Letters
1. Mafi JN, McCarthy EP, Davis RB, Landon BE. Worsening trends in the management and treatment of back pain. JAMA Intern Med. 2013;173(17):15731581. 2. Haldeman S, Carroll L, Cassidy JD, Schubert J, Nygren A; Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. The Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders: executive summary. Spine (Phila Pa 1976). 2008;33(4)(suppl):S5-S7. 3. Chou R, Qaseem A, Snow V, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians; American College of Physicians; American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147(7): 478-491. 4. van Tulder M, Becker A, Bekkering T, et al; COST B13 Working Group on Guidelines for the Management of Acute Low Back Pain in Primary Care. Chapter 3: European guidelines for the management of acute nonspecific low back pain in primary care. Eur Spine J. 2006;15(suppl 2):S169-S191. 5. Airaksinen O, Brox JI, Cedraschi C, et al; COST B13 Working Group on Guidelines for Chronic Low Back Pain. Chapter 4: European guidelines for the management of chronic nonspecific low back pain. Eur Spine J. 2006;15(suppl 2):S192-S300.
plicated endocarditis, early disease, heart failure), but subsequent reports are conflicting3-5 and the role of surgery on mortality in PVE remains unclear. We agree with the authors that further study is indicated, ideally a randomized clinical trial with randomization to surgery within a clearly defined time frame vs medical therapy. Alternatively, a prospective follow-up of a large cohort of patients with prosthetic valves (potentially by a comprehensive registry) could enable an analysis of all patients who develop PVE and eliminate any potential referral bias. Sanjiv M. Baxi, MD, MS Catherine Liu, MD Author Affiliations: Division of Infectious Diseases, Department of Medicine, University of California, San Francisco. Corresponding Author: Sanjiv M. Baxi, MD, MS, Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, 513 Parnassus Ave, Room S380, San Francisco, CA 94143 ([email protected]). Conflict of Interest Disclosures: None reported.
Mortality and Timing of Surgery for Prosthetic Valve Endocarditis To the Editor We read with interest the recent large prospective cohort study published by Lalani and colleagues1 that evaluated outcomes associated with early surgery vs medical therapy for prosthetic valve endocarditis (PVE). After adjusting for selection and survival bias, no mortality benefit was observed with early surgery. We encourage researchers and especially clinicians to interpret this finding with caution. Although the authors should be commended for their rigorous efforts to control for treatment selection and survivor bias, they failed to account for the selection and survival biases introduced as a function of patient referral from outside facilities, which accounted for approximately 40% of all patients. Patients were excluded from outside transfer if (1) they already died prior to transfer, (2) they were too sick to transfer but may have benefited from surgical expertise, or (3) they already had surgery (an exclusion criterion for entry into the study). These exclusions, which were built into the design of the study for feasibility, may have selected out a subgroup of individuals who may have had a differential impact on the outcome. Another important limitation is that the timing of PVE diagnosis relative to the timing of valve replacement surgery was not assessed. Notably, “early surgery” was defined liberally and included replacement or repair of the infected prosthetic valve at any point during the initial hospitalization without specifying a time frame. The median time from admission to surgery was 8 days (quintile 1 to 3, 4-20 days). In contrast, in a recently published randomized trial that demonstrated benefit of early surgery for native valve endocarditis, patients underwent surgery within 48 hours of diagnosis, with a median time to surgery of 24 hours.2 Thus, clinicians should be cognizant of how differences in definitions of “early surgery” may affect outcomes when extrapolating the results of this study into clinical care. Early studies showed a possible mortality benefit of surgical intervention over nonoperative management in fairly specific clinical settings (eg, Staphylococcus aureus infection, com480
1. Lalani T, Chu VH, Park LP, et al; International Collaboration on Endocarditis–Prospective Cohort Study Investigators. In-hospital and 1-year mortality in patients undergoing early surgery for prosthetic valve endocarditis. JAMA Intern Med. 2013;173(16):1495-1504. 2. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012;366(26):2466-2473. 3. Wolff M, Witchitz S, Chastang C, Régnier B, Vachon F. Prosthetic valve endocarditis in the ICU: prognostic factors of overall survival in a series of 122 cases and consequences for treatment decision. Chest. 1995;108(3):688-694. 4. López J, Revilla A, Vilacosta I, et al. Definition, clinical profile, microbiological spectrum, and prognostic factors of early-onset prosthetic valve endocarditis. Eur Heart J. 2007;28(6):760-765. 5. Chirouze C, Cabell CH, Fowler VG Jr, et al; International Collaboration on Endocarditis Study Group. Prognostic factors in 61 cases of Staphylococcus aureus prosthetic valve infective endocarditis from the International Collaboration on Endocarditis merged database. Clin Infect Dis. 2004;38(9):1323-1327.
