Letters
evaluation of nonverbal responses that may have resulted in a higher response rate to religious issues. Last, although the Accreditation Council for Graduate Medical Education does require trainees in Pulmonary and Critical Care Medicine to demonstrate some fluency in communicating well during end-of-life discussions, formal training on such issues remain program or hospital specific.4 The result is that many intensivists never receive the sort of evidence-based training in end-of-life discussions that may enhance the nature of these interactions, despite the fact that the majority of fellows recommend that such training be mandatory.5
Natalie C. Ernecoff, MPH Farr A. Curlin, MD Douglas B. White, MD, MAS Author Affiliations: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Ernecoff, White); The Trent Center for Bioethics, Humanities, and History of Medicine, Duke University, Durham, North Carolina (Curlin); The Duke Divinity School, Duke University, Durham, North Carolina (Curlin). Corresponding Author: Douglas B. White, MD, MAS, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 608 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261 ([email protected]). Additional Contributions: We thank Praewpannarai Buddadhumaruk, RN, MS, coauthor of the original manuscript, for statistical support in the preparation of the original manuscript.
Nikhil Barot, MD Katherine Yu, MD Author Affiliations: Department of Medicine, Olive View – UCLA Medical Center, Sylmar, California.
1. Ernecoff NC, Curlin FA, Buddadhumaruk P, White DB. Health care professionals’ responses to religious or spiritual statements by surrogate decision makers during goals-of-care discussions. JAMA Intern Med. 2015;175 (10):1662-1669.
Corresponding Author: Nikhil Barot, MD, Department of Medicine, Olive View – UCLA Medical Center, 14445 Olive View Dr, Ste 2B-182, Sylmar, CA 91342 ([email protected])
2. Lo B, Ruston D, Kates LW, et al; Working Group on Religious and Spiritual Issues at the End of Life. Discussing religious and spiritual issues at the end of life: a practical guide for physicians. JAMA. 2002;287(6):749-754.
1. Ernecoff NC, Curlin FA, Buddadhumaruk P, White DB. Health care professionals’ responses to religious or spiritual statements by surrogate decision makers during goals-of-care discussions. JAMA Intern Med. 2015;175 (10):1662-1669. 2. Curlin FA, Lantos JD, Roach CJ, Sellergren SA, Chin MH. Religious characteristics of U.S. physicians: a national survey. J Gen Intern Med. 2005;20 (7):629-634. 3. Montague E, Chen P, Xu J, Chewning B, Barrett B. Nonverbal interpersonal interactions in clinical encounters and patient perceptions of empathy. J Particip Med. 2013;5:e33. 4. Accreditation Council for Graduate Medical Education. ACGME program requirements for graduate medical education in critical care medicine. 2013. http://www.acgme.org/acgmeweb/Portals/0/PFAssets/2013-PR-FAQ-PIF/142 _critical_care_int_med_07132013.pdf. Accessed January 5, 2016. 5. Arnold RM, Back AL, Barnato AE, et al. The Critical Care Communication project: improving fellows’ communication skills. J Crit Care. 2015;30(2):250-254.
In Reply We thank Drs Barot and Yu for their comments regarding the complex factors contributing to goals-of-care conversations. They are correct that in our study1 we were not able to quantify discussions hospital chaplains may have had with families outside of conferences that included clinicians. The primary observation remains that clinicians rarely discussed spiritual concerns with families of critically ill patients, even when families seemed to raise such concerns. Although we agree that nonverbal communication is important, we cannot imagine how such concerns could have been adequately addressed without words. We agree with Drs Barot and Yu that further training for physicians may be warranted—training where physicians practice asking questions about how patients and families are doing spiritually and where they practice responding to the types of verbal cues that observed in this study.1 Lo et al2 provide guidelines for physicians that provide minimum best practices for supporting patients religious and spiritual needs. We believe the most salient conclusion of the study1 was the infrequency that clinicians and physicians addressed or assessed religious or spiritual concerns among family members of the critically ill. Addressing religious and spiritual concerns needs to become part of the culture of caring for patients at the end of life. jamainternalmedicine.com
Proposed Guidelines for Future Vitamin D Studies To the Editor The trial by Hansen and colleagues1 was designed to study the effects of vitamin D supplementation on calcium absorption, bone mineral density (BMD), muscle function, and muscle mass. Serum 25-hydroxyvitamin D (25[OH]D) concentrations increased from 21 to 27 ng/mL (to convert to nanomoles per liter, multiply by 2.496) for low-dose vitamin D (LDD) and 42 ng/mL for high-dose vitamin D (HDD) by the end of the year-long trial. Total-hip BMD increased by 0.4% for LDD and 0.7% for HDD. Femoral neck BMD decreased by 0.1% for LDD and increased by 0.5% for HDD. The 95% CI ranged from 1.0% to 2.5%. Since only small effects were found, the results of this trial were interpreted as implying that 25 (OH)D concentrations of 20 ng/mL are adequate. However, an alternate approach is to look at BMD as a function of 25(OH)D concentration. According to Figure 3 in a study by Kuchuk et al,2 there is a change in hip trochanter BMD as a function of 25(OH)D concentration for postmenopausal women. It was 0.4% higher for 27 ng/mL vs 21 ng/mL and 1.7% higher for 42 ng/mL vs 21 ng/mL. These values are larger than found in the trial, but the 95% CIs include these values. Applying the guidelines for clinical