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Medication News & Update

Aspirin and clopidogrel combination less effective and no safer than warfarin therapy in atrial fibrillation

William E. Dager, Pharm.D., FCSHP

Dr. Wager wrote this article recently it is posted on Clotcare.com and excellent site for keeping up with the latest in anticoagulant and anti-thrombolytic therapies.
December, 2006

Reference: ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006 Jun 10;367(9526):1903-12.

The ACTIVE trial involved analysis of several adjuncts for preventing complications in atrial fibrillation. In the ACTIVE W portion, patients assigned to receive open treatment oral anticoagulation targeting an INR of 2-3 (n=3371) were compared to clopidogrel 75mg orally daily plus low dose (75-100mg) aspirin (n=3335). Both groups had similar CHADS2 stroke risk scores. Warfarin was well controlled with 64% of INR values between 2-3. Interm analysis for the incidence of primary outcomes for occurrence of stroke, non-CNS systemic embolus, myocardial infarction or vascular related death suggested a significant benefit with the use of warfarin compared to the combined anti-platelet therapies (relative risk reduction of 8.3%/yr vs 6.5%/year favoring oral anticoagulation p = 0.0008). Because of the clear benefit observed with warfarin, the trial was stopped prematurely. The benefit was especially notable in those patients who had already been receiving oral anticoagulation therapy prior to enrolling into the trial (77% had been on oral anticoagulation prior to randomization). The primary area of benefit with oral anticoagulation therapy was a reduction ischemic stroke with a relative risk reduction of 2.4%/yr vs 1.4%/yr p = 0.0001, or an absolute risk reduction of 1%/yr. Significance was achieved despite the relatively low incidence rate. Most of the benefit was seen with a lower incidence of small, non-disabling strokes and non-CNS systemic embolism. The incidence of major hemorrhage was similar between the groups (relative risk 2.4% for clopidogrel/ASA vs 2.2% for warfarin).

For patients who were not receiving oral anticoagulation therapy prior to enrolling in the trial, a benefit of improved outcomes was noted at approximately one year while incurring a higher rate of major bleeding. Those subsequently randomized to receive oral anticoagulation were twice as likely to stop therapy during the trial. In contrast, patients previously receiving an oral anticoagulant at trial entry did not show any benefit in reduced major bleeding until approximately one year out, but a notable benefit in primary outcome was observed from the onset. Overall, the observations of the ACTIVE W trial suggest a benefit with continued well-controlled oral anticoagulation therapy if the individual was already receiving it. It still leaves in question the management of individuals who are not receiving oral anticoagulants or antiplatelet therapy, or have previously stopped such therapy.

Specific Drug Information

Aspirin, ASA
Acuprin® 81 | Ascriptin® Enteric | Aspergum® Orginal | Aspir-Low® | Aspirtab® | Aspir-trin® | Bayer® Adult Low Strength Enteric Coated Aspirin | Bayer® Aspirin | Bayer® Children Aspirin | Bayer® Childrens Aspirin | Bayer® Extra Strength | Bayer® Low Strength | Bayer® Migraine Pain | Bayer® Plus | Bayer® Therapy | Bayer® Womens | Easprin® | Ecotrin® | Ecotrin® Maximum Strength | Empirin® | Entercote® | Extra Strength Bayer® | Genacote® | Gennin® FC | Genprin® | Halfprin® | Litecoat® Aspirin | Minitabs® | Norwich® Aspirin | Ridiprin® | St. Joseph® Aspirin | St. Joseph® Aspirin Adult Chewable | St. Joseph® Aspirin Adult EC | Stanback® Analgesic | Therapy Bayer® | Uni-Tren® | Valomag® | Zero Order™ Aspirin | ZORprin®

Classification:
• Analgesics
    • Salicylates
• Hematological Agents
    • Platelet Inhibitors
        • Salicylates
• Musculoskeletal Agents
    • Antiinflammatory Agents
        • Salicylates

Description, Mechanism of Action, Pharmacokinetics

Description: Aspirin, the salicylic ester of acetic acid, was introduced into medicine in 1899 and is used for its analgesic, antiinflammatory, antipyretic, and antithrombotic effects. The antiinflammatory and analgesic effects of aspirin are roughly equivalent to those of many other NSAIDs. Aspirin is used in the treatment of many inflammatory and autoimmune conditions such as juvenile arthritis, rheumatoid arthritis, and osteoarthritis. Because of its antithrombotic effects, aspirin is useful in preventing or reducing the risk of myocardial infarction in patients with a history of myocardial infarction, coronary bypass, angioplasty, angina, stroke [7011], transient ischemic attacks (TIAs), or peripheral vascular disease [1961] and recurring transient ischemic attacks (TIAs). Observational studies have suggested that aspirin reduces the risk of colorectal cancer. However, long-term follow-up of the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer.[4045] In contrast, randomized trials have shown that aspirin reduces the risk of recurrent adenomas in persons with a history of colorectal cancer or adenomas.[4047] [4048] The role of aspirin in the chemoprevention of colorectal cancer, either as primary or secondary prophylaxis, has not been determined. Aspirin was officially approved by the FDA in 1939. A sustained-release aspirin (Asacard) was approved for use in the UK in February 1998 and is under investigation in the US.

