Effects of Combining Aspirin with Non-Steroidal Anti-Inflammatory Drugs or COX-2 Inhibitors on Shear-Induced Platelet Aggregation.

Aspirin has been widely used as a cardiac protective drug, often with hemostasis inhibition and bleeding risks. This concern becomes even more significant when it is used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors, both of which may have independent effects on platelets. To study how hemostasis may be affected by these drugs, we conducted a multiple-dose, single-blind, parallel-group study to determine the effects of aspirin combined with over-the-counter NSAIDs or COX-2 inhibitors on shear-induced platelet aggregation (SIPA). For this study, 87 healthy individuals (age 40 to 75) who met inclusion and exclusion criteria were recruited. All subjects received 81 mg of aspirin (non-enteric coated and chewable) daily for eight days. In addition, beginning 2 hours after low-dose aspirin, the subjects also received one of the following drugs: acetaminophen (4 doses of 1000 mg daily), ibuprofen (3 doses of 400 mg daily), naproxen sodium (440 mg morning and 220 mg evening), additional aspirin (4 doses of 650 mg daily), celecoxib (2 doses of 200 mg daily) and rofecoxib (1 dose of 25 mg daily). The second drugs were given 2 hrs after initial aspirin intake. The control group received only 81 mg of aspirin. Blood was drawn before the treatment and at 24 hr and 7 days (before any medications on Day 8) after the initial drug intake. Shear-induced platelet aggregation (SIPA) on a collagen matrix with either ADP or epinephrine was measured in citrated whole blood using a platelet function analyzer. The aggregation was defined as closure time (sec) under a constant shear rate of 1500 ^−s, a level of pathological high shear stress. We found that the closure time with the collagen/ADP cartridge was not affected by any of the treatments (83 – 108 sec). In contrast, SIPA with the collagen/epinephrine cartridge showed a time-dependent inhibition by 81 mg of aspirin with the mean closure times being 118, 138, and 222 sec before drug administration, 24 hr and 7 day after treatments, respectively. The course of low-dose aspirin inhibition of SIPA was not changed by acetaminophen, celecoxib, or rofecoxib. In contrast, the mean closure time at 24 hr after the treatment was 249 and 264 sec for samples from individuals on a combined treatment of low-dose aspirin with either naproxen sodium or a high dose of aspirin (2600 mg), significantly longer than those of other treatment groups (P< 0.001). It has been demonstrated that SIPA, which is primarily initiated by the GP Ib-VWF interaction, is insensitive to aspirin. Our results suggest that aspirin inhibits SIPA induced in the presence of collagen and epinephrine, but not collagen and ADP. Furthermore, this effect was significantly enhanced by either naproxen sodium or a higher dose of aspirin (2600 mg), suggesting that the simultaneous intake of low-dose aspirin and either analgesic doses of aspirin or naproxen may enhance the risk of aspirin-induced bleeding tendency.