11. Fibrinolytics, antiplatelets, anticoagulants Flashcards
Agents used to prevent & treat thrombosis
Platelet inhibitors - Prevent the effects of arterial thrombogenesis (ACS, TIA)
Anticoagulants limit thrombus formation & prevent thromboembolism (AF, ACS)
Fibrinolytics dissolve the clot in acute arterial thrombosis & occlusion (STEMI)
Thrombotic response
- Atherosclerotic plaques are thrombogenic
- Thrombosis is triggered by plaque rupture &/or erosion
- Allows blood constituents to contact pro-thrombotic factors
- Platelet activation leads to platelet aggregation
- Simultaneously, coagulation cascade is triggered
Antiplatelet therapy - Aspirin
- Inactivates COX-1 activity
- Platelet is inactivated for 8-10 days
- Vascular endothelium can produce prostaglandins within hours
- Clinically the effect of aspirin is antithrombotic
Clinical use of Aspirin in CVD
Primary prevention of CVD:
- Reduces risk of ischaemic events but with a higher risk of bleeding
- Current evidence does not support routine use of aspirin in healthy individuals
Secondary prevention of CVD:
- Reduces risk of adverse cardiovascular events - absolute benefit outweighs risk or major-extra-cranial bleeding
- Consider 100 mg OD in patients with prior MI or revascularisation
Aspirin for cardiovascular indications
- Acute coronary syndrome
- Coronary artery bypass graft (CABG) surgery
- Transient ischaemic attack (TIA)
- Arteriovenous shunts
- Stroke prevention
P2Y12 blockers: Clopidogrel/Ticagrelor
- Selectively bind to P2Y12 - ADP receptors on platelets
- This binding inhibits ADP-induced activation of the platelet GP IIb/IIIa-receptor & prevents platelet aggregation
Indications for P2Y12 use - Secondary prevention of CVD
Clopidogrel 75 mg OD is recommended:
- Alternative to aspirin if intolerant
- Provides slightly greater CVD risk reduction than aspirin
Ticagrelor:
- More rapid & consistent onset of action than clopidogrel
- Prevention of thrombotic events in patients with ACS
- Reduces ischaemic events with no higher rate of overall bleeding
Dual Antiplatelet therapy (DAPT)
DAPT: Aspirin + P2Y12 inhibitor
- Reduces major adverse cardiovascular events (MACE) in the year after an ACS event compared with aspirin alone
- DAPT incorporating ticagrelor reduces MACE compared with clopidogrel
- Used for 1 year
GP IIb/IIIa blockers
Selectively binds to platelet glycoprotein IIb/IIIa receptors preventing them from interacting with fibrinogen, vWF, reversibly blocking platelet aggregation & thrombosis formation
- Reduce the incidence of cardiac events when used in the setting of PCI
- Given in conjunction with aspirin + heparin + P2Y12 inhibitor
Anticoagulant therapy
Prevent thromboembolism:
- Limit & prevent thrombus formation
- Do not dissolve clots
- Coagulation cascade more important than platelet activation in development of cardioembolism
- AF & cardioembolic stroke risk - disruption of laminar flow & local inflammation
Anticoagulants: Warfarin
- Warfarin antagonises carboxylation of clotting proteins
- Dose as per target INR - narrow therapeutic index
- Onset of action delayed by 2-7 days
- Medication & food interactions
Non-vitamin K antagonist oral anticoagulants (NOACs)
- Provide more convenient therapeutic options
- Have demonstrated at least equivalent efficacy in comparison to warfarin, in large phase III clinical trials
- E.g. Dabigatran, Rivaroxaban, Apixaban
Oral Anticoagulants (OAC) in thromboembolism prevention
Atrial fibrillation (AF):
- OAC is strongly recommended based on CHA2DS2-VASc score:
+ ≥ 2 (men) or ≥ 3 (women) (I, A)
+ In those with a CHA2DS2-VASc score of 1 (men) or 2 (women), consider long-term OAC (IIa, B)
- Where possible, a NOAC is preferred over a VKA (I, A)
- Mechanical prosthetic valves (VKA)
+ Target INR = 2.0 – 3.5 - Venous thromboembolism (DVT/PE)
Choosing between VKAs & NOACs
NOACs offer superior stroke protection
- Except in situations with no robust data such as moderate/severe mitral stenosis, metallic valves prosthesis, very poor renal function or poor compliance
Where possible, a NOAC is preferred over a VKA
Dabigatran therapy considerations
Risk factors for bleeding include patients:
- Being aged ≥ 75 years
- Moderate renal impairment (creatinine clearance [CrCl] 30-50 mL/min)
- With medication or condition(s) that increase the risk of bleeding
- Should not be used in patients with CrCl < 30 mL/min
- Compared to warfarin-lower risk of ischaemic stroke & intracranial bleeding
NOACs - summary
- Offer better efficacy, safety & convenience compared with warfarin (VKA)
- Should be considered instead of warfarin in most patients (AF, DVT/PE)
- Insufficient evidence to recommend in mechanical heart valves
- Advantages over warfarin – no monitoring required, no interactions with food or most medications
Parenteral anticoagulants - Unfractioned heparin
- UFH simultaneously binds to antithrombin & thrombin (factor IIa)
- Heparin-antithrombin complex also inhibits factor Xa
- Parenteral administration (IV, SC)
- Dose-effect difficult to predict
- Dose adjusted to activated Partial Thromboplastin Time (aPTT) or Activated Clotting Time (ACT)
- Bleeding reversed by protamine
- Complication is HIT/HITT
+ Stop & use bivalirudin (PCI for ACS) or fondaparinux (CI in PCI unless heparin bolus)
+ Regular platelet monitoring required
Parenteral anticoagulants: Low Molecular Weight Heparins (LMWH)
- 1/3 of the weight of UFH
- Bind to antithrombin to inhibit factor Xa & some of thrombin (factor IIa)
- The binding ratio factor Xa:IIa is 3-4:1
- Mostly given subcutaneously in a fixed dose
- HIT less likely (≥ 5 days; < 1%)
- Prevention & treatment of systemic thrombosis
Parenteral anticoagulants: Bivalirudin
- Direct thrombin (factor IIa) inhibitor
- Inhibits conversion of fibrinogen to fibrin
- Inactivates fibrin-bound & free thrombin
- Monitored with coagulation tests – aPTT & ACT
- Trials – ACS with planned PCI
+ Similar outcomes to combination of UFH & GP IIb/IIIa, but less bleeding - Patients with HITT who are undergoing PCI should have bivalirudin
Parenteral anticoagulants: Fondaparinux
- Selective factor Xa inhibitor
- Specific anti-Xa activity 7 times higher than LMWH
- OASIS-5 trial – fondaparinux is superior to enoxaparin in NSTE-ACS
- Risk of catheter thrombosis (lack of anti-IIa activity) in PCI – use of bolus UFH injection
- Difficult to monitor (no aPTT or ACT) (anti-Xa assay)
- Advantage – OD dosing
Fibrinolytic therapy
Plasminogen activator system binds to the clot surface & breaks down the clot
Rapid therapeutic effect achieved with:
- Tissue plasminogen activator (tPA)
- Tenecteplase (TNK)
- Reteplase (rPA)
Alteplase (tPA)
Clot specific – binds to fibrin in the clot & converts plasminogen to plasmin
Indications:
- STE-ACS (with aspirin, clopidogrel, UFH)
- Treatment of acute ischaemic stroke
- Treatment of pulmonary embolism
- Used as an IV infusion
Tenecteplase
- Increased fibrin specificity
- ASSENT-2 trial (in STE-ACS), single bolus dose TNK vs tPA regimen
- Same stroke rate & mortality at 30 days
- Less major bleeding
- Preferred to tPA
- Unapproved in NZ
