Farmaci usati prima dellintervento Basi farmacologiche del loro uso La prevenzione del tromboembolismo.

Farmaci usati prima dell’intervento

Basi farmacologiche del loro usoLa prevenzione del tromboembolismo

Hyers, Arch Intern Med, 163, 759-768, 2003

• A timeline from approximately 1960 to the present indicates the seminal clinical trials that have influenced the use of emerging drugs for VTE prevention and treatment. HFS indicates hip fracture surgery; HITTS, heparin-induced thrombocytopenia thrombosis syndrome; LMWH, low-molecular-weight heparin; OA, oral anticoagulants; PE, pulmonary embolism; THR, total hip replacement; TKR, total knee replacement; and UFH, unfractionated heparin.

Management milestones in venous thromboembolism (VTE).

Hyers, Arch Intern Med, 163, 759-768, 2003

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

General Surgery (I)

• No specific prophylaxis other than early ambulation is recommended in low-risk general surgery patients: those who are undergoing minor procedures, are <40 years of age, and have no additional risk factors (grade 1C).

• Prophylaxis with low-dose UFK, LMWH, ES, or IPC is recommended in moderate-risk general surgery patients: those who are undergoing minor procedures but have additional risk factors or are between 40–60 years of age or those who are undergoing major operations but are younger than 40 years of age and have no additional risk factors (grade 1A).

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

General Surgery (II)

• Prophylaxis with low-dose UFH, LMWH, or IPC is recommended in high-risk general surgery patients: those who are undergoing nonmajor surgery who are older than 60 years or have additional risk factors or those who are undergoing major surgery who are older than 40 years of age or have additional risk factors (grade 1A).

• ES or IPC is recommended in higher-risk general surgery patients with a greater-than-usual risk of bleeding (grade 1C).

• Low-dose UFH or LMWH combined with ES or IPC is recommended in very high-risk patients with multiple risk factors (grade 1C).

• Consider postdischarge LMWH or perioperative warfarin (INR 2.0–3.0) in selected very high-risk patients (grade 2C).

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

Gynecologic Surgery

• Early ambulation is recommended for brief procedures for benign disease (grade 1C) 

• Patients having major surgery for benign disease without additional risk factors should be treated with low-dose UFH twice daily (grade 1A); alternatives include LMWH once daily or IPC started just before surgery and continued for several days postoperatively (grade 1C+) 

• Patients having extensive surgery for malignancy should be treated with low-dose UFH three times daily (grade 1A); alternatives include low-dose UFH plus ES or IPC or higher doses of LMWH (grade 1C).

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

Urologic Surgery.

• Early ambulation is recommended in patients undergoing transurethral or other low-risk procedures (grade 1C) 

• Low-dose UFH, LMWH, ES, or IPC is recommended for major procedures (grade 1B)

• Low-dose UFH or LMWH combined with ES or IPC is recommended for patients at the highest risk (grade 1C).

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

Major Orthopedic Surgery (I)

• For patients undergoing elective hip replacement, LMWH should be started 12 hours before surgery, 12–24 hours after surgery, or 4–6 hours after surgery at half the usual high-risk dose, should be used and then continued with the usual high-risk dose the following day or warfarin (INR 2.0–3.0) started preoperatively or immediately after surgery (grade 1A)

• For patients undergoing elective knee replacement, LMWH or warfarin (INR 2.0–3.0) is recommended (grade 1A); optimal use of IPC is an alternative option (grade 1B); low-dose UFH is not recommended (grade 1C+)

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

Major Orthopedic Surgery (II)

• For patients undergoing hip fracture surgery, use LMWH or warfarin (INR 2.0–3.0) (grade 1B); low-dose UFH is an alternative option (grade 2B)

• At least 7 to 10 days of prophylaxis is recommended after total hip replacement or total knee replacement (grade 1A)

• LMWH prophylaxis beyond 7 to 10 days after surgery is recommended for high-risk patients undergoing major orthopedic surgery (grade 2A)

• Routine duplex ultrasonography screening is not recommended at the time of hospital discharge or during outpatient follow-up in asymptomatic total hip replacement or total knee replacement patients (grade 1A).

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

Neurosurgery.

