Letters
less than 7.0%, and systolic blood pressure less than 130 mm Hg. These recommendations, therefore, became the standard for patients randomized to the control group or screened with no evidence of CAD. Because the 2006 American Heart Association/American College of Cardiology guidelines3 recommended that an LDL-C target level less than 70 mg/dL was reasonable for patients with known CAD, we chose that as a target for patients assigned to aggressive medical management. Because there was enough evidence to support testing a target HbA1c of less than 6% in the intensive treatment group of the ACCORD glucose management trial,4 we chose that as our target. However, as Potier and colleagues note, when the ACCORD glucose management trial was stopped early due to increased risk of mortality among patients randomized to intensive glucose management, this recommended target was abandoned in FACTOR-64. Because there was enough evidence to support testing a target systolic blood pressure less than 120 mm Hg for patients with diabetes in the ACCORD blood pressure trial,5 we chose that as our target. However, unlike the ACCORD glucose management trial, the results of the ACCORD blood pressure trial were not so definitive. Specifically, the annual rates of the primary end point in the groups receiving intensive therapy vs standard therapy were a nonsignificant 1.87% vs 2.09%, respectively. However, the annual rates of stroke were significantly reduced in the group receiving intensive therapy (0.32% vs 0.53% for the group receiving standard therapy; hazard ratio, 0.59; P = .01). Therefore, it was our opinion that the correct blood pressure target for patients with diabetes was still not confirmed, and we did not change our blood pressure recommendations for FACTOR-64. We think our decision was also justified by the later initiation of the Systolic Blood Pressure Intervention Trial6 designed to test a systolic blood pressure target of less than 120 mm Hg for patients without diabetes. In addition, less than 50% of the patients identified for aggressive medical therapy in FACTOR-64 actually reached the individual targets for LDL-C, HbA1c, or blood pressure. Much remains to be accomplished in the areas of adherence and tolerability in relation to aggressive medical management to achieve the optimal targets for prevention, whatever those targets ultimately turn out to be, for asymptomatic patients with diabetes. Only when those targets are actually achieved in appropriately powered randomized trials can the hypothesis of individualized therapy for asymptomatic patients with diabetes, risk-stratified by advanced imaging, be adequately tested. Joseph B. Muhlestein, MD Donald L. Lappe, MD Jeffrey L. Anderson, MD
2. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care. 2007;30(suppl 1):S4-S41. 3. Smith SC Jr, Allen J, Blair SN, et al; AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113 (19):2363-2372. 4. Gerstein HC, Miller ME, Genuth S, et al; ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818-828. 5. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585. 6. Ambrosius WT, Sink KM, Foy CG, et al; SPRINT Study Research Group. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials. 2014;11(5):532-546.
Duty Hour Reforms and Patient Outcomes To the Editor The study by Dr Patel and colleagues1 examined the association between the adoption of duty hour reforms for residents and various clinical outcomes such as patient mortality. The efficacy of the reforms is of great interest because these regulations necessitate expensive and timeconsuming changes in organizational structure. Despite such large changes, the authors found no significant correlation between adoption of the reforms and clinical outcomes. However, as the authors mentioned in the discussion, associations between duty hour reforms and clinical outcomes are called into question by the absence of directly reported rates of compliance. Previous studies have shown rates of compliance to be far from 100%. In a study by Landrigan et al2 studying rates of compliance with the 2003 duty hour reforms, 83.6% of interns reported violating work-hour regulations during at least 1 month of the study. More recently, in 2013, Drolet et al3 verified violations of compliance and reported that 42.9% of residents in their study admitted to falsifying their work hours at some point in time. Using stated reform adoption as a metric for reform implementation could lead to biased estimates of compliance. Given the above considerations, the study by Patel et al should have directly measured rates of compliance with duty hour regulations. Haley Hunter-Zinck, PhD Author Affiliation: Federal University of Rio Grande do Sul, Porto Alegre, Brazil. Corresponding Author: Haley Hunter-Zinck, PhD, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves 9500, Porto Alegre, RS 91501-970, Brazil ([email protected]).
