Prevenzione del TEV in Chirurgia

Ginecologica:

Eparine a basso peso molecolare

Luigi SteidlCentro Trombosi ed Emostasi

U.O. di Medicina Interna I

Ospedale di CircoloVarese

“Trombosi ed Emostasi in Ostetricia e Ginecologia”

Varese, 22 settembre 2012

Aula Magna-Dipartimento di Biologia-Università degli Studi dell’Insubria-Via Dunant, 3-Varese-

Pre-operatorio Post-operatorioIntra-operatorio

Rischio emorragico

Rischio trombotico

- -

- -

+++* - +*

Il rischio peri-operatorio standard

*Secondo la procedura chirurgica

+++* +++*

Prevenzione del TEV in Chirurgia Ginecologica:Eparine a basso peso molecolare

Premessa

Dimensioni del problema

Metodi di tromboprofilassi farmacologica e non farmacologica

Stratificazione del rischio trombotico ed emorragico

Tempi e dosi

Linee Guida

Prevenzione del TEV in Chirurgia Ginecologica

• Dati estrapolati e derivati da studi in pazienti di chirurgia generale e addomino-pelvica

• Mancanza di dati recenti specifici in ginecologia

• Bilancio tra benefici (riduzione dell’incidenza di TEV) e costi in termini di eventi emorragici

Horlander KT , et al. Arch Intern Med. 2003; 163 (14): 1711-1717Geerts WH, Bergqvist D, Pineo GH, et al., Chest 2008;133: 381-453

Incidenza di tromboembolismo

venoso nei pazienti ricoverati

Pazienti internistici 10-20%

Chirurgia generale 15-40%

Chirurgia ginecologica 15-40%

Chirurgia urologica 15-40%

Neurochirurgia 15-40%

Chirurgia ortopedica maggiore 40-60%

Traumi maggiori 40-80%

Terapia intensiva 10-80%

Trauma spinale 50-100%National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism in inpatients undergoing

surgery. NICE clinical guideline No. 46:1–160. Available at: http://www.nice.org.uk/CG046. Accessed March 31, 2008

Levels of Thromboembolism Risk and Recommended Thromboprophylaxis in Hospital Patients

Lassen MR, Borris LC, Backs S, et al. Blood Coagul Fibrinolysis 1999; 10(suppl 2):S45–S51

Risk factors for VTE

Surgery

Trauma (major or lower extremity)

Immobility, paresis

Malignancy

Cancer therapy (hormonal, chemotherapy, or radiotherapy)

Previous VTE

Increasing age

Central venous catheterization

Pregnancy and the postpartum period

Estrogen-containing oral contraception or hormone replacement therapy

Selective estrogen receptor modulators

Acute medical illness

Prevention of Venous ThromboembolismThe Seventh ACCP Conference on Antithrombotic and Thrombolytic TherapyChest 2004;126:338S-400S

Rationale for Thromboprophylaxis in Hospitalized Patients

W. H. Geerts et al., CHEST 2004; 126:338S–400S

Prevenzione del TEV in Chirurgia

Calze elastiche

Compressione pneumatica intermittente

Eparina non frazionata a basse dosi

EBPM a dosi profilattiche

Fondaparinux

Ac. Acetilsalicilico

Filtri cavali

Sorveglianza periodica con c-US

Advantages and Limitations of Mechanical

Thromboprophylaxis ModalitiesAdvantages

• Do not increase the risk of bleeding

• Can be used in patients at high bleeding risk

• Efficacy has been demonstrated in a number of patient groups

• May enhance the effectiveness of anticoagulant thromboprophylaxis

• May reduce leg swelling

Limitations• Not as intensively studied as pharmacologic

thromboprophylaxis (fewer studies and smaller)

• No established standards for size, pressure, or physiologic features

• Many specific mechanical devices have never been assessed in any clinical trial

• Almost all mechanical thromboprophylaxis trials were unblinded and therefore have a potential for bias

• In high-risk groups are less effective than anticoagulant thromboprophylaxis

• Greater effect in reducing calf DVT than proximal DVT

• Effect on PE and death unknown

• May reduce or delay the use of more effective anticoagulant thromboprophylaxis

• Compliance by patients and staff often poor

• Trials may overestimate the protection compared with routine use

• Cost: associated with purchase, storage, dispensing, and cleaning of the devices, as well as ensuring optimal compliance

A brief history of anticoagulant therapy

1930s

1940s

1980s

1990s

2000s

Oral

Parenteral

Parenteral

Parenteral

Oral

Oral

Parenteral Unfractionated heparins: antithrombin (AT)-dependent

inhibition of Factor Xa and IIa in a 1:1 ratio

Vitamin K antagonists: indirectly affect

synthesis of multiple coagulation factors

Low molecular weight heparin:

AT-dependent inhibition of Factor Xa >IIa

Direct Factor IIa inhibitors

Indirect Factor Xa inhibitors

Direct Factor IIa

inhibitorsDirect Factor Xa

inhibitors

Alban, Eur J Clin Invest 2005

Link, Circulation 1959

REGIMENS TO PREVENT VENOUS THROMBOEMBOLISM

Surgical conditions

LMWH

Enoxaparin 40 mg sc once daily

Nadroparin 2850-3400 U sc once daily

Dalteparin 2500-5000 U sc once daily

Danaparoid 750 U sc q12h

LDUH

Heparin 5000 U sc q8-12h

Nicolaides et al, Int Angiol, 1997

Risk Stratification in General, Abdominal-Pelvic, Gynecologic Surgery

Risk of VTEprocedure-specific factors

low-risk procedures

laparoscopic surgery, appendectomy, transurethral prostatectomy, inguinal herniorrhaphy, unilateral or bilateral mastectomy

high-risk procedures

Open-abdominal and open-pelvic procedures

Cancer surgery

patient-specific factorsage, prior VTE, cancer, anesthesia >2 h, bed rest >4 days, male sex, sepsis, pregnancy or postpartum state, central venous access

Andtbacka RH , et al. Ann Surg . 2006 ; 243 ( 1 ): 96 – 101Clarke-Pearson DL, et al.Obstet Gynecol . 2003 ; 101 ( 1 ): 157 - 163

Caprini Risk Assessment Model (modified)

Caprini JA . Dis Mon . 2005 ; 51 ( 2-3 ): 70 – 78Caprini JA, Arcelus JI, Hasty JH, Tamhane AC, Fabrega F. Semin Thromb Hemost . 1991

VTE risk categorization:•very low (0-1 point)•low (2 points)•moderate (3-4 points)•high (≥5 points)

Rogers Risk Assessment Model

Rogers SO Jr , Kilaru RK , Hosokawa P , Henderson WG , Zinner MJ , Khuri SF. J Am Coll Surg. 2007; 204 (6): 1211-1221

VTE risk categorization:•low (< 7 points)•moderate (7-10 points)•high (> 10 points)

Risk Assessment Models (RAM)

Limiti:

• Mancanza di validazione clinica

• Time-consuming

Baseline Risk and Risk Factors for Major Bleeding Complications

• Meta-analysis of seven randomized trials of LMWH in absence of prophylaxis:

– major bleeding in the control groups: 1.2% (95% CI, 0.9%-1.7%)

• Meta-analysis of thirty-three randomized trials of LMWH in absence of prophylaxis:

– major bleeding in the control groups: 0.7% (95% CI, 0.92%-1.57%)

• Bleeding risk with LMWH:

– Major bleeding (RR, 2.03; 95% CI, 1.37-3.01)

– Wound hematoma (RR, 1.88; 95% CI, 1.54-2.28)

Mismetti P, et al. Br J Surg . 2001 ; 88 ( 7 ): 913 - 930

Leonardi MJ, et al. Arch Surg . 2006 ; 141 ( 8 ): 790 - 797.

Sweetland S, et al. Million Women Study Collaborators. BMJ . 2009 ; 339

DVT After Laparoscopic Procedures

Higher VTE Risk in Cancer Surgery Patients

Increased age

Longer immobilisation (pre and post operatively)

Associated treatment with

Radiotherapy

Chemotherapy

Central venous catheters

Longer operative procedures

Traumatic and extensive surgery

Bergqvist D. Thromb Res 2001; 102:V209-13.

The risk of postoperative DVT is increased after general surgery for cancer

Prandoni P et al. Haematologica 1999;84:437-45

Cancer patients Non-cancer patients

Kakkar et al. 1970 24/59 (41%) 38/144 (26%)

Hills et al. 1972 8/16 (50%) 7/34 (21%)

Walsh et al. 1974 16/45 (35%) 22/217 (10%)

Rosenberg et al. 1975 28/66 (42%) 29/128 (23%)

Sue-Ling et al. 1986 12/23 (52%) 16/62 (26%)

Allan et al. 1983 31/100 (31%) 21/100 (21%)

Multicenter Trial 1984 9/37 (22%) 13/53 (24%)

All 128/346 (37%) 146/738 (20%)

2.7%8.1%Major haemorrhage

1.5%4.8%Death

1.2%1.8%Clinical VTE

0.4%0.8%Clinical PE

4.8%6%DVT

Non-Cancer surgeryCancer surgeryOutcome

Outcomes in Cancer Patients Undergoing Surgery*

Mismetti P, et al. Br J Surg 2001; 88: 913-30.

