Letters To The Editor

To the Editor: In their excellent review of cervical cancer screening,¹Jin and colleagues discussed the current screening guidelines advocated by various medical organizations. The authors wisely advised clinicians to modify these guidelines when the lifestyle of an individual patient differs from the expected behavior of the patient’s peer group. For example, they said “it is probably reasonable to continue screening in women age 70 and older who are sexually active with multiple partners and who have a history of abnormal Pap test results.”

To this I would add that it seems reasonable to continue screening a woman over 70 who is sexually active with multiple partners, even if she still has no history of abnormal Pap test results. Similar reasoning might be applied to the statement, “women age 30 and older who had negative results on both Pap and HPV testing should be screened no more often than every 3 years.” This makes sense on a population-wide basis, since women over 30 are more likely to be married and have fewer sexual partners. But why should women who continue to have multiple sex partners into their 30s be screened any less frequently than women in their 20s?

The high negative predictive value of HPV-plus-Pap testing is based on the risk characteristics of the population being screened, as well as on the technical characteristics of the tests. Rigid adherence to screening guidelines may be a disservice to individuals whose lifestyles place them at higher risk than the norm for their age cohort.

To the Editor: In their excellent review of cervical cancer screening,¹Jin and colleagues discussed the current screening guidelines advocated by various medical organizations. The authors wisely advised clinicians to modify these guidelines when the lifestyle of an individual patient differs from the expected behavior of the patient’s peer group. For example, they said “it is probably reasonable to continue screening in women age 70 and older who are sexually active with multiple partners and who have a history of abnormal Pap test results.”

To this I would add that it seems reasonable to continue screening a woman over 70 who is sexually active with multiple partners, even if she still has no history of abnormal Pap test results. Similar reasoning might be applied to the statement, “women age 30 and older who had negative results on both Pap and HPV testing should be screened no more often than every 3 years.” This makes sense on a population-wide basis, since women over 30 are more likely to be married and have fewer sexual partners. But why should women who continue to have multiple sex partners into their 30s be screened any less frequently than women in their 20s?

The high negative predictive value of HPV-plus-Pap testing is based on the risk characteristics of the population being screened, as well as on the technical characteristics of the tests. Rigid adherence to screening guidelines may be a disservice to individuals whose lifestyles place them at higher risk than the norm for their age cohort.

To the Editor: In their excellent review of cervical cancer screening,¹Jin and colleagues discussed the current screening guidelines advocated by various medical organizations. The authors wisely advised clinicians to modify these guidelines when the lifestyle of an individual patient differs from the expected behavior of the patient’s peer group. For example, they said “it is probably reasonable to continue screening in women age 70 and older who are sexually active with multiple partners and who have a history of abnormal Pap test results.”

To this I would add that it seems reasonable to continue screening a woman over 70 who is sexually active with multiple partners, even if she still has no history of abnormal Pap test results. Similar reasoning might be applied to the statement, “women age 30 and older who had negative results on both Pap and HPV testing should be screened no more often than every 3 years.” This makes sense on a population-wide basis, since women over 30 are more likely to be married and have fewer sexual partners. But why should women who continue to have multiple sex partners into their 30s be screened any less frequently than women in their 20s?

The high negative predictive value of HPV-plus-Pap testing is based on the risk characteristics of the population being screened, as well as on the technical characteristics of the tests. Rigid adherence to screening guidelines may be a disservice to individuals whose lifestyles place them at higher risk than the norm for their age cohort.

In Reply: We thank Dr. Keller for his excellent comment. The rationale for discontinuing screening in a woman over 70 who has multiple sexual partners without a history of an abnormal Pap test is that she is at lower risk of new-onset cervical intraepithelial neoplasia (CIN) than a younger woman because of her decreased rate of metaplasia and less accessible transformation zone. In addition, postmenopausal mucosal atrophy may predispose to false-positive cytology. False-positive results are likely to be followed by additional invasive procedures, anxiety, and cost to the patient. However, she is still at risk for acquiring human papillomavirus (HPV) and CIN. Given that cervical cancer develops slowly and risk factors decrease with age, it is reasonable to stop screening at this point. Also, the recommendation of the 3-year screening interval in women over 30 with multiple sexual partners who had negative Pap and HPV tests is based on the fact that they can acquire HPV the day after screening and subsequently develop CIN, but we can detect HPV and CIN in the next round of screening (3 years later) and so will not miss the opportunity to treat cervical dysplasia.

