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Research Priorities in Venous Disease

Research Priorities in Venous Disease. Mark H. Meissner, MD Professor of Surgery University of Washington School of Medicine Seattle, WA. Research Priorities in Venous Disease 27 Original Questions.

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Research Priorities in Venous Disease

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  1. Research Priorities in Venous Disease Mark H. Meissner, MD Professor of Surgery University of Washington School of Medicine Seattle, WA

  2. Research Priorities in Venous Disease27 Original Questions • What is the role of prophylactic IVC filters – Is PE/death reduced compared to other methods of VTE prophylaxis or duplex surveillance or both? • What are the outcomes of treated isolated calf vein thrombosis compared with the natural history of untreated calf DVT? • Develop best practices for management of chronic venous ulceration • What is the comparative effectiveness of compression therapy versus ablation in preventing the progression of chronic venous disease? • What is the role of Chronic Cerebrospinal Venous Insufficiency (CCSVI) in Multiple Sclerosis?

  3. What is the role of prophylactic IVC filters – Is PE/death reduced compared to other methods of VTE prophylaxis or duplex surveillance or both?

  4. Trends in IVC FiltrationStein PD, Am J Med 2001 • National Hospital Discharge Survey 1979 – 2006 • Increased filter use from 1979 (17,000) to 2006 (803,000) • 3X increase in prophylactic filter use after 2003 • 2001 – 0.02% of discharge sample • 2006 – 0.06% of discharge sample Retrievable Filters

  5. Venous Thromboembolism & Trauma • Thromboembolic risk in seriously injured patients • Distal DVT – 58% • Proximal DVT – 18% • 3rd leading case of death in patients surviving 24 hrs • 22% with ongoing bleeding or high risk of bleeding • 3X increased risk with delayed prophylaxis (96 vs 48 hrs) • No benefit for LDUFH vs placebo (OR 0.96, 0.36 – 2.96) • No benefit for SCDs vs placebo (OR 0.77, 0.26 – 2.23)

  6. DVT Prophylaxis in TraumaGeerts et al, N Engl J Med 1996 • 344 patients followed with venography • Heparin 5000u bid - 136 patients • Enoxaparin 30 mg bid - 129 patients

  7. ACCP Guidelines for TraumaGeerts et al, Chest 2008

  8. EAST GuidelinesRogers FB et al, J Trauma 2002

  9. IVC Filters & TraumaRajesekhar et al, J Thromb Thrombolysis 2011 • Metanalysis of 7 cohort studies (No randomized trials) • 1900 high-risk trauma patients • Permanent Greenfield filter in 6/7 studies • Lower PE risk with IVC filter (OR 0.21, 0.009 – 0.49) • Trend towards increased DVT (OR 1.6, 0.76 – 3.37) • Limitations • Inconsistent use of pharmacologic prophylaxis • 3/6 studies prior to 1996 Insufficient evidence to support prophylactic filters in trauma

  10. Cost Effectiveness of VTE ProphylaxisChiasson TC, Plos 2011 • Severely injured patient cohort (N = 10115) • 2 wk contraindication to anticoagulants • ISS > 12 • Head / neck or abdomen / pelvis AIS ≥ 3 • Markov modeling of 3 prophylactic strategies • Duplex surveillance strategy dominant • VCF filter costs • 11 additional DVTS per PE prevented • $204,000 per PE prevented

  11. Is Pharmacologic Prophylaxis Contraindicated?Koehler et al, J Trauma 2011 • 669 patients with acute intracranial hemorrhage (ICH) • Enoxaparin 30 mg q 12 hours • Early (0 – 72 hrs) prophylaxis - 268 (40.1%) • Late ( > 72 hrs) prophylaxis - 401 (59.9%) • No deaths from ICH pregression • 1 death (late prophylaxis) from PE “ Early prophylaxis appears safe for patients with TBI”

  12. FDA Warninghttp://www.fda.gov/MedicalDevices/Safety/AlertsandNotices • Concern regarding 921 adverse event reports since 2005 • Device migration – 328 • Embolization – 146 • IVC perforation – 70 • Fracture – 56 • Planned risk / benefit decision analysis • “FDA recommends that implanting physicians and clinicians responsible for the ongoing care of patients with retrievable IVC filters consider removing the filter as soon as protection from PE is no longer needed”

  13. CER Research – Registry Approacheswww.venousregistry.org The trusted venous resource • American Venous Forum Registries • Venous stent module • Varicose vein module (launched 11/10) • “Real world” comparison of • Technical outcomes (patency, closure rates) • Clinical outcomes (VCSS)

  14. Conclusions • Anticoagulation remains gold standard • Paucity of quality evidence to support filters • Standard indications - 2C • Prophylaxis - 1A Against • Filter choice dependent on design • Single stage filtration • Deep conical design • Short radius hooks • Permanent filters for permanent indication • Consider temporary filters • Age < 65 • No malignancy

  15. What are the outcomes of treated isolated calf vein thrombosis compared with the natural history of untreated calf DVT?

