Letters To The Editor

In Reply: We agree with Dr. Khan that the duration of ACE inhibitor therapy should never be used to rule out ACE inhibitor-associated angioedema. In an Italian study of 85 cases of angioedema with ACE inhibitor therapy, the mean ACE inhibitor exposure was a full 12 months before angioedema was diagnosed.¹ More disturbing was the fact that another 12 months elapsed before the ACE inhibitor actually was discontinued. This would indicate that neither the patient nor the physician related the angioedema to ACE inhibitor therapy. In patients with visceral angioedema, since the diagnosis is unusually challenging, even a further delay can be expected.

Angioedema has been reported with aliskiren, but the 0.04% incidence reported by White et al² may reflect very simply that physicians are more alert and on the lookout now more than they ever were when ACE inhibitors were first available. Obviously, greater awareness will lead to more frequent diagnosis. As Dr. Khan points out, there is no known mechanism by which aliskiren should cause angioedema, whereas there is fairly solid evidence that ACE inhibitor-associated angioedema is mediated by bradykinin.^3,4

In Reply: We agree with Dr. Khan that the duration of ACE inhibitor therapy should never be used to rule out ACE inhibitor-associated angioedema. In an Italian study of 85 cases of angioedema with ACE inhibitor therapy, the mean ACE inhibitor exposure was a full 12 months before angioedema was diagnosed.¹ More disturbing was the fact that another 12 months elapsed before the ACE inhibitor actually was discontinued. This would indicate that neither the patient nor the physician related the angioedema to ACE inhibitor therapy. In patients with visceral angioedema, since the diagnosis is unusually challenging, even a further delay can be expected.

Angioedema has been reported with aliskiren, but the 0.04% incidence reported by White et al² may reflect very simply that physicians are more alert and on the lookout now more than they ever were when ACE inhibitors were first available. Obviously, greater awareness will lead to more frequent diagnosis. As Dr. Khan points out, there is no known mechanism by which aliskiren should cause angioedema, whereas there is fairly solid evidence that ACE inhibitor-associated angioedema is mediated by bradykinin.^3,4

In Reply: We agree with Dr. Khan that the duration of ACE inhibitor therapy should never be used to rule out ACE inhibitor-associated angioedema. In an Italian study of 85 cases of angioedema with ACE inhibitor therapy, the mean ACE inhibitor exposure was a full 12 months before angioedema was diagnosed.¹ More disturbing was the fact that another 12 months elapsed before the ACE inhibitor actually was discontinued. This would indicate that neither the patient nor the physician related the angioedema to ACE inhibitor therapy. In patients with visceral angioedema, since the diagnosis is unusually challenging, even a further delay can be expected.

Angioedema has been reported with aliskiren, but the 0.04% incidence reported by White et al² may reflect very simply that physicians are more alert and on the lookout now more than they ever were when ACE inhibitors were first available. Obviously, greater awareness will lead to more frequent diagnosis. As Dr. Khan points out, there is no known mechanism by which aliskiren should cause angioedema, whereas there is fairly solid evidence that ACE inhibitor-associated angioedema is mediated by bradykinin.^3,4

In Reply: We know from autopsy studies that most patients with giant cell arteritis, if not all, develop aortitis at some point during the course of their disease, but we don’t know (and no study yet has completely addressed) the following questions:

• What is the most clinically appropriate and cost-effective method of screening?
• How often should we be screening these patients?

Given the high cost of the most accurate and detailed available test, ie, magnetic resonance angiography of the aorta, annual chest radiography has been recommended by some experts in the field.

Although the high frequency of thoracic aneurysm justifies high clinical vigilance, we don’t know the most adequate and cost-effective test for screening for aortic aneurysm. Until we have an answer to these questions it is difficult to formulate specific guidelines, and different experts will continue to have different practices that are based on their own experience.

At this time, I carefully listen for bruits and murmurs on physical examination and check the blood pressure in all four extremities during patient follow-up visits. If I detect any abnormalities suggesting pathology of the aorta or major branches, I order magnetic resonance angiography of the entire aorta and its main branches.

