Antiplatelet Drugs

The commonly used antiplatelet drugs include aspirin, thienopyridines (ticlopidine, clopidogrel and prasugrel), ticagrelor, dipyridamole, and GP IIb/IIIa antagonists, with distinct sites of action.

Aspirin

The most widely used antiplatelet agent worldwide is aspirin. Because it is an inexpensive and effective drug, aspirin serves as the foundation of most antiplatelet strategies.

Mechanism of Action

Aspirin produces its antithrombotic effect by irreversibly acetylating

and inhibiting platelet COX-1, a critical enzyme in the

biosynthesis of thromboxane A2. At high doses (≈1 g/day), aspirin

also inhibits COX-2, an inducible COX isoform found in endothelial

cells and inflammatory cells. In endothelial cells, COX-2 initiates the

synthesis of prostacyclin, a potent vasodilator and inhibitor of platelet

activation that antagonizes the effects of thromboxane A2.

Indications

Aspirin is widely used for secondary prevention in patients with

established coronary, cerebrovascular, or peripheral arterial disease.

In such patients, aspirin produces a 25% reduction in the risk for

cardiovascular death, myocardial infarction, or stroke. Use of aspirin for primary prevention is more controversial. Meta-analyses suggest that daily aspirin use produces a 25% reduction in the risk for a first cardiovascular event in patients at moderate to high risk for cardiovascular disease. Recent studies, however, have questioned whether the benefits of daily aspirin for primary cardiac protection outweigh its associated risks for gastrointestinal and intracerebral hemorrhage. Consequently, aspirin is no longer recommended for primary cardiac prevention unless the baseline cardiovascular risk is at least 1% per year and 10% at 10 years.

Dosages

Usually administered at dosages of 75 to 325 mg once daily, there is no evidence that higher-dose aspirin is more effective than lower doses, and some meta-analyses suggest reduced efficacy with higher doses. Because the side effects of aspirin, particularly gastrointestinal bleeding, are dose dependent, daily aspirin doses of 75 to 150 mg are recommended for most indications. When rapid platelet inhibition is required, an initial dose of aspirin of at least 160 mg should be used.

Side Effects

The most common side effects are gastrointestinal and range from dyspepsia to erosive gastritis or peptic ulcers with bleeding and perforation. Use of enteric-coated or buffered aspirin in place of plain aspirin does not eliminate the risk for gastrointestinal side effects. The risk for major bleeding with aspirin is 1% to 3% per year. With concomitant use of aspirin and anticoagulants such as warfarin, the risk for bleeding increases. When combined with warfarin, use of low-dose aspirin (75 to 100 mg daily) is best. Eradication of Helicobacter pylori infection and administration of proton pump inhibitors may reduce the risk for aspirin-induced upper gastrointestinal bleeding in patients with peptic ulcer disease.

Patients with a history of aspirin allergy characterized by bronchospasm should not receive aspirin. This problem occurs in approximately 0.3% of the general population but is more common in patients with chronic urticaria or asthma, particularly those with coexisting nasal polyps or chronic rhinitis. Aspirin overdose is associated with hepatic and renal toxicity.

Aspirin Resistance

The term aspirin resistance is used to describe both clinical and laboratory phenomena. A diagnosis of clinical aspirin resistance, defined as failure of aspirin to protect patients from ischemic vascular events, can be made only after such an event occurs. This retrospective diagnosis provides no opportunity to modify therapy. Furthermore, it is unrealistic to expect aspirin, which selectively blocks thromboxane A2–induced platelet activation, to prevent all vascular events. The biochemical definition of aspirin resistance involves failure of the drug to inhibit thromboxane A2 synthesis and/or arachidonic acid–induced platelet aggregation. Potential mechanisms for aspirin resistance include poor adherence, reduced or delayed absorption of aspirin as a consequence of its enteric coating, thromboxane A2 generation via pathways distinct from COX-1, increased activity of thromboxane A2–independent pathways of platelet activation, use of concomitant medications that interfere with the action of aspirin, and pharmacogenetic factors. These tests have not been standardized, however, and there is no evidence that they identify patients at risk for recurrent vascular events or that resistance can be reversed either by giving higher doses of aspirin or by adding other antiplatelet drugs.

Thienopyridines

The thienopyridines include ticlopidine, clopidogrel, and prasugrel— drugs that target P2Y12, a key ADP receptor on platelets.

