Νικόλαος Φραγκάκης

Επίκουρος Καθηγητής Καρδιολογίας ΑΠΘ

Γ΄ Πανεπιστημιακή Καρδιολογική Κλινική

Γ.Ν. Ιπποκράτειο, Θεσσαλονίκης

Διαχείριση ασθενούς με αιμορραγία που λαμβάνει DOACs

Δήλωση συμφερόντων

Ο ομιλητής έχει λάβει αμοιβές για ομιλίες σε εκπαιδευτικά

σεμινάρια από τις κάτωθι φαρμακευτικές εταιρείες:

▪ Bayer Healthcare, Menarini, Mylan, St Jude,

Abbot, Pfizer

DOAC 4-trial Meta-analysis Full Dose

Ruff C, et al. Lancet 2013

TrialStroke and

Systemic Embolismp Major Bleeding p

RE-LY 0.0001 0.34

ROCKET-AF 0.12 0.72

ARISTOTLE 0.012 <0.0001

ENGAGE

TIMI 480.10 0.0002

Combined

Pre-specified meta-analysis of all 71,683 patients

Favours DOAC0.5 1 Favours DOAC

0.5 1

Patients with AF on NOACs

a 66-year-old woman with

severe sharp chest pain

Idarucizumab led to normal

haemostasis during surgery

a 68-year-old man….

on dabigatran, 110 mg twice a day, for paroxysmal

AF, hypertension and old inferior MI

At 7.05 AM, he noticed sudden onset of visual

disturbances, dizziness, and slight headache

According to his wife, the patient took his last

dabigatran dose around 6:00 pm, ≈1 hour before the

start of symptoms

Emergency department

50 min later…

Right sided homonymous hemianopsia and evidence of

aphasic disturbances

dTT= 218 sec (normal range: 15–36 sec)

APTT= 73 sec (normal range: 20–40 sec)

The remaining routine laboratory values, including

creatinine clearance, were normal

acute ischemic stroke

Need to perform

thrombolysis with t-PA

Considering

1) hemianopsia as a functionally relevant deficit

2) presence of a diffusion-weighted imaging mismatch

3) early time window

NOACS- in acute ischemic stroke

Raval AN, et al. Circulation. 2017;135:e604–e633

NOACs – Acute ischemic stroke

GLOBAL USE OF NOACs

Reasons for Underuse of

Anticoagulation

Novel oral anticoagulants and reversal agents: Considerations for clinical development . White paper

cosponsered by the FDA.

Sarich TC et al. Am Heart J. 2015 Jun;169(6):751-7. doi: 10.1016/j.ahj.2015.03.010. Epub 2015 Mar 26.

REAL LIFE RISK OF NOACs

COMPLICATIONS

Patients on anticoagulants may have to undergo emergency

surgery or interventions

Often the need for emergency surgery is not causally associated with

the intake of an anticoagulant itself

Emergency surgery may become

necessary for a variety of reasons

Especially given the high-risk

population of patients with AF

Acute abdomen (e.g. appendicitis)

Incarcerated hernia

Bone fractures

Infection

Urgent PCI for treatment

of ACS

Thrombolysis for acute stroke

Acute renal failure

Pacemaker implant

Rapid reversal of the anticoagulant effects of NOACs may be

required in certain emergency situations

Emergency

surgery

Uncontrolled

bleeding

A specific reversal agent could take the NOAC

out of the equation in these situations

What are the characteristics of an ideal reversal

agent?

What are the key

characteristics of

idarucizumab?

14

Idarucizumab was designed as a specific reversal

agent for the anticoagulant activity of dabigatran

Adapted from Schiele et al. Blood 2013; Eikelboom et al. Circulation 2015; Praxbind SPC, 2017;

Schmohl et al. Thromb Haemost 2017

Dabigatran

Idarucizumab

Humanized antibody

fragment (Fab)

Specific to dabigatran

Binding affinity for

dabigatran ~350×

higher than dabigatran

to thrombin, resulting

in essentially

irreversible binding

No endogenous targets

Ready to use solutions

for IV administration

Immediate onset

of action

No intrinsic

procoagulant or

anticoagulant activity

Idarucizumab–dabigatran

complex is eliminated

quickly

(within a few hours)

16

Pollack et al. N Engl J Med 2017

RE-VERSE AD was a multicentre, open-label, single-arm

Phase III trial

aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; ECT, ecarin clotting time; TT, thrombin time

Pollack et al. N Engl J Med 2017; Pollack et al. Thromb Haemost 2015

Secondary endpoints

12 h 24 h 30 d 90 d

follow-up

Haemostasis within

24 hours (non-ICH)

Haemostasis during

procedure/surgery

Determined

locally

Hospital arrival

Group A: Uncontrolled bleeding

Group B: Emergency surgery or procedure

Between

vials

Baseline

5 g idarucizumab

(2×2.5 g intravenously)

