Iliofemoral DVT: Miminizing Post-Thrombotic Syndrome

Iliofemoral DVT: Miminizing Post-Thrombotic Syndrome Catherine K. Chang, MD FACS Vascular Surgery San Diego Southern California Permanente Medical Group Acute Deep Venous Thrombosis Incidence & Outcomes 117 of 100,000 person years in US Recurrent DVT in ~30% within 5-10 years Post-thrombotic syndrome (PTS) in ~40% within 2 years Rutherford s Vascular Surgery 8 th Edition Post-thrombotic syndrome (PTS) PTS: Villalta scale 20-50% of DVT patients in 1-2 years Symptoms and signs vary Severe in 5-10% Kahn SR. Thrombosis Research 2011; 127:S89-92 Vasquez SR et al. Best Practice & Research Clinical Haematology 2012; 25:391-402 PTS after Acute DVT Prospective study of 387 patients Villalta scale from 1 to 24 months PTS Severity Prevalence Mild: 5-9 30% Moderate: 10-14 10% Severe: >14 or ulcer 3% Predictors of Higher Scores Increase in Score Common femoral or iliac DVT +2.23 (+1.29 to +3.16) Previous ipsilateral DVT +1.78 (+0.69 to +2.87) Severity at 1 month +1.97, +5.03, +7.00 DVT Classification Proximal vs distal LET classification I - isolated calf vein thrombosis II - femoral-popliteal vein thrombosis III - common femoral and/or iliac vein thrombosis IV - IVC thrombosis Non-occlusive thrombus in common femoral vein graded as class II Kahn SR et al. Ann Intern Med 2008; 149:698-707 Strijkers R. et al Phlebology 2015; 30(1S): 14-19 1

Duplex Iliofemoral DVT Iliofemoral DVT: Natural History Common channel of venous drainage from involved lower extremity obliterated Sequela with anticoagulation alone Persistent obstruction 70% Chronic venous insufficiency >90% Venous claudication 40% Venous ulceration 15% Recurrent VTE 11.8% in 3 months OR 2.4 (95% CI 0.95 to 5.9) Treatment of Acute DVT Anticoagulation Compression stockings Catheter directed thrombolysis (CDT) Pharmacomechanical adjuncts Venoplasty and stenting Akesson H et al. Euro J Vasc Surg 1990; 4(1): 43-8 Delis KT et al. Ann Surg 2004; 239(1): 118-26 Douketis JD et al. Am J Med 2001; 110(7):515-9 CDT: Meta-analysis 4 studies: thrombolysis vs anticoagulation Quality generally low Egypt Trial 1 st randomized controlled trial N=35 CDT + anticoagulation (N=18) Anticoagulation alone (N=17) Iliofemoral DVT <10 days old Streptokinase: pulse spray continuous infusion venogram 12 hour intervals Venous function at 6 months Extent of residual thrombus Venous reflux and venous outflow Casey E et al. J Vasc Surg 2012; 55:1463-73 Elsharawy M. Eur J Vasc Endovasc Surg 2002; 24:209-214 2

Egypt Trial Egypt Trial Catheter directed thrombolysis was better than anticoagulation alone No major bleeding complications Symptomatic PE 6% - anticoagulant group Elsharawy M. Eur J Vasc Endovasc Surg 2002; 24:209-214 Elsharawy M. Eur J Vasc Endovasc Surg 2002; 24:209-214 Norwegian randomized trial N=209 CDT + anticoagulation (N=101) Anticoagulation alone (N=108) 1 st DVT above mid thigh 21 days Alteplase infusion venogram daily Adjunctive angioplasty and stenting (<50% stenosis) Co-primary outcomes Iliofemoral patency at 6 months PTS by Villalta score at 24 months PTS 24 months: ARR 14.4% (95% CI: 0.2-27.9) with CDT, NNT 7 Iliofemoral patency: ARR 24.4% (95% CI:9.8 37.6; P=.001) Iliofemoral DVT <50% Compliance with compression stockings higher in CDT group % of patients on anticoagulation with INR 2-3 100 90 80 70 61.1 65.4 60 52.6 50 50 40 30 20 10 0 6 Months 24 months CDT Control 3

