Estudios clínicos: ¿disponemos de evidencia contundente, ruido o señal?

Dr. Costantini, RicardoCardioangiología Intervencionista

Jornadas Intervencionistas

Arteriales y Venosas del Hospital Austral

(JAVA) 2019

The incidence of first-episode deep vein thrombosis (DVT) is estimated at

300,000 cases per year / USA.1,2

Anticoagulant drugs have been successful for primary prevention of DVT and pulmonary embolism (PE),

and secondary prevention of late recurrent venous thromboembolic

events 3.

1. US Department of Health and Human Services. The Surgeon General’s Call to Action toprevent deep vein thrombosis and pulmonary embolism. http://www.surgeongeneral.gov/topics/deepvein.

2. Heit JA, Cohen AT, Anderson FA; Estimated annualnumber of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events. Blood.

2005;106:267a.3. Kearon C, Kahn SR, Agnelli G, et al. American College of Chest Physicians Evidence-Based Clinical Practice

Guidelines (8th Edition). Chest. 2008;133(6 suppl):454S-545S.

Causas de trombosis en miembros superiores

Primarias

Traumáticas Asociada al esfuerzo, injuria vascular.

Aumento de la presión venosa distal

Costilla cervical, compresión por vértebra cervical, síndrome del opérculo torácico, Sme de Paget Schroetter.

Estados de hipercoagulabilidad

Paraneoplásico, síndrome antifosfolipídico, Factor V de Leiden, déficit de antitrombina III, déficit de proteína C y S, mutación del gen 20210 de la protrombina, hiperhomocisteinemia, embarazo, anticonceptivos.

Secundarias

Dispositivos o catéteres

Acceso venoso central de corta o larga duración, marcapasos, desfibriladores.

Cáncer Linfoma, leucemia, pancreas, mama, pulmón, mesotelioma, esófago, tracto digestivo, quimioterapia, radioterapia.

10%

20%

80%

Despite the routine use of anticoagulanttherapy, posthrombotic syndrome (PTS) is

known to develop in 25% to 50% of proximal DVT patients. 1-3

Patients with PTS experience leg pain, swelling, heaviness, and/or fatigue; severely affected patients develop lifestyle-limiting

venous claudication, work disability, and/or venous ulcers.

1.The long-term clinical course of acute DVT. Ann Intern Med. 1996;125:1-7.2. Below-knee elastic compression stockings to prevent the PTS:

a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.3. Randomized trial of effect of compression stockings in

symptomatic proximal-vein thrombosis. Lancet. 1997;349:759-762.

Incidence of PTS with ACO plus compression stockings

Kahn SR. Effectiveness of compression stockings to prevent the post-thrombotic syndrome (the SOX Trial and Bio-SOX biomarker substudy): a randomized controlled trial.

BMC Cardiovasc Disord. 2007 Jul 24;7:21.

n % PTS

2008 Kahn et al. 387 40 – 60%

2014 SOX trial. 806 52%

An update on etiology, prevention, and therapy of postthrombotic syndromePeter K. Henke and Anthony J. Comerota - J Vasc Surg 2011;53:500-09

Síntomas por compresión anatómica aislada (obstrucción primaria)y también pueden desarrollar obstrucción postrombótica luego de trombosis venosa

profunda ilíaca o cava (obstrucción secundaria).

Total score of 0 to 4 indicates no

postthromboticsyndrome (PTS);

score of ≥5 indicates PTS.

PTS severity: total score of 5 to 9, mild PTS; score of 10 to 14,

moderate PTS; and score of ≥15 or venous ulcer present, severe

PTS.

La presentación clínica de los pacientes y la historia natural de la evolución del

trombo dependen de la distribución anatómica, de la extensión y el grado de

oclusión de la vena involucrada.

La eficacia de la trombólisis sistémica se ve

disminuida dado que una pequeña porción del

activador del plasminógeno está en contacto con

el trombo oclusivo,

y las complicaciones relacionadas con sangrado

son sustancialmente elevadas dadas las dosis

elevadas del trombolítico necesarias para producir

un estado lítico sostenido.

Goldhaber SZ, Buring JE, Lipnick RJ. Polled analyses of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis.

Am J med 1984;76:393-397.

Trombolisis dirigida por catéter

473 patients with symptomatic LE DVT(287 patients treated with CDT: UK 7.8 million IU - mean of 53.4 hours)

DVT symptoms were classified:

- Acute (≤10 days) in 188 (66%)- Chronic (>10 days) in 45 (16%)

-Acute and chronic in 54 (19%)

- Grade III (complete) lysis in 96 (31%) III 79%- Grade II (50%-99% lysis) in 162 (52%) II 58%-Grade I (< 50% lysis) in 54 (17%) I 32%

-# Major bleeding 11%

National multicenter registryCatheter-directed thrombolysis for lower extremity DVT

Mewissen MW, Seabrook GR, Meissner MH, Cynamon J, Labopoulos N, Haughton SH.

Radiology 1999;213:930

Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis.

