR performed:

ANGIOPLASTY PERIPHERAL – of common iliac stenosis PERIPHERAL VASCULAR STENT PLACEMENT – into common iliac SELECTIVE ABDOMINAL/PELVIC VENOGRAM – failed attempt to

remove IVC filter PHARMACEUTICAL INFUSION CATHETER

Tuesday am – failed attempt at IVC filter removal from the R side

Case Study

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 LMWHTransitioned to Warfarin x 6mo Indefinite ASAOT saw patient for compression (-) Hypercoaguable workupPatient stable at 1 and 4mo f/u

Case Study

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

Traditional Treatments for PTS (ACCP 2008)

66% RRR in recanalization of thrombosed veinsAm 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

Longer LMWH “may” be better

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 yearsCochrane Database of Systematic Reviews 2004;1:2004

Traditional Treatments for PTS (ACCP 2008)

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

Traditional Treatments for PTS (ACCP 2008)

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

Traditional Treatment Strategies for PTS

NO CURE

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;15:377-384J Vasc Surg 1993;18:596-608

Iliofemoral veins with DVT: Are recanalized in only 5% of patients with anticoagulation alone

Ann Surg 2004;239:118-126Ann Intern Med 2008;149:698-707

Natural Progression with Anticoagulation

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

What About Evidence??

The Details

• 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