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![• Platelets, "thrombocytes", are blood cells whose function (along with the
coagulation factors) is to stop bleeding.
• Platelets have no nucleus: they are fragments of cytoplasm which are derived
from the megakaryocytes[2] of the bone marrow,
• The ratio of platelets to red blood cells in a healthy adult is 1:10 to 1:20.
• The main function is to contribute to hemostasis:
1. adhesion :platelets attach to substances outside the interrupted endothelium:
2. activation, they change shape, turn on receptors and secrete chemical
messengers
3. Aggregation: they connect to each other through receptor bridges:.
• Formation of this platelet plug (primary hemostasis)
• fibrin deposition and linking (secondary hemostasis).
Overview](https://image.slidesharecdn.com/random-170404173605/75/anti-platelet-therapy-and-dual-therapy-3-2048.jpg)
![Dipyridamole [® Cardoxin forte ® Aggrenox]
1. Pharmacokinetics : Peak : 2-2.5 hr Duration of action: 6 hr Protein Bound: 99% Excretion: Feces
Dialyzable: No metab.: Liver
2. Effect can take 2-3 weeks. Short t ½ 3-4 times a day
1. Dosage : 75mg-100mg PO qhr 6 ; net dose 225mg-450mg per day
2. Side effects : >10% Chest pain (20%) Angina exacerbation, IV (19.7%) Abnormal ECG (15.9%)
Headache.
1. Contraindication : use with caution in case of other vasodialators e.g.[diprophylline , PDE5 inhibitors
,theophylline]. Category: B enters breast milk
1. In over dose :
a) aminophylline which reverses its hemodynamic effects (vasodilation)
b) 99% protein affinity dialysis is not likely to be of benefit.
• Clinical use :
1. Vasodilation in healthy and stenoted arties .
2. Dipyridamole is an indirect vasodilator increased adenosine levels
3. thus it can be used in Myocardial Perfusion SPECT.
4. Less efficient as monotherapy . In combo with aspirin [ Aggrenox ]](https://image.slidesharecdn.com/random-170404173605/75/anti-platelet-therapy-and-dual-therapy-12-2048.jpg)
![Irreversibly blocking the ADP receptor on platelets
The antithrombotic effects of clopidogrel are dose-dependent;
within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited.
Indications :
1. Prior to PCI or prior to fibrinolysis
2. After stent imblantaion
3. After CABG
4. Patients who cant tolerate aspirin
Dosage:
1. 1. Loading dose of 600mg , previous dose 300mg
2. The maintenance dose of clopidogrel is 75 mg/d, which achieves maximum platelet
inhibition.
3. “ CURRENT study “ – better prognosis with 150mg maintenance dose
4. Maintenance dose for 1 year
5. The duration effect is 7–10 days
Adverse effects
1. ticlopidine include nausea, dyspepsia, and diarrhea in up to 20% of patients,
hemorrhage in 5%, and, most seriously, leukopenia in 1% [ within first 3 months]
2. Major bleeding
Clopidogrel ® Plavix ; Ticlopidine ® Ticlid](https://image.slidesharecdn.com/random-170404173605/75/anti-platelet-therapy-and-dual-therapy-14-2048.jpg)
![Clopidogrel's use in ACS was evaluated in CURE (2001), CLARITY-TIMI
28 (2005),[1] and ARMYDA-2 (2005),[2] and remains the standard of care in ACS](https://image.slidesharecdn.com/random-170404173605/75/anti-platelet-therapy-and-dual-therapy-18-2048.jpg)
![Prasugrel ® Effient
• more rapid antiplatelet effect compared with clopidogrel owing to its faster metabolic
activation.
• prasugrel is a prodrug activated by CYP3A4, CYP2B6
• Pharmacology:
• Start within15 min after a 60-mg loading dose
• maximal plasma concentration at 30 min.
