Savvato 9 Tselepis

ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ

Αντιπηκτική αγωγή σε ασθενείς με κολπική μαρμαρυγή και συνοδά νοσήματα

Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχημείας - Κλινικής Χημείας

Πρωτογενής Αιμόσταση

Δευτερογενής Αιμόσταση (φάση έναρξης)

Δευτερογενής Αιμόσταση (φ.ενίσχυσης) Δευτερογενής Αιμόσταση (εκθετική φ.)

Αιμόσταση: Πήξη και σταθεροποίηση θρόμβου Εξωγενής οδός

Ενδογενής οδός

XII XI

Ιστικός Παράγων (TF)

IX VII

VIII AT

X V

II Ινωδογόνο FXa Θρομβίνη

Ινώδες

FXa

Ca ++ FVa Φωσφολιπίδια Προθρομβινάση

Vascular Damage (PCI)

Platelet activation and aggregation

Cell-based model of coagulation

Monroe DM, et al. Arterioscler Thromb Vasc Biol. 2002;22:1381-89

TF Pathway IX

TF Prothrombin (II) IXa

VIIa

Xa TFPI

Thrombin (IIa) Fibrinogen

Soft clot Fibrin XIIIa

Hard clot Fibrin

Triggers of arterial and venous thrombosis Artery

Vein

Nigel Mackman, Nature (2008) 451:914-918

8

Αντιθρομβωτικά φάρμακα

Αντιαιμοπεταλιακά Χρησιμοποιούνται κυρίως στην αρτηριακή θρόμβωση γιατί οι θρόμβοι αυτοί είναι πλούσιοι σε αιμοπετάλια, ενώ οι θρόμβοι στο φλεβικό σύστημα έχουν σχετικά μικρή περιεκτικότητα σε αιμοπετάλια

Αντιπηκτικά Χρησιμοποιούνται στην πρόληψη και θεραπεία της θρόμβωσης τόσο στο αρτηριακό όσο και στο φλεβικό σύστημα

Components of Virchow’s Triad for thrombogenesis in AF

Watson T, et al. Lancet 2009; 373: 155–66

Mechanisms of thrombogenesis in AF Abnormal blood stasis In addition to stasis consequent on the failure of atrial systole, the presence of nonvalvular atrial fi brillation seems to promote progressive left atrial (LA) dilatation thus amplifying the potential for stasis.

Abnormal blood constituents-Prothrombotic state Abnormal changes in coagulation Platelet activation?

Abnormal changes in fi brinolysis What drives the prothrombotic state in AF? Low-grade infl ammation and release of various growth factors.

Endothelial dysfunction Renin-angiotensin-aldosterone system (RAAS)

3. Thrombus formation in the left auricle (computer graphics superimposed on in-body photograph) The irregular beating of the heart in atrial fibrillation creates ideal conditions for thrombus formation in the left auricle, especially in patients with mitral valve insufficiency.

6. Thrombotic material in the aortic arch (computer graphics superimposed on in-body photograph) Once fragments of the thrombus are in the blood stream they may be carried to any part of the body.

Small fragments may result in a transient cerebral ischaemic attack. Larger pieces may have more devastating consequences.

7. Cerebral thromboembolism (computer graphics superimposed on in-body photograph) 25 percent of the blood flow from the heart is pumped to the brain. Cerebral thromboemboli most frequently affect the middle cerebral artery.

Stroke in Atrial fibrillation Cerebral circulation

Right atrium

Stroke

Left atrium Results in adnormal blood flow and stasis in the atria

Oral Anticoagulants in AF

Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction Treatment Better

Treatment Worse

Warfarin vs.

Placebo/Control

6 Trials n = 2,900

Antiplatelet drugs vs. Placebo

8 Trials n = 4,876

100%

50%

Hart R, et al. Ann Intern Med 2007;146:857.

0

-50%

Thromboembolic prophylaxis



Aspirin reduces stroke by



Warfarin reduces stroke by Maintain INR 2-3

20%

60-68%

Primary Efficacy Outcome Stroke or Systemic Embolism Hazard ratio with apixaban, 0.45 (95% CI, 0.32, 0.62) 0.05

C umulative Haz ard

1.0

As pirin

0.04

0.8

0.03

Apixaban

0.02

0.6

0.01

P <0.001

0.4 0.00 0

0.2

3

6

9

12

18

0 0

3

6

9

12

18

Months

Number at risk Aspirin

2791

2716

2530

2112

1543

628

Apixaban

2808

2758

2566

2125

1522

615

Connolly SJ, et al. N Engl J Med. 2011;364:806â&#x20AC;&#x201C;817

Oral Anticoagulant Target Sites Factor IX

Factor VII Factor X

FVIIa

FIXa

VKA •Warfarin

Anti-FXa •Apixaban •Rivaroxaban •Edoxaban

Factor Xa Antithrombin

Anti-FIIa Factor II (Prothrombin)

