Opinion statement. Coronary Artery Disease (PH Stone, Section Editor)

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1 Current Treatment Options in Cardiovascular Medicine (2012) 14:24 38 DOI /s Coronary Artery Disease (PH Stone, Section Editor) Optimal Management of Antiplatelet Therapy and Proton Pump Inhibition Following Percutaneous Coronary Intervention Mark R. Thomas, BMedSci BMBS 1,* Robert F. Storey, BSc BM DM 2 Address *,1 Cardiovascular Medicine, Queen s Medical Centre, Nottingham, NG7 2UH, UK markthomas@doctors.org.uk 2 Cardiovascular Science, University of Sheffield, Sheffield, S10 2RX, UK Published online: 20 December 2011 * Springer Science+Business Media, LLC 2011 Keywords Antiplatelet therapy I clopidogrel I prasugrel I ticagrelor I proton pump inhibitors I omeprazole I pantoprazole I lansoprazole I acute coronary syndromes Opinion statement Dual antiplatelet therapy (aspirin and a P2Y 12 antagonist) is required after the insertion of a coronary artery stent. If the stent has been inserted in the context of an acute coronary syndrome (ACS), then clopidogrel or a high-potency P2Y 12 antagonist such as prasugrel or ticagrelor should be considered. Current indications for the use of prasugrel in this situation include ST elevation, diabetes, or previous stent thrombosis on clopidogrel therapy. If the stent has been inserted electively for stable ischemic heart disease, then the patient should normally receive clopidogrel. Next, it is important to consider the patient s bleeding risk. The CRUSADE score can be used to determine the likelihood of a subsequent gastrointestinal (GI) bleed. For patients treated with aspirin and clopidogrel who are at high risk of a GI bleed, the current evidence suggests that a proton pump inhibitor (PPI) is the most effective way to reduce this risk. There is evidence that omeprazole may attenuate the pharmacodynamic effect of clopidogrel and, therefore, it would be reasonable to use an alternative PPI that has less risk of negative pharmacokinetic and pharmacodynamic interaction, such as pantoprazole. If a patient is at moderate or low risk of bleeding, then a PPI should be avoided in combination with clopidogrel as the risk of negative interaction is greater than the risk of GI bleeding. There is no substantive evidence that PPIs attenuate the therapeutic effect of prasugrel

2 Antiplatelet therapy and PPIs after PCI Thomas and Storey 25 or ticagrelor; therefore, patients at moderate or high risk of GI bleeding should be offered a PPI. Introduction Ischemic heart disease is the leading cause of death worldwide [1]. Platelets are central in the pathophysiology of acute coronary syndromes (ACS), and antiplatelet therapy has taken a key role in the management of ischemic heart disease. Clopidogrel is an antiplatelet agent that is prescribed routinely in the management of ACS and after percutaneous coronary intervention (PCI). There is conflicting evidence as to whether the therapeutic effect of clopidogrel may be attenuated by an interaction with proton pump inhibitors (PPIs), a type of medication that is commonly co-administered. Even a relatively small decrease in the effect of clopidogrel would be of great importance from a public health perspective, due to the high prevalence of ischemic heart disease, the well-established benefit of clopidogrel, the high prevalence of use of clopidogrel, and the high rate of co-administration of PPIs. We have developed the following flow chart, based on the evidence described in the rest of the article, to help guide decision making regarding antiplatelet therapy and proton pump inhibitors (Fig. 1). P2Y 12 receptor antagonists Platelets express many types of receptors that lead to platelet activation, aggregation, and adhesion to subendothelial components. Atherosclerotic plaque rupture within the coronary arteries triggers this activation and aggregation of platelets and the formation of a thrombus that may partially or completely occlude the artery, causing subsequent myocardial ischaemia. Of particular interest are the P2Y 12 ADP receptors because of their involvement in amplifying the thrombotic response of platelets to other agonists that are released during the rupture of atherosclerotic plaques, such as thrombin and collagen [2]. Thienopyridines, such as clopidogrel and prasugrel, produce active metabolites that bind irreversibly to the P2Y 12 receptor, leading to receptor blockade. It has been shown that a high level of P2Y 12 receptor blockade is needed to consistently inhibit several aspects of platelet function, such as VASP phosphorylation [3]. It has also been shown that the degree of receptor blockade correlates closely with the concentration of active metabolite. Clopidogrel metabolism Clopidogrel is a prodrug, and so the concentration of its active metabolite in the plasma is dependent on its metabolism. Hepatic cytochrome P450 (CYP) enzymes convert clopidogrel into its active metabolite, whereas intestinal esterases convert it into inactive metabolites [4]. CYP2C19 is of particular importance as it contributes to both oxidative steps involved in the formation of the active metabolite of clopidogrel. Firstly, clopidogrel is oxidized to 2-oxo-clopidogrel by CYP1A2, CYP2B6, and CYP2C19. This is then further oxidized into the active metabolite by CYP2B6, CYP2C9, CYP2C19, and CYP3A4 [5]. Genetic polymorphisms that confer a loss of function of certain CYP enzymes (particularly CYP2C19) have been shown to lead to reduced levels of active metabolite, reduced platelet inhibition, and a higher rate of atherothrombotic events. A recent meta-analysis showed that clopidogrel-treated patients who were carriers of the loss of function CYP2C19*2 allele had a 30% increase in the risk of major adverse cardiac events (MACE) compared to noncarriers [6]. Clopidogrel interactions Many different medications are known to either increase or decrease the activity of CYPs. Rifampicin increases the activity of several CYPs, including CYP2C19. Treatment with clopidogrel in the presence of rifampicin leads to a higher level blockade of platelet P2Y 12 receptors and less platelet aggregation [7]. Ketoconazole is a potent inhibitor of CYP3A4 and has been shown to reduce the formation of the clopidogrel active metabolite after clopidogrel administration in healthy volunteers [8]. There has been much discussion of a theoretical interaction of PPIs with clopidogrel. PPIs are also metabolized by hepatic CYPs, particularly CYP2C19 and CYP3A4 [9]. Therefore, it has been hypothesized that

