Oral Antiplatelet Agents
Aspirin
Aspirin was first used as an analgesic and antipyretic drug in 1899, and has quickly become the most widely used drug in the history of medicine.62 During the 1960s, the antiplatelet properties of aspirin were discovered.62 Since then, aspirin has become the most comprehensively studied and least expensive of all antiplatelet medications.5 Aspirin blocks the synthesis of thromboxane A2 from arachidonic acid in platelets by inhibiting the enzyme cyclooxygenase 1 (Figure 1). Thromboxane A2 is necessary for platelet aggregation and promotes blood clotting. The inhibitory effect of aspirin on the formation of this substance is irreversible and lasts for the life of the platelet, which is 7 days to 10 days. In fact, a single dose of aspirin impairs platelet aggregation for up to 4 days, until new platelets enter the circulation in sufficient numbers to exert a thrombotic effect.63
Aspirin reduces mild to moderate pain, inflammation, and fever.29 Aspirin is also used for the primary prevention of MI in patients at increased risk, and for the secondary prevention of ischemic cardiovascular events, such as stroke.62 Further, aspirin is used as an adjunctive therapy during revascularization procedures (eg, coronary bypass).29 Aspirin should be available in the dental office as a pre-hospitalization drug for use in patients experiencing MI. It is thought that the fibrinolytic properties of aspirin, given at an 81-325 mg dose, may help to reperfuse the ischemic myocardium.64
Despite the cardioprotective benefits of this drug, aspirin is still underused by many at-risk populations.65 It is important to note that although aspirin is not approved for primary prevention of ischemic events, it may be possible for people who are at an even higher risk than those who have already experienced an adverse cardiovascular event to benefit from the effects of aspirin. The potential number of people in this highest risk category exceeds the number of people who are already taking the drug.62 Safety concerns, including risks for hemorrhage and gastrointestinal (GI) ulceration and bleeding, are thought to limit the recommendations of this drug by physicians to their patients.62 However, many patients choose to self-medicate with aspirin, and may be unaware of its potential adverse effects.
In addition to data that supports the benefits of aspirin in patients with cardiovascular disease, data from 55 000 individuals supports aspirin use for the prevention of first MI in healthy individuals, with an overall risk reduction of 32%.66 Both the American Heart Association (AHA) and the U.S. Preventive Services Task Force (USPSTF) have published guidelines for the use of aspirin for the primary prevention of MI.3,67,68
A meta-analysis of all available randomized, placebo-controlled clinical trials evaluating the effects of low-dose aspirin therapy for secondary prevention revealed that aspirin reduces the risk of death by approximately 20%. Further, aspirin also reduces the relative risk for cardiovascular events (eg, MI) and cerebrovascular events (stroke) by 20% to 30%.69
The most common adverse event associated with aspirin use is GI ulceration and hemorrhage. These GI complications are attributed to aspirin’s inhibitory effect on prostaglandin synthesis, which stops the production of protective prostaglandins that coat the walls of the stomach that normally form a barrier between the hydrochloric acid and the gastric mucosa. Further, aspirin inhibits the synthesis of prostaglandins that protect the kidney. Notably, chronic aspirin use can lead to kidney damage and renal failure. Hemorrhagic stroke is also a risk associated with long-term aspirin use. A meta-analysis of 16 clinical trials demonstrated an increased absolute risk of 12 hemorrhagic stroke events per 10 000 aspirin users.70 Although aspirin increases risk for adverse bleeding events, the cardioprotective benefits of the drug outweigh these risks when used appropriately in at-risk patient populations.62
Many adverse events caused by aspirin are dose-related and are extremely rare with low-dose therapy (81 mg per day). Bleeding risk increases with concurrent use of other medications that alter hemostasis, including NSAIDS, warfarin, and alcohol. Drinking more than 3 alcoholic beverages per day significantly increases risk for GI hemorrhage. Aspirin use should be discontinued if patients develop tinnitus or hearing loss. Caution should be used when using aspirin in patients with bleeding or platelet disorders, peptic ulcer disease, and liver or kidney dysfunction.
