Drug Criteria & Outcomes
Aspirin/extended-release dipyridamole for stroke
By Donna Givone, PharmD candidate
Medical University of South Carolina
Charleston
Indications
Aspirin/extended-release dipyridamole (Aggrenox), by Boehringer Ingelheim Pharmaceuticals Inc., is indicated for the secondary prevention of stroke in patients who have experienced a transient ischemic attack (TIA) or an ischemic stroke due to thrombosis.1-6
Pharmacology
Dipyridamole and aspirin have additive effects on the inhibition of platelet aggregation. The enzyme cyclo-oxygenase is responsible for the production of prostaglandins, specifically thromboxane A2. Thromboxane A2 induces platelet aggregation and causes vasoconstriction. Aspirin inhibits cyclo-oxygenase, thereby irreversibly inhibiting platelet aggregation. Dipyridamole inhibits phosphodiesterase which increases cyclic-3’, 5’-adenosine monophosphate (cAMP) within platelets. This increase in cAMP inhibits platelet aggregation in response to various stimuli such as platelet activating factor, collagen, and adenosine diphosphate. Additionally, dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells, and erythrocytes. Adenosine inhibits platelet reactivity. Dipyridamole is also an inhibitor of thromboxane A2 synthesis.1-7
Pharmacokinetics
Dipyridamole: The extended-release dipyridamole pellets in Aggrenox capsules are coated with a polymeric, gastrointestinal pH-dependent, retardant lacquer. This provides an acidic microenvironment for improved dissolution. Each capsule contains a set ratio of pellets that release drug at different rates. The peak plasma concentration of extended-release dipyridamole is achieved in 1.5 to 3 hours (range 1 to 6 hours). Absorption of dipyridamole from the gastrointestinal tract exhibits inter-individual variation, with the bioavailability ranging from 37% to 66%. At steady state, the volume of distribution is approximately 92 L; however, it does not cross the blood-brain barrier. Protein binding to alpha1-acid glycoprotein and albumin is extensive, ranging from 91% and 99%. Dipyridamole undergoes hepatic metabolism, via conjugation, to inactive monoglucuronides. Excretion is mainly through the bile into the feces. Renal excretion of the parent compound and glucuronide metabolite is minimal. Immediate-release dipyridamole undergoes biphasic elimination. However, because of the prolonged absorption of the sustained-release preparation compared to the immediate-release preparation, only the terminal half-life is apparent (13.6 hours).1,2,5,7-11
Aspirin: Aspirin is rapidly and completely absorbed after an oral dose, and yields a peak plasma concentration in 0.25 to 2 hours. It is partially hydrolyzed to salicylic acid in the liver and gastrointestinal wall, with approximately 50% to 75% of a given dose reaching the systemic circulation as aspirin. Aspirin distributes into all body tissues and fluids with a volume of distribution of approximately 0.15 to 0.2 L/kg. It is rapidly hydrolyzed to salicylic acid principally by the liver. Salicylic acid is highly protein-bound to albumin (90%) at low serum salicylate concentrations; however, as serum concentrations increase, the binding affinity decreases. The dose of aspirin in Aggrenox has a half-life of 0.33 hours for the parent compound and 1.71 hours for the metabolite. Renal elimination follows zero order pharmacokinetics and is dependent on urinary pH.1,2,5,7,11-13
Selected clinical trials
The European Secondary Prevention Study-2 (ESPS-2) is the largest clinical trial evaluating secondary stroke prevention.14 Diener and colleagues conducted a randomized, double-blind, placebo-controlled, multicenter trial that included 6,602 patients. The objectives of this trial were to determine the efficacy of sustained-release dipyridamole and aspirin as monotherapy for the secondary prevention of stroke; to determine if the combination of dipyridamole and aspirin is superior to either agent given as monotherapy; and to determine if a daily low dose of aspirin 50 mg orally would minimize the risk of bleeding. The primary endpoints of this trial were fatal and nonfatal stroke, death, and the combined endpoint stroke and/or death. Secondary endpoints included TIA, myocardial infarction, ischemic events, and other vascular events.14
