Thrombosis and antithrombotic therapy in cardiovascular disorders

With the endorsement of the Working Group on Thrombosis of the European Society of Cardiology and Ukrainian Association of Acute Cardiovascular Care

Joint Educational Course of the International Society on Thrombosis and Haemostasis (ISTH), the Mediterránean League on Thromboembolic Disease (MLTD) and the Ukrainian Association of Cardiology

Thrombosis and antithrombotic therapy in cardiovascular disorders Kiev, April 4-5 2013

Session Systemic cardiogenic thromboembolism and stroke April 5, 2013 – 11:30-14:00

Prevention of cardioembolism with traditional and new anti-thrombotics Raffaele De Caterina “G. d’Annunzio” University – Chieti and “G. Monasterio” Foundation – Pisa, Italy April 5, 2013 – 13:15-13:35 + disc.

Prof. Raffaele De Caterina Disclosures

 



Co-author of 2010-2012 ESC Guidelines on Atrial Fibrillation Steering Committee member, National Coordinator for Italy, and Co-author of ACTIVE, APPRAISE-2, ARISTOTLE, AVERROES Fees, honoraria and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi-Sankyo

Outline  A brief

history of oral anticoagulants  NOACs in trials  NOACs in clinical practice

Outline ď ˝ A brief

history of oral anticoagulants ď ˝ NOACs in trials

Oral anticoagulants: warfarin  Dosing  Oral; varies, depending on coagulation monitoring tests

 Monitoring  Usually monthly, testing INR  INR target of 2.5, range 2.0–3.0

 Adverse events  Bleeding, bruising  Many significant and potential food and drug interactions

 Unique advantage ● Only anticoagulant available for long-term use Harvey & Champe. Pharmacology 1997

Precursors of clotting Factors: prothrombin, VII, IX, X, protein C, protein S O2

Vitamin KH2 (reduced)

C C NH O CH2 CH2 COOH

Vitamin K epoxide reductase

CO2

Warfarin

Vitamin K epoxide (oxidized) Active clotting Factors: prothrombin, VII, IX, X, protein C, protein S

C C NH O CH2 CH2 COOCOO-

Wisconsin Alumni Research Foundation - WARF WARFarin

The discovery of warfarin 

The sweet clover problem



Link’s isolation of the oral anticoagulant



From test tube to rat poison – Karl Link



From rat poison to clinical application

1951 advertisement for warfarin

Warfarin for stroke prevention in AF*  n=2,837

AFASAK I (n=1,007)

 205 strokes

AFASAK II (n=677)

 RRR 36% (95% CI: 14%–52%) for all stroke

EAFT (n=1,007) PATAF (n=729)

 RRR 46% (27%–60%) for ischaemic stroke

SPAF II (n=1,100) All trials (n=3,420) 100

50

Warfarin better than ASA

0

–50

Warfarin worse than ASA

*Valvular and non-valvular; RRR, relative risk reduction Hart et al. Ann Intern Med 1999

–100

…and, in addition, VKA have allowed    

Prevention and treatment of venous thromboembolism The development of prosthetic heart valves Ventricular assist devices The artificial heart

Warfarin: contraindications 

Pregnancy 

 

Associated with developmental abnormalities

Threatened abortion, eclampsia and pre-eclampsia Recent surgery 





CNS; eye; traumatic surgery, resulting in large open surfaces

Bleeding tendencies associated with active ulceration or overt bleeding 

GI, GU or RT



Cerebrovascular haemorrhage aneurysms– cerebral, dissecting aorta



Pericarditis and pericardial effusions



Bacterial endocarditis

Unsupervised patients with 

Senility



Alcoholism



Psychosis, or



Other lack of patient co-operation



Spinal puncture



Any diagnostic or therapeutic procedures with potential for uncontrollable bleeding



