Cytochrome P450 interactions

Transcription

1 Cytochrome P450 interactions Learning objectives After completing this activity, pharmacists should be able to: Explain the mechanism of action of clopidogrel-ppi interaction Assess the risks and benefits of PPI use with clopidogrel Identify patients at high risk of adverse cardiovascular events due to the interaction Advise prescribers and patients on how to manage concomitant use of clopidogrel and a PPI Appraise drug interaction resources specific to CYP interactions The competency standards addressed by this activity include (but may not be limited to) 3.1.1, 3.1.2, 3.1.3, 3.2.2, 6.1.1, 6.1.2, 6.1.3, 6.2.1, 6.2.2, Introduction Cytochrome P450 (CYP450) enzymes metabolise most medications, and the most important of these enzymes are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In determining the clinical significance of CYP interactions it is important to consider the binding affinity (Ki value), whether the drug is a pro-drug and requires metabolism to an active metabolite, and multiple metabolic pathways to determine the likely clinical significance of the interaction. The CYP450 enzyme CYP2C19 is at least partly involved in the metabolism of many drugs. Drugs metabolised by CYP2C19 often have other pathways. If the patient is deficient in CYP2C19, the other pathways may become more important. Inhibitors of CYP2C19 will tend to have the greatest effect on drugs for which CYP2C19 is the primary pathway. It is always important to check a range of resources as well as being aware of emerging evidence in the primary literature. Cytochrome P450 interactions can be considered from theoretical principles using tables of substrates, inhibitors and inducers in emims, AMH, APF and websites such as and The SHPA website also provides free access to three excellent articles written on cytochrome P450 interactions and genetic polymorphism. The Hansten and Horn website has a series of one page articles on CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 as well as other current topics in drug interactions. The interaction between clopidogrel and PPIs is currently receiving a lot of discussion and debate in the medical literature, with conflicting evidence and opinions. It is important for all pharmacists to have knowledge of CYP450 interactions and be able to provide prescribers and patients with options to manage the interaction. CLOPIDOGREL - PPIS Clopidogrel Clopidogrel is indicated following an acute myocardial infarction (AMI) or in patients with unstable angina, as well as those being treated after percutaneous coronary intervention (PCI) with a stent insertion. Australian guidelines recommend that all patients undergoing reperfusion therapy for ST-segment-elevation myocardial infarction (STEMI) (PCI or fibrinolysis) should be given aspirin and clopidogrel unless these are contraindicated. 1 Combination use of clopidogrel and aspirin (dual antiplatelet therapy) has been shown to reduce the risk of a second heart attack, stroke or death by 20% compared to aspirin alone. 2

2 Internal bleeding occurs in around 14% of patients on clopidogrel. 3 Low-dose aspirin at least doubles GI risk. About 3% of patients taking aspirin and clopidogrel after stent placement will stop taking clopidogrel early because of nuisance bleeding. Nuisance bleeding is defined as easy bruising, bleeding from small cuts, petechiae, and ecchymoses and occurs in around one-third of patients taking clopidogrel. 32 Guidelines suggest prophylactic PPIs for high-risk patients to reduce the risk of GI bleeding. 4 The majority of acute coronary syndrome patients on clopidogrel are also taking a PPI as prophylaxis to prevent a GI bleed. 5 Concurrent use of PPIs in patients with serious coronary heart disease treated with clopidogrel is associated with 50% fewer hospitalizations for gastroduodenal bleeding. 6 The absolute magnitude of this protective effect is increased with increasing numbers of bleeding risk factors. However, a significant proportion of patients remain at risk for subsequent death, myocardial infarction (MI), stent thrombosis, and stroke because of insufficient clopidogrel-induced platelet inhibition. Patients on clopidogrel plus a PPI have a significantly higher risk of rehospitalisation for MI or coronary stent placement than patients receiving clopidogrel alone. 7 Clopidogrel & CYP450 Clopidogrel is a prodrug. It is metabolised in the liver to the active form that irreversibly inhibits the platelet ADP receptor, P2Y12. Cytochrome P450 2C19 (CYP2C19) and 3A4 (CYP3A4) are two major isoenzymes involved in the activation of clopidogrel. All PPIs are also metabolised by CYP2C19 to varying degrees. In addition, some PPIs are strong inhibitors of CYP2C19. Therefore some PPIs may reduce the antiplatelet effect of clopidogrel through inhibition of metabolism to the active form. Omeprazole is a potent inhibitor of CYP2C19 and markedly inhibits clopidogrel's antiplatelet activity, whereas pantoprazole and rabeprazole have the least affinity for CYP2C19. PPI Substrate (major) (minor) Inhibitor Clopidogrel 2C19 & 3A4 2C9 & PGP 2C C9 ++ Omeprazole 2C19 2C19 ++ Esomeprazole 3A4 2C19 2C19 ++ Lansoprazole 2C19 3A4 3A4 ++ Pantoprazole 2C19 3A4 PGP ++

