Platelets play an integral and complex role in the process of thrombosis, including both physiological and pathophysiological mechanisms. Antiplatelet therapy with aspirin and clopidogrel has been confirmed to be a cornerstone in the management of patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) in recent years.1 Sometimes, acute stress ulcer might take place in ACS patients, especially during PCI; proton-pump inhibitors (PPIs) are necessary during this period in order to prevent the gastrointestinal bleeding from stress ulcer. Till now, several studies have noted that many PPIs, especially omeprazole, often administered in combination with clopidogrel or aspirin to reduce the risk of gastrointestinal bleeding,2,3 can reduce the clinical effects of clopidogrel.4,5
Nearly all types of PPIs have been reported to inhibit the antiplatelet activity of clopidogrel during the therapy for coronary artery disease and were associated with a higher risk for major cardiovascular events, increasing 24.3% risk in lansoprazole and 29.2% in pantoprazole.6-8 However, other trials during the same period involving about 13 800 patients with ACS produced the conflicting results, these studies did not find an association between the use of a PPI in combination with clopidogrel and an increased risk of adverse events after retrospective analyses.9 The results from the PRINCIPLE-TIMI 44 trial (Prasugrel In Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation) and TRITON-TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) do not present the influences of co-administration of clopidogrel and PPIs on the clinical events.10,11 A recent randomized clinical trial from 5000 patients also does not show the meaningful difference in cardiovascular events due to use of omeprazole.12
We designed this study to assess how the co-administration of omeprazole blunts the efficacy of clopidogrel in residual platelet activity and clinical thrombosis or bleeding events in Chinese ACS patients undergoing elective PCI.
One hundred and seventy-two patients with high-risk ACS were enrolled. A 600 mg loading dose of clopidegrel and 300 mg loading dose of aspirin were administered to all patients prior to elective PCI. And then, maintenance dose of clopidegrel 75 mg/d for 1-1.5 years as well as aspirin 100 mg/d for life span were followed. At the beginning of elective PCI, all patients were randomized to receiving omeprazole (20 mg/d) or placebo for 30 days. No patients received any glycoprotein (GP) IIb/IIIa inhibitor.
The study protocol was approved by the ethics committee of the Chinese People’s Liberation Army General Hospital, and conformed to the principles outlined in the Declaration of Helsinki. All participants were informed the details of study and signed the written informed consents.
Blood samples were taken after 5 days of using omeprazole (Figure). Thromboelastography (TEG) mapping was used to detect the various states of platelet activity and potential activity, to calculate the residual platelet activity after treatment, and to analyze the distribution effects and comparative effects of aspirin and clopidegrel.
In these elective PCI patients, the following conditions were used to define high risk for bleeding and thrombosis if the patients had any one condition showed below.
High risk for bleeding: age >70 years; liver function slight or moderate incomplete; renal insufficiency with estimated glomerular filtration rate (eGRF) <30 ml·min-11.73 m-2; platelet count <100 × 109/L but >50 × 109/L; long-term combined application of glucocorticoid or recent application of high-dose glucocorticoid; active gastrointestinal ulcers appeared within the recent three months or gastrointestinal bleeding appeared within the recent six months but healed now; positive history of cerebral hemorrhage but negative within the recent six months.
High risk for thrombosis: diabetic diffuse lesions in coronary arteries; long stent ≥28 mm; fine stent ≤2.5 mm; bifurcation stent; left main or nearly left main coronary stent; renal insufficiency with eGRF <60 ml·min-11.73 m-2; malignant tumor; significant aneurysmal dilatation or diffused dilation in coronary artery confirmed by imaging with apparent diffuse or multiple endothelial broken, brittle or ulcerative changes; suspected clopidogrel or aspirin resistance; connective tissue disease (especially lupus erythematosus, scleroderma, systemic sclerosis, etc.); autoimmune disorders (such as severe ulcerative colitis); platelet count >300 × 109/L.
The following conditions were used as exclusive criteria: significantly slow coronary blood flow during or after stenting, which should be given GP IIb/IIIa; aspirin or clopedogrel allergy; primery PCI; patients with peri-operative severe bleeding which should stop anti-coagulation or anti-platelet therapy.