In Reply: We know from autopsy studies that most patients with giant cell arteritis, if not all, develop aortitis at some point during the course of their disease, but we don’t know (and no study yet has completely addressed) the following questions:

• What is the most clinically appropriate and cost-effective method of screening?
• How often should we be screening these patients?

Given the high cost of the most accurate and detailed available test, ie, magnetic resonance angiography of the aorta, annual chest radiography has been recommended by some experts in the field.

Although the high frequency of thoracic aneurysm justifies high clinical vigilance, we don’t know the most adequate and cost-effective test for screening for aortic aneurysm. Until we have an answer to these questions it is difficult to formulate specific guidelines, and different experts will continue to have different practices that are based on their own experience.

At this time, I carefully listen for bruits and murmurs on physical examination and check the blood pressure in all four extremities during patient follow-up visits. If I detect any abnormalities suggesting pathology of the aorta or major branches, I order magnetic resonance angiography of the entire aorta and its main branches.

In Reply: We know from autopsy studies that most patients with giant cell arteritis, if not all, develop aortitis at some point during the course of their disease, but we don’t know (and no study yet has completely addressed) the following questions:

• What is the most clinically appropriate and cost-effective method of screening?
• How often should we be screening these patients?

Given the high cost of the most accurate and detailed available test, ie, magnetic resonance angiography of the aorta, annual chest radiography has been recommended by some experts in the field.

Although the high frequency of thoracic aneurysm justifies high clinical vigilance, we don’t know the most adequate and cost-effective test for screening for aortic aneurysm. Until we have an answer to these questions it is difficult to formulate specific guidelines, and different experts will continue to have different practices that are based on their own experience.

At this time, I carefully listen for bruits and murmurs on physical examination and check the blood pressure in all four extremities during patient follow-up visits. If I detect any abnormalities suggesting pathology of the aorta or major branches, I order magnetic resonance angiography of the entire aorta and its main branches.

To the Editor: As a practicing internist, I found Dr. Alexandra Villa-Forte’s review of giant-cell arteritis (Cleve Clin J Med 2011; 78:265–270) both interesting and useful, as usual for the Cleveland Clinic Journal of Medicine. However, she did not mention the recommendation by some experts that patients who have had temporal arteritis should receive annual chest x-rays, for a decade or longer, to screen for the development of thoracic aortic aneurysm. Does she agree with this precaution? Is it advisable, in addition, to screen for abdominal aortic aneurysm by means of abdominal ultrasonography? If so, at what time intervals should this be done?

To the Editor: As a practicing internist, I found Dr. Alexandra Villa-Forte’s review of giant-cell arteritis (Cleve Clin J Med 2011; 78:265–270) both interesting and useful, as usual for the Cleveland Clinic Journal of Medicine. However, she did not mention the recommendation by some experts that patients who have had temporal arteritis should receive annual chest x-rays, for a decade or longer, to screen for the development of thoracic aortic aneurysm. Does she agree with this precaution? Is it advisable, in addition, to screen for abdominal aortic aneurysm by means of abdominal ultrasonography? If so, at what time intervals should this be done?

To the Editor: As a practicing internist, I found Dr. Alexandra Villa-Forte’s review of giant-cell arteritis (Cleve Clin J Med 2011; 78:265–270) both interesting and useful, as usual for the Cleveland Clinic Journal of Medicine. However, she did not mention the recommendation by some experts that patients who have had temporal arteritis should receive annual chest x-rays, for a decade or longer, to screen for the development of thoracic aortic aneurysm. Does she agree with this precaution? Is it advisable, in addition, to screen for abdominal aortic aneurysm by means of abdominal ultrasonography? If so, at what time intervals should this be done?

To the Editor: In their article, “Is iron therapy for anemia harmful in the setting of infection?” in the March 2011 issue, Daoud et al¹ illustrated an interesting aspect we often encounter, especially in nephrology practice. However, I believe several points should be clarified in this context.

