Background: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. Methods: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130–140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6–4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87–1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60–0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70–1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. Interpretation: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.
|Number of pages||12|
|Publication status||Published - 2019 Mar 2|
Bibliographical noteFunding Information:
Individual, de-identified participant data used in these analyses will be shared by request from any qualified investigator following approval of a protocol and signed data access agreement via the Research Office of The George Institute for Global Health, Australia. Acknowledgments The study is supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (project grant numbers 1020462 and 1101113 ); the UK Stroke Association (TSA 2012/01 and 2015/01 ); the Ministry of Health and the National Council for Scientific and Technological Development of Brazil (CNPQ 467322/2014–7 and 402388/2013–5 ); the Ministry for Health, Welfare, and Family Affairs of South Korea (HI14C1985; for the alteplase-dose arm); and a research grant from Takeda for conduct of the study in China. The research team acknowledges the support of the National Institute for Health Research (NIHR) Clinical Research Network for conduct of the trial in the UK, and the EuroQol Group for use of the EQ-5D-3L. CSA is a Senior Principal Research Fellow for the NHMRC. TGR and PMB are NIHR Senior Investigators. PMB is the Professor of Stroke Medicine for the Stroke Association. We thank the investigators and research staff at the participating sites ( appendix ), members of the trial steering and data and safety monitoring board committees ( appendix ), and executive staff of The George institute for Global Health for their support of the study. We also thank the participants, and their families and friends.
After confirmation of patient eligibility, 1:1 randomisation was done centrally via a password-protected, web-based program at The George Institute for Global Health (Sydney, Australia). A minimisation algorithm was used to achieve approximate balance in randomisation according to three key prognostic factors: site of recruitment, time from the onset of symptoms (<3 h or ≥3 h), and severity of neurological impairment according to the National Institutes of Health Stroke Scale (NIHSS) score (<10 points or ≥10 points). Final follow-up was done at 90 days, in person or by telephone, by trained and certified staff who were unaware of the randomised treatment assignment. Central adjudication of safety outcomes was also done by assessors unaware of treatment allocation or clinical details.
Our trial was driven by uncertainty over whether any benefit of intensive blood pressure lowering in terms of improving outcome in patients with acute ischaemic stroke, gained largely from a reduced risk of thrombolysis-related intracerebral haemorrhage, could be offset by the harm of promoting cerebral ischaemia. The main finding was that, in thrombolysis-treated patients with acute ischaemic stroke of predominantly mild-to-moderate severity, a strategy of intensive blood pressure lowering (target systolic blood pressure 130–140 mm Hg within 1 h) compared with current guideline-recommended blood pressure management (target <180 mm Hg) after intravenous alteplase therapy was not associated with a significant difference in functional recovery, as assessed by a shift in the distribution of mRS scores at 90 days. This result was consistent in sensitivity and per-protocol analyses, and across key prespecified subgroups. However, intensive blood pressure lowering was associated with a significant reduction in the incidence of intracranial haemorrhage, as well as slight (non-significant) reductions in major intracerebral haemorrhage, consistent across different measures. The ENCHANTED trial adds important new information on the role of early intensive blood pressure lowering in the context of thrombolysed patients with acute ischaemic stroke, but it also highlights some of the challenges of doing an open trial in a critical illness with temporal change in the level of equipoise. Although we recruited to our target sample size and achieved a high rate of follow-up over 90 days, the average systolic blood pressure difference of 6 mm Hg between randomised groups was much smaller than the 15 mm Hg envisaged, and decreased as the trial progressed. In part, this finding reflected a shift in clinician behaviour towards targeting lower systolic blood pressure in the guideline group than is recommended in guidelines derived from the protocol of the National Institutes of Neurological Diseases and Stroke (NINDS) recombinant tissue plasminogen activator trial in acute ischaemic stroke. 13 It also relates to complexities in the titration of systolic blood pressure to the target according to the study protocol for patients in the intensive group: this target might have been considered too low for some clinicians, or reflected difficulties of aggressive blood pressure lowering in acute ischaemic stroke. Systolic blood pressure is an important prognostic factor after acute stroke, with a systolic blood pressure target of 140–150 mm Hg being associated with best outcome in several observational studies. 14,15 To date, randomised evaluations of blood pressure lowering treatment in acute ischaemic stroke with a broad time window from the onset of symptoms and modest systolic blood pressure reductions have been neutral. 