10 October 2011
NICE has published updated guidance on the management of hypertension (clinical guideline 127, August 2011). This update was made in collaboration with, and is endorsed by, the British Hypertension Society.
Among other things, important changes from previous guidance include:
- Using ambulatory or home blood pressure monitoring to confirm the diagnosis of hypertension.
- Offering treatment with a calcium-channel blocker (C) as first choice step 1 antihypertensive drug for people aged over 55 years and black people of African or Caribbean family origin of any age.
- Offering an ACE inhibitor or a low-cost angiotensin-II receptor antagonist (A2RA*) as step 1 antihypertensive drug for non-black people younger than 55 years,
- Offering an ACE inhibitor or low cost A2RA in combination with C for people of any age if this is necessary to achieve suitable blood pressure reduction (step 2 drug treatment).
- Offering chlortalidone or indapamide in preference to bendroflumethiazide or hydrochlorothiazide if diuretic therapy (D) is to be changed or initiated:
- as an alternative to C at step 1 or step 2 if C is not tolerated or the person has oedema, evidence of heart failure or a high risk of heart failure, or
- in combination with C and an ACE inhibitor or low-cost A2RA if necessary to achieve suitable blood pressure reduction (step 3 drug treatment).
- Offering spironolactone 25 mg once daily as first choice additional treatment (if the person’s blood potassium level is 4.5 mmol/L or less) at step 4.
*The NICE guidance uses the abbreviation ARB for ‘angiotensin receptor blocker’ instead of A2RA for ‘angiotensin 2 receptor antagonist’
Healthcare professionals, managers and commissioners should familiarise themselves with this guideline and collaborate to develop local care pathways that promote optimal management of people with hypertension. In particular, they should note that:
- Healthcare professionals, managers and commissioners should make active plans to introduce ambulatory blood pressure monitoring in accordance with the new guideline as soon as practicable.
- Healthcare professionals taking blood pressure measurements need adequate initial training and periodic review of their performance (see 1.1.1).
- Healthcare providers must ensure that devices for measuring blood pressure are properly validated, maintained and regularly recalibrated according to manufacturers’ instructions (see 1.1.3).
- The guidance recommends that if an A2RA is used, it should be a low-cost A2RA (see 1.6.6).
- The recommendation to consider a low-cost A2RA as an alternative to an ACE inhibitor when a renin–angiotensin (RAS) drug is indicated in hypertension does not extend to other conditions where RAS drugs are used, such as heart failure or diabetes (CG 127 does not apply to people with diabetes), where ACE inhibitors remain the first choice type of RAS drug.
- ACE inhibitors and A2RAs should not be used in combination to treat hypertension (see 1.6.7).
- The guidance specifically states (see 1.6.10) that people who are already having treatment with bendroflumethiazide or hydrochlorothiazide and whose blood pressure is stable and well controlled should continue treatment with this drug: their diuretic should not be switched routinely to indapamide or chlortalidone.
- Similarly, the guidance does not include a recommendation that people who are already having treatment with diuretics and whose blood pressure is stable and well controlled should have their treatment switched to a calcium channel blocker.
- Although beta-blockers are not a preferred initial therapy for hypertension, they may be considered in some patients (such as women of child-bearing potential and others in whom RAS drugs are contraindicated: see 1.6.11). Beta-blockers may also be indicated in other conditions, such as angina (see recent NICE guidance), heart failure or after a myocardial infarction (MI), which are outside the scope of this guidance, and with which hypertension may co-exist. The guidance does not recommend discontinuing the beta-blocker in these circumstances, nor in patients with hypertension without these other conditions whose blood pressure is stable and well controlled.
- Prescribers and prescribing managers should note the current difference in cost between the modified-release and standard release indapamide products available, and the difference in costs of generic and branded calcium channel blockers
The cost-effectiveness modelling study which supports the updated NICE guidance on the method for the diagnosis of high blood pressure in primary care has recently been published. This was funded by NICE and compared three diagnostic strategies—further blood pressure measurement in the clinic, at home, and with an ambulatory monitor—in terms of lifetime costs, quality-adjusted life years, and cost-effectiveness. It concluded:
‘Ambulatory monitoring as a diagnostic strategy for hypertension after an initial raised reading in the clinic would reduce misdiagnosis and save costs. Additional costs from ambulatory monitoring are counterbalanced by cost savings from better targeted treatment. Ambulatory monitoring is recommended for most patients before the start of antihypertensive drugs’
Active plans need to be made locally to move practice towards the new guideline as soon as practicable. During this transitional period, and until arrangements to introduce ambulatory and/or home blood pressure monitoring have been put in place, it seems reasonable to continue to follow the previous, 2006 guidance and ask patients (who do not have signs/symptoms of malignant hypertension) to return at least twice for further measurement in clinic, normally at monthly intervals. They should ensure that they use properly validated, maintained and regularly recalibrated devices with immaculate technique.