First, “iron therapy” and “iron stores” are quite different things when we talk about infection. As Daoud et al state, human studies involving iron therapy and infection are conflicting in their results. The explanation is likely that iron therapy per se does not always translate to increased iron stores, while iron stores do correlate with increased risk of infection and death, whether in hemodialysis patients² or in the general population.³ Intravenous iron therapy mostly gains the association with risk of infection when dosed greater than a certain amount or for an extended duration. In addition, Pieracci et al⁴ showed that oral iron therapy for anemia does not boost the infection rate during critical illness when equivalent iron markers are achieved.

This mounting evidence solidifies the view that iron stores underlie the infection susceptibility. But to prove this concept, a randomized controlled study consisting of achieving similar iron stores by component therapy or intravenous iron supplementation would be the best option.

Second, I wish to add a category of infection omitted in their article, ie, fungal infection (mucormycosis). Mucormycosis, a rare but life-threatening disease, is caused by fungi of the class Zygomycetes that spread systemically in immunocompromised hosts, with a high death rate. Iron overload, whether or not accompanied by the use of deferoxamine (Desferal), is an established risk factor for mucormycosis. These fungi possess a high-affinity iron permease and produce siderophores, both of which facilitate the uptake of iron.⁵ An abundant host iron pool further enhances their scavenging process, resulting in devastating proliferation and tissue damage. This disease category should be borne in mind when dealing with immunocompromised patients undergoing iron therapy.

To the Editor: In their article, “Is iron therapy for anemia harmful in the setting of infection?” in the March 2011 issue, Daoud et al¹ illustrated an interesting aspect we often encounter, especially in nephrology practice. However, I believe several points should be clarified in this context.

First, “iron therapy” and “iron stores” are quite different things when we talk about infection. As Daoud et al state, human studies involving iron therapy and infection are conflicting in their results. The explanation is likely that iron therapy per se does not always translate to increased iron stores, while iron stores do correlate with increased risk of infection and death, whether in hemodialysis patients² or in the general population.³ Intravenous iron therapy mostly gains the association with risk of infection when dosed greater than a certain amount or for an extended duration. In addition, Pieracci et al⁴ showed that oral iron therapy for anemia does not boost the infection rate during critical illness when equivalent iron markers are achieved.

This mounting evidence solidifies the view that iron stores underlie the infection susceptibility. But to prove this concept, a randomized controlled study consisting of achieving similar iron stores by component therapy or intravenous iron supplementation would be the best option.

Second, I wish to add a category of infection omitted in their article, ie, fungal infection (mucormycosis). Mucormycosis, a rare but life-threatening disease, is caused by fungi of the class Zygomycetes that spread systemically in immunocompromised hosts, with a high death rate. Iron overload, whether or not accompanied by the use of deferoxamine (Desferal), is an established risk factor for mucormycosis. These fungi possess a high-affinity iron permease and produce siderophores, both of which facilitate the uptake of iron.⁵ An abundant host iron pool further enhances their scavenging process, resulting in devastating proliferation and tissue damage. This disease category should be borne in mind when dealing with immunocompromised patients undergoing iron therapy.

To the Editor: In their article, “Is iron therapy for anemia harmful in the setting of infection?” in the March 2011 issue, Daoud et al¹ illustrated an interesting aspect we often encounter, especially in nephrology practice. However, I believe several points should be clarified in this context.

First, “iron therapy” and “iron stores” are quite different things when we talk about infection. As Daoud et al state, human studies involving iron therapy and infection are conflicting in their results. The explanation is likely that iron therapy per se does not always translate to increased iron stores, while iron stores do correlate with increased risk of infection and death, whether in hemodialysis patients² or in the general population.³ Intravenous iron therapy mostly gains the association with risk of infection when dosed greater than a certain amount or for an extended duration. In addition, Pieracci et al⁴ showed that oral iron therapy for anemia does not boost the infection rate during critical illness when equivalent iron markers are achieved.