Author Affiliations: Intermountain Medical Center Heart Institute, Murray, Utah.
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1. Young LH, Wackers FJ, Chyun DA, et al; DIAD Investigators. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 2009;301(15): 1547-1555.
Corresponding Author: Joseph B. Muhlestein, MD, Intermountain Medical Center, Cardiovascular Department, 5121 S Cottonwood St, Murray, UT 84107 ([email protected]).
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES).
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA. 2014;312(22):2364-2373.
JAMA March 24/31, 2015 Volume 313, Number 12 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Letters
2. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 3. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373.
In Reply We evaluated the association of the 2011 Accreditation Council for Graduate Medical Education duty hour reforms with 30-day all-location mortality and 30-day allcause readmissions. This nationwide study evaluated 6 384 273 admissions from 2 790 356 patients at 3104 hospitals. We compared outcomes in more intensive teaching hospitals relative to less intensive or nonteaching hospitals. In the first year after the reforms, there were no significant associations between the 2011 duty hour reforms and patient outcomes. In our risk-adjusted models, the odds ratios for mortality were 1.00 (95% CI, 0.96-1.03) for combined medical conditions and 0.99 (95% CI, 0.94-1.04) for combined surgical conditions. Similarly, for readmissions, the adjusted odds ratios were 1.00 (95% CI, 0.97-1.02) for combined medical conditions and 1.00 (95% CI, 0.98-1.03) for combined surgical conditions. Because our findings showed odds ratios so close to 1, there would have to be a very large rate of noncompliance for our model to have missed an actual substantial effect on patient outcomes associated with the reforms because noncompliers, by definition, would have an odds ratio of 1. If we think of our results as a mixture of compliers and noncompliers, and we assume a noncompliance rate of 20%, it would only increase the upper 95% confidence bound of the mortality estimate for combined medical conditions from 1.03 to 1.04 (calculation based on the method of Freedman 1 and Zeger et al 2 ). Given the scope and strengths of our study, as well as the proximity of our odds ratio estimates to 1.0, it is extremely unlikely that any reasonable estimate of noncompliance would appreciably change our results. Furthermore, the 2 studies referenced by Dr HunterZinck described survey responses on violations of duty hour rules.3,4 Although we agree that compliance rates were likely not 100%, based on the data presented, we disagree with the conclusion that the rates are extremely low. Neither of the studies cited directly measured rates of hospital compliance with duty hour reforms or resident behavior. Instead they presented the percentage of residents or program directors that cited some noncompliance. Consider, for example, a teaching hospital that adopts the new reforms. Some of the residents within that hospital may violate the rules on rare occasions during the year. However, overall compliance rates may still be quite high. Indeed, Drolet et al 4 found that 90.7% of respondents reported that they either mostly or always agreed with the statement “I comply with ALL duty hour regulations.” Furthermore, a national survey found that there was significant concern among residents that the 2011 duty hour reforms may have led to an increase in medical errors.5 The fact that
such a concern existed suggests that there was enough compliance to justify this worry. Mitesh S. Patel, MD, MBA, MS Dylan S. Small, PhD Jeffrey H. Silber, MD, PhD Author Affiliations: University of Pennsylvania, Philadelphia. Corresponding Author: Mitesh S. Patel, MD, MBA, MS, University of Pennsylvania, 423 Guardian Dr, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Freedman DA. Randomization does not justify logistic regression. Stat Sci. 2008;23:237-249. 2. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44(4):1049-1060. 3. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 4. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373. 5. Sen S, Kranzler HR, Didwania AK, et al. Effects of the 2011 duty hour reforms on interns and their patients: a prospective longitudinal cohort study. JAMA Intern Med. 2013;173(8):657-662.
