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platelets play an important role in cardiovascular diseases, the final event leading to ACS is a spontaneous atherosclerotic plaques which initiates a platelet response with platelet adhesion to vascular wall with activation and agregation and finally clot formation with clinical sequences od CV deaths, MI and myocardial ischemia and arrhythmias, so atiplatelet therapy is crucial in treatment of ACS, in the topic I review the traditional agents and new agents , focusing on guidelines and real world of their cinical uses .
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IN THE NAME OF ALLAH,THE MOST GRACIOUS,THE MOST MERCIFUL
Antiplatelet Therapy: There is a Gap Between Guidelines
and Implementation
By
Dr.Abdelsalam SherifMD Cardiology
Held at Intercontinantal hotel, Riyadh, KSAOn 20/10/2014
Introduction
Noncommunicable diseases:Noncommunicable diseases: Infectious diseases/ injuries:
Infectious diseases/ injuries:
Deaths by cause in the world Deaths by cause in the world
(WHO, 2008 data)
Heart disease
Cancer
Diabetes
Other chronic diseases
HIV/AIDS
Tuberculosis
Malaria
OtherInfectiousDiseases
Injuries
Total57 M
63% (36 million) of the total deaths/year
(48% of all NCDs)
Percentage breakdown of deaths from cardiovascular diseases
(United States: 2006 preliminary)
52
17
77 4 14
Coronary HeartDisease
Stroke
HF*
High BloodPressure
Diseases of theArteries
Other
The Sequence Of events leading to Clot formation
The Receptors On the Surface of Platelets
The Four Possible targets For Antiplatelet Action
The Mechanisms of Actions Of Newer Antiplatelet Agents
Antiplatelet AgentsAgents Mechanism
Aspirin Thx A2 Inhibitors
PicotamideDazoxiben
Thx Synthase Inhibitors
TiclodipineClopedogrelNewer agents( Prasugrel, Ticagrelor, Canegrelor and Elinogrel)
ADP Receptor Inhibitor( P2Y12 antagonists)
AbciximabTirofibanEptifibatide
GP IIb/ IIIa Inhibitors
VorapaxarAtopaxar
Thrombin Receptor Inhibitors( PAR1 and 4)
GP V1 antagonist ( revacept)GP1b receptor antagonistsvWF antagonists
Collagen Receptor Antagonist
Platelet Gq antagonistsPDE inhibitors
Others ( investigational)
Antiplatelet Therapy: Targets
CollagenThrombin
TXA2
ADP
(FibrinogenReceptor)
ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2
clopidogrel bisulfate
TXA2
phosphodiesterase
ADP
Gp IIb/IIIa Activation
COX
ticlopidine hydrochloride
aspirin
Gp 2b/3a Inhibitors
dipyridamole
Schafer AI. Am J Med 1996;101:199–209
Aspirin
Aspirin: Mechanism of Action
Membrane Phospholipids
Arachadonic Acid
Prostaglandin H2
COX-1
Thromboxane A2
Platelet AggregationVasoconstriction
Prostacyclin Platelet Aggregation
Vasodilation
Aspirin
ASPIRIN MEN Women
32% relative risk reductionfor MI
17% relative risk reduction for strokes
No effect on stroke or all-cause mortality
No effect on MI or all-causemortality
Aspirin (81 mg daily or 100 mg every other day) in at risk women >65 years of age
Aspirin in at risk women <65 years of age for ischemic stroke prevention
Aspirin in optimal risk women <65 years of age
Primary Prevention (Women)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
CHD=Coronary heart disease
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Aspirin Recommendations
Aspirin Recommendations
Aspirin (75-162 mg daily) in those at intermediate risk (10 year risk of CHD >10%)
Primary Prevention (Men*)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
CHD=Coronary heart disease
*Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines
Aspirin Recommendations (Continued)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Aspirin (75-162 mg daily) if known
CHD/ASVD
Aspirin (162-325 mg daily) for at least 3 months after sirolimus-eluting stent implantation and at least 6 months after paclitaxel-eluting stent implantation after which aspirin (75-162 mg daily) should be continued indefinitely
Secondary Prevention
ASVD=Atherosclerotic vascular disease, CABG=Coronary artery bypass graft, CHD=Coronary heart disease
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Aspirin Recommendations (Continued)
Aspirin (75-162 mg daily) as the initial dose after stent implantation in those at higher bleeding risk
Aspirin (100-325 mg daily) following CABG surgery*
Secondary Prevention
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
*To be administered within the first 48 hours after surgery in order to reduce the risk of saphenous vein graft failure. Doses >162 mg/day may be continued for up to one year
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Thienopyridines
Thienopyridine: Mechanism of Action
ADP / ATP
P2Y1P2X1 P2Y12
Gi2 coupled
Gq coupled
Ca2+ Ca2+ cAMP
Platelet shape change Transient
aggregation
No effect on fibrinogen receptor
Cation influxCalcium
mobilization
Fibrinogen receptor activation
Thromboxane A2
generationSustained Aggregation Response
Savi P et al. Biochem Biophys Res Commun 2001; 283:379–83 and Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000: pp.15–35
Clopidogrel or Ticlopidine
Primary End Point - MI/Stroke/CV Death ( CURE Trial)
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cu
mu
lati
ve H
azar
d R
ate
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.
0.15
0.10
0.05
0.0
0 100 200 300 400
Days of follow-up
12.6%
8.8%
31% RRRP = 0.002N = 2658
Clopidogrel+ ASA*
Placebo+ ASA*
Cu
mu
lati
ve H
azar
d R
ate
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.
Composite of cardiovascular death or MI from randomization to end of follow-up
Overall Long-Term Results( PCI-CURE)
* In combination with standard therapy† Up to 12 months
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
Conclusions( PCI-CURE)
For the composite of MI or cardiovascular death in the 2658 patients who underwent PCI in the CURE trial:
› clopidogrel plus aspirin* demonstrated a 31% relative risk reduction from randomization to the end of follow-up (P = 0.002)
› clopidogrel plus aspirin* demonstrated a 25% relative risk reduction in the composite of MI or cardiovascular death with long-term use† from PCI to end of follow-up (P = 0.04)
› clopidogrel in addition to aspirin and other standard therapy provides early beneficial effects and sustained long-term† benefit in ACS patients requiring PCI
† Up to 12 months
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
Conclusions( cont.)› Long-term† administration of clopidogrel plus
aspirin* resulted in an overall 25% relative risk reduction in MI and CV death from PCI to end of follow-up Pretreatment with clopidogrel plus aspirin*
resulted in a 30% relative risk reduction in CV death, MI and target vessel revascularization in 30 days post PCI
› There was an increase in minor bleeding, but was no significant difference in major or life-threatening bleeding between the two treatment groups
A subanalysis of patients from the CHARISMA trial found that those with prior myocardial infarction (MI) experienced a 23% relative reduction in the composite end point of cardiovascular death, MI, or stroke with dual antiplatelet therapy (clopidogrel
plus ...
