Research Effects of blood pressure lowering in patients with acute ischemic stroke and carotid artery stenosis Mirza Jusufovic1†, Else Charlotte Sandset1†, Philip M. W. Bath2, Björn W. Karlson3,4, Eivind Berge5*, on behalf of the Scandinavian Candesartan Acute Stroke Trial (SCAST) Study Group Background The Scandinavian Candesartan Acute Stroke Trial (SCAST) showed no beneficial clinical effects of blood pressure lowering with the angiotensin receptor blocker candesartan in the acute phase of stroke. In the present analysis we wanted to see if the effects of blood pressure lowering are harmful in the subgroup of patients with carotid artery stenosis. Methods SCAST was a randomized- and placebo-controlled, double-masked trial of 2029 patients with acute stroke and high systolic blood pressure (≥140 mmHg). Of 1733 patients with ischemic stroke 993 underwent carotid artery imaging, and the degree of stenosis was categorized as no/insignificant (0–49%, n = 806), moderate (50–69%, n = 97) or severe (≥70%, n = 90). The trial’s two co-primary effect variables were the composite end-point of vascular death, stroke or myocardial infarction, and functional outcome at six-months, according to the modified Rankin Scale. Results Among patients with moderate or severe carotid artery stenosis the vascular end-point occurred in 9 of 87 patients (10·3%) treated with candesartan and in 17 of 100 controls (17·0%), and there was no evidence of a different risk in patients with severe stenosis (adjusted hazard ratio 0·74, 95% confidence interval 0·28–1·96, P = 0·54). For functional outcome there was also no clear difference, although in patients with severe stenosis the risk of a poor outcome was somewhat higher than in any of the other groups (adjusted odds ratio 2·24, 95% confidence interval 0·71–7·09, P = 0·16). Progressive stroke also occurred more often in patients with carotid artery stenosis treated with candesartan (10 of 87 patients (11·5%) vs. 4 of 100 patients (4·0%)), with a trend towards an increased risk with increasing severity of stenosis (P-value for linear trend = 0·04). Correspondence: Eivind Berge*, Oslo University Hospital, Dept of Internal Medicine, Kirkeveien 166, NO-0407 Oslo, Norway. E-mail: [email protected] 1 Dept of Neurology, Oslo University Hospital, Oslo, Norway 2 Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK 3 AstraZeneca R&D, Mölndal, Sweden 4 Dept of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 5 Dept of Internal Medicine, Oslo University Hospital, Oslo, Norway Received: 11 April 2014; Accepted: 13 October 2014; Published online 3 December 2014 Conflict of interest: M. J. and E. C. S. have no potential conflicts of interest to declare. P. M. B. received travel support from AstraZeneca to attend meetings in the trial steering committee. B. W. K. is senior clinical research physician in AstraZeneca. E. B. received payment for lectures given at meetings arranged by AstraZeneca. Sources of funding: The trial was funded by grants from the South Eastern Norway Regional Health Authority and Oslo University Hospital. AstraZeneca supplied the study drugs and AstraZeneca and Takeda supported the trial with limited unrestricted grants. †
These authors contributed equally to the article.
DOI: 10.1111/ijs.12418
354
Vol 10, April 2015, 354–359
Conclusions There is no clear evidence that the effect of candesartan is qualitatively different in patients with carotid artery stenosis, but there are signals that patients with severe stenosis are at particularly high risk of stroke progression and poor functional outcome. Key words: acute stroke, blood pressure, candesartan, carotid stenosis, cerebral autoregulation
Introduction Patients with carotid artery stenosis often have high blood pressure during the acute phase of ischemic stroke (1,2). High blood pressure in the acute phase is associated with a poor prognosis (3–5), and in patients with severe carotid artery stenosis, cerebral arterial autoregulation is often severely dysfunctional (6–9). This means that high systemic blood pressure will lead to high cerebral perfusion pressure and an increased risk of hemorrhage or edema, whereas blood pressure lowering treatment may lead to a further reduction in blood flow to the infarcted brain. However, there is limited evidence to guide treatment of high blood pressure in this important patient subgroup (10). The Scandinavian Candesartan Acute Stroke Trial (SCAST) was the first large trial of blood pressure lowering treatment in the acute phase of stroke, and showed no beneficial effects of treatment in a general stroke population (11). The protocol prespecified a separate analysis of patients with carotid artery stenosis, to see if the same result applies to these patients, or whether a different effect of treatment can be observed.
