Letters To The Editor

In Reply: At this time, the financial incentives for acquiring NCQA medical home certification depend on your geographic location. According to a June 5th publication in Health Care Payer News,¹ 26 states have adopted policies to make payments to healthcare providers that have met medical home standards. These payments and their specific requirements vary from state to state.

Your question underscores the importance of our recommendation to partner with your local health insurance provider. By reaching out to them, you can learn about what incentive programs are in place in your area or are under development. The model that many insurance companies have used is to give higher reimbursements for practices that are medical homes or that meet certain quality insurance markers. If you align your medical home quality insurance markers with your local insurance company’s incentive plan, then your medical home work can translate into real dollars for your practice. This concept of an incentive plan for quality care is becoming more and more prevalent. Furthermore, the public (ie, patients) are also becoming more savvy about the concepts of the medical home and quality. Becoming a medical home has great marketing potential that can turn into financial benefits for a practice, as well.

In Reply: At this time, the financial incentives for acquiring NCQA medical home certification depend on your geographic location. According to a June 5th publication in Health Care Payer News,¹ 26 states have adopted policies to make payments to healthcare providers that have met medical home standards. These payments and their specific requirements vary from state to state.

Your question underscores the importance of our recommendation to partner with your local health insurance provider. By reaching out to them, you can learn about what incentive programs are in place in your area or are under development. The model that many insurance companies have used is to give higher reimbursements for practices that are medical homes or that meet certain quality insurance markers. If you align your medical home quality insurance markers with your local insurance company’s incentive plan, then your medical home work can translate into real dollars for your practice. This concept of an incentive plan for quality care is becoming more and more prevalent. Furthermore, the public (ie, patients) are also becoming more savvy about the concepts of the medical home and quality. Becoming a medical home has great marketing potential that can turn into financial benefits for a practice, as well.

In Reply: At this time, the financial incentives for acquiring NCQA medical home certification depend on your geographic location. According to a June 5th publication in Health Care Payer News,¹ 26 states have adopted policies to make payments to healthcare providers that have met medical home standards. These payments and their specific requirements vary from state to state.

Your question underscores the importance of our recommendation to partner with your local health insurance provider. By reaching out to them, you can learn about what incentive programs are in place in your area or are under development. The model that many insurance companies have used is to give higher reimbursements for practices that are medical homes or that meet certain quality insurance markers. If you align your medical home quality insurance markers with your local insurance company’s incentive plan, then your medical home work can translate into real dollars for your practice. This concept of an incentive plan for quality care is becoming more and more prevalent. Furthermore, the public (ie, patients) are also becoming more savvy about the concepts of the medical home and quality. Becoming a medical home has great marketing potential that can turn into financial benefits for a practice, as well.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

To the Editor: I have the following comments and questions regarding the excellent Medical Grand Rounds article on Parkinson disease by Dr. Fernandez in your January 2012 issue.¹

The author mentions that when “cost may be of concern, levodopa is the preferred starting drug.”¹ Generic versions of pramipexole and ropinirole are now available and have made these medications more affordable. For example, the cash price of generic ropinirole 5 mg was recently $66 for 100 tablets, comparable with generic carbidopa/levodopa (25/100 mg priced at $46 for 100 tablets.² And even though the price of generic pramipexole was $240 for 90 tablets, seniors with Medicare Part D drug coverage can usually get any generic medication for a low copay.

When choosing a dopamine agonist, how does Dr. Fernandez decide between ropinirole and pramipexole (aside from the price difference noted above)? Pramipexole has a longer elimination half-life (8 to 12 hours) compared with ropinirole (6 hours).³ Does this imply a significantly longer effective dosing interval for pramipexole? Are there other significant clinical differences between these agents?

Isradipine (DynaCirc CR), a dihydropyridine calcium channel blocker, has shown promise as a neuroprotective agent for slowing the progression of Parkinson disease in epidemiologic and laboratory studies, as noted by the author. In addition, immediate-release isradipine, with its relatively short elimination half-life of 8 hours,³ may be well suited for treating Parkinson patients whose essential hypertension is complicated by episodes of orthostatic hypotension. It should be noted that dihydropyridines that do not cross the blood-brain barrier (such as amlodipine [Norvasc]) have shown no evidence of neuroprotection.