Mechanism of Action: The activity of aspirin is due to its ability to inhibit cyclooxygenase (COX). Cyclooxygenase is responsible for the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step in prostaglandin synthesis and precursor to prostaglandins of the E and F series. Cyclooxygenase exists in 2 isozymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). In vivo, aspirin is hydrolyzed to salicylic acid and acetate. However, hydrolysis is not required for aspirin activity. Aspirin irreversibly inhibits COX by acetylation of a specific serine moiety (serine 530 of COX-1 and serine 516 of COX-2). Aspirin is about 170-times more potent in inhibiting COX-1 than COX-2. In comparison, salicylic acid has little or no ability to inhibit COX in vitro despite inhibiting prostaglandin synthesis at the site of inflammation in vivo. The exact mechanism of prostaglandin inhibition by salicylic acid is unclear; however, salicylates produce the majority of classic NSAID effects. Theories regarding the potential mechanism for salicylic acid include inactivation of transcriptional regulatory proteins (e.g., NF-kappaB), which regulate expression of inflammatory proteins. Aspirin appears to inhibit COX through two pathways and seems to have a different mechanism of action than other salicylates. Aspirin does not inhibit the peroxidase activity of COX and does not suppress leukotriene synthesis by lipoxygenase pathways.
•Antithrombotic Actions: Aspirin-induced inhibition of thromboxane A2 (TXA2) and prostacyclin (PGI2) has opposing effects on hemostasis. Thromboxane A2 is a potent vasoconstrictor and platelet agonist, while PGI2 inhibits platelet aggregation and vasodilation. However, data suggest that the effects of aspirin-induced TXA2 inhibition predominate clinically. This may be due to the ability of vascular endothelial cells to regenerate new COX and recover normal function, while COX inhibition in platelets is irreversible due to the limited amount of mRNA and protein synthesis in these cells.[3070] This distinction also allows for the use of very low doses of aspirin to retard platelet aggregation. The antithrombotic actions of aspirin are primarily mediated by COX-1 inhibition. Aspirin may also inhibit platelet activation by neutrophils. The antiplatelet effects of aspirin result in a prolonged bleeding time, which returns to normal roughly 36 hours after the last dose of the drug. Antiplatelet effects occur before acetylsalicylic acid is detectable in the peripheral blood due to exposure of platelets in the portal circulation.[3070] Aspirin may also decrease the progression of atherosclerosis by protecting LDL from oxidative modification and improve endothelial dysfunction in atherosclerotic vessels. More recently, it has been proposed that the beneficial effect of aspirin in MI prophylaxis might be related to its ability to reduce circulating levels of C-reactive protein.[1442] In very high and toxic doses, aspirin also exerts a direct inhibitory effect on vitamin K-dependent hemostasis by inhibiting the synthesis of vitamin K-dependent clotting factors. Prothrombin synthesis is impaired, resulting in hypoprothrombinemia.
•Antiinflammatory Actions: The antiinflammatory action of aspirin is believed to be a result of peripheral inhibition of COX-1 and COX-2, but aspirin may also inhibit the action and synthesis of other mediators of inflammation. It is thought that COX-2 is the more important pathway for the inflammatory response since COX-2 is inducible in settings of inflammation by cytokines. Inhibition of COX-2 by aspirin suppresses the production of prostaglandins of the E and F series. These prostaglandins induce vasodilation and increase tissue permeability, which, in turn, promote the influx of fluids and leukocytes. Ultimately, the classic symptoms of inflammation result: swelling, redness, warmth, and pain. Aspirin does not only decrease capillary permeability (which reduces swelling and the influx of inflammatory mediators), but it can also reduce the release of destructive enzymes from lysozymes.
•Analgesic Actions: Salicylates are effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, salicylates have an indirect analgesic effect by inhibiting the production of further prostaglandins and do not directly affect hyperalgesia or the pain threshold. Salicylates may also interfere with pain perception centrally by activity within the hypothalamus. The total serum salicylate levels associated with analgesic activity are 30—100 mcg/ml.
•Antipyretic Actions: Salicylates promote a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Salicylates rarely decrease body temperature in afebrile patients. Paradoxically, toxic doses of salicylates may increase body temperature by increasing oxygen consumption and metabolic rate. The total serum salicylate levels associated with antipyretic activity are 30—100 mcg/ml.
•Antiproliferative Actions: Even though aspirin acetylates COX-2, acetylated COX-2 retains the ability to metabolize arachidonic acid to produce the monohydroxy fatty acid 15R-hydroxyeicosatetraenoic acid (15R-HETE). Hydroxy fatty acids are thought to have antiproliferative effects.[1625] It is unclear if aspirin's prostaglandin-reducing effect contributes to its antitumor activity.
•Gastrointestinal Effects: Adverse gastrointestinal effects from salicylates may be mediated through decreased prostaglandin synthesis due to inhibition of COX-1. A direct irritant effect on gastric mucosa may also be involved. Salicylates increase the permeability of the gastric mucosa to cations, thus increasing the entry of acid into the mucosa. Salicylates are also known to stimulate the chemoreceptor trigger zone, resulting in nausea and vomiting.
•Respiratory Effects: The respiratory effects of salicylates lead to acid/base changes and alterations in electrolyte and water balance. Salicylates stimulate respiration directly and indirectly resulting in respiratory alkalosis. This is caused by a salicylate-induced increase in oxygen consumption, primarily in skeletal muscle, leading to increased carbon dioxide production and respiratory stimulation. Increased alveolar ventilation balances the increased carbon dioxide production; therefore, plasma carbon dioxide (PaCO2) does not change. Salicylate-induced respiratory alkalosis is compensated for by increasing renal excretion of bicarbonate, which is accompanied by increased sodium and potassium excretion. The serum bicarbonate level is then lowered and the serum pH returns to normal (i.e., compensated respiratory alkalosis). However, if the respiratory response to hypercapnia has been depressed (e.g., administration of a barbiturate or opiate agonist), salicylates will cause a significant increase in PaCO2 and respiratory acidosis. Hyperventilation also occurs due to direct stimulation of the respiratory center in the medulla. At high salicylate plasma concentrations (>= 350 mcg/ml), marked hyperventilation will occur, and at serum concentrations of about 500 mcg/ml, hyperpnea will be seen. Finally, at high-therapeutic and at toxic doses, aspirin can affect oxidative phosphorylation, however, this action is insignificant at lower doses. Other changes in acid-base status (e.g., metabolic and respiratory acidosis) and electrolyte and water balance (hypokalemia, hypernatremia, dehydration) may be seen during salicylate intoxication (see Adverse Reactions).
•Renal Effects: In addition to changes in sodium and fluid status secondary to acid/base changes, salicylates may decrease renal blood flow and glomerular filtration rate, which may be accompanied by water and potassium retention, in sodium-restricted patients and patients with impaired renal function or hypovolemic states. Changes in renal function are due to inhibition of renal prostaglandin synthesis, which increase renal blood flow and maintain normal renal function. Salicylate-induced renal effects are uncommon in patients with normal renal function.
•Uricosuric Effects: Salicylates act on the renal tubules to affect uric acid excretion. Lower doses (e.g., 1—2 g/day) of salicylates inhibit the active secretion of uric acid into the urine via the proximal tubules. However, high doses (> 5 g/day) of salicylates inhibit the tubular reabsorption of uric acid, resulting in a uricosuric effect. Uric acid secretion is not changed at intermediate dosages. While once used for their uricosuric properties, other agents have replaced salicylates for this purpose.
•Uterine Effects: Salicylates produce various effects on the uterus due to inhibition of prostaglandin synthesis. Alleviation of dysmenorrhea may be due to inhibition of prostaglandins of the E and F series. Administration of salicylates late in pregnancy may prolong gestation and labor.
•Other Actions: In the treatment of vernal conjunctivitis, aspirin prevents the formation of prostaglandin D2, a secondary mast cell mediator of allergic conditions. Single doses of aspirin do not exert detrimental effects on exercise metabolism or exercise performance.[1626] Salicylates have complex actions on carbohydrate and cholesterol metabolism. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. By inhibiting prostaglandin E2 synthesis, salicylates can indirectly increase insulin secretion.

Pharmacokinetics: Aspirin is usually administered orally in adults, but can be given rectally as suppositories in children. Aspirin is absorbed via passive diffusion as unchanged drug and hydrolyzed salicylic acid from the upper intestine and partly from the stomach. Approximately 70% of an aspirin dose reaches the circulation unchanged; the remaining 30% is hydrolyzed to salicylic acid during absorption by esterases in the GI tract, plasma, or liver. The rate of absorption is dependent upon many factors including oral formulation, gastric and intestinal pH, gastric emptying time, and the presence of food. Effervescent and soluble tablets are most rapidly absorbed, followed by un-coated or film-coated tablets, and then enteric coated tablets and extended-release formulations. Food decreases the rate, but not the extent, of absorption. Salicylic acid is more ionized as the pH increases; however, a rise in pH increases the solubility of ionized salicylic acid and increases the dissolution of aspirin tablets. The overall effect of increased pH is an increase in absorption. Time to peak aspirin concentrations is 15—240 minutes depending upon the formulation. Plasma aspirin concentrations decrease as salicylic acid levels increase. Peak plasma salicylate levels occur in approximately 30—60 minutes for effervescent tablets, 45—120 minutes for film-coated tablets, 4—12 hours for extended-release tablets, and 8—14 hours for enteric-coated tablets. Steady-state salicylate serum concentrations are similar after administration of plain, uncoated tablets and enteric-coated tablets.[98] Salicylic acid is widely distributed with high concentrations in the liver and kidney. Salicylic acid crosses the placenta and is excreted in breast milk. During chronic administration, salicylate levels in the fetus may be higher than those in the mother. Aspirin is poorly protein bound as compared to salicylic acid. However, aspirin may acetylate albumin resulting in changes the ability of albumin to bind other drugs. Protein binding of salicylic acid to albumin varies with serum salicylate and albumin concentrations. At salicylate levels of <= 100 mcg/ml, salicylic acid is 90—95% protein bound; approximately 70—85% protein bound at 100—400 mcg/ml; and only 20—60% protein bound at serum concentrations of > 400 mcg/ml.

