10/12/2015

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Top Four Most Important Recent Developments in Venous Disease

Gregory L. Moneta, M.D.Professor and Chief, Vascular Surgery

Oregon Health & Science UniversityKnight Cardiovascular Institute

Portland. Oregon, USA

Considered But Rejected

• Venous etiology of multiple sclerosis

• Endovenous saphenous ablation

• Retrievable venous filters

• Foam sclerotherapy

• American Board of Phlebology

• Accreditation process for outpatient venous

centers

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Randomized Trials

Tight Glucose Control in Type II Diabetes

No Benefit!

NEJM 2009; 360: 129-139

Good Idea / No Benefit

Aspirin for Primary Prevention of Vascular

Disease

No Benefit!

Lancet 2009; 373:1849-1850

Good Idea / No Benefit

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#4 Efficacy of Thrombolytic Therapy

for Acute Iliofemoral DVT

Possible Correlates With PTS Post DVT

•Thrombus Location, Propagation,

Recurrence, and Resolution

•Reflux: Development, Location,

Severity

•Residual Obstruction

Post Thrombotic Syndrome

• Open-label, randomized, controlled trial of catheter

directed thrombolytic therapy (alteplase) in addition to

standard treatment vs. standard treatment alone in

patients 18-75 years old with first time iliofemoral DVT

• 21 days within symptom onset

• Objective confirmation of DVT

• Primary outcomes:

-PTS at 24 months assessed by Villalta score

-Iliofemoral patency at 6 months

CaVenT Study*

*Lancet 2012; 379:7-13

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CaVenT Study*

(Short and Long-Term Results)

Standard Treatment

and Catheter Directed

Thrombolysis

(n= 90)

Standard Treatment

Only

(n=99)

P value

n %

(95% CI)n %

(95%CI)

PTS @ 6

months27 30%

(22 - 41)

32 32%

(24 - 42)

0.77

Iliofemoral

patency @ 6

months

58 66%

(56 - 75)

45 47%

(38 - 57)

0.012

PTS @ 24

months37 41%

(32 - 51)

55 56%

(46- 65)

0.047

CaVenT Study*

CaVenT Study*

•No improvement in PTS at 6 months.

•Improved iliofemoral patency at 6 months.

•14% improvement in PTS at 24 months.

•Number needed to treat is 7.

•Per-protocol: 17% improvement; NNT: 6

*Lancet 2012; 379:7-13

(Short and Long-Term Results)

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(Stroke and Death at 5-years)

ICA Stenosis Medical Group Surgical Group NNT

NASCET (Symptomatic ICA stenosis)

70% - 99% 26.1% 12.9% 8

50% - 69% 22.2% 15.7% 15

60% - 99% 11% 5% 19

ACAS (Asymptomatic ICA stenosis)

Carotid Endarterectomy Trials

ATTRACT Trial

•Open-label, controlled, multicenter trial

•NIH sponsored

•692 patients with proximal DVT

•Anticipated completion 2015

•NCT00790335

Thrombolytic Therapy for Iliofemoral DVT

The Claim: Thrombolytic therapy decreases

rates of PTS following iliofemoral DVT

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#3 Proliferation of Venous Stents

More venous stents than

the entire planet!

“Venous stents can be

safely placed in the

venous system across

the inguinal crease with

no risk of stent

fractures, narrowing

due to external

compression, focal

development of severe

in-stent re-stenosis and

no effect on long term

patency.”

JVS 2008; 48:1255-1261

What we are Asked to Believe

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• “Iliac venous stenting alone is sufficient to control

symptoms in the majority of patients with combined

outflow obstruction and deep reflux” (JVS 2009)

• Venous stenting results in “major symptom relief in

patients with chronic venous disease not

consistently reflected in any substantial

hemodynamic improvement by conventional

measurement. Benefit is regardless of presence of

remaining reflux, adjunct saphenous procedures or

etiology of obstruction.”

