|MISCELLANEOUS - JOURNAL CLUB
|Year : 2015 | Volume
| Issue : 3 | Page : 297-298
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||23-Feb-2016|
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Palakshachar A. ADAPT-DES study. J Pract Cardiovasc Sci 2015;1:297-8
| Article|| |
Weisz G, Smilowitz NR, Kirtane AJ, Rinaldi MJ, Parvataneni R, Xu K, et al. Proton pump inhibitors, platelet reactivity, and cardiovascular outcomes after drug-eluting stents in clopidogrel-treated patients: The ADAPT-DES study. Circ Cardiovasc Interv 2015;8. pii: e001952.
| Background|| |
Proton pump inhibitors (PPIs) sometimes interfere with clopidogrel metabolism, attenuating P2Y12 receptor inhibition. Previous trials report conflicting results regarding the significance of this interaction, and Weisz et al.  examined the interaction between the concomitant administration of PPI and clopidogrel on platelet reactivity and clinical outcomes in the Assessment of Dual Anti-Platelet Therapy with Drug-Eluting Stents (ADAPT-DES) study.
| Methods|| |
Totally, 8582 patients were enrolled. Around 2697 (31.4%) patients were taking a PPI. P2Y12 platelet reactivity testing was performed using the VerifyNow assay. PPIs' prescription was at the choice of the treating physicians.
| Results|| |
High-risk baseline patient characteristics were associated with PPI use. Patients receiving PPI were older, more often female, with higher rates of hypertension, diabetes mellitus, peripheral arterial disease, kidney disease, and established cardiovascular disease.
By propensity-adjusted multivariable analysis, PPI use was independently associated with increased risk for postdischarge major adverse cardiac events (cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 2-year follow-up.
| Comment|| |
This is a sub-study of main ADAPT-DES study. The study question is whether the use of PPIs with clopidogrel affects the clinical outcomes, mainly stent thrombosis, in postpercutaneous coronary intervention patients. Clopidogrel increases the gastrointestinal (GI) bleeding 2-3 times when used along with aspirin with randomized studies showing increased risk from 0.6% to 2.0%.  In a cohort study, PPI has been shown to decrease the clopidogrel-induced GI bleeding by 50%. An H2 receptor antagonist is less effective and is not proven consistently in studies for gastroprotection from clopidogrel-induced bleeds.  Consensus guidelines have proposed PPI as being the first choice for preventing GI bleeding associated with dual anti-platelet therapy (DAPT) in high-risk patients.  Pharmacologically, clopidogrel activation is affected by PPI that utilizes the same CYP2C19 enzymes for their degradation and ABCB1 transporter. Previous studies have shown conflicting outcomes with some studies showing significant interaction and adverse outcomes and others showing no effect. , There are no enough randomized control studies.
Starting from methodology, it is an observational study. PPI administration to patients was nonrandomized and at physician discretion. There is no documentation of follow-up prescription. No measure was taken for compliance of patients taking a PPI and clopidogrel. Platelet reactivity was tested only one time during hospitalization, and there was no follow-up test. Hence, the study does not have the power to show objectively that clopidogrel interference is responsible for the outcome. If we see the baseline characteristics of patients, there is a significant difference between the groups. These characteristics also increase the risk of stent thrombosis. Propensity scores have been used in the analysis to account for this difference in characteristics. However, even after adjustments, unknown bias still exists that affects the outcome.
Propensity scores are probability score assigned to covariates present in both control and treatment groups that are known to affect the treatment outcome for improving the similarities between two groups. It is most commonly used in observational studies where control and treatment groups are already chosen and in studies where it is difficult to create fully matched groups. It tries to make the study look like a randomized control trial and gives whether observed effect of treatment is significant or not. It was first described by Rosenbaum and Rubin.  They proposed the principle on two basic laws by which treatment or intervention allotment is independent of baseline covariates and all the patients are included in any one group, and no patient is left behind. Propensity scores are usually calculated for covariates that are known to affect the outcome using logistic regression analysis.
The study is not well-matched even after propensity score matching. The study does not mention the specific types of PPI that are used in the study because not all PPIs have drug interactions with clopidogrel. Omeprazole is most commonly implicated in interactions whereas newer PPIs such as pantoprazole are less commonly implicated in clinical studies. This confounding bias is not addressed in the study to account for clinical outcomes. Only the discharge prescription of a PPI is taken as evidence for intake of the drug. High platelet reactivity as shown by this test in the PPI group may not translate to high thrombosis rates. Studies examining dose adjustment of clopidogrel by platelet reactivity do not show superiority to standard treatment.  Aspirin effect has also not been taken into account for clinical events because 20-30% of patient exhibit aspirin resistance also. The primary outcome of stent thrombosis was not achieved. The main clinical outcome difference was increased number of ischemia-driven revascularization not related to stent thrombosis. However, clopidogrel does not have a major influence on restenosis and proliferative disease in stents. The study does not explain these results, and this confounds the overall result of the study without answering the study question.
Hence, interpreting this study for causality of PPI use in target lesion revascularization and stent thrombosis cannot be done. Further, well-balanced studies are required to address these questions. However, the study concludes that higher clinical event occurs with PPI. It should be viewed with a word of caution because of the above limitations and should only warrant more studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Proton pump inhibitors, platelet reactivity, and cardiovascular outcomes after drug-eluting stents in clopidogrel-treated patients: The ADAPT-DES Study. Circ Cardiovasc Interv 2015;8. pii: e001952.
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