Proton Pump Inhibitors: The Latest News
Proton Pump Inhibitors: The Latest News
Hello. I am Dr. David Johnson. Welcome to another session of GI Common Concerns -- Computer Consult. In this series, I try to answer questions that commonly come up, and today I wanted to bring you up to date on the news about proton pump inhibitors (PPIs).
[ CLOSE WINDOW ]
(Enlarge Slide)
PPIs always seem to be in the news, so I wanted to give you a brief overview of the news that is out there and is yet to come.
We have talked in the past about the issues related to C difficile and PPIs, and there is not a whole lot of news since the last time we spoke, but recognize that this was a concern listed by the US Food and Drug Administration (FDA) in a product alert going forward. It remains to be seen how this will play out with respect to product labeling.
Concern continues about the interaction between clopidogrel and PPIs, and the FDA, as you recall, narrowed this down to omeprazole and esomeprazole.
A physiologic study done in healthy volunteers, published in the April issue of Journal of the American College of Cardiology, showed that dexlansoprazole had no significant effect on clopidogrel and was essentially equivalent to placebo. Lansoprazole had a lesser effect with respect to interference with clopidogrel compared with omeprazole, which was a study drug.
[ CLOSE WINDOW ]
(Enlarge Slide)
As you probably have seen, the language on the product labels for dexlansoprazole as well as pantoprazole has been changed, suggesting that these drugs have no significant physiologic effect on platelet function, nor do they impair clopidogrel's function of making platelets "less sticky."
We have talked before about the data on clinical outcomes -- which still have not shown any significant effects between the PPIs and clopidogrel -- but some clinicians are comforted by the FDA labeling, and this will give those who have that concern some medicolegal support for using this co-therapy in appropriate patients.
To that end, further information is now available from outcome studies. A study recently published in Circulationis a follow-up of 2 studies that have been previously published, one in the New England Journal of Medicine and the other in American Heart Journal.
[ CLOSE WINDOW ]
(Enlarge Slide)
Basically, this study included nearly 19,000 patients who were randomly assigned to receive either clopidogrel or ticagrelor (both antiplatelet agents). The data were retrospectively analyzed for concomitant exposure to PPIs. The bottom line on this study reiterates the lack of significant clinical outcomes in patients who were taking PPIs. The primary outcome was cardiovascular events, whether the patients were taking PPIs or not. Once again, the findings of this retrospective study reflected stratification bias. This study, the PLATO study, diminishes concern about clinical outcomes associated with combined therapy involving PPIs and antiplatelet agents.
There is news with respect to emerging concerns with methotrexate and PPIs.
This dates to an FDA alert issued in December 2011, following case reports describing patients who received high-dose induction methotrexate intravenously and who had very high serum levels of methotrexate, which were potentially attributed to exposure to a PPI -- in this case, omeprazole.
Another case involved a patient who was receiving intramuscular methotrexate and who had high serum levels of methotrexate and the metabolite, 7-hydroxy methotrexate. These levels were in the toxic range and led to concern that this was potentially caused by an interaction with a PPI.
In the first case, the PPI was omeprazole, and in the second, it was pantoprazole.
[ CLOSE WINDOW ]
(Enlarge Slide)
These reports led the FDA to at least issue a warning about this potential relationship, which in turn led to a label change on methotrexate that said concomitant PPIs should be used with caution and potentially withheld during the intravenous or high-dose administration of methotrexate.
This association between PPIs and oral, intravenous, or intramuscular methotrexate has not yet been evaluated at all by any physiologic study, but nonetheless, we should recognize that the FDA suggested a label change for methotrexate. So again, be aware of this in your patients you are treating with PPIs, and be cognizant of the label changes for methotrexate.
Bone density continues to be an issue with respect to PPIs. Patients ask me about this all the time. Studies continue to suggest an increased risk for fractures with long-term use of PPIs.
[ CLOSE WINDOW ]
(Enlarge Slide)
A study (that is yet to be published) by Laura Targownik and her group in Canada showed an increased risk for osteoporosis and fracture with exposure to PPIs. However, when patients were followed longitudinally for 5-10 years, the risk went away. It doesn't make sense that the longer patients are exposed to a PPI, the less likely they are to incur a fracture. The data are coming down on the side of no fracture risk.
A study will be published shortly in the British Medical Journal:an extension of the Nurses' Health Study by Khalili and colleagues, looking at fracture risk with PPIs. When I previously reported on the study by Khalili and colleagues, I suggested that no significant risk was identified. However, in this study to be published in the British Medical Journal, they are saying that there is potentially a risk. The odds ratio is around 1.3, but when they went back and stratified that risk for other mitigating factors (in particular, smoking), the increased fracture risk was only evident in the smokers. Still, they concluded that the risk for fracture was increased because they conducted a meta-analysis of 10 other studies that were fairly heterogeneous. They were not reasonable to put all of these studies together in their meta-analysis, but they put them together and concluded that there may be a long-term increased risk for osteoporosis and bone fractures with PPIs, with an odds ratio of 1.3. However, what do you think the odds ratio is for fracture risk as an independent variable for smoking? It is also about 1.3, so it seems to be overlying the PPI risk.
