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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