Blood Pressure in Acute Stroke
2018; Lippincott Williams & Wilkins; Volume: 49; Issue: 7 Linguagem: Inglês
10.1161/strokeaha.118.021254
ISSN1524-4628
AutoresPhilip M. Bath, Jason P. Appleton, Kailash Krishnan, Nikola Sprigg,
Tópico(s)Neurological Disorders and Treatments
ResumoHomeStrokeVol. 49, No. 7Blood Pressure in Acute Stroke Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBBlood Pressure in Acute StrokeTo Treat or Not to Treat: That Is Still the Question Philip M. Bath, DSc, FMedSci, Jason P. Appleton, MRCP(UK), Kailash Krishnan, MRCP(UK), PhD and Nikola Sprigg, FRCP, DM Philip M. BathPhilip M. Bath Correspondence to Philip M. Bath, DSc, FMedSci, Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, City Hospital Campus, Nottingham NG5 1PB, United Kingdom. E-mail E-mail Address: [email protected] From the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, United Kingdom. , Jason P. AppletonJason P. Appleton From the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, United Kingdom. , Kailash KrishnanKailash Krishnan From the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, United Kingdom. and Nikola SpriggNikola Sprigg From the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, United Kingdom. Originally published30 Jul 2018https://doi.org/10.1161/STROKEAHA.118.021254Stroke. 2018;49:1784–1790One of the oldest questions in acute stroke management, and perhaps the most challenging since it has yet to be solved after more than half a century of published research, is how to manage high blood pressure (BP). The problem might be summed up as follows:To treat, or not to treat: that is the question:Whether 'tis nobler in the mind to sufferThe slings and arrows of outrageous pressure,Or to take drugs against a sea of blood,And by opposing end them? To live: to walk;—With apologies to Shakespeare, Hamlet Act III, Scene ITo treat, or not to treat, high BP was debated >30 years ago in 1985,1–3 and yet there is no definitive answer here in 2018. Part of the debate is driven by opposing arguments based on epidemiology and pathophysiology and part by the failure of every large trial to provide a definitive answer. There is considerable evidence that high BP is associated independently with a poor outcome after ischemic stroke (IS) whether defined by early recurrence or death, or late death and dependency.4,5 Similarly, high BP is related to hematoma expansion6 and functional outcome after intracerebral hemorrhage (ICH).7 A straightforward conclusion of this epidemiological evidence is that high BP should be lowered. In contrast, pathophysiological concerns are based on the presence of dysfunctional cerebral autoregulation during acute stroke, and so lowering BP will reduce tissue perfusion, increase lesion size, and thereby worsen outcome.8There are many causes of high BP in acute stroke, including prior hypertension, acute neuroendocrine stimulation (via the renin-angiotensin-aldosterone system [RAAS], sympathetic autonomic nervous, and corticotrophin-cortisol systems), the Cushing reflex (due to raised intracranial pressure), and stress associated with admission to hospital and concurrent pain (eg, due to urinary retention).9 These factors offer multiple targets for treatment.The principle of uncertainty (or clinical equipoise) has driven the completion of many medium- and large-sized trials in acute IS, hemorrhagic, or mixed stroke (Table 1). Although varying considerably in design, the trials each compared active or intensive lowering of BP with no or guideline-based lowering. Whereas some smaller trials involving a few hundreds of patients were negative (ie, treatment worsened outcome: BEST [β-Blocker Stroke Trial], Bridgers et al,14 INWEST [Intravenous Nimodipine West European Stroke Trial]15,20), larger trials (involving a thousand or more patients) have all been neutral (SCAST [Scandinavian Candesartan Acute Stroke Trial], INTERACT-2 [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2], CATIS [China Antihypertensive Trial in Acute Ischemic Stroke], ENOS [Efficacy of Nitric Oxide in Stroke], ATACH-2 [Antihypertensive Treatment of Acute Cerebral Hemorrhage-2]12,13,16,21,22). For the sake of this review, SCAST can be considered to be negative because the presence of 2 primary outcomes meant that the shift in modified Rankin Scale (mRS) in a negative direction (P=0.048) just missed statistical significance at P<0.025.21 Equally, INTERACT-2 can be considered to be positive because although it was neutral on its primary dichotomous analysis of the mRS (P=0.06), intensive BP lowering was associated with a positive shift analysis (P=0.04) and improved quality of life (P=0.002).12Table 1. Medium and Large Randomized Controlled Trials of Blood Pressure Lowering in Acute StrokeIntervention/Class (Agent)SizeOTR (h)Result; Comment(s)ICH (SCAST-ICH10ARA [candesartan po]274<30Negative) INTERACT11Intensity, multiple classes: a-AA (urapidil IV, phentolamine) 63%; loop diuretic (furosemide) 35%; NO donor (nitroglycerin) 13%404<6Neutral INTERACT-212Intensity, multiple classes: a-AA (urapidil IV) 32.5%; NO donor (nitroglycerin, nitroprusside) 27.0%; CCB (nicardipine) 16.2%; combined α-AA/β-RA (labetalol) 14.4%; diuretic (furosemide) 12.4%2794<6Neutral; positive on ordinal analysis ATACH-213CCB (nicardipine IV)1000<4.5Neutral INTERACT-3 bundleIntensity, multiple classes (+glucose and temperature control, and reversal of anticoagulation)≈8621<6Ongoing ICH-ADAPT-2Intensity using labetalol, hydralazine, enalapril≈270<6OngoingIS Bridgers et al14CCB (nimodipine IV)204<24Negative tendency INWEST15CCB (nimodipine IV)Negative CATIS16ACE (enalapril IV) then CCB then diuretic4071<24Neutral (SCAST-IS17ARA [candesartan po]<30Neutral) VENTURE18ARA (valsartan po)393<48Neutral ENCHANTED-BP19Intensity (mainly a-AA, urapidil IV)OngoingMixed BEST20β-RA (atenolol, propranolol po)302<48Negative SCAST21ARA (candesartan po)2029<30Neutral; negative if recurrence coprimary ignored ENOS22NO donor (NTG td)4011<48Neutral (ENOS early23NO donor [NTG td]273<6Positive) RIGHT-224NO donor (NTG td)≈1105<4Ongoing MR-ASAPNO donor (NTG td)≈1400<3OngoingThe relevant subgroups of trials are shown in brackets. a-AA indicates α–receptor antagonist; ACE, angiotensin-converting enzyme; ARA, angiotensin receptor antagonist; ATACH, Antihypertensive Treatment of Acute Cerebral Hemorrhage; BEST, β-Blocker Stroke Trial; BP, blood pressure; CATIS, China Antihypertensive Trial in Acute Ischemic Stroke; CCB, calcium channel blocker; ENCHANTED-BP, Enhanced Control of Hypertension and Thrombolysis in Stroke Study; ENOS, Efficacy of Nitric Oxide in Stroke; ICH, intracerebral hemorrhage; ICH-ADAPT-2, Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial-2; INTERACT, Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial; INWEST, Intravenous Nimodipine West European Stroke Trial; IS, ischemic stroke; IV, intravenous; MR-ASAP, Multicenter Randomized Trial of Acute Stroke Treatment in the Ambulance With a Nitroglycerin Patch; NO, nitric oxide; NTG, nitroglycerin/glyceryl trinitrate; OTR, onset to randomization; RA, adrenoceptor antagonists; RIGHT-2, Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial-2; SCAST, Scandinavian Candesartan Acute Stroke Trial; td, transdermal and VENTURE, Valsartan Efficacy on Modest Blood Pressure Reduction in Acute Ischemic Stroke.INTERACT-3: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03209258.ICH-ADAPT: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02281838.MR_ASAP: URL: http://www.isrctn.com. Unique identifier: ISRCTN99503308.RIGHT-2: URL: http://right-2.ac.uk. Unique identifier: ISRCTN26986053.Without definitive positive trials, a conclusion at this stage could be that the epidemiological observations are epiphenomena and do not predict the effect of intervention, as has been seen in other areas of medicine such as vitamin supplementation,25 and, therefore, that BP does not need to be lowered. However, an alternative hypothesis is that lowering BP may be a useful marker of efficacy but effects on outcome depend on which sort of stroke is being