Miscellaneous 

Major regional



Lumbar block anaesthesia



Malignant hypertension



Known warfarin hypersensitivity

CNS, central nervous system; GI, gastrointestinal; GU, genitourinary; RT, reproductive tract www.rxlist.com/cgi/generic/warfarin_ad.htm

Warfarin: drug interactions  Many drugs have the potential to interact with warfarin Specific drugs reported acetaminophen alcohol allopurinol aminosalicylic acid amiodarone HCl argatroban acetylsalicylic acid atenolol atorvastatin azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate chlorpropamide cholestyramine cimetidine ciprofloxacin cisapride clarithromycin clofibrate COUMADIN overdose cyclophosphamide danazol dextran dextrothyroxine diazoxide diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate

fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemfibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine lovastatin mefenamic acid methimazole methyldopa methylphenidate methylsalicylate ointment (topical) miconazole (intravaginal, metronidazole oral, systemic) moricizine hydrochloride nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone

pantoprazole penicillin G, paroxetine intravenous pentoxifylline phenylbutazone phenytoin piperacillin piroxicam pravastatin prednisone propafenone propoxyphene propranolol propylthiouracil quinidine quinine rabeprazole ranitidine rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E zafirlukast zileuton



Highlights     



Atorvastatin, simvastatin Esomeprazole, lansoprazole Paracetamol, ASA, ibuprofen Propranolol, naproxen Chloramphenicol, clarithromycin, tetracycline, penicillin G, metronidazole …

Alcohol

www.rxlist.com/cgi/generic/warfarin_ad.htm

Underutilization of anticoagulation in AF* Approximately half of high-risk patients with AF receive warfarin therapy 13 community hospitals

21 academic hospitals Warfarin therapy No warfarin therapy

53%

47%

*US population January–December 2002 Waldo et al. J Am Coll Cardiol 2005

53%

47%

Tifacogin NAPc2 rFVIIai

TF/VIIa

Initiation

X AmplificationPropagation

IX

VIIIa

IXa

TB-402 Drotrecogin Recomodulin Solulin

Va Indirect UFH LMWH Fondaparinux Idrabiotaparinux Semuloparin M118

Xa

Direct Otamixaban Rivaroxaban Apixaban Edoxaban Darexaban Betrixaban TAK-442 -

Thrombin activity Indirect UFH LMWH

II

Pegnivacogin

IIa

Direct Dabigatran AZD0837

Fibrinogen

Fibrin

De Caterina R, Husted S, Wallentin L et al. J Am Coll Cardiol, 2012

TF/VIIa

Initiation

X AmplificationPropagation

IX

VIIIa

IXa

Va Xa

Direct Rivaroxaban Apixaban Edoxaban

Thrombin activity

II Fibrinogen

IIa

Direct Dabigatran

Fibrin

De Caterina R, Husted S, Wallentin L et al. Thromb Haemost, 2012, submitted

RE-LY® – study design Atrial fibrillation with ≥ 1 risk factor Absence of contraindications

R Warfarin 1 mg, 3 mg, 5 mg (INR 2.0-3.0) N=6000

Dabigatran etexilate 110 mg bid N=6000

Dabigatran etexilate 150 mg bid N=6000

 Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin  Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up Ezekowitz MD, et al. Am Heart J 2009;157:805-10.

Connolly SJ., et al. NEJM published online on Aug 30th 2009.

DOI 10.1056/NEJMoa0905561

Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

Stroke or systemic embolism (SSE) Noninferiority p-value

Dabigatran 110 mg vs. warfarin

Margin = 1.46

Dabigatran 150 mg vs. warfarin

0.50

0.75

1.00

1.25

Superiority p-value

<0.001

0.34

<0.001

<0.001

1.50

HR (95% CI) Connolly SJ., et al. NEJM published online on Aug 30th 2009.

