Χειρισμός Αντιθρομβωτικής Αγωγής σε μη ... · 2015-05-01 ·...

Patras University Hospital

Χειρισμός Αντιθρομβωτικής Αγωγής σε μη

Καρδιοχειρουργικές Επεμβάσεις

PeriklisA. Davlouros, Assistant Professor of Cardiology

Invasive Cardiology & Congenital Heart Disease



No conflict to declare


Antithrombotic Therapy

Antiplatelet agents (ASA, Clopidogrel,

Prasugrel, Ticagrelor)

Anticoagulant agents

VKA (Coumadins)

Parenteral (Heparins, etc.)

NOACs (anti-Xa, antithrombins)


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


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


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)


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…


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


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


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…


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)


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…


Antiplatelet Therapy


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…


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)


Incidence of surgery within 1 year of

coronary stenting (5-8%)…

Savonitto et al. Journal of Thromb and Haemost 2011


Incidence of surgery within 1 year of

coronary stenting


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!!!


The Perfect Storm


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


839 pts from 4 studies

p=0.35


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…


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…


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


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)


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



Single anti-platelet therapy (preferably with

ASA) should be continued…

ESC guidelines 2014



In pts needing surgery within a few days…

ESC guidelines 2014



Dual anti-platelet therapy should be resumed

as soon as possible after surgery and, if

possible, within 48 hours…

ESC guidelines 2014



Platelet function tests for optimal timing of

surgery not recommended…

‘Ideal’ platelet function assay or ‘bleeding cut-off’…

ESC guidelines 2014


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%


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?


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


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


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…


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


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


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


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


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


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


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.


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


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…


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…


Anticoagulation Therapy


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


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…


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…


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)


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)


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)


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…


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)



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…



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…


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…


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...



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…



Ευχαριστώ


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



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...



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%)…


Symptomatic treatment

Lack of specific

antidotes

Potential benefit for

PCC or aPCC

Haemodialysis

(dabigatran)

Χειρισμός Αντιθρομβωτικής Αγωγής σε μη ... · 2015-05-01 ·...

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