Evidence review for step 4 treatment

National Guideline Centre (UK)

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Evidence review for step 4 treatment

Hypertension in adults: diagnosis and management

Evidence review G

NICE Guideline, No. 136

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2019 Aug.

ISBN-13: 978-1-4731-3503-1

1. Step 4 treatment

1.1. Review question: What is the most clinically and cost-effective sequence for step 4 treatment for hypertension?

1.2. Introduction

Antihypertensive treatment is usually very effective in lowering blood pressure to within normal limits. However, in some individuals, blood pressure remains elevated despite being prescribed multiple antihypertensive medications, and these individuals remain at an elevated risk of cardiovascular events. The term ‘resistant hypertension’ is commonly applied to individuals who are prescribed 3 antihypertensive medications including a diuretic, but their blood pressure remains above the target. Those with resistant hypertension have double the risk of cardiovascular events than those without resistant hypertension, thus making them an important group to study. Estimates vary as to what proportion of those with hypertension have ‘resistant hypertension’, but it is generally thought to be around 5%.

Current clinical practice when selecting a step 4 treatment is to choose 1 of a number of medications based on the person’s and the clinician’s preference without robust evidence as to which might lower blood pressure the most effectively. During the guideline scoping process, a number of recently published clinical studies were highlighted that were designed to identify which medication(s) would be the optimal choice as step 4 treatment. In this chapter, the evidence for choosing a step 4 medication was reviewed.

1.3. PICO table

For full details, see the review protocol in appendix A.

Table 1

PICO characteristics of review question.

1.4. Clinical evidence

1.4.1. Included studies

No relevant clinical studies comparing step 4 antihypertensive pharmacological treatment received for a minimum of 1 year were identified.

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.

1.4.2. Excluded studies

One Cochrane review relevant to this review question was identified.⁴⁴ This was excluded because it included crossover studies without the minimum washout period of 4 weeks as required for inclusion within this review. The references were checked for any relevant studies.

See the excluded studies list in appendix I. Table 14 outlines the full excluded studies list, and Table 13 provides additional detail of studies that were included in the previous guideline iteration (CG127) but excluded from this update.

See the excluded studies list in appendix I.

1.5. Economic evidence

1.5.1. Included studies

No relevant health economic studies were identified.

1.5.2. Excluded studies

No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.

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

1.5.3. Resource costs

Costs are illustrated below for average doses of the most commonly used drugs from each class listed on the review protocol, based on committee opinion.

Table 2

UK costs of step 4 drugs.

1.6. Evidence statements

1.6.1. Clinical evidence statements

No relevant published evidence was identified.

1.6.2. Health economic evidence statements

No relevant economic evaluations were identified.

1.7. The committee’s discussion of the evidence

1.7.1. Interpreting the evidence

1.7.1.1. The outcomes that matter most

The committee considered all-cause mortality, quality of life, stroke and myocardial infarction to be critical outcomes for decision-making. Heart failure, vascular procedures, angina and discontinuation or dose reduction due to side effects were also considered important for decision-making.

No relevant clinical studies were identified therefore no evidence was available for any of these outcomes.

1.7.1.2. The quality of the evidence

No clinical studies relevant to the review question were identified.

1.7.1.3. Benefits and harms

No clinical studies relevant to this review protocol were identified.

The committee discussed the use of different step 4 antihypertensive treatments. It agreed that there was very little evidence within this area, so the committee formed consensus recommendations based on their clinical experience. They were aware of a trial (PATHWAY-2) that assessed the step 4 treatment in resistant hypertension. Afterdiscussing the findings of the PATHWAY-2 trial, they agreed that this study did not meet the inclusion criteria for this review due to having a short follow-up and no outcomes relevant to the agreed protocol. Nevertheless, it suggested that adding spironolactone could be effective at reducing blood pressure as a step 4 treatment. It was noted that higher doses of spironolactone were used (25 mg–50 mg), and the 50 mg dose was noted to lower blood pressure more. However, it was unclear what proportion of people were receiving the 50 mg dose. The study also suggested that amiloride could be as effective as spironolactone in lowering blood pressure. However, the committee noted that amiloride is more expensive, and it is taken twice a day, whereas spironolactone is taken only once daily making it a more convenient option for people who are already taking multiple medications. The committee agreed that changes in blood pressure alone, without information on cardiovascular events was not very informative to patient important outcomes, however they agreed that there was no evidence to suggest a better treatment option was available than spironolactone, which was now part of common clinical practice, and so it should still be recommended as step 4 treatment for those who had an inadequate response to 3 previous treatments.

