Francesco MarongiuUniversità di Cagliari, Policlinico di Monserrato, Medicina Interna

marongiu@medicina.unica.it

Pavia, 21-22 giugno 2012

Pavia Spring Meeting on ThrombosisAspetti Clinici e di Laboratorio del Tromboembolismo Venoso ed Arterioso

alla luce delle Linee Guida ACCP 2012

Farmaci anticoagulanti vecchi e nuovi

Professor Diakonov nel suo articolo del 1809,Changes ofhuman blood in the leechnel 1809, scrisse che “lack of bloodcoagulation and dissolution of red blood corpuscles in the leech’s intestinal duct testifies that some dissolving agent exists there”

IRUDINA

Historical Article: Hirudo medicinalis: ancient origins of, and trends in the use of medicinal leeches throughout history. Br J Oral and Maxillofacial Surg 2004;42: 133-7

McLean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41: 250-7McLean J. The discovery of heparin. Circulation 1959; 19: 75-8.

Jay McLean

M W 15,000 (range: 3.000 to 30.000 d)Only one third of heparin molecules contain the high-affinity

pentasaccharide (AT) required for anticoagulant activity

UFH

Heparin doses Half-life min

25 U/Kg (1750 U) 30

100 U/Kg (7000 U) 45-60

400 U/Kg (28000 U) 46-150

Chest 2008;133;141-159

Highly sulphated mucopolysaccharide

Heparin binds to plasma proteins, endothelial cells, macrophages and AT.

Plasma proteins

Endothelial cells

Antithrombin

Macrophages

Chest 2008;133;141-159

LMWH Molecular WeightRatio

anti-Xa/anti-IIa

Enoxaparin 4500 3.9

Dalteparin 6000 2.5

Tinzaparin 6500 1.6

Nadroparin 4300 3.2

Certoparin 5400 2.4

Bemiparin 3600 9.7

Reviparin 4400 4.2

Thromb Haemost 2008; 99: 807–818

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism

Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No.:

CD001100

Petra MG Erkens, Martin H Prins

.2 1 5 10

OR 0.71; 0.56 to 0.90

23 studies Follow-up3 months

Thrombosis

recurrence

LMWH:3382

NadroparinDalteparinCertoparinTinzaparinEnoxaparinReviparin

3.6 % (122)

5.2 % (164)

UH: 3169

OR 0.88 (0.48-1.63)

No significant difference

between:

LMWH (n=670) versus UFH (n=559)

in patients with pulmonary embolism

Pros and Cons versus UFH

1 bioavailability (they do not link to plasma proteins)

2 longer half-lifes (up to 4 times)

3 subcutaneoulsly administered (so at home)

4 they do not need lab monitor (in general)

Not recommended if GF<30 ml/min (may be accumulated)

Difficult reverse with protamine sulphate (about 40 %)

300 milioni di maiali

100 tonnellate di eparina

per anno

Eparine

Cina

Circa l’85 % del mercato mondialedelle eparine

Fondaparinux :

The first of a new class of synthetic selective inhibitors of factor Xa

• Five saccharide units

• Synthetic

• Highly selective for AT 3

• Factor Xa inhibition

• No binding with plasma proteins

• No effect on platelet function

• No thrombocytopenia

Fondaparinux (N=1103) UFH (N=1110)

Fondaparinux - UFH (95 % CI )

Matisse PE

-1.2% = 3.5%0 0.5%-3.0%

Fatal PE 16 (1.5 %) 15 (1.4 %)

Non-fatal PE or DVT 26 (2.4 %) 41 (3.6 %)

Total symptomatic recurrent VTE 42 (3.8 %) 56 (5.0 %)

AT

I SS

E

M .

..

. ..

.

Primary Efficacy Outcome - 3 months -

(The Matisse Investigators; NEJM 2003;349:1695)

Fondaparinux

Metilazione dei gruppi idrossilici

Idraparinux(O-methyle, O-sulphate

Pentasaccharide)‏

•Alta affinità per l’AT

•Emi-vita= 100 h

•Somministrazione:

•Una volta/settimana

The Van Gogh Investigators. New Engl J Med 2007; 357: 1094-104

3 %

2.9 %

3.4 %

1.6 %

Kaplan-Meier cumulative incidence curves of first clinically relevant bleedingduring the randomised treatment period

Amadeus Study

Sanguinamento

maggiore

346

226

Lancet 2008; 371: 315–21

Idrobiotaparinux

In the BOREALIS trial, idrabiotaparinux was developed for the prevention of

thromboembolic events in patients with atrial fibrillation.

