Platelet function following administration of a novel formulation of intravenous diclofenac sodium versus active comparators: a randomized, single dose, crossover study in healthy male volunteers.
OBJECTIVE
To assess platelet function and safety following single-dose administration of a novel formulation of intravenous (IV) diclofenac sodium (Dyloject) 37.5 mg versus oral diclofenac 50 mg, IV ketorolac 30 mg, and oral acetylsalicylic acid (ASA) 325 mg.


METHODS
Open-label, randomized, single-dose, 4-treatment crossover study.


METHODS
Clinical research unit.


METHODS
30 healthy, ASA physical status I adult men.


METHODS
Subjects were randomized to one of 6 treatment sequences that included 4 single-dose treatments. Study drug administration occurred on Days 1, 3, 5, and 7.


METHODS
Platelet count, closure time as measured by platelet function analyzer (PFA-100), prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma concentrations of the study drugs were obtained over 24 hours after each treatment. The primary endpoint was the area under the curve for PFA collagen-epinephrine (CEPI) closure time difference from 0-6 hours post-drug administration (AUC(0-6h)). Secondary endpoints included the maximum change from baseline in PFA CEPI closure time.


RESULTS
AUC(0-6h) (mean ± SD) for CEPI closure time difference was significantly smaller after IV diclofenac 37.5 mg (249 ± 216 sec.hrs) than after ketorolac [and ASA (950 ± 287 sec.hrs and 834 ± 237 sec.hrs, respectively); P ≤ 0.0001 for both] but not after the oral diclofenac control (286 ± 265 sec.hrs; P = 0.40). Similarly, the maximum change from baseline in PFA CEPI closure time was lower after IV diclofenac than after ketorolac or ASA across all time intervals examined. There were no significant changes in PT or aPTT at any time point with any treatment. There was a low frequency of adverse events.


CONCLUSIONS
Acetylsalicylic acid and ketorolac both substantially disrupted platelet function in contrast to IV diclofenac 37.5 mg or oral diclofenac 50 mg control. Diclofenac, with its balanced COX-1 and COX-2 inhibitory profile, may pose less risk of postoperative bleeding than nonsteroidal antiinflammatory drugs (NSAIDs) such as ketorolac and ASA, which predominantly inhibit COX-1.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Kenneth A
KA
Bauer
William
W
Gerson
Curtis
C
Wright
Jianyuan
J
Wang
Ewan
E
McNicol
Ryan K
RK
Lanier
William
W
Kramer
Daniel B
DB
Carr
D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019540:Area Under Curve; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004837:Epinephrine / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D020910:Ketorolac / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D010979:Platelet Function Tests / Q000379:methods; D013997:Time Factors; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D004008:Diclofenac; D003094:Collagen; D001241:Aspirin; D004837:Epinephrine; D020910:Ketorolac