However, practice guidelines are never meant to replace a physician’s sound clinical decision made on an individual basis.

In Reply: We thank Dr. Keller for his excellent comment. The rationale for discontinuing screening in a woman over 70 who has multiple sexual partners without a history of an abnormal Pap test is that she is at lower risk of new-onset cervical intraepithelial neoplasia (CIN) than a younger woman because of her decreased rate of metaplasia and less accessible transformation zone. In addition, postmenopausal mucosal atrophy may predispose to false-positive cytology. False-positive results are likely to be followed by additional invasive procedures, anxiety, and cost to the patient. However, she is still at risk for acquiring human papillomavirus (HPV) and CIN. Given that cervical cancer develops slowly and risk factors decrease with age, it is reasonable to stop screening at this point. Also, the recommendation of the 3-year screening interval in women over 30 with multiple sexual partners who had negative Pap and HPV tests is based on the fact that they can acquire HPV the day after screening and subsequently develop CIN, but we can detect HPV and CIN in the next round of screening (3 years later) and so will not miss the opportunity to treat cervical dysplasia.

However, practice guidelines are never meant to replace a physician’s sound clinical decision made on an individual basis.

In Reply: We thank Dr. Keller for his excellent comment. The rationale for discontinuing screening in a woman over 70 who has multiple sexual partners without a history of an abnormal Pap test is that she is at lower risk of new-onset cervical intraepithelial neoplasia (CIN) than a younger woman because of her decreased rate of metaplasia and less accessible transformation zone. In addition, postmenopausal mucosal atrophy may predispose to false-positive cytology. False-positive results are likely to be followed by additional invasive procedures, anxiety, and cost to the patient. However, she is still at risk for acquiring human papillomavirus (HPV) and CIN. Given that cervical cancer develops slowly and risk factors decrease with age, it is reasonable to stop screening at this point. Also, the recommendation of the 3-year screening interval in women over 30 with multiple sexual partners who had negative Pap and HPV tests is based on the fact that they can acquire HPV the day after screening and subsequently develop CIN, but we can detect HPV and CIN in the next round of screening (3 years later) and so will not miss the opportunity to treat cervical dysplasia.

However, practice guidelines are never meant to replace a physician’s sound clinical decision made on an individual basis.

To the Editor: In their response to a letter to the editor (December 2011), Drs. Wartak and Bartholomew suggested the use of recombinant activated factor VIIa (NovoSeven) for bleeding in patients on dabigatran. They based this recommendation on a review by Stangier and Clemens,¹ which was based on phase II and III data on the efficacy and safety of dabigatran. There have been no controlled trials or prospective data on the use of this agent for this indication, nor are there data on its use in bleeding after intracranial hemorrhage, bleeding related to cardiac surgery, or trauma-related bleeding. In a systematic review, Yank et al² found that there is no lower mortality rate and an increased risk of thromboembolism when activated factor VIIa is used off-label. This agent is approved for use only in patients with hemophilia, and in fact Novo Nordisk paid a $25 million settlement for off-label promotion of this drug for nonapproved indications.³ Recombinant factor VIIa costs up to $10,000 per vial, and if it is used off-label, that cost is not reimbursed to the hospital.

Just because we can do something does not mean that we should do it. The use of recombinant factor VIIa for dabigatran-related bleeding needs to be studied in a controlled trial before it is routinely used. As seen in the cited review, indication drift can lead to adverse patient outcomes and will certainly lead to financial peril in hospitals across the country.

