Andrikopoulos

Νέοι από του στόματος χορηγούμενοι άμεσοι αναστολείς της θρομβίνης. Αποτελέσματα πρόσφατων κλινικών μελετών

Γεώργιος Ανδρικόπουλος, MD, PhD, FESC Αν. Δ/ντής, ΓΝΑ «Ερρίκος Ντυνάν»

The Net Clinical Benefit of Warfarin Anacoagulaaon in Atrial Fibrillaaon

(13559 adults with nonvalvular atrial fibrilla5on, 66000 person-­‐years of follow-­‐up)

Ann Intern Med. 2009 September 1; 151(5): 297–305.

Patients: 4060 patients who were aged ≥65 years old or who had other risk factors for stroke or death. Of these, 70.8% were hypertensive, and 38.2% had coronary heart disease.

Follow-up and primary endpoint: Οverall mortality, mean follow-up 3.5 years.

30

Mortality in the AFFIRM study

25 Rhythm control

Cumulaave mortality (%)

20 15

P = 0.08

Rate control

10 5 0

0

1

2

3

4

5 yrs

Sinus rhythm at the 5-­‐year visit : 62.6% of pa5ents in the rhythm-­‐control arm Time (years) 34.6% in the rate-­‐control arm AFFIRM Atrial Fibrilla5on Follow-­‐up Inves5ga5on of Rhythm Management

AFFIRM inves5gators. New Engl J Med 2002;347:1825-­‐33

The AFFIRM study PM monitoring Comment on the role of (88%) symptoms and ECG monitoring in the evaluaaon of thromboembolic risk ECG monitoring (46%)

57% of strokes in the rhythm control arm occurred in pa5ents who had their an5coagula5on stopped

Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in paKents with atrial fibrillaKon. N Eng J Med 2002;347:1825– 33.

Relaaonships Between Sinus Rhythm, Treatment, and Survival in the Atrial Fibrillaaon Follow-­‐Up Invesagaaon of Rhythm Management (AFFIRM) Study PM monitoring (88%) Covariate Age at enrollment* Coronary artery disease

p 0.0001 0.0001

HR 1.06 1.56

95% CI 1.05 - 1.08 1.20 - 2.04

Congestive heart failure ECG monitoring (46%)

0.0001

1.57

1.18 - 2.09

Diabetes

0.0001

1.56

1.17 -2.07

Stroke or transient ischemic attack

0.0001

1.70

1.24 -2.33

Smoking

0.0001

1.78

1.25 -2.53

Left ventricular dysfunction

0.0065

1.36

1.02 -1.81

Mitral regurgitation

0.0043

1.36

1.03 -1.80

Sinus rhythm

0.0001

0.53

0.39 -0.72

Warfarin use

0.0001

0.50

0.37 -0.69

Digoxin use

0.0007

1.42

1.09 -1.86

Rhythm-control drug use

0.0005

1.49

1.11 -2.01

The AFFIRM InvesKgators . CirculaKon. 2004;109:1509-­‐1513

Long-­‐Term Risk of Recurrent Atrial Fibrillaaon as Documented by an Implantable Monitoring Device

PM monitoring (88%)

ECG monitoring (46%)

•110 pts, 19±11 months follow up •class I indica5on for physiologic pacing •history of AF Carsten W. Israel, MD, Gerian Gronefeld, MD, Joachim R. Ehrlich, MD, Yi-­‐Gang Li, MD, Stefan H. Hohnloser. JACC 2004;43:47–52

ΜΠΟΡΟΥΜΕ ΝΑ ΠΡΟΒΛΕΨΟΥΜΕ ΤΗΝ ΚΟΛΠΙΚΗ ΜΑΡΜΑΡΥΓΗ;

Increased variance of P wave dura.on on the electrocardiogram dis.nguishes pa.ents with idiopathic paroxysmal atrial fibrilla.on

Andrikopoulos GK, Dilaveris PE, Richter DJ, Gialafos EJ, Synetos AG, Gialafos JE. Increased variance of P wave dura5on on the electrocardiogram dis5nguishes pa5ents with idiopathic paroxysmal atrial fibrilla5on. Pacing Clin Electrophysiol 2000;23(7):1127-­‐32

“……. AF dura5on and frequency play a subordinate role for predic5ng stroke”

