Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor

Abstract

on behalf of the Platelet Inhibition and Patient Outcomes (PLATO) Trial InvestigatorsBackground-The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. Methods and Results-We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (nϭ6539) compared with those not on a PPI (nϭ12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04 -1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79 -1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14 -1.49). Conclusions-The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events. Clinical Trial Registration-http://www.clinicaltrials.gov. Unique identifier: NCT00391872. Key Words: acute coronary syndrome Ⅲ clopidogrel Ⅲ mortality Ⅲ myocardial infarction Ⅲ ticagrelor I n patients with both ST-segment and non-ST-segment elevation acute coronary syndromes (ACS), current clinical practice guidelines recommend the use of dual antiplatelet therapy with acetylsalicylic acid and P2Y12 inhibition. 1,2 Conflicting data exist regarding the potential adverse interaction between the effects on clinical events of the P2Y12 inhibitor clopidogrel and proton pump inhibitors (PPIs), whereas the importance of such an interaction with other P2Y12 inhibitors is less investigated. Clinical Perspective on p 986Several pharmacodynamic studies have shown that some PPIs reduce the inhibition of platelet aggregation achieved with clopidogrel treatment. [3][4][5][6][7][8][9][10] This phenomenon seems meContinuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. ). Relevant exclusions to trial participation included an increased risk of bleeding (eg, active bleeding, major surgery Յ30 days), clinically im...

Response to Letter Regarding Article, “Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor: Insights From PLATO”

“…1 We agree that other unmeasured factors could be associated with our findings that the use of a proton pump inhibitor (PPI) was independently associated with a higher rate of cardiovascular events in patients with an acute coronary syndrome receiving clopidogrel. However, there was a similar association between cardiovascular events and PPI use during treatment with ticagrelor, a directly acting adenosine diphosphate (P2Y 12 ) inhibitor that does not require biotransformation and without known interaction with PPIs.…”

Blood Pressure–Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor

“…38 In an extension, this would imply that the beneficial cardiovascular effects of nitrate-rich vegetables, 8 such as lettuce, beetroots, and spinach, 12 may be partly lost in patients taking PPIs. Interestingly, PPIs have been described to interfere with the efficacy of antiplatelet drugs, such as clopidogrel, 5 aspirin, 8 and ticagrelor, 7 which in turn has been associated with adverse clinical outcomes, especially in high cardiovascular risk populations. 6 In line with this, inorganic nitrite and nitrate have been shown to inhibit platelet aggregation.…”

“…6 Other studies have associated chronic use of PPI with increased cardiovascular risk, independently of treatment with clopidogrel 4 or CYP2C19 metabolism. 7,8 In addition, a recent study in diabetic patients indicates that PPIs increase blood pressure. 9 The mechanisms behind these effects are still unclear, but a reduced vascular bioavailability of NO has been suggested.…”

Concomitant Use of Proton Pump Inhibitors and Thienopyridines in Acute Coronary Syndrome Patients Followed Up in the Intensive Cardiac Care Unit

“…İlk sonuçlara göre klopidogrel kullanımı ile klopidogrel ve birlikte omeprazol kullanan hastalar arasında kardiyovasküler sonlanım açısından önemli fark saptanmadı. Son yıllarda yapılan çalışma-ların sonucuna göre omeprazol ile klopidogrel arasındaki ilaç etkileşiminin klinik önemi net değildir (22) . PLATO çalışmasında klopidogrel veya tikagrelor kullanan AKS hastalarında PPI kullanımının etkisi araştırılmıştır.…”