• Indications :
• like other anti platelets drugs [ ACS , prior to PCI ,STEMI,NSTEMI ]
• Gold standard drug in STEMI
• Contraindications :
A. age >75
B. weight <60kg
C. Hemorrhagic events history mainly CNS , TIA ,CVA
• Dosage:
1) loading dose of 60mg > 600mg of Plavix
2) Maintenance dose of 10mg for 9 months > 75mg of plavix](https://image.slidesharecdn.com/random-170404173605/75/anti-platelet-therapy-and-dual-therapy-20-2048.jpg)
![Ticagrelor ®(Brilinta)
• non-thienopyridine,direct selective reversible antagonist of the P2Y12 receptor.
• Brilinta> Plavix
• Pharmacology:
• No metabolic activation required
• noncompetitive allosteric antagonism
• It is rapidly absorbed in the small intestine
• plasma half-life is approximately 6–8 .
• Contraindication : unlike prasugrel [ age , weight ]
• Side effects: 10-15% dyspnea due to increased bradykinin , 1st AV block
• Interactions : increases levels of lomitapide [treatment of familial hypercholesterolemia]
• Elimination Ticagrelor is eliminated in the feces, with less than 1% found in the urine, suggesting that
renal dose adjustment is not necessary.
• Dosage:
• Twice daily due to short t1/2.
• Loading dose of 180 mg PO (two 90mg tablets)
• Maintenance dose 90 mg every 12 hr for mean 9 months
• Brilinta 180mg>Plavix 600mg – according to PLATO study](https://image.slidesharecdn.com/random-170404173605/75/anti-platelet-therapy-and-dual-therapy-23-2048.jpg)
![• PCI and high-risk ACS, DAPT treatment is recommended for 1 year irrespective of stent type.
• In NSTEMI Brilinta > Prasugrel ® Effient In STEMI Prasugrel ® Effient > Brilinta
• Brilinta > ® Effient if : age >75 , weight <60kg , [previous TIA ]***
• Combo with aspirin 75mg-81mg* is favored
• Aspirin is COX1 inhibitor - GI complications In secondary prevention – risk Vs benefit
• Plavix is favored if prasugrel or Ticagrelor aren’t tolerated .
• Prasugrel and Plavix = indirect irreversible
• Ticagrelor = direct reversible
Before surgery :
1. Plavix or Ticagrelor at least 5 days
2. Prasugrel should least 7-10 days
3. Abciximab [ ReoPro] at least 10-12hr
4. (®Tirofiban) Aggrastat- (® Eptifabetite) Integrilin at least 4hr](https://image.slidesharecdn.com/random-170404173605/75/anti-platelet-therapy-and-dual-therapy-34-2048.jpg)
Uploaded bySackler's faculty of medicine . Tel-Aviv.Uni
anti platelet therapy and dual-therapy
This document provides an overview of antiplatelet agents, detailing their mechanisms, pharmacokinetics, indications, dosages, side effects, contraindications, and expert consensus on their use in various clinical settings. It highlights the roles of different drugs like aspirin, clopidogrel, prasugrel, and ticagrelor in managing conditions such as ischemic stroke and acute coronary syndromes, as well as recommendations for primary and secondary prevention. Additionally, it emphasizes the importance of tailored treatment based on patient-specific factors.
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anti platelet therapy and dual-therapy
- 1. מחאג'ד פנימית מוחמדנה'השומר תל
- 2. • Overview • indications •Available drugs • Special usage • Side effect • Contraindications • Drug interactions Anti platelets
- 3. • Platelets, "thrombocytes",are blood cells whose function (along with the coagulation factors) is to stop bleeding. • Platelets have no nucleus: they are fragments of cytoplasm which are derived from the megakaryocytes[2] of the bone marrow, • The ratio of platelets to red blood cells in a healthy adult is 1:10 to 1:20. • The main function is to contribute to hemostasis: 1. adhesion :platelets attach to substances outside the interrupted endothelium: 2. activation, they change shape, turn on receptors and secrete chemical messengers 3. Aggregation: they connect to each other through receptor bridges:. • Formation of this platelet plug (primary hemostasis) • fibrin deposition and linking (secondary hemostasis). Overview
- 4. White clot vsred clot
- 6. Thromboxane A2 inhibitors •Amplifies the initial signal of the platelets activation • Produced from the arachidonic acid by COX enzymes • Platelets express only COX 1 . • Aspirin and non selective COX inhibitors are preferred • causes platelets to change shape, release their granules, and aggregate • interfere with platelet aggregation in vitro prolong the bleeding time in vivo.