Khalili and colleagues adjusted for other risk factors, such as previous fractures, obesity, and benzodiazepine exposure, but I still think that the reason that these people are having hip and other bone fractures is because of smoking, and that certainly is an identifiable risk factor.
I haven't changed my practice at all. I don't make any recommendations for monitoring these patients. If patients are on PPIs, they should be monitored if they need monitoring. They should be on bone density support with vitamin D or calcium if needed, not because they are on a PPI.
I think we will see more data from the group in Canada reach the literature, and that will be the nail in the coffin. Nonetheless, this issue may produce a little bit of noise as the British Medical Journal article comes out, so be aware of that.
I wanted to conclude with some emerging data on 2 commonly used antidepressants.
One is citalopram, a drug that is basically a racemic mixture. It is metabolized through the cytochrome P450 system, the 2C19 pathway, where the PPIs are also metabolized. Certainly, these agents can compete for this pathway, just like clopidogrel and PPIs. Data suggest that if patients have a slow metabolism, they are at risk for higher drug levels, particularly with citalopram. It has been recommended that no more than 40 mg daily be prescribed. These are selective serotonin reuptake inhibitors, and when high doses are used, there have been reports of patients incurring torsade de pointe ventricular dysrhythmias. The FDA has suggested that high doses in those patients should not be used.
Now, the combination of PPIs and citalopram has raised some concern, particularly with the racemic mixture. This drug has (R) and (S) enantiomers, and the (S) (the left side) is the one involved in the antidepressant effect. The same is true for escitalopram, a drug that many of you may prescribe and that can contribute to the toxicity of QRS prolongation in torsade de pointe.
[ CLOSE WINDOW ]
(Enlarge Slide)
As you start to look at these drugs, recognize as you give PPIs that these findings occurred in healthy volunteers. The levels may go up and the areas under the curve may increase when combined with PPIs. The FDA has not requested a label change, but there has been an alert from the FDA on this back in December 2011, and there is some pressure (at least from what I am hearing) from pharmaceutical companies that this may lead to some type of change in product labeling.
In patients who are taking citalopram or escitalopram, be aware that problems with higher drug concentrations might occur in these patients and they may be more prone to ventricular dysrhythmias.
So, a lot of things out there need to be put in perspective. Hopefully, our discussion today has done that for you. The next time you get a question from one of your peers or patients, hopefully this computer consult will have served you well.
I'm Dr. David Johnson. Thanks again for listening. See you next time.
PPIs in the News
Hello. I am Dr. David Johnson. Welcome to another session of GI Common Concerns -- Computer Consult. In this series, I try to answer questions that commonly come up, and today I wanted to bring you up to date on the news about proton pump inhibitors (PPIs).
[ CLOSE WINDOW ]
(Enlarge Slide)
PPIs always seem to be in the news, so I wanted to give you a brief overview of the news that is out there and is yet to come.
PPIs and Clostridium difficile
We have talked in the past about the issues related to C difficile and PPIs, and there is not a whole lot of news since the last time we spoke, but recognize that this was a concern listed by the US Food and Drug Administration (FDA) in a product alert going forward. It remains to be seen how this will play out with respect to product labeling.
PPIs and Clopidogrel
Concern continues about the interaction between clopidogrel and PPIs, and the FDA, as you recall, narrowed this down to omeprazole and esomeprazole.
A physiologic study done in healthy volunteers, published in the April issue of Journal of the American College of Cardiology, showed that dexlansoprazole had no significant effect on clopidogrel and was essentially equivalent to placebo. Lansoprazole had a lesser effect with respect to interference with clopidogrel compared with omeprazole, which was a study drug.
[ CLOSE WINDOW ]
(Enlarge Slide)
As you probably have seen, the language on the product labels for dexlansoprazole as well as pantoprazole has been changed, suggesting that these drugs have no significant physiologic effect on platelet function, nor do they impair clopidogrel's function of making platelets "less sticky."
We have talked before about the data on clinical outcomes -- which still have not shown any significant effects between the PPIs and clopidogrel -- but some clinicians are comforted by the FDA labeling, and this will give those who have that concern some medicolegal support for using this co-therapy in appropriate patients.
To that end, further information is now available from outcome studies. A study recently published in Circulationis a follow-up of 2 studies that have been previously published, one in the New England Journal of Medicine and the other in American Heart Journal.
[ CLOSE WINDOW ]
(Enlarge Slide)
Basically, this study included nearly 19,000 patients who were randomly assigned to receive either clopidogrel or ticagrelor (both antiplatelet agents). The data were retrospectively analyzed for concomitant exposure to PPIs. The bottom line on this study reiterates the lack of significant clinical outcomes in patients who were taking PPIs. The primary outcome was cardiovascular events, whether the patients were taking PPIs or not. Once again, the findings of this retrospective study reflected stratification bias. This study, the PLATO study, diminishes concern about clinical outcomes associated with combined therapy involving PPIs and antiplatelet agents.
PPIs and Methotrexate
There is news with respect to emerging concerns with methotrexate and PPIs.