3 26 Coronary Artery Disease (PH Stone, Section Editor) Figure 1. Risk of cardiovascular events on clopidogrel treatment. ACS acute coronary syndrome; GI gastrointestinal; GRACE Global Registry of Acute Coronary Events. PPIs may competitively inhibit the formation of clopidogrel active metabolite, thus reducing the efficacy of clopidogrel. This interaction is discussed below in the relevant sections. Treatment Pharmacologic treatment Antiplatelet agents Dual antiplatelet therapy, usually aspirin plus a P2Y 12 antagonist, is used routinely in the management of ACS and following PCI. The mechanism of action of aspirin is through irreversible inhibition of cyclooxygenase-1. This prevents the formation of thromboxane A 2, which is a potent platelet agonist. Aspirin s benefit is well established in the management of ACS [10, 11], and its use has long been recommended for PCI to prevent atherothrombotic events. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial investigated 12,562 patients with non-st elevation ACS and randomly assigned them to receive either clopidogrel or placebo in addition to aspirin [12]. Clopidogrel, compared with placebo,

4 Antiplatelet therapy and PPIs after PCI Thomas and Storey 27 significantly reduced the risk of cardiac death, myocardial infarction (MI), or stroke from 11.4% to 9.3% (20% relative risk reduction). However, the risk of major bleeding was increased from 2.7% to 3.7% (38% relative risk increase). The Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) trial investigated 3491 patients with ST elevation ACS treated with fibrinolysis and randomized them to receive clopidogrel or placebo in addition to aspirin [13]. Clopidogrel, compared with placebo, significantly reduced the risk of death, MI, or occluded artery on angiography from 21.7% to 15.0% (36% relative risk reduction). The PCI-CURE trial investigated 2658 patients with non-st elevation ACS undergoing PCI in the CURE trial who had been randomly assigned to treatment with clopidogrel or placebo in addition to aspirin [14]. Clopidogrel, compared with placebo, significantly reduced the risk of cardiac death, MI, or urgent target vessel revascularization within 30 days of PCI from 6.4% to 4.5% (30% relative risk reduction). The Clopidogrel for the Reduction of Events During Observation (CREDO) trial investigated 2116 patients who were to undergo elective PCI and randomly assigned them to receive clopidogrel or placebo prior to PCI in addition to aspirin followed by an extended 12 months of treatment with clopidogrel or placebo in the respective groups beyond routine clopidogrel treatment for 1 month post-pci [15]. Clopidogrel, compared to placebo, significantly reduced the risk of cardiac death, MI, or urgent target vessel revascularization from 11.5% to 8.5% (27% relative risk reduction). The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events-Organization to Assess Strategies in Ischemic Syndromes 7 (CURRENT-OASIS 7) trial investigated 25,086 patients with ST and non-st elevation ACS and randomized them to receive a combination of either high or low doses of both aspirin and clopidogrel [16]. Overall, the high dose of clopidogrel, compared to the low dose of clopidogrel, did not significantly reduce the primary outcome (cardiovascular death, MI or stroke at 30 days). However, in the subgroup of patients who underwent PCI (17,263) the high dose of clopidogrel, compared to the low dose significantly reduced the primary outcome from 4.5% to 3.9% (15% risk reduction) and significantly reduced the incidence of stent thrombosis from 2.3% to 1.6% (32% relative risk reduction). The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial investigated 13,608 patients with ST and non-st elevation ACS and randomized them to receive either prasugrel or clopidogrel in addition to aspirin [17]. Prasugrel, compared to clopidogrel, significantly reduced the incidence of the primary endpoint (a composite of cardiovascular death, MI, or

