AHFS Class:

• Salicylates 28:08.04.24

Generic Name(s):

• Aspirin

• Acetaminophen and Aspirin

• Acetaminophen, Aspirin, and Caffeine

• Oxycodone and Aspirin

Associated Monographs

• Salicylates General Statement

Aspirin (the prototype of the salicylates) is a nonsteroidal anti-inflammatory agent (NSAIA) and also exhibits antithrombotic, analgesic, and antipyretic activity.

Aspirin is used extensively in the treatment of mild to moderate pain, fever, and inflammatory diseases. Aspirin is also used in the prevention of arterial and venous thrombosis. Aspirin, however, should be used with extreme caution, if at all, in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by other salicylates or other NSAIAs. (See Cautions: Sensitivity Reactions in the Salicylates General Statement 28:08.04.24.)

Pain

Aspirin is used to relieve headache, neuralgia, myalgia, arthralgia, and other low-intensity pain of nonvisceral origin, particularly pain associated with inflammation. Aspirin may also relieve mild to moderate postoperative pain, postpartum pain, oral surgery or other dental pain, dysmenorrhea, or other visceral pain such as that associated with trauma or cancer. Many studies have shown that the analgesic effects of aspirin are greater than those of placebo in the treatment of these types of pain. The drug, however, does not usually relieve severe acute pain of visceral origin. In addition, use of chewing gum tablets or gargles containing aspirin has not been shown to be effective in relieving sore throat pain.

The analgesic effect of aspirin appears to increase with increasing single oral doses up to at least 1.2 g; however, single oral doses of aspirin exceeding 650 mg apparently do not result in a greater incidence or degree of pain relief in most patients. Multiple oral doses of aspirin exceeding 650 mg each have not been shown to be more effective in relieving pain than multiple oral doses of 650 mg.

When used to relieve postoperative pain, 600-mg oral doses of aspirin appear to be as effective as 60-mg oral doses of codeine or 50-mg oral doses of pentazocine. When used to relieve oral surgery pain, 650-mg oral doses of aspirin appear to be more effective than 30-mg oral doses of codeine, as effective as 650-mg oral doses of acetaminophen, and less effective than 250-mg, 500-mg, or 1-g oral doses of diflunisal.

In the treatment of postpartum uterine pain, the analgesic effect of 650-mg oral doses of aspirin is about equal to that of 300- or 600-mg oral doses of naproxen or 275-mg oral doses of naproxen sodium and greater than that of 60-mg oral doses of codeine or codeine sulfate. When used to relieve episiotomy pain, several studies have shown that 600-mg to 1.2-g oral doses of aspirin are more effective than placebo; in one study, the analgesic effect of 900-mg oral doses of aspirin was about equal to that of 300- or 900-mg oral doses of ibuprofen. In another study, the analgesic effect of 600-mg oral doses of aspirin was less than that of 500-mg oral doses of diflunisal.

In the treatment of nonspecific pain associated with cancer, 650-mg oral doses of aspirin appear to be at least as effective as 650-mg oral doses of acetaminophen, 65-mg oral doses of codeine, 250-mg oral doses of mefenamic acid, or 50-mg oral doses of pentazocine, and more effective than 75-mg oral doses of ethoheptazine citrate or 65-mg oral doses of propoxyphene hydrochloride (no longer commercially available in the US). When used to relieve nonspecific pain associated with cancer, 650-mg oral doses of aspirin in combination with oral doses of codeine (65 mg), oxycodone (976 mcg), or pentazocine hydrochloride (25 mg) appear to be more effective than 650-mg oral doses of aspirin alone or in combination with oral doses of caffeine (65 mg), ethoheptazine citrate (75 mg), pentobarbital sodium (25 mg), promazine hydrochloride (25 mg), or propoxyphene napsylate (100 mg) (no longer commercially available in the US).

Results of studies comparing aspirin (500-650 mg 4 times daily) with placebo to relieve primary dysmenorrhea have been inconsistent. Although the effects of higher dosages of aspirin remain to be evaluated, most clinicians consider aspirin to be one of the least effective NSAIAs currently available for the treatment of primary dysmenorrhea.

In several double-blind placebo-controlled studies with small numbers of patients with migraine, prophylactic therapy with aspirin (650 mg twice daily) alone or aspirin (300 mg twice daily) with dipyridamole (25 mg 3 times daily) has reportedly been effective in reducing the frequency of headache; however, further evaluation is needed. In addition, aspirin in fixed combination with acetaminophen and caffeine (aspirin 500 mg, acetaminophen 500 mg, and caffeine 130 mg per dose) is used for the temporary relief of mild to moderate pain associated with migraine headache.701,702,703,704 Some experts state that an NSAIA (e.g., aspirin alone or in fixed combination with acetaminophen and caffeine) is a reasonable first-line therapy for mild to moderate migraine attacks or for severe attacks that have responded in the past to similar NSAIAs or non-opiate analgesics.778 The efficacy of oral aspirin in fixed combination with acetaminophen and caffeine for the management of mild to moderate pain associated with migraine headache was established by 3 double-blind, randomized, parallel-group, placebo-controlled studies (one of them a population-based study) in adults who had migraine with aura or migraine without aura as defined by criteria established by the International Headache Society (IHS).703,704 The efficacy of therapy for management of pain associated with migraine headache in these studies was evaluated in terms of a reduction in headache severity as rated by the patient (i.e., a reduction in pain from at least moderate to mild or to absent 2 hours after dosing using a 4-point scale).703,704 Pooled analysis of data from the 3 studies indicated that about 59% of patients receiving 500 mg of aspirin in fixed combination with acetaminophen 500 mg and caffeine 130 mg attained relief of pain associated with migraine headache (i.e., mild or no headache) within 2 hours compared with about 33% of placebo recipients; at 6 hours, about 79 and 52%, respectively, of drug- and placebo-treated patients had mild or no headache pain.703,704 In addition, about 21% of patients receiving the combination were pain-free 2 hours after dosing versus about 7% of those receiving placebo, while at 6 hours, 51% of drug-treated patients were pain-free versus 24% of those receiving placebo.703,704 It appears that this combination also may relieve manifestations of migraine other than headache, including nausea, vomiting, photophobia, and phonophobia.703,704 Patients in whom pain associated with migraine headache is not relieved by aspirin in fixed combination with acetaminophen and caffeine should consult their clinician about possible alternatives (e.g., use of prescription drugs including ergot alkaloids or vascular serotonin type 1-like receptor agonists) based on evaluation of their medical condition.702 In several double-blind controlled studies in patients with acute migraine headache, aspirin 900 or 1000 mg given as a single dose with or without metoclopramide 10 mg (as an antiemetic) was more effective than placebo and had efficacy generally similar to that of sumatriptan 50 or 100 mg for relief of pain and associated symptoms of migraine (nausea, vomiting, photophobia, phonophobia).951 For further information on management and classification of migraine headache, see General Principles in Migraine Therapy under Uses: Vascular Headaches, in Sumatriptan 28:32.28.

Aspirin has been used in the treatment of pain in various combinations with acetaminophen, caffeine, opiates, salicylamide, and/or other agents. However, combinations of aspirin with agents such as acetaminophen, caffeine, or salicylamide have not been clearly shown to have greater analgesic effect than an optimal dose of aspirin alone. In addition, there is little evidence that such combinations cause fewer adverse effects than higher doses of the individual agents alone. In one study, the simultaneous administration of 325- or 650-mg oral doses of acetaminophen with 650-mg oral doses of aspirin resulted in increased blood concentrations of unhydrolyzed aspirin compared with 650-mg oral doses of aspirin alone; however, the clinical importance of such an effect remains to be established. Aspirin (650-mg oral doses) in combination with oral doses of an opiate (e.g., codeine, oxycodone) produces greater analgesic effect than that produced by either aspirin or higher doses of the opiate alone. There is also some evidence that aspirin/opiate combinations may cause fewer adverse effects than equianalgesic doses of the individual drugs alone.

Fever

Aspirin is used frequently to lower body temperature in febrile patients in whom fever may be deleterious or in whom considerable relief is obtained when fever is lowered. However, antipyretic therapy is generally nonspecific, does not influence the course of the underlying disease, and may obscure the course of the patient's illness. For information on salicylates and Reye's syndrome, see Cautions: Pediatric Precautions, in the Salicylates General Statement 28:08.04.24.

Aspirin and acetaminophen are equally effective as antipyretics. In one study in febrile children, the combination of oral doses of aspirin and acetaminophen was at least as effective in reducing fever as either drug alone, and the duration of fever reduction was longer with the combination than with the individual drugs. However, because of the study design, it could not be concluded that the combination had additive effects. Many clinicians use regimens of alternating doses of aspirin and acetaminophen; however, combined overdosage with both drugs has occurred with such a regimen and the efficacy and safety of these regimens remain to be established.

Several clinical studies have shown that the antipyretic effect of usual dosages of aspirin is about equal to that of usual dosages of mefenamic acid and naproxen, and less than that of usual dosages of indomethacin. However, efficacy of these other NSAIAs as antipyretics remains to be clearly established and they should not be used for routine treatment of fever because of their potential adverse effects.

Inflammatory Diseases

Aspirin is used for anti-inflammatory and analgesic effects in the initial and/or long-term symptomatic treatment of rheumatoid arthritis, juvenile arthritis, and osteoarthritis. Aspirin may also be useful in the treatment of other polyarthritic conditions (e.g., psoriatic arthritis, Reiter's syndrome, ankylosing spondylitis), systemic lupus erythematous, and nonarticular inflammation; however, other NSAIAs may be preferred in the treatment of some of these conditions (e.g., ankylosing spondylitis).

Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis

Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual dosages of aspirin in the treatment of rheumatoid arthritis or osteoarthritis are greater than those of placebo and about equal to those of usual dosages of fenoprofen calcium, ibuprofen, indomethacin, meclofenamate sodium, naproxen, piroxicam, sulindac, and tolmetin sodium. In the treatment of juvenile arthritis, the anti-inflammatory and analgesic effects of usual dosages of aspirin are about equal to those of usual dosages of fenoprofen, naproxen, or tolmetin sodium. Patient response to NSAIAs is variable, however, and patients who do not respond to one agent may be successfully treated with a different agent.

Aspirin has been used in conjunction with other NSAIAs in the treatment of some patients with rheumatoid arthritis, but such combination therapy is generally not recommended because there is inadequate proof that such combination therapy is more efficacious than the individual agents alone and the potential for adverse reactions may be increased. In addition, there is evidence that aspirin alters plasma concentrations of some other NSAIAs.

Psoriatic Arthritis and Reiter's Syndrome

Aspirin may be effective in the treatment of some patients with psoriatic arthritis or Reiter's syndrome but usually only when the disease is mild. Aspirin is seldom effective in the treatment of ankylosing spondylitis unless the disease is mild. In one study in patients with ankylosing spondylitis, the anti-inflammatory and analgesic effects of aspirin were less than those of indomethacin or phenylbutazone.

Systemic Lupus Erythematous

Some clinicians consider aspirin to be a drug of first choice for the treatment of fever, arthritis, pleurisy, and pericarditis in patients with systemic lupus erythematous (SLE). In one study in patients with SLE, the anti-inflammatory and analgesic effects of aspirin were greater than those of ibuprofen. The anti-inflammatory and analgesic effects of aspirin may also be useful in the symptomatic treatment of nonarticular inflammation such as bursitis and/or tendinitis (e.g., acute painful shoulder) and fibrositis.

Rheumatic Fever

Most clinicians consider aspirin to be the salicylate of choice when salicylate therapy is indicated in the treatment of rheumatic fever†.For information on salicylate therapy in the treatment of rheumatic fever, see Uses: Rheumatic Fever, in the Salicylates General Statement 28:08.04.24.

Thrombosis

Generally accepted indications for prophylactic aspirin therapy include its use for reducing the risk of recurrent vascular events (e.g., recurrent stroke, death) in men and women who have had single or multiple transient ischemic attacks (TIAs)† or ischemic stroke†, for reducing the risk of vascular mortality in patients with suspected acute myocardial infarction† (MI), for reducing the risk of recurrent nonfatal MI and/or death in patients with previous MI or unstable angina†, for reducing the risk of MI and sudden death in patients with chronic stable angina pectoris† , and for reducing cardiovascular risks in patients undergoing percutaneous coronary intervention [PCI] or certain revascularization procedures (e.g., coronary artery bypass grafting [CABG]). Aspirin also has been used to prevent thrombosis in patients undergoing percutaneous transluminal angioplasty (PTA) of the lower extremities†,1011 and for postoperative thromboprophylaxis in children undergoing surgery for placement of modified Blalock-Taussig shunts†, 718,1013 surgery for univentricular heart lesions (i.e., Fontan procedure†), surgery for placement of ventricular assist devices†,1013 or surgery for hypoplastic left heart (i.e., Norwood procedure)†.1013 Aspirin also has been used to prevent thromboembolism in patients with atrial fibrillation† or atrial flutter†, valvular heart disease† (e.g., mitral valve prolapse), chronic limb ischemia (e.g., intermittent claudication)†,996,999,1011 or prosthetic heart valves†.749,880,996,1008

Transient Ischemic Attacks and Acute Ischemic Stroke

Aspirin is used for secondary prevention of vascular events (e.g., recurrent stroke, death) in patients who have had an acute ischemic stroke or TIAs.842,990,1009 The American College of Chest Physicians (ACCP), the American Stroke Association (ASA), the American Heart Association (AHA), and other clinicians recommend antiplatelet therapy over oral anticoagulation (e.g., warfarin) for secondary prevention of ischemic atherothrombotic (noncardioembolic) stroke or TIAs in patients with prior TIAs or ischemic stroke who do not have atrial fibrillation.990,1009

