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Evidence review for maintenance of homeostasis

Stroke and transient ischaemic attack in over 16s: diagnosis and initial management

Evidence review E

NICE Guideline, No. 128

.

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-3386-0

1. Restoration or maintenance of homeostasis

1.1. Review question: What is the safety and efficacy of measures to lower blood pressure versus standard treatment in people with acute intracerebral haemorrhage?

1.2. Introduction

Elevated blood pressure is common after acute stroke. Patients may have pre-existing hypertension or blood pressure changes may occur as a result of disturbed cardiovascular autonomic regulation. Evidence has consistently shown that there is no benefit of lowering blood pressure acutely in ischaemic stroke however there is still clinical uncertainty regarding the safety and efficacy of lowering blood pressure in acute intracerebral haemorrhage. Uncontrolled hypertension in acute intracerebral haemorrhage may result in haemorrhagic expansion and a worse neurological outcome, however there is clinical concern that aggressive blood pressure lowering may reduce blood flow to the brain and other vital organs resulting in adverse outcomes such as cerebral and cord ischaemia, acute kidney injury, and myocardial infarction.

People with intracerebral haemorrhage have a mortality of around 40% with 60-70% of those who survive having moderate or severe disability54 and there are currently no treatment options beyond supportive management. If lowering blood pressure is safe and effective this may provide the opportunity improve the outcome in this type of stroke. As a number of clinical trials addressing the safety and efficacy of blood pressure lowering in acute intracerebral haemorrhage have been completed since the original guideline was published in 2008 it was important to review the current evidence regarding this clinical question.

1.3. PICO table

For full details see the review protocol in appendix A.

Table 1. PICO characteristics of review question.

Table 1

PICO characteristics of review question.

1.4. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual.18 Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy upto March 2018, and NICE’s 2018 conflicts of interest policy from April 2018.

1.5. Clinical evidence

1.5.1. Included studies

Seven studies were included in the review1, 3, 15, 32, 33, 41, 63 and evidence from these studies is summarised in the clinical evidence summary below (Table 2). The studies all compare intensive blood pressure therapy with standard blood pressure therapy; although some of the blood pressure lowering protocols had different targets. One study33 was a subgroup analysis of those with intracerebral haemorrhage within a randomised trial.11 Stroke type (ischaemic or haemorrhagic) was a pre-speicfied subgroup that was used as a stratification variable before intial randomisation; therefore, randomisation was not lost and the subgroup data were eligible for inclusion.

See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E and GRADE tables in appendix F.

1.5.2. Excluded studies

See the excluded studies list in appendix H.

1.5.3. Summary of clinical studies included in the evidence review

Table 2. Summary of studies included in the evidence review.

Table 2

Summary of studies included in the evidence review.

See appendix D for full evidence tables.

1.5.4. Quality assessment of clinical studies included in the evidence review

Table 3. Clinical evidence summary: Intensive blood pressure versus standard treatment.

Table 3

Clinical evidence summary: Intensive blood pressure versus standard treatment.

See appendix F for full GRADE tables.

Table 4. Data not suitable for meta-analysis.

Table 4

Data not suitable for meta-analysis.

1.6. Economic evidence

1.6.1. Included studies

No relevant health economic studies were included.

1.6.2. Excluded studies

Two economic studies relating to this review question were identified but were excluded as they were not applicable.39, 52, 58 These are listed in appendix H, with reasons for exclusion given.

See also the health economic study selection flow chart in appendix G.

1.6.3. Unit costs

UK costs of drugs to lower blood pressure are presented in Table 5 and Table 6.

Table 5. UK costs of drugs to lower blood pressure.

Table 5

UK costs of drugs to lower blood pressure.

Table 6. UK costs of blood pressure lowering with labetalol.

Table 6

UK costs of blood pressure lowering with labetalol.

The clinical review found that 39 people with haemorrhagic stroke would need to be treated to yield one additional person with an mRS 0-2. At a total cost of £250.66 per person, the cost of treating 39 people with haemorrhagic stroke is £9,776 (Table 6). According to published literature, the cost saving between mRS 0-2 and mRS 3-5 is £7,813 within three months of stroke onset and £10,182 over the first year after stroke23. Over a lifetime time horizon, further cost savings are therefore likely to be accrued. The committee therefore considered that the cost of treating 39 people with intravenous labetalol (£9,776) were likely to be recuperated over a year and would be cost saving over a lifetime time horizon. Nursing costs are not included in this calculation and it may be that additional nursing time is required for monitoring, however this is difficult to quantify as people will already be being managed in a high dependency area of an emergency department or hyperacute stroke unit and the additional time required is unclear.

