NeLM In-Focus Reviews

Population-based study of the drug interaction between

proton pump inhibitors and clopidogrel

Date Published:12/02/2009

Author:Joanne

Author surname:McEntee

Author affiliation:Medicines Information Pharmacist

North West Medicines Information Centre, Liverpool.

Source: CMAJ 2009. Published early online 28/01/2009.

Resource links:

What is this study?
This Canadian population-based case control study was conducted to assess whether use of proton pump inhibitors (PPIs) in patients taking clopidogrel after discharge from hospital following treatment for acute myocardial infarction (MI) is associated with an increased rate of re-infarction [1].

Study design

13,636 patients aged 66 years or older (median age 76 years; 55.6% men) who started clopidogrel within three days of being discharged from hospital following treatment for acute MI between April 2002 and December 2007 were identified from prescription, hospital discharge and health insurance databases. Patients were excluded if they had taken clopidogrel, ticlopidine or dipyridamole in the year before their MI, were in long-term care or had received a PPI as part of Helicobacter pylori eradication therapy in the 90 days before or after any subsequent re-admission for acute MI. Compliance with clopidogrel therapy was confirmed by checking that patients obtained repeat prescriptions at intervals not exceeding 1.2 times the number of days’ supply of clopidogrel from the previous prescription.

Patients were followed for 90 days after hospital discharge or until first re-admission for acute MI. Each case of re-infarction was randomly matched to at least one control (maximum of three)who was at risk of, but did not experience, a recurrent MI. They were matchedby age (born within three years), percutaneous coronary intervention (PCI), date of hospital discharge (within four days) and predicted probability of short-term mortality as determined by a validated cardiac risk prediction model. Use of PPIs by patients was classed as current (within 30 days before re-infarction), previous (31 to 90 days before re-infarction) or remote (91 to 180 days before re-infarction).Compliance with PPI therapy was not assessed. After discharge 2,682 (19.7%) patients received a PPI within the first 30 days and 4,224 (31%) received one within 90 days.

The primary outcome was the rate of re-admission for acute MI in patients currently using a PPI. The analysis was adjusted for age, sex, income, co-morbidity (using the Charlson index), length of hospital stay following the initial MI, medical conditions associated with increased short-term mortality following acute MI (diabetes with complications, dysrhythmias, pulmonary oedema, cardiogenic shock, acute and chronic renal insufficiency, congestive heart failure and cerebrovascular disease), and use of cardiovascular medicines or other medicines that inhibit or induce cytochrome (CY) P450 isoenzymes 2C19 or 3A4.

Secondary analyses examined the effect of using histamine H2-receptor antagonists, risk of recurrent MI or death within one year of hospital discharge, and risk of recurrent MI with pantoprazole alone compared with all other PPIs combined.

What were the results?

782 (5.7%) patients were re-admitted for acute MI within 90 days of hospital discharge and 734 (93.9%) of these cases were matched to 2,057 event-free controls. Baseline characteristics of cases and controls were similar for age, sex, PCI and rate of cardiac dysrhythmia. However patients with re-infarction were significantly more likely to have congestive heart failure, diabetes mellitus with complications, acute renal insufficiency (all p<0.001) and be taking angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel antagonists or statins. No information was available on smoking status, blood pressure or lipid profile and use of over-the-counter (OTC) medicines.

194 (26.4%) of the 734 patients with recurrent MI were currently using a PPI compared to 424 (20.6%) of the 2,057 controls. The risk of re-infarction was increased by current use of PPIs (adjusted odds ratio (OR) 1.27; [95% confidence interval (CI) 1.03 to 1.57]). There was no increase in risk with previous use of PPIs (0.86; [0.63 to 1.19]) or remote use (0.81; [0.46 to 1.41]). The risk of death within 90 days or one year was not increased (0.82; [0.57 to 1.18] and 0.89; [0.67 to 1.18], respectively). Use of histamine H2-receptor antagonists (famotidine, nizatidine and ranitidine) was not associated with re-infarction (0.94; [0.63 to 1.40]).

