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Three Part Question

In [patients with spontaneous intracerebral haemorrhage] does [targeted blood pressure management in the hyper-acute and acute stages] improve [functional neurological outcomes]?

Clinical Scenario

A 62-year-old women is brought to the emergency department (ED) with sudden onset left sided hemiplegia. Computed tomography (CT) scan of her head shows an acute right basal thalamic intracerebral haemorrhage (ICH). Her blood pressure in the ED is 195/100. You wonder whether you should treat this patient’s hypertension in the ED?

Search Strategy

Evidence was searched using Medline and Embase via Ovid interface.

Ovid MEDLINE(R) (1940 to week 4 June 2015): The following terms were searched:
1. exp Cerebral Hemorrhage/
2. ((cereb* or brain or stroke or intracereb* or intracrani*) adj5 h?emorrhag*).mp.
3. 1 or 2
4. (“blood pressure” or hypertens* or BP or antihypertens*) adj5 (lower* or manage* or treat* or reduc* or target* or therapy*).mp.
5. (treatment* or neurolog* or function*) adj5 (measure* or outcome*).mp.
6. Treatment Outcome/
7. 5 or 6
8. 3 and 4 and 7

EMBASE (1947-Present): The following terms were searched:
1. exp brain hemorrhage/
2. ((cereb* or brain or stroke or intracereb* or intracrani*) adj5 h?emorrhag*).mp.
3. 1 or 2
4. (blood pressure or hypertens* or BP or antihypertens*) adj5 (lower* or manage* or treat* or reduc* or target* or therapy*).mp.
5. (treatment* or neurolog* or function*) adj5 (measure* or outcome*).mp.
6. treatment outcome/
7. 5 or 6
8. 3 and 4 and 7
9. limit 8 to (english language and yr=‘2011 - 2015’)

Reference lists of all relevant papers were searched for secondary references. The search was current as of 30th June 2015.

