reviewed by Dr. Pascal Vranckx, August 2021
Platelets play an essential role in the pathogenesis of atherothrombotic events, justifying the use of antiplatelet agents in their prevention [1]. The use of antiplatelet agents, especially in secondary prevention of recurrent cardiovascular events is supported by several studies that evaluated their efficacy and safety [2-6]. In primary prevention, the potential benefit of the preventive use of Acetylsalicylic acid (ASA) should be carefully assessed and individualized [7-9]. Advances in understanding the mechanisms by which platelets participate in atherothrombotic processes have led to the search for the development of new drugs capable of consistently inhibiting platelet activity with maximum safety (figure 1).
Different platelet receptors are activated by various agonists and serve as the target of various antiplatelets, which have been evaluated in large randomized clinical trials. AA: arachidonic acid; ADP, adenosine diphosphate; CYP, cytochrome P450; GP indicates glycoprotein; TP, thromboxane receptor; and TxA2, thromboxane A2.
Acetylsalicylic acid (ASA)
The beneficial effects of ASA appear to occur at a dose of a minimum of 75 mg daily, with no additional benefit provided using higher doses. Bleeding events are increased by aspirin and seem to be higher at doses of >100 mg. Bleeding events with ASA are more commonly of gastric origin, and occur at a frequency of ≈2% per year. Biochemical ASA resistance is rare in patients who are actually taking and absorbing the agent, and routine testing is not indicated [10]. In patients reacting allergic to ASA (usually with an exanthema), a sensitisation strategy might help to get rid of symptoms within a few days [11].
P2Y12-inhibitors
Given the synergistic importance of the adenosine diphosphate (ADP)-P2Y12 and the human thromboxane (TxA2-TP) pathways in amplifying platelet activation, dual antiplatelet therapy with a P2Y12 inhibitor in combination with aspirin is the most widely used strategy in high-risk patients. The currently available oral P2Y12 receptor blockers are the peroral thienopyridines (clopidogrel, and prasugrel) and ticagrelor.
Thienopyridines are orally administered prodrugs that require metabolic activation by the cytochrome P450 pathway. The active thiolactone metabolite of thienopyridines irreversibly prevents the ADP-induced receptor-mediated signalling and platelet aggregation ‘for the life of platelets” by binding to the ADP receptor P2Y12. Ticagrelor does not prevent ADP binding to P2Y12, but instead reversibly inhibits the ADP-induced receptor conformational change and G-protein activation by binding to a site distinct from the ADP-binding site. Ticagrelor is associated with a more rapid onset of action, a greater level of inhibition and a more rapid offset of pharmacodynamic action compared with clopidogrel.
Vorapaxar
Vorapaxar, a synthetic tricyclic 3-phenylpyridine derived from the natural product himbacine, is a first in class, selective, reversibly binding, orally administered, high-affinity protease-activated receptor-1 antagonist that selectively inhibits thrombin-induced platelet aggregation Its antiplatelet effect is virtually irreversible due to a very slow dissociation constant [12].
| Indication | Dose | Dose Adjustment | Comments | |
|---|---|---|---|---|
| acetylsalicylic acid | Primary and secondary atherothrombotic prevention | LD (if ACS): 150-300 mg oralMD: 75-100 mg once daily | Major contraindications: Gastrointestinal bleeding – active peptic ulcer | |
| clopidogrel | ACS + PCI or medical management only (patients who cannot receive ticagrelor or prasugrel) and in ACS patients at high bleeding risk (e.g. patients who require oral anticoagulation) | LD: 300-600mg oralMD: 75mg oral once daily | ||
| STEMI + fibrinolysis <75 years of age | LD: 300-600 mg oral MD: 75mg oral once daily |
Prasugrel or ticagrelor have not been studied as adjuncts to fibrinolysis | ||
| STEMI + fibrinolysis ≥75 years of age | LD: 75 mg oral MD: 75 mg oral once daily |
|||
| Secondary prevention > 12 months post coronary stenting | MD: 75 mg oral once daily | |||
| prasugrel | ACS with planned PCI | LD: 60 mg oral MD: 10 mg oral once daily |
MD: 5 mg once daily If weight <60 kg |
Major contraindications: Previous stroke and TIA. Prasugrel is generally not recommended in elderly, and if positive risk/benefit 5mg is recommended |
| ticagrelor | ACS (all patients at moderate-to-high risk of ischaemic events) | LD: 180 mg oral MD: 90 mg oral BID |
Major contraindications: Previous intracerebral haemorrhage |
|
| Secondary prevention 1-3 years post Myocardial infarction | MD: 60 mg oral twice daily | |||
| vorapaxar | Co-administered with aspirin and, where appropriate, clopidogrel, in patients with a history of myocardial infarction or peripheral artery disease | 2.08 mg oral once daily | Initiated at least two weeks after a myocardial infarction and ideally within the first 12 months. Major contraindications: Active pathologic bleeding, increased bleeding risk, history of stroke/TIA, severe hepatic dysfunction. |
LD denotes loading dose; ACS, acute coronary syndromes; MD: maintenance dose; PCI, percutaneous coronary prevention; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischaemic attack.
Adapted from the ACVC Clinical Decision-Making Toolkit chapter 8.
Bleeding avoidance strategy
Gastrointestinal haemorrhage is the most common serious bleeding complication that results from a long-term antiplatelet therapy. The use of a proton pump inhibitor (PPI) is recommended in combination with dual antiplatelet therapy [13-16].
Switching between antiplatelet drugs
When a switch between P2Y12 inhibitors is needed for clinical reasons (i.e. side effects or drug intolerance), switching algorithms based on pharmacodynamics studies should be considered.
Oral anti-platelet therapy, coronary stents and non-cardiac surgery
Management of patients on DAPT who have undergone recent coronary stent treatment and who are referred for surgical procedures involves consideration of: (1) the risk of stent thrombosis (particularly if DAPT needs to be interrupted); (2) the consequences of delaying the surgical procedure; and (3) the increased intra- and peri-procedural bleeding risk and possible consequences of such bleeding if DAPT is continued [17]. Administration of DAPT is recommended for at least 1 month on all patients regardless of the type of implanted stent (i.e. bare-metal stent or newer generation DES), in cases where surgery cannot be delayed for a longer period; however, such surgical procedures should be performed in hospitals where catheterization laboratories are available 24/7, so as to treat patients immediately in case of perioperative thrombotic events.
Single anti-platelet therapy (preferably with aspirin) should be continued independently of the timeframe between stent implantation and surgery. Figure 2 shows two possible bridging protocols that can be used with patients on aspirin plus a P2Y12 receptor inhibitor for (non-cardiac surgery)(adapted from Capodanno et al) [18]. The use of low-molecular-weight heparin for bridging in these patients should be avoided. Dual anti-platelet therapy should be resumed as soon as possible after surgery and, if possible, within 48 hours.
Figure 2. For patients requiring surgery within a few days, the recommendation is to withold clopidogrel and ticagrelor for five days and prasugrel for seven days prior to surgery. For patients with a very high risk of stent thrombosis, bridging therapy with intravenous, reversible glycoprotein inhibitors (e.g. eptifibatide or tirofiban) or cangrelor should be considered.
Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac surgery. Circulation 2013;128(25):2785-98
Antiplatelet agents and nonsteroidal anti-inflammatory drugs
Healthcare professionals should be aware of an interaction between low-dose aspirin and ibuprofen, which might render aspirin less effective when used for its anti-platelet cardioprotective effect [19].
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