3 Rabeprazole 2C19 & 3A4 Clopidogrel resistance It is estimated that between 5 and 15% of patients have no response to clopidogrel. 8 This resistance to clopidogrel can be explained by strong associations with genetic polymorphism for CYP2C19. A number of different alleles of CYP2C19 have been identified, showing normal, diminished or increased enzymatic activity. This can lead to variability in patient response to a therapeutic benefit susceptibility to adverse effects and variability in response between different ethnic groups. Approximately 30% of individuals of Caucasians, 40% African ancestry, and more than 50% Asian ancestry are poor metabolisers of CYP2C19. The CYP2C19*1 has full enzymatic activity, whereas *2 and *3 alleles are the most common variants and have complete loss of enzymatic activity. Carriers of the loss of function allele CYP2C19*2 have a 30% increased risk of major adverse cardiovascular events (MACE) compared with noncarriers. 9 Carriers of CYP2C19*2 allele and/or users of PPIs had a 40% increased risk of MACE when they are treated with clopidogrel. This single gene variant was also associated with an excess of mortality and a 3 to 6 fold higher risk of stent thrombosis. It has been suggested that the impact of PPIs might only be significant in patients with high baseline cardiovascular risk, whereas the impact of the CYP2C10*2 allele was observed in all patients. 97 Carriers of the CYP2C19*17 allele and the ultrarapid metaboliser phenotype appear to be protected from adverse clinical consequences of concomitant PPI and clopidogrel use. Around 40% of Caucasians and 45% of African-Americans, but only less than 5% of Asians carry this allele. Genetic variant Prevalence CYP2C19 enzymatic activity Degree of platelet aggregation with clopidogrel *1 Normal Normal *2 25% Caucasian None Reduced 30% Black 40-50% Asian *3 < 1% Caucasian None Reduced < 1% Black 7% Asian *4 and *5 < 1% Caucasians, Blacks None n/a and Asians *17 Nearly 40% Caucasians, Blacks and Asians Increased Increased Source: Interaction with PPIs In recent years a significant number of papers have been published, mainly from retrospective, observational and registry data, showing variable outcomes in patients taking clopidogrel and PPIs. A retrospective analysis of over 8000 patients showed a 25% increase in the risk of death or rehospitalisation for acute coronary syndrome in patients taking concomitant clopidogrel and a PPI. 54 In this study 60% of patients were taking omeprazole, 3% rabeprazole and nearly 37% were prescribed more than one PPI during the 1.5 years follow-up. Another six-year population based study of more than 13,000 patients taking clopidogrel following a heart attack, showed concurrent use of omeprazole, lansoprazole or rabeprazole was associated with a 27% increase in

4 the risk of another myorardial infarction (MI). 8 The risk was only evident in patients currently taking the PPI and not in past users. There was no increased risk in patients taking pantoprazole or H2 receptor antagonists. The authors of this study estimated that 5 to 15% of early readmissions due to MI among patients taking clopidogrel could be the result of this drug interaction. 6 In a small series of patients taking clopidogrel, the risk of MI was more than 300% higher among those who were highly adherent to PPIs than among those not taking PPIs. 10 Other studies have shown a significantly reduced antiplatelet activity of clopidogrel in patients treated concurrently with aspirin and omeprazole. 11 In this randomised controlled trial of 124 patients undergoing coronary artery stent implantation, patients received aspirin 75mg/day, clopidogrel 75mg/day and omeprazole 20mg/day or placebo. Clopidogrel effect was tested on days 1 and 7. At day 7, omeprazole had significantly decreased clopidogrel activity on platelets. Conversely, the TRITON-TIMI 38, COGENT and CREDO 12 studies showed no effect on combined clopidogrel-ppi therapy on clinical outcomes. The TRITON-TIMI 38 was a retrospective analysis of a randomised control trial and COGENT is the one prospective study on this interaction. The TRITON-TIMI 38 trial of clopidogrel versus prasugrel in patients with acute coronary syndrome (ACS) undergoing PCI interventions did not find an increased risk with PPIs. 13 The COGENT study randomised patients to take clopidogrel plus omeprazole or placebo. The study was stopped early having shown that the combination reduced GI events with no effect on cardiovascular outcomes. 14 In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor. 15 The debate continues as to whether the interaction is a class effect. One study has reported that intake of pantoprazole and esomeprazole is not associated with impaired response to clopidogrel. 16 In another retrospective cohort study pantoprazole was not associated with a statistically significant increased risk for serious cardiovascular disease. 65 A recent meta-analysis of 23 studies with over 90,000 patients concluded there was conflicting and inconsistent evidence on the impact of the clopidogrel PPI interaction on cardiovascular outcomes and no evidence of harmful effect on mortality. 17 Subsequent to publication of this meta-analysis, the Clopidogrel Medco Outcomes Study, a population-based, retrospective study of 16,690 patients showed concomitant use was associated with a higher rate of major adverse cardiovascular events within 1 year after coronary stent placement. 18 Patients taking clopidogrel plus a PPI were 1.5 times more likely to experience a MACE. Key points Dual antiplatelet therapy (clopidogrel & aspirin) reduces the risk of CV events in patients with ACS Dual antiplatelet therapy is associated with increase risk for serious bleeding (especially GIT) PPIs are recommended as prophylaxis against GI bleeding with dual antiplatelet therapy There is an increased risk of MACE with concomitant clopidogrel and PPI therapy versus clopidogrel without PPI May be class effect but most evidence is with omeprazole Effect of PPIs on outcomes in clopidogrel-treated patients is modest, except for sub-set of patients CYP2C19*1/*2 genotype may be most affected Avoid use of concomitant NSAIDs which increase the risk of GI bleeding