Search Outcome

The literature search yielded 275 results on Medline and 243 results on Embase. The titles and abstracts of these papers were scanned and 37 relevant papers were identified. Of these, 6 papers answered the three part question, were of sufficient quality and represent the best evidence. These are summarised in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
SAMURI-ICH, Sakamoto et al, 2013, Japan	211 patients who presented within 3 hours of spontaneous ICH onset with hypertension (initial SBP >180 mmHg) were given IV nicardipine for 24 hours; target SBP <160 mmHg (range 120-160 mmHg).	Prospective, multi-centre, observational study. Level IIc evidence.	Neurological deterioration (decrease of ≥2 points in GCS or an increase of ≥4 points in NIHSS) at 72 hours.	Neurological deterioration was observed in 17 (8%) patients.	Observational study; did not compare groups with different SBP targets. The number of patients in the different SBP interval groups were not balanced (e.g. 27 patients had a mean SBP >145 compared to 59 with a mean SBP of 135-140).
			Unfavourable outcome, defined as mRS 4-6 at 3 months or patients who underwent surgical intervention for ICH.	Unfavourable outcome was observed in 87 (41%) patients. The mean SBP in the first 24 hours after the initiation of BP treatment was higher in patients with unfavourable (139 [134-143] mmHg) than with favourable (137 [131-141] mmHg) outcome (p=0.012). Results of multivariate logistic regression analysis found every 10 mmHg increase of mean SBP was associated with a 4.5-fold increase in neurological deterioration and 2.0-fold increase in unfavourable outcome after adjusting for known predictive factors. Patients with a mean SBP <130 mmHg (n=33) had the lowest proportions of unfavourable clinical outcomes. Based on these results, the authors concluded the optimum target SBP in acute ICH might be approximately 130 mmHg.
Koch et al, 2008, USA	42 patients who presented within 8 hours of spontaneous ICH onset and with a MAP >110 mmHg were randomly assigned to either: Standard/AHA guideline recommended BP treatment; target MAP 110-130 mmHg (n=21) OR Aggressive BP treatment; target MAP <110 mmHg (n=21).	Prospective, randomised controlled trial. Level IIb evidence.	Primary outcome: Neurological deterioration defined as an increase of ≥2 points in NIHSS from baseline to 48 hours.	No significant differences in neurological deterioration at 48 hours between the groups. Clinical deterioration occurred in 2 patients in the aggressive treatment arm and 1 patient in the standard group (p=0.55).	Single centre. Primarily designed to test safety of BP reduction. No power calculation reported. Small sample size. Antihypertensive agents for BP management not standardised.
			Secondary outcome: Favourable outcome, at 90 days, defined as mRS ≤2.	18 patients had a favourable outcome at 90 days (10 in standard therapy group vs. 8 in the aggressive therapy group, p=0.43). At 90 days, 6 patients had died, 3 in each group (p=1.00).
ICH ADAPT, Butcher et al, 2013,4 Canada 2013, Canada	75 patients who presented within 24 hours of spontaneous ICH onset with a SBP >150 mmHg were randomly assigned to either: Intensive BP lowering; target SBP <150 mmHg to achieve within 1 hour of randomisation (n=39) OR Standard treatment; target SBP <180 mmHg (n=36). 2 hours after randomisation patients underwent a CT brain scan and perfusion scan.	Multi-centre, prospective, randomised clinical trial. Level IIb evidence	Primary outcome: Difference in relative CBF within the perihaematoma region between the two treatment groups.	There was no significant difference in relative CBF within the perihaematoma region between the two groups (p=0.19). Shows cerebral ischemia is not precipitated by rapid BP reductions in acute ICH patients.	Patients were enrolled within 24 hours of ICH onset, this is a larger time window compared to other studies. As a result, the median time to randomisation was 7.4 hours which is later than other studies. Study not powered to assess difference in functional neurological outcomes. Assignment of interventions was open (unblinded). Therefore participants and clinicians knew whether the treatment was intensive or guideline-recommended management. The risk of performance bias is unclear.
			Secondary outcomes: Mortality at 30 days and functional scores (mRS, Barthel index) at 90 days post randomisation.	Clinical end-points such as mortality and functional scores were not significantly different between the groups. 30-day mortality in intensive-treatment group was 7 vs. 4 in the standard-treatment group (p=0.40). 90-day median mRS was 2.5 in the intensive group vs. 4 in the standard group (p=0.65). Median Barthel Index score was 95 in both groups (p=0.51)
