Letters To The Editor

In Reply: We thank Dr. Hamilton for his interest in our article and for providing more recent literature than was available at the time we submitted our manuscript.

There are multiple points of view toward allergy testing. But the bottom line, as emphasized by Dr. Hamilton and in our article, is that serum IgE testing should not be used as the sole diagnostic tool because it is an indicator of sensitization, not disease, and that clinical history should always be used in conjunction to ensure proper diagnosis.

It is our experience that some clinicians indiscriminately order large panels of serum IgE tests. As Dr. Hamilton indicates, patients can have positive serum IgE results but not display allergy symptoms, which can lead to unnecessary food avoidance. In addition, false-negative results from injudiciously ordered tests (ie, not based on pretest probability) can lead to missed diagnoses. All of these points should be kept in mind in delivering good clinical care, and as such, Choosing Wisely has highlighted the importance of using this test appropriately.

In response to the origin of the sensitivities and specificities used to calculate the sum, the values were curated from available literature and thus limited the number of allergens that could be profiled. A cutoff of 0.35 kU/L was used because this was the cutoff used by the references. 

In Reply: We thank Dr. Hamilton for his interest in our article and for providing more recent literature than was available at the time we submitted our manuscript.

There are multiple points of view toward allergy testing. But the bottom line, as emphasized by Dr. Hamilton and in our article, is that serum IgE testing should not be used as the sole diagnostic tool because it is an indicator of sensitization, not disease, and that clinical history should always be used in conjunction to ensure proper diagnosis.

It is our experience that some clinicians indiscriminately order large panels of serum IgE tests. As Dr. Hamilton indicates, patients can have positive serum IgE results but not display allergy symptoms, which can lead to unnecessary food avoidance. In addition, false-negative results from injudiciously ordered tests (ie, not based on pretest probability) can lead to missed diagnoses. All of these points should be kept in mind in delivering good clinical care, and as such, Choosing Wisely has highlighted the importance of using this test appropriately.

In response to the origin of the sensitivities and specificities used to calculate the sum, the values were curated from available literature and thus limited the number of allergens that could be profiled. A cutoff of 0.35 kU/L was used because this was the cutoff used by the references. 

In Reply: We thank Dr. Hamilton for his interest in our article and for providing more recent literature than was available at the time we submitted our manuscript.

There are multiple points of view toward allergy testing. But the bottom line, as emphasized by Dr. Hamilton and in our article, is that serum IgE testing should not be used as the sole diagnostic tool because it is an indicator of sensitization, not disease, and that clinical history should always be used in conjunction to ensure proper diagnosis.

It is our experience that some clinicians indiscriminately order large panels of serum IgE tests. As Dr. Hamilton indicates, patients can have positive serum IgE results but not display allergy symptoms, which can lead to unnecessary food avoidance. In addition, false-negative results from injudiciously ordered tests (ie, not based on pretest probability) can lead to missed diagnoses. All of these points should be kept in mind in delivering good clinical care, and as such, Choosing Wisely has highlighted the importance of using this test appropriately.

In response to the origin of the sensitivities and specificities used to calculate the sum, the values were curated from available literature and thus limited the number of allergens that could be profiled. A cutoff of 0.35 kU/L was used because this was the cutoff used by the references. 

To the Editor: Two considerations concerning the interpretation of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial are not addressed in the article by Sabe et al regarding a new class of drugs for systolic heart failure.¹ First of all, the PARADIGM-HF trial compared the maximal dose of sacubitril with a less-than-maximal dose of enalapril. Secondly, sacubitril lowered blood pressure more than enalapril.

The angiotensin receptor blocker dose in sacubitril 200 mg is equivalent to valsartan 160 mg.² Accordingly, the angiotensin receptor blocker in sacubitril 200 mg twice daily is equivalent to the maximal dosage of valsartan approved by the US Food and Drug Administration. The dosage of enalapril in the PARADIGM-HF trial was 10 mg twice daily. While the target enalapril dosage for heart failure is 10 to 20 mg twice daily,³ the dosage of enalapril in PARADIGM-HF was half the maximal approved dosage.

In the PARADIGM-HF trial, sacubitril 200 mg twice daily reduced the incidence of cardiovascular death by 19% compared with enalapril 10 mg twice daily (the rates were 16.5% vs 13.3%, respectively).² That sacubitril lowered mean systolic blood pressure 3.2 ± 0.4 mm Hg more than enalapril^2,4 may account for much of this benefit.