Eur Heart J 2008;29:915–922

Επιλογή ασθενών για αντιαιμοπεταλιακή/ αντιπηκτική αγωγή

↓ Καρδιαγγειακών

↑ Αιμορραγικών

Συμβάντων

Συμβάντων

Pa5ent sa5sfac5on with AF treatments. Physicians’ es5mates and percep5ons of their pa5ents’ sa5sfac5on with AF treatments compared with pa5ents’ own sa5sfac5on ra5ngs for AF treatments

Europace 2010;12:626–633

Management of AF in clinical practice: prescription of vitamin K antagonists No anacoagulaaon Vitamin K antagonists n = 23,657 Medicare cohort, U.S.A.

Birman-­‐Deych E, et al. Stroke 2006; 37: 1070

n = 5,333 EuroHeart survey

Nieuwlaat R, et al. Eur Heart J 2005; 26:2422

n = 11,379 ATRIA cohort (managed care system, California, U.S.A.) Go AS, et al. JAMA 2003; 290: 2685

Potenaally Preventable Strokes in High-­‐Risk Paaents With Atrial Fibrillaaon Who Are Not Adequately Anacoagulated Registry of the Canadian Stroke Network, 597 pa5ents admiued with an acute ischemic stroke who (1) had a known history of atrial fibrilla5on; (2) were classified as high risk for systemic emboli according to published guidelines; and (3) had no known contraindica5ons to an5coagula5on

“In high-­‐risk pa5ents with atrial fibrilla5on admiued with a stroke, and who were candidates for an5coagula5on, most were either not taking warfarin or were subtherapeu5c at the 5me of ischemic stroke” Gladstone DJ, et al. Stroke. 2009;40:235-­‐240

Idraparinux in the dose regimen tested (2.5 mg SC per week) is not a subsatute for adjusted-­‐dose VKAs for AF paaents

p<0.0001

Kaplan-­‐Meier cumula5ve incidence curves of first confirmed symptoma5c recurrent stroke or non-­‐CNS systemic embolism

Kaplan-­‐Meier cumula5ve incidence curves of first clinically relevant bleeding during the randomised treatment period

Lancet 2008; 371: 315–21

Dabigatran etexilate Αμεσος αναστρέψιμος αναστολέας της θρομβίνης που χορηγείται από του στόματος και δεν απαιτεί εργαστηριακό έλεγχο της πήξης To dabigatran etexilate αναπτύχθηκε για να γίνει εφικτή η ΡΟ χορήγηση

Dabigatran etexilate Stangier J et al BriKsh Journal of Clinical Pharmacology 2007, DOI:10.1111/j.1365-­‐2125.2007.02899. Sorbera LA et al Dabigatran/Dabigatran Etexilate Drugs of the Future 2005; 30 (9): 877-­‐885. Belch S et al. DMB 2007; doi:10.1124/dmb.107.019083

Mηχανισµός δράσης Το Dabigatran •είναι εξαιρετικά εκλεκτικό για τη θροµβίνη1 •αναστέλλει αµφότερες την ελεύθερη και τη συνδεδεµένη στο θρόµβο θροµβίνη, παρέχοντας πιο αποτελεσµατική αναστολή της θροµβίνης από ό,τι oι ηπαρίνες (οι οποίες αδρανοποιούν µόνο την ελεύθερη θροµβίνη)2 •επεµβαίνει στη θροµβίνη και τη δράση της στον καταρράκτη πήξεως, π.χ.:1,2 • µετατροπή του ινωδογόνου σε ινώδες από τη θροµβίνη • ενεργοποίηση αιµοπεταλίων από τη θροµβίνη • ενεργοποίηση των Παραγόντων πήξεως V, VIII και XI από τη θροµβίνη •αποδεσµεύεται από τη θροµβίνη, αφήνοντας µία µικρή ποσότητα ενεργούς θροµβίνης διαθέσιµη για αιµόσταση2

1. Sorbera LA et al. Drugs Future 2005; 30:877–885.

2. Di Nisio M et al. NEJM 2005; 353:1028–1040. 3.

Gurm HS et al. Am J Heart 2005; 149:S43–S53.