treated, how and when BP is lowered, and what other effects the treatment has. This review examines the hypothesis that it is how and when BP is first lowered, and in what stroke type, that is important rather than lowering BP per se. The review uses the results of published medium- and large-sized trials, as summarized in 2 Cochrane Collaboration systematic reviews26,27 along with more recent studies. Where relevant, reference to small mechanistic or pharmacodynamic trials is also made. It does not address whether antihypertensive drugs taken before stroke should be continued or stopped temporarily28 or whether and how antihypertensive agents should be taken long term for secondary prevention.29Antihypertensive therapy is rich with multiple evidence-based drug classes, and 7 classes have been tested in acute stroke (Tables 2 and 3). There are no medium- to large-sized trials involving centrally acting drugs, endothelin antagonists, or renin inhibitors.Table 2. Characteristics of Antihypertensive Drug Classes on Additional MechanismsClassCBFCOHRBPVNPPltWBCRAASSANSOutcomeCommentsa-AA(↑)↓↓↓ICH ↑?Positive early after ICH? ENCHANTED-BPIS?ACE inhibitors→↑↓↓IS →Neutral after IS. Avoid in ICH?ARA→↑+30↓↓↓ICH ↓?SCAST-ICH: Negative—AT2 receptor effects? SCAST-IS, VENTUREIS →β-RA↓↓↑↓31↓IS ↓Enhance hypoperfusion?CCB→(↓)(↓)↓+32↓↑IS →↓Neutral after IS,33 with some negative trialsICH →Diuretics↓↑Onset slow (thiazide like)34NO→↑(↑)↓+35(↓)(↓)ICH ↑?Positive early after IS and ICH? Supplement low vascular levels.36,37 Enhance reperfusion? Spontaneous NO donors (eg, SNP), but not nitrates, have antiplatelet activity38IS ↑?a-AA indicates α–receptor antagonists; ACE, angiotensin-converting enzyme; ARA, angiotensin receptor antagonists; BPV, blood pressure variability; β-RA, β–receptor antagonists; CBF, cerebral blood flow; CCB, calcium channel blockers; CO, cardiac output; HR, heart rate; ICH, intracerebral hemorrhage; IS, ischemic stroke; NO, nitric oxide donors; NP, neuroprotection; Plt, platelet function; RAAS, renin-angiotensin-aldosterone system; SANS, sympathetic autonomic nervous system; SNP sodium nitroprusside; and WBC, white blood cell effects.Table 3. Summary of Results Divided by Time From Onset-To-Treatment, Stroke Type, and Class of Antihypertensive Agent in Patients With Acute StrokeTimeStroke Typea-AANODiureticACE InhibitorsARACCBβ-RA 6ICH0−/0…IS000……Trial results: −, negative; 0, neutral; +, positive;?, ongoing trial(s). a-AA indicates α–receptor antagonist; ACE, angiotensin-converting enzyme; ARA, angiotensin receptor antagonist; β-RA, β–receptor antagonist; CCB, calcium channel blocker; IS, ischemic stroke; and NO, nitric oxide donor.Antihypertensive Drug Classes of Relevance in Acute Strokeα–Adrenoceptor AntagonistsStimulation of α1–adrenergic receptors increases smooth muscle contraction under catecholamine control. Antagonism of these receptors by drugs such as doxazosin and urapidil leads to vasorelaxation. A third of patients (32.5%) in the INTERACT-2 trial in ICH received an α–adrenoceptor antagonist (a-AA), typically urapidil (Table 1).12 Treatment improved the mRS, and the results are compatible with the hypothesis that blocking noradrenaline and adrenaline may be beneficial. Nevertheless, the first and smaller INTERACT trial had a higher utilization of a-AA but was neutral.11 The ENCHANTED-BP study (Enhanced Control of Hypertension and Thrombolysis in Stroke Study) is using a similar approach of testing intensity of BP lowering in patients with hyperacute IS,19 and interim data suggest a high utilization of a-AA (C. Anderson, personal communication, results expected early 2019).Angiotensin-Converting Enzyme InhibitorsAngiotensin-converting enzyme (ACE) converts the inactive hormone angiotensin I to the active vasoconstrictor angiotensin II. Hence, ACE inhibitors such as enalapril cause vasorelaxation. The large CATIS trial in acute IS reported a neutral effect of intravenous enalapril on mRS (Table 1).16 No large trials of ACE inhibitors for acute ICH have been