Extent of Thrombolysis Achieved 11% 48% 41% Complete 50-99% <50% Adjunctive Procedures 1% 17% 57% 25% Complications CDT: Mean duration 2.4 days (SD 1.1) 20 bleeding 3 major, 5 clinically relevant CDT should be considered in 4 non-bleeding patients No ICH, no PE, with no deathshigh proximal DVT and low risk of bleeding Anticoagulation alone: no bleeding AngioJet Venous stents Balloon angioplasty None : Results at 5 years N=176 patients (84% of intial 209) CDT N=87 ARR 28% (95% CI: 14-42), NNT = 4 No difference in QOL Anticoagulation N=89 P value PTS 43% 71% <.0001 Severe PTS 5% 1% Multicenter, randomized, open-label, assessor blinded, controlled trial Symptomatic, proximal DVT <14 days Iliac, common femoral, &/or femoral vein DVT No prior DVT within 2 years Randomization stratified Anatomical extent (common femoral ± iliac vein) Primary outcome PTS at 24 months Villalta Scale Haig et al. Lancet Haematol 2016; 3(2):e64-71 Vedantham S et al. Am Heart J 2013; 165:523-530 Anticoagulation Heparin + Coumadin Duration 3 months PCDT Pharmacomechanical catheter directed thrombolysis 30-40 mmhg knee high compression stockings at 10 day FU PCDT Good inflow into popliteal vein Isolated thrombolysis Trellis Powerpulse thrombolysis AngioJet Poor inflow into popliteal vein Infusion-first thrombolysis rt-pa infusion at 0.01 mg/kg/hr Max rt-pa 35 mg, 30 hours Adjunctive treatment PTA ± stenting of obstructive lesions Vedantham S et al. Am Heart J 2013; 165:523-530 Vedantham S et al. Am Heart J 2013; 165:523-530 4

N = 692 patients, 24 month FU PCDT N = 337 Anticoagulation N = 355 No difference in any PTS (Villalta >5 or ulcer) No difference in QoL measures No difference when stratified by level of DVT P value PTS 46.7% 48.2%.56 Generic QoL (SF-36) 11.8 10.1.37 Venous QoL (VEINES) 27.7 23.5.08 PCDT N = 337 Anticoagulation N = 355 PCDT reduced PTS severity Difference in PTS severity seen mostly in iliofemoral DVT patients P value Moderate or Severe PTS 17.9% 23.7%.035 Iliofemoral DVT 18.4% 28.2% Femoropopliteal DVT 17.1% 18.1% Vedantham S et al NEJM 2017; 377:2240-52 PCDT N = 337 Anticoagulation N = 355 PCDT less effective in patients 65 years Limitations: Losses to FU (2/3 risk in control of group) PTS.? Generalizability: 28,507 pts met inclusion criteria Sample size limited power in subgroup analysis Multiple PCDT methods P value Recurrent DVT 12.5% 8.5%.09 Bleeding Among patients 4.5% with 1.7% acute.034 Major bleeding 1.7% 0.3%.049 proximal DVT, addition of PCDT did not result in lower Mean thrombus removal 76% Vedantham S et al NEJM 2017; 377:2240-52 Residual Thrombus after CDT Retrospective study: N=71 Iliofemoral DVT CDT Quantity of residual thrombus on venogram Blinded assessment Group 1: 50% Group 2: >50% Villalta and CEAP scores: N=63 Blinded assessment Residual Thrombus after CDT Group 1 50% Group 2 >50% P value Mean clot lysis 42% 85% CEAP (median) 4 1.025 Villalta (mean) 7.13 2.21.011 Residual thrombus associated with increased risk of PTS Comerota A et al. J Vasc Surg 2012; 55:768-73 Comerota A et al. J Vasc Surg 2012; 55: 768-73 5