Materials and methods SCAST was a randomized- and placebo-controlled, doublemasked trial of the angiotensin receptor blocker candesartan in 2029 patients presenting within 30 hours of acute ischemic or hemorrhagic stroke and with systolic blood pressure ≥140 mmHg. The design of the trial has been reported elsewhere (11,12). In brief, patients were treated with candesartan or placebo for seven days, with doses increasing from 4 to 16 mg once daily during the first three days, and were followed for six months. The trial had two co-primary effect variables: the composite end-point of vascular death, stroke or myocardial infarction, and functional outcome, as measured by the modified Rankin Scale (mRS). The trial was registered (ISRCTN13643354) and approved by ethics committees in all participating countries. The present analyses focus on patients with ischemic stroke who underwent carotid artery examination. Carotid artery examinations were performed on clinical indication and according to routine clinical practice at each site, with the use of © 2014 World Stroke Organization
Research
M. Jusufovic et al. ultrasound, contrast-enhanced magnetic resonance angiography, contrast-enhanced computed tomographic angiography, and/or digital subtraction angiography. Presence of, and degree of, carotid artery stenosis was assessed according to clinical practice at each site, and degree of stenosis was categorized as no/insignificant (0–49%), moderate (50 to 69%), or severe (≥70%) (13,14). We used the trial’s predefined primary effect variables, and good functional outcome was defined as a mRS score of 0, 1 or 2. We included early stroke progression as a secondary effect variable, since in the overall study population, a statistically significant difference had been observed for this end-point, in disfavor of candesartan (11,12). Stroke progression was defined as a neurological deterioration of ≥2 points on the Scandinavian Stroke Scale, occurring within the first 72 hours of stroke onset and believed to be caused by the index stroke, after exclusion of recurrent stroke or systemic reasons for deterioration. We used one-way ANOVA, the χ2 test, or the Mann-Whitney U test to compare patients at baseline, and independent sample t-test to compare blood pressure values during the treatment period. The composite vascular end-point was analyzed using Cox proportional hazard models, and functional outcome (mRS) and stroke progression were analyzed using logistic regression analysis, and we assessed heterogeneity of treatment effect by including an interaction term in the models. We used the MantelHaenzel test for linear trend, and adjusted all multivariable analyses for the following predefined key variables: age, Scandinavian Stroke Scale score and systolic blood pressure. All analyses were performed using spss (version 18·0; SPSS Statistics, Chicago, IL, USA).
Results Of the 1733 patients with ischemic stroke, 993 (57·3%) underwent carotid artery imaging (491 in the candesartan group and 502 in the placebo group). In most cases (880 patients) imaging was performed with ultrasound. Of the 993 patients who underwent imaging, 806 (81·2%) had no or insignificant stenosis, 97 (9·8%) had moderate stenosis, and 90 (9·1%) had severe stenosis. Table 1 shows the clinical characteristics of patients with different degrees of carotid artery stenosis and of patients without carotid artery data, for comparison. Patients with severe stenosis had somewhat more severe strokes and received thrombolytic treatment more often than patients with less severe stenosis. Patients without carotid artery data were older and had more often atrial fibrillation. Blood pressure fell in both treatment arms during the treatment period, but was lower in patients treated with candesartan already from day 2, and from day 4 onwards the mean difference was 5/2 mmHg (data not shown) (11). Fig. 1 shows blood pressures in the three groups with, and in the group without carotid artery data. In all four groups, treatment with candesartan was associated with modest and statistically significant reduction in blood pressure. Figure 2 shows the effect of candesartan on the risk of the composite vascular endpoint, for patients with different degrees of carotid artery stenosis. Among patients with moderate or severe carotid artery stenosis, the composite end-point occurred in 9 of 87 patients (10·3%) treated with candesartan and in 17 of 100 controls (17·0%). After adjustment there was no difference in risk with candesartan, for any degree of stenosis (Fig. 2).
Table 1 Baseline characteristics for patients with different degrees of carotid artery stenosis and patients without carotid artery data No/insignificant stenosis (n = 806) Age (years) Gender (female) Premorbid mRS Medical history Hypertension Atrial fibrillation Diabetes mellitus Previous stroke or TIA Baseline SBP (mmHg) Baseline DBP (mmHg) SSS score Duration of symptoms (h) OCSP syndrome Total anterior Partial anterior Posterior Lacunar Current use of an ACE inhibitor Thrombolysis before randomization Treatment with candesartan
Moderate stenosis (n = 97)
Severe stenosis (n = 90)
No carotid artery data (n = 740)
68·1 (10·4) 330 (40·9%) 0 (0-0)
72·0 (10·2) 35 (36·1%) 0 (0-0)
68·8 (10·1) 25 (27·8%) 1 (1-1)
75·6 (10·4) 368 (49·7%) 0 (0-0)
532 (66·0%) 130 (16·1%) 148 (18·4%) 154 (19·1%) 170·1 (18·4) 91·4 (13·7) 47 (38–53) 17·9 (8·0)
69 (71·1%) 14 (14·4%) 21 (21·6%) 25 (25·8%) 170·6 (16·7) 86·7 (13·3) 45 (34–52) 19·1 (7·8)
67 (74·4%) 13 (14·4%) 17 (18·9%) 24 (26·7%) 169·9 (17·9) 85·8 (13·5) 43 (25–49) 18·5 (8·5)
495 (66·9%) 191 (25·8%) 102 (13·8%) 204 (27·6%) 170·3 (19·0) 88·1 (14·0) 40 (29–48) 18·5 (7·9)
32 (4·0%) 405 (50·2%) 83 (10·3%) 282 (35·0%) 238 (29·5%) 88 (10·9%) 404 (50·1%)
11 (11·3%) 50 (51·5%) 15 (15·5%) 20 (20·6%) 22 (22·7%) 5 (5·1%) 44 (45·4%)
6 (6·7%) 45 (50·0%) 21 (23·3%) 18 (20·0%) 28 (31·1%) 17 (18·9%) 43 (47·8)
80 (10·8%) 350 (47·3%) 117 (15·8%) 190 (25·7%) 180 (24·3%) 38 (5·1%) 371 (50·1%)
Data are n (%), mean (SD), or median (IQR). ACE, angiotensin converting enzyme; DBP, diastolic blood pressure; mRS, modified Rankin Scale; OCSP, Oxfordshire Community Stroke Project; SBP, systolic blood pressure; SD, standard deviation; SSS, Scandinavian Stroke Scale.
