La profilassi in Medicina e Chirurgia. Dr. Angelo Ghirarduzzi SSD di Angiologia ASMN Reggio Emilia

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1 La profilassi in Medicina e Chirurgia Dr. Angelo Ghirarduzzi SSD di Angiologia ASMN Reggio Emilia

2 Cover.gif Dr. Angelo Ghirarduzzi Reggio Emilia

3 Razionale per la Profilassi antitrombotica Natura silente della malattia: EP FATALE, possibile prima manifestazione. Mortalità > 2 volte rispetto a mortalità associata di AIDS, tumore mammella, tumore prostata, incidenti stradali ) SEVERA SPT: 5-10% IPERTENSIONE POLMONARE CRONICA: 1% Metodiche strumentali di screening (eco-doppler) poco affidabili 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%

4 LE CATEGORIE DI PAZIENTI Paziente Ricoverato - Reparto medico - Reparto chirurgico - Ortopedia Day Hospital, Day Surgery Dimissione Precoce Lungodegenza Casa di riposo ADI Paziente Sano a domiclio Con totale allettamento Con parziale allettamento Deambulante

5 LE CATEGORIE DI PAZIENTI 1/1000/anno Paziente Ricoverato 10/100/anno 80/100/anno 1/100/anno 1/1000/anno Day Hospital, Day Surgery Dimissione Precoce Lungodegenza Casa di riposo ADI Con totale allettamento Con parziale allettamento Deambulante Paziente Sano a domiclio 1/1000/anno >3/100/anno 1/1000/anno 1/10000/anno 1/100000/anno

6 Risk of VTE over Time Risk of VTE? Surgery ICU Discharge Time

7 VTE Prophylaxis in acutely ill medical patients VTE without any prophylaxis Internal medicine General surgery Stroke Orthopaedic surgery Asymptomatic DVT 17% 25% 50% moderate risk but responsible for 75% of VTE Leizorovicz & Mismetti. Circulation 2004

8 Studio Endorse: use of ACCP recommended prophylaxis among overall population at risk of VTE Mean = 50% n = Algeria Australia Bangladesh Brazil Bulgaria Colombia Czech Rep Egypt Fra nce Germ any Gree ce Hungary India Irelan d Kuwa it Mexico Pakistan Poland Portuga l Roman ia Russia % Saudi Arabia Slova kia Spain Switzerland Thailand Tunisia Turkey UAE UK USA Ven ezuela Cohen AT, et al. XXIst Conference of the ISTH; July 2007; Geneva, Switzerland [abstract O-S-002].

9 Score Ginevra Fattori di rischio Punteggio Scompenso cardiaco 2 Insufficienza respiratoria 2 Ictus recente 2 Infarto miocardico recente 2 Malattia infettiva acuta (sepsi inclusa) Malattia reumatica acuta 2 Cancro 2 Sindrome mieloproliferativa 2 Sindrome nefrosica 2 Anamnesi di tromboembolismo venoso 2 2 Fattori di rischio Stato ipercoagulativo riconosciuto Immobilizzazione (<30 minuti di camminata/die) per 3 giorni Punteggio Recente viaggio (>6 ore) 1 Età >60 anni 1 Obesità (BMI >30) 1 Insufficienza venosa cronica 1 Gravidanza 1 Terapia ormonale (contraccettiva o sostitutiva) Disidratazione Tromboprofilassi indicata se punteggio 3 Chopard P et al. J Thromb Haemost 2006;4:

10 Fattori di rischio Score Barbar 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

11 3 homogeneous RCTs versus Placebo MEDENOX 1999 PREVENT 2004 ARTEMIS 2006 Enoxaparin placebo 4000 IU 6-14 days all DVT Venography At d6-14 Dalteparin placebo 5000 IU 6-14 days Proximal DVT Ultrasound At d21 Fondaparinux placebo 2.5 mg 6-14 days all DVT Venography At d6-14 Follow-up 90 days Follow-up 90 days Follow-up 30 days

12 Thromboprophylaxis of Medical Patients: Clear Benefits Over Placebo Study RRR NNT Prophylaxis Patients with VTE, % MEDENOX 1 63% 10 Placebo 14.9 * (n=288) P<0.001 Enoxaparin 40 mg 5.5 (n=291) PREVENT 2 49% 45% 45 Placebo P= Dalteparin ARTEMIS 3 47% 20 Placebo P=0.029 Fondaparinux 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. NNT = number needed to treat; RRR = relative risk reduction. 1 Samama MM, et al. N Engl J Med. 1999;341: Leizorovicz A, et al. Circulation. 2004;110: Cohen AT, et al. J Thromb Haemost. 2003;1 Suppl 1:P2046.