Cessation criteria were as follows: severe bleeding, which should stop anti-coagulation and anti-platelet therapy, occured during the treatment process, whenever the patients wanted to stop the observation.
ACS was diagnosed according to the criteria of the American Heart Association, which includes acute myocardial infarction and unstable angina pectoris. This study only included those patients with unstable angina pectoris and myocardial infarction attacked more than 10 days, excluding the cardiac shock or state supported by device, such as intra-aortic balloon pump (IABP).
Diabetes mellitus was diagnosed according to the criteria of the American Diabetes Association, which means fasting serum glucose level ≥7.0 mmol/L or 2-hour postprandial glucose level ≥11.1 mmol/L after taking hypoglycemic agents in two measurements. Patients with fasting serum glucose level in the range of 5.6-7.0 mmol/L or 2-hour postprandial glucose level in the range of 7.8-11.1 mmol/L received oral glucose tolerance test for further diagnosis.
Blood sampling and measurement
Measurement of platelet function was conducted between 8:00-9:00 AM, following oral taking omeprazole for 5 days as well as loading and maintaining doses of clopidogrel and aspirin using TEG. Samples were obtained under negative pressure using citrate (9NC coagulation sodium citrate 3, 2%) and heparin anticoagulation tubes (BD Company, USA). Blood samples were analyzed using TEG mapping assay (Haemoscope Corp., USA) in the TEG5000. Whole blood was available and the process achieved nearly point-of-care testing (POCT) by this method. All platelet aggregometry tracings were confirmed by a single reader, who was unaware of randomized treatment assignment, at a central clinical laboratory (Center for Platelet Function Studies, People’s Liberation Army General Hospital, Beijing, China).
Platelet mapping was performed using TEG, with 2 μmol/L adenosine 5'-diphosphate (ADP) as the platelet activator. For the ADP pathway (2 μmol/L ADP), the sensitivity was 80% and specificity was 86%. For the arachidonic acid (AA) pathway (1 mmol/L AA), the sensitivity was 100% and specificity was 92%, respectively.
In this study, thienopyridine hyporesponsiveness was defined as less than 30% inhibition of platelet aggregation with 2 μmol/L ADP. Inhibition of platelet aggregation was defined as: (100-((MApi-MAf)/(MAt-MAf))×100%. In this formula: MApi=MAADP or MAAA, MAf=MAfibrin, MAt=MAthrombin including MACK or MACKH, MA means maximal amplitude (which means maximal platelet aggregation activity), MACKH means giving the maximal response for thrombin generation in the presence of citrate, kaolin and heparinase, MACK means giving the maximal response for thrombin generation in the presence of citrate and kaolin.
All patients were randomly assigned to take omeprazole or placebo. Omeprazole (20 mg/d) or placebo was taken for 30 days after the elective PCI no matter whether there were symptoms of stomach ache. Patients were classified as receiving PPI if they took omeprazole on the same day when the platelet function test was conducted (Figure).
Significant clinical events were classified as: (1) coronary artery ischemia, which was divided into 5 classes according to the ischemia severity, such as slight chest pressure for score 1, occasional angina for score 2, frequent angina for score 3, acute myocardial infaction for score 4, and no chest pressure for score 0; (2) cerebral artery events, which included transient ischemia attack (TIA), ischemic stroke and bleeding stroke; (3) gastrointestinal bleeding.
Slight chest pressure means the patients with a little chest pressure without aggravation by accelerated speed movements. During the attack, the ongoing speed and strength are not restricted and there are not any elevated or decreased ST-segment shifts in electrocardiograph (ECG). Occasional angina is defined as an attack of angina 1-2 times during one month period when patients are in speeding movement and fatigue, over excited, anxious or angry emotion. During the attack, the patients need to stop movement in order to rest or take nitroglycerin in order to suspend the symptoms. The patients can be recorded the elevated or decreased shifts in ST segment in ECG. Frequent angina is defined as an attack of angina more than 3 times during one month period when patients are in normal speed movement and emotion. Acute myocardial infarction (AMI) includes ST segment elevated and non-ST segment elevated AMI diagnosed according to the criteria of the American Heart Association. TIA, ischemic stroke and bleeding stroke are diagnosed according to the criteria of the American Stroke Association.