Mechanism of Action

The thienopyridines selectively inhibit ADP-induced platelet aggregation by irreversibly blocking P2Y12. Ticlopidine and clopidogrel are prodrugs that require metabolic activation by the hepatic cytochrome P-450 (CYP) enzyme system. Consequently, when given in usual doses, ticlopidine and clopidogrel have a delayed onset of action. Although prasugrel is also a prodrug that requires metabolic activation, its onset of action is more rapid than that of ticlopidine or clopidogrel, and it produces greater and more predictable inhibition of ADP-induced platelet aggregation. These characteristics reflect the rapid and complete absorption of prasugrel from the gut and its more efficient activation pathways. Although all of absorbed prasugrel undergoes activation, only 15% of absorbed clopidogrel undergoes metabolic activation; the remainder is inactivated by esterases. Ticlopidine is rarely used because of the risk for myelosuppression and because of the greater potency and better safety profile of newer drugs.

The active metabolites of the thienopyridines bind irreversibly to P2Y12. Consequently, these drugs have prolonged action, which can present problems if patients require urgent surgery. To reduce the risk for bleeding, thienopyridine therapy must be stopped at least 5 days before surgery.

Indications

When compared with the use of aspirin in patients with recent ischemic stroke, myocardial infarction, or peripheral arterial disease, clopidogrel reduced the risk for cardiovascular death, myocardial infarction, and stroke by 8.7%. Therefore clopidogrel is marginally more effective than aspirin, but it is more expensive than aspirin. The combination of clopidogrel and aspirin capitalizes on their capacity to block complementary pathways of platelet activation. For example, this combination is recommended for at least 4 weeks after implantation of a bare metal stent in a coronary artery and for at least 1 year in those with a drug-eluting stent.

The combination of clopidogrel and aspirin is also effective in patients with unstable angina. However, combining clopidogrel with aspirin increases the risk for major bleeding to approximately 2% per year—a risk that persists even with a daily aspirin dose of 100 mg or less. Therefore use of clopidogrel plus aspirin should be restricted to situations in which there is clear evidence of benefit. For example, this combination has not proved to be superior to clopidogrel alone in patients with acute ischemic stroke or to aspirin alone for primary prevention in those at risk for cardiovascular events.

Prasugrel was compared with clopidogrel in 13,608 patients with acute coronary syndromes scheduled to undergo percutaneous coronary intervention (PCI). The incidence of the primary efficacy endpoint—a composite of cardiovascular death, myocardial infarction, and stroke—was significantly lower with prasugrel than with clopidogrel, mainly because of a reduction in the incidence of nonfatal myocardial infarction. The incidence of stent thrombosis was also significantly lower with prasugrel than with clopidogrel. These advantages, however, were at the expense of significantly higher rates of fatal bleeding with prasugrel. Because patients older than 75 years and those with a history of previous stroke or transient ischemic attack have a particularly high risk for bleeding, prasugrel should be avoided in older patients, and the drug is contraindicated in those with a history of cerebrovascular disease. Caution is required if prasugrel is used in patients weighing less than 60 kg or in those with renal impairment.

Dosing

Clopidogrel is given once daily at a dose of 75 mg. Because its onset of action is delayed for several days, 300- to 600-mg loading doses of clopidogrel are given when rapid ADP receptor blockade is desired. After a loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg. Patients older than 75 years or weighing less than 60 kg should receive a daily prasugrel dose of 5 mg.

Side Effects

The most common side effects of ticlopidine are gastrointestinal. More serious are hematologic side effects, which include neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura. These side effects usually occur within the first few months of starting treatment. Therefore blood counts must be carefully monitoring when initiating therapy with ticlopidine. Gastrointestinal and hematologic side effects are rare with clopidogrel and prasugrel.

Clopidogrel Resistance. The capacity of clopidogrel to inhibit ADP-induced platelet aggregation varies among subjects. This variability reflects, at least in part, genetic polymorphisms in the CYP isoenzymes involved in the metabolic activation of clopidogrel. Polymorphisms in both these enzymes have been linked to adverse clinical outcomes. In contrast to their effect on the metabolic activation of clopidogrel, polymorphisms in CYP2C19 and CYP3A4 do not appear to influence activation of prasugrel, nor do they affect the response to ticagrelor.

Although concomitant administration of clopidogrel with proton pump inhibitors, which inhibit CYP2C19, reduces the effect of clopidogrel on ADP-induced platelet aggregation, this interaction has questionable clinical significance. Atorvastatin, a competitive inhibitor of CYP3A4, reduced the inhibitory effect of clopidogrel on ADP-induced platelet aggregation in one study, a finding unconfirmed in subsequent investigations.

