La profilassi in Medicina e Chirurgia -...

La profilassi in Medicina e Chirurgia

Dr. Angelo GhirarduzziSSD di Angiologia

ASMN Reggio Emilia

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Dr. Angelo Ghirarduzzi Reggio Emilia 09.06.09

Razionale per la Profilassi antitrombotica

• Natura silente della malattia: EP FATALE, possibile prima manifestazione. Mortalità > 2 volte rispetto a mortalitàassociata di AIDS, tumore mammella, tumore prostata, incidenti stradali…)

• SEVERA SPT: 5-10% • IPERTENSIONE POLMONARE CRONICA: 1%

• Metodiche strumentali di screening (eco-Doppler) pocoaffidabili nel paziente asintomatico

• Utile se: incidenza di TVP prox+EP > 3% = EP fatale > 0.1%

• Indispensabile se: incidenza di TVP prox+EP >10% = EP fatale > 1%

LE CATEGORIE DI PAZIENTI

• Paziente Ricoverato

- Reparto medico- Reparto chirurgico- Ortopedia

• Paziente “Sano” a domiclio

• Day Hospital, Day Surgery

• Dimissione Precoce

• Lungodegenza• Casa di riposo• ADI

• Con totale allettamento• Con parziale allettamento• Deambulante

LE CATEGORIE DI PAZIENTI

• Paziente Ricoverato

• Paziente “Sano” a domiclio

• Day Hospital, DaySurgery

• Dimissione Precoce

• Lungodegenza• Casa di riposo• ADI

• Con totale allettamento• Con parziale allettamento• Deambulante

1/1000/anno

10/100/anno 1/1000/anno

1/1000/anno

1/100/anno

80/100/anno >3/100/anno

1/1000/anno

1/10000/anno

1/100000/anno

Risk of VTE

ICU

Discharge

Time

?

Risk of VTE over Time

Surgery

VTE Prophylaxis in acutely ill medical patients

VTE without any prophylaxis

moderate risk but responsible for 75% of VTE

Leizorovicz & Mismetti. Circulation 2004

Asymptomatic DVT 17% 25% 50%

Internal medicineGeneral surgery

Stroke

Orthopaedic surgery

Studio Endorse: use of ACCP recommended prophylaxis

among overall population at risk of VTE

0

10

2030

40

50

60

7080

90

100

Algeria

Austra

liaBan

glade

shBra

zilBulg

aria

Colombia

Czech

Rep

Egypt

Franc

eGerm

any

Greece

Hunga

ryInd

iaIre

land

Kuwait

Mexico

Pakist

anPola

ndPor

tuga l

Roman

iaRus

sia

Saudi

Arabia

SlovakiaSpa

in

Switzer

land

Thaila

ndTun

isia

Turke

yUAE UKUSA

Venez

uela

%

Mean = 50%

n = 35 329

Cohen AT, et al. XXIst Conference of the ISTH; July 2007; Geneva, Switzerland [abstract O-S-002].

“Score Ginevra”Fattori di rischio Punteggio

Scompenso cardiaco 2

Insufficienza respiratoria 2

Ictus recente 2

Infarto miocardico recente 2

Malattia infettiva acuta (sepsi inclusa)

2

Malattia reumatica acuta 2

Cancro 2

Sindrome mieloproliferativa 2

Sindrome nefrosica 2

Anamnesi di tromboembolismo venoso

2

Fattori di rischio Punteggio

Stato ipercoagulativoriconosciuto

2

Immobilizzazione (<30 minuti di camminata/die) per ≥3 giorni

1

Recente viaggio (>6 ore) 1

Età >60 anni 1

Obesità (BMI >30) 1

Insufficienza venosa cronica 1

Gravidanza 1

Terapia ormonale (contraccettiva o sostitutiva)

1

Disidratazione 1

Tromboprofilassi indicata se punteggio ≥ 3

Chopard P et al. J Thromb Haemost 2006;4:915-916

“Score Barbar”Fattori di rischio Punteggio

Cancro in fase attiva 3

Pregresso TEV 3

Mobilità ridotta* 3

Conosciuta condizione trombofilica** 3

Recente (≤1 mese) trauma e/o chirurgia 2

Età ≥70 anni 1

Scompenso cardiaco NYHA III/IV e/o insufficienza respiratoria 1

IMA o ictus ischemico 1

Infezione acuta e/o malattia reumatica 1

Obesità (BMI≥30) 1

Trattamento ormonale in corso 1

*Allettato, ma si reca autonomamente ai servizi igienici; **difetti di antitrombina, proteina C o S, fattore V di Leiden, mutazione G20210A della protrombina, sindrome da anticorpi antifosfolipidi