In Reply We agree with Baxi and colleagues that it is important to consider the inherent limitations of this observational study even with our efforts to reduce treatment selection and survival biases. Referral bias affecting eligibility for the International Collaboration on Endocarditis (ICE) prospective registry may influence our findings because ICE participating sites are tertiary care centers and patients are largely transferred for complications related to endocarditis requiring surgery.1 Unfortunately, the ICE–Prospective Cohort Study registry did not capture information on patients who are not transferred or receive surgery prior to transfer. Baxi and Liu correctly emphasize that these patients represent a subgroup with urgent surgical needs and for whom earlier surgery could influence survival. However, surgical urgency was one of the strongest variables associated with higher operative mortality in the Society of Thoracic Surgery database.2 Regarding timing of surgical intervention for infective endocarditis, the small, randomized trial, Early Surgery Versus Conventional Treatment in Infective Endocarditis (EASE), showed that early surgery within 48 hours of diagnosis of native valve infective endocarditis was associated with reduced embolic events.3 However, there was no mortality benefit compared with delayed surgery. Furthermore, because the major-
JAMA Internal Medicine March 2014 Volume 174, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida Atlantic University User on 05/24/2015
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Letters
ity of patients in the EASE cohort had other indication for surgery, this study does not allow comparison of outcome for surgery vs medical therapy. Additional studies to assess the timing of surgery need to consider other potential factors, including specific indication for surgery and its timing related to diagnosis, operative risk, and other clinical factors that may affect whether and when surgery is performed for complicated infective endocarditis. Tahaniyat Lalani, MD, MHS Andrew Wang, MD Author Affiliations: Infectious Disease Clinical Research Program, Bethesda, Maryland (Lalani); Duke University Medical Center, Durham, North Carolina (Wang). Corresponding Author: Tahaniyat Lalani, MD, MHS, Naval Medical Center Portsmouth, 620 John Paul Jones Cir, Bldg 3, First Floor, Portsmouth, VA 23708 ([email protected]). Conflict of Interest Disclosures: None reported.
diuretics may simply reflect an oversight, albeit unjustified, in not switching to oral therapy when warranted. A report of the percentage change in loop diuretic dose from admission to discharge would be beneficial. Lastly, although caution should be exercised when initiating β-blocker therapy soon after intravenous inotrope administration, a report of the average initial β-blocker dosage as well as the average length of stay among patients who received inotropes would be valuable to determine if the time frame between inotrope discontinuation and loop diuretic initiation makes initiation of β-blocker therapy justifiable, ideally with a cautious low initial dose. In addition, an analysis of inotrope use would be of interest, since the concomitant administration of β-blockers with milrinone is preferred. Because initiation of low-dose β-blocker therapy in stable patients prior to discharge has revealed favorable mortality effects, a careful assessment of ideal candidates following adherence to performance measures should be realized.
1. Kanafani ZA, Kanj SS, Cabell CH, et al. Revisiting the effect of referral bias on the clinical spectrum of infective endocarditis in adults. Eur J Clin Microbiol Infect Dis. 2010;29(10):1203-1210.
Marta A. Miyares, PharmD, BCPS
2. Gaca JG, Sheng S, Daneshmand MA, et al. Outcomes for endocarditis surgery in North America: a simplified risk scoring system. J Thorac Cardiovasc Surg. 2011;141(1):98-106.
Author Affiliation: Department of Pharmacy, Jackson Memorial Hospital, Miami, Florida.
3. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012;366(26):2466-2473.
Corresponding Author: Marta A. Miyares, PharmD, BCPS, Department of Pharmacy, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami, FL 33136 ([email protected]). Conflict of Interest Disclosures: None reported.