Categorical variables were expressed as frequencies (n (%)) and the comparisons of characteristics of the two groups were done by the chi-square test (α=0.05). Continuous variables were presented as the mean ± standard deviation (SD) and the statistical significance was evaluated by the t test. All statistical analyses were performed using SPSS 16.0. A P value less than 0.05 was considered statistically significant.
For all landmark analyses, patients who had bleeding events after randomization and before the landmark date were excluded to keep the probability of confounding data by indication to a minimum.
Baseline characteristics of patients
Among the 172 patients enrolled in this study, 86 (50%) took omeprazole at the time of randomization. Baseline characteristics of all patients are showed in Table 1.
Generally, Table 2 shows that the mean platelet activation inhibition rates using the ADP-induced method and TEG-mapping between the two groups (with and without omeprazole) were similar (P=0.2895); the mean values for residual platelet activity were not significantly different regardless of the used method, such as LTA or TEG-mapping assay (P=0.7958 and P=0.2896, respectively). The highest potential platelet activities (MA-max) detected with TEG mapping were not significantly different between the two groups (P=0.1562); the results were different from a recent report of O’Donoghue et al.13
The patients were divided into 5 levels according to the platelet activation inhibition rates (Table 3), the frequency distribution in these 5 levels between the two groups showed a significant difference (P=0.0062). There were significant decreases of the frequency of higher platelet activation inhibition rates with omeprazole, in the range of 80%-95%. However, no significant change was seen in the distribution of the highest or lowest inhibiting levels (>95% and <30% inhibition rate), which meant the high risk of bleeding and thrombosis derived from the clopidogrel efficacy. Omeprazole did not increase the no-responders group number (inhibition rate <30%) or the more-high-responder group number (inhibition rate >95%).
After the clinical chest pressure being divided into 5 classes according to severity of ischemia, no significant differences in ischemic clinical events or the whole ischemic and bleeding events were seen between the two groups (with and without omeprazole) one month after elective PCI (P >0.05). Overt upper gastraintesternal bleeding occurred in two patients without using omeprazole (up to 2%), none in the group with combination of omeprazole, although there were no statistically significant (P=0.1889, Table 4).
Light-transmittance platelet aggregation (LTA) is a gold-standard method to evaluate in vitro platelet aggregation by far; it is necessary for this method to get platelet-rich plasma (PRP) and platelet-poor plasma (PPP) by centrifuging the whole blood before testing platelet aggregation immediately after adopting the blood sample at laboratory without using tourniquet by a skilled nurse.14-16 Additionally, hyperlipidemia and heparin can influence the results, and the procedures require highly skilled operators; it is complicated and has a low reproducibility in the clinical protocol. These methods are insufficient for monitoring residual platelet activity of ACS patients. Because of the lack of white blood cells, red blood cells and those factors influenced by the blood cells, these classic methods are not objectively compared with whole blood tests.11,16,17 Although the classical platelet function test is adequate, it can not be widely applied in clinic because its difficulties of quality control.
The POPULARity study18,19 compared several methods for evaluating platelet function and their association with therapies; however, this study did not involve the TEG mapping.3-5,13
New tests are based on the whole blood detection and have been used in clinic. These methods include TEG mapping, VerifyNow, VASP, Plateletworks, Impact cone, and platelet analyzers.3-5,9-12,18,20 TEG, a rapid whole blood monitoring method,14,15,20 can measure platelet-fibrin clot formation and thrombolysis, provide complete information regarding clotting, platelet aggregation, fibrinolysis, and the effect of platelets on clot shear elasticity. 2,3,14,15 TEG mapping can also differentiate the effects of multiple medications. Its advantages included rapid operation, high stability, high reproducibility, heperin independence, low dependence on operators, easy control, and high platelet aggregation sensitivity;14,15 this method is adopted recently, and the device and reagent used for this method are available in China. Based on the above, the best available method for rapid, consistent, and reproducible measurements of platelet function in China is TEG mapping.