Fibrinogen

•Dabigatran

Factor IIa (Thrombin)

Fibrin

Ο κύκλος της Βιταμίνης K

VKOR subunit 1 (VKORC1) C1173T polymorphism

Marín F, et al. J Am Coll Cardiol 2009;54:1041–57

Μηχανισμός δράσης ανταγωνιστών της Βιταμίνης Κ

Βιταμίνη K

Ανταγωνισμός της Βιταμίνης Κ

Warfarin

VII IX X II

Σύνθεση μη λειτουργικών παραγόντων πήξης

Vit K Antagonists ď ś Slow onset and offset of action Protein

Prothrombin (II)

Half Life (Hours)

60-100

Factor VII

6-8

Factor IX

20-30

Factor X

24-40

Protein C

8-10

Protein S

40-60

Mechanism of Action of Vit K Antagonists

New Oral Anticoagulants

Bauer KA J Thromb Haemost 2011; 9 (Supl):12-19

New Oral Anticoagulants

Comparison of the active center in the crystal structures of thrombin and factor Xa Thrombin

Flat

Large

Xa

Deep

Straub A, et al. Angew. Chem. Int. Ed. 2011, 50, 4574 â&#x20AC;&#x201C; 4590

Binding of Dabigatran and Rivaroxaban to thrombin and Fa Dabigatran-Thrombin

Rivaroxaban-Xa

Straub A, et al. Angew. Chem. Int. Ed. 2011, 50, 4574 â&#x20AC;&#x201C; 4590

Binding mode of apixaban

Wong PC, et al. J Thromb Thrombolysis (2011) 31:478â&#x20AC;&#x201C;492

Δράση των άμεσων αναστολέων της Θρομβίνης FXa στο σύμπλεγμα της Προθρομβινάσης

Άμεσοι Αναστολείς της Θρομβινης

FΙΙa στο Ινώδες FΙΙa • Οι άμεσοι αναστολείς της θρομβίνης αναστέλλουν τόσο τη ελεύθερη όσο και τη δεσμευμένη στο ινώδες θρομβίνη

Δράσεις των άμεσων αναστολέων του Xa FXa στο σύμπλεγμα της Προθρομβινάσης

Άμεσοι Αναστολείς του Fxa

FXa στο Ινώδες FXa • Οι άμεσοι αναστολείς του Xa αναστέλλουν τόσο τον ελεύθερο όσο και τον δεσμευμένο Xa στο σύμπλεγμα της προθρομβινάσης και στο ινώδες

Comparison of the characteristics of new oral anticoagulants

Protein binding

>90%

>87%

55%

35% (dialysable)

Weitz JI, et al. Thromb Res. 127 Suppl. 2 (2011) S5â&#x20AC;&#x201C;S12

Dabigatran Etexilate Dabigatran Amidine group High polarity not oraly available

Dabigatran etexilate Oraly available

+ tartaric acid

Dabigatran etexilate: προφάρμακο

Εστεράσες

Dabigatran: ενεργός μεταβολίτης

Dabigatran etexilate

Comparison of the characteristics of new oral anticoagulants

(Active 36%) Active 36% Protein binding Hepatic metabolism

Inactive 30% >90% >87% CYP3A4

CYP3A4

55%

35% (dialysable)

CYP3A4

Conjugation

Weitz JI, et al. Thromb Res. 127 Suppl. 2 (2011) S5â&#x20AC;&#x201C;S12

Renal Profiles of Anticoagulants Dabigatran

Rivaroxaban

.

Apixaban excretion is also partly dependent on renal function Harder S. J Clin Pharmacol, 2012,

Clinical Pharmacology of the new oral anticoagulants

Potpara TS , et al. Adv Ther (2012) 29(6):491â&#x20AC;&#x201C;507

Mean plasma concentration-time profiles of Dabigatran in healthy volunteers and patients with moderaten hepatic impairment, after a single 150-mg dose of dabigatran etexilate

Stangier J, et al. J Clin Pharmacol, 2008;48:1411-1419

New Oral Anticoagulants In AF

ARISTOLE

RE-LY

ROCKET-AF

RE-LY Safety Outcomes

Connolly SJ et al. N Engl J Med 2009;361:1139â&#x20AC;&#x201C;51

ROCKET-AF Rates of Bleeding Events

Connolly SJ et al. Presented at ESC 2010

Patel MR, et al. NEJM. 2011

ARISTOTLE: Bleeding Outcomes Apixaban (N=9088)