• Acute iliofemoral DVT (<10 days)

• Life expectancy > 6 months - Age < 70

• Streptokinase (SK infusion at 100,000 U/hr) + Pulse spray (Jet lysis® catheter, Angiomed, Bard)

• Venography at 15 min intervals

• N= 35 patients (angioplasty and stent 18 / Heparin 17)

Elsharawy M, Elzayat E. Eur J Vasc Endovasc Surg 2002;24:209-14.

- Grade III (complete) lysis in 13 (72%) vs 2 (12%)- Grade II (50%-99% lysis) in 5 (28%) vs 8 (47%)-Grade I (< 50% lysis) in 0(0%) vs 7 (41%)

Elsharawy M, Elzayat E. Eur J Vasc Endovasc Surg 2002;24:209-14.

At 6-month f/u, venous reflux was:41% (7/17) after AC vs 11% (2/18) after CDT (p = 0.04).

At 6-month f/u, patency rate was:72% (13/18) after CDT vs 12% (2/17 ) after AC (p < 0.001)

1° RCT = CDT IS SUPERIOR TO ACO

Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis.

Long‐term results using CDT: catheter directed thrombolysis in 103 lower limbs with acute

iliofemoral venous thrombosis.

Follow-up duplex US for vessel patency and valvefunction: 6 weeks, 3, 6 and 12 months and

yearly up to 6 years

Baekgaard N, Broholm R, Just S, Jørgensen M, Jensen LP.

Eur J Vasc Endovasc Surg 2010; 39:112‐7.

Pacientes muy seleccionados

Long‐term results using CDT: catheter directed thrombolysis in 103 lower limbs with acute

iliofemoral venous thrombosis.

Baekgaard N, Broholm R, Just S, Jørgensen M, Jensen LP.

Eur J Vasc Endovasc Surg 2010; 39:112‐7.

Open veins without reflux were achieved in 82 - 86% of the

affected lower extremities after 6 years without any mortality, or new PE and only a few cases of

new DVT (7 cases).

The patients with restored venous iliofemoral segments

showed no sign of PTS such as venous claudication, eczema or

ulceration.

Postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral DVT.

Comerota AJ, Grewal N, Martinez JT, et al.

J Vasc Surg. 2012; 55:768-73.

The TORPEDO TrialEndovenous Therapy for Deep Venous Thrombosis:

(Thrombus Obliteration by Rapid Percutaneous Endovenous intervention in Deep venous Occlusion.

Sharifi M, Mehdipour M, Bay C, Smith G, Sharifi J. - Catheter Cardiovasc Interv. 2010;76(3):316-25.

0

5

10

15

20

25

30

PEVI (n=91) Control (n=92)

2.3

14.8

3.4

27.2

ReTVP PTS

p= 0,003

p= < 0,001

%

SóloEnoxaparina

oHNF

The TORPEDO Trial(Thrombus Obliteration by Rapid Percutaneous Endovenous intervention in Deep venous Occlusion.

Sharifi M. et al - J Endovasc Ther 2012; 19:273-280

Resultados a 30 meses

CaVenT trial

(Catheter Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis):

open-label, randomised controlled trial

CaVenT trial - Lancet 2012; 379: 31–38

Pacientes (n=209) con un primer evento de trombosis venosa profunda iliofemoral

dentro de los 21 días de inicio de los síntomas.

CDT = tPA 0.01 mg/kg per hr (maximum 96 h - maximum dose was 20 mg/24 h) -

15% received venous stent.

2° RCT = CDT IS SUPERIOR TO AC

At 5 year follow-up data were available for 176 patients (84% of the 209 patients originally randomised)—87 originally assigned to catheter-directed thrombolysis and 89 originally

assigned to the control group.

(CaVenT): 5-year follow-up

The Lancet Haematology - Vol 3, No. 2, e64–e71, February 2016

0

10

20

30

40

50

60

70

PTS

43

63

CDT

Std Tto

Absolute RR 28% (95% CI 14–42)

NNT 4 (95% CI 2–7).

%

(p<0,001)

Post-thrombotic syndrome

ATTRACT 2-Year Data

A total 692 patients with either iliofemoral or femoropopliteal acute DVT to receive either PCDT and standard DVT therapy n= 337 or standard DVT therapy alone n=355

The primary outcome measure will be the cumulative incidence of PTS over 2-year follow-up using the Villalta PTS scale.

If the popliteal vein was occluded or the inferior vena cava was involved, physicians were required to use “infusion-first” therapy, which started with rt-PA infusion through a multi-sidehole catheter of the physician’s choice for no longer than 30 hours. For the remaining patients, physicians were required to first attempt single-session thrombus removal with rapid delivery of rt-PA through the AngioJet Rheolytic Thrombectomy System (Boston Scientific) or the Trellis Peripheral Infusion System (Covidien) and then to infuse rt-PA for no longer than 24 hours if residual thrombus was present.Stenting : lesions that were causing 50% or greater narrowing of the diameter of the vein, robust collateral filling, or a mean pressure gradient of more than 2 mm Hg.