* Patients all receiving unfractionated

heparin

Meta-analysis of all randomised studies comparing LMWH and UFH in

patients undergoing general surgery (18 – 46,000 patients)

Ris

ch

io d

i T

EV

Chirurgia Dimissione

Tempo

?

Incidenza di TEV nel tempo

Standard duration of thromboprophylaxis after general surgery

In thromboprophylaxis studies

in general and abdominal-pelvic surgery

7-10 days

Geerts WH et al. Chest 2004;126;338S-400S

Standard duration of thromboprophylaxis after general surgery

In thromboprophylaxis studies

in general and abdominal-pelvic surgery

-oncology setting-

4 weeks

Bergqvist D, Agnelli G, Cohen AT, et al. N Engl J Med 2002; 346:975–980

International guidelines

Nessuna grande variazione rispetto a edizioni precedenti (2001-2004-2008)

Scomparsa del capitolo specifico sulla Chirurgia ginecologica ricompresonella chirurgia generale

3.6.1. For general and abdominal-pelvic surgery patients at very low risk for VTE (<0.5%; Rogers score, <7; Caprini score, 0), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation.

Prevention of VTE in Non-orthopedic Surgical PatientsANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Chest 2012;141:227S-277S

3.6.2. For general and abdominal-pelvic surgery patients at low risk for VTE ( 1.5%; Rogers score, 7-10; Caprini score, 1-2), we suggest mechanical prophylaxis, preferably with IPC, over no prophylaxis (Grade 2C) .

3.6.3. For general and abdominal-pelvic surgery patients at moderate risk for VTE (3.0%; Rogers score, >10; Caprini score, 3-4) who are not at high risk for major bleeding complications, we suggest LMWH (Grade 2B), LDUH (Grade 2B), or mechanical prophylaxis, preferably with IPC (Grade 2C), over no prophylaxis.

Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Chest 2012;141:227S-277S

3.6.4. For general and abdominal-pelvic surgery patients at moderate risk for VTE (3.0%; Rogers score, >10; Caprini score, 3-4) who are at high risk for major bleeding complications or those in whom the consequences of bleeding are thought to be particularly severe, we suggest mechanical prophylaxis, preferably with IPC, over no prophylaxis (Grade 2C) .

3.6.5. For general and abdominal-pelvic surgery patients at high risk for VTE (6.0%; Caprini score, ≥5) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH (Grade 1B) or LDUH (Grade 1B) over no prophylaxis. We suggest that mechanical prophylaxis with ES or IPC should be added to pharmacologic prophylaxis (Grade 2C) .

Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Chest 2012;141:227S-277S

3.6.6. For high-VTE-risk patients undergoing abdominal or pelvic surgeryfor cancer who are not otherwise at high risk for major bleeding complications, we recommend extended-duration pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B) .

3.6.7. For high-VTE-risk general and abdominal-pelvic surgery patients who are at high risk for major bleeding complications or those in whom the consequences of bleeding are thought to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C) .

Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF

THROMBOSIS, 9TH ED: ACCP GUIDELINES

Chest 2012;141:227S-277S

Rischio trombotico

Rischio emorragico

Durata Profilassi farmacologica

Profilassi non farmacologica

Molto basso Nessuna(1B) Nessuna (2C)

Basso Nessuna(1B) CPI (2C) o CE

Moderato Basso EBPM o ENF BD (2B) CPI (2C)

Moderato Alto Nessuna CPI (2C)

Alto Basso EBPM o ENF BD (1B) + CE o CPI (2C)

Alto (+neoplasia)

Basso 4 settimane EBPM (1B)

Alto Alto Nessuna CPI (2C) sino a rischio emorragico basso

CPI: compressione pneumatica intermittente; CE: calze elastiche; EBPM: eparine a basso PM; ENF BD: eparina non frazionata a basso dosaggio

Prevention of Venous ThromboembolismAmerican College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)CHEST 2008; 133:381S–453S

2.3.1. For low-risk gynecologic surgery patients who are undergoing minor procedures and have no additional risk factors, we recommend against the use of specific thromboprophylaxis other than early and frequent ambulation (Grade 1A).

2.3.2. For gynecology patients undergoing entirely laparoscopic procedures, we recommend against routine thromboprophylaxis, other than early and frequent ambulation (Grade 1B).

2.3.3. For gynecology patients undergoing entirely laparoscopic procedures in whom additional VTE risk factors are present, we recommend the use of thromboprophylaxis with one or more of LMWH, LDUH, IPC, or GCS (Grade 1C).

Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Chest 2012;141:227S-277S

3.6.8. For general and abdominal-pelvic surgery patients at high risk for VTE (6%; Caprini score, ≥5) in whom both LMWH and unfractionated heparin are contraindicated or unavailable and who are not at high risk for major bleeding complications, we suggest low-dose aspirin (Grade 2C) , fondaparinux (Grade 2C) , or mechanical prophylaxis, preferably with IPC (Grade 2C) , over no prophylaxis

3.6.9. For general and abdominal-pelvic surgery patients, we suggest that an IVC filter should not be used for primary VTE prevention (Grade 2C) .

