Use of Novel Anticoagulants

& Antiplatlet Therapy

Jong-Yoon Yi, MD, FACC
President, Heartland Education & Research Foundation

Disclosures
Speaker
Forest Pharmaceuticals
Research
ENGAGE AF-TIMI 48

The Balance
Bleeding

Clotting

Therapy in ACS is Complex

Anticoagulants: UFH LMWH Fondaparinux Bivalirudin
Antiplatelets: ASA Clopidogrel Prasugrel Ticagrelor
IV anitplatelets: None Abciximab Eptifibatide/Tirofiban
Cath strategy:

Early Delayed

Never

144 Different Combinations with Different effect on

Bleeding and Thrombosis Risk

Targets for antiplatelet therapies

Ticlopidine
Clopidogrel
Prasugrel
AZD6140
Cangrelor
PRT060128

ADP

SCH 530348

Thrombin

PDE

ADP

cAMP

PAR-1

Activation

Abciximab
Eptifibatide
Tirofiban
GP IIb/IIIa
(Fibrinogen
receptor)

Dipyridamole

ADP

Collagen
TXA2

COX
TXA2

ASA

cAMP = cyclic adenosine monophosphate, COX = cyclooxygenase, PAR =

protease-activated receptor, PDE = phosphodiesterase

Courtesy of BM Scirica, MD.

Adapted from Schafer AI.
Am J Med. 1996;101:199-209.

Aspirin Pharmacology

Prodrug: metabolized to salicylate

Absorption: affected by food, antacid buffer, enteric
coating, chewing
Irreversible COX-1, COX-2 inhibition
Effect within minutes, peak in 1-2 hours

Aspirin
Beneficial in PTCA
77% reduction in ischemic complications
Dosing for PCI
On ASA, then 75 to 325mg before PCI
No ASA, then 325 mg >2 hrs before PCI
Maintenance dose 81-162 mg
Low dose has similar efficacy but decreased
bleeding than with higher doses

Clopidogrel:
Thienopyridine Pharmacology

Absorption: Not affected by food or antacids

Prodrug converted by liver to active metabolites
Elimination half life = 8 hours
Irreversible binding: biologic effects = platelet life

CREDO 28-day outcome

Time to Effect of 300mg Loading dose

300 mg has insignificant effect

If <6 hrs before PCI

Clopidogrel load prior to PCI

2-12 hrs : 600mg
>12 hrs: 300mg

Prasugrel

Absorption: may be taken with food/antacids, although

absorption decreased after fatty meal
Prodrug: intestinal/liver conversion to active
Elimination half-life = 7hours
Irreversible binding to P2Y12 receptor:
biologic effects = platelet life (5-10days)

Prasugrel is more potent than clopidogrel

Single 60 mg dose with peak effect Within 2hours
and more effective than single 300mg dose clopidogrel

Less MI, but more bleeding

Prasugrel
Alternative to clopidogrel at time of PCI
Caution in age >75 or weight <60 kg
Due to rapid onset and higher potency, it is reasonable to

wait until coronary anatomy defined before loading

Discontinue 7 days prior to CABG

FDA Black Box Warning

Avoid use in patients with
Prior Stroke or TIA
Absolute Contraindication

Ticagrelor
Cyclopentyltriazolopyrimidine pharmacology

Absorption: not affected by food or antacids

Non-Prodrug: Onset of action within 1-2 hours
Elimination half-life = 8 hours
Reversible binding: biologic t1/2 = 6 hours
clinical effect 3-5 days

PLATO Trial (High Risk ACS)

CV Death, MI or Stroke
11.7
9.8

No Increase in Bleeding

JACC 2010

Reductions in All Cause Mortality,

CV Mortality, MI, Stent Thrombosis

PLATO Trial (High Risk ACS)

CV Death, MI or Stroke

No Increase in Bleeding

Reductions in All Cause Mortality,

CV Mortality, MI, Stent Thrombosis

Ticagrelor
Ventricular pauses 3 seconds in first week
Dyspnea
Creatinine (reversible)

FDA boxed warning

aspirin doses above 100 mg/day
Decrease the effectiveness of the medication.

Long Term Antiplatelet Rx.

