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Patras University Hospital
Χειρισμός Αντιθρομβωτικής Αγωγής σε μη
Καρδιοχειρουργικές Επεμβάσεις
PeriklisA. Davlouros, Assistant Professor of Cardiology
Invasive Cardiology & Congenital Heart Disease
Patras University Hospital
Patras University Hospital
No conflict to declare
Patras University Hospital
Antithrombotic Therapy
Antiplatelet agents (ASA, Clopidogrel,
Prasugrel, Ticagrelor)
Anticoagulant agents
VKA (Coumadins)
Parenteral (Heparins, etc.)
NOACs (anti-Xa, antithrombins)
Patras University Hospital
Is interruption of antithrombotic therapy in the perioperative
period needed?
In pts who are having a major surgical or other major
invasive procedure, interruption required to minimize the
risk for perioperative bleeding...
In pts who are undergoing minor surgical or invasive
procedure (eg, dental, skin, or cataract), interruption may
not be required...
Perioperative Antithrombotic Tx: Key Questions
Patras University Hospital
Risk Stratification for Bleeding
High bleeding-risk surgeries/procedures include:
Urologic surgery/procedures: TURP, bladder resection or tumor
ablation, nephrectomy or kidney biopsy (untreated tissue damage after
TURP and endogenous urokinase release)
Colonic polyp resection, especially >1-2 cm sessile polyps (bleeding
occurs at transected stalk after hemostatic plug release)
Bowel resection (bleeding may occur at anastomosis site)
Vascular organ surgery: thyroid, liver, spleen
Patras University Hospital
Risk Stratification for Bleeding
High bleeding-risk surgeries/procedures include:
Major surgery involving considerable tissue injury: cancer surgery,
joint arthroplasty, reconstructive plastic surgery
Cardiac, intracranial, intraoccular, or spinal surgery (small bleeds
can have serious clinical consequences)
Pacemaker or ICD implantation (separation of infraclavicular fascia
and no suturing of unopposed tissues may lead to hematoma)…
BRUISE CONTROL study less pocket hematoma @ cont. Warfarin, (3.5% versus
16%; relative risk 0.19; 95% CI 0.10-0.36)
Patras University Hospital
Perioperative Antithrombotic Tx: Key Questions
For intermediate bleeding risk surgery is interruption of
antithrombotic Tx needed?
If antithrombotic therapy is interrupted before surgery, is
“Bridging Anticoagulation” needed?
This depends on Thrombosis-Bleeding risk
balance…
Patras University Hospital
If antithrombotic therapy should be stopped
before surgery to minimize bleeding risk…
~ 12-24 hours for UFH/LMWH
~ 2-3 days for NOACs
~5 days for warfarin
~7-10 days for antiplatelet drugs
Minimizing the Risk of Perioperative Bleeding
Patras University Hospital
In resuming treatment after surgery, it takes:
- 2-3 days for anticoagulant effect to begin after starting
VKAs…
- 3-5 h for peak anticoagulant effect after starting LMWH
- 2-3h for peak anticoagulant effect after starting NOACs
- Mins for an antiplatelet effect to begin after starting ASA
- 1-6 Hrs for an antiplatelet effect to begin after starting a
maintenance dose of clop/pras/ticag…
Minimizing the Risk of Perioperative Bleeding
Patras University Hospital
Most surgery/procedures done out-of-hospital and
potential TE or bleeding complications occur during
the initial 2 wks after surgery while patient is at home…
- Close pt FU during early postop period allows early
detection and treatment of complications…
Minimizing the Risk of Perioperative Events…
Patras University Hospital
Perioperative Antithrombotic Tx: Thrombotic Risk
Patients' estimated risk for thromboembolism (TE):
High-risk pts: need to prevent TE will dominate management
irrespective of bleeding risk; (the potential consequences of TE may
justify bridging)
Moderate-risk pts: a single perioperative strategy is not dominant and
management will depend on individual patient risk assessment
Low-risk pts: need to prevent TE will be less dominant; (bridging may
be avoided)
Patras University Hospital
Perioperative Antithrombotic Tx: Bridging…
Patients' estimated risk for thromboembolism (TE):
In all patients, judicious use of postoperative
bridging is needed to minimizing bleeding that
would have the undesired effect of delaying
resumption of antithrombotic therapy after
surgery…
Patras University Hospital
Antiplatelet Therapy
Patras University Hospital
Patients With ACS: Facts…
DAPT is mandatory for 1 year following an ACS
Newer antiplatelet agents (NAPA) are more potent
than clopidogrel in reducing ischemic end-points
NAPA increase bleeding risk compared to clopidogrel
Patients with increased ischemic risk also have
increased bleeding risk…
Patras University Hospital
DAPT duration for stable CAD@PCI?