DOI 10.1056/NEJMoa0905561

Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

Risk Factors

Study Design Atrial Fibrillation Rivaroxaban 20 mg daily 15 mg for Cr Cl 30-49 ml/min

Randomize Double Blind / Double Dummy (n ~ 14,000)

• CHF • Hypertension At least 2 or 3 required* • Age ≥ 75 • Diabetes OR • Stroke, TIA or Systemic embolus

Warfarin INR target - 2.5 (2.0-3.0 inclusive)

Monthly Monitoring Adherence to standard of care guidelines

Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Primary Efficacy Outcome Stroke and non-CNS Embolism Cumulative event rate (%)

6 5

Event Rate

Rivaroxaban

Warfarin

1.71

2.16

Warfarin

4

Rivaroxaban

3

HR (95% CI): 0.79 (0.66, 0.96)

2

P-value Non-Inferiority: <0.001

1 0

P-value for superiority: N.S. 0

No. at risk: Rivaroxaban 6958 Warfarin 7004

120

240

360

480

600

720

840

960

Days from Randomization 6211 6327

5786 5911

5468 5542

Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

4406 4461

3407 3478

2472 2539

1496 1538

634 655

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke Inclusion Inclusion risk risk factors factors Age Age ≥≥ 75 75 years years Prior Prior stroke, stroke, TIA, TIA, or or SE SE HF HF or or LVEF LVEF ≤≤ 40% 40% Diabetes Diabetes mellitus mellitus Hypertension Hypertension

Randomize double blind, double dummy (n = 18,201)

Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients)

Major Major exclusion exclusion criteria criteria Mechanical Mechanical prosthetic prosthetic valve valve Severe Severe renal renal insufficiency insufficiency Need Need for for aspirin aspirin plus plus thienopyridine thienopyridine

Warfarin (target INR 2-3)

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism

P (non-inferiority)<0.001 21% RRR

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66â&#x20AC;&#x201C;0.95); P (superiority)=0.011

No. at Risk Apixaban Warfarin

9120 9081

8726 8620

8440 8301

6051 5972

3464 3405

1754 1768

dabigatran 150 mg b.i.d.

dabigatran 110 mg b.i.d.

De Caterina R, Husted S, Wallentin L et al.

rivaroxaban 20 mg o.d.

apixaban 5 mg b.i.d.

dabigatran 150 mg b.i.d.

dabigatran 110 mg b.i.d.

De Caterina R, Husted S, Wallentin L et al.

rivaroxaban 20 mg o.d.

apixaban 5 mg b.i.d.

Less intracranial bleeding (consistently) 4

RE-LY

3

*

ROCKET AF

Major bleed (%/year)

*

2 Patients (%/year)

ARISTOTLE

1 0 4 3

Intracranial haemorrhage (%/year)

2 1 0

*

*

*

150 mg 110 mg Warfarin

20 mg Warfarin

Dabigatran

Rivaroxaban

*P<0.05 vs warfarin

* 5 mg

Warfarin

Apixaban

Connolly SJ, et al. N Engl J Med 2009;Aug 30:[Epub] Patel MR, et al. N Engl J Med 2011;Aug 10:[Epub] Granger CB, et al. N Engl J Med 2011 (doi 10.1056/NEJMoa1107039)

Weighted Net Clinical Benefit of Antithrombotic Therapy: An Evidenced-Based Method For Its Assessment and Application to ACTIVE A - The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events Running title: Weighted Net Clinical Benefit

Ann Intern Med, 2011

1

Stuart J. Connolly M.D , John Eikelboom1, Jack Hirsh1, Jennifer Ng1, Salim Yusuf1, Janice Pogue1, Raffaele de Caterina MD2, Stefan Hohnloser MD3, Robert G. Hart, M.D4 On behalf of the ACTIVE Steering Committee and Investigators (Drs. Hart and Connolly contributed equally to this paper)

