COMMENTARY

Proton-Pump Inhibitors and Clopidogrel: Back to the Future?

David A. Johnson, MD

Disclosures

October 05, 2009

Pharmacodynamic Effect and Clinical Efficacy of Clopidogrel and Prasugrel With or Without a Proton-Pump Inhibitor: An Analysis of Two Randomised Trials

O'Donoghue ML, Braunwald E, Antman EM, et al
Lancet. 2009;374:989-997. Epub 2009 Aug 31

Proton-pump inhibitors (PPIs) are often administered concurrently with thienopyridines, such as clopidogrel (Plavix®), especially when combined with other antiplatelet therapies, such as aspirin. Recent joint consensus guidelines from the American College of Gastroenterology (ACG), the American College of Cardiology (ACC), and the American Heart Association (AHA) endorsed the use of PPIs in patients judged to be at higher risk for gastrointestinal (GI) ulceration and related complications.[1] However, a number of other recent studies have revealed possible complications when clopidogrel and a PPI are used together. This concern stemmed from in vitro studies that demonstrated a pharmacodynamic interaction between clopidogrel and omeprazole that resulted in an attenuated antiplatelet effect, as measured by adenosine diphosphate (ADP)-induced platelet aggregation and elevated platelet activity.[2] Clopidogrel is a prodrug, and requires biotransformation to the active compound. This bioactivation occurs via the hepatic cytochrome P450 (CYP) enzyme system, which coincidentally is the same metabolic pathway used by PPIs. Competitive interference within the P450 pathway could conceivably lead to a reduced amount of clopidogrel undergoing biotransformation to the active drug required to effect a change in platelet inhibition.

Recommendations to Avoid PPIs With Clopidogrel

The inference in regard to PPIs and clopidogrel first arose from the combined use of clopidogrel and omeprazole, although several other PPIs have subsequently been found to be associated with a smaller or insignificant attenuation of the clopidogrel antiplatelet effect; these PPIs included pantoprazole, esomeprazole, and -- to a lesser degree -- lansoprazole.[3,4,5] However, these in vitro data were quickly extrapolated in several high-profile retrospective database evaluations (reported primarily in abstract form to date) that found higher cardiac event rates (stent thrombosis, myocardial infarct, and death) in patients who were taking clopidogrel with any PPI vs those on clopidogrel alone.[6,7,8]

The results of the Clopidogrel Medco Outcomes Study,[8] presented at The Society for Cardiovascular Angiography and Interventions (SCAI) meeting in May 2009, prompted the SCAI to issue a recommendation urging "healthcare providers who are treating post-stenting patients on dual-antiplatelet therapy to consider prescribing a histaminergic (H2) blocker (such as Zantac® or Tagamet®) or antacids instead of a PPI, considering the high risk for adverse events shown in this study.[9]" The US Food and Drug Administration (FDA) followed with a recommendation that "healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC®, in patients taking clopidogrel. Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including Prilosec OTC®.[10]"

In Europe, the European Medicines Agency (EMEA) also issued a statement that concomitant use of PPIs and clopidogrel is not advisable unless absolutely necessary, due to concerns that PPIs may reduce the effectiveness of clopidogrel. In a public statement on the possible interaction between these agents, the EMEA also said that product information for all clopidogrel-containing medicines will be amended to reflect this advice.[11]

It would be fair to say that pandemonium then set in. Healthcare providers who tried to prescribe a PPI with clopidogrel subsequent to these agency releases were often blocked by their local pharmacists who would not fill the prescriptions without a release by the prescribing healthcare provider. The pendulum had clearly swung from clinicians being proactive about GI prophylaxis in patients who require clopidogrel for dual antiplatelet therapy to clinicians being reactive and risk-averse in their management of these patients. Unfortunately, these reactions were based on the results of retrospective data analyses that did not adequately adjust for confounding risk variables, and were therefore potentially biased.

CYP2C19 Phenotypes and Clopidogrel Effectiveness

Do we have data to suggest that the pharmacodynamic observation about clopidogrel and PPIs might not be clinically relevant? A similar inference was made a few years ago about the potential adverse combination of statin drugs and clopidogrel, for the same reason -- competitive interactions within the P450 pathway. When this interaction was further analyzed in more than 15,000 patients in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, no clinically evident adverse cardiac events occurred as a result of simultaneous exposure to these 2 medications.[12] Furthermore, according to data published earlier this year in The New England Journal of Medicine,[13] the antiplatelet effect and influence on adverse cardiac events are associated with genetic polymorphisms that affect the bioactivation of clopidogrel. Variation in antiplatelet activity is at least in part determined by the presence of the CYP2C19 reduced-function allele.