Dabigatran Etexilate

DABIGATRAN -­‐ Βιοδιαθεσιμότητα Το Dabigatran etexilate διαλύεται δύσκολα σε υδάτινο περιβάλλον: • Η διάλυση του φαρμάκου στο έντερο εξαρτάται από το χαμηλό γαστρικό pH Αυτό το πρόβλημα αντιμετωπίστηκε με την φαρμακοτεχνική μορφή:

Η κάψουλα ενισχύθηκε με τρυγικό οξύ που αυξάνει τη διάλυση του φαρμάκου και καθιστά την απορρόφηση ανεξάρτητη του γαστρικού pH

DABIGATRAN – Φαρμακοτεχνική μορφή Pradaxa Το Dabigatran etexilate διαλύεται δύσκολα σε υδάτινο περιβάλλον: • Η διάλυση του φαρμάκου στο έντερο εξαρτάται από το χαμηλό γαστρικό pH

Μεταβολισμός του dabigatran

RE-­‐LY: largest AF outcomes trial RE-­‐LY: Randomized Evaluaaon of Long term anacoagulant therapy  18 113 pa5ents randomized during 2 years1,2  50% of enrolled pa5ents are naïve to previous oral AC  Median treatment dura5on: 2 years  951 centres in 44 countries  December 2005 to March 2009

AC = an5coagulant; ESC = European Society of Cardiology

1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51

RE-­‐LY: study design Atrial fibrilla5on with ≥1 risk factor Absence of contraindica5ons

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

CongesQve Heart Failure (1) Hypertension (1) Age 75 or older (1) Diabetes mellitus (1) Stroke or TIA (2)

Dabigatran etexilate 110 mg BID N=6000

Dabigatran etexilate 150 mg BID N=6000

Primary objec5ve: to establish the non-­‐inferiority of dabigatran etexilate to warfarin Minimum 1 year follow-­‐up, maximum of 3 years and median of 2 years of follow-­‐up BID = twice daily; INR = Interna5onal Normalized Ra5o

Ezekowitz MD et al. Am Heart J 2009;157:805–10 Connolly SJ et al. N Engl J Med 2009;361:1139–51

RE-­‐LY: inclusion criteria 1. Documented atrial fibrilla5on and 2. One addi5onal risk factor for stroke: a. History of previous stroke, TIA, or systemic embolism b. LVEF less than 40% c. Symptoma5c heart failure, NYHA Class II or greater d. Age of 75 years or more e. Age of 65 years or more and one of the following

addi5onal risk factors: diabetes mellitus, CAD or hypertension

Ezekowitz MD et al. Am Heart J 2009;157:805–10 Connolly SJ et al. N Engl J Med 2009;361:1139–51

RE-­‐LY: outcome measures Primary efficacy endpoint All stroke (ischaemic + haemorrhagic) and systemic embolism

MI = myocardial infarc5on

Connolly SJ et al. N Engl J Med 2009;361:1139–51

Secondary efficacy endpoints All stroke (ischaemic + haemorrhagic) Systemic embolism All death All stroke (ischaemic + haemorrhagic) Systemic embolism Pulmonary embolism Acute MI Vascular death (incl. deaths from bleeding)

Safety criteria include Bleeding events (major and minor)

Intracranial haemorrhage Cerebral haemorrhage Subdural haematoma Subarachnoid haemorrhage

Elevations in liver enzymes or hepatic dysfunction

Baseline characteristics Characteristic

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

Randomized (n)

6015

6076

6022

Mean age (yrs)

71.4

71.5

71.6

Male (%)

64.3

63.2

63.3

CHADS2 score (mean) 0/1 (%) 2 (%) 3+ (%)

2.1 32.6 34.7 32.7

2.2 32.2 35.2 32.6

2.1 30.9 37.0 32.1

Prior stroke/TIA (%)

19.9

20.3

19.8

Prior MI (%)

16.8

16.9

16.1

CHF (%)

32.2

31.8

31.9

Baseline ASA (%)

40.0

38.7

40.6

Warfarin-naïve (%)

50.1

50.2

48.6

ASA = acetylsalicyclic acid (aspirin); CHF = conges5ve heart failure; MI = myocardial infarc5on; TIA = transient ischaemic auack

Connolly SJ et al. N Engl J Med 2009;361:1139–51

RE-­‐LY

Η σημασία του χρόνου εντός θεραπευτικών ορίων 1.99.9% complete follow-­‐up a. 20 pa5ents of 18 113 lost to follow-­‐up