Outcome

Primary safety outcome: ISTH major bleeding*

Warfarin (N=9052)

Event Rate Event Rate (%/yr) (%/yr)

HR (95% CI)

P Value

2.13

3.09

0.69 (0.60, 0.80)

<0.001

Intracranial

0.33

0.80

0.42 (0.30, 0.58)

<0.001

Gastrointestinal

0.76

0.86

0.89 (0.70, 1.15)

0.37

Major or clinically relevant non-major bleeding

4.07

6.01

0.68 (0.61, 0.75)

<0.001

GUSTO severe bleeding

0.52

1.13

0.46 (0.35, 0.60)

<0.001

TIMI major bleeding

0.96

1.69

0.57 (0.46, 0.70)

<0.001

Any bleeding

18.1

25.8

0.71 (0.68, 0.75)

<0.001

Granger CB, et al. N Engl J Med 2011; 365:981-992

Oral Anticoagulants in ACS

APPRAISE-2: Apixaban 5 mg bd with Antiplatelet Therapy after ACS Kaplanâ&#x20AC;&#x201C;Meier Curves for the Primary Efficacy Outcome

Connolly SJ et al. Presented at ESC 2010

Alexander JH, et al. NEJM 2011;365:699-708

APPRAISE-2 Kaplanâ&#x20AC;&#x201C;Meier Curves for the Primary Safety Outcome

Connolly SJ et al. Presented at ESC 2010

Alexander JH, et al. NEJM 2011;365:699-708

ATLAS ACS 2â&#x20AC;&#x201C;TIMI 51 Rivaroxaban in Patients with a Recent ACS

Mega JL, et al. N Engl J Med 2012;366:9-19

Connolly SJ et al. Presented at ESC 2010

ATLAS ACS 2â&#x20AC;&#x201C;TIMI 51: Rivaroxaban in Patients with a Recent ACS

Connolly SJ et al. Presented at ESC 2010

Mega JL, et al. N Engl J Med 2012;366:9-19

ATLAS ACS 2â&#x20AC;&#x201C;TIMI 51

Connolly SJ et al. Presented at ESC 2010

Mega JL, et al. N Engl J Med 2012;366:9-19

Prothrombin Time (PT) INR

Thrombin Time (TT)

Vit K Antagonists: Require monitoring (PT, INR)

Courtesy of Patrik Michel, adapted from Hylek et al. NEJM 1996; 335:540-6

Nο Laboratory Monitoring in Daily Practice

Predictable pharmacokinetics and pharmacodynamics Rapid onset of action

Wide therapeutic window Fixed dose

Clinical trials without monitoring

Laboratory Monitoring is Sometimes necessary  Bleeding or thrombotic event  High risk for bleeding  Elective or urgent surgery  Suspected overdose  Renal or hepatic dysfunction

 Bridging from one anticoagulant to another  Compliance monitoring  Pts with low body weight or obese pts  Co-medications (potential drug interactions)

Rivaroxaban Monitoring

Correlation between PT and Rivaroxaban plasma concentration

Prothrombin Time (s)

40

Prothrombin time Model

30 r = 0.958

20

10

0

0

100

200

300

400

500

600

Plasma Concentration of Rivaroxaban (Âľg/l) Perzborn et al. JTH; 2005; Hillarp et al JTH; 2011

Validation of the efficacy of the rivaroxaban-Standardized prothrombin time (PT) ratio (Riva-PT-ratio) PT – ratio = (PTpatient / PTnormal) INR = (PTpatient / PTnormal) ISI Riva –PT – ratio = (PTpatient / PTnormal)RivaSI

Tripodi A. JTH. 2012;11:576-578

Anti-Xa activity of rivaroxaban : Chromogenic method

Samama MM, et al. Thromb Haemost. 2010

Apixaban monitoring  Limited information available  Minimal impact on PT and APTT  Increases Dilute Prothrombin time (diluted

thromboplastin reagents) in a concentration dependent manner  Prolongs Hep test  Chromogenic anti-Factor Xa assays

- promising results/variability

Dabigatran Monitoring

Effect of dabigatran on clotting tests

*

***

***

*

Van Ryn et al Thromb Haemost 2010

The HCT test for Dabigatran

Dabigatran

Correlation of HCT test with plasma concentration of Dabigatran

Van Ryn et al Thromb Haemost 2010

Influence of NOACs on clotting tests

  PT

  aPTT   TT or Ecarin Clotting Time  Anti-Xa

 Anti-IIa (HCT)

Dabigatran

Rivaroxaban Apixaban

+

++

+

-

+++

-

-

+++

+++

-