Letters
Corresponding Author: Peter S. Hussey, PhD, RAND, 20 Park Plaza, Boston, MA 02116 ([email protected]).
Table 2. Order Cancellations and Changes Following Feedback of an Inappropriate Rating No. (%) of Orders
No. of orders initially rated as inappropriatea
Alternative Presentedb Yes
No
2242
895
1347
Canceled
42 (1.9)
4 (0.4)
38 (2.8)
Changed
108 (4.8)
89 (9.9)
19 (1.4)
To one rated as appropriatec
47 (2.1)
40 (4.5)
7 (0.5)
To one rated as not appropriatec,d
61 (2.7)
49 (5.4)
12 (0.9)
2092 (93.3)
802 (89.6)
1290 (95.8)
Not canceled or changed a
Initially Rated as Inappropriatea
Refers to the order each clinician enters into a clinical decision support (CDS) system before being presented with feedback on the appropriateness of the order, which occurred during the intervention period only. Some initial orders that were not rated, rated as appropriate, or rated as equivocal were changed to final orders that were rated as inappropriate.
b
These columns are subsets of all initial orders rated as inappropriate.
c
The denominators used to calculate the percentages for these rows are in row 1.
d
Includes final orders rated as equivocal, as inappropriate, and those not rated because the CDS systems did not find matching appropriateness criteria or the final order was not a study procedure.
A strength of this study is the scale and diversity of settings included. Previous studies of CDS systems for advanced diagnostic imaging ordering were mostly conducted within single organizations or settings and reported mixed results, with some showing an association with increased appropriateness and some reporting low uptake by clinicians.1 Limitations included reliance on clinical data entered by ordering clinicians, who may have imprecisely specified patient characteristics, and variation in how the CDS systems incorporated characteristics into their algorithms. The pre-post design could lead to selection bias or reflect concomitant initiatives or secular trends. Participants may not be representative of all clinicians and settings using CDS systems. The descriptive presentation of results does not indicate statistical significance; heterogeneity of participating organizations requires a more detailed statistical analysis. Implementing CDS systems in real-world settings has many challenges that must be addressed to meaningfully affect patient care. Peter S. Hussey, PhD Justin W. Timbie, PhD Lane F. Burgette, PhD Neil S. Wenger, MD David J. Nyweide, PhD Katherine L. Kahn, MD Author Affiliations: RAND, Boston, Massachusetts (Hussey); RAND, Arlington, Virginia (Timbie, Burgette); RAND-UCLA, Los Angeles, California (Wenger, Kahn); Centers for Medicare & Medicaid Services, Baltimore, Maryland (Nyweide). 2182
Author Contributions: Dr Hussey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hussey, Timbie, Nyweide, Kahn. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Hussey, Timbie, Burgette. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Hussey, Timbie, Burgette. Obtained funding: Hussey, Kahn. Administrative, technical, or material support: Hussey, Nyweide, Kahn. Study supervision: Hussey, Nyweide, Kahn. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: Funding for this project was provided by the Centers for Medicare & Medicaid Services under contract HHSM-500-2005-00028I/ T0003. Role of the Funder/Sponsor: Dr Nyweide (an employee of the Centers for Medicare & Medicaid Services) was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and views expressed are solely those of the authors and are not meant to reflect the views or policies of the US government. Additional Contributions: We thank Ian Brantley, MPH (Remedy Partners), for his assistance in the analysis of clinical decision support data while a paid employee of RAND. 1. Garg AX, Adhikari NK, McDonald H, et al. Effects of computerized clinical decision support systems on practitioner performance and patient outcomes: a systematic review. JAMA. 2005;293(10):1223-1238. 2. Blumenthal D, Tavenner M. The “meaningful use” regulation for electronic health records. N Engl J Med. 2010;363(6):501-504. 3. Protecting Access to Medicare Act of 2014, HR 4302, 113th Congress, 2nd Session, §218 (2014). 4. Centers for Medicare & Medicaid Services. Medicare Imaging Demonstration. http://innovation.cms.gov/initiatives/Medicare-Imaging/. Accessed February 25, 2015. 5. Lewin Group Inc. Medicare Appropriateness of Use Imaging Demonstration: Implementation Report. Falls Church, VA: Lewin Group Inc; 2014.