1.7. Resource costs

The recommendation made by the committee based on this review (see section Error! Reference source not found.) that rapid blood pressure lowering should be offered in people with acute intracerebral haemorrhage and systolic blood pressure between 150 and 220 mmHg and presenting within 6 hours of symptom onset is not expected to have a substantial impact on resources to the NHS in England. The committee also made a recommendation based on this review (see section Error! Reference source not found.) that controlled blood pressure lowering should be ‘considered’ for people with acute intracerebral haemorrhage who present beyond 6 hours of symptom onset or have a systolic Stroke and transient ischaemic attack in over 16s: evidence review E FINAL (May 2019) Restoration or maintenance of homeostasis blood pressure greater than 220 mmHg. Unlike for stronger recommendations stating that interventions should be adopted, it is not possible to make a judgement about the potential resource impact to the NHS of recommendations regarding interventions that could be used, as uptake is too difficult to predict. There was also uncertainty about current practice in this population. However, the committee noted that where this recommendation is implemented there would be additional costs relating to drug treatment to lower systolic blood pressure and there is potential for downstream cost savings if health outcomes are improved.

1.8. Evidence statements

1.8.1. Clinical evidence statements

  • Seven trials in 5119 people were included investigating intensive blood pressure lowering within 48 hours of symptom onset in acute intracerebral haemorrhage versus standard blood pressure lowering. No clinical difference at 90 days was reported for mortality (7 trials, 5119 people, High quality), recurrent stroke (3 trials, 3832 people, Low quality), myocardial infaction (1 trial, 629 people, Low quality) and quality of life (EQ-5D utility index) (2 trials, 3030 people, Moderate quality). No clinical difference at 24 hours was reported for neurological deterioration (2 trials, 3764 people, Very Low quality) and haematoma expansion (4 trials, 2228 people, Moderate quality).
  • Three trials in 3832 people examining functional outcome showed a clinical meaningful benefit of intensive blood pressure lowering versus standard blood pressure lowering as measured by mRS 0 to 2 at 90 days (Moderate quality). This was supported by the ordinal shift analysis of the mRS at 90 days from the same studies (Moderate quality).
  • Four trials in 1647 people examining renal failire at 90 days showed clinical harm for intensive blood pressure lowering versus standard blood pressure lowering (Moderate quality).

1.8.2. Health economic evidence statements

  • No relevant economic evaluations were identified.

1.9. The committee’s discussion of the evidence

1.9.1. Interpreting the evidence

1.9.1.1. The outcomes that matter most

The critical outcomes identified for this review were the mRS at 90 days and 1 year, and mortality at 24 hours and 90 days. The committee considered both outcomes to be vital in decision making. Important outcomes included symptomatic cerebral ischaemia, haemorrhagic expansion, neurological deterioration, renal failure, spinal cord infarction, myocardial infarction, and quality of life.

No evidence was available for the adverse event outcomes of symptomatic cerebral ischaemia and spinal cord infarction.

1.9.1.2. The quality of the evidence

Seven studies were included in the review. Two large trials provided the majority of the body of evidence. The trials were all prospective randomized open blinded end-point (PROBE) trials. This meant that patient and care givers were not blinded to the intervention, but the outcome assessors were. Subjective outcomes (mRS and quality of life) were therefore downgraded for risk of bias. Outcomes such as renal failure and myocardial infarction had very few events resulting in estimates of effect with wide confidence intervals and therefore they were downgraded for imprecision.

Evidence ranged from very low to high quality, with the majority of the evidence rated as moderate quality. The good quality evidence from a large number of participants found that intensive or rapid systolic blood pressure lowering is likely to be safe therefore a strong recommendation was made.

1.9.1.3. Benefits and harms

The committee noted that for the recommended strategy there was no evidence of blood pressure lowering causing harm in people after intracerebral haemorrhage with high blood pressure, with no signal of increased neurological deterioration due to reduced blood flow to the brain. Rapid blood pressure lowering did not adversely affect renal function in the majority of trials. The exception was in a trial that used a more aggressive blood pressure reduction protocol, with a target for systolic blood pressure of 110-139 mmHg and treatment started within 4.5 hours of onset, where there was evidence of increased renal failure with 19 more cases per 1000 compared to the control rate of 14 per 1000. The committee agreed that rapid lowering of systolic blood pressure is safe when using less aggressive protocols, and so have included detail on the blood pressure target and time window in the recommendation. While there was no clear difference in the pooled common odds ratio from the mRS ordinal shift analysis, the committee considered the absolute benefit demonstrated for the dichotomous outcome of mRS 0 to 2 to be sufficiently clinically meaningful to recommend systolic blood pressure lowering. These outcomes were supported by the evidence for quality of life at 90 days from the INTERACT2 trial (but not in the pooled data for this outcome) and haematoma growth at 24 hours, which also favoured rapid treatment with no indication of harm.

