Evidence review for step 1 treatment

National Guideline Centre (UK)

Evidence review for step 1 treatment

Hypertension in adults: diagnosis and management

Evidence review E

NICE Guideline, No. 136

Authors

National Guideline Centre (UK).

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

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

1. Step 1 treatment

1.1. Review question: Is monotherapy or combination antihypertensive therapy more clinically and cost effective for step 1 treatment for hypertension?

1.2. Introduction

Most individuals on treatment for hypertension are prescribed more than 1 medication to achieve their target blood pressure. One of the reasons for this is that different medications act on different pathways of blood pressure regulation. When 1 pathway is modified by a medication, the other pathways may compensate to keep the blood pressure elevated. It may therefore be more clinically and cost-effective to start more than 1 antihypertensive medication at the same time, thus potentially achieving the target blood pressure quicker and with fewer visits to the healthcare provider. In this chapter, the evidence for this approach is compared to that for starting with monotherapy.

1.3. PICO table

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

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.¹⁵⁵ 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.

1.5. Clinical evidence

1.5.1. Included studies

Three studies were included in the review¹³^, ¹⁴^, ⁴⁷^, ⁵²^, ¹³³^, ¹³⁹^, ¹⁴⁸; these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below (Table 3).

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

Cochrane reviews relevant to this review question were identified. Li 2014¹³² was excluded due to an incorrect population. Garjon 2017⁸⁹ was excluded due to no relevant outcomes.

See the excluded studies list in appendix I.

1.5.3. Summary of clinical 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: monotherapy versus combination (adults with hypertension and type 2 diabetes strata).

Table 4

Clinical evidence summary: monotherapy versus combination (adults with hypertension and without type 2 diabetes strata).

See appendix F for full GRADE tables.

1.6. Economic evidence

1.6.1. Included studies

No relevant health economic studies were identified.

1.6.2. Excluded studies

Five economic studies relating to this review question were identified but were excluded due to limited applicability or methodological limitations.¹¹⁹^,¹⁴⁶^,²¹⁵^,¹⁹²^,²⁰⁴ This includes 1 study included in the previous guideline that was not applicable because it compared treatment to no treatment as opposed to combination therapy versus monotherapy.

These are listed in appendix I with the reasons for exclusion given.

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

1.6.3. Resource costs

Some illustrative costs are demonstrated below of monotherapies and combination therapies, based on the drugs that were used in the clinical evidence identified.

Table 5

UK costs of anti-hypertensives (monotherapies or combinations).

Also illustrated below are costs of cardiovascular events to demonstrate costs that might be avoided from avoiding events. It is important to note that these are from NHS reference costs and are therefore the costs related to initial hospitalisation ONLY.

Table 6

Costs of hospitalisation from cardiovascular events.

Example costings

Assumptions:

The medications are those used in the trials in the clinical review: monotherapy is Enalapril 10 mg per day, and dual therapy is perindopril erbumine plus indapamide in separate pills of dose 2 mg and 1.5 mg per day respectively.

This may not necessarily be the most common drugs that would be used in UK practice.

Table 7

Cost trade-off illustration.

1.7. Evidence statements

1.7.1. Clinical evidence statements

Monotherapy versus combination (adults with hypertension and type 2 diabetes strata)

Very low quality evidence from 1 study with 481 participants showed a clinically important benefit of combination therapy compared to monotherapy for serious cardiovascular events in people with type 2 diabetes.

Very low to low quality evidence from 1 study with 481 participants showed no clinically important difference for change in creatinine clearance, discontinuation due to adverse events and dizziness. Very low quality evidence from 1 study with 538 participants showed no clinically important difference for discontinuation due to adverse events.

Monotherapy versus combination (adults with hypertension and without type 2 diabetes strata)

High quality evidence from 1 study with a total of 457 participants showed no clinically important difference between monotherapy or combination therapy for change in creatinine. Very low quality evidence from 1 study with 418 participants showed no clinically important difference for discontinuation due to adverse events.

1.7.2. Health economic evidence statements

No relevant economic evaluations were identified.

1.8. The committee’s discussion of the evidence

1.8.1. Interpreting the evidence

1.8.1.1. The outcomes that matter most

The committee considered all-cause mortality, quality of life, stroke and myocardial infarction (MI) to be critical outcomes for decision-making. Heart failure, angina, vascular procedures, and discontinuation due to adverse events as well as specific adverse events and resource use were considered important outcomes for decision-making. In the population without type 2 diabetes, evidence was identified for adverse events only (discontinuation due to adverse events, change in creatinine levels). In people with type 2 diabetes, the only evidence identified was an indirect outcome of major cardiovascular events and adverse event outcomes (change in creatinine clearance, dizziness and discontinuation due to adverse events).

1.8.1.2. The quality of the evidence

The committee discussed that the evidence was limited; from 3 studies, only 1 of which reported a critical outcome (serious cardiovascular events), albeit an indirect composite measure of the individual outcomes the committee were interested in. All of the evidence for people with hypertension and type 2 diabetes was low or very low quality due mainly to risk of bias, indirectness and imprecision. Risk of bias was rated as high because of high attrition rates due to participants dropping out of trials or being lost to follow up. The evidence was also downgraded due to population indirectness. Some participants included within the evidence were outside of the scope of this review question, such as those with moderate to severe chronic kidney disease (CKD). The population included within the evidence was based on studies with small sample sizes.

The only high quality evidence available was for change in creatinine for adults with hypertension and without type 2 diabetes. However, this was also only from a single, relatively small study.

1.8.1.3. Benefits and harms

The committee discussed that there was an indication that initiating dual therapy may be better than monotherapy as the step 1 treatment option, in terms of reducing cardiovascular events in a diabetes population, albeit from very low quality evidence. The evidence for people without type 2 diabetes was more limited, with evidence available for the outcomes of change in creatinine and discontinuation due to adverse events, neither of which were cardiovascular events so determining the benefit of treatment was not possible.

It was noted that there was conflicting evidence from 2 separate studies in terms of discontinuation due to adverse events; however, the committee agreed it was more intuitive to see more discontinuation in people with dual therapy. Although this was also low quality evidence and a relatively small numbers of events, the committee considered that this did not demonstrate any substantial increase in harm from dual therapy.

In considering the body of evidence, the committee discussed that it was disappointing that there was not more evidence on patient important outcomes available to demonstrate a benefit of dual therapy as a step 1 treatment option. The committee was aware of epidemiological and observational evidence suggesting that many people do start on 2 drugs and have good outcomes as a result such as quicker reductions in blood pressure, which result in mortality benefit; furthermore, observational evidence suggests that not optimising management for people with hypertension early can have a substantial impact on subsequent quality of life. However, the committee agreed that the level of available evidence identified in this review was insufficient to change the recommendations from CG127.

The committee discussed the evidence identified in 2011 in CG127¹⁵⁴ related to step 1 treatment. The recommendations were stratified by age and family origin reflecting data from clinical trials showing differential effects of the different classes of blood pressure lowering drugs on blood pressure lowering and clinical outcomes in younger (less than 55 years old) versus older people and in black people of African or Caribbean descent. Three studies and an age-stratified analysis from a fourth study also compared blood pressure response across various drug classes and identified ACE inhibitors and beta-blockers as more effective at lowering blood pressure in younger people, when compared to calcium channel-blockers or thiazide-type diuretics. The evidence for ACE inhibitor and ARBs were closely correlated (although lacked head-to-head evidence) and the previous guideline recommended that these treatments should be treated as equal in terms of efficacy; however, due to cost differences, it was considered that ACE inhibitors should be initiated first and an ARB considered an alternative for when an ACE inhibitor was poorly tolerated. The 2011 guideline did not identify evidence to show any consistent trend favouring 1 drug class over the other. The committee agreed it was appropriate to retain these recommendations but to keep in mind that ACE inhibitors and ARBs are now equal in terms of both cost and efficacy.

The committee also discussed step 1 treatment in people with type 2 diabetes, and noted that NG28 recommended ACE inhibitors as step 1 treatment rather than ARBs. The committee noted that this was based both on differences in costs and on limited evidence of a difference in reno-protective benefits between the two treatments. The committee agreed that from their current clinical experience ARBs and ACE inhibitors were similarly effective are were not aware of evidence to contradict this.

However, the committee agreed that beta-blockers are not often used as antihypertensive treatment in current practice and recent meta-analysis (not relevant to this review protocol) have demonstrated this class to be low efficacy for the treatment of hypertension in terms of improving cardiovascular outcomes. The committee discussed whether these drugs are ever an appropriate choice for people with hypertension. They discussed people with evidence of a high sympathetic drive and noted that the primary cause should be addressed rather than treating the hypertension primarily and that in these cases, beta-blockers would not be the most appropriate choice of drug. The committee therefore agreed not to retain the recommendations related to the use of beta-blockers in people under 55 years.