reported.Angiotensin Receptor AntagonistsThe angiotensin II receptor-1 is activated by the vasoconstrictor angiotensin II. Antagonism of the receptor with drugs such as candesartan and valsartan leads to vasorelaxation. The large SCAST trial assessed oral candesartan, with doses rising over the treatment period, in patients with acute IS and hemorrhagic stroke (Table 1). Practically, the trial can be considered to be negative,21 with all the harm occurring in patients with ICH and a neutral effect in IS.10,17 The medium-sized VENTURE trial (Valsartan Efficacy on Modest Blood Pressure Reduction in Acute Ischemic Stroke) of oral valsartan for acute IS was also neutral.18 One interpretation is that elevated angiotensin II levels in acute ICH are important and their effects should not be blocked. Alternatively or additionally, blockade of the angiotensin II AT1 receptor leaves the AT2 receptor exposed, and agonism of this leads to inhibition of cell growth and neuronal regeneration.39 The neutral findings of CATIS, SCAST, and VENTURE suggest that the RAAS is not a useful target in acute stroke.β–Adrenoceptor AntagonistsStimulation of β1–adrenergic receptors increases cardiac muscle contraction (inotropic effect) and heart rate (chronotropic effect) under catecholamine control. As a result, antagonism of these receptors by drugs such as atenolol and propranolol reduces cardiac output and heart rate. The BEST trial in acute mixed stroke found that these agents, when given orally, increased mortality at 1 month (Table 1).20 Although BEST was not large and separate results for ICH and IS are not published, one interpretation that is plausible biologically is that reducing cardiac output in acute stroke is potentially hazardous.Some drugs have antagonist effects on both α and β receptors, such as labetalol (where β-antagonist effects dominate). Although some guidelines recommend using this agent in acute stroke,40 there is limited evidence on the effect of labetalol on functional outcome after stroke to support this assertion, with just 14% of INTERACT-2 treated with labetalol.Calcium Channel BlockersThe movement of calcium through L-type channels in cell membranes drives smooth muscle contraction. Hence blockade of these channels with dihydropyridine calcium channel blockers (CCBs), such as nicardipine and nimodipine, causes vasorelaxation. Numerous trials of CCBs have been performed in acute stroke, usually testing nimodipine as a putative neuroprotectant. Although nimodipine had no overall effect in IS,32 2 trials found that high-dose intravenous therapy was associated with a worse functional outcome.14,15 The moderately large ATACH-2 trial assessed intravenous nicardipine in hyperacute ICH and was neutral leading to the trial being stopped early for futility (Table 1).13 Since dihydropyridine CCBs have some antiplatelet activity,41,42 their use in ICH (as recommended in guidelines, Table I in the online-only Data Supplement) might be considered questionable.DiureticsOf the multiple types of diuretics, loop diuretics (furosemide) have been used in acute stroke. They act by inhibiting the renal luminal Na-K-Cl cotransporter in the thick ascending limb of the loop of Henle. A small proportion of patients (12.4%) in the positive INTERACT-2 trial in ICH received a loop diuretic. A small trial of bendroflumethiazide, a thiazide diuretic, found that it had minimal BP effect over the first week of treatment in patients with acute stroke.34Nitric Oxide DonorsNitric oxide (NO) is a potent endogenous mixed arterial and venous vasodilator and has significant hypotensive effects. Vascular levels of NO are low after stroke36,37 so it is plausible to supplement it. NO may be administered as a nitrate (such as nitroglycerin [NTG] also known as glyceryl trinitrate) or spontaneous NO donor (such as sodium nitroprusside). The large ENOS trial of transdermal NTG found that it did not alter mRS,22 although hyperacute administration within 6 hours was associated with improved functional outcome in a predefined