Tromboprofilassi indicata se punteggio ≥ 4

Barbar S et al. J Thromb Haemost 2009;7(suppl 2):Abstract OC-MO-049

3 homogeneous RCTs versus Placebo

®

Enoxaparin placebo4000 IU6-14 days

all DVTVenography

At d6-14

Follow-up90 days

367 371

MEDENOX 1999 PREVENT 2004 ARTEMIS 2006

®

Dalteparin placebo5000 IU6-14 days

Proximal DVTUltrasound

At d21

Follow-up90 days

1848 1833

®

Fondaparinux placebo2.5 mg6-14 days

all DVTVenography

At d6-14

Follow-up30 days

429 420

MEDENOX1 63% 10 Placebo

Enoxaparin 40 mg

PREVENT2 49% 45 Placebo

Dalteparin

ARTEMIS3 47% 20 Placebo

Fondaparinux

Study RRR NNT Prophylaxis Patients with VTE, %

1Samama MM, et al. N Engl J Med. 1999;341:793-800.2Leizorovicz A, et al. Circulation. 2004;110:874-9.

3Cohen AT, et al. J Thromb Haemost. 2003;1 Suppl 1:P2046.

P<0.001

P=0.0015

P=0.029

NNT = number needed to treat; RRR = relative risk reduction.

RRR

63%

45%

47%

14.9* (n=288)

5.5 (n=291)

5.0 (n=1,473)†

2.8 (n=1,518)

10.5‡ (n=323)

5.6 (n=321)

*VTE at day 14; †VTE at day 21; ‡VTE at day 15.

Thromboprophylaxis of Medical Patients: Clear Benefits Over Placebo

VTE Prophylaxis in acutely ill medical patientsupdated meta-analysis

Heparins (UFH & LMWH) versus control : 9 RCTs = 19.958 pts

fatal PE

symptomatic DVT

major bleedings

Dentali et al. Ann Intern Med 2007

RR= 0.38 [0.21-0.69]

RR= 0.47 [0.22-1.00]

RR= 0.32 [0.73-2.37]

0.5 1 2

symptomatic PE

all-cause mortality

RR= 0.43 [0.26-0.71]

RR= 0.97 [0.79-1.19]

Raccomandazioni ACCP per pazienticon patologie mediche acute

• Per i pazienti con patologie mediche acute ammessi in ospedale con scompenso cardiaco o malattia respiratoria grave o allettati con uno o più fattori di rischio addizionali, che includono cancro in fase attiva, pregresso TEV, sepsi, patologia acuta neurologica o malattia infiammatoria dell’intestino, si raccomanda la profilassi con:

– EBPM [Grado 1A]

– ENF a basso dosaggio [Grado 1A]

– fondaparinux [Grado 1A]

Geerts WH et al. Chest 2008;133:381S-453S

Reccomendations & Critical Care

- Chest 2008 -

• For patients admitted to a critical care unit, we recommendroutine assessment for VTE risk and routine TP in most (Grade1A)• For critical care patients who are at moderate risk for VTE (medically ill or post-operative general surgery patients) = LDUH or LMWH TP (Grade 1A).• For critical care patients who are at higher risk for VTE (following major trauma or orthopedic surgery) = LMWH TP (Grade 1A)• For critical care patients who are at high risk for bleeding = MECHANICAL PROPHYLAXIS with GCS and/or IPC until the bleeding risk decreases (Grade 1 A). When the high bleeding risk decreases, recommend that pharmacological TP be substituted for or added to the mechanical TP (Grade 1 C)

L’intervento chirurgico ed il rischio di trombosi

Fattori di rischioaddizionali possonocondizionare ilrischio nel singolointervento chirurgico

Consensus Europeodel Cardiovascular Disease

Educational and Research Trust -St. Mary’s Hospital Medical School

Windsor,UK, 1991

• Traumi del midollo spinale• Artroplastica di ginocchio• Amputazioni di gamba• Chirurgia delle fratture d’anca• Artroplastica d’anca• Fratture dell’arto inferiore• Prostatectomia aperta• Chirurgia generale addominale• Chirurgia ginecologica• Chirurgia toracica non cardiaca• Neurochirurgia• Meniscectomia aperta

TipoTipo di chirurgia e frequenza di trombosidi chirurgia e frequenza di trombosi

75-80%

20-25%


… and Risk of VTE in contemporary general surgical patients ?Uncertain = studies without thromboprophilaxis are no longer

performed

Factor risk-reducing Factor risk-heightening

Improvements in general peri-operative care,

Rapid mobilization

Regional anesthesia

TP

Older and sicker patients

Pre-operative chemotherapy

Shorter lenghts of stay in Hospital (= shorter durations of TP ?)