Patients were included if they were at least 18 years of age and had experienced a TIA or completed stroke in the three months prior to study entry. Exclusion criteria included the following: a recent history of peptic ulcer, gastrointestinal bleeding, hypersensitivity or intolerance to dipyridamole or aspirin, bleeding disturbances, any condition requiring continued use of aspirin or anticoagulants, or any life-threatening condition. The patients were then randomized to receive aspirin 25 mg orally twice daily (n = 1649), dipyridamole 200 mg by mouth twice daily (n = 1654), the oral combination of aspirin 25 mg twice daily and dipyridamole 200 mg twice daily (n = 1650), or matching oral placebo (n = 1649). Patients were evaluated at 3-month intervals during follow-up checkups. Compliance and safety were also assessed at the follow-up visits. Compliance was assessed by asking the patients if they were taking the medication, by counting the remaining capsules at each renewal, and by random assays of plasma salicylic acid and dipyridamole concentrations. Safety assessment was determined by questioning the patients if they were experiencing adverse events, particularly bleeding, gastrointestinal complaints, or headache.14
Regarding the primary endpoint, it was determined the combination of aspirin and dipyridamole produced an additive effect when used to prevent strokes. The risk of stroke was reduced by 18.1% (p = 0.013) with aspirin alone, by 16.3% (p = 0.039) with dipyridamole alone, and by 37% (p < 0.001) with the combination. For the endpoint of stroke, the combination yielded a relative risk reduction (RRR) of 23.1% (p = 0.006) over aspirin alone and 24.7% (p = 0.002) over dipyridamole alone. The RRRs for the combined endpoint of stroke and/or death were 13.2% (p = 0.016) for aspirin, 15.4% (p = 0.015) for dipyridamole, and 24.4% (p < 0.001) for combination treatment. Reduction in the number of deaths or fatal strokes did not differ between treatment groups. The RRRs for combination therapy vs. each agent alone were 12.9% and 10.7% (p = 0.056 for aspirin, p = 0.073 for dipyridamole, respectively).14
Analysis of the secondary endpoints also revealed significant differences between treatment groups. Aspirin and dipyridamole significantly reduced the risk of TIAs by 21.9% and 18.3% (p < 0.01 for both), respectively. However, the combination yielded a statistically significant additive risk reduction (35.9%, p < 0.001) when compared to placebo. Other secondary endpoints included myocardial infarction; vascular events such as lung embolism, deep venous thrombosis, obstruction of peripheral arteries, retinal artery occlusion; and ischemic events (combined endpoint: stroke and/or myocardial infarction and/or sudden death). The combination demonstrated a greater reduction than either agent as monotherapy for these secondary endpoints as well. Combination therapy had significant results for vascular events (p < 0.01) and ischemic events (p < 0.001).14
Adverse events associated with combination treatment were gastrointestinal events, vomiting (8.4%), diarrhea (12.7%), headache (39.2%), and bleeding at any site. Bleeding most frequently occurred with aspirin alone and the combination product. Patients receiving aspirin monotherapy experienced bleeding at a rate of 8.2% compared to 8.7% for those receiving combination therapy. Approximately 4.7% of patients in the dipyridamole monotherapy group experienced bleeding compared to 4.5% of patients who received placebo. Moderate to severe/fatal bleeds were experienced by 39.3% of the patients receiving aspirin monotherapy, 41.7% for those receiving combination therapy, 31.2% of the dipyridamole monotherapy patients, and 29.7% of the patients who were randomized to placebo.14
Adverse reactions
Adverse effects associated with Aggrenox are consistent with the adverse effects of each individual agent. Adverse effects that occurred with Aggrenox in at least 1% of patients in the ESPS-2 trial, and with a greater frequency than in those patients receiving placebo, include headache, dyspepsia, abdominal pain, nausea, diarrhea (> 10%); vomiting, pain, fatigue, back pain, arthralgia (5% to 10%), convulsions, rectal hemorrhage, melena, hemorrhoids, GI hemorrhage, accidental injury, malaise, asthenia, confusion, anorexia, somnolence, arthritis, arthrosis, myalgia, coughing, upper respiratory tract infection, cardiac failure, epistaxis, purpura, and anemia.1,4,5,14
Pregnancy/lactation
