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The Evolution and History of the ADP Receptor Inhibitor
Larry M. Diamond, PharmD
Clinical Pharmacy Specialist – Cardiology
Oakwood Hospital and Medical Center
∗ The importance of the ADP receptor blockers in ACS
∗ How the ADP receptor blockers work
∗ What are the differences.
Objectives
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AMI Stats∗ Incidence in the United States*
∗ Estimated 900,000 will suffer AMI this year
∗ ~565,000 will be new attacks (avg. age- 65.8yrs/males,
70.4yrs/female)
∗ ~300,000 will be recurrent attacks
∗ 42% of AMI pts will die within 1 year
∗ Approximately half of these deaths occur before reaching the emergency department
∗ Most cardiac deaths are the result of fatal arrhythmias
∗ Types of arrival/discharge AMIs**
∗ Upon arrival: STEMI on 1st ECG-26%; STEMI on 1st or subsequent ECG-35%; NSTEMI-65%
∗ Non-Q-wave: 75% Q-wave: 25%
*American Heart Association. Heart Disease & Stroke Statistics-2004 Update
**NRMI 4 Quarterly Data Report (Nation). South San Francisco, Calif: Genentech Inc; June, 2004.
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The Role of Platelets in Atherothrombosis
Slide modified from Cannon CP, et al. Available at http://www.theheart.org/viewArticle.do?primaryKey=119759.
Accessed April 20, 2005.
Activation2
Adhesion1 Aggregation3
Results from cross-linking of platelets by fibrinogen at
platelet receptors GP IIb-IIIaat site of plaque rupture
Platelet
Fibrinogen
Rupturedplaque
GP IIb-IIIa
NSTE ACS is generally caused by partially occlusive,
platelet-rich thrombus in a
coronary artery
Unobstructedlumen
Thrombus
Artery wall
Van de Werf F. Thromb Haemost. 1997;78(1):210-213; Moser M, et al. J Cardiovasc Pharmacol. 2003;41(4):
586-592; Reprinted with permission from Davies MJ. Heart. 2000;83(3):361-366. © BMJ Publishing Group Ltd. 2005.
The Role of the Platelet in Non-ST-segmentElevation Acute Coronary Syndrome (NSTE ACS)
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The Thrombus in STEMIResults from stabilization by fibrin
mesh of a platelet aggregate at site of plaque rupture
platelet
RBC*
fibrin mesh
STEMI is generally caused by a completely occlusive fibrin-rich thrombus in a coronary artery
*RBC = red blood cell.
GP IIb-IIIa inhibitors are not indicated for STEMI.
Van de Werf F. Thromb Haemost. 1997;78(1):210-213; White HD. Am J Cardiol. 1997;80(4A):2B-10B;
Davies MJ. Heart. 2000;83(3):361-366.
ACS PathophysiologyPlaque Rupture, Thrombosis and Microembolization
Quiescent plaque
Plaque rupture
ProcessPlaque formation
Inflammation
Multiple factors
? Infection
Plaque Rupture
? Macrophages
Metalloproteinases
Thrombosis
Platelet Activation
Thrombin
ProcessPlaque formation
Inflammation
Multiple factors
? Infection
Plaque Rupture
? Macrophages
Metalloproteinases
Thrombosis
Platelet Activation
Thrombin
MarkerCholesterol
LDL
C-Reactive Protein
Adhesion Molecules
Interleukin 6, TNFα,α,α,α,
sCD-40 ligand
MDA Modified LDL
D-dimer, Complement,
Fibrinogen, Troponin,
CRP, CD40L
MarkerCholesterol
LDL
C-Reactive Protein
Adhesion Molecules
Interleukin 6, TNFα,α,α,α,
sCD-40 ligand
MDA Modified LDL
D-dimer, Complement,
Fibrinogen, Troponin,
CRP, CD40L
Vulnerable plaque
Macrophages
Foam Cells
Collagen →
platelet activation
TF → Clotting Cascade
Lipid coreLipid core
Metalloproteinases
Inflammation
Platelet-thrombin micro-emboli
Thrombus
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Sites of Anti-thrombotic Drug Action
Intrinsic, ExtrinsicPathways
Plasma clottingcascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet aggregation
Conformational activation of GPIIb/IIIa
Platelet Agonists
Thromboxane A2
ADP
AT III
FactorXa
Coagulation
cascade
Coagulation
cascade
PlateletcascadePlateletcascade
BivalirudinHirudin
ArgatrobanXimelagatran
UF HeparinFondaparinux
Thrombo-lytics
EnoxaparinDX-9065a
Aspirin
TiclopidineClopidogrelPrasugrelTicagrelor
GPIIb/IIIainhibitors
The Platelet and Medications
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Oral Antiplatelet Agents
Mechanism of Action
collagenthrombin
TXA2
ADP
(FibrinogenReceptor)
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Schafer AI. Am J Med. 1996;101:199–209.