3.Percent Time in Therapeu5c Range (TTR) a. 64%: all warfarin-­‐treated pa5ents b.67%: warfarin-­‐experienced c. 61%: warfarin-­‐naïve

Connolly SJ et al. N Engl J Med 2009;361:1139–51 Ezekowitz MD. ESC 2009; oral presenta5on #5019

Country based variaaon in average TTR AMPs=Coumadin GR-­‐RELY GR-­‐Registries

AHA 2009

RELY average

INR control: RCTs vs Clinical Practice

% of eligible pa5ents receiving warfarin

INR* control in clinical trial versus clinical prac5ce (TTR**) 66%

Clinical trial1 Clinical prac5ce2,3

38%

44%

25% 18% 9%

<2.0 *INR = Interna5onal normalized ra5o

2.0 – 3.0

>3.0 INR

** TTR = Time in Therapeu5c Range (INR2.0-­‐3.0)

1. Kalra L, et al. BMJ 2000;320:1236-1239 * Pooled data: up to 83% to 71% in individualized trials; 2. Samsa GP, et al. Arch Int Med 2000 3. Matchar DB, et al. Am J Med 2002; 113:42-51.

RE-­‐LY: ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΤΗΤΑ

Stroke or systemic embolism (SSE) Superiority P value

<0.001

0.34

<0.001

<0.001

Margin = 1.46

Dabigatran 110 mg BID vs. warfarin

Non-­‐inferiority P value

Dabigatran 150 mg BID vs. warfarin 0.50

0.75

1.00 Hazard ra5o

Error bars = 95% CI; BID = twice daily; HR = hazard ra5o

Connolly SJ et al. N Engl J Med 2009;361:1139–51

1.25

1.50

Time to first stroke / SSE

Cumula5ve hazard rates

0.05

RR 0.91 (95% CI: 0.74–1.11) P<0.001 (NI) P=0.34 (Sup)

Warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID

0.04

RRR 34%

0.03 RR 0.66 (95% CI: 0.53–0.82) P<0.001 (NI) P<0.001 (Sup)

0.02 0.01 0.00 0.0

0.5

1.0

1.5

2.0

Years BID = twice daily; CI = confidence interval; NI = non-­‐inferior; RR = rela5ve risk; RRR = rela5ve risk reduc5on; Sup = superior

Connolly SJ et al. N Engl J Med 2009;361:1139–51

2.5

Stroke / SSE RR 0.91 (95% CI: 0.74–1.11) P<0.001 (NI) RR 0.66 (95% CI: 0.53–0.82)

1.8

Stroke / SSE (%/yr)

1.5

P<0.001 (Sup)

1.69 RRR 34%

1.53

1.2 1.11

0.9 0.6 0.3 0.0

Events / N:

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

182 / 6015

134 / 6076

199 / 6022

BID = twice daily; CI = confidence interval; NI = non-­‐inferior; RR = rela5ve risk; RRR = rela5ve risk reduc5on; Sup = superior

Connolly SJ et al. N Engl J Med 2009;361:1139–51

Time to first stroke / SSE: VKA-­‐naïve vs. VKA-­‐experienced All pa5ents

Cumula5ve hazard rates

0.05

Warfarin

0.04 0.03

Dabigatran 110 mg BID

0.02

Dabigatran 150 mg BID

0.01 0.00 0.0

0.5

1.0

1.5

2.0

2.5

Years

VKA-­‐naïve

VKA-­‐experienced

0.05 Cumula5ve hazard rates

Cumula5ve hazard rates

0.05 0.04 0.03 0.02 0.01 0.00

0.04 0.03 0.02 0.01 0.00

0.0

0.5

1.0

1.5 Years

2.0

2.5

0.0

0.5

1.0

BID = twice-­‐daily; VKA = vitamin K antagonist

Connolly SJ et al. N Engl J Med 2009;361:1139–51; Ezekowitz MD. ESC 2009; oral presenta5on #5019

1.5 Years

2.0

2.5

Vascular mortality RR 0.90 (95% CI: 0.77–1.06) P=0.21 (Sup) RR 0.85 (95% CI: 0.72–0.99)