What We Are Asked to Believe

(JVS 2007; 46:979-990)

Stenting and Healed Ulcers

70% at 2 years

Neglen et al JVS 2007; 46:979-90

Non-Operative Treatment of Venous Ulcer

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Non-Operative Treatment of Venous Ulcer

M Marsten W, et al. JVS 1999; 30:491-498

Marsten W, et al. JVS 1999; 30:491-498M

*Marsten W, et al. JVS 1999; 30:491-498

Non-Operative Treatment of Venous Ulcer

Non-Operative Treatment of Venous Ulcer

*Guest, et al. Brit J Surg 1999; 86:1437-1440

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Stenting and Healed Ulcers

70% at 2 years

Neglen et al JVS 2007; 46:979-90

Venous Stents for Treatment of Venous Ulcer

The Claim: Venous stents are all that are

needed to heal venous ulcers

#2 FDA Warning: IVC Filters

• Since 2005 there were 921 adverse event

reports:

-328 migrations

-146 embolizations of device components

-70 IVC perforations

-56 filter fractures

( Posted August 9, 2010)

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IVC Filters

• 1979: 2000 filters

• By 1990: >120,000

Greenfield filters had

been placed

• 2000: 50,000/yr

• 2009:>130,000/yr

(Increasing Utilization)

IVC Filters

• First IVC filter

• Developed in late 1960s

• Initial favorable reports

• Late reports:

-50% IVC occlusion rate

-High rate of PE

-Migration

(Mobin Uddin Filter)

IVC Filters

• 469 patients

• 146 long-term follow-up (mean 43 months)

• 190 lost to follow-up

• 133 died (33%)

• 4% PE rate (17 fatal, 9 nonfatal)

• 4% IVC occlusion

• 44% with post thrombotic syndrome

(Kimray-Greenfield Filter: 1988 report*)

*Surgery 1988; 104: 706-712

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IVC Filters

• Served as evidence for efficacy of IVC filters

• Likely would not be sufficient evidence by

modern standards:

-Half the patients lost by either death or LTFU

-No control group

-No follow-up imaging

(Kimray-Greenfield Filter: 1988 report*)

*Surgery 1988; 104: 706-712

IVC Filters

• U.S. Food and Drug Administration (FDA) approval

process for vena cava filters:

- all filters approved through the 510 (k) process for

devices

- NOT based on safety

- NOT based on efficacy

- Based on similarity to an existing product

(How Did We Get Where we Are?)

IVC Filters

• 510 (k) process in 1976 served as the basis of

approval of the Mobin Uddin filter

-there was no previous approved filter!

• 510 (k) process in 1985 served as the basis of

approval of the Greenfield filter

-based on approval of the Mobin Uddin filter!

510 (k) process: Titanium Greenfield, Bird’s Nest,

VenaTech, Gunther Tulip, etc

• IOM recommends 510 (k) process be stopped!

(How Did We Get Where we Are?)

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IVC Filters

• More than 600 reports

• Virtually all retrospective analysis of single

institution case-series

• Only ONE randomized, controlled trial

(Literature)

IVC Filters

• Published in 1988

• 400 consecutive patients with acute

proximal DVT with or without PE

• Considered ‘high-risk” by their physicians

(PREPIC Study: Prevention du Risque

d’Pulmonarie par Interruption Cave )

IVC Filters

• No mortality difference with or without filter

• Filter patients: 10% higher DVT rate (95%

CI, 11.6% to 20.8%)

• Nonstatistically significant reduction in PE,

p=0.16

•

(PREPIC Study: Two-year Results)

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IVC Filters

• in symptomatic PE in the filter group

-6.2% vs. 15.2% (p =0.008)

• in DVT in the filter group

-35.7% vs. 27.5% (p= 0.04)

• No difference in mortality

(PREPIC Study: Eight-year Results)

IVC Filters

• Annual phone calls:

-Questioned for symptoms suggestive of VTE

-Imaging recommended based on answers

• Therefore not just symptoms drove patients to

hospital

• Is discovering a condition evident only on probing a

valid patient-centered outcome?