studies of nutrient effects3 to vitamin D trials, the study design should start with an understanding of the 25(OH)D concentration-health outcome relation, measure 25(OH)D concentration of prospective participants, enroll only those with values near the low end of the relation, supplement with sufficient vitamin D to raise 25(OH)D concentration to near the upper end of the range, measure achieved 25(OH)D concentration, and optimize conutrient status. Had Hansen et al1 followed these guidelines, they might have enrolled people with mean 25(OH)D concentration near 10 ng/mL. In that case, raising 25(OH)D concentration to 27 ng/mL and 42 ng/mL would have resulted in increases of BMD of 2.7%, and 4.0%, respectively. Further evidence that lower baseline 25(OH)D concentrations are desirable for trials is found in a recent meta-analysis of vitamin D trials4 looking for beneficial effects on biomark(Reprinted) JAMA Internal Medicine February 2016 Volume 176, Number 2
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ers of inflammation. For trials with baseline 25(OH)D concentration below 19 ng/mL, 50% of the trials found beneficial effects, while for concentrations above 19 ng/mL, only 26% of the trials found benefits. Achieved 25(OH)D concentration was relatively unimportant. Unfortunately, the major vitamin D trials currently under way such as VITAL (the VITamin D and OmegA-3 TriaL)5 did not seek to enroll people with low 25(OH)D concentrations, so they may not find many benefits of vitamin D supplementation. William B. Grant, PhD Luca Mascitelli, MD Mark R. Goldstein, MD, FACP Author Affiliations: Sunlight, Nutrition, and Health Research Center, San Francisco, California (Grant); Comando Brigata Alpina “Julia,” Multinational Land Force, Medical Service, Udine, Italy (Mascitelli); NCH Physician Group, Naples, Florida (Goldstein). Corresponding Author: William B. Grant, PhD, Sunlight, Nutrition, and Health Research Center, PO Box 641603, San Francisco, CA 94164-1603 ([email protected]). Conflict of Interest Disclosures: Dr Grant receives funding from Bio-Tech Pharmacal, Inc, the Vitamin D Council, and the Vitamin D Society. No other conflicts are reported. 1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175(10):1612-1621.
Ayse Nur Tufan, MD Fatih Tufan, MD Author Affiliations: Division of Rheumatology, Department of Internal Medicine, Uludag University, Bursa, Turkey (A. N. Tufan); Division of Geriatrics, Department of Internal Medicine, Istanbul University, Istanbul, Turkey (F. Tufan). Corresponding Author: Fatih Tufan, MD, Associate Professor, Division of Geriatrics, Department of Internal Medicine, Istanbul University, P.B. 34093, Sehremini, Istanbul, Turkey ([email protected]). Conflict of Interest Disclosures: None reported.
2. Kuchuk NO, van Schoor NM, Pluijm SM, Chines A, Lips P. Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. J Bone Miner Res. 2009;24(4):693-701.
1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175(10):1612-1621.
3. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54.
2. House AA, Eliasziw M, Cattran DC, et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA. 2010;303(16):1603-1609.
4. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol. 2014;6(1):e983401. 5. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33(1):159-171.
To the Editor We read with interest the article by Hansen et al1 suggesting that neither low-dose nor high-dose cholecalciferol have beneficial effects on bone or muscle health. We have comments about this well-designed and well-performed study. First, as the authors underlined, secondary hyperparathyroidism (SH) occurs in only 10% to 33% of people with vitamin D insufficiency and subjects without SH might not benefit from vitamin D treatment. Although the authors did not report the rate of SH in their study, median vitamin D and parathyroid hormone levels indicate that SH was infrequent in these patients. Thus, this study may be considered a contribution to the growing body of evidence indicating that supplementing what is sufficient is not beneficial, if not harmful.2-4 Second, the authors mentioned diabetes mellitus among exclusion criteria because the disease and its medications may affect skeletal health. However, they did not mention hypertension in their study population, in whom the expected rate of hypertension would be high. Thiazide diuretics may reduce urinary calcium levels, and loop diuretics may increase urinary calcium levels. Thus, diuretics may affect calcium ab280
sorption, an outcome of the study. Furthermore, many antihypertensive agents may be associated with hypotensionrelated fatigue, reduced physical activity, and orthostatism related falls, which are also among the study outcomes. Last, chronic inflammatory diseases like rheumatoid arthritis and Sjögren syndrome are prevalent among postmenopausal women and affect bone health significantly. Sjögren syndrome–associated renal tubular acidosis may also affect urinary calcium levels as well. However, Hansen et al1 did not mention inflammatory conditions like rheumatoid arthritis and Sjögren syndrome among exclusion criteria. Although hazardous effects of smoking on bone health are well known,5 the authors did not mention smoking rates in the study groups. Absence of evaluation of these confounders would better be mentioned as limitations.
3. Qin T, Du M, Du H, Shu Y, Wang M, Zhu L. Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials. Sci Rep. 2015;5:12044. 4. Wang L, Sesso HD, Glynn RJ, et al. Vitamin E and C supplementation and risk of cancer in men: posttrial follow-up in the Physicians’ Health Study II randomized trial. Am J Clin Nutr. 2014;100(3):915-923. 5. Cusano NE. Skeletal Effects of Smoking. Curr Osteoporos Rep. 2015;13(5): 302-309.
