- Email: [email protected]
Should blood pressure be lowered in acute ischemic stroke? The CATIS trial
Journal of the American Society of Hypertension 9(5) (2015) 331–333
Commentary
Should blood pressure be lowered in acute ischemic stroke? The CATIS trial Philip B. Gorelick, MD, MPHa,b,* a
Department of Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI; and b Hauenstein Neuroscience Center, Mercy Health, Grand Rapids, MI
In acute ischemic stroke (AIS), beyond few exceptions, the management of blood pressure (BP) remains uncertain.1–3 Past guidance has recommended that one may withhold antihypertensive agents in AIS unless diastolic BP is >120 mm Hg or systolic BP is >220 mm Hg or there is some other compelling reason to treat BP acutely (eg, intravenous tPA administration, acute myocardial infarction, aortic dissection, malignant hypertension).2,3 More recent American Heart Association/American Stroke Association (AHA/ASA) guidance recommends that it is reasonable to lower BP by 15% during the first 24 hours after stroke onset, noting also that patients may have a spontaneous decline of BP during the first 24 hours after stroke.1 On the one hand, it is argued that too aggressive BP–lowering in AIS may lead to extension of brain infarction in already threatened tissue of the ischemic penumbra, which may have poor autoregulatory capability. Also, too high a BP may potentiate leaky ischemic blood vessels to be more susceptible to mediating brain edema, hemorrhagic transformation, and neurologic worsening.2 Therefore, the clinician is caught in a position of clinical equipoise in relation to BP management in AIS. We now review the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and select related studies to answer the question: should BP be lowered in AIS?
CATIS CATIS was a multicenter, randomized controlled trial designed to test whether moderate lowering of BP within the first 48 hours after onset of AIS could reduce death and major disability at 14 days or hospital discharge.4 Key elements of the study design are listed in the Table 1. CATIS patients were in their early 60s, randomized within about 15 hours from stroke onset, had entry BPs of w166.7/96.8 mm Hg, and National Institute of Health Stroke Scale scores suggesting mild impairment. CATIS emphasized acute BP reduction rather than a specific BP–lowering regimen. In CATIS, study BP targets were met. Within 24 hours, the active BP–lowering treatment group had mean systolic BP reduced by 12.7%, whereas that in the control group was reduced by 7.2%.4 At day 7, mean systolic BP was 137.3 mm Hg in the active treatment group and 146.5 mm Hg in the control group. However, the primary outcome of death and major disability did not differ between the comparative groups (683 vs. 681 events). Furthermore, the secondary outcome of death and major disability at 3 months did not significantly differ between the two comparator groups (500 vs. 502 events).
This manuscript was not supported by any outside funding or assistance with the writing of the manuscript. *Corresponding author: Dr Philip B. Gorelick, MD, MPH, Department of Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, 220 Cherry St SE, Grand Rapids, MI 49503. Tel: 616-685-6455; Fax: 616-685-4351. E-mail: [email protected] 1933-1711/$ - see front matter Ó 2015 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2015.02.017
332
P.B. Gorelick / Journal of the American Society of Hypertension 9(5) (2015) 331–333
Table 1 Key components of China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) trial design 1. 2. 3. 4. 5. 6.
Multicenter, single–blind, blinded endpoints, randomized trial 26 sites in China 4071 patients, 22 years of age and older, ischemic stroke confirmed by CT or MRI head, within 48 hours of symptom onset Systolic BP between 140 mm Hg and less than 220 mm Hg and diastolic BP up to 120 mm Hg Exclusions: severe heart failure, aortic dissection, cerebrovascular stenosis, resistant hypertension, intravenous tPA use, and deep coma BP–lowering goals: in the active treatment group, lower systolic BP by 10%–25% within the first 24 hours after randomization, and <140/90 mm Hg within 7 days and maintaining this level of BP during the remainder of hospitalization vs. no antihypertensive treatment 7. The study tested BP reduction and not a specific BP–lowering regimen based on use of first–line (intravenous angiotensin–converting enzyme inhibitor), second–line (calcium channel blocker), and third–line (diuretic) drugs. 8. After hospital discharge, both treatment groups received BP–lowering medications according to guidelines 9. Primary outcome: combination of death within 14 days after randomization and major disability (modified Rankin Scale ¼ 3–5) at 14 days or at hospital discharge BP, blood pressure; CT, computed tomography; MRI, magnetic resonance imaging; tPA, tissue plasminogen activator.