© 2014 World Stroke Organization
Vol 10, April 2015, 354–359
355
Research
M. Jusufovic et al.
Fig. 1 Blood pressures during the treatment period, in patients with different degrees of carotid artery stenosis and patients without carotid artery data.
Fig. 2 Risk of the composite vascular endpoint during six-months’ follow-up (vascular death, stroke, or myocardial infarction). *Adjusted for age, Scandinavian Stroke Scale score and systolic blood pressure. CI, confidence interval; HR, hazard ratio.
The second co-primary effect variable was functional outcome as measured by the mRS (Fig. 3). The logistic regression analysis showed no evidence of a different risk with candesartan in any of the stenosis groups (p-value for interaction = 0·53), although in patients with severe stenosis, the risk of a poor outcome was
356
Vol 10, April 2015, 354–359
somewhat higher than in the other groups (adjusted odds ratio 2·24, 95% confidence interval 0·71–7·09, P = 0·16). Figure 4 shows the risk of stroke progression in the different subgroups. Progressive stroke occurred more often in patients with moderate or severe carotid artery stenosis treated with © 2014 World Stroke Organization
M. Jusufovic et al.
Research
Fig. 3 Functional outcomes at six-months, for patients with different degrees of carotid artery stenosis and patients without carotid artery data. *Adjusted for age, Scandinavian Stroke Scale score and systolic blood pressure. CI, confidence interval; OR, odds ratio.
Fig. 4 Stroke progression during the treatment period. *Adjusted for age, Scandinavian Stroke Scale score and systolic blood pressure. CI, confidence interval; OR, odds ratio.
candesartan (10 of 87 patients (11·5%) vs. 4 of 100 patients given placebo (4·0%)). The risk of stroke progression with candesartan was higher with increasing severity of carotid artery stenosis (p-value for linear trend = 0·04), and in patients with severe stenosis the adjusted odds ratio was 5·01 (95% confidence interval 0·85–29·3, P = 0·07).
Discussion It has long been a controversy whether blood pressure should be actively lowered in the acute phase of ischemic stroke, and guidelines have often favored a conservative approach, recommending careful blood pressure lowering only for patients with very high blood pressure, or for patients who receive thrombolytic therapy (15,16). For patients with severe carotid artery stenosis no specific recommendations exist, but the view is generally held that for this subgroup of patients intensive blood pressure lowering treatment should not be given in the acute phase (10). The Scandinavian Candesartan Acute Stroke Trial (SCAST) was the first large trial of blood pressure lowering treatment in acute stroke and indicated that, in a general stroke population, treatment with the angiotensin receptor blocker candesartan is associated with an increased risk of stroke progression in the early phase, and of poor functional outcome in the longer run (11). For the subgroup of patients with carotid artery stenosis the present analysis shows that, although there were no clear signs that the effect of treatment is qualitatively different in patients with © 2014 World Stroke Organization
carotid artery stenosis, these patients seem to be at particularly high risk of stroke progression and poor functional outcome. There are limited data available about the effects of blood pressure lowering treatment in patients with acute ischemic stroke and carotid artery stenosis. Studies have shown that independent of treatment, prognosis is worse for those with severe stenosis (17) and those with low blood pressure at baseline (18), but there are no well-controlled studies to inform whether it is safe to give blood pressure lowering treatment to these patients. Our findings are, however, in keeping with pathophysiological observations and thinking. In patients with severe carotid artery stenosis cerebral autoregulation is often severely dysfunctional (6–9), and cerebral blood flow becomes passively dependent on systemic blood pressure (3,19,20). This means that a small decrease in blood pressure might compromise blood flow even further (21), increasing cerebral ischemia and the size of the infarct (22). There are some limitations to this analysis. First, since we have carotid artery data on only 57% of the patients in the trial, one might question whether patient selection can have influenced the results. Carotid artery examinations were done on clinical indication, and patients without carotid artery data were older and had more often atrial fibrillation. However, all patients were randomly allocated to treatment, and all analyses were adjusted for key prognostic variables, so in each subgroup the difference in outcome most probably reflects the effects of candesartan. Accordingly, more complete carotid artery data would probably not have made a qualitative change to the results, but would Vol 10, April 2015, 354–359
357
Research instead have increased the precision of the risk estimates. Second, since carotid artery data were adjudicated by investigators at each site, there is a risk of misclassification of degree of stenosis. However, the investigators were blinded to treatment, and the effect of a random misclassification would only be to dilute the differences, if there really are differences between the groups. Third, relatively few patients had carotid artery stenosis (for example, compared to studies of blood pressure management for long-term prevention of stroke (10)), and there is a risk that the observed differences reflect the play of chance. Still, we included around 1000 patients, of whom around 100 had moderate and 100 had severe stenosis, and the statistical uncertainty is adequately reflected in the 95% confidence intervals. Moreover, due to limited numbers, we have adjusted for a number of predefined, key prognostic variables, to reduce the risk of confounding. It is also a possibility that the effects of blood pressure lowering in this trial are specific to angiotensin receptor blockers. We chose a blocker of the renin-angiotensin system based on their favorable effects in preclinical (23–26) and clinical studies in acute stroke (27,28), as well as in trials of secondary prevention (29–31). Other drug classes may have different pharmacological effects. For example, glyceryl trinitrate has promising effects in preclinical and small clinical studies, and one large randomized-controlled trial of blood pressure lowering treatment with transdermal glyceryl trinitrate in patients with acute stroke (including patients with carotid artery stenosis) is under way (32). In summary, there was no clear evidence that the effect of blood pressure lowering with candesartan is harmful in patients with acute ischemic stroke and carotid artery stenosis. However, the results are consistent with the signals from the main analysis, that treatment involves risk of stroke progression and poor functional outcome. On-going trials will help clarify whether this is a class effect, or whether there are other and safer ways of lowering blood pressure in patients with acute ischemic stroke.
