Letters
Kasia J. Lipska, MD, MHS Joseph S. Ross, MD, MHS Holly K. Van Houten, BA David Beran, MSc, PhD John S. Yudkin, MD, FRCP Nilay D. Shah, PhD
6. Ginde AA, Blanc PG, Lieberman RM, Camargo CA Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008;8:4.
COMMENT & RESPONSE
Antihypertensive Therapy After Acute Ischemic Stroke
Author Affiliations: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut (Lipska, Ross); Faculty of Medicine, University of Geneva, Geneva, Switzerland (Beran); University College London, London, England (Yudkin); Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota (Van Houten, Shah). Corresponding Author: Kasia J. Lipska, MD, MHS, Department of Internal Medicine, Yale School of Medicine, PO Box 208020, New Haven, CT 06520 ([email protected]). Author Contributions: Dr Shah 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: Lipska, Ross, Beran, Yudkin, Shah. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Lipska, Beran, Yudkin. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Van Houten, Yudkin, Shah. Obtained funding: Shah. Administrative, technical, or material support: Yudkin, Shah. Study supervision: Yudkin, Shah. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lipska reported receiving support from the Centers for Medicare & Medicaid Services to develop ambulatory care performance measures; being supported by the Pepper Center career development award (P30 AG21342); receiving grant R03 AG045086 (Grants for Early Medical/Surgical Specialists’ Transition to Aging Research) from the National Institute on Aging; and receiving a scholar award (grant UL1 TR000142) through the Yale Center for Clinical Investigation. Dr Ross reported being a member of a scientific advisory board for FAIR Health Inc; receiving grant funding from Pew Charitable Trusts, Medtronic Inc, and Johnson & Johnson; receiving funding from the Centers for Medicare & Medicaid Services to develop and maintain performance measures used for public reporting; receiving funding from the US Food and Drug Administration to develop methods for postmarket surveillance of medical devices; being supported by grant K08 AG032886 from the National Institute on Aging; receiving funding from the American Federation for Aging Research through the Paul B. Beeson career development award program; and receiving personal fees from Pew Charitable Trusts outside the submitted work. Dr Shah reported receiving other from Optum Labs outside the submitted work. No other disclosures were reported. Funding/Support: This project was supported by grant R21HS17628 from the Agency for Healthcare Research and Quality. Role of the Sponsor: The Agency for Healthcare Research and Quality had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We thank Harlan Krumholz, MD, SM (Department of Medicine, Yale University School of Medicine), and Victor Montori, MD, MSc (Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic), for their valuable comments on an earlier draft. No compensation was received. 1. Horvath K, Jeitler K, Berghold A, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;(2):CD005613. 2. Gale EA. Newer insulins in type 2 diabetes. BMJ. 2012;345:e4611. 3. Gill GV, Yudkin JS, Keen H, Beran D. The insulin dilemma in resource-limited countries: a way forward? Diabetologia. 2011;54(1):19-24. 4. Holden SE, Poole CD, Morgan CL, Currie CJ. Evaluation of the incremental cost to the National Health Service of prescribing analogue insulin. BMJ Open. 2011;1(2):e000258. 5. Consumer price indexes for major expenditure classes, 1965-2009. http: //www.gpo.gov/fdsys/pkg/ERP-2010/pdf/ERP-2010-table60.pdf. Accessibility verified May 22, 2014.
To the Editor The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) study reported that antihypertensive therapy immediately after an acute ischemic stroke did not reduce the likelihood of death or major disability compared with placebo.1 In the trial, the effects of antihypertensive therapy seemed to be time dependent. Although the study revealed no effect of antihypertensive therapy when treatment was administered within the first day of stroke, blood pressure lowering was associated with a 27% reduction in the primary outcome among patients treated after 24 hours of stroke onset. This finding is in accordance with the results from the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study,2 in which candesartan was administered an average of 30 hours after recognition of stroke symptoms. Did Dr He and colleagues1 perform a formal interaction test3 to verify this finding? This finding comes from a subgroup analysis and can only be considered hypothesis generating, requiring further testing in future trials. The type of drugs used in the active group raises some concerns. Intravenous enalapril was chosen as the first-line agent combined with an oral calcium antagonist. Although we do not object to the choice of drugs, intravenous enalapril was used in the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) and was not found to be beneficial in patients with myocardial infarction when given within 24 hours after the onset of chest pain.4 This negative result was attributed to hypotension resulting from the use of intravenous enalapril and was in contrast with all studies performed later that established angiotensin-converting enzyme (ACE) inhibition as the cornerstone of postmyocardial infarction therapy.5 Could He et al provide the adverse events in the active and control groups and especially the hypotensive events in each group? Barbara Nikolaidou, MD Antonios Lazaridis, MD Michael Doumas, MD, PhD Author Affiliations: Aristotle University of Thessaloniki, Thessaloniki, Greece (Nikolaidou, Lazaridis); George Washington University, Washington, DC (Doumas). Corresponding Author: Michael Doumas, MD, PhD, 50 Irving St NW, Washington, DC 20422 ([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. He J, Zhang Y, Xu T, et al; CATIS Investigators. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA. 2014;311(5):479-489. 2. Schrader J, Lüders S, Kulschewski A, et al; Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group. The ACCESS study: evaluation of Acute Candesartan Cilexitil Therapy in Stroke Survivors. Stroke. 2003;34(7): 1699-1703.