Aspirin has a half-life of 15—20 minutes as it is rapidly hydrolyzed by the liver to salicylic acid. Salicylic acid is primarily metabolized in the liver. Metabolites include salicyluric acid (glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. In addition, a small amount is metabolized to gentisic acid (2,5-dihydroxybenzoic acid) and 2,3-dihydroxybenzoic and 2,3,5-dihydroxybenzoic acids. Salicyluric acid and salicyl phenolic glucuronide are formed via saturable enzyme pathways, and therefore, exhibit non-linear pharmacokinetics. The elimination half-life of salicylic acid varies with dosage. After a single low dose, the serum half-life of salicylic acid is 2—3 hours but can increase to 15—30 hours after high doses. Because of decreased serum protein binding, the effect of increasing doses is more pronounced on free salicylate levels than total salicylate levels. Approximately 80—100% of the salicylic acid from a single salicylate dose is excreted within 24—72 hours in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides, and gentisic acid (< 1%). The excretion of free salicylic acid is variable and depends upon the dose and the urinary pH. In alkaline urine, > 30% of the dose may be eliminated as free salicylic acid, but in acidic urine only about 2% is eliminated as free salicylic acid.

Description, Mechanism of Action, Pharmacokinetics last revised 11/23/2004 9:47:00 AM

Indications

† non-FDA-approved indication

Dosage

For the treatment of rheumatoid arthritis or osteoarthritis in adults:
Oral dosage:
Adults: 2.6—5.4 g/day PO in 4 or more divided doses.

For the treatment of juvenile rheumatoid arthritis (JRA):
Oral or rectal dosage:
Children weighing > 25 kg: 2.4—3.6 g/day in divided doses.
Children weighing <= 25 kg: 60—90 mg/kg/day PO or PR in divided doses.

For the treatment of fever or mild pain, or for the temporary relief of headache, myalgia, back pain, bone pain†, dental pain (e.g., toothache), dysmenorrhea, arthralgia, or minor aches and pains associated with the common cold or flu:
Oral or rectal dosage:
Adults and adolescents: 325—650 mg PO or PR every 4 hours, as needed. Alternatively, 1000 mg PO or PR every 6 hours, as needed. For self-medication, the maximum recommended dose is 4 g/day PO. Do not take aspirin for pain for more than 10 days or for fever for more than 3 days unless directed by a physician.
Children: 10—15 mg/kg PO or PR every 4—6 hours. Maximum daily dose is 4 g/day PO. Do not take aspirin for pain for more than 10 days or for fever for more than 3 days unless directed by a physician.

For the treatment of acute ischemic stroke in patients not eligible for thrombolysis:
Oral dosage:
Adults: The American College of Chest Physicians' (ACCP) recommends early aspirin therapy in doses of 160—325 mg PO once daily for patients in the acute phase of ischemic stroke who are not receiving thrombolysis. ASA should be initiated within 48 hours of stroke onset and may be used in combination with low-dose SC heparin. The use of ASA in this fashion has been shown to reduce stroke recurrence risk and mortality within 14 days of the acute event. Patients who are ASA recipients for up to 4 weeks after the acute event have also showed reductions in these events at 6 months.

For stroke prophylaxis:
•in patients with a history of transient ischemic attack (TIA) or noncardioembolic (atherosthrombotic, lacunar, or crytogenic) stroke:
Oral dosage:
Adults: Some controversy exists regarding the appropriate dose of aspirin in this setting. Aspirin has been effective in doses ranging from 30—1300 mg/day PO. The American College of Chest Physicians (ACCP) recommends aspirin as one of the first-line antiplatelet agents at a dose of 50—325 mg PO once daily; in patients with documented, unexplained TIA, the recommendation is long-term aspirin therapy of 160—325 mg/day PO. Patients intolerant of aspirin may be candidates for alternative antiplatelet therapy.[4037] The Dutch TIA Trial Study Group found that a lower ASA dose was as effective a higher dose (e.g., 30 mg PO once daily vs 283 mg PO once daily).[1258] [1259] In addition, fewer bleeding events occurred with the lower ASA dose. Meta-analyses of multiple studies have shown no important differences in daily doses of aspirin from 30 to 1300 mg PO in the prevention of stroke or related vascular events.
•in patients with atrial fibrillation with moderate risk factors:
Oral dosage:
Adults: The optimal dosage of aspirin in patients with atrial fibrillation has not been clearly established. In patients with one moderate risk factor (e.g., age 65—75 years, diabetes, or CAD with preserved LV systolic function), long-term therapy with aspirin (325 mg PO once daily) or warfarin is appropriate. The American College of Chest Physicians' Consensus Guidelines state that the risk/benefit is unclear for the use of aspirin (325 mg PO once daily) in patients < 65 years and no clinical of echocardiographic evidence of cardiovascular disease.[1275] Aspirin therapy decreases the risk of stroke in patients with atrial fibrillation, but to a much lesser extent than warfarin therapy. The Stroke Prevention in Atrial Fibrillation (SPAF) study found a dose of 325 mg PO enteric-coated aspirin once daily to be effective but a lower dose of 75 mg/day was not beneficial in the Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK) study. This latter study, however, enrolled fewer patients and confidence intervals were wide.

For the treatment of an evolving acute myocardial infarction (AMI):
Oral dosage:
Adults: The American College of Chest Physicians (ACCP) recommends that 75—162.5 mg non-enteric-coated aspirin be chewed and swallowed as soon as possible after the diagnosis of acute MI is made and repeated once daily indefinitely, regardless if thrombolytic therapy will be given. If heparin is to be given, aspirin should be used concomitantly; if warfarin is to be given, aspirin should be withheld until the course of therapy has been completed.[1961] ACC/AHA guidelines recommend aspirin doses of 160—325 mg be given on day 1 of AMI and continue indefinitely.[1483]

For myocardial infarction prophylaxis:
•for primary myocardial infarction prophylaxis:
Oral dosage:
Adults > 50 years: It is recommend aspirin 75—162.5 mg PO once daily may be considered for those who have at least one additional risk factor for coronary artery disease. Men at high-risk for cardiovascular events may be offered warfarin as an alternative to aspirin. In men at very high-risk for cardiovascular events consider low-dose aspirin (75—80 mg/day) with low-intensity warfarin (INR 1.5) as an alternative to either drug alone. Because of the trend towards a higher hemorrhagic stroke rate in patients who received aspirin rather than placebo, the routine use of aspirin in those <= 50 years of age without a history of MI, stroke, or TIA is not recommended by the 2001 ACCP antithrombotic therapy guidelines.[1961]
•for secondary myocardial infarction prophylaxis in patients with a previous history of myocardial infarction (i.e., postmyocardial infarction):
Oral dosage:
Adults: 75—162.5 mg PO once daily. Clinicians may consider low-dose aspirin (75—80 mg PO once daily) with low-intensity warfarin (INR 1.5) in patients with recurrent ischemic episodes following an acute myocardial infarction.[1961]

For the treatment of stable angina and chronic coronary artery disease (CAD):
Oral dosage:
Adults: The American College of Chest Physicians recommends that all patients with stable angina or clinical or laboratory evidence of CAD receive aspirin 75—162.5 mg/day PO indefinitely.[1961]

For the treatment of unstable angina:
Oral dosage:
Adults: As soon as possible after the detection of unstable angina, patients should chew and swallow 162.5 mg of non-enteric coated aspirin. Aspirin 75—162.5 mg PO once daily should continue daily. Hospitalized patients with unstable angina should be treated with heparin or low-molecular weight heparin for at least 48 hours or until the unstable pain pattern resolves, in addition to aspirin.[1595] Patients with continuing ischemia or other high-risk features should receive concomitant tirofiban or epitfiatide with aspirin and heparin, especially if elevations in serum troponin T or I exist.[1961]