3.0 Vascular mortality (%/yr)

P=0.04 (Sup)

2.43 2.0

2.28

RRR 15%

2.69

1.0

0.0 Events / N:

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

289 / 6015

274 / 6076

317 / 6022

BID = twice daily; CI = confidence interval; RR = rela5ve risk; RRR = rela5ve risk reduc5on; Sup = superior

Connolly SJ et al. N Engl J Med 2009;361:1139–51

All cause mortality RR 0.91 (95% CI: 0.80–1.03) P=0.13 (Sup) RR 0.88 (95% CI: 0.77–1.00) P=0.051 (Sup)

All cause mortality (%/yr)

4.0

4.13 3.75

3.64

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

446 / 6015

438 / 6076

487 / 6022

3.0 2.0 1.0 0.0

Events / N:

BID = twice daily; CI = confidence interval; RR = rela5ve risk; RRR = rela5ve risk reduc5on; Sup = superior

Connolly SJ et al. N Engl J Med 2009;361:1139–51

RE-­‐LY: ΑΣΦΑΛΕΙΑ

↓ Καρδιαγγειακών

↑ Αιμορραγικών

Συμβάντων

Συμβάντων

Total bleeding rates RR 0.78 (95% CI: 0.73–0.83) p<0.001 (sup) RRR 22%

RR 0.91 (95% CI: 0.85–0.96) p=0.002 (sup)

% per year

RRR 9%

1754 / 6,015 Connolly SJ., et al. N Engl J Med 2009; 361:1139-­‐1151.

1993 / 6,076

2166 / 6,022

Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke preven5on for pa5ents with atrial fibrilla5on

Major bleeding RR 0.80 (95% CI: 0.69–0.93) P=0.003 (Sup) RR 0.93 (95% CI: 0.81–1.07)

3.5

RRR 20%

Major bleeding (%/yr)

3.0 2.5

P=0.31 (Sup)

3.36 3.11

2.71

2.0 1.5 1.0 0.5 0.0

Events / N:

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

322 / 6015

375 / 6076

397 / 6022

BID = twice daily; CI = confidence interval; RR = rela5ve risk; RRR = rela5ve risk reduc5on; Sup = superior

Connolly SJ et al. N Engl J Med 2009;361:1139–51

Hemorrhagic stroke RR 0.31 (95% CI: 0.17–0.56)

Haemorrhagic stroke (no. of events)

P<0.001 (Sup) RR 0.26 (95% CI: 0.14–0.49)

50

P<0.001 (Sup)

45

40

0.38%

30 RRR 69%

20 10

14 0.12%

0 N:

RRR 74%

12 0.10%

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

6015

6076

6022

BID = twice daily; CI = confidence interval; RR = rela5ve risk; RRR = rela5ve risk reduc5on; Sup = superior

Connolly SJ et al. N Engl J Med 2009;361:1139–51

Μείζονα αιμορραγικά κατά κατηγορία

Warfarin

P value D 110 mg vs. W

P value D 150 mg vs. W

6076

6022

–

–

2.71

3.11

3.36

– Life threatening

1.22

1.45

1.80

– Non-life threatening

1.66

1.88

1.76

0.56

– Gastrointestinal

1.12

1.51

1.02

0.43

Dabigatran 110 mg BID

Dabigatran 150 mg BID

Patients (N)

6015

Major bleeding

Characteristic

Connolly SJ et al. N Engl J Med 2009;361:1139–51

0.003

<0.001

0.31

0.04

0.47

<0.001

Data represents %/yr; BID = twice-­‐daily; D = dabigatran; W = warfarin

Most common adverse events Dabigatran 110 mg BID

Adverse event (%)

Dabigatran 150 mg BID

Warfarin

Dyspepsia*

11.8

11.3

5.8

Dyspnoea

9.3

9.5

9.7

Dizziness

8.1

8.3

9.4

Peripheral oedema

7.9

7.9

7.8

Fatigue

6.6

6.6

6.2

Cough

5.7

5.7

6.0

Chest pain

5.2

6.2

5.9

Arthralgia

4.5

5.5

5.7

Back pain

5.3

5.2

5.6

Nasopharyngitis

5.6

5.4

5.6

Diarrhoea

6.3

6.5

5.7

Urinary tract infection

4.5

4.8

5.6

Upper respiratory tract infection

4.8

4.7

5.2

Adverse events occuring in >5% of pa5ents in any treatment group; *Occurred more commonly on dabigatran, P<0.001; BID = twice-­‐daily Connolly SJ et al. N Engl J Med 2009;361:1139–51

Connolly SJ, et al. Ν Εngl J Med 363;19, November 4, 2010

DABIGATRAN COMPARED WITH WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION AND PREVIOUS TRANSIENT ISCHAEMIC ATTACK OR STROKE: A SUBGROUP ANALYSIS OF THE RE-­‐LY TRIAL

Lancet Neurol. 2011 Jan;10(1):27.