• IPC with or without ES is recommended in patients undergoing intracranial neurosurgery (grade 1A)

• Low-dose UFH or postoperative LMWH are acceptable alternatives (grade 2A because of concerns about clinically important intracranial hemorrhage)

• ES or IPC and LMWH or low-dose UFH prophylaxis may be more effective than either modality alone in high-risk patients (grade 1B).

Recommendations for Prevention of Venous Thromboembolism in Patients Undergoing

Trauma Surgery

• Trauma patients with a risk factor for thromboembolism should receive prophylaxis if possible. LMWH should be used as soon as it is considered safe to do so (grade 1A)

• Use ES and/or IPC if LMWH prophylaxis will be delayed or is contraindicated (grade 1C)

• In patients at high risk for thromboembolism who have received suboptimal prophylaxis, consider screening with duplex ultrasound (grade 1C)

• Insert an inferior vena cava filter if proximal deep vein thrombosis is documented and anticoagulation is contraindicated (grade 1C+); do not use an inferior vena cava filter for primary prophylaxis (grade 1C).

Aronow WS, J. Gerontology A: Biological Sciences and Medical Sciences 59:M42-M47 (2004)

• Abbreviations: UFH = unfractionated heparin; LMWH = low-molecular-weight heparins; IPC = intermittent pneumatic compression; ES = elastic (graduated compression) stockings; INR = international normalized ratio.

• GradeStrength of Recommendation• 1A - Strong recommendation applicable to most patients with risk/benefit

clear based on high-quality randomized controlled studies• 1B - Strong recommendation likely to apply to most patients with risk/benefit

clear based on randomized controlled studies with limitations• 1C+ - Strong recommendation likely to apply to most patients with risk/benefit

clear based on extrapolation from randomized controlled studies or on strong evidence from observational studies

• 1C - Intermediate-strength recommendation with risk/benefit clear based on observational studies only

• 2A - Weaker recommendation with risk/benefit unclear based on high-quality randomized studies

• 2B - Weak recommendation with risk/benefit unclear based on randomized studies with limitations; alternate approaches may be better in some patients

• 2C - Very weak recommendation with risk/benefit unclear based on observational studies only; alternatives may be equal or better in most patients

A schematic representation of blood coagulation

• Initiation: tissue factor (TF) is exposed by vessel damage; coagulation factor VIIa (FVIIa) binds to TF and activates small amounts of FX to FXa and FIX to FIXa. This leads to trace amounts of thrombin.

• Amplification: the trace amounts of thrombin activate the co-factors FV and FVIII to FVa and FVIIIa and platelets (via cleavage of protease-activated receptors, PAR1 and PAR4), which leads to the formation of complexes of factors for more efficient thrombin generation.

• Propagation: more thrombin is available leading to activation of FXI (to FXIa) for more thrombin generation, fibrin formation, activation of FXIII (to FXIIIa) to reinforce the fibrin structure and activation of thrombin activatable fibrinolysis inhibitor (TAFI) for prevention of fibrinolysis.

• Termination: thrombin leaking out of the clotting area activates protein C (to APC), which inactivates FVa and FVIIIa. This is important because it restricts the blood coagulation to the area of vessel damage.

• Amber arrows: direct effects of thrombin; green arrows: indirect effects of thrombin that stimulate plasma coagulation and platelet aggregation; red arrows: indirect effects of thrombin that inhibit plasma coagulation and fibrinolysis.

Gustafsson et al., Nature Reviews Drug Discovery 3, 649-659 (2004)

Hyers, Arch Intern Med, 163, 759-768, 2003

Agents Mechanism of ActionOnset of Action

and Route of administration

Application Controindications

Heparin

With ATIII, prevents thrombin activity (anti-

IIa) and to a lesser extent thrombin

generation (anti-Xa) Ineffective on clot-

bound thrombin

Immediate

IV or subcutaneous

Prevention

and treatment of VTE

Severe active bleeding;

documented hypersensitivity

HIT

LMW heparins and heparinoids

With ATIII, inhibits thrombin generation by

an effect on Xa, to a lesser extent on IIa

Ineffective on clot-bound thrombin

Immediate

SubcutaneousPrevention of VTE

Severe active bleeding;

documented hypersensitivity

HIT

Hirudin and direct

thrombin inhibitors

Inhibits thrombin activity directly

Immediate

IVPrevention and

treatment of VTE; treatment of HIT

Severe active bleeding;

documented hypersensitivity

WarfarinInhibits proper

synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X)