5 28 Coronary Artery Disease (PH Stone, Section Editor) Aspirin nonfatal stroke) from 12.1% to 9.9% (19% relative risk reduction). However, the risk of major bleeding was increased from 1.8% to 2.4% (32% relative risk increase) including an increased risk of fatal bleeding. The Platelet Inhibition and Patient Outcomes (PLATO) trial investigated 18,624 patients with ST and non-st elevation ACS and randomized them to receive either ticagrelor or clopidogrel in addition to aspirin [18]. Ticagrelor, compared to clopidogrel, significantly reduced the incidence of the primary endpoint (a composite of vascular death, MI, or nonfatal stroke) from 11.7% to 9.8% (16% relative risk reduction). The overall rates of major as well as fatal bleeding were not significantly different for patients treated with clopidogrel or ticagrelor, whereas non coronary artery bypass graft (CABG)-related bleeding was increased from 3.5% to 4.8% (37% relative risk increase). Summary: there is substantial evidence for the benefit of aspirin and clopidogrel for patients undergoing elective PCI and for patients undergoing PCI in the context of ACS. For patients with ACS who are undergoing PCI, there is evidence that both prasugrel and ticagrelor significantly reduce the risk of subsequent cardiovascular events compared to clopidogrel. Prasugrel, however, is associated with an increased risk of major bleeding events compared to clopidogrel. Ticagrelor, compared to clopidogrel, is not associated with an increased risk of overall major bleeding events but is associated with an increased risk of spontaneous bleeding. Clopidogrel Standard dosage Contraindications Main drug interactions Main side effects Loading dose of 300 mg of aspirin prior to PCI, followed by 75 mg once a day. Children under 16, previous or active peptic ulceration, hemophilia, sensitivity to NSAIDs. See below for discussion of interaction with PPIs. Gastrointestinal irritation with slight asymptomatic blood loss, increased bleeding time, bronchospasm, skin reactions. Cost/cost-effectiveness 300-mg 32-tablet pack costs $0.50 [19]. Standard dosage Contraindications Main drug interactions Main side effects Loading dose of 300 to 600 mg prior to PCI or following ACS, followed by 75 mg once a day (with the option of using 150 mg once a day for 6 days following PCI for ACS). Active bleeding. See below for discussion of interaction with PPIs. Dyspepsia, abdominal pain, diarrhea, bleeding disorders (including gastrointestinal and intracranial), rash. Cost/cost-effectiveness 75-mg 30-tablet pack costs 2.33 [19].