- 7. Cardiopirin ® ,Cartia ® , Micropirin ®, Tevapirin®
- 8. aspirin • aspirin inhibitsthe synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase. Indications : Ischemic Stroke, Angina Pectoris , Thromboembolic Stroke (CABG): (PTCA): For carotid endarterectomy, Kawasaki vasculitis prophylaxis ;secondary prevention Dosage: 1. The FDA has approved the use of 325 mg/d for primary prophylaxis of myocardial infarction. 1. Maintenance and secondary prevention - 75-100 mg daily. Side effects: mainly gastrointestinal side effects • Large doses of salicylate, a metabolite of aspirin, cause temporary tinnitus • Reye's syndrome, a rare but severe illness ‘acute encephalopathy and fatty liver, can occur when children or adolescents are given aspirin for a fever or other illnesses or infections • FDA recommends ,should not be given to under the age of 12
- 9. Contraindications • people whoare allergic to ibuprofen or naproxen,or who have salicylate intolerance • caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. • peptic ulcers, or gastritis ,stomach • Patients with hemophilia or other bleeding tendencies • Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency, particularly in large doses and depending on the severity of the disease. • People with kidney disease, hyperuricemia, or gout should not take aspirin because it inhibits the kidneys' ability to excrete uric acid.
- 10. Primary prevention Vssecondary prevention ESC Expert Consensus Document Expert Consensus Document on the Use of Antiplatelet Agents European Heart Journal (2004) 25, 166–181
- 11. cAMP and cGMPtargeted drugs Mechanism of Action • Non-nitrate coronary vasodilator in high doses over short time therapy • Inhibition adenosine uptake inhibiting platelet reactivity • Phosphodiesterase inhibition increased cAMP in platelet reduced aggregation • Inhibition of Thromboxane A2 formation
- 12. Dipyridamole [® Cardoxinforte ® Aggrenox] 1. Pharmacokinetics : Peak : 2-2.5 hr Duration of action: 6 hr Protein Bound: 99% Excretion: Feces Dialyzable: No metab.: Liver 2. Effect can take 2-3 weeks. Short t ½ 3-4 times a day 1. Dosage : 75mg-100mg PO qhr 6 ; net dose 225mg-450mg per day 2. Side effects : >10% Chest pain (20%) Angina exacerbation, IV (19.7%) Abnormal ECG (15.9%) Headache. 1. Contraindication : use with caution in case of other vasodialators e.g.[diprophylline , PDE5 inhibitors ,theophylline]. Category: B enters breast milk 1. In over dose : a) aminophylline which reverses its hemodynamic effects (vasodilation) b) 99% protein affinity dialysis is not likely to be of benefit. • Clinical use : 1. Vasodilation in healthy and stenoted arties . 2. Dipyridamole is an indirect vasodilator increased adenosine levels 3. thus it can be used in Myocardial Perfusion SPECT. 4. Less efficient as monotherapy . In combo with aspirin [ Aggrenox ]
- 13. ADP receptor antagonists Thienopyridine •ADP is stored in dense bodies inside blood platelets and is released upon platelet activation. • ADP receptors found on platelets (P2Y1, P2Y12, and P2X1), which leads to platelet activation. 1. P2Y1 :initiate platelet aggregation and shape change 2. P2Y12 :amplify the response to ADP