AHA and ASA recommend aspirin for primary prevention or secondary prevention of ischemic stroke in high-risk women (i.e., women with established coronary heart disease, cerebrovascular disease, peripheral arterial disease, abdominal aortic aneurysm, end-stage or chronic kidney disease, diabetes mellitus, or a 10-year Framingham risk exceeding 20%).952,1017 AHA and ASA also suggest that low-dose aspirin therapy can be useful in women 65 years of age or older in whom the benefits for ischemic stroke and MI prevention are likely to outweigh the risk of GI bleeding and hemorrhagic stroke and may be reasonable to consider in women younger than 65 years of age in whom the benefits for ischemic stroke prevention are likely to outweigh the adverse effects of aspirin.952,1017 Results of several trials suggest that use of aspirin therapy for primary prevention of stroke in men without a history of TIAs or stroke may be associated with a slightly increased risk of stroke, particularly hemorrhagic stroke, and aspirin is not recommended for primary prevention of ischemic stroke in men.575,659

Restoring perfusion (e.g., with thrombolytic therapy) is the principal goal of acute stroke therapy, with the second goal being prevention of early recurrence of cerebrovascular events with anticoagulants and antiplatelet agents.1009 Unless contraindicated or unless too much time (i.e., more than 3-4.5 hours†) has elapsed since the event, thrombolytic therapy generally is preferred for the acute treatment of ischemic stroke.917,918,919,920,921,922,923,950,1009 (See Uses: Acute Ischemic Stroke, in Alteplase 20:12.20.) In patients with acute ischemic stroke or TIA in whom thrombolytic therapy is contraindicated or not appropriate, early aspirin therapy (160-325 mg initially, followed by 75-100 mg daily to reduce bleeding risk)1009 is recommended.699,700,1009 Aspirin should be initiated within 48 hours of stroke onset.1009 The rationale for antithrombotic therapy such as aspirin in patients with acute ischemic stroke is to reduce the risk of stroke progression or recurrent cerebral thromboembolism and prevent thromboembolic complications.1009 Current evidence indicates that aspirin therapy initiated within 48 hours of stroke onset is relatively safe and can produce a small but definite net benefit by reducing both stroke recurrence risk and mortality.1009

For secondary prevention of ischemic stroke in patients with cerebrovascular disease, including patients with a history of TIAs or previous ischemic stroke, aspirin is the most widely studied and used antiplatelet agent.646,682,1009 Secondary prevention with aspirin has been shown to reduce the combined endpoint of stroke, MI, and/or vascular death by 13-25%.646,682,1009 Data from numerous clinical studies have shown that aspirin reduces the risk of these cardiovascular events in a wide variety of patients at high risk for these atherosclerotic outcomes.646,682,1009

Because there is evidence from clinical studies to support the efficacy of low dosages of aspirin (e.g., 50-325 mg daily) in patients with a history of TIAs or cerebral ischemia and considerable evidence supporting the antithrombotic efficacy of such dosages in patients with MI, these dosages have supplanted the moderate- to high-dose regimens employed in the past. Further supporting this change in dosage recommendations is evidence that efficacy is not compromised with low-dosage regimens, but patient tolerance is improved. Although early evidence supporting the beneficial effects of aspirin in patients with TIAs came from studies that included mainly men, more recent studies have shown numerically similar results for men and women, and favorable trends generally have been seen in both genders.646 Current data suggest that an aspirin dosage of 75-81 mg daily may be sufficient for long-term cardiovascular prevention and is associated with less GI bleeding risk.907

Aspirin in fixed combination with extended-release dipyridamole is used to reduce the risk of recurrent stroke in patients who have had TIAs or completed ischemic stroke caused by noncardioembolic thrombosis (e.g., atherothrombotic, lacunar, cryptogenic).738,739,743,1009 In a randomized, comparative, placebo-controlled study, patients who had experienced either an ischemic stroke or TIAs were assigned to receive treatment with aspirin (25 mg twice daily), extended-release dipyridamole (200 mg twice daily), aspirin plus extended-release dipyridamole (25 and 200 mg twice daily, respectively), or placebo.738,755 All active treatments reduced the risk of the primary end points of stroke (nonfatal or fatal) or stroke and/or death compared with placebo.755 Aspirin plus dipyridamole reduced the risk of stroke by about 23% compared with aspirin alone and by about 25% compared with dipyridamole alone at 2 years of follow-up; the effects of combined therapy on risk reductions with aspirin and dipyridamole were additive but not synergistic.755 Aspirin, dipyridamole, and the combination also reduced the incidence of TIAs and other vascular events in a manner consistent with these treatments' effects on the risk of stroke.755 None of the treatments had a statistically significant effect on the end point of death (i.e., no effect on survival).738,745,755 Headache and GI events were the most common adverse effects in this study, occurring more frequently in the dipyridamole-treated groups, while bleeding from the GI tract or from any site was more common in the aspirin-treated groups.755

In another randomized, placebo-controlled, open-label study (European/Australasian Stroke Prevention in Reversible ischemia Trial [ESPRIT]) in patients who had experienced a TIA or minor stroke within the previous 6 months, treatment with aspirin (median dosage 75 mg daily, range 30-325 mg daily) in combination with dipyridamole (200 mg twice daily) resulted in a reduction in the overall risk of the composite primary outcome (death from all vascular causes, nonfatal stroke, nonfatal MI, major bleeding complication) compared with that in patients receiving aspirin alone.883 Approximately 34% of patients discontinued treatment with the aspirin-dipyridamole combination during the study because of adverse effects, principally headache.883 Results from other trials evaluating combination therapy with aspirin (900 mg to 1.3 g daily) and dipyridamole (150-300 mg daily) also have been reported to reduce the risk of cerebral infarction in patients with TIAs or mild stroke. A meta-analysis of data from the ESPRIT and several prior studies comparing aspirin with or without dipyridamole in patients with cerebral ischemia of presumed arterial origin demonstrated an overall reduction of 18% in the incidence of primary outcome events with combined aspirin and dipyridamole treatment compared with aspirin alone.

ACCP, ASA, AHA, and other clinicians recommend long-term antiplatelet therapy for secondary prevention of ischemic atherothrombotic (noncardioembolic) stroke or TIAs in patients with prior TIAs or stroke.863,990,1009 In such patients, ACCP states that aspirin, clopidogrel, the combination of aspirin and dipyridamole, or cilostazol are all acceptable options for long-term antithrombotic therapy.1009 Based on a somewhat greater risk reduction for stroke, ACCP suggests that clopidogrel or the combination of aspirin and dipyridamole may be preferred over the other options for secondary prevention of noncardioembolic stroke.1009 When selecting an appropriate antiplatelet regimen for the secondary prevention of noncardioembolic stroke, factors such as the patient's individual risk for recurrent stroke, tolerance, and cost of the different agents should be considered.990 Oral anticoagulation (e.g., warfarin) rather than antiplatelet therapy is recommended for the secondary prevention of cardioembolic stroke in patients with a history of ischemic stroke or TIA and concurrent atrial fibrillation; however, in patients who cannot take or choose not to take warfarin (e.g., those with difficulty maintaining stable international normalized ratios [INRs], compliance issues, dietary restrictions, cost limitations), dual antiplatelet therapy with aspirin and clopidogrel is recommended.1009

In children with acute arterial ischemic stroke†, aspirin is recommended as one of the options for initial antithrombotic therapy until cerebral arterial dissection and embolic causes have been excluded.1013 Once dissection and cardioembolic causes have been excluded, secondary prevention with aspirin therapy (in prophylactic dosages for at least 2 years) is suggested.1013 Children who experience recurrent arterial ischemic stroke or TIAs despite aspirin therapy may be switched to clopidogrel or anticoagulant therapy with a low molecular weight heparin or warfarin.1013

Coronary Artery Disease and Myocardial Infarction

ST-Segment-Elevation Myocardial Infarction

The current standard of care in patients with ST-segment-elevation MI (STEMI) is timely reperfusion (with primary PCI or thrombolytic therapy).527,994 Adjunctive therapy with anticoagulant (e.g., heparin) and antiplatelet (e.g., aspirin and clopidogrel) agents should be used during and after successful coronary artery reperfusion for the prevention of early reocclusion and death, unless contraindicated.527 Aspirin reduces the risk of stroke, recurrent infarction, and death in adults with STEMI and should be administered in all such patients regardless of the reperfusion strategy.527,579,842,992,1010 Aspirin in a dose of 162-325 mg, initiated as soon as possible after the clinical impression of an evolving acute STEMI is formed and continued indefinitely at a dosage of 81-325 mg daily, also is strongly recommended for the acute management of all patients (unless contraindicated) with suspected STEMI, regardless of whether thrombolytic therapy is to be given.527 Some experts prefer the use of a maintenance dosage of 81 mg daily because of a decreased risk of bleeding and lack of definitive evidence demonstrating that higher dosages confer greater benefit in this setting.527 A P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) should be administered in conjunction with aspirin in patients with STEMI.527,992,993,994,1010

In a large, multicenter study (Second International Study of Infarct Survival; ISIS-2) of patients with an evolving STEMI allocated to treatment early (within 24 hours of symptom onset), therapy with aspirin 162.5 mg daily for 1 month was shown conclusively to be associated with a vascular mortality reduction at 5 weeks of 23% compared with placebo.579,635 In this study, a statistically significant difference in both vascular and all-cause mortality, which persisted for at least a median of 15 months after treatment, was observed.579 Patients receiving aspirin had fewer nonfatal reinfarctions and nonfatal strokes compared with those given placebo and, when given concomitantly with IV streptokinase therapy, aspirin appeared to prevent the increase in reinfarction observed with streptokinase treatment alone.579 Compared with placebo, aspirin treatment resulted in a small increase in the incidence of minor bleeding complications but no increase in major bleeding (e.g., intracranial hemorrhage).579 When aspirin is combined with thrombolytic therapy (streptokinase), the reduction in mortality associated with acute STEMI is even greater, being reported as a 42% reduction.635 Pooled analysis of clinical studies indicates that aspirin reduces coronary reocclusion and recurrent ischemic events after thrombolytic therapy with streptokinase or alteplase.635,735 At doses of at least 160 mg, aspirin produces a rapid clinical antithrombotic effect via immediate and near-total inhibition of thromboxane A₂.635 As a result, aspirin is an important therapy in the early management of suspected acute STEMI.527

In patients with STEMI who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves), many experts recommend the addition of warfarin (INR 2-3) to antiplatelet therapy; in some cases, triple antithrombotic therapy (warfarin, low-dose aspirin, and clopidogrel) is suggested, such as in patients with an anterior STEMI and left ventricular thrombosis undergoing PCI with coronary artery stent implantation.993,996,1007,1010 However, triple-drug antithrombotic regimens are associated with an increased risk of bleeding. (See Uses: ST-Segment Elevation Myocardial Infarction, in Warfarin 20:12.04.08.)

Secondary Prevention of Cardiovascular Events

Unless contraindicated, therapy with low-dose aspirin currently is recommended by AHA and the American College of Cardiology Foundation (ACCF) for all patients with coronary artery disease in order to reduce the risk of vascular events ( secondary prevention ).992 ACCP recommends long-term, single-drug antiplatelet therapy with aspirin or clopidogrel in patients with established coronary artery disease (i.e., 1 year after ACS with prior revascularization, coronary stenosis greater than 50% by coronary angiogram, and/or evidence of cardiac ischemia on diagnostic testing).1010 The efficacy of aspirin for secondary prevention of cardiovascular events does not appear to be influenced by gender or age.579,682 The American Diabetes Association (ADA) currently recommends low-dose aspirin (e.g., 75-162 mg daily) for secondary prevention of cardiovascular events (e.g., MI) in patients with diabetes mellitus and a history of atherosclerotic cardiovascular disease (ASCVD).1116

Primary Prevention of Ischemic Cardiac Events

The beneficial effects of aspirin for secondary prevention of cardiovascular disease are well established;992,1116 however, use of aspirin for primary prevention of cardiovascular disease remains controversial.1112,1117,1118,1119 Low-dose aspirin (e.g., 75-162 mg daily) has been used to reduce the risk of a first cardiac event ( primary prevention †) in patients with at least a moderate risk factor for a coronary event.573,574,658,659,660,661,666,667,668,676,783,784 However, recent evidence suggests that aspirin therapy should not be used routinely for primary prevention of cardiovascular disease because of a lack of net benefit.646,658,661,674,675,676,783,784,847,1110

Most clinical studies that demonstrated the beneficial effect of aspirin for primary prevention of cardiovascular disease (e.g., the US Physicians' Health Study [men 40-84 years of age without a history of ischemic heart disease], the British Doctors' Study [men younger than 60 up to 79 years of age without ischemic heart disease], the Medical Research Council's Thrombosis Prevention Trial [men 45-69 years of age with an increased risk of ischemic heart disease], the Hypertension Optimal Treatment [HOT] trial [men and women 50-80 years with hypertension], the Primary Prevention Project [PPP] [patients at least 50 years of age who had at least one major cardiovascular risk factor]) were conducted prior to modern preventative and therapeutic practices (i.e., emphasis on stricter blood pressure control, smoking cessation, and cholesterol reduction).573,574,575,576,659,660,666,667 785,786,1111,1112,1118 While low-dose aspirin may still confer benefits in selected patients, there is less certainty regarding the drug's widespread use for primary prevention.1111,1117,1118,1119 In 3 recently conducted randomized, placebo-controlled primary prevention studies evaluating the use of low-dose aspirin regimens (100 mg once daily in all 3 studies) in various patient populations, there was no substantial net clinical benefit with low-dose aspirin therapy largely because of an increased risk of bleeding with aspirin use.1112,1113,1114,1115 In the ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) study, which included patients 55 years of age or older without diabetes mellitus and with a low to moderate cardiovascular risk, low-dose aspirin did not substantially reduce the combined outcome of first MI, stroke, cardiovascular death, unstable angina, or transient ischemic attack but was associated with an increased risk of GI bleeding.1115 In the ASCEND (A Study of Cardiovascular Events In Diabetes) study, which included patients 40 years of age or older with type 1 or type 2 diabetes mellitus who did not have known cardiovascular disease, the use of low-dose aspirin for 7.4 years was associated with a 12% reduction in the rate of serious vascular events at the cost of a 29% increase in major bleeding.1112 In this study, there was no substantial difference in all-cause mortality among patients who received aspirin therapy and those who did not.1112 In the ASPREE (ASPirin in Reducing Events in the Elderly) study, which included healthy patients 65 years of age and older without cardiovascular disease, low-dose aspirin use resulted in a substantially higher risk of major hemorrhage (composite of hemorrhagic stroke, symptomatic intracranial bleeding, or clinically important extracranial bleeding) and did not substantially reduce the risk of cardiovascular disease.1113