A 2002 study by Lewington et al⁵ found that a 2-mm Hg decrease in systolic blood pressure reduces the risk of cardiovascular death by 7% in middle-aged adults. Granted, this study did not involve heart failure patients, but if its results are remotely applicable, a 3.2-mm Hg reduction in systolic blood pressure might be expected to reduce the rate of cardiovascular deaths by 10% to 11%.

Would sacubitril be superior to enalapril if the maximal dose of enalapril were compared to the maximal dose of sacubitril? Would sacubitril be superior to enalapril if blood pressure were lowered comparably between the two groups? These are relevant questions that the PARADIGM-HF trial fails to answer.

To the Editor: Two considerations concerning the interpretation of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial are not addressed in the article by Sabe et al regarding a new class of drugs for systolic heart failure.¹ First of all, the PARADIGM-HF trial compared the maximal dose of sacubitril with a less-than-maximal dose of enalapril. Secondly, sacubitril lowered blood pressure more than enalapril.

The angiotensin receptor blocker dose in sacubitril 200 mg is equivalent to valsartan 160 mg.² Accordingly, the angiotensin receptor blocker in sacubitril 200 mg twice daily is equivalent to the maximal dosage of valsartan approved by the US Food and Drug Administration. The dosage of enalapril in the PARADIGM-HF trial was 10 mg twice daily. While the target enalapril dosage for heart failure is 10 to 20 mg twice daily,³ the dosage of enalapril in PARADIGM-HF was half the maximal approved dosage.

In the PARADIGM-HF trial, sacubitril 200 mg twice daily reduced the incidence of cardiovascular death by 19% compared with enalapril 10 mg twice daily (the rates were 16.5% vs 13.3%, respectively).² That sacubitril lowered mean systolic blood pressure 3.2 ± 0.4 mm Hg more than enalapril^2,4 may account for much of this benefit.

A 2002 study by Lewington et al⁵ found that a 2-mm Hg decrease in systolic blood pressure reduces the risk of cardiovascular death by 7% in middle-aged adults. Granted, this study did not involve heart failure patients, but if its results are remotely applicable, a 3.2-mm Hg reduction in systolic blood pressure might be expected to reduce the rate of cardiovascular deaths by 10% to 11%.

Would sacubitril be superior to enalapril if the maximal dose of enalapril were compared to the maximal dose of sacubitril? Would sacubitril be superior to enalapril if blood pressure were lowered comparably between the two groups? These are relevant questions that the PARADIGM-HF trial fails to answer.

To the Editor: Two considerations concerning the interpretation of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial are not addressed in the article by Sabe et al regarding a new class of drugs for systolic heart failure.¹ First of all, the PARADIGM-HF trial compared the maximal dose of sacubitril with a less-than-maximal dose of enalapril. Secondly, sacubitril lowered blood pressure more than enalapril.

The angiotensin receptor blocker dose in sacubitril 200 mg is equivalent to valsartan 160 mg.² Accordingly, the angiotensin receptor blocker in sacubitril 200 mg twice daily is equivalent to the maximal dosage of valsartan approved by the US Food and Drug Administration. The dosage of enalapril in the PARADIGM-HF trial was 10 mg twice daily. While the target enalapril dosage for heart failure is 10 to 20 mg twice daily,³ the dosage of enalapril in PARADIGM-HF was half the maximal approved dosage.

In the PARADIGM-HF trial, sacubitril 200 mg twice daily reduced the incidence of cardiovascular death by 19% compared with enalapril 10 mg twice daily (the rates were 16.5% vs 13.3%, respectively).² That sacubitril lowered mean systolic blood pressure 3.2 ± 0.4 mm Hg more than enalapril^2,4 may account for much of this benefit.

A 2002 study by Lewington et al⁵ found that a 2-mm Hg decrease in systolic blood pressure reduces the risk of cardiovascular death by 7% in middle-aged adults. Granted, this study did not involve heart failure patients, but if its results are remotely applicable, a 3.2-mm Hg reduction in systolic blood pressure might be expected to reduce the rate of cardiovascular deaths by 10% to 11%.

Would sacubitril be superior to enalapril if the maximal dose of enalapril were compared to the maximal dose of sacubitril? Would sacubitril be superior to enalapril if blood pressure were lowered comparably between the two groups? These are relevant questions that the PARADIGM-HF trial fails to answer.

In Reply: We thank Dr. Blankfield for raising these two important points. Although the findings of the PARADIGM-HF study are compelling, the design and results of this trial have incited many questions.