5 Consider use of histamine H 2 -receptor antagonists as alternate to PPI therapy (less protective than PPIs) If PPI is necessary, the majority of evidence supports using pantoprazole Allowing time interval between doses of clopidogrel and PPI will not avert the interaction The bottom line There is no doubt that PPIs attenuate the antiplatelet effect of clopidogrel through inhibition of CYP2C19. The most evidence is with omeprazole, and on a mechanistic basis plus pharmacodynamic data, pantoprazole is least likely to cause this effect. The uncertainty lies in the extent to which this interaction affects clinical outcomes and increases the risk of major adverse cardiovascular events. Specific subgroups of patients with genetic polymorphism of the CYP2C19*2 allele may be more likely to experience harm from the combination. The benefits of reduced gastrointestinal bleeding versus the risk for increased adverse cardiovascular outcomes needs to be assessed for the individual patient. MCQs 1. Which of the following proton pump inhibitors has the least affinity for CYP2C19? a. Omeprazole b. Esomeprazole c. Lansoprazole d. Pantoprazole 2. Which of the following alleles is most likely to produce a reduced response to treatment with clopidogrel? a. CYP2C19*1 b. CYP2C19*2 c. CYP2C19*4 d. CYP2C19*17 3. Which of the following PPIs may inhibit CYP2C19? a. Esomeprazole b. Lansoprazole c. Omeprazole d. All of the above 4. Which of the following strategies is least appropriate for managing the PPI-clopidogrel interaction?

6 a. Separate the dosing of PPI and clopidogrel by 12 hours b. Consider H 2 -antagonist or antacid, if appropriate c. Consider pantoprazole when a PPI is indicated d. Evaluate the necessity of PPI therapy 5. Which statement is true? a. The risk of GI bleeding is greater with clopidogrel than with aspirin b. Combination use of clopidogrel and aspirin increases the risk of myocardial infarction compared to aspirin alone c. PPIs reduce the risk of GI bleeding in patients taking dual antiplatelet therapy d. Patients on clopidogrel and omeprazole have a lower risk of rehospitalisation for MI than clopidogrel alone References 1 Guidelines for the management of acute coronary syndromes Med J Aust 2006;184:S1-S30. 2 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: Roy P, et al. Impact of "nuisance" bleeding on clopidogrel compliance in patients undergoing intracoronary drug-eluting stent implantation. Am J Cardiol 2008;102: Bhatt DL, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008;118: Ho PM, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301: Ray WA, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors. Ann Intern Med 2010;152: Stockl KM, et al. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med 2010;170(8): Juurlink DN, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel CMAJ 2009;180(7):DOI: /cmaj Hulot JS, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochorme P450 2C19*2 loss-of-function allele or proton pump inhibitor coadminstration. J Am Coll Cardiol 2010;56: Pezalla E, et al. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol 2008;52:

7 11 Gilard M, 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: Steinhubl SR, Berger PB, Mann JT for the CREDO Investigators. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention. A Randomized Controlled Trial. JAMA. 2002;288: O'Donoghue ML, 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: Bhatt D. COGENT: A Prospective, Randomized, Placebo-Controlled Trial of Omeprazole in Patients Receiving Aspirin and Clopidogrel. Presented at: Transcatheter Cardiovascular Therapeutics; Sept , 2009; San Francisco. 15 Dunn SP, Macaulay TE, Brennan DM, et al. Baseline proton pump inhibitor use associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation 2008; 118:S_ Siller-Matula JM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1-148.e5. 17 Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010;31: Kreutz RP, et al. Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: The Clopidogrel Medco Outcomes Study. Pharmacother 2010;30(8):