For people of black African or African Caribbean family origin with type 2 diabetes, the previous recommendation from the type 2 diabetes guideline (NG28) was to offer an ACE inhibitor and either a diuretic or a calcium-channel blocker as step 1 dual therapy. The committee discussed what had informed those recommendations. There were no trials looking at combination treatments in this group and so results from monotherapy studies were considered. There was evidence that CCBs provided better cardiovascular outcomes in black individuals with hypertension compared to ACEi, and that A drugs resulted in improved outcomes in all individuals with diabetes. Additionally, physiological studies suggested lower efficacy of A drugs in black and/or older individuals. Based on these observations it was decided by consensus that for black, hypertensive, diabetic individuals the first-line combination of A+C/D should be used. Although there was some evidence identified for this question on people with hypertension and diabetes, it was only from a single small study, and the committee did not consider this strong enough to base a recommendation on. People with hypertension but no diabetes are offered a CCB in the hypertension guideline, but an ACE inhibitor or ARB is more suitable for those with diabetes as mentioned above. It was discussed how in practice the step 1 dual therapy recommendation for people of black African or African Caribbean family origin is not generally current practice. Black people often show inadequate response to ACE inhibitors and therefore require additional drugs. What tends to happen is an ACE inhibitor is given for step 1 instead of the more appropriate ARB and hence treatment may be escalated more quickly to dual therapy for this group. In summary, the recommendation for step 1 dual therapy was not retained for this group in NG28. The committee noted that considerations may apply in the presence of target organ damage such as microalbuminuria as these patients are at higher CVD risk. The recommendation to offer an ARB in preference for an ACE inhibitor for people of black African or African Caribbean family origin either with or without type 2 diabetes was also retained. The previous guideline committee (CG127) considered that people of black African or Caribean family origin that take ACE inhibitors have an increased risk of developing angioedema which can be life threatening. Although the incidence of this adverse event is low, the previous committee suggested that an ARB in preference to an ACE inhibitor should be considered for such patients.

1.8.2. Cost effectiveness and resource use

Five studies were identified that may be relevant for this question but were selectively excluded due to methodological limitations. One of these was a study included in the previous guideline comparing treatment versus no treatment based on resource use from the HYVET study in an elderly population. A no treatment comparison is not of interest in this question but that study fell under the question of step 1 treatment in people aged over 80 in the previous guideline and has therefore been selectively excluded because the comparison is not relevant to this update of the review.

The committee was presented with some examples of unit costs of monotherapy and dual therapy based on the drugs used in the clinical studies, as well as some illustrative hospitalisation costs for cardiovascular events.

Dual therapy treatments are likely to have higher costs. In theory, 2 medications instead of 1 may also lead to more adverse events, which also needs to be traded off against benefit. This was not clear from the clinical review, which found no difference in discontinuation rates. The major impact on effectiveness that would be traded-off against the additional drug use is the impact on cardiovascular events or mortality. The clinical review showed that there were 39 fewer serious cardiovascular events with the dual therapy treatment than with the monotherapy, in a population with hypertension and type 2 diabetes. Cardiovascular events are likely to be events like myocardial infarction or stroke, which are very costly to treat and can have a long-term impact on quality of life. Therefore, any events avoided could be argued as being significant. This evidence was of very low quality, however, and was from only 1 study and therefore may not be sufficient evidence to change practice, as the committee cannot be confident that these outcomes are likely to represent the true outcomes in the general population with such little evidence.

As an example of some costing illustrations, a cohort of 1000 people taking monotherapy or dual therapy for 12 months would lead to higher intervention costs for the dual therapy arm (£19,945 versus £63,997 respectively) (based on the drugs that were used in the included trial). Trading this off against the cardiovascular event outcomes from the clinical review, shows that monotherapy is overall more expensive than dual therapy. This is a very simplified example, and there are a number of factors that haven’t been captured. Cardiovascular event costs are likely to be higher than just initial hospitalisation costs such as including follow-ups and rehabilitation perhaps. There is no quality of life captured, but events would have a detriment to quality of life. These factors are likely to favour dual therapy. However, different drugs also have different costs, and dual therapy in a single pill may be more expensive because of the ease of having to take only 1 pill but have the benefit of 2 drugs. There are no adverse events included or other costs associated with treatment like monitoring, which might be higher in a dual therapy strategy. Therefore, even if dual therapy was overall a more expensive strategy, it is uncertain if this would be cost effective.

It is also uncertain in what timeframe people might be reviewed, in which case some people on monotherapy would go on to other lines of treatment anyway. This argument is implying that if people do not stay on monotherapy for very long (with uncontrolled hypertension), then the difference in intervention will only apply for a short duration. Effectively, what is being compared is bringing forward step 2 treatment versus starting on step 1 treatment. Some data from UK GP practices on the proportion of hypertensives on different numbers of drugs showed (depending on age and sex) that around 40–60% of people are on 1 drug, 30–40% of people are on 2 drugs, and 10–20% are on 3 drugs. Therefore, most people tend to stay on 1 drug, implying it would be a big change to start on 2 drugs. However, it is unclear if their hypertension is controlled or uncontrolled on 1 drug. Those who remain controlled on 1 drug would have lower medication costs for the same outcome although 2 drugs are known to get a person to a target more quickly. If monitoring following initiation of monotherapy occurred in a timely way, then those uncontrolled on 1 drug would be stepped up to step 2 drugs more quickly. However, being on step 2 treatment from the beginning may avoid some events that would have happened in that space of time. In summary, there are many factors to consider that make it uncertain if starting on dual therapy is cost effective.

The committee were not able to make a recommendation about starting on dual therapy (whether that is 2 drugs in 1 pill or separately) because of the limited clinical evidence, and there was no robust cost effectiveness evidence. The committee discussed the potential for treatment inertia and the factors related to that such as people being asymptomatic and the discussion that happens about benefits and risks of taking, changing or adding treatments. The frequency of monitoring to assess the effectiveness of treatment can also be variable. As the committee couldn’t make a recommendation favouring starting with dual therapy, a research recommendation was made to identify in which groups dual therapy should be initiated.

Some of the recommendations from the previous hypertension guideline were edited, including removing a recommendation on when to use beta-blockers, as these are not used very much in practice, and removing references to low cost ARBs, as ACE inhibitors and ARBs are similarly low cost now. In general, the previous recommendations were agreed to still be appropriate and represent good practice. These were based on a combination of clinical evidence and cost effectiveness evidence, as a model in the 2004 guideline comparing monotherapies for step 1 treatment (for which costs were updated in the 2011 guideline) showed that CCBs were generally the most cost effective. In higher risk people, thiazides were shown to be the most cost effective for people at high risk of heart failure. A sensitivity analysis on age showed that ACE inhibitors or ARBs were likely to be the most cost effective.

The committee’s view was that a monotherapy of an ACE inhibitor could be offered to anyone with diabetes of any age or family origin, as the dual therapy recommendation for the black people of African or African Caribbean family origin population is not generally followed in practice and was not based on evidence. Given that current practice generally already offers an ACE inhibitor to people with diabetes regardless of age or family origin with an ARB as an alternative, this is unlikely to have a large impact on practice.

1.8.3. Other factors the committee took into account

The committee reviewed the wording of the recommendations in the previous 2011 hypertension guideline (CG127) and highlighted that if a thiazide like diuretic was being offered, indapamide is likely to be the drug that is used. The previous wording of the recommendation may have implied chlortalidone should be first choice, by the nature of it being listed first; however, chlortalidone hasn’t become more widely available to European market as was hoped, and therefore this has been removed from the recommendation.

The committee further noted that there were safety concerns regarding the use of ACE inhibitors and ARBs in pregnant women. A footnote was added to this recommendation to alert to MHRA safety updates.

It was noted that it was important to highlight that medicines should be taken as prescribed in order to be most effective, and so a recommendation was made to highlight that this should be discussed with the person and that adherence should be supported.

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Appendices

Appendix A. Review protocols

Table 8. Review protocol: Step 1 antihypertensive treatment

Table 9. 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.

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 10. Database date parameters and filters used

Table 11. Medline (Ovid) search terms

Table 12. Embase (Ovid) search terms

Table 13. 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 14. Database date parameters and filters used

Table 15. Medline (Ovid) search terms

Table 16. Embase (Ovid) search terms

Table 17. 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 1 antihypertensive treatment

Appendix D. Clinical evidence tables

Download PDF (177K)

Appendix E. Forest plots

E.1. Combination versus monotherapy in adults with primary hypertension and type 2 diabetes

Figure 2. Serious cardiovascular events at 12 months

Figure 3. Change in creatinine at 12 months

Figure 4. Discontinuation due to adverse events at 12 months

Figure 5. Discontinuation due to adverse events at 12 months (including type 2 diabetes)

Figure 6. Hypotension (dizziness) at 12 months

E.2. Combination versus monotherapy in adults with primary hypertension without type 2 diabetes

Figure 7. Change in creatinine (μmol/L) at 12 months

Figure 8. Discontinuation due to adverse events at 12 months

Appendix F. GRADE tables

Table 18. Clinical evidence profile: combination versus monotherapy in adults with primary hypertension and type 2 diabetes

Table 19. Clinical evidence profile: combination versus monotherapy in adults with primary hypertension and without type 2 diabetes

Appendix G. Health economic evidence selection

Figure 9. 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 20. Studies excluded from the clinical review

I.2. Excluded health economic studies

Table 21. Studies excluded from the health economic review

Appendix J. Research recommendations

J.1. Dual therapy

Research question: Are there subgroups of people with hypertension who should start on dual therapy?

Why this is important:

The physiological control of blood pressure results from the interaction of multiple biological pathways, including those acting on the kidneys and blood vessels. Most antihypertensive medication act on a single component of these pathways and so are intrinsically limited in their ability to lower blood pressure. This is the principle reason that many people prescribed antihypertensive medication require more than 1 type of medication to achieve their target blood pressure.

In the evidence review for step 1 treatment, the committee considered whether individuals with hypertension should be commenced on single or dual therapy. Only limited evidence on cardiovascular events was available from a single study, and this was felt to be insufficient to determine confidently whether dual therapy may be beneficial. The theoretical benefit of starting dual therapy is that more rapid achievement of target blood pressure may lead to a reduction in cardiovascular events. It is unknown whether dual therapy may be of benefit to all individuals commencing antihypertensive medication or just certain subgroups such as those with type 2 diabetes, established cardiovascular disease or chronic kidney disease.