6 Antiplatelet therapy and PPIs after PCI Thomas and Storey 29 Prasugrel Ticagrelor Standard dosage Contraindications Main drug interactions Main side effects Loading dose of 60 mg prior to PCI or following ACS, followed by 10 mg once a day (or 5 mg once a day if weight under 60 kg or age over 75 years). Active bleeding, history of stroke or transient ischemic attack. See below for discussion of interaction with PPIs. Hemorrhage (including gastrointestinal and intracranial), hematoma, anemia, rash. Cost/cost-effectiveness 10-mg 30-tablet pack costs $76.07 [19]. Standard dosage Loading dose of 180 mg prior to PCI or following ACS, followed by 90 mg twice a day. Contraindications Active bleeding, history of intracranial hemorrhage, coadministration with strong CYP3A4 inhibitors (eg, ketoconazole). Main drug interactions See below for discussion of interaction with PPIs. Main side effects Hemorrhage (including intracranial), dyspnea, abdominal discomfort, rash Cost/cost-effectiveness 90-mg 56-tablet pack costs $ Proton pump inhibitors Dual antiplatelet therapy is associated with adverse gastrointestinal (GI) events, most notably GI bleeding. Age over 65 years, history of upper GI bleeding, and use of other medications that increase the risk of bleeding are all recognized risk factors for GI bleeding during dual antiplatelet therapy. PPIs are commonly prescribed alongside antiplatelet agents in an attempt to reduce this risk, and the protective effect is greater if an individual has multiple risk factors [20]. Meta-analysis [21] hasshownareduction in adverse GI events in patients receiving concomitant PPIs (odds ratio 0.4; 95% CI, ). One large case control study showed that concomitant use of a PPI and clopidogrel was associated with an 81% relative risk reduction of upper GI bleeding compared to clopidogrel alone. The same study showed that concomitant use of histamine H2 receptor antagonists (H2RA) and clopidogrel was not associated with a risk reduction of upper GI bleeding compared to clopidogrel alone [22]. However, there are no randomized control trials that have directly compared the GI-protective effect of H2RAs and PPIs. The CRUSADE bleeding score [23] can be used to determine the likelihood of adverse bleeding events in patients who have had non- ST elevation ACS. This validated score can be used as an objective means of stratifying risk of GI bleeding and thus judging the need for GI-protective medications such as PPIs.

7 30 Coronary Artery Disease (PH Stone, Section Editor) Interactions with clopidogrel Pharmacokinetic studies Although it has been established that all PPIs competitively inhibit CYP2C19 and CYP3A4, it has not been clearly shown which of the PPIs are the most potent inhibitors [24]. Although most pharmacokinetic studies agree that omeprazole is a potent inhibitor of CYP2C19, it is less clear if other PPIs, such as pantoprazole, affect CYP2C19 to the same degree. In fact, pharmacodynamic studies have tended to show no attenuation of the therapeutic effect of clopidogrel in the presence of pantoprazole [25 ]. Observational pharmacodynamic studies Platelet function testing can be used to establish the pharmacodynamic response of a patient to an antiplatelet agent. It has been shown that high on-treatment platelet reactivity (and hence low response to antiplatelet agent), as defined by either vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, light transmission aggregometry (LTA), VerifyNow assay (Accumetrics, San Diego, CA) or multiple electrode aggregometry (MEA), is associated with increased risk of an adverse cardiovascular outcome [26]. Platelet function testing is used as a surrogate marker for response to antiplatelet agents and has been used to investigate interactions between clopidogrel and PPIs. Early observational data showed that patients treated with clopidogrel in the context of high-risk coronary angiography had higher platelet reactivity, as assessed by VASP phosphorylation, if they were also treated with omeprazole [27]. In general, there have been conflicting results from subsequent observational pharmacodynamic studies that have aimed to examine the effect of concomitant PPI use on the therapeutic effect of clopidogrel. Although some of these studies have attempted to account for confounding factors by using sophisticated multivariate analysis and propensity scoring, they are difficult to interpret and draw conclusions from due to their observational nature. Patients on PPIs are statistically more likely to be diabetic and have hypertension, past history of MI, renal disease, and heart failure [28], so clearly the factors influencing PPI prescription overlap with the risk factors for ischemic heart disease. Post hoc analysis of the CREDO trial showed that PPI use was associated with a higher rate of cardiovascular events even if the patient was not taking clopidogrel. Therefore, use of a PPI is likely to be a marker for higher risk of ischaemic events, which is difficult to separate from the effect of the PPI itself in observational studies. However, four studies have randomized patients to receive either omeprazole or placebo or an alternative PPI during treatment with dual antiplatelet therapy.

