Clopidogrel is relatively contraindicated in patients at risk of gastrointestinal bleeding. To reduce this risk, proton-pump inhibitors (PPI) which are often co-prescribed. Many PPIs undergo hepatic metabolism by the cytochrome (CYP) P450 isoenzymes, thus CYP P450-metabolised drugs, including clopidogrel become vulnerable to drug-drug interaction.
Gilard et al first highlighted the negative impact of PPIs, on the pharmacodynamic response to clopidogrel in the randomised, double-blind Omeprazole CLopidogrel Aspirin (OCLA) trial. A randomised trial of omeprazole and pantoprazole conducted by Cuisset et al also demonstrated that after 1 month, patients receiving pantoprazole had significantly better platelet response to clopidogrel than those receiving omeprazole. Population-based studies have suggested that concomitant use of PPI with clopidogrel results in significantly increased risk of adverse outcomes. Anxieties brought on by such studies have been largely allayed by the recently presented results of the COGENT trial. This major randomised controlled trial, comparing clopidogrel with omeprazole vs clopidogrel alone demonstrated no difference in the risk of cardiovascular events between groups.
We assessed the impact of PPI co-prescription on clopidogrel response using a verified near patient test, prospectively in 269 patients (mean age 63±11, 85 female) admitted with high risk ACS (characterised by electrocardiographic changes of ischaemia and/or raised troponin I). Loading and maintenance of clopidogrel was as per contemporary UK practice. Eighty-eight patients were prescribed a PPI concomitantly as in-patients. Platelet response to clopidogrel in whole blood samples, taken at the time of angiography, was assessed using a VerifyNow analyser (Accumetrics, California, US).
Of the 269 patients recruited, 151 (56%) proceeded to PCI, 40 (15%) underwent coronary artery bypass grafting (CABG), 78 (29%) were treated medically. The clinical endpoint was adverse clinical events (ACE) at 18 months (death, MI, repeat revascularisation, CABG, stroke or unplanned cardiovascular hospitalisation). Co-administration of PPI and clopidogrel was associated with significantly reduced clopidogrel P2Y12 activity (p=0.022) (Abstract 41 Figure 1a) but not clinical outcome (ACE, p=0.123, Abstract 41 Figure 1b). Groups were well matched for age, gender, body mass index, current smoking, presence of diabetes and hyperlipidaemia. More patients in the PPI group had suffered a previous MI (36% vs 20%, p=0.007) and had received previous PCI treatment (20% vs 8%, p=0.005).
As near patient tests of clopidogrel activity find their position in the care of patients with ischaemic heart disease, physicians may wish to use this technology to test patients at high risk of stent thrombosis who are also taking medications which pose a risk of inhibiting platelet clopidogrel response.
- proton pump inhibitor