NICE has produced a number of resources to help with implementation of the guidance:
- Baseline assessment tool
- Clinical audit tool
- Clinical case scenarios
- Costing report
- Costing template
- Electronic audit tool
- Implementation advice
- Slide set
- ABPM implementation podcast.
This Rapid Review covers the key points in the guidance for prescribers and prescribing managers, explaining the evidence rationale behind the recommendations.
Summary of drug therapy guidance (taken from the guideline, page 36)
A = ACE inhibitor or low-cost A2RA. Consider a low cost A2RA, in preference to an ACE inhibitor, in combination with a calcium channel blocker in black people of African or Caribbean family origin at step 2
C = Calcium channel blocker (C). This is preferred but consider a thiazide-like diuretic (D) if C is not tolerated or the person has oedema, evidence of heart failure or a high risk of heart failure.
D = thiazide-like diuretic: Offer chlortalidone (12.5–25 mg once daily) or indapamide (1.5 mg modified-release or 2.5 mg once daily) in preference to bendroflumethiazide or hydrochlorothiazide if diuretic therapy is to be changed or initiated.
- Consider a low dose of spironolactone or higher doses of a thiazide-like diuretic.
- At the time of publication (August 2011), spironolactone did not have a UK marketing authorisation for this indication. Informed consent should be obtained and documented.
- Consider an alpha- or beta-blocker if further diuretic therapy is not tolerated, or is contraindicated or ineffective.
Why did the guideline development group (GDG) conclude that ACE inhibitors and A2RAs are equivalent? (pages 208–212 of the full guideline)
The GDG looked for systematic reviews and randomised controlled trials (RCTs) comparing ACE inhibitors and A2RAs for first line treatment of primary hypertension, published since December 2005 (the cut-off for searches for the previous edition of the NICE hypertension guidance). Three RCTs which met the inclusion criteria were found:
- ONTARGET compared ramipril 10 mg/day with telmisartan 80 mg/day and a combination of the two in 25,620 people and had a median follow-up time of 56 months.
- A second RCT compared enalapril 20 mg/day with losartan 50 mg/day in 560 people with hypertension and had a follow-up time of 24 months.
- CORD IB compared ramipril 5 mg/day with losartan 50 mg/day in 3860 people and had a follow-up time of 12 months.
Looking at the results from these, the GDG concluded that A2RAs were significantly better than ACE inhibitors in terms of producing fewer study drug withdrawals. There was no statistically significant difference between ACE inhibitors and A2RAs for the following outcomes:
- all cause mortality
- fatal and non-fatal MI
- fatal and non-fatal stroke
- angina requiring hospitalisation
- coronary revascularisation
- new onset diabetes
- heart failure.
The GDG concluded that ACE inhibitors and A2RAs should be considered equivalent with regard to their effect on clinical outcomes. The GDG noted (page 258) that no relevant cost effectiveness analyses comparing ACE inhibitors and A2RAs were identified. However, the difference between the lowest cost A2RA and the lowest cost ACE inhibitor has reduced considerably due to the recent availability of generic losartan. Patent expiry is imminent for many other A2RAs and the GDG considered it likely that the costs of ACE inhibitors and A2RAs will become similar over the lifetime of this guideline update.
The issue of ACE inhibitors versus A2RAs was raised by consultees to the guideline. Two highlighted the meta-analysis (MA) by Law et al, published in 2009. This found a statistically significant reduction in the risk of coronary heart disease (CHD) events and stroke associated with ACE inhibitors compared to placebo (relative risk [RR] for CHD events 0.83, 95% confidence interval [CI] 0.78 to 0.89; RR for stroke RR 0.78, 95%CI 0.66 to 0.92). The confidence interval for the reduction in risk of CHD associated with A2RAs versus placebo was wide and the result was not statistically significant (RR 0.86, 95%CI 0.53 to 1.40). No data were included for the effects of A2RAs on stroke versus placebo. There was no significant difference for either drug compared with any other class of drug in risk of CHD events (RR for ACE inhibitors 0.97, 95%CI 0.90 to 1.03; RR for A2RAs 1.04, 95%CI 0.94 to 1.16) or risk of stroke (RR for ACE inhibitors 1.06, 95%CI 0.94 to 1.20; RR for A2RAs 0.90, 95%CI 0.71 to 1.13)
Another, more recent MA relevant to this question was published in 2011 and was not included in the evidence review. This attempted to determine whether or not A2RAs increase the risk of cardiovascular (CV) events, (MI, all-cause or CV mortality, or angina) as was once a concern from earlier data. The MA provides reassuring evidence that they do not, at least not substantially. However, the MA found no statistically significant reduction in the risk of these outcomes associated with use of A2RAs compared with placebo. It did, however, find a statistically significant reduction in risk of stroke with A2RAs compared to placebo (RR 0.91, 95%CI 0.85 to 0.98).