Comparative Safety of CDT Observational study: NIS from 2005 2010 Proximal or caval DVT CDT + Anticoagulation in 4.1% Increase from 2.3% 2005 to 5.9% in 2010 Propensity scores 2 matched groups of N=3594 patients Outcomes Primary: in-hospital mortality Secondary: bleeding complications Comparative Safety of CDT Small trials may underestimate harm of CDT No significant difference in mortality Increased blood transfusion, ICH, PE and IVC filter placement with CDT. Bashir R et al. JAMA Intern Med 2014; 174(9):1494-1501 Bashir R et al. JAMA Intern Med 2014; 174(9):1494-1501 Pharmacomechanical adjuncts: Advantages Local administration of thrombolytic agent Reduced thrombolytic dose Reduced thrombolytic infusion time Decreasing bleeding complications Reduced ICU stay Reduced overall hospital treatment cost TORPEDO Trial Randomized trial N=183 Anticoagulation ± PEVI (Percutaneous endovascular intervention) Symptomatic, proximal DVT Femoropopliteal, iliac veins, or IVC Outcomes 6 months, final FU Recurrent VTE PTS 2 new symptoms + clinical sign (edema + reflux or venous stasis changes) Sharifi M et al. J Endovasc Ther 2012; 19:273-280 TORPEDO Trial 50% with no known history of DVT had venographic evidence of prior DVT TORPEDO Trial All patients had IVC filter placed before PEVI Infusion thrombolysis 37% Balloon venoplasty 76% Stenting 30% Total 47 stents: 21 in femoropopliteal veins Sharifi M et al. J Endovasc Ther 2012; 19:273-280 Sharifi M et al. J Endovasc Ther 2012; 19:273-280 6

TORPEDO Trial Primary Endpoints at 30 Months PEVI N=88/91 Control N=81/92 P value PTS 6 (6.8%) 24 (29.6%) <.001 VTE 4 (4.5%) 13 (16.0%).02 PEVI is superior to anticoagulation alone in reducing PTS and VTE Limitations PTS not defined by validated scale PEVI more likely to be on aspirin and Plavix Aspirin with RR 0.37 (95% CI 0.19 0.74) for PTS Sharifi M et al. J Endovasc Ther 2012; 19:273-280 Pharmacomechanical Catheter Directed Thrombolysis: Patient Selection! Highest anatomical extent of DVT Iliofemoral DVT Length and degree of symptoms Acute <14 days Risk factors for PTS Risk factors for bleeding Functional status Vedantham S. Tech Vasc Interv Radiol 2014; 17(2):103-8 Venous Stenting Recognition and treatment of obstructive lesions of iliac veins impacts success of CDT Criteria for stenting Pressure gradient of 5 mmhg? 50% stenosis by IVUS Venous collaterals Self expanding stents Elastic recoil after venoplasty from fibrosis Oversized (14-16 mm) Baekgaard N et al. Phlebology 2014; 29(15): 112-118 Baekgaard N et al. Phlebology 2014; 29(15): 112-118 Venous Stenting Pooled analysis 19 studies (N=1046) CDT ± percutaneous mechanical thrombectomy Acute DVT in 88%, Iliofemoral DVT 66% Stents in 46% National Venous Registry CDT in 303 limbs in 287 of 473 patients with DVT Acute DVT in 85%, Iliofemoral DVT 71% Stents 33% Patency 1 year: 74% with iliac stent vs 53% without (P<.001) Vedantham S. et al. J Vasc Interv Radiol 2009; 20:S227-239 Mewissen MW et al. Radiology 1999; 211(1): 39-49 Durable Patency after Venous Stenting Retrospective analysis N=61: CDT + venous stenting Acute iliofemoral DVT ( 10 days) 92% 88% 90% 85% Xue G et al. Ann Vasc Surg 2014; 28:957-963 7