Event

Ischemic Stroke

Hemorrhagic Stroke

Subdural Hemorrhage

Extracranial Hemorrhage

Weighting

1.00

3.00

0.64

0.63

Study design Largest Study in AF N = >20,500

AF on Electrical Recording < 12 mo Intended oral A/C Double>blind CHADS 2 2

Only Factor Xa inhibitor with two exposures in phase III

Low Exposure Strategy Edoxaban 30 mg QD

R

High ExposureOnce daily Strategy Edoxaban 60 mg QD

Median duration of follow up 24-months Primary Objective Edoxaban: Therapeutically as good as Warfarin 1º EP = Stroke or SEE (Non inferiority Boundary HR 1.38) 2º EP = Stroke or SEE or All-Cause Mortality Safety EPs = Major Bleeding, Hepatic Function SEE=systemic embolic event

Active Control Warfarin (INR 2.0 – 3.0)

Outline  A brief

history of oral anticoagulants  NOACs in trials  NOACs in clinical practice

Plasma Concentrations of DE Depend on Renal Clearance Dabigatran etexilate / 50, 150 and 300 mg bid Cpre,ss dose normalized Visit 3, 5 and 7 3.0 y = 26.924 x -0.8805 R2 = 0.2468

2.5 2.0 1.5 [ng/mL/mg] Dabigatran Cpre,ss,norm

1.0 0.5 0.0 0

20

40

60

80

100

120

140

160

180

200

CLCR [mL/min] Individual data

25Trial % No.: of 1160.0020 interindividual BI

variability is explained by differences in CRCL

..\BIBR1048MS\1160_0020\Evaluation\Graphs\[SU_1160_0020_PK_trough_CLCR_V1_050301.JNB]

http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm

Control of activity

PK/PD Correlation of DE With Coagulation Parameters at Steady State aPTT vs BIBR 953

INR vs BIBR 953

2.7

3.0

aPTT (ratio)

2.1 1.8 1.5

2.7 INR (none)

y =0.87 + 0.06776x½ r2=0.80462

2.4

2.4 2.1 1.8 1.5

1.2

1.2

0.9

0.9 0

0

100 200 300 400 500 Plasma Concentration BIBR 953 (ng/mL) ECT vs BIBR 953

100 200 300 400 500 Plasma Concentration BIBR 953 (ng/mL) Thrombin Time vs BIBR 953

35

5.9 y=1.10 + 0.01122x r2=0.9465

4.9 3.9 2.9 1.9

30 TT (ratio)

ECT (ratio)

y=1.11 + 0.00190x r2=0.8589

25

y=1.33 + 0.06954x r2= 0.9146

20 15 10 5 0

0.9 0

100 200 300 400 500 Plasma Concentration BIBR 953 (ng/mL)

0 100 200 300 400 500 Plasma Concentration BIBR 953 (ng/mL)

And for rivaroxaban, apixaban, edoxaban

 FXa

activity probably the best test  Some idea of whether a patient is on the drug by the PT (at least for rivaroxaban), BUT NOT RELYING ON THE USUAL COAGULATION RANGES

Tackling bleeding

Bleeding with NOACs None so far has a specific antidote  General measures to stop bleeding, charcoal adsorption, charcoal hemoperfusion, dialysis (for dabigatran)  Plasma transfusion (poor efficacy)  PCC o aPCC, o FVIIa (NovoSeven®) 

rivaroxaban

dabigatran

TF/FVIIa FX

FIX

FVIIIa

platelet activation

FVa

thrombin

anti-fibrinolysis fibrinogen

Vitamin K antagonists FIXa inhibitors: TTP 889 Protein C pathway activators: APC, drotrecogin, sTM

FXa Prothrombin Complex Concentrates

FIXa

Vitamin K angatonists Tissue factor pathway inhibitors: rTFPI NAPc2 rFVIIai (ASIS) TF MoAb, tifagosin