For arterial thromboembolism prophylaxis:
•in combination with warfarin in patients with prosthetic heart valves:
Oral dosage:
Adults: The American College of Chest Physicians (ACCP) guidelines recommend warfarin in combination with aspirin 80—100 mg/day PO for patients with caged ball or caged disk valves. An alternative to warfarin alone for patients with tilting disk valves, bileaflet mechanical valves in the mitral position, or bileaflet mechanical valves in the aortic position with atrial fibrillation is warfarin plus aspirin 80—100 mg/day PO. In patients who have mechanical valves and additional risk factors or a history of systemic embolism despite adequate oral anticoagulation, a combination of warfarin and aspirin 81 mg/day PO is recommended. A randomized, double-blind, placebo-controlled study demonstrated that the addition of enteric-coated, slow-release aspirin 100 mg/day PO to warfarin provided better reduction of morbidity and mortality than warfarin alone. The combination of warfarin with aspirin was also associated with an increased risk of bleeding as compared to warfarin alone.[39]
•for chronic extremity arterial insufficiency in patients with intermittent claudication† from arteriosclerosis:
Oral dosage:
Adults: 80—325 mg PO once daily alone or in combination with dipyridamole, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction. Consider lifelong aspirin therapy in patients with no contraindications.[1218]
•following vascular reconstruction of high-flow, low-resistance arteries > 6 mm in diameter†:
Oral dosage:
Adults: 80—325 mg PO once daily, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction. Do not offer antithrombotic therapy to maintain patency of reconstruction.[1218]
•following prosthetic femoral-popliteal bypass surgery†:
Oral dosage:
Adults: 80—325 mg PO once daily, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction; consider addition of dipyridomole.[1218]
•following saphenous vein femoral-popiteal or distal bypass surgery:†
Oral dosage:
Adults: 80—325 mg PO once daily, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction.[1218]
•for patients who are at high-risk of graft thrombosis following infrainguinal bypass:
Oral dosage:
Adults: 75—80 mg PO once daily in combination with warfarin.[1218]
•following carotid endarterectomy†:
Oral dosage:
Adults: 80—325 mg PO once daily indefinitely, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction.[1218]
•for patients following saphenous vein or internal mammary artery bypass grafting performed for coronary artery disease (CAD):
NOTE: Aspirin therapy is not recommended when grafting is performed for conditions other than CAD.
Oral dosage:
Adults: 325 mg PO once daily beginning 6 hours after surgery, or if delayed by bleeding, as soon as possible. Aspirin therapy should be continued for at least one year to reduce the frequency of graft closure.[49]

For thrombosis prophylaxis† in patients undergoing percutaneous coronary intervention (PCI)† to reduce the frequency of early ischemic complicatons:
Oral dosage:
Adults: Pretreat with aspirin 80—325 mg PO once daily and continue with long-term treatment for secondary prevention.[1748]

For the treatment of migraine:
Oral dosage:
Adults: 900 mg PO at the onset of the migraine has been recommended.[350] When metoclopramide was administered concomitantly to overcome gastric stasis that occurs during a migraine attack, aspirin 900 mg PO was found as effective as oral sumatriptan and caused fewer adverse reactions.[972]

For the treatment of Kawasaki disease† (mucocutaneous lymph node syndrome):
Oral dosage:
Children: In addition to IV gamma globulin, 80—100 mg/kg/day PO divided in 4 daily doses during the febrile phase (up to 14 days). After patient defervesces for 36 hours, decrease to 3—5 mg/kg/day PO once daily for >= 7 weeks to prevent the formation of coronary aneurysm thrombosis.[1653]

For the treatment of idiopathic or viral pericarditis†:
Oral dosage:
Adults: 325—900 mg PO four times daily.

For colorectal cancer prophylaxis†:
Oral dosage:
Adults: The role of aspirin as primary or secondary chemoprevention for colorectal cancer has yet to be determined. Observational studies have indicated a trend in reducing the risk of developing colorectal cancer. However, results of a long-term study where males participants were randomized to receive aspirin 325 mg PO every other day conflict with these results. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk of colorectal cancer of 1.03 (95% confidence interval, 0.83 to 1.28).[4045] A cost-effectiveness analysis found that aspirin prophylaxis was generally not cost-effective for persons who follow appropriate colorectal cancer screening programs (NOTE: results of this anaylsis were very sensitive to changes in assumptions regarding aspirin's effects).[4046] In patients with previous colorectal cancer randomized to receive either aspirin 325 mg PO once daily or placebo, one or more adenomas was found in significantly less patients in the aspirin group vs. the placebo group (17% vs. 27%). Aspirin appeared to delay the the development of adenomas; however, the mean size of the adenomas and the proportion of patients with advanced adenomas did not differ between the groups.[4047] In another trial, patients with a recent history of adenomas were randomized to receive placebo, aspirin 81 mg, or aspirin 325 mg PO once daily. After a mean duration of 33 months, the incidence of 1 or more adenomas was 47% in the placebo group, 38% in those given aspirin 81 mg, and 45% in those given aspirin 325 mg. The rate of recurrence was significantly lower in the low-dose aspirin group as compared to placebo, but the higher dose of aspirin did not significantly reduce the recurrance rate.[4048]

For preeclampsia prophylaxis†:
Oral dosage:
Adult females: Data are contradictory regarding the ability of aspirin to prevent preeclampsia. Several small studies showed a protective effect, with no associated risk to the mother or fetus, however several larger placebo-controlled trials revealed no beneficial effects of aspirin. In one study pregnant women at high risk for preeclampsia, aspirin 60 mg PO once daily or placebo was initiated between gestational weeks 13—26. The incidences of preeclampsia, perinatal death, and preterm birth were similar in the aspirin and placebo groups.[2035] In another study of nulliparous women who were 13—25 weeks pregnant, subjects were randomized to aspirin 60 mg PO once daily or placebo until onset of labor. The incidence of preeclampsia was significantly lower in the aspirin group than in the placebo group (4.6% vs. 6.3%); however, the benefit was small and limited to women who had elevated systolic blood pressures at baseline. There were no significant differences in the infants' birth weight or in the incidence of fetal growth retardation, post-partum hemorrhage, or neonatal bleeding problems between the two groups. The incidence of abruptio placentae, however, was greater among the women who received aspirin.[923]

For the treatment of vernal keratoconjunctivitis†:
Oral dosage:
Adults: A dosage of 650 mg PO 3 times daily has been recommended. Doses of 0.5—1.5 g/day have been given to provide symptomatic relief in some patients whose symptoms were not controlled by cromolyn or corticosteroids.[1390]

Therapeutic Drug Monitoring:
Most patients experience salicylate toxicity when the total salicylate level is > 300—350 mcg/ml; however, the elderly may show signs of toxicity at lower levels.

Patients with hepatic impairment:
No dosage adjustment recommendations are available. Patients with hepatic disease are at increased risk of salicylate-induced adverse reactions.

Patients with renal impairment:
CrCl < 10 ml/min: Avoid aspirin in patients with severe renal failure.

Intermittent hemodialysis:
Not applicable; aspirin should be avoided in severe renal failure. Hemodialysis is used to enhance salicylate elimination in aspirin overdosage.

†non-FDA-approved indication

Indications...Dosage last revised 7/28/2003 2:52:00 PM

Administration Guidelines

Oral Administration
•Film-coated tablets: May help to reduce the unpleasant taste or aftertaste, burning in the throat, or difficulty in swallowing associated with uncoated tablets.
•Enteric-coated or extended-release tablets: May help to reduce gastric irritation and/or symptomatic GI disturbances associated with uncoated tablets.
•Chewable 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.
•All preparations: Administer with food or large amounts (240 ml) of water or milk to minimize GI irritation.

Rectal Administration
•For use in patients unable to take or retain oral aspirin; however, absorption may be slow and incomplete. Do not use aspirin tablets rectally because they are likely to cause irritation and erosion of rectal mucosa.
•Instruct patient on proper use of suppository (see Patient Information).
•Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.

Administration last revised 7/1/2002

Contraindications/Precautions

• Absolute contraindications are in italics.

Patients with a tartrazine dye hypersensitivity or salicylate hypersensitivity should avoid aspirin. The risk of cross-sensitivity with other nonsteroidal antiinflammatory drugs is significantly greater with aspirin than other salicylates; avoid use in patients with a known NSAID hypersensitivity. Patients with nasal polyps or with allergic reactions (e.g. urticaria) to aspirin are at risk of developing bronchoconstriction or anaphylaxis and should not receive aspirin. Patients with asthma are at risk of developing severe and potentially fatal exacerbations of asthma after taking aspirin. Aspirin should be avoided in asthmatics with a history of aspirin-induced acute bronchospasm.

