An Aspirin a Day (Before an NSAID) Keeps the Doctor Away

Abstract & Commentary

Synopsis: This study suggests that the beneficial effects of aspirin in preventing coronary disease and stroke may be offset by taking ibuprofen before aspirin.

Source: Catella-Lawson F, et al. N Engl J Med. 2001;345:1809-1817.

Study subjects were nonsmokers without cerebrovascular disease who were randomized to 1 of 4 groups as detailed in Table 1 below. Subjects were blindly given 1 of the 2 medications, and the second medication 2 hours later. A baseline thromboxane B2 level was obtained prior to the administration of the medications, and sequentially at 2, 6, 12, and 24 hours thereafter.

After 6 days of therapy, study subjects underwent a 2-week washout period during which they received no medications. They then received the same medications but in reverse order of administration from the first protocol. Thromboxane B2 levels were again obtained prior to the administration of the medications, and sequentially at 2, 6, 12, and 24 hours thereafter. One subgroup was randomized to receive enteric-coated aspirin before multiple doses of ibuprofen (3 times a day) or diclofenac (twice a day).

Table
Percent Inhibition of Thromboxane B2 Production

Percent inhibition of Thromboxane B2 production
6 hours after dosing

Percent inhibition of Thromboxane B2 production 24 hours after dosing


Aspirin before ibuprofen 99% 98%
Ibuprofen before aspirin 80% 53%
Aspirin before acetaminophen 99% 96%
Acetaminophen before aspirin 99% 96%
Aspirin before rofecoxib 99% 99%
Rofecoxib before aspirin 99% 97%
Aspirin before ibuprofen (TID) 97% 67%
Aspirin before diclofenac 97% 92%

Comment by Jeff Wiese, MD

Aspirin reduces the risk of myocardial infarction and stroke by irreversibly inhibiting platelet cyclooxygenase.1 Thromboxane A2, the end product of this enzyme, is a potent platelet aggregator. Inhibition of production of thromboxane A2 reduces platelet aggregation, and thereby reduces the risk for coronary thrombosis. Thromboxane B2 is a stable byproduct of thromboxane A2, and is used to measure the activity of platelet cyclooxygenase, and, thus, overall platelet aggregation.

Unlike aspirin that irreversibly acetylates cyclooxygenase, nonsteroidal medications reversibly occupy the enzyme, decreasing platelet aggregation for up to 24 hours.2

This study suggests that the inhibitory effect of aspirin, as measured by a reduction of thomboxane B2, is reduced when ibuprofen is given prior to aspirin. There was no reduction in the thromboxane B2 level when aspirin was given before ibuprofen. This finding is consistent with Catella-Lawson and colleagues’ hypothesis that ibuprofen may reversibly occupy the cyclooxygenase enzyme when given prior to aspirin, thereby preventing aspirin from inhibiting the enzyme. Catella-Lawson et al also found that multiple doses of ibuprofen (TID dosing) inhibited aspirin’s effects even if aspirin preceeded these doses each day.

There was no effect of acetaminophen, rofecoxib (a COX-2 selective inhibitor), or diclofenac (an NSAID) on aspirin’s effectiveness, regardless of sequence of dosing.

Although there are no clinical end points to this study, this study suggests that the beneficial effects of aspirin in preventing coronary disease and stroke may be offset by taking ibuprofen before aspirin. Final conclusions will require clinical trials investigating the interaction of aspirin with other nonsteroidal medications. Until that time, physicians should advise patients who depend on aspirin for platelet inhibition (ie, those with coronary disease, prior stroke, and atrial fibrillation) to avoid taking ibuprofen prior to aspirin, and to exercise caution when taking multiple doses of ibuprofen. Acetaminophen, rofecoxib, or diclofenac may be safer alternatives for these patients.

References

1. Patrono C, et al. Chest. 2001;119:39S-63S.

2. Fornaro G, et al. Circulation. 1993;87:162-164.

Dr. Wiese, Chief of Medicine, Charity, and University Hospitals, Associate Chairman of Medicine, Tulane Health Sciences Center, is Associate Editor of Internal Medicine Alert.