Platelet aggregation inhibitors
Platelet aggregation inhibitors such as acetylsalicylic acid (ASA),
clopidogrel, prasugrel, and ticagrelor are frequently prescribed for the
prevention of (recurrent) thrombotic disease in high-risk patients.
Clopidogrel and prasugrel, both thienopyridines, and ticagrelor, a
cyclopentyltriazolopyrimidine, are oral P2Y12 receptor
antagonists. While clopidogrel and prasugrel both need metabolic
activation, ticagrelor acts directly on the P2Y12receptor. ASA, which is also a prodrug, exerts its effects by
irreversible COX inhibition, which in turn leads to a reduction in the
production of prostaglandin thromboxane A2 and
inhibition of platelet aggregation.
Several studies have shown that elevated bodyweight results in higher
platelet reactivity, and therefore altered regimens for ASA98–103 and clopidogrel 98,105–107have been explored that might provide a more optimal platelet inhibition
in obese patients. The relevance of the higher platelet reactivity in
obese patients and its consequence for dosing of platelet inhitibitors
is unknown.
To date, four studies have investigated the effect of bariatric surgery
on the pharmacokinetic profile of platelet aggregation inhibitors. Three
studies describe the effect on ASA 27,102,108. The
other study investigates the effect of surgery on the pharmacodynamics
on ticagrelor 109.
As previously described, Mitrov-Winkelmolen et al. studied in an
open-label longitudinal repeated-measure study the effect of RYGB on ASA
pharmacokinetics. In their study, Tmax was shorter, and both Cmax and
AUC0-24 (14.1 and 11.4 mg/l respectively
p<0.001) higher after surgery. Although statistically
significant, the authors argue that there are no clinically relevant
changes in ASA pharmacokinetics since the changes are still within the
recommended dosing range for platelet aggregation inhibition27.
Norgard and colleagues studied the effect of bariatric surgery on the
aspirin-induced platelet inhibition and subsequent platelet
aggregability 102. Ten patients undergoing bariatric
surgery (8 RYGB and 2 SG) were administrated two 7-day courses of ASA,
before and three months after surgery. After the last dose, platelet
reactivity expressed as aspirin reaction units (ARU) was tested and
compared to data of normal-weighted subjects. They showed that before
surgery, the platelet reactivity was significantly higher in patients
with obesity compared to normal-weight subjects (469 ± 60 vs. 419 ± 52
ARU p=0.016) when using ASA. After surgery, the platelet reactivity was
significantly reduced (432 ± 143 vs. 469 ± 60 ARU p=0.03), which was
also seen in RYGB patients who did not use ASA (602 ± 59 vs. 531 ± 78
ARU p=0.035). This shows that the reduced reactivity after surgery
compared to preoperative values may not be solely related to ASA102.
The safety of low-dose ASA was studied by Kang and colleagues108. They followed a group of 1016 patients undergoing
RYGB surgery, of whom 145 used ASA. The incidence of ulceration was not
significantly different between the two treatment groups. Although it
was a small study, the authors conclude that patients were not at
increased bleeding risk when using low-dose ASA 108.
In contrast, Caruana et al. reported an overall rate of upper
gastrointestinal bleeding of 4 of 11 bariatric surgery patients within
2-3.5 weeks after starting clopidogrel (25-234 days after surgery)110. As such, it seems that prophylactic PPIs are
indicated for at least six months after bariatric surgery when platelet
inhibitors are given.
Ma et al. measured the influence of ticagrelor on whole blood impedance
platelet aggregability induced by adenosine in obese patients undergoing
bariatric surgery and in healthy normal weighted control subjects109. The half-maximal inhibitory concentration
(IC50) value was 34.0 nM six weeks before bariatric
surgery, which reduced to 23.1 nM 12 weeks after surgery whereas in
controls, the IC50 level of ticagrelor was 14.5 nM. This
suggests that bariatric surgery improves the ticagrelor pharmacodynamic
response that was blunted by obesity, which is also showed in the study
of Norgard described above 102.
In conclusion, although obese patients seem to differ from non-obese
patients with respect to platelet activity, it seems that platelet
aggregation inhibitors do exert an effect after bariatric surgery.
However, it is difficult to distinguish between the influence of the
reduction of obesity versus the effect of the platelet inhibitor. From
the available results, it seems that there is no indication for dose
adjustments of platelet inhibitors after bariatric surgery.