This mounting evidence solidifies the view that iron stores underlie the infection susceptibility. But to prove this concept, a randomized controlled study consisting of achieving similar iron stores by component therapy or intravenous iron supplementation would be the best option.

Second, I wish to add a category of infection omitted in their article, ie, fungal infection (mucormycosis). Mucormycosis, a rare but life-threatening disease, is caused by fungi of the class Zygomycetes that spread systemically in immunocompromised hosts, with a high death rate. Iron overload, whether or not accompanied by the use of deferoxamine (Desferal), is an established risk factor for mucormycosis. These fungi possess a high-affinity iron permease and produce siderophores, both of which facilitate the uptake of iron.⁵ An abundant host iron pool further enhances their scavenging process, resulting in devastating proliferation and tissue damage. This disease category should be borne in mind when dealing with immunocompromised patients undergoing iron therapy.

In Reply: We agree that iron therapy is different than iron stores, but iron therapy should be started on the basis of depleted iron stores; otherwise, it is unjustifiable. We also agree that elevated iron stores are dangerous in the setting of infection, more than iron therapy itself. This is really an unproven theory. Most studies that showed worse outcomes of iron therapy found that elevated ferritin is a risk factor.¹ The problem, as we outlined in our paper, is that most serum markers of iron are unreliable in case of inflammation or infection or in the critically ill.² Evaluation of bone marrow stores is probably the most accurate.³

In Reply: We agree that iron therapy is different than iron stores, but iron therapy should be started on the basis of depleted iron stores; otherwise, it is unjustifiable. We also agree that elevated iron stores are dangerous in the setting of infection, more than iron therapy itself. This is really an unproven theory. Most studies that showed worse outcomes of iron therapy found that elevated ferritin is a risk factor.¹ The problem, as we outlined in our paper, is that most serum markers of iron are unreliable in case of inflammation or infection or in the critically ill.² Evaluation of bone marrow stores is probably the most accurate.³

In Reply: We agree that iron therapy is different than iron stores, but iron therapy should be started on the basis of depleted iron stores; otherwise, it is unjustifiable. We also agree that elevated iron stores are dangerous in the setting of infection, more than iron therapy itself. This is really an unproven theory. Most studies that showed worse outcomes of iron therapy found that elevated ferritin is a risk factor.¹ The problem, as we outlined in our paper, is that most serum markers of iron are unreliable in case of inflammation or infection or in the critically ill.² Evaluation of bone marrow stores is probably the most accurate.³

To the Editor: I congratulate Drs. O’Grady and Chertow for their excellent review on bloodstream infections.¹ I just want to call attention to one aspect that the authors forgot. In Figure 1, they classified patients as being mildly or moderately ill if they had no hypotension or organ failure, and subdivided this group into those having or not having high-risk factors. The high-risk factors included evidence of severe sepsis, which by definition needs dysfunction or failure of one or more organs.²

As has been demonstrated by epidemiologic studies, severe sepsis is associated with a high risk of death,³ twice as high as in patients with only catheter-related bloodstream infection.⁴ So, according to the joint guidelines of the American College of Chest Physicians and the Society of Critical Care Medicine,² severe sepsis implies dysfunction or failure of at least one organ. I believe that patients with severe sepsis should be classified in the group of seriously ill.

To the Editor: I congratulate Drs. O’Grady and Chertow for their excellent review on bloodstream infections.¹ I just want to call attention to one aspect that the authors forgot. In Figure 1, they classified patients as being mildly or moderately ill if they had no hypotension or organ failure, and subdivided this group into those having or not having high-risk factors. The high-risk factors included evidence of severe sepsis, which by definition needs dysfunction or failure of one or more organs.²

As has been demonstrated by epidemiologic studies, severe sepsis is associated with a high risk of death,³ twice as high as in patients with only catheter-related bloodstream infection.⁴ So, according to the joint guidelines of the American College of Chest Physicians and the Society of Critical Care Medicine,² severe sepsis implies dysfunction or failure of at least one organ. I believe that patients with severe sepsis should be classified in the group of seriously ill.