jama.com
JAMA June 11, 2014 Volume 311, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/25/2015
2333
Letters
3. Sun X, Briel M, Busse JW, et al. Credibility of claims of subgroup effects in randomized controlled trials: systematic review. BMJ. 2012;344:e1553.
2. Wallace JD, Levy LL. Blood pressure after stroke. JAMA. 1981;246(19):21772180.
4. Swedberg K, Held P, Kjekshus J, Rasmussen K, Rydén L, Wedel H. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992;327(10):678-684.
3. Geeganage C, Bath PM. Vasoactive drugs for acute stroke. Cochrane Database Syst Rev. 2010;7(7):CD002839.
5. Smith SC Jr, Benjamin EJ, Bonow RO, et al; World Heart Federation and the Preventive Cardiovascular Nurses Association. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124(22):24582473.
To the Editor Dr He and colleagues1 reported no beneficial effects on death and major disability among patients with ischemic stroke who were promptly treated to reduce blood pressure. In previous studies, elevated blood pressure is present in about 80% of patients with ischemic stroke, and in the next few days a spontaneous decline often happens.2 Although elevated blood pressure contributes to a poor outcome, several trials have failed to demonstrate a clinical benefit of moderate to intensive blood pressure reduction during the acute phase.3 The mechanisms of this transitory elevation (eg, the increase in plasma catecholamines due to autonomic nervous system activation, the response to decreased focal cerebral perfusion, or the site of the brain lesion, especially brain stem4) are not well understood. Considering this last hypothesis, it might be interesting for He et al1 to report the location and size of the cerebral ischemia in enrolled patients. Because most of the ischemic stroke subtypes in the CATIS study were thrombotic, it also might be useful to report the site of arterial occlusion. Indeed, large arterial occlusions cause large infarcts that could change cerebral autoregulation. An immediate and significant reduction of blood pressure, as reported in this trial with about a 21% blood pressure reduction in only 6 hours, could reduce the perfusion of the ischemic penumbra and diminish collateral flow. The result might be an enlargement of the ischemic core and a failure to improve outcomes. In future trials, transcranial Doppler ultrasound could be used at the bedside to verify the effects of antihypertensive treatment on cerebral hemodynamics. Until more data are available, blood pressure reduction should be personalized depending on the clinical and neuroradiological features. Simone Vidale, MD Claudio Pini, MD Marco Arnaboldi, MD Author Affiliations: Department of Neurology and Stroke Unit, Sant’Anna Hospital, Como, Italy. Corresponding Author: Simone Vidale, MD, Department of Neurology and Stroke Unit, Sant’Anna Hospital, Via Napoleona 60, 22100 Como, Italy (simone [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. He J, Zhang Y, Xu T, et al; CATIS Investigators. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA. 2014;311(5):479-489. 2334
4. Qureshi AI. Acute hypertensive response in patients with stroke: pathophysiology and management. Circulation. 2008;118(2):176-187.
In Reply Dr Nikolaidou and colleagues correctly pointed out that a 27% reduction in the composite outcome of death and major disability was identified (odds ratio, 0.73 [95% CI, 0.550.97], P = .03) at the 3-month posttreatment follow-up among patients who received antihypertensive treatment 24 hours or longer after stroke onset. The P value for homogeneity (interaction test) among 3 subgroups by time from stroke symptom onset to antihypertensive treatment (
Kasia J. Lipska, MD, MHS Joseph S. Ross, MD, MHS Holly K. Van Houten, BA David Beran, MSc, PhD John S. Yudkin, MD, FRCP Nilay D. Shah, PhD
6. Ginde AA, Blanc PG, Lieberman RM, Camargo CA Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC Endocr Disord. 2008;8:4.
