Many Short-term Readmissions for MI Preventable

Up to 15% of short term readmissions for acute myocardial infarction could be prevented through changes to prescribing patterns. That is the conclusion of a recently released study which examined the effect of concomitant use of clopidogrel and proton pump inhibitors in elderly Canadian individuals, who had been discharged from hospital following myocardial infarction.1

The study, a large case control study, identified cases and controls over a period of more than five years, from a population of Ontario residents aged >65 years, who filled a script for clopidogrel within three days of hospital discharge. The cases were those individuals who were readmitted to hospital for a second myocardial infarct within the 90 day follow up period. They were matched to one or more controls (i.e. individuals who did not experience a second myocardial infarct in the follow up period).¹

The researchers compared the concomitant use of clopidogrel and proton pump inhibitors between cases and controls. Clopidogrel is a prodrug, with anti-platelet properties, which works by inhibiting the platelet P2Y adenosine diphosphate receptor. However the pharmacokinetics of clopidogrel are mediated by the cytochrome P450 2C19, which plays a major role in the bio-activation of clopidogrel. Thus drugs which inhibit cytochrome P450 2C19 diminish the anti-platelet effect of clopidogrel, and in theory reduce its clinical benefit vis-à-vis myocardial infarction.¹

Most proton pump inhibitors (omeprazole (marketed in Australia as Losec, Probitor, Meprazol, Acimax, Omepral),³ lansoprazole (marketed as Zoton)⁴ and rabeprazole (marketed as Pariet)) inhibit cytochrome P450 2C19 and thus theorectically reduce the benefits of clopidogrel.¹ The proton pump inhibitor pantoprazole (marketed as Somac))² inhibits specifically and dose-proportionately H+/K+-ATPase, the enzyme which is responsible for gastric acid secretion in the parietal cells of the stomach.⁷

Associate Professor Peter Katelaris, senior staff specialist at the Department of Gastroenterology, Concord Hospital, said, “The possibility of such an interaction is certainly biologically plausible based on what is known about the metabolism of PPIs and clopidogrel and it has been suggested that such an interaction may be an issue. Now we have supportive case control data to say that this appears to be the case.”

PPIs are prescribed to treat acid related disorders such as gastroesophageal reflux diseas (GORD) and peptic ulcer and also to protect the gastric mucosa from the injurious effects of NSAIDs and antiplatelet agents.^2,3,4,5 Collectively proton pump inhibitors are amongst the most widely prescribed medications in the world and are commonly prescribed concomitantly with clopidogrel.¹ However guidelines from National Heart Associations (including the National Heart Foundation of Australia)⁶ provide no warning of the risks associated with such concomitant use, although, most guideline bodies are now reviewing their position in the light of this new data.

The Canadian study found that 31% of participants in the study were prescribed clopidogrel and proton pump inhibitors concomitantly, within 90 days of discharge. Analysis of the study data revealed concomitant clopidogrel/proton pump inhibitor therapy post-discharge, significantly increased risk of readmission to hospital for infarct within 90 days.¹

When concomitant therapy with all proton pump inhibitors was considered, individuals who had used a proton pump inhibitor and clopidogrel in the 30 days prior to readmission for infarction, were 27% more likely to be readmitted to hospital than individuals who used clopidogrel alone. More distant use of proton pump inhibitors (i.e. use >30 days prior to readmission) was not however associated with an increased risk of reinfarction.¹

The researchers then examined concomitant therapy only with proton pump inhibitors which inhibit cytochrome P450 2C19 (i.e. omeprazole, lansoprazole and rabeprazole but not pantoprazole). Concomitant use of these proton pump inhibitors in the 30 days prior to readmission was associated with a 1.4 times increased risk of readmission for infarction.¹

“The three PPIs implicated were studied collectively and the investigators did not report whether the reported risk was distributed equally among the three drugs, nor indeed what proportion of the total cases studied were on each drug. Because of this, we don’t know whether these PPIs are equally responsible for the effect. There are theoretical reasons, based on an awareness or the metabolism of each PPI, to think that this may not be the case.” said A/Prof Katelaris.

The results of the study are clinically significant. The authors of the study attributed at least 7% of readmissions for infarct in the study group to the concomitant therapy. They further reported that between 5-15% of readmissions for myocardial infarct could be prevented, in populations where 20-40% of patients currently receive concomitant clopidogrel/proton pump inhibitor therapy. The concomitant prescription of these drugs definitely reduces, and possibly even abolishes, any clinical benefits derived from clopidogrel prescription.¹

While no statistics are available about the extent of concomitant clopidogrel/proton pump inhibitor therapy in Australia, given similar prescribing recommendations, it seems fair to assume that concomitant therapy is commonly prescribed. Thus the results of this study appear to apply to the Australian clinical context.

A/Prof Katelaris said “This study is important but it does have significant methodological flaws and not all other available data is in agreement. However, while it is not the best level of evidence we would hope to have, it is the best available evidence, so for the time being, for patients on clopidogrel to prevent heart attack who also need a PPI, pantoprazole is preferred. Further reports from other investigators are expected to be available soon and hopefully these will clarify if the effect is real and also determine the relative risk of individual PPIs.”

The current study had several limitations, including its observational design and inability to control for a number of known risk factors for myocardial infarct (e.g. smoking). Thus further research, and particularly experimental research, is necessary to confirm or contradict the results. However the authors of the study recommend that until such evidence can be produced, the concomitant prescription of clopidogrel and proton pump inhibitors be minimised. If such drug combination is found necessary, preferential use of the proton pump inhibitor pantoprazole, which does not inhibit cytochrome P4502C19, is recommended.¹

A/Prof Katelaris’ message for doctors is “Only use a PPI in patients that require clopidogrel for vascular prophylaxis if there is a good clinical indication. When a PPI is required in this setting, until we know differently, use pantoprazole but watch the literature to see if the effect is verified by subsequent reports with stronger methodology. Given that any switch in PPI will be between drugs of similar efficacy there is no major issue in that regard for patients.”

References

1. Juurlink, D.N. Gomes, T. Ko, D.T. et al, “A population based study of the drug interaction between proton pump inhibitors and clopidogrelclopidogrel” in CMAJ, 2009, 180(7): DOI:10.1503/cmaj.082001, available from: http://www.cmaj.ca/
2. Australian Government Department of Health and Ageing, Pharmaceutical Benefits Schedule- Pantoprazole, 2009, available from: http://www.pbs.gov.au/html/consumer/search/results?term=pantoprazole&scope=PBS+STATIC&form-type=simple
3. Australian Government Department of Health and Ageing, Pharmaceutical Benefits Schedule- Omeprazole, available from: http://www.pbs.gov.au/html/consumer/search/results?term=omeprazole
4. Australian Government Department of Health and Ageing, Pharmaceutical Benefits Schedule- Lansoprazole, 2009, available from: http://www.pbs.gov.au/html/consumer/search/results?term=lansoprazole
5. Australian Government Department of Health and Ageing, Pharmaceutical Benefits Schedule- Rabeprazole, 2009, available from: http://www.pbs.gov.au/html/consumer/search/results?term=rabeprazole&scope=PBS+STATIC&form-type=simple
6. National Heart Foundation of Australia, Quality use of Medicines for Cardiovascular Health, 2006, available from: http://www.heartfoundation.org.au/SiteCollectionDocuments/res QUM Report.pdf
7. Somac (Pantoprazole) Product Information. North Ryde NSW: Nycomed Pty Limited, 2007 July 16.