Determinanti del rischio di TEV:TIPO DI CHIRURGIA

Moderato-elevato

Basso-moderato

Livello diRischio

0.1-1.01-42-810-40ChirurgiaMaggiore

0.002-0.40.2-20.4-42-20Chirurgiaminore

EP fatale (%)

EP (%)TVP prossimale

(%)

TVP distale

(%)


Additional Factors affecting the risk of VTE in general surgery

Postoperative infection

Duration of Surgery

In the absence of pharmacologic TP, the risk is lower following spinal/epidural anesthesia than after general anesthesia. This protective effect is less apparent when pharmacologic TP is used

Type of Anesthesia

?Increasing Age

Gangireddy C, et al. Risk factors and clinical impact of postoperative symptomatic venousthromboembolism. J Vasc Surg 2007; 45:335–342

Turpie AG, et al. Fondaparinux combined withintermittent pneumatic compression versusintermittent pneumatic compression alone forprevention of venous thromboembolism after abdominal surgery: a randomized, double-blindcomparison. J Thromb Haemost 2007; 5:1854–1861

Agnelli G, et al. A clinical outcomebased prospectivestudy on venous thromboembolism after cancersurgery: the ARISTOS project. Ann Surg2006;243:89–95

Prins MH, Hirsh J. A comparison of general anesthesiaand regional anesthesia as a risk factor fordeep vein thrombosis following hip surgery: a critical review. Thromb Haemost 1990; 64:497–500

? White RH, et al. Effect of age on the incidence of venous thromboembolism after major surgery J Thromb Haemost 2004

•Cancer

•Previous VTE

•Obesity

•Delayed mobilization

Traditional Risk Factors



• RCT

• 3000 pts

• Major abdominal Surgery

• 2.5 mg SC qd started postoperatively

• Vs. Dalteparin 5000 IU sc qdstarted before surgery

Pegasus Study

0

1

2

3

4

5

6

7

VTE % MajorBleeding

Death

ArixtraFragmin

Conclusion: Postoperative fondaparinux was at least as effectiveas perioperative dalteparin in patients undergoing high-riskabdominal surgery.


General surgery: recommendations

Highest/high risk

8th ACCP1

• UFH or LMWH, high-dose or fondaparinux (Grade 1A). For highest-risk patients, UFH, LMWH or fondaparinux plus mechanical prophylaxis (Grade 1C)

• Mechanical prophylaxis for patients at high risk of bleeding (Grade 1A)

• High risk patients undergoing major cancer surgery, LMWH, UFH or fondaparinux (Grade 1A)

• Against VTE prophylaxis with aspirin for any patient group (Grade 1A)

ICS2

• Low-dose UFH, LMWH (Grade A), or IPC (Grade B) or combination (Grade B)

• For patients at high risk of bleeding, mechanical prophylaxis

• Against the use of dextran and aspirin

1. Geerts WH, et al. Chest 2008;133:381S-453S.

2. Nicolaides AN, et al. Int Angiol 2006;25:101-161.

ACCP = American College of Chest Physicians.

ICS = International Consensus Statement.

Moderate risk

8th ACCP1

• UFH ,LMWH or fondaparinux low-dose (Grade 1A)

• Against VTE prophylaxis with aspirin for any patient group (Grade 1A)


ICS2

• Low-dose UFH, LMWH, or mechanical prophylaxis (Grade A)

• Against the use of dextran and aspirin

Low risk ACCP1

• No prophylaxis other than early and persistent mobilization (Grade 1A)


ICS2

• No prophylaxis

1. Geerts WH, et al. Chest 2008;133:381S-453S.2. Nicolaides AN, et al. Int Angiol 2006;25:101-161.

General surgery: recommendations

Vascular Surgery: Recommendations

2.2.1. For patients undergoing vascular surgery procedures who do not have additional thromboembolic risk factors, we suggest that clinicians not routinely use specific TP other than early and frequent ambulation (Grade 2B).

2.2.2. For patients undergoing major vascularsurgery who have additional thromboembolic risk factors, we recommend TP with LMWH, LDUH, or fondaparinux (Grade 1C).


• < 18 mmHg = preventivo-riposante (70-140 den)• > 18 mmHg = terapeutica

• Classe 1 = 15-22 mmHg = post-chirurgia (controllo edema)

• Classe 2 = 23-33 mmHg = post TVP • Classe 3 = 34-47 mmHg = post-TVP per due anni,

CEAP 5-6• Classe 4 = > 49 mmHg

A. Ghirarduzzi Reggio Emilia 18.06.09

Calza Elastocompressiva: classi di compressione

When to stop prophylaxis ?