8 Antiplatelet therapy and PPIs after PCI Thomas and Storey 31 Randomized pharmacodynamic studies The Omeprazole Clopidogrel Aspirin (OCLA) study investigated 124 patients who had undergone PCI and randomized them to receive either omeprazole or placebo in addition to dual antiplatelet therapy [29 ]. It showed that after 7 days, patients who had received omeprazole had significantly higher platelet reactivity, as assessed by VASP phosphorylation, than those that received placebo (PG ). The Proton Pump Inhibitors And Clopidogrel Association (PACA) study investigated 104 patients with ACS who were undergoing PCI and randomized them to receive either omeprazole or pantoprazole in addition to dual antiplatelet therapy [30]. Concomitant use of omeprazole, compared to pantoprazole, led to higher platelet reactivity as assessed by VASP phosphorylation (P=0.007). Interestingly, this was not seen when platelet reactivity was assessed by LTA, which may reflect the VASP phosphorylation method s higher specificity for assessing activation of the P2Y 12 receptor. A four-way crossover study investigated a total of 282 healthy volunteers who were given clopidogrel [31 ]. It investigated the pharmacodynamic effect of simultaneous omeprazole vs placebo, the effect of separating the administration of clopidogrel and omeprazole by 12 h, the effect of high-dose clopidogrel and simultaneous omeprazole, and the effect of omeprazole compared to pantoprazole. After 5 days, concomitant use of omeprazole, compared to placebo, increased platelet reactivity by 20.7% (PG ), as assessed by VASP phosphorylation, and by 8.0% (P G ) as assessed by LTA. When the administration of omeprazole and clopidogrel was separated by 12 h, there was still an increase in platelet reactivity of 27.1% as assessed by VASP phosphorylation and 5.6% as assessed by LTA. This increase in platelet reactivity caused by omeprazole was also seen with increased doses of clopidogrel. Concomitant use of pantoprazole had less effect on platelet reactivity than omeprazole, causing a nonsignificant increase in platelet reactivity of 3.9% (P=0.33) as assessed by VASP phosphorylation and a significant increase of 4.3% (P=0.014) as assessed by LTA. The same group very recently reported another crossover study that randomized 20 healthy volunteers to receive clopidogrel alone or pantoprazole, either simultaneously with clopidogrel or 8 to 12 h later [25 ]. The study was adequately powered to detect a 10% absolute difference in platelet reactivity as assessed by VASP phosphorylation. The addition of pantoprazole did not cause a change in platelet reactivity compared to clopidogrel alone as assessed by VASP phosphorylation, VerifyNow, or LTA. This was true regardless of whether the pantoprazole was administered simultaneously with clopidogrel or delayed by 8 to 12 h.

9 32 Coronary Artery Disease (PH Stone, Section Editor) Observational pharmacodynamic studies comparing the effect of different PPIs The differential effect of omeprazole, pantoprazole, and esomeprazole has been compared in one observational study of 1000 patients who underwent coronary angiography and were treated with clopidogrel. This study found that patients treated with omeprazole had higher platelet reactivity, as assessed by MEA, than patients who were not treated with a PPI. This study found no effect of concomitant treatment with either pantoprazole or esomeprazole on platelet reactivity [32]. This study also identified that diabetes mellitus, body mass index, renal insufficiency, active smoking, previous MI, and platelet count also had an independent association with high platelet reactivity during treatment with clopidogrel. Another observational study compared the association of pantoprazole and esomeprazole with platelet reactivity, as assessed by VASP phosphorylation and LTA, in 300 patients undergoing elective PCI. They found no significant difference in platelet reactivity in patients treated with either pantoprazole or esomeprazole compared to those who were not treated with a PPI [33]. Pharmacodynamic assessment as a therapeutic tool There has been growing interest in the clinical use of platelet function tests to tailor antiplatelet therapy based on measurements of on-treatment platelet reactivity. These platelet function tests could potentially be used at the time of PCI to ensure that patients treated with the combination of clopidogrel and a PPI have had an adequate response to clopidogrel. Potential options in patients who have had a poor response would include changing to a more potent antiplatelet agent, such as prasugrel or ticagrelor, increasing the dose of clopidogrel, or stopping the PPI. Studies assessing new treatment strategies based on platelet function testing are currently ongoing. The only published clinical trial to date in this field is the Gauging Responsiveness With A VerifyNow Assay Impact on Thrombosis and Safety (GRAVITAS) trial [34]. This trial investigated 5429 patients undergoing PCI who had been treated with clopidogrel and randomized them to receive a standard dose of clopidogrel or a tailored dose of clopidogrel based on platelet reactivity as assessed by VerifyNow. The patients who received a tailored dose of clopidogrel did not have a significantly different rate of cardiovascular death, MI, or stent thrombosis compared to those who received a standard dose of clopidogrel (hazard ratio [HR] 1.01; 95% CI, ). Due to the lower than expected number of cardiovascular events that occurred in the study (2.3%) the confidence intervals were wide and neither