3.6.10. For general and abdominal-pelvic surgery patients, we suggest that periodic surveillance with VCU should not be performed (Grade 2C) .

All women who have had an emergency caesarean section (category 1–3) should be considered for thromboprophylaxis with LMWH for 7 days after delivery.

All women who have had an elective caesarean section (category 4) who have one or more additional risk factors (such as age over 35 years, BMI greater than 30) should be considered for thromboprophylaxis with LMWH for 7 days after delivery.

Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Chest 2012;141:227S-277S

6.2.1. For women undergoing cesarean section without additional thrombosis risk factors, we recommend against the use of thrombosis prophylaxis other than early mobilization (Grade 1B).

6.2.2. For women at increased risk of VTE after cesarean section because of the presence of one major or at least two minor risk factors, we suggestpharmacologic thromboprophylaxis (prophylactic LMWH) or mechanical prophylaxis (elastic stockings or intermittent pneumatic compression) in those with contraindications to anticoagulants while in hospital following delivery rather than no prophylaxis (Grade 2B).

6.2.3. For women undergoing cesarean section who are considered to be at very high risk for VTE and who have multiple additional risk factors for thromboembolism that persist in the puerperium, we suggest that prophylactic LMWH be combined with elastic stockings and/or intermittentpneumatic compression over LMWH alone (Grade 2C) .

Conclusioni (take home messages)

Nessuna grande novità nel panorama recente

Indicazioni personalizzate sulle RAM

Rischio di sanguinamento

Efficacia e sicurezza delle EBPM

Non ancora studiati i Nuovi Anticoagulanti Orali (NAO)

La COC e’ un fattore di rischio per TEV?

Si (OR: 5)

E la contraccezione per altra via di somministrazione?

Si (≠IUD medicato, impianto sc, progestinico iniettabile)

Se si, è un fattore di rischio minore o maggiore?

Minore (20-40aa=baseline: 1/10000COC: 3-6/10000)

E’ utile lo screening trombofilico a tutte le donne?

No, solo “famiglie trombofiliche”

E’ anche un fattore di rischio cardiocerebrovascolare?

Si (OR: 2)

E la terapia ormonale sostitutiva?

Si (OR: 3,5)

Contraccezione ormonale e HRT e rischio tromboembolicoTake-home messages [1]

Esami di Trombofilia Venosa

Antitrombina

Proteina C ed S della coagulazione

FII mutazione G20210A

FV Leiden

Omocisteina

FVIIIC

Anticorpi antifosfolipidi (ACA + antiB2GPI) + LAC (aPTT + DVVRT)

Eseguire la determinazione primadella somministrazione di contraccettivi !!

Approccio razionale alla prescrizione della contraccezione ormonale: Take-home messages [1]

1- Tipo del contraccettivo ed entità del rischio :

L’estradiolo è la componente di un COC che impatta maggiormente sul rischio di TEV.

Il rischio di TEV è strettamente correlato e direttamente proporzionale alla dose di EtinilEstradiolo.

I diversi progestinici modificano l’effetto protrombotico degli estrogeni.

2- I progestinici di III generazione hanno un RR doppio di TEV rispetto a quelli di II

Generazione.

3- Non ci sono chiare evidenze sul minor rischio di TEV di COCs con estrogeni

naturali e/o COC somministrati per vie alternative (ring-cerotto), benchè senz’altro i

suddetti COCs abbiano un migliore profilo metabolico.

4- Screening trombofilie mirato e non su larga scala!

La gravidanza puo’ già in donne sane e senza fattori di rischio aggiuntivi, essere

considerata uno stress test sul sistema coagulatorio e una storia ostetrica negativa

per TEV in queste donne puo’ essere un’indicazione sufficiente alla prescrizione di

OC.

5- Controindicazione alla prescrizione di COC nelle pazienti con pregresso TEV!

Take-home messages [2]

Consigli pratici prima della prescrizione della COCs:

• Accurata anamnesi personale & familiare

• Misurazione PA

• Non si raccomanda né prima di prescrivere un contraccettivo né durante l’uso l’esecuzione routinaria di :

-Esami ematochimici generici

-Test generici di coagulazione

-Test specifici per trombofilia

• Partire con CO a basso dosaggio (20-30 γ) + progestinico di II generazione

• Attenzione a fumo ed obesità!!

Tutto il resto non è indispensabile.

2008 Consensus Conference SNLG

“Prevenzione delle complicanze trombotiche

associate all’uso di E/P nell’età riproduttiva