ATTRACT 2-Year Data

Comentarios relacionados a ATTRACT:

# Resultado clínico mas relevante (formas moderadas y severas PTS) como EP secundario. Las formas leves son frecuentes tanto para TVP iliacas como las femoropopliteas.

# El implante de stent sugerido en caso de gradiente translesional (> 2mmHg): en territorio venoso no esta establecido tal parámetro hemodinámico.Venografía parecería inadecuada para valorar la extensión de enfermedad de la pared. Sensibilidad 60% . Probabilidad de mayor retrombosis.

# La tasa de uso de stent en ATTRACT 28%; en registros > 60%. El 80% de los stentsutilizados no son dedicados para territorio venoso.

# Pérdida de la oportunidad para evaluar hipótesis de la “vena abierta”:

Kuo WT. Optimizing catheter-directed thrombolysis for acute DVT: Validating the Open Vein Hypothesis.

J Vasc Interv Radiol 2013; 24:24-26.

Reducir la masa trombótica en la etapa aguda, lograr una mayor tasa de

repermeabilización y minimizar el daño vascular

con el objetivo de disminuir la incidencia del síndrome pos trombótico.

Trombolisis dirigida por catéter

TromboaspiraciónFragmentación / Maceración

con angioplastia

Implante de stent

“Hipótesis de la vena abierta”:

inmediata y efectiva remoción de trombos venosa aguda para disminuir

el riesgo de PTS.

AngioplastiaFármaco mecánica

Safety and Effectiveness of Stent Placement for IliofemoralVenous Outflow Obstruction

Systematic Review and Meta-Analysis

37 estudios; 2869 pacientes:

Éxito técnico 94 – 96%Sangrado mayor 0,3 – 1.1%Embolia pulmonar 0,2 – 0,9%Mortalidad 0,1 – 0,7%

Trombosis temprana 1 – 6.8%

Razavi M ; Jaff D; Miller L. - Circ Cardiovasc Interv. 2015;8:e002772

NT= nonthrombotic AT= acute thrombotic CPT= chronic post-thrombotic

Opciones:

The Leipzig Interventional Course - January 2019

Black Stephen et al - Eur J Vasc Endovasc Surg 2018; 56: 710 - 718

Vici Venous Stent™: Recanalización de lesiones crónicas en vena iliaca

0

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20

30

40

50

60

70

2003 - 2010 2011 - 2013 2014 - 2018

62

67

Procedimientos

0

2

4

6

8

10

12

14

16

18

20

2013 2014 2015 2016 2017 2018

1

89

1615

20

0

2

5 5

2 2

0

3 3

10

12

17

1

3

1 1 1 10

21 1

8

11

Total MMSS MMII Vena Cava May Thurner

n

Intervenciones en Grandes Venas - Progresión

Telayna, JM; Telayna, JM (h); Costantini, RA; Colimodio, P; Aris Cancela ME

TCT 2018 – poster 1017

RETHROMBOSIS AND REINTERVENTION PREDICTORS

IN MAY THURNER SYNDROME

Long term Outcomes of Endovascular Treatment in Large Veins - HUA

Telayna, Juan Manuel; Telayna, Juan Manuel (h); Costantini, Ricardo A; Paganini Ines; Colimodio, Pablo; María E. Aris Cancela. - VIVA Veins 2017

50 interventions:Age 39 ± 16 years; Women 27 (54%); Contraceptives 9 (20%); Hereditary family history 2 (5%); Recent surgery 14 (28%); Cancer 11 (22%);

Mean time symptom - treatment 10.8 ± 10.5 days;

Associated pulmonary embolism 13(26%);

VCF before intervention 21 (42%). Collateral circulation 30 (60%); Thromboaspiration 30 (60%); RTPA 26 (52%); Stent implantation 25 (50%).

020406080

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Resultados

A mean follow-up of 24 months was obtained in 30 interventions (67%) with a requirement for a new

intervention in 2 (4%).

%

Conclusiones I:

o Campo de la patología venosa en expansión más rápida que la base del conocimiento( muchas preguntas aún sin respuestas).

o Individualizar cuales pacientes se benefician más con estos procedimientos

o Los estudios sugieren (Fuerte Señal) que la remoción de trombos no sólo restaura la permeabilidad de las venas sino que también reduce la recurrencia trombótica y la morbilidad del síndrome postrombótico.

Conclusiones II:

o El implante de stents en territorio venoso es seguro y efectivo.

o Evitar la re-trombosis temprana y mantener la permeabilidad a largo plazo es el principal desafío terapéutico tanto en casos agudos como crónicos para el grupo multidisciplinario de trabajo.

o Los médicos comprometidos en medicina cardiovascular debemos repensar nuestra práctica, el tratamiento sólo del corazón y las arterias no es suficiente; debemos balancear el “lado rojo” con el “lado azul” e integrar el manejo de la patología venosa a la patología arterial.

Muchas Gracias