COMMENT & RESPONSE
Antihypertensive Therapy After Acute Ischemic Stroke
Author Affiliations: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut (Lipska, Ross); Faculty of Medicine, University of Geneva, Geneva, Switzerland (Beran); University College London, London, England (Yudkin); Division of Health Care Policy and Research, Mayo Clinic, Rochester, Minnesota (Van Houten, Shah). Corresponding Author: Kasia J. Lipska, MD, MHS, Department of Internal Medicine, Yale School of Medicine, PO Box 208020, New Haven, CT 06520 ([email protected]). Author Contributions: Dr Shah 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: Lipska, Ross, Beran, Yudkin, Shah. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Lipska, Beran, Yudkin. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Van Houten, Yudkin, Shah. Obtained funding: Shah. Administrative, technical, or material support: Yudkin, Shah. Study supervision: Yudkin, Shah. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lipska reported receiving support from the Centers for Medicare & Medicaid Services to develop ambulatory care performance measures; being supported by the Pepper Center career development award (P30 AG21342); receiving grant R03 AG045086 (Grants for Early Medical/Surgical Specialists’ Transition to Aging Research) from the National Institute on Aging; and receiving a scholar award (grant UL1 TR000142) through the Yale Center for Clinical Investigation. Dr Ross reported being a member of a scientific advisory board for FAIR Health Inc; receiving grant funding from Pew Charitable Trusts, Medtronic Inc, and Johnson & Johnson; receiving funding from the Centers for Medicare & Medicaid Services to develop and maintain performance measures used for public reporting; receiving funding from the US Food and Drug Administration to develop methods for postmarket surveillance of medical devices; being supported by grant K08 AG032886 from the National Institute on Aging; receiving funding from the American Federation for Aging Research through the Paul B. Beeson career development award program; and receiving personal fees from Pew Charitable Trusts outside the submitted work. Dr Shah reported receiving other from Optum Labs outside the submitted work. No other disclosures were reported. Funding/Support: This project was supported by grant R21HS17628 from the Agency for Healthcare Research and Quality. Role of the Sponsor: The Agency for Healthcare Research and Quality had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We thank Harlan Krumholz, MD, SM (Department of Medicine, Yale University School of Medicine), and Victor Montori, MD, MSc (Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic), for their valuable comments on an earlier draft. No compensation was received. 1. Horvath K, Jeitler K, Berghold A, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;(2):CD005613. 2. Gale EA. Newer insulins in type 2 diabetes. BMJ. 2012;345:e4611. 3. Gill GV, Yudkin JS, Keen H, Beran D. The insulin dilemma in resource-limited countries: a way forward? Diabetologia. 2011;54(1):19-24. 4. Holden SE, Poole CD, Morgan CL, Currie CJ. Evaluation of the incremental cost to the National Health Service of prescribing analogue insulin. BMJ Open. 2011;1(2):e000258. 5. Consumer price indexes for major expenditure classes, 1965-2009. http: //www.gpo.gov/fdsys/pkg/ERP-2010/pdf/ERP-2010-table60.pdf. Accessibility verified May 22, 2014.