Dipyridamole is classified as a pregnancy category B agent by the FDA.1,5-7 This means that animal teratology studies have not shown this drug to impair fertility or cause harm in the fetus.15 Animal studies using doses several times in excess of human doses have not led to any reports of congenital defects or harm to the fetus.1,5-7,15 Aspirin is classified as a pregnancy category D agent.1,5-7 This means that there is positive evidence of risk to a human fetus.15 Aspirin use during pregnancy can lead to such problems as maternal anemia, antepartum or postpartum bleeding, prolonged gestation and labor, perinatal mortality, intrauterine growth retardation, low birth weight, stillbirths, and premature closure of the ductus arteriosus.1,5-7,15 The Aggrenox combination should only be used in pregnancy if the potential benefit to the patient justifies the potential risk to the fetus. Because of the aspirin component, this combination should be avoided during the third trimester of pregnancy.1,5-7
Both dipyridamole and aspirin are excreted in breast milk.1,5-7,15,16 Dipyridamole is considered to be compatible with breast feeding; however, the American Academy of Pediatrics recommends that aspirin be used cautiously in a lactating female. The use of Aggrenox should be avoided during lactation.1,5-7,15,16
Contraindications
Aggrenox is contraindicated in patients with a hypersensitivity to dipyridamole, aspirin, or any component of this product. Patients with asthma, rhinitis, and nasal polyps should not take aspirin because it may cause severe urticaria, angioedema, or bronchospasm. Patients allergic to nonsteroidal anti-inflammatory agents should not take aspirin. Children and teenagers with a viral infection, with or without fever, should not be given aspirin due to the risk of Reye’s syndrome.1,5-7
Warnings/precautions
Alcohol: Patients who consume three or more alcoholic beverages daily and those who are chronic, heavy consumers of alcohol should be warned about the increased risk of bleeding when taking Aggrenox.1,5-7
Coagulation Abnormalities: Patients with inherited or acquired bleeding disorders (e.g., liver disease, vitamin K deficiency, warfarin use) should be counseled that even low doses of aspirin can inhibit platelet function and cause an increase in bleeding time.1,7
Gastrointestinal: Patients with a history of active peptic ulcer disease should not take aspirin due to irritation of the gastric mucosa and increased risk of bleeding. Physicians should remain alert for signs of gastric ulceration, even in patients without a history of ulcerative disease or adverse gastrointestinal signs or symptoms. They should inform patients of the signs and symptoms of bleeding and instruct them on what action to take if they occur.1,7
Coronary Artery Disease: Because dipyridamole is a vasodilatory agent, this product should be used with caution in patients with severe coronary artery disease (e.g., unstable angina, recent myocardial infarction). Aggrenox may aggravate chest pain in patients with underlying coronary artery disease. The dose of aspirin in this product may not be sufficient for prophylaxis of stroke, TIA, myocardial infarction, or angina.1,5,6
Hepatic Insufficiency: Dipyridamole has been associated with elevations in hepatic enzymes and hepatic failure.1,5-7
Hypotension: Aggrenox should be used with caution in hypotensive patients due to the vasodilatory properties of dipyridamole.1,5-7
Dosage and administration
The dose of Aggrenox is one capsule taken orally twice daily, one in the morning and one in the evening. The capsule should be swallowed whole. Currently, there is no dosing modification necessary for geriatric patients. This product has not been evaluated in the pediatric population. Aspirin should be avoided in patients with severe renal impairment (glomerular filtration rate less than 10 mL/min) and in those with hepatic insufficiency.1-5
Drug interactions
To date, no drug-drug interaction studies have been conducted with this specific formulation of aspirin and dipyridamole. Information regarding drug-drug interactions has been obtained from studies conducted with the individual components of Aggrenox.1,5
Dipyridamole: Dipyridamole has been reported to interact with both adenosine and cholinesterase inhibitors. Concomitant use of adenosine and dipyridamole has led to increased plasma concentrations of adenosine. Cardiovascular events such as bradycardia may occur due to an increase in adenosine concentrations. Therefore, the dose of adenosine may need to be adjusted. Dipyridamole has the potential to counteract the effect of cholinesterase inhibitors, and therefore may aggravate the symptoms of myasthenia gravis.1,5,6,17
Aspirin: Aspirin can interfere with the hyponatremic and hypotensive effects of angiotensin converting enzyme (ACE) inhibitors by inhibiting prostaglandin synthesis. It also inhibits renal prostaglandins, which can decrease the effectiveness of beta-blockers and diuretics. This leads to decreased renal blood flow and the retention of salt and fluid.
The concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin may also lead to a decrease in renal blood flow. It may also increase the risk of bleeding because of the effect on platelets, as would concomitant anticoagulant therapy (e.g., heparin and warfarin). Aspirin can displace highly protein-bound drugs such as warfarin, phenytoin, and valproic acid. The interaction between aspirin and phenytoin decreases the total concentration of phenytoin, whereas the interaction between aspirin and valproic acid increases serum concentrations of valproic acid.
The effect of aspirin on acetazolamide is twofold. Aspirin can displace acetazolamide from its plasma protein binding sites and it competes for renal tubular secretion. This can result in the accumulation of acetazolamide, which may lead to central nervous system (CNS) depression and metabolic acidosis. Additionally, carbonic anhydrase inhibitor induced acidosis caused by acetazolamide can increase the potential for unionized aspirin penetration into the CNS.
When aspirin and methotrexate are used together, aspirin can inhibit the renal clearance of methotrexate and decrease the plasma protein binding of methotrexate, leading to increased methotrexate toxicity (e.g., bone marrow toxicity), especially in the elderly and in those with renal impairment. Aspirin interacts with uricosuric agents such as probenecid and sulfinpyrazone by an unknown mechanism. This leads to inhibition of the uricosuric action of these drugs. The concomitant use of aspirin and oral hypoglycemic agents can lead to increased hypoglycemia.1,5-7,17
Drug-food interactions
To date, drug-food interactions have not been reported with Aggrenox.1
Dosage forms available
Aggrenox is available as a hard gelatin capsule, with a red cap and ivory-colored body that contains 200 mg of extended-release dipyridamole as yellow pellets and 25 mg of immediate-release aspirin as a round white tablet. The capsule body is imprinted in red with the Boehringer Ingelheim logo and "01A." This product is available in bottles of 60.1
Potential for medication errors
The trade name Aggrenox may be mistaken for either Lovenox (enoxaparin) or Aggrastat (integrelin). Aggrenox is not interchangeable with the individual ingredients, aspirin and immediate-release dipyridamole.1-5
Discussion
The ESPS-2 trial showed that individually, aspirin and modified-release dipyridamole had a statistically significant effect on the secondary prevention of stroke. Furthermore, the combination of the two agents was found to have an additive effect in reducing stroke recurrence with minimal adverse effects. The risk of bleeding is greater with both aspirin alone and Aggrenox vs. dipyridamole alone or placebo.14
Currently, ESPS-2 is the only clinical trial showing statistically significant results with the combination of aspirin and dipyridamole. Despite the apparent positive findings of ESPS-2, the value of the results when used to make clinical decisions may be minimized by controversy that surrounds the trial. Two years after publication of ESPS-2, an article was published in Science that described fraud and ethics charges against the investigators of ESPS-2. It is alleged that one of the physicians fabricated data causing more than 400 patients to be disqualified from one center. At another center, inconsistencies in patient case record forms and compliance assay determinations were found. An independent review revealed that a portion of the 438 patients "enrolled" at that center were fictional.18
Ticlopidine has been evaluated in two large clinical trials. The Canadian American Ticlopidine Study (CATS) evaluated ticlopidine vs. placebo for secondary prevention of vascular events. A total of 1053 patients were randomized to receive 250 mg of ticlopidine orally twice daily or placebo. The RRR for the combined endpoint of stroke, myocardial infarction, or vascular death was 23.3%. The second trial, the Ticlopidine Aspirin Stroke Study (TASS) compared ticlopidine with aspirin for primary or secondary prevention of stroke. A total of 3,069 patients were randomized to receive either ticlopidine 250 mg orally twice daily or aspirin 650 mg orally twice daily. The RRR for stroke at three years was 21%. Compared to aspirin, ticlopidine therapy provided a 12% reduction in the risk of stroke and all-cause mortality. The usefulness of ticlopidine is limited by side effects (e.g., diarrhea, neutropenia). Clopidogrel has been evaluated in a trial of 19,185 patients. The Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared clopidogrel 75 mg orally once daily and aspirin 325 mg orally once daily. The primary endpoint was prevention of ischemic stroke, myocardial infarction, or vascular death. Clopidogrel therapy resulted in a statistically significant RRR of 8.7%. The safety profile of clopidogrel was similar to aspirin. There are no active comparison trials among ticlopidine, clopidogrel,19 or Aggrenox. Additionally, trials comparing Aggrenox and the two agents given individually with daily doses that are approximate to those in Aggrenox would also be beneficial. Other trials with dipyridamole and aspirin using varying doses of each agent have been inconclusive.20 Sufficient data are not yet available to support routine addition of Aggrenox to hospital formularies.
