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

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1 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- Prevenzione del TEV in Chirurgia Ginecologica: Eparine a basso peso molecolare Luigi Steidl Centro Trombosi ed Emostasi U.O. di Medicina Interna I Ospedale di Circolo Varese

2 Il rischio peri-operatorio standard Pre-operatorio Intra-operatorio Post-operatorio Rischio emorragico * - +* Rischio trombotico * +++* *Secondo la procedura chirurgica

3 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

4 Prevention of VTE in Surgical Patients VTE is a common cause of preventable death in hospitalized patients Approximately one-third of the 150,000 to 200,000 VTE-related deaths per year in the United States occur following surgery The availability of effective methods of prevention mandate that thromboprophylaxis should be considered in every surgical patient Unfortunately, there have been few randomized clinical trials of thromboprophylaxis in gynecologic surgery in the past decade Trade-offs between benefits (VTE rate reduction) and harms (bleeding) of pharmacologic prophylaxis Horlander KT, et al. Arch Intern Med. 2003; 163 (14): Geerts WH, Bergqvist D, Pineo GH, et al., Chest 2008;133:

5 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): Geerts WH, Bergqvist D, Pineo GH, et al., Chest 2008;133:

6 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% National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism in inpatients undergoing surgery. NICE clinical guideline No. 46: Available at: Accessed March 31, 2008 Chirurgia ortopedica maggiore 40-

7 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

8 Prevention of Venous Thromboembolism The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126:338S-400S 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

9 Rationale for Thromboprophylaxis in Hospitalized Patients W. H. Geerts et al., CHEST 2004; 126:338S 400S

10 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

11 Advantages and Limitations of Mechanical Thromboprophylaxis Modalities Advantages 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

12 A brief history of anticoagulant therapy Parenteral Oral Parenteral 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 1990s 1980s 1940s 1930s Parenteral Oral Oral Indirect Factor Xa inhibitors Direct Factor IIa inhibitors Direct Factor Xa inhibitors 2000s Alban, Eur J Clin Invest 2005 Link, Circulation 1959

13 REGIMENS TO PREVENT VENOUS THROMBOEMBOLISM Surgical conditions LMWH Enoxaparin 40 mg sc once daily Nadroparin U sc once daily Dalteparin U sc once daily Danaparoid 750 U sc q12h LDUH Heparin 5000 U sc q8-12h Nicolaides et al, Int Angiol, 1997

14 Risk Stratification in General, Abdominal-Pelvic, Gynecologic Surgery Risk of VTE procedure-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 factors age, 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 ; 243 ( 1 ): Clarke-Pearson DL, et al.obstet Gynecol ; 101 ( 1 ):

15 Caprini Risk Assessment Model (modified) VTE risk categorization: very low (0-1 point) low (2 points) moderate (3-4 points) high ( 5 points) Caprini JA. Dis Mon ; 51 ( 2-3 ): Caprini JA, Arcelus JI, Hasty JH, Tamhane AC, Fabrega F. Semin Thromb Hemost. 1991

16 Rogers Risk Assessment Model VTE risk categorization: low (< 7 points) moderate (7-10 points) high (> 10 points) Rogers SO Jr, Kilaru RK, Hosokawa P, Henderson WG, Zinner MJ, Khuri SF. J Am Coll Surg. 2007; 204 (6):

17 Risk Stratification for VTE in General, Abdominal-Pelvic Surgery Rogers SO Jr, et al. J Am Coll Surg ; 204 ( 6 ):

18 Limiti: Risk Assessment Models (RAM) Mancanza di validazione clinica Time-consuming

19 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%) Mismetti P, et al. Br J Surg ; 88 ( 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%) Leonardi MJ, et al. Arch Surg ; 141 ( 8 ): Bleeding risk with LMWH: Major bleeding (RR, 2.03; 95% CI, ) Wound hematoma (RR, 1.88; 95% CI, ) Sweetland S, et al. Million Women Study Collaborators. BMJ ; 339