To address his first point, about the differential dosages of the two drugs, we agree, and we did mention in our review that one concern about the results of PARADIGM-HF is the unequal dosages of valsartan and enalapril in the two different arms. We mentioned that this dosage of enalapril was chosen based on its survival benefit in previous trials. However, this still raises the question of whether the benefit seen in the sacubitril-valsartan group was due to greater inhibition of the renin-angiotensin-aldosterone system rather than to the new drug.

To address his second point, the decrease in blood pressure in the sacubitril-valsartan arm was significant, and the patients taking this drug were more likely to have symptomatic hypotension, which may contribute to patient intolerance and difficulty initiating treatment with this drug. Dr. Blankfield brings up an interesting point regarding reduction of blood pressure driving the decrease of events in the sacubitril-valsartan group. In the original trial results section, the authors mentioned that when the difference in blood pressure between the two groups was examined as a time-dependent covariate, it was not a significant predictor of the benefit of sacubitril-valsartan.¹

Furthermore, although higher blood pressure is associated with worse cardiovascular outcomes in the general population, higher blood pressure has been shown to be protective in heart failure patients.² Several studies have shown that the relationship between blood pressure and the mortality rate in patients with heart failure is paradoxical and complex.^2–4 Lee et al³ found that this relationship was U-shaped, with increased mortality risk in those with high and low blood pressures (< 120 mm Hg). Ather et al⁴ also showed that the relationship was U-shaped in patients with a mild to moderate reduction in left ventricular ejection fraction, but linear in those with severely reduced ejection fraction. This study also found that a decrease in systolic blood pressure below 110 mm Hg was associated with increased mortality risk.

The findings of PARADIGM-HF have sparked much conversation and implementation of practice change in the treatment of heart failure patients, and we await additional data on the use and limitations of sacubitril-valsartan in this group of patients.

In Reply: We thank Dr. Blankfield for raising these two important points. Although the findings of the PARADIGM-HF study are compelling, the design and results of this trial have incited many questions.

To address his first point, about the differential dosages of the two drugs, we agree, and we did mention in our review that one concern about the results of PARADIGM-HF is the unequal dosages of valsartan and enalapril in the two different arms. We mentioned that this dosage of enalapril was chosen based on its survival benefit in previous trials. However, this still raises the question of whether the benefit seen in the sacubitril-valsartan group was due to greater inhibition of the renin-angiotensin-aldosterone system rather than to the new drug.

To address his second point, the decrease in blood pressure in the sacubitril-valsartan arm was significant, and the patients taking this drug were more likely to have symptomatic hypotension, which may contribute to patient intolerance and difficulty initiating treatment with this drug. Dr. Blankfield brings up an interesting point regarding reduction of blood pressure driving the decrease of events in the sacubitril-valsartan group. In the original trial results section, the authors mentioned that when the difference in blood pressure between the two groups was examined as a time-dependent covariate, it was not a significant predictor of the benefit of sacubitril-valsartan.¹

Furthermore, although higher blood pressure is associated with worse cardiovascular outcomes in the general population, higher blood pressure has been shown to be protective in heart failure patients.² Several studies have shown that the relationship between blood pressure and the mortality rate in patients with heart failure is paradoxical and complex.^2–4 Lee et al³ found that this relationship was U-shaped, with increased mortality risk in those with high and low blood pressures (< 120 mm Hg). Ather et al⁴ also showed that the relationship was U-shaped in patients with a mild to moderate reduction in left ventricular ejection fraction, but linear in those with severely reduced ejection fraction. This study also found that a decrease in systolic blood pressure below 110 mm Hg was associated with increased mortality risk.

The findings of PARADIGM-HF have sparked much conversation and implementation of practice change in the treatment of heart failure patients, and we await additional data on the use and limitations of sacubitril-valsartan in this group of patients.

In Reply: We thank Dr. Blankfield for raising these two important points. Although the findings of the PARADIGM-HF study are compelling, the design and results of this trial have incited many questions.

To address his first point, about the differential dosages of the two drugs, we agree, and we did mention in our review that one concern about the results of PARADIGM-HF is the unequal dosages of valsartan and enalapril in the two different arms. We mentioned that this dosage of enalapril was chosen based on its survival benefit in previous trials. However, this still raises the question of whether the benefit seen in the sacubitril-valsartan group was due to greater inhibition of the renin-angiotensin-aldosterone system rather than to the new drug.

