Congresso Chiarella

Norm
Prudence
Kelvin
Anna Bagenholm, 29, trainee surgeon, northern Norway
BLEEDING RISK
How to react to risk and perception of risk is a complicated issue
Complexity
Building on complexity: no shortcuts
End points for trials of clinical bleeding (GI bleeding) and hemostatic efficacy
Message
Systematic approach to be safe on average does not work for MDs
Scores: Limited predictive power
Bias
Personal lessons (mistakes/choices ending to deaths for patients)
Probability and odds
Odds are important for families, for journals, for TV programs, for lawyers
NOAC and BLEEDING
Highlights
to be associated with a net clinical benefit when compared to VKA
Without routine coagulation monitoring
RCT approved
Net clinical benefit (events are not created equally: concept of weighted net benefit)
Shaking ground
Not any more TAO doctors, but Cardiologists, Neurologists, Ortopedics
Risk of the «fire and forget» approach
Duration of triple therapy
Responsability to educate patients: not formally established
Therapeutic Plan in case of emergency: again missing
A Fib # DVT and PE because Afib represents a persistent RF for thromboemb. events
Acute Scenario of bleeding
Handled by Hospital Doctors who do not know the patient (ER, Neurosurgery, GI
Doctors, Urology Doctors)
Evolving protocols
Need of urgent surgery on NOAC
NOAC
Come gestire il sanguinamento ?
Prof Mario Iannetti
Prescription doesn’t come as a free lunch
NOAC pt information card
 To regularly educate pt at each visit
 Strict adherence to prescribed dose regimen
Modality of intake # Food in case of rivaroxaban
 Educate that NOAC should not be discontinued
 Educate to compliance
NB: OD dosing regimen # Patients prefer INR monitoring
NOAC
Come gestire il sanguinamento ?
Prof Mario Iannetti
Prescription doesn’t come as a free lunch
NOAC pt information card
 Checklist
 Assess Hb, GOT-GPT, eGFR (CKD-EPI, Cockroft)
 Name and telephone number of the doctor
Family member involvment
Pre-specified follow-up
Bleeding risk (HAS-BLED) (poor to target ICH events)
Cardio-embolic risk (CHADS-VASC)
Atherothrombotic risk (acute: GRACE) (stable: REACH-SYNTAX)
Angiographic burden (GENSINI score)
Recurrence of DVT/PE (Vienna score)
SCORES
Donna di 69 aa
BMI 36, DM
Interv ortopedico
Dispnea ribelle
ECG: fibr atriale
K coda pancreas,
noduli epatici
GB 13,000
Khorana Score 4
Cancer
Uomo di 82 aa
BMI 21
2010: Frattura femore:
TEV
ECG: fibr atriale
Cardiopatia strutturale
2015: recidiva TEV
Vienna prediction for
recurrent TVE: 7.7 (5.311.1)
Systemic
TEV
Uomo di 89 aa
FC 102 PAS 110 Crea 1.2
TnI pos ST change
DM, A Fib pluriennale
SCA: PCI + DES
GRACE ACS Risk model
MI/morte a 6 mesi:
40%(30%)
IHD
CHADSVASC2
7.2% (10%)
11.2% (15.7%)
4.8% (6.7%)
Increased Number of
Bleeding Episodes
NET CLINICAL BENEFIT
NET CLINICAL BENEFIT
CLINICAL RELEVANCE
OF BLEEDING
Highlights
 bleeding sometimes triggers anemia
 Anemia early after surgery decreases body defenses and leads to infections
 Cardiac Consult after surgery in Pts with important intra/peri-operative bleeding
avoid use of anti-hypertensive drugs when systolic BP is low
 Bleeding is prothrombotic (release young platelets and release megacariocytes rich
in TF)
Shaking ground
Obese ? Care of elederly ? Reduced eGFR ? Cancer ?