Ibuprofen is another drug that has fairly strong epidemiologic and laboratory evidence that it might be neuroprotective,⁴ although the other nonsteroidal anti-inflammatory drugs (NSAIDs) have proven disappointing as a class.⁵ Lacking any prospective randomized trials, the evidence is not strong enough to recommend ibuprofen solely for neuroprotection. Does Dr. Fernandez, however, consider it reasonable to suggest ibuprofen to Parkinson patients who need to take an NSAID for an approved indication (such as pain)?

Dexpramipexole has recently demonstrated great promise in a phase 3 clinical trial as a neuroprotective agent in amyotrophic lateral sclerosis.⁶ How does this compound relate to pramipexole, and does the author believe it may offer neuroprotection in other neurodegenerative diseases like Parkinson disease?

The author discusses the use of catechol-O-methyltransferase (COMT) inhibitors (such as Comtan and Tasmar) and the monoamine oxidase (MAO) type-B inhibitors rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) for prolonging the effects of levodopa by slowing the breakdown of dopamine. However, it is important to note that it is contraindicated to prescribe both a COMT inhibitor and an MAO-B inhibitor, because these agents also inhibit the breakdown of other catecholamines and can lead to adrenergic crisis when taken concomitantly.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

In Reply: We agree and thank Dr. Keller for raising this valid point. The two classes of calcium channel blockers are distinct in their actions, and the warning about not combining a calcium channel blocker with a beta-blocker because of the increased risk of developing significant bradycardia applies only to the nondihydropyridine class.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

To the Editor: In their thorough review of essential tremor,¹Drs. Abboud, Ahmed, and Fernandez make a statement that needs clarification. In their list of absolute contraindications to propranolol (Inderal), the authors include “concurrent use of a calcium channel blocker.” This warning applies only to the nondihydropyridine calcium channel blockers, which are diltiazem (Cardizem) and verapamil (Calan). These two medications slow the heart rate and generally should not be combined with beta-blockers such as propranolol unless the patient requires this combination to control tachycardia. Most calcium channel blockers are dihydropyridines, which include amlodipine (Norvasc), nifedipine (Procardia), felodipine (Plendil), nisoldipine (Sular), isradipine (DynaCirc CR), and nicardipine (Cardene). These agents do not slow the heart rate significantly and therefore can be used freely in combination with propranolol. Of course, the dose of the calcium channel blocker may need to be decreased because of the antihypertensive effect of propranolol.

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

In Reply: We thank Drs. Rodríguez-Gutiérrez and Gonzálvez-Gonzálvez and Dr. Keller for their thoughtful comments.

In our paper, we did not elaborate on the low-dose cosyntropin stimulation test. The 1-μg test, in particular, has been shown to have similar or better sensitivity, with similar or lower specificity, compared with the 250-μg dose, depending on the study design. Unfortunately, the administration of the 1-μg dose presents more technical difficulty than the 250-μg dose, thus limiting its use. Cosyntropin (used in the United States) comes in a vial with 250 μg of powder. This must be reconstituted with 250 mL of normal saline, and only 1 mL is to be given. Adherence to the plastic tubing may occur, and more precise timing is needed as the cortisol levels may decrease.^1–3

Responding to Dr. Keller, we were unable to find any systematic reviews comparing inhaled corticosteroids that have a “higher therapeutic index” as a class vs older inhaled corticosteroids. There are several studies, however, comparing individual inhaled corticosteroid preparations with each other in terms of adrenal effects, and we feel that it is beyond the scope of this response to perform a systematic analysis. In addition, the determination of adrenal function used in studies comparing one inhaled corticosteroid with another were varied, including cosyntropin stimulation tests and surrogates such as the urinary cortisolcreatinine ratio, a morning plasma cortisol level less than 5 μg/L, and serum cortisol concentration curves, preventing more definitive conclusions even if the data were to be pooled.^4–6 A double-blind, randomized study comparing the adrenal effects of ciclesonide and fluticasone showed a smaller reduction in the peak serum cortisol level achieved with ciclesonide compared with fluticasone, in both low-dose and high-dose cosyntropin stimulation tests, with the results in the ciclesonide group being similar to placebo.⁷ However, the mean peak serum cortisol levels after exposure to these inhaled corticosteroids were not presented in table format, and the results have to be inferred from the figures and the narrative description of the baseline mean peak cortisol levels⁸ (ie, before exposure to these inhaled corticosteroids). Case reports have suggested that changing the inhaled corticostseroid formulation from fluticasone to ciclesonide allowed for improvement of adrenal function.⁸ The purported mechanism of decreased adrenal effects of ciclesonide is its greater deposition in the lungs and, hence, less entry into the systemic circulation and fewer systemic adverse effects.⁹

To the Editor: Drs. Lansang and Hustak¹ provide a comprehensive and useful review of steroid-induced diabetes and adrenal suppression.