To the Editor: In their response to a letter to the editor (December 2011), Drs. Wartak and Bartholomew suggested the use of recombinant activated factor VIIa (NovoSeven) for bleeding in patients on dabigatran. They based this recommendation on a review by Stangier and Clemens,¹ which was based on phase II and III data on the efficacy and safety of dabigatran. There have been no controlled trials or prospective data on the use of this agent for this indication, nor are there data on its use in bleeding after intracranial hemorrhage, bleeding related to cardiac surgery, or trauma-related bleeding. In a systematic review, Yank et al² found that there is no lower mortality rate and an increased risk of thromboembolism when activated factor VIIa is used off-label. This agent is approved for use only in patients with hemophilia, and in fact Novo Nordisk paid a $25 million settlement for off-label promotion of this drug for nonapproved indications.³ Recombinant factor VIIa costs up to $10,000 per vial, and if it is used off-label, that cost is not reimbursed to the hospital.

Just because we can do something does not mean that we should do it. The use of recombinant factor VIIa for dabigatran-related bleeding needs to be studied in a controlled trial before it is routinely used. As seen in the cited review, indication drift can lead to adverse patient outcomes and will certainly lead to financial peril in hospitals across the country.

To the Editor: In their response to a letter to the editor (December 2011), Drs. Wartak and Bartholomew suggested the use of recombinant activated factor VIIa (NovoSeven) for bleeding in patients on dabigatran. They based this recommendation on a review by Stangier and Clemens,¹ which was based on phase II and III data on the efficacy and safety of dabigatran. There have been no controlled trials or prospective data on the use of this agent for this indication, nor are there data on its use in bleeding after intracranial hemorrhage, bleeding related to cardiac surgery, or trauma-related bleeding. In a systematic review, Yank et al² found that there is no lower mortality rate and an increased risk of thromboembolism when activated factor VIIa is used off-label. This agent is approved for use only in patients with hemophilia, and in fact Novo Nordisk paid a $25 million settlement for off-label promotion of this drug for nonapproved indications.³ Recombinant factor VIIa costs up to $10,000 per vial, and if it is used off-label, that cost is not reimbursed to the hospital.

Just because we can do something does not mean that we should do it. The use of recombinant factor VIIa for dabigatran-related bleeding needs to be studied in a controlled trial before it is routinely used. As seen in the cited review, indication drift can lead to adverse patient outcomes and will certainly lead to financial peril in hospitals across the country.

To the Editor: The article “Dabigatran: Will it change clinical practice”¹ has a dangerous error. In its Key Points, it says “dabigatran is a potent, reversible direct thrombin inhibitor.” In fact, it is not reversible.²

Shamefully poor editing.

To the Editor: The article “Dabigatran: Will it change clinical practice”¹ has a dangerous error. In its Key Points, it says “dabigatran is a potent, reversible direct thrombin inhibitor.” In fact, it is not reversible.²

Shamefully poor editing.

To the Editor: The article “Dabigatran: Will it change clinical practice”¹ has a dangerous error. In its Key Points, it says “dabigatran is a potent, reversible direct thrombin inhibitor.” In fact, it is not reversible.²

Shamefully poor editing.

In Reply: This is not an error. When we¹ and others² said that dabigatran is a reversible direct thrombin inhibitor, we were referring to its effect at the molecular level, the appropriate description of its mechanism of action. However, we suspect that Dr. Smith means that there is no antidote to give in cases of bleeding or overdose. We share his concern and we discussed this in our article.

Unlike heparin, direct thrombin inhibitors act independently of antithrombin and inhibit thrombin bound to fibrin or fibrin degradation products. There are two types of direct thrombin inhibitors: bivalent (eg, hirudin) and univalent (eg, argatroban, ximelagatran, and dabigatran). The bivalent ones block thrombin at its active site and at an exosite and form an irreversible complex with it. The univalent ones interact with only the active site and reversibly inhibit thrombin, eventually dissociating from it and leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions. Therefore, in contrast to the hirudins, they produce relatively transient thrombin inhibition.^2–4

As we pointed out in our article, the lack of an antidote for dabigatran and the lack of experience in treating bleeding complications are major concerns. Fortunately, the drug has a short half-life (12–14 hours) so that the treatment is to withhold the next dose while maintaining adequate diuresis and giving transfusions as indicated. Activated charcoal, given orally to reduce absorption, is under evaluation but must be given within 1 or 2 hours after the dabigatran dose.¹ Dabigatran can be removed by dialysis (in part because it is a reversible inhibitor), a measure that may be necessary in life-threatening cases. Recombinant activated factor VII or prothrombin complex concentrates may be additional treatment options.^1,4 With time will come experience and, we hope, evidence-based guidelines.