Based on available evidence including the results of these recent clinical studies, experts from the American College of Cardiology and American Heart Association (ACC/AHA) recommend that low-dose aspirin (e.g., 75-100 mg daily) for primary prevention be reserved for adults 40-70 years of age who have a higher risk of cardiovascular disease without an increased risk of bleeding (e.g., patients with a history of previous GI bleed, peptic ulcer disease, thrombocytopenia, coagulopathy, chronic kidney disease, concomitant use of drugs that increase bleeding risk [e.g., nonsteroidal anti-inflammatory drugs, corticosteroids, direct oral anticoagulants, warfarin]).1110,1111 When determining a patient's risk for ASCVD, these experts state that the totality of patient risk factors should be considered (e.g., strong family history of premature MI; inability to achieve lipid, blood pressure, or blood glucose targets; substantial elevation in coronary artery calcium score) in conjunction with patient and clinician preferences.1110 High-risk patients also include adults 40-70 years of age without diabetes mellitus who have a 10-year ASCVD risk of at least 20% and those with diabetes mellitus who have a 10-year ASCVD risk of at least 10%.1111 Low-dose aspirin for primary prevention is not recommended for adults with a low ASCVD risk, and the routine use of aspirin for primary prevention is not recommended in patients younger than 40 years of age or older than 70 years of age.1110,1111 In addition, such experts state that it is unclear whether low-dose aspirin should be continued in patients already taking aspirin who turn 70 years of age.1111 Additional studies are needed to clarify aspirin's role in the primary prevention of cardiovascular disease.1111

Based on a systematic review of evidence, the US Preventive Services Task Force (USPSTF) has concluded that the beneficial effects of aspirin for primary prevention of cardiovascular disease are modest and occur at daily dosages of 100 mg or less; subpopulation analyses suggest a greater relative benefit for MI prevention in older age groups.1117

The ADA states that the use of aspirin for primary prevention of cardiovascular disease should be carefully considered and generally may not be recommended.1116 ADA states that primary prevention with low-dose aspirin may be considered in patients with type 1 or type 2 diabetes mellitus who are at high risk for cardiovascular events (i.e., familial history of premature ASCVD, smoking, hypertension, chronic kidney disease/albuminuria, elevated blood cholesterol or triglyceride concentrations) and have a low bleeding risk.1116 ADA also states that aspirin use is not recommended for patients at low risk of ASCVD (e.g., men and women younger than 50 years of age with diabetes mellitus and no other major risk factors) as the risk of bleeding is likely to outweigh the small benefit.1116 For patients older than 70 years of age (with or without diabetes mellitus), the risks associated with the use of low-dose aspirin appear to outweigh any potential benefits1116

Non-ST-Segment-Elevation Acute Coronary Syndromes

Aspirin is used to reduce the risk of death and/or nonfatal MI in patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS).613,614,615,616,617,618,619,620,621,682,684,736,740,1100 Patients with NSTE ACS have either unstable angina or non-ST-segment-elevation MI (NSTEMI); because these conditions are part of a continuum of acute myocardial ischemia and have indistinguishable clinical features upon presentation, the same initial treatment strategies are recommended.1100,1102 The American Heart Association/American College of Cardiology (AHA/ACC) guideline for the management of patients with NSTE ACS recommends an early invasive strategy (angiographic evaluation with the intent to perform revascularization procedures such as PCI with coronary artery stent implantation or CABG) or an ischemia-guided strategy (initial medical management followed by cardiac catheterization and revascularization if indicated) in patients with definite or likely NSTE ACS; standard medical therapies for all patients should include a β-adrenergic blocking agent (β-blocker), antiplatelet agents, anticoagulant agents, nitrates, and analgesic agents regardless of the initial management approach.1100 Aspirin is the mainstay of antiplatelet therapy in patients with NSTE ACS and should be administered in all such patients unless contraindicated; a loading dose of aspirin should be administered as soon as possible after diagnosis, followed by a maintenance dosage that should be continued indefinitely unless such therapy is not tolerated or contraindicated.681,682,993,1010,1100 A P2Y12-receptor antagonist (e.g., clopidogrel, ticagrelor) should be administered in conjunction with aspirin for up to 12 months unless contraindicated.992,993,994,1010,1100

Aspirin therapy has been shown to substantially reduce the rates of total mortality or cardiac death and nonfatal MI in patients with NSTE ACS.613,614,615,616,617,618,619,620,621,622,682,684 Several randomized, placebo-controlled studies indicate that prophylactic aspirin therapy is associated with a reduction of at least 50% in the risk of death and/or nonfatal MI in men and women with NSTE ACS.613,614 In another randomized, controlled study in men with NSTE ACS who received 75 mg of aspirin daily, the risk of MI and death was reduced by 57-69% at least 5 days after initiation of therapy.617

Chronic Stable Angina

In patients with chronic stable angina, low-dose aspirin is used to reduce the risk of MI and sudden death.646,680,681,682,728,736,822 Experts recommend that aspirin therapy (75-162 mg daily) be continued indefinitely in patients with stable ischemic heart disease who do not have contraindications.1101 There is some evidence suggesting that an aspirin dosage not exceeding 75-81 mg daily may be sufficient for long-term cardiovascular prevention and is associated with less GI bleeding risk.907 Clopidogrel may be used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin.822,1101

Evidence from a large, randomized, placebo-controlled study in patients with stable chronic angina pectoris showed that aspirin (75 mg daily) combined with sotalol therapy is associated with 34% reduction in the primary endpoint of fatal or nonfatal MI and sudden death and a 22-32% reduction in secondary endpoints (vascular events, vascular death, all-cause mortality, stroke).646,680,728,736 There also was a reduction in nonfatal MI, the principal component of benefit of the primary end point.646,680 Although not significantly different from placebo, aspirin therapy also was associated with a favorable trend in decreasing vascular deaths and all-cause mortality when considered separately.646 Because all patients in this study received sotalol concomitantly, this study did not establish whether aspirin alone is effective in patients with chronic stable angina.646,681 However, the ability of aspirin to decrease the rate of thrombotic vascular events in various conditions has not depended on concomitant β-blocker therapy to date, and therefore it is likely that aspirin therapy would be beneficial in patients with chronic stable angina pectoris regardless of concomitant β-blocker therapy.646

Percutaneous Coronary Intervention and Revascularization Procedures

Aspirin is used to reduce early ischemic complications in patients with ACS undergoing PCI (e.g., coronary angioplasty, coronary stent implantation).646,866,887,888,889,992,993,994,1010 ACCF, AHA, and the Society for Cardiovascular Angiography and Interventions (SCAI) recommend pretreatment with aspirin (81-325 mg in those already receiving long-term aspirin therapy, otherwise 325 mg as non-enteric-coated aspirin) at least 2, and preferably 24, hours before the procedure.994 In addition to aspirin, a loading dose of a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) is recommended in patients undergoing PCI with stent placement.994 Aspirin should be continued indefinitely after PCI, while a P2Y12-receptor antagonist generally should be continued for at least 12 months following stent placement.992,993,994

In patients with anterior MI and left ventricular thrombus (or at high risk for left ventricular thrombus) who undergo stent placement, ACCP suggests the use of warfarin and clopidogrel in addition to aspirin therapy; the recommended duration of such triple antithrombotic therapy is dependent on whether the patient has a bare-metal or drug-eluting stent.1010 However, such triple antithrombotic regimens are associated with an increased risk of bleeding.

An increased incidence of late stent thrombosis has been reported in patients with drug-eluting stents, often coincident with discontinuance of clopidogrel after initially recommended durations of dual-drug antiplatelet therapy.886,890,891,892,893,894,895,896,897,898,899,900 Stent thrombosis can be a catastrophic event leading to MI and/or death,886,890,891 and a broad range of experts currently recommend that dual-drug therapy with aspirin and a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) be continued for at least 12 months in patients with any type of coronary artery stent (drug-eluting or bare-metal) who are not at high risk of bleeding.886,887,888,890,891,892,894,902,993,994,1010 Some evidence suggests that an even longer duration of dual antiplatelet therapy (more than 12 months) may be beneficial in some patients with drug-eluting stents, but such prolonged therapy may be associated with a higher risk of bleeding and other adverse effects.1019,1020 (See Uses: Prevention of Stent Thrombosis, in Clopidogrel 20:12.18.)

Aspirin is used to prevent reocclusion of the aortocoronary bypass graft in patients undergoing coronary revascularization procedures (e.g., CABG),646,683,992 and there is some evidence indicating that early (within 48 hours) administration of aspirin (75-325 mg daily) after CABG also is associated with a substantially reduced risk of both fatal and nonfatal (e.g., ischemic complications) outcomes in patients undergoing saphenous vein CABG.687,781,782 In a multicenter, prospective, longitudinal study, data on nonfatal and fatal outcomes (e.g., MI, heart failure, stroke, renal dysfunction or failure, GI ischemia or infarction) were recorded for patients with CHD who were refractory to medical therapy and who underwent CABG.781 Use of aspirin (total dose of 80-650 mg) within the first 48 hours following CABG was associated with a reduction in overall mortality during hospitalization of about 68% and reductions of 48, 50, 74, and 62% in the incidences of MI, stroke, renal failure, and bowel infarction, respectively.781 Duration of hospitalization also was shorter in patients receiving aspirin compared to those who did not (9.5 versus 11.5 days, respectively).781 Aspirin use was not associated with an increased risk of bleeding, gastritis, infection, or impaired wound healing.781 Subset analysis of data suggested that discontinuance of aspirin use prior to CABG and institution of hemostatic therapies (e.g., platelet transfusions, antifibrinolytic agents) during the perioperative period (i.e., during reperfusion following CABG) was associated with an increased risk of mortality and ischemic complications.781

Some clinicians suggest that early administration of aspirin now be considered standard therapy in all patients undergoing CABG, including internal mammary artery bypass grafting, unless specifically contraindicated.781,782,880,992 AHA and ACCF recommend that aspirin therapy be initiated within 6 hours after CABG and continued for up to 1 year to reduce saphenous vein graft closure; aspirin dosages of 100-325 mg daily appear to be effective for this use.992 For long-term therapy after 1 year, ACCP recommends the use of low-dose aspirin in all patients with established coronary artery disease, including those with prior CABG.1010 There are some data suggesting that an aspirin dosage not exceeding 75-81 mg daily may be sufficient for long-term cardiovascular prevention and is associated with less GI bleeding risk.907

Aspirin has been used in combination with dipyridamole to prevent thrombosis in vein grafts in patients who undergo aortocoronary-artery bypass.557,560,561,562,563,683,720,721,722 However, dipyridamole does not appear to enhance the efficacy of aspirin, regardless of aspirin dosage, in patients receiving saphenous vein or internal mammary artery grafts.646,885

Embolism Associated with Atrial Fibrillation

Antiplatelet agents (e.g., aspirin) have been used as an alternative or adjunct to warfarin therapy to reduce the incidence of thromboembolic episodes in selected patients with chronic atrial fibrillation†.749,880,999,1007 ACC, AHA, ACCP, ASA, and other experts currently recommend that antithrombotic therapy be administered to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated.989,990,999,1007,1017,1021,1022,1023

Recommendations regarding choice of antithrombotic therapy in patients with atrial fibrillation are based on the patient's risk for stroke and bleeding.999,1007,1021,1022,1023 In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with atrial fibrillation who have a high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke.999,1007,1017,1021,1022,1023 Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., 75 years or older), history of hypertension, diabetes mellitus, or congestive heart failure.990,999,1007,1021,1022,1023 In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients 75 years of age or older, and AHA and ASA recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk.1017 One such tool is the CHA₂DS₂-VASc score, an extension of the CHADS₂ system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous MI, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points).1017,1024 Pooled analyses of data from a number of comparative studies evaluating therapy with a coumarin derivative (e.g., warfarin) or aspirin suggest that warfarin therapy is more effective than aspirin in reducing thromboembolic complications (e.g., TIAs, ischemic stroke) in patients with atrial fibrillation.744,748,749,750,1007 However, the anticipated greater benefit of warfarin compared with aspirin must be weighed against the greater risk of bleeding with warfarin.999,1007 Because the net clinical benefit with warfarin relative to aspirin appears to be greatest in patients with a high (and possibly also intermediate) risk of stroke, ACCP and other experts recommend the use of warfarin (target INR 2-3) over aspirin in such patients.999,1007 Some experts also suggest that a non-vitamin K antagonist oral anticoagulant (e.g., apixaban, dabigatran, rivaroxaban) may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions) and may be considered as alternative therapy to warfarin in selected patients.989,1017,1025,1026,1027,1028,1029,1030 (See Uses: Embolism Associated with Atrial Fibrillation, in Apixaban 20:12.04.14.) For patients at low risk of stroke, the expected benefits of warfarin may not outweigh the risks of bleeding, and thus, aspirin is preferred.999,1007

Results of a study comparing dual antiplatelet therapy (clopidogrel and aspirin) with aspirin in patients with atrial fibrillation who had an increased risk of stroke but were unable to take warfarin showed that the combination of clopidogrel and aspirin was more effective than aspirin in reducing the risk of stroke; however, such dual antiplatelet therapy was associated with an increased risk of bleeding.998,1007 Based on these findings, ACCP and other experts recommend the use of clopidogrel and aspirin rather than aspirin alone as an alternative to warfarin in patients with atrial fibrillation at increased risk of stroke who cannot take or choose not to take warfarin (e.g., those with difficulty maintaining stable INRs).998,1007

The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation.999 In addition, many patients with atrial flutter have alternating periods of atrial fibrillation.1007 Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.999,1007

Peripheral Arterial Disease

Aspirin also has been used for primary and secondary prophylaxis of cardiovascular events in patients with peripheral arterial disease, including those with intermittent claudication or carotid artery stenosis and those undergoing revascularization procedures (peripheral artery percutaneous transluminal angioplasty or peripheral arterial bypass graft surgery, carotid endarterectomy).1011 ACCP recommendations for the use of aspirin in patients with peripheral arterial disease are largely similar to those in patients with coronary arterial disease.1011 In general, aspirin is suggested in patients with asymptomatic disease (primary prevention) because of some evidence demonstrating a slight reduction in total mortality when the drug is taken over a period of 10 years.1011 For patients with symptomatic peripheral arterial disease or those undergoing revascularization procedures, single-drug antiplatelet therapy with aspirin or clopidogrel is recommended; dual antiplatelet therapy with aspirin and clopidogrel generally is not suggested except in patients receiving below-the-knee prosthetic bypass grafts.1011 AHA and ASA state that unless contraindicated, aspirin is recommended in patients who are to undergo carotid endarterectomy because aspirin was used in every trial that demonstrated the efficacy of this procedure.1017 Aspirin or the combination of aspirin and dipyridamole also are recommended as 2 of several options for long-term antiplatelet therapy in patients with symptomatic carotid stenosis†, including those who have undergone recent carotid endarterectomy.1011,1017

Although aspirin has generally been ineffective in preventing thrombosis after arterial catheterization, a single 600-mg oral dose the evening before surgery has been reported to reduce the incidence of thrombosis following radial-artery catheterization for surgery.