•

(PREPIC Study: How was PE determined?)

IVC Filters

• Benefits: Difficult to prove

• Complications: Are now obvious:

-Bird’s Nest: 0.34% procedural deaths

-VenaTech: 22% IVC occlusion at 5 years

33% IVC occlusion at 9 years

-Bard Retrievable: 16% risk stent fracture

(How Did We Get Where we Are?)

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IVC Filters

•29 year old male with a

perforated duodenum from an

IVC filter.

•4 unit drop in Hematocrit

• Ruptured infrarenal aortic

pseudoaneurysm discovered at

exploration.

•Treated with rifampin soaked

Dacron aortic interposition graft

IVC Filters

• American college of Chest Physicians

• American Heart Association

• British Committee for Standards in Hematology

• Thrombosis Interest Group of Canada

(Guidelines)

Only consensus is placement in patients

with VTE and a contraindication to

anticoagulation!

Vena Cava Filters

The Claim: Vena cava filters save lives

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1. Dabigatran

2. Rivaroxaban

3. Apixaban

#1: New Antithrombotic Agents

Venous Thrombosis

Drug Thrombosis Bleeding

Dabigatran Equal Equal

Rivaroxaban Equal Equal/Better

Apixaban Equal Better

Apixaban

• Oral Xa Inhibitor

• Bioavailability: 66%

• Onset of action: 1-3 hours

• Half-life : 8-15 hours

• Renal excretion: 25%

• Drug interactions: CYP 3A4

– Multiple other pathways

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Apixaban and Treatment of Acute VTE*

• Double-blind, randomized, controlled trial

• 5395 patients with acute VTE

-10mg Apixaban twice daily for 7 days

followed by 5mg twice daily for 6 months

-Enoxaparin followed by warfarin

• Primary endpoint: recurrent symptomatic

VTE or VTE related death

• Safety endpoint: major bleeding

*New Engl J Med 2013; 369: 799-808

Apixaban and VTE: Randomization Process

New Engl J Med 2013; 369: 799-808

Apixaban and VTE: Primary Endpoint

New Engl J Med 2013; 369: 799-808

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Apixaban and VTE: Major Bleeding Complications

New Engl J Med 2013; 369: 799-808

Apixaban - Surgery

• Normal renal function – hold 24 hours

• Impaired renal function – hold 48 hours

New Anticoagulants and Venous

Thromboembolism

The Claim: The new anticoagulants are likely

to be preferred to warfarin

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• Catheter directed thrombolytic therapy for acute

iliofemoral DVT appears to improve late iliofemoral

venous patency.

• Catheter directed thrombolytic therapy for acute

iliofemoral DVT appears to decrease late PTS.

• Results of the ATTRACT trial are pending.

#4 Thrombolytic Therapy for

Iliofemoral DVTSummary

• Venous stents stay open in the short-term.

• Perhaps with the exception of short-term treatment

of May-Thurner syndrome there is no consensus on

use of venous stents.

• Long-term efficacy is unclear.

• There is no proof venous stents alone heal venous

ulcers or can serve as the only treatment of > C3

disease.

#2 Venous StentsSummary

• It is unclear why IVC filters were ever approved.

• There is no consensus on the use of IVC filters.

• There is clear evidence IVC filters can cause harm.

• There is no convincing evidence IVC filters save lives.

#2 IVC FiltersSummary

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• The new anticoagulants are equal to warfarin in the

treatment of non-valvular artrial fibrillation.

• The new anticoagulants are equal to warfarin in the

treatment of venous thromboembolism.

• The new anticoagulants are safer than warfarin.

• Issues: reversal, missed doses, renal function, etc.

#1 The New AnticoagulantsSummary

Cascade Mountains, Oregon

Questions?