Criteria for selecting high-priority research recommendations

Final

Intervention evidence review underpinning recommendations 1.4.30 to 1.4.37 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: NBK578061PMID: 35188723

Table 1PICO characteristics of review question

Population	Adults (over 18 years) with primary hypertension who are not on current pharmacological treatment for hypertension (minimum wash-out 4 weeks)
Intervention	Combination antihypertensive therapy – adjunct or non-adjunct (definition: 2 antihypertensive medications prescribed simultaneously – may be in 1 pill or 2). Examples include: Angiotensin-converting enzyme (ACE) inhibitor and calcium channel blocker (CCB) Angiotensin-II receptor blocker (ARB) and CCB ACE inhibitor and diuretic (thiazide like or conventional) ARB and diuretic (thiazide like or conventional) ACE inhibitor and CCB (Trandolapril and verapamil; TARKA) Beta blocker and CCB (atenolol and nifedipine) Beta blocker and thiazides (atenolol and chlortalidone, chlortalidone; timolol and bendroflumethiazide) Non-thiazide and thiazide diuretic (amiloride and hydrochlorothiazide)
Comparison	Antihypertensive Monotherapy. Examples include: ACE inhibitor or low-cost ARB) Thiazide-like diuretic (such as chlortalidone chlortalidoneor indapamide) Conventional thiazide diuretic (such as bendroflumethiazide or hydrochlorothiazide) CCB Beta-blockers Aliskiren (direct renin inhibitors) Doxazosin, prazosin, terazosin, (alpha blockers) Clonidine, moxonidine, methyldopa (centrally acting anti-HTN)
Outcomes	Assessed 12 months or more (using final endpoint) Critical All-cause mortality Health-related quality of life Stroke (ischaemic or haemorrhagic) Myocardial infarction (MI) Important Heart failure needing hospitalisation Vascular procedures (including both 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: Changes in eGFR or creatinine 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]
Study design	Randomised control trials (RCT) and Systematic reviews (SR)

Table 2Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Asmar 2003 (REASON trial) ¹⁴ ^, ¹³ ^, ¹³³ ^, ¹³⁹ ^, ⁵²

Combination:

Perindopril 2 mg plus indapamide 0.625 mg (n=235)

Monotherapy:

Atenolol 50 mg (n=234)

Hypertension (Systolic BP 160–210; Diastolic BP 95–110 mmHg) without type 2 diabetes (n=471)

At 12 months:

Discontinuation due to adverse events
Change in creatinine

Mixed population; 65% had received previous medication

Dahlof 2005 (PIXCEL trial) ⁴⁷

Combination:

Perindopril 2 mg plus indapamide 0.625 mg (n=341)

Monotherapy:

Enalapril 10 mg (n=338)

Hypertension with or without type 2 diabetes (n=679)

At 12 months:

Discontinuation due to adverse events

Number of participants with type 2 diabetes not specified

Mogensen 2003 (PREMIER trial) ¹⁴⁸

Combination:

Perindopril 2 mg plus indapamide 0.625 mg (n=237)

Monotherapy:

Enalapril 10 mg (n=244)

Hypertension with type 2 diabetes (n=481)

At 12 months

Serious cardiovascular events
Change in creatinine clearance
Discontinuation due to adverse events
Hypotension

Table 3Clinical evidence summary: monotherapy versus combination (adults with hypertension and type 2 diabetes strata)

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with Control	Risk difference with Combination versus monotherapy (95% CI)
Serious cardiovascular events	481 (1 study) 12 months	VERY LOW¹^,²^,³ due to risk of bias, indirectness, imprecision	RR 0.39 (0.15 to 0.98)	63 per 1,000	39 fewer per 1,000 (from 1 fewer to 54 fewer)
Change in creatinine clearance (ml/min)	481 (1 study) 12 months	LOW¹ due to risk of bias		The mean change in creatinine in the control group was −4.8	The mean change in creatinine in the intervention groups was 0.7 higher (1.19 lower to 2.59 higher)
Discontinuation due to adverse events	481 (1 study) 12 months	VERY LOW¹^,³ due to risk of bias, imprecision	RR 0.88 (0.49 to 1.59)	89 per 1,000	11 fewer per 1,000 (from 47 fewer to 50 more)
Discontinuation due to adverse events⁶	538 (1 study) 12 months	VERY LOW¹^, ³^, ⁴ due to risk of bias, imprecision, indirectness	RR 1.21 (0.41 to 3.56)	22 per 1,000	5 more per 1,000 (from 13 fewer to 54 more)
Dizziness (hypotension)	481 (1 study) 12 months	VERY LOW¹^,³^, ⁵ due to risk of bias, imprecision, indirectness	RR 0.58 (0.14 to 2.41)	21 per 1,000	9 fewer per 1,000 (from 18 fewer to 30 more)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded by 1 increment because the majority of the evidence had indirect outcomes

3: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

4: Downgraded by 1 increment because the majority of the evidence had an indirect population

5: Downgraded by 1 increment because the majority of the evidence had indirect outcomes; unclear if dizziness related to hypotension

6: Mixed population (including people with type 2 diabetes)

Table 4Clinical evidence summary: monotherapy versus combination (adults with hypertension and without type 2 diabetes strata)

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with Control

Risk difference with Combination versus monotherapy (95% CI)

Change in creatinine (μmol/L)

457

(1 study)

12 months

HIGH

The mean change in creatinine in the control group was 1.7

The mean change in creatinine in the intervention groups was 2.3 higher (0.7 to 3.9 higher)

Discontinuation due to adverse events

418

(1 study)

12 months

VERY LOW¹^,²

due to risk of bias, imprecision

RR 0.89

(0.49 to 1.62)

99 per 1,000

11 fewer per 1,000 (from 52 fewer to 58 more)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

Table 5UK costs of anti-hypertensives (monotherapies or combinations)

Drug	Detail	Daily dose	Cost/ month (£)	Cost/year (£)
Monotherapies
Perindopril erbumine (ACE inhibitor)	2 mg tablets, pack of 30 = £1.86	2 mg	£1.89	£22.63
Enalapril maleate (ACE inhibitor)	10 mg tablets, pack of 28 = £1.53	10 mg^(a)	£1.66	£19.94
Atenolol (Beta blocker)	50 mg tablets, pack of 28 = £0.54	50 mg	£0.59	£7.04
Losartan (ARB)	50 mg tablets, pack of 28 = £0.82	50 mg^(b)	£0.89	£10.69
Combination
Perindopril erbumine (ACE inhibitor) and	2 mg tablets, pack of 30 = £1.86	2 mg	£1.89	£22.63
Indapamide (thiazide)	1.5 mg tablets, pack of 30 = £3.40	1.5 mg^(c)	£3.45	£41.37
Separate pills				£64.00
Losartan and hydrochlorothiazide single pill	50 mg Losartan, 12.5 mg thiazide, pack of 28 = £1.13	50 mg Losartan, 12.5 mg thiazide^(b)	£1.23	£14.73

: Source: BNF (Drug Tariff price)²⁷, DATE: 03 May 2019.

(a): Dose from clinical review

(b): Clinical review 100 mg but used 50 mg here as combination was 50 mg so comparing the same dose in monotherapy and combination.

(c): Clinical review used 2 mg perindopril and 0.625 mg indapamide but these doses weren’t available in the BNF.

Table 6Costs of hospitalisation from cardiovascular events

HRG code

HRG code description

Weighted average cost

EB10A to EB10E

Myocardial infarction

Actual or Suspected Myocardial Infarction, with CC Score 13+

Actual or Suspected Myocardial Infarction, with CC Score 10–12

Actual or Suspected Myocardial Infarction, with CC Score 7–9

Actual or Suspected Myocardial Infarction, with CC Score 4–6

Actual or Suspected Myocardial Infarction, with CC Score 0–3

£1,515

AA35A to AA35F

Stroke

Stroke with CC Score 16+

Stroke with CC Score 13–15

Stroke with CC Score 10–12

Stroke with CC Score 7–9

Stroke with CC Score 4–6

Stroke with CC Score 0–3

£3,339

EB13A to EB13D

Angina

Angina with CC Score 12+

Angina with CC Score 8–11

Angina with CC Score 4–7

Angina with CC Score 0–3

£716

(a): From NHS reference costs 2017/18, total Healthcare resource group (HRG) schedule. {NHS Improvement, 2018 #1855}

Table 7Cost trade-off illustration

Intervention	Drug cost (per 1000)^(a)	Cardiovascular events (per 1000)^(b)	Cardiovascular event cost	Total cost
CV event = MI
Monotherapy	£19,945	63	£95,436	£115,381
Dual therapy	£63,997	25	£37,220	£101,217
CV event = Stroke
Monotherapy	£19,945	63	£210,382	£230,327
Dual therapy	£63,997	25	£82,049	£146,046

(a): 12 month cost as clinical studies were over a 12 month period.