Valvular Heart Disease

In selected patients with mitral valve prolapse and atrial fibrillation (i.e., those younger than 65 years of age who have no history of mitral valve regurgitation, hypertension, or heart failure), aspirin therapy (e.g., 75-325 mg daily) is recommended by ACC and AHA.996 Aspirin also is recommended for symptomatic patients with mitral valve prolapse who experience a TIA.996

Prosthetic Heart Valves

Aspirin is used for the prevention of thromboembolism in selected patients with prosthetic heart valves†.996,1008 Warfarin generally is recommended in patients with mechanical heart valves because of the high risk of thromboembolism associated with these valves.996,1008 In patients with a bioprosthetic heart valve in the aortic position who are in sinus rhythm and who have no other indications for warfarin, ACCP and ACC/AHA suggest the use of low-dose aspirin (50-100 mg daily) for initial (i.e., first 3 months after valve insertion) and long-term antithrombotic therapy.996,1008 Warfarin therapy is suggested by ACCP in patients with bioprosthetic heart valves in the mitral position, at least for the first 3 months after valve insertion; after the first 3 months, aspirin may be substituted for warfarin therapy, provided the patient is in normal sinus rhythm.1008

Because warfarin therapy alone does not completely prevent thrombosis in patients with prosthetic mechanical heart valves†, aspirin has been used in conjunction with warfarin to reduce the incidence of thrombosis in these patients. The combination of aspirin and warfarin appears to be more effective than warfarin alone in patients with prosthetic mechanical valves, but the risk of bleeding complications may be increased.1008 Pooled analysis of several randomized, controlled studies comparing combined therapy with an antiplatelet agent (aspirin or dipyridamole) and an oral anticoagulant (e.g., warfarin) versus oral anticoagulant monotherapy in patients who had received mechanical prosthetic heart valves showed that combined therapy substantially reduced systemic thromboembolism (principally manifested as stroke) and overall mortality compared with oral anticoagulant therapy alone; however, the risk of bleeding complications (e.g., hemorrhage, major GI hemorrhage) also was increased with combined therapy.693 In this analysis, it was estimated that for every 1.6 patients who had stroke prevented by combined therapy, there was an excess of one major GI bleeding episode, suggesting that the benefits derived from enhanced antithrombotic activity outweigh the risks resulting from enhanced bleeding potential.693 Subgroup analyses also showed that such benefits occur when only studies in which combined aspirin and oral anticoagulant therapy were considered, but that the increased risk of bleeding occurred mainly in patients receiving an oral anticoagulant combined with aspirin rather than with dipyridamole.693 Of 4 studies involving aspirin, 3 employed moderate (500 mg daily) or high (1 g daily) aspirin dosages, with the remaining one employing a low dosage of 100 mg daily.693

Based on current evidence, ACCP and other experts recommend the addition of an antiplatelet agent such as low-dose aspirin to warfarin therapy in all patients with mechanical heart valves who are at low risk of bleeding.996,1008 Combination therapy with aspirin and warfarin also is recommended by ACC/AHA in patients with bioprosthetic heart valves who have additional risk factors for thrombosis (e.g., atrial fibrillation, previous thromboembolism, left ventricular dysfunction, hypercoagulable condition).996

In pregnant women with prosthetic heart valves, a low molecular weight heparin or unfractionated heparin is substituted for warfarin because of concerns about warfarin embryopathy.1012 Based on extrapolation of data from nonpregnant patients with prosthetic heart valves, aspirin (75-100 mg daily) may be added to therapy with a low molecular weight heparin or unfractionated heparin in pregnant women with prosthetic heart valves who are at high risk for thrombosis.1012

In patients with a prosthetic heart valve receiving long-term oral antithrombotic therapy (warfarin and/or aspirin) who require surgical procedures, the risk of perioperative bleeding should be weighed against the increased risk of thromboembolism that may occur as a result of temporary discontinuance of oral antithrombotic therapy.741,1004 Oral antithrombotic therapy generally should not be discontinued for procedures in which bleeding is unlikely or inconsequential, such as minor dental, dermatologic, or ophthalmologic procedures.1004

Thrombosis Associated with Heart Surgery in Children

ACCP recommends aspirin (1-5 mg/kg daily) or unfractionated heparin followed by warfarin for the prevention of thromboembolic complications in children undergoing Fontan surgery† (the definitive palliative surgical treatment for most congenital univentricular heart lesions).1013 However, despite even aggressive antithrombotic therapy in children who have undergone the Fontan procedure, thromboembolic events associated with the procedure result in a high mortality rate and respond to therapy in less than 50% of patients.1013 There currently is no consensus on the optimal type or duration of antithrombotic therapy following Fontan surgery, and a wide variety of prophylactic regimens currently are in use.1013

Venous Thromboembolism

Thromboprophylaxis in Orthopedic Surgery

Aspirin has been used for the prevention of venous thromboembolism in patients undergoing major orthopedic surgery (total-hip replacement†, total-knee replacement†, or hip-fracture surgery†).1003 Although aspirin generally is not considered the drug of choice for this use,1003 there is some evidence suggesting that aspirin may provide some benefit over placebo or no antithrombotic prophylaxis in patients undergoing major orthopedic surgery.953,954,1003 (See Hip-Replacement, Knee-Replacement, or Hip-Fracture Surgery under Venous Thromboembolism: Prophylaxis, in Uses in Enoxaparin 20:12.04.16.) Results of a large, randomized placebo-controlled study (The Randomized Placebo-controlled Pulmonary Embolism Prevention [PEP] Trial) in patients undergoing hip-fracture surgery or elective arthroplasty showed that aspirin was associated with a modest reduction in the risk of symptomatic deep-vein thrombosis at the expense of a possible increased risk of major bleeding and nonfatal MI.1003 Based on these findings, ACCP considers the use of aspirin to be an acceptable option for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery.1003 When selecting an appropriate thromboprophylaxis regimen, ACCP states that factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered.1003 For additional information on the prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Thromboprophylaxis in General Surgery

Aspirin also has been used for thromboprophylaxis in patients undergoing general (e.g., abdominal) surgery who are at high risk of venous thromboembolism.1002 If pharmacologic prophylaxis is indicated in such patients undergoing general surgery, ACCP states that a low molecular weight heparin or low-dose unfractionated heparin is preferred, but when these agents are contraindicated or not available, aspirin or fondaparinux may be considered.1002

For additional information on the prevention of venous thromboembolism in patients undergoing surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Pericarditis

In addition to its use for reducing the risk of death and/or nonfatal recurrent MI (secondary prevention) (see Coronary Artery Disease and Myocardial Infarction under Uses: Thrombosis), aspirin also is used for the treatment of pain associated with acute pericarditis that develops after an acute MI.527

ACCF and AHA recommend that pericarditis be considered in the differential diagnosis of recurrent chest pain after STEMI.527 Pericarditis probably is not responsible for clinically important chest pain during the initial 24 hours after infarction and may not become evident for up to several weeks after an acute MI.635,821 Recurrent pain occurring during the initial 12 hours after onset of infarction usually is considered related to the original infarction itself.635,821 Pericarditis in acute MI occurs with extension of myocardial necrosis throughout the epicardial wall.635,821 The Multicenter Investigation of the Limitation of Infarct Size (MILIS) study found that pericarditis (defined as presence of pericardial friction rub) occurred in about 20% of patients following acute MI.635 In patients not treated with thrombolytic therapy, pericarditis occurs in about 25% of patients as evidenced by either typical symptoms or pericardial friction rub, but the incidence averages only 14% when the presence of a friction rub is required for diagnosis.635 Patients with pericarditis have larger infarcts, lower ejection fractions, and a higher incidence of congestive heart failure.635,821 Although anterior chest discomfort mimicking ischemia can occur with pericarditis, pericardial pain usually exhibits distinguishing characteristics, including pleural or positional discomfort; radiation to the left shoulder, scapula, or trapezius muscle; and a pericardial rub, ECG J-point elevation with concave upward ST-segment elevation, and PR depression.527,635,821 It is important to distinguish between pain caused by pericarditis and that caused by ischemia since management will differ.635 On occasion, pericarditis may be a clinical clue to the presence of subacute myocardial rupture.821 Although pericarditis is not an absolute contraindication to anticoagulation, ACCF and AHA state that anticoagulation therapy should be used with caution due to the potential for hemorrhagic conversion.527

In one study, the effects of 2.6 g of oral aspirin daily were comparable to those of 100-200 mg of oral indomethacin daily, with either drug relieving symptoms within 48 hours. Although other NSAIAs (e.g., indomethacin, ibuprofen) or corticosteroids also can provide symptomatic relief, these drugs may be associated with adverse cardiac effects (e.g., increased coronary vascular resistance, thinning of the developing scar, myocardial rupture).527,635,821 The possibility that cardiac rupture, which occurs in about 1-4% of patients hospitalized for acute MI, may account for recurrent pain should be considered since use of NSAIAs may be a risk factor in its development.635 ACCF and AHA state the administration of acetaminophen, colchicine, or opiate analgesics may be reasonable if pain relief with aspirin therapy is ineffective.527

Kawasaki Disease

The American Academy of Pediatrics (AAP), AHA, and ACCP recommend aspirin therapy used in conjunction with immune globulin IV (IGIV) for initial treatment of the acute phase of Kawasaki disease†; aspirin also is used alone or in conjunction with other antiplatelet agents or anticoagulants for follow-up treatment.638,916,1013

High-dose aspirin therapy (80-100 mg/kg daily for up to 14 days) combined with a single dose of IGIV (2 g/kg) initiated within 10 days of the onset of fever is more effective than aspirin therapy alone for preventing or reducing the occurrence of coronary artery aneurysms associated with Kawasaki disease; fever and other manifestations of inflammation also may resolve more rapidly with concomitant therapy.638,639,640,916,1013 Aspirin then is continued alone in lower dosages (i.e., 1-5 mg/kg daily) for antiplatelet effects for 6-8 weeks in those without coronary artery changes or with only transient coronary artery ectasia or dilatation (disappearing within the initial 6-8 weeks of illness).638,916,1013 For additional information on initial treatment of Kawasaki disease, see Uses: Kawasaki Disease and also see Kawasaki Disease under Dosage and Administration: Dosage for Immune Globulin IV, in Immune Globulin 80:04.

Coronary artery abnormalities develop in 15-25% of children with Kawasaki disease if they are not treated within 10 days of onset of fever;638,916 2-4% of patients develop coronary artery abnormalities despite prompt treatment with aspirin and IGIV.638 Long-term management of those who develop coronary abnormalities depends on the severity of coronary involvement and may include low-dose aspirin (with or without clopidogrel or dipyridamole), anticoagulant therapy with warfarin or low molecular weight heparin, or a combination of antiplatelet and anticoagulant therapy (usually low-dose aspirin and warfarin).638,916,1013 If giant coronary aneurysms are present, AHA and ACCP suggest long-term low-dose aspirin therapy in conjunction with warfarin for primary thromboprophylaxis.950,1013 Specialized references should be consulted for additional information on long-term management of Kawasaki disease in individuals with coronary abnormalities.916,1013

Complications of Pregnancy

Aspirin should be used during pregnancy only when clearly needed,646 weighing carefully the potential benefits versus the possible risks to the mother and fetus.648,652,653 (See Cautions: Pregnancy, Fertility, and Lactation, in the Salicylates General Statement 28:08.04.24.)