Treatment to Prevent Hepatitis B Virus Reactivation in Patients With Lymphoma Receiving Chemotherapy To the Editor Dr Huang and colleagues1 showed the benefits of using a drug with a better resistance profile (entecavir) in preventing hepatitis B virus (HBV) reactivation in patients with lymphoma receiving chemotherapy who were seropositive for the hepatitis B surface antigen. Only 6.6% (n = 4) of patients experienced HBV reactivation in the entecavir group. Entecavir has an extremely favorable resistance profile with only 1.2% of patients experiencing viral breakthrough due to resistance after 5 years of treatment.2 In addition, high HBV DNA levels have been associated with increased risk of resistance.2 Patients included in this study were both treatment naive and had a baseline HBV DNA titer of less than 1000 copies/mL, which is very low. Considering these baseline characteristics, the viral breakthrough rate of 6.6% seems higher than what would be expected. One possible explanation for the relatively high breakthrough rate in this study is the widespread availability of lamivudine in China, which may have caused selection pressure leading to lamivudine-resistant viruses circulating in the community.3,4 Cross-resistance between lamivudine and entecavir is well-known, and even in the setting of lamivudine exposure with no documented resistance to lamivudine, the risk of entecavir resistance is increased.2,5 Thus, even if the patients in this study were treatment naive, they still could have been infected with a resistant virus, which may explain the relatively high breakthrough rate. The authors did not report the resistance profile of the patients who experienced viral reactivation. If entecavir resistance is demonstrated in these patients, this may have important clinical implications for countries with high lamivudine
jama.com
(Reprinted) JAMA March 24/31, 2015 Volume 313, Number 12
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Rice University User on 05/20/2015
1269
less than 7.0%, and systolic blood pressure less than 130 mm Hg. These recommendations, therefore, became the standard for patients randomized to the control group or screened with no evidence of CAD. Because the 2006 American Heart Association/American College of Cardiology guidelines3 recommended that an LDL-C target level less than 70 mg/dL was reasonable for patients with known CAD, we chose that as a target for patients assigned to aggressive medical management. Because there was enough evidence to support testing a target HbA1c of less than 6% in the intensive treatment group of the ACCORD glucose management trial,4 we chose that as our target. However, as Potier and colleagues note, when the ACCORD glucose management trial was stopped early due to increased risk of mortality among patients randomized to intensive glucose management, this recommended target was abandoned in FACTOR-64. Because there was enough evidence to support testing a target systolic blood pressure less than 120 mm Hg for patients with diabetes in the ACCORD blood pressure trial,5 we chose that as our target. However, unlike the ACCORD glucose management trial, the results of the ACCORD blood pressure trial were not so definitive. Specifically, the annual rates of the primary end point in the groups receiving intensive therapy vs standard therapy were a nonsignificant 1.87% vs 2.09%, respectively. However, the annual rates of stroke were significantly reduced in the group receiving intensive therapy (0.32% vs 0.53% for the group receiving standard therapy; hazard ratio, 0.59; P = .01). Therefore, it was our opinion that the correct blood pressure target for patients with diabetes was still not confirmed, and we did not change our blood pressure recommendations for FACTOR-64. We think our decision was also justified by the later initiation of the Systolic Blood Pressure Intervention Trial6 designed to test a systolic blood pressure target of less than 120 mm Hg for patients without diabetes. In addition, less than 50% of the patients identified for aggressive medical therapy in FACTOR-64 actually reached the individual targets for LDL-C, HbA1c, or blood pressure. Much remains to be accomplished in the areas of adherence and tolerability in relation to aggressive medical management to achieve the optimal targets for prevention, whatever those targets ultimately turn out to be, for asymptomatic patients with diabetes. Only when those targets are actually achieved in appropriately powered randomized trials can the hypothesis of individualized therapy for asymptomatic patients with diabetes, risk-stratified by advanced imaging, be adequately tested. Joseph B. Muhlestein, MD Donald L. Lappe, MD Jeffrey L. Anderson, MD
2. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care. 2007;30(suppl 1):S4-S41. 3. Smith SC Jr, Allen J, Blair SN, et al; AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113 (19):2363-2372. 4. Gerstein HC, Miller ME, Genuth S, et al; ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818-828. 5. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585. 6. Ambrosius WT, Sink KM, Foy CG, et al; SPRINT Study Research Group. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials. 2014;11(5):532-546.
