Transcript Dr. Abraham`s Antthrombotics Presentation

Antithrombotics and Endoscopy:
Advice for Endoscopy Nurses from
Cardiogastroenterology Clinic
Neena S. Abraham MD, MSc (EPID), FACG, FASGE, AGAF
Professor of Medicine, Mayo Clinic College of Medicine
Arizona Site Director, Mayo Clinic Robert D. and Patricia E. Kern Center for the
Science of Health Care Delivery
Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ
Division of Health Care Policy & Research, Department of Health Sciences
Research, Mayo Clinic, Rochester, MN
US Population: Age 65+ & Cardiac disease
By 2030, >40% of US adults will have ≥ 1 form of
cardiovascular disease.
Millions
100
*Expected aggressive increase in antiplatelet and
anticoagulant use for primary and secondary
prevention.
80
60
40
20
0
1900 1920 1940 1960 1980 2000 2011 2020 2040 2060
Administration on Aging- 2012; Heidenreich et al. Circulation 2011.
Learning Objectives
1. Understand the GI bleeding risk of
patients on antithrombotic regimens


Antiplatelets
Anticoagulants
2. Review best-practice recommendations
for peri-endoscopic antithrombotic
management
 ASA + Plavix (DAPT)
 Coumadin- when/how/why to hold
 Novel Oral Anticoagulants (Pradaxa, Xarelto,
Eliquis, Lixiana) and procedure implications
Disclaimers--
THERE ARE NO RECIPES…
ONE SIZE DOES NOT FIT ALL…
General Principles to follow for your education
Use Your Resources:
a) ANTICOAGULATION Clinic….
b) Referring physician/PCP/cardiologist
Low- vs. High-Risk Thromboembolic Conditions
Low-Risk
Uncomplicated or
paroxysmal nonvalvular
atrial fibrillation
High-Risk
Atrial fibrillation associated with:
Valvular heart disease Hypertension
Prosthetic valves
Active CHF
Bioprosthetic valve
Diabetes mellitus
Age >75 yrs
LVEF <35%
History of thromboembolic event
Mechanical valve in the
aortic position
Deep-vein thrombosis
Mechanical valve in any position and
previous thromboembolic event
 Prior stent occlusion
 Recently (~1 yr) placed coronary stent
 Acute coronary syndrome
Non-stented PCI after MI
Anderson et al. Gastrointest Endosc 2009.
Endoscopic Bleeding Risks
Bleeding risk varies with procedure type and presence/absence of
therapeutic interventions.
Low Risk (<2% @ 48 hours)
High Risk (>2% @ 48 hours)
• Diagnostic + biopsy
 EGD
 Double balloon
enteroscopy
 Colonoscopy
• Biliary/pancreatic stent
without sphincterotomy
• ERCP without sphincterotomy
• EUS without FNA
• Flexible sphincterotomy +
biopsy
• Endosonography without FNA
• Wireless capsule endoscopy
• Polypectomy:
 Gastric (7.2%)
 Duodenal/ampullary
 1-3 cm (4.5%)
 >3 cm (10.3%)
• Endoscopic mucosal resection (22%)
• Biliary sphincterotomy (2.0-3.2%)
• PEG placement (0.2-2.5%)
• Endosonography-guided FNA (0.5-2.9%)
• Laser ablation and coagulation (1.1%)
• Treatment of varices (2.4-25.4%)
Becker et al. Am J Gastroenterol 2009; Kwok et al. Am J Gastroenterol 2009; Anderson et al. GIE 2009.
Antiplatelets
Decrease platelet aggregation
and inhibit thrombus formation
Aspirin
(ASA)
Irreversible
Mechanism of inhibition
Action
of COX-1
and COX-2
Required time
to recover
adequate
platelet
function
7 days
P2Y12 Receptor-Antagonist
Clopidogrel Prasugrel Ticagrelor
(Plavix)
(Effient)
(Brilinta)
Irreversible
inhibition of
P2Y12
receptor
5-7 days
Irreversible Reversible
inhibition of inhibition of
P2Y12
P2Y12
receptor
receptor
7-9 days
3-5 days
Management of ASA Monotherapy
Antiplatelet
Agent
Procedure
Case
Control
Bleeding
Risk
Yousfi
et al.
2004
ASA use
within 3
days prior
Colonoscopy +
polypectomy
40%
33%
OR 1.41
(0.68-3.04)
Hussain
et al.
2007
ASA or
clopidogrel
within 10
days prior
Sphincterotomy
16%
17%
OR 0.41
(0.13-1.31)
Study
It is reasonable to perform endoscopic
procedures in patients taking ASA.
Becker et al. Am J Gastroenterol 2009.
2012-2013 Indications:
Dual Antiplatelet Therapy
Updated to include ticagrelor and prasugrel.
Post-Stent
Post-ACS