Aspirin has been used alone or in combination with other drugs (e.g., unfractionated heparin, low molecular weight heparins, corticosteroids, immune globulin) for the prevention of complications of pregnancy† (e.g., preeclampsia, pregnancy loss in women with a history of antiphospholipid syndrome and recurrent fetal loss).594,595,596,597,598,599,600,601,605,626,627,628,648,650,651,652,653,654,705,706,707,708,709,710,711,712,713,714,715,726,857,1012,1017 Maternal and fetal hemorrhagic complications observed with maternal ingestion of large dosages (e.g., 12-15 g daily) of aspirin594,595,597,611,612 generally have not been observed in studies in which dosages of 50-150 mg daily of the drug were used during the second and third trimesters for prevention of complications of pregnancy (e.g., preeclampsia, recurrent spontaneous abortions, prematurity, intrauterine growth retardation, stillbirth, low birthweight), including those associated with autoimmune disorders such as antiphospholipid syndrome, poor paternal blocking antibody production, or systemic lupus erythematosus.594,595,596,597,598,599,600,601,605,626,627,629,630,631,632,649,1012

Results of several controlled studies suggest that low dosages of aspirin administered from preconception through delivery alone or in combination with heparin or corticosteroids in high-risk women may prevent the development of preeclampsia and fetal growth retardation and reduce perinatal death,594,595,596,597,598,599,600,601,603,604,605,608,610,626,627,628,1017 possibly by suppressing thromboxane A₂-mediated vasospasm, ischemia, and thrombosis.597,599,601,603,604,606,607,609,627,628,630 The presence of maternal antiphospholipid antibodies is associated with an increased risk of thrombosis and pregnancy loss.1012 Data from several small comparative studies indicate that combined prophylaxis with heparin and low dosages of aspirin may be more effective than aspirin alone or aspirin combined with a corticosteroid in preventing recurrent pregnancy loss (fetal death, miscarriage), preeclampsia, or premature delivery in women with antiphospholipid syndrome (Hughes syndrome).626,627,628,629,650,651,652,653,726,1012 In at least one study in women with antiphospholipid antibodies and at least 2 prior pregnancy losses, combined aspirin (100 mg daily) and corticosteroid (prednisone 0.5-0.8 mg/kg daily) therapy was not effective in promoting live birth and was associated with an increased risk of prematurity.714 The beneficial effect of prophylactic therapy with aspirin and heparin may result from aspirin-induced suppression of thromboxane₂-mediated vasospasm, ischemia, and thrombosis in the placental vasculature597,599,601,603,604,606,607,609,627,628,630,650,726 and by heparin-induced anticoagulation combined with binding to phospholipid antibodies that protects the trophoblast from antibody attack and thus promotes successful implantation in early pregnancy.650

Women with antiphospholipid syndrome and a history of multiple pregnancy losses are candidates for prophylactic therapy†,650,651,652,653,726 and most experts currently recommend combined prophylactic therapy with low dosages of aspirin and unfractionated heparin or low molecular weight heparin, followed by postpartum warfarin therapy.650,651,652,653,726,857,1012 ACCP states that women with antiphospholipid antibody (APLA) syndrome and a history of multiple pregnancy losses (at least 3) should receive antepartum prophylaxis with low-dose aspirin in combination with subcutaneous unfractionated heparin or a low molecular weight heparin.1012 (See Uses: Thromboembolism Occurring During Pregnancy, in Enoxaparin 20:12.04.16.)

Because of experience in women with antiphospholipid syndrome, aspirin and heparin (often combined with immune globulin) also have been used to prevent venous thromboembolism and early pregnancy loss in women who have undergone in vitro fertilization†.648,656,657,1012 However, current evidence suggests that the overall absolute risk of symptomatic thrombosis appears to be low in women undergoing in vitro fertilization.1012 Therefore, ACCP recommends against routine thromboprophylaxis in most women undergoing assisted reproduction.1012

Aspirin in low dosages throughout pregnancy also has been used to prevent preeclampsia† in pregnant women at high risk, including those with pregestational diabetes mellitus, obesity, age exceeding 40 years, chronic hypertension, nulliparity, multifetal gestations, preexisting vascular disease, collagen vascular disease, renal disease, and/or antiphospholipid syndrome (see preceding discussion), and those with a history of preeclampsia during prior pregnancy.594,595,596,597,598,599,600,601,602,603,604,608,610,705,706,707,708,709,710,711,712,713,715,1012,1017 The rationale for aspirin prophylaxis is that hypertension and coagulation abnormalities in preeclampsia are caused in part by an imbalance between vasodilating and vasoconstricting prostaglandins (prostacyclin and thromboxane A₂, respectively); by preferentially inhibiting thromboxane A₂ production at low doses, aspirin was postulated to provide some protection against the abnormalities associated with preeclampsia.705,710,711 Some clinicians have suggested that prophylaxis with low dosages of aspirin be considered in selected high-risk women (e.g., those with chronic hypertension,594,597,599,604,1017 a history of early or recurrent preeclampsia594,597,599,604,1017 , diabetes mellitus, underlying renal disease, high body mass index, those 35 years of age or older) who do not have thrombophilia.1012

Systematic reviews involving large numbers of patients have suggested beneficial effects of low-dose aspirin on preeclampsia and its complications.1017,1018 In a systematic review based on pooled data in more than 12,000 women with historical risk factors for preeclampsia, aspirin prophylaxis (generally 50-150 mg daily) was associated with a reduction of about 15% in the risk of preeclampsia and also some benefit on perinatal death, spontaneous preterm birth, and birth weight.816 Another systematic review in more than 30,000 women receiving prophylaxis with antiplatelet drugs (usually aspirin in a dosage of up to 75 mg daily) demonstrated similar findings.816,817 Neither of these reviews found evidence of a harmful effect of aspirin prophylaxis in these women.814,815,816 ACCP, AHA, and ASA recommend the use of low-dose aspirin during pregnancy (starting from the second trimester) in women who are at high risk for preeclampsia, including those with chronic primary or secondary hypertension or previous pregnancy-related hypertension.1012,1017

Prevention of Cancer

While data principally from observational studies suggest that aspirin or other NSAIAs may reduce the risk of various cancers† (e.g., colorectal, breast, gastric),864,870,871,872,873 results of several randomized, placebo-controlled studies generally have not confirmed these observations.864,874,875,876 A large, long-term randomized study (Women's Health Study) in women with no history of cancer or cardiovascular disease indicated no reduction in the risk of developing cancer overall or at specific sites, including breast, colorectal, or lung cancer, with use of low dosages of aspirin (100 mg every other day).864 In this study, approximately 40,000 predominantly middle-aged (mean age 54.6 years at study entry) women received aspirin or placebo in a 2 x 2 factorial design (patients also were randomized to receive vitamin E or placebo as part of the study; no effect of the vitamin E treatment arm was noted on the aspirin results); patients received aspirin for an average of 10 years.864 Aspirin use also was not associated with a reduction in overall cancer mortality, including deaths due to breast or colorectal cancer.864 However, a statistically significant reduction in lung cancer mortality and a trend toward a reduction in the risk of lung cancer were noted in patients taking aspirin.864 Given the variability of aspirin's effects on lung cancer reported in other trials,870,877 it has been suggested that the positive findings in this study may be due to chance; however, data from this study cannot rule out a protective effect of aspirin on lung cancer.864

Observational studies and a few randomized, placebo-controlled trials in patients with a history of colorectal adenomas have shown a reduction in the risk of recurrent colorectal adenomas† with regular (e.g., daily) use of aspirin or other NSAIAs.789,790,791,792,793,794,795,796,797,798,799,800,801,802,803,804,805,806,807,808,809,810,811,812,813,814,815 However, evidence that aspirin and other NSAIAs prevent colorectal cancer itself currently is based principally on observational studies,791,814 and available data suggest that beneficial effects on cancer may only be evident following at least a decade of regular aspirin therapy.793,802,814 Almost all evidence indicates that the beneficial effects of NSAIAs in reducing colorectal cancer risk dissipate following discontinuance of NSAIA therapy.791,792,793,794,795 Current data suggest that the potential clinical benefits of aspirin for primary or secondary prevention of colorectal cancer may be small considering the efficacy of screening and removal of colorectal adenomas in preventing cancer and the risks of bleeding complications associated with long-term aspirin therapy in patients at average risk for colorectal cancer.789,814 Therefore, most clinicians state that such preventive therapy with aspirin currently is not recommended and, because randomized trials indicate that aspirin does not completely eliminate adenomas, it should not be considered a replacement for colorectal cancer screening and surveillance.790,793,794,795,796,814 Further studies are necessary to determine whether aspirin therapy can lessen the required intensity or frequency of such surveillance measures.789 Certain other NSAIAs, particularly selective inhibitors of cyclooxygenase-2 (COX-2) (e.g., celecoxib), currently are used as adjunctive therapy to reduce the number of colorectal polyps in patients with familial adenomatous polyposis;794,801,805,809 such patients are at particularly high risk for developing colorectal cancer.792,809 (See Uses: Colorectal Polyps, in Celecoxib 28:08.04.08.)

Epidemiologic studies have consistently demonstrated a 40-50% reduction789,793,794,799 in the risk of colorectal neoplasia with aspirin use that is not explained by differences in study design, study populations, patterns of aspirin use, or outcomes.789,790,791,792,793,802,803,804 The mechanism by which aspirin and other NSAIAs prevent the development of colorectal adenomas or neoplasms has not been fully elucidated, but some evidence suggests that NSAIAs may restore apoptosis in adenomatous colorectal polyps and/or inhibit angiogenesis, both through COX-2 inhibition and COX-independent mechanisms.791,792,793,794,795,800,806,809,810,811 (See Pharmacology: GI Effects, in Celecoxib 28:08.04.08.) Since most colorectal cancers arise from benign adenomas but have a long latency period (e.g., 5-10 years), prevention of adenomas has been used as a surrogate end point in clinical prevention trials of colorectal cancer.789,790 Several randomized, placebo-controlled trials involving patients with prior colorectal neoplasia have demonstrated reductions in the incidence of recurrent colorectal adenomas with regular use of aspirin.790,791,814,815

Administration

Aspirin is usually administered orally, preferably with food or a large quantity (240 mL) of water (unless the patient is fluid restricted) or milk to minimize gastric irritation. In patients unable to take or retain oral medication, aspirin suppositories may be administered rectally; however, rectal absorption may be slow and incomplete. (See Pharmacokinetics: Absorption.) Aspirin tablets should not be administered rectally, since they are likely to cause irritation and erosion of the rectal mucosa. Aspirin preparations should not be used if a strong vinegar-like odor is present. (See Chemistry and Stability: Stability.)

If an unpleasant taste or aftertaste, burning in the throat, or difficulty in swallowing occurs with uncoated aspirin-containing tablets, these effects may be reduced with film-coated tablets. Although specific data are not available, these effects are also likely to be reduced with enteric-coated tablets. If gastric irritation and/or symptomatic GI disturbances occur with uncoated aspirin-containing tablets, these effects may be reduced with enteric-coated tablets or extended-release tablets. If a liquid dosage form of aspirin is desired for short-term treatment of pain, an oral solution may be prepared from commercially available effervescent tablets (e.g., Alka-Seltzer^®) by dissolving tablets in 120 mL of water; ingest the entire solution to ensure adequate dosing.843,844

In addition to potentially reducing adverse GI effects, some clinicians suggest that enteric-coated tablets may be swallowed more easily by children receiving chronic therapy with the drug and may therefore result in increased compliance.

Aspirin or buffered aspirin preparations should not be chewed before swallowing for at least 7 days following tonsillectomy or oral surgery because of possible injury to oral tissues from prolonged contact with aspirin particles. In addition, aspirin or buffered aspirin tablets should not be placed directly on a tooth or gum surface because of possible injury to tissues.

Capsules containing the fixed combination of aspirin and extended-release dipyridamole should be swallowed whole and should not be chewed.738

Chewable aspirin tablets may be chewed, crushed, and/or dissolved in a liquid, or swallowed whole, followed by approximately 120 mL of water, milk, or fruit juice immediately after administration of the drug.

For information on the concomitant administration of aspirin with nonsteroidal anti-inflammatory agents (NSAIAs), see Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in the Salicylates General Statement 28:08.04.24.

Dosage

Dosage of aspirin must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. When used at high (e.g., anti-inflammatory) dosages, the development of tinnitus can be used as a sign of elevated serum salicylate concentrations, except in patients with high-frequency hearing impairment.

When preparations containing aspirin in fixed combination with other drugs are used, the cautions, precautions, and contraindications applicable to each ingredient must be considered.

Pain and Fever

Aspirin should not be used for self-medication of pain for longer than 10 days in adults or 5 days in children, unless directed by a physician, since pain of such intensity and duration may indicate a pathologic condition requiring medical evaluation and supervised treatment. Aspirin, including chewing gum pieces, should not be used for self-medication of sore throat pain for longer than 2 days in adults or children, unless directed by a physician, since prolonged use could cause mucosal erosions in the mouth. Patients should be warned that the risk of GI bleeding is increased in geriatric patients 60 years of age or older, in patients with a history of GI ulcers or bleeding, when recommended dosages and durations of self-medication are exceeded, when anticoagulants or corticosteroids are used concomitantly, in patients receiving more than one NSAIA, and in those consuming 3 or more alcohol-containing beverages daily. (See Cautions: GI Effects, in the Salicylates General Statement 28:08.04.24)

Aspirin should not be used in adults or children for self-medication of marked fever (exceeding 39.5°C), fever persisting longer than 3 days, or recurrent fever, unless directed by a physician, since such fevers may indicate serious illness requiring prompt medical evaluation.

Aspirin should not be used in adults or children for self-medication of sore throat for longer than 2 days, and should be discontinued and a clinician consulted if sore throat persists or is accompanied by fever, headache, rash, nausea, or vomiting.837

To minimize the risk of overdosage, no more than 5 doses of aspirin should be administered to children for analgesia or antipyresis in any 24-hour period, unless directed by a physician.

For analgesia or antipyresis in adults or children older than 12 years of age, the usual oral or rectal dosage of aspirin is 324-650 mg every 4 hours as necessary, but should not exceed 3.9 g daily;840,841 higher single doses (e.g., 975 mg or 1 g) may be useful for analgesia in some patients. If a rapid response is required, the more slowly absorbed dosage forms (i.e., enteric-coated, extended-release tablets) should not be used. In children 2-11 years of age, the usual oral or rectal dosage for analgesia or antipyresis is 1.5 g/m² daily, administered in 4-6 divided doses; total daily rectal dosage should not exceed 2.5 g/m². Alternatively, children may receive the following approximate oral or rectal doses every 4 hours as necessary: children 11-12 years of age, 320-480 mg; children 9-11 years of age, 320-400 mg; children 6-7 years of age, 320-325 mg; children 4-6 years of age, 240 mg; and children 2-4 years of age, 160 mg. Dosage in children younger than 2 years of age must be individualized.

The usual dosage of aspirin (as chewing gum pieces) for analgesia and antipyresis in adults and children older than 12 years of age is 454 mg, repeated every 4 hours as necessary (maximum 3.632 g daily).837 The chewing gum pieces should be thoroughly chewed for about 15 minutes to ensure adequate dosing and then the gum should be expelled from the mouth and discarded. Children 6-12 years of age may be given 227-454 mg, repeated as necessary up to 4 times daily. Children 3-6 years of age may be given 227 mg, repeated as necessary up to 3 times daily. Aspirin chewing gum pieces should not be used in children younger than 3 years of age unless directed by a physician; dosage must be individualized.