subgroup (Table 1).23 NO donors (NTG, sodium nitroprusside) were used in 27% of patients with ICH in the positive hyperacute INTERACT-2 trial.12 The ongoing RIGHT-2 trial (Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial-2) is assessing NTG administered by paramedics before hospital admission (with results expected in early 2019).Stroke TypeTrials of BP lowering have been performed in ICH alone, IS alone, and mixed groups of patients (Table 1). Although probable efficacy was seen in the INTERACT-2 trial in ICH,12 nicardipine was neutral in ATACH-2,13 and candesartan (angiotensin receptor antagonists [ARA]) appeared to be harmful in the subgroup of SCAST patients with ICH.10 Opposing results were also seen in trials of mixed groups of patients; although 2 studies of NTG were positive in both stroke types when given early,23,43 β–adrenoceptor antagonists (β-RA) were negative in BEST.20TimingThe trials varied considerably in their time window from onset to randomization, this ranging from <6 to 4000 participants (CATIS, ENOS) will not have been large enough to detect small but potentially clinically worthwhile effect sizes. The ongoing INTERACT-3 trial aims to recruit more than twice the number of participants of these already large trials. (Table 1).Additional Effects of Antihypertensive AgentsThe various antihypertensive drug classes exhibit multiple other (collateral) effects (Table 2), some of which might be considered advantageous (such as potential neuroprotection) and others a disadvantage (such as reducing cardiac output).Cerebral Blood Flow/PerfusionMany small studies have been performed that assessed cerebral blood flow (CBF) or CBF velocity after administration of ACE inhibitors, ARA, β-RA (labetalol), CCB, diuretic, or NO donor.38,47–49 Although no difference in CBF was seen in randomized controlled trials, an increase in CBF was seen with CCBs in before-after studies. However, all these studies were small (median size 24 participants) and tended to be of low-medium quality. No CBF studies investigated β-RA or labetalol. There is an urgent need for large high-quality randomized trials using modern imaging techniques and assessing the effects of antihypertensives on CBF, especially those agents recommended in guidelines or that are widely used (labetalol, nicardipine, NTG, urapidil).Cardiac Outputβ-RA such as propranolol and atenolol reduce cardiac output which may then reduce CBF, a debateable aim when this is already reduced in the penumbral area of IS and in ischemic areas around hematoma. This sequence might explain increased deaths seen in the BEST trial.20 Exploring the relationship between cardiac output and CBF is important because labetalol, which has significant β-RA activity, is recommended in guidelines and is widely used. Verapamil, a phenylalkylamine CCB, also has negative inotropic, chronotropic, and dromotropic effects, but this drug has not been assessed in IS.BP VariabilityHigh BP and many derivatives, including mean arterial pressure, pulse pressure, BP variability, peak systolic BP, and rate-pressure product, are each associated with early events and late poor outcome in both acute IS5,50 and ICH.51 Although all the antihypertensive drug classes discussed here lower BP (by definition), they have varying effects on variability52: whereas CCBs and nonloop diuretics reduce interindividual variance, ACE, ARA, and β-RA increase variability. Further, these differences seen in variability appear to explain, in part, differences seen in the effects of these drug classes on stroke.52 NTG, a NO donor, also reduces variability.53 Whether effects on variability explain the results of acute stroke BP trials remains unclear because neutral or negative results were seen with agents that both reduce (CCBs) or increase (ACE, ARA, and β-RA) variability.NeuroprotectionSeveral antihypertensive drug classes (ARA, CCB, NO donors) have putative neuroprotective properties,30,32,35 at least in animal models of stroke. The relevance of this is unclear because