16 By contrast, post-hoc analysis of the pivotal NINDS trial showed that the use of blood pressure lowering therapy after randomisation in hypertensive patients in the recombinant tissue plasminogen activator group was associated with less favourable outcome compared with that of patients who did not receive any such treatment. 13 However, blood pressure elevations are higher in patients who are less likely to reperfuse, have bigger strokes, and are thus more likely to get blood pressure lowering treatment. Conversely, post-hoc analysis from the more recent Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), specifically in patients with large vessel occlusion, showed a U-shaped relationship between baseline systolic blood pressure and outcome, with a systolic blood pressure nadir of 120 mm Hg being associated with best outcome. 17 Many clinicians are concerned that rapid blood pressure reductions in the absence of mechanical or pharmacological reperfusion might worsen cerebral ischaemia from potential hypoperfusion with compromised autoregulation and collateral flow. 8 In our trial, any benefit from intensive blood pressure reduction on outcome due to reduction in intracranial haemorrhage might have been offset by hypoperfusion of the ischaemic penumbra. However, we observed no significant heterogeneity of treatment effect in subgroups where large vessel occlusion might be anticipated, including acute ischaemic stroke subtypes classified on the basis of clinician-diagnosis of large vessel disease, cardioemboli, or lacunar acute ischaemic stroke, and in post-hoc analysis of stroke severity based on quartiles of increasing NIHSS score. Since CT or magnetic resonance angiography was not mandated in this pragmatic study, artery status was not assessed in most patients and large vessel occlusion was only confirmed in 97 patients in the intensive group on CT or magnetic resonance angiography. Thus, further studies of intensive blood pressure lowering in the context of mechanical and pharmacological reperfusion therapy in cases of proven large vessel occlusion are required. In the ENCHANTED trial, we also assessed the potential benefit of intensive blood pressure control in terms of the incidence of intracranial haemorrhage. From the SITS-ISTR of 11 080 patients, Ahmed and colleagues 7 reported a linear association between systolic blood pressure and symptomatic intracerebral haemorrhage up to 24 h after thrombolysis. Similarly, in a post-hoc analysis of the third International Stroke Trial (IST-3), Berge and colleagues 18 reported an association between each 10 mm Hg higher baseline systolic blood pressure and risk of symptomatic intracerebral haemorrhage, with large systolic blood pressure declines over 24 h significantly associated with decreased risk of symptomatic intracerebral haemorrhage. As the only randomised trial of intensive blood pressure reduction in thrombolysis-treated acute ischaemic stroke patients, ENCHANTED suggests that there are benefits in lowering the risk of intracranial haemorrhage, despite no observed statistically significant decrease in adjudicated symptomatic intracerebral haemorrhage. This finding might reflect variable benefit of intensive blood pressure reduction on petechial, alteplase-associated, intracerebral haemorrhage in a hypertensive population with evidence of brain vessel fragility compared with large, space-occupying, alteplase-associated, parenchymal intracerebral haemorrhage, as previously suggested by Butcher and colleagues. 19 However, as ENCHANTED recruited mainly patients with acute ischaemic stroke of mild-to-moderate severity, the study was under-powered to assess the effects of treatment on symptomatic intracerebral haemorrhage, for which the frequencies of death and major neurological deterioration were low. Even so, the lower incidence of symptomatic intracerebral haemorrhage was consistent across all classifications in the intensive group versus the guideline group, and there were non-significant reductions in both petechial (haemorrhagic infarction 1 and 2) and space-occupying (parenchymal haemorrhage 1 and 2) intracerebral haemorrhage, and borderline significant reduction in any parenchymal haemorrhage, in adjudicated brain images. Finally, it is important to note that the ENCHANTED trial excluded patients with systolic blood pressure of more than 185 mm Hg, in keeping with the licensed indication for the use of intravenous alteplase, and thus no comment can be made with respect to the risk of intracranial haemorrhage or the benefit of blood pressure reduction in severely hypertensive patients. However, others have reported that such protocol violations are associated with significantly more frequent symptomatic intracerebral haemorrhage. 20 The key strengths of this randomised controlled trial were its large size and international recruitment, which enhance the generalisability of the results and the possibility of influencing clinical practice worldwide. We used robust methodologies to ensure masking during assessment of the key efficacy measure (through central coordination of mRS follow-up by staff unaware of treatment allocation) and of the safety outcomes (with central adjudication of intracranial haemorrhage by assessors masked to clinical details and group allocation). Nonetheless, the study had several potential limitations. First, the trial involved patients with acute ischaemic stroke of predominantly mild-to-moderate severity, with a median NIHSS score of 7, in contrast to previous trial and registry data of patients with acute ischaemic stroke with median NIHSS scores of 12 and 13, respectively. 2,3 However, with increasing use of intravenous thrombolysis, an NIHSS score of 7 is more reflective of the usual treated acute ischaemic stroke population, including those in clinical trials. For example, in a comparison of tenecteplase with alteplase, published in 2017, the median NIHSS was 4. 