COMMENT & RESPONSE
Lowering Blood Pressure in Patients With Diabetes To the Editor In their meta-analysis, Dr Emdin and colleagues1 stated that for persons with diabetes and a baseline systolic blood pressure lower than 140 mm Hg, they observed “lower risks of stroke, retinopathy, and progression of albuminuria,” and therefore recommended further blood pressure lowering for these patients “in contrast with the recommendations of the JNC 8 [eighth Joint National Committee] guidelines.” However, Figure 3 in the article showed no significant reduction in retinopathy with a blood pressure lower than 140 mm Hg, and it is clear from eFigures 4 and 8 that the findings for stroke and albuminuria resulted almost entirely from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.2 The primary outcome in the ACCORD trial, a composite of cardiovascular events, was negative for benefit, as was all-cause mortality, and there was a significant increase in
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serious adverse events attributed to intensive therapy. Despite significant reductions in the secondary outcome of stroke and the surrogate measure of albuminuria, the ACCORD trial authors properly concluded their trial to be negative. Emdin and colleagues did not specify a primary outcome for their meta-analysis, but they also found no benefit in cardiovascular events or all-cause mortality for patients with baseline blood pressure below 140 mm Hg. However, they determined serious adverse event data to be “too disparate to allow formal meta-analysis.” They defended this omission by noting that in the ACCORD trial, the rate of serious adverse events was “substantially lower than that of the primary outcome.” However, this was not true for the more relevant comparison with strokes, which were less frequent in the ACCORD trial than were serious adverse events attributed to intensive therapy (98 vs 107). In effect, Emdin and colleagues based their conclusion on a reinterpretation of the ACCORD trial findings without the constraints of a primary outcome or an accounting of harms.
A systematic review also showed that only 30% to 80% of all known published randomized clinical trials were identifiable using MEDLINE.5 Even if relevant records are in MEDLINE, it can be difficult to retrieve them. Therefore, a search of multiple databases (CENTRAL, MEDLINE, and EMBASE) is required not only to collect more clinical trials than from MEDLINE alone but also to obtain a more accurate conclusion, particularly for meta-analyses of large-scale randomized clinical trials.5 In addition, an exhaustive search for a systematic review should include gray literature databases and hand searching, such as conference proceedings, books, journal articles, and other literature. Failure to identify trials reported in the gray literature might affect the results of a systematic review. Clinical decision making has benefited enormously from the availability of systematic reviews and meta-analyses because they represent the highest level in the hierarchy of evidence. Thus, a more extensive literature search is mandatory before the conclusions of this meta-analysis can be used in clinical practice. Min Li, MS Zhenyu Tang, PhD
Frank A. Lederle, MD Author Affiliation: Center for Chronic Disease Outcomes Research, VA Medical Center, Minneapolis, Minnesota. Corresponding Author: Frank A. Lederle, MD, Center for Chronic Disease Outcomes Research, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015; 313(6):603-615. 2. 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.
To the Editor Dr Emdin and colleagues1 investigated the associations between treatment for blood pressure lowering and macrovascular and microvascular outcomes in patients with type 2 diabetes. Lowering blood pressure in individuals with diabetes has become an important topic in research about vascular risk and mortality. However, we would like to add some cautionary words. The authors stated that they complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for meta-analyses of interventional studies and they searched MEDLINE from 1966 to 2014. Nonetheless, this meta-analysis was based solely on 1 database, which may not be sufficient and has the potential to compromise the validity of results.2 Previous studies have demonstrated that use of a single search engine reduces sensitivity to as low as 66%.3 A comparison of EMBASE and MEDLINE4 found that a search of EMBASE retrieved twice as many citations as MEDLINE. In addition, Dickersin et al2 found that a search of MEDLINE alone was not adequate.