- 14. Irreversibly blocking theADP receptor on platelets The antithrombotic effects of clopidogrel are dose-dependent; within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. Indications : 1. Prior to PCI or prior to fibrinolysis 2. After stent imblantaion 3. After CABG 4. Patients who cant tolerate aspirin Dosage: 1. 1. Loading dose of 600mg , previous dose 300mg 2. The maintenance dose of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. 3. “ CURRENT study “ – better prognosis with 150mg maintenance dose 4. Maintenance dose for 1 year 5. The duration effect is 7–10 days Adverse effects 1. ticlopidine include nausea, dyspepsia, and diarrhea in up to 20% of patients, hemorrhage in 5%, and, most seriously, leukopenia in 1% [ within first 3 months] 2. Major bleeding Clopidogrel ® Plavix ; Ticlopidine ® Ticlid
- 18. Clopidogrel's use inACS was evaluated in CURE (2001), CLARITY-TIMI 28 (2005),[1] and ARMYDA-2 (2005),[2] and remains the standard of care in ACS
- 19. INTERPRETATION: • In patientsundergoing PCI for acute coronary syndromes, a 7-day double- dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. • Efficacy and safety did not differ between high-dose and low-dose aspirin. • A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI
- 20. Prasugrel ® Effient •more rapid antiplatelet effect compared with clopidogrel owing to its faster metabolic activation. • prasugrel is a prodrug activated by CYP3A4, CYP2B6 • Pharmacology: • Start within15 min after a 60-mg loading dose • maximal plasma concentration at 30 min. • Indications : • like other anti platelets drugs [ ACS , prior to PCI ,STEMI,NSTEMI ] • Gold standard drug in STEMI • Contraindications : A. age >75 B. weight <60kg C. Hemorrhagic events history mainly CNS , TIA ,CVA • Dosage: 1) loading dose of 60mg > 600mg of Plavix 2) Maintenance dose of 10mg for 9 months > 75mg of plavix
- 21.
- 22. • Safety :Significant increase in serious bleeding (32% increase) • In ischemia guided strategy prasugrel has no superiority • As first line therapy prior to PCI prasugrel < clopidogrel. • Patients with stents prasugrel > clopidogrel
- 23. Ticagrelor ®(Brilinta) • non-thienopyridine,directselective reversible antagonist of the P2Y12 receptor. • Brilinta> Plavix • Pharmacology: • No metabolic activation required • noncompetitive allosteric antagonism • It is rapidly absorbed in the small intestine • plasma half-life is approximately 6–8 . • Contraindication : unlike prasugrel [ age , weight ] • Side effects: 10-15% dyspnea due to increased bradykinin , 1st AV block • Interactions : increases levels of lomitapide [treatment of familial hypercholesterolemia] • Elimination Ticagrelor is eliminated in the feces, with less than 1% found in the urine, suggesting that renal dose adjustment is not necessary. • Dosage: • Twice daily due to short t1/2. • Loading dose of 180 mg PO (two 90mg tablets) • Maintenance dose 90 mg every 12 hr for mean 9 months • Brilinta 180mg>Plavix 600mg – according to PLATO study
- 24. PLATO n-=18,000 Compared to clopidogrel,ticagrelor significantly reduced the rate of CV death, MI, or stroke without an increase in the rate of overall major bleeding
- 26. glycoprotein 2b3a receptorantagonist