In Reply: This is not an error. When we¹ and others² said that dabigatran is a reversible direct thrombin inhibitor, we were referring to its effect at the molecular level, the appropriate description of its mechanism of action. However, we suspect that Dr. Smith means that there is no antidote to give in cases of bleeding or overdose. We share his concern and we discussed this in our article.

Unlike heparin, direct thrombin inhibitors act independently of antithrombin and inhibit thrombin bound to fibrin or fibrin degradation products. There are two types of direct thrombin inhibitors: bivalent (eg, hirudin) and univalent (eg, argatroban, ximelagatran, and dabigatran). The bivalent ones block thrombin at its active site and at an exosite and form an irreversible complex with it. The univalent ones interact with only the active site and reversibly inhibit thrombin, eventually dissociating from it and leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions. Therefore, in contrast to the hirudins, they produce relatively transient thrombin inhibition.^2–4

As we pointed out in our article, the lack of an antidote for dabigatran and the lack of experience in treating bleeding complications are major concerns. Fortunately, the drug has a short half-life (12–14 hours) so that the treatment is to withhold the next dose while maintaining adequate diuresis and giving transfusions as indicated. Activated charcoal, given orally to reduce absorption, is under evaluation but must be given within 1 or 2 hours after the dabigatran dose.¹ Dabigatran can be removed by dialysis (in part because it is a reversible inhibitor), a measure that may be necessary in life-threatening cases. Recombinant activated factor VII or prothrombin complex concentrates may be additional treatment options.^1,4 With time will come experience and, we hope, evidence-based guidelines.

In Reply: This is not an error. When we¹ and others² said that dabigatran is a reversible direct thrombin inhibitor, we were referring to its effect at the molecular level, the appropriate description of its mechanism of action. However, we suspect that Dr. Smith means that there is no antidote to give in cases of bleeding or overdose. We share his concern and we discussed this in our article.

Unlike heparin, direct thrombin inhibitors act independently of antithrombin and inhibit thrombin bound to fibrin or fibrin degradation products. There are two types of direct thrombin inhibitors: bivalent (eg, hirudin) and univalent (eg, argatroban, ximelagatran, and dabigatran). The bivalent ones block thrombin at its active site and at an exosite and form an irreversible complex with it. The univalent ones interact with only the active site and reversibly inhibit thrombin, eventually dissociating from it and leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions. Therefore, in contrast to the hirudins, they produce relatively transient thrombin inhibition.^2–4

As we pointed out in our article, the lack of an antidote for dabigatran and the lack of experience in treating bleeding complications are major concerns. Fortunately, the drug has a short half-life (12–14 hours) so that the treatment is to withhold the next dose while maintaining adequate diuresis and giving transfusions as indicated. Activated charcoal, given orally to reduce absorption, is under evaluation but must be given within 1 or 2 hours after the dabigatran dose.¹ Dabigatran can be removed by dialysis (in part because it is a reversible inhibitor), a measure that may be necessary in life-threatening cases. Recombinant activated factor VII or prothrombin complex concentrates may be additional treatment options.^1,4 With time will come experience and, we hope, evidence-based guidelines.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

To the Editor: I read with interest the article by Drs. Callahan and Baranowski¹ in your April 2011 issue about managing newly diagnosed atrial fibrillation. I believe several issues merit further discussion.

First of all, as mentioned in the article, pulmonary vein isolation, or radiofrequency catheter ablation of the left atrium, can cure paroxysmal atrial fibrillation. Callahan and Baranowski described the optimal indication for this procedure, but they failed to mention the potential adverse effects, that is, esophageal ulcer and atrio-esophageal fistula.² Owing to the proximity of the esophagus and the accompanying vagus nerve to the posterior wall of the left atrium, it is estimated that 47% of patients develop thermal mucosal injury and 18% develop esophageal ulcer after ablation, while 0.5% develop atrio-esophageal fistula.³ Gastric hypomotility and pyloric spasm are reported as well. It would therefore be prudent to inform patients of such risks if a persistently symptomatic young patient demands this procedure, since the damage might be long-lasting.