To address his second point, the decrease in blood pressure in the sacubitril-valsartan arm was significant, and the patients taking this drug were more likely to have symptomatic hypotension, which may contribute to patient intolerance and difficulty initiating treatment with this drug. Dr. Blankfield brings up an interesting point regarding reduction of blood pressure driving the decrease of events in the sacubitril-valsartan group. In the original trial results section, the authors mentioned that when the difference in blood pressure between the two groups was examined as a time-dependent covariate, it was not a significant predictor of the benefit of sacubitril-valsartan.¹

Furthermore, although higher blood pressure is associated with worse cardiovascular outcomes in the general population, higher blood pressure has been shown to be protective in heart failure patients.² Several studies have shown that the relationship between blood pressure and the mortality rate in patients with heart failure is paradoxical and complex.^2–4 Lee et al³ found that this relationship was U-shaped, with increased mortality risk in those with high and low blood pressures (< 120 mm Hg). Ather et al⁴ also showed that the relationship was U-shaped in patients with a mild to moderate reduction in left ventricular ejection fraction, but linear in those with severely reduced ejection fraction. This study also found that a decrease in systolic blood pressure below 110 mm Hg was associated with increased mortality risk.

The findings of PARADIGM-HF have sparked much conversation and implementation of practice change in the treatment of heart failure patients, and we await additional data on the use and limitations of sacubitril-valsartan in this group of patients.

To the Editor: In the article “An unusual cause of vitamin B₁₂ and iron deficiency,”¹ the diagnosis of vitamin B₁₂ deficiency was made only by a vitamin B₁₂ level of 108 pg/mL.

According to Harrison’s Principles of Internal Medicine, 18th edition, page 870, the diagnosis of vitamin B₁₂ deficiency requires measurement of methylmalonic acid. Either this test was not performed on the 76-year-old woman described in the article, or the result was not entered. Without a methylmalonic acid level, the title of this article seems incorrect, or the article itself is incomplete by not including this level. The correct diagnosis of anemia due to an intestinal tapeworm was made by capsule endoscopy. She received appropriate therapy and her anemia cleared quickly.

If there is an updated concept for diagnosing vitamin B₁₂ deficiency, I’m open to learning about it.

To the Editor: In the article “An unusual cause of vitamin B₁₂ and iron deficiency,”¹ the diagnosis of vitamin B₁₂ deficiency was made only by a vitamin B₁₂ level of 108 pg/mL.

According to Harrison’s Principles of Internal Medicine, 18th edition, page 870, the diagnosis of vitamin B₁₂ deficiency requires measurement of methylmalonic acid. Either this test was not performed on the 76-year-old woman described in the article, or the result was not entered. Without a methylmalonic acid level, the title of this article seems incorrect, or the article itself is incomplete by not including this level. The correct diagnosis of anemia due to an intestinal tapeworm was made by capsule endoscopy. She received appropriate therapy and her anemia cleared quickly.

If there is an updated concept for diagnosing vitamin B₁₂ deficiency, I’m open to learning about it.

To the Editor: In the article “An unusual cause of vitamin B₁₂ and iron deficiency,”¹ the diagnosis of vitamin B₁₂ deficiency was made only by a vitamin B₁₂ level of 108 pg/mL.

According to Harrison’s Principles of Internal Medicine, 18th edition, page 870, the diagnosis of vitamin B₁₂ deficiency requires measurement of methylmalonic acid. Either this test was not performed on the 76-year-old woman described in the article, or the result was not entered. Without a methylmalonic acid level, the title of this article seems incorrect, or the article itself is incomplete by not including this level. The correct diagnosis of anemia due to an intestinal tapeworm was made by capsule endoscopy. She received appropriate therapy and her anemia cleared quickly.

If there is an updated concept for diagnosing vitamin B₁₂ deficiency, I’m open to learning about it.

In Reply: We thank Dr. Phillips for his inquiry.

In general, serum vitamin B₁₂ concentrations vary greatly, and we acknowledge that serum vitamin B₁₂ may be normal in up to 5% of patients with documented B₁₂ deficiency.¹ In a prospective study of 1,599 patients, Matchar et al² demonstrated that a single vitamin B₁₂ level less than 200 pg/mL had a specificity greater than 95% at predicting vitamin B₁₂ deficiency.² We acknowledge that additional metabolite testing is necessary in equivocal cases in which the vitamin B₁₂ level is between 200 and 300 pg/mL, which is often considered to be the normal range, but the patient has symptoms of vitamin B₁₂ deficiency such as dementia and unexplained macrocytosis, and neurologic symptoms.³

Based on the patient’s symptoms of neuropathy and fatigue in conjunction with a vitamin B₁₂ level well below 200 pg/mL, we believe that the diagnosis can be made.^2,3 Nonetheless, although we did not mention it in our article, we did indeed send for a methylmalonic acid measurement at the time of the initial evaluation, and the level was elevated at 396 nmol/L (normal 87–318 nmol/L), further confirming her vitamin B₁₂ deficiency.