CATIS and Other Trials The main study result that, in AIS, BP reduction does not reduce the risk of death or major disability in the short or longer term are consistent with other trial observations. For example, the Efficacy of Nitric Oxide in Stroke (ENOS) study highlights treatment with transdermal glyceryl trinitrate for 7 days within 48 hours of ischemic or hemorrhagic stroke onset versus control and shows that active BP treatment significantly reduces BP and is safe but does not improve functional outcome as measured by the modified Rankin Scale.5 In the Scandinavian Candesartan Acute Stroke Trial (SCAST) of ischemic or hemorrhagic stroke patients, which compared short–term use of candesartan versus placebo, the risk of the co–primary composite endpoint of vascular death, myocardial infarction, or stroke at 6 months was not significantly reduced by active therapy, and, based on the modified Rankin Scale, there was an increased risk of poor outcome with candesartan that met statistical criteria for one but not all levels of statistical significance.6 In the Continue or Stop post–Stroke Antihypertensives Collaboration Study (COSSACS), continuation of BP–lowering treatment did not reduce 2–week death or dependency and cardiovascular events or mortality at 6 months, and there was no increase in adverse events compared with those in the acute stoppage of medication group.7 The latter study was underpowered from a statistical standpoint. In the Controlling Hypertension and Hypotension Immediately Post–Stroke (CHHIPS) trial, oral and sublingual lisinopril and oral and intravenous labetalol effectively lowered BP in AIS and hemorrhagic stroke and did not increase the likelihood of early neurological deterioration. However, the study was not sufficiently powered to detect a difference in disability or death at 2 weeks, but there was a 3–month difference in mortality in favor of active treatment.8 Finally, if one considers the 1360 patients with mild ischemic stroke enrolled within 72 hours of AIS in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) and who were randomized to telmisartan versus placebo, active treatment appeared to be safe but with no significant effect on functional dependency, death, or recurrence of stroke at up to 90 days.9 CATIS certainly has inherent strengths and limitations.10 Of the latter, there were mild stroke enrollees, and thus, good outcomes could be expected. In addition, the population of interest was restricted to Chinese who were generally younger and smoked cigarettes. The study was open label, excluded large artery cervical disease, and treatment was not generally initiated hyperacutely or within hours after stroke onset.
P.B. Gorelick / Journal of the American Society of Hypertension 9(5) (2015) 331–333
333
Conclusion In relation to AIS and BP management, we have not heard the last word, as more research is needed including targeted research for ischemic or hemorrhagic stroke individually.11 Paying more attention to variability of BP related to AIS seems wise,12 as does concentrated study in the very early time period after AIS (eg, first 6 hours), when it may be possible to make a difference.5 Although it seems that treatment with BP–lowering therapies is generally safe when used after AIS, there has been concern that secondary outcomes may be worse. Thus, there has been a call for withholding BP–lowering medication in AIS until patients are considered medically and neurologically stable, and thus have suitable oral or enteral access to allow safe drug administration.5 Based on the weight of the evidence, this approach is reasonable. The importance of eventual reinstitution of BP–lowering medication after AIS is emphasized as it is an important pathway to reduce recurrent stroke and other major vascular events.13
References 1. Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke. A Guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870–947. 2. Gorelick PB, Aiyagari V. The management of hypertension for an acute stroke: what is the blood pressure goal? Curr Cardiol Rep 2013;15:366. 3. Aiyagari V, Gorelick PB. Management of blood pressure for acute and recurrent stroke. Stroke 2009;40: 2251–6. 4. He J, Zhang Y, Xu T, Zhao Q, Wang D, Chen CS, et al. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke. The CATIS randomized clinical trial. JAMA 2014;311:479–89. 5. The ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomized controlled trial. Lancet 2015;385:617–28. 6. Sandset EC, Bath PMW, Boysen G, Jatuzis D, K~orv J, L€ uders S, et al., on behalf of the SCAST Study Group. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomized, placebocontrolled, double-blind trial. Lancet 2011;371:741–50.
