1. Rocky Mountain ACP Internal Medicine Conference November 22, 2012 Brian Wirzba, MD, FRCPC, FACP

2. 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.

3.  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).

4.  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

5.  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.”

6.  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?

7.  PTS is the end stage sequelae of DVT resulting from inadequate treatment of the acute DVT or from chronic subclinical DVT.  When acute clot does not resolve, the clot hardens leading to chronic obstruction.  There is also venous valve damage, calf muscle dysfunction and inflammation  Venous Hypertension  Venous Valvular Reflux Br J Haematol. 2009;145:286-295.

8.  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

9.  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

10.  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 anticoagulation  Older Age – not consistent  Female – not consistent  NOT influenced by cause of DVT, intensity or duration of anticoagulation

11.  “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

12.  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 Thrombolysis

13.  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

14.  Hydrodynamic or Rheolytic thrombectomy catheter  Based on industrial technology  Multiple generations since 1992 introduction

19.  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 beneficial Radiology 1999;211:39

20.  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)

21.  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 NNT 7

22. 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

23.  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 Thrombolysis NOT recommended over routine Anticoagulation in most patients ACCP 2012 Guidelines Compression Stockings ARE recommended for all Acute Symptomatic Leg DVT’s (Grade 2B)

24.  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

26. 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)

27.  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

28.  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.”

30.  NIH funded, multicenter, randomized, open-label, assessor-blinded controlled clinical trial  692 patients in 28 centers  Patients 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?

31.  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

34.  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

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

36.  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.”

37.  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

38.  Sunday am – tPA discontinued due to low fibrinogen level  Radiologist 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

39.  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

40.  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

41.  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

42.  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

43.  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

44. 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 NO CURE

45.  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

46.  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

47. 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