To the Editor The recent article by Hansen et al1 described a randomized clinical trial on the treatment of vitamin D insufficiency in postmenopausal women. This is a topic of great interest to us, and we would like to express some serious concerns regarding the conclusions drawn by Hansen et al. The aim of this study was to compare the effect of placebo, low-dose cholecalciferol (800 IU daily), and high-dose cholecalciferol (50 000 IU twice monthly) on total fractional calcium absorption (TFCA), bone density, and muscle outcomes. Although this study had the adequate power to detect changes in TFCA, the primary outcome, there is lack of discussion regarding the power of this study to detect the differences in muscle outcomes and bone mineral density. Based on the reported standard deviation of muscle outcomes and bone mineral density, the current study is not equipped with adequate power to detect the proposed difference, if any. Thus, it is premature for the authors to conclude that high-dose cholecalciferol therapy failed to improve bone density and muscle outcomes.
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This study further demonstrated that low-dose cholecalciferol failed to increase serum 25-hydroxyvitamin D level to 30 ng/mL (to convert to nanomoles per liter, multiply by 2.496) in most of patients. Furthermore, low-dose cholecalciferol also failed to improve calcium absorption in postmenopausal women with vitamin D insufficiency, which provided evidence against treatment with low-dose cholecalciferol. Alternatively, the failure to show improvement in calcium absorption could be owing to issues in the measurement of TFCA. Last, we would like to point out contradictive conclusions between the abstract and body of the paper. In the abstract, the authors concluded that “High-dose cholecalciferol therapy increased calcium absorption,”1(p1612) while in the conclusion section the author stated that “One year of highdose cholecalciferol…had a negligible effect on calcium absorption.”1(p1619) Our main concern is the negative publicity of vitamin D supplement that could very well be type 1 error and dissuade physicians to prescribe vitamin D supplements and patients to take vitamin D supplements. The only conclusion that should be drawn from this study is that this study cannot exclude the beneficial effect of vitamin D replacement on bone outcomes. Rudruidee Karnchanasorn, MD Horng-Yih Ou, MD, PhD Ken C. Chiu, MD Author Affiliations: Division of Endocrinology, Department of Medicine, University of Kansas Medical Center, Kansas City (Karnchanasorn); Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Ou); Department of Clinical Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, California (Chiu). Corresponding Author: Ken C. Chiu, MD, Department of Clinical Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010-3000 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175(10):1612-1621.
In Reply We thank our colleagues for expressing interest in our study.1 Grant et al felt that we would have detected benefits of low-dose vitamin D had we recruited subjects with lower 25- hydroxyvitamin D (25[OH]D) levels. However, we purposefully excluded subjects with vitamin D deficiency, for whom
benefits of therapy are established.2 Instead, we designed our study to directly address controversy regarding the highest 25 (OH)D level needed to experience benefits of vitamin D as stated in our introduction,1 with some experts recommending levels 30 ng/mL or greater (to convert to nanomoles per liter, multiply by 2.496) and others recommending levels 20 ng/mL or greater.2 Therefore, we recruited subjects with levels less than 30 ng/mL and randomized one-third to a highdose vitamin D regimen that kept their 25(OH)D higher than 30 ng/mL. We anticipated that most subjects in the low-dose and placebo arms would have levels less than 30 ng/mL during the trial and enhanced that likelihood by dispensing sunscreen to all subjects. Karnchanasorn et al wondered if total fractional calcium absorption (TFCA) (data represented in eFigure 2 of our online supplemental material) did not improve with lowdose vitamin D because of flawed measurement methods. We used the Eastell gold-standard approach3 to measure TFCA as stated in the methods section of our study,1 including a 24-hour inpatient urine collection and replication of dietary habits. We therefore disagree with Karnchanasorn et al that TFCA did not increase in the low-dose arm due to flawed measurement methods. We estimated power for secondary and tertiary outcomes in the grant supporting the trial. In a pilot study of highdose vitamin D in postmenopausal women,4 the standard deviations for the 1-year change in hip BMD and muscle mass were 2% and 4%, respectively, while the TUG test improved by a mean (SD) of 16% (8%). In another trial5 in postmenopausal women, means (SD) hip bone mineral density (BMD) increased 1.6% (0.6%) with 1 year of low-dose vitamin D relative to placebo. Thus, a sample size of 70 women per treatment arm provided approximately 90% power to detect a 1% or greater change in hip BMD, a 2% or greater change in muscle mass, and a 4% or greater change in the Timed Up and Go test between treatment arms, using a 2-sided α of .05. While observational data can suggest vitamin D levels at which BMD maximizes, placebo-controlled trials must confirm such observations. Grant et al highlighted a post-hoc analysis6 of a bazedoxifene clinical trial that explored the relationship between baseline 25(OH)D and spine, hip, femoral neck, and trochanter BMD in 7441 postmenopausal osteoporotic women. When controlling for confounders, locally weighted regression smoothing plots demonstrated a positive association between 25(OH)D and trochanter BMD but not with BMD at other sites. Interestingly, authors felt that tro-
Table. Distribution of Patient Characteristics No. (%) Vitamin D Characteristic
Placebo (n = 76)
Low-Dose (n = 75)
High-Dose (n = 79)
P Value
Tobacco use
8 (11)
6 (8)
6 (8)
Hypertension
21 (27)
27 (36)
21 (27)
.38
Thiazide use
8 (11)
18 (24)
12 (15)
.08
Secondary hyperparathyroidisma
4 (5)
4 (5)
4 (5)
>.99
Rheumatologic disorder
0 (0)
1 (1)
1 (1)
>.99
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.78
a
Serum intact parathyroid hormone greater than 72 pg/mL (to convert to ng/L, multiply by 1.0).