Author contributions MJ performed the statistical analyses and wrote the first version of the manuscript. ECS collected the data, wrote the analysis plan, supervised the statistical analyses, and commented on the manuscript. PMB participated in the planning and conduction of the study, conceived the analyses and commented on the manuscript. BWK participated in the planning and conduction of the study, and commented on the manuscript. EB supervised the study, the analyses and the writing of the manuscript.
References 1 Wolff T, Guirguis-Blake J, Miller T, Gillespie M, Harris R. Screening for carotid artery stenosis: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2007; 147:860–70. 2 Spence JD. Management of resistant hypertension in patients with carotid stenosis: high prevalence of renovascular hypertension. Cerebrovasc Dis 2000; 10:249–54. 3 Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA, IST Collaborative Group. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002; 33:1315–20.
358
Vol 10, April 2015, 354–359
M. Jusufovic et al. 4 Sprigg N, Gray LJ, Bath PM et al. Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial. J Hypertens 2006; 24:1413–7. 5 Qureshi AI, Ezzeddine MA, Nasar A et al. Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med 2007; 25:32–8. 6 van der Grond J, Balm R, Kappelle LJ et al. Cerebral metabolism of patients with stenosis or occlusion of the internal carotid artery. A 1H-MR spectroscopic imaging study. Stroke 1995; 26:822–8. 7 Vernieri F, Pasqualetti P, Passarelli F, Rossini PM, Silvestrini M. Outcome of carotid artery occlusion is predicted by cerebrovascular reactivity. Stroke 1999; 30:593–8. 8 Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol 1991; 29:231–40. 9 Grubb RL Jr, Derdeyn CP, Fritsch SM et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998; 280:1055–60. 10 Rothwell PM, Howard SC, Spence JD. Carotid Endarterectomy Trialists’ Collaboration. Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease. Stroke 2003; 34:2583–90. 11 Sandset EC, Bath PM, Boysen G et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet 2011; 377:741–50. 12 Sandset EC, Murray G, Boysen G et al. Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003). Int J Stroke 2010; 5:423–7. 13 European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991; 337:1235–43. 14 North American Symptomatic Carotid Endarterectomy Trial Steering Committee. North American symptomatic carotid endarterectomy trial. Methods, patient characteristics, and progress. Stroke 1991; 22:711–20. 15 Jauch EC, Saver JL, Adams HP et al. American heart association stroke council; council on cardiovascular nursing; council on peripheral vascular disease; council on clinical cardiology. 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. 16 European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25:457– 507. 17 Sare GM, Gray LJ, Wardlaw J, Chen C, Bath PM. Is lowering blood pressure hazardous in patients with significant ipsilateral carotid stenosis and acute ischaemic stroke? Interim assessment in the ‘Efficacy of Nitric Oxide in Stroke’ trial. Blood Press Monit 2009; 14:20–5. 18 Paciaroni M, Agnelli G, Caso V et al. Effect of carotid stenosis on the prognostic value of admission blood pressure in patients with acute ischemic stroke. Atherosclerosis 2009; 206:469–73. 19 Stead LG, Gilmore RM, Decker WW, Weaver AL, Brown RD Jr. Initial emergency department blood pressure as predictor of survival after acute ischemic stroke. Neurology 2005; 65:1179–83. 20 Vemmos KN, Tsivgoulis G, Spengos K et al. U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med 2004; 255:257–65. 21 Britton M, de Faire U, Helmers C. Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 1980; 207:253–7. 22 Ruff RL, Talman WT, Petito F. Transient ischemic attacks associated with hypotension in hypertensive patients with carotid artery stenosis. Stroke 1981; 12:353–5. © 2014 World Stroke Organization
M. Jusufovic et al. 23 Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 2000; 31:2478–86. 24 Fornes P, Richer C, Vacher E, Bruneval P, Giudicelli JF. Losartan’s protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal. J Cardiovasc Pharmacol 1993; 22:305–13. 25 Inada Y, Wada T, Ojima M et al. Protective effects of candesartan cilexetil (TCV-116) against stroke, kidney dysfunction and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. Clin Exp Hypertens 1997; 19:1079–99. 26 Wada T, Kanagawa R, Ishimura Y, Inada Y, Nishikawa K. Role of angiotensin II in cerebrovascular and renal damage in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 1995; 13:113–22. 27 Walters MR, Bolster A, Dyker AG, Lees KR. Effect of perindopril on cerebral and renal perfusion in stroke patients with carotid disease. Stroke 2001; 32:473–8.