no large clinical trials of putative neuroprotectants have led to their introduction in clinical practice.AntiplateletMultiple antihypertensive classes (ARA, β-RA, CCB, spontaneous NO donors such as sodium nitroprusside) exhibit antiplatelet activity. Intravenous CCBs are widely used for the hyperacute management of high BP after stroke in spite of neutral results in ICH (nicardipine in ATACH-213) and some negative results in IS (nimodipine in Bridgers et al,14 INWEST15). Although there are many hypotheses why INTERACT-2 and ATACH-2 gave different results in hyperacute ICH (Table II in the online-only Data Supplement),54 a key potential explanation is that the mild antiplatelet effects of dihydropyridine CCBs (which includes nicardipine)41,42 neutralized its BP effects in ATACH-2.Anti-White Cell EffectsNitric oxide and some NO donors (eg, sodium nitroprusside but not NTG), ACE inhibitors and ARA, have anti-white cell activity manifest through reduction of leukocyte migration, adhesion, and other functions.55–58 In contrast, the effect of other antihypertensive classes on leukocyte activity is unclear. Accentuated white cell function occurs soon after stroke with neutrophils then monocytes invading the brain; 1 trial of an antileukocyte monoclonal in acute IS was negative with increased death and worse functional outcome.59 Hence, there is a risk that antihypertensives with antileukocyte activity might be harmful; pharmacodynamics studies examining white cell function in acute stroke are urgently needed.Inhibition of RAASACE inhibitors, ARA, and β-RA exert some or all of their BP-lowering effect by attenuating the RAAS. Although acute stroke is associated with RAAS stimulation, attenuating this activity appears unhelpful because trials have found that ACE inhibitors and ARA were neutral in IS (CATIS, SCAST16,17), ARA was negative in ICH (SCAST10), and β-RA were negative in mixed stroke.20Inhibition of the Sympathetic Autonomic Nervous SystemNoradrenaline is a key vasoconstrictor, and levels are elevated in acute stroke.60 Hence, blocking its effects will lower BP and might improve cerebral perfusion. No large pure a-AA trials have been performed, but they are frequently used in China (typically with urapidil) and a significant minority of patients took them in the INTERACT studies11,12 and are on them in the ongoing ENCHANTED-BP trial.The FutureThe hypothesis presented here is that it is when and how BP is lowered, and in which type of stroke, that is important, not whether BP is lowered per se. Further, it is the additional effects of antihypertensives that may drive effects on outcome. This hypothesis is data driven and depends on the results of completed medium- and large-sized trials. In essence, intervention probably needs to be started within the ultra- and hyperacute phase of stroke (<6 hours) if a beneficial effect is to be seen, and efficacy may be localized to 1 or 2 classes, a-AA and NO donors. The evidence for a-AA is less clear because urapidil was used more in INTERACT, which showed no tendency to an effect on functional outcome, than the positive INTERACT-2 trial. Further, these results apply only to ICH. Although ENOS was neutral for treatment within 48 hours, NTG appeared to improve mRS in both IS and ICH if given within 6 hours in both ENOS and RIGHT.61 If the observations for a-AA and NTG are true, then attenuating sympathetic activity and/or supplementing vascular NO46 may be key mechanisms for facilitating efficacy when lowering BP.However, the findings are soft and more trials are required, and the ongoing ENCHANTED-BP, ICH-ADAPT-2 (Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial-2), INTERACT-3, MR-ASAP (Multicenter Randomized Trial of Acute Stroke Treatment in the Ambulance With a Nitroglycerin Patch), and RIGHT-2 trials (Table 1) will help test these hypotheses. If none of these predictions deliver, then it is possible that BP is a bystander in very acute stroke and lowering it is unimportant. New studies are required to further assess the