Effect on platelet inhibition strength and ischemic events
Although several studies showed that PPIs blunted the antiplatelet effect of clopidogrel, this study demonstrated that there were no significant differences in potential platelet activity, residual platelet activity, or the inhibition of platelet activity as determined by LTA or TEG evaluation methods in general patients. When the patients were divided into 5 degrees according to the platelet activation inhibition, more patients with higher degree inhibition rate (inhibition rate 80%-95%) were in without co-administration of omeprazole group (P=0.0062). However, omeprazole administration did not increase the size of the non-responder group (inhibition rate <30%) and the over high-responder group (inhibition rate >95%), although it increased the number of moderate lower response patients (inhibition rate 30%-49%) through decreasing the number of moderate and high response patients (inhibition rate 80%-95%). In this study, omeprazole decreased clopidogrel related platelet inhibition slightly, while it did not increase the non-responders group. The results imply that PPI do not influence the clinical effects of clopidogrel, while not the platelet activity distribution. In this study, there was no significant rise in ischemic clinical events in the co-administration of PPI treatment group during one month after PCI (Table 4), which is similar to the current report from PRINCIPLE-TIMI 44 and TRITON-TIMI 3813 and the study of clopidogrel with or without omeprazole in coronary artery disease.12
Because different results can be derived from different assays of platelet activity and different analysis methods, some researchers question the relationship between ex vivo platelet assays and clinical outcomes, especially with regard to the assessment of PPI interactions. Some studies demonstrated that TEG mapping, a more convenient and reproducible complete blood evaluation test, had a high correlation with complicated classic LTA method which need rigorous laboratory condition in platelet activity test;14-23 TEG mapping data also related with clinical events in PCI.16,21,24,25 From this study, we find that although omeprazole can affect the platelet activity strength distribution, it does not increase the size of the non-responder group significantly following a 600 mg clopidogrel and a 300 mg aspirin loading dose. Co-administration of omeprazole dose not increase the ischimic events. This finding may be a reason for the lack of influence on clinical outcomes in some studies although appear blunt the clopidogrel ability of inhibiting platelet activity in other studies, when using omeprazole during treatment of ACS.
Clopidogrel must be converted to an active metabolite to inhibit the platelet aggregation. The conversion mainly depends on the hepatic cytochrome P450 isoenzyme system particularly CYP2C19, a main part participating in clopidogrel metabolism.22 Many drugs including PPIs such as omeprazole are metabolized through the CYP2C19 isoenzyme,26 and drug interactions are inevitable.6,7,23,27 Co-administration of omeprazole in those patients receiving clopidogrel was associated with a decreased inhibition of platelet aggregation and an increase in the risk of recurrent myocardial infarction in some randomized double-blind placebo-controlled studies in patients undergoing elective coronary artery stenting and subsequent meta analysis.6,7,23,26-28 Some reports suggested that such results might represent a class effect for PPIs;8,26 however, other studies demonstrated that there were no differences for major adverse cardiac events (MACEs) in patients with elective PCI, although there was a decrease in the inhibition of platelet aggregation through the ADP pathway when omeprazole was co-administered with clopidogrel respectively. 7,13,26,29 This study gives a rational explanation about what strength the omeprazole inhibits the efficacy of clopidogrel and affects the clinical ischemic events attack.
Effect on bleeding events
Gastrointestinal bleeding is an important potential complication of antiplatelet therapy, especially in ACS undergoing PCI patients. Some previous studies showed that co-administration of PPIs or H2-receptor antagonists could reduce the risk of ascertained ulcers in patients receiving aspirin or combination antiplatelet therapy,12,29 although there are no significant differences in ischemic events between two groups in this study. On the contrary, there are two overt gastraintesternal bleeding events turning up in the group without co-administration of PPI only during the first month after PCI, but none in co-administration of PPI group. This might be due to omeprazole protecting gastraintestin from ulcer or erosion associated with combined antiplatelet remedy and stress attacks.12 It is more important to evaluate the drug interactions of PPI with clopidogrel integrally than to simply estimate the clopidogrel antiplatelet efficacy; some patients need more higher doses of clopidogrel or aspirin.
In this randomized study of patients with ACS undergoing PCI and taking clopidogrel and aspirin dual therapy, no significant effects of omeprazole were found on the anti-platelet activity of clopidogreal when it was measured by the inhibition of platelets determined by TEG mapping. Co-administration of omeprazole significantly decreased the distribution frequency of higher platelet inhibition rates induced by clopidogrel without increasing the clopidogrel non-responder rate and clinical ischimic events. At the same time, clopidogrel co-administration of omeprazole might decrease the gastraintesternal bleeding events. Thus we do not recommend stopping omeprazole administration during anti-platelet dual therapy for ACS.