© 2014 World Stroke Organization
Research 28 Schrader J, Luders S, Kulschewski A et al. The ACCESS Study: evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke 2003; 34:1699–703. 29 PROGRESS Collaborative Group. Randomised trial of a perindoprilbased blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033– 41. 30 Schrader J, Luders S, Kulschewski A et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005; 36:1218–26. 31 Yusuf S, Diener HC, Sacco RL et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008; 359:1225–37. 32 The ENOS Trial Investigators. Glyceryl trinitrate vs. control, and continuing vs stopping temporarily prior antihypertensive therapy, in acute stroke: rationale and design of the Efficacy of Nitric Oxide in Stroke (ENOS) trial (ISRCTN99414122). Int J Stroke 2006; 1:245–9.
Vol 10, April 2015, 354–359
359
Copyright of International Journal of Stroke is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
These authors contributed equally to the article.
DOI: 10.1111/ijs.12418
354
Vol 10, April 2015, 354–359
Conclusions There is no clear evidence that the effect of candesartan is qualitatively different in patients with carotid artery stenosis, but there are signals that patients with severe stenosis are at particularly high risk of stroke progression and poor functional outcome. Key words: acute stroke, blood pressure, candesartan, carotid stenosis, cerebral autoregulation
Introduction Patients with carotid artery stenosis often have high blood pressure during the acute phase of ischemic stroke (1,2). High blood pressure in the acute phase is associated with a poor prognosis (3–5), and in patients with severe carotid artery stenosis, cerebral arterial autoregulation is often severely dysfunctional (6–9). This means that high systemic blood pressure will lead to high cerebral perfusion pressure and an increased risk of hemorrhage or edema, whereas blood pressure lowering treatment may lead to a further reduction in blood flow to the infarcted brain. However, there is limited evidence to guide treatment of high blood pressure in this important patient subgroup (10). The Scandinavian Candesartan Acute Stroke Trial (SCAST) was the first large trial of blood pressure lowering treatment in the acute phase of stroke, and showed no beneficial effects of treatment in a general stroke population (11). The protocol prespecified a separate analysis of patients with carotid artery stenosis, to see if the same result applies to these patients, or whether a different effect of treatment can be observed.
Materials and methods SCAST was a randomized- and placebo-controlled, doublemasked trial of the angiotensin receptor blocker candesartan in 2029 patients presenting within 30 hours of acute ischemic or hemorrhagic stroke and with systolic blood pressure ≥140 mmHg. The design of the trial has been reported elsewhere (11,12). In brief, patients were treated with candesartan or placebo for seven days, with doses increasing from 4 to 16 mg once daily during the first three days, and were followed for six months. The trial had two co-primary effect variables: the composite end-point of vascular death, stroke or myocardial infarction, and functional outcome, as measured by the modified Rankin Scale (mRS). The trial was registered (ISRCTN13643354) and approved by ethics committees in all participating countries. The present analyses focus on patients with ischemic stroke who underwent carotid artery examination. Carotid artery examinations were performed on clinical indication and according to routine clinical practice at each site, with the use of © 2014 World Stroke Organization
Research
M. Jusufovic et al. ultrasound, contrast-enhanced magnetic resonance angiography, contrast-enhanced computed tomographic angiography, and/or digital subtraction angiography. Presence of, and degree of, carotid artery stenosis was assessed according to clinical practice at each site, and degree of stenosis was categorized as no/insignificant (0–49%), moderate (50 to 69%), or severe (≥70%) (13,14). We used the trial’s predefined primary effect variables, and good functional outcome was defined as a mRS score of 0, 1 or 2. We included early stroke progression as a secondary effect variable, since in the overall study population, a statistically significant difference had been observed for this end-point, in disfavor of candesartan (11,12). Stroke progression was defined as a neurological deterioration of ≥2 points on the Scandinavian Stroke Scale, occurring within the first 72 hours of stroke onset and believed to be caused by the index stroke, after exclusion of recurrent stroke or systemic reasons for deterioration. We used one-way ANOVA, the χ2 test, or the Mann-Whitney U test to compare patients at baseline, and independent sample t-test to compare blood pressure values during the treatment period. The composite vascular end-point was analyzed using Cox proportional hazard models, and functional outcome (mRS) and stroke progression were analyzed using logistic regression analysis, and we assessed heterogeneity of treatment effect by including an interaction term in the models. We used the MantelHaenzel test for linear trend, and adjusted all multivariable analyses for the following predefined key variables: age, Scandinavian Stroke Scale score and systolic blood pressure. All analyses were performed using spss (version 18·0; SPSS Statistics, Chicago, IL, USA).