Up to 12 months following
unstable angina or
NSTEMI managed without
PCI
At least 14 days (12
months in some) following
STEMI

Jneid et al. J Am Coll Cardiol 2012; O’Gara et al. Circulation 2013.
ASA indefinitely and
clopidogrel or ticagrelor for:
 Up to 12 months after
bare metal stent (BMS)
placement
 At least 12 months after
drug-eluting stent (DES)
placement
Risk of Clinical Events After Clopidogrel
Cessation Among Patients with ACS
Incidence of Death or MI
Medically Treated Patients
PCI-Treated Patients
Significantly higher risk of
adverse events (~2-fold increase)
during first 0-90 days post-ACS
with clopidogrel discontinuation
75.0%
60.0%
45.0%
30.0%
15.0%
0.0%
0-90d
Ho et al. JAMA 2008.
181-270d
91-180d
Days Post-Clopidogrel Cessation
Stent Thrombosis Post-DES: Risk with Antiplatelet
Cessation
Short-term discontinuation of thienopyridine is safe in patients
with DES if ASA therapy maintained
Time from Drug
Discontinuation to
Thrombotic Event
122 days
120
P<0.0001
P<0.0001
60
7 days
7 days
0
Patients with Thrombotic Event
ASA and thienopyridine discontinued simultaneously (n=33)
ASA discontinued after thienopyridine previously discontinued (n=15)
Only thienopyridine discontinued; ASA continued (n=94)
Eisenberg M et al. Circulation 2009.
ASA After Endoscopic Control of Peptic Ulcer
Bleeding
• Low-dose ASA (n=78) vs. placebo (n=78)
RCT
• 30-day recurrent bleeding: 10.3% vs. 5.4%
 ARR: 4.9%; NNT=20
• 30-day mortality: 1.3% vs. 9.0%
 ARI: 7.7%; NNH= 13
Hospitalbased
cohort
• N=118
• Discontinued ASA therapy: Mortality and CV
event HR 6.3 (1.3-31.3)
Discontinuation of ASA CV patients is associated with
increased mortality.
Sung et al. Ann Intern Med 2010.
Derogar M et al. Clin Gastroenterol Hepatol 2013.
Post-Polypectomy Bleeding
With and Without Antithrombotic Therapy
ASA/NSAID (n=502)
No ASA/NSAID (n=672)
Percent (%)
6
5
4
Clopidogrel (n=142)
No Clopidogrel (n=1243)
Cessation of ASA/NSAID
before
colonoscopy/polypectomy
is unnecessary.
100%
on ASA
3
P=0.02
P=NS
2
1
0
P=NS
Overall
P=NS
P=NS
Immediate Delayed
(at endoscopy) (< 4 weeks)
P=NS
Overall
Immediate Delayed
(at endoscopy) (< 4 weeks)
Post-Polypectomy Bleeding Type
Manocha D et al. Am J Med 2012.
Singh M et al. Gastrointest Endosc 2010.
Major Bleeding
(non-CABG) (%)
Second Generation Thienopyridine
Drugs: Rates of Bleeding Events
TRITON-TIMI 38 Trial
3.5
3
2.8%
2.4%
2
1.5
1
HR 1.32 (1.03-1.68)
HR 1.19 (1.02-1.38)
0.5
0
Prasugrel
Clopidogrel
Ticagrelor
Clopidogrel
Wallentin et al. N Engl J Med 2009.
2nd generation thienopyridine agents





