Two studies involving the use of Clopidogrel and PPIs have been published in the September issues of two medical journals. One of them reports that PPI therapy did not modify the effect of clopidogrel on cardiovascular outcomes and that PPI use was associated with increased cardiovascular risk independent of concomitant use of clopidogrel.
And the other states that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.
A Study has been published in the September issue of Annals of Internal Medicine which involved all patients discharged after first-time myocardial infarction from 2000 to 2006 in all the hospitals in Denmark. A total of 71 987 patients were admitted with myocardial infarction from 2000 to 2006. Of these, 1889 patients with previous myocardial infarction were excluded, 13 324 patients who died during hospitalization or within 30 days of discharge, and 368 patients with partially missing data. Of the 56 406 patients included in the study, 24 704 (43.8%) claimed a prescription for clopidogrel within 30 days of discharge. Of these, 6753 patients (27.3%) claimed at least 1 prescription for PPIs within 1 year of discharge. The use of PPIs was equal in the 2 cohorts and independent of clopidogrel use
The study is nationwide on unselected population that represents the average patient who has had a myocardial infarction.
It has been demonstrated that PPI therapy did not modify the effect of clopidogrel on cardiovascular outcomes and that PPI use was associated with increased cardiovascular risk independent of concomitant use of clopidogrel.
A reduction in risk for gastrointestinal bleeding related to PPI therapy for patients who received clopidogrel, although it did not reach statistical significance was also demonstrated.
The data set provided no evidence of differences in risk between the subtypes of PPIs, with or without clopidogrel. Sensitivity analyses also provided no evidence of differences in risk related to heart failure, diabetes, age, hospitals, or PPI dosages. However, a statistically significant interaction between PCI and PPIs in the group that received clopidogrel was found.
Limitations: No self-reported patient data regarding adherence.
The authors suspect that the increased cardiovascular risk in all patients who received a PPI can be explained by differences in baseline comorbid conditions that were unmeasured or measured imperfectly.
Strengths: large size of our cohort based on a nationwide, unselected population that represents average patients in a contemporary clinical setting who have had a myocardial infarction.
The patients who received clopidogrel and PPIs at discharge after a first-time myocardial infarction had similar risks for cardiovascular death, myocardial infarction, or stroke as did those of patients who received PPIs alone.
In conclusion, PPIs seem to be associated with an increased risk for adverse cardiovascular outcomes regardless of clopidogrel use, but concomitant PPI and clopidogrel use was not associated with any additional increase in risk over that observed for patients who received a PPI alone.
The authors believe that the increased cardiovascular risk associated with PPI use independent of clopidogrel is caused by unmeasured confounders. These results seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy.
Another study has been published in the Journal of Clinical Pharmacology and Therapeutics titled Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies. In this four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects.
The groups were:
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and omeprazole (80 mg) administered simultaneously (study 1);
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) with omeprazole (80 mg) given 12 hours later.
Increasing the clopidogrel dose to 600-mg loading/150-mg/day maintenance and omeprazole (80 mg) administered simultaneously.
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and pantoprazole (80 mg) administered simultaneously
Results:
Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, co administration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively;
· increased maximal platelet aggregation (MPA) induced by 5 µmol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively;
· and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively.
The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.
The authors believe that the increased cardiovascular risk associated with PPI use independent of clopidogrel is caused by unmeasured confounders. These results seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy.
Another study has been published in the Journal of Clinical Pharmacology and Therapeutics titled Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies. In this four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects.
The groups were:
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and omeprazole (80 mg) administered simultaneously (study 1);
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) with omeprazole (80 mg) given 12 hours later.
Increasing the clopidogrel dose to 600-mg loading/150-mg/day maintenance and omeprazole (80 mg) administered simultaneously.
Clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and pantoprazole (80 mg) administered simultaneously
Results:
Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, co administration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively;
· increased maximal platelet aggregation (MPA) induced by 5 µmol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively;
· and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively.
The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.
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