TXA2
ADP
dipyridamole
phosphodiesterase
ADP
GP IIb/IIIa Activation
COX
clopidogrel bisulfate
ticlopidine HCl
aspirin
prasugrel
Ticagrelor
Think “PPI”
∗ P – Plaque
∗ P – Platelets
∗ I - Inflammation
Angry Platelet
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∗ Predictable pharmacodynamic profile
∗ Rapid onset
∗ Rapid offset
∗ No interactions
∗ Potent anthrombotic/anti-platelet activity
∗ Low risk of bleeding
∗ Low cost
∗ Easy administration – once a day dosing
∗ Proven efficacy in improving clinical outcomes
The Perfect ADP Inhibitor
Figure 1 Mechanisms of platelet adhesion and activation
Raju NC et al. (2008) Platelet ADP-receptor antagonists for cardiovascular
disease: past, present and futureNat Clin Pract Cardiovasc Med doi:10.1038/ncpcardio1372
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Figure 2 Sites of action of platelet inhibitors
Raju NC et al. (2008) Platelet ADP-receptor antagonists for cardiovascular disease: past, present and future
Nat Clin Pract Cardiovasc Med doi:10.1038/ncpcardio1372
Figure 1. Central role of P2Y12 in platelet aggregation.
Cattaneo M Circulation 2010;121:171-179
Copyright © American Heart Association
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∗ Ticlopidine – December 1991
∗ Clopidogrel – approved for ACS February 2002
∗ Prasugrel – July 2009
∗ Ticagrelor – July 2011
ADP receptor blockersTimeline
Antiplatelet Therapy in ACS
Placebo APTC CURE TRITON-TIMI 38
Single
Antiplatelet Rx
Dual
Antiplatelet Rx
Higher
IPA
ASAASA + Clopidogrel
ASA +
Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reductionin
IschemicEvents
Increasein
Major Bleeds
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Clopidogrel Prasugrel Ticagrelor
Target Irreversible P2Y12 Irreversible P2Y12 Reversible P2Y12
Hrs to Peak Inhib 2-6 hr 2 2
CYP Metabolism 2C19 3A2B6 3A4
T 1/2 6 hours 7 – 8 hours 7 hours
ADP Inhibitors Pharmacokinetics
∗ It means the medication is inactive and needs to go throught the liver to become active
∗ Clopidogrel and Prasugrel are prodrugs
Prodrugs
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Clopidogrel Clopidogrel Prasugrel Ticagelor
RCT PCI-Cure1 Clarity TIMI 282
(COMMIT)Triton TIMI 383 PLATO4
ACS syndrome
NSTEMI STEMI NSTEMI/STEMI NSTEMI/STEMI
Dose 300 mg LD then75 mg/d vsplacebo
300 mg LD then75 mg/d vsplacebo
Pras 60 mg LD then 10 mg/d vsClop 300 mg LD then 75 mg/d
Ticag 180 mg LD then 90 mg BID vsClop 300 mg LD then 75 mg/d
n = 2,658 3,491 13,600 18,624
Endpts Death/MI, urgent revasc
Adj Odds Ratio 0.54
(95% CI 0.35-0.85)P=0.008TIMI Major RR 1.12,P = 0.64Life threatening
Bleeding: NS