The influence of genetic polymorphisms on clinical outcomes with clopidogrel has raised the possibility that pharmacogenetic profiling and/or point-of-care platelet function testing could be used to identify clopidogrel-resistant patients so that they could be targeted for more intensive antiplatelet therapy. Consequently, there is no indication for clopidogrel resistance testing at this time. Because their antiplatelet effects are more predictable, some guidelines recommend prasugrel or ticagrelor instead of clopidogrel for high-risk patients.

Dipyridamole

A relatively weak antiplatelet agent on its own, an extended-release

formulation of dipyridamole combined with low-dose aspirin, a preparation marketed as Aggrenox, is used for prevention of stroke in patients with transient ischemic attacks.

Mechanism of Action

By inhibiting phosphodiesterase, dipyridamole blocks the breakdown of cAMP. Increased levels of cAMP reduce intracellular calcium and inhibit platelet activation. Dipyridamole also blocks the uptake of adenosine by platelets and other cells. With more extracellular adenosine, there is a further increase in local cAMP levels because the platelet adenosine A2 receptor and adenylate cyclase are coupled.

Dosing

Aggrenox is given twice daily. Each capsule contains 200 mg of extended-release dipyridamole and 25 mg of aspirin.

Side Effects

Because dipyridamole has vasodilatory effects, caution is necessary in patients with coronary artery disease. Gastrointestinal complaints, headache, facial flushing, dizziness, and hypotension can also occur. These symptoms often subside with continued use of the drug.

Indications

Dipyridamole plus aspirin was compared with aspirin or dipyridamole alone and with placebo in patients with an ischemic stroke or transient ischemic attack. The combination reduced the risk for stroke by 22.1% in comparison to aspirin and by 24.4% in comparison to dipyridamole. Although the combination of dipyridamole plus aspirin compares favorably with aspirin, the combination is not superior to clopidogrel.

Although Aggrenox can replace aspirin for stroke prevention, because of the vasodilatory effects of dipyridamole and the paucity of data supporting the usefulness of this drug in patients with symptomatic coronary artery disease, Aggrenox is contraindicated in such patients; clopidogrel is a better choice in patients with coronary artery disease.

Ticagrelor

As an orally active inhibitor of P2Y12, ticagrelor differs from the thienopyridines in that it does not require metabolic activation and it produces reversible inhibition of the ADP receptor.

Mechanism of Action

Like the thienopyridines, ticagrelor inhibits P2Y12. Because it does not require metabolic activation, ticagrelor has a more rapid onset and offset of action than clopidogrel does and it produces greater and more predictable inhibition of ADP-induced platelet aggregation.

Dosing

Ticagrelor is initiated with an oral loading dose of 180 mg followed by 90 mg twice daily. The dose does not need adjustment in patients with renal impairment, but caution is needed in patients with hepatic impairment or in those receiving potent inhibitors or inducers of CYP3A4 because ticagrelor is metabolized in the liver via CYP3A4. Ticagrelor is usually administered in conjunction with aspirin; the daily aspirin dose should not exceed 100 mg.

Side Effects

In addition to bleeding, the most common side effects of ticagrelor

are dyspnea, which can develop in up to 15% of patients, and asymptomatic ventricular pauses. The dyspnea, which tends to occur soon after initiating ticagrelor, is usually self-limited and mild in intensity. The mechanism responsible for this side effect is unknown.

Indications

Ticagrelor was also superior to clopidogrel in patients with acute coronary syndrome who underwent PCI or cardiac surgery. Based on these observations, some guidelines give ticagrelor preference over clopidogrel, particularly in higher-risk patients.

Glycoprotein IIb/IIIa Receptor Antagonists

As a class, parenteral GP IIb/IIIa receptor antagonists have a niche in patients with acute coronary syndromes. The three agents in this class are abciximab, eptifibatide, and tirofiban.

Mechanism of Action

A member of the integrin family of adhesion receptors, GP IIb/IIIa is expressed on the surface of platelets and megakaryocytes. With approximately 80,000 copies per platelet, GP IIb/IIIa is the most abundant receptor. GP IIb/IIIa is inactive on resting platelets. With platelet activation, however, inside-outside signal transduction pathways trigger conformational activation of the receptor. Once activated, GP IIb/IIIa binds fibrinogen and, under high-shear conditions, vWF. Once bound, fibrinogen and vWF bridge adjacent platelets together to induce platelet aggregation.

