Michelle O’Donoghue from Boston, USA presented data which suggest that PPIs, often prescribed to reduce the risk of gastrointestinal bleeding, do not interfere with the clinical benefits of the antiplatelet drugs clopidogrel or prasugrel.
“The current findings do not support the need to avoid concomitant use of PPIs in patients treated with thienopyridines,” said O’Donoghue.
A drug interaction was first described in January 2008 by Martine Gilard from Brest, France, who reported that the PPI omeprazole significantly reduced the antiplatelet effects of clopidogrel. This and subsequent observational studies prompted the US and European regulatory agencies (FDA and EMEA) to post safety warnings about the use of PPIs with clopidogrel unless absolutely necessary.
Professional guidelines on both sides of the Atlantic, however, continue to recommend the use of PPIs in selected patients (ESC Guidelines 2007; ACCF/ACG/AHA 2008 expert consensus). The guideline writers may now be vindicated by the latest research.
In O’Donoghue’s study, published simulataneously in the Lancet, data on patients in two randomised trials were analysed: the PRINCIPLE-TIMI 44 and the TRITON-TIMI 38 trials.
The smaller PRINCIPLE-TIMI 44 trial included 201 patients undergoing elective PCI who were randomly assigned to prasugrel or clopidogrel. The reanalysis by O’Donoghue’s group did indeed find that mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI six hours after a clopidogrel loading dose. A more modest effect was seen in patients on prasugrel.
`However, this laboratory finding did not translate into clinical effect. The TRITON-TIMI 38 trial included 13,608 patients with an acute coronary syndrome undergoing planned PCI. They were, again, randomly assigned to prasugrel or clopidogrel. Among the 4529 patients on a PPI at randomisation, after adjustment for potential confounders, no significant association remained between use of a PPI and risk of the primary endpoint (a composite of cardiovascular death, non-fatal MI, or non-fatal stroke).
The lack of association held both for patients on clopidogrel (0.94, 95% CI 0.80-1.11, p=0.46) and for those on prasugrel (1.00, 95% CI 0.84-1.20, p=0.97).
An editorial in the Lancet urged caution when prescribing PPIs for patients with an intrinsically reduced response to thienopyridines, but was otherwise reassuring. While the interaction of PPIs with thienopyridines is a fact in terms of pharmacodynamics, it stated, for clinical outcomes the interaction “seems to be a fiction” for most patients with a risk profile similar to the TRITON group. “Such patients can safely be treated with a PPI on top of their thienopyridine,” it concluded.
At the session, O’Donoghue said that only a randomised trial of PPI can definitively establish the safety of combining these two classes of drugs. Discussant Kurt Huber (Vienna, Austria) added that until such data is available, “careful selection of patients who need extra protection should be performed.”