Death/MI stroke AdjOdds Ratio 0.54
(95% CI 0.35-0.85)
P=0.008TIMI Major and CABG bleeding NS
CV Death/MI/StrokeHR 0.70P<0.001 TIMI Major Non CABG Bleeds HR 1.32 P=0.03
CV Death/MI/StrokeHR 0.80 (95% CI 0.70–0.91), p<0.001Non-CABGTIMI major bleeding increased vs clop p=0.025CABG Bleeding NS
Trials
1Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-412Sabatine MS, N Engl J Med 2005;352:1179-89
NEJM 357: 2001-2015, 20074N Engl J Med 2009; 361:1045-1057
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Clinical Investigations in:
Recent MI Stroke and TIA UA/Non–Q-Wave MIPCI Acute MI Peripheral BypassPAD A-fib High-Risk Primary Prevention
Clopidogrel Clinical Trials Time LineClopidogrel Clinical Trials Time Line
2002
CREDO(N=2,116)
MATCH(N=7,600)
200719981996
CAPRIE(N=19,185)
CLASSICS(N=1,020)
PCI-CURE(N=2,658)
2001
CURE(N=12,562)
CARESS(N=100)
2005 2006 2008
CHARISMA(N=15,200)
SPS3(N=2,500)
ACTIVE(N=14,000)
CASPAR(N=1,460)
COMMIT(N=40,000)
CLARITY(N=3,500)
20001994 20042003
ATCMeta-
analysis
Plavix
approval
CURE
Clopidogrel 75mg q.d. + ASA 75-325
mg q.d.* (6259 patients)
Placebo + ASA 75-325 mg q.d.*(6303 patients)
Patients withAcute Coronary
Syndrome
(unstable angina or non-ST-segment
elevation MI)
R
R = Randomization* In combination with other standard therapy
The CURE Trial Investigators. N Engl J Med.
2001;345:494-502.
Study Design
3 months ≤≤≤≤ double-blind treatment ≤≤≤≤ 12 months
Clopidogrel 300 mg
loading dose
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CURE
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14C
um
ula
tiv
e H
az
ard
Ra
te
Clopidogrel + ASA*
3 6 9
Placebo + ASA*
Months of Follow-Up
11.4%
9.3%
20% RRRP < 0.001
N = 12,562
0 12
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Primary End Point - MI/Stroke/CV Death
CURE
CV death, MI,
stroke (Primary 11.4% 9.3% 20% < 0.001end point)
MI 6.7% 5.2% 23%
Stroke 1.4% 1.2% 14%
CV death 5.5% 5.1% 7%
Relative Risk Reduction P valueOutcome
Placebo + ASA*N = 6303
Clopidogrel + ASA*N = 6259
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Main Efficacy Results - Primary Endpoint
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CURE
Placebo+ ASA*N = 6303
Clopidogrel + ASA*N = 6259
Major bleeding 2.7% 3.7%**
Life-threatening bleeding 1.8% 2.2% †
Non-life-threatening bleeding 0.9% 1.5% ‡
Minor bleeding 2.4% 5.1% §
End Point
* In combination with standard therapy
** P = 0.001; † P = NS; ‡ P = 0.002; § P < 0.001.
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Bleeding Results
CURE
PCI-CURE: Study Design
RPCI
PLACEBO+ ASA
CLOPIDOGREL+ ASA
30 d. post PCI*Follow-up (to 12 m
after rand.)