Author Affiliations: Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China. Corresponding Author: Zhenyu Tang, PhD, Department of Neurology, Second Affiliated Hospital of Nanchang University, No. 1, Minde Rd, Nanchang, Jiangxi 330006, PR China ([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. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015; 313(6):603-615. 2. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ. 1994;309(6964):1286-1291. 3. Lemeshow AR, Blum RE, Berlin JA, Stoto MA, Colditz GA. Searching one or two databases was insufficient for meta-analysis of observational studies. J Clin Epidemiol. 2005;58(9):867-873. 4. Wilkins T, Gillies RA, Davies K. EMBASE versus MEDLINE for family medicine searches: can MEDLINE searches find the forest or a tree? Can Fam Physician. 2005;51:848-849. 5. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Oxford, England: Cochrane Collaboration; 2011.
In Reply Dr Lederle states that Figure 3 showed no significant reduction in retinopathy for the subgroup with a baseline systolic blood pressure of less than 140 mm Hg. However, because the test for interaction by baseline blood pressure was not significant, it is inappropriate to take the subgroup results as stand-alone results. The overall estimate is the best estimate of an effect across subgroups. 1 Thus, an appropriate interpretation of Figure 3 is that blood pressure lowering was associated with a 13% (95% CI, 1%-24%) reduction in retinopathy, regardless of whether the baseline systolic blood pressure was above or below 140 mm Hg.
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Lederle is correct in pointing out that the standardized analyses of lower initial blood pressure levels were dominated by the results of the ACCORD trial for many outcomes, but this was not the case for retinopathy (eFigure 7). Furthermore, even with the exclusion of the ACCORD trial, the effect of blood pressure lowering on preventing the development or progression of albuminuria and stroke remained significant regardless of initial blood pressure level (relative risk [RR], 0.70 [95% CI, 0.63-0.78] for albuminuria and RR, 0.74 [95% CI, 0.640.86] for stroke after excluding the ACCORD trial). In addition, we reject the notion of needing to prespecify a primary outcome for these meta-analyses. We aimed to understand the effects of blood pressure lowering on all patientrelevant outcomes that have been reported. Even though adverse events were too disparate to pool, we stated in the discussion that “the risk of adverse events associated with [blood pressure] BP-lowering treatments needs to be considered. This requires individualized assessment of the likely absolute benefits and risks with shared decision making between patients and clinicians.” Drs Li and Tang state that “this meta-analysis was based solely on 1 database, which may not be sufficient and has the potential to compromise the validity of results.” However, a key inclusion criterion was the need for trials to have at least 1000 patient-years of follow-up in each group. Although they are correct in noting that MEDLINE may not include citations for all randomized clinical trials, it is unlikely that trials of at least 2000 patient-years in size would have been missed. However, despite the low likelihood of missing relevant trials, we supplemented our search of MEDLINE with the results of a previous meta-analysis2 for which a search of MEDLINE, Web of Science, and Cochrane Collaboration was conducted. In addition, we conducted a hand search of all previous meta-analyses and trials. Therefore, we view our search strategy as having provided a comprehensive search of the relevant literature. Connor A. Emdin, HBSc Kazem Rahimi, DM, MSc Anushka Patel, PhD Author Affiliations: George Institute for Global Health, University of Oxford, Oxford, England (Emdin, Rahimi); George Institute for Global Health, University of Sydney, Sydney, Australia (Patel). Corresponding Author: Kazem Rahimi, DM, MSc, George Institute for Global Health, Oxford Martin School, University of Oxford, 34 Broad St, Oxford OX1 3DB, England ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rahimi reported receiving grants from the National Institute for Health Research and the Oxford Martin School. Dr Patel reported receiving grants from the National Health and Medical Research Council of Australia; and funding to her institution for her participation in an industry advisory board and from Servier Laboratories. The George Institute for Global Health has received grants from several pharmaceutical companies to conduct clinical trials in patients with diabetes. No other disclosures were reported. 1. Matthews JN, Altman DG. Statistics notes: interaction 2: compare effect sizes not P values. BMJ. 1996;313(7060):808. 2. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. 2184