10 Antiplatelet therapy and PPIs after PCI Thomas and Storey 33 proved nor disproved a benefit of tailored antiplatelet therapy. Other limitations of this study were that the measurement of platelet reactivity and intervention occurred the day after PCI, rather than at the time of PCI, and that the treatment strategy for patients with high on-treatment platelet reactivity was conservative, involving only a modest increase in the dose of clopidogrel (further 600-mg loading dose and increase to 150-mg maintenance dose). Studies investigating outcome The association of PPIs with subsequent major adverse coronary events (MACE) in patients treated with clopidogrel has been investigated by a recent systematic review and meta-analysis [35 ]. This study included 18 studies published between September 2009 and April The total study population was 159,138 patients with cardiovascular disease who were treated with clopidogrel. It showed that concomitant treatment with a PPI was associated with a 29% relative risk increase of MACE (95% CI=HR ). This metaanalysis included five studies that examined the effect of pantoprazole separately, and it did not show an association of pantoprazole with increased risk of MACE. The study showed a 50% relative risk reduction in gastrointestinal bleeding during concomitant treatment with a PPI (95% CI=HR ). The studies included in this investigation were observational and heterogeneous, making interpretation difficult due to confounding factors. A previous meta-analysis [6] analyzed 11 studies published prior to October 2009 regarding the association of PPI usage with cardiovascular events in patients treated with clopidogrel. This meta-analysis also demonstrated that PPI users had an increased risk of cardiovascular events (odds ratio 1.41; 95% CI, ). Randomized studies investigating outcome The Clopidogrel and the Optimization of GI Events Trial (COGENT) trial [36 ] is the only study to date to have randomized patients receiving dual antiplatelet therapy to also receive either omeprazole or placebo. Although it planned to enroll 5000 patients, only 3873 patients were enrolled before the trial ran out of finances. In this trial, concomitant use of omeprazole with clopidogrel was not associated with an increased risk of subsequent cardiovascular events (HR 0.99; 95% CI, ). Due to the lower than expected number of cardiovascular events that occurred in the study group (2.8%) and the lower than planned sample size, the study s confidence interval for hazard ratio was wide, including up to a 44% increased risk of cardiovascular events. Furthermore, most of the cardiovascular events were repeat revascularization and there were only two cases of definite or probable stent thrombosis in the whole study. Therefore, this

11 34 Coronary Artery Disease (PH Stone, Section Editor) study was underpowered to rule out a clinically significant attenuation of the effect of clopidogrel. Another limitation of this trial was that 94% of the patients enrolled were white and were therefore less likely to have co-existent CYP2C19 loss-of-function polymorphisms compared to other ethnicities. It may be difficult and not financially feasible to perform a large enough, adequately powered randomized clinical trial to prove or disprove an interaction of clopidogrel with PPIs. The original CURE trial investigated 12,562 patients and showed that clopidogrel treatment led to an absolute risk reduction of approximately 2%. It would take a much larger study to show that PPIs lead to a small reduction in this already small 2% benefit. Therefore, randomized pharmacodynamic studies and meta-analysis of observational outcome studies may be the strongest form of evidence that will ever be available. Interactions with other antiplatelet therapy One case control study showed that stable patients with coronary artery disease treated with aspirin had higher platelet reactivity, as assessed by MEA, if they also received a PPI [37]. It was suggested that this could be due to changes in gastric ph interfering with the absorption of aspirin. However, it may well be that the factors that lead to patients being treated with PPIs are also factors that confer higher platelet reactivity and therefore the association is due to confounding. The PLATO PLATELET substudy investigated 69 patients who had been enrolled into the PLATO trial [38]. It showed that platelet reactivity, as assessed by VASP phosphorylation and LTA, was significantly lower in patients treated with ticagrelor compared to patients treated with clopidogrel. Using these measurements of platelet reactivity it also showed that PPIs had no effect on ticagrelor s pharmacodynamic effect. Post hoc analysis of the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) and TRI- TON-TIMI 38 trials showed that patients treated with prasugrel and a PPI had higher platelet reactivity than those treated with prasugrel alone [39]. Overall, however, very few patients showed a low response to prasugrel, even if they were taking a PPI, and patients who received both prasugrel and a PPI did not have a worse cardiovascular outcome. Summary of evidence for interaction of proton pump inhibitors with P2Y 12 antagonists Randomized pharmacodynamic studies have shown that concomitant use of omeprazole causes an increase in platelet reactivity in patients who are treated with clopidogrel. Meta-analysis of observational outcome studies has shown that concomitant use of omeprazole is associated with an increased