The usual oral dosage of aspirin as a highly buffered effervescent solution (Alka-Seltzer^® Original, Lemon-Lime) for analgesia in adults and children 12 years of age or older is 650 mg every 4 hours as necessary; total dosage in any 24-hour period should not exceed 2.6 g.838,843 Alternatively, in adults and children 12 years of age or older, the usual dosage of Alka-Seltzer Extra Strength is 1 g every 6 hours; total dosage in any 24-hour period should not exceed 3.5 g 844 Because of the high sodium content of this preparation (approximately 24 mEq of sodium per 325 mg of aspirin), it should be used with extreme caution, if at all, in patients in whom excessive amounts of sodium may be harmful. The usual oral dosage of aspirin (Alka-Seltzer^® lemon-Lime or Original) for patients 60 years of age or older is 650 mg every 4 hours as necessary, not to exceed 1.3 g in any 24-hour period.838,843 The usual dosage of aspirin (Alka-Seltzer^® Extra Strength) for patients 60 years of age or older is 1 g every 6 hours; total dosage in any 24-hour period should not exceed 2 g.844 The manufacturer states that the preparation should not be used in children younger than 12 years of age unless directed by a physician. In addition, higher than usually recommended dosages of this preparation should not be used unless directed by a physician.

The usual oral dosage of aspirin (as 650-mg extended-release tablets) for analgesia in adults is 650 mg to 1.3 g every 8 hours as necessary, not to exceed 3.9 g daily. For patients who have difficulty swallowing the 650-mg tablets whole, the tablets may be gently broken or crumbled before administration (or in the mouth), but they must not be ground up if they are to retain the property of extended release. An 800-mg extended-release aspirin tablet is also commercially available but is indicated for use only in the symptomatic treatment of inflammatory disease; the 800-mg tablet cannot be broken or crumbled and must be swallowed whole. Most clinicians believe that extended-release aspirin tablets offer no therapeutic advantage over other types of aspirin tablets; this is particularly true at high dosages since the elimination half-life of salicylate is dose dependent and prolonged at high dosages. However, symptomatic GI disturbances and/or occult GI bleeding may be reduced with extended-release tablets.

For self-medication for the temporary relief of mild to moderate pain associated with migraine headache in adults, the recommended oral aspirin dosage is 500 mg (combined with 500 mg of acetaminophen and 130 mg of caffeine) as a single dose of an immediate-release (conventional) preparation taken with a full glass of water; no more than 500 mg of aspirin (in combination with 500 mg of acetaminophen and 130 mg of caffeine) should be taken in a 24-hour period unless directed by a clinician.701 Individuals younger than 18 years of age should consult their clinician before using this combination preparation.701 Patients receiving the combination for self-medication should be advised to discontinue the drug and consult a clinician if an allergic reaction occurs, if migraine headache pain worsens or persists after the first dose, or if new or unexpected symptoms, including tinnitus (ringing in the ears) or hearing loss, occur.701

For temporary relief of acute migraine headache pain and associated symptoms (nausea, vomiting, photophobia, phonophobia) in adults, aspirin 900 or 1000 mg has been given as a single dose with or without metoclopramide 10 mg (as an antiemetic).951

Inflammatory Diseases

For the symptomatic treatment of rheumatoid arthritis, osteoarthritis, or other polyarthritic or inflammatory conditions (e.g., spondyloarthropathies, arthritis and pleurisy of systemic lupus erythematosus [SLE]), the usual initial adult dosage of aspirin is 2.4-3.6 g daily, administered in divided doses. When necessary, dosage is generally increased by 325 mg to 1.2 g daily at intervals of 1 week or more. The usual adult maintenance dosage is 3.6-5.4 g daily; however, higher dosages may be necessary. Dosage should be adjusted according to the patient's response, tolerance, and serum salicylate concentration. (See Dosage: Inflammatory Diseases under Dosage and Administration, in the Salicylates General Statement 28:08.04.24.)

For the symptomatic treatment of juvenile arthritis, the usual initial dosage is 60-130 mg/kg daily in children weighing 25 kg or less, or 2.4-3.6 g daily in children weighing more than 25 kg, administered in divided doses. Alternatively, some clinicians recommend an initial dosage of 1.5 g/m² daily, administered in divided doses. When necessary, dosage is generally increased by 10 mg/kg daily no more frequently than at weekly intervals. The usual maintenance dosage is 80-100 mg/kg daily; up to 130 mg/kg daily may be required in some children. Although some clinicians have reported a high incidence of chronic intoxication in children receiving 90-100 mg/kg daily, this has not been found by many others. However, it appears that dosages of at least 100 mg/kg daily should not be used in children weighing more than 25 kg. Based on body surface area, dosage should generally not exceed 3 g/m² daily. Dosage should be adjusted according to the patient's response, tolerance, and serum salicylate concentration. (See Dosage: Inflammatory Diseases under Dosage and Administration, in the Salicylates General Statement 28:08.04.24.)

Because of the prolonged elimination half-life of salicylate at high dosages, at least 5-7 days are generally required to achieve steady-state serum salicylate concentrations in the treatment of inflammatory diseases. Therefore, some clinicians have suggested that loading-dose regimens of aspirin may be useful to more rapidly attain serum concentrations associated with an anti-inflammatory effect. In one small study, healthy individuals were given oral dosages of 650 mg of aspirin every 4 hours for 4 days (conventional-dose regimen) or two 1.3-g doses 4 hours apart followed 2 hours later by initiation of a maintenance dosage of 650-mg oral doses every 4 hours through 4 days (loading-dose regimen). In this study, the time required to reach a serum salicylate concentration of 150 mcg/mL was approximately 15 hours with the loading-dose regimen and approximately 48 hours with the conventional-dose regimen; serum salicylate concentrations were higher during the first 36 hours with the loading-dose regimen. However, the actual clinical importance of any difference between these regimens in patients with inflammatory diseases is not known; further evaluation of loading-dose regimens in such patients is needed.

Rheumatic Fever

For the symptomatic treatment of rheumatic fever†, dosage and duration of aspirin therapy are generally determined by the severity and duration of acute manifestations. For maximal suppression of acute inflammation, the usual initial dosage of aspirin is 4.9-7.8 g daily in adults and 90-130 mg/kg daily in children, administered in divided doses every 4-6 hours. Patients with only polyarthritis and fever usually respond to lower dosages. Subsequent dosage should be adjusted according to the patient's response, tolerance, and serum salicylate concentration. The initial dosage is generally administered for up to 1-2 weeks, then decreased to approximately 60-70 mg/kg daily for 1-6 weeks or as long as necessary, and then gradually withdrawn over 1-2 weeks. Various aspirin regimens have been suggested depending on the severity of acute manifestations, and the clinician should consult published protocols for more information on specific dosages and schedules of administration.

In patients with carditis and cardiomegaly or congestive heart failure who are treated with corticosteroids, aspirin therapy is usually initiated as steroid therapy is gradually withdrawn. In these patients, some clinicians recommend an aspirin dosage of 60 mg/kg daily, administered in divided doses. High dosages should be used with caution in patients with carditis since congestive heart failure or pulmonary edema may be precipitated. Aspirin is usually administered for approximately 2-4 weeks after steroids are discontinued. Only extremely severe clinical rebounds of rheumatic activity require reinstitution of therapy, in which case aspirin is administered in the usual dosage for 3-4 additional weeks.

Thrombosis

Transient Ischemic Attacks and Acute Ischemic Stroke

For secondary prevention of vascular events (e.g., death, recurrent stroke) in patients with transient ischemic attacks (TIAs) or stroke, the usual oral dosage of aspirin in adults is 50-325 mg daily, continued long term.646,990 In patients with noncardioembolic ischemic stroke or TIA, the American College of Chest Physicians (ACCP) recommends an aspirin dosage of 75-100 mg daily, continued long term.1009 While dosages up to 1.3 g daily, administered in 2 or 4 divided doses, have been recommended, there is little evidence supporting superiority of such dosages relative to currently recommended low dosages, and the risk of adverse effects (e.g., GI intolerance, bleeding) is increased with increasing dosage. Current data suggest that an aspirin dosage not exceeding 75-81 mg daily may be sufficient for long-term cardiovascular prevention and is associated with less GI bleeding risk.907

For the acute treatment of ischemic stroke in patients who are not receiving a thrombolytic agent, the usual oral dosage of aspirin when given as monotherapy in adults is 150-325 mg initiated within 24-48 hours of stroke onset.699,700,829,1009 In children with acute arterial ischemic stroke†, aspirin 1-5 mg/kg daily is recommended as an option for initial anticoagulation until dissection and embolic causes have been excluded.1013 When cerebral arterial dissection and cardioembolic causes have been excluded, the usual suggested dosage of aspirin for secondary prevention in such children is 1-5 mg/kg daily for a minimum of 2 years.1013 If aspirin is used in children with acute arterial ischemic stroke secondary to non-Moyamoya vasculopathy, ACCP recommends at least 3 months of therapy; ongoing antithrombotic therapy should be determined by repeat cerebrovascular imaging.1013

When aspirin is given in combination with dipyridamole to reduce the risk of stroke in patients who have had noncardioembolic stroke or TIAs,744,745 the usual dosage of aspirin in fixed combination with extended-release dipyridamole (200 mg) is 25 mg (1 capsule) twice daily in the morning and evening.738

The American Heart Association (AHA) and American Stroke Association (ASA) state that unless contraindicated, an aspirin dosage of 75-325 mg daily is recommended for secondary prevention of ischemic stroke in high-risk women and is reasonable in selected women (e.g., those with diabetes mellitus) for primary prevention of ischemic stroke†.952,1017 (See Transient Ischemic Attacks and Acute Ischemic Stroke under Uses: Thrombosis for definition of high risk.) If the benefit of aspirin for the prevention of ischemic stroke or myocardial infarction (MI) in women is considered to outweigh the risks of therapy, a dosage of 81 mg daily or 100 mg every other day has been suggested by AHA and ASA.952,1017

Coronary Artery Disease

For the secondary prevention of cardiovascular events in patients with coronary artery disease, a low dosage of aspirin (e.g., 75-162 mg daily) generally is recommended.822,992,1116 ACCP recommends long-term, single-drug antiplatelet therapy with aspirin 75-100 mg daily in patients with established coronary artery disease (i.e., 1 year after ACS with prior revascularization, coronary stenosis greater than 50% by coronary angiogram, and/or evidence of cardiac ischemia on diagnostic testing).1010

ST-Segment-Elevation Myocardial Infarction

As an adjunct in the acute management of suspected acute ST-segment-elevation MI (STEMI), the usual initial adult oral dose of aspirin for prevention of early recurrence or extension of infarction and mortality reduction is 162-325 mg.527,579,646,842 Such acute aspirin therapy should be initiated as soon as possible after the clinical impression of an evolving acute STEMI is formed, preferably by chewing and/or swallowing a conventional tablet.527,579,646

Aspirin therapy for the management of STEMI should be continued indefinitely at a dosage of 81-325 mg daily.527 Some experts prefer the use of a maintenance dosage of 81 mg daily because of a decreased risk of bleeding and lack of definitive evidence demonstrating that higher dosages confer greater benefit.527 Although higher dosages of aspirin have been used in patients surviving an MI (900 mg to 1.5 g daily in divided doses), lower-dosage regimens appear to be equally effective and may minimize adverse GI effects. Some data suggest that 75-81 mg of aspirin daily is sufficient for long-term cardiovascular disease prevention and is associated with less GI bleeding risk.907

In patients with STEMI who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves), warfarin (INR 2-3) should be administered in addition to aspirin therapy; in some cases (e.g., patients with an anterior STEMI and left ventricular thrombosis undergoing percutaneous coronary intervention [PCI] with stenting), both warfarin (INR 2-3) and clopidogrel 75 mg daily may be added to aspirin therapy (triple antithrombotic therapy).993,996,1007,1010

For primary prevention† to reduce the risk of atherosclerotic cardiovascular disease (ASCVD), including first STEMI in patients 40-70 years of age at increased risk for ASCVD but without an increased bleeding risk, the usual oral dosage of aspirin is 75-162 mg daily.1110,1116 The efficacy of dosages lower than 75 mg daily has not been established.783,784 An oral aspirin dosage of 325 mg every other day has been used573,658,659 but is no longer preferred.681,682

Non-ST-Segment-Elevation Acute Coronary Syndromes

In patients with non-ST-segment-elevation acute coronary syndromes (NSTE ACS), the American College of Cardiology (ACC) and AHA recommend an initial aspirin dose of 162-325 mg as soon as possible after presentation, unless such therapy is contraindicated, followed by a maintenance dosage of 81-325 mg daily.1100 Aspirin should be used in conjunction with a P2Y12-receptor antagonist (e.g., clopidogrel, ticagrelor) for up to 12 months.992,994,1010,1100 When used in conjunction with ticagrelor, aspirin should be administered in a maintenance dosage of 75-100 mg daily since aspirin dosages exceeding 100 mg daily have been associated with reduced efficacy of ticagrelor.955

Percutaneous Coronary Intervention and Revascularization Procedures

To reduce the incidence of early ischemic complications in patients undergoing PCI (e.g., coronary angioplasty, coronary stent placement), ACCF, AHA, and the Society for Cardiovascular Angiography and Interventions (SCAI) recommend pretreatment with 81-325 mg of aspirin, initiated at least 2, and preferably 24, hours before the procedure.994 In patients not already receiving long-term aspirin therapy, an aspirin dose of 325 mg (as the non-enteric-coated formulation) initiated at least 2, and preferably 24, hours prior to PCI is recommended.994

In addition to aspirin, a loading dose of a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) should be administered in patients with ACS undergoing PCI with stent placement (bare-metal or drug-eluting).994 Aspirin should be continued indefinitely after PCI, while a P2Y12-receptor antagonist generally should be continued for at least 12 months following placement of an intracoronary stent.992,993,994

