Research Priorities in Venous Disease

Mark H. Meissner, MDProfessor of Surgery

University of Washington School of MedicineSeattle, WA

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?

What is the role of prophylactic IVC filters – Is PE/death reduced compared to other methods of VTE prophylaxis

or duplex surveillance or both?

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

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)

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

Heparin Enoxaparin p

DVT 44% 31% 0.014Proximal DVT 15% 6% 0.012Major Bleeding 0.6% 2.9% 0.12

ACCP Guidelines for TraumaGeerts et al, Chest 2008

Guideline GRADE Recommendation

For major trauma patients, in the absence of a major contraindication, we recommend LMWH thromboprophylaxis starting as soon as it is considered safe

1A

If LMWH is contraindicated due to active bleeding or high risk for clinically important bleeding, we recommend mechanical thromboprophylaxis

1B

We recommend against routine DUS screening .. But, we do recommend DUS screening in patients at high risk for VTE (i.e. SCI) and who have received suboptimal or no prophylaxis

1C

We recommend against the use of an IVC filter for thromboprophylaxis

1C

EAST GuidelinesRogers FB et al, J Trauma 2002

Guideline Level of Evidence

Little evidence exists to support LDUFH as a sole agent for prophylaxis

II

No benefit of the use of SCDs over no prophylaxis. In the subset of head injured patients, SCDs may have some benefit.

III

LMWH can be used with the following injury patterns 1) Pelvic fractures, 2) Complex lower extremity fractures, 3) Spinal cord injury

II

Insertion of a prophylactic IVC filter should be considered in very high risk trauma patients who cannot receive anticoagulation

III

Serial duplex ultrasound imaging of asymptomatic patients may be cost effective and decrease the incidence of PE

III

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

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

Outcome SCD only SCD + Duplex Prophylactic VCFDVT % 14.9 15.0 25.7

PE % 2.9 1.5 0.3

Mortality % 24.5 24.4 24.5

Cost ($ Can) 55, 831 55, 334 57, 377

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 Late Prophylaxis pICH Progression 1.46% 1.54% 0.9

Pulmonary Embolism 1.5% 2.2% 0.49

Proximal DVT 1.5% 3.5% 0.1

Distal DVT 3.7% 6.7% 0.09

“ Early prophylaxis appears safe for patients with TBI”

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”

CER Research – Registry Approacheswww.venousregistry.org

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)

The trusted venous resource

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

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

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

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

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)

Is There Data to Guide Management?

Natural History Studies

Observational (cohort) studies

Randomized trials

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

Natural History Based Mathematical ModelsModified from Raskob, 1996

Isolated Calf Vein Thrombosis

20% Propagation No Propagation

20 - 50% Recurrent VTE

5-10% SymptomaticPE

10% Fatal PE

1% Fatal PE

?? Embolic Risk

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/SPre-Test Probability (Well’s)

D-Dimer

Positive U/S(n = 370)

Low PTPNegative U/SNegative D-

Dimer(n = 1212)High PTP

Negative U/S(n = 327)

Low PTPNegative U/S

Positive D-Dimer(n = 1561)

Enrolled in study(n = 431)

Complete U/S including calf veinsPhysician / patient blinded to results

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

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

Isolated Calf Vein ThrombosisWhat is the evidence to guide anticoagulation?

Data Anticoagualtion?

Grade of Evidence

Natural History Studies

20% propagation, 10% concurrent PE, 23% PTS Favors C

Cohort Studies 7.8% Recurrent VTE Favors C

RCTsCVT – 29% Recurrent VTE

MCVT – 5.7% Recurrent VTE

CVT – FavorsMCVT - No B

Mathematical Models

5 – 10 % Recurrent VTE2 % Fatal PE Favors C

But…High Quality (Grade A) Data Is Lacking

Isolated Calf Vein Thrombosis

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

AgeMalignancy

Hypercoagulability

Idiopathic DVT

Immobile

Inpatient

Axial CVT

Transient Risk FactorsSurgeryTraumaEstrogen

Ambulatory

Outpatient

Muscular CVT

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

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 factorsBiomarkers

Long term outcome – PTS & quality of lifeCost

Develop best practices for the management of chronic venous

ulceration

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

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)

Guideline Inclusion Strongly Recommended RecommendedClinical Exam 14 (100%) 3 (23%) 4 (31%)

Diagnosis Doppler ABI 14 (100) 6 (46) 4 (31)

Venous Duplex 9 (64) 4 (44) 2 (22)

Cleanse Wound 13 (93) 3 (25) 4 (33)

