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, 0.66–0.95); 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 – 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. 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. 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. 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!