12 Antiplatelet therapy and PPIs after PCI Thomas and Storey 35 Omeprazole risk of cardiovascular events in patients who are treated with clopidogrel. The only randomized control trial to examine the effect of the concomitant use of omeprazole on cardiovascular outcome in patients treated with clopidogrel did not show an increased risk of cardiovascular events. However, it was underpowered to rule out a clinically significant increase in risk. The majority of studies have shown no association of the concomitant use of pantoprazole with an attenuation of the pharmacodynamic effect of clopidogrel or an increase in risk of cardiovascular events. There is no substantive evidence for an effect of concomitant use of omeprazole or other PPIs on the therapeutic effect of prasugrel or ticagrelor. Pantoprazole Standard dosage Contraindications Main drug interactions Main side effects mg once daily. Hypersensitivity reaction to omeprazole. See above for discussion of interaction with clopidogrel. Gastrointestinal disturbances (including nausea, vomiting, abdominal pain, flatulence, diarrhea, constipation) and headache. Cost/cost-effectiveness 20-mg 28-tablet pack costs $3.26 [19]. Rabeprazole Standard dosage mg once daily. Contraindications Hypersensitivity reaction to pantoprazole. Main drug interactions See above for discussion of interaction with clopidogrel. Main side effects Similar to omeprazole, also raised cholesterol and triglycerides. Cost/cost-effectiveness 20-mg 28-tablet pack costs $4.25 [19]. Standard dosage 20 mg once daily. Contraindications Hypersensitivity reaction to rabeprazole. Main drug interactions See above for discussion of interaction with clopidogrel. Main side effects Similar to omeprazole, also cough, influenza-like symptoms, and rhinitis. Cost/cost-effectiveness 20-mg 28-tablet pack costs $31.26 [19]. Lansoprazole Standard dosage Contraindications Main drug interactions Main side effects mg once daily. Hypersensitivity reaction to lansoprazole. See above for discussion of interaction with clopidogrel. Similar to omeprazole, may also cause glossitis, pancreatitis, anorexia, restlessness, tremor, impotence, petechiae, and purpura.

13 36 Coronary Artery Disease (PH Stone, Section Editor) Cost/cost-effectiveness 30-mg 28-tablet pack costs $4.45 [19]. Esomeprazole Standard dosage 20 mg once daily. Contraindications Hypersensitivity reaction to esomeprazole. Main drug interactions See above for discussion of interaction with clopidogrel. Main side effects Similar to omeprazole. Cost/cost-effectiveness 30-mg 28-tablet pack costs $40.32 [19]. Disclosure M.R. Thomas: none; R.F. Storey is a consultant for AstraZeneca, Eli Lilly/Daiichi Sankyo, Novartis, Merck, The Medicines Company, Eisai, Accumetrics, and Sanofi-Aventis/Bristol-Myers Squibb; has received grants (all paid to his institution) from AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, Dynabyte, and Accumetrics; has received payments for lectures (including service on speakers bureaus) from AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, and GlaxoSmithKline; has received payment for manuscript preparation from AstraZeneca and Eli Lilly/Daiichi Sankyo; and has had travel/accommodations/meeting expenses covered by AstraZeneca and Eli Lilly/Daiichi Sankyo. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. World Health Organisation, gho/mortality_burden_disease/causes_death_2008/ en/index.html. Accessed 25/5/ Storey RF, Sanderson HM, White AE, et al. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol. 2001;110 (4): Judge HM, Buckland RJ, Sugidachi A, et al. Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function. Thromb Haemost. 2010;103(6): Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360 (4): Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Pharmacology. 2010;38(1): Hulot J-S, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010;56 (2): Judge HM, Patil SB, Buckland RJ, et al. Potentiation of clopidogrel active metabolite formation by rifampicin leads to greater P2Y12 receptor blockade and inhibition of platelet aggregation after clopidogrel. J Thromb Haemostasis: JTH. 2010;8 (8): Farid N, Payne CD, Small DS, et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007;81 (5): Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet. 1996;31:9 28.