A patient with acetaminophen hypersensitivity may also be hypersensitive to aspirin. Of 13 patients with acetaminophen hypersensitivity, 3 had aspirin or ibuprofen hypersensitivity.[8423] Of 163 patients with a history of urticaria induced by aspirin but without a history of chronic urticaria, 11% had cross-reactivity to acetaminophen.[8424] The mechanism(s) of hypersensitivity cross-reactivity have not been clearly elucidated. Some cases of cross-reactivity appear to be caused by prostaglandin inhibition, and some cases appear to be caused by an IgE-mediated mechanism. Although unproven, the metabolic breakdown of the parent molecule of some NSAIDs and acetaminophen could yield structurally similar chemical moieties, which could result in IgE production. Patients with a history of aspirin-induced anaphylaxis may be more likely to cross-react to acetaminophen.

Aspirin has been associated with the occurrence of Reye's syndrome when given to children with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with varicella, influenza, or other viral infection. If children are receiving chronic aspirin therapy, aspirin should be discontinued immediately if a fever develops, and not resumed until diagnosis confirms that the febrile viral illness has run its course and the absence of Reye's syndrome.

Aspirin can induce gastric or intestinal ulceration that can occasionally be accompanied by iron-deficiency anemia or other anemia from the resultant blood loss. Aspirin should be used cautiously, if at all, in patients with a history of or active GI disease including erosive gastritis, esophagitis, GI bleeding, peptic ulcer disease, or previous NSAID-induced bleeding. Such patients should be monitored closely, with special caution in tobacco smoking patients or in patients with alcoholism. All patients receiving chronic treatment should be routinely monitored for potential GI ulceration and bleeding. In patients who develop gastric or duodenal ulcers during aspirin treatment, the drug should be discontinued due to an increased risk of bleeding and/or perforation. In addition, patients should not self-medicate with aspirin if they consume 3 or more alcoholic beverages per day because of the potential increased risk for GI bleeding. In patients with anemia, this condition may be exacerbated during aspirin therapy due to GI blood loss. Hematocrit should be monitored periodically in patients receiving prolonged or high-dose aspirin therapy since iron deficiency anemia may occur. Traditionally, aspirin has been recommended to be discontinued for a time interval (e.g., 1 week) prior to surgery to minimize postoperative bleeding. However, data presented at the 2003 meeting of the American College of Chest Physicians indicates a risk of increased coronary events with abrupt discontinuation of aspirin in patients with pre-existing coronary artery disease.[4425] Patients with stable coronary disease developed acute coronary events within one week of stopping aspirin therapy; these events included unstable angina and myocardial infarction. Until the results of this trial are published and/or consensus recommendations are available, the decision whether to discontinue aspirin therapy abruptly should include a careful evaluation of the overall risks and benefits given the patient's coexisting conditions and the type of surgery or procedure. The use of aspirin is generally not recommended in patients expected to require CNS surgery due to the increased risk of perioperative bleeding.

Since even low doses of aspirin inhibit platelet aggregation and increases bleeding time, aspirin should be used cautiously in patients with coagulopathy, hemophilia, pre-existing thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), or in patients receiving anticoagulant therapy or thrombolytic therapy (see Drug Interactions). It should also be avoided in patients with aplastic anemia, agranulocytosis, or pancytopenia. Aspirin should be used with caution in patients with immunosuppression or neutropenia following myelosuppressive chemotherapy. Aspirin may mask signs of infection, such as fever and pain, in patients with bone marrow suppression.

Because of the possibility of interference with platelet function, aspirin should be avoided in patients with potential for intracranial bleeding (e.g., subarachnoid aneurysm, head trauma, increased intracranial pressure).

Because salicylates may cause or aggravate hemolysis in patients with G6PD deficiency, some reference texts state that aspirin should be used cautiously in these patients. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. Otherwise, hemolysis only occurs at high concentrations.[1281]

Intramuscular injections should be administered cautiously to patients receiving aspirin. IM injections may cause bleeding, bruising, or hematomas due to aspirin-induced inhibition of platelet aggregation.

Liver function should be monitored in patients receiving large doses of aspirin (e.g., for treatment of rheumatoid arthritis) or in patients with preexisting hepatic disease in order to prevent reversible, dose-dependent hepatotoxicity. Large doses also can cause hypoprothrombinemia, which can be reversed by vitamin K. Patients with vitamin K deficiency should be closely monitored if taking large doses of aspirin.

Salicylates should be used with caution in patients with renal impairment and with extreme caution, if at all, in patients with advanced, chronic renal failure since salicylic acid and its metabolites are excreted in the urine. In addition, these patients may be at increased risk of developing salicylate-induced nephrotoxicity. In a case-controlled study of patients with early renal failure, the regular use of aspirin (without acetaminophen) was associated with a risk of chronic renal failure that was 2.5-times as high as that for non-aspirin users.[4064] The risk increased significantly with increasing cumulative lifetime dose and increasing average dose during periods of regular use; duration of therapy was not associated with increased risk. When aspirin was given regularly in analgesic doses (> 500 g per year during periods of regular use) the odds ratio for chronic renal failure was 3.5 (95% confidence interval 1.4 to 8). Low-dose aspirin use for cardiovascular prophylaxis was not significantly associated with the development of renal failure. In this study, it appears that pre-existing renal disease or systemic disease is a required precursor to the development of analgesic-induced renal failure; patients without preexisting renal disease who used analgesics had only a small risk of developing end-stage renal disease. Renal function should be monitored periodically in patients receiving prolonged or high-dose salicylate therapy. Salicylates should be used cautiously in patients with renal disease or systemic lupus erythematosus (SLE) due to the risk of decreased glomerular filtration rate in these patients.

Elderly patients may be at increased risk of salicylate toxicity possibly due to decreased renal function. Elderly patients seem to tolerate GI ulceration or bleeding less well than younger individuals and many spontaneous reports of fatal GI events are in this population. Elderly patients at the highest risk for the development of gastric or duodenal ulcers are those using both NSAIDs and corticosteroids, with a prior history of peptic ulcer disease or NSAID-related GI bleeding, high-dose NSAID therapy, complaints of dyspepsia, and those with concurrent disease states that increase their risk of mortality from a GI bleed or perforation. In addition, elderly patients are more likely to have concomitant disease states, which may exacerbate salicylate-induced renal changes. Care should be taken in dose selection and the lowest effective dose should be used in patients at risk. After initiating salicylate therapy, elderly patients should be monitored for the development of pedal edema, rales, blood pressure elevation, or changes in creatinine or BUN levels. Monitoring of stool for occult blood, serum potassium levels, and a complete blood count should be considered at baseline and periodically during chronic salicylate therapy.

Sodium-restricted patients or patients with hypovolemic states (e.g., ascites, dehydration, heart failure, hypertension, or hypovolemia) may be more susceptible to adverse renal effects of salicylate therapy. Buffered aspirin contains a high sodium content. In patients with carditis, high doses of salicylates may precipitate congestive heart failure or pulmonary edema.

The respiratory effects of salicylates may contribute to serious acid/base imbalance in patients with underlying acid/base disorders (e.g., metabolic acidosis, metabolic alkalosis, respiratory acidosis, or respiratory alkalosis) or in overdose situations. Patients who are unable to compensate for salicylate-induced metabolic acidosis (i.e., respiratory response to CO2 is depressed) may develop respiratory acidosis and increased levels of plasma CO2.

In patients with gout, salicylates may increase serum uric acid levels, resulting in hyperuricemia, and interfere with the efficacy of uricosuric agents.