To the Editor: I congratulate Drs. O’Grady and Chertow for their excellent review on bloodstream infections.¹ I just want to call attention to one aspect that the authors forgot. In Figure 1, they classified patients as being mildly or moderately ill if they had no hypotension or organ failure, and subdivided this group into those having or not having high-risk factors. The high-risk factors included evidence of severe sepsis, which by definition needs dysfunction or failure of one or more organs.²

As has been demonstrated by epidemiologic studies, severe sepsis is associated with a high risk of death,³ twice as high as in patients with only catheter-related bloodstream infection.⁴ So, according to the joint guidelines of the American College of Chest Physicians and the Society of Critical Care Medicine,² severe sepsis implies dysfunction or failure of at least one organ. I believe that patients with severe sepsis should be classified in the group of seriously ill.

In Reply: We thank Dr. Dias for his careful read of our article, “Managing bloodstream infections in patients who have short-term central venous catheters,” and we acknowledge that he is correct to point out that, by definition, severe sepsis is sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Given this, he is correct that patients with severe sepsis should be categorized in the “seriously ill” patient group in our Figure 1.

In effect, however, the recommendations for patients in the “high-risk-factor” group are the same as the recommendations for the “seriously ill” patient group, which are to remove the catheter, draw at least two sets of blood cultures with at least one from a peripheral vein, and start empiric antibiotic therapy.

In Reply: We thank Dr. Dias for his careful read of our article, “Managing bloodstream infections in patients who have short-term central venous catheters,” and we acknowledge that he is correct to point out that, by definition, severe sepsis is sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Given this, he is correct that patients with severe sepsis should be categorized in the “seriously ill” patient group in our Figure 1.

In effect, however, the recommendations for patients in the “high-risk-factor” group are the same as the recommendations for the “seriously ill” patient group, which are to remove the catheter, draw at least two sets of blood cultures with at least one from a peripheral vein, and start empiric antibiotic therapy.

In Reply: We thank Dr. Dias for his careful read of our article, “Managing bloodstream infections in patients who have short-term central venous catheters,” and we acknowledge that he is correct to point out that, by definition, severe sepsis is sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Given this, he is correct that patients with severe sepsis should be categorized in the “seriously ill” patient group in our Figure 1.

In effect, however, the recommendations for patients in the “high-risk-factor” group are the same as the recommendations for the “seriously ill” patient group, which are to remove the catheter, draw at least two sets of blood cultures with at least one from a peripheral vein, and start empiric antibiotic therapy.

In Reply: I thank Dr. Keller for his interest in my review on the side effects and drug interactions of proton pump inhibitors (PPIs).¹ In particular, the concern about the potentially increased risk of a cardiovascular event in patients taking a PPI while on clopidogrel is a matter of active research. Since the prevention of death, myocardial infarction, or stroke is the desired outcome in patients receiving antiplatelet therapy, any reduction in the antiplatelet effect of clopidogrel could put patients at increased risk. Because of the enormous number of patients on both PPIs and clopidogrel, investigators are studying the effect of PPIs on clopidogrel to determine the true significance in day-to-day practice. We should expect that the data will continue to evolve in the coming years as more research is done on this important interaction.

The FDA Web site that Dr. Keller brings up² was posted a few months after the submission of my manuscript. But even with the FDA’s cautionary words, it is important to realize that the risk that purportedly exists with the interaction of omeprazole and clopidogrel and the suggestion for the alternative use of pantoprazole are both based on pharmacokinetic, pharmacodynamic, and epidemiologic studies, not on clinical outcome data.

