Platelets and Blood Cells
© Schattauer 2010
Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation Ioannis Tentzeris1; Rudolf Jarai1; Serdar Farhan1; Ivan Brozovic1; Peter Smetana1; Alexander Geppert1; Johann Wojta2; Jolanta Siller-Matula3; Kurt Huber1 13rd
Medical Department with Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria; 2Department of Cardiology, Medical University of Vienna, Vienna, Austria; 3Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Summary The aim of the study was to evaluate the effect of the concomitant treatment with proton-pump inhibitors (PPIs) and clopidogrel on the incidence of stent thrombosis, acute coronary syndrome (ACS) and death in patients who underwent percutaneous coronary intervention (PCI) and stent implantation. In total, 1,210 patients under dual antiplatelet therapy, who underwent PCI and stent implantation, were included in a prospective registry from January 2003 until December 2006. The patients were divided retrospectively into those with or without long-term PPI treatment (for the duration of dual antiplatelet therapy). All-cause mortality, cardiovascular death, re-hospitalisation for reACS, stent thrombosis, as well as the combined endpoint all-cause death, re-ACS or stent thrombosis were evaluated over a mean followup period of 7.8 (± 3.63) months (range 1–12 months). Propensity score analysis was performed to reduce potential selection bias and exhibited
Correspondence to: Dr. Ioannis Tentzeris 3rd Department of Medicine, Cardiology and Emergency Medicine Wilhelminen Hospital, Montleartstrasse 37 Vienna, A- 1160 Austria Tel.: +43 1 491502301, Fax: +43 1 49150 2309 E-mail:
[email protected]
Introduction Clopidogrel is activated by the CYP2C19 which also metabolizes proton pump inhibitors (PPIs) (1–3). PPIs are frequently administered in combination with aspirin and clopidogrel (dual antiplatelet therapy, DAPT) to reduce the risk for gastrointestinal bleeding, a strategy that is recommended by existing consensus guidelines (4). As many PPIs inhibit CYP2C19, it has been hypothesised that PPIs might interfere with the antiplatelet effect of clopidogrel and therefore reduce its clinical benefit (5). Indeed, trials examining the effect of PPIs on pharmacodynamics of clopidogrel demonstrated that omeprazole reduces the antiplatelet effect of clopidogrel (6–9). In contrast such a negative effect of concomitant PPI use has not been shown for pantoprazole, lansoprazole or esomeprazole, respectively (3, 8–10). Accordingly, retrospective data analyses from large registries suggested that the concomitant treatment with clopidogrel and PPIs increases the rate of major cardiac
no significant difference between the two study groups with respect to all-cause mortality, cardiovascular death, re-ACS, stent thrombosis and the combined endpoint. In pre-specified subgroup analyses performed in patients presenting with ACS and referred for acute PCI or for stable patients referred for elective PCI, receiving drug-eluting stents or bare metal stents, in diabetics or non-diabetics, in males or females, and in patients older than 75 years or ≤75 years of age use of PPIs had no significant impact on clinical outcome. Our data suggest that a combined use of clopidogrel as part of dual antiplatelet therapy (DAPT) after coronary stenting and PPIs does not significantly influence the clinical outcome.
Keywords Stent implantation, clopidogrel, proton pump inhibitors, acute coronary syndrome, stent thrombosis
Received: April 7, 2010 Accepted after major revision: August 20, 2010 Prepublished online: October 12, 2010 doi:10.1160/TH10-04-0218 Thromb Haemost 2010; 104: 1211–1218
adverse events (MACE) (11–16). In contrast, other studies (17–24), especially the prospective COGENT trial (22) as well as post-hoc analyses of the randomised CREDO (23) and TRITONTIMI 38 (24) trials showed no such correlation. Despite these findings, there is still uncertainty under experts with respect to the safety of PPI use in patients under DAPT. Moreover, although stent thrombosis is the clinical endpoint of highest interest with regard to clopidogrel efficacy (25–28), only one trial reported rates of stent thrombosis in patients under DAPT with or without additional use of PPIs (24). In contrast, the majority of studies investigated the impact of PPIs on combined endpoints of MACE. However, due to different definitions of MACE this approach might be biased. As hard clinical outcome parameters should be preferably used as a measure of outcome, it was the aim of our study to demonstrate a potential influence of PPIs on stent thrombosis, re-hospitalisation for acute coronary syndrome (ACS) and cardiovascular and all-cause mortality. Thrombosis and Haemostasis 104.6/2010
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Tentzeris et al. Clopidogrel and proton pump inhibitors after stent implantation
Methods
Clinical endpoints
Patients
All-cause mortality, cardiovascular death, re-hospitalisation for ACS, stent thrombosis as well as the combined clinical endpoint allcause death or re-ACS or stent thrombosis after discharge of hospital were evaluated during a follow-up period of 7.8 (± 3.6) months (range 1–12 months). Stent thrombosis was defined as definite according to the ARC-criteria (30). ACS was defined as angina pectoris at rest and elevated troponin I levels. In patients who could not be contacted, mortality data were obtained from Statistics Austria (Statistics Austria is an independent and non-profit-making federal institution under public law and supports scientific services). Endpoint data were available for all patients (100% follow-up).
In total 1,210 consecutive patients under DAPT with aspirin (100 mg/day) and clopidogrel (loading dose 300 to 600 mg, followed by a maintenance dose of 75 mg/day) who underwent successful percutaneous coronary intervention (PCI) and stent implantation at our department were included in this prospective registry from January 2003 until December 2006. This permanent registry is performed in order to control quality of treatment and includes information about patients, material and medication used as well as clinical outcome data. During the given period use or non-use of PPIs was at discretion of the treating physician. Patients were subgrouped retrospectively into those who were consistently under PPIs for the full duration of DAPT after discharge or not. All interventions were done according to current practice guidelines for PCI (29).
Risk factors Arterial hypertension was defined as a reported blood pressure of >140/90 mmHg or actual antihypertensive therapy. Diabetes mellitus was defined according to the WHO definition as fasting blood glucose level of >126 mg/dl or >200 mg/dl 2 hours after oral glucose tolerance test or permanent medical antidiabetic therapy. Hyperlipidaemia was defined as total blood cholesterol levels of >180 mg/dl or LDL-cholesterol levels of > 130 mg/dl or when patients were under permanent treatment with lipid lowering agents. Impaired renal function was defined as eGFR of