13 VTE Prophylaxis in acutely ill medical patients updated meta-analysis Heparins (UFH & LMWH) versus control : 9 RCTs = pts symptomatic PE fatal PE symptomatic DVT major bleedings all-cause mortality RR= 0.43 [ ] RR= 0.38 [ ] RR= 0.47 [ ] RR= 0.32 [ ] RR= 0.97 [ ] Dentali et al. Ann Intern Med 2007

14 Raccomandazioni ACCP per pazienti con 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

15 Reccomendations & Critical Care - Chest For patients admitted to a critical care unit, we recommend routine assessment for VTE risk and routine TP in most (Grade 1A) 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)

16 L intervento chirurgico ed il rischio di trombosi Tipo di chirurgia e frequenza di trombosi 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 75-80% 20-25% Fattori di rischio addizionali possono condizionare il rischio nel singolo intervento chirurgico Consensus Europeo del Cardiovascular Disease Educational and Research Trust - St. Mary s Hospital Medical School Windsor,UK, 1991 Dr. Angelo Ghirarduzzi Reggio Emilia

17 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?) Dr. Angelo Ghirarduzzi Reggio Emilia

18 Determinanti del rischio di TEV: TIPO DI CHIRURGIA Livello di Rischio TVP distale (%) TVP prossimale (%) EP (%) EP fatale (%) Chirurgia minore Bassomoderato Chirurgia Maggiore Moderato -elevato Dr. Angelo Ghirarduzzi Reggio Emilia

19 Additional Factors affecting the risk of VTE in general surgery Traditional Risk Factors Increasing Age Type of Anesthesia Duration of Surgery Postoperative infection Cancer Previous VTE Obesity Delayed mobilization? 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 Gangireddy C, et al. Risk factors and clinical impact of postoperative symptomatic venous thromboembolism. J Vasc Surg 2007; 45: Turpie AG, et al. Fondaparinux combined with intermittent pneumatic compression versus intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison. J Thromb Haemost 2007; 5: Agnelli G, et al. A clinical outcomebased prospective study on venous thromboembolism after cancer surgery: the ARISTOS project. Ann Surg 2006;243:89 95 Prins MH, Hirsh J. A comparison of general anesthesia and regional anesthesia as a risk factor for deep vein thrombosis following hip surgery: a critical review. Thromb Haemost 1990; 64: ? White RH, et al. Effect of age on the incidence of venous thromboembolism after major surgery J Thromb Haemost 2004 Dr. Angelo Ghirarduzzi Reggio Emilia

20 Dr. Angelo Ghirarduzzi Reggio Emilia

21 RCT 3000 pts Major abdominal Surgery 2.5 mg SC qd started postoperatively Vs. Dalteparin 5000 IU sc qd started before surgery Dr. Angelo Ghirarduzzi Reggio Emilia

22 Pegasus Study Arixtra Fragmin 1 0 VTE % Major Bleeding Death Conclusion: Postoperative fondaparinux was at least as effective as perioperative dalteparin in patients undergoing high-risk abdominal surgery. Dr. Angelo Ghirarduzzi Reggio Emilia

23 General surgery: recommendations Highest/ high risk 8 th ACCP 1 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) ICS 2 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 ACCP = American College of Chest Physicians. ICS = International Consensus Statement. 1. Geerts WH, et al. Chest 2008;133:381S-453S. 2. Nicolaides AN, et al. Int Angiol 2006;25:

24 General surgery: recommendations Moderate risk 8th ACCP 1 UFH,LMWH or fondaparinux low-dose (Grade 1A) Against VTE prophylaxis with aspirin for any patient group (Grade 1A) Mechanical prophylaxis for patients at high risk of bleeding (Grade 1A) ICS 2 Low-dose UFH, LMWH, or mechanical prophylaxis (Grade A) Against the use of dextran and aspirin Low risk ACCP 1 No prophylaxis other than early and persistent mobilization (Grade 1A) Mechanical prophylaxis for patients at high risk of bleeding (Grade 1A) ICS 2 No prophylaxis 1. Geerts WH, et al. Chest 2008;133:381S-453S. 2. Nicolaides AN, et al. Int Angiol 2006;25:

25 Vascular Surgery: Recommendations 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) For patients undergoing major vascular surgery who have additional thromboembolic risk factors, we recommend TP with LMWH, LDUH, or fondaparinux (Grade 1C). Dr. Angelo Ghirarduzzi Reggio Emilia

26 Calza Elastocompressiva: classi di compressione < 18 mmhg = preventivo-riposante ( den) > 18 mmhg = terapeutica Classe 1 = mmhg = post-chirurgia (controllo edema) Classe 2 = mmhg = post TVP Classe 3 = mmhg = post-tvp per due anni, CEAP 5-6 Classe 4 = > 49 mmhg A. Ghirarduzzi Reggio Emilia

27 When to stop prophylaxis? At around 1 week At around 2 weeks At around 1 month Further prolongation in some risk groups Dr. Angelo Ghirarduzzi Reggio Emilia

28 Most of VTE in the outpatients setting presents after hospital discharge 1897 confirmed episode of VTE 67% of events occurred within 3 months after hospital discharge Incidence of VTE (%) % 20% 12% 65% 0-29 days post-discharge days post-discharge days post-discharge 18% 13% Medical hospitalization only Hospitalization with surgery 66.9% VTE within 1 month after hospital discharge not undergone surgery Spencer FA Arch Intern Med 2007; 167: 1471

29 Durata della tromboprofilassi Nella popolazione di pazienti chirurgici: pazienti sottoposti ad artroprotesi totale d anca (Hull et 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: ; 2.Bergqvist D et al. NEJM 2002;346: ; 3. Rasmussen MS et al. J Thromb Haemost 2006;4:

30 EXCLAIM: Summary of Efficacy and Safety End of the double-blind period Placebo Enoxaparin p=0.001 p=0.004 p= NNT=46 Incidence (%) NNT= NNH= VTE events Symptomatic DVT Major Bleeding

31 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.

32 Prevenzione e US? Solo nel paziente sintomatico (dopo avere eseguito score di Wells)? C-CUS (± seriata) in asintomatici ad alto rischio? C-CUS al posto della flebografia nei RCT?

33 EC INSTABILE = emorragia attiva o ad alto rischio progressione Calze antitrombo/cpi C-CUS D4-7^ NEG TVD TVP C-CUS D10-14^ LMWH-LD Enoxaparina 4000 UI SC die Dalteparina 5000 UI SC die LMWH-LD Enoxaparina 4000 UI SC die Dalteparina 5000 UI SC die C-CUS D10-14^ FC ± LMWH-LD

34 Venographic thrombosis as a surrogate for clinically relevant venous thromboembolism Asymptomatic DVT Symptomatic 20-25% 7% DVT PTS? PTS! PE 1.6% PE FATAL 0.9% Dr. Angelo Ghirarduzzi Reggio Emilia

35 ADOPT Systematic CUS exam for the assessment of asymptomatic proximal DVT Color or Power Doppler imaging may be used to identify the veins, but compression should be done in gray-scale. F.Becker A.Leizorovicz

36 Documentation on the film 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 Thrombosis of GSV Thrombosis of CFV

37 Different views and color SFA Partially occluded SFV Cross-section view Free floating thrombus in SFV Longitudinal-section view

38 See a complete demo CUS exam

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40 Potential VTE Management Landscape Agent Half life (hrs) Bioavailability Elimination Dosing/Class APIXABAN % 25% renal 70% hepatic Bid oral direct axa RIVAROXABAN 5-13 > 80% 30% renal qd oral 70% hepatic direct axa DABIGATRAN % 80% renal Qd oral DTI

41 MATERIALI e METODI angelo.ghirarduzzi@asmn.re.it