Table 3, Review protocol: Step 4 treatment - Evidence review for step 4 treatment

Field	Content
Review question	What is the most clinically and cost-effective step 4 antihypertensive drug treatment for hypertension in adults?
Type of review question	Intervention review A review of health economic evidence related to the same review question was conducted in parallel with this review. For details, see the health economic review protocol for this NICE guideline.
Objective of the review	To establish which step 4 treatment is most clinically and cost effective in adults with hypertension that remains uncontrolled following step 3 treatment.
Eligibility criteria – population / disease / condition / issue / domain	Population: Adults (over 18 years) with primary hypertension are taking the maximally tolerated doses of at least 3 drugs (including a diuretic) and their blood pressure is still uncontrolled. Stratify by: Presence or absence of type 2 diabetes The drug class(es) previously received
Eligibility criteria – intervention(s) / exposure(s) / prognostic factor(s)	Step 4 antihypertensive pharmacological treatment received for a minimum of 1 year. Alpha-blockers Beta-blockers Other or further diuretics such as amiloride and spironolactone Aliskiren (direct renin inhibitors) Clonidine, minoxidil, methyldopa, moxonidine (centrally acting antihypertensive)
Eligibility criteria – comparator(s) / control or reference (gold) standard	Compared against each other (class comparisons) Compared to placebo (class compared to placebo)
Outcomes and prioritisation	All outcomes to be measured at a minimum of 12 months. Where multiple time points are reported within each study, the longest time point only will be extracted. Critical All-cause mortality Health-related quality of life Stroke (ischaemic or haemorrhagic) MI Important Heart failure needing hospitalisation Vascular procedures (including lower limb, coronary and carotid artery procedures) Angina needing hospitalisation Discontinuation or dose reduction due to side effects Side effect 1: Acute kidney injury Side effect 2: New onset diabetes Side effect 3: Change in creatinine or eGFR Side effect 4: Hypotension (dizziness) [Combined cardiovascular disease outcomes in the absence of MI and stroke data] [coronary heart disease outcome in the absence of MI data]
Eligibility criteria – study design	RCTs and SRs
Other inclusion exclusion criteria	Minimum follow up time: 1 year Exclusions: Studies including participants with type 1 diabetes or chronic kidney disease (A3 or above [heavy proteinuria]). For the type 2 diabetes strata studies including participants with or chronic kidney disease (A2 or above [heavy proteinuria]) Indirect populations with secondary causes of hypertension such as tumours or structural vascular defects (Conn’s adenoma, phaeochromocytoma, renovascular hypertension) Pregnant women Children (aged under 18 years) Crossover trials (unless washout is 4 weeks or more) Reserpine (withdrawn from UK market) – exclude studies using this treatment.
Proposed sensitivity / subgroup analysis, or metaregression	Subgroups to explore heterogeneity: Age (under 55, 55–74 and 75 or older)* Family origin (African and Caribbean, White, South Asian) *To note that we will also extract evidence in those >80 years old if this evidence is reported separately.
Selection process – duplicate screening / selection / analysis	A senior research fellow will undertake quality assurance prior to completion.
Data management (software)	Pairwise meta-analyses will be performed using Cochrane Review Manager (RevMan5). GRADEpro will be used to assess the quality of evidence for each outcome. Endnote will be used for bibliography, citations, sifting and reference management.
Information sources – databases and dates	Medline, Embase, the Cochrane Library Language: Restrict to English only Key papers: PATHWAY-2 trial (2015) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00257-3/abstract
Identify if an update	Yes, 2011
Author contacts	https://www.nice.org.uk/guidance/cg127
Highlight if amendment to previous protocol	For details, please see section 4.5 of Developing NICE guidelines: the manual.
Search strategy – for 1 database	For details, please see appendix B
Data collection process – forms / duplicate	A standardised evidence table format will be used, and published as appendix D of the evidence report.
Data items – define all variables to be collected	For details, please see evidence tables in appendix D (clinical evidence tables) or H (health economic evidence tables).
Methods for assessing bias at outcome / study level	Standard study checklists were used to appraise individual studies critically. For details, please see section 6.2 of Developing NICE guidelines: the manual The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis	For details, please see section 6.4 of Developing NICE guidelines: the manual.
Methods for quantitative analysis – combining studies and exploring (in)consistency	For details, please see the separate Methods report for this guideline.
Meta-bias assessment – publication bias, selective reporting bias	For details, please see section 6.2 of Developing NICE guidelines: the manual.
Confidence in cumulative evidence	For details, please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual.
Rationale / context – what is known	For details, please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the evidence review. The committee was convened by the National Guideline Centre (NGC) and chaired by Anthony Wierzbicki in line with section 3 of Developing NICE guidelines: the manual. Staff from the NGC undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details, please see Developing NICE guidelines: the manual.
Sources of funding / support	The NGC is funded by NICE and hosted by the Royal College of Physicians.
Name of sponsor	The NGC is funded by NICE and hosted by the Royal College of Physicians.
Roles of sponsor	NICE funds the NGC to develop guidelines for those working in the NHS, public health and social care in England.
PROSPERO registration number	Not registered

Field

Content

Review question

What is the most clinically and cost-effective step 4 antihypertensive drug treatment for hypertension in adults?

