Non Steroidal Anti-Inflammatory Drugs and the antiplatelet effects of acetylsalicylic acid

While prophylactic use of acetylsalicylic acid and NSAID*s is often used
concomitantly for long periods of time, there is concern about the safety of
this combination in preventing cardiovascular disease. There is still a debate
about the inhibitory effect of NSAID*s on the cardio protective effect of
acetylsalicylic acid.
There is conflict in results of observational research, where combination of
ibuprofen and acetylsalicylic acid increased, or decreased the cardiovascular
risk compared to acetylsalicylic acid alone, and a pharmacodynamic study where
ibuprofen inhibited the effect of acetylsalicylic acid, taken 12 hours before
the acetylsalicylic dose. Based on this study, pharmacists advise to give
diclofenac instead of ibuprofen in combination with acetylsalicylic acid.
However, in meta-analysis on the overall risk of cardiovascular disease,
diclofenac seems to be relatively harmful while naproxen tends to be relatively
save. Pharmacodynamic research to the interaction between naproxen and
acetylsalicylic acid, shows only a just significant inhibitory effect of
naproxen on the platelet-aggregation-inhibitory effect of acetylsalicylic acid,
while naproxen itself gave a strong blood-platelet-aggregation-inhibitory
effect.
This is a decisive study on the potential naproxen + acetylsalicylic acid
interaction.

To measure the pharmacodynamic interaction between naproxen + acetylsalicylic
acid as compared to the placebo + acetylsalicylic interaction. Also the
pharmacodynamic interaction between acetylsalicylic acid and other in The
Netherlands often used NSAID's will be examined: ibuprofen, meloxicam and
etorixocib (also compared to placebo + acetylsalicylic acid).

A prospective, ex-vivo, randomized, placebo-controlled, investigator blinded,
serial cross-over trial, in 30 healthy volunteers.

Subjects will receive 2 doses of etoricoxib 90 mg and meloxicam 15 mg, or 3
doses of naproxen 500 mg and ibuprofen 600 mg, mg (one NSAID per cycle).
Subjects will also receive three times one dose of acetylsalicylic acid 80 mg
(one during each cycle). As a comparator subjects will receive 3 times one
placebo tablet (during one of the three cycles).

The burden associated with participation consists of:
- Three site visits per cycle. Nine site visits in total.
- One venapunction at baseline and one venapunction per visit. Ten
venapunctions in total.
- Three or three doses of an NSAID per cycle for two cycles. Four or six doses
of an NSAID in total.
- Three doses of placebo per cycle for one cycle. Three doses in total.
- One dose of acetylsalicylic acid per cycle. Three doses in total.

Risks associated with intake of the investigational medical products are
negligible. Venapunctions will be done by well educated personnel, to minimize
any risks or burden for the participant.