DAPT @ Clopidogrel
1-6 months depending on stent type I(A/B)
< 6 mo if bleeding risk, > 6 mo if isch/bl risk IIb(A/C)
Patras University Hospital
Patras University Hospital
Incidence of surgery within 1 year of
coronary stenting (5-8%)…
Savonitto et al. Journal of Thromb and Haemost 2011
Patras University Hospital
Incidence of surgery within 1 year of
coronary stenting
Patras University Hospital
What Does the Surgeon Recommend if a Pt
with a Recent Stent Needs Surgery?
Fear of excessive bleeding leads to the generally
accepted policy of discontinuing antiplatelet
agents 7-10 days before surgery…
Not uncommonly surgeons recommend
discontinuation for 14 days, or even 2-3 days!!!
Patras University Hospital
Patras University Hospital
Patras University Hospital
The Perfect Storm
Patras University Hospital
Perioperative Stent Thrombosis in pts
with DES as a function of the time elapsed
since stent implantation
Perioperative MACEs in pts with DES as a
function of the time elapsed since stent
implantation
839 pts from 4 studies
p=0.04p=0.35
404 pts/6 studies
Stent Thrombosis MACEs
Patras University Hospital Savonitto et al. Journal of Thromb and Haemost 2011
Perioperative MACEs in pts with DES as a function
of the time elapsed since stent implantation
Patras University Hospital
839 pts from 4 studies
p=0.35
Patras University Hospital
DAPT may not be protective perioperatively
Most urgent interventions performed in a proinflammatory
and prothrombotic milieu, (cancer, trauma, and anemia)…
Operative trauma: hypercoagulable state...
Increased PLTs, von Willebrand factor, fibrinogen, etc, impaired
deformability of erythrocytes, decreased proteins that oppose
formation of stable fibrin
CABG: cardiopulmonary bypass circuit may also induce systemic
prothrombotic state by activating tissue factor, kallikrein, and
complement
Clopidogrel: poorly absorbed and requires extensive
metabolism, a process that is dramatically impaired in
acutely ill pts because of splanchnic and liver
hypoperfusion, and reduced gastric emptying resulting
from the use of opioids for analgesia and sedation…
Patras University Hospital
Perioperative Events in Stented Pts…
The incidence of perioperative death, MI and ST decreases over time…
Particularly high (up to 30%) in the 1st mo regardless of the type of implanted
stent; 10–15% at 2-6 mos; and< 10% after 6 mos
The indication for index stenting SAP vs. ACS is probably more
important than the type of stent deployed, or even timing...
The risk of cardiac adverse events in pts @ recent PCI does not seem to
depend on ST alone, but on the more general coronary risk …
The first postoperative week is the most critical: in the EVENT Registry,
the risk of death, MI or ST was 27-fold higher in the week following NCS
than in any other week after stent implantation…
Patras University Hospital
Key Issues to be Addressed…
Whether continuing perioperative DAPT protects against
cardiac ischemic events
The extent to which it increases the risk of surgical
bleeding
How to balance the potential benefits and risks in individual
patients
This subject has been discussed by cardiovascular surgeons for
20 years with regard to aspirin, and for a few years with regard to
clopidogrel added to aspirin
Patras University Hospital
Patients With Coronary Stents Having Surgery
Recommendation: In pts with a coronary stent who are
receiving DAPT and require surgery, we recommend deferring
surgery for at least 6 wks after placement of a BMS and for
at least 6 mos after placement of a DES (Grade 1C)
Recommendation: In pts who require surgery within 6 wks of
placement of a BMS or 6 mos of placement of a DES, we
suggest continuing DAPT around the time of surgery instead
of stopping DAPT 7-10 days before surgery (Grade 2C)
Patras University Hospital
What does ESC recommend?