Wound Debride Wound 12 (86) 4 (36) 3 (27)

Care Dressings 14 (100) 10 (77) 2 (15)

Compression 14 (100) 9 (75) 3 (23)

Adjunctive Skin Graft 10 (71) 5 (56) 4 (44)

Treatment Pentoxyfylline 11 (79) 7 (64) 2 (18)

Prevention of BK Stockings 13 (93) 7 (58) 2 (18)

Recurrence Superficial Surgery 11 (79) 8 (73) 1 (9)

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) engagedPlanned systematic reviews & meta-analysesObvious need for SVS involvement & support

50% Reduction in VLU within 10 yrs

What is the comparative effectiveness of compression therapy versus

ablation in preventing the progression of chronic venous disease?

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

Conservative Surgery Mean Difference

Mean NHS Cost £344.53 £733.10 £388.57

AUC SF-6D 1.42 1.50 0.083

ICER * £4682* Incremental cost effectiveness ratio

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

Treatment 5 Yr Costs (£)

Incremental QALY Gained

ICER (£ / QALY)

Conservative 0 - -UGFS 429 0.314 1360Laser 1031 0.104 5799

Radiofrequency 1110 0.005 17,360Stripping/phleb 1242 0.007 19,012

However, substantial uncertainty in estimatesRobust comparative effectiveness data is needed

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?

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

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

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

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

What is the leading cause of disability in young & middle aged

people in the developed world?

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

Chronic Cerebrospinal Venous Insufficiency (CCSVI)Zamboni, Phlebology 2010

IJV / Azygous Stenosis in 56% - 100% of MS

patients

Venous Reflux

Decreased Shear

Leukocyte Activation, Adhesion, Migration

Endothelial Activation

RBC Extravasation

Protein Extravasation

Inflammation

Perivenous Iron DepositionFibrin Cuffing

Chronic Cerebrospinal Venous InsufficiencyZamboni, J Neurol Neurosurg Psychiatry 2009

Transcranial Doppler / Duplex Ultrasound Criteria MS (n = 65)

Controls (n = 235)

Reflux in IJVs or vertebral veins (VVs) > 0.88 s 71% 0%Reflux in deep cerebral veins > 0.5 s 61% 0% IJV stenosis by B mode (Cross sectional area ≤ 0.3 cm2) 37% 0%No Doppler flow in IJVs or VVs 52% 0%Increase in IJV cross sectional area supine to sitting 55% 0%

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

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

Cerebrocervical Venous Congestion in MSDoepp, Ann Neurol 2010

Criteria Patientsn = 56

Controlsn = 20

Reflux > 0.88 sec in IJVs and/or VVs 13/38 (38%) 6/30 (30%)

Reflux in the DCV 1 0

Proximal IJV stenosis (B mode) 0 0

Absent Doppler flow in both IJVs and or both VVs 5 1

Absent IJV lumen reduction with standing 4 3

One CCSVI criteria 10 4

Two CCSVI criteria 0 0

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

Pre-PTA 18 mo F/u p

Relapse Free % 27% 50% <.0014

MRI Gad + lesions % 50% 12% <.0001

MSQOL, physical 66 ± 18 84 ± 16 .01

MSQOL, mental 61 ± 22 82 ± 13 .003

MS Functional Composite 5e-18 ± 0.7 0.65 ± 0.5 .008

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

GeographyStrong association with Epstein-Barr infectionLow 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

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”

CCSVI Clinical Trials University of Ferrara, Ferrara, It (Paulo Zamboni, PI)

500 multiple (RR & SP) patients randomizedInterventional treatment (angioplasty)Sham interventional treatment

Standard immunomodulatory treatment maintained Endpoints

Objective neurologic scoresMRI

Albany Medical College, Albany, NY (Manny Mehta, PI) 2:1 randomization (600 patients)

AngioplastySham interventional treatment

Blinded assessment by participating neurologist Endpoints

EDSS, MsQoL, Fatigue impairment scoresMRI

Chronic Cerobrospinal Venous Insufficiency Current problems

Lack of clinical equipoise among many neurologists Patient driven interventions (Will placebo be accepted?) Willing interventionalists outside of trials

But, … this one eventually requires a multicenter RCT Vascular surgeons should own this investigation

Initial description (Paulo Zamboni) Diagnostic technology (Vascular Lab) Limited durability of percutaneous approaches in young

patients may eventually drive an operative solution Will require close collaboration with neurological community

Although technological approaches to standard diseases have evolved, this may be the first NEW vascular disease in our lifetimes

(and one that a smoking cessation and a statin won’t “cure”)