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Coagulation

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Antiplatelet Therapies

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Coagulation

  1. 1. ANTIPLATELET THERAPY Alireza Kashani SET 2 Cardiothoracic Training Liverpool Hospital
  2. 2. Thrombus Formation
  3. 3. What is Tissue Factor? • A cell surface glycoprotein : • Abundantly expressed in damaged endothelial and exposed subendothelial cells and also in the atherosclerotic plaques • Also derived from circulating microparticles (MPs) released during plaque rupture • Forms a complex with and activates factor VII • VII > VIIa • X > Xa and IX > IXa • Prothrombin > Thrombin
  4. 4. Platelet Activation Self-Amplification
  5. 5. Aspirin • Acetyl-Salicylic Acid • Platelet COX Inhibition by Acetylation • COX I: • Cardiovascular Protection • Toxic Gastric Side Effects • Reduction in TXA2 • COX II: NOT INHIBITED AS MUCH • PGE2 : Inflammatory Response • At low dose permits production of PGI2 • Until the end of life of the platelets • Vascular Endothelial COX I: • Reduction in both TXA2 and PGI2 • However this enzyme can be reproduced here
  6. 6. Aspirin • GI Bleeding requiring hospitalization: • 2/1000 patients treated per year • Small Increase in haemorrhagic stroke • Bleeding is dose-dependent • Doubling as the dose is increased from less than 100 mg to less than 200 mg • Blocks platelet aggregation in response to TXA2; however, this can be overcome by other stimuli, in particular with thrombin. • Anti-inflammatory effects through blocking platelet-neutrophil interactions through higher doses.
  7. 7. Aspirin Nonresponsiveness • Present in16% of those with prior MI and is associated with 4x increase in: • DEATH • RE-INFARCTION • RE-HOSPITALIZATION Over 12 Months
  8. 8. Aspirin Nonresponsiveness • Definition: • High urinary concentration of TXA2 metabolite ≈ 2X risk of MI • Platelet function tests and presumed clinical unresponsiveness ≈ 3X lifetime risk of: • MI • Stroke • Death • Mechanism: • GP polymorphism • Platelet activation by pathways other than COX • Enhanced inflammatory activity with increased expression of COX- 2
  9. 9. Aspirin Nonresponsiveness • Detection: • Not a straight forward test • What to do? • Add-On Clopidogrel might help • Those with Aspirin resistance might be resistant to clopidogrel
  10. 10. Aspirin • Primary Prevention: • Assessing potential risk versus overall benefit (including cancer prevention) is the key • Secondary Prevention • The balance strongly favors the benefits • All patients with prior CV events • Prior MI : 25% reduction in re-MI • Stable Angina > β-blockers + Aspirin 75 mg/d : 34% reduction in MI or sudden death in comparison with placebo • UAP: 46% risk reduction • Coronary Angioplasty: 53% • Prior Stroke: 22% • Peripheral Arterial Disease : 23%
  11. 11. Aspirin • Cancer Prevention • Cardiovascular Indications: • ACS: • AMI + Fibrinolytic Therapy / Primary PCI • UAP + Conservative/Invasive Strategies • Antiinflammatory: • It is an important point to factor in the inflammatory response in the genesis of cardiovascular disease. Hence, the preventative effects of aspirin is not limited only to platelet inhibition.
  12. 12. Aspirin • Other: • Post CABG : should be started within 48h. It reduces the total mortality by 2/3 • Prevention of AF-Related Stroke: • Warfarin Contraindicated • CHADS-VASc Score of <2 : CHF, HTN, >75, DM, CVA, TIA, TE, Vascular Disease • Arteriovenous Shunts • Stroke Prevention in intra-cranial arterial stenosis : HIGH DOSE ASPIRIN (325-1300 mg/day) WAS BETTER THAN WARFARIN • Urgent Therapy in TIAs and minor strokes: • Part of the regimen : Aspirin + Clopidogrel + Statin + Anti-HTN ± Anti- Coagulation
  13. 13. Aspirin • What Dose? • 75-150 mg/d covers a wide range of conditions • NSTE ACS : 75-100 mg/d • 80 mg/d completely blocks platelet aggregation through COX • 30 mg/d to prevent TIA • This takes 2 days before it is effective • AMI : 160 mg to achieve a much faster inhibition • Side Effects: • The most serious is GIT Bleeding • The most common is GI Upset : Dyspepsia, Nausea, and Vomiting • GI Side Effects: Dose Dependent • Enteric-Coated: • Reduced Gastric Side Effects • Reduced Bio-Availability • Increased Risk of Cardiovascular Side Effects • Kidney Injury, decreased uric acid secretion, increased risk of gout: more commonly seen in elderly even with low-dose aspirin
  14. 14. Aspirin Contraindications • Absolute: • Aspirin Intolerance • Hx of GI Bleeding • PUD • Other potential source of GI or GU Bleeding • Relative: • Gout • Dyspepsia • IDA • Possibility of increased peri-operative bleeding • Note: • Hemophilia in case of strong cardiovascular indications is not an absolute contraindication.