Although abciximab, eptifibatide, and tirofiban all target the GP IIb/IIIa receptor, they are structurally and pharmacologically distinct. Abciximab is a Fab fragment of a humanized murine monoclonal antibody directed against the activated form of GP IIb/IIIa. Abciximab binds to the activated receptor with high affinity and blocks the binding of adhesive molecules. In contrast to abciximab, eptifibatide and tirofiban are synthetic molecules. Eptifibatide is a cyclical heptapeptide that binds GP IIb/IIIa because it incorporates the KGD motif, whereas tirofiban is a nonpeptidic tyrosine derivative that acts as a RGD mimetic. With its long half-life, abciximab persists on the surface of platelets for up to 2 weeks. Eptifibatide and tirofiban have shorter half-lives.

Dosing

All the GP IIb/IIIa antagonists are given as an intravenous bolus followed by an infusion. Because of their renal clearance, eptifibatide and tirofiban doses require reduction in patients with renal insufficiency.

Side Effects

In addition to bleeding, thrombocytopenia is the most serious complication. Antibodies directed against neoantigens on GP IIb/IIIa that are exposed on antagonist binding cause thrombocytopenia, which is immune mediated. With abciximab, thrombocytopenia occurs in up to 5% of patients and is severe in approximately 1% of these individuals. Thrombocytopenia is less common with the other two agents and occurs in approximately 1% of patients.

Indications

Abciximab and eptifibatide are used in patients undergoing PCI, particularly those with acute myocardial infarction, whereas tirofiban and eptifibatide are used in high-risk patients with unstable angina.

Newer Antiplatelet Agents

New agents in advanced stages of development include cangrelor, a parenteral reversible P2Y12 antagonist, and vorapaxar, an orally active inhibitor of PAR-1, the major thrombin receptor on platelets . The adenosine analogue cangrelor binds reversibly to P2Y12 and inhibits its activity. The drug has a half-life of 3 to 6 minutes after intravenous administration. When stopped, platelet function recovers within 60 minutes. Recent trials comparing cangrelor with placebo during PCI or comparing cangrelor with clopidogrel after such procedures revealed little or no advantage of cangrelor. Consequently, identification of a role for cangrelor requires additional studies.

Recommendations for Oral Antiplatelet Agents

Aspirin should be given to all patients without contraindications at an initial loading dose of 150-300 mg and at a maintenance dose of 75-100 mg daily long-term regardless of treatment strategy (Class I).

A P2Y12 inhibitor should be added to aspirin as soon as possible and maintained over a period of 12 months unless there are contraindications such as excessive risk for bleeding (Class I).

A proton pump inhibitor (preferably not omeprazole) in combination with DAPT is recommended in patients with a history of gastrointestinal hemorrhage or peptic ulcer and is appropriate for patients with multiple other risk factors (Helicobacter pylori infection, ≥65 years, concurrent use of anticoagulants or steroids) (Class I).

Prolonged or permanent withdrawal of P2Y12 inhibitors within 12 months after the index event is discouraged unless clinically indicated (Class I).

Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended for all patients at moderate to high risk for ischemic events (e.g., elevated troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is commenced) (Class I).

Prasugrel (60-mg loading dose, 10-mg daily dose) is recommended for P2Y12 inhibitor–naïve patients (especially diabetic individuals) in whom the coronary anatomy is known and who are proceeding to PCI unless there is a high risk for life-threatening bleeding or other contraindications (Class I).

Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel (Class I).

A 600-mg loading dose of clopidogrel (or a supplementary 300-mg dose at PCI following an initial 300-mg loading dose) is recommended for patients scheduled for an invasive strategy when ticagrelor or prasugrel is not an option (Class I).

A higher maintenance dose of clopidogrel, 150 mg daily, should be considered for the first 7 days in patients managed with PCI and without increased risk for bleeding (Class IIa).

Increasing the maintenance dose of clopidogrel based on platelet function testing is not advised as routine but may be considered in selected cases (Class IIb).

Genotyping and/or platelet function testing may be considered in selected cases when clopidogrel is used (Class IIb).

In patients pretreated with P2Y12 inhibitors who need to undergo nonemergency major surgery (including CABG), postponing surgery for at least for 5 days after cessation of ticagrelor or clopidogrel and for 7 days for prasugrel should be considered if clinically feasible and if the patient is not at high risk for ischemic events (Class IIa).

Starting (or restarting) ticagrelor or clopidogrel after CABG should be considered as soon as considered safe (Class IIa).

The combination of aspirin with an NSAID (selective COX-2 inhibitors and nonselective NSAID) is not recommended (Class III).