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chanter BMD reached a threshold around a 25(OH)D level of 50 nM, which equals 20 ng/mL. Our randomized, placebocontrolled clinical trial concurs. Patient use of tobacco, thiazides, hypertension, secondary hyperparathyroidism, and chronic inflammatory diseases were equally distributed across treatment arms (Table). Thus, we do not feel these conditions limit our study’s findings. Karen E. Hansen, MD, MS Michael G. Johnson, MS Author Affiliations: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison. Corresponding Author: Karen E. Hansen, MD, MS, Associate Professor of Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Rm 4124 MFCB, Madison, WI 53792 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. JAMA Intern Med. 2015;175(10):1612-1621. 2. Institute of Medicine. Dietary reference intakes for calcium and vitamin D Washington. DC: The National Academies Press; 2011. 3. Eastell R, Vieira NE, Yergey AL, Riggs BL. One-day test using stable isotopes to measure true fractional calcium absorption. J Bone Miner Res. 1989;4(4): 463-468.
ing) forms of medical malpractice, comprising as many as 40% of medical malpractice cases. Second, there is increasing popularity of physicianpatient shared-decision making3 where physicians provide advice, and the patients become the final decision maker. This model contrasts with the traditional practice model where the physician serves as the commander-in-chief. In addition, in an Internet-driven world, we have witnessed an explosive proliferation of websites for patient-satisfaction surveys, physician online ratings, etc. Many of these forprofit online rating sites are actually physician bashing sites. 4 Under these circumstances, many physicians feel pressured to succumb to ordering diagnostic tests and imaging when they are requested by patients to avoid a negative rating. Especially when hospitals and insurance payers increasingly link patient satisfaction survey scores to pay-for performances. Recently, Mark Cuban stirred up a controversy by calling for universal quarterly blood testing “for everything available…so you have a baseline of your own personal health.”5 Around the same time, Arizona passed a law allowing consumers to obtain any laboratory test directly from licensed laboratories without a physician's order.5 It will be challenging to find the fair balance of less is more.
4. Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Engelke JA, Shafer MM. Vitamin D insufficiency: disease or no disease? J Bone Miner Res. 2008;23(7): 1052-1060.
Katherine Bydalek, MSN, FNP-BC, PhD Xiulu Ruan, MD
5. Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P. Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab. 1995;80(4):1052-1058.
Author Affiliations: College of Nursing, University of South Alabama, Mobile (Bydalek); Department of Anesthesiology, Louisiana State University Health Science Center, New Orleans (Ruan).
6. Kuchuk NO, van Schoor NM, Pluijm SM, Chines A, Lips P. Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. J Bone Miner Res. 2009;24(4):693-701.
Corresponding Author: Xiulu Ruan, MD, Department of Anesthesiology, Louisiana State University Health Science Center, 1542 Tulane Ave, New Orleans, LA 70112 ([email protected]). Conflict of Interest Disclosures: None reported.
Finding the Balance of Less Is More To the Editor The article by Dr O’Brien1 published with the label “Less Is More” in a recent issue of JAMA Internal Medicine was very interesting. The author reported an incredible medical history regarding her misdiagnosis of Chagas disease that resulted from her injudicious laboratory request. The initial laboratory test for Chagas disease was misinterpreted as positive and led to her subsequent ordeal that tortured her physically, emotionally, and professionally. Based on her experience, Dr O’Brien cautions other physicians when faced with injudicious requests from patients. While we agree with the concept that less is more, we wonder how many physicians actually follow this concept in their practice of medicine. It is becoming increasingly difficult to achieve a fair balance in this regard. First, the medicolegal consequences of delayed diagnosis and/or misdiagnosis can be a source of serious concern to many physicians. A recent study2 of a 25-year summary of US malpractice claims for diagnostic errors (ie, diagnoses that are missed, wrong, or delayed as detected by a subsequent definitive test or finding) concluded that diagnostic errors appeared to be the most common, most costly, and most dangerous of medical mistakes. Misdiagnosis and delayed diagnosis are 2 of the most common (and potentially damag282
1. O’Brien M. An injudicious request—performing a test that is not indicated. JAMA Intern Med. 2015;175(10):1606-1607. 2. Saber Tehrani AS, Lee H, Mathews SC, et al. 25-Year summary of US malpractice claims for diagnostic errors 1986-2010: an analysis from the National Practitioner Data Bank. BMJ Qual Saf. 2013;22(8):672-680. 3. Charles C, Gafni A, Whelan T. Decision-making in the physician-patient encounter: revisiting the shared treatment decision-making model. Soc Sci Med. 1999;49(5):651-661. 4. Ma L, Kaye AD, Bean M, Vo N, Ruan X. A five-star doctor? online rating of physicians by patients in an internet driven world. Pain Physician. 2015;18(1): E15-E18. 5. Chokshi DA. Finding the sweet spot in medicine. Lancet. 2015;385(9982):2037.