Lancet Neurol. 2011 Jan;10(1):27.

Lancet Neurol. 2011 Jan;10(1):27.

Lancet Neurol. 2011 Jan;10(1):27.

On the basis of this subgroup analysis, the balance of evidence would suggest that 110 mg dabigatran might be the preferred treatment op5on in pa5ents who have had a previous stroke or transient ischaemic auack.

This is because there was no significant difference in the rate of stroke or systemic embolism between doses in this subgroup analysis, but there was a significant reduc5on in the adverse bleeding events of haemorrhagic stroke (although seen in both doses the effect was greater with 110 mg dabigatran), major bleeding, and intracerebral haemorrhage, with no significant increase in major gastrointes5nal bleeding. There was an overall net clinical benefi t with 110 mg dabigatran compared with warfarin (RR 0・ 81, 95% CI 0・66–1・00) that was not evident with the higher dose. Unfortunately, head to head comparisons of efficacy and safety between the two doses of dabigatran were not reported in this subgroup analysis

Deirdre A Lane, Gregory Y H Lip. www.thelancet.com/neurology Published online November 8, 2010 DOI:10.1016/S1474-­‐4422(10)70275-­‐1

RE-­‐LY: ANALYSIS OF PATIENTS UNDERGOING CARDIOVERSION

Stroke/systemic embolism (%)

1.8

A total of 1983 cardioversions were performed in 1270 paQents P=0.71

1.5 1.2

P=0.40

0.9 0.6

0.8 0.6

0.3 0 n:

0.3 Dabigatran 110 mg BID

Dabigatran 150 mg BID

Warfarin

647

672

664

Major bleeding rates D110: 1.7%, D150: 0.6%, Warfarin: 0.6% (D110 versus warfarin, p=0.06; D150 versus warfarin, p=0.99).

Circulation.2011;123:131-136.

A total of 1983 cardioversions were performed in 1270 paQents

Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P0.06; D150 versus warfarin, P0.99).

NagarakanK R., et al. CirculaKon. 2011;123:131-­‐136

NagarakanK R., et al. CirculaKon. 2011;123:131-­‐136

RE-­‐LY: ΣΥΜΠΕΡΑΣΜΑΤΑ 110 mg dose vs. warfarin 1. Συγκρίσιμα ποσοστά ΑΕΕ/Συστηματικών εμβολών 2. Στατιστικά σημαντική μείωση των αιμορραγικών ΑΕΕ 3. Στατιστικά σημαντική μείωση των μειζόνων αιμορραγικών συμβάντων

150 mg dose vs. warfarin Στατιστικά σημαντική μείωση των ΑΕΕ/Συστηματικών εμβολών Στατιστικά σημαντική μείωση των αιμορραγικών ΑΕΕ Στατιστικά σημαντική μείωση της καρδιαγγειακής θνησιμότητας Συγκρίσιμα ποσοστά αιμορραγικών συμβάντων Σημαντική μείωση των αιμορραγικών επεισοδίων των απειλητικών για τη ζωή και των ενδοκρανιακών αιμορραγιών Connolly SJ et al. N Engl J Med 2009;361:1139–51

Cost-effectiveness of fixed-dose dabigatran, 110 mg (low dose) and 150 mg (high dose) twice daily, compared with adjusteddose warfarin anticoagulation at varying daily costs of dabigatran.The slope of the cost-effectiveness line for high-dose dabigatran was lower than for low-dose dabigatran, so that at a pricing ratio â&#x2030;Ľ1.66 ($9.50 per day for low-dose and $15.73 per day for high-dose dabigatran), high-dose dabigatran no longer achieved extended dominance over low-dose dabigatran.