Clopidogrel requires transformation by CYP enzymes to an active metabolite for its antiplatelet effect. The genes encoding the CYP enzymes are polymorphic, with common alleles conferring reduced function. A patient who is a normal or even rapid biotransformer would achieve the intended prodrug activation, but the patient with the slow biotransformer phenotype does not have the same capability, and would metabolize and excrete some of the drug without sufficient bioactivation of the prodrug. It was apparent that up to one third of patients were slow biotransformers, a genetic phenotype that was correlated with adverse cardiac events. Of interest, in one of these 2 studies, the authors adjusted for exposure to PPIs and found no significant additional adverse effects related to PPI use, regardless of the genetic CYP2C19 phenotype.[14]

Prospective Trials of PPI-Clopidogrel Interaction and Patient Outcomes

Prospective trials that evaluated the effect of PPIs when combined with clopidogrel have been lacking, but we now have data from 3 recent randomized controlled trials. At the European Society of Cardiology meeting in Barcelona, Spain, on September 9, 2009, investigators presented data from 2 prospective trials[15] that found that patients who have a PPI and a thienopyridine (clopidogrel or prasugrel) on board when they undergo stenting do not receive the full antiplatelet effect of those drugs (assessed by platelet aggregometry). However, they have no increased risk for myocardial infarction, stroke, or death. These 2 studies, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation -- Thrombolysis in Myocardial Infarction 44 Trial (PRINCIPLE-TIMI 44) and the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38, have been published.[15]

In the PRINCIPLE-TIMI 44 trial,[15] 201 patients scheduled for elective percutaneous interventions were randomly assigned to prasugrel or high-dose clopidogrel. In the TRITON-TIMI 38 trial,[15] 13,608 patients with acute coronary syndrome were randomly assigned to receive either prasugrel or clopidogrel. In both trials, concomitant use of a PPI was at the discretion of the treating physician. In these 2 trials, 26.4% and 33.3% of patients were taking PPIs at the time of randomization. No association between PPI use and risk for adverse cardiac endpoints was evident. The investigators concluded that their findings did not support the need to avoid concomitant use of PPIs when clinically indicated in patients taking thienopyridines.

The third prospective trial data were presented at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in San Francisco, California, on September 24, 2009.[16] Dr. Deepak Bhatt and colleagues evaluated the data from the Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial, in which 3627 patients received either a combination pill that contained clopidogrel and omeprazole or clopidogrel alone. Both cardiovascular (CV) and GI endpoints were evaluated, and all adverse events were adjudicated. The CV endpoint was the composite of CV-related death, nonfatal myocardial infarction, coronary artery bypass graft or percutaneous coronary intervention, or ischemic stroke. The GI endpoint was upper GI bleeding, a presumed occult GI bleed with a decrease in hemoglobin of ≥ 2 g/dL or a decrease in hematocrit of ≥ 10%, symptomatic gastroduodenal ulcer confirmed by endoscopy or radiography, pain of presumed GI origin with underlying multiple erosive disease confirmed by endoscopy, obstruction, or perforation.

No differences in the 136 adjudicated CV events were found between groups. A favorable difference in GI outcomes was evident with the addition of a PPI to clopidogrel; this was associated with a 45% relative risk reduction for GI bleeding events compared with clopidogrel alone (P = .007). Although the study intended to follow patients for a year, it was terminated due to bankruptcy of the principal company. The mean follow-up was 133 days with a maximum of 362 days. Nonetheless, most significant adverse GI and CV events occur early after the onset of acute coronary syndrome and percutaneous coronary intervention. No current PPI/clopidogrel data set has more adjudicated CV endpoints with risk stratification and adjustment for PPI exposure. The COGENT trial data provide strong reassurance that there is no clinically relevant adverse CV interaction between clopidogrel and PPIs.

Viewpoint

These results question the exact relationship between ex vivo platelet assays and clinical outcomes, especially with regard to the assessment of drug interactions. Platelet assays and observational data may be factual but are not always appropriate for extrapolation to clinical care, as evidenced by what we have seen during the last several months with the prescribing recommendations for PPI and clopidogrel usage. Platelet assays and observational data are not substitutes for randomized controlled trial data.

Appropriate use is the key consideration for any medication. Healthcare providers should be attuned to the need for PPI therapy in patients who exhibit signs or symptoms of acid-related disease, as well as in asymptomatic patients treated with nonsteroidal anti-inflammatory drugs or antiplatelet agents who meet risk stratification criteria to justify GI prophylaxis (cotherapy with a PPI). Hopefully these new studies will allow us to get back to where new consensus guidelines by the ACG, ACC, and AHA were moving us -- toward reduced risk for GI injury in patients at risk!

Abstract

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