High risk in pts naife from VKA/NOAC who start treatment
Define vulnerability window
What to do after an important bleeding
ACUTE SCENARIOS
OF BLEEDING ON VKA
Grade of bleeding and VKA
Low risk
stop for 1-2 days VKA
(gum bleed # nose bled < 30 minutes)
Moderate risk
ice/compressive bandage/lack of haemostatic measures
(joint/broken arm # nose bled > 30 minutes)
Severe risk
Temporary VKA stop + vit K + PPSB + volume packed
(bleeding aneurysm)
ACUTE SCENARIOS
OF BLEEDING ON NOAC
Acute ingestion of overdose
Overdose suspicion
 Activated charcoal
 Coagulation tests
 Wait and see management
ACUTE SCENARIOS
OF BLEEDING ON NOAC
Non specific reversal
Non specific reversal
Mechanical compression, surgical haemostasis, fluid replacement, other haemodynamic support, TIME
Dabigatran: dyalisis (puncture!!!) (68% removal in 4 hrs) : poor efficacy in Xa inhibitors due to plasma binding
Required immediate haemostatic support
PCC (25-50 U/Kg) / Feiba (max 200 U/Kg/24h) normalize anticoagulation parameters but do not reverse bleeding
Antifibrinolytics (Tranexamic acid)
Fresh frozen plasma (as a volume expander only, it does not reverse coagulation)
ACUTE SCENARIOS
OF BLEEDING
Reversal VKA: PCC # Fresh frozen plasma # Vitamin K
NOAC reversal: antidotes effective in normalising coagulation times in minutes
Idarucizumab
Restoration of coagulation tests
does not equal good clinical outcome
How to prevent Acute
Scenarios of Bleeding
How to prevent Acute
Scenarios of Bleeding
Best estimation of CrCl: Cockroft-Gault method
Clearance <60 mL/min: independent predictor of stroke/systemic embolism and of bleeding
Clearance <30 mL/min: ESC recommend against their use
Clearance <15 mL/min: avoid NOAC ( VKA…)
How to prevent Acute
Scenarios of Bleeding
No clinically important bleeding risk
Adequate haemostasis possible/Dental procedures/cataract/glaucoma
Atraumatic spinal/epidural anaesthesia and clean lumbar puncture
restart 6 h post
Minor bleeding risk and immobilisation
If post-op haemostasis accomplished: reduced dose of enoxaparin from 6 to 48 h, then NOAC (not tested reduced
dose)
Major bleeding risk (spinal and epidural anaesthesia # lumbar puncture)
reduced dose of enoxaparin from 24 to 72 h, then NOAC (not tested reduced dose)
How to prevent Acute
Scenarios of Bleeding
Try to get to a 12 h, ideal 24 h from last dose of NOAC
When delay is not an option
Reversal
Idarucizumab for Dabigatran
ACUTE SCENARIOS
OF BLEEDING
Dabigatran
Aripazine
*
Andexanet
idarucizumab
NOAC Reversal
Rivaroxaban Apixaban
*
*
*
*
Edoxaban
*
*
*
Open questions:
Are antidotes effective in critically ill patients?
What are the consequences of the immediate interruption of anticoagulation?
Does it provoke thromboembolic events?
Which antidote will provide the safest way to antagonise anticoagulation?
Among Xa and IIa inhibitors: what is the best choice for the net effect of
best anticoagulatory profile and safest management of bleeding ?
VKA
Major hemorrhage: 1.7-3.4%
>60,000 visits in ER
Reversal takes hours
Risks associated to plasma (less $)
ABO typing # thawing plasma
Large volumes and overload
Pathogens’ transmission and lung injury
4F-PCC vs plasma in pts with INR>2 and
Life-threatening bleeding
Acute bleeding + Hb<2g/L
Acute bleeding needing transfusion
AIMS
Effective hemostasis over 24h
Rapid reduction INR (<1.3 at 30 min)
Safety (SAE+Thromboembolic
Events + deaths)
64.1 % vs 65.1%
Infused Volumes (median):
99.4 cc vs 813.5 cc
RE-VERSE AD – NCT02104947
Mab binding free and IIa-bound dabigatran
Mab with high affinity (350x) Dabi vs IIa
Outcomes
Safety of iv Idarucizumab (2.5 gr # 15 min # 2.5 gr) in 90 patients who
Group A (n:51): have overt life-threatening bleeding requiring reversal
Group B (n:39): require surgery/invasive procedure with no delay (8 h)
Rapid lab reversal (DTT-ECT: at 4 h) of anticoagulant effects of specific NOAC
Clinical outcomes
Group A: extent of bleeding and hemodynamic stability (GUSTO scale)(Rankin scale)
Group B: haemostasis during intervention (normal, mild-moderate-severe abnormality)
Other Adverse events (time interval: 90 days)
thrombotic events and deaths (vascular [include bleeding] or nonvascular)
Group A (n:51): have overt life-threatening bleeding requiring reversal
Group B (n:39): require surgery/invasive procedure with no delay (8 h)
31% group A pts: hemodinamically unstable
Group B pts: surgery
Reversal assessed in 68/90 pts with initial prolonged clotting times
Reversal: 98% [89%](group A) and 93% [88%] (group B)
Renal function
Group A and clotting times
Normal – eGFR 67
Abnormal – eGFR 48
Clinical outcomes
Median investigator-reported time
of the cessation of bleeding: 11.4 hrs
Normal intraoperative hemostasis:
Normal 92% # Mildly 6% # Moderate 2%
Deaths
Group A (n:51): 9 (17.5%)
Group B (n:39): 9 (23%)
10 for vascular causes (5 fatal bleed)
9 within 96 hrs for index event
9 later deaths: coexisting conditions
Thrombotic events ( no Tx)
1 DVT/PE (2 d)
1 DVT/PE/atrial thr (9 d)
1 DVT (7 d)
1 SCA (13 d)
1 isch stroke (26 d)
SAE
2 GI haemorrage
4 other
 Every year 30,000 luggage are left unattended in the tube
 ….The key to surviving such hypothermia included
«a spirit not to give up» ….