Freeman J V et al. Ann Intern Med doi: 10.1059/0003-4819-154-1-201101040-00289

ESC 2010 Guidelines for the Management of Paaents with Atrial Fibrillaaon Where oral an5coagula5on is appropriate therapy, dabigatran may be considered, as an alterna5ve to adjusted dose VKA therapy.

1.

If a pa5ent is at low risk of bleeding (e.g. HAS-­‐BLED score of 0–2; see Table 10 for HAS-­‐ BLED score defini5on), dabigatran 150 mg b.i.d. may be considered, in view of the improved efficacy in the preven5on of stroke and systemic embolism (but lower rates of intracranial haemorrhage and similar rates of major bleeding events, when compared with warfarin);

2.

If a pa5ent has a measurable risk of bleeding (e.g. HAS-­‐BLED score of ≥3), dabigatran etexilate 110 mg b.i.d. may be considered, in view of a similar efficacy in the preven5on of stroke and systemic embolism (but lower rates of intracranial haemorrhage and of major bleeding compared with VKA).

3.

(b) In pa5ents with one ‘clinically relevant non-­‐major’ stroke risk factor, dabigatran 110 mg b.i.d. may be considered, in view of a similar efficacy with VKA in the preven5on of stroke and systemic embolism but lower rates of intracranial haemorrhage and major bleeding compared with the VKA and (probably) aspirin.

ESC 2010 Guidelines for the Management of Paaents With Atrial Fibrillaaon

Dabigatran και θρομβοπροφύλαξη

Vorapaxar Novel, orally ac5ve, potent thrombin receptor inhibitor selec5ve for the protease-­‐ac5vated receptor-­‐1 (PAR-­‐1)

Calif Med. 1950 Aug;73(2):166-­‐70.

ΕΡΩΤΗΣΗ 1 Το dabigatran είναι…..

1. Ανταγωνιστής των υποδοχέων της θρομβίνης 2. Ανταγωνιστής των Xa υποδοχέων 3. Αμεσος αναστολέας της θρομβίνης 4. Ανταγωνιστής του παράγοντα V.

ΕΡΩΤΗΣΗ 1 Το dabigatran είναι…..

1. Ανταγωνιστής των υποδοχέων της θρομβίνης 2. Ανταγωνιστής των Xa υποδοχέων 3. Αμεσος αναστολέας της θρομβίνης 4. Ανταγωνιστής του παράγοντα V.

ΕΡΩΤΗΣΗ 2 Ασθενής 60 ετών με κολπική μαρμαρυγή και χωρίς άλλο παράγοντα καρδιοεμβολικού κινδύνου ……

1. Πρέπει να λαμβάνει αντιθρομβωτική αγωγή 2. ΔΕΝ πρέπει να λαμβάνει αντιθρομβωτική αγωγή 3. Πρέπει να λάβει ασπιρίνη 4. Δεν γνωρίζουμε με βάση αυτά τα δεδομένα αν πρέπει να λαμβάνει αντιθρομβωτική αγωγή

ΕΡΩΤΗΣΗ 2 Ασθενής 60 ετών με κολπική μαρμαρυγή και χωρίς άλλο παράγοντα καρδιοεμβολικού κινδύνου ……

1. Πρέπει να λαμβάνει αντιθρομβωτική αγωγή 2. ΔΕΝ πρέπει να λαμβάνει αντιθρομβωτική αγωγή 3. Πρέπει να λάβει ασπιρίνη 4. Δεν γνωρίζουμε με βάση αυτά τα δεδομένα αν πρέπει να λαμβάνει αντιθρομβωτική αγωγή

ΕΡΩΤΗΣΗ 3 Η συχνότερη ανεπιθύμητη ενέργεια του dabigatran στη μελέτη RELY ήταν ….

1. Βήχας 2. Δυσπεψία 3. Ηπατική δυσλειτουργία 4. Δύσπνοια 5. Αιμορραγικά επεισόδια

ΕΡΩΤΗΣΗ 3 Η συχνότερη ανεπιθύμητη ενέργεια του dabigatran στη μελέτη RELY ήταν ….

1. Βήχας 2. Δυσπεψία 3. Ηπατική δυσλειτουργία 4. Δύσπνοια 5. Αιμορραγικά επεισόδια