The responses of the GDG to the comments made by consultees indicate that it valued the results of head-to-head studies of ACE inhibitors versus A2RAs above those of comparisons with placebo. Neither of the two MAs referred to above found a statistically significant difference with either ACE inhibitors or A2RAs compared with active controls for the outcomes discussed.
It is important to note that the GDG’s conclusion on the equivalence of ACE inhibitors and A2RAs applies only to hypertension. It does not extend to other conditions where RAS drugs are used, such as heart failure or diabetes. In those situations, ACE inhibitors remain the first choice type of RAS drug, with A2RAs reserved for people who cannot tolerate them. These clinical conditions were outside the scope of the review.
Why did the GDG recommend considering using an A2RA in preference to an ACE inhibitor (in combination with C) in black people of African or Caribbean family origin at step 2? (page 262 of the full guideline)
This recommendation is based on evidence relating to ACE inhibitor + C, but the GDG considered it likely that these results would be replicated with an A2RA + C. The GDG also considered that in black people of African or Caribbean family origin, ACE inhibitors are associated with an increased risk of developing angioedema, which can be life threatening. Although the incidence of this adverse effect is low, the GDG suggested that an A2RA in preference to an ACE inhibitor should be considered for such patients when step 2 treatment is required. Prescribers should note that the BNF advises that angioedema has also been reported with some A2RAs.
Why did the GDG recommend that if diuretic treatment is to be initiated or changed, chlortalidone or indapamide should be used in preference to bendroflumethiazide or hydrochlorothiazide? (pages 258–60 of the full guideline)
The predominant thiazide-type diuretic used in the UK for the treatment of hypertension is bendroflumethiazide 2.5 mg daily. This drug is rarely used anywhere else in the world for this indication. In addition, although often grouped together as thiazide-type diuretics, from a pharmacological perspective, there are two broad groups:
- classical thiazide diuretics (e.g. bendroflumethiazide and hydrochlorthiazide)
- thiazide-like diuretics (e.g. chlorthalidone and indapamide).
These two groups differ in some pharmacological properties, the relevance of which to their effects on clinical outcomes is unknown.
The GDG noted that no direct comparisons between the different diuretics looked at clinical outcomes. Comparison studies which examined effects on blood pressure were underpowered. Interpretation of data from trials comparing diuretics with placebo or other antihypertensive drugs is complicated by the markedly different diuretic doses used across studies. The data demonstrating benefits of bendroflumethiazide on clinical outcomes come from older studies in which the dose was 10 mg daily – four times the usual dose in current practice; and there is no study evaluating and confirming the benefit of low dose bendroflumethiazide on clinical outcomes. There is also limited evidence confirming the benefits of initial therapy with low doses of hydrochlorothiazide on clinical outcomes. This does not mean that bendroflumethiazide 2.5 mg daily is ineffective but it does make it difficult to assess whether it is as effective at preventing clinical outcomes as other thiazide-like diuretics, e.g. chlortalidone and indapamide, for which there is evidence for benefits on a range of clinical outcomes when used at low doses.
The full guideline explains that having undertaken this analysis it was difficult for the GDG to recommend treatment with low dose bendroflumethiazide or hydrochlorothiazide, for which there is no evidence of a benefit on clinical outcomes. Consequently, the GDG recommended that when thiazide-type diuretics are used for the treatment for primary hypertension, thiazide-like diuretics, e.g. chlortalidone (12.5–25 mg once daily) or indapamide (1.5 mg modified release or 2.5 mg daily) should be preferred to conventional thiazide diuretics. The GDG did not consider it necessary to recommend that those people already treated with low dose bendroflumethiazide in whom blood pressure is controlled should be switched to chlortalidone or indapamide.
In the consultation, it was pointed out that chlortalidone is currently available only as a 50 mg tablet in the UK. The GDG responded that it anticipated that the pharmaceutical industry would be responsive in making most appropriate doses available. Prescribers and prescribing managers should note the difference in cost between the modified-release and standard release indapamide products available.
Why did the GDG recommend C over D at step 1 for people aged over 55 years and black people or African or Caribbean family origin of any age? (pages 260–1 of the full guideline)
Since 2006 (i.e. the last update of the guidance) the cost of antihypertensive drugs has decreased; in particular the cost of calcium channel blockers and A2RAs. The GDG re-ran the cost-effectiveness analysis with updated costs. The sensitivity analysis undertaken in 2006 was also rerun to evaluate whether and how the results varied by age, sex, and by varying the risks of CVD, heart failure and diabetes.