Caution Warranted When Defining Contraindications in Initiating β-Blocker Therapy To the Editor Dharmarajan and colleagues1 are to be commended for their review of hospitalized patients with acute decompensated heart failure initiated on β-blocker therapy during predefined periods of clinical instability, which showed that at least 40% of those initiated had at least 1 possible contraindication (care in an intensive care unit, administration of intravenous loop diuretic on the day of discharge, or having received an intravenous inotrope during hospitalization). Though the authors of this study attempted to include patients newly started on β-blocker therapy, defined as no β-blocker treatment on hospital days 1 and 2 and initiation of β-blocker therapy by the day of discharge, there are a few aspects of this study that deserve emphasis and further clarification. It would be interesting to note the use of β-blockers prior to hospitalization, as guideline recommendations2 state to continue maintenance therapy if hemodynamically stable and no contraindications exist. The question relates to how many of those categorized as new therapy starts were actually receiving β-blocker therapy prior to admission and inadvertently stopped when they could have continued or at least have a dose reduction. Essentially, grouping those patients in a cohort of those who should have continued treatment would be most fitting. Second, the authors assume that those receiving intravenous loop diuretics on the day of discharge had unresolved volume overload. Depending on physical findings, laboratory levels, and net fluid change at discharge, patients may have indeed achieved optimal volume status, as reflected by a decrease in loop diuretic dose from admission. Continued intravenous loop jamainternalmedicine.com
1. Dharmarajan K, Masoudi FA, Spertus JA, Li SX, Krumholz HM. Contraindicated initiation of β-blocker therapy in patients hospitalized for heart failure. JAMA Intern Med. 2013;173(16):1547-1549. 2. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.
In Reply Dr Miyares raises several excellent points, correctly noting that our study sample may include persons receiving β-blocker therapy prior to admission who had treatment temporarily withheld early during hospitalization. Without access to outpatient pharmacy claims, we could not ascertain the proportion of our study sample in this category. However, even in the unlikely scenario that three-quarters of our sample had received β-blocker therapy prior to hospitalization, our findings still imply that many thousands of patients hospitalized for acute heart failure in the United States are initiated on β-blocker treatment despite potential contraindications. In addition, the receipt of β-blocker therapy prior to hospitalization does not imply that reinitiating treatment prior to discharge is necessarily safe. This finding has yet to be demonstrated and would require a large, prospective clinical trial to avoid confounding. Dr Miyares also correctly notes that some patients may receive intravenous diuretics despite euvolemia because of physician oversight. However, there is no evidence that this practice is widespread. Furthermore, a reduction in diuretic dose from the day of admission cannot be assumed to imply that euvolemia has been reached, as Dr Miyares suggests. Dose reduction can occur in multiple settings, including poor hemoJAMA Internal Medicine March 2014 Volume 174, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida Atlantic University User on 05/24/2015
481
1. Mafi JN, McCarthy EP, Davis RB, Landon BE. Worsening trends in the management and treatment of back pain. JAMA Intern Med. 2013;173(17):15731581. 2. Haldeman S, Carroll L, Cassidy JD, Schubert J, Nygren A; Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. The Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders: executive summary. Spine (Phila Pa 1976). 2008;33(4)(suppl):S5-S7. 3. Chou R, Qaseem A, Snow V, et al; Clinical Efficacy Assessment Subcommittee of the American College of Physicians; American College of Physicians; American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147(7): 478-491. 4. van Tulder M, Becker A, Bekkering T, et al; COST B13 Working Group on Guidelines for the Management of Acute Low Back Pain in Primary Care. Chapter 3: European guidelines for the management of acute nonspecific low back pain in primary care. Eur Spine J. 2006;15(suppl 2):S169-S191. 5. Airaksinen O, Brox JI, Cedraschi C, et al; COST B13 Working Group on Guidelines for Chronic Low Back Pain. Chapter 4: European guidelines for the management of chronic nonspecific low back pain. Eur Spine J. 2006;15(suppl 2):S192-S300.
plicated endocarditis, early disease, heart failure), but subsequent reports are conflicting3-5 and the role of surgery on mortality in PVE remains unclear. We agree with the authors that further study is indicated, ideally a randomized clinical trial with randomization to surgery within a clearly defined time frame vs medical therapy. Alternatively, a prospective follow-up of a large cohort of patients with prosthetic valves (potentially by a comprehensive registry) could enable an analysis of all patients who develop PVE and eliminate any potential referral bias. Sanjiv M. Baxi, MD, MS Catherine Liu, MD Author Affiliations: Division of Infectious Diseases, Department of Medicine, University of California, San Francisco. Corresponding Author: Sanjiv M. Baxi, MD, MS, Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, 513 Parnassus Ave, Room S380, San Francisco, CA 94143 ([email protected]). Conflict of Interest Disclosures: None reported.