4-5 days

OralLong-term

treatment of VTE; prevention of VTE

Severe active bleeding;

pregnancy; documented

hypersensitivity

AgentsMechanism of

Action

Onset of Action and

Route of administration

Application Controindications

Streptokinase

Activates plasminogen,

dissolves fibrin; degrades fibrinogen

and several other plasma proteins

Immediate

IV

Treatment of severe or life-threatening PE or DVT

Active bleeding; recent surgery; stroke; or severe trauma; any

hemorrhagic disease; recent streptococcal infection or treatment

with streptokinase documented

hypersensitivity

Urokinase

Activates plasminogen,

dissolves fibrin; degrades fibrinogen

and several other plasma proteins

Immediate

IV

Treatment of severe or life-

threatening PE or DVT

Active bleeding; recent surgery; severe trauma; any hemorrhagic disease

Alteplase, Reteplase

Activates plasminogen bound to fibrin; dissolves

fibrin

Immediate

IV

Treatment of severe or life-

threatening PE or DVT

Active bleeding; intracranial pathologic condition; recent surgery; severe trauma; any hemorrhagic disease

Eparina

• Glicosaminoglicano (mucopolissaccaride solfatato) di origine naturale

• Non frazionata: 3000-30000 Da• LMWH: < 7000 Da• Forma complessi con alcuni fattori della

coagulazione, attivandoli (antitrombina) o inattivandoli (trombina)

• Attiva delle lipasi con effetto “chiarificante” del sangue

Heparin

A molecular model of the ternary complex of ATIII, thrombin and heparin.

• Heparin acts as a template to facilitate ATIII-mediated inhibition of thrombin. Heparin forms a bridge of six to eight monosaccharide units.

• ABD = Antithrombin Binding Domain• TBD = Thrombin Binding Domain

De Kort et al., Drug Discov Today. 10:769-779, 2005

Indicazioni terapeutiche Eparina

• Onset: immediato• Durata d’azione: 3-6h• Dosi: 35000 U/die suddivisa ogni 8-12h s.c.; 5000 U

(bolo iniziale), poi 1200-1600 U/hr in infusione (DVT). aPTT (activated partial thromboplastin time) = 2-2.5 volte il normale.

• Trattamento della trombosi venosa profonda ed embolismo polmonare (infusione, anche 5000 U/2-3 die)

• Tromboprofilassi in chirugia (5000 U/2-3 die)• Dopo un intervento di fibrinolisi• L’effetto non è strettamente dose-dipendente. La

biodisponibilità s.c. è 30%.

Indicazioni terapeutiche LMWH (Eparina a basso peso

Molecolare)• Onset: immediato• Durata d’azione: 3-6h• Dosi: 5000 U/die suddivisa ogni 8-12h s.c.• Profilassi trombosi venosa profonda ed

embolismo polmonare• Tromboprofilassi in chirugia• Dopo un intervento di fibrinolisi• Risposta dose-dipendente. Biodisponibilità: 90%

s.c.

French & Faxon, Rev Cardiovasc Med. 3: 176-182, 2002

Feature LMWH Fondaparinux

Idraparinux

Bioavailability 80-90% 100% 100%

Half-life (hours) 4 17 80

Target FXa, THR FXa FXa

Renal clearance Yes Yes Yes

Neutralized by PF4 Little None None

Potential for HIT Low None None

Neutralized by protamine sulfate

Partial No No

Comparison of the properties of LMWH, fondaparinux and idraparinux

Effetti collaterali

• Sanguinamento (2 – 33%)• Trombocitopenia (eparina non

frazionata)

• Con le LMWH si hanno meno effetti collaterali

• Le eparine non sono attive sulla generazione di trombina nel coagulo.

Model of the interaction of the blood protein platelet factor 4

with a sulfated heparin polysaccharide.