Considering recent therapeutic advances in this field, this compound does

not appear able to bring significant improvement in the care of these

patients. Therefore, the development in this indication is discontinued.

Sanofi-Aventis Press Release dec 21, 2009

Lancet 2012; 379:123-9

Idrabiotaparinux versus warfarin: 3202 randomized patientsEnoxaparin for all patients in the first 10 days

Recurrent venous thromboembolism:Idrabiotaparinux 2 % versus W 3 %

Idrabiotaparinux

A favore

SinteticoProtegge dopo molti mesiComoda somministrazione

Antidoto (avidina)

Contro

Emivita estremamente lungaPossibilità di accumulo

Possibili reazioni avverseall’avidina

R

Semuloparin sodium (AVE5026; Sanofi-Aventis)

E’ una nuova ultra-low-molecular-weight heparin

(PM: 2400 Da), con attività anti-Xa predominante

(ratio anti-FXa/anti-FIIa >30) ed emivita: 11-22 h

Somministrabile SC una volta al giorno

.

Ottenuta per depolimerizzazione di eparina da mucosa

suina. Non neutralizzabile con protamina

Utilizzata in chirurgia ortopedica

Meta-analisi di tre studi: OR 0.85; 0.60-1.18

Pathophysiol HaemostThromb 2009-10; 37(Suppl. 1): OC332

Otamixaban (Sanofi-Aventis)

Potente ed altamente selettivo anti-Xa per IV

Rapida massima attività: 3 min

(Emivita: 30 minuti)

Escrezione biliare (soprattutto)

Antidoto: no

Sindromi Coronariche Acute

OTAMIXABAN Composite outcomes

0.035 mg/Kg/h 7.2 %

0.07 mg/Kg/h 4.6 %

0.105 mg/Kg/h 3.8 %

0.140 mg/Kg/h 3.6 %

0.175 mg/Kg/h 4.3 %

Control group: Heparin (60 IU/kg IV bolus followed by an infusion of 12 IU/kg/h) + eptifibatide (180 mg/kg IV bolus followed by an infusion of 1.0-2.0 mg/kg/min).

6.2 %

Otamixaban: alternativa all’eparina nelle ACS ?

Lancet 2009; 374: 787-795

SEPIA-ACS1 TIMI 42 trial; 3200 pazienti (dose-finding trial)

Pegmusirudin (PEG-hirudin; SPP200; LU87981)DTI con lunga emivita (fino a 36 h)

Antidoto: no

Emodialisi

Studio di fase II su 127 pazientiPEG-Hirudin: 0.052 o 0.065 mg/kg

Occlusione accesso vascolarePEG-hirudin 11 % versus Heparin 40 %

Sanguinamento maggiorePEG-Hirudin 8.4 % versus Heparin 5.4 %

Sanguinamento minore: 57.8 versus 32.4 %

J Am Soc Nephrol 17: F-PO769

Pentasaccaride + DTI +

biotina

Neutralizzato da avidina

EP217609: aggiunge soprattutto l’attività verso la trombina legata alla fibrina

Antidote

The REG1 anticoagulation system is composed of the drug RB006 and the oligonucleotide antidote to RB006 (RB007), which binds to RB006 via Watson-Crick base pairing and thereby neutralizes its pharmacological effect.

Anti-IX

Aptamer

Eur Heart J 2011;32:2412-9

Pegnivacogin results in near complete FIX inhibition in acute coronary syndrome patients: RADAR pharmacokinetic and

pharmacodynamic substudy.

The REG1 system (Regado Biosciences, Basking Ridge, NJ) consists of pegnivacogin (RB006), an RNA aptamer that directly inhibits factor IXa, and anivamersen (RB007), its complementary control agent.

RADAR is a Phase 2b study investigating the use of pegnivacogin in patients (n = 800) with ACS undergoing planned early cardiac catheterization.

Pegnivacogin 1 mg/kg rapidly achieved a high pegnivacogin plasmaconcentration (26.1 ± 4.6 µg/mL), prolonged the aPTT (mean aPTT 93.0 ±9.5 s), and approached near complete factor IX inhibition.