2.2%
1.8%
2.5
Wiviott et al. NEJM 2007

PLATO Trial
Higher levels of platelet inhibition than clopidogrel  higher bleeding risk
Most common bleeding location= GI
Absolute increase greatest in elderly patients*
Ticagrelor and Prasugrel unaffected by variants of CYP2C19 genotype
Prasugrel unaffected by variants of ABCB1 genotype
Bliden KP et al. Am Heart J 2011; Husted S et al. Circ Cardiovasc Qual Outcomes 2012; Cayla G QJM 2012; O’Gara et al. Circulation 2013.
Vorapaxar: New PAR-1 Inhibitor
 Vorapaxar (Zontivity©)–protease-activated receptor 1
(PAR-1) inhibitor; First-in-class antiplatelet medication
 Approved January 2014 and prescribed with DAPT
 TRA 20 TIMI-50 trial (N=26,499)
 13% reduction of MI, stroke, CV death and
revascularization in patients with a previous MI or
peripheral artery disease (v. placebo)
 Increased moderate or severe bleeding in 4.2% (v.
2.5% placebo); 66% increased risk of bleeding overall
 Black Box Warning: contraindicated with history of
stroke, TIA and intracranial hemorrhage due to high-risk of
bleeding
Bhatt D L et al. Circulation Research. 2014;114:1929-1943
Summary:
Peri-Endoscopic Antiplatelet Management
1. Avoid stopping all antiplatelets simultaneously.
2. When thienopyridine drugs are discontinued, you must maintain
patient on ASA monotherapy.
3. Avoid cessation of thienopyridine drugs (even when ASA is continued)
within the first 30 days of PCI and DES or BMS placement.
4. Avoid stopping DAPT in the first 90 days post-ACS.
5. Defer elective endoscopic procedures until patients finishes
appropriate course of thienopyridine drug therapy, possibly up to 12
months following PCI and DES placement.
6. Perform elective high-risk endoscopic procedures 5-7 days after
clopidogrel cessation, 7-9 days after prasugrel cessation, and 3-5 days
after ticagrelor cessation.
7. Resume DAPT once hemostasis is achieved.
8. Continue antiplatelet therapy during elective low-risk endoscopy.
Becker et al. Am J Gastroenterol 2009; Anderson et al. Gastrointest Endosc 2009; Boustiere C et al. Endoscopy 2011;
Jneid et al. Circulation 2012; O’Gara Circulation 2013.
Oral Anticoagulants
Direct Oral Anticoagulants
Warfarin
Dabigatran
(Pradaxa)
Rivaroxaban
(Xarelto)
Apixaban
(Eliquis)*
Mechanism
of Action
Inhibition of Vitamin
K-dependent γcarboxylation
Direct
thrombin
inhibitor
Direct factor
Xa inhibitor
Direct factor
Xa inhibitor
Metabolism
Liver
Renal
Renal
Renal/Liver
90 d for circulating
drug; ~5-7 d for a
therapeutic INR
1.25-3 h
2-4 h
1-3 h
36-42 h for circulating
drug; ~5 d to
normalize INR
12-14 h
9-13 h
8-15 h
92% renal
80% renal
66% renal
~25% renal
Time to
maximum
effect
Half-life
Excretion
FDA Approves Edoxaban
• Approved by FDA January 2015

Oral, reversible Factor Xa inhibitor

62% bioavailable & [T Max]:1-2 Hrs

50% renal excretion
• AFIB Stroke Prevention, DVT/PE
• ENGAGE AF-TIMI 48 Trial

warfarin vs. edoxaban (N=21,105)