In their section on local steroids, they discuss the side effects of topical and inhaled glucocorticosteroids. Much has been made of the fact that certain steroids, such as mometasone (Elocon, Nasonex) and fluticasone (Flonase), have a higher “therapeutic index” or ratio of local anti-inflammatory effect to systemic side effects, due to extensive hepatic first-pass metabolism, than older agents such as beclomethasone (Qvar) and betamethasone (Diprosone).² Ciclesonide (Alvesco, Omnaris), a newer inhaled steroid, is said to have an enhanced therapeutic index because it is a prodrug that is activated by metabolism in the lungs; it reportedly has an even less suppressive effect on hypothalamic-pituitaryadrenal axis function.³

Are the authors aware of any other evidence that clinical outcome, such as adrenal suppression or hyperglycemia, is improved by the use of steroids with a higher therapeutic index?

To the Editor: Drs. Lansang and Hustak¹ provide a comprehensive and useful review of steroid-induced diabetes and adrenal suppression.

In their section on local steroids, they discuss the side effects of topical and inhaled glucocorticosteroids. Much has been made of the fact that certain steroids, such as mometasone (Elocon, Nasonex) and fluticasone (Flonase), have a higher “therapeutic index” or ratio of local anti-inflammatory effect to systemic side effects, due to extensive hepatic first-pass metabolism, than older agents such as beclomethasone (Qvar) and betamethasone (Diprosone).² Ciclesonide (Alvesco, Omnaris), a newer inhaled steroid, is said to have an enhanced therapeutic index because it is a prodrug that is activated by metabolism in the lungs; it reportedly has an even less suppressive effect on hypothalamic-pituitaryadrenal axis function.³

Are the authors aware of any other evidence that clinical outcome, such as adrenal suppression or hyperglycemia, is improved by the use of steroids with a higher therapeutic index?

To the Editor: Drs. Lansang and Hustak¹ provide a comprehensive and useful review of steroid-induced diabetes and adrenal suppression.

In their section on local steroids, they discuss the side effects of topical and inhaled glucocorticosteroids. Much has been made of the fact that certain steroids, such as mometasone (Elocon, Nasonex) and fluticasone (Flonase), have a higher “therapeutic index” or ratio of local anti-inflammatory effect to systemic side effects, due to extensive hepatic first-pass metabolism, than older agents such as beclomethasone (Qvar) and betamethasone (Diprosone).² Ciclesonide (Alvesco, Omnaris), a newer inhaled steroid, is said to have an enhanced therapeutic index because it is a prodrug that is activated by metabolism in the lungs; it reportedly has an even less suppressive effect on hypothalamic-pituitaryadrenal axis function.³

Are the authors aware of any other evidence that clinical outcome, such as adrenal suppression or hyperglycemia, is improved by the use of steroids with a higher therapeutic index?

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: We found the article by Drs. Lansang and Kramer¹ on glucocorticoid-induced diabetes and adrenal suppression in the November 2011 issue to be a useful and clinically oriented review. However, we strongly believe there is an issue that should be addressed.

It is well accepted that the short cosyntropin (Cortrosyn) stimulation test is the best screening maneuver for assessing adrenocortical insufficiency. The authors state, however, that 250 μg is preferable to lower doses (10 μg or 1 μg), since these are not yet widely accepted, and refer to an article by Axelrod from 1976.²

Based on studies showing that 250 μg of cosyntropin is a pharmacologic rather than a physiologic stimulus that may overstimulate partially atrophied or mildly dysfunctional adrenal glands, multiple studies in the last 20 years have shown that the low-dose test has an equal or better result than the classic 250-μg dose test.³ Dorin et al,⁴ in a meta-analysis of the diagnosis of adrenocortical insufficiency that included more than 30 studies, found similar sensitivity and specificity in primary and secondary adrenal insufficiency comparing the 250-μg dose vs the low dose. In cases of mild primary adrenal failure, the low-dose test has better performance. A previous investigation in our research center contrasting 250 μg vs 10 μg proved that 10 μg had a better sensitivity than the standard dose, with excellent reproducibility and interchangeability.⁵ Similar findings have been shown by other authors contrasting 1 μg vs 250 μg of cosyntropin.⁶

We believe that the limited use of the low-dose cosyntropin test is not a matter of acceptance or performance but a consequence of the lack of vials containing lower doses of cosyntropin (1 to 10 μg), which makes this test technically challenging.^2,4 The steps needed for one-dose testing and the preservation time of the preparation are strong limitations to its wide use in clinical practice and endocrine laboratories.