(b): Data taken from the clinical review

Table 8Review protocol: Step 1 antihypertensive treatment

Field	Content
Review question	Is monotherapy or combination antihypertensive therapy more clinically and cost effective for step 1 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 whether monotherapy or combination therapy is most clinically and cost effective as a step 1 treatment for primary hypertension
Eligibility criteria – population / disease / condition / issue / domain	Population: Adults (over 18 years) with primary hypertension who are not on current pharmacological treatment for hypertension (minimum wash-out 4 weeks) Stratify by presence or absence of type 2 diabetes
Eligibility criteria – intervention(s) / exposure(s) / prognostic factor(s)	Antihypertensive pharmacological combination therapy received for a minimum of 1 year (either adjunct or non-adjunct, defined as 2 antihypertensive medications prescribed simultaneously – may be in 1 pill or 2). Examples include: ACE inhibitor and CCB ARB and CCB ACE inhibitor and diuretic (thiazide-like or conventional) ARB and diuretic (thiazide-like or conventional) ACE inhibitor and CCB (Trandolapril and verapamil; TARKA) Beta blocker and CCB (atenolol and nifedipine) Beta blocker and thiazides (atenolol and chlortalidone; timolol and bendroflumethiazide) Non-thiazide and thiazide (amiloride and hydrochlorothiazide)
Eligibility criteria – comparator(s) / control or reference (gold) standard	Antihypertensive pharmacological monotherapy received for a minimum of 1 year. Examples include: ACE inhibitor Low-cost ARB Thiazide-like diuretic (such as chlortalidone or indapamide) Conventional thiazide diuretic (such as bendroflumethiazide or hydrochlorothiazide) CCB Beta-blockers Aliskiren (direct renin inhibitors) Doxazosin, prazosin, terazosin, (alpha blockers) Clonidine, moxonidine, methyldopa (centrally acting antihypertensive)
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. All-cause mortality Health-related quality of life Stroke (ischaemic or haemorrhagic) MI Important Heart failure needing hospitalisation (including lower limb, coronary and carotid artery procedures)Angina needing hospitalisation 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) Discontinuation or dose reduction due to side effects [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 type 2 diabetes strata studies including participants with 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 Crossover trials (unless washout is ≥ 4 weeks) Children (younger than 18 years)
Proposed sensitivity / subgroup analysis, or meta-regression	Subgroups for analysis of heterogeneity: Age (75 as a cut off)* Family origin (African and Caribbean, White, South Asian) Severity (moderate [stage 1 BP 140–59/90–99] versus high [stage 2 BP 160/100]) *To note that we will also extract evidence in those aged over 80 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: Cochrane review (2017): http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010316.pub2/full
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 critically individual studies. 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

Table 9Health economic review protocol

Review question	All questions – health economic evidence
Objectives	To identify health economic studies relevant to any of the review questions.
Search criteria	Populations, interventions and comparators must be as specified in the clinical review protocol above. Studies must be of a relevant health economic study design (cost–utility analysis, cost-effectiveness analysis, cost–benefit analysis, cost–consequences analysis, comparative cost analysis). Studies must not be a letter, editorial or commentary, or a review of health economic evaluations. (Recent reviews will be ordered although not reviewed. The bibliographies will be checked for relevant studies, which will then be ordered.) Unpublished reports will not be considered unless submitted as part of a call for evidence. Studies must be in English.
Search strategy	A health economic study search will be undertaken using population-specific terms and a health economic study filter – see appendix B below. No date cut-off from the previous guideline was used.
Review strategy	Studies not meeting any of the search criteria above will be excluded. Studies published before 2002, abstract-only studies and studies from non-OECD countries or the US will also be excluded. Studies published after 2002 that were included in the previous guideline(s) will be reassessed for inclusion and may be included or selectively excluded based on their relevance to the questions covered in this update and whether more applicable evidence is also identified. Each remaining study will be assessed for applicability and methodological limitations using the NICE economic evaluation checklist which can be found in appendix H of Developing NICE guidelines: the manual (2014).¹⁵⁵ Inclusion and exclusion criteria If a study is rated as both ‘Directly applicable’ and with ‘Minor limitations’, then it will be included in the guideline. A health economic evidence table will be completed and it will be included in the health economic evidence profile. If a study is rated as either ‘Not applicable’ or with ‘Very serious limitations’, then it will usually be excluded from the guideline. If it is excluded then a health economic evidence table will not be completed and it will not be included in the health economic evidence profile. If a study is rated as ‘Partially applicable’, with ‘Potentially serious limitations’ or both, then there is discretion over whether it should be included. Where there is discretion The health economist will make a decision based on the relative applicability and quality of the available evidence for that question in discussion with the guideline committee if required. The ultimate aim is to include health economic studies that are helpful for decision-making in the context of the guideline and the current NHS setting. If several studies are considered of sufficiently high applicability and methodological quality that they could all be included, then the health economist, in discussion with the committee if required, may decide to include only the most applicable studies and to exclude selectively the remaining studies. All studies excluded based on applicability or methodological limitations will be listed with explanation in the excluded health economic studies appendix below. The health economist will be guided by the following hierarchies. Setting: UK NHS (most applicable). OECD countries with predominantly public health insurance systems (for example, France, Germany, Sweden). OECD countries with predominantly private health insurance systems (for example, Switzerland). Studies set in non-OECD countries or in the US will be excluded before being assessed for applicability and methodological limitations. Health economic study type: Cost–utility analysis (most applicable). Other type of full economic evaluation (cost–benefit analysis, cost-effectiveness analysis, cost–consequences analysis). Comparative cost analysis. Non-comparative cost analyses including cost-of-illness studies will be excluded before being assessed for applicability and methodological limitations. Year of analysis: The more recent the study, the more applicable it will be. Studies published in 2002 or later (including any such studies included in the previous guideline[s]) but that depend on unit costs and resource data entirely or predominantly before 2002 will be rated as ‘Not applicable’. Studies published before 2002 (including any such studies included in the previous guideline[s]) will be excluded before being assessed for applicability and methodological limitations. Quality and relevance of effectiveness data used in the health economic analysis: The more closely the clinical effectiveness data used in the health economic analysis match with the outcomes of the studies included in the clinical review, the more useful the analysis will be for decision-making in the guideline. Generally, economic evaluations based on excludes from the clinical review will be excluded.

Table 10Database date parameters and filters used

Database

Dates searched

Search filter used

Medline (OVID)

1946–02 October 2018

Exclusions

Randomised controlled trials

Systematic review studies

Embase (OVID)

1974–02 October 2018

Exclusions

Randomised controlled trials

Systematic review studies

The Cochrane Library (Wiley)