- 27. Abciximab ®ReoPro • Chimericmonoclonal antibody; prevents binding of fibrinogen, vWF to glycoprotein IIb/IIIa receptor sites on platelets Pharmacokinetics • Half-life: 30 min Onset: 10 min Peak time: ~30 min (platelet inhibition) • Duration: 72 hr Platelet binding: Remains bound for 15 days Indications :Adjunct to PCI A. Prevention of cardiac ischemic complications in patients undergoing PCI B. Indicated for prevention of cardiac complications in patients with unstable angina with PCI planned within 24 hr dosage • 0.25 mg/kg IV bolus over at least 1 min, 10-60 min before start of PCI, THEN • 0.125 mcg/kg/min IV continuous infusion for 12 hr; • > infusion rate of 10 mcg/min Adverse Effects >10% Bleeding, minor (70-82%) Bleeding, major (17-21%) Hypotension (14-21%) Contraindications Active major bleeding, thrombocytopenia, CVA (within 2 years) Peptic ulcer ;Recent surgery; trauma, increased bleeding with Oral anticoagulant use within 7 days
- 28. abciximab is notbeneficial as first-line medical treatment in patients admitted with ACS
- 29. (®Tirofiban) Aggrastat- (®Eptifabetite) Integrilin Small molecules that Blocks binding of fibrinogen and vWb factor to IIb/IIIa receptors Favored above ReoPro , cheaper , safer , shorter t1/2 Indications : • to reduce the rate of thrombotic cardiovascular in patients with(NSTE-ACS) • Prior/during PCI Pharmacology : Half-life: 2 hr ; Duration: 4 hr Excretion: Urine (65%); feces (25%) Dialyzable: Yes Adverse Effects >10% Bleeding, minor (11%) Contraindications : bleeding ; thrombocytopenia ;trauma ; renal impairment ClCr<30 ESC Expert Consensus Document Expert Consensus Document on the Use of Antiplatelet Agents European Heart Journal (2004) 25, 166–181
- 33. Quick summary 1. Recommendationand guidelines 2. STEMI VS NSTEMI 3. PRIMARY prevention 4. Secondary prevention 5. CONTRAINDICATIONS Canadian Journal of Cardiology 29 (2013) 1334e1345 European Heart Journal (2014) 35, 2383–2431 doi:10.1093/eurheartj/ehu282 November 2013 NICE clinical guideline 94 guidance.nice.org.uk/cg94
- 34. • PCI andhigh-risk ACS, DAPT treatment is recommended for 1 year irrespective of stent type. • In NSTEMI Brilinta > Prasugrel ® Effient In STEMI Prasugrel ® Effient > Brilinta • Brilinta > ® Effient if : age >75 , weight <60kg , [previous TIA ]*** • Combo with aspirin 75mg-81mg* is favored • Aspirin is COX1 inhibitor - GI complications In secondary prevention – risk Vs benefit • Plavix is favored if prasugrel or Ticagrelor aren’t tolerated . • Prasugrel and Plavix = indirect irreversible • Ticagrelor = direct reversible Before surgery : 1. Plavix or Ticagrelor at least 5 days 2. Prasugrel should least 7-10 days 3. Abciximab [ ReoPro] at least 10-12hr 4. (®Tirofiban) Aggrastat- (® Eptifabetite) Integrilin at least 4hr
- 35. NSTEMI • Ticagrelor 90mg X2 day > clopidogrel 75 mg daily for 12yr in patients with moderate to high risk as defined in PLATOstudy http://www.nejm.org/doi/full/10.1056/NEJMoa0904327 • prasugrel 10 mg daily > clopidogrel 75mg daily for 12 months in patients with NSTEMI after PCI (Strong Recommendation, High-Quality Evidence). • We recommend avoiding prasugrel in patients with previous TIA or stroke or in patients who are not treated with PCI • Patients in whom clopidogrel is to be used, a higher maintenance dose of 150 mg daily be considered for the first 6 days in patients with NSTEMI treated with PCI • Ticagrelor > prasugrel in PCI, CABG, or medical therapy alone, • whereas prasugrel should be used only in patients undergoing PCI. • In patients 75 years of age or older or weight 60 kg, when available, prasugrel 5 mg daily could be considered.
- 36. STEMI • prasugrel 10mg daily or Ticagrelor 90 mg X 2 day for 12 months in combo with 75 mg aspirin after primary PCI Not tolerable clopidogrel 75 mg daily day for 12 months maintenance dose of 150 mg daily for the first 6 days is favored
- 38.