To the Editor In her first-person account of performing a test for Chagas disease that was not indicated,1 O’Brien perfectly illustrates the blind faith we have in tests and, likewise, the ease at which we often ignore clinical reasoning when interpreting and acting upon test results. Fortunately, the Bayes theorem can assist us in the interpretation of unexpected test results. As O’Brien noted, Chagas disease disproportionately affects individuals in living in poverty in South America and Central America; the risk for travelers contracting Chagas disease is very low.2 Despite millions of visitors to endemic regions (eg, 2.7 million US visitors to Central America in 20143), there are
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evaluation of nonverbal responses that may have resulted in a higher response rate to religious issues. Last, although the Accreditation Council for Graduate Medical Education does require trainees in Pulmonary and Critical Care Medicine to demonstrate some fluency in communicating well during end-of-life discussions, formal training on such issues remain program or hospital specific.4 The result is that many intensivists never receive the sort of evidence-based training in end-of-life discussions that may enhance the nature of these interactions, despite the fact that the majority of fellows recommend that such training be mandatory.5
Natalie C. Ernecoff, MPH Farr A. Curlin, MD Douglas B. White, MD, MAS Author Affiliations: Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Ernecoff, White); The Trent Center for Bioethics, Humanities, and History of Medicine, Duke University, Durham, North Carolina (Curlin); The Duke Divinity School, Duke University, Durham, North Carolina (Curlin). Corresponding Author: Douglas B. White, MD, MAS, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 608 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261 ([email protected]). Additional Contributions: We thank Praewpannarai Buddadhumaruk, RN, MS, coauthor of the original manuscript, for statistical support in the preparation of the original manuscript.
Nikhil Barot, MD Katherine Yu, MD Author Affiliations: Department of Medicine, Olive View – UCLA Medical Center, Sylmar, California.
1. Ernecoff NC, Curlin FA, Buddadhumaruk P, White DB. Health care professionals’ responses to religious or spiritual statements by surrogate decision makers during goals-of-care discussions. JAMA Intern Med. 2015;175 (10):1662-1669.
Corresponding Author: Nikhil Barot, MD, Department of Medicine, Olive View – UCLA Medical Center, 14445 Olive View Dr, Ste 2B-182, Sylmar, CA 91342 ([email protected])
2. Lo B, Ruston D, Kates LW, et al; Working Group on Religious and Spiritual Issues at the End of Life. Discussing religious and spiritual issues at the end of life: a practical guide for physicians. JAMA. 2002;287(6):749-754.
1. Ernecoff NC, Curlin FA, Buddadhumaruk P, White DB. Health care professionals’ responses to religious or spiritual statements by surrogate decision makers during goals-of-care discussions. JAMA Intern Med. 2015;175 (10):1662-1669. 2. Curlin FA, Lantos JD, Roach CJ, Sellergren SA, Chin MH. Religious characteristics of U.S. physicians: a national survey. J Gen Intern Med. 2005;20 (7):629-634. 3. Montague E, Chen P, Xu J, Chewning B, Barrett B. Nonverbal interpersonal interactions in clinical encounters and patient perceptions of empathy. J Particip Med. 2013;5:e33. 4. Accreditation Council for Graduate Medical Education. ACGME program requirements for graduate medical education in critical care medicine. 2013. http://www.acgme.org/acgmeweb/Portals/0/PFAssets/2013-PR-FAQ-PIF/142 _critical_care_int_med_07132013.pdf. Accessed January 5, 2016. 5. Arnold RM, Back AL, Barnato AE, et al. The Critical Care Communication project: improving fellows’ communication skills. J Crit Care. 2015;30(2):250-254.
In Reply We thank Drs Barot and Yu for their comments regarding the complex factors contributing to goals-of-care conversations. They are correct that in our study1 we were not able to quantify discussions hospital chaplains may have had with families outside of conferences that included clinicians. The primary observation remains that clinicians rarely discussed spiritual concerns with families of critically ill patients, even when families seemed to raise such concerns. Although we agree that nonverbal communication is important, we cannot imagine how such concerns could have been adequately addressed without words. We agree with Drs Barot and Yu that further training for physicians may be warranted—training where physicians practice asking questions about how patients and families are doing spiritually and where they practice responding to the types of verbal cues that observed in this study.1 Lo et al2 provide guidelines for physicians that provide minimum best practices for supporting patients religious and spiritual needs. We believe the most salient conclusion of the study1 was the infrequency that clinicians and physicians addressed or assessed religious or spiritual concerns among family members of the critically ill. Addressing religious and spiritual concerns needs to become part of the culture of caring for patients at the end of life. jamainternalmedicine.com
Proposed Guidelines for Future Vitamin D Studies To the Editor The trial by Hansen and colleagues1 was designed to study the effects of vitamin D supplementation on calcium absorption, bone mineral density (BMD), muscle function, and muscle mass. Serum 25-hydroxyvitamin D (25[OH]D) concentrations increased from 21 to 27 ng/mL (to convert to nanomoles per liter, multiply by 2.496) for low-dose vitamin D (LDD) and 42 ng/mL for high-dose vitamin D (HDD) by the end of the year-long trial. Total-hip BMD increased by 0.4% for LDD and 0.7% for HDD. Femoral neck BMD decreased by 0.1% for LDD and increased by 0.5% for HDD. The 95% CI ranged from 1.0% to 2.5%. Since only small effects were found, the results of this trial were interpreted as implying that 25 (OH)D concentrations of 20 ng/mL are adequate. However, an alternate approach is to look at BMD as a function of 25(OH)D concentration. According to Figure 3 in a study by Kuchuk et al,2 there is a change in hip trochanter BMD as a function of 25(OH)D concentration for postmenopausal women. It was 0.4% higher for 27 ng/mL vs 21 ng/mL and 1.7% higher for 42 ng/mL vs 21 ng/mL. These values are larger than found in the trial, but the 95% CIs include these values. Applying the guidelines for clinical studies of nutrient effects3 to vitamin D trials, the study design should start with an understanding of the 25(OH)D concentration-health outcome relation, measure 25(OH)D concentration of prospective participants, enroll only those with values near the low end of the relation, supplement with sufficient vitamin D to raise 25(OH)D concentration to near the upper end of the range, measure achieved 25(OH)D concentration, and optimize conutrient status. Had Hansen et al1 followed these guidelines, they might have enrolled people with mean 25(OH)D concentration near 10 ng/mL. In that case, raising 25(OH)D concentration to 27 ng/mL and 42 ng/mL would have resulted in increases of BMD of 2.7%, and 4.0%, respectively. Further evidence that lower baseline 25(OH)D concentrations are desirable for trials is found in a recent meta-analysis of vitamin D trials4 looking for beneficial effects on biomark(Reprinted) JAMA Internal Medicine February 2016 Volume 176, Number 2