  15. 15. Aspirin Interactions • Warfarin : Increased risk of bleeding • NSAIDS: • COX-1 inhibitors: Interfere with cardioprotective effects of aspirin • Ibuprofen, Naproxen • COX-2 inhibitors: less than above • ACE-Inh: opposing effects on haemodynamics of the kidneys. • ACE-Inh when chronically used for HF, Post MI Protection, or high-risk protection even when the aspirin was given they were still beneficial. Aspirin might reduce but can not eliminate this effect. • A good policy is to keep the aspirin at a low dose. • Phenobarbital, phenytoin, and rifampin by inducing the hepatic metabolizing enzymes reduce the efficacy of the aspirin • Effects of OHA and Insulin are enhanced by aspirin. • Combination of Thiazides and Aspirin : Increased risk of Gout
  16. 16. ADP-Mediated Antiplatelets • ADP • Released during platelet activation • Externalized • Coupled with G Proteins: • P2Y1 • Platelet shape change • GPIIb/IIIa activation initiation • P2Y12 • Perpetuates GPIIb/IIIa activation • Stabilizes the platelet aggregation • Rapid activation of intravascular TF
  17. 17. ADP-Mediated Antiplatelets • ADP Antagonism: • Inhibit platelet shape change • Inhibit platelet GPIIb/IIIa activation • Reduce activation of intravascular TF • Hence: • Reduce platelet aggregation • Destabilize the aggregated platelets • Potentially disaggregate the platelets • Anticoagulation effects • Group: • Ticlopidine • Clopidogrel • Prasugrel • Ticagrelor
  18. 18. Ticlopidine • The first of this group • Adverse reactions: • Neutropenia which occurs within the first 3 months and patients that are started on this should undergo FBC check prior to commencement and every 2 weeks up to 3 months • TTP • Liver Abnormalities • Indications: • Prevent repeat stroke or TIA in those intolerant of or resistant to Aspirin • Coronary artery stenting in combination with aspirin for up to 30 days • Due to the above ADRs it is rarely used; however, it is still available to those: • Allergic to or intolerant of Clopidogrel • Living in countries in which Clopidogrel is not readily available
  19. 19. Ticlopidine Pharmacokinetics • Nonlinear • Markedly decreased clearance on repeated dosing • To achieve maximum platelet aggregation inhibition : 4-7 days when given with aspirin • This can be expedited by oral loading • The plasma half-life during constant dosing 4-5 days • Metabolism: • Hepatic Metabolism • Renal Excretion
  20. 20. Clopidogrel • P2Y12 ADP Receptor Inhibitor • Prevention of GPIIb/IIIa receptor activation and transformation • Substantially less myelotoxic than ticlopidine • Less major GI bleeding than aspirin • The same as aspirin, the clopidogrel resistance also occurs
  21. 21. Clopidogrel • Inactive prodrug requires in vivo oxidation by hepatic or intestinal cytochrome isoenzymes: • CYP3A4 • 2C19 • Onset of action: • A single oral dose: within hours, and reaches a steady state in 3-7 days • Upstream before PCI • 600 mg : 2 hours • 300 mg : 24 – 48 hours
  22. 22. Clopidogrel • It is recommended that clopidogrel should be stopped for 5 days before CABG to avoid major bleeding. • Dose adjustment is not necessary in elderly and those with renal disease. • Side effects: • Neutropenia : 0.02% • Major bleeding without an increase in intracranial bleeding • Contraindication: • Major bleeding • Interactions: • PPIs and Statins inhibit hepatic activation of Clopidogrel esp. those which inhibit P450 Cytochrome like Omeprazole or Atorvastatin • This is not proven in vivo