Cochrane Reviews to Issue 8 of 12, August 2018

CENTRAL to Issue 7 of 12, July 2018

DARE and NHS EED to Issue 2 of 4, April 2015

HTA to Issue 4 of 4, October 2016

None

Table 11Medline (Ovid) search terms

1.	exp Hypertension/
2.	hypertens*.ti,ab.
3.	(elevat* adj2 blood adj pressur*).ti,ab.
4.	(high adj blood adj pressur*).ti,ab.
5.	(increase* adj2 blood pressur*).ti,ab.
6.	((systolic or diastolic or arterial) adj2 pressur*).ti,ab.
7.	or/1–6
8.	exp pregnancy/
9.	exp Hypertension, Pregnancy-Induced/ not exp Hypertension/
10.	(pre eclampsia or pre-eclampsia or preeclampsia).ti,ab.
11.	exp Hypertension, Portal/ not exp Hypertension/
12.	exp Hypertension, Pulmonary/ not exp Hypertension/
13.	exp Intracranial Hypertension/ not exp Hypertension/
14.	exp Ocular Hypertension/ not exp Hypertension/
15.	exp Diabetes Mellitus, Type 1/ not exp Diabetes Mellitus, Type 2/
16.	or/9–15
17.	7 not 16
18.	letter/
19.	editorial/
20.	news/
21.	exp historical article/
22.	Anecdotes as Topic/
23.	comment/
24.	case report/
25.	(letter or comment*).ti.
26.	or/18–25
27.	randomized controlled trial/ or random*.ti,ab.
28.	26 not 27
29.	animals/ not humans/
30.	exp Animals, Laboratory/
31.	exp Animal Experimentation/
32.	exp Models, Animal/
33.	exp Rodentia/
34.	(rat or rats or mouse or mice).ti.
35.	or/28–34
36.	17 not 35
37.	(exp child/ or exp pediatrics/ or exp infant/) not (exp adolescent/ or exp adult/ or exp middle age/ or exp aged/)
38.	36 not 37
39.	limit 38 to English language
40.	Drug Combinations/
41.	Drug Therapy, Combination/ or *Drug Therapy/
42.	drug therap*.ti,ab.
43.	((combination* or combined or multiple or single) adj (therap* or agent* or drug* or treatment*)).ti,ab.
44.	(monotherap* or mono therap*).ti,ab.
45.	or/40–44
46.	39 and 45
47.	exp Angiotensin-Converting Enzyme Inhibitors/
48.	Angiotensin-converting enzyme inhibitor*.ti,ab.
49.	(ACE inhibitor* or ACEI).ti,ab.
50.	(Captopril or Enalapril or Fosinopril or Imidapril or Lisinopril or Moexipril or Perindopril or Quinapril or Ramipril or Trandolapril or Capoten or Ecopace or Noyada or Innovace or Tanatril or Zestril or Perdix or Coversil or Accupro or Tritace).ti,ab.
51.	exp Calcium Channel Blockers/
52.	Calcium channel blocker*.ti,ab.
53.	CCB.ti,ab.
54.	(Amlodipine or Clevidipine or Diltiazem or Felodipine or Isradipine or Lacidipine or Lercanidipine or Nicardipine or Nifedipine or Verapamil or Amlostin or Istin or Adizem or Angitil or Dilcardia or Dilzem or Slozem or Tildiem or Viazem or Zemtard or Kenzem or Cardioplen or Felendil or Neofel or Parmid or Plendil or Pinefeld or Vascalpha or Molap or Motens or Zanidip or Cardene or Adalat or Adipine or Coracten or Fortipine or Nifedipress or Tensipine or Valni or Securon or Verapress or Vertab or Univer or Zolvera or Cleviprex).ti,ab.
55.	exp Angiotensin Receptor Antagonists/
56.	(Angiotensin II adj3 (antagonist* or blocker*)).ti,ab.
57.	ARB.ti,ab.
58.	(Azilsartan or Candesartan or Eprosartan or Irbesartan or Losartan or Olmesartan or Telmisartan or Valsartan or Edarbi or Amias or Teveten or Aprovel or Ifirmasta or Sabervel or Cozaar or Olmetec or Tolura or Micardis or Diovan).ti,ab.
59.	Diuretics/
60.	Diuretics, Thiazide/
61.	((thiazide or thiazide-like or non-thiazide or conventional or potassium sparing) adj3 diuretic*).ti,ab.
62.	(Amiloride or Cyclopenthiazide or Spironolactone or Bendroflumethiazide or Hydrochlorothiazide or Co-amilozide or Co-triamterzide or Co-zidocapt or Chlortalidone or Indapamide or Metolazone or Xipamide or Carace or Zestoretic or Coversyl or Accuretic or Cozaar or Sevikar or Olmetec or Actelsar or Tolucombi or Co-Diovan or Hygroton or Co-tenidone or Kalspare or Natrilix or Cardide or Indipam or Rawel or Tensaid or Alkapamid or Zaroxolyn or Diurexan or Aprinox or Neo-Naclex or CoAprovel or Lisoretic or Dyazide or Navispare or Lasilactone).ti,ab.
63.	Adrenergic beta-Antagonists/
64.	(adrenergic beta antagonist* or beta blocker* or b blocker*).ti,ab.
65.	(Carvedilol or Labetalol or Atenolol or Nadolol or Oxprenolol or Pindolol or Propranolol or Timolol or Acebutolol or Bisoprolol or Celiprolol or Esmolol or Metoprolol or Nebivolol or Carvedilol or Tenormin or Tenif or Corgard or Slow-Trasicor or Visken or Viskladix or Bedranol or Beta-Prograne or Syprol or Betim or Sectral or Cardicor or Congescor or Celectol or Breviblock or Betaloc or Lopresor or Nebilet).ti,ab.
66.	exp Adrenergic alpha-Antagonists/
67.	(adrenergic alpha antagonist* or alpha adrenoreceptor blocker* or alpha blocker*).ti,ab.
68.	(Doxazosin or Prazosin or Terazosin or Cardura or Doxadura or Raporsin or Slocinx or Doxzogen or Larbex or Hypovase or Hytrin).ti,ab.
69.	Antihypertensive Agents/
70.	centrally acting antihypertensive*.ti,ab.
71.	(Clonidine or Moxonidine or Methyldopa or Catapres or Dixarit or Aldomet or Physiotens).ti,ab.
72.	renin inhibitor*.ti,ab.
73.	(Aliskiren or Rasilez).ti,ab.
74.	((trandolapril and verapamil) or TARKA).ti,ab.
75.	or/47–74
76.	46 and 75
77.	randomized controlled trial.pt.
78.	controlled clinical trial.pt.
79.	randomi#ed.ti,ab.
80.	placebo.ab.
81.	randomly.ti,ab.
82.	Clinical Trials as topic.sh.
83.	trial.ti.
84.	or/77–83
85.	Meta-Analysis/
86.	exp Meta-Analysis as Topic/
87.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
88.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
89.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
90.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
91.	(search* adj4 literature).ab.
92.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
93.	cochrane.jw.
94.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
95.	or/85–94
96.	76 and (84 or 95)

Table 12Embase (Ovid) search terms

1.	exp Hypertension/
2.	hypertens*.ti,ab.
3.	(essential adj hypertension).ti,ab.
4.	(isolat* adj hypertension).ti,ab.
5.	(elevat* adj2 blood adj pressur*).ti,ab.
6.	(high adj blood adj pressur*).ti,ab.
7.	(increase* adj2 blood pressur*).ti,ab.
8.	((systolic or diastolic or arterial) adj2 pressur*).ti,ab.
9.	or/1–8
10.	exp pregnancy/
11.	exp Maternal Hypertension/
12.	(pre eclampsia or pre-eclampsia or preeclampsia).ti,ab.
13.	exp Hypertension, Portal/ not exp Hypertension/
14.	exp Hypertension, Pulmonary/ not exp Hypertension/
15.	exp Intracranial Hypertension/
16.	exp Ocular Hypertension/ not exp Hypertension/
17.	exp Diabetes Mellitus, Type 1/ not exp Diabetes Mellitus, Type 2/
18.	or/10–17
19.	9 not 18
20.	letter.pt. or letter/
21.	note.pt.
22.	editorial.pt.
23.	case report/ or case study/
24.	(letter or comment*).ti.
25.	or/20–24
26.	randomized controlled trial/ or random*.ti,ab.
27.	25 not 26
28.	animal/ not human/
29.	nonhuman/
30.	exp Animal Experiment/
31.	exp Experimental Animal/
32.	animal model/
33.	exp Rodent/
34.	(rat or rats or mouse or mice).ti.
35.	or/27–34
36.	19 not 35
37.	(exp child/ or exp pediatrics/) not (exp adult/ or exp adolescent/)
38.	36 not 37
39.	limit 38 to English language
40.	Drug Combinations/
41.	Therapy/ or Drug Therapy/
42.	drug therap*.ti,ab.
43.	((combination* or combined or multiple or single) adj (therap* or agent* or drug* or treatment*)).ti,ab.
44.	(monotherap* or mono therap*).ti,ab.
45.	or/40–44
46.	39 and 45
47.	exp *Angiotensin-Converting Enzyme Inhibitors/
48.	Angiotensin-converting enzyme inhibitor*.ti,ab.
49.	(ACE inhibitor* or ACEI).ti,ab.
50.	(Captopril or Enalapril or Fosinopril or Imidapril or Lisinopril or Moexipril or Perindopril or Quinapril or Ramipril or Trandolapril or Capoten or Ecopace or Noyada or Innovace or Tanatril or Zestril or Perdix or Coversil or Accupro or Tritace).ti,ab.
51.	exp *Calcium Channel Blockers/
52.	Calcium channel blocker*.ti,ab.
53.	CCB.ti,ab.
54.	(Amlodipine or Clevidipine or Diltiazem or Felodipine or Isradipine or Lacidipine or Lercanidipine or Nicardipine or Nifedipine or Verapamil or Amlostin or Istin or Adizem or Angitil or Dilcardia or Dilzem or Slozem or Tildiem or Viazem or Zemtard or Kenzem or Cardioplen or Felendil or Neofel or Parmid or Plendil or Pinefeld or Vascalpha or Molap or Motens or Zanidip or Cardene or Adalat or Adipine or Coracten or Fortipine or Nifedipress or Tensipine or Valni or Securon or Verapress or Vertab or Univer or Zolvera or Cleviprex).ti,ab.
55.	exp *Angiotensin Receptor Antagonists/
56.	(Angiotensin II adj3 (antagonist* or blocker*)).ti,ab.
57.	ARB.ti,ab.
58.	(Azilsartan or Candesartan or Eprosartan or Irbesartan or Losartan or Olmesartan or Telmisartan or Valsartan or Edarbi or Amias or Teveten or Aprovel or Ifirmasta or Sabervel or Cozaar or Olmetec or Tolura or Micardis or Diovan).ti,ab.
59.	Diuretics/
60.	Diuretics, Thiazide/
61.	((thiazide or thiazide-like or non-thiazide or conventional or potassium sparing) adj3 diuretic*).ti,ab.
62.	(Amiloride or Cyclopenthiazide or Spironolactone or Bendroflumethiazide or Hydrochlorothiazide or Co-amilozide or Co-triamterzide or Co-zidocapt or Chlortalidone or Indapamide or Metolazone or Xipamide or Carace or Zestoretic or Coversyl or Accuretic or Cozaar or Sevikar or Olmetec or Actelsar or Tolucombi or Co-Diovan or Hygroton or Co-tenidone or Kalspare or Natrilix or Cardide or Indipam or Rawel or Tensaid or Alkapamid or Zaroxolyn or Diurexan or Aprinox or Neo-Naclex or CoAprovel or Lisoretic or Dyazide or Navispare or Lasilactone).ti,ab.
63.	*Adrenergic beta-Antagonists/
64.	(adrenergic beta antagonist* or beta blocker* or b blocker*).ti,ab.
65.	(Carvedilol or Labetalol or Atenolol or Nadolol or Oxprenolol or Pindolol or Propranolol or Timolol or Acebutolol or Bisoprolol or Celiprolol or Esmolol or Metoprolol or Nebivolol or Carvedilol or Tenormin or Tenif or Corgard or Slow-Trasicor or Visken or Viskladix or Bedranol or Beta-Prograne or Syprol or Betim or Sectral or Cardicor or Congescor or Celectol or Breviblock or Betaloc or Lopresor or Nebilet).ti,ab.
66.	exp *Adrenergic alpha-Antagonists/
67.	(adrenergic alpha antagonist* or alpha adrenoreceptor blocker* or alpha blocker*).ti,ab.
68.	(Doxazosin or Prazosin or Terazosin or Cardura or Doxadura or Raporsin or Slocinx or Doxzogen or Larbex or Hypovase or Hytrin).ti,ab.
69.	*Antihypertensive Agents/
70.	centrally acting antihypertensive*.ti,ab.
71.	(Clonidine or Moxonidine or Methyldopa or Catapres or Dixarit or Aldomet or Physiotens).ti,ab.
72.	renin inhibitor*.ti,ab.
73.	(Aliskiren or Rasilez).ti,ab.
74.	((trandolapril and verapamil) or TARKA).ti,ab.
75.	or/47–74
76.	46 and 75
77.	random*.ti,ab.
78.	factorial*.ti,ab.
79.	(crossover* or cross over*).ti,ab.
80.	((doubl* or singl) adj blind).ti,ab.
81.	(assign* or allocat* or volunteer* or placebo*).ti,ab.
82.	crossover procedure/
83.	single blind procedure/
84.	randomized controlled trial/
85.	double blind procedure/
86.	or/77–85
87.	systematic review/
88.	meta-analysis/
89.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
90.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
91.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
92.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
93.	(search* adj4 literature).ab.
94.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
95.	cochrane.jw.
96.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
97.	or/87–96
98.	76 and (86 or 97)

