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
7. 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
8. 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.
9. Aspirin Nonresponsiveness
• Present in16% of those with prior MI and is associated
with 4x increase in:
• DEATH
• RE-INFARCTION
• RE-HOSPITALIZATION
Over 12 Months
10. 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
11. 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
12. 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%
13. 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.
14. 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
15. 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
16. 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.
17. 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
18. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
28. 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
29. 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)
30. 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.
31. 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.
32. 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
33. 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
34. 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.
35. 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
36. 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.
37. 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.
38. 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.
39. 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)
40. 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)
41. 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)
Editor's Notes
Exposure of Subendothelial Tissue Factor to Circulating Blood
Tissue factor activation of coagulation factors to produce Thrombin and converting Fibrinogen to Fibrin
Platelet Adhesion, Activation, and Aggregation as a result of:
Direct platelet exposure to subendothelial factors (collagen, VWF, etc.)
Thrombin effect on the platelets and also produced fibrin stabilizing the cross-linkage between platelets
Fibrin Cross-Linkage
Different platelet inhibitors act at different sites and on different mechanisms, ultimately to inhibit the calcium-dependent pathways of platelet activation. Note the self- amplification platelet activation cycle on the right side of the figure, initiated by platelet membrane damage that “exposes” and alters membrane configuration, and activates crucial receptors (thrombin, thromboxane A2 [TXA2], glycoprotein (Gp) IIb/IIIa, and others). AC, Adenyl cyclase; ADP, adenosine diphosphate; Ca2, calcium; ER, endoplasmic reticulum; Gi, G protein, inhibitory form; Gs, G protein, stimulatory form; PAR, protease-activated receptors; PLC, phospholipase c; Rho, Rho kinase; vWF, von Willebrand factor.
Juul-Möller S, et al. For the Swedish Angina Pectoris Aspirin Trial (SAPAT) Group. Double- blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet 1992;340:1421–1425.
The largest study on aspirin and bleeding comes from the Italian National Health System on new users of low-dose aspirin (#300 mg) from 2003 to 2008.33 The study authors selected 186,425 patient’s using propensity-score matching and compared them with an equal number not currently taking low-dose aspirin. During a median follow-up of 5.7 years, there were 1.6 million person-years of observation. For those currently taking aspirin, the rate of total hemorrhagic events per 1000 person-years was 5.58,whereas the rate was 3.60 per 1000 person-years in those not taking aspirin, with an incidence rate ratio (IRR) of 1.55 (confidence interval [CI], 1.48-1.63). The excess aspirin-induced bleeding was similar in numbers to the expected aspirin-induced reduction of major cardiovascular events for those with a 10-year risk of between 10% and 20%. Of note, an increased intake of proton pump inhibitors (PPIs) was associated with reduced major bleeding.A major problem with this study is that “low dose” could be 300 mg daily, much higher than our recommendation
Ticlopidine : The first of this group, a lot of adverse reactions. Neutropenia which occurs within the first 3 months, TTP, Liver Abnormalities. Prior to commencement the patient should have FBC
In a prospective trial,in a secondary analysis double-dose clopidogrel (a loading dose of 600 mg and then150 mg for 7 days) was superior to standard-dose prior (a loading dose of 300 mg and then 75 mg/day) for PCI for ACS at 30 days.
Nonetheless, higher doses of clopidogrel (600 mg) and atorvastatin (40-80 mg as currently used) may interact, as is being tested in the prospective SPICE trial.
The FDA states that prasugrel’s greater treatment effect and greater bleeding rate in TRITON might in part be explained by the decreased conversion of clopidogrel to active metabolites in approxi- mately 30% of white patients, and also because the concurrent use of PPIs in an unspecified number of the subjects in the trial might have led to a genetically based interaction that also decreased clopidogrel’s effective activity. Another factor is that clopidogrel was intentionally given at the same time as prasugrel in TRITON, whereas ideally it should have been given earlier for an optimal effect