References
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2. Hervey PS, Goa KL. Extended-release dipyridamole/aspirin. Drugs 1999; 58(3):469-77.
3. "Aggrenox: An anticlotting drug for prevention of recurrent stroke." pharminfo.com/pubs/druginfoline/druginfo2_12.html. (Accessed January 2000.)
4. Abramowicz M, ed. "Aggrenox: a combination of antiplatelet drugs for stroke prevention." The Medical Letter 2000; 42(1071):11-12.
5. Aggrenox. Product Information Form for AHFS Drug Information. Boehringer Ingelheim Pharmaceuticals Inc.; 1999.
6. Mitchell J, ed. GenRx 9th ed. St. Louis: Mosby; 1999.
7. Burnham TH, ed. Drug Facts and Comparisons. St. Louis: Wolters Kluwer Co.; 2000.
8. Aggrenox. Data on file. Boehringer Ingelheim Pharmaceuticals Inc. April 7, 2000.
9. Dress A, Chevolet C, Delapierre D, et al. Pharmacokinetics of oral dipyridamole (Persantine) and its effect on platelet adenosine uptake in man. Eur J Clin Pharmacol 1982; 23:229-34.
10. Gelman CR, Moore MB, Hutchison T, Anderson M, Shahan DR, eds. Drugdex System. Dipyridamole (drug evaluation monograph). Englewood, CO: Micromedex, June 2000.
11. McEvoy GK, ed. AHFS Drug Information. Bethesda: American Society of Health-System Pharmacists, Inc.; 1999.
12. Gelman CR, Moore MB, Hutchison T, Anderson M, Shahan DR, eds. Drugdex System. Aspirin (Drug Evaluation Monograph). Englewood, CO: Micromedex Inc., 6/2000.
13. Brantmark B, Wahlin-Boll E, Melander A. Bioavailability of acetylsalicylic acid and salicylic acid from rapid- and slow-release formulations, and in combination with dipyridamole. Eur J Clin Pharmacol 1982; 22:309-14.
14. Diener HC, Cunha L, Forbes C, et al. European stroke prevention study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neur Sciences 1996; 143:1-13.
15. Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: A reference guide to fetal and neonatal risk 5th ed. Baltimore: Williams & Wilkins; 1998.
16. Lauwers J, Woessner C, eds. Chemical agents and breast milk: A comprehensive list of drugs and other agents and their effects on the nursing infant. Garden City Park: Avery Publishing Group Inc.; 1990.
17. Tatro DS, ed. Drug Interaction Facts. St. Louis: Facts and Comparisons; 2000.
18. Enserink M. Fraud and ethics charges hit stroke drug trial. Science 1996; 274:2004-5.
19. Albers GW, Easton JD, Sacco RL et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 1998;114(5):683S-98S.
20. Diener HC. Dipyridamole trials in stroke prevention. Neurology 1998; 51(Suppl 3):S17-S19.
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