In the stratified analysis according to type of PPI used, current use of pantoprazole did not increase the risk of recurrent MI (adjusted OR 1.02; [0.70 to 1.47]), with 46 (6.3%) of those patients re-admitted with an MI and 125 (6.1%) controls taking pantoprazole. None of the other PPIs were analysed separately so it is not possible to determine whether they are also not associated with an increased risk of re-infarction.

What is the impact of this study?

The findings of this retrospective study indicate that patients who concurrently take PPIs with clopidogrel following acute MI are at an increased risk of recurrent MI.5.7% of patients were re-admitted with MI in the 90 days after discharge. The data indicate that the risk of re-infarction is increased by 27% in those taking PPIs. However the 95% confidence intervals (1.03 to 1.57) indicate that the risk could actually be increased by between 3 and 57%. Differences in the demographics of cases and controls are acknowledged and have been adjusted for. However it is not known whether there were any differences between the two groups in other risk factors that could have influenced the risk of MI, such as smoking status, hypertension, lipid profile, and OTC use of anti-platelet drugs or statins.

The suggested mechanism of the interaction is that PPIs reduceconversion of clopidogrel, a pro-drug, to its active form, by competitively inhibiting theCYP450 isoenzyme 2C19. Patients with loss-of-function polymorphisms of this isoenzyme may have lower levels of the active metabolite of clopidogrel and an increased risk of cardiovascular events [1]. No attempt was made in this study to determine the prevalence of poor metabolisers due to CYP2C19 polymorphisms. Studies with other CYP2C19 inhibitors, such as cimetidine, have shown that the pharmacodynamics of clopidogrel are not significantly influenced by concurrent use [2,3]. In addition, there is conflicting information about the relative importance of CYP2C19 in the activation of clopidogrel. The authors of the study report that CYP2C19 has a major role in converting clopidogrel to its active metabolite [1], and this is supported by recent genetic studies [4]. In contrast, the Plavix® Summary of Product Characteristics states that the CYP isoenzymes with primary responsibility are2B6 and 3A4, with 1A1, 1A2 and 2C19 involved to a lesser extent [2]. Of note, several large scale studies (CREDO and CHARISMA) have demonstrated that statins, which are competitive inhibitors of CYP3A4, do not have any negative effect on clinical outcomes even though they appear to reduce the antiplatelet effect of clopidogrel[3].

The authors analysed the effect of pantoprazole on re-infarction separately from the other PPIs. They suggest that pantoprazole is the only PPI that does not inhibit CYP2C19 and therefore, unlike the others (esomeprazole, omeprazole, lansoprazole and rabeprazole), should not interfere with the metabolic activation of clopidogrel. They support this statement by quoting in vitro data comparing the potency and specificity of the five PPIs on a range of CYP enzymes using human liver microsomal preparations and recombinant CYP2C19 [5].Lansoprazole was shown to be the most potent CYP2C19 inhibitor, whilst pantoprazole was the least potent. In contrast, pantoprazole had the strongest inhibitory effect on CYP3A4 metabolism and lansoprazole the weakest. However similar effects are not necessarily found in vivo [5,6]. Compared to omeprazole and esomeprazole, the other PPIs (lansoprazole, pantoprazole and rabeprazole) all appear to be associated with lower incidences of drug interactions, resulting either from reduced affinity for specific CYP isoenzymes or the involvement of additional elimination processes [6]. Unfortunately, the current study did not analyse the effects of each PPI separately. It is also difficult to assess the influence of differences in volume of PPI use from the data presented.Of the 734 patients readmitted with an MI, 46(6.3%) werecurrently taking pantoprazole; the authors did not report how many of the 4,224 patients taking a PPI within 90 days of discharge received pantoprazole. In view of thesesmall patient numbers and the width of the 95% confidence interval around the pantoprazole adjusted OR(0.70 to 1.47),and the possibility of unaccounted differencesin risk factors for MI or poor metaboliser status between cases and controls, it is important that this research is repeated in other populations with data presented for all five PPIs.

