Khawar Kazmi

Thrombosis LipidsInflammation Thrombus Platelets and thrombin Quiescent Plaque Plaque rupture PATHOGENESIS ACUTE CORONARY SYNDROME

Oxygen Pain relief Beta blockers Nitrates Supportive Specific ACUTE CORONARY SYNDROME Optimal 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 ACUTE CORONARY SYNDROME Optimal Management 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* ACUTE CORONARY SYNDROME Optimal Management *J Am Coll Cardiol. 2010

ACUTE CORONARY SYNDROME Optimal Management  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 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

ACUTE CORONARY SYNDROME Optimal Management 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 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 ACUTE CORONARY SYNDROME Optimal Management

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 ACUTE CORONARY SYNDROME Optimal Management

CILOSTAZOL  Triple therapy lowers platelet response on VerifyNow assay but  Results do not translate to lower ischemic events in DES patients CILON- T trial ACUTE CORONARY SYNDROME Optimal Management

 LMWH vs. UFH  Enoxaparin vs. Foundaparinaux  Bivalirudin vs. GPIIb/IIIa plus Heparin Anticoagulants ACUTE CORONARY SYNDROME Optimal Management

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 / MI Bleeding 1988 ASA 1992 ASA+ Heparin 1998 ASA+ Heparin+ Anti- GPIIb/IIIa 2003 ASA+ 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: 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 NSTEMISTEMI ** In-hospital death (%) In hospital major bleeding Yes No

Strong, Independent Association Between Bleeding and Death, MI and Stroke Outcome Major Bleed No Major Bleed Hazard (Adjusted) P- Value Death 60/470 (12.8%) 833/33676 (2.5%) 5.37 ( ) < MI 46/436 (10.6%) 1375/33710 (4.1%) 4.44 ( ) < Stroke 12/469 (2.6%) 187/33677 (0.6%) 6.46 ( ) < Eikelboom JW et al. Circulation 2006;114(8): N = 34,126 OASIS Registry, OASIS-2, CURE

The OASIS 5 Study N Engl J Med 2006;354:

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:

ACUTE CORONARY SYNDROME Optimal Management 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 Recommendations a)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

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