Catheter-Based Treatment of DVT: Who & When? Karun Sharma, MD, PhD Interventional Radiology Children’s National Medical Center Sheikh Zayed Institute for Pediatric Surgical Innovation

Karun Sharma, MD, PhD   I have no relevant financial relationships

Overview DVT and standard therapy Catheter Directed Treatment Who ? When ? Why ? Phlegmasia cerulea dolens: Rare – all venous return from LE occluded, painful, swollen and cyanotic, comprimised arterial inflow, emergency, venous gangrene, massive PE and death

Virchow’s Triad: Cumulative Risk Factors Surgery Prior DVT Central venous access Cancer chemotherapy or radiotherapy Estrogen use Cancer Family history IBD Nephrotic syndrome Blood transfusions Thrombophilia Risk factors for Venous thromboembolic disease which included DVT and PE – red is more PEDS. Cumulative risk and that hospitalized patients usually have multiple risk factors. Age >40 years Immobilization MI CHF Paralysis Anatomic Abnormality 5. Geerts et al. Chest. 2004;126(suppl):338S-400S.

DVT Treatment Options Pharmacological Options: Endovascular Options: Anticoagulants (STANDARD DVT TREATMENT): Unfractionated Heparin (UFH) Low Molecular Weight Heparins (LMWH) - Enoxaparin Direct thrombin inhibitors - Bivalirudin, Lepirudin, Argatroban Vitamin K antagonists - Warfarin Newer, more specific agents – Fondaparinux and Ximelagatran Thrombolytics (systemic): FDA approved for MI, Stroke and PE Streptokinase Urokinase tPA Endovascular Options: IVC Filtration Catheter Directed Thrombolysis Catheter Based Pharmacomechanical Thrombolysis

Catheter Based DVT Treatment Options tPA infusion + Device for local delivery Multisidehole infusion catheter Trellis – Balloons to localize tPA and wire to fragment thrombus – aspiration port Angiojet – Rheolytic device for tPA delivery, microfragmentation of thrombus and concurrent aspiration Ekos – US to “soften” thrombus and allow better tPA binding

WHO to treat with catheter based treatment? Phlegmasia May-Thurner Syndrome Iliofemoral DVT in healthy patients Worsening symptoms despite anticoagulation Phlegmasia cerulea dolens: Rare – all venous return from LE occluded, painful, swollen and cyanotic, comprimised arterial inflow, emergency, venous gangrene, massive PE and death

WHO: Phlegmasia Cerulea Dolens Rare – all venous return from LE occluded painful, swollen and cyanotic comprimised arterial inflow emergency venous gangrene, massive PE and death

WHO: May Thurner Anatomy AKA left iliac vein compression syndrome Anatomic constriction of L CIV by R CIA Repetitive trauma leading to venous injury

WHO else ? Iliofemoral DVT in healthy, active patients Patients with lack of symptomatic improvement or worsening despite therapeutic anticoagulation When ? – Acute DVT (< 14 days, ? up to 21 days) Why ? To prevent PTS Iliofemoral DVT Accounts for 20% of lower extremity DVT Etiologies: propagation of femoro-popliteal DVT (10-20%), pelvic mass, May Thurner syndrome Unique: relatively resistant to anticoagulation, rarely completely recanalize, more frequently results in post thrombotic syndrome

Post Thrombotic Syndrome (PTS) Anticoagulants do not quickly eliminate thrombus. 25-40% of patients with proximal DVT who are on therapeutic anticoagulation and use compression stockings develop PTS Valvular Damage from residual thrombus Valvulur Reflux in deep and superficial systems Venous hypertension Edema, tissue hypoxia and calf pump dysfunction Pruritis, Stasis dermatitis Chronic, debilitating leg pain and swelling Skin ulceration

WHO should be treated with catheter based treatment? Catheter based DVT treatment is commonly performed but… Not endorsed by the American College of Chest Physicians (ACCP) guidelines; lack of strong evidence Many supportive retrospective, non-randomized studies CaVENT - Enden et al. Lancet 2012 ATTRACT (results expected in 2015) American Society of Hematology (ASH) Society of Interventional Radiology (SIR) CaVenT (Norway) - Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis--the CaVenT study first randomized trial to evaluate CDT in preventing PTS, CDT vs. anti - coagulation and compression stockings, PTS decreased by 24% in CDT group, Patency of iliac veins increased in CDT group at 6 months. ATTRACT (US – on going) = randomized trial, phase 3, open label, pharmacomechanical CDT vs. anticoagulation, results pending. Stratification…IF vs. FP ATTRACT : ACUTE VENOUS THROMBOSIS: THROMBUS REMOVAL WITH ADJUNCTIVE CATHETER-DIRECTED THROMBOLYSIS