Anticoagulant Hours to

[C] maxHalf-life

hours

Renal

elimination

Dabigatran 2 12-14 80 %

Rivaroxaban 2-4 9-13 33 (66) %

Apixaban 1-3 8-15 25 %

Ericksson BI, Clin Phatmacokinet 2009

Ruff CR, Am Heart J 2010

General characteristics of NOA

Study name Statistics for each study Risk ratio and 95% CI

Risk Lower Upper ratio limit limit Z-Value p-Value

Apixaban AF 0,797 0,667 0,952 -2,501 0,012

Re-ly 150 0,667 0,538 0,828 -3,668 0,000

Re-ly 110 0,916 0,751 1,116 -0,873 0,383

ROCKET AF 0,880 0,750 1,033 -1,559 0,119

0,822 0,749 0,901 -4,167 0,000

0,5 1 2

Favours NOA Favours Warfarin

NOA versus Warfarin

Meta Analysis

Stroke

Hazard ratios and 95% confidence intervals of the primary safety

outcome (major bleeding) in the 3 pivotal trials comparing new oral

anticoagulants with warfarin in nonvalvular atrial fibrillation.

JACC 2012; 59:1413–25

Anticoagulant CHADS2

score

Heart failure

%

Dabigatran 2.10 32

Rivaroxaban 3.48 63

Apixaban 2.10 35

Complexity of patients

Anticoagulant M. B. % y ICH % y

Dabigatran 150 mg

Dabigatran 110 mg

Warfarin 2.0-3.0 INR

3.11

2.71

3.36

0.10

0.12

0.38

Rivaroxaban 20 mg*

Warfarin 2.0-3.0 INR

3.60

3.40

0.50

0.70

Apixaban 5 mg

Warfarin 2.0-3.0 INR

2.13

3.09

0.24

0.47

* Once daily

NOA and Atrial Fibrillation:

Major bleeding with warfarin: 3.09-3.36 %y

an unrealistic result

Anticoagulant Gastrointestinal

bleeding

Rivaroxaban 20 mg 224 (3.15 %)

Warfarin 2.0-3.0 INR 154 (2.16 %)

p<0.001

More gastroenteric bleeding with

Rivaroxaban

Anticoagulant Gastrointestinal

bleeding

Dabigatran 150 mg 182 (1.51 % y)

Warfarin 2.0-3.0 INR 120 (1.02 % y)

RR: 1.50 (1.19-1.89) p<0.001

More gastroenteric bleeding with

Dabigatran 150 mg (t.d.))

Anticoagulant Dispepsia

Dabigatran 150 mg 688 (11.3 %) *

Dabigatran 110 mg 707 (11.8 %) *

Warfarin 2.0-3.0 348 (5.8 %)

More dyspepsia with Dabigatran)

* p<0.001

unreliable result

(never seen)

Questions and answers on the use of dabigatran and

perpectives on the use of other new oral anticoagulants

in patients with atrial fibrillation

A consensus document of the Italian Federation of

Thrombosis Centers (FCSA)

Vittorio Pengo; Luciano Crippa; Anna Falanga; Guido

Finazzi; Francesco Marongiu; Gualtiero Palareti; Daniela

Poli; Sophie Testa; Eros Tiraferri; Alberto Tosetto;

Armando Tripodi; Cesare Manotti

Thromb Haemost 2011;106:868-76

Which naive patient should be treated with NOA ?

All the patients with characteristics similar to those of

patients enrolled in the NOA studies.

Patients on VKAs with a TTR (time spent in the

therapeutic range) below 50-55 % (Grade A).

Patients at high risk of stroke (Grade A).

Patients willing to be prescribed the new drugs.

Patients with logistic problems or those confined to

home due to physical problems.

Which patients are definitely to remain on VKAs ?

Patients with both a stable INR and a low bleeding risk

(Grade A).

Patients with frequent dyspepsia (Grade A).

Patients who prefer to continue with VKAs after having

received complete information on the pros and cons of

NOA.

Patients with severe renal failure (Grade A).

Patients with previous myocardial infarction.

Should we expect significant drug interactions ?

What is recommended for the follow-up ?

Enter patient’s data into a registry

(indication, type of NOA, adverse events

etc.).

Follow-up after 3 and 6 months. Then,

every six months.