14 Antiplatelet therapy and PPIs after PCI Thomas and Storey ISIS-2 Collaborative group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet. 1998;2: Antithrombotic Trialists Collaboration. Collaborative meta-analysis of the randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke among high risk patients. BMJ. 2002;324: Yusuf S, Zhao F, Mehta S. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The New England. 2001;345(7): Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12): Mehta DR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358(9281): Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA: The J Am Med Assoc. 2002;288(19): Mehta SR, Bassand J, Chrolavicius S, et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010;363 (10): Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): British National Formulary, Accessed June Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010;152 (6): Kwok CS, Nijjar RS, Loke YK, et al. Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis. Drug Safety: An International Journal Of Medical Toxicology And Drug Experience. 2011;34(1): Lanas A, García-Rodríguez L, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol. 2007;102(3): Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding in non-st-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation. 2009;119(14): Li XQ. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 Activities. Drug Metabol Dispos. 2004;32(8): Ferreiro JL, Ueno M, Tomasello SD, et al. Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study. Circulation Cardiovasc Interv. 2011;4:00 0. This study showed that concomitant use of pantoprazole did not significantly increase platelet reactivity, as assessed by LTA, VASP phosphorylation and VerifyNow, in normal volunteers who were treated with clopidogrel. 26. Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010;56(12): Gilard M, Arnaud B, Le Gal G, et al. Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost. 2006;4 (11): Siller-Matula JM, Jilma B, Schrör K, et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost. 2010;8: Gilard M, Arnaud B, Cornily J-C, 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 (3): This study was the first randomized pharmacodynamic study that showed that concomitant treatment with omeprazole caused an increase in platelet reactivity in patients treated with clopidogrel. 30. Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol. 2009;54(13): Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebocontrolled, crossover comparison studies. Clin Pharmacol Ther. 2011;89(1): This study assessed the pharmacodynamic effect of concomitant use of omeprazole and pantoprazole in a variety of

15 38 Coronary Artery Disease (PH Stone, Section Editor) different settings in normal volunteers who were treated with clopidogrel. It showed that omeprazole increased platelet reactivity and that delaying the administration of omeprazole might have had a small reduction in this effect. It showed that increasing the dose of clopidogrel did not overcome the effect of omeprazole. It also showed that pantoprazole had much less effect on platelet reactivity than omeprazole. 32. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemostasis. 2009; Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Hear J. 2009;157(1): Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc. 2011;305: Siller-Matula JM, Jilma B, Schrör K, et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemostasis 2010; This is the most recent meta-analysis of the association of concomitant use of PPIs with cardiovascular events in patients who are treated with clopidogrel. It showed that concomitant use of PPI was associated with a significantly increased risk of cardiovascular events. This increased risk of cardiovascular events was not seen in patients who were treated with pantoprazole. 36. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20): This is the only randomized control trial that has investigated the effect of concomitant treatment with omeprazole on cardiovascular outcomes in patients who are treated with clopidogrel. It did not show an increased incidence of subsequent cardiovascular events in patients treated with omeprazole but was underpowered to rule out a clinically significant interaction. 37. Würtz M, Grove EL, Kristensen SD, et al. The antiplatelet effect of aspirin is reduced by proton pump inhibitors in patients with coronary artery disease. Heart (British Cardiac Society). 2010;96(5): Storey RF, Angiolillo DJ, Patil SB, et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol. 2010;56(18): O Donoghue ML, Braunwald E, Antman EM, 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(9694):