DAPT for at least 1 mo after BMS in stable CAD, 6 mo
after ng-DES, and up to 1 yr after ACS, irrespective of
revascularization strategy
A minimum of 1 (BMS) to 3 (ng-DES) mo of DAPT might
be acceptable, independently of the acuteness of CAD,
in cases when surgery cannot be delayed for a longer
period
Such surgical procedures should be performed in hospitals
where 24/7 catheterization laboratories are available…
ESC guidelines 2014
Patras University Hospital
What does ESC recommend?
Single anti-platelet therapy (preferably with
ASA) should be continued…
ESC guidelines 2014
Patras University Hospital
What does ESC recommend?
Single anti-platelet therapy (preferably with
ASA) should be continued…
ESC guidelines 2014
Patras University Hospital
What does ESC recommend?
In pts needing surgery within a few days…
ESC guidelines 2014
Patras University Hospital
What does ESC recommend?
Dual anti-platelet therapy should be resumed
as soon as possible after surgery and, if
possible, within 48 hours…
ESC guidelines 2014
Patras University Hospital
What does ESC recommend?
Platelet function tests for optimal timing of
surgery not recommended…
‘Ideal’ platelet function assay or ‘bleeding cut-off’…
ESC guidelines 2014
Patras University Hospital
Thrombelastography (TEG) to determine the timing of CABG in pts on
clopidogrel was evaluated in the first prospective study, TARGET CABG
which showed that pts non–responsive by TEG had no greater chest
tube output when operated within 24 hrs of last clopidogrel dose
compared to clopidogrel naïve pts.
Compared with the guidelines, this individualized
approach reduced the pre-operative waiting
period by about 50%
Patras University Hospital
Need for non-CABG surgery…
68-year-old pt @ DM, mild CRF, and
colorectal cancer diagnosed following
bleeding on DAPT, needs surgery 5
months post-ACS/PCI @ DES in LAD
bifurcation…
Best approach?
Patras University Hospital
Clinical Factors
ACS
Low EF
Diabetes
CRF
Cancer
Surgery
Interrupting DAPT: Thrombotic Risk
Angiographic/Technical Factors
BMS < 1 mo
DES < 6-12 mo (New generation
DES…)
DES > 12 mo and
Long lesions, Multiple stents, Small
vessels, Bifurcations, LM disease,
Last remaining vessel
Patras University Hospital
Bridging: ESC recommendation…
For patients with a very high
risk of ST, bridging with IV,
reversible GPIs, should be
considered…
Cangrelor, is not yet available...
The use of LMWH for bridging in
these pts should be avoided.