Aspirin is classified as FDA pregnancy category risk C during the first and second trimesters and should only be used during pregnancy if clearly needed. Because regular use of full-dose aspirin late in pregnancy may result in constriction or premature closure of the fetal ductus arteriosus, aspirin is classified as FDA pregnancy risk category D during the third trimester of pregnancy. Fetal and newborn effects from aspirin exposure in utero may include increased perinatal mortality, intrauterine growth retardation, congenital salicylate intoxication, or depressed albumin-binding capacity. However, a large prospective study involving over 40,000 patients, 64% of whom used aspirin sometime during gestation, failed to show that aspirin was a cause of stillbirths, neonatal deaths, or reduced birth weight.[2036] The lack of adverse effects of aspirin therapy in this study may have been related to the use of relatively low aspirin doses. Several groups have evaluated low-dose aspirin (60—150 mg/day) administered during the second and third trimesters of pregnancy as an agent to prevent preeclampsia. One group found that the efficacy in preventing preeclampsia was only marginal and a higher risk of abruptio placentae was seen.[923] The other group concluded that aspirin appears to be safe for the mother and the fetus.[2037] The safety of higher doses and/or administration during the first trimester, however, is uncertain. Full doses of aspirin administered to pregnant women near term have been associated with toxicities such as hemorrhage, premature closure of the ductus arteriosus, pulmonary hypertension, prolonged gestation, and prolonged labor.

Salicylates are excreted into breast milk and could cause adverse effects in infants. The American Academy of Pediatrics recommends that aspirin be used cautiously during breast-feeding.[4201]

Contraindications last revised 10/31/2005 4:27:00 PM

Drug Interactions

Many prescription and non-prescription medicines contain aspirin, ASA. Based on the pharmacology of aspirin [5717], patients receiving salicylate therapy should avoid non-prescription medications containing salicylates to prevent increased salicylic acid concentrations and toxicity. Repeated or maximum doses of bismuth subsalicylate-containing preparations (e.g., Pepto-Bismol®) could lead to salicylate toxicity in patients receiving concurrent aspirin therapy. Bismuth subsalicylate administration results in significant salicylate serum concentrations in adults.[3166] Avoid concurrent use of aspirin with products that contain aspirin and in patients who are taking aspirin on a regular basis. Advise patients to carefully read the ingredients of any other medicines they are taking with aspirin.[5717]

Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. In a case-controlled study of patients with early renal failure, the regular use of aspirin and acetaminophen was associated with an odds ratio of 2.2 (95% confidence interval 1.4 to 3.5) when regular aspirin users were the reference group.[4064] The trend toward greater risk with an increasing cumulative life-time dose of acetaminophen was statistically significant with a risk that was 2.4-times as high for subjects who had consumed a total > 500 g of acetaminophen in combination with aspirin than for those who had used aspirin alone. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.

The coadministration of high-dose aspirin with carbonic anhydrase inhibitors, such as acetazolamide and methazolamide, has resulted in anorexia, tachypnea, lethargy, coma and death. Both acetazolamide and aspirin undergo renal tubular secretion and competition for renal tubular secretion may occur.[6412] Accumulation of the carbonic anhydrase inhibitor may result in increased CNS depression and metabolic acidosis. The acidosis may allow greater CNS penetration of the salicylate. High-dose salicylates should not be prescribed with carbonic anhydrase inhibitors. With normal doses of salicylates, carbonic anhydrase inhibitor-induced urinary alkalinization will result in increased excretion and lowered plasma concentrations of salicylates, which may or may not be clinically significant. Consideration of carbonic anhydrase inhibitor dose reduction and observance for any adverse effects from acetazolamide or methazolamide is warranted.[5717]

Caution should be exercised when aspirin is given in combination with methotrexate. Concomitant administration of salicylates with high-dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any salicylate be used cautiously with methotrexate even when lower doses of methotrexate are given for the treatment of rheumatoid arthritis or psoriasis. Elderly patients and patients with renal impairment may be at particular risk. As both methotrexate and salicylates are weak acids, aspirin can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites.[5067] [5232]

Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents may lead to additive nephrotoxicity. Also, the plasma salicylic acid concentration is increased by conditions that reduce the glomerular filtration rate or tubular secretion.[7823] Salicylates should be given with caution to patients taking aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin. Monitor renal function carefully during concurrent therapy.

Concomitant use of ketorolac and aspirin is contraindicated. Increased adverse gastrointestinal and other effects are possible if ketorolac is used with salicylates. In addition, concomitant administration of salicylates and ketorolac has resulted in a reduction in protein binding and a two-fold increase in unbound plasma concentrations of ketorolac. Also, because ketorolac can cause GI bleeding, inhibit platelet aggregation, and may prolong bleeding time, additive effects may be seen in patients receiving aspirin.[5060]

The concurrent use of aspirin with other nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because this may increase bleeding or lead to decreased renal function.[5717] The use of aspirin together with nonsalicylate NSAIDs (e.g., indomethacin) can lead to additive GI toxicity.[5232] Due to competition for plasma protein binding sites and/or reduced renal clearance, aspirin may enhance the toxicity of naproxen.[7827] Avoid concurrent use of NSAIDs and aspirin. Concurrent use of chronic ibuprofen therapy (800 mg three times daily) seems to antagonize the inhibition of platelet cyclooxygenase (COX)-1 activity and impairment of platelet aggregation by low-dose aspirin (81 mg once daily) per an ex vivo analysis.[4062] Interestingly in this study, diclofenac or rofecoxib therapy, agents with less activity at COX-1 than ibuprofen, did not affect inhibition of platelet aggregation by aspirin.[4062] An in vitro study has shown that the antagonism of aspirin platelet inhibition probably involves competition at platelet-derived COX-1 and is related to the NSAIDs' ability to inhibit COX-1 mediated thromboxane B2 production in platelets.[4063] However, whether this interference with aspirin's activity leads to adverse clinical consequences or occurs with NSAIDs other than ibuprofen and naproxen (see naproxen monograph) has not been determined.

The concomitant administration of cidofovir and NSAIDs, such as aspirin is contraindicated due to the potential for increased nephrotoxicity. Aspirin should be discontinued 7 days prior to beginning cidofovir.[5118]

The risk of bleeding is increased if aspirin, ASA, is administered to patients already receiving anticoagulants or thrombolytic agents. Aspirin can potentiate the anticoagulant effects and can increase the risk of bleeding because of its effect on platelet aggregation and interaction with heparin and warfarin.[5717] Aspirin can displace warfarin from protein-binding sites leading to increased prothrombin time and bleeding time. Aspirin should be used cautiously in patients receiving warfarin therapy; clinicians should note that dosage adjustment of warfarin therapy may be required.[6412] In addition, large doses of salicylates (>= 3—4 g/day) can cause hypoprothrombinemia,[5170] an additional risk factor for bleeding. Combination therapy with both aspirin and warfarin has been shown to reduce mortality compared to warfarin therapy alone in patients with artificial heart valves.[39] Also use caution in combining aspirin therapy with other platelet inhibitors due to the potential for additive effects; however, some combinations are therapeutic.

Salicylates may have hypoprothrombinemic effects.[5170] Selected cephalosporins (cefoperazone, cefamandole, cefotetan), due to the presence of a methylthiotetrazole (MTT) side chain, have been associated with prolongation of the prothrombin time. Such cephalosporins may also interfere with the synthesis of vitamin K clotting factors and also disturb metabolism of vitamin K by a second, unknown mechanism.[5377] [6654] In selected circumstances such cephalosporins may cause additive effects when given concurrently with salicylates.

Because aspirin, ASA, can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, an increased risk of bleeding may be seen in patients receiving agents that cause clinically significant thrombocytopenia. Notable interactions may occur with antithymocyte globulin [6303], strontium-89 chloride [4694], or imatinib, STI-571 [4966].