Results Of the 1733 patients with ischemic stroke, 993 (57·3%) underwent carotid artery imaging (491 in the candesartan group and 502 in the placebo group). In most cases (880 patients) imaging was performed with ultrasound. Of the 993 patients who underwent imaging, 806 (81·2%) had no or insignificant stenosis, 97 (9·8%) had moderate stenosis, and 90 (9·1%) had severe stenosis. Table 1 shows the clinical characteristics of patients with different degrees of carotid artery stenosis and of patients without carotid artery data, for comparison. Patients with severe stenosis had somewhat more severe strokes and received thrombolytic treatment more often than patients with less severe stenosis. Patients without carotid artery data were older and had more often atrial fibrillation. Blood pressure fell in both treatment arms during the treatment period, but was lower in patients treated with candesartan already from day 2, and from day 4 onwards the mean difference was 5/2 mmHg (data not shown) (11). Fig. 1 shows blood pressures in the three groups with, and in the group without carotid artery data. In all four groups, treatment with candesartan was associated with modest and statistically significant reduction in blood pressure. Figure 2 shows the effect of candesartan on the risk of the composite vascular endpoint, for patients with different degrees of carotid artery stenosis. Among patients with moderate or severe carotid artery stenosis, the composite end-point occurred in 9 of 87 patients (10·3%) treated with candesartan and in 17 of 100 controls (17·0%). After adjustment there was no difference in risk with candesartan, for any degree of stenosis (Fig. 2).
Table 1 Baseline characteristics for patients with different degrees of carotid artery stenosis and patients without carotid artery data No/insignificant stenosis (n = 806) Age (years) Gender (female) Premorbid mRS Medical history Hypertension Atrial fibrillation Diabetes mellitus Previous stroke or TIA Baseline SBP (mmHg) Baseline DBP (mmHg) SSS score Duration of symptoms (h) OCSP syndrome Total anterior Partial anterior Posterior Lacunar Current use of an ACE inhibitor Thrombolysis before randomization Treatment with candesartan
Moderate stenosis (n = 97)
Severe stenosis (n = 90)
No carotid artery data (n = 740)
68·1 (10·4) 330 (40·9%) 0 (0-0)
72·0 (10·2) 35 (36·1%) 0 (0-0)
68·8 (10·1) 25 (27·8%) 1 (1-1)
75·6 (10·4) 368 (49·7%) 0 (0-0)
532 (66·0%) 130 (16·1%) 148 (18·4%) 154 (19·1%) 170·1 (18·4) 91·4 (13·7) 47 (38–53) 17·9 (8·0)
69 (71·1%) 14 (14·4%) 21 (21·6%) 25 (25·8%) 170·6 (16·7) 86·7 (13·3) 45 (34–52) 19·1 (7·8)
67 (74·4%) 13 (14·4%) 17 (18·9%) 24 (26·7%) 169·9 (17·9) 85·8 (13·5) 43 (25–49) 18·5 (8·5)
495 (66·9%) 191 (25·8%) 102 (13·8%) 204 (27·6%) 170·3 (19·0) 88·1 (14·0) 40 (29–48) 18·5 (7·9)
32 (4·0%) 405 (50·2%) 83 (10·3%) 282 (35·0%) 238 (29·5%) 88 (10·9%) 404 (50·1%)
11 (11·3%) 50 (51·5%) 15 (15·5%) 20 (20·6%) 22 (22·7%) 5 (5·1%) 44 (45·4%)
6 (6·7%) 45 (50·0%) 21 (23·3%) 18 (20·0%) 28 (31·1%) 17 (18·9%) 43 (47·8)
80 (10·8%) 350 (47·3%) 117 (15·8%) 190 (25·7%) 180 (24·3%) 38 (5·1%) 371 (50·1%)
Data are n (%), mean (SD), or median (IQR). ACE, angiotensin converting enzyme; DBP, diastolic blood pressure; mRS, modified Rankin Scale; OCSP, Oxfordshire Community Stroke Project; SBP, systolic blood pressure; SD, standard deviation; SSS, Scandinavian Stroke Scale.
© 2014 World Stroke Organization
Vol 10, April 2015, 354–359
355
Research
M. Jusufovic et al.
Fig. 1 Blood pressures during the treatment period, in patients with different degrees of carotid artery stenosis and patients without carotid artery data.
Fig. 2 Risk of the composite vascular endpoint during six-months’ follow-up (vascular death, stroke, or myocardial infarction). *Adjusted for age, Scandinavian Stroke Scale score and systolic blood pressure. CI, confidence interval; HR, hazard ratio.
The second co-primary effect variable was functional outcome as measured by the mRS (Fig. 3). The logistic regression analysis showed no evidence of a different risk with candesartan in any of the stenosis groups (p-value for interaction = 0·53), although in patients with severe stenosis, the risk of a poor outcome was
356
Vol 10, April 2015, 354–359
somewhat higher than in the other groups (adjusted odds ratio 2·24, 95% confidence interval 0·71–7·09, P = 0·16). Figure 4 shows the risk of stroke progression in the different subgroups. Progressive stroke occurred more often in patients with moderate or severe carotid artery stenosis treated with © 2014 World Stroke Organization
M. Jusufovic et al.
Research
Fig. 3 Functional outcomes at six-months, for patients with different degrees of carotid artery stenosis and patients without carotid artery data. *Adjusted for age, Scandinavian Stroke Scale score and systolic blood pressure. CI, confidence interval; OR, odds ratio.