0–15 min

• Thrombotic

events

• Restart of

anticoagulation

• Mortality

• aPTT / TT

• Dabigatran

plasma levels

• Immunogenicity

503 dabigatran-treated patients

at 173 sites in 39 countries

2 h 4 h1 h~20 min

Maximum

reversal

within

4 hrs with

dTT and

ECT

measures

Primaryendpoint

Blood sample time points

22

RE-VERSE AD™ Multicentre, Open-label, Single-arm, Phase

III Study

Pollack et al. N Engl J Med 2017

Group A:

Uncontrolled

bleeding

N=301 (60%)

Group B:

Emergency surgery

or procedure

N=202 (40%)

45.5% had GI bleeds 32.6% had ICH In 25.9% trauma was cause of bleed

Main index events were acute abdomen, bone fractures, and cardiovascular

i

i

Reversal of Dabigatran Anticoagulation

Group A Group B

dTT normalized* within 4 hours in 241/244 patients (98.8%) in Group A

and 150/152 patients (98.7%) in Group B

Group A: bleeding stopped within 2.5 hours in patients

with extracranial haemorrhage

*Serial CT scans were not mandated by the protocol; †Cessation confirmed within 24 hours in 134/198 – bleeding stopped before

treatment in two patients and could not be determined in 67 patients; ‡Local investigator-determined time to bleeding cessation.

301 patients with bleeding

type classed as:

Assessable non-ICH (n=198)

The 198 assessable

non-ICH bleeds† were:

With a median time to

bleeding cessation‡ of:

Non-assessable non-ICH (n=5)

ICH (non-assessable)* (n=98)

2.5 hrs

GI (n=120)

Non-GI (n-78)

Group B: most patients had normal haemostasis during

surgery

197/202 (97.5%) patients underwent

surgery/procedure with periprocedural

haemostasis classed as:

Overall median time from

first vial to procedure:

1.6 hrs

Normal (93%)

Moderately abnormal (1%)

Mildly abnormal (5%)

Severely abnormal (0%)

Post-reversal Thromboembolic Events

Thrombotic events (%) Group A (n=301) Group B (n=202) Total (N=503)

30 days 4.6 5.0 4.8

90 days 6.3 7.4 6.8

16 of the 24 patients who experienced a thrombotic event were not anticoagulated

at the time of the event

No evidence of a prothrombotic effect

Mortality

Mortality (%) Group A (n=301) Group B (n=202)

30 days 13.5 12.6

90 days 18.8 18.9

Most of the deaths occurring within 5 days appeared to be related to the

severity of the index event or to coexisting conditions,

whereas deaths that occurred after 30 days were more likely to be independent events or

related to coexisting conditions

Re-initiation of Antithrombotic Treatment

➢ During the 90-day follow-up, antithrombotic therapy was

restarted

❖ in 72.8% of the patients in group A and

❖ in 90.1% in group B,

✓ at a mean of 13.2 days and 3.5 days, respectively, after the

administration of idarucizumab.

➢ By 72 hours after the administration of idarucizumab,

antithrombotic therapy was restarted

❖ in 69 of the 301 patients in group A (22.9%), with 10.1% of those

patients receiving dabigatran,

❖ and in 135 of the 202 patients in group B (66.8%), with 25.9%

receiving dabigatran

Regardless of the

clinical situation

Fixed 5 g dose

Idarucizumab is Easy to Administer and has no

Contraindications

Infuse or inject intravenously

Shelf life: 30 months

refrigerated at 2–8°C

Storage

Dabigatran can be

re-started after 24 hours

Heparin can be initiated at

any time

Re-starting anticoagulation

\\\\\\

Idarucizumab is Widely Available Worldwide

EHRA guidance on the management of bleeding in patients

using NOACs

Heidbuchel et al. Europace 2015

Consider

• For dabigatran-treated

patients, idarucizumab 5 g IV

• PCC 50 U/kg + 25 U/kg if

indicated

• aPCC 50 U/kg;

max 200 U/kg/day

• rFVIIa 90 µg/kg

Supportive measures

• Mechanical compression

• Endoscopic haemostasis if GI bleed

• Surgical haemostasis

• Fluid replacement (colloids if needed)

• RBC transfusion if needed

• FFP (as plasma expander)

• Platelet transfusion

(if platelet count ≤60×109/L)

Dabigatran-treated patients

• Idarucizumab 5 g IV

• Maintain adequate diuresis

• Consider haemodialysis

+ +

Bleeding while using a NOAC

• Delay or discontinue next dose

• Reconsider concomitant

medication

Mild bleeding Moderate/severe bleeding Life-threatening bleeding

• Enquire about last NOAC intake• Blood sample to determine CrCl, haemoglobin, white blood cells• Enquire with lab about possibility of rapid coagulation assessment

‘In patients treated with

dabigatran, idarucizumab is

the preferred reversal agent

when it becomes available’

NOAC Reversal Agents Change

the Game!

The available reversal agent idarucizumab for dabigatran

has been shown to be safe. Patients will get a quick and

effective bleeding management in case of emergency!

Idarucizumab is easy to handle and does not do any harm

NOAC Reversal Agents Change

the Game!

The availability of specific reversal agents provides

reassurance, removes one of the perceived barriers

to the widespread use of NOACs and gives…..

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