It was discussed that the previous spironolactone dose recommendation of 25 mg once daily was too specific given the limited evidence base; instead, the committee decided to leave this more open as a ‘low-dose’ if the potassium level was 4.5 mmol/l or lower. The committee suggested that they were aware of recent evidence, outside of the remit for this reviwew, which suggested a smaller dose of 12.5 mg could be effective as a step 4 treatment. The committee also agreed that there was no evidence with hard outcomes data to warrant recommending a higher dose thiazide in people with higher potassium levels, and it was agreed that in this case alpha- or beta-blockers should be considered instead, as higher dose thiazide diuretics are not more effective than lower dose thiazide diuretics.

The need for further research to inform choice of step 4 treatment was discussed; however, the committee considered this would be unlikely to be funded, as the PATHWAY-2 trial had addressed this question previously, despite not including the hard cardiovascular outcomes this committee considered necessary to make a strong recommendation on the topic.

The committee discussed the need to seek specialist advice in order to investigate alternative reasons for a lack of response to treatment, such as adherence issues or secondary causes of hypertension to better manage treatment. The previous guideline recommendation stated that specialist advice should be sought regardless of whether a fourth antihypertensive drug was already added. The committee agreed that its clinical experience suggested the decision to seek specialist advice would be made on a case-by-case basis, but generally, it would either be appropriate to treat a person with resistant hypertension or to seek specialist advice. The committee highlighted the importance of taking the person’s preference into account, particularly where people might be concerned that they are already on 3 drugs and hadn’t responded well to these. The committee therefore agreed to reword the previous recommendation to clarify that either option should be considered.

The committee discussed the long-term implications of spironolactone treatment. Although there was no evidence identified for this within the review, including a lack of information on adverse events, the committee agreed that the multiple known harms of consistently high blood pressure outweighed this uncertainty. They did agree, however, that further evidence was required in order for healthcare professionals and people with hypertension to understand the choice of drugs available and the benefit and harms associated with each of these.

The committee discussed the use of ambulatory or home blood pressure measurement to confirm elevated blood pressure levels based on their experience and current practice. It was agreed that this is generally the method used in current practice to confirm resistant hypertension. Although there could be some variation in current practice, the committee agreed that this is the best and most accurate method of identifying people with resistant hypertension. Screening for postural hypotension was also considered an important factor to include in a recommendation, as it could affect whether additional treatment could be harmful.

1.7.2. Cost effectiveness and resource use

No economic evidence was identified for this question.

The drugs that could be used for resistant hypertension can vary in price; for example, amiloride hydrochloride is more expensive than spironolactone. The population affected with resistant hypertension, although being a small proportion of those with hypertension (around 6%), still results in a large amount of people given the size of the hypertensive population.

It was discussed how the measurement method to confirm resistant hypertension is important and best practice would be to confirm elevated measurements using ambulatory or home blood pressure recordings. This has been added as a recommendation and is generally already believed to be current practice. But where it is not, it will be of benefit because it will more accurately identify those with resistant hypertension. The committee considered that the population on 3 drugs who actually have resistant hypertension is likely to be smaller than those labelled as having resistant hypertension. This could mean a reduction in treatment as there might be some overtreatment of resistant hypertension in practice due to inappropriate measurement (overtreatment can however also be because people are not properly adhering to their medication, rather than their medication is not working – although this is more difficult to identify). There might be some additional diagnostic costs involved if some areas do not currently confirm resistant hypertension in this way, but this depends on the measurement method; for example, if someone is already using home monitoring with their own device then that person could use the same method to diagnose if the hypertension is resistant.