Open-label thienopyridine
Pretreatment
Open-label thienopyridine
Pretreatment N=2,658 patients undergoing PCI
N = 1345
N = 1313
CURE PCI-CURE
*1o Outcome: CV Death, MI, Urg Revasc. Mehta SR et al. Lancet 2001:358:527-33
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CURE
0.0
0.0
50.1
00.1
5
0 40 100 200 300 40010 100 200 300 400
A BDays following PCI
Cu
mu
lati
ve H
azard
Rate
RR 0.6995% CI 0.54-0.87P=0.002
Clopidogrel
Placebo
A=median time to PCIB=30 days after PCI
Overall Results: CV Death or MI
Mehta SR et al. Lancet 2001:358:527-33
High Loading Dose clopidogrel
600 mg Pre-PCIn=126
High Loading Dose clopidogrel
600 mg Pre-PCIn=126
� Primary Endpoint: Composite of death, MI, or target vessel revascularization (TVR) at 30 days
� Secondary Endpoint: Post-procedural biomarker increase > upper limit of normal (CK MB > 2 times upper limit of normal), peak CK MB, troponin I, and myoglobin post-procedure, occurrence of any vascular / hemorrhagic complication
� Primary Endpoint: Composite of death, MI, or target vessel revascularization (TVR) at 30 days
� Secondary Endpoint: Post-procedural biomarker increase > upper limit of normal (CK MB > 2 times upper limit of normal), peak CK MB, troponin I, and myoglobin post-procedure, occurrence of any vascular / hemorrhagic complication
ARMYDA-2 Trial
Presented at ACC 2005Presented at ACC 2005
Standard Loading Dose clopidogrel
300 mg Pre-PCI� n=129
Standard Loading Dose clopidogrel
300 mg Pre-PCI� n=129
255 patients with stable coronary artery disease or
non-ST-elevation ACS prior to PCI
Excluding those with Primary intervention for AMI, baseline levels CK-MB > upper normal limit,
contraindications to antithrombotic/antiplatelet therapy, high risk bleeding, CABG in past 3 mos,
or clopidogrel treatment within 10 days of randomization
23% female, mean age 64 years
13% received IIb/IIa inhibitors and 20% drug-eluting stents
255 patients with stable coronary artery disease or
non-ST-elevation ACS prior to PCI
Excluding those with Primary intervention for AMI, baseline levels CK-MB > upper normal limit,
contraindications to antithrombotic/antiplatelet therapy, high risk bleeding, CABG in past 3 mos,
or clopidogrel treatment within 10 days of randomization
23% female, mean age 64 years
13% received IIb/IIa inhibitors and 20% drug-eluting stents
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Clopidogrel ResistanceO
dd
s R
ati
oO
dd
s R
ati
o
5 µµµµmol ADP5 µµµµmol ADP
p=0.01
Circulation 2003;107:.2908-2913
Resistance = 63%
2 Hours After Stenting 24 Hours After Stenting
% o
f P
ati
en
ts
% o
f P
ati
en
ts
∆∆∆∆ Aggregation (%) ∆∆∆∆ Aggregation (%)
Resistance = 31%
Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL
300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke
2o endpoints: CV death, MI, Stroke, Rehosp-Rec IschCV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
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0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
HR 0.80
P=0.0003
HR 0.77
P=0.0001
Days
Pri
mary
En
dp
oin
t (%
)
12.1(781)
9.9 (643)
Primary Endpoint
CV Death,MI,Stroke
NNT= 46
ITT= 13,608 LTFU = 14 (0.1%)
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)
P=0.03
Prasugrel
Clopidogrel1.8
2.4
138events
35events
Balance of
Efficacy and Safety
CV Death / MI / Stroke
TIMI Major
NonCABG Bleeds
NNT = 46
NNH = 167
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Net Clinical BenefitDeath, MI, Stroke,
Major Bleed (non CABG)
0
5
10
15
0 30 60 90 180 270 360 450
Days
En
dp
oin
t (%
)
HR 0.87P=0.004
13.9
12.2
Prasugrel
ClopidogrelITT= 13,608
-23
6
-25
-20
-15
-10
-5
0
5
10
Events per 1000 pts
MIMajor Bleed
(non CABG)
+All CauseMortality
Clop 3.2%
Pras 3.0 %P=0.64
August 30, 2009
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Ticagrelor (AZD 6140):
an oral reversible P2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
OH
OH
O
OH
N
F
S
NH
NN
NN
F
• Direct acting
– Not a prodrug; does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor
– Greater inhibition of platelet aggregation than clopidogrel
• Reversibly bound
– Degree of inhibition reflects plasma concentration
– Faster offset of effect than clopidogrel
– Functional recovery of all circulating platelets
PLATO study design
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
6–12-month exposure
ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)
Ticagrelor180 mg loading dose, then90 mg bid maintenance;(additional 90 mg pre-PCI)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;randomised within 24 hours of index event (N=18,624)
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
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8,688
8,763
0 10 20 30
8
6
4
2
0
Cum
ula
tive incid
ence (
%)
Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
Cum
ula
tive incid
ence (
%)
Primary efficacy endpoint over time
(composite of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cum
ula
tive incid
ence (
%)
Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Myocardial infarction Cardiovascular death
Cum
ula
tive incid
ence (
%)
Secondary efficacy endpoints over time
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Total major bleeding
NS
NS
NS
NS
NS
0K-M
estim
ate
d r
ate
(%
per
year)
PLATO major
bleeding
1
2
3
4
5
6
7
8
9
10
12
11
13
TIMI major
bleeding
Red cell
transfusion*
PLATO life-
threatening/
fatal bleeding
Fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; *Proportion of patients (%); NS = not significant
11.611.2
7.97.7
8.9 8.9
5.8 5.8
0.3 0.3
Ticagrelor
Clopidogrel
Therapeutic
considerations• Based on 1,000 patients admitted to hospital for ACS, using ticagrelor
instead of clopidogrel for 12 months resulted in
– 14 fewer deaths
– 11 fewer myocardial infarctions
– 6–8 fewer cases with stent thrombosis
– No increase in bleedings requiring transfusion
– 9 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnea
• Treating 54 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke
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Clopidogrel Prasugrel Ticagrelor
TIMI Major 3.7% 2.4% 2.2%
Life Threatening 2.2% 1.4% Not reported alone (reported as life threatening or fatal bleeding
Fatal 0.2% 0.4% 0.3%
Bleeding ComparisonsComparison Chart of ADP receptor blockers
∗ Predictable pharmacodynamic profile
∗ Rapid onset
∗ Rapid offset
∗ No interactions
∗ Potent anthrombotic/anti-platelet activity
∗ Low risk
∗ Low cost
∗ Easy administration
The Perfect ADP Inhibitor ChecklistClopidogrel Prasugrel Ticagrelor
Predicable pharmacodynamics
No Yes Yes
Rapid onset No Yes Yes
Rapid offset No No Yes
Interactions Yes Maybe No
Potent antithrombotic
Yes Yes Yes
Cost to Hosp $5.80/75mg tab $5.36/10 mg tab $6.88/180mg tab
Low cost Yes generic May 2012
No No
Easy admin. Yes (Daily dosing)
Yes (Daily dosing)
No (twice a day dosing)
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∗Ticlopidine-
∗Clopidogrel -
∗Prasugrel -
∗Ticagrelor –
Which one(s) to add, keep or take off Formulary
∗ Based on Evidence, Efficacy, Safety, Risk and Cost
∗ Take off Ticlopidine
∗ Keep Clopidogrel (Based on evidence, guidelines and cost)
∗ Keep Prasugrel (Based on evidence, guidelines)
∗ Add Ticagrelor (Based on evidence, fast onset, fast offset for surgical patients)
Which one(s) to add, keep or take off Formulary