Duty Hour Reforms and Patient Outcomes To the Editor The study by Dr Patel and colleagues1 examined the association between the adoption of duty hour reforms for residents and various clinical outcomes such as patient mortality. The efficacy of the reforms is of great interest because these regulations necessitate expensive and timeconsuming changes in organizational structure. Despite such large changes, the authors found no significant correlation between adoption of the reforms and clinical outcomes. However, as the authors mentioned in the discussion, associations between duty hour reforms and clinical outcomes are called into question by the absence of directly reported rates of compliance. Previous studies have shown rates of compliance to be far from 100%. In a study by Landrigan et al2 studying rates of compliance with the 2003 duty hour reforms, 83.6% of interns reported violating work-hour regulations during at least 1 month of the study. More recently, in 2013, Drolet et al3 verified violations of compliance and reported that 42.9% of residents in their study admitted to falsifying their work hours at some point in time. Using stated reform adoption as a metric for reform implementation could lead to biased estimates of compliance. Given the above considerations, the study by Patel et al should have directly measured rates of compliance with duty hour regulations. Haley Hunter-Zinck, PhD Author Affiliation: Federal University of Rio Grande do Sul, Porto Alegre, Brazil. Corresponding Author: Haley Hunter-Zinck, PhD, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves 9500, Porto Alegre, RS 91501-970, Brazil ([email protected]).
Author Affiliations: Intermountain Medical Center Heart Institute, Murray, Utah.
1268
1. Young LH, Wackers FJ, Chyun DA, et al; DIAD Investigators. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 2009;301(15): 1547-1555.
Corresponding Author: Joseph B. Muhlestein, MD, Intermountain Medical Center, Cardiovascular Department, 5121 S Cottonwood St, Murray, UT 84107 ([email protected]).
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES).
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Patel MS, Volpp KG, Small DS, et al. Association of the 2011 ACGME resident duty hour reforms with mortality and readmissions among hospitalized Medicare patients. JAMA. 2014;312(22):2364-2373.
JAMA March 24/31, 2015 Volume 313, Number 12 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Rice University User on 05/20/2015
jama.com
Letters
2. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 3. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373.
In Reply We evaluated the association of the 2011 Accreditation Council for Graduate Medical Education duty hour reforms with 30-day all-location mortality and 30-day allcause readmissions. This nationwide study evaluated 6 384 273 admissions from 2 790 356 patients at 3104 hospitals. We compared outcomes in more intensive teaching hospitals relative to less intensive or nonteaching hospitals. In the first year after the reforms, there were no significant associations between the 2011 duty hour reforms and patient outcomes. In our risk-adjusted models, the odds ratios for mortality were 1.00 (95% CI, 0.96-1.03) for combined medical conditions and 0.99 (95% CI, 0.94-1.04) for combined surgical conditions. Similarly, for readmissions, the adjusted odds ratios were 1.00 (95% CI, 0.97-1.02) for combined medical conditions and 1.00 (95% CI, 0.98-1.03) for combined surgical conditions. Because our findings showed odds ratios so close to 1, there would have to be a very large rate of noncompliance for our model to have missed an actual substantial effect on patient outcomes associated with the reforms because noncompliers, by definition, would have an odds ratio of 1. If we think of our results as a mixture of compliers and noncompliers, and we assume a noncompliance rate of 20%, it would only increase the upper 95% confidence bound of the mortality estimate for combined medical conditions from 1.03 to 1.04 (calculation based on the method of Freedman 1 and Zeger et al 2 ). Given the scope and strengths of our study, as well as the proximity of our odds ratio estimates to 1.0, it is extremely unlikely that