Treatment for Hospitalized Patients With Severe Community-Acquired Pneumonia To the Editor Dr Torres and colleagues1 reported that a substantial subgroup of patients with severe community-acquired pneumonia met criteria for septic shock and severe sepsis.2 The prevalence of septic shock was 23% (28/120). A proportion of patients met severe sepsis criteria (68% [82/ 120]) based on having ratios of PaO2 to fraction of inspired oxygen of less than 250 mm Hg. Could the authors please clarify the volumes of fluid resuscitation administered to the methylprednisolone and placebo groups during the first 5 days after randomization? In addition, did Torres and colleagues observe any interactions between methylprednisolone therapy and the volume of administered fluid? This information is important because the volume of administered fluid may affect radiographic progression. In prior literature, a negative fluid balance during the first 3 days of septic shock predicted survival.3 Also, a conservative strategy of fluid management in patients with acute lung injury improved lung function and shortened the duration of mechanical ventilation and intensive care.4 Dominique J. Pepper, MBChB, MD Author Affiliation: National Institutes of Health, Bethesda, Maryland. Corresponding Author: Dominique J. Pepper, MBChB, MD, Critical Care Medicine Department, National Institutes of Health, Bethesda, MD 20892 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313(7):677-686. 2. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637. 3. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest. 2000;117(6):1749-1754. 4. Wiedemann HP, Wheeler AP, Bernard GR, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575.
In Reply Dr Pepper raises an interesting question related to the potential interaction between fluid balance and radiographic progression, mainly in patients with shock and severe sepsis. Unfortunately, we do not have data on fluid balance during the first 5 days after randomization. Although we cannot specifically answer this question, our general practice was to keep patients in a negative or at least even fluid balance. Because the study was blinded and randomized, we do not think that changes in fluid balance accounted for differences in radiographic resolution. Furthermore, we do not know of any mechanism whereby corticosteroid use could promote a negative fluid balance and result in radiographic improvement. We agree
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Corresponding Author: Peter S. Hussey, PhD, RAND, 20 Park Plaza, Boston, MA 02116 ([email protected]).
Table 2. Order Cancellations and Changes Following Feedback of an Inappropriate Rating No. (%) of Orders
No. of orders initially rated as inappropriatea
Alternative Presentedb Yes
No
2242
895
1347
Canceled
42 (1.9)
4 (0.4)
38 (2.8)
Changed
108 (4.8)
89 (9.9)
19 (1.4)
To one rated as appropriatec
47 (2.1)
40 (4.5)
7 (0.5)
To one rated as not appropriatec,d
61 (2.7)
49 (5.4)
12 (0.9)
2092 (93.3)
802 (89.6)
1290 (95.8)
Not canceled or changed a
Initially Rated as Inappropriatea
Refers to the order each clinician enters into a clinical decision support (CDS) system before being presented with feedback on the appropriateness of the order, which occurred during the intervention period only. Some initial orders that were not rated, rated as appropriate, or rated as equivocal were changed to final orders that were rated as inappropriate.
b
These columns are subsets of all initial orders rated as inappropriate.
c
The denominators used to calculate the percentages for these rows are in row 1.
d
Includes final orders rated as equivocal, as inappropriate, and those not rated because the CDS systems did not find matching appropriateness criteria or the final order was not a study procedure.