In addition, in deciding on long-term anticoagulation for patients with atrial fibrillation, the CHADS₂ score is often utilized (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack). Although it is validated and widely applicable, the CHADS₂ score carries the disadvantages of oversimplification and of overclassifying atrial fibrillation patients into the intermediate-risk category.⁴ Lip et al,⁵ in a seminal article surveying a large group of patients who had nonvalvular atrial fibrillation, proposed using a new and also simple risk stratification scheme, the 2009 Birmingham scheme. This scheme uses the acronym CHA₂DS₂-VASc and differs from the CHADS₂ score in that patients age 75 or older get 2 points, those age 65 to 74 get 1 point, those with vascular disease get 1 point, and women get 1 point. They show that this new scheme fares marginally better than the original CHADS₂ score, with fewer patients wrongly assigned to the intermediate-risk category. That means a lower percentage of patients will receive unnecessary anticoagulation and suffer from unneeded anguish. Subsequent studies also prove that this newer scoring index possesses higher sensitivity and predicts thromboembolic events more accurately than the CHADS₂ score. Thus, I believe this should also be factored into the decision process when initiating warfarin in atrial fibrillation patients, especially in light of the fact that scanty evidence exists for the use of newer anticoagulants based on the CHADS₂ score.

To the Editor: I read with interest the article by Drs. Callahan and Baranowski¹ in your April 2011 issue about managing newly diagnosed atrial fibrillation. I believe several issues merit further discussion.

First of all, as mentioned in the article, pulmonary vein isolation, or radiofrequency catheter ablation of the left atrium, can cure paroxysmal atrial fibrillation. Callahan and Baranowski described the optimal indication for this procedure, but they failed to mention the potential adverse effects, that is, esophageal ulcer and atrio-esophageal fistula.² Owing to the proximity of the esophagus and the accompanying vagus nerve to the posterior wall of the left atrium, it is estimated that 47% of patients develop thermal mucosal injury and 18% develop esophageal ulcer after ablation, while 0.5% develop atrio-esophageal fistula.³ Gastric hypomotility and pyloric spasm are reported as well. It would therefore be prudent to inform patients of such risks if a persistently symptomatic young patient demands this procedure, since the damage might be long-lasting.

In addition, in deciding on long-term anticoagulation for patients with atrial fibrillation, the CHADS₂ score is often utilized (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack). Although it is validated and widely applicable, the CHADS₂ score carries the disadvantages of oversimplification and of overclassifying atrial fibrillation patients into the intermediate-risk category.⁴ Lip et al,⁵ in a seminal article surveying a large group of patients who had nonvalvular atrial fibrillation, proposed using a new and also simple risk stratification scheme, the 2009 Birmingham scheme. This scheme uses the acronym CHA₂DS₂-VASc and differs from the CHADS₂ score in that patients age 75 or older get 2 points, those age 65 to 74 get 1 point, those with vascular disease get 1 point, and women get 1 point. They show that this new scheme fares marginally better than the original CHADS₂ score, with fewer patients wrongly assigned to the intermediate-risk category. That means a lower percentage of patients will receive unnecessary anticoagulation and suffer from unneeded anguish. Subsequent studies also prove that this newer scoring index possesses higher sensitivity and predicts thromboembolic events more accurately than the CHADS₂ score. Thus, I believe this should also be factored into the decision process when initiating warfarin in atrial fibrillation patients, especially in light of the fact that scanty evidence exists for the use of newer anticoagulants based on the CHADS₂ score.

To the Editor: I read with interest the article by Drs. Callahan and Baranowski¹ in your April 2011 issue about managing newly diagnosed atrial fibrillation. I believe several issues merit further discussion.