In patients with anterior MI and left ventricular thrombus (or at high risk for left ventricular thrombus) undergoing stent placement, ACCP suggests the use of warfarin (INR 2-3) and clopidogrel 75 mg daily in addition to aspirin therapy; the recommended duration of such triple antithrombotic therapy is dependent on whether the patient has a bare-metal or drug-eluting stent.1010

When aspirin is used to prevent reocclusion in adults undergoing coronary artery bypass grafting (CABG), ACCF/AHA recommends a dosage of 100-325 mg daily; aspirin should be initiated within 6 hours after surgery and continued for up to 1 year.992 For long-term therapy after 1 year, ACCP recommends aspirin 75-100 mg daily.1010 There are some data suggesting that an aspirin dosage not exceeding 75-81 mg daily may be sufficient for long-term cardiovascular prevention and is associated with less GI bleeding risk.907

Managing Antiplatelet Therapy in Patients Undergoing Invasive Procedures

Temporary interruption of long-term aspirin therapy generally is not necessary for patients undergoing surgery or other invasive procedures.1004 In patients receiving dual antiplatelet therapy (e.g., with aspirin and clopidogrel) who require surgery within 6 weeks of bare-metal stent implantation or within 6 months of drug-eluting stent implantation, ACCP suggests continuation of dual antiplatelet therapy during the periprocedural period.1004 In patients receiving dual antiplatelet therapy (e.g., with aspirin and clopidogrel) who require CABG, interruption of clopidogrel therapy is recommended 5 days prior to surgery; however, aspirin may be continued around the time of surgery in such patients.1004 For additional information on the perioperative management of antithrombotic therapy, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Embolism Associated with Atrial Fibrillation

When aspirin is used for the prevention of thromboembolism in patients with atrial fibrillation†, a dosage of 75-325 mg daily has been suggested.1007

Experts recommend that atrial flutter† generally be managed in the same manner as atrial fibrillation.999,1007

Valvular Heart Disease

Aspirin therapy at a dosage of 75-325 mg daily is recommended by ACC and AHA for selected patients with mitral valve prolapse† (i.e., symptomatic patients who experience a TIA or patients younger than 65 years of age with concurrent atrial fibrillation and no history of mitral valve regurgitation, hypertension, or heart failure).996

Peripheral Arterial Disease

To reduce vascular morbidity and mortality in patients with asymptomatic peripheral arterial disease ( primary prevention ), ACCP suggests that aspirin be given a dosage of 75-100 mg daily.1011

For secondary prevention of cardiovascular events in patients with symptomatic peripheral arterial disease, ACCP recommends aspirin 75-100 mg daily.1011 In patients with refractory intermittent claudication, ACCP suggests the use of cilostazol in addition to aspirin therapy.1011

Peripheral Artery Bypass Graft Surgery

To reduce graft occlusion in patients undergoing peripheral artery bypass graft surgery, aspirin 75-100 mg daily is recommended by ACCP; aspirin should be initiated preoperatively and continued long term.1011 ACCP suggests the addition of clopidogrel 75 mg daily to aspirin therapy in patients undergoing below-the-knee prosthetic graft bypass surgery.1011

Prosthetic Heart Valves

In patients with a bioprosthetic heart valve† in the aortic position who are in sinus rhythm and who have no other indications for warfarin therapy, ACCP suggests aspirin 50-100 mg daily for initial (i.e., first 3 months after valve insertion) and long-term antithrombotic therapy.1008 Aspirin 50-100 mg daily also may be used for long-term antithrombotic therapy after an initial 3 months of treatment with warfarin in patients with bioprosthetic heart valves in the mitral position.1008 996 In all patients with a mechanical heart valve who are at low risk of bleeding, ACCP suggests the addition of low-dose aspirin (50-100 mg daily) to warfarin anticoagulation.1008 Combination therapy with aspirin and warfarin also is recommended by ACC/AHA for patients with bioprosthetic heart valves with additional risk factors for thromboembolism.996

In pregnant women with prosthetic heart valves who are at high risk for thromboembolism, aspirin (75-100 mg daily) may be added to therapy with a low molecular weight heparin or unfractionated heparin.1012

Thrombosis Associated with Heart Surgery in Children

Following the Fontan procedure† in children, aspirin in a dosage of 1-5 mg/kg daily is recommended by ACCP; the optimal duration of therapy in such patients is unknown.1013

Kawasaki Disease

For initial treatment of the acute phase of Kawasaki disease†, the American Academy of Pediatrics (AAP), AHA, and ACCP recommend that aspirin therapy be initiated as soon as possible (optimally within 7-10 days of illness) and given in a dosage of 80-100 mg/kg daily in 4 equally divided doses for up to 14 days; a single dose (2 g/kg) of immune globulin IV (IGIV) also should be administered as soon as possible (optimally within 7-10 days of illness). 638,916,1013 Although absorption of aspirin may be impaired or is highly variable during the initial phase of the illness,636,637,638 AAP states that it is not necessary to monitor aspirin concentrations in most patients.638

After the patient has been afebrile for 48 hours or longer (usually about day 14 of illness), the aspirin dosage should be decreased to 1-5 mg/kg once daily to provide antiplatelet effects for prevention of coronary aneurysm, thrombosis, and subsequent infarction.636,637,638,916,1013 In patients without coronary artery changes or with only transient coronary artery ectasia or dilatation (disappearing within the initial 6-8 weeks of illness), low-dose aspirin therapy usually is discontinued at 6-8 weeks.638,916,1013 In those with coronary abnormalities, long-term low-dose aspirin therapy (with or without anticoagulants) may be indicated.638,916,1013 (See Uses: Kawasaki Disease.)

Complications of Pregnancy

In women with antiphospholipid antibody (APLA) syndrome† and a history of multiple pregnancy losses (at least 3), ACCP recommends antepartum administration of aspirin (75-100 mg daily) plus prophylactic- or intermediate-dose subcutaneous unfractionated heparin or prophylactic-dose low molecular weight heparin.1012

In women at high risk for preeclampsia, including those with chronic primary or secondary hypertension or previous pregnancy-related hypertension, ACCP, AHA, and the American Stroke Association (ASA) recommend low-dose aspirin during pregnancy, starting from the second trimester.1012,1017

Pharmacology

Aspirin exhibits analgesic, anti-inflammatory, and antipyretic activity. Although aspirin hydrolyzes to salicylate and acetate, the drug does not require hydrolysis to produce its effects and appears to have some pharmacologic effects that are distinct from those of salicylate. The ability of aspirin to acetylate proteins (e.g., platelet proteins, hormones, DNA, hemoglobin) results in some effects, such as inhibition of platelet aggregation, that other currently available salicylates do not exhibit.

Aspirin acetylates prostaglandin endoperoxide synthase (prostaglandin G/H-synthase) and irreversibly inhibits its cyclooxygenase (COX) activity. 1016 The enzyme catalyzes the conversion of arachidonic acid to PGH₂, the first committed step in prostanoid biosynthesis.1016 Two isoforms of prostaglandin endoperoxide synthase exist, PGHS-1 and PGHS-2 (also referred to as COX-1 and COX-2, respectively).679,1016 PGHS-1 (COX-1) is expressed constitutively in most cell types, including platelets.679 PGHS-2 (COX-2) is undetectable in most mammalian cells, but its expression can be induced rapidly in response to mitogenic and inflammatory stimuli.679,1016 Aspirin is a relatively selective inhibitor of platelet PGHS-1 (cyclooxygenase-1, COX-1).1016 The existence of 2 isoenzymes with different aspirin sensitivities, coupled with extremely different recovery rates of their cyclooxygenase (COX) activity following inactivation by aspirin, at least partially explains the different dosage requirements and durations of aspirin effects on platelet function versus the drug's analgesic and anti-inflammatory effects.1016 Human platelets and vascular endothelial cells process PGH₂ to produce thromboxane A₂ and prostacyclin (epoprostenol, PGI₂), respectively.1016 Thromboxane A₂ induces platelet aggregation and vasoconstriction, while prostacyclin inhibits platelet aggregation and induces vasodilation.1016 Aspirin is antithrombotic in a wide range of doses inhibiting thromboxane A₂ and prostacyclin.1016 (See Pharmacology: Antithrombotic Effects.)

Analgesic, Anti-inflammatory, and Antipyretic Effects

While unhydrolyzed aspirin has been shown to be more potent than sodium salicylate in relieving pain in animals, it remains to be clearly established that aspirin has greater analgesic effect than salicylate in humans. A direct correlation between onset, intensity, or duration of analgesia and the time course of serum aspirin (or salicylate) concentrations or peak serum aspirin (or salicylate) concentrations also remains to be established. There are relatively few controlled comparative studies of aspirin and other salicylates (e.g., salicylate salts), but the analgesic, anti-inflammatory, and antipyretic effects of aspirin and other salicylates are generally considered to be comparable. However, in terms of antipyretic activity, aspirin is approximately 1.6 times as potent as sodium salicylate on an equimolar basis.

For further information on analgesic, anti-inflammatory, antipyretic, and other effects of aspirin, see Pharmacology in the Salicylates General Statement 28:08.04.24.

Hematologic Effects

At usual dosages (e.g., 1.3-6 g daily), aspirin may rarely prolong the prothrombin time (usually only by 2-3 seconds) by inhibiting hepatic synthesis of blood coagulation factors VII, IX, and X.

Aspirin (but not other salicylates) inhibits platelet aggregation induced by epinephrine or low concentrations of collagen but not that induced by thrombin or high concentrations of collagen. Aspirin inhibits the second phase of platelet aggregation by preventing release of adenosine diphosphate (ADP) from platelets. The drug also prevents release of platelet factor 4 from platelets. Mean bleeding time may be prolonged by several minutes (approximately doubled) in healthy individuals and longer in children or in patients with bleeding disorders (e.g., hemophilia). In healthy individuals receiving a single 325-mg oral dose of aspirin, bleeding time may increase to a maximum within 12 hours and generally return to normal within 24 hours; any increase is usually of little clinical significance. Some clinicians have reported that mean bleeding time is progressively prolonged with increasing single doses of up to 1 g, but may be only slightly prolonged or unaffected by higher single doses; however, this has not been consistently found. The effect on bleeding time depends on the measurement method (e.g., Duke, Ivy, Mielke) used and technical variables (e.g., venostasis), and this may partially account for conflicting reports.

Like the analgesic and anti-inflammatory effects, the effects of aspirin on platelets appear to be mainly associated with inhibition of prostaglandin synthesis. Aspirin irreversibly acetylates and inactivates cyclooxygenase in circulating platelets and possibly in megakaryocytes. A single 325-mg oral dose of the drug results in about 90% inhibition of the enzyme in circulating platelets. This inactivation prevents platelet synthesis of prostaglandin endoperoxides and thromboxane A₂, compounds which induce platelet aggregation and constrict arterial smooth muscle. Since cyclooxygenase in platelets is not resynthesized, this effect of aspirin on platelet function persists for the life span of platelets (4-7 days). When approximately 20% of circulating platelets have not been exposed to aspirin (about 36 hours after the last dose), the hemostatic function of the platelet pool generally returns to normal; however, altered hemostasis has been reported to persist longer in some patients receiving long-term therapy.

Antithrombotic Effects

Because of its ability to inhibit platelet aggregation via platelet cyclooxygenase inhibition, aspirin has been extensively investigated for potential therapeutic effects in the prevention of thrombosis (particularly arterial thrombosis). (See Uses: Thrombosis.) Aspirin has also been found to inactivate cyclooxygenase in venous endothelium and thereby inhibit venous synthesis of prostacyclin (epoprostenol, PGI₂). Since prostacyclin inhibits platelet aggregation and causes vasodilation, it appears to oppose the effects of thromboxane A₂ (and prostaglandin endoperoxides) on hemostasis. Therefore, it has been suggested that the relative extent to which the formation of these compounds is inhibited by aspirin might result in an increased or decreased likelihood of thrombosis. It has not been established whether interruption of prostacyclin formation is a sufficient stimulus to initiate the thrombotic process, but studies in mice deficient in the gene that encodes the prostacyclin receptor support the importance of this prostanoid in the prevention of arterial thrombosis.678 Although prostacyclin is synthesized by arterial endothelium and in vitro studies suggest that arterial cyclooxygenase is less sensitive to inhibition by aspirin than venous cyclooxygenase, the actual effects of aspirin on arterial synthesis of prostacyclin in healthy or diseased human arteries remain to be established.

In some clinical studies that evaluated the effect of aspirin in preventing thrombosis, the dosages of aspirin (900 mg to 1.5 g daily in divided doses) probably inhibited the synthesis of prostacyclin as well as that of thromboxane A₂. Although concomitant inhibition of prostacyclin synthesis by aspirin may potentially decrease the antithrombotic efficacy of the drug, it is unlikely that this effect increases the risk of thrombosis since an increased risk has not been observed in these studies or in patients with rheumatoid arthritis receiving higher dosages of the drug. Cyclooxygenase in both platelets and venous endothelium has been found to be inhibited by single oral aspirin doses of 80-300 mg. However, at these doses, the duration of inhibition of thromboxane A₂ synthesis in platelets (about 48-96 hours) is longer than inhibition of prostacyclin synthesis in venous endothelium (about 24-48 hours), apparently because cyclooxygenase is resynthesized in venous endothelium but not in platelets. Since cyclooxygenase in platelets appears to be more sensitive to inactivation than cyclooxygenase in venous endothelium, it has been suggested that low dosages of aspirin might prevent thrombosis by selectively inhibiting prostaglandin endoperoxide and thromboxane A₂ synthesis. In addition, limited data indicate that modifying the absorption rate of aspirin to limit its systemic availability may result in such selective effects. Uncoated or film-coated, plain aspirin or buffered aspirin tablets or capsules have been used in most studies in which aspirin has been shown to prevent thrombosis, and limited data indicate that differences in the systemic availability of unhydrolyzed aspirin may be associated with different effects of the drug on thromboxane A₂ and prostacyclin synthesis, which might theoretically affect antithrombotic efficacy. In a comparative study in healthy men, administration of aspirin 75 mg daily as a controlled-release matrix formulation designed to release 10 mg of drug per hour produced essentially complete suppression of thromboxane A₂ formation (as determined by thromboxane B₂ concentrations) while having only modest effects on basal or bradykinin-stimulated prostacyclin synthesis. Suppression of thromboxane A₂ production and prolongation of template bleeding time in individuals receiving the controlled-release preparation daily for 28 days were comparable to those produced by immediate-release aspirin given as 162.5 mg daily or 325 mg every other day. Doses as low as 50-80 mg of enteric-coated aspirin have been shown to produce near-maximal inhibition of thromboxane A₂ synthesis, and some studies demonstrate that enteric-coated and controlled-release aspirin produce similar, although somewhat delayed, inhibition of cyclooxygenase activity and platelet aggregation compared with the same doses of plain or buffered aspirin. However, an optimum aspirin dose and administration schedule required to achieve these selective effects have not been clearly determined, and the actual clinical importance of such a selective inhibitory effect remains to be clearly established. In addition, salicylate appears to competitively inhibit the effect of aspirin on platelets; the relevance of this effect to the prevention of thrombosis is not known.