A strength of this study is the scale and diversity of settings included. Previous studies of CDS systems for advanced diagnostic imaging ordering were mostly conducted within single organizations or settings and reported mixed results, with some showing an association with increased appropriateness and some reporting low uptake by clinicians.1 Limitations included reliance on clinical data entered by ordering clinicians, who may have imprecisely specified patient characteristics, and variation in how the CDS systems incorporated characteristics into their algorithms. The pre-post design could lead to selection bias or reflect concomitant initiatives or secular trends. Participants may not be representative of all clinicians and settings using CDS systems. The descriptive presentation of results does not indicate statistical significance; heterogeneity of participating organizations requires a more detailed statistical analysis. Implementing CDS systems in real-world settings has many challenges that must be addressed to meaningfully affect patient care. Peter S. Hussey, PhD Justin W. Timbie, PhD Lane F. Burgette, PhD Neil S. Wenger, MD David J. Nyweide, PhD Katherine L. Kahn, MD Author Affiliations: RAND, Boston, Massachusetts (Hussey); RAND, Arlington, Virginia (Timbie, Burgette); RAND-UCLA, Los Angeles, California (Wenger, Kahn); Centers for Medicare & Medicaid Services, Baltimore, Maryland (Nyweide). 2182
Author Contributions: Dr Hussey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hussey, Timbie, Nyweide, Kahn. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Hussey, Timbie, Burgette. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Hussey, Timbie, Burgette. Obtained funding: Hussey, Kahn. Administrative, technical, or material support: Hussey, Nyweide, Kahn. Study supervision: Hussey, Nyweide, Kahn. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: Funding for this project was provided by the Centers for Medicare & Medicaid Services under contract HHSM-500-2005-00028I/ T0003. Role of the Funder/Sponsor: Dr Nyweide (an employee of the Centers for Medicare & Medicaid Services) was involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and views expressed are solely those of the authors and are not meant to reflect the views or policies of the US government. Additional Contributions: We thank Ian Brantley, MPH (Remedy Partners), for his assistance in the analysis of clinical decision support data while a paid employee of RAND. 1. Garg AX, Adhikari NK, McDonald H, et al. Effects of computerized clinical decision support systems on practitioner performance and patient outcomes: a systematic review. JAMA. 2005;293(10):1223-1238. 2. Blumenthal D, Tavenner M. The “meaningful use” regulation for electronic health records. N Engl J Med. 2010;363(6):501-504. 3. Protecting Access to Medicare Act of 2014, HR 4302, 113th Congress, 2nd Session, §218 (2014). 4. Centers for Medicare & Medicaid Services. Medicare Imaging Demonstration. http://innovation.cms.gov/initiatives/Medicare-Imaging/. Accessed February 25, 2015. 5. Lewin Group Inc. Medicare Appropriateness of Use Imaging Demonstration: Implementation Report. Falls Church, VA: Lewin Group Inc; 2014.
COMMENT & RESPONSE
Lowering Blood Pressure in Patients With Diabetes To the Editor In their meta-analysis, Dr Emdin and colleagues1 stated that for persons with diabetes and a baseline systolic blood pressure lower than 140 mm Hg, they observed “lower risks of stroke, retinopathy, and progression of albuminuria,” and therefore recommended further blood pressure lowering for these patients “in contrast with the recommendations of the JNC 8 [eighth Joint National Committee] guidelines.” However, Figure 3 in the article showed no significant reduction in retinopathy with a blood pressure lower than 140 mm Hg, and it is clear from eFigures 4 and 8 that the findings for stroke and albuminuria resulted almost entirely from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.2 The primary outcome in the ACCORD trial, a composite of cardiovascular events, was negative for benefit, as was all-cause mortality, and there was a significant increase in
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serious adverse events attributed to intensive therapy. Despite significant reductions in the secondary outcome of stroke and the surrogate measure of albuminuria, the ACCORD trial authors properly concluded their trial to be negative. Emdin and colleagues did not specify a primary outcome for their meta-analysis, but they also found no benefit in cardiovascular events or all-cause mortality for patients with baseline blood pressure below 140 mm Hg. However, they determined serious adverse event data to be “too disparate to allow formal meta-analysis.” They defended this omission by noting that in the ACCORD trial, the rate of serious adverse events was “substantially lower than that of the primary outcome.” However, this was not true for the more relevant comparison with strokes, which were less frequent in the ACCORD trial than were serious adverse events attributed to intensive therapy (98 vs 107). In effect, Emdin and colleagues based their conclusion on a reinterpretation of the ACCORD trial findings without the constraints of a primary outcome or an accounting of harms.