  23. 23. Clopidogrel • Genetic Testing: • The CYP2C19*2 allele: • Increased rates of ischemic events and stent thrombosis after PCI • 30% of Western Europeans • 40% of Asians and Africans • Indications: • Reduction of atherosclerotic events (MI, Stroke, Vascular Death) in patients with recent stroke, recent MI, or with established arterial disease • ACS whether or not PCI (with or without stent) or CABG is performed • Dosage: • For loading 600 mg is better • How Long After PCI? • DES : at least 12 months • BMS : 1 month
  24. 24. Prasugrel • Newer thienopyridine • Irreversible and noncompetitively inhibits P2Y12 exactly the same as Clopidogrel • A prodrug Digestion Hydrolyzed By Intestinal Cells to Thiolactone Single Step Activation in the Liver by either CYP3A4 or CYP2B6
  25. 25. Prasugrel • The active metabolite’s elimination half-life: 7 hours (2-15 hours) • CYP3A Inhibitors: • Verapamil and Diltiazem • Do not alter its activity but decrease the maximum concentration by 34-46% • Its platelet aggregation inhibition is 5-9 times more potent than that of Clopidogrel • Initiation of Action : 1 hour
  26. 26. Prasugrel • TRITON-TIMI 38 Trial: • 2 arms in patients undergoing PCI: • Prasugrel: 60 mg then 10 mg/d • Clopidogrel: 300mg then 75 mg/d • Follow Up for 6-15 months • Prasugrel •  Primary endpoint of cardiovascular death, MI, and stroke from 12% to 9.9% (p<0.001) •  Stent Thrombosis from 2.4% to 1.1% (p<0.001) • 46 patients needed to be treated for 5 months to avoid one primary end point as opposed to 167 patients treated to result in one major bleeding (not CABG related)
  27. 27. Prasugrel • Indication: • Patients with ACS who are to be managed with PCI for: • Unstable Angina • NSTEMI • STEMI (either primary or delayed) • Risks: • FDA Black Box Warning: • Serious Bleeding • Occasionally TTP • If possible the bleeding should be managed without stopping prasugrel, esp. in the first few weeks after ACS • Risk factors based on TRITON 38 data analysis: • Use of GPIIb/IIIa Inhibitor even for short period of time • A history of stroke or TIA • Age 75 years or older • Female gender • Body weight < 60 kg • Femoral Access • Patients with a history of stroke or TIA or low body weight should not receive prasugrel.
  28. 28. Ticagrelor • Oral Reversibly Binding Noncompetitive P2Y12 receptor inhibitor • Half Life: 12 hours • The level of inhibition is determined by plasma ticagrelor level and to a lesser extent an active metabolite • More rapid and consistent action than clopidogrel • Quicker Offset than Prasugrel • NO HEPATIC ACTIVATION IS REQUIRED.
  29. 29. Ticagrelor • Inhibits hepatic CYP3A • Increase blood levels of drugs such as : • Amlodipine • Simvastatin • Atorvastatin • Moderate CYP3A inhibitors: • Diltiazem, Verapamil, and Amlodipine • Increase levels of Ticagrelor • Reduce the speed of offset
  30. 30. Ticagrelor • PLATO Trial: • Patient pool: • Moderate-high risk NSTE-ACS planned for either conservative or invasive management • STEMI planned for primary PCI • Randomized: • Clopidogrel: 300 mg Loading / 75 mg D (9333 patients) • Ticagrelor: 180 mg Loading / 90 mg BD (9291 patients) • Results: • Death 4.5% vs. 5.9% P < 0.001 • Primary PCI group death 9.8% vs. 11.7% P < 0.001 • General composite endpoint 9% vs. 10.7% P : 0.0025
  31. 31. Ticagrelor • Adverse Effects: • Bleeding • Dyspnea • Most frequently within the first week of Rx • Maybe transient or persistent until the Rx is ceased • It is not linked to deterioration in cardiac or pulmonary function. • Increased Frequency of Ventricular Pauses • Asymptomatic Uric Acidaemia • Mechanism of Vent. Pauses and Dyspnea remains unclear • Caution: • Advanced SA nodal dysfunction • 2nd/3rd-degree AV blocks • PLATO trial stated that Ticagrelor effects are less when combined with high-dose aspirin.