  16. Fibrinogen Uptake and Post-Operative DVTWhy we are talking about this today • “Minimal” calf vein thrombosis • Diagnosed by 125I-labeled fibrinogen uptake • Sensitive to small (or non-existent) tibial vein thrombi • Frequently • Small, non-occlusive • Asymptomatic • Early resolution • Doouss TW (1976) - 84% resolved by discharge • Kakkar et al (1969) - 35% resolved within 72 hrs • Low incidence of propagation • Low incidence of symptomatic pulmonary embolism Don’t treat “below knee” DVT

  17. Venous Duplex Ultrasonography • Most widely used diagnostic test for DVT • Sensitivity and specificity > 90% for symptomatic proximal DVT The relevance (and even the need to look for) of ultrasound identified calf vein thrombosis remains controversial

  18. ACCP Consensus Guidelines • 2001 - “symptomatic isolated calf vein thrombosis should be treated with anticoagulation for 6 - 12 weeks. (Grade 1A) If for any reason anticoagulation is not administered, we recommend that serial non-invasive studies of the lower extremity should be performed…” • 2004 - ??? • 2008 - “For patients with a first isolated distal DVT that is unprovoked, we suggest that 3 months of anticoagulation is sufficient rather than indefinite therapy” (Grade 2B)

  19. Is There Data to Guide Management? • Natural History Studies • Observational (cohort) studies • Randomized trials

  20. Natural History of DVT Meissner et al, J Vasc Surg 1996 • 499 patients with DVT in 576 limbs • 452 (91%) with proximal thrombosis • 47 (9%) with isolated CVT • Duplex f/u at 1 day, 1 month, q 3 months X 1yr, q yr • Median follow-up 111 days • Outcomes • Proximal propagation in 6 (16%) of isolated CVT • 11% concurrent PE • PTS (1 yr) – 54% proximal versus 23% isolated CVT • D-Dimer > 1000 ug/ml highly predictive of propagation

  21. Natural History Based Mathematical ModelsModified from Raskob, 1996 Isolated Calf Vein Thrombosis 20% Propagation No Propagation 20 - 50% Recurrent VTE 1% Fatal PE ?? Embolic Risk 5-10% Symptomatic PE 10% Fatal PE

  22. Cohort Studies – The CALTHRO StudyPalareti G, Thromb Haemost 2010 • 431 pts with (–) proximal U/S and… • High PTP or… • Low PTP and (+) D-Dimer • Complete U/S results withheld • (+) CVT – 65 (15%) • (-) CVT – 359 (18%) • Proximal DVT/PE at 3 mo (p = .003) • Untreated CVT – 5 / 65 (7.8%) • No CVT – 3 / 359 (0.8%) • Limitations • Non consecutive enrollment • Outpatients only Symptomatic Outpatients (N = 3470) Proximal Compression U/S Pre-Test Probability (Well’s) D-Dimer Low PTP Negative U/S Negative D-Dimer (n = 1212) Positive U/S (n = 370) Low PTP Negative U/S Positive D-Dimer (n = 1561) High PTP Negative U/S (n = 327) Enrolled in study (n = 431) Complete U/S including calf veins Physician / patient blinded to results

  23. Randomized Clinical TrialsLagerstedt al, Lancet 1985 • Randomized study of 51 patients with CVT • Heparin X 5 Days (N=28) • Heparin X 5 Days Warfarin X 3 mo (N=23) • Warfarin group • No recurrence • 9% (N=2) major hemorrhage • Heparin only group • 29% recurrence • 18% proximal propagation

  24. Randomized Trials – ICMVTSchwarz et al, J Vasc Surg 2010 • 109 consecutive pts with muscular calf vein thrombosis • 89% outpatients • 69 (63%) soleal, 40 (37%) gastrocnemial thrombi • Randomized to • Therapeutic LMWH X 10 days + compression stockings • Compression stockings • Progression to deep axial veins at 3 months (p = ns) • LMWH – 3 / 54 (5.6%) at 20 and 28 days • Compression – 3 / 53 (5.7%) at 8 and 31 days • No proximal DVT, symptomatic PE, or death

  25. Isolated Calf Vein ThrombosisWhat is the evidence to guide anticoagulation? But… High Quality (Grade A) Data Is Lacking