There was no clinical evidence identified; therefore, the committee agreed to carry forward previous recommendations with some minor amendments. These included deleting a recommendation on considering higher dose thiazide-like diuretic therapy for those with high blood potassium levels, as this was not considered to be current practice and people would generally go onto step 4 of alpha or beta-blockers.

It was also discussed how the recommendation around seeking specialist advice for those in whom blood pressure was uncontrolled on 3 drugs was unclear, as it stated specialist advice should be sought even if a step 4 treatment was already added. The committee’s opinion was that not all clinicians would seek specialist advice, as some would be more comfortable trying a step 4 treatment and some would prefer to seek advice first. The recommendation was changed to make it clearer that step 4 treatment could be considered or specialist advice could be sought. As the previous recommendation was a consider recommendation, practice was variable as to whether people were seeking specialist advice; therefore, this wording change is unlikely to have an impact on practice. It was also discussed whether it should be specified if seeking advice means referring a person to a more specialist service, or if it should be stated who this individual might be. However, the committee agreed that asking for advice is more flexible because the advice may well be to refer the person, or it may be more of an informal discussion between clinicians. Additionally, specifying whether the specialist should be a hypertension specialist was thought to be too restrictive because the specialist could also be another role such as a cardiologist, nephrologist or endocrinologist and would really depend on local services.

On balance, the recommendations are not expected to have a resource impact.

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Appendices

Appendix A. Review protocols

Table 3. Review protocol: Step 4 treatment

Table 4. Health economic review protocol

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.

For more detailed information, please see the Methodology Review. [Add cross reference]

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 5. Database date parameters and filters used

Table 6. Medline (Ovid) search terms

Table 7. Embase (Ovid) search terms

Table 8. Cochrane Library (Wiley) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to hypertension in adults 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, economic modelling and quality of life studies.

Table 9. Database date parameters and filters used

Table 10. Medline (Ovid) search terms

Table 11. Embase (Ovid) search terms

Table 12. NHS EED and HTA (CRD) search terms

Appendix C. Clinical evidence selection

Figure 1. Flow chart of clinical study selection for the review of step 4 treatment

Appendix D. Clinical evidence tables

None.

Appendix E. Forest plots

None.

Appendix F. GRADE tables

None.

Appendix G. Health economic evidence selection

Figure 2. Flow chart of health economic study selection for the guideline

Appendix H. Health economic evidence tables

None.

Appendix I. Excluded studies

I.1. Excluded clinical studies

Table 13. Studies excluded from the clinical review that were included in the previous guideline (CG127)

Table 14. Studies excluded from the clinical review

I.2. Excluded health economic studies

No health economic studies were found.

Final

Intervention evidence review underpinning recommendations 1.4.44 to 1.4.50 in the guideline

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.

Bookshelf ID: NBK578063PMID: 35188724

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National Guideline Centre (UK). Evidence review for step 4 treatment: Hypertension in adults: diagnosis and management: Evidence review G. London: National Institute for Health and Care Excellence (NICE); 2019 Aug. (NICE Guideline, No. 136.)
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Evidence review for step 4 treatment

1. Step 4 treatment

1.1. Review question: What is the most clinically and cost-effective sequence for step 4 treatment for hypertension?

1.2. Introduction

1.3. PICO table

Table 1

1.4. Clinical evidence

1.4.1. Included studies

1.4.2. Excluded studies

1.5. Economic evidence

1.5.1. Included studies

1.5.2. Excluded studies

1.5.3. Resource costs

Table 2

1.6. Evidence statements

1.6.1. Clinical evidence statements

1.6.2. Health economic evidence statements

1.7. The committee’s discussion of the evidence

1.7.1. Interpreting the evidence

1.7.1.1. The outcomes that matter most

1.7.1.2. The quality of the evidence

1.7.1.3. Benefits and harms

1.7.2. Cost effectiveness and resource use

References

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

B.1. Clinical search literature search strategy

B.2. Health Economics literature search strategy

Appendix C. Clinical evidence selection

Appendix D. Clinical evidence tables

Appendix E. Forest plots

Appendix F. GRADE tables

Appendix G. Health economic evidence selection

Appendix H. Health economic evidence tables

Appendix I. Excluded studies

I.1. Excluded clinical studies

I.2. Excluded health economic studies

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