In accordance with evidence from the trials where rapid systolic blood pressure lowering was found to be safe it was recommended that treatment should start within 6 hours and continue for 7 days, and that the target should be 130-140 mmHg within 1 hour. Regarding the target range, this was consistent with what was achieved in the INTERACT-2 trial and also avoids the potenetially harmful aggressive reduction to a lower target, as in ATACH-2, that could be associated with renal failure. Also, lowering the systolic blood pressure below 130 mmHg was noted to risk of excessive reduction, requiring intervention to raise the blood pressure back to a safe level in these patients and so should be avoided.

It was noted that this should be a strong recommendation because:

  • There is good evidence that intensive or rapid systolic blood pressure lowering is safe and has some signal for effectiveness, which could have been underestimated by including ATACH2 in the meta-analysis, which has a more aggressive regimen in the control arm that is similar to the intervention arm of the other main trial, INTERACT-2
  • The mortality rate from intracerebral haemorrhage without intervention is reported to be around 40% at 1 month54 so any intervention to reduce this is important
  • Up to 60% of those who survive currently have moderate or severe disability54
  • It will likely standardise care in this condition where much inconsistency is known to exist.

Additionally, based on the exclusion criteria for the INTERACT-2 trial, those with an underlying structural cause (for example tumour, artereovenous malformation or aneurysm), a GCS of below 6, a massive haematoma with a poor expected prognosis or who are going to have early neurosurgery to evacuate the haematoma are not included in the recommendation as there is no evidence of benefit or absence of harm in these people because they were not included in the trial. Also, it will often not be appropriate to undertake an active management approach in these people because they are likely to be entering a palliative care pathway.

While there was limited evidence for people presenting after 6 hours (only one small study recruiting within 8 hours of presentation), the committee agreed that rapid systolic blood pressure lowering could be recommended for people presenting after 6 hours. No evidence of harm was found in the earlier presenting group, and there is no reason to believe that this would be different in the later group. Therefore, the consensus of the group was that the evidence could be extrapolated to people presenting beyond 6 hours.

Similarly, although the majority of the evidence was from trials that did not include people with a systolic blood pressure over 220 mmHg the committee agreed that current practice is to implement systolic blood pressure reduction as part of initiating secondary prevention as soon as possible. The committee also believed that this should not pose any greater harm than rapid systolic blood pressure reduction in those with a systolic blood pressure below 220 mmHg. The committee noted that the ‘consider’ recommendation would allow clinical discretion in these groups for instances where rapid lowering may not be appropriate, for example if the initial systolic blood pressure was more than 230 mmHg.

Overall, it was agreed that although there was little or no evidence for those presenting beyond 6 hours and those with a systolic blood pressure over 220 mmHg, it is logical to extrapolate from the available data to these groups and that guidance on how to manage these patients is required.

The committee noted that very aggressive systolic blood pressure lowering should be avoided in all groups because of the risk for renal impairment.

1.9.2. Cost effectiveness and resource use

No relevant economic evaluations were identified which addressed the cost effectiveness of measures to manipulate systolic blood pressure versus treatment as usual in people with acute intracerebral haemorrhage. The committee expressed that there is variation between centres and consultants in current practice of systolic blood pressure lowering. Intravenous labetalol is commonly used as the first-line treatment for systolic blood pressure lowering in the UK. In the absence of relevant economic evaluations, the committee considered the unit costs of systolic blood pressure lowering agents. Labetalol 100mg/20ml solution for injection ampoules currently have a unit cost of £10.44. For a two-day course of 50 mg/hour intravenous labetalol, the current total cost per person is £250.66.

Upon considering the cost of treatment with intravenous labetalol, the committee considered that the clinical evidence indicated that treatment of approximately 39 people within 6 hours of acute intracerebral haemorrhage would yield an additional person with an mRS score of 0-2 at 90 days. At a total cost of £250.66 per person, the total cost of treating 39 people with haemorrhagic stroke is £9,776. The committee noted that nursing costs are not included in this calculation and it may be that additional nursing time is required for monitoring, however this is difficult to quantify as people will already be being managed in a high dependency area of an emergency department or hyperacute stroke unit and the additional time required is unclear. In addition, the clinical evidence associated with rapid blood pressure lowering, found an absence of harm and a higher quality of life at 90 days in the intervention group than in the control. The committee noted, however, that very aggressive systolic blood pressure lowering (e.g. from a high baseline to a low target, as in ATACH2) could have deleterious effects on renal function and consequently impact long term costs and quality of life.