In Reply: We thank Dr. Phillips for his inquiry.

In general, serum vitamin B₁₂ concentrations vary greatly, and we acknowledge that serum vitamin B₁₂ may be normal in up to 5% of patients with documented B₁₂ deficiency.¹ In a prospective study of 1,599 patients, Matchar et al² demonstrated that a single vitamin B₁₂ level less than 200 pg/mL had a specificity greater than 95% at predicting vitamin B₁₂ deficiency.² We acknowledge that additional metabolite testing is necessary in equivocal cases in which the vitamin B₁₂ level is between 200 and 300 pg/mL, which is often considered to be the normal range, but the patient has symptoms of vitamin B₁₂ deficiency such as dementia and unexplained macrocytosis, and neurologic symptoms.³

Based on the patient’s symptoms of neuropathy and fatigue in conjunction with a vitamin B₁₂ level well below 200 pg/mL, we believe that the diagnosis can be made.^2,3 Nonetheless, although we did not mention it in our article, we did indeed send for a methylmalonic acid measurement at the time of the initial evaluation, and the level was elevated at 396 nmol/L (normal 87–318 nmol/L), further confirming her vitamin B₁₂ deficiency.

In Reply: We thank Dr. Phillips for his inquiry.

In general, serum vitamin B₁₂ concentrations vary greatly, and we acknowledge that serum vitamin B₁₂ may be normal in up to 5% of patients with documented B₁₂ deficiency.¹ In a prospective study of 1,599 patients, Matchar et al² demonstrated that a single vitamin B₁₂ level less than 200 pg/mL had a specificity greater than 95% at predicting vitamin B₁₂ deficiency.² We acknowledge that additional metabolite testing is necessary in equivocal cases in which the vitamin B₁₂ level is between 200 and 300 pg/mL, which is often considered to be the normal range, but the patient has symptoms of vitamin B₁₂ deficiency such as dementia and unexplained macrocytosis, and neurologic symptoms.³

Based on the patient’s symptoms of neuropathy and fatigue in conjunction with a vitamin B₁₂ level well below 200 pg/mL, we believe that the diagnosis can be made.^2,3 Nonetheless, although we did not mention it in our article, we did indeed send for a methylmalonic acid measurement at the time of the initial evaluation, and the level was elevated at 396 nmol/L (normal 87–318 nmol/L), further confirming her vitamin B₁₂ deficiency.

To the Editor: I read with great interest your 1-Minute Consult and the accompanying editorial on preoperative testing. I have long requested from my local hospitals the rationale for the long list of tests that used to be mandated for any surgery. I could not even get the courtesy of a reply from the department of anesthesia. For a while, in addition to the complete blood cell count and chemistry panel, one hospital demanded a urinalysis for cataract surgery.

Finally, without any explanation, the testing is now no longer mandated for cataract surgery but is still required for surgery such as the meniscus repair that was referenced.

These are not tests I want to order, but I am forced to order them or the surgery won’t be done. Certainly, in a diabetic patient or a patient treated with a complex regimen for hypertension, tests may be needed.

Thank you for the opportunity to comment.

To the Editor: I read with great interest your 1-Minute Consult and the accompanying editorial on preoperative testing. I have long requested from my local hospitals the rationale for the long list of tests that used to be mandated for any surgery. I could not even get the courtesy of a reply from the department of anesthesia. For a while, in addition to the complete blood cell count and chemistry panel, one hospital demanded a urinalysis for cataract surgery.

Finally, without any explanation, the testing is now no longer mandated for cataract surgery but is still required for surgery such as the meniscus repair that was referenced.

These are not tests I want to order, but I am forced to order them or the surgery won’t be done. Certainly, in a diabetic patient or a patient treated with a complex regimen for hypertension, tests may be needed.

Thank you for the opportunity to comment.

To the Editor: I read with great interest your 1-Minute Consult and the accompanying editorial on preoperative testing. I have long requested from my local hospitals the rationale for the long list of tests that used to be mandated for any surgery. I could not even get the courtesy of a reply from the department of anesthesia. For a while, in addition to the complete blood cell count and chemistry panel, one hospital demanded a urinalysis for cataract surgery.

Finally, without any explanation, the testing is now no longer mandated for cataract surgery but is still required for surgery such as the meniscus repair that was referenced.

These are not tests I want to order, but I am forced to order them or the surgery won’t be done. Certainly, in a diabetic patient or a patient treated with a complex regimen for hypertension, tests may be needed.

Thank you for the opportunity to comment.