ALEXANDER J H Cleveland Clinic Journal of Medicine 2009;76:S16-S23
©2009 by Cleveland Clinic
Antiplatelet Therapy On Vascular Events
Clopidogrel Evidence: Secondary PreventionClopidogrel versus Aspirin in Patients at Risk of
Ischemic Events (CAPRIE) Trial
Months Treated
Even
t R
ate
for
MI
(%)
(fata
l or
nonfa
tal)
0
1
2
3
5
3 6 9 12 15 18 21 24 27 30 33 36
Aspirin
Clopidogrel
4
P = 0.008
CAPRIE Steering Committee. Lancet 1996;348:1329-39
CVA=Cerebrovascular accident, MI=Myocardial infarction, PAD=Peripheral arterial disease
19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin (325 mg) or clopidogrel (75 mg) for 2
years
Clopidogrel provides slightly greater risk reduction
Overall 12562 9.3 11.4
Associated MI 3283 11.3 13.7No associated MI 9279 8.6 10.6
Male sex 7726 9.1 11.9Female sex 4836 9.5 10.7
£65 yr old 6354 5.4 7.6> 65 yr old 6208 13.3 15.3
ST-segment deviation 6275 11.5 14.3No ST-segment deviation 6287 7.0 8.6
Enzymes elevated at entry 3176 10.7 13.0Enzymes not elevated at entry 9386 8.8 10.9
Diabetes 2840 14.2 16.7No diabetes 9722 7.9 9.9
Low risk 4187 5.1 6.7Intermediate risk 4185 6.5 9.4High risk 4184 16.3 18.0
History of revascularization 2246 8.4 14.4No history of revascularization 10316 9.5 10.7
Revascularization after randomization 4577 11.5 13.9No revascularization after randomization 7985 8.1 10.0
Placebo + ASA*Characteristic
No. ofPatients
Clopidogrel + ASA*
Percentage of Patients with Event
Placebo BetterClopidogrel Better Relative Risk (95%
CI)
1.21.00.80.60.4
Beneficial Outcomes with Clopidogrel in Various Subgroups
Life-Threatening Bleeding
Life-Threatening 1.8 2.2
Fatal 0.2 0.2
5 g/dL drop hemoglobin 0.9 0.9
Hypotension-inotropic therapy 0.5 0.5
Surgery required 0.7 0.7
Hemorrhagic stroke0.1 0.1
4 Blood units 1.0 1.2
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.
In the CURE trial of patients with acute coronary syndromes, the risk of major bleeding increased significantly with aspirin dose (x
axis), with or without concomitant use of clopidogrel (P < .001 for trend across aspirin doses).
ALEXANDER J H Cleveland Clinic Journal of Medicine 2009;76:S16-S23©2009 by Cleveland Clinic
Thienopyridine Recommendations
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
No data to support the use of thienopyridines in primary prevention
Clopidogrel (75 mg daily) if aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI; Class IIa, Level B in those with stable angina)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Primary PreventionIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Secondary Prevention
NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI
Ticlopidine* (250 mg twice daily) for aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI)
Clopidogrel* (75 mg daily) in addition to aspirin for a minimum of 1 month (Class I, Level A) and ideally 1 year (Class I, Level B) after a NSTE-ACS
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Secondary Prevention
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Thienopyridine Recommendations (Continued)
*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 14 days (Class I, Level A) and up to 1 year (Class IIa, Level C) in those treated with fibrinolytic therapy or no reperfusion therapy after a STEMI
Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 1 month and ideally for 12 months after bare metal stent implantation and for at least 12 months after drug-eluting stent implantation in those at low bleeding risk
Secondary Prevention
STEMI=ST-segment elevation myocardial infarction
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Thienopyridine Recommendations (Continued)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Updated Guidelines
The Current StatusACTION ( Acute Coronary Treatment and Intervention Outcome Network) RegistryAim:-1. Assess Patient Characteristics, treatment
and short-short term outcomes in patients with ACS
2. Offers guidance on measuring ACS outcomes and establishing programs for implementing evidence – based guideline recommendations in clinical practice, improving the quality and safety of ACS care .
3. Investigate novel quality –improvement methods
Data Interpretation of ACTION Registry ( 2008)
• 31,036 patients with ACS from US hospitals. 1) Intervention rates :- 85% of patients with NSTEMI underwent CA, 53%
underwent PCI and 13% underwent CABG.
2) Antiplatelet therapy :- ASA used acutely (< 24 hrs) in 97% of patients
Clopidogrel used in 59 % , and GPIIb/IIIa
inhibitors were used in 44%. A full 28% of patients not used neither
Clopidogrel nor a GP IIb/IIIa inhibitors, contrary to current guidelines.
Data Interpretation of ACTION Registry(Cont.)
3) Antiplatelet therapy at discharge :- (97 % of patients were being treated with ASA and 73 % with clopidogrel
As regarding , use of clopidogrel 97 % of PCI patient used clopidogrel 53 % of medically treated patients used clopidogrel 31 % of CABG patients used clopidogrel
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