To the Editor: I read with interest the review of dabigatran (Pradaxa) by Drs. Wartak and Bartholomew, which provides an excellent overview of this new oral anticoagulant.¹

This article does not mention clearly two key points about the guidelines for using dabigatran, which are different in the United States than in the other 75 countries where it has been approved.¹ First, the RE-LY trial^2,3 excluded patients with a creatinine clearance rate less than 30 mL/min/1.73 m², a common situation in the elderly. Second, in contrast to other countries, the US Food and Drug Administration (FDA) approved dabigatran for patients with a creatinine clearance rate of 15 to 30 mL/min/1.73 m², although at a lower dose.³ No dose adjustment is suggested in patients with less severe (mild or moderate) renal impairment.³ This may lead to potential misuse and problems. In fact, lethal side effects have been reported in France by Legrand et al.⁴ Furthermore, a report is in press on dabigatran-associated acute renal failure,⁵ and recently the German publication Die Zeit reported 50 deaths from bleeding in patients with atrial fibrillation treated with dabigatran.⁶

Therefore, despite suggestions that dabigatran does not require monitoring of its effects during treatment,^1,3 renal, hematologic, and hepatic variables should be monitored before and after initiation of dabigatran⁵ until more experience is gained with this new drug, and especially in the elderly and those with chronic kidney disease that is stage 4 (estimated glomerular filtration rate 15–29 mL/min/1.73 m²) or stage 5 (< 15 mL/min/1.73 m²).

To the Editor: I read with interest the review of dabigatran (Pradaxa) by Drs. Wartak and Bartholomew, which provides an excellent overview of this new oral anticoagulant.¹

This article does not mention clearly two key points about the guidelines for using dabigatran, which are different in the United States than in the other 75 countries where it has been approved.¹ First, the RE-LY trial^2,3 excluded patients with a creatinine clearance rate less than 30 mL/min/1.73 m², a common situation in the elderly. Second, in contrast to other countries, the US Food and Drug Administration (FDA) approved dabigatran for patients with a creatinine clearance rate of 15 to 30 mL/min/1.73 m², although at a lower dose.³ No dose adjustment is suggested in patients with less severe (mild or moderate) renal impairment.³ This may lead to potential misuse and problems. In fact, lethal side effects have been reported in France by Legrand et al.⁴ Furthermore, a report is in press on dabigatran-associated acute renal failure,⁵ and recently the German publication Die Zeit reported 50 deaths from bleeding in patients with atrial fibrillation treated with dabigatran.⁶

Therefore, despite suggestions that dabigatran does not require monitoring of its effects during treatment,^1,3 renal, hematologic, and hepatic variables should be monitored before and after initiation of dabigatran⁵ until more experience is gained with this new drug, and especially in the elderly and those with chronic kidney disease that is stage 4 (estimated glomerular filtration rate 15–29 mL/min/1.73 m²) or stage 5 (< 15 mL/min/1.73 m²).

To the Editor: I read with interest the review of dabigatran (Pradaxa) by Drs. Wartak and Bartholomew, which provides an excellent overview of this new oral anticoagulant.¹

This article does not mention clearly two key points about the guidelines for using dabigatran, which are different in the United States than in the other 75 countries where it has been approved.¹ First, the RE-LY trial^2,3 excluded patients with a creatinine clearance rate less than 30 mL/min/1.73 m², a common situation in the elderly. Second, in contrast to other countries, the US Food and Drug Administration (FDA) approved dabigatran for patients with a creatinine clearance rate of 15 to 30 mL/min/1.73 m², although at a lower dose.³ No dose adjustment is suggested in patients with less severe (mild or moderate) renal impairment.³ This may lead to potential misuse and problems. In fact, lethal side effects have been reported in France by Legrand et al.⁴ Furthermore, a report is in press on dabigatran-associated acute renal failure,⁵ and recently the German publication Die Zeit reported 50 deaths from bleeding in patients with atrial fibrillation treated with dabigatran.⁶

Therefore, despite suggestions that dabigatran does not require monitoring of its effects during treatment,^1,3 renal, hematologic, and hepatic variables should be monitored before and after initiation of dabigatran⁵ until more experience is gained with this new drug, and especially in the elderly and those with chronic kidney disease that is stage 4 (estimated glomerular filtration rate 15–29 mL/min/1.73 m²) or stage 5 (< 15 mL/min/1.73 m²).