ESC guidelines 2014
Patras University Hospital
Urgent surgery in pts with a recently implanted DES: a phase II study of
‘bridging’ antiplatelet therapy with tirofiban during temporary
withdrawal of clopidogrel
Savonitto et al. BJA 2010
30 pts with a mean age (range) of 65 (25–80) yr
There were no adverse cardiac events during the index hospitalization,
and no patient required surgical re-exploration because of bleeding:
Point estimate of the primary endpoint rate was 0% (one-tailed 97.5% CI
0–11.6%)
No patient experienced any major or minor TIMI bleeding during the
preoperative phase, although one received 2 U of RBCs due to pre-
existing anaemia…
Patras University Hospital
Day -7 -6 -5 -4 -3 -2 -1 -4-6 hrs 0 +4-6 hrs FU until
discharge
Stop
Prasugrel
Stop
Clopidogrel
Ticagrelor
StartSmall molecule
GPI (Tirof/Eptif)
StopSmall molecule
GPI (Tirof/Eptif)
Surgery
ResumeSmall molecule
GPI (Tirof/Eptif)
Resume
Clopidogrel
Tirofiban 0.1 mcg/kg/min
Eptifibatide 2 mcg/kg/mi
If CrCl < 50 ml/min half dose
300-600 mg LD ASAP
ASA continued throughout
Patras University Hospital
The main findings of our study are that, in
patients undergoing major surgery after
DES implantation requiring interruption of
thienopyridine administration,
preoperative administration of a
glycoprotein IIb/IIIa inhibitor
(a)may not prevent postoperative stent
thrombosis, and
(b)may be associated with high risk for
thrombocytopenia and bleeding
Patras University Hospital
N N
NN
NH
SCF
3
OHOH
OO
PO
O
PP
OO
OClCl
OO
O
S
4Na+
Cangrelor
Intravenous ADP–P2Y12 receptor antagonist
Rapid acting: quick onset, quick offset
Plasma half-life of 3 – 6 minutes
60 minutes for return to normal platelet function
Patras University Hospital 44
The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet P2Y12
Inhibitor In Patients Awaiting Cardiac Surgery:
Results Of the BRIDGE Trial
Dominick J. Angiolillo MD, PhD, Michael S. Firstenberg MD, Matthew J. Price
MD, Pradyumna E. Tummala MD, Martin Hutyra MD, Ian J. Welsby MD,
Michele D. Voeltz MD, Harish Chandna MD, Chandrashekhar Ramaiah MD,
Miroslav Brtko MD, PhD, Louis Cannon MD, Cornelius Dyke MD Tiepu Liu MD,
PhD, Gilles Montalescot MD, Steven V. Manoukian MD, Jayne Prats PhD, Eric J.
Topol MD for the BRIDGE Investigators
Patras University Hospital
Trial design: Stage II
Randomized, Double-Blind,
Placebo-Controlled
45
Treat per Standard of Care
(CABG
rule-in)0
100
200
300
400
-1 0 1 2 3 4 5-7
Elapsed Days
PR
U
Bridge Stage II: Demonstration of Effective Cangrelor Infusion Dose
CABG
Thru Hospital Discharge
Demonstrate that cangrelor infusion of maintains PRU< 240
Cangrelor/Placebo InfusionDose Determined in Stage I :
0.75 µg/kg/min
• Patients with an ACS or treated with a coronary stent (BMS or DES) on a thienopyridine (ticlopidine, clopidogrel or prasugrel) awaiting CABG.
• After thienopyridine discontinuation (<72 hours), patients were administered cangrelor/placebo for at least 48 hours and up to 7 days, which was discontinued 1-6 hours prior to CABG.
• Objective: demonstrate that cangrelor would maintain levels of platelet reactivity <240 P2Y12 Reaction Units (PRU) throughout the pre-operative period as measured by the VerifyNow™ P2Y12 test.
Clopidogrel
or prasugrel
Patras University Hospital
0
50
100
150
200
250
300
350
400
Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Last
on-infusion
sample
Pre-CABG
sample
Time Point
n=80n=70
n=55 n=33n=7
n=1
n=6
n=85
n=84
n=78
Cangrelor Placebo
Verify
No
w P
RU
N indicates number of patients with valid samples in the intention to treat population; PRU= P2Y12 reaction units; Data expressed as mean±SD
Platelet reactivity by day
n=76n=73
n=57 n=34 n=24
n=14n=86
n=2n=84
n=75
Patras University Hospital
Bleeding endpoint
Excessive CABG-related bleeding (primary safety endpoint)*
*Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or post-operative hospitalization: Surgical re-exploration, 24 hour CT output > 1.5 liters, Incidence of PRBC transfusion > 4 units.