Fig. 4 Stroke progression during the treatment period. *Adjusted for age, Scandinavian Stroke Scale score and systolic blood pressure. CI, confidence interval; OR, odds ratio.
candesartan (10 of 87 patients (11·5%) vs. 4 of 100 patients given placebo (4·0%)). The risk of stroke progression with candesartan was higher with increasing severity of carotid artery stenosis (p-value for linear trend = 0·04), and in patients with severe stenosis the adjusted odds ratio was 5·01 (95% confidence interval 0·85–29·3, P = 0·07).
Discussion It has long been a controversy whether blood pressure should be actively lowered in the acute phase of ischemic stroke, and guidelines have often favored a conservative approach, recommending careful blood pressure lowering only for patients with very high blood pressure, or for patients who receive thrombolytic therapy (15,16). For patients with severe carotid artery stenosis no specific recommendations exist, but the view is generally held that for this subgroup of patients intensive blood pressure lowering treatment should not be given in the acute phase (10). The Scandinavian Candesartan Acute Stroke Trial (SCAST) was the first large trial of blood pressure lowering treatment in acute stroke and indicated that, in a general stroke population, treatment with the angiotensin receptor blocker candesartan is associated with an increased risk of stroke progression in the early phase, and of poor functional outcome in the longer run (11). For the subgroup of patients with carotid artery stenosis the present analysis shows that, although there were no clear signs that the effect of treatment is qualitatively different in patients with © 2014 World Stroke Organization
carotid artery stenosis, these patients seem to be at particularly high risk of stroke progression and poor functional outcome. There are limited data available about the effects of blood pressure lowering treatment in patients with acute ischemic stroke and carotid artery stenosis. Studies have shown that independent of treatment, prognosis is worse for those with severe stenosis (17) and those with low blood pressure at baseline (18), but there are no well-controlled studies to inform whether it is safe to give blood pressure lowering treatment to these patients. Our findings are, however, in keeping with pathophysiological observations and thinking. In patients with severe carotid artery stenosis cerebral autoregulation is often severely dysfunctional (6–9), and cerebral blood flow becomes passively dependent on systemic blood pressure (3,19,20). This means that a small decrease in blood pressure might compromise blood flow even further (21), increasing cerebral ischemia and the size of the infarct (22). There are some limitations to this analysis. First, since we have carotid artery data on only 57% of the patients in the trial, one might question whether patient selection can have influenced the results. Carotid artery examinations were done on clinical indication, and patients without carotid artery data were older and had more often atrial fibrillation. However, all patients were randomly allocated to treatment, and all analyses were adjusted for key prognostic variables, so in each subgroup the difference in outcome most probably reflects the effects of candesartan. Accordingly, more complete carotid artery data would probably not have made a qualitative change to the results, but would Vol 10, April 2015, 354–359
357
Research instead have increased the precision of the risk estimates. Second, since carotid artery data were adjudicated by investigators at each site, there is a risk of misclassification of degree of stenosis. However, the investigators were blinded to treatment, and the effect of a random misclassification would only be to dilute the differences, if there really are differences between the groups. Third, relatively few patients had carotid artery stenosis (for example, compared to studies of blood pressure management for long-term prevention of stroke (10)), and there is a risk that the observed differences reflect the play of chance. Still, we included around 1000 patients, of whom around 100 had moderate and 100 had severe stenosis, and the statistical uncertainty is adequately reflected in the 95% confidence intervals. Moreover, due to limited numbers, we have adjusted for a number of predefined, key prognostic variables, to reduce the risk of confounding. It is also a possibility that the effects of blood pressure lowering in this trial are specific to angiotensin receptor blockers. We chose a blocker of the renin-angiotensin system based on their favorable effects in preclinical (23–26) and clinical studies in acute stroke (27,28), as well as in trials of secondary prevention (29–31). Other drug classes may have different pharmacological effects. For example, glyceryl trinitrate has promising effects in preclinical and small clinical studies, and one large randomized-controlled trial of blood pressure lowering treatment with transdermal glyceryl trinitrate in patients with acute stroke (including patients with carotid artery stenosis) is under way (32). In summary, there was no clear evidence that the effect of blood pressure lowering with candesartan is harmful in patients with acute ischemic stroke and carotid artery stenosis. However, the results are consistent with the signals from the main analysis, that treatment involves risk of stroke progression and poor functional outcome. On-going trials will help clarify whether this is a class effect, or whether there are other and safer ways of lowering blood pressure in patients with acute ischemic stroke.
Author contributions MJ performed the statistical analyses and wrote the first version of the manuscript. ECS collected the data, wrote the analysis plan, supervised the statistical analyses, and commented on the manuscript. PMB participated in the planning and conduction of the study, conceived the analyses and commented on the manuscript. BWK participated in the planning and conduction of the study, and commented on the manuscript. EB supervised the study, the analyses and the writing of the manuscript.