  26. The evidence supports anticoagulating at least some isolated CVT in at least some patients at least some of the time But…. All isolated CVT are not equal Irreversible Risk Factors Age Malignancy Hypercoagulability Outpatient Axial CVT Idiopathic DVT Immobile Muscular CVT Inpatient Ambulatory Transient Risk Factors Surgery Trauma Estrogen Isolated Calf Vein Thrombosis

  27. Summary of the Evidence • Natural history differs from proximal DVT • Fewer risk factors • Lower prevalence of malignancy • More rapid recanalization • Complications fewer but not trivial • 20% risk of propagation • Symptomatic PE in 10% at presentation • Recurrent VTE in 5-10%, fatal PE in 1% untreated • One quarter remain symptomatic at 1 year • Anticoagulation is appropriate in at least some patients and those not anticoagulated should be followed with serial U/S • What we don’t know is who can be safely followed • At present, clinical judgment is critical

  28. Pending Randomized Trials • CACTUS University Hospital, Montpellier, France • 600 patients with isolated CVT • Nadroparin X 6 weeks vs placebo • 1º Outcome – 6 week U/S extension to proximal veins • DiVeTAS University of Washington, Seattle, WA • 600 patients (6 centers) with isolated CVT • Warfarin X 3 months vs duplex U/S surveillance • 1º outcome – Propagation, PE, bleeding & mortality (composite) • 2º outcomes • Identification of high risk groups • Clinical & anatomic factors • Biomarkers • Long term outcome – PTS & quality of life • Cost

  29. Develop best practices for the management of chronic venous ulceration

  30. Venous Leg UlcerationThe Public Health Impact • 1 – 1.5% Prevalence of active ulcers in Western populations • 100% recurrence without effective treatment • Limitations comparable to other chronic diseases • 10% unable to work • 2,000,000 lost work days per year • 90% require medical treatment • 1% of healthcare costs of Western European countries • Mean cost of € 9569 ($13, 130) / patient / year (Germany) • Annual costs of £ 300 to 600 million in the UK

  31. The Landscape of VLU guidelinesO’Donnell TF, J Vasc Surg 2011 • Systematic survey of published VLU guidelines (N = 14) • Poorly coordinated • Poorly adopted • Many areas not addressed (e.g perforator surgery)

  32. The 6th Pacific Vascular SymposiumHenke P, J Vasc Surg 2011 • Monthly conference calls initiated in December 2010 • Initial priorities • Establish current ulcer prevalence in the U.S • Venous guidelines (Bill Marston & Tom O’Donnell) • Key wound care societies (WHS & AAWC) engaged • Planned systematic reviews & meta-analyses • Obvious need for SVS involvement & support 50% Reduction in VLU within 10 yrs

  33. What is the comparative effectiveness of compression therapy versus ablation in preventing the progression of chronic venous disease?

  34. The Utility of Venous InterventionsThe REACTIV Trial (Ratcliffe , Br J Surg 2006) • 246 patients extensive vv and saphenous reflux randomized to • Conservative measures (n = 122) • Saphenous stripping / phlebectomy (n = 124) • 24 mo cost effectiveness of £4682 per QALY gained • Below NHS threshold of £20,000 per QALY * Incremental cost effectiveness ratio

  35. Venous Disease – Comparative EffectivenessGohel, BJS 2010 • Markov model based on 2 metanalyses, 1 RCT • Odds ratio of GSV occlusion (Stripping versus…) • Laser ablation – 0.97 • Radiofrequency ablation – 0.84 • U/S guided foam sclerotherapy – 3.01 • 0.1 QALY / yr gained with intervention However, substantial uncertainty in estimates Robust comparative effectiveness data is needed

  36. Intervention improves QALYs, but…CVD is a chronic disease and is there any evidence that intervention is effective in preventing progression? • What is the number need to treat to prevent 1 ulcer? • What is the cost of preventing 1 ulcer? • What is the comparative effectiveness of different treatments?