Acute & Stable Coronary Syndrome
Medical
Theraphy
Without stent or
PTCA alone

ASA 162-325 mg/d

indefinitely
+
Clodpidogrel 75mg/d
or ? Prasugrel
or ?Ticagrelor
for at least 1 mo (class
1A) & up to 12 months

Bare-metal
Stent group

ASA 162-325 mg/d

for 1mo then
75-100mg/d indefinitely
+
Clodpidogrel 75mg/d or
Prasugrel 10mg/d or
Ticagrelor 90mg BID for
at 6-12 months
Shorter duration if
bleeding risk >benefit

Drug-eluting
Stent group

ASA 162-325mg/d for

at least 3 mo for SES,
6mo for PES, then
75-100mg/d indefinitely
+
Clodpidogrel 75mg/d or
Prasugrel 10mg/d or
Ticagrelor 90mg BID
for at 6-12 months
Shorter duration if
bleeding risk >benefit

Conclusions
ASA, CV events & is foundation of acute & long-term

therapy
All ADP antagonists should be given 2-6 hours before PCI
Routine genetic testing & POC platelet function testing
unnecessary
2nd Generation ADP antagonists are superior to clopidogrel
*Reduced MACE & mortality
*Increased Bleeding
*Novel adverse effects, restrictions.

New Data on Prevention of Stroke

in Nonvalvular AF

AF in the USA
Approx 5 million people
Increase with age
Increasing incidence & prevalence
Life time Risk: 25%
Independent predictor of mortality
Risk of stroke 3-7%/year
Increase with age
Almost half of all embolic strokes
About 100,000 strokes/year
A growing Epidemic

Appox 15M
by 2050

Stroke Risk Stratification

CHADS2 Risk Score
CHF
Hypertension

1
1

Age >75

DM

CVA or TIA

Total

Score

CVA
(%/Yr)

1.9%

2.8 %

4.0%

5.9%

8.5%

12.5%

18.2%

CHADS2-VASc Score
CHF

Score

CVA
(%/Yr)

0%

1.3%

2.2%

Hypertension

Age>75

DM

3.2%

CVA/TIA

4.0%

Vascular Ds
(MI, PAD)

6.7%

Aged 65-74

9.8%

9.6%

Female

6.7%

Total

15.2%

Prevention of Stroke in pt with AF

Trials (no.)
ASA > Placebo
7
ASA + Clopidogrel > aspirin

Warfarin > placebo

5
Warfarin > ASA
9
Warfarin > ASA = clopidogrel

Adjusted-dose warfarin >

low-dose (fixed) warfarin + ASA 1

Limitations of Vit K Antagonists

Narrow
Therapeutic Range

Slow Onset &

Offset of action

Limitations
Variable & Unpredictable
anticoagulation effect

Genetic polymorphism
Food & drug interactions
Concurrent disease

Need for monitoring

of A/C effect &
dose adjustments

Rivaroxaban
Apixaban

Dabigatran

Dabigatran

Dabigatran: Advantages & Disadvantages

Stroke
ICH
No INR monitoring
Convenient
Inability to assess efficacy
Advantage
Rapid onset of effect

Costs
Costs Socieetal
Socieetal
Pt
related
Pt related impact
impact on
on compliance
compliance

MI:
Play
of
chance
MI:
Play of chance
Direct
Direct cause
cause
Wrfarin
Wrfarin effect
effect
Lack
of
ASA
Lack of ASA
Use
in
Use in pts
pts on
on dual
dual antiplatelet
antiplatelet therapy
therapy

Twice-daily dosing Effect on

compliance?
Irreversibility
Dose in pt with renal
dysfunction & age >75yr
Confusing Disadvantage
Dyspepsia (11-12%)

Rivaroxaban

ANY
FATAL
ICH

Rates of Major Bleeding

No./100 patient-year
Rivaroxaban Warfarin
2.13
3.09
0.4
0.8
0.33
0.80

<0.001
0.003
<0.001

Apixaban

Stroke risk Reductions:From the RCT

Recommendations for Converting

Between Anticoagulants
From Parenteral A/C to dabigatran From Warfarin to
Dabigatran Start when INR <2.0
or rivaroxaban
Rivaroxaban start when INR <3.0
Heparin First dose at time
heparin is discontinued
LMWH First dose at time next
From dabigatran to warfarin
dose is due
CrCl >50 mL/min start 3D before
discontinuing
To parenteral A/C from
CrCl 30-50 mL/min start 2D before
Dabigatran
discontinuing
CrCl >30 mL/min wait 12hrs after last
CrCl 15-30 mL/min start 1 D before
dose
discontinuing

CrCl <30 mL/min, wait 24hrs after

last dose

Rivaroxaban

At time of next scheduled dose

From rivaroxaban to wartarin

Use parental anticoagulation bridge

Thank you