Khawar Kazmi. Thrombosis LipidsInflammation Thrombus Platelets and thrombin Quiescent Plaque Plaque...

Khawar Kazmi

Thrombosis

LipidsInflammation

Thrombus

Plateletsand thrombin

QuiescentPlaque

Plaque rupture

PATHOGENESISACUTE CORONARY SYNDROME

• Oxygen

• Pain relief

• Beta blockers

• Nitrates

Supportive Specific

ACUTE CORONARY SYNDROMEOptimal Management

It is crucial to ensure prompt recognition and rapid delivery of care

• Anti Platelets

• Anti Coagulants

Clopidogrel Early use in all cases as benefit in all risk

categories with or without revascularization*

Loading dose 300 vs. 600mg# Reloading in NSTMI prior to PCI No benefit in stable angina+

*CURE, CREDO Trials#ARMYDA-2 Trial+CHARISMA Trial


DUAL ANTI PLATLET

Clopidogrel Resistance

Resistance vs. Treatment Failure: “NONRESPONSE”

Definite entity but wide variation (4 – 30%) Variable response to ADP Genetic Variability Positive interaction with Omega 3*


*J Am Coll Cardiol. 2010


Data on PPI plus Clopidogrel show inconsistent risk of adverse outcome

Meta Analysis show no increased risk of CV events or mortality Ailment Pharmacol Ther.

2010

Clopidogrel and PPIs •Adding PPI to Clopidogrel increases re-hospitalization for MI/ stenting•Subgroup analysis reveals significant risk specifically with pantaprazole Arch Intern Med. 2010


Clopidogrel : Duration and cessation

• Halting Clopidogrel in ACS patients more than double risk of death / MI within 90 days vs. 91 – 360 days

• Tapering may help but more research needed Circ Cardiovasc Qual Outcomes. 2010

• Similar rates of cardiac death, MI regardless of stopping clopidogrel after 12 months•Trend towards higher rates of MI, Stroke, or all cause death with prolonged dual therapy•Under powered study does not provide definite answer to issue of optimal duration

N Engl J Med. 2010

PRASUGREL More effective esp. in patients with

Clopidogrel Non Response Better primary efficacy endpoint (9.9 vs. 12.1%.. Triton- TIMI 38) Increased Bleeding including life

threatening (2.4 vs. 1.8%)But mainly in patients with H/O stroke or TIA,

patients >75 years and those with body weight <60kg


Ticagrelor

Ticagrelor more effective than Clopidogrel without increasing bleeding*

Lowers CV death, MI, Stroke vs. Clopidogrel in STEMI

Antiplatelet effect of Ticagrelor kicks in more rapidly than high dose Clopidogrel**

Ticagrelor improves platelet inhibition regardless of initial Clopidogrel response***

Urgent bypass pts on prior Ticagrelor have better survival than those on Clopidogrel*

*PLATO Trial. Lancet 2010 ** The ONSET/OFFSET Study ***Respond Study. Circulation 2010


CILOSTAZOL

Triple therapy lowers platelet response on VerifyNow assay but

Results do not translate to lower ischemic events in DES patients

CILON- T trial


LMWH vs. UFH

Enoxaparin vs. Foundaparinaux

Bivalirudin vs. GPIIb/IIIa plus

Heparin

Anticoagulants


Benefit-to-Risk Ratio of Antithrombotics in UA/NSTEMI in the Last Decade: Increased Efficacy at the Price of Increased Bleeding

16-20% 12-15% 8-12% 6-10% 4-8%Death

/ M

I

Bleeding

1988ASA

1992ASA+

Heparin

1998 ASA+

Heparin+Anti-

GPIIb/IIIa

2003ASA+

LMWH +Clopidogrel +Intervention

Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS

Patients

Moscucci et al. Eur Heart J 2003;24:1815-23

GRACE Registry in 24,045 ACS patients

40

*After adjustment for comorbidities, clinical presentation and hospital therapies**p<0.001 for differences in unadjusted death rates

OR (95% CI) 1.64 (1.18 to 2.28*)

0

Overall ACS UA NSTEMI STEMI

10

20

30 **

****

**

5.1

18.6

3.0

16.1

5.3

15.3

7.0

22.8

In-h

os

pit

al d

ea

th (

%)

In hospital major bleeding Yes

No

Strong, Independent Association Between Bleeding and Death, MI and Stroke

OutcomeMajorBleed

No MajorBleed

Hazard (Adjusted)

P-Value

Death 60/470(12.8%)

833/33676(2.5%)

5.37(3.97-7.26)

<0.0001

MI46/436(10.6%)

1375/33710(4.1%)

4.44(3.16-6.24)

<0.0001

Stroke12/469

(2.6%)

187/33677

(0.6%)

6.46

(3.54-11.79)<0.0001

Eikelboom JW et al. Circulation 2006;114(8):774-82.

N = 34,126

OASIS Registry, OASIS-2, CURE

The OASIS 5 Study

N Engl J Med 2006;354:1464-76

In Patients with UA/NSTEMI

1. Fondaparinux was as effective as enoxaparin in reducing the composite of death, MI or refractory ischemia at day 9

2. Fondaparinux significantly reduced the risk of death by 17% compared with enoxaparin at day 30 and this benefit was maintained at 6 months

3. Fondaparinux was associated with a significant 48% reduction in the risk of major bleeding versus enoxaparin

4. Consistent results were observed in every subgroup examined

5. Fondaparinux consistently reduced the rate of major bleeding irrespective of renal function and baseline risk

6. The lower rate of bleeding in fondaparinux-treated patients translated into a lower mortality rate

OASIS 5 Investigators. N Engl J Med 2006;354:1464-76


Bivalirudin

• Bivalirudin alone compared to heparin and GPIIb/IIIa inhibitors resulted in comparable rates of MI and stent thrombosis, with significantly reduced rates of major bleeding and mortality(all cause and cardiac)

At 2 years•36% reduction in major bleeding and 25% reduction in reinfarction• 41% reduction in cardiac mortality and 25% reduction in all cause mortality•But the benefits were variable among the sub groups HORIZON AMI Trial

2007 AHA/ACC UA/NSTEMI Guidelines: Recommendation for Anticoagulation

Class I Recommendationsa) For patients in whom an invasive strategy is selected,

regimens with established efficacy include fondaparinux, enoxaparin, UFH or bivalirudin

b) For patients in whom a conservative strategy is selected, regimens with established efficacy include fondaparinux, enoxaparin or UFH

c) In patients in whom a conservative strategy is selected and who have an increased risk of bleeding, fondaparinux is preferable.

JACC 2007;50 (7):e1-157 LOA B for fonda and bivalirudin; A for enoxaparin or UFH

thank you

Khawar Kazmi. Thrombosis LipidsInflammation Thrombus Platelets and thrombin Quiescent Plaque Plaque...

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