The sub-group analysis of cost-effectiveness was particularly sensitive to the relative effects of drug therapy on the prevention of diabetes and heart failure. The model predicts that for people at low to intermediate risk of heart failure, C is the most cost-effective option because it is associated with a low risk of developing diabetes, especially when compared to thiazide type diuretics, and C also has a good effectiveness profile across the range of other CV disease risks. Conversely, when people are judged to be at a high risk of developing heart failure, D was estimated to be the most cost-effective option, provided that they do not also have a high risk of diabetes. For people with a high risk of both heart failure and diabetes, A may be the most cost-effective option.
Most people with primary hypertension are at low to intermediate risk of heart failure and have an increased risk of developing diabetes. This suggests that C would be the most cost-effective step 1 therapy for most people aged over 55 years. The caveat to this conclusion is that the risk of heart failure increases with increasing age, especially in the elderly (i.e. 80 years or older), in whom D would be a more cost effective treatment. Moreover, some people might not tolerate C or may have evidence of oedema that might benefit from the preferred used of D.
The GDG concluded that C is the most cost-effective initial therapy for most people aged over 55 years with primary hypertension, and indeed, cost saving when compared to no intervention. It was considered that the evidence supporting this conclusion was stronger than in 2006. In addition the GDG discussions around this recommendation highlighted new data demonstrating that:
- C appears to be the most effective treatment option to suppress blood pressure variability, which in turn appears to be an independent predictor of cardiovascular disease risk in people with treated hypertension, and
- new evidence suggests that for treatment at step 2, the combination of A+C will usually be preferred to A+D, thereby impacting on the preferred choice of therapy for step 1 treatment (see below).
Consequently, the GDG recommended that C should be the preferred initial therapy for people with primary hypertension and aged >55 years. D is considered a suitable alternative for those who cannot tolerate C or who have developed, or are at high risk of developing heart failure.
Why did the GDG give preference to A+C over A+D at step 2? (page 262 of the full guideline)
Significant numbers of people with hypertension require more than one drug to control their blood pressure. The recommendation to give preference to A+C over A+D is based on the ACCOMPLISH study. This examined the effect of benazepril + amlodipine versus benazepril + hydrochlorothiazide in 11,506 people with hypertension for a follow-up of 24 months. It found that ACE inhibitor + C was significantly more effective at preventing MI when compared to ACE inhibitor + diuretic. Study withdrawal was also significantly lower in patients randomised to treatment with ACE inhibitor + C. The other clinical outcomes were not significantly different between groups but all numerically favoured the ACE inhibitor + C combination. The ACCOMPLISH trial was stopped earlier than planned because the primary composite outcome was significantly in favour of the ACE inhibitor + C. Thus, the study had inadequate power to address individual cardiovascular outcomes. There were no quality of life data identified.
The GDG concluded that the combination of ACE inhibitor + C had a treatment advantage over ACE inhibitor + D. It noted that this is based on a single large study and that benazepril is not used in the UK but concluded that there was unlikely to be an important difference between benazepril and other ACE inhibitors. Likewise, the GDG considered it likely that the results with the ACE inhibitor + C would be replicated with an A2RA + C.
The GDG concluded that these data from the ACCOMPLISH trial, taken together with the updated cost-effectiveness analysis and the data on blood pressure variability, all favour the combination of A+C versus A+D; with the caveat that the differences between C and D in each of these areas of analysis, although usually favouring C, were not large. The GDG emphasised that although C should usually be preferred over D as step 1 and step 2 therapy for most people, D is a highly effective alternative and is preferred in people with evidence of, or at high risk of developing heart failure.
Why did the GDG recommend spironolactone as first choice addition at step 4? (page 263 of the full guideline)
To inform the recommendations at step 4, the literature was searched for all years and all study types were included. Populations which were exclusively diabetic or had chronic kidney disease were excluded. The data search failed to indentify a single head-to-head RCT that met the search criteria. Six studies did meet the search criteria; however, these were all retrospective cohort studies – i.e. post-hoc analyses of studies in which patients had been treated with four or more antihypertensive therapies.
The GDG noted that all of these studies evaluated the use of low doses of spironolactone, usually 25 mg daily. Together, the review of these data suggested that low dose spironolactone was effective in resistant hypertension based on the surrogate outcome of blood pressure lowering. There were no data on other clinical outcomes. The full guideline points out that it is unclear from these very limited data whether spironolactone is always the most effective treatment option for every patient with resistant hypertension. Furthermore, spironolactone is not licensed for the treatment of hypertension in the UK but this does not preclude its use.
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