In Reply: Dabigatran has gained significant popularity in the United States. From its approval in October 2010 and through August 2011, approximately 1.1 million prescriptions for it were dispensed, and 371,000 patients received it from US outpatient retail pharmacies.¹ We appreciate the letters from Drs. Pazmiño and Hirsch and believe there are reasons to be vigilant when using dabigatran.

In response to the letter from Dr. Pazmiño, we agree with his concerns and have covered them in our review. We would like to emphasize that our review was intended to help US clinicians understand this new drug and was not restricted to the RE-LY trial. The limitations of the trials of dabigatran to date (including the lack of patients with renal impairment in the RE-LY trial) have been mentioned in many articles, including ours. Please see the section TOPICS OF FUTURE INTEREST.²

The FDA did not recommend any dose adjustment for patients with moderate renal impairment (creatinine clearance 30–50 mL/min), as it was convinced that the 150-mg dose had a superior risk-benefit profile, even for patients with a higher risk of bleeding, compared with the 110-mg dose.³ It is hard for us to comment on the specific reasoning behind the FDA’s approval for using 75 mg of dabigatran in patients with creatinine clearance between 15 and 30 mL/min. However, we know this was based on pharmacokinetic and pharmacodynamic modeling and not on efficacy and safety data.³ With respect to dosing and monitoring, we did stress this point in our article, stating that the use of dabigatran obviates the need for routine laboratory monitoring. However, one may measure the drug’s activity in certain situations (suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children). Please see the section DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED? in our review.²

Dr. Pazmiño suggests renal, hematologic and hepatic variables should be monitored before and after starting dabigatran. We agree that renal function should be monitored and have covered this point. Please see the section WHO SHOULD NOT RECEIVE DABIGATRAN.² Hematologic and hepatic variables can be monitored if a clinician decides to do so, but this is not limited specifically to dabigatran. Also, to clarify, dabigatran is not approved for those with stage 5 chronic kidney disease. And we share his concern about the lack of experience with this new drug, and we included a word of caution in the section ADVANTAGES AND DISADVANTAGES OF DABIGATRAN.²

We agree with Dr. Hirsch’s concerns about recombinant factor VIIa. We are not recommending its use as a routine practice but as an available option. Our article was a global review on dabigatran, and our aim was to cover the best available evidence and treatment options in a comprehensive way. However, in response to Dr. Hirsch’s comments, the systematic review by Yank et al⁴ drew its data from 16 randomized controlled trials but excluded patients on anticoagulants (except for those in a few observational studies), and factor VIIa was compared with placebo.⁴ So these findings are not applicable to patients with dabigatran-related bleeding, and to draw any definite conclusion would not be correct. If recombinant factor VIIa has failed to show a benefit in terms of a lower mortality rate, we could also point out that there was no mortality benefit seen in reversing warfarin anticoagulation in patients with acute intracranial hemorrhage with the use of vitamin K, fresh-frozen plasma, or prothrombin complex concentrate.⁵ This should not lead one to stop using these treatments.

Clinicians are well accustomed to managing warfarin- or heparin-related bleeding using specific antidotes. It is very important to understand the mechanism of action of dabigatran, and to realize that there is no antidote. Recombinant factor VIIa is a potent hemostatic agent, and there are many published case reports and case series highlighting its efficacy in preventing bleeding.^6–12 It is used when all other options are exhausted. It is never a routine practice: it is always a last resort a clinician takes to prevent catastrophic bleeding. We believe economic concerns are very important, but it will be difficult to extrapolate a specific benchmark while treating for an individual case. At present, it seems unlikely that a randomized trial of recombinant factor VIIa will be conducted, and guidance is to be based on available animal studies and clinical anecdotes. A recent review on reversing anticoagulation therapy¹³ proposes treating major bleeding complications of direct thrombin inhibitors with activated prothrombin complex and recombinant factor VIIa.¹³

We acknowledge that serious, even fatal bleeding events have been reported with dabigatran. The FDA is evaluating postmarketing reports and is also using an active surveillance system to compare new users of dabigatran and warfarin with respect to the likelihood of their being hospitalized for bleeding.¹ With time and experience, we will learn more.