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ers of inflammation. For trials with baseline 25(OH)D concentration below 19 ng/mL, 50% of the trials found beneficial effects, while for concentrations above 19 ng/mL, only 26% of the trials found benefits. Achieved 25(OH)D concentration was relatively unimportant. Unfortunately, the major vitamin D trials currently under way such as VITAL (the VITamin D and OmegA-3 TriaL)5 did not seek to enroll people with low 25(OH)D concentrations, so they may not find many benefits of vitamin D supplementation. William B. Grant, PhD Luca Mascitelli, MD Mark R. Goldstein, MD, FACP Author Affiliations: Sunlight, Nutrition, and Health Research Center, San Francisco, California (Grant); Comando Brigata Alpina “Julia,” Multinational Land Force, Medical Service, Udine, Italy (Mascitelli); NCH Physician Group, Naples, Florida (Goldstein). Corresponding Author: William B. Grant, PhD, Sunlight, Nutrition, and Health Research Center, PO Box 641603, San Francisco, CA 94164-1603 ([email protected]). Conflict of Interest Disclosures: Dr Grant receives funding from Bio-Tech Pharmacal, Inc, the Vitamin D Council, and the Vitamin D Society. No other conflicts are reported. 1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175(10):1612-1621.
Ayse Nur Tufan, MD Fatih Tufan, MD Author Affiliations: Division of Rheumatology, Department of Internal Medicine, Uludag University, Bursa, Turkey (A. N. Tufan); Division of Geriatrics, Department of Internal Medicine, Istanbul University, Istanbul, Turkey (F. Tufan). Corresponding Author: Fatih Tufan, MD, Associate Professor, Division of Geriatrics, Department of Internal Medicine, Istanbul University, P.B. 34093, Sehremini, Istanbul, Turkey ([email protected]). Conflict of Interest Disclosures: None reported.
2. Kuchuk NO, van Schoor NM, Pluijm SM, Chines A, Lips P. Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. J Bone Miner Res. 2009;24(4):693-701.
1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175(10):1612-1621.
3. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54.
2. House AA, Eliasziw M, Cattran DC, et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA. 2010;303(16):1603-1609.
4. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol. 2014;6(1):e983401. 5. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33(1):159-171.
To the Editor We read with interest the article by Hansen et al1 suggesting that neither low-dose nor high-dose cholecalciferol have beneficial effects on bone or muscle health. We have comments about this well-designed and well-performed study. First, as the authors underlined, secondary hyperparathyroidism (SH) occurs in only 10% to 33% of people with vitamin D insufficiency and subjects without SH might not benefit from vitamin D treatment. Although the authors did not report the rate of SH in their study, median vitamin D and parathyroid hormone levels indicate that SH was infrequent in these patients. Thus, this study may be considered a contribution to the growing body of evidence indicating that supplementing what is sufficient is not beneficial, if not harmful.2-4 Second, the authors mentioned diabetes mellitus among exclusion criteria because the disease and its medications may affect skeletal health. However, they did not mention hypertension in their study population, in whom the expected rate of hypertension would be high. Thiazide diuretics may reduce urinary calcium levels, and loop diuretics may increase urinary calcium levels. Thus, diuretics may affect calcium ab280
sorption, an outcome of the study. Furthermore, many antihypertensive agents may be associated with hypotensionrelated fatigue, reduced physical activity, and orthostatism related falls, which are also among the study outcomes. Last, chronic inflammatory diseases like rheumatoid arthritis and Sjögren syndrome are prevalent among postmenopausal women and affect bone health significantly. Sjögren syndrome–associated renal tubular acidosis may also affect urinary calcium levels as well. However, Hansen et al1 did not mention inflammatory conditions like rheumatoid arthritis and Sjögren syndrome among exclusion criteria. Although hazardous effects of smoking on bone health are well known,5 the authors did not mention smoking rates in the study groups. Absence of evaluation of these confounders would better be mentioned as limitations.
3. Qin T, Du M, Du H, Shu Y, Wang M, Zhu L. Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials. Sci Rep. 2015;5:12044. 4. Wang L, Sesso HD, Glynn RJ, et al. Vitamin E and C supplementation and risk of cancer in men: posttrial follow-up in the Physicians’ Health Study II randomized trial. Am J Clin Nutr. 2014;100(3):915-923. 5. Cusano NE. Skeletal Effects of Smoking. Curr Osteoporos Rep. 2015;13(5): 302-309.
To the Editor The recent article by Hansen et al1 described a randomized clinical trial on the treatment of vitamin D insufficiency in postmenopausal women. This is a topic of great interest to us, and we would like to express some serious concerns regarding the conclusions drawn by Hansen et al. The aim of this study was to compare the effect of placebo, low-dose cholecalciferol (800 IU daily), and high-dose cholecalciferol (50 000 IU twice monthly) on total fractional calcium absorption (TFCA), bone density, and muscle outcomes. Although this study had the adequate power to detect changes in TFCA, the primary outcome, there is lack of discussion regarding the power of this study to detect the differences in muscle outcomes and bone mineral density. Based on the reported standard deviation of muscle outcomes and bone mineral density, the current study is not equipped with adequate power to detect the proposed difference, if any. Thus, it is premature for the authors to conclude that high-dose cholecalciferol therapy failed to improve bone density and muscle outcomes.