Table 13Cochrane Library (Wiley) search terms

#1.	MeSH descriptor: [Hypertension] explode all trees
#2.	hypertens*:ti,ab
#3.	(elevat* near/2 blood next pressur*):ti,ab
#4.	(high near/1 blood near/1 pressur*):ti,ab
#5.	(increase* near/2 blood pressur*):ti,ab
#6.	((systolic or diastolic or arterial) near/2 pressur*):ti,ab
#7.	(or #1-#6)
#8.	MeSH descriptor: [Angiotensin-Converting Enzyme Inhibitors] explode all trees
#9.	Angiotensin-converting enzyme inhibitor*:ti,ab
#10.	(ACE inhibitor* or ACEI):ti,ab
#11.	(Captopril or Enalapril or Fosinopril or Imidapril or Lisinopril or Moexipril or Perindopril or Quinapril or Ramipril or Trandolapril or Capoten or Ecopace or Noyada or Innovace or Tanatril or Zestril or Perdix or Coversil or Accupro or Tritace):ti,ab
#12.	MeSH descriptor: [Calcium Channel Blockers] explode all trees
#13.	Calcium channel blocker*:ti,ab
#14.	CCB:ti,ab
#15.	(Amlodipine or Clevidipine or Diltiazem or Felodipine or Isradipine or Lacidipine or Lercanidipine or Nicardipine or Nifedipine or Verapamil or Amlostin or Istin or Adizem or Angitil or Dilcardia or Dilzem or Slozem or Tildiem or Viazem or Zemtard or Kenzem or Cardioplen or Felendil or Neofel or Parmid or Plendil or Pinefeld or Vascalpha or Molap or Motens or Zanidip or Cardene or Adalat or Adipine or Coracten or Fortipine or Nifedipress or Tensipine or Valni or Securon or Verapress or Vertab or Univer or Zolvera or Cleviprex):ti,ab
#16.	MeSH descriptor: [Angiotensin Receptor Antagonists] explode all trees
#17.	(AngiotensinII near/3 (antagonist* or blocker*)):ti,ab
#18.	ARB:ti,ab
#19.	(Azilsartan or Candesartan or Eprosartan or Irbesartan or Losartan or Olmesartan or Telmisartan or Valsartan or Edarbi or Amias or Teveten or Aprovel or Ifirmasta or Sabervel or Cozaar or Olmetec or Tolura or Micardis or Diovan):ti,ab
#20.	MeSH descriptor: [Diuretics] this term only
#21.	MeSH descriptor: [Sodium Chloride Symporter Inhibitors] this term only
#22.	((thiazide or thiazide-like or non-thiazide or conventional or potassium sparing) near/3 diuretic*):ti,ab
#23.	(Amiloride or Cyclopenthiazide or Spironolactone or Bendroflumethiazide or Hydrochlorothiazide or Co-amilozide or Co-triamterzide or Co-zidocapt or Chlortalidone or Indapamide or Metolazone or Xipamide or Carace or Zestoretic or Coversyl or Accuretic or Cozaar or Sevikar or Olmetec or Actelsar or Tolucombi or Co-Diovan or Hygroton or Co-tenidone or Kalspare or Natrilix or Cardide or Indipam or Rawel or Tensaid or Alkapamid or Zaroxolyn or Diurexan or Aprinox or Neo-Naclex or CoAprovel or Lisoretic or Dyazide or Navispare or Lasilactone):ti,ab
#24.	MeSH descriptor: [Adrenergic beta-Antagonists] this term only
#25.	(adrenergic beta antagonist* or beta blocker* or b blocker*):ti,ab
#26.	(Carvedilol or Labetalol or Atenolol or Nadolol or Oxprenolol or Pindolol or Propranolol or Timolol or Acebutolol or Bisoprolol or Celiprolol or Esmolol or Metoprolol or Nebivolol or Carvedilol or Tenormin or Tenif or Corgard or Slow-Trasicor or Visken or Viskladix or Bedranol or Beta-Prograne or Syprol or Betim or Sectral or Cardicor or Congescor or Celectol or Breviblock or Betaloc or Lopresor or Nebilet):ti,ab
#27.	MeSH descriptor: [Adrenergic alpha-Antagonists] explode all trees
#28.	(adrenergic alpha antagonist* or alpha adrenoreceptor blocker* or alpha blocker*):ti,ab
#29.	(Doxazosin or Prazosin or Terazosin or Cardura or Doxadura or Raporsin or Slocinx or Doxzogen or Larbex or Hypovase or Hytrin):ti,ab
#30.	MeSH descriptor: [Antihypertensive Agents] this term only
#31.	centrally acting antihypertensive*:ti,ab
#32.	(Clonidine or Moxonidine or Methyldopa or Catapres or Dixarit or Aldomet or Physiotens):ti,ab
#33.	renin inhibitor*:ti,ab
#34.	(Aliskiren or Rasilez):ti,ab
#35.	((trandolapril and verapamil) or TARKA):ti,ab
#36.	(or #8-#35)
#37.	#7 and #36
#38.	MeSH descriptor: [Drug Combinations] this term only
#39.	MeSH descriptor: [Drug Therapy, Combination] this term only
#40.	MeSH descriptor: [Drug Therapy] this term only
#41.	drug therap*:ti,ab
#42.	((combination* or combined or multiple or single) near/1 (therap* or agent* or drug* or treatment*)):ti,ab
#43.	(monotherap* or mono therap*):ti,ab
#44.	(or #38-#43)
#45.	#37 and #44

Table 14Database date parameters and filters used

Database

Dates searched

Search filter used

Medline

2014–28 August 2018

Exclusions

Health economics studies

Embase

2014–28 August 2018

Exclusions

Health economics studies

Centre for Research and Dissemination (CRD)

HTA - Inception–28 August 2018

NHS EED - Inception to March 2015

None

Table 15Medline (Ovid) search terms

1.	exp Hypertension/
2.	hypertens*.ti,ab.
3.	(elevat* adj2 blood adj pressur*).ti,ab.
4.	(high adj blood adj pressur*).ti,ab.
5.	(increase* adj2 blood pressur*).ti,ab.
6.	((systolic or diastolic or arterial) adj2 pressur*).ti,ab.
7.	or/1–6
8.	letter/
9.	editorial/
10.	news/
11.	exp historical article/
12.	Anecdotes as Topic/
13.	comment/
14.	case report/
15.	(letter or comment*).ti.
16.	or/8–15
17.	randomized controlled trial/ or random*.ti,ab.
18.	16 not 17
19.	animals/ not humans/
20.	exp Animals, Laboratory/
21.	exp Animal Experimentation/
22.	exp Models, Animal/
23.	exp Rodentia/
24.	(rat or rats or mouse or mice).ti.
25.	or/18–24
26.	7 not 25
27.	limit 26 to English language
28.	Economics/
29.	Value of life/
30.	exp “Costs and Cost Analysis”/
31.	exp Economics, Hospital/
32.	exp Economics, Medical/
33.	Economics, Nursing/
34.	Economics, Pharmaceutical/
35.	exp “Fees and Charges”/
36.	exp Budgets/
37.	budget*.ti,ab.
38.	cost*.ti.
39.	(economic* or pharmaco?economic*).ti.
40.	(price* or pricing*).ti,ab.
41.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
42.	(financ* or fee or fees).ti,ab.
43.	(value adj2 (money or monetary)).ti,ab.
44.	or/28–43
45.	27 and 44

Table 16Embase (Ovid) search terms

1.	exp Hypertension/
2.	hypertens*.ti,ab.
3.	(elevat* adj2 blood adj pressur*).ti,ab.
4.	(high adj blood adj pressur*).ti,ab.
5.	(increase* adj2 blood pressur*).ti,ab.
6.	((systolic or diastolic or arterial) adj2 pressur*).ti,ab.
7.	or/1–6
8.	letter.pt. or letter/
9.	note.pt.
10.	editorial.pt.
11.	case report/ or case study/
12.	(letter or comment*).ti.
13.	or/8–12
14.	randomized controlled trial/ or random*.ti,ab.
15.	13 not 14
16.	animal/ not human/
17.	nonhuman/
18.	exp Animal Experiment/
19.	exp Experimental Animal/
20.	animal model/
21.	exp Rodent/
22.	(rat or rats or mouse or mice).ti.
23.	or/15–22
24.	7 not 23
25.	limit 24 to English language
26.	health economics/
27.	exp economic evaluation/
28.	exp health care cost/
29.	exp fee/
30.	budget/
31.	funding/
32.	budget*.ti,ab.
33.	cost*.ti.
34.	(economic* or pharmaco?economic*).ti.
35.	(price* or pricing*).ti,ab.
36.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
37.	(financ* or fee or fees).ti,ab.
38.	(value adj2 (money or monetary)).ti,ab.
39.	or/26–38
40.	25 and 39