Finally, as with any new drug, the absence of data on long-term safety and efficacy is an important issue and should be considered when prescribing this new medication.

In Reply: Dabigatran has gained significant popularity in the United States. From its approval in October 2010 and through August 2011, approximately 1.1 million prescriptions for it were dispensed, and 371,000 patients received it from US outpatient retail pharmacies.¹ We appreciate the letters from Drs. Pazmiño and Hirsch and believe there are reasons to be vigilant when using dabigatran.

In response to the letter from Dr. Pazmiño, we agree with his concerns and have covered them in our review. We would like to emphasize that our review was intended to help US clinicians understand this new drug and was not restricted to the RE-LY trial. The limitations of the trials of dabigatran to date (including the lack of patients with renal impairment in the RE-LY trial) have been mentioned in many articles, including ours. Please see the section TOPICS OF FUTURE INTEREST.²

The FDA did not recommend any dose adjustment for patients with moderate renal impairment (creatinine clearance 30–50 mL/min), as it was convinced that the 150-mg dose had a superior risk-benefit profile, even for patients with a higher risk of bleeding, compared with the 110-mg dose.³ It is hard for us to comment on the specific reasoning behind the FDA’s approval for using 75 mg of dabigatran in patients with creatinine clearance between 15 and 30 mL/min. However, we know this was based on pharmacokinetic and pharmacodynamic modeling and not on efficacy and safety data.³ With respect to dosing and monitoring, we did stress this point in our article, stating that the use of dabigatran obviates the need for routine laboratory monitoring. However, one may measure the drug’s activity in certain situations (suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children). Please see the section DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED? in our review.²

Dr. Pazmiño suggests renal, hematologic and hepatic variables should be monitored before and after starting dabigatran. We agree that renal function should be monitored and have covered this point. Please see the section WHO SHOULD NOT RECEIVE DABIGATRAN.² Hematologic and hepatic variables can be monitored if a clinician decides to do so, but this is not limited specifically to dabigatran. Also, to clarify, dabigatran is not approved for those with stage 5 chronic kidney disease. And we share his concern about the lack of experience with this new drug, and we included a word of caution in the section ADVANTAGES AND DISADVANTAGES OF DABIGATRAN.²

We agree with Dr. Hirsch’s concerns about recombinant factor VIIa. We are not recommending its use as a routine practice but as an available option. Our article was a global review on dabigatran, and our aim was to cover the best available evidence and treatment options in a comprehensive way. However, in response to Dr. Hirsch’s comments, the systematic review by Yank et al⁴ drew its data from 16 randomized controlled trials but excluded patients on anticoagulants (except for those in a few observational studies), and factor VIIa was compared with placebo.⁴ So these findings are not applicable to patients with dabigatran-related bleeding, and to draw any definite conclusion would not be correct. If recombinant factor VIIa has failed to show a benefit in terms of a lower mortality rate, we could also point out that there was no mortality benefit seen in reversing warfarin anticoagulation in patients with acute intracranial hemorrhage with the use of vitamin K, fresh-frozen plasma, or prothrombin complex concentrate.⁵ This should not lead one to stop using these treatments.

Clinicians are well accustomed to managing warfarin- or heparin-related bleeding using specific antidotes. It is very important to understand the mechanism of action of dabigatran, and to realize that there is no antidote. Recombinant factor VIIa is a potent hemostatic agent, and there are many published case reports and case series highlighting its efficacy in preventing bleeding.^6–12 It is used when all other options are exhausted. It is never a routine practice: it is always a last resort a clinician takes to prevent catastrophic bleeding. We believe economic concerns are very important, but it will be difficult to extrapolate a specific benchmark while treating for an individual case. At present, it seems unlikely that a randomized trial of recombinant factor VIIa will be conducted, and guidance is to be based on available animal studies and clinical anecdotes. A recent review on reversing anticoagulation therapy¹³ proposes treating major bleeding complications of direct thrombin inhibitors with activated prothrombin complex and recombinant factor VIIa.¹³

We acknowledge that serious, even fatal bleeding events have been reported with dabigatran. The FDA is evaluating postmarketing reports and is also using an active surveillance system to compare new users of dabigatran and warfarin with respect to the likelihood of their being hospitalized for bleeding.¹ With time and experience, we will learn more.

Finally, as with any new drug, the absence of data on long-term safety and efficacy is an important issue and should be considered when prescribing this new medication.

In Reply: Dabigatran has gained significant popularity in the United States. From its approval in October 2010 and through August 2011, approximately 1.1 million prescriptions for it were dispensed, and 371,000 patients received it from US outpatient retail pharmacies.¹ We appreciate the letters from Drs. Pazmiño and Hirsch and believe there are reasons to be vigilant when using dabigatran.

In response to the letter from Dr. Pazmiño, we agree with his concerns and have covered them in our review. We would like to emphasize that our review was intended to help US clinicians understand this new drug and was not restricted to the RE-LY trial. The limitations of the trials of dabigatran to date (including the lack of patients with renal impairment in the RE-LY trial) have been mentioned in many articles, including ours. Please see the section TOPICS OF FUTURE INTEREST.²

The FDA did not recommend any dose adjustment for patients with moderate renal impairment (creatinine clearance 30–50 mL/min), as it was convinced that the 150-mg dose had a superior risk-benefit profile, even for patients with a higher risk of bleeding, compared with the 110-mg dose.³ It is hard for us to comment on the specific reasoning behind the FDA’s approval for using 75 mg of dabigatran in patients with creatinine clearance between 15 and 30 mL/min. However, we know this was based on pharmacokinetic and pharmacodynamic modeling and not on efficacy and safety data.³ With respect to dosing and monitoring, we did stress this point in our article, stating that the use of dabigatran obviates the need for routine laboratory monitoring. However, one may measure the drug’s activity in certain situations (suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children). Please see the section DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED? in our review.²

Dr. Pazmiño suggests renal, hematologic and hepatic variables should be monitored before and after starting dabigatran. We agree that renal function should be monitored and have covered this point. Please see the section WHO SHOULD NOT RECEIVE DABIGATRAN.² Hematologic and hepatic variables can be monitored if a clinician decides to do so, but this is not limited specifically to dabigatran. Also, to clarify, dabigatran is not approved for those with stage 5 chronic kidney disease. And we share his concern about the lack of experience with this new drug, and we included a word of caution in the section ADVANTAGES AND DISADVANTAGES OF DABIGATRAN.²

We agree with Dr. Hirsch’s concerns about recombinant factor VIIa. We are not recommending its use as a routine practice but as an available option. Our article was a global review on dabigatran, and our aim was to cover the best available evidence and treatment options in a comprehensive way. However, in response to Dr. Hirsch’s comments, the systematic review by Yank et al⁴ drew its data from 16 randomized controlled trials but excluded patients on anticoagulants (except for those in a few observational studies), and factor VIIa was compared with placebo.⁴ So these findings are not applicable to patients with dabigatran-related bleeding, and to draw any definite conclusion would not be correct. If recombinant factor VIIa has failed to show a benefit in terms of a lower mortality rate, we could also point out that there was no mortality benefit seen in reversing warfarin anticoagulation in patients with acute intracranial hemorrhage with the use of vitamin K, fresh-frozen plasma, or prothrombin complex concentrate.⁵ This should not lead one to stop using these treatments.

Clinicians are well accustomed to managing warfarin- or heparin-related bleeding using specific antidotes. It is very important to understand the mechanism of action of dabigatran, and to realize that there is no antidote. Recombinant factor VIIa is a potent hemostatic agent, and there are many published case reports and case series highlighting its efficacy in preventing bleeding.^6–12 It is used when all other options are exhausted. It is never a routine practice: it is always a last resort a clinician takes to prevent catastrophic bleeding. We believe economic concerns are very important, but it will be difficult to extrapolate a specific benchmark while treating for an individual case. At present, it seems unlikely that a randomized trial of recombinant factor VIIa will be conducted, and guidance is to be based on available animal studies and clinical anecdotes. A recent review on reversing anticoagulation therapy¹³ proposes treating major bleeding complications of direct thrombin inhibitors with activated prothrombin complex and recombinant factor VIIa.¹³

We acknowledge that serious, even fatal bleeding events have been reported with dabigatran. The FDA is evaluating postmarketing reports and is also using an active surveillance system to compare new users of dabigatran and warfarin with respect to the likelihood of their being hospitalized for bleeding.¹ With time and experience, we will learn more.

Finally, as with any new drug, the absence of data on long-term safety and efficacy is an important issue and should be considered when prescribing this new medication.