11,8%10,4%
0%
5%
10%
15%
Cangrelor Placebo
Excessive CABG-related bleeding
P=0.76
Patras University Hospital
Summary results
When used as a bridging strategy to CABG after
thienopyridine discontinuation, cangrelor (at 0.75
µg/kg/min) achieves levels of platelet inhibition known to
be associated with a low risk of thrombotic events:
Without increased risk of bleeding before or during CABG,
although with a numerical increase in minor pre-CABG bleeding
Independent of prior thienopyridine dose & time of
discontinuation
Consistent pharmaocdynamic effect during IV infusion
Rapid offset after IV discontinuation prior to surgery
No increased incidence of adverse events (e.g.
dyspnea) or laboratory abnormalities despite extended
dosing.
Patras University Hospital
Day -7 -6 -5 -4 -3 -2 -1 -4-6 hrs 0 +4-6 hrs FU until
discharge
Stop
Prasugrel
Stop
Clopidogrel
Ticagrelor
Surgery
ResumeCangrelor
Resume
Clopidogrel
Within 72 hrs 0.75 μg/kg/min
for a min 48 hrs and max 7 ds
300-600 mg LD ASAP
ASA continued throughout
Start StopCangrelor Cangrelor
Patras University Hospital
Patras University Hospital
Patras University Hospital
Bridging strategy: Limitations
Requires prolonged hospitalization
Carries increased risk for bleeding
Is costly
Does not address the risk during the
immediate postoperative period, when the ST
risk is highest
Unknown if it could reduce MACES…
Patras University Hospital
Patras University Hospital
Carefully balance
Bleeding risk (intracranial/spine/abdominal/prostate/etc)
Ischemic risk (recent ACS, stent type, lesion type)
ASA should be continued (especially if DES < 12 mo)
If Low Thrombotic Risk
Stop Prasugrel 7 days before surgery
Stop Clopidogrel-Ticagrelor 5 days before surgery
Stop clopidogrel 5 days before surgery, or less, if a validated platelet function
testing method shows a poor response to clopidogrel…
Start Clopidogrel (LD), (or Ticagrelor?) ASAP
Prasugrel contraindicated immediately postoperatively
If High thrombotic risk pts bridging may be considered…
Patras University Hospital
Anticoagulation Therapy
Patras University Hospital
Suggested Risk Stratification: Mechanical Heart Valves…
High Risk
Any mitral valve prosthesis
Older (caged-ball or tilting disc) aortic valve prosthesis
Recent (within 6 months) stroke or TIA
Moderate Risk
Bileaflet aortic valve and at least one of:
Afib, or CHADS ≥ 1
Low Risk
Bileaflet aortic valve without AF and no other RFs for stroke
Patras University Hospital
High Risk
Rheumatic valvular heart disease
Recent (within 3 months) stroke or TIA
CHADS2 score = 5-6
Moderate Risk
CHADS2 score = 3-4
Low Risk
CHADS2 score = 0-2 and no prior stroke or TIA
N.B. Individual pt characteristics (eg, prior embolic stroke or
perioperative stroke/TIA) may override suggested risk
stratification
Suggested Risk Stratification: Afib…
Patras University Hospital
High Risk
Recent VTE (<3 months ago)
Severe thrombophilia (eg, antiphospholipid antibodies)
Moderate Risk
VTE within the past 3-12 months
Recurrent VTE
Nonsevere thrombophilia (eg, heterozygous factor V)
Active cancer (treated within 6 months or palliative)
Low Risk
Prior VTE >12 months ago and no other risk factors
Suggested Risk Stratification: VTE…
Patras University Hospital
Patients Requiring Minor Procedures
Recommendation: Minor dental surgery, either continue
VKA with co-administration of an oral prohemostatic agent or
stop VKAs 2-3 days before the procedure (Grade 2C)
Recommendation: Minor skin procedures, continue
VKAs and optimize local hemostasis (Grade 2C)
Recommendation: Cataract surgery, continue VKAs
(Grade 2C)
Patras University Hospital
Pts at High Risk for TE having Major Surgery
Recommendation: In pts who require temporary interruption
of a VKA before surgery, we recommend stopping VKAs
approximately 5 days before surgery (Grade 1C)
Recommendation: In pts who require temporary interruption