INTERACT (pilot trial), Anderson et al, 2008, Australia	404 patients who presented within 6 hours of spontaneous ICH onset and had a SBP between 150 and 220 mmHg were randomly assigned to either: Intensive BP lowering treatment; target SBP <140 mmHg to achieve within 1 hour of randomisation and maintain for 7 days (n=203) OR Standard/AHA guideline recommended treatment; target SBP <180 mmHg (n=201).	Multi-centre, prospective, randomised, pilot trial. 44 centres in 3 countries (Australia, China, South Korea) enrolled patients. Level IIb evidence.	The main clinical endpoint was death or dependency (mRS 3-5) at 90 days.	At 90 days, there was no significant difference in death or dependency between the groups (95 patients had an outcome of death or dependency in both the intensive-treatment group and the guideline-treatment group; p=0.81).	Study not powered to assess difference in functional neurological outcomes. Assignment of interventions was open (unblinded). Therefore participants and clinicians knew whether the treatment was intensive or guideline-recommended management. The risk of performance bias is unclear. Antihypertensive agents not standardised across centres and this may have had an effect on outcomes.
			For safety analysis, the primary outcome was death from any cause and the secondary outcomes were early neurological deterioration (drop in GCS by ≥2 points or a gain of ≥4 points in the NIHSS from baseline to 72 hours).	Intensive lowering of BP had no significant excess adverse effect on death or on any of the clinical scales.
INTERACT2, Anderson et al, 2013, Australia	2839 patients who presented within 6 hours of spontaneous ICH onset and had a SBP between 150 and 220 mmHg were randomly assigned to either: Intensive BP lowering treatment; target SBP <140 mmHg to achieve within 1 hour of randomisation and maintain for 7 days (n=1403) OR Standard/AHA guideline recommended treatment; target SBP <180 mmHg (n=1436).	Multi-centre, prospective, randomised, clinical trial. 144 centres in 21 countries enrolled patients. Level Ib evidence	Primary outcome: death or major disability (mRS 3-5) at 90 days was defined as a poor outcome	At 90 days, there was no significant difference in poor outcomes between the groups (719 (52%) patients in the intensive-treatment group vs 785 (55.6%) in the standard-treatment group had a poor outcome; p=0.06).	Assignment of interventions was open (unblinded). Therefore participants and clinicians knew whether the treatment was intensive or guideline-recommended management. The initiation of treatment was significantly quicker in the intensive treatment group. This may have been due to the differences in the management strategies for the two groups. The risk of performance bias is unclear. BP management protocols were based on local availability of agents. Therefore antihypertensive agents were not standardised and this may have had an effect on outcomes. Only one-third of patients in the intensive treatment group achieved the target SBP level within 1 hour (half achieved the target by 6 hours).
			Secondary outcomes: Physical function across all 7 levels of the mRS.	Patients in the intensive BP-lowering group had a significantly better functional recovery. Ordinal analysis of the mRS showed a significant favourable shift in the distribution of scores with intensive BP-lowering treatment (pooled odds ratio for shift to higher mRS 0.87; 95% CI, 0.77 to 1.00; p=0.04).
			Five dimensions of health-related quality of life (mobility, self care, usual activities, pain or discomfort, and anxiety or depression), as assessed with the EQ-5D questionnaire.	At 90 days, patients in the intensive treatment group reported fewer problems and had significantly better overall health related quality of life as per the EQ-5D questionnaire (mean score 0.60 vs. 0.55; p=0.002).
Tsivgoulis et al, 2014, Multi-national	Meta-analysis of RCTs; 4 studies met the inclusion criteria. 3315 patients who presented acutely (within 24 hours) with spontaneous ICH and hypertension (SBP >150 mmHg or MAP >110 mmHg) were randomly assigned to either: Intensive BP lowering treatment or Standard/AHA guideline recommended treatment. Aim to assess the safety and efficacy of intensive BP reduction.	Systematic review and meta-analysis of RCTs. Studies included: ICH ADAPT, INTERACT I, INTERACT II, Koch et al. Level 1a evidence.	Safety: Mortality rates 3 months after randomisation	Mortality rates were similar between patients randomised to intensive BP-lowering treatment and those receiving standard guideline recommended BP lowering treatment (OR 1.01, 95% CI 0.83-1.23; p=0.914). Authors concluded, intensive lowering of BP in acute-onset ICH is safe.	All RCTs included had open-label protocols (assignment of interventions was unblinded). This was probably unavoidable. The risk of performance bias cannot be ruled out. 84% of the overall patients and pooled data was from 1 study (INTERACT 2).
			Efficacy: Unfavourable outcome was defined as death or dependency (mRS >2) at 3-months.	Intensive BP-lowering treatment was associated with lower rates of death or dependency at 3 months (OR 0.87, 95% CI: 0.76-1.01; p=0.062). However the difference between the groups was not statistically significant.