20 Risk Factors for Major Bleeding Complications M.K. Gould ; D.A. Garcia; S.M. Wren; P.J. Karanicolas; J.I. Arcelus; J.A. Heit and C.M. Samama. Chest 2012;141:227S-277S

21 DVT After Laparoscopic Procedures

22 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:V

23 The risk of postoperative DVT is increased after general surgery for cancer Cancer patients Non-cancer patients Kakkar et al /59 (41%) 38/144 (26%) Hills et al /16 (50%) 7/34 (21%) Walsh et al /45 (35%) 22/217 (10%) Rosenberg et al /66 (42%) 29/128 (23%) Sue-Ling et al /23 (52%) 16/62 (26%) Allan et al /100 (31%) 21/100 (21%) Multicenter Trial /37 (22%) 13/53 (24%) All 128/346 (37%) 146/738 (20%) Prandoni P et al. Haematologica 1999;84:437-45

24 Outcomes in Cancer Patients Undergoing Surgery* Meta-analysis of all randomised studies comparing LMWH and UFH in patients undergoing general surgery (18 46,000 patients) Outcome DVT Clinical PE Clinical VTE Death Major haemorrhage Cancer surgery 6% 0.8% 1.8% 4.8% 8.1% Non-Cancer surgery 4.8% 0.4% 1.2% 1.5% 2.7% * Patients all receiving unfractionated heparin Mismetti P, et al. Br J Surg 2001; 88:

25 Incidenza di TEV nel tempo Rischio di TEV? Chirurgia Dimissione Tempo

26 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

27 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:

28 International guidelines Nessuna grande variazione rispetto a edizioni precedenti ( ) Scomparsa del capitolo specifico sulla Chirurgia ginecologica ricompreso nella chirurgia generale

29 Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES Chest 2012;141:227S-277S 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 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) 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.

30 Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES Chest 2012;141:227S-277S 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) 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).

31 Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES Chest 2012;141:227S-277S For high-vte-risk patients undergoing abdominal or pelvic surgery for cancer who are not otherwise at high risk for major bleeding complications, we recommend extended-duration pharmacologic prophylaxis (4 weeks) with LMWH over limitedduration prophylaxis (Grade 1B) 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).

32 Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES Chest 2012;141:227S-277S Rischio trombotic o Molto basso Rischio emorragic o Durata Profilassi farmacologica Nessuna(1B) Profilassi non farmacologica 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) Alto Basso Alto 4 settimane EBPM (1B) Nessuna CPI: compressione pneumatica intermittente; CE: calze elastiche; EBPM: eparine a basso PM; ENF BD: eparina non frazionata a basso dosaggio CPI (2C) sino a rischio emorragico basso

33 Prevention of Venous Thromboembolism American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) CHEST 2008; 133:381S 453S 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) For gynecology patients undergoing entirely laparoscopic procedures, we recommend against routine thromboprophylaxis, other than early and frequent ambulation (Grade 1B) 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).

34 Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES Chest 2012;141:227S-277S 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 For general and abdominal-pelvic surgery patients, we suggest that an IVC filter should not be used for primary VTE prevention (Grade 2C) For general and abdominal-pelvic surgery patients, we suggest that periodic surveillance with VCU should not be performed (Grade 2C).

35 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.

36 Prevention of VTE in Non-orthopedic Surgical Patients ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES Chest 2012;141:227S-277S For women undergoing cesarean section without additional thrombosis risk factors, we recommend against the use of thrombosis prophylaxis other than early mobilization (Grade 1B) 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 suggest pharmacologic 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) 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 intermittent pneumatic compression over LMWH alone (Grade 2C).

37 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)

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39 Contraccezione ormonale e HRT e rischio tromboembolico Take-home messages [1] La COC e 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: 1/10000 COC: 3-6/10000) 3 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)

40 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 prima della somministrazione di contraccettivi!!

41 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!

42 Take-home messages [2] Consigli pratici prima della prescrizione della COCs: Accurata anamnesi personale & familiare Misurazione PA 2008 Consensus Conference SNLG Prevenzione delle complicanze trombotiche associate all uso di E/P nell età riproduttiva 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.