Data? Primary patency 63-90% at one year post CDT Most data from non randomized trials and registries CaVenT (Norway) first randomized trial to evaluate CDT in preventing PTS CDT vs. anti - coagulation and compression stockings Patency of iliac veins increased in CDT group at 6 months PTS decreased by 24% in CDT group ATTRACT (US – on going) Randomized, multicenter, phase 3 trial (n=692) pharmacomechanical CDT vs. anticoagulation and compression results expected in 2015 Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) Am Heart J. 2007 Nov;154(5):808-14. Epub 2007 Sep 6. Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis--the CaVenT study

Standard therapy only (n = 99) Long-Term Outcome After Additional Catheter-Directed Thrombolysis versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (The CaVenT Study): A Randomised Controlled Trial Outcome Additional CDT (n = 90) Standard therapy only (n = 99) p-value n % (95% CI) PTS after 6 mo 27 30.3 (21.8-40.5) 32 32.2 (23.9-42.1) 0.77 PTS after 24 mo 37 41.1 (31.5-51.4) 55 55.6 (45.7-65.0) 0.047 Iliofemoral patency after 6 mo* 58 65.9 (55.5-75.0) 45 47.4 (37.6-57.3) 0.012 PTS is defined as a Villalta score ≥5. p-values stated are from an unadjusted Chi-square test. Absolute risk reduction of long-term endpoint PTS at 24 months of follow-up in CDT versus standard therapy: 14.4% (95% CI 4-502). Enden T et al. Lancet 2012;379(9810):31-8.

Standard treatment (n = 108) Adverse Events (AEs) AEs Additional CDT (n = 101) Standard treatment (n = 108) Bleeding complications Major bleeding complications Clinically relevant bleeding complications 20 3 5 Deaths NR Pulmonary embolisms Cerebral hemorrhages Nonbleeding complications 4 Recurrent VTE at 24 mo 10 18 Enden T et al. Lancet 2012;379(9810):31-8.

Author Conclusions Additional CDT improved the clinically relevant long-term outcome after iliofemoral DVT by decreasing PTS compared to conventional therapy. The CaVenT study demonstrates that additional CDT should be considered as treatment for patients with a high proximal DVT and low risk of bleeding. Enden T et al. Lancet 2012;379(9810):31-8.

Contraindications to Catheter-Directed Thrombolysis Absolute Contraindications Active internal bleeding or disseminated intravascular coagulation Recent cerebrovascular event (including transient ischemic attacks), neurosurgery (intracranial, spinal), or intracranial trauma ( < 3 months) Absolute contraindication to anticoagulation Strong Relative Contraindications Recent cardiopulmonary resuscitation, major surgery, obstetrical delivery, organ biopsy, or major trauma ( <10 days) Intracranial tumor, other intracranial lesion, or seizure disorder Uncontrolled hypertension: systolic > 180 mm Hg, diastolic > 110 mm Hg Recent major gastrointestinal bleeding (< 3 months) Serious allergic or other reaction to thrombolytic agent, anticoagulant, or contrast media (not controlled by steroid/antihistamine pretreatment) Severe thrombocytopenia Known right-to-left cardiac or pulmonary shunt or left heart thrombus Massive PE with hemodynamic compromise Suspicion for infected venous thrombus Other Relative Contraindications Renal failure (serum creatinine 2.0 mg/dL) Pregnancy or lactation Severe hepatic dysfunction Bacterial endocarditis Diabetic hemorrhagic retinopathy

Take Home Points: Who ? When ? Phlegmasia cerulea dolens May-Thurner syndrome Healthy, active patients with low bleeding risk and symptomatic proximal DVT (Iliofemoral) Patients with proximal DVT and persistent or worsening symptoms despite therapeutic anticoagulation When ? – Acute DVT (< 14 days, maybe up to 21 days) Iliofemoral DVT is often refractory to standard anticoagulation and associated with higher rates of PTS which can be debilitating

Thank You Children's National Medical Center kvsharma@cnmc.org pager: 202-259-5213 office: 202-476-1283 fax: 202-476-5279

PTS After 24 Months in Patients with Iliofemoral Patency or Insufficient Recanalization After 6 Months Outcome Regained iliofemoral patency (n = 103) Insufficient recanalization (n = 80) p-value n % (95% CI) PTS after 24 mo 38 36.9 (28.2-46.5) 49 61.3 (50.3-71.2) 0.001 Absolute gain in short-term endpoint iliofemoral patency after 6 months in CDT versus standard therapy group: 18.5% (95% CI 4.2–31.8). Absolute risk reduction in the frequency of PTS after 24 months in patency versus insufficient recanalization: 24.4% (95% CI 9.8–37.6). Enden T et al. Lancet 2012;379(9810):31-8.

Initial imaging: CT