EDX High Dose: 60 mg/day

EDX Low Dose: 30 mg/day

Both doses non-inferior to warfarin

23% increased GIB risk (High)

33% fewer bleeds overall (Low)

Dose reduce with modest renal
impairment, <60 kg, P-glycoprotein
inhibitor use
Giugliano et al. NEJM 2013; 369:22
Coumadin– Facts
 Discontinue 5 days before procedure
 Resume with hemostasis (immediately in
most)
 Peak onset within 72-96 hours; half-life 2060 hours; 100% bioavailability
 Reversal agents: FFP (fast), Vit K (slow)
 High-risk thromboembolic patients
 Bridge vs. no bridge?
Bridge Therapy –Who?
Thromboembolic
Risk Category
Atrial Fibrillation
Mechanical
Heart Valve
Venous
Thromboembolism
(VTE)
Annual Risk >10%
CHADS2* - 5 or 6
CVA/TIA w/in 3 mos
Rheumatic valvular
Disease
Mechanical
Mitral Valve
Caged-ball or
tilting disk
aortic valve
CVA/TIA w/in 3
mos
VTE within 3 mos
High-risk
thrombophlebitis
*CHF, HTN,
Age >75, DM,
Stroke
Annual risk 5-10%
CHADS2 - 3 or 4
Bileaflet Aortic
VTE 3-12 mos ago
Valve in high-risk
patient
Annual Risk <5%
CHADS2 - ≤ 2
No prior CVA/TIA
Bileaflet Aortic
Valve in low risk
patient
VTE > 12 mos ago
Bridge Therapy organized thru Anticoagulation Clinic
New Data Regarding Bridge Therapy
 BRIDGE investigators RCT (2015)
 1884 non-valvular atrial fibrillation patients
 May not apply to valvular afib, mechanical valves,
LVADs, recently diagnosed thromboembolism (<3
months), Afib patients with CHF, post ACS setting etc.
 Elective endoscopic and surgical procedures
 Randomized to bridging vs. no bridging
 Bridging Group (when compared to no
bridging)
 More major bleeding (3.2% vs. 1.3%)
 No difference in thromboembolism risk (0.3% vs, 0.4%)
Douketis et al. NEJM 2015;373:823-833.
Supratherapeutic Warfarin Bleed
INR at time of
endoscopy is not
predictive of
rebleeding
Normalizing INR
does not reduce
rebleeding but
delays endoscopy
Adjusted OR*: 0.50 (0.21-1.16)
*Controlling for age, comorbidity, antiplatelet use, postprocedure heparin and PPI use, hypotension, ulcer as bleeding
source, and active bleeding at endoscopy
• N=102 INR >1.3; Mean INR 1.8 (1.3-2.7)
• Rebleeding rate similar with and without
reversal agent: 24.7% vs. 30.0% (p=0.54)
• Significant delay in endoscopy with
normalization of INR: 20.9 h vs. 73.6 h (p<0.0001)
• Important stigmata identified in 83% of cases
Endoscopic therapy is very effective– even in patients with
moderately elevated INR.
Choudari & Palmer. Gut 1994; Wolf A. Am J Gastroenterol 2007.
Resuming Warfarin After GI Bleeding (GIB)
90-Day Thrombosis
90-Day Recurrent GI Bleeding
P=0.002
P=0.10
Warfarin Resumption
within 4-7 days
HR: 0.05 (0.01-0.58)
Time in Days
Warfarin Resumption
Within 4-7 days
HR: 1.32 (0.50-3.57)
Time in Days
Patients with warfarin-associated GIB and indications for continued
long-term antithrombotic therapy should resume anticoagulation
within the first week following hemorrhage.
Witt DM et al. Arch Intern Med 2012.
Trends in DOAC Prescription
Barnes et al. Am J Med 2015
Temporary interruption of NOAC prior to endoscopic
procedure
Last dose prior to
Last dose prior to
Drug (Creatinine Clearance) low–risk endoscopic high–risk endoscopic
procedure *
procedure **
Dabigatran (>50 mL/min)
1 day
2 days
Dabigatran (31- 50 mL/min)
2 days