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This study further demonstrated that low-dose cholecalciferol failed to increase serum 25-hydroxyvitamin D level to 30 ng/mL (to convert to nanomoles per liter, multiply by 2.496) in most of patients. Furthermore, low-dose cholecalciferol also failed to improve calcium absorption in postmenopausal women with vitamin D insufficiency, which provided evidence against treatment with low-dose cholecalciferol. Alternatively, the failure to show improvement in calcium absorption could be owing to issues in the measurement of TFCA. Last, we would like to point out contradictive conclusions between the abstract and body of the paper. In the abstract, the authors concluded that “High-dose cholecalciferol therapy increased calcium absorption,”1(p1612) while in the conclusion section the author stated that “One year of highdose cholecalciferol…had a negligible effect on calcium absorption.”1(p1619) Our main concern is the negative publicity of vitamin D supplement that could very well be type 1 error and dissuade physicians to prescribe vitamin D supplements and patients to take vitamin D supplements. The only conclusion that should be drawn from this study is that this study cannot exclude the beneficial effect of vitamin D replacement on bone outcomes. Rudruidee Karnchanasorn, MD Horng-Yih Ou, MD, PhD Ken C. Chiu, MD Author Affiliations: Division of Endocrinology, Department of Medicine, University of Kansas Medical Center, Kansas City (Karnchanasorn); Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Ou); Department of Clinical Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, Duarte, California (Chiu). Corresponding Author: Ken C. Chiu, MD, Department of Clinical Diabetes, Endocrinology, and Metabolism, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010-3000 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of vitamin D insufficiency in postmenopausal women: a randomized clinical trial. JAMA Intern Med. 2015;175(10):1612-1621.
In Reply We thank our colleagues for expressing interest in our study.1 Grant et al felt that we would have detected benefits of low-dose vitamin D had we recruited subjects with lower 25- hydroxyvitamin D (25[OH]D) levels. However, we purposefully excluded subjects with vitamin D deficiency, for whom
benefits of therapy are established.2 Instead, we designed our study to directly address controversy regarding the highest 25 (OH)D level needed to experience benefits of vitamin D as stated in our introduction,1 with some experts recommending levels 30 ng/mL or greater (to convert to nanomoles per liter, multiply by 2.496) and others recommending levels 20 ng/mL or greater.2 Therefore, we recruited subjects with levels less than 30 ng/mL and randomized one-third to a highdose vitamin D regimen that kept their 25(OH)D higher than 30 ng/mL. We anticipated that most subjects in the low-dose and placebo arms would have levels less than 30 ng/mL during the trial and enhanced that likelihood by dispensing sunscreen to all subjects. Karnchanasorn et al wondered if total fractional calcium absorption (TFCA) (data represented in eFigure 2 of our online supplemental material) did not improve with lowdose vitamin D because of flawed measurement methods. We used the Eastell gold-standard approach3 to measure TFCA as stated in the methods section of our study,1 including a 24-hour inpatient urine collection and replication of dietary habits. We therefore disagree with Karnchanasorn et al that TFCA did not increase in the low-dose arm due to flawed measurement methods. We estimated power for secondary and tertiary outcomes in the grant supporting the trial. In a pilot study of highdose vitamin D in postmenopausal women,4 the standard deviations for the 1-year change in hip BMD and muscle mass were 2% and 4%, respectively, while the TUG test improved by a mean (SD) of 16% (8%). In another trial5 in postmenopausal women, means (SD) hip bone mineral density (BMD) increased 1.6% (0.6%) with 1 year of low-dose vitamin D relative to placebo. Thus, a sample size of 70 women per treatment arm provided approximately 90% power to detect a 1% or greater change in hip BMD, a 2% or greater change in muscle mass, and a 4% or greater change in the Timed Up and Go test between treatment arms, using a 2-sided α of .05. While observational data can suggest vitamin D levels at which BMD maximizes, placebo-controlled trials must confirm such observations. Grant et al highlighted a post-hoc analysis6 of a bazedoxifene clinical trial that explored the relationship between baseline 25(OH)D and spine, hip, femoral neck, and trochanter BMD in 7441 postmenopausal osteoporotic women. When controlling for confounders, locally weighted regression smoothing plots demonstrated a positive association between 25(OH)D and trochanter BMD but not with BMD at other sites. Interestingly, authors felt that tro-
Table. Distribution of Patient Characteristics No. (%) Vitamin D Characteristic
Placebo (n = 76)
Low-Dose (n = 75)
High-Dose (n = 79)
P Value
Tobacco use
8 (11)
6 (8)
6 (8)
Hypertension
21 (27)
27 (36)
21 (27)
.38
Thiazide use
8 (11)
18 (24)
12 (15)
.08
Secondary hyperparathyroidisma
4 (5)
4 (5)
4 (5)
>.99
Rheumatologic disorder
0 (0)
1 (1)
1 (1)
>.99
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.78
a
Serum intact parathyroid hormone greater than 72 pg/mL (to convert to ng/L, multiply by 1.0).