7. Robinson TG, Potter JF, Ford GA, Bulpitt CJ, Chernova J, Jagger C, et al. Effects of antihypertensive treatment after acute strokein the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomized, open, blinded-endpoint trial. Lancet Neurol 2010;9:767–75. 8. Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al. Controlling hypertension and hypotension immediately post stroke (CHHIPS): a randomized controlled trial. Health Technol Assess 2009;13:1–73. 9. Bath PMW, Martin RH, Palesch Y, Cotton D, Yusuf S, Sacco RL, et al. Effect of telmisartan on functional outcome, recurrence, and blood pressure in patients with acute mild ischemic stroke. A PRoFESS subgroup analysis. Stroke 2009;40:3541–6. 10. Saver JL. Blood pressure management in early ischemic stroke. JAMA 2014;311:469–70. 11. Feldstein CA. Early treatment of hypertension in acute ischemic and intracerebral hemorrhagic stroke: progress achieved, challenges, and perspectives. J Am Soc Hypertens 2014;8:192–202. 12. Kang J, Ko Y, Park JH, Kim WJ, Jang MS, Yang MH, et al. Effect of blood pressure on 3-month functional outcome in the subacute stage of ischemic stroke. Neurology 2012;79:2018–24. 13. Gorelick PB. Is reduction of blood pressure in acute stroke justified? Lancet Neurol 2011;10:295–6.
Commentary
Should blood pressure be lowered in acute ischemic stroke? The CATIS trial Philip B. Gorelick, MD, MPHa,b,* a
Department of Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI; and b Hauenstein Neuroscience Center, Mercy Health, Grand Rapids, MI
In acute ischemic stroke (AIS), beyond few exceptions, the management of blood pressure (BP) remains uncertain.1–3 Past guidance has recommended that one may withhold antihypertensive agents in AIS unless diastolic BP is >120 mm Hg or systolic BP is >220 mm Hg or there is some other compelling reason to treat BP acutely (eg, intravenous tPA administration, acute myocardial infarction, aortic dissection, malignant hypertension).2,3 More recent American Heart Association/American Stroke Association (AHA/ASA) guidance recommends that it is reasonable to lower BP by 15% during the first 24 hours after stroke onset, noting also that patients may have a spontaneous decline of BP during the first 24 hours after stroke.1 On the one hand, it is argued that too aggressive BP–lowering in AIS may lead to extension of brain infarction in already threatened tissue of the ischemic penumbra, which may have poor autoregulatory capability. Also, too high a BP may potentiate leaky ischemic blood vessels to be more susceptible to mediating brain edema, hemorrhagic transformation, and neurologic worsening.2 Therefore, the clinician is caught in a position of clinical equipoise in relation to BP management in AIS. We now review the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and select related studies to answer the question: should BP be lowered in AIS?