Mortality and Timing of Surgery for Prosthetic Valve Endocarditis To the Editor We read with interest the recent large prospective cohort study published by Lalani and colleagues1 that evaluated outcomes associated with early surgery vs medical therapy for prosthetic valve endocarditis (PVE). After adjusting for selection and survival bias, no mortality benefit was observed with early surgery. We encourage researchers and especially clinicians to interpret this finding with caution. Although the authors should be commended for their rigorous efforts to control for treatment selection and survivor bias, they failed to account for the selection and survival biases introduced as a function of patient referral from outside facilities, which accounted for approximately 40% of all patients. Patients were excluded from outside transfer if (1) they already died prior to transfer, (2) they were too sick to transfer but may have benefited from surgical expertise, or (3) they already had surgery (an exclusion criterion for entry into the study). These exclusions, which were built into the design of the study for feasibility, may have selected out a subgroup of individuals who may have had a differential impact on the outcome. Another important limitation is that the timing of PVE diagnosis relative to the timing of valve replacement surgery was not assessed. Notably, “early surgery” was defined liberally and included replacement or repair of the infected prosthetic valve at any point during the initial hospitalization without specifying a time frame. The median time from admission to surgery was 8 days (quintile 1 to 3, 4-20 days). In contrast, in a recently published randomized trial that demonstrated benefit of early surgery for native valve endocarditis, patients underwent surgery within 48 hours of diagnosis, with a median time to surgery of 24 hours.2 Thus, clinicians should be cognizant of how differences in definitions of “early surgery” may affect outcomes when extrapolating the results of this study into clinical care. Early studies showed a possible mortality benefit of surgical intervention over nonoperative management in fairly specific clinical settings (eg, Staphylococcus aureus infection, com480
1. Lalani T, Chu VH, Park LP, et al; International Collaboration on Endocarditis–Prospective Cohort Study Investigators. In-hospital and 1-year mortality in patients undergoing early surgery for prosthetic valve endocarditis. JAMA Intern Med. 2013;173(16):1495-1504. 2. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012;366(26):2466-2473. 3. Wolff M, Witchitz S, Chastang C, Régnier B, Vachon F. Prosthetic valve endocarditis in the ICU: prognostic factors of overall survival in a series of 122 cases and consequences for treatment decision. Chest. 1995;108(3):688-694. 4. López J, Revilla A, Vilacosta I, et al. Definition, clinical profile, microbiological spectrum, and prognostic factors of early-onset prosthetic valve endocarditis. Eur Heart J. 2007;28(6):760-765. 5. Chirouze C, Cabell CH, Fowler VG Jr, et al; International Collaboration on Endocarditis Study Group. Prognostic factors in 61 cases of Staphylococcus aureus prosthetic valve infective endocarditis from the International Collaboration on Endocarditis merged database. Clin Infect Dis. 2004;38(9):1323-1327.
In Reply We agree with Baxi and colleagues that it is important to consider the inherent limitations of this observational study even with our efforts to reduce treatment selection and survival biases. Referral bias affecting eligibility for the International Collaboration on Endocarditis (ICE) prospective registry may influence our findings because ICE participating sites are tertiary care centers and patients are largely transferred for complications related to endocarditis requiring surgery.1 Unfortunately, the ICE–Prospective Cohort Study registry did not capture information on patients who are not transferred or receive surgery prior to transfer. Baxi and Liu correctly emphasize that these patients represent a subgroup with urgent surgical needs and for whom earlier surgery could influence survival. However, surgical urgency was one of the strongest variables associated with higher operative mortality in the Society of Thoracic Surgery database.2 Regarding timing of surgical intervention for infective endocarditis, the small, randomized trial, Early Surgery Versus Conventional Treatment in Infective Endocarditis (EASE), showed that early surgery within 48 hours of diagnosis of native valve infective endocarditis was associated with reduced embolic events.3 However, there was no mortality benefit compared with delayed surgery. Furthermore, because the major-
JAMA Internal Medicine March 2014 Volume 174, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida Atlantic University User on 05/24/2015
jamainternalmedicine.com
Letters
ity of patients in the EASE cohort had other indication for surgery, this study does not allow comparison of outcome for surgery vs medical therapy. Additional studies to assess the timing of surgery need to consider other potential factors, including specific indication for surgery and its timing related to diagnosis, operative risk, and other clinical factors that may affect whether and when surgery is performed for complicated infective endocarditis. Tahaniyat Lalani, MD, MHS Andrew Wang, MD Author Affiliations: Infectious Disease Clinical Research Program, Bethesda, Maryland (Lalani); Duke University Medical Center, Durham, North Carolina (Wang). Corresponding Author: Tahaniyat Lalani, MD, MHS, Naval Medical Center Portsmouth, 620 John Paul Jones Cir, Bldg 3, First Floor, Portsmouth, VA 23708 ([email protected]). Conflict of Interest Disclosures: None reported.