To the Editor The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) study reported that antihypertensive therapy immediately after an acute ischemic stroke did not reduce the likelihood of death or major disability compared with placebo.1 In the trial, the effects of antihypertensive therapy seemed to be time dependent. Although the study revealed no effect of antihypertensive therapy when treatment was administered within the first day of stroke, blood pressure lowering was associated with a 27% reduction in the primary outcome among patients treated after 24 hours of stroke onset. This finding is in accordance with the results from the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study,2 in which candesartan was administered an average of 30 hours after recognition of stroke symptoms. Did Dr He and colleagues1 perform a formal interaction test3 to verify this finding? This finding comes from a subgroup analysis and can only be considered hypothesis generating, requiring further testing in future trials. The type of drugs used in the active group raises some concerns. Intravenous enalapril was chosen as the first-line agent combined with an oral calcium antagonist. Although we do not object to the choice of drugs, intravenous enalapril was used in the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) and was not found to be beneficial in patients with myocardial infarction when given within 24 hours after the onset of chest pain.4 This negative result was attributed to hypotension resulting from the use of intravenous enalapril and was in contrast with all studies performed later that established angiotensin-converting enzyme (ACE) inhibition as the cornerstone of postmyocardial infarction therapy.5 Could He et al provide the adverse events in the active and control groups and especially the hypotensive events in each group? Barbara Nikolaidou, MD Antonios Lazaridis, MD Michael Doumas, MD, PhD Author Affiliations: Aristotle University of Thessaloniki, Thessaloniki, Greece (Nikolaidou, Lazaridis); George Washington University, Washington, DC (Doumas). Corresponding Author: Michael Doumas, MD, PhD, 50 Irving St NW, Washington, DC 20422 ([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. He J, Zhang Y, Xu T, et al; CATIS Investigators. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA. 2014;311(5):479-489. 2. Schrader J, Lüders S, Kulschewski A, et al; Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group. The ACCESS study: evaluation of Acute Candesartan Cilexitil Therapy in Stroke Survivors. Stroke. 2003;34(7): 1699-1703.
jama.com
JAMA June 11, 2014 Volume 311, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/25/2015
2333
Letters
3. Sun X, Briel M, Busse JW, et al. Credibility of claims of subgroup effects in randomized controlled trials: systematic review. BMJ. 2012;344:e1553.
2. Wallace JD, Levy LL. Blood pressure after stroke. JAMA. 1981;246(19):21772180.
4. Swedberg K, Held P, Kjekshus J, Rasmussen K, Rydén L, Wedel H. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992;327(10):678-684.
3. Geeganage C, Bath PM. Vasoactive drugs for acute stroke. Cochrane Database Syst Rev. 2010;7(7):CD002839.
5. Smith SC Jr, Benjamin EJ, Bonow RO, et al; World Heart Federation and the Preventive Cardiovascular Nurses Association. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124(22):24582473.
To the Editor Dr He and colleagues1 reported no beneficial effects on death and major disability among patients with ischemic stroke who were promptly treated to reduce blood pressure. In previous studies, elevated blood pressure is present in about 80% of patients with ischemic stroke, and in the next few days a spontaneous decline often happens.2 Although elevated blood pressure contributes to a poor outcome, several trials have failed to demonstrate a clinical benefit of moderate to intensive blood pressure reduction during the acute phase.3 The mechanisms of this transitory elevation (eg, the increase in plasma catecholamines due to autonomic nervous system activation, the response to decreased focal cerebral perfusion, or the site of the brain lesion, especially brain stem4) are not well understood. Considering this last hypothesis, it might be interesting for He et al1 to report the location and size of the cerebral ischemia in enrolled patients. Because most of the ischemic stroke subtypes in the CATIS study were thrombotic, it also might be useful to report the site of arterial occlusion. Indeed, large arterial occlusions cause large infarcts that could change cerebral autoregulation. An immediate and significant reduction of blood pressure, as reported in this trial with about a 21% blood pressure reduction in only 6 hours, could reduce the perfusion of the ischemic penumbra and diminish collateral flow. The result might be an enlargement of the ischemic core and a failure to improve outcomes. In future trials, transcranial Doppler ultrasound could be used at the bedside to verify the effects of antihypertensive treatment on cerebral hemodynamics. Until more data are available, blood pressure reduction should be personalized depending on the clinical and neuroradiological features. Simone Vidale, MD Claudio Pini, MD Marco Arnaboldi, MD Author Affiliations: Department of Neurology and Stroke Unit, Sant’Anna Hospital, Como, Italy. Corresponding Author: Simone Vidale, MD, Department of Neurology and Stroke Unit, Sant’Anna Hospital, Via Napoleona 60, 22100 Como, Italy (simone [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. He J, Zhang Y, Xu T, et al; CATIS Investigators. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA. 2014;311(5):479-489. 2334
4. Qureshi AI. Acute hypertensive response in patients with stroke: pathophysiology and management. Circulation. 2008;118(2):176-187.
In Reply Dr Nikolaidou and colleagues correctly pointed out that a 27% reduction in the composite outcome of death and major disability was identified (odds ratio, 0.73 [95% CI, 0.550.97], P = .03) at the 3-month posttreatment follow-up among patients who received antihypertensive treatment 24 hours or longer after stroke onset. The P value for homogeneity (interaction test) among 3 subgroups by time from stroke symptom onset to antihypertensive treatment (