  32. 32. Cangrelor • Rapid-acting, reversible, potent, competitive inhibitor of the P2Y12 receptor • Intravenous • Onset of action (85% inhibition of AD-induced platelet aggregation) 20 minutes • CHAMPION Trial: Cangrelor use in NSTE ACS patients undergoing PCI was associated with significant reduction in early ischaemic events when compared with clopidogrel. • When Cangrelor is added to Clopidogrel: further reduction in platelet reactivity but did not alter cardiac surgery-related bleeding
  33. 33. Vorapaxar • A potent, competitive PAR-1 antagonist • In a large outcome trials (12944 patients) • Failed to improve the primary end point of a composite major cardiovascular events • Reduced the secondary endpoint of cardiovascular death, MI, or stroke (p = 0.02) • Significant increase in major bleeding including ICH (p < 0.0001) • Trial was terminated. • In another large trial with 26499 the same endpoints met but indicated those without a history of stroke have a lesser risk of ICH.
  34. 34. Atopaxar • The same group of medication • No outcome trials are available • Current Phase 2 trial on patients with NSTE ACS has failed to show any benefits.
  35. 35. Dipyridamole & Sulfinpyrazone • Dipyridamole: • Site of action is the same as prostacyclin. • It helps to reduce recurrent stroke when given with aspirin* • Sulfinpyrazone: • Site of action is similar to aspirin and it inhibits the COX pathway. • Requires multiple daily doses and is more expensive • It is a uricosuric agent and is indicated in chronic or intermittent gouty arthritis.
  36. 36. Dual Antiplatelet Therapy • Substantial data shows that adding clopidogrel to aspirin is beneficial in the setting of acute vascular injury, whether procedure-induced as in stenting, or spontaneous as in ACS, including AMI. • CHARISMA Trial: high-risk subgroups benefited from dual antiplatelet therapy. • ACS Recommends: • STEMI, NSTEMI patients with intended PCI: • 300-600 mg Loading of Clopidogrel • 75 mg/d for 1 year • OASIS-7 Trial: • 17263 patients randomized to two arms of standard and double-dose loading: • 600 mg day 1, 150 mg on days 2-7, and 75 mg/d: • Reduced cardiovascular events and stent thrombosis at 30 days when compared with standard dosing • Efficacy and safety did not differ between high-dose and low-dose aspirin • CURE Trial (12562 patients) • Clopidogrel + Aspirin : reduced the composite of combined death, MI, and stroke at 9 months by 20% (p < 0.001) • Clopidogrel increased major bleeding (3.7% vs. 2.7% P = 0.003)
  37. 37. 2011 ACC/AHA Guidelines • Preoperative: • CLASS I: • Aspirin (100 mg to 325 mg daily) should be administered to CABG patients preoperatively (Level of Evidence: B) • In patients referred for elective CABG, clopidogrel and ticagrelor should be discontinued for at least 5 days before surgery (Level of Evidence: B) and prasugrel for at least 7 days (Level of Evidence: C) to limit blood transfusions. • In patients referred for urgent CABG, clopidogrel and ticagrelor should be discontinued for at least 24 hours to reduce major bleeding complications. (Level of Evidence: B) • In patients referred for CABG, short-acting intravenous GPIIb/IIIa inhibitors (eptifibatide or tirofiban) should be discontinued for at least 2 to 4 hours before surgery and abciximab for at least 12 hours beforehand to limit blood loss and transfusions. (Level of Evidence: B) • CLASS IIb: • In patients referred for urgent CABG, it may be reasonable to perform surgery less than 5 days after clopidogrel or ticagrelor has been discontinued and less than 7 days after prasugrel has been discontinued. (Level of Evidence: C)
  38. 38. 2011 ACC/AHA Guidelines • Postoperative: • CLASS I: • If aspirin (100 mg to 325 mg daily) was not initiated preoperatively, it should be initiated within 6 hours postoperatively and then continued indefinitely to reduce the occurrence of SVG closure and adverse cardiovascular events. (Level of Evidence: A) • CLASS IIa: • For patients undergoing CABG, clopidogrel 75 mg daily is a reasonable alternative in patients who are intolerant of or allergic to aspirin. (Level of Evidence: C)

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