Conditions Dabigatran Rivaroxaban Apixaban

Heart valve disorders Excluded Excluded Excluded

Disabling stroke within the previous six months or any

stroke within the previous 14 d

Excluded Excluded NR

Increased risk of bleeding

a) previous surgery within the previous month Excluded Excluded NR

b) history of intracranial, intraocular, spinal

retroperitoneal or a traumatic intra-articular bleeding

Excluded Excluded Excluded

c) Gastrointestinal haemorrhage within the past year Excluded Excluded NR

e) Ulcer disease in the previous 30 days Excluded NR NR

f) Recent malignancy or radiation therapy Excluded NR NR

Severe renal impairment: creatinine clearance less than

30ml/min

Excluded Excluded Excluded

Anaemia (Hb<10g/dl) or thrombocytopenia (<100-90 x

109/L)

Excluded Excluded Excluded

Planned cardioversion NR Excluded NR

Indication for anticoagulation other than AF Excluded Excluded Excluded

Major surgery or invasive procedure planned NR Excluded NR

Simultaneous treatment with both aspirin and a

thienopyridine

NR Excluded Excluded

Fibrinolytic treatment within 2 to 10 days Excluded Excluded NR

Liver disease Excludded Excluded NR

NOA: Exclusion criteria

4.3 Contraindications

In general, patient populations not studied in the clinical trial

programme should be mentioned in section 4.4 (4.4 Special

warnings and precautions) for use and not in this section unless a

safety issue can be predicted (e.g. use of renally eliminated

substances with narrow therapeutic margin in renal failure

patients).

If, however, patients have been excluded from studies due to a

contraindication on grounds of safety, they should be mentioned

in this section. If applicable a cross-reference to section 4.4

should be made.

Advantages of NOA

1 No INR need

2 Predictable activity

3 Less strokes and major bleeding

events (Dabigatran and Apixaban)

4 Rapid anticoagulation activity

Circulation 2012;125:165-170

Disadvantages of New Oral Anticoagulants

ad alto rischio (CHADS2 >2): Rivaroxaban

a basso-medio rischio (CHADS2 1-2): dabigatran 150 o apixaban

con precedente emorragia gastroenterica: Apixaban

con dispepsia e basso e medio rischio (CHADS2 1-2): apixaban

con dispepsia ed alto rischio: rivaroxaban

Scelta dei nuovi anticoagulanti orali nei pazienti selezionati (1)

a basso rischio (CHADS2 1): dabigatran 150 o apixaban

con insufficienza renale moderata (Cr Cl: 30-50): apixaban se CHADS2 2 o Rivaroxaban se CHADS2 >2

con età >75 anni, indipendentemente dal rischio, apixaban o rivaroxaban (possibile rapido declino della funzione renale)

con molti farmaci (>5-6 al giorno per due volte): Rivaroxaban

Scelta dei nuovi anticoagulanti orali nei pazienti selezionati (2)

NOA:

What about

deep vein

thrombosis

and

pulmonary

embolism ?

Dabigatran versus Warfarin in VTE

Dabigatran 1274 patients Warfarin 1265 patients

after initial treatment with UHF, LMWH or fondaparinux

6-month incidence of recurrent symptomatic,

objectively confirmed VTE

D

2.4 %

W

2.1 %

P<0.001 for non-inferiority

New Engl J Med 2009; 361:2342–2352

Rivaroxaban versus Warfarin in VTE

Rivaroxaban 1731 patients VKAs 1718 patients

12-month incidence of recurrent symptomatic,

objectively confirmed VTE

R

2.1 %

VKA

3.0 %

after initial treatment

with UHF, LMWH or

fondaparinux

15 mg twice/day for 3 weeks

followed by 20 mg/day

N Engl J Med 2010; 363: 2499–2510

HR: 0.68, 0.44-1.04, p<0.001 for non-inferiority

Rivaroxaban versus Warfarin in PE

Rivaroxaban: 2419 patients VKAs: 2413 patients

9-month incidence of recurrent symptomatic,

objectively confirmed PE

R

2.1 %

VKA

1.8 %

after initial treatment

with UHF, LMWH or

fondaparinux

15 mg twice/day for 3 weeks

followed by 20 mg/day

N Engl J Med 2012; 366:1287–1297

HR: 1.12, 0.75–1.68, p= 0.003 for non-inferiority

Conclusioni1 Sapremo tra qualche anno se le vecchie eparine potranno essere sostituite da nuovi farmaci (efficacia, sicurezza e costi).

2 I nuovi anticoagulanti orali potranno essere somministrati a pazienti selezionati con l’impegno di un follow-up periodico documentato.

3 Sulla base degli studi può essere possibile scegliere tra i diversi NOA.

4 Sembra ottimale il loro utilizzo nel TEV.

5 Gli AVK possono però rappresentare ancora la prima scelta in determinate condizioni.