The cost of treating 39 people with haemorrhagic stroke was interpreted in light of the costs, obtained from the literature, of being in mRS 0-2 compared with mRS 3-5. A cost utility analysis from the UK NHS perspective obtained annual costs (adjusted to 2013/2014 UK pounds) of being in the independent and dependent health states from a second study. This study applied UK NHS reference costs to the resource use from a UK, single centre randomised controlled trial to calculate the costs of stroke. It did not differentiate between haemorrhagic and ischaemic strokes and excluded very mild and very severe strokes, as defined by the Barthel Index. The study assumed that mild and moderate strokes correspond to independent stroke survivors and severe stroke described the cost of dependent stroke survivors. These studies indicate that estimated cost savings of £7,813 within three months of stroke onset and £10,182 over the first year after stroke could be made by shifting one person from mRS 3-5 to mRS 0-2. Over a lifetime time horizon, further cost savings are therefore likely to be accrued. The committee therefore considered that the cost of treating 39 people with intravenous labetalol (£9,776) was likely to be recuperated over a year and would be cost saving over a lifetime time horizon.

The committee also noted that for the population of people with acute intracerebral haemorrhage, the distribution of mRS scores in those surviving is likely to be skewed towards higher scores, as up to 60% of survivors have moderate to severe disability. The cost differences between those with mRS scores of 5 and mRS scores 0-2 are likely to be higher than those mentioned above. In addition, the committee acknowledged the heterogeneity in the trials. The committee thought that by delivering the intervention in line with the trial with more favourable results (INTERACT 2), the treatment effect might be improved and the number needed to treat reduced, producing larger cost savings. On this basis, the committee agreed that rapid systolic blood pressure reduction could be offered to this population. While there is variation in current practice, this protocol is already being widely implemented in most trusts so the committee does not expect a very large impact on practice or a substantial resource impact to the NHS in England.

No clinical or economic evidence was identified for those presenting at 6-24 hours of symptom onset nor with systolic blood pressure exceeding 220 mmHg. The committee however agreed that rapid systolic blood pressure lowering should also be considered in this population, because haematoma expansion – the therapeutic target for rapid blood pressure reduction – can still occur up to 24 hours after symptom onset.

The committee noted that the unit costs of oral systolic blood pressure lowering agents are currently significantly lower than those of intravenous systolic blood pressure lowering agents. The committee stressed that after an intravenous course with an approximate duration of up to two days, people with haemorrhagic stroke should be maintained on oral systolic blood pressure drugs when possible. Oral systolic blood pressure medicines should be introduced as soon as possible to prevent rebound of systolic blood pressure when the intravenous course is discontinued and maintain smooth blood pressure control beyond the hyperacute phase.

In conclusion, no relevant economic evaluations were identified which addressed the cost effectiveness of measures to manipulate systolic blood pressure versus treatment as usual in people with haemorrhagic stroke. The committee’s discussion was informed by evidence that a greater proportion of people have mRS 0-2 at 90 days following rapid systolic blood pressure reduction than with usual care, with concomitant cost savings exceeding the costs of the intervention. The committee was confident in recommending that rapid systolic blood pressure lowering is offered to people presenting within 6 hours of symptom onset for acute intracerebral haemorrhage as it is likely to be cost saving, and confer health benefits to people with haemorrhagic stroke. They also agreed that it was reasonable to extrapolate this evidence to those presenting after 6 hours or with a systolic blood pressure exceeding 220 mmHg and that rapid blood pressure lowering should be considered in these groups.

1.9.3. Other factors the committee took into account

A recommendation to lower systolic blood pressure could encourage greater overall monitoring and drive up overall care quality. The committee were aware of emerging evidence that more intensive monitoring, which would be associated with blood pressure control, encourages a more intensive multimodal approach to patients with intracerebral haemorrhage and leads to overall improved outcomes in this patient cohort.

The committee also noted the distinction between acute treatment, which is designed to reduce effects of the index event by reducing systolic blood pressure, and secondary prevention. It was agreed that it is unclear at what point management changes from acute treatment to secondary prevention, but that one indicator may be when treatment is changed from IV to oral route of administration. However, this evidence review is primarily concerned with treatment within the first 48 hours.

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Appendices

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017 https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869

For more detailed information, please see the Methodology Review.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 9. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to the stroke population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics.

Table 10. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix D. Clinical evidence tables

Download PDF (417K)

Appendix H. Excluded studies

H.2. Excluded health economic studies

Published health economic studies that met the inclusion criteria (relevant population, comparators, economic study design, published 2002 or later and not from non-OECD country or USA) but that were excluded following appraisal of applicability and methodological quality are listed below. See the health economic protocol for more details.

Table 13. Studies excluded from the health economic review

FINAL

Intervention evidence review

This evidence review was developed by the National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Copyright © NICE 2019.
Bookshelf ID: NBK577866PMID: 35167205

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