A systematic review also showed that only 30% to 80% of all known published randomized clinical trials were identifiable using MEDLINE.5 Even if relevant records are in MEDLINE, it can be difficult to retrieve them. Therefore, a search of multiple databases (CENTRAL, MEDLINE, and EMBASE) is required not only to collect more clinical trials than from MEDLINE alone but also to obtain a more accurate conclusion, particularly for meta-analyses of large-scale randomized clinical trials.5 In addition, an exhaustive search for a systematic review should include gray literature databases and hand searching, such as conference proceedings, books, journal articles, and other literature. Failure to identify trials reported in the gray literature might affect the results of a systematic review. Clinical decision making has benefited enormously from the availability of systematic reviews and meta-analyses because they represent the highest level in the hierarchy of evidence. Thus, a more extensive literature search is mandatory before the conclusions of this meta-analysis can be used in clinical practice. Min Li, MS Zhenyu Tang, PhD
Frank A. Lederle, MD Author Affiliation: Center for Chronic Disease Outcomes Research, VA Medical Center, Minneapolis, Minnesota. Corresponding Author: Frank A. Lederle, MD, Center for Chronic Disease Outcomes Research, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015; 313(6):603-615. 2. 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.
To the Editor Dr Emdin and colleagues1 investigated the associations between treatment for blood pressure lowering and macrovascular and microvascular outcomes in patients with type 2 diabetes. Lowering blood pressure in individuals with diabetes has become an important topic in research about vascular risk and mortality. However, we would like to add some cautionary words. The authors stated that they complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for meta-analyses of interventional studies and they searched MEDLINE from 1966 to 2014. Nonetheless, this meta-analysis was based solely on 1 database, which may not be sufficient and has the potential to compromise the validity of results.2 Previous studies have demonstrated that use of a single search engine reduces sensitivity to as low as 66%.3 A comparison of EMBASE and MEDLINE4 found that a search of EMBASE retrieved twice as many citations as MEDLINE. In addition, Dickersin et al2 found that a search of MEDLINE alone was not adequate.
Author Affiliations: Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China. Corresponding Author: Zhenyu Tang, PhD, Department of Neurology, Second Affiliated Hospital of Nanchang University, No. 1, Minde Rd, Nanchang, Jiangxi 330006, PR China ([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. Emdin CA, Rahimi K, Neal B, Callender T, Perkovic V, Patel A. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2015; 313(6):603-615. 2. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ. 1994;309(6964):1286-1291. 3. Lemeshow AR, Blum RE, Berlin JA, Stoto MA, Colditz GA. Searching one or two databases was insufficient for meta-analysis of observational studies. J Clin Epidemiol. 2005;58(9):867-873. 4. Wilkins T, Gillies RA, Davies K. EMBASE versus MEDLINE for family medicine searches: can MEDLINE searches find the forest or a tree? Can Fam Physician. 2005;51:848-849. 5. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Oxford, England: Cochrane Collaboration; 2011.
In Reply Dr Lederle states that Figure 3 showed no significant reduction in retinopathy for the subgroup with a baseline systolic blood pressure of less than 140 mm Hg. However, because the test for interaction by baseline blood pressure was not significant, it is inappropriate to take the subgroup results as stand-alone results. The overall estimate is the best estimate of an effect across subgroups. 1 Thus, an appropriate interpretation of Figure 3 is that blood pressure lowering was associated with a 13% (95% CI, 1%-24%) reduction in retinopathy, regardless of whether the baseline systolic blood pressure was above or below 140 mm Hg.