CATIS CATIS was a multicenter, randomized controlled trial designed to test whether moderate lowering of BP within the first 48 hours after onset of AIS could reduce death and major disability at 14 days or hospital discharge.4 Key elements of the study design are listed in the Table 1. CATIS patients were in their early 60s, randomized within about 15 hours from stroke onset, had entry BPs of w166.7/96.8 mm Hg, and National Institute of Health Stroke Scale scores suggesting mild impairment. CATIS emphasized acute BP reduction rather than a specific BP–lowering regimen. In CATIS, study BP targets were met. Within 24 hours, the active BP–lowering treatment group had mean systolic BP reduced by 12.7%, whereas that in the control group was reduced by 7.2%.4 At day 7, mean systolic BP was 137.3 mm Hg in the active treatment group and 146.5 mm Hg in the control group. However, the primary outcome of death and major disability did not differ between the comparative groups (683 vs. 681 events). Furthermore, the secondary outcome of death and major disability at 3 months did not significantly differ between the two comparator groups (500 vs. 502 events).
This manuscript was not supported by any outside funding or assistance with the writing of the manuscript. *Corresponding author: Dr Philip B. Gorelick, MD, MPH, Department of Translational Science and Molecular Medicine, Michigan State University College of Human Medicine, 220 Cherry St SE, Grand Rapids, MI 49503. Tel: 616-685-6455; Fax: 616-685-4351. E-mail: [email protected] 1933-1711/$ - see front matter Ó 2015 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2015.02.017
332
P.B. Gorelick / Journal of the American Society of Hypertension 9(5) (2015) 331–333
Table 1 Key components of China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) trial design 1. 2. 3. 4. 5. 6.
Multicenter, single–blind, blinded endpoints, randomized trial 26 sites in China 4071 patients, 22 years of age and older, ischemic stroke confirmed by CT or MRI head, within 48 hours of symptom onset Systolic BP between 140 mm Hg and less than 220 mm Hg and diastolic BP up to 120 mm Hg Exclusions: severe heart failure, aortic dissection, cerebrovascular stenosis, resistant hypertension, intravenous tPA use, and deep coma BP–lowering goals: in the active treatment group, lower systolic BP by 10%–25% within the first 24 hours after randomization, and <140/90 mm Hg within 7 days and maintaining this level of BP during the remainder of hospitalization vs. no antihypertensive treatment 7. The study tested BP reduction and not a specific BP–lowering regimen based on use of first–line (intravenous angiotensin–converting enzyme inhibitor), second–line (calcium channel blocker), and third–line (diuretic) drugs. 8. After hospital discharge, both treatment groups received BP–lowering medications according to guidelines 9. Primary outcome: combination of death within 14 days after randomization and major disability (modified Rankin Scale ¼ 3–5) at 14 days or at hospital discharge BP, blood pressure; CT, computed tomography; MRI, magnetic resonance imaging; tPA, tissue plasminogen activator.
CATIS and Other Trials The main study result that, in AIS, BP reduction does not reduce the risk of death or major disability in the short or longer term are consistent with other trial observations. For example, the Efficacy of Nitric Oxide in Stroke (ENOS) study highlights treatment with transdermal glyceryl trinitrate for 7 days within 48 hours of ischemic or hemorrhagic stroke onset versus control and shows that active BP treatment significantly reduces BP and is safe but does not improve functional outcome as measured by the modified Rankin Scale.5 In the Scandinavian Candesartan Acute Stroke Trial (SCAST) of ischemic or hemorrhagic stroke patients, which compared short–term use of candesartan versus placebo, the risk of the co–primary composite endpoint of vascular death, myocardial infarction, or stroke at 6 months was not significantly reduced by active therapy, and, based on the modified Rankin Scale, there was an increased risk of poor outcome with candesartan that met statistical criteria for one but not all levels of statistical significance.6 In the Continue or Stop post–Stroke Antihypertensives Collaboration Study (COSSACS), continuation of BP–lowering treatment did not reduce 2–week death or dependency and cardiovascular events or mortality at 6 months, and there was no increase in adverse events compared with those in the acute stoppage of medication group.7 The latter study was underpowered from a statistical standpoint. In the Controlling Hypertension and Hypotension Immediately Post–Stroke (CHHIPS) trial, oral and sublingual lisinopril and oral and intravenous labetalol effectively lowered BP in AIS and hemorrhagic stroke and did not increase the likelihood of early neurological deterioration. However, the study was not sufficiently powered to detect a difference in disability or death at 2 weeks, but there was a 3–month difference in mortality in favor of active treatment.8 Finally, if one considers the 1360 patients with mild ischemic stroke enrolled within 72 hours of AIS in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) and who were randomized to telmisartan versus placebo, active treatment appeared to be safe but with no significant effect on functional dependency, death, or recurrence of stroke at up to 90 days.9 CATIS certainly has inherent strengths and limitations.10 Of the latter, there were mild stroke enrollees, and thus, good outcomes could be expected. In addition, the population of interest was restricted to Chinese who were generally younger and smoked cigarettes. The study was open label, excluded large artery cervical disease, and treatment was not generally initiated hyperacutely or within hours after stroke onset.
