Cardiology

Antiplatelet Therapy: Thromboxane Antagonists

General

Antiplatelet therapy

Currently, there are three different classes of antiplatelet agents that are approved for the treatment and/or prevention of recurrent events in acute coronary syndrome (ACS)/percutaneous coronary interventions (PCI) patients. These include thromboxane (TxA2) antagonists, adenosine diphosphate (ADP) P2Y12 receptor antagonists, and glycoprotein (GP) IIb/IIIa inhibitors.

Aspirin and other thromboxane (TxA2) antagonists

The main therapeutic agent used to block platelet TxA2 activation is aspirin, which exerts its function in an indirect way by inhibiting the COX-1 enzyme. Moreover, aspirin is the mainstay of antiplatelet therapy for secondary prevention of recurrent ischemic events in patients with various clinical manifestations of coronary artery disease (CAD), including stable CAD and all ACS subsets, and those undergoing coronary revascularization (percutaneous or surgical). The benefit of aspirin therapy in the management of patients with ACS has been repeatedly demonstrated in earlier trials.

There are several randomized trials demonstrating the beneficial effects of aspirin in patients with unstable angina (UA)/ non-ST elevation myocardial infarction (NSTEMI) showing an approximately 50% reduction in the risk of death or myocardial infarction (MI). The benefits of aspirin in reducing recurrent ischemic events, including cardiovascular death, MI, and stroke in patients with CAD has also led to the near-universal use of this medication for patients undergoing PCI, which currently represents the predominant management strategy in patients with ACS (60% to 70% of ACS patients undergo PCI).

The initial studies involving aspirin in PCI included combined antiplatelet regimens with dipyridamole or ticlopidine. Aspirin has been shown to be effective in reducing recurrent ischemic events in patients undergoing intracoronary stent placement, especially in combination with a thienopyridine.

There are several new compounds that inhibit TxA2 activation that are in early stages of development, such as NCX-4016 or terutroban among many others. However, none of the compounds have shown to have the efficacy of aspirin and are not yet available for clinical use.

Differences between drugs within the class

Different mechanisms are targeted by the drugs in this class in order to block TxA2-mediated platelet activation. Aspirin when used at low doses irreversibly inactivates COX-1, which is the main representative of this class. On the other hand, NCX-4016 is the prototype of COX-inhibiting nitric oxide (NO) donors (CINODS), novel compounds designed to reduce the toxicity of nonsteroidal antiinflammatory drugs (NSAIDs).

They combine a COX inhibitor that reduces TXA2 synthesis plus nitroxibutil or nitrosothiol, which release NO counteracting the NSAIDs-induced decrease in gastric mucosal prostaglandins. Terutroban (S18886 or Triplion), is a new oral, selective and reversible direct platelet thromboxane receptor (TP) antagonist. Other compounds, which have both TxA2 synthetase (TS) and TP antagonist effects, are under development.

Administration

Aspirin

In high-risk patients, particularly those with ACS and undergoing PCI, aspirin should be given as promptly as possible, at an initial dose of 162 to 325 mg. The optimal maintenance dose of aspirin for prevention of cardiovascular events has been the subject of controversy. Registry data have shown that oral aspirin doses of 75 to 150 mg/day are as effective as higher doses for long-term prevention of ischemic events.

Importantly, higher doses of aspirin (>150 mg) do not offer greater protection from recurrent ischemic events. In addition, some recent concerns have risen about the potential for a negative interaction with the new P2Y12 receptor inhibitor ticagrelor. Moreover, bleeding events, in particular gastrointestinal bleedings, are significantly increased.

These registry findings are in line with the CURRENT/OASIS-7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes) trial, which did not show any ischemic benefit between patients randomized to high (300 to 325 mg) and low-dose aspirin (75 to 100 mg). Based on these findings, the most updated PCI guidelines state that it is reasonable to consider 81 mg/day as a maintenance dose regimen.

Pharmacologic action

Aspirin

Aspirin is an irreversible inhibitor of COX activity of prostaglandin H (PGH) synthase 1 and synthase 2, also referred to as COX-1 and COX-2, respectively. These enzymes catalyze the conversion of arachidonic acid to PGH2, which is a substrate for the generation of prostanoids, such as thromboxane A2 (TXA2) and prostacyclin (PGI2).

TXA2 is an amplifier of platelet activation and also a vasoconstrictor. It is mainly derived from platelet COX-1 and is highly sensitive to inhibition by aspirin. On the contrary, vascular PGI2, a platelet inhibitor and a vasodilator, is derived largely from COX-2 and is less susceptible to inhibition by low-doses of aspirin.

Low doses of aspirin are sufficient to inhibit COX-1 activity leading to antiplatelet effects, while only high doses of aspirin can inhibit COX-2, which has antiinflammatory and analgesic effects. Aspirin is rapidly absorbed in the upper gastrointestinal tract leading to detectable platelet inhibition within 60 minutes. The plasma half-life of aspirin is approximately 20 minutes and peak plasma levels are achieved within 30 to 40 minutes.

However, enteric-coated aspirin delays absorption and peak plasma levels are achieved approximately 3 to 4 hours after ingestion. Platelets have a limited capacity for protein synthesis. Therefore, since aspirin induces irreversible COX-1 blockade, COX-mediated TXA2 synthesis is prevented for the entire life span of the platelet (approximately 7 to 10 days).

Indications and contraindications

Aspirin

Aspirin is indicated for all patients with atherosclerotic disease manifestations. In patients undergoing PCI, a loading dose before intervention should be given and a maintenance dose should be taken life-long. If the patient is already on aspirin daily, a loading dose of 81 to 325 mg should be given before PCI. If the patient is not on aspirin previously, a nonenteric 325 mg of aspirin should be given.

Some nonsteroidal antiinflammatory drugs (NSAIDs), such as naproxen and ibuprofen, may interfere with the action of aspirin when administered concomitantly by competing for the COX-1 active site, attenuating its antiplatelet effects. This may contribute in reducing the cardioprotective effects of aspirin. Therefore, prescription of NSAIDs should be carefully considered in aspirin treated patients. Aspirin should not be prescribed in patients with hypersensitivity reactions. Desensitization using escalating doses of oral aspirin is a therapeutic option for these patients.

Undesirable effects

Aspirin

The side effects of aspirin are primarily gastrointestinal. These side effects are dose related, with an increased prevalence at higher doses, and include gastric erosions, hemorrhage, and ulcers that can contribute to anemia.

The increased risk of extracranial bleeding is approximately 60%. In the CURRENT-OASIS 7 trial, although there were no differences in major bleeds between the two aspirin doses, a trend toward an increased rate of gastrointestinal bleeds in the high-dose group (0.38% vs. 0.24%; P = .051) was observed at 30 days.

Alternative approaches

In patients presenting with allergy or intolerance to aspirin, clopidogrel is the treatment of choice.

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