  37. Primary Venous DiseaseThe Bonn Vein Study, J Vasc Surg 2008 • Cross sectional sample of 3072 subjects • 2% per year progression to CVI (C3 – C6) • Risk factors for progression • Age • Arterial hypertension • Obesity

  38. CVD Progression – The ProblemsPacific Vascular Symposium 6, J Vasc Surg 2010 • Most patients with CVD do not progress to C4 – 6 • Advanced CVD is a multifactorial disease • Age • Obesity • Gender • Hypertension • Occupation • HFE polymorphisms • AT deficiency • Number needed to prevent 1 ulcer (NNT) is unknown

  39. Could a CER Analysis Be Done? • Theoretical randomized trial to reduce progression from C1-2 to C3-6 by 50% • Observation only • Superficial venous intervention • Assumptions • 2% per year progression • 5 year reduction in progression from 10% to 5% • Alpha error = 0.5, 80% power • 20% loss to follow-up • 440 patients per group • 1056 patients required • 5 year claudication CER study cost $12 million PROBABLY REQUIRES AN OBSERVATIONAL DESIGN

  40. Venous InterventionsComparative Effectiveness • The United States health care quandry • Regulatory environment favors innovation over effectiveness • Increases in technology costs are unsustainable • Cost-consequence analysis and comparative effectiveness are increasingly important • What we know • Venous interventions improve quality of life • Venous interventions are cost effective at standard willingness to pay thresholds • Some effective interventions are far cheaper than others • Device costs based on “what the market will bear” probably can’t continue • What we don’t know • Cost-effectiveness of interventions to prevent progression • Comparative effectiveness of different interventions

  41. What is the leading cause of disability in young & middle aged people in the developed world?

  42. Multiple SclerosisKoch-Henriksen, Lancet Neurology 2010 • Demyelinating immune mediated CNS disease • Leading cause of disability in young / middle aged patients • Epidemiology • Peak incidence at age 30 • Peak prevalence at age 50 • North American incidence of 100 – 200/100,000 • Increasing incidence, particularly in females • Complex etiology • Genetic factors • Environmental factors • Socioeconomic factors But …. Is MS a primary vascular disorder

  43. Chronic Cerebrospinal Venous Insufficiency (CCSVI)Zamboni, Phlebology 2010 Leukocyte Activation, Adhesion, Migration RBC Extravasation Protein Extravasation Inflammation Venous Reflux Decreased Shear Endothelial Activation IJV / Azygous Stenosis in 56% - 100% of MS patients Perivenous Iron Deposition Fibrin Cuffing

  44. Chronic Cerebrospinal Venous InsufficiencyZamboni, J Neurol Neurosurg Psychiatry 2009 • Extra-cranial venous stenoses in all patients with 2 / 5 criteria • Azygous – 86% • Internal jugular – 91% • Lumbar plexus atresia – 18% • No lesions in 48 controls undergoing venography

  45. CCSVI & Multiple SclerosisLaupacis, CMAJ 2011 • Meta-analysis of U/S parameters (8 studies) • MS patients • Healthy controls or patients with other neurologic diseases • Problems with the data • Convenience sample (non-consecutive patients) • Inconsistent / poorly described blinding • Unexplained heterogeneity

  46. Cerebrocervical Venous Congestion in MSDoepp, Ann Neurol 2010

  47. Endovascular Treatment of CCSVIZamboni, J Vasc Surg 2009 • 65 MS patients with CCSVI by TCD / Duplex U/S • PTA of IJV and azygous stenoses • IJV – 53% patency at 18 months • Azygous – 96% patency at 18 months • Neurologic improvement only in relapsing remitting MS

  48. CCSVI – The CritisismsKhan, Ann Neurol 2010 • CCSVI does not adequately account for • Autoimmune features of MS • Genetic susceptibility (MHC and non-MHC linkage) • Environmental factors • Geography • Strong association with Epstein-Barr infection • Low vitamin D levels • Primary demyelination not seen with other causes of cerebral venous hypertension • Central venous thrombosis • Idiopathic intracranial hypertension • Pulmonary hypertension • COPD • Non-invasive findings not entirely reproducible

  49. CCSVI & The Power of Social NetworkingChaffe et al, Nature 2011 • The evidence – 22 published papers • The reality • 650, 000 Google results • Educated, organized patient population • Significant placebo effect in MS treatment • Many interventionalists willing to offer procedure • “In today's era of 'Facebook equipoise', it may make sense in rare cases to conduct a clinical trial before the desired weight of scientific evidence accumulates; for instance, if thousands of patients are exposing themselves to risks and costs of unevaluated medical procedures”

  50. CCSVI Clinical Trials • University of Ferrara, Ferrara, It (Paulo Zamboni, PI) • 500 multiple (RR & SP) patients randomized • Interventional treatment (angioplasty) • Sham interventional treatment • Standard immunomodulatory treatment maintained • Endpoints • Objective neurologic scores • MRI • Albany Medical College, Albany, NY (Manny Mehta, PI) • 2:1 randomization (600 patients) • Angioplasty • Sham interventional treatment • Blinded assessment by participating neurologist • Endpoints • EDSS, MsQoL, Fatigue impairment scores • MRI

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