Aggrenox

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Boehringer ingelheim pharmaceuticals has teamed two old staples—aspirin and dipyridamole—to create a new agent for the prevention of stroke in patients who have had a previous stroke or a transient ischemic attack (TIA). The company received FDA approval in November for aspirin and extended release dipyridamole, which will be marketed under the trade name Aggrenox. It joins aspirin, ticlopidine, and clopidogrel on the list of drugs that are used for stroke prevention.

Indications

Aggrenox is approved to reduce the risk of stroke in patients who have had transient ischemia of the brain or complete ischemic stroke due to thrombosis.

Dosage

The recommended dose is aspirin 25 mg and dipyridamole 200 mg (1 Aggrenox capsule) twice daily. Drug- food interaction has not been studied.1

Potential Advantages

The fixed combination product offers two different mechanisms of antiplatelet action. Aspirin is a cyclooxygenase inhibitor, while dipyridamole is believed to affect platelet aggregation by inhibiting phosphodiesterase.2 Results from the two-year European Stroke Prevention Study (ESPS-2) of 6602 patients indicated that this fixed combination reduced the risk of stroke (fatal or nonfatal) by 37% compared to placebo. There was also a 16.3% reduction in stroke end points compared to dypyridamole alone and an 18.1% reduction over aspirin alone (50 mg/day).6

Potential Disadvantages

The frequency of common side effects include headache (38.2% vs 33.1% for aspirin only) and diarrhea (12.1% vs 6.6% for aspirin alone). These tend to diminish over time.2 Aggrenox has been associated with a decline in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13 × 106/mm3.1

Comments

The ESPS-2 trial is the first trial to demonstrate that a fixed combination of aspirin and dipyridamole is more effective than aspirin alone. However, the 50 mg daily aspirin dose used in the trial was at the low end of the recommended dose range (50-325 mg). The results from previous trials of this combination have generally been unimpressive. After a review of randomized trials involving combinations of aspirin and dipyridamole, the Antiplatelet Trialists concluded that the difference between aspirin and dipyridamole and aspirin alone is likely to be smaller than the difference between antiplatelet and no antiplatelet treatment.3,4 The ESPS-2 results, based on an intent-to-treat analysis, indicated that the fixed combination, compared to aspirin alone, reduced the risk of all strokes (22%, P = 0.008) and frequency of TIAs (24.4%, P < 0.001). However, no statistical difference was observed in combined endpoints of stroke or death, death from any cause, or myocardial infarction. The rates of myocardial infarction were, however, low in the study groups.1 While therapy may lengthen the time to a subsequent stroke, it does not appear to affect the severity of the recurrent stroke.5

Aggrenox costs $2.95 per day, which is significantly more than aspirin and and generic dipyridamole (< $1.00). The manufacturer states in Aggrenox labeling that this product is not interchangeable with the individual components of aspirin and dipyridamole, although this claim does not seem to be backed up by scientific evidence.

Clinical Implications

Stroke is the third leading cause of death after heart disease and cancer, and is the leading cause of serious, long-term disability. About 730,000 people have a stroke each year and, of these, more than 80% are first attacks.8 Risk factors for stroke include increasing age, male gender, hypertension, hyperlipidemia, diabetes, carotid artery disease, heart disease, tobacco, previous stroke, and transient ischemic attacks. Unless contraindicated, antiplatelet therapy is recommended for stroke prevention in persons with a history of transient ischemic attack or a previous thromboembolic stroke.

Aspirin has been the most frequently prescribed drug and is considered the standard. To balance effectiveness and tolerability, a lower dose of aspirin (50-325 mg) has been recommended.7 Several newer products have been approved by the FDA on the basis of studies compared to aspirin. These include ticlopidine, clopidogrel, and the fixed combination of aspirin/dipyridamole, all of which have shown varying degrees of benefit over aspirin. It is not clear if one of these products would replace aspirin as the standard. There are currently no comparative trials among the newer products.

References

1. Aggrenox Product Information. November 1999. Boehringer Ingelheim Pharmaceuticals.

2. Hervey PS, et al. Drugs 1999;58(3):469-475.

3. Wilterdin JL, et al. Arch Neurol 1999;56:1087-1092.

4. Antiplatelet Trialists’ Collaboration. BMJ 1994;308: 81-106.

5. Sivenius J, et al. Neurology 1999;53:825-829.

6. ESPS Group. European Stroke Prevention Study. Stroke 1990;21(8):1122-1130.

7. Albers GW, et al. Neurology 1999;53(7 Suppl 4): S25-31.

8. Statistics from the National Stroke Association and American Heart Association.