diuretics may simply reflect an oversight, albeit unjustified, in not switching to oral therapy when warranted. A report of the percentage change in loop diuretic dose from admission to discharge would be beneficial. Lastly, although caution should be exercised when initiating β-blocker therapy soon after intravenous inotrope administration, a report of the average initial β-blocker dosage as well as the average length of stay among patients who received inotropes would be valuable to determine if the time frame between inotrope discontinuation and loop diuretic initiation makes initiation of β-blocker therapy justifiable, ideally with a cautious low initial dose. In addition, an analysis of inotrope use would be of interest, since the concomitant administration of β-blockers with milrinone is preferred. Because initiation of low-dose β-blocker therapy in stable patients prior to discharge has revealed favorable mortality effects, a careful assessment of ideal candidates following adherence to performance measures should be realized.
1. Kanafani ZA, Kanj SS, Cabell CH, et al. Revisiting the effect of referral bias on the clinical spectrum of infective endocarditis in adults. Eur J Clin Microbiol Infect Dis. 2010;29(10):1203-1210.
Marta A. Miyares, PharmD, BCPS
2. Gaca JG, Sheng S, Daneshmand MA, et al. Outcomes for endocarditis surgery in North America: a simplified risk scoring system. J Thorac Cardiovasc Surg. 2011;141(1):98-106.
Author Affiliation: Department of Pharmacy, Jackson Memorial Hospital, Miami, Florida.
3. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med. 2012;366(26):2466-2473.
Corresponding Author: Marta A. Miyares, PharmD, BCPS, Department of Pharmacy, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami, FL 33136 ([email protected]). Conflict of Interest Disclosures: None reported.
Caution Warranted When Defining Contraindications in Initiating β-Blocker Therapy To the Editor Dharmarajan and colleagues1 are to be commended for their review of hospitalized patients with acute decompensated heart failure initiated on β-blocker therapy during predefined periods of clinical instability, which showed that at least 40% of those initiated had at least 1 possible contraindication (care in an intensive care unit, administration of intravenous loop diuretic on the day of discharge, or having received an intravenous inotrope during hospitalization). Though the authors of this study attempted to include patients newly started on β-blocker therapy, defined as no β-blocker treatment on hospital days 1 and 2 and initiation of β-blocker therapy by the day of discharge, there are a few aspects of this study that deserve emphasis and further clarification. It would be interesting to note the use of β-blockers prior to hospitalization, as guideline recommendations2 state to continue maintenance therapy if hemodynamically stable and no contraindications exist. The question relates to how many of those categorized as new therapy starts were actually receiving β-blocker therapy prior to admission and inadvertently stopped when they could have continued or at least have a dose reduction. Essentially, grouping those patients in a cohort of those who should have continued treatment would be most fitting. Second, the authors assume that those receiving intravenous loop diuretics on the day of discharge had unresolved volume overload. Depending on physical findings, laboratory levels, and net fluid change at discharge, patients may have indeed achieved optimal volume status, as reflected by a decrease in loop diuretic dose from admission. Continued intravenous loop jamainternalmedicine.com
1. Dharmarajan K, Masoudi FA, Spertus JA, Li SX, Krumholz HM. Contraindicated initiation of β-blocker therapy in patients hospitalized for heart failure. JAMA Intern Med. 2013;173(16):1547-1549. 2. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.
In Reply Dr Miyares raises several excellent points, correctly noting that our study sample may include persons receiving β-blocker therapy prior to admission who had treatment temporarily withheld early during hospitalization. Without access to outpatient pharmacy claims, we could not ascertain the proportion of our study sample in this category. However, even in the unlikely scenario that three-quarters of our sample had received β-blocker therapy prior to hospitalization, our findings still imply that many thousands of patients hospitalized for acute heart failure in the United States are initiated on β-blocker treatment despite potential contraindications. In addition, the receipt of β-blocker therapy prior to hospitalization does not imply that reinitiating treatment prior to discharge is necessarily safe. This finding has yet to be demonstrated and would require a large, prospective clinical trial to avoid confounding. Dr Miyares also correctly notes that some patients may receive intravenous diuretics despite euvolemia because of physician oversight. However, there is no evidence that this practice is widespread. Furthermore, a reduction in diuretic dose from the day of admission cannot be assumed to imply that euvolemia has been reached, as Dr Miyares suggests. Dose reduction can occur in multiple settings, including poor hemoJAMA Internal Medicine March 2014 Volume 174, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Florida Atlantic University User on 05/24/2015
481