This dates to an FDA alert issued in December 2011, following case reports describing patients who received high-dose induction methotrexate intravenously and who had very high serum levels of methotrexate, which were potentially attributed to exposure to a PPI -- in this case, omeprazole.
Another case involved a patient who was receiving intramuscular methotrexate and who had high serum levels of methotrexate and the metabolite, 7-hydroxy methotrexate. These levels were in the toxic range and led to concern that this was potentially caused by an interaction with a PPI.
In the first case, the PPI was omeprazole, and in the second, it was pantoprazole.
[ CLOSE WINDOW ]
(Enlarge Slide)
These reports led the FDA to at least issue a warning about this potential relationship, which in turn led to a label change on methotrexate that said concomitant PPIs should be used with caution and potentially withheld during the intravenous or high-dose administration of methotrexate.
This association between PPIs and oral, intravenous, or intramuscular methotrexate has not yet been evaluated at all by any physiologic study, but nonetheless, we should recognize that the FDA suggested a label change for methotrexate. So again, be aware of this in your patients you are treating with PPIs, and be cognizant of the label changes for methotrexate.
PPIs and Bone Density
Bone density continues to be an issue with respect to PPIs. Patients ask me about this all the time. Studies continue to suggest an increased risk for fractures with long-term use of PPIs.
[ CLOSE WINDOW ]
(Enlarge Slide)
A study (that is yet to be published) by Laura Targownik and her group in Canada showed an increased risk for osteoporosis and fracture with exposure to PPIs. However, when patients were followed longitudinally for 5-10 years, the risk went away. It doesn't make sense that the longer patients are exposed to a PPI, the less likely they are to incur a fracture. The data are coming down on the side of no fracture risk.
A study will be published shortly in the British Medical Journal:an extension of the Nurses' Health Study by Khalili and colleagues, looking at fracture risk with PPIs. When I previously reported on the study by Khalili and colleagues, I suggested that no significant risk was identified. However, in this study to be published in the British Medical Journal, they are saying that there is potentially a risk. The odds ratio is around 1.3, but when they went back and stratified that risk for other mitigating factors (in particular, smoking), the increased fracture risk was only evident in the smokers. Still, they concluded that the risk for fracture was increased because they conducted a meta-analysis of 10 other studies that were fairly heterogeneous. They were not reasonable to put all of these studies together in their meta-analysis, but they put them together and concluded that there may be a long-term increased risk for osteoporosis and bone fractures with PPIs, with an odds ratio of 1.3. However, what do you think the odds ratio is for fracture risk as an independent variable for smoking? It is also about 1.3, so it seems to be overlying the PPI risk.
Khalili and colleagues adjusted for other risk factors, such as previous fractures, obesity, and benzodiazepine exposure, but I still think that the reason that these people are having hip and other bone fractures is because of smoking, and that certainly is an identifiable risk factor.
Implications for Practice?
I haven't changed my practice at all. I don't make any recommendations for monitoring these patients. If patients are on PPIs, they should be monitored if they need monitoring. They should be on bone density support with vitamin D or calcium if needed, not because they are on a PPI.
I think we will see more data from the group in Canada reach the literature, and that will be the nail in the coffin. Nonetheless, this issue may produce a little bit of noise as the British Medical Journal article comes out, so be aware of that.
PPIs and Antidepressants
I wanted to conclude with some emerging data on 2 commonly used antidepressants.
One is citalopram, a drug that is basically a racemic mixture. It is metabolized through the cytochrome P450 system, the 2C19 pathway, where the PPIs are also metabolized. Certainly, these agents can compete for this pathway, just like clopidogrel and PPIs. Data suggest that if patients have a slow metabolism, they are at risk for higher drug levels, particularly with citalopram. It has been recommended that no more than 40 mg daily be prescribed. These are selective serotonin reuptake inhibitors, and when high doses are used, there have been reports of patients incurring torsade de pointe ventricular dysrhythmias. The FDA has suggested that high doses in those patients should not be used.
Now, the combination of PPIs and citalopram has raised some concern, particularly with the racemic mixture. This drug has (R) and (S) enantiomers, and the (S) (the left side) is the one involved in the antidepressant effect. The same is true for escitalopram, a drug that many of you may prescribe and that can contribute to the toxicity of QRS prolongation in torsade de pointe.
[ CLOSE WINDOW ]
(Enlarge Slide)
As you start to look at these drugs, recognize as you give PPIs that these findings occurred in healthy volunteers. The levels may go up and the areas under the curve may increase when combined with PPIs. The FDA has not requested a label change, but there has been an alert from the FDA on this back in December 2011, and there is some pressure (at least from what I am hearing) from pharmaceutical companies that this may lead to some type of change in product labeling.
In patients who are taking citalopram or escitalopram, be aware that problems with higher drug concentrations might occur in these patients and they may be more prone to ventricular dysrhythmias.
Summary
So, a lot of things out there need to be put in perspective. Hopefully, our discussion today has done that for you. The next time you get a question from one of your peers or patients, hopefully this computer consult will have served you well.
I'm Dr. David Johnson. Thanks again for listening. See you next time.
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