References 1 Wolff T, Guirguis-Blake J, Miller T, Gillespie M, Harris R. Screening for carotid artery stenosis: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2007; 147:860–70. 2 Spence JD. Management of resistant hypertension in patients with carotid stenosis: high prevalence of renovascular hypertension. Cerebrovasc Dis 2000; 10:249–54. 3 Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA, IST Collaborative Group. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 2002; 33:1315–20.
358
Vol 10, April 2015, 354–359
M. Jusufovic et al. 4 Sprigg N, Gray LJ, Bath PM et al. Relationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke: data from the TAIST trial. J Hypertens 2006; 24:1413–7. 5 Qureshi AI, Ezzeddine MA, Nasar A et al. Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med 2007; 25:32–8. 6 van der Grond J, Balm R, Kappelle LJ et al. Cerebral metabolism of patients with stenosis or occlusion of the internal carotid artery. A 1H-MR spectroscopic imaging study. Stroke 1995; 26:822–8. 7 Vernieri F, Pasqualetti P, Passarelli F, Rossini PM, Silvestrini M. Outcome of carotid artery occlusion is predicted by cerebrovascular reactivity. Stroke 1999; 30:593–8. 8 Powers WJ. Cerebral hemodynamics in ischemic cerebrovascular disease. Ann Neurol 1991; 29:231–40. 9 Grubb RL Jr, Derdeyn CP, Fritsch SM et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998; 280:1055–60. 10 Rothwell PM, Howard SC, Spence JD. Carotid Endarterectomy Trialists’ Collaboration. Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease. Stroke 2003; 34:2583–90. 11 Sandset EC, Bath PM, Boysen G et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet 2011; 377:741–50. 12 Sandset EC, Murray G, Boysen G et al. Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003). Int J Stroke 2010; 5:423–7. 13 European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991; 337:1235–43. 14 North American Symptomatic Carotid Endarterectomy Trial Steering Committee. North American symptomatic carotid endarterectomy trial. Methods, patient characteristics, and progress. Stroke 1991; 22:711–20. 15 Jauch EC, Saver JL, Adams HP et al. American heart association stroke council; council on cardiovascular nursing; council on peripheral vascular disease; council on clinical cardiology. 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. 16 European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25:457– 507. 17 Sare GM, Gray LJ, Wardlaw J, Chen C, Bath PM. Is lowering blood pressure hazardous in patients with significant ipsilateral carotid stenosis and acute ischaemic stroke? Interim assessment in the ‘Efficacy of Nitric Oxide in Stroke’ trial. Blood Press Monit 2009; 14:20–5. 18 Paciaroni M, Agnelli G, Caso V et al. Effect of carotid stenosis on the prognostic value of admission blood pressure in patients with acute ischemic stroke. Atherosclerosis 2009; 206:469–73. 19 Stead LG, Gilmore RM, Decker WW, Weaver AL, Brown RD Jr. Initial emergency department blood pressure as predictor of survival after acute ischemic stroke. Neurology 2005; 65:1179–83. 20 Vemmos KN, Tsivgoulis G, Spengos K et al. U-shaped relationship between mortality and admission blood pressure in patients with acute stroke. J Intern Med 2004; 255:257–65. 21 Britton M, de Faire U, Helmers C. Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 1980; 207:253–7. 22 Ruff RL, Talman WT, Petito F. Transient ischemic attacks associated with hypotension in hypertensive patients with carotid artery stenosis. Stroke 1981; 12:353–5. © 2014 World Stroke Organization
M. Jusufovic et al. 23 Nishimura Y, Ito T, Saavedra JM. Angiotensin II AT(1) blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 2000; 31:2478–86. 24 Fornes P, Richer C, Vacher E, Bruneval P, Giudicelli JF. Losartan’s protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal. J Cardiovasc Pharmacol 1993; 22:305–13. 25 Inada Y, Wada T, Ojima M et al. Protective effects of candesartan cilexetil (TCV-116) against stroke, kidney dysfunction and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. Clin Exp Hypertens 1997; 19:1079–99. 26 Wada T, Kanagawa R, Ishimura Y, Inada Y, Nishikawa K. Role of angiotensin II in cerebrovascular and renal damage in deoxycorticosterone acetate-salt hypertensive rats. J Hypertens 1995; 13:113–22. 27 Walters MR, Bolster A, Dyker AG, Lees KR. Effect of perindopril on cerebral and renal perfusion in stroke patients with carotid disease. Stroke 2001; 32:473–8.
© 2014 World Stroke Organization
Research 28 Schrader J, Luders S, Kulschewski A et al. The ACCESS Study: evaluation of acute candesartan cilexetil therapy in stroke survivors. Stroke 2003; 34:1699–703. 29 PROGRESS Collaborative Group. Randomised trial of a perindoprilbased blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033– 41. 30 Schrader J, Luders S, Kulschewski A et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005; 36:1218–26. 31 Yusuf S, Diener HC, Sacco RL et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008; 359:1225–37. 32 The ENOS Trial Investigators. Glyceryl trinitrate vs. control, and continuing vs stopping temporarily prior antihypertensive therapy, in acute stroke: rationale and design of the Efficacy of Nitric Oxide in Stroke (ENOS) trial (ISRCTN99414122). Int J Stroke 2006; 1:245–9.
Vol 10, April 2015, 354–359
359
Copyright of International Journal of Stroke is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