Other serious reactions include hypersensitivity reactions and idiosyncratic reactions.
Patients who are sensitive to tartrazine dyes, or who have nasal polyps or asthma are more likely to be sensitive to aspirin. In patients with bronchial asthma, aspirin and other NSAIDS may precipitate a condition known as aspirin-induced asthma (AIA), a syndrome characterized by aggressive and continuous inflammatory disease of the airways. AIA progresses from the upper to lower respiratory tract and affects women more than men, with an average age of onset at 30 years. Rhinorrhea and nasal congestion are the first symptoms, with asthma and aspirin hypersensitivity developing 2 years to 15 years later. Once developed, aspirin intolerance remains throughout life. 71 Further, patients who are allergic to NSAIDS may not take aspirin or aspirin-containing products.29
There is increasing concern about the number of individuals who exhibit aspirin resistance, also known as hypo-responsiveness, to the effects of aspirin. These individuals experience first MI or suffer a second adverse event while taking aspirin. For some reason, aspirin therapy is not enough to stop thrombotic activity. Three possible explanations have been offered to explain aspirin resistance: platelets become activated by pathways not blocked by aspirin; patients require a higher dose of aspirin to produce an effect; or patients generate thromboxane A2 despite aspirin therapy.72 Early data suggests that aspirin resistance may be dose related; resistance is found more often during low-dose therapy (< 100 mg daily) than at higher doses (> 300 mg daily). Platelet aggregation studies of these individuals reveal no biochemical activity of aspirin. Urinary concentrations of a thromboxane metabolite (11-dehydrothromboxane B2), a marker for aspirin resistance, may be used to identify potential aspirin-resistant individuals. Patients who are aspirin resistant should continue to take aspirin for its anti-inflammatory effects, but may require additional antiplatelet therapies for risk reduction.72,73
Aspirin has many drug interactions, and dental professionals should consult a drug reference text prior to prescribing any medications to patients taking this drug. For example, concurrent use of aspirin with NSAIDS may decrease the serum concentration of some NSAIDS.29 Dental professionals must remember that the effects of this drug are irreversible; therefore, additional bleeding will be evident during any invasive procedure. There is no evidence to support the discontinuation of low-dose aspirin therapy prior to dental procedures or dental surgery, as the risk for an adverse cardiovascular event outweighs the risk for intraoperative and postoperative bleeding in dental patients.8,29 Such bleeding can be managed locally with the use of hemostatic agents. However, a physician consultation is warranted to discuss whether patients who require major surgery require an alteration in aspirin therapy. The decision to discontinue therapy must take into account the risks to the patient. If the decision is to discontinue aspirin, the patient should stop taking aspirin 10 days to14 days prior to surgery to allow for the synthesis of new platelets.
Dipyridamole
Dipyridamole (Persantine®) stimulates the release of prostacyclin or prostaglandin D2 (PGD2), inhibiting platelet aggregation and producing coronary vasodilation. The drug is primarily used to prevent angina pectoris, and to maintain the opening of the coronary arteries following bypass surgery. This drug is often used in combination with aspirin to prevent coronary artery thrombosis, or with warfarin, to decrease the risk of thrombosis in patients with mechanical heart valves. It may also be used prophylactically to prevent myocardial reinfarction.27,29 The drug is administered orally and intravenously.