21 Even so, our results are potentially influenced by selection bias: clinicians might have excluded cases of severe stroke with high perceived risks from intensive blood pressure lowering treatment, but the effects of intravenous alteplase are modest in mild acute ischaemic stroke. Second, there might be concerns about the generalisability of the trial results to all populations because nearly three-quarters of patients in the sample were Asian. We acknowledge reduced statistical power in the subgroup analyses; however, importantly, there was no heterogeneity of treatment effect by ethnicity, even though the high prevalence of intracranial atherosclerosis (and related intracranial stenosis) and of cerebral small vessel disease present in Asian populations might have increased the risks of hypoperfusion related to intensive blood pressure control. 22 In addition, the increased prevalence of hypertension and associated small vessel disease in Asian patients could have increased the risk of symptomatic intracerebral haemorrhage. 23 Finally, the smaller-than-anticipated systolic blood pressure difference between groups probably resulted in the trial being underpowered. In part, this reduced difference might be attributed to a natural fall in systolic blood pressure following recanalisation and reperfusion in both groups, but probably also reflected the effect of the high proportion (54·3%) of participants in the guideline group who received some form of blood pressure lowering therapy, and 35·3% who received any intravenous therapy in the first 24 h; and these patients had worse outcomes than those who did not receive treatment. The use of post-randomisation intravenous blood pressure lowering agents might reflect increased familiarity with local blood pressure lowering protocols in stroke units since the publication and international guideline adoption of the results of the main Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2), albeit in intracerebral haemorrhage patients. 24 Although most participants in the intensive group of our trial had blood pressure lowering treatment initiated soon after administration of intravenous alteplase, when the risk of reperfusion-related intracerebral haemorrhage is greatest, uncertainty remains over the most appropriate timing, approach, and agent(s) for blood pressure lowering, pre-thrombolysis and post-thrombolysis. Intensive blood pressure lowering during and for up to 72 h after intravenous thrombolysis in predominantly Asian patients with acute ischaemic stroke of mild-to-moderate severity did not improve functional outcome at 90 days compared with that of patients who received guideline-recommended blood pressure management. Overall, the results indicate that intensive blood pressure lowering is safe in this patient group, with significantly decreased incidence of intracranial haemorrhage compared with that of the guideline group, and consistency in the reduced frequency of major intracerebral haemorrhage. However, these results might not support a major shift in clinical practice towards more intensive blood pressure lowering in those receiving thrombolysis for acute ischaemic stroke of mild-to-moderate severity. Because the observed reduction in intracerebral haemorrhage did not improve clinical outcome, further research is required to understand the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in patients with hyperacute acute ischaemic stroke. Contributors CSA, JC, RIL, TGR, and YH conceived the trial. CSA was the chief investigator. CSA, RIL, XC, JC, TGR, and ACD were responsible for the day-to-day running of the trial. RIL led the adjudication of neuroimaging. QL did the statistical analysis with supervision from LB. TGR, CSA, JC, and YH wrote the first draft of the manuscript; all authors revised this draft. All authors read and approved the final version. Declaration of interests CSA has received grants from the National Health and Medical Research Council (NHMRC) of Australia and Takeda China, honoraria for advisory board activities for Boehringer Ingelheim and Amgen, and speaker fees from Takeda. RIL and MWP have received research grants from the NHMRC of Australia. HA has received lecture fees from Bayer, Daiichi-Sankyo, Fukuda Denshi, Takeda and Teijin, and personal fees for consultancy to Kyowa-Kirin. PMB has received honoraria for advisory board activities from DiaMedica, Moleac, Nestlé, Phagenesis and ReNeuron. JPB has received grants from the National Institute of Neurological Diseases and Stroke, and Genentech. AMD has received speaker fees from Medtronic. PML has received research grants from Bayer, Boehringer Ingelheim, Conicyt, The George Institute for Global Health, and Clínica Alemana. CL has received research grants from NHMRC and honoraria from Boehringer Ingelheim. SOM has received speaker fees from Boehringer Ingelheim, Pfizer, Bayer, and Medtronic. VVO has received research grants from Clínica Alemana de Santiago, The George Institute for Global Health, Boehringer Ingelheim, Lundbeck Chile, and Conicyt. GAD has received advisory committee and speaker fees from Allergan, Amgen, Boehringer Ingelheim, Moleac, and Servier. OMP-N has received speaker fees from Boehringer Ingelheim, Pfizer, and Medtronic. SR has received travel support from Bayer. SS has worked as a medical expert for Bayer, Japan, from the end of the study. MW has received personal fees for consultancy to Amgen. JC has received research grants from NHMRC and Idorsia. TGR and JMW have received research grants from the UK Stroke Association. YH, XC, GC, QL, LB, CD, ACD, T-HL, JDP, VKS, FS, LS, NHT, J-GW, and XW declare no competing interests.
© 2019 Elsevier Ltd
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