• At around 1 week

• At around 2 weeks

• At around 1 month

• Further prolongation in some risk groups


65%

20%

12%

65%

18%13%

0

20

40

60

80

100

Incidence of VTE (%)

Medical hospitalization only Hospitalization with surgery

0-29 days post-discharge



Most of VTE in the outpatients setting presents Most of VTE in the outpatients setting presents

after hospital dischargeafter hospital discharge

67% of events occurred within 3 months after hospital discharge67% of events occurred within 3 months after hospital discharge

Spencer FA Spencer FA ArchArch InternIntern MedMed 2007; 167: 14712007; 167: 1471

1897 confirmed episode of VTE1897 confirmed episode of VTE

66.9% VTE 66.9% VTE withinwithin 1 1 monthmonth after hospital after hospital dischargedischarge notnot undergoneundergone surgerysurgery

Durata della tromboprofilassi

• Nella popolazione di pazienti chirurgici:

– pazienti sottoposti ad artroprotesi totale d’anca (Hullet al.1)4-5 settimane vs 1-2 settimane EBPM – 64% RRR per TEV sintomatica

– chirurgia oncologica (ENOXACAN II)2

4 settimane vs 1 settimana EBPM – 60% RRR per TEV

– chirurgia addominale maggiore (Rasmussen et al.3)4 settimane vs 1 settimana EBPM – 55% RRR per TEV

1.Hull RD et al. Ann Intern Med 2001;135:858-869; 2.Bergqvist D et al. NEJM 2002;346:975-980; 3. Rasmussen MS et al. J Thromb Haemost 2006;4:2384-2390

EXCLAIM: Summary of Efficacy and SafetyEnd of the double-blind period

PlaceboEnoxaparin

VTE events Symptomatic DVT

p=0.001

Inci

denc

e (%

)

p=0.004 p=0.019

4.90

2.8

1.10

0.300.60

Major Bleeding

0.15

NNT=46

NNT=121

NNH=224

Conclusions

• In EXCLAIM, extended-duration prophylaxis with enoxaparin was superior to short-term prophylaxis, reducing the rate of VTE by 44%

• This benefit was also shown for proximal DVT and symptomatic VTE, reducing the rate by 34% and 73%, respectively

• The efficacy of enoxaparin was consistent across all primary diagnoses and major risk factors

• The overall rate of major bleeding was low but statistically significant higher in the active treatment arm. There was no significant difference in all cause mortality

• The benefit of extended-duration prophylaxis with enoxaparin translates in a number needed to avoid one VTE of 46, versus a number needed to cause major bleeding of 224.

Prevenzione e US ?

Solo nel paziente sintomatico (dopoavere eseguito score di Wells) ?

C-CUS (± seriata) in asintomaticiad alto rischio ?

C-CUS al posto della flebografianei RCT ?

EC INSTABILE = emorragia attiva o ad alto rischio progressione

Calze antitrombo/CPI

C-CUS D4-7^

NEG TVD TVP

FC ±

LMWH-LD

LMWH-LDEnoxaparina 4000 UI SC die

Dalteparina 5000 UI SC die

LMWH-LDEnoxaparina 4000 UI SC die

Dalteparina 5000 UI SC die

C-CUS D10-14^

C-CUS D10-14^

Venographic thrombosis as a “surrogate” for clinically relevant

venous thromboembolism

Asymptomatic

DVT

Symptomatic

DVT

PTS ?

PE PE

PTS !

FATAL

20-25% 7%

1.6%

0.9%


Color or Power Doppler imaging may be used to identify the veins, but compression should be done in gray-scale.

ADOPTSystematic CUS exam for the assessment

of asymptomatic proximal DVT

F.Becker A.Leizorovicz

Thrombosis of GSV

Thrombosis of CFV

If a thrombus is suspected, it

should be explored in more

details and characterized

by:

• Marking the thrombus (text

on the video)

• Different views (transversal

and longitudinal)

• Measurement of the largest

diameter of the occluded vein

• Color flow imaging

Documentation on the film

Different views and color

Free floating thrombus in SFV

SFA

Longitudinal-section viewCross-section view

Partially occluded SFV

See a complete demo CUS exam

Potential VTE Management Landscape

80% renal

30% renal

70% hepatic

25% renal

70% hepatic

Elimination

Qd oralDTI

5%14-17DABIGATRAN

Bid oral direct aXa

50-85%8-15APIXABAN

qd oral

direct aXa

> 80%5-13RIVAROXABAN

Dosing/ClassBioavailabilityHalf life (hrs)

Agent

MATERIALI e METODIMATERIALI e METODI

[email protected]@asmn.re.it

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