Table 17NHS EED and HTA (CRD) search terms

#1.	MeSH DESCRIPTOR Hypertension EXPLODE ALL TREES IN NHSEED,HTA
#2.	(Hypertens*) IN NHSEED, HTA
#3.	(elevat* adj2 blood adj pressur*) IN NHSEED, HTA
#4.	(high adj blood adj pressur*) IN NHSEED, HTA
#5.	(increase* adj2 blood pressur*) IN NHSEED, HTA
#6.	((systolic or diastolic or arterial) adj2 pressur*) IN NHSEED, HTA
#7.	#1 OR #2 OR #3 OR #4 OR #5 OR #6

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

Figure 2Serious cardiovascular events at 12 months

Figure 3Change in creatinine at 12 months

Figure 4Discontinuation due to adverse events at 12 months

Figure 5Discontinuation due to adverse events at 12 months (including type 2 diabetes)

Figure 6Hypotension (dizziness) at 12 months

Figure 7Change in creatinine (μmol/L) at 12 months

Figure 8Discontinuation due to adverse events at 12 months

Table 18Clinical evidence profile: combination versus monotherapy in adults with primary hypertension and type 2 diabetes

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Combination versus monotherapy	Control	Relative (95% CI)	Absolute	Quality	Importance
Serious cardiovascular events (follow-up 12 months)
1	randomised trials	serious¹	no serious inconsistency	serious²	serious³	none	6/244 (2.5%)	15/237 (6.3%)	RR 0.39 (0.15 to 0.98)	39 fewer per 1000 (from 1 fewer to 54 fewer)	⨁◯◯◯ VERY LOW	CRITICAL
Change in creatinine (ml/min; follow-up 12 months; Better indicated by lower values)
1	randomised trials	very serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	237	244	-	MD 0.7 higher (1.19 lower to 2.59 higher)	⨁⨁◯◯ LOW	IMPORTANT
Discontinuation due to adverse events (follow-up 12 months)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious³	none	19/244 (7.8%)	21/237 (8.9%)	RR 0.88 (0.49 to 1.59)	11 fewer per 1000 (from 47 fewer to 50 more)	⨁◯◯◯ VERY LOW	IMPORTANT
Discontinuation due to adverse events – overall strata (follow-up 12 months)
1	randomised trials	serious¹	no serious inconsistency	Serious⁴	very serious³	none	7/264 (2.7%)	6/274 (2.2%)	RR 1.21 (0.41 to 3.56)	5 more per 1000 (from 13 fewer to 54 more)	⨁◯◯◯ VERY LOW	IMPORTANT
Dizziness (hypotension; follow-up 12 months)
1	randomised trials	serious¹	no serious inconsistency	Serious⁵	very serious³	none	3/244 (1.2%)	5/237 (2.1%)	RR 0.58 (0.14 to 2.41)	9 fewer per 1000 (from 18 fewer to 30 more)	⨁◯◯◯ VERY LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded by 1 increment because the majority of the evidence had indirect outcomes

3: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

4: Downgraded by 1 increment because the majority of the evidence had an indirect population

5: Downgraded by 1 increment because the majority of the evidence had indirect outcomes; unclear if dizziness related to hypotension

Table 19Clinical evidence profile: combination versus monotherapy in adults with primary hypertension and without type 2 diabetes

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Combination versus monotherapy	Control	Relative (95% CI)	Absolute	Quality	Importance
Change in creatinine (mmol/L; follow-up 12 months; Better indicated by lower values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	232	225	-	MD 2.3 higher (0.7 to 3.9 higher)	⨁⨁⨁⨁ HIGH	IMPORTANT
Discontinuation due to adverse events (follow-up 12 months)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²	none	19/216 (8.8%)	20/202 (9.9%)	RR 0.89 (0.49 to 1.62)	11 fewer per 1000 (from 52 fewer to 58 more)	⨁◯◯◯ VERY LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias and downgraded by 2 increments if the majority of the evidence was at very high risk of bias

2: Downgraded by 1 increment if the confidence interval crossed 1 MID or by 2 increments if the confidence interval crossed both MIDs.

Figure 9Flow chart of health economic study selection for the guideline

* Non-relevant population, intervention, comparison, design or setting; non-English language