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chanter BMD reached a threshold around a 25(OH)D level of 50 nM, which equals 20 ng/mL. Our randomized, placebocontrolled clinical trial concurs. Patient use of tobacco, thiazides, hypertension, secondary hyperparathyroidism, and chronic inflammatory diseases were equally distributed across treatment arms (Table). Thus, we do not feel these conditions limit our study’s findings. Karen E. Hansen, MD, MS Michael G. Johnson, MS Author Affiliations: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison. Corresponding Author: Karen E. Hansen, MD, MS, Associate Professor of Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, 1685 Highland Ave, Rm 4124 MFCB, Madison, WI 53792 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Hansen KE, Johnson RE, Chambers KR, et al. Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial. JAMA Intern Med. 2015;175(10):1612-1621. 2. Institute of Medicine. Dietary reference intakes for calcium and vitamin D Washington. DC: The National Academies Press; 2011. 3. Eastell R, Vieira NE, Yergey AL, Riggs BL. One-day test using stable isotopes to measure true fractional calcium absorption. J Bone Miner Res. 1989;4(4): 463-468.
ing) forms of medical malpractice, comprising as many as 40% of medical malpractice cases. Second, there is increasing popularity of physicianpatient shared-decision making3 where physicians provide advice, and the patients become the final decision maker. This model contrasts with the traditional practice model where the physician serves as the commander-in-chief. In addition, in an Internet-driven world, we have witnessed an explosive proliferation of websites for patient-satisfaction surveys, physician online ratings, etc. Many of these forprofit online rating sites are actually physician bashing sites. 4 Under these circumstances, many physicians feel pressured to succumb to ordering diagnostic tests and imaging when they are requested by patients to avoid a negative rating. Especially when hospitals and insurance payers increasingly link patient satisfaction survey scores to pay-for performances. Recently, Mark Cuban stirred up a controversy by calling for universal quarterly blood testing “for everything available…so you have a baseline of your own personal health.”5 Around the same time, Arizona passed a law allowing consumers to obtain any laboratory test directly from licensed laboratories without a physician's order.5 It will be challenging to find the fair balance of less is more.
4. Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Engelke JA, Shafer MM. Vitamin D insufficiency: disease or no disease? J Bone Miner Res. 2008;23(7): 1052-1060.
Katherine Bydalek, MSN, FNP-BC, PhD Xiulu Ruan, MD
5. Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P. Prevention of bone loss by vitamin D supplementation in elderly women: a randomized double-blind trial. J Clin Endocrinol Metab. 1995;80(4):1052-1058.
Author Affiliations: College of Nursing, University of South Alabama, Mobile (Bydalek); Department of Anesthesiology, Louisiana State University Health Science Center, New Orleans (Ruan).
6. Kuchuk NO, van Schoor NM, Pluijm SM, Chines A, Lips P. Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. J Bone Miner Res. 2009;24(4):693-701.
Corresponding Author: Xiulu Ruan, MD, Department of Anesthesiology, Louisiana State University Health Science Center, 1542 Tulane Ave, New Orleans, LA 70112 ([email protected]). Conflict of Interest Disclosures: None reported.
Finding the Balance of Less Is More To the Editor The article by Dr O’Brien1 published with the label “Less Is More” in a recent issue of JAMA Internal Medicine was very interesting. The author reported an incredible medical history regarding her misdiagnosis of Chagas disease that resulted from her injudicious laboratory request. The initial laboratory test for Chagas disease was misinterpreted as positive and led to her subsequent ordeal that tortured her physically, emotionally, and professionally. Based on her experience, Dr O’Brien cautions other physicians when faced with injudicious requests from patients. While we agree with the concept that less is more, we wonder how many physicians actually follow this concept in their practice of medicine. It is becoming increasingly difficult to achieve a fair balance in this regard. First, the medicolegal consequences of delayed diagnosis and/or misdiagnosis can be a source of serious concern to many physicians. A recent study2 of a 25-year summary of US malpractice claims for diagnostic errors (ie, diagnoses that are missed, wrong, or delayed as detected by a subsequent definitive test or finding) concluded that diagnostic errors appeared to be the most common, most costly, and most dangerous of medical mistakes. Misdiagnosis and delayed diagnosis are 2 of the most common (and potentially damag282
1. O’Brien M. An injudicious request—performing a test that is not indicated. JAMA Intern Med. 2015;175(10):1606-1607. 2. Saber Tehrani AS, Lee H, Mathews SC, et al. 25-Year summary of US malpractice claims for diagnostic errors 1986-2010: an analysis from the National Practitioner Data Bank. BMJ Qual Saf. 2013;22(8):672-680. 3. Charles C, Gafni A, Whelan T. Decision-making in the physician-patient encounter: revisiting the shared treatment decision-making model. Soc Sci Med. 1999;49(5):651-661. 4. Ma L, Kaye AD, Bean M, Vo N, Ruan X. A five-star doctor? online rating of physicians by patients in an internet driven world. Pain Physician. 2015;18(1): E15-E18. 5. Chokshi DA. Finding the sweet spot in medicine. Lancet. 2015;385(9982):2037.
To the Editor In her first-person account of performing a test for Chagas disease that was not indicated,1 O’Brien perfectly illustrates the blind faith we have in tests and, likewise, the ease at which we often ignore clinical reasoning when interpreting and acting upon test results. Fortunately, the Bayes theorem can assist us in the interpretation of unexpected test results. As O’Brien noted, Chagas disease disproportionately affects individuals in living in poverty in South America and Central America; the risk for travelers contracting Chagas disease is very low.2 Despite millions of visitors to endemic regions (eg, 2.7 million US visitors to Central America in 20143), there are
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