4 days
Dabigatran (<30 mL/min)
4 days
6 days
Rivaroxaban/Apixaban/
Edoxaban (>50 mL/min)
1 days
2 days
Rivaroxaban/Apixaban/
1-2 days
Edoxaban (31 to 50 mL/min)
3-4 days
Rivaroxaban/Apixaban/
Edoxaban (< 30 mL/min)
4 days
2 days
* A low-risk procedure has a 48 hour risk of major bleeding of 0% to 2%; a
high-risk procedure ** has a 48 hour risk of major bleeding of 2% to 4%
Management of DOAC Bleeding
Initial Assessment and Risk Stratification: The ABC’s
A= Airway; B= Breathing; C= Circulation
Mild
Bleeding
 Delay next
dose
 Anticoagulant
effect dissipates
24 h (with no
renal failure)
T1/2= 12-17 h
Moderate-Severe
Bleeding
 Correct hemodynamics to
perfuse kidneys
Blood-product transfusion
Endoscopic evaluation
 +/- hemodialysis with renal
failure
 Oral charcoal (if ingestion
<2h)*; PPI probably helpful if
recent ingestion (decreases
absorption)
*Recommendations based on limited nonclinical data
** PCC= prothrombin concentrate complex
Life-Threatening
Bleeding
 Consider
rFVIIa or **PCC
 Charcoal filtration
van Ryan et al. Thromb Heamost 2010.
NOAC reversal agents: 2015 or 2016
• Idarucizumab (Praxbind®)
•Humanized monoclonal antibody with high affinity for
dabigatran; binds free and thrombin-bound dabigatran
• Clinical outcomes (Pollock CV et al. NEJM 2015):
•N=90 bleeding patients on Dabi or with need for
surgery.
•2.5 gram bolus IV X 2 normalized dilute thrombin
time in 93-98% of patients.
•Cessation of bleeding in 11.4 hours; normal surgical
hemostasis in 92%
•Approved 10/16/15 by FDA for “life threatening
hemorrhage/need for emergency surgery or
procedures”; REVERSE-AD trial ongoing (N=450)
DOAC reversal agents: In Development
• Andexanet alpha
•
•
•
Phase II study in healthy volunteers
Decreased anti-Xa activity and plasma concentration of
free apixaban
Future studies required in the setting of major
hemorrhage
• Aripazine (PER977)
•Synthetic molecule binds to heparin, LMWH and NOACs in
animals
• Whole blood clotting time (in vitro) show reduction of
edoxaban effect within 10 minutes of IV infusion (restoration
to 10% over baseline)
•Needs human studies and clinical trials
My Top 10 Cardiogastroenterology Tips
1. It is safe to perform endoscopy on ASA monotherapy.
2. Avoid stopping thienopyridine in first 90 days postACS.
3. Continue ASA therapy when stopping thienopyridine.
4. GIB leading to ACS should be scoped 48-72 h postACS.
  chance of finding high-risk endoscopic stigmata
 Leads to faster cardiac catheterization in 43%
5. Endoscopic therapy is effective in patients with
moderately elevated INR (< 2.7). No need to normalize
INR.
My Top 10 Cardiogastroenterology Tips
6. Warfarin should be resumed within 4-7 days post-GIB.
7. New oral anticoagulants have  GIB risk.
8. DAPT + new oral anticoagulants (triple antithrombotic
therapy) associated with 3-fold  risk of GIB.
9. NOAC-related bleeding Support hemodynamics to
promote renal excretion of drug.
10. Elective peri-procedural NOAC management depends
on patient’s CrCl:
 With normal CrCl:
o
o
High-risk endoscopy Hold 2-3 days prior to case
Low-risk endoscopy Hold 1-2 days prior to case
 With impaired CrCL:
o
o
High-risk endoscopy Hold 4-6 days prior to case
Low-risk endoscopy Hold 2-3 days prior to case