FXa inhibitors: Vitamin K antagonists + Indirect: UFH, LMWH, fondaparinux, idraparinux Direct: oral (xabans): razaxaban, rivaroxaban, apixaban, DU 176-b, LY 5157117, YM 150

protein C activation anticoagulation inflammation thrombin inhibitors: Vitamin K antagonists + Indirect: UFH, LMWH fibrin Direct: parenteral: melagatran, argatroban, hirudins oral: ximelagatran, dabigatran etexilate

39

R. De Caterina

De Caterina et al. ESC WG 18 Task Force on Anticoagulants in Heart Disease â&#x20AC;&#x201C; EHJ 2007; 28: 880-913

RELY-ABLE® goals and design Goals – To describe the long-term efficacy and safety of ongoing dabigatran therapy following RE-LY®

Methods – Patients eligible at completion of RE-LY® study if: • Alive and still receiving study dabigatran • Being followed at centre participating in RELY-ABLE®

– Dabigatran blinded dose continued in RELY-ABLE ® for 2.3 years

Analysis – Two follow-up periods described • RELY-ABLE® (post-RE-LY®) • RE-LY® + RELY-ABLE® (beginning of RE-LY® to end of RELY-ABLE®) Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double-blind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives.&nbsp; Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012. http://www.newshome.com/af-stroke/atrial-fibrillation-stroke/rely-able-webcast-connolly.aspx Disclaimer: L'indicazione "Prevenzione di ictus ed embolia sistemica in pazienti adulti con fibrillazione atriale" è in attesa di determinazione del regime di rimborsabilità da parte di AIFA

Nov 2012

Bleeding events: RELY-ABLE® RELY-ABLE® only D150 (%/yr)

D110 (%/yr)

HR

95% CI

3.74

2.99

1.26

1.04–1.53

Life-threatening

1.79

1.57

1.14

0.87–1.49

GI

1.54

1.56

0.99

0.75–1.31

Intra-cranial

0.33

0.25

1.31

0.68–2.51

Extra-cranial

3.43

2.82

1.23

1.01–1.49

Fatal

0.24

0.25

0.94

0.46–1.89

9.70

8.19

1.21

1.07–1.36

Event Major bleeding

Minor bleeding

5851 patients followed for mean of 2.3 years D150 and D110 = dabigatran 150 and 110 mg twice daily, respectively; HR = hazard ratio Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double-blind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives.&nbsp; Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012. http://www.newshome.com/af-stroke/atrial-fibrillation-stroke/rely-able-webcast-connolly.aspx Disclaimer: L'indicazione "Prevenzione di ictus ed embolia sistemica in pazienti adulti con fibrillazione atriale" è in attesa di determinazione del regime di rimborsabilità da parte di AIFA

Nov 2012

Conclusions During 2.3 years of additional treatment after RE-LY® (total mean follow-up 4.3 years), rates of stroke and major bleeding remain low on dabigatran and are consistent with those seen during RE-LY® Dabigatran 150 vs dabigatran 110 – Both doses have very low rates of haemorrhagic stroke over 4+ years – With dabigatran 150, there is a lower rate of ischaemic stroke but a higher rate of major bleeding – Both doses have similar mortality

Connolly SJ, et al. Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the RELY-ABLE Double-blind Randomized Trial. CS.04. Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives.&nbsp; Presented on 7 November 2012 at the American Heart Association Scientific Sessions 2012. http://www.newshome.com/af-stroke/atrial-fibrillation-stroke/rely-able-webcast-connolly.aspx Disclaimer: L'indicazione "Prevenzione di ictus ed embolia sistemica in pazienti adulti con fibrillazione atriale" è in attesa di determinazione del regime di rimborsabilità da parte di AIFA

Nov 2012

General conclusion 

 

Novel oral anticoagulants: a major leap forward in cardiovascular medicine, especially for the large population of patients with non-valvular atrial fibrillation Practice “in the field” being accrued, confirming expectations from clinical trial results … for those countries who have the privilege of reimbursing them

Thank you! Grazie!