Pharmacokinetics

Since both unhydrolyzed aspirin and its metabolite, salicylate, are pharmacologically active, the pharmacokinetics of both compounds must be considered. For additional information on the distribution and elimination of salicylate, see Pharmacokinetics in the Salicylates General Statement 28:08.04.24.

Absorption

Approximately 80-100% of an oral dose of aspirin is absorbed from the GI tract. However, the actual bioavailability of the drug as unhydrolyzed aspirin is lower since aspirin is partially hydrolyzed to salicylate in the GI mucosa during absorption and on first pass through the liver. There are relatively few studies of the bioavailability of unhydrolyzed aspirin. In one study in which aspirin was administered IV and as an oral aqueous solution, it was shown that the solution was completely absorbed but only about 70% reached the systemic circulation as unhydrolyzed aspirin. In another study in which aspirin was administered IV and orally as capsules, only about 50% of the oral dose reached the systemic circulation as unhydrolyzed aspirin. There is some evidence that the bioavailability of unhydrolyzed aspirin from slowly absorbed dosage forms (e.g., enteric-coated tablets) may be substantially decreased. Food does not appear to decrease the bioavailability of unhydrolyzed aspirin or salicylate; however, absorption is delayed and peak serum aspirin or salicylate concentration may be decreased. There is some evidence that absorption of salicylate following oral administration may be substantially impaired or is highly variable during the febrile phase of Kawasaki disease.

Most studies reported to date determined the bioavailability of aspirin preparations in terms of salicylate. Effervescent or noneffervescent oral aqueous solutions of aspirin appear to be completely absorbed. Oral buffered aspirin tablets, uncoated plain aspirin tablets, and methylcellulose film-coated (non-enteric) plain aspirin tablets are approximately 80-100% absorbed. Erratic and incomplete absorption of some enteric-coated aspirin tablets (particularly those with shellac coatings) has been reported, but recent studies indicate that the extent of absorption of currently available enteric-coated aspirin tablets is similar to that of buffered, uncoated plain, and film-coated plain aspirin tablets. Although well-designed studies are lacking, the extent of absorption of extended-release aspirin tablets appears to be similar to that of uncoated plain aspirin tablets. There are apparently no published studies on the bioavailability of aspirin capsules. Following rectal administration as a suppository, aspirin is slowly and variably absorbed; the extent of absorption increases with increasing rectal retention time. In general, 20-60% of the dose is absorbed if the suppository is retained for 2-4 hours and 70-100% is absorbed if the suppository is retained for at least 10 hours.

The rate of absorption of aspirin depends on the same factors that determine the rate of absorption of other salicylates and the relative rates of absorption from various oral aspirin dosage forms are generally the same as for oral dosage forms of other salicylates (e.g., aqueous solutions are the most rapidly absorbed). As with other salicylates, dissolution is usually the rate-limiting process in the absorption of tablets containing aspirin; however, the in vitro dissolution rate of a specific preparation does not necessarily reflect the in vivo absorption rate. According to the manufacturer, the in vitro dissolution of film-coated aspirin tablets does not differ from that of uncoated plain tablets; however, the film-coated tablet does not undergo dissolution in the mouth during administration.

Buffered Aspirin

There has been controversy over the relative rates of absorption of buffered aspirin tablets and uncoated plain aspirin tablets and their relative potential for producing gastric irritation and analgesia.

The buffers contained in buffered aspirin tablets may increase the pH in the microenvironment of aspirin particles and thereby increase solubility of the drug in surrounding GI fluids; as a result, the dissolution rate of the tablets may be increased. However, it cannot be stated that all buffered aspirin tablets are dissolved and absorbed more rapidly than all uncoated plain aspirin tablets. The types and amounts of buffers affect dissolution rate, and claims for a specific preparation should be substantiated by appropriate data. Conflicting reports of the relative rates of absorption of buffered or uncoated plain aspirin tablets are most likely due to differences in the specific preparations studied. Some studies have shown that, like aqueous aspirin solutions, some buffered aspirin tablet preparations may be absorbed slightly more rapidly than some uncoated plain aspirin tablet preparations and may produce slightly higher peak serum salicylate concentrations; however, clinically important differences in the onset or intensity of analgesia produced by these dosage forms or specific preparations have not been established. Crossover studies directly comparing peak serum concentrations of unhydrolyzed aspirin attained with these dosage forms are lacking.

It has been suggested that buffered aspirin tablets cause less gastric irritation than uncoated plain aspirin tablets since the potentially more rapid dissolution of the former may reduce contact time between aspirin particles and gastric mucosa. However, several recent, well-designed studies indicate that buffered aspirin tablets do not cause less gastric irritation than uncoated plain aspirin tablets.

Rapidly Absorbed Dosage Forms

Following oral administration of single doses of rapidly absorbed aspirin dosage forms, salicylate is detected in serum within 5-30 minutes, and peak serum salicylate concentrations are attained within 0.25-2 hours, depending on dosage form and specific formulation. Clinically important differences in the onset or intensity of analgesia produced by rapidly absorbed dosage forms or specific preparations have not been established.

Following oral administration of a single 650-mg dose of aspirin as an effervescent or noneffervescent aqueous solution in healthy adults, average peak plasma aspirin concentrations of about 13 mcg/mL are attained within 15-40 minutes and average peak plasma salicylate concentrations of about 40-55 mcg/mL are attained within 30-60 minutes. After a single 650-mg oral dose of aspirin (as two 325-mg uncoated plain tablets) in fasting healthy adults, average peak plasma aspirin concentrations of about 7-9 mcg/mL occur within 25-40 minutes and average peak plasma salicylate concentrations of about 35-50 mcg/mL occur within 1.5-2 hours. Following oral administration of a single 650-mg dose of buffered aspirin (as 2 tablets, each containing 325 mg of aspirin), average peak plasma salicylate concentrations of about 40-60 mcg/mL are attained within 45-60 minutes.

In one study in healthy fasting adults given a single 975-mg oral dose of aspirin (as three 325-mg uncoated plain tablets), peak serum salicylate concentrations averaged 60-75 mcg/mL and occurred within 2 hours. In another study in fasting rheumatoid arthritis patients given a single 1.95-g oral dose of aspirin (as six325-mg uncoated plain tablets), peak plasma aspirin concentrations of about 12-16 mcg/mL occurred within 1 hour and peak plasma salicylate concentrations of about 110-160 mcg/mL occurred within 4 hours. When these patients were given the same dose of buffered aspirin (as 6 tablets, each containing 325 mg of aspirin), peak plasma aspirin concentrations of about 14-18 mcg/mL occurred within 1-2 hours and peak plasma salicylate concentrations of about 140-160 mcg/mL occurred within 1-2 hours.

Enteric-Coated Aspirin

There are few published studies reporting plasma aspirin or salicylate concentrations after single oral doses of enteric-coated aspirin tablets. In one crossover study, following single 975-mg oral doses (three 325-mg tablets) of 2 commercially available enteric-coated aspirin preparations in healthy adults, average peak serum salicylate concentrations of 48 mcg/mL occurred at 8 hours with one preparation, and average peak serum salicylate concentrations of 25 mcg/mL occurred at 14 hours with the other preparation. In one study in fasting rheumatoid arthritis patients given a single 1.92-g oral dose (as six 320-mg enteric-coated tablets), peak plasma aspirin concentrations of about 4-7 mcg/mL occurred within about 4 hours and average peak plasma salicylate concentrations of about 70 mcg/mL occurred within about 8 hours.

Extended-Release Aspirin

There are few published studies reporting plasma aspirin or salicylate concentrations after single oral doses of extended-release aspirin tablets. Combining data from several small studies, some clinicians report that following a single 1.3-g oral dose of aspirin as two 650-mg extended-release tablets, an average peak serum aspirin concentration of about 3 mcg/mL was attained within 1 hour and peak serum salicylate concentrations of about 70-80 mcg/mL were attained within 4 hours; the serum aspirin concentration declined to less than 1 mcg/mL by 3 hours and the serum salicylate concentration was about 60 mcg/mL at 8 hours, 45 mcg/mL at 12 hours, and 25 mcg/mL at 16 hours. Following a single 1.6-g oral dose (as two 800-mg tablets) of one commercially available extended-release aspirin preparation in healthy adults in one crossover study, an average peak plasma aspirin concentration of about 1 mcg/mL was attained within 2 hours and average peak plasma salicylate concentrations of about 22 mcg/mL were attained within 8-12 hours; the plasma salicylate concentration declined to about 15 mcg/mL by 24 hours.

Suppositories

In one study in children given a rectal dose of 150-300 mg of aspirin as a suppository, peak serum salicylate concentrations of 20-140 mcg/mL generally occurred within 3-4 hours.

Distribution

Aspirin is rapidly and widely distributed, apparently into most body tissues and fluids. The volume of distribution of aspirin is approximately the same as that of salicylate and is generally 0.15-0.2 L/kg.

In one study in patients with rheumatic disease who received a single 650-mg oral dose of buffered aspirin, aspirin was detected in synovial fluid within 10-30 minutes and salicylate was detected in synovial fluid within 15-35 minutes. In this study, peak aspirin concentrations in synovial fluid occurred after an average of 1.3 hours and were about 75% of peak blood concentrations; peak salicylate concentrations in synovial fluid occurred after an average of 2.2 hours and were about 60% of peak blood concentrations.

Aspirin is poorly bound to plasma proteins; the unhydrolyzed drug is 33% bound at a serum salicylate concentration of 120 mcg/mL. However, aspirin acetylates serum albumin at the Ε-amino group of lysine; the acetylation may alter binding of other drugs (e.g., phenylbutazone) to the protein. Acetylation of serum albumin by aspirin is inhibited by salicylate.

Elimination

The elimination half-life of aspirin in plasma is approximately 15-20 minutes. Unlike salicylate, unhydrolyzed aspirin does not undergo capacity-limited metabolism and does not accumulate in plasma following multiple doses.

Following oral administration, aspirin is partially hydrolyzed to salicylate during absorption by esterases in the GI mucosa. Following absorption, unhydrolyzed aspirin is rapidly and almost completely hydrolyzed by esterases principally in the liver but also in plasma, erythrocytes, and synovial fluid; hydrolysis occurs more slowly in synovial fluid apparently because the amounts of esterases in synovial fluid are lower. It has been reported that aspirin may be hydrolyzed more slowly in women because women apparently have lower amounts of plasma aspirin esterases.

Only about 1% of an oral dose of aspirin is excreted unhydrolyzed in urine. The remainder is excreted in urine as salicylate and its metabolites.

Chemistry and Stability

Chemistry

Aspirin, the prototype of the salicylates, is a nonsteroidal anti-inflammatory agent (NSAIA). Aspirin is the salicylate ester of acetic acid. In vivo, the drug rapidly hydrolyzes to salicylate and acetate. Aspirin occurs as white crystals, which are usually tabular or needle-like, or as a white, crystalline powder. Aspirin is available in fixed combination with dipyridamole as a hard gelatin capsule containing dipyridamole as extended-release pellets and aspirin as an immediate-release tablet.738 The drug may have a faint odor, is slightly soluble in water and freely soluble in alcohol, and has a pK_a of 3.5. Each gram of aspirin contains approximately 760 mg of salicylate.

Stability

Aspirin is stable in dry air. However, in moist air or in aqueous or hydroalcoholic solutions, the drug gradually hydrolyzes to salicylate and acetate and emits a strong vinegar-like odor; the rate of hydrolysis is increased by heat and is pH dependent.

In aqueous solutions, aspirin is most stable at a pH of 2-3, less stable at a pH of 4-8, and least stable at a pH less than 2 or exceeding 8. In a saturated aqueous solution at a pH of 5-7, aspirin is almost completely hydrolyzed within 1 week at 25°C. If a liquid dosage form of aspirin is desired for short-term treatment of pain, an oral solution may be prepared from commercially available buffered effervescent tablets (Alka-Seltzer^®). Following dissolution of 1 Alka-Seltzer^® tablet in approximately 90 mL of water, the solution has a pH of 6-7. In the resultant solution, aspirin is about 99% ionized and is at least 90% unhydrolyzed for approximately 10 hours at room temperature and about 90 hours at 5°C.

Chewable aspirin tablets containing 81 mg of the drug should be stored in child-resistant containers holding not more than 36 tablets each in order to limit the potential toxicity associated with accidental ingestion in children. Aspirin extra-strength (Anacin^®) tablets should be stored at 20-25°C and protected from moisture.836 Aspirin (Bayer products, excluding Alka-Seltzer^® products) tablets or caplets should be stored at room temperature;839,840,841,842 high humidity and excessive heat (40°C) should be avoided.840 Aspirin effervescent antacid and pain relief tablets (Alka-Seltzer^® products) should be protected from excessive heat.838,843,844 Aspirin gum should be stored at 15-25°C and protected from excessive moisture.837 Aspirin suppositories should be stored at 2-15°C. The fixed-combination preparation of extended-release dipyridamole with aspirin should be stored at 25°C and protected from excessive moisture, but may be exposed to temperatures ranging from 15-30 degrees.738

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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