The authors thank WANG Cheng-bin, LI Jian and WANG Hai, Department of Cardiology, for their technical assistance, Dr. WANG Chun-ya, Department of Emergency, the Chinese People’s Liberation Army General Hospital, and Dr. WANG Hong-ye from the Department of Cardiovascular Diseases of the 309 Hospital.
1. Wang TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel
resistance: an emerging clinical entity. Eur Heart J 2006; 27: 647-654.
2. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of omeprazole on the antiplatelet action of clopidogrel
associated with aspirin: the randomized, double-blind OCLA (Omeprazole Clopidogrel
Aspirin) study. J Am Coll Cardiol 2008; 51: 256-260.
3. Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel
. Thromb Haemost 2009; 101: 714-719.
4. Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel
. CMAJ 2009; 180: 713-718.
5. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel
and proton pump inhibitors following acute coronary syndrome
. JAMA 2009; 301: 937-944.
6. Lau WC, Gurbel PA. The drug-drug interaction between proton pump inhibitors and clopidogrel
. CMAJ 2009; 180: 699-700.
7. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, et al. Influence of Omeprazole on the antiplatelet action of clopidogrel
associated with aspirin. J Am Coll Cardiol 2008; 51: 256-260.
9. Dunn SP, Macaulay TE, Brennan DM. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel
in the CREDO trial. Circulation 2008; 118: 815A.
10. Wiviott SD, Trenk D, Frelinger AL, O’Donoghue M, Neumann FJ, Michelson AD, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel
in patients with planned percutaneous coronary intervention: the prasugrel in comparison to clopidogrel
for inhibition of platelet activation
and aggregation-thrombolysis in myocardial infarction 44 trial. Circulation 2007; 116: 2923-2932.
11. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel
in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
12. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et al. Clopidogrel
with or without Omeprazole in Coronary Artery Disease. N Engl J Med 2010; 363: 1909-1917.
13. O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel
and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009; 374: 989-997.
14. Craft RM, Chavez JJ, Bresee SJ, Wortham DC, Cohen E, Carroll RC. A novel modification of the Thrombelastograph assay, isolating platelet function, correlates with optical platelet aggregation. J Lab Clin Med 2004; 143: 301-309.
15. Hobson AR, Agarwala RA, Swallow RA, Dawkins KD, Curzen NP. Thrombelastography: current clinical applications and its potential role in interventional cardiology. Platelets 2006; 17: 509-518.
16. Ben-Dor I, Kleiman NS, Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel
therapy. Am J Cardiol 2009; 104: 227-233.
17. Ren YH, Wang HY, Wang CY, Wang Y, Yang TS, Gai LY, et al. The comparative study of modified TEG graphy and flow cytometry about the effects of tirofiban on ACS. Chin J Cardiol (Chin) 2007; 35: 366-367.
18. Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ruven HJ, Bal ET, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010; 303: 754-762.
20. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel
for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
21. Katori N, Szlam F, Levy JH, Tanaka KA. A novel method to assess platelet inhibition by eptifibatide with thrombelastograph. Anesth Analg 2004; 99: 1794-1799.
22. Ren YH, Wang HY, Wang CY, Wang Y, Yang TS, Gai LY, et al. Evaluation of triple anti-platelet therapy by modified thrombelastography in patients with acute coronary syndrome
. Chin Med J 2008; 121: 850-852.
23. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, et al. Clopidogrel
effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
24. Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel
therapy undergoing percutaneous coronary intervention is the current antiplatelet therapy adequate? J Am Coll Cardiol 2007; 49: 657-666.
25. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, et al. Clopidogrel
resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
26. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel
. Alimentary Pharmacol Ther 2010; 31: 810-823.
27. Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel
. CMAJ 2009; 180: 713-718.
28. Schwab M, Schaeffeler E, Klotz U, Treiber G. CYP2C19 polymorphism is a major predictor of treatment failure in white patients by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylori. Clin Pharmacol Ther 2004; 76: 201-209.
29. Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet 2009; 374: 119-125.