any reasonable estimate of noncompliance would appreciably change our results. Furthermore, the 2 studies referenced by Dr HunterZinck described survey responses on violations of duty hour rules.3,4 Although we agree that compliance rates were likely not 100%, based on the data presented, we disagree with the conclusion that the rates are extremely low. Neither of the studies cited directly measured rates of hospital compliance with duty hour reforms or resident behavior. Instead they presented the percentage of residents or program directors that cited some noncompliance. Consider, for example, a teaching hospital that adopts the new reforms. Some of the residents within that hospital may violate the rules on rare occasions during the year. However, overall compliance rates may still be quite high. Indeed, Drolet et al 4 found that 90.7% of respondents reported that they either mostly or always agreed with the statement “I comply with ALL duty hour regulations.” Furthermore, a national survey found that there was significant concern among residents that the 2011 duty hour reforms may have led to an increase in medical errors.5 The fact that
such a concern existed suggests that there was enough compliance to justify this worry. Mitesh S. Patel, MD, MBA, MS Dylan S. Small, PhD Jeffrey H. Silber, MD, PhD Author Affiliations: University of Pennsylvania, Philadelphia. Corresponding Author: Mitesh S. Patel, MD, MBA, MS, University of Pennsylvania, 423 Guardian Dr, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Freedman DA. Randomization does not justify logistic regression. Stat Sci. 2008;23:237-249. 2. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44(4):1049-1060. 3. Landrigan CP, Barger LK, Cade BE, Ayas NT, Czeisler CA. Interns’ compliance with accreditation council for graduate medical education work-hour limits. JAMA. 2006;296(9):1063-1070. 4. Drolet BC, Schwede M, Bishop KD, Fischer SA. Compliance and falsification of duty hours: reports from residents and program directors. J Grad Med Educ. 2013;5(3):368-373. 5. Sen S, Kranzler HR, Didwania AK, et al. Effects of the 2011 duty hour reforms on interns and their patients: a prospective longitudinal cohort study. JAMA Intern Med. 2013;173(8):657-662.
Treatment to Prevent Hepatitis B Virus Reactivation in Patients With Lymphoma Receiving Chemotherapy To the Editor Dr Huang and colleagues1 showed the benefits of using a drug with a better resistance profile (entecavir) in preventing hepatitis B virus (HBV) reactivation in patients with lymphoma receiving chemotherapy who were seropositive for the hepatitis B surface antigen. Only 6.6% (n = 4) of patients experienced HBV reactivation in the entecavir group. Entecavir has an extremely favorable resistance profile with only 1.2% of patients experiencing viral breakthrough due to resistance after 5 years of treatment.2 In addition, high HBV DNA levels have been associated with increased risk of resistance.2 Patients included in this study were both treatment naive and had a baseline HBV DNA titer of less than 1000 copies/mL, which is very low. Considering these baseline characteristics, the viral breakthrough rate of 6.6% seems higher than what would be expected. One possible explanation for the relatively high breakthrough rate in this study is the widespread availability of lamivudine in China, which may have caused selection pressure leading to lamivudine-resistant viruses circulating in the community.3,4 Cross-resistance between lamivudine and entecavir is well-known, and even in the setting of lamivudine exposure with no documented resistance to lamivudine, the risk of entecavir resistance is increased.2,5 Thus, even if the patients in this study were treatment naive, they still could have been infected with a resistant virus, which may explain the relatively high breakthrough rate. The authors did not report the resistance profile of the patients who experienced viral reactivation. If entecavir resistance is demonstrated in these patients, this may have important clinical implications for countries with high lamivudine
jama.com
(Reprinted) JAMA March 24/31, 2015 Volume 313, Number 12
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Rice University User on 05/20/2015
1269