Aspirin with dipyridamole
Combination aspirin with extended-release dipyridamole is an antiplatelet drug known as Aggrenox®. Aggrenox® is used to reduce the risk of stroke in patients who have had either transient brain ischemia or an ischemic stroke due to thrombosis. The drug contains 25 mg of aspirin and 200 mg of dipyridamole. The aspirin inhibits platelet aggregation by inhibiting platelet cyclooxygenase and the generation of thromboxane A2. Dipyridamole stimulates the release of prostacyclin, the antagonist of thromboxane A2. The antithrombotic effects of this drug are irreversible, given the aspirin component of the drug.27,29
Clopidogrel
Clopidogrel (Plavix®) inhibits platelet aggregation by a different mechanism than aspirin. This drug inhibits the binding of ADP to its platelet receptors, which prevents the binding of fibrogen between platelets, reducing platelet adhesion and aggregation. Clopidogrel also blocks the amplification of platelet activation caused by released ADP. Plavix® is used as an antithrombotic for the prevention of myocardial infarction, stroke and vascular death in patients with atherosclerosis. It is also prescribed for the prevention of thromboembolic events following the placement of coronary stents.27,29
Plavix® was developed for use for patients who are unable to tolerate the adverse gastrointestinal effects of aspirin, and has recently replaced ticlopidine (Ticlid®) as the drug of choice for patients who are allergic or intolerant to aspirin.27 Evidence supports that both clopidogrel and ticlopidine are more effective than aspirin in preventing stroke and other serious vascular events in high risk patients.74 Like aspirin, this drug produces irreversible effects that last for the life of the platelet. Patients can receive routine dental procedures, including oral prophylaxis, without altering the dose of the drug.5,8 However, patients that are scheduled to undergo invasive surgical procedures, including dental surgery, are advised to discontinue the drug for 7 days prior to surgery.5 Consultation with the patient’s physician prior to discontinuing the drug is warranted to ensure patient safety.
Risk for hemorrhage is associated with this drug and bleeding may occur at any site, including the oral cavity. Risk for hemorrhage increases with concurrent use of other drugs that alter hemostasis, including anticoagulants and antiplatelet drugs. Avoid the use of herbs that demonstrate antiplatelet activity (Table I). Concurrent use of clopidogrel with naproxen has resulted in GI blood loss. Cases of thrombotic thrombocytopenia purpura have been reported with use of this drug, usually occurring within the first 2 weeks of therapy.29
At high doses, clopidogrel may alter the metabolism of some NSAIDS, which can result in toxicity reactions. Finally, CYP3A4 inhibitors, including the macrolide antibiotics, may decrease the effects of clopidogrel. Dental patients who are prescribed these antibiotics should be closely monitored.29
Cilostazole
Cilostazole (Pletal®) is an oral antiplatelet drug used to manage the symptoms of peripheral vascular disease. This drug and its metabolites inhibit phosphodiesterase III, which increases cyclic adenosine monophosphate (AMP), causing inhibition of platelet aggregation and vasodilation. Inhibiting phosphodiesterase III increases cardiac contractility, atrioventricular (AV) nodal conduction, ventricular automaticity, heart rate, and coronary blood flow.29
The blood levels of cilostazole may be increased by erythromycin. Increased blood concentrations of this drug are observed with concurrent use of CYP3A4 inhibitors, including the macrolide antibiotics and the systemic azole antifungals. Inhibition of platelet aggregation caused by aspirin is potentiated with concurrent use of cilostazole.29
Ticlopidine
Ticlopidine (Ticlid®) is an irreversible platelet aggregation inhibitor used to reduce the risk for thrombotic stroke. The other primary indication for use is to reduce the incidence of thrombotic complications in patients with coronary stents. Use of this drug is typically reserved for patients who are intolerant to aspirin, and for those whose aspirin therapy has failed. Ticlopidine has a mechanism of action that is unique from other platelet aggregation inhibitors. While the drug inhibits adenosine diphosphate (ADP) platelet receptor fibrinogen binding (like Plavix®), this drug also significantly increases bleeding time. The increase in bleeding time can be further prolonged by the addition of aspirin.29
Ticlopidine has been associated with life-threatening hematologic disorders, including neutropenia and thrombotic thrombocytopenic purpura. 75 Thus, use of clopidogrel has surpassed this drug due to a better safety profile. Ticlopidine use may increase the effect and risk for toxicity of aspirin, anticoagulants, and NSAIDS.29