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Letters
Lederle is correct in pointing out that the standardized analyses of lower initial blood pressure levels were dominated by the results of the ACCORD trial for many outcomes, but this was not the case for retinopathy (eFigure 7). Furthermore, even with the exclusion of the ACCORD trial, the effect of blood pressure lowering on preventing the development or progression of albuminuria and stroke remained significant regardless of initial blood pressure level (relative risk [RR], 0.70 [95% CI, 0.63-0.78] for albuminuria and RR, 0.74 [95% CI, 0.640.86] for stroke after excluding the ACCORD trial). In addition, we reject the notion of needing to prespecify a primary outcome for these meta-analyses. We aimed to understand the effects of blood pressure lowering on all patientrelevant outcomes that have been reported. Even though adverse events were too disparate to pool, we stated in the discussion that “the risk of adverse events associated with [blood pressure] BP-lowering treatments needs to be considered. This requires individualized assessment of the likely absolute benefits and risks with shared decision making between patients and clinicians.” Drs Li and Tang state that “this meta-analysis was based solely on 1 database, which may not be sufficient and has the potential to compromise the validity of results.” However, a key inclusion criterion was the need for trials to have at least 1000 patient-years of follow-up in each group. Although they are correct in noting that MEDLINE may not include citations for all randomized clinical trials, it is unlikely that trials of at least 2000 patient-years in size would have been missed. However, despite the low likelihood of missing relevant trials, we supplemented our search of MEDLINE with the results of a previous meta-analysis2 for which a search of MEDLINE, Web of Science, and Cochrane Collaboration was conducted. In addition, we conducted a hand search of all previous meta-analyses and trials. Therefore, we view our search strategy as having provided a comprehensive search of the relevant literature. Connor A. Emdin, HBSc Kazem Rahimi, DM, MSc Anushka Patel, PhD Author Affiliations: George Institute for Global Health, University of Oxford, Oxford, England (Emdin, Rahimi); George Institute for Global Health, University of Sydney, Sydney, Australia (Patel). Corresponding Author: Kazem Rahimi, DM, MSc, George Institute for Global Health, Oxford Martin School, University of Oxford, 34 Broad St, Oxford OX1 3DB, England ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rahimi reported receiving grants from the National Institute for Health Research and the Oxford Martin School. Dr Patel reported receiving grants from the National Health and Medical Research Council of Australia; and funding to her institution for her participation in an industry advisory board and from Servier Laboratories. The George Institute for Global Health has received grants from several pharmaceutical companies to conduct clinical trials in patients with diabetes. No other disclosures were reported. 1. Matthews JN, Altman DG. Statistics notes: interaction 2: compare effect sizes not P values. BMJ. 1996;313(7060):808. 2. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. 2184
Treatment for Hospitalized Patients With Severe Community-Acquired Pneumonia To the Editor Dr Torres and colleagues1 reported that a substantial subgroup of patients with severe community-acquired pneumonia met criteria for septic shock and severe sepsis.2 The prevalence of septic shock was 23% (28/120). A proportion of patients met severe sepsis criteria (68% [82/ 120]) based on having ratios of PaO2 to fraction of inspired oxygen of less than 250 mm Hg. Could the authors please clarify the volumes of fluid resuscitation administered to the methylprednisolone and placebo groups during the first 5 days after randomization? In addition, did Torres and colleagues observe any interactions between methylprednisolone therapy and the volume of administered fluid? This information is important because the volume of administered fluid may affect radiographic progression. In prior literature, a negative fluid balance during the first 3 days of septic shock predicted survival.3 Also, a conservative strategy of fluid management in patients with acute lung injury improved lung function and shortened the duration of mechanical ventilation and intensive care.4 Dominique J. Pepper, MBChB, MD Author Affiliation: National Institutes of Health, Bethesda, Maryland. Corresponding Author: Dominique J. Pepper, MBChB, MD, Critical Care Medicine Department, National Institutes of Health, Bethesda, MD 20892 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313(7):677-686. 2. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637. 3. Alsous F, Khamiees M, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA. Negative fluid balance predicts survival in patients with septic shock: a retrospective pilot study. Chest. 2000;117(6):1749-1754. 4. Wiedemann HP, Wheeler AP, Bernard GR, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575.
In Reply Dr Pepper raises an interesting question related to the potential interaction between fluid balance and radiographic progression, mainly in patients with shock and severe sepsis. Unfortunately, we do not have data on fluid balance during the first 5 days after randomization. Although we cannot specifically answer this question, our general practice was to keep patients in a negative or at least even fluid balance. Because the study was blinded and randomized, we do not think that changes in fluid balance accounted for differences in radiographic resolution. Furthermore, we do not know of any mechanism whereby corticosteroid use could promote a negative fluid balance and result in radiographic improvement. We agree
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