Durable Patency after Venous Stenting Retrospective analysis N=32: CDT in 92% + iliac vein stenting Acute DVT 78% Compression Stockings: Significant Reduction in PTS Proximal DVT Active stockings vs no stockings for 2 years Outcome PTS (5 years FU) Study Timing Group N PTS P value Brandjes 2-3 weeks Stockings 96 20% <.001 Control 98 47% Prandoni 5-10 days Stockings 90 24.5%.011 Control 90 49.1% Warner CJ et al. Vasc and Endovasc surg 2013; 47(5):331-334 Brandjes DPM et al. Lancet 1997; 349:759-62 Prandoni P et al. Ann Intern Med 2004; 141(4):249-56 Compression Stockings: Sox Trial Multicenter, randomized trial 1 st proximal DVT <40% common femoral and iliac veins Active vs placebo elastic compression stockings (ECS) for 2 years 30-40 mmhg vs <5 mmhg at ankle Applied within 2 weeks Outcome: PTS at 6 months Sox Trial: PTS by Ginsberg s criteria 1º outcome: Leg pain + swelling 1 month HR 1.13, 95% CI (0.73 1.76) Kahn SR et al Lancet 2014; 383:880-88 Kahn SR et al Lancet 2014; 383:880-88 Sox Trial: PTS by Villalta Score 2º outcome: 5 or venous ulcer No difference in outcomes HR 1.00, 95% CI (0.81 1.24) Findings do not support routine use of elastic compression stockings after DVT Kahn SR et al Lancet 2014; 383:880-88 Kahn SR et al Lancet 2014; 383:880-88 8

Sox Trial: Limitations in Methodology Timing of ECS application (delayed) Fitting of ECS (mailed, no training) Evaluation of compliance (interview, frequent defined as 3-6 days) Compliance low Study 69% by 24 months Compliance Brandjes 56% used ECS 76% 3 always days/week at 24 Prandoni months 87% 80% of daytime hours Kahn (SOX) Not justifiable to entirely abandon compression stockings to prevent PTS 56% 3 days/week IDEAL DVT Study Multicenter, single blinded, assessor blinded randomized trial (Netherlands, Italy) Proximal DVT: N=864 All: ECS for 6 months Knee length graduated (ankle pressure 40 mmhg) Standard (24 months) vs Tailored Tailored: duration based on Villalta scores at 3 and 6 months Primary outcome: PTS at 24 months Ten Cate-Hoek A et al. BMJ Open 2014; 4:e005265 Anticoagulation: Poor Quality and Increased PTS Calculated time spent < INR 2-3 1 st DVT treated with vitamin K antagonist N=244 median FU 4.9 years 30% of time INR <2 33% developed PTS Patients with >50% subtherapeutic INR associated with increased risk of PTS OR 2.7, 95% CI 1.4 to 5.1 Van Dongen CJJ et al. J Thromb Haemost 2005; 3: 939-42 Duration of Anticoagulation: >3 months for Unprovoked DVT 3 months + 24 months warfarin vs placebo PREVENT: low intensity warfarin (INR 1.5 to 2.0) vs placebo after full dose anticoagulation (6.5 months) Kearon C et al. NEJM 1999; 340:901-7 Ridker PM et al. NEJM 2003; 348:1425-34 Warfarin N=79 Placebo N=83 P value Recurrent VTE 1.3% 27.4% <.0001 Bleeding 3.8% 0.09 Warfarin N=255 Placebo N=253 P value Recurrent VTE 2.6% 7.2% <.001 Bleeding 0.9 0.4%.25 Duration of Anticoagulation: >3 months for Unprovoked DVT Low vs conventional intensity warfarin Conventional N=369 Low Intensity N=369 HR Recurrent VTE 0.7% 1.9% 2.8 (1.1-7.0) Bleeding 0.9% 1.1% 1.2 (0.8-2.1) ACCP guidelines: Long term treatment Unprovoked proximal DVT/PE + low/moderating bleeding risk Cancer associated thrombosis Conclusions Iliofemoral DVT associated with significant PTS PCDT can reduce PTS Patient selection! Mechanism to identify patients with iliofemoral DVT Adjuncts to improve risks and outcomes of CDT Minimize thrombolysis time Treat residual stenosis Compression stockings for 6 months Indefinite anticoagulation if unprovoked Kearon C et al. NEJM 2003; 349:631-9 9