Due to aspirin's effect on platelet aggregation and GI mucosa, aspirin should be used cautiously in patients with thrombocytopenia following treatment with antineoplastic agents due to an increased risk of bleeding.[5717] In general, because certain antineoplastic agents can cause clinically significant thrombocytopenia, they may increase the risk of aspirin-associated bleeding (i.e. GI bleeding, inhibited platelet aggregation, and prolonged bleeding time). Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives.[6859] Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Although usually seen with large salicylate doses, aspirin may displace mercaptopurine, 6-MP from secondary binding sites, resulting in bone marrow toxicities and blood dyscrasias.[5232] Special consideration should be given to myelosuppressed patients prior to receiving aspirin.

Ethanol can cause an increased risk of gastric irritation and GI mucosal bleeding when given with aspirin, as both ethanol and aspirin are mucosal irritants and aspirin decreases platelet aggregation. Patients that consume 3 or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.[5717] Administration of aspirin should be limited or avoided altogether in patients with alcoholism or who consume ethanol regularly. Chronic alcoholism is often associated with hypoprothrombinemia, which increases the risk of aspirin-induced bleeding.

Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar and may potentiate the effects of other antidiabetic agents. This mechanism may explain how salicylates can potentiate the clinical effects of sulfonylureas; however, displacement of sulfonylureas from protein binding sites has also been reported.[1310] In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose or use of greater than maximum recommended daily dosages, salicylates can cause either hypoglycemia or hyperglycemia. Due to the potential severity of the interaction, patients who take a sulfonylurea with aspirin should carefully monitor their blood glucose concentrations, especially during the first few hours after aspirin administration. Avoidance of aspirin for patients with hypoglycemia unawareness while receiving sulfonylurea therapy may be desirable. Large doses of aspirin should be used cautiously in patients who receive antidiabetic agents.[5232]

Preclinical data suggest that agents that affect platelet function and inhibit prostaglandin synthesis could decrease the efficacy of photosensitizing agents used during photodynamic therapy.[6359]

Concurrent administration of high doses of antacids (e.g., sodium bicarbonate 4 g or aluminum and magnesium hydroxide 60—120 ml) or other urinary alkalinizing agents [7648] (e.g., sodium bicarbonate) may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. Antacids do not appear to affect the bioavailability of aspirin, but may cause earlier release of aspirin from enteric-coated products.

Aspirin should not be used concurrently with probenecid or sulfinpyrazone when these are used to treat hyperuricemia or gout, because aspirin can decrease the uricosuric effects.[5232] [5035] In addition, sulfinpyrazone can decrease salicylic acid excretion leading to increased plasma concentration.

Corticosteroids enhance the renal clearance of salicylates. Thus, cessation of corticosteroid use may lead to salicylism.[5232] Dose adjustments may be necessary in patients receiving both corticosteroids and aspirin. Also, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin. Combinations of aspirin with corticosteroids may be just as likely as combinations of nonsalicylate NSAIDs with corticosteroids to cause gastric mucosal injury.[1163]

Due to the high protein binding of salicylic acid, it could be displaced from binding sites, or could displace other highly protein-bound drugs, such as barbiturates (e.g., thiopental) [7823], penicillins, and sulfonamides.[6859] [7109] An enhanced effect of the displaced drug may occur.

Aspirin, ASA may interact with hydantoin anticonvulsants (e.g., phenytoin or fosphenytoin) via several mechanisms. Aspirin and phenytoin are both highly protein bound. Large doses of salicylates (i.e., > 2000 mg/day) can displace phenytoin from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug.[5503] Displacement of phenytoin from binding sites can lead to a decrease in the total phenytoin serum concentration.[5717] Close monitoring for excessive toxicity or decreased efficacy is recommended in patients receiving these drugs in combination with aspirin.

Aspirin and valproic acid are both highly protein bound. Displacement of valproic acid from binding sites can lead to an increase in the serum valproic acid concentration.[5717] The displacement of valproic acid can cause an increase in valproic acid free drug concentrations. In such cases, a patient may experience valproic acid toxicity even if the total drug concentration is within the therapeutic range. Careful drug concentration assessment is needed when concomitant aspirin and valproic acid or divalproex sodium is used.

No adverse events associated with the use of salicylates after varicella vaccination have been reported. However, the manufacturer of varicella virus vaccine live recommends the avoidance of salicylates or aspirin, ASA, use for 6 weeks after vaccination.[5065] Reye's syndrome, which exclusively affects children under 15 years old, has been associated with aspirin use following active varicella infection. Vaccination with close clinical monitoring is recommended for children who require therapeutic aspirin therapy; according to the CDC the use of attenuated, live varicella virus vaccine is thought to present less risk than natural varicella disease to such children.

Aspirin should be used with caution in patients who are taking alendronate. Patients taking aspirin, ASA, or aspirin-containing products concurrently with alendronate have an increased incidence of GI adverse events, such as gastric ulceration. In clinical trials, the incidence of upper gastrointestinal adverse events was increased in patients that received aspirin-containing medicines with alendronate 10 mg daily or higher. One patient with a history of peptic ulcer disease and gastrectomy that received alendronate 10 mg daily and aspirin got an anastomotic ulcer with mild hemorrhage. The patient recovered upon alendronate and aspirin discontinuation.[5375]

Concurrent use of mycophenolate mofetil with salicylates can decrease the protein binding of mycophenolic acid (MPA) resulting in an increase in the free fraction of MPA. Mycophenolic acid is more than 98% bound to albumin. Patients should be observed for increased clinical effects from mycophenolate as well as additive adverse effects (i.e., GI effects).[4873]

The efficacy of selected antihypertensive agents needs to be carefully assessed during aspirin usage. During antihypertensive therapy with beta-blockers, high concentrations of vasodilatory prostaglandins are produced in response to reflex-mediated pressor mechanisms (e.g., sympathetic tone). Concurrent use of beta-blockers with aspirin may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.[5717] Aspirin can increase the risk of renal insufficiency in patients receiving diuretics, secondary to the effects of aspirin on renal blood flow. Aspirin inhibits renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Thus, the effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin.[5717] Aspirin may decrease the hyperuricemic effect of thiazide diuretics (e.g., hydrochlorothiazide) or loop diuretics like furosemide. Concomitant use of aspirin and potassium-sparing diuretics, such as triamterene or spironolactone, may cause hyperkalemia.[5717] The hyponatremic and hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors may be diminished by concurrent use of aspirin; the inhibition of cyclooxygenase by aspirin prevents the formation of vasodilatory prostaglandins.[5717] Furthermore, reduced renal blood flow is expected from the decreased pressure gradient created in the glomeruli when aspirin is used with an ACE inhibitor.[5718] Low-dose aspirin (e.g., 81 mg/day) may be less likely to attenuate the antihypertensive or cardioprotective effects of ACE inhibitors; however, the dose-related effect is controversial.[6439] The established benefits of using low-dose aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh concerns, especially with appropriate renal function and serum potassium monitoring.[5718] [6060] [6439] Monitor the patient's blood pressure, renal function, and clinical status for the desired responses and adjust therapy accordingly.

The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA may elevate the risk for an upper GI bleed.[4115] SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Clomipramine, a tricyclic antidepressant with serotonergic activity may produce similar results when combined with aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in >26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. Clomipramine was included in the SSRI category in this study. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.[4115]

Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation [1900] and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents.[5200] A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba® commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period.[1706] Other clinical data exist [1707] that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.

Several pungent constituents of ginger, Zingiber officinale are reported to inhibit arachidonic acid (AA) induced platelet activation in human whole blood.[6708] The constituent (8)-paradol is the most potent inhibitor of COX-1 and exhibits the greatest anti-platelet activity versus other gingerol analogues.[6708] The mechanism of ginger-associated platelet inhibition may be related to decreased COX-1/Thomboxane synthase enzymatic activity.[6708] Patients receiving aspirin, ASA, also a potent platelet inhibitor [5717], should use ginger with caution. The risk of bleeding is theoretically increased in patients receiving anticoagulants, platelet inhibitors, or thrombolytic agents, however, no clinical data describing such interactions are available.[5200]

Garlic, Allium sativum may produce clinically-significant antiplatelet effects [2233]; until more data are available, garlic should be used cautiously in patients receiving drugs with a potential risk for bleeding such as platelet inhibitors (e.g., aspirin, ASA).[5200] A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.[2245] Patients who choose to consume garlic supplements while receiving aspirin should be observed clinically for evidence of adverse effects.