An added consideration is data from an ad-hoc retrospective sub-analysis of the CREDO trial that showed use of PPIs by patients on aspirin needing a PCI significantly increased theirone-year relative risk of MI, stroke or death, regardless of whether theyalso received clopidogrel or placebo (hazard ratio 1.5; [1.1 to 2.1]: p=0.012)[7]. Clopidogrel was equally effective in reducing cardiovascular events in patients who took PPIs and those who did not (abstract only available).

The US Food and Drug Administration (FDA) has begun a safety review of clopidogrel in view of a number of reports suggesting that it may be less effective in some patients because of genetic differences in how clopidogrel is metabolised or concurrent use of potentially interacting drugs [8]. The FDAnote that there have been some studies that do not support an interaction between clopidogrel and PPIs. They expect to take several months to publish the results of their review and in the interim advise that:

  • Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke.
  • Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including OTC preparations, in patients taking clopidogrel.
  • Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI.

No action is currently being taken by the European Medicines Evaluation Agency or the Medicines and Healthcare products Regulatory Agency.

It is important that healthcare professionals continue to follow NICE guidance on clopidogrel [9-10]. They should consider the need for concurrent therapy with a gastroprotective agent carefully and take general measures to reduce the patient’s risk of gastrointestinal adverse events (e.g. avoid regular concomitant NSAIDs) [11]. When choosing an appropriate drug, prescribers should be aware of the possibility of a drug interaction between clopidogrel and any of the PPIs. Histamine H2-receptor antagonists (famotidine, nizatidine or ranitidine) do not inhibit CYP isoenzymes, but are not licensed for prophylaxis of NSAID-induced gastric/duodenal ulceration [12-14].

References

  1. Juurlink DN, Gomes T, Ko DT, SzmitkoPE, Austin PC, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. Published early at on 28/01/2009.
  2. Summary of Product Characteristics – Plavix. Sanofi-Aventis and Bristol Myers Squibb SNC. Accessed via on 05/02/2009.
  3. Baxter K (Ed). Stockley’s Drug Interactions. London: Pharmaceutical Press. 2008. Accessed via on 06/02/2009.
  4. Personal communication. Professor Munir Pirmohamed. NHS Chair of Pharmacogenetics. 11/02/2009.
  5. Li X-Q, Andersson TB, Ahlstrom M and Weidolf L. Comparison of inhibitory effects of the proton-pump inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Disp 2004; 32: 821-7.
  6. Blume H, Donath F, Warnke A and Schug BS. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Safety 2006; 29: 767-84.
  7. Dunn SP, Macaulay TE, Brennan DM, Campbell CL, Charnigo RJ, et al. Abstract 3999: 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: S815.
  8. Food and Drug Administration. Early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). Accessed via on 04/02/2009.
  9. NICE. Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome. TA80. 2004. Accessed via on 06/02/2009.
  10. NICE. Clopidogrel and dipyridamole for the prevention of artherosclerotic events. TA90. 2005. Accessed via on 06/02/2009.
  11. Clinical Knowledge Summaries. Antiplatelet treatment. Last revised January 2008. Accessed via on 09/02/2009.
  12. Summary of Product Characteristics – Axid capsules. Flynn Pharma Ltd. Accessed via 09/02/2009.
  13. Summary of Product Characteristics – Pepcid 20mg and 40mg tablets. Merck Sharp & Dohme Ltd. Accessed via 09/02/2009.
  14. Summary of Product Characteristics – Zantac 150mg tablets. GlaxoSmithKline Ltd. Accessed via 09/02/2009.

NeLM In-Focus- Clopidogrel and proton pump inhibitors 12/02/2009