of a VKA before surgery, we recommend resuming VKAs
approximately 12-24 hrs after surgery (evening of or next
morning) when there is adequate hemostasis (Grade 2C)
Patras University Hospital
Pts at High Risk for TE having Major Surgery
Recommendation: In pts with a mechanical
heart valve, Afib or VTE at high risk for TE,
we suggest bridging anticoagulation
(Grade 2C)
Patras University Hospital
Pts at Low Risk for TE Having Major Surgery
Recommendation: In pts with a mechanical heart valve,
Afib or VTE at low-risk for TE, we suggest no bridging
(Grade 2C)
N.B. In pts at moderate-risk for TE, the bridging or no
bridging approach chosen is, as in the higher and lower risk
pts, based on an assessment of individual patient- and
surgery-related factors…
Patras University Hospital
Perioperative Administration of Bridging
Recommendation: In pts who are receiving bridging
anticoagulation with therapeutic-dose SC LMWH, we suggest
administering the last preoperative dose approximately 24 h
before surgery instead of 12 h before surgery (Grade 2C)
Recommendation: In pts who are receiving bridging
anticoagulation with therapeutic-dose SC LMWH and are
undergoing high bleeding-risk surgery, we suggest
resuming therapeutic-dose LMWH 48-72 h after surgery
instead of resuming LMWH within 24 h after surgery (Grade
2C)
Patras University Hospital
What does ESC recommend?
Stop VKA 3–5 days before surgery (depending on the
type of VKA),with daily INR measurements, until ≤1.5 is
reached, and that LMWH or UFH therapy be started
one day after discontinuation of VKA—or later, as
soon as the INR is 2.0
The last dose of LMWH should be administered no later
than 12 hrs before the procedure…
Patras University Hospital
What does ESC recommend?
LMWH or UFH is resumed at the pre-procedural dose
1–2 days after surgery, depending on the patient’s
haemostatic status, but at least 12 hours after the
procedure
VKAs should be resumed on day 1 or 2 after surgery—
depending on adequate haemostasis—with the pre-
operative maintenance dose plus a boosting dose of
50% for two consecutive days…
Patras University Hospital
NOACs: ESC guidelines…
In pts treated with the NOACs, all of which
have a well-defined ‘on’ and ‘off’ action,
‘bridging’ to surgery is in most cases
unnecessary, due to their short biological
half-lives…
Patras University Hospital
Patras University Hospital
Stop NOACs for..
2–3 times their respective biological half-lives
prior to surgery in surgical interventions with
‘normal’ bleeding risk…
4–5 times the biological half-lives before
surgery in surgical interventions with high
bleeding risk...
NOACs: ESC guidelines…
Patras University Hospital
Because of the fast ‘on’-effect of NOACs,
resumption of treatment after surgery should
be delayed for 1–2 (in some cases 3–5)
days, until post-surgical bleeding tendency is
diminished…
NOACs: ESC guidelines…
Patras University Hospital
Ευχαριστώ
Patras University Hospital
Reversal of anticoagulant therapy
VKAs: low-dose (2.5–5.0 mg) IV or oral
vitamin K…
Effect on INR will first be apparent after 6–12 hs
More immediate reversal: fresh-frozen
plasma or prothrombin complex
concentrate (PCC), in addition to low-dose
vitamin K
Patras University Hospital
Reversal of anticoagulant therapy
UFH (IV): coagulation is usually normal 4
hours after cessation
UFH (SC): anticoagulant effect more prolonged
Immediate reversal: protamine sulphate,
dose calculated by assessment of the amount
of heparin received in the previous 2 hrs...
1 U per 1 U of heparin sodium...
Patras University Hospital
Reversal of anticoagulant therapy
LMWHs: anticoagulant effect reversed within
8 hours of the last dose
Immediate reversal: IV protamine sulphate
can be used, but anti-Xa activity is never
completely neutralized (maximum 50%)…
Patras University Hospital
Symptomatic treatment
Lack of specific
antidotes
Potential benefit for
PCC or aPCC
Haemodialysis
(dabigatran)