As much as we would like to rely on such studies, pharmacokinetic and pharmacodynamic studies do not address clinical outcomes, and observational studies cannot account for every confounder, because patients in these studies are not randomly assigned to the intervention, which is the rationale behind the necessity for a prospective trial. The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) study,³ a prospective randomized controlled trial with 3,761 analyzed patients, found no differences in adjudicated cardiovascular outcomes between groups who received a clopidogrel plus omeprazole vs clopidogrel alone.³ Although the COGENT study ended prematurely because of bankruptcy of the funding source, these outcomes represent the only randomized prospective data that can be found to date on PubMed. With such large numbers of patients in each group (1,876 and 1,885, respectively) and no differences in outcomes, it stands to reason that only a study with massive sample sizes would be able to detect a statistically significant difference. Differences between clopidogrel-treated patients taking and not taking omeprazole are likely be found in a well-designed prospective trial; however, it would be virtually impossible to find differences among PPIs.

To make matters even less convincing that therapy should be altered, the Working Group on High On-treatment Platelet Reactivity stated in their recent consensus paper that there are “limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes.” ⁴ Additionally, a recent multisociety Expert Consensus Document discussing the concomitant use of PPIs and thienopyridine drugs to reduce gastrointestinal complications further supports this argument.⁵ Therefore, it is difficult to justify a marked increase in cost of the PPI selected (pantoprazole costs nearly seven times more per dose than omeprazole, according to one Web site⁶) for a benefit that is supported only by theoretical and observational data, not by outcome data.

As Dr. Keller also mentions, Aggrenox can be used for secondary stroke prophylaxis, but a discussion about a therapeutic exchange between clopidogrel and other antiplatelet agents was beyond the scope of my review. A recently published joint guideline of the American Heart Association and the American Stroke Association guideline should be consulted for further information.⁷

Other gastroprotective therapies are available. However, misoprostol (as mentioned) is associated with significant gastrointestinal side effects and must be taken four times a day. H2-receptor antagonists are not considered to be as effective as PPIs.^8,9

In Reply: I thank Dr. Keller for his interest in my review on the side effects and drug interactions of proton pump inhibitors (PPIs).¹ In particular, the concern about the potentially increased risk of a cardiovascular event in patients taking a PPI while on clopidogrel is a matter of active research. Since the prevention of death, myocardial infarction, or stroke is the desired outcome in patients receiving antiplatelet therapy, any reduction in the antiplatelet effect of clopidogrel could put patients at increased risk. Because of the enormous number of patients on both PPIs and clopidogrel, investigators are studying the effect of PPIs on clopidogrel to determine the true significance in day-to-day practice. We should expect that the data will continue to evolve in the coming years as more research is done on this important interaction.

The FDA Web site that Dr. Keller brings up² was posted a few months after the submission of my manuscript. But even with the FDA’s cautionary words, it is important to realize that the risk that purportedly exists with the interaction of omeprazole and clopidogrel and the suggestion for the alternative use of pantoprazole are both based on pharmacokinetic, pharmacodynamic, and epidemiologic studies, not on clinical outcome data.

As much as we would like to rely on such studies, pharmacokinetic and pharmacodynamic studies do not address clinical outcomes, and observational studies cannot account for every confounder, because patients in these studies are not randomly assigned to the intervention, which is the rationale behind the necessity for a prospective trial. The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) study,³ a prospective randomized controlled trial with 3,761 analyzed patients, found no differences in adjudicated cardiovascular outcomes between groups who received a clopidogrel plus omeprazole vs clopidogrel alone.³ Although the COGENT study ended prematurely because of bankruptcy of the funding source, these outcomes represent the only randomized prospective data that can be found to date on PubMed. With such large numbers of patients in each group (1,876 and 1,885, respectively) and no differences in outcomes, it stands to reason that only a study with massive sample sizes would be able to detect a statistically significant difference. Differences between clopidogrel-treated patients taking and not taking omeprazole are likely be found in a well-designed prospective trial; however, it would be virtually impossible to find differences among PPIs.

To make matters even less convincing that therapy should be altered, the Working Group on High On-treatment Platelet Reactivity stated in their recent consensus paper that there are “limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes.” ⁴ Additionally, a recent multisociety Expert Consensus Document discussing the concomitant use of PPIs and thienopyridine drugs to reduce gastrointestinal complications further supports this argument.⁵ Therefore, it is difficult to justify a marked increase in cost of the PPI selected (pantoprazole costs nearly seven times more per dose than omeprazole, according to one Web site⁶) for a benefit that is supported only by theoretical and observational data, not by outcome data.