Theoretically feverfew, Tanacetum parthenium may enhance the effects of the platelet inhibitors (including aspirin, ASA) via inhibition of platelet aggregation or via antithrombotic activity.[2913] [2914] [2915] Feverfew also inhibits the secretion of various substances (e.g., arachidonic acid, and serotonin) from the platelet.[1797] Clinical interactions have not yet been reported; however, avoidance of the use of feverfew during antiplatelet therapy seems prudent.[5314] In addition, feverfew appears to inhibit prostaglandin synthesis, reportedly at a different step in the prostaglandin pathway than salicylates.[2911][2912] Theoretically, salicylates might decrease the effectiveness of feverfew, Tanacetum parthenium.[5314]

Drug interactions with fish oil, omega-3 fatty acids are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation [6320], caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events.[3535]

Psyllium can interfere with the absorption of certain oral drugs if administered concomitantly. For example, psyllium fiber can adsorb salicylates [6107]. Per the psyllium manufacturers, administration of other prescribed oral drugs should be separated from the administration of psyllium by at least 2 hours.

Flaxseed fiber can impair the absorption of oral drugs when administered concomitantly.[6099] However, no drug interaction studies have been performed to assess the degree to which the absorption of oral drugs may be altered. Based on interactions of other plant seed fiber (e.g., psyllium) used as a bulk-forming laxative, flaxseed fiber may adsorb salicylates [6107]. Administration of prescribed oral agents should be separated from the administration of flaxseed fiber by at least 2 hours.

Prasterone, dehydroepiandrosterone, DHEA appears to have anti-platelet effects [2459], which may prolong bleeding times. Inhibition of platelet aggregation by DHEA has been demonstrated in vivo in humans; the rate of arachidonate-stimulated platelet aggregation was prolonged or completely inhibited.[2459] In addition, DHEA is converted to androgens and estrogens within the human body and thus, may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X.[4744] Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of these potential, varied effects on coagulation, patients receiving DHEA concurrently with other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.

Drug interactions with Horse chestnut, Aesculus hippocastanum are not well documented. Coumarin compounds with the potential for anticoagulant activity have been isolated from the herb.[5279] [5875] It is possible that the use of horse chestnut may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin), thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, and others).[5875] [6504] Reparil® Dragees (Madaus AG, Germany) a drug derived from horse chestnut and containing aescin (escin), is labeled with a precaution that the action of anticoagulants may be potentiated by aescin.[6505] Caution and careful monitoring of clinical and/or laboratory parameters are warranted if horse chestnut is coadministered with any of these agents.

Green tea has demonstrated antiplatelet and fibrinolytic actions in animals.[6434] [6440] It is possible that the use of green tea may increase the risk of bleeding if co-administered with aspirin. Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with platelet inhibitors.

Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can have a significant effect on salicylate excretion.[6859] Urine acidifying agents (e.g., ammonium chloride, ascorbic acid, vitamin C, potassium chloride, or phosphate salts) may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal. Increases in salicylic acid levels are more likely in patients receiving acidifying agents with a baseline urinary pH > 6.5.

Interactions last revised 5/13/2005 10:59:00 AM

Adverse Reactions

Symptomatic GI disturbances occur in 2—10% of individuals receiving normal doses of aspirin for analgesia or fever, 10—30% of individuals receiving doses > 3.6 grams/day, and 30—90% of patients with preexisting GI disease. Nausea/vomiting, dyspepsia, abdominal pain, pyrosis (heartburn), and other symptoms of gastric distress can be reduced if aspirin is taken with food or a full glass of water. Diarrhea or constipation may also occur. Melena, hemorrhoids, and rectal hemorrhage have occurred with aspirin therapy. Rare cases of esophagitis have been reported in patients receiving aspirin. Aspirin-induced esophagitis is characterized by sudden onset odynophagia, retrosternal pain, and dysphagia. Severe complications such as GI perforation, esophageal ulceration, esophageal stricture, bleeding, and perforation have been reported rarely. Risk factors for aspirin-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication. Penetration of the gastric or esophageal mucosal cell by unionized molecules is one mechanism by which aspirin causes mucosal damage.[100] Raising the intragastric pH increases the amount of aspirin in the unionized form, and some data indicate that agents such as cimetidine or antacids can reduce mucosal injury from aspirin. Chronic aspirin therapy may induce peptic ulcer disease. Gastric or peptic ulcers up to 1 cm in diameter induced by salicylates may heal despite continued therapy when oral cimetidine or high dose antacids are used concomitantly. Duodenal mucosal damage appears to be less common when enteric-coated tablets are used when compared with buffered or uncoated tablets.[1036] GI bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and an increased bleeding time. In general, the severity of GI bleeding with aspirin is dose-related. Occult GI bleeding occurs in many patients and is not necessarily correlated with GI distress. While the amount of blood lost is usually not significant, blood loss can result in iron deficiency anemia. Patients taking aspirin in large doses (> 15 tablets per week) or regularly (>= 4 days/week) are at increased risk of GI bleeding or gastric ulceration. GI bleeding is more common with aspirin than with other salicylates and is not reduced by administering aspirin with food.

Tinnitus and hearing loss may occur in patients receiving high-dose and/or long-term salicylate therapy. These effects are early manifestations of salicylate toxicity. Tinnitus and hearing loss are usually dose-related and reversible upon dose reduction or discontinuation. Tinnitus is commonly associated with salicylate levels > 200—300 mcg/ml. Maximum hearing loss occurs most frequently at salicylate levels of >= 400 mcg/ml.

Anaphylactoid reactions, including angioedema, laryngeal edema, and acute bronchospasm, may occur with aspirin therapy. Most allergic reactions occur within minutes and almost always within an hour of ingestion, although delayed reactions have been noted. Aspirin hypersensitivity may manifest as a respiratory reaction including rhinitis and/or asthma or with urticaria and angioedema. Aspirin hypersensitivity, however, is uncommon and occurs in only 0.3% of the general population. Patients with chronic urticaria have the highest incidence (20%), followed by patients with asthma (4%) and patients with chronic rhinitis (1.5%). Sensitivity is manifested primarily as bronchospasm in asthmatic patients and is most commonly associated with nasal polyps. The correlation of aspirin hypersensitivity, asthma, and nasal polyps is known as the aspirin triad. Hypersensitivity reactions are more common with aspirin than other salicylates. Patients sensitive to aspirin may develop cross-sensitivity to other analgesics, NSAIDs, and azo dyes such as tartrazine. Acetaminophen and other salicylate salts are not cross-sensitive and may be used cautiously in patients with aspirin-induced asthma.

Salicylates may cause reversible hepatotoxicity primarily manifested as mild focal hepatic necrosis and portal hypertension with elevated hepatic enzymes (usually transaminases) and hyperbilirubinemia. Jaundice has been reported in some patients. Rarely, salicylates are associated with hypoprothrombinemia resulting in a prolonged prothrombin time and chronic hepatitis. Usually salicylate-induced hepatotoxicity is mild, but in some cases fatalities or hepatic encephalopathy have occurred.

Reye's syndrome, which exclusively affects children under 15 years of age, has been associated with aspirin use following active varicella infection or other viral illnesses. Reye's syndrome is a multisystem disorder evidenced by persistent vomiting, altered sensorium, elevated hepatic enzymes, hypoprothrombinemia, and hyperammonemia.

Dermatologic reactions are uncommon; usually reported in patients who receive salicylate therapy for > 1 week continually or with overdosage. These reactions include acneiform rash, erythema nodosum, maculopapular rash, pruritus, purpura, and urticaria. Rarely, aspirin has been associated with Stevens-Johnson syndrome and toxi