effects of the various antihypertensive classes on additional mechanisms as listed in Table 2, including parameters such as BP variability.62 Imaging studies in IS need to assess effects of BP lowering on CBF, collateral circulation, penumbral size, influence of intra and extracranial stenosis, and interaction with mechanical thrombectomy. Similarly, imaging studies in ICH need to assess induction of ischemia (as is being investigated in ICH-ADAPT-2) and effects on hematoma characteristics such as spot sign, edema, intraventricular hemorrhage, and proximal ischemia. Ongoing and future large trials will need to assess the role of lowering BP not just by stroke type but by severity and etiology; for example, BP lowering may have differential effects in stroke related to small vessel disease in comparison with large artery and cardioembolic stroke. Further, future trials may need to be much larger (as with the ongoing INTERACT-3 bundle trial, Table 1) and so able to detect small but clinically meaningful effect sizes.In contrast to remaining questions about efficacy within 6 hours, no agents appear to be beneficial when given later than 6 hours; worse, some classes appear to be hazardous including ARA in ICH, intravenous CCB in IS, and β-RA in either stroke type. Guidelines that recommend the use of labetalol (with predominant β-RA activity) and CCB for lowering BP in acute stroke may need to be revised (Table I in the online-only Data Supplement).AcknowledgmentsThis review builds on presentations by P.M. Bath at the European Stroke Conference (2013) and 2018 International Stroke Conference, Cerebrovascular Education and Discovery (CED) Talks.DisclosuresP.M. Bath was chief investigator of ENOS; receives research grant funding from the British Heart Foundation as the Chief Investigator for the RIGHT-2 trial; has received modest honoraria for speaking at symposia sponsored by Nestle HealthScience; has received modest honoraria for consultancy for Phagenesis Ltd; has modest ownership interests in Platelet Solutions Ltd and DiaMedica Therapeutics Inc; is Stroke Association Professor of Stroke Medicine; and is an National Institute for Health Research Senior Investigator. J.P. Appleton is funded by the British Heart Foundation through the RIGHT-2 trial. The other authors report no conflicts.FootnotesPresented in part at the International Stroke Conference, Los Angeles, CA, January 24–26, 2018.The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.118.021254.Correspondence to Philip M. Bath, DSc, FMedSci, Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, City Hospital Campus, Nottingham NG5 1PB, United Kingdom. E-mail philip.[email protected]ac.ukReferences1. Yatsu FM, Zivin J. Hypertension in acute ischemic strokes. Not to treat.Arch Neurol. 1985; 42:999–1000.CrossrefMedlineGoogle Scholar2. Spence JD, Del Maestro RF. Hypertension in acute ischemic strokes. Treat.Arch Neurol. 1985; 42:1000–1002.CrossrefMedlineGoogle Scholar3. Hachinski V. Hypertension in acute ischemic strokes.Arch Neurol. 1985; 42:1002.CrossrefMedlineGoogle Scholar4. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA; IST Collaborative Group. Blood pressure and clinical outcomes in the International Stroke Trial.Stroke. 2002; 33:1315–1320.LinkGoogle Scholar5. Sprigg N, Gray LJ, Bath PM, Boysen G, De Deyn PP, Friis Pet al; TAIST Investigators. Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial.J Hypertens. 2006; 24:1413–1417. doi: 10.1097/01.hjh.0000234123.55895.12.CrossrefMedlineGoogle Scholar6. Ohwaki K, Yano E, Nagashima H, Hirata M, Nakagomi T, Tamura A. Blood pressure management in acute intracerebral hemorrhage: relationship between elevated blood pressure and hematoma enlargement.Stroke. 2004; 35:1364–1367. doi: 10.1161/01.STR.0000128795.38283.4b.LinkGoogle Scholar7. Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent outcome: a systematic review.Hypertension. 2004; 43:18–24. doi: 10.1161/01.HYP.0000105052.65787.35.LinkGoogle Scholar8. Owens WB. Blood pressure control in acute c
Referência(s)