P.B. Gorelick / Journal of the American Society of Hypertension 9(5) (2015) 331–333
333
Conclusion In relation to AIS and BP management, we have not heard the last word, as more research is needed including targeted research for ischemic or hemorrhagic stroke individually.11 Paying more attention to variability of BP related to AIS seems wise,12 as does concentrated study in the very early time period after AIS (eg, first 6 hours), when it may be possible to make a difference.5 Although it seems that treatment with BP–lowering therapies is generally safe when used after AIS, there has been concern that secondary outcomes may be worse. Thus, there has been a call for withholding BP–lowering medication in AIS until patients are considered medically and neurologically stable, and thus have suitable oral or enteral access to allow safe drug administration.5 Based on the weight of the evidence, this approach is reasonable. The importance of eventual reinstitution of BP–lowering medication after AIS is emphasized as it is an important pathway to reduce recurrent stroke and other major vascular events.13
References 1. Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke. A Guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870–947. 2. Gorelick PB, Aiyagari V. The management of hypertension for an acute stroke: what is the blood pressure goal? Curr Cardiol Rep 2013;15:366. 3. Aiyagari V, Gorelick PB. Management of blood pressure for acute and recurrent stroke. Stroke 2009;40: 2251–6. 4. He J, Zhang Y, Xu T, Zhao Q, Wang D, Chen CS, et al. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke. The CATIS randomized clinical trial. JAMA 2014;311:479–89. 5. The ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomized controlled trial. Lancet 2015;385:617–28. 6. Sandset EC, Bath PMW, Boysen G, Jatuzis D, K~orv J, L€ uders S, et al., on behalf of the SCAST Study Group. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomized, placebocontrolled, double-blind trial. Lancet 2011;371:741–50.
7. Robinson TG, Potter JF, Ford GA, Bulpitt CJ, Chernova J, Jagger C, et al. Effects of antihypertensive treatment after acute strokein the Continue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomized, open, blinded-endpoint trial. Lancet Neurol 2010;9:767–75. 8. Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al. Controlling hypertension and hypotension immediately post stroke (CHHIPS): a randomized controlled trial. Health Technol Assess 2009;13:1–73. 9. Bath PMW, Martin RH, Palesch Y, Cotton D, Yusuf S, Sacco RL, et al. Effect of telmisartan on functional outcome, recurrence, and blood pressure in patients with acute mild ischemic stroke. A PRoFESS subgroup analysis. Stroke 2009;40:3541–6. 10. Saver JL. Blood pressure management in early ischemic stroke. JAMA 2014;311:469–70. 11. Feldstein CA. Early treatment of hypertension in acute ischemic and intracerebral hemorrhagic stroke: progress achieved, challenges, and perspectives. J Am Soc Hypertens 2014;8:192–202. 12. Kang J, Ko Y, Park JH, Kim WJ, Jang MS, Yang MH, et al. Effect of blood pressure on 3-month functional outcome in the subacute stage of ischemic stroke. Neurology 2012;79:2018–24. 13. Gorelick PB. Is reduction of blood pressure in acute stroke justified? Lancet Neurol 2011;10:295–6.