Comment(s)

Acute ICH is responsible for 9-27% of all strokes globally,[7] with an estimated >1 million people affected each year, many of whom either die or are left with severe neurological disability.[8] There are no proven therapeutic interventions for ICH and hematoma expansion in the acute stages is a key factor associated with poorer neurological outcomes.[3, 9, 10] Hematoma expansion occurs in about one third of patients with ICH and blood pressure (BP) is often elevated in these patients which is thought to contribute to haematoma growth.[9, 11] Targeted BP lowering in the acute stages has been shown to limit hematoma growth but is controversial as many have debated the early elevations of blood pressure are an adaptive response to maintain perfusion to an ischemic penumbra surrounding the hematoma.[9, 12] The question is whether intensive BP lowering following acute spontaneous ICH is safe and improves functional neurological outcomes. The ICH ADAPT trial [4] established intensive lowering of BP to a target SBP <150 mmHg following acute ICH was safe and did not reduce peri-hematoma cerebral blood flow. Functional outcome scores were not significantly different between patients treated with intensive BP lowering and those given standard treatment (target SBP <180 mmHg). The multi-centre pilot randomised controlled trail (RCT), INTERACT1, involving 404 ICH patients found intensive BP lowering in the hyper-acute stage (within 6 hours) to a target SBP <140 mmHg was safe and did not increase rates of early neurological deterioration, mortality or dependency at 3-months compared to patients treated with a target SBP <180 mmHg.[1] In an observational study by Sakamoto and colleagues,[3] 211 patients who presented within 3 hours of spontaneous ICH onset and hypertension (SBP >180 mmHg) received IV nicardipine for 24 hours to maintain a SBP target of <160 mmHg. The best 3-month functional outcomes were seen in patients who had a mean SBP <130 mmHg in the first 24 hours following acute ICH. INTERACT 2,[5] involving 2839 patients, is the largest RCT evaluating the effect of intensive BP lowering on functional outcomes. In patients who presented within 6 hours of ICH onset and hypertension (SBP between 150 and 220 mmHg), intensive lowering of BP (target SBP <140 mmHg) did not significantly improve rates of death or major disability at 90 days. On a key secondary outcome, ordinal analysis of modified Rankin Scale (mRS) scores showed a significant favourable shift in the distribution of scores in those patients treated with intensive BP lowering. Patients in the intensive treatment group also reported better overall health-related quality of life. However, overall the clinical benefits of intensive BP lowering are modest, the number of patients needed to treat to prevent one poor outcome, defined as death or major disability (mRS 3-5), was 28. There was also no clear relationship between outcome and the time from onset of ICH to commencing treatment.

Editor Comment

AHA, American Heart Association; BP, blood pressure; CBF, cerebral blood flow; EQ-5D, European Quality of Life-5 Dimensions; ICH, intracerebral haemorrhage; IV, intravenous; MAP, mean arterial pressure; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; RCT, randomised controlled trial; SBP, systolic blood pressure. BB Editor SC

Clinical Bottom Line

Overall, the current evidence suggests in patients with hypertension (SBP between 150 and 220) following spontaneous ICH, intensive lowering of SBP to a target of less than 140 mmHg in the hyper-acute and acute stages is safe and may improve functional recovery.

Level of Evidence

Level 1 - Recent well-done systematic review was considered or a study of high quality is available.

References

1. Sakamoto Y, Koga M, Yamagami H, et al. Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment Stroke 2013; 44(7):1846-1851.
2. Koch S, Romano JG, Forteza AM, et al. Rapid blood pressure reduction in acute intracerebral hemorrhage: feasibility and safety. Neurocrit Care 2008; 8(3):316-321.
3. Butcher KS, Jeerakathil T, Hill M, et al. The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial. Stroke 2013; 44(3):620-626.
4. Anderson CS, Huang Y, Wang JG, et al. Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008; 7:391-399.
5. Anderson CS, Heeley E, Huang Y, et al. Rapid Blood Pressure Lowering in Patients with Acute Intracerebral Hemorrhage. N Engl J Med 2013; 368:2355-2365.
6. Tsivgoulis G, Katsanos AH, Butcher KS, et al. Intensive blood pressure reduction in acute intracerebral hemorrhage: a meta-analysis. Neurology 2014; 83(17):1532-1539.
7. Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral haemorrhage. Int J Stroke 2014; 9(7):840-855.
8. Arima H, Anderson CS, Wang JG, et al. Lower treatment blood pressure is associated with greatest reduction in hematoma growth after acute intracerebral haemorrhage. Hypertension 2010; 56(5): 852-858.
9. Xi G, Hua Y, Keep RF. Blood pressure lowering in acute perihematomal brain edema after intracerebral haemorrhage. Stroke 2014; 45(5):1241-1242.
10. Zhang Y, Reilly KH, Tong W, et al. Blood pressure and clinical outcome among patients with acute stroke in inner Mongolia, China. J Hypertens 2008; 26(7):1446-1452.
11. Rodriguez-Luna D, Pineiro S, Rubiera M, et al. Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhage. Eur J Neurol 2013; 20(9):1277-1283.
12. Frontera JA. Blood pressure in intracerebral hemorrhage - how low should we go? N Engl J Med 2013; 368(25):2426-7.