As Dr. Keller also mentions, Aggrenox can be used for secondary stroke prophylaxis, but a discussion about a therapeutic exchange between clopidogrel and other antiplatelet agents was beyond the scope of my review. A recently published joint guideline of the American Heart Association and the American Stroke Association guideline should be consulted for further information.⁷

Other gastroprotective therapies are available. However, misoprostol (as mentioned) is associated with significant gastrointestinal side effects and must be taken four times a day. H2-receptor antagonists are not considered to be as effective as PPIs.^8,9

In Reply: I thank Dr. Keller for his interest in my review on the side effects and drug interactions of proton pump inhibitors (PPIs).¹ In particular, the concern about the potentially increased risk of a cardiovascular event in patients taking a PPI while on clopidogrel is a matter of active research. Since the prevention of death, myocardial infarction, or stroke is the desired outcome in patients receiving antiplatelet therapy, any reduction in the antiplatelet effect of clopidogrel could put patients at increased risk. Because of the enormous number of patients on both PPIs and clopidogrel, investigators are studying the effect of PPIs on clopidogrel to determine the true significance in day-to-day practice. We should expect that the data will continue to evolve in the coming years as more research is done on this important interaction.

The FDA Web site that Dr. Keller brings up² was posted a few months after the submission of my manuscript. But even with the FDA’s cautionary words, it is important to realize that the risk that purportedly exists with the interaction of omeprazole and clopidogrel and the suggestion for the alternative use of pantoprazole are both based on pharmacokinetic, pharmacodynamic, and epidemiologic studies, not on clinical outcome data.

As much as we would like to rely on such studies, pharmacokinetic and pharmacodynamic studies do not address clinical outcomes, and observational studies cannot account for every confounder, because patients in these studies are not randomly assigned to the intervention, which is the rationale behind the necessity for a prospective trial. The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) study,³ a prospective randomized controlled trial with 3,761 analyzed patients, found no differences in adjudicated cardiovascular outcomes between groups who received a clopidogrel plus omeprazole vs clopidogrel alone.³ Although the COGENT study ended prematurely because of bankruptcy of the funding source, these outcomes represent the only randomized prospective data that can be found to date on PubMed. With such large numbers of patients in each group (1,876 and 1,885, respectively) and no differences in outcomes, it stands to reason that only a study with massive sample sizes would be able to detect a statistically significant difference. Differences between clopidogrel-treated patients taking and not taking omeprazole are likely be found in a well-designed prospective trial; however, it would be virtually impossible to find differences among PPIs.

To make matters even less convincing that therapy should be altered, the Working Group on High On-treatment Platelet Reactivity stated in their recent consensus paper that there are “limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes.” ⁴ Additionally, a recent multisociety Expert Consensus Document discussing the concomitant use of PPIs and thienopyridine drugs to reduce gastrointestinal complications further supports this argument.⁵ Therefore, it is difficult to justify a marked increase in cost of the PPI selected (pantoprazole costs nearly seven times more per dose than omeprazole, according to one Web site⁶) for a benefit that is supported only by theoretical and observational data, not by outcome data.

As Dr. Keller also mentions, Aggrenox can be used for secondary stroke prophylaxis, but a discussion about a therapeutic exchange between clopidogrel and other antiplatelet agents was beyond the scope of my review. A recently published joint guideline of the American Heart Association and the American Stroke Association guideline should be consulted for further information.⁷

Other gastroprotective therapies are available. However, misoprostol (as mentioned) is associated with significant gastrointestinal side effects and must be taken four times a day. H2-receptor antagonists are not considered to be as effective as PPIs.^8,9

To the Editor: Thank you for the excellent review on proton pump inhibitors (PPIs) in the January 2011 issue.¹ I would like to make the following comments about Dr. Madanick’s suggested algorithm (see Figure 2 in the article) for deciding whether to use a PPI in patients requiring clopidogrel:

A posting dated October 27, 2010, on the Web site of the US Food and Drug Administration (FDA) states the following: “With regard to the proton pump inhibitor (PPI) drug class, this recommendation [against the concomitant use of Plavix (clopidogrel) and omeprazole (Prilosec)] applies only to omeprazole and not to all PPIs. Not all PPIs have the same inhibitory effect on the enzyme [CYP2C19] that is crucial for conversion of Plavix into its active form. Pantoprazole (Protonix) may be an alternative PPI for consideration. It is a weak inhibitor of CYP2C19 and has less effect on the pharmacological activity of Plavix than omeprazole.”² Thus, when it is deemed necessary to coadminister clopidogrel with a PPI, pantoprazole appears to be the preferred PPI.

If the patient is taking clopidogrel for stroke prophylaxis, one can consider switching to Aggrenox (aspirin plus extended-release dipyridamole), which has no warnings regarding coadministration with PPIs.

Patients taking aspirin plus clopidogrel may benefit by the addition of misoprostol (Cytotec), which is indicated for reducing the risk of aspirin-induced gastric ulcers in patients at high risk of complications from gastric ulcer.

To the Editor: Thank you for the excellent review on proton pump inhibitors (PPIs) in the January 2011 issue.¹ I would like to make the following comments about Dr. Madanick’s suggested algorithm (see Figure 2 in the article) for deciding whether to use a PPI in patients requiring clopidogrel:

A posting dated October 27, 2010, on the Web site of the US Food and Drug Administration (FDA) states the following: “With regard to the proton pump inhibitor (PPI) drug class, this recommendation [against the concomitant use of Plavix (clopidogrel) and omeprazole (Prilosec)] applies only to omeprazole and not to all PPIs. Not all PPIs have the same inhibitory effect on the enzyme [CYP2C19] that is crucial for conversion of Plavix into its active form. Pantoprazole (Protonix) may be an alternative PPI for consideration. It is a weak inhibitor of CYP2C19 and has less effect on the pharmacological activity of Plavix than omeprazole.”² Thus, when it is deemed necessary to coadminister clopidogrel with a PPI, pantoprazole appears to be the preferred PPI.

If the patient is taking clopidogrel for stroke prophylaxis, one can consider switching to Aggrenox (aspirin plus extended-release dipyridamole), which has no warnings regarding coadministration with PPIs.

Patients taking aspirin plus clopidogrel may benefit by the addition of misoprostol (Cytotec), which is indicated for reducing the risk of aspirin-induced gastric ulcers in patients at high risk of complications from gastric ulcer.

To the Editor: Thank you for the excellent review on proton pump inhibitors (PPIs) in the January 2011 issue.¹ I would like to make the following comments about Dr. Madanick’s suggested algorithm (see Figure 2 in the article) for deciding whether to use a PPI in patients requiring clopidogrel:

A posting dated October 27, 2010, on the Web site of the US Food and Drug Administration (FDA) states the following: “With regard to the proton pump inhibitor (PPI) drug class, this recommendation [against the concomitant use of Plavix (clopidogrel) and omeprazole (Prilosec)] applies only to omeprazole and not to all PPIs. Not all PPIs have the same inhibitory effect on the enzyme [CYP2C19] that is crucial for conversion of Plavix into its active form. Pantoprazole (Protonix) may be an alternative PPI for consideration. It is a weak inhibitor of CYP2C19 and has less effect on the pharmacological activity of Plavix than omeprazole.”² Thus, when it is deemed necessary to coadminister clopidogrel with a PPI, pantoprazole appears to be the preferred PPI.

If the patient is taking clopidogrel for stroke prophylaxis, one can consider switching to Aggrenox (aspirin plus extended-release dipyridamole), which has no warnings regarding coadministration with PPIs.

Patients taking aspirin plus clopidogrel may benefit by the addition of misoprostol (Cytotec), which is indicated for reducing the risk of aspirin-induced gastric ulcers in patients at high risk of complications from gastric ulcer.