Table 20Studies excluded from the clinical review

Reference	Reason for exclusion
Aalbers 2010¹	Incorrect study design
Abate 1998²	Less than minimum duration
Amir 1994³	Incorrect study design
Anan 2005⁴	Less than minimum duration
Andersson 1999⁵	Less than minimum duration
Anderton 1988⁶	No washout period
Andreadis 2010⁷	Less than minimum duration
Andreadis 2005⁸	Less than minimum duration
Anonymous 1988¹⁰	Less than minimum duration
Anonymous (Veterans Administration cooperative study group) 1983⁹	Less than minimum duration
Aoki 1977¹¹	Less than minimum duration
Applegate 1997¹²	Inappropriate washout period
Bakris 2013¹⁵	No washout period
Basile 2011¹⁶	Less than minimum duration
Bays 2014¹⁷	Systematic review; references checked
Benedict group 2003¹⁸	Incorrect study design
Benjamin 1988¹⁹	Incorrect study design
Bennett 2017²⁰	Systematic review; references checked
Beretta-Piccoli 1987²¹	Less than minimum duration
Bielmann 1991²²	Less than minimum duration
Black 2008²³	Incorrect interventions
Black 2002²⁴	Incorrect study design
Black 2003²⁵	Incorrect interventions
Black 1998²⁶	Study protocol
Bohm 2017²⁸	Incorrect population
Bomback 2012²⁹	Less than minimum duration
Bradley 1975³⁰	Incorrect study design
Breithaupt-Grogler 1998³¹	Less than minimum duration
Bremner 1997³²	Wrong comparison
Bremner 1997³³	Wrong comparison
Brown 2015³⁸	Less than minimum duration
Brown 2000³⁴	Less than minimum duration
Brown 2001³⁵	Less than minimum duration
Brown 1985³⁶	No relevant outcomes
Brown 2008³⁷	Incorrect study design
Chalmers 1999³⁹	Less than minimum duration
Chaugai 2018⁴⁰	Wrong comparison
Chung 2009⁴¹	Less than minimum duration
Ciulla 2009⁴²	Incorrect study design
Ciulla 2004⁴³	Less than minimum duration
Cushman 1998⁴⁴	No useable outcomes
Dafgard 1981⁴⁵	No useable outcomes
Dahlof 2005⁴⁸	Incorrect study design
Dahlof 1987⁴⁶	Incorrect study design
Damian 2016⁴⁹	Wrong population
De Galan 2009⁵¹	Wrong comparison
Degl’Innocenti 2004⁵³	Wrong comparison
Delea 2009⁵⁴	Not article
DeQuattro 1997⁵⁶	Less than minimum duration
DeQuattro 1997⁵⁷	Less than minimum duration
Derosa 2016⁶⁵	Inappropriate washout period
Derosa 2015⁶⁴	No relevant outcomes
Derosa 2014⁵⁸	No useable outcomes
Derosa 2013⁵⁹	Incorrect study design
Derosa 2013⁶⁰	Inappropriate washout period
Derosa 2014⁶²	Inappropriate washout period
Derosa 2013⁶¹	Article retracted
Derosa 2014⁶³	Article retracted
Destro 2008⁶⁶	Inappropriate washout period
Dickson 2008⁶⁷	Incorrect study design
Divitiis 1984⁵⁰	Inappropriate washout period
Drayer 1995⁶⁸	Less than minimum duration
Duckett 1990⁶⁹	Incorrect study design
Dzurik 1990⁷⁰	Less than minimum duration
Elliot 1987⁷²	Less than minimum duration
El-Mehairy 1979⁷¹	No useable outcomes
Family Physicians Hypertension Study Group 1984⁷³	Less than minimum duration
Fang 2014⁷⁴	No useable outcomes
Feldman 2009⁷⁵	Less than minimum duration
Fell 1990⁷⁶	Incorrect study design
Ferrari 2008⁷⁷	Systematic review; references checked
Fogari 2008⁸⁰	Incorrect washout period
Fogari 2007⁷⁸	Incorrect comparison
Fogari 2002⁷⁹	Wrong population/inappropriate washout
Forette 2002⁸¹	Wrong comparison
Franklin 1996⁸²	Less than minimum duration
Franz 1990⁸³	Not in English
Freytag 2002⁸⁴	Incorrect study design
Frishman 1995⁸⁵	Less than minimum duration
Fu 2017⁸⁶	Systematic review; references checked
Fujisaki 2014⁸⁷	Incorrect study design
Garcia de Vinuesa 2001⁸⁸	Wrong population
Garjon 2017⁸⁹	Systematic review; no relevant outcomes
Girerd 1998⁹⁰	Less than minimum duration
Goodman 1985⁹¹	Incorrect study design
Goyal 2014⁹²	Less than minimum duration
Grassi 2010⁹³	Systematic review; references checked
Grimm 1996⁹⁴	Incorrect study design
Gupta 2008⁹⁵	Incorrect study design
Guyot 1990⁹⁶	Not in English
Hall 1998⁹⁸	Less than minimum duration
Hall 1998⁹⁷	Incorrect study design
Harmankaya 2003⁹⁹	No useable outcomes, less than minimum duration
Hasegawa 2004¹⁰⁰	Wrong population
He 2017¹⁰¹	Systematic review; references checked
Heidbreder 1992¹⁰³	Inappropriate washout period, less than minimum duration
Heidbreder 1991¹⁰²	Wrong population
Helmer 2018¹⁰⁴	Systematic review; references checked
Herlitz 2001¹⁰⁵	Wrong comparison
Hersh 1995¹⁰⁶	Incorrect study design
Hill 1985¹⁰⁷	Less than minimum duration, incorrect study design
Hilleman 1999¹⁰⁸	Systematic review; references checked
Hofling 1991¹⁰⁹	Not in English
Holzgreve 1989¹¹¹	Wrong population
Holzgreve 2003¹¹⁰	Not article
Home 2009¹¹²	Wrong population/interventions
Ihm 2016¹¹³	Less than minimum duration
Ishimitsu 1997¹¹⁴	Incorrect study design
Jang 2015¹¹⁵	Less than minimum duration
Jicheng 2009¹³⁵	Wrong interventions
Johnson 1994¹¹⁷	Incorrect study design; no relevant outcomes
Johnson 2005¹¹⁶	Wrong study design, wrong population
Katayama 2006¹¹⁸	Incorrect study design
Kim 2011¹²²	Less than minimum duration
Kim 2014¹²⁰	Wrong population
Kim 2016¹²¹	Wrong population, less than minimum duration
Kinouchi 2011¹²³	No useable outcomes
Kjeldsen 2016¹²⁴	Less than minimum duration
Kjeldsen 2008¹²⁶	Wrong comparison
Kjeldsen 2002¹²⁵	Incorrect study design
Kostis 2004¹²⁸	Abstract
Kostis 1997¹²⁷	Wrong population
Kuschnir 2004¹²⁹	Less than minimum duration, inappropriate washout
Lassila 2000¹³⁰	Wrong population/wrong interventions
Laurent 2001¹³¹	Literature review
Li 2014¹³²	Incorrect population
Lucas 1985¹³⁴	Less than minimum duration
MacDonald 2015¹³⁶	Incorrect study design
MacKay 1996¹³⁷	Less than minimum duration
Malacco 2008¹³⁸	Less than minimum duration
Mancia 2017¹⁴⁰	Subgroup analysis
Mancia 2012¹⁴¹	Wrong population
Marques da Silva 2015¹⁴²	Incorrect comparison
Masao 1994¹⁴³	Not in English
Matsuzaki 2011¹⁴⁴	Wrong comparison
Mayaudon 1995¹⁴⁵	Not in English
Miyoshi 2017¹⁴⁷	Less than minimum duration
Morgan 2002¹⁴⁹	Inappropriate washout period
Morgan 2004¹⁵⁰	Less than minimum duration
MRC Working Party 1992¹⁵¹	Incorrect study design
Nakao 2004¹⁵²	Incorrect study design
Nalbantgil 2003¹⁵³	Less than minimum duration
Nedogoda 2005¹⁵⁶	Not in English
Neldam 2012¹⁵⁷	Systematic review; references checked
Neldam 2012¹⁵⁸	Systematic review; references checked
Nelson 1982¹⁵⁹	Incorrect study design
Neutel 2000¹⁶²	Less than minimum duration
Neutel 1999¹⁶¹	Less than minimum duration. Wrong population
Neutel 2014¹⁶⁰	Incorrect study design
Obel 1990¹⁶³	Less than minimum duration
Olivan Martinez 1993¹⁶⁴	Not in English
Packer 2013¹⁶⁵	Wrong population
Pannier 2002¹⁶⁶	Not in English
Papademetriou 2009¹⁶⁷	Incorrect study design
Papademetriou 1998¹⁶⁸	Incorrect study design
Park 2016¹⁷¹	Less than minimum duration
Park 2016¹⁶⁹	Wrong population, less than minimum duration
Park 2016¹⁷⁰	Incorrect population
Patel 2007¹⁷²	Incorrect study design, less than minimum duration
Paz 2016¹⁷³	Systematic review; references checked
Perez-Maraver 2005¹⁷⁴	Wrong population
Persson 1976¹⁷⁵	Less than minimum duration
Pessina 2006¹⁷⁶	Incorrect study design
Petelina 2005¹⁷⁷	Not in English
Petersen 2001¹⁷⁸	Wrong population
Petrie 1975¹⁷⁹	Inappropriate washout period, less than minimum duration
Pool 2009¹⁸⁰	Less than minimum duration
Prisant 1998¹⁸¹	Less than minimum duration
Radevski 2000¹⁸³	Wrong population
Radevski 1999¹⁸²	Wrong comparison
Rakesh 2017¹⁸⁴	No useable outcomes
Ratnasabapathy 2003¹⁸⁵	Wrong comparison
Redon 2012¹⁸⁶	Wrong comparison
Roca-Cusachs 2001¹⁸⁷	Less than minimum duration
Rosenfeld 1989¹⁸⁸	Incorrect study design
Ruggenenti 2011¹⁹¹	Incorrect study design
Ruggenenti 2004¹⁹⁰	Wrong population
Ruggenenti 2011¹⁸⁹	Incorrect study design
Saruta 2015¹⁹³	Wrong comparison
Sassano 1989¹⁹⁴	Less than minimum duration
Seedat 1984¹⁹⁶	Less than minimum duration
Seedat 1983¹⁹⁵	Incorrect study design
Shaifali 2014¹⁹⁷	No useable outcomes
Shi 2017¹⁹⁸	No relevant outcomes
Shimamoto 2015¹⁹⁹	Inappropriate washout period
Smith 2007²⁰⁰	Less than minimum duration
Sohn 2017²⁰¹	Less than minimum duration
Soucek 2007²⁰²	Not in English
Sung 2016²⁰³	Less than minimum duration
Thijs 2010²⁰⁵	Incorrect study design
Timofeeva 2006²⁰⁶	Not in English
Umemoto 2017²⁰⁸	Subgroup analysis
Umemoto 2016²⁰⁷	Subgroup analysis
Uzui 2014²⁰⁹	Wrong comparison
Wang 2017²¹⁰	Less than minimum duration
Weinberger 1982²¹¹	Less than minimum duration
Weir 2001²¹²	Less than minimum duration
White 1995²¹³	Incorrect study design
Wilhelmsen 1987²¹⁴	Incorrect study design
Yip 2008²¹⁶	Incorrect study design
Yu 2011²¹⁷	Not in English
Yusuf 2016²¹⁸	Wrong comparison
Yusuf 2008²¹⁹	Wrong population
Zanchetti 2006²²⁰	Literature review
Zhang 2010²²¹	Inappropriate washout
Zhu 2013²²²	Less than minimum duration

Table 21Studies excluded from the health economic review

Reference	Reason for exclusion
Kato 2015¹¹⁹	This study was assessed as partially applicable with very serious limitations because it was a before-and-after study comparing whether switching from monotherapy to combination therapy is cost effective. Clinical data does not meet the requirements of clinical review.
Mazza 2017¹⁴⁶	This study was assessed as partially applicable with very serious limitations because it is based on retrospective data, and blood pressure lowering is used for effect rather than clinical endpoints. Therefore, clinical data does not meet the requirements of clinical review.
Saito 2008¹⁹²	This study was assessed as partially applicable with very serious limitations because the effectiveness of the combination treatment is based on an assumption (assumption of on-treatment blood pressure) rather than being based on a clinical trial. This also seems to have been put through a risk calculator, which should ideally be used for baseline risks rather than risks post treatment. Therefore, clinical data does not meet the requirements of clinical review.
Wisloff 2012²¹⁵	This study was assessed as partially applicable with very serious limitations because the effectiveness of the combination treatment is multiplicative rather than being based on a clinical trial. Therefore, clinical data does not meet the requirements of clinical review.
Szucs 2010²⁰⁴	This was a study included in the previous guideline. This study was assessed as not applicable because treatment is being compared to no treatment.

Criteria for selecting high-priority research recommendations

PICO question	Population: Adults (over the age of 18) who meet the criteria for medication to be initiated for the treatment of hypertension, split into subgroups including type 2 diabetes, history of stroke, history of cardiovascular disease, or pre-existing CKD. Intervention(s): Dual therapy as an initial treatment strategy in the treatment of hypertension. Comparison: Single agent therapy. Outcome(s): Critical: All-cause mortality, stroke (ischaemic or haemorrhagic), myocardial infarction, health related quality of life, and development or progression of chronic kidney disease (CKD). Important: Time to reach blood pressure target,
Importance to patients or the population	Impact would be delay in the development of or slowing the progression of adverse outcomes without an increase in adverse events as a result of the treatment regimen.
Relevance to NICE guidance	This would impact the recommendations within the NICE clinical guideline for hypertension as to whether staged treatment (as per current guideline) is retained or whether dual therapy would be recommended for any specific subgroups of people.
Relevance to the NHS	If blood pressure targets are attained in a more timely fashion without additional adverse effects, this may be cost effective in terms of number of clinic appointments or consultations required. If improved cardiovascular outcomes, this would be cost effective and would reduce the QALY associated with treatment of hypertension.
National priorities	N/A
Current evidence base	Although there was some evidence identified for using dual therapy, this was not in hard clinical outcomes and therefore further evidence with these outcomes could inform future updates of the guideline.
Equality	There are no expected equality issues.
Study design	This question would be best answered by an RCT although the duration of follow up required means that a long-term (at least 5 years) study would be required.
Feasibility	The study would need a 5-year follow-up. Technically, it should be straight forward, but funding could be an issue.
Other comments	As the medications used for the treatment of hypertension are generic, it is unlikely that any funding would be forthcoming from the pharmaceutical industry, so the research would need to be funded by a central body.
Importance	Medium: the research is relevant to the recommendations in the guideline, but the research recommendations are not key to future updates.