•The basic residues of platelet factor 4 (PF4) are colored blue. • PF4 is released by activated blood platelets and contains many basic amino acids on its surface, which can form strong interactions with UFH. •HIT is caused by antibodies formed by the antigenic complex of heparin and PF4.

De Kort et al., Drug Discov Today. 10:769-779, 2005

Table 1. Limitations of heparin and their consequences

Limitation Consequence

Binds to plasma proteins Variable anticoagulant response so monitoring is requiredNeutralised by platelet Reduced activity in the vicinity factor 4 of platelet-rich thrombi Forms complexes with platelet Causes heparin-induced factor 4 thrombocytopenia with or without thrombosisLimited capacity to inhibit Incomplete attenuation of factor Xa within the Thrombus growtprothrombinase complex ortrhombin bound to fibrin

Crowther & Weitz Expert Opin. Investig. Drugs (2004) 13 (4):403-413

Warketin TE, Best Pract Res Clin Haematol. 17:105-125, 2004

Warketin TE, Best Pract Res Clin Haematol. 17:105-125, 2004

Warfarin (anticoagulante orale)

• Blocca la sintesi dei fattori della coagulazione vit. K dipendenti (II, VII, IX, X)

• Il INR (international normalized ratio, una misura standardizzata del tempo di protrombina-TP) deve essere tra 2 e 4 (TP 1.5 –2 quello normale)

Goodman & Gilman’s

Warfarin

• L’effetto del warfarin si osserva normalmente dopo 4-5 giorni di terapia

• La dose è di 1.5 mg/die che determina un INR (international normalized ratio, una misura standardizzata del tempo di protrombina-TP) tra 2 e 4 (TP 1.5 –2 quello normale).

• Molte molecole interferiscono con il warfarin.• Esistono varianti genetiche del CYP2C9 (enzima

che metabolizza il warfarin). Nei pazienti con dette varianti alleliche (10-20% Caucasici), la dose deve essere diminuita per ottenere un INR tra 2 e 4. In questi pazienti aumenta il rischio di emoraggie.

Effetti collaterali warfarin

• Effetto collaterale grave: sanguinamento, emorragie (5%). Antidoto: vit.K, ma poiché occorrono circa 24h per la “de novo” sintesi dei fattori vit.K dipendenti, trasfusioni.

• L’effetto è potenziato da antiaggreganti e da tutti i farmaci che spiazzano il warfarin dalle proteine plasmatiche (il warfarin si lega per il 95-98%).

• Una volta spiazzato dalle proteine plasmatiche è metabolizzato più rapidamente con una perdita di efficacia

Indicazioni terapeutiche Warfarin

• Profilassi trombosi venosa profonda ed embolismo polmonare

• Tromboprofilassi in chirurgia ortopedica (femore, bacino) e nella fibrillazione atriale

• Profilassi trombosi nei pazienti con valvole cardiache

• Onset: dopo almeno 24h almeno

• Durata: 3-5 die

Scilla (colei che dilania)

………………………..ma Scilla è atroceMostro, e sino a un dio, che a lei si fesse,Non mirerebbe in lei senza ribrezzo,..…………………………. Odissea, XII

Cariddi (colei che risucchia)

……………………………..e sotto Cariddi gloriosamente l'acqua lividaassorbe.……………………………. Odissea, XII

Echman et al., Ann Intern Med. 2003; 138 :W15-24

Echman et al., Ann Intern Med. 2003; 138 :W15-24

Hyers, Arch Intern Med, 163, 759-768, 2003

Rivaroxaban, an oral directfactor Xa inhibitor

Piccini et al., Expert Opin.Investig. Drugs 2008, 17: 925-937

Rivaroxaban

• Rivaroxaban is a small molecule, direct Factor Xa inhibitor and may be a potentially attractive alternative to vitamin K antagonists.

• Rivaroxaban is being investigated for the prevention and treatment of venous and arterial thrombosis.

• At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in Phase II and Phase III trials involving over 24,000 patients. Additionally, rivaroxaban is being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation.

Ma Q., Br J Clin Pharmacol. 2007, 64: 263–265.

Efficacy of Rivaroxaban

(rivaroxaban)

Time for New anticoagulants