Type of review question

Intervention review

A review of health economic evidence related to the same review question was conducted in parallel with this review. For details, see the health economic review protocol for this NICE guideline.

Objective of the review

To establish which step 4 treatment is most clinically and cost effective in adults with hypertension that remains uncontrolled following step 3 treatment.

Eligibility criteria – population / disease / condition / issue / domain

Population: Adults (over 18 years) with primary hypertension are taking the maximally tolerated doses of at least 3 drugs (including a diuretic) and their blood pressure is still uncontrolled.

Stratify by:

Presence or absence of type 2 diabetes
The drug class(es) previously received

Eligibility criteria – intervention(s) / exposure(s) / prognostic factor(s)

Step 4 antihypertensive pharmacological treatment received for a minimum of 1 year.

Alpha-blockers
Beta-blockers
Other or further diuretics such as amiloride and spironolactone
Aliskiren (direct renin inhibitors)
Clonidine, minoxidil, methyldopa, moxonidine (centrally acting antihypertensive)

Eligibility criteria – comparator(s) / control or reference (gold) standard

Compared against each other (class comparisons)
Compared to placebo (class compared to placebo)

Outcomes and prioritisation

All outcomes to be measured at a minimum of 12 months. Where multiple time points are reported within each study, the longest time point only will be extracted.

Critical

All-cause mortality
Health-related quality of life
Stroke (ischaemic or haemorrhagic)
MI

Important

Heart failure needing hospitalisation
Vascular procedures (including lower limb, coronary and carotid artery procedures)
Angina needing hospitalisation
Discontinuation or dose reduction due to side effects
Side effect 1: Acute kidney injury
Side effect 2: New onset diabetes
Side effect 3: Change in creatinine or eGFR
Side effect 4: Hypotension (dizziness)
[Combined cardiovascular disease outcomes in the absence of MI and stroke data]
[coronary heart disease outcome in the absence of MI data]

Eligibility criteria – study design

RCTs and SRs

Other inclusion exclusion criteria

Minimum follow up time: 1 year

Exclusions:

Studies including participants with type 1 diabetes or chronic kidney disease (A3 or above [heavy proteinuria]). For the type 2 diabetes strata studies including participants with or chronic kidney disease (A2 or above [heavy proteinuria])
Indirect populations with secondary causes of hypertension such as tumours or structural vascular defects (Conn’s adenoma, phaeochromocytoma, renovascular hypertension)
Pregnant women
Children (aged under 18 years)
Crossover trials (unless washout is 4 weeks or more)
Reserpine (withdrawn from UK market) – exclude studies using this treatment.

Proposed sensitivity / subgroup analysis, or metaregression

Subgroups to explore heterogeneity:

Age (under 55, 55–74 and 75 or older)*
Family origin (African and Caribbean, White, South Asian)

*To note that we will also extract evidence in those >80 years old if this evidence is reported separately.

Selection process – duplicate screening / selection / analysis

A senior research fellow will undertake quality assurance prior to completion.

Data management (software)

Pairwise meta-analyses will be performed using Cochrane Review Manager (RevMan5).

GRADEpro will be used to assess the quality of evidence for each outcome.

Endnote will be used for bibliography, citations, sifting and reference management.

Information sources – databases and dates

Medline, Embase, the Cochrane Library

Language: Restrict to English only

Key papers: PATHWAY-2 trial (2015) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00257-3/abstract

Identify if an update

Yes, 2011

Author contacts

https://www.nice.org.uk/guidance/cg127

Highlight if amendment to previous protocol

For details, please see section 4.5 of Developing NICE guidelines: the manual.

Search strategy – for 1 database

For details, please see appendix B

Data collection process – forms / duplicate

A standardised evidence table format will be used, and published as appendix D of the evidence report.

Data items – define all variables to be collected

For details, please see evidence tables in appendix D (clinical evidence tables) or H (health economic evidence tables).

Methods for assessing bias at outcome / study level

Standard study checklists were used to appraise individual studies critically. For details, please see section 6.2 of Developing NICE guidelines: the manual

The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/

Criteria for quantitative synthesis

For details, please see section 6.4 of Developing NICE guidelines: the manual.

Methods for quantitative analysis – combining studies and exploring (in)consistency

For details, please see the separate Methods report for this guideline.

Meta-bias assessment – publication bias, selective reporting bias

For details, please see section 6.2 of Developing NICE guidelines: the manual.

Confidence in cumulative evidence

For details, please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual.

Rationale / context – what is known

For details, please see the introduction to the evidence review.

Describe contributions of authors and guarantor

A multidisciplinary committee developed the evidence review. The committee was convened by the National Guideline Centre (NGC) and chaired by Anthony Wierzbicki in line with section 3 of Developing NICE guidelines: the manual. Staff from the NGC undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details, please see Developing NICE guidelines: the manual.

Sources of funding / support

The NGC is funded by NICE and hosted by the Royal College of Physicians.

Name of sponsor

The NGC is funded by NICE and hosted by the Royal College of Physicians.

Roles of sponsor

NICE funds the NGC to develop guidelines for those working in the NHS, public health and social care in England.

PROSPERO registration number

Not registered

From: Evidence review for step 4 treatment

Cover of Evidence review for step 4 treatment

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.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Table 3Review protocol: Step 4 treatment