Blood pressure guidelines – where are we now?
Relevant BNF section: 2.2, 2.4, 2.5, 2.6
In June 2006, the National Institute for Health and Clinical Excellence (NICE) updated its recommendations on the management of patients with hypertension (published in 2004), in light of “significant new data” relating to drug treatment.1,2 The update, published in collaboration with the British Hypertension Society (BHS), recommended first-line use of a calcium-channel blocker or a thiazide-type diuretic in patients aged over 55 years or an ACE inhibitor in those aged under 55 years, and advised that beta-blockers should no longer be used for routine initial therapy.1 Recently published data from England suggest that primary care prescribing has changed in line with this new guideline.3 However, interpretation of the evidence that underpins some of the key recommendations is open to debate, particularly as there are differences from some other major guidelines in the recommendations for first-line therapy. Here we consider the updated NICE guideline, the rationale for its treatment recommendations, and the subsequent change in clinical practice. In particular, we focus on the initial drug management of adults without conditions such as diabetes mellitus or coronary heart disease that would in themselves be a key determinant of management.
WHAT DOES NICE RECOMMEND?
Which patient, threshold and target?
NICE recommends that drug therapy should be offered to the following groups:
patients with blood pressure measurements persistently above, or equal to, 160/100 mmHg;
patients at raised cardiovascular risk (i.e. with a 10-year risk of cardiovascular disease of at least 20%, or existing cardiovascular disease, or target organ damage) with a blood pressure persistently above, or equal to, 140/90 mmHg.1
NICE also recommends “adding different drugs if necessary, to achieve a target of 140/90mmHg, or until further treatment is inappropriate or declined”, noting that patients who do not achieve the target blood pressure, or for whom further treatment is inappropriate or declined, will still receive worthwhile benefit from some lowering of blood pressure.1 Of note, this target level set by NICE differs from the Quality and Outcomes Framework (QOF) indicators for GPs working in England, which specify a target below 150/90 mmHg for patients with hypertension.4 The basis for this difference in treatment target is unclear but some specialists suggest that the higher target level of the QOF indicator was negotiated to provide an achievable minimum treatment standard. The QOF target blood pressure is also the same as the “audit standard” recommended by the BHS.5 The use of two target blood pressures (one a clinical standard, the other an audit standard) is potentially confusing.
Which drug first?
Before NICE published its updated guideline in 2006, two separate guidelines on hypertension were available from NICE6