antiplatelet therapy there is a gap between guidelines and implementation

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



Aspirin Recommendations

Aspirin Recommendations

Aspirin (75-162 mg daily) in those at intermediate risk (10 year risk of CHD >10%)

Primary Prevention (Men*)


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)


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


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*



*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


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

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azar

d R

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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


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

(%)


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


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)



Primary PreventionIII 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

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




NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI


Thienopyridine Recommendations (Continued)

*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile


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


STEMI=ST-segment elevation myocardial infarction


Thienopyridine Recommendations (Continued)



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

Thanks

antiplatelet therapy there is a gap between guidelines and implementation

Health & Medicine

composite of mi

associated mi

relative riskreduction

clopidogrel evidence

risk women

relative reduction

priormyocardial infarction

cv death