First of all, as mentioned in the article, pulmonary vein isolation, or radiofrequency catheter ablation of the left atrium, can cure paroxysmal atrial fibrillation. Callahan and Baranowski described the optimal indication for this procedure, but they failed to mention the potential adverse effects, that is, esophageal ulcer and atrio-esophageal fistula.² Owing to the proximity of the esophagus and the accompanying vagus nerve to the posterior wall of the left atrium, it is estimated that 47% of patients develop thermal mucosal injury and 18% develop esophageal ulcer after ablation, while 0.5% develop atrio-esophageal fistula.³ Gastric hypomotility and pyloric spasm are reported as well. It would therefore be prudent to inform patients of such risks if a persistently symptomatic young patient demands this procedure, since the damage might be long-lasting.

In addition, in deciding on long-term anticoagulation for patients with atrial fibrillation, the CHADS₂ score is often utilized (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack). Although it is validated and widely applicable, the CHADS₂ score carries the disadvantages of oversimplification and of overclassifying atrial fibrillation patients into the intermediate-risk category.⁴ Lip et al,⁵ in a seminal article surveying a large group of patients who had nonvalvular atrial fibrillation, proposed using a new and also simple risk stratification scheme, the 2009 Birmingham scheme. This scheme uses the acronym CHA₂DS₂-VASc and differs from the CHADS₂ score in that patients age 75 or older get 2 points, those age 65 to 74 get 1 point, those with vascular disease get 1 point, and women get 1 point. They show that this new scheme fares marginally better than the original CHADS₂ score, with fewer patients wrongly assigned to the intermediate-risk category. That means a lower percentage of patients will receive unnecessary anticoagulation and suffer from unneeded anguish. Subsequent studies also prove that this newer scoring index possesses higher sensitivity and predicts thromboembolic events more accurately than the CHADS₂ score. Thus, I believe this should also be factored into the decision process when initiating warfarin in atrial fibrillation patients, especially in light of the fact that scanty evidence exists for the use of newer anticoagulants based on the CHADS₂ score.

In Reply: Dr. Chao raises several important points regarding our manuscript on the management of newly diagnosed atrial fibrillation.¹

Dr. Chao mentions some of the complications of pulmonary vein antrum isolation. A review of catheter ablation for atrial fibrillation was outside the scope of our manuscript, so the details of the procedure and potential complications were not covered. Dr. Chao does mention some of the important potential complications. However, the complication rates he cites are not generally supported by the available medical literature. Thermal mucosal injury of the esophagus was reported at rates as low as 4% in the same studies cited by Dr. Chao in patients undergoing pulmonary vein antrum isolation with conscious sedation. The rate of 47% was seen in patients undergoing the procedure with general anesthesia. The rate of atrio-esophageal fistula is not well known. As of 2010, about 49 cases were reported in the literature.² Rates have been described ranging from 0.01% to 0.2%,^3–9 far lower than the rate mentioned by Dr. Chao. A careful review with the patient of the risks, benefits, and alternatives is standard practice before any elective, invasive procedure.

Multiple anticoagulation schemes have been proposed, including the Birmingham 2009 scheme.¹⁰ We included the CHADS₂ score in our paper because it is widely accepted and well validated. The Birmingham 2009 scheme acknowledges other potential risk factors such as female sex, history of vascular disease, and age between 65 and 75 years. It will be interesting to see if it will ever supplant the CHADS₂ score. However, no risk stratification scheme should replace sound clinical judgment. Individual patient factors must be considered when deciding whether anticoagulation is appropriate for an individual patient.

In Reply: Dr. Chao raises several important points regarding our manuscript on the management of newly diagnosed atrial fibrillation.¹

Dr. Chao mentions some of the complications of pulmonary vein antrum isolation. A review of catheter ablation for atrial fibrillation was outside the scope of our manuscript, so the details of the procedure and potential complications were not covered. Dr. Chao does mention some of the important potential complications. However, the complication rates he cites are not generally supported by the available medical literature. Thermal mucosal injury of the esophagus was reported at rates as low as 4% in the same studies cited by Dr. Chao in patients undergoing pulmonary vein antrum isolation with conscious sedation. The rate of 47% was seen in patients undergoing the procedure with general anesthesia. The rate of atrio-esophageal fistula is not well known. As of 2010, about 49 cases were reported in the literature.² Rates have been described ranging from 0.01% to 0.2%,^3–9 far lower than the rate mentioned by Dr. Chao. A careful review with the patient of the risks, benefits, and alternatives is standard practice before any elective, invasive procedure.

Multiple anticoagulation schemes have been proposed, including the Birmingham 2009 scheme.¹⁰ We included the CHADS₂ score in our paper because it is widely accepted and well validated. The Birmingham 2009 scheme acknowledges other potential risk factors such as female sex, history of vascular disease, and age between 65 and 75 years. It will be interesting to see if it will ever supplant the CHADS₂ score. However, no risk stratification scheme should replace sound clinical judgment. Individual patient factors must be considered when deciding whether anticoagulation is appropriate for an individual patient.

In Reply: Dr. Chao raises several important points regarding our manuscript on the management of newly diagnosed atrial fibrillation.¹

Dr. Chao mentions some of the complications of pulmonary vein antrum isolation. A review of catheter ablation for atrial fibrillation was outside the scope of our manuscript, so the details of the procedure and potential complications were not covered. Dr. Chao does mention some of the important potential complications. However, the complication rates he cites are not generally supported by the available medical literature. Thermal mucosal injury of the esophagus was reported at rates as low as 4% in the same studies cited by Dr. Chao in patients undergoing pulmonary vein antrum isolation with conscious sedation. The rate of 47% was seen in patients undergoing the procedure with general anesthesia. The rate of atrio-esophageal fistula is not well known. As of 2010, about 49 cases were reported in the literature.² Rates have been described ranging from 0.01% to 0.2%,^3–9 far lower than the rate mentioned by Dr. Chao. A careful review with the patient of the risks, benefits, and alternatives is standard practice before any elective, invasive procedure.

Multiple anticoagulation schemes have been proposed, including the Birmingham 2009 scheme.¹⁰ We included the CHADS₂ score in our paper because it is widely accepted and well validated. The Birmingham 2009 scheme acknowledges other potential risk factors such as female sex, history of vascular disease, and age between 65 and 75 years. It will be interesting to see if it will ever supplant the CHADS₂ score. However, no risk stratification scheme should replace sound clinical judgment. Individual patient factors must be considered when deciding whether anticoagulation is appropriate for an individual patient.

To the Editor: The interesting report by Korniyenko and colleagues of the delayed diagnosis of visceral angioedema due to angiotensin-converting enzyme (ACE) inhibitor therapy¹ should alert readers that a long duration of use of ACE inhibitors should not rule out the diagnosis of ACE inhibitor-induced angioedema, as symptoms can be delayed for up to a decade.

Risk factors for angioedema for patients on ACE inhibitor therapy that have been identified so far include black race, the XPNPEP2 C-2399A polymorphism in men (which leads to decreased aminopeptidase P activity),² and concomitant use of the mTOR inhibitors sirolimus (Rapamune) or everolimus (Afinitor) in renal transplant recipients.³ All of these factors further decrease metabolism of the vasoactive peptide bradykinin. However, the effect of cofactors such as use of nonsteroidal anti-inflammatory drugs, aspirin, simvastatin, estrogen, or a tendency for angioedema (such as in patients with recurrent or episodic idiopathic angioedema) on lowering the threshold for angioedema or increasing the severity of the angioedema episode or episodes after starting ACE inhibitor therapy remains unknown.

Physicians should also be aware of angioedema as a significant side effect of the new renin inhibitor aliskiren (marketed by Novartis Pharmaceuticals as Rasilez in the United Kingdom and as Tekturna in the United States) for treatment of essential hypertension.⁴ A pooled analysis of 31 studies in 12,188 patients showed the incidence of angioedema associated with aliskiren monotherapy to be 0.4%, similar to that with ACE inhibitors: relative risk 0.31, 95% confidence interval 0.07–1.47 for 150 mg; relative risk 0.57, 95% confidence interval 0.17–1.89 for 300 mg).⁵ However, no patients were hospitalized with a serious angioedema event.

Although the mechanism of action of aliskiren via renin inhibition would suggest that bradykinin may not be the causative agent of angioedema, physicians should ensure that patients who report significant angioedema episodes or those who present with angioedema have their medication history thoroughly reviewed to prevent a serious untoward event.

To the Editor: The interesting report by Korniyenko and colleagues of the delayed diagnosis of visceral angioedema due to angiotensin-converting enzyme (ACE) inhibitor therapy¹ should alert readers that a long duration of use of ACE inhibitors should not rule out the diagnosis of ACE inhibitor-induced angioedema, as symptoms can be delayed for up to a decade.

Risk factors for angioedema for patients on ACE inhibitor therapy that have been identified so far include black race, the XPNPEP2 C-2399A polymorphism in men (which leads to decreased aminopeptidase P activity),² and concomitant use of the mTOR inhibitors sirolimus (Rapamune) or everolimus (Afinitor) in renal transplant recipients.³ All of these factors further decrease metabolism of the vasoactive peptide bradykinin. However, the effect of cofactors such as use of nonsteroidal anti-inflammatory drugs, aspirin, simvastatin, estrogen, or a tendency for angioedema (such as in patients with recurrent or episodic idiopathic angioedema) on lowering the threshold for angioedema or increasing the severity of the angioedema episode or episodes after starting ACE inhibitor therapy remains unknown.

Physicians should also be aware of angioedema as a significant side effect of the new renin inhibitor aliskiren (marketed by Novartis Pharmaceuticals as Rasilez in the United Kingdom and as Tekturna in the United States) for treatment of essential hypertension.⁴ A pooled analysis of 31 studies in 12,188 patients showed the incidence of angioedema associated with aliskiren monotherapy to be 0.4%, similar to that with ACE inhibitors: relative risk 0.31, 95% confidence interval 0.07–1.47 for 150 mg; relative risk 0.57, 95% confidence interval 0.17–1.89 for 300 mg).⁵ However, no patients were hospitalized with a serious angioedema event.

Although the mechanism of action of aliskiren via renin inhibition would suggest that bradykinin may not be the causative agent of angioedema, physicians should ensure that patients who report significant angioedema episodes or those who present with angioedema have their medication history thoroughly reviewed to prevent a serious untoward event.

To the Editor: The interesting report by Korniyenko and colleagues of the delayed diagnosis of visceral angioedema due to angiotensin-converting enzyme (ACE) inhibitor therapy¹ should alert readers that a long duration of use of ACE inhibitors should not rule out the diagnosis of ACE inhibitor-induced angioedema, as symptoms can be delayed for up to a decade.

Risk factors for angioedema for patients on ACE inhibitor therapy that have been identified so far include black race, the XPNPEP2 C-2399A polymorphism in men (which leads to decreased aminopeptidase P activity),² and concomitant use of the mTOR inhibitors sirolimus (Rapamune) or everolimus (Afinitor) in renal transplant recipients.³ All of these factors further decrease metabolism of the vasoactive peptide bradykinin. However, the effect of cofactors such as use of nonsteroidal anti-inflammatory drugs, aspirin, simvastatin, estrogen, or a tendency for angioedema (such as in patients with recurrent or episodic idiopathic angioedema) on lowering the threshold for angioedema or increasing the severity of the angioedema episode or episodes after starting ACE inhibitor therapy remains unknown.

Physicians should also be aware of angioedema as a significant side effect of the new renin inhibitor aliskiren (marketed by Novartis Pharmaceuticals as Rasilez in the United Kingdom and as Tekturna in the United States) for treatment of essential hypertension.⁴ A pooled analysis of 31 studies in 12,188 patients showed the incidence of angioedema associated with aliskiren monotherapy to be 0.4%, similar to that with ACE inhibitors: relative risk 0.31, 95% confidence interval 0.07–1.47 for 150 mg; relative risk 0.57, 95% confidence interval 0.17–1.89 for 300 mg).⁵ However, no patients were hospitalized with a serious angioedema event.

Although the mechanism of action of aliskiren via renin inhibition would suggest that bradykinin may not be the causative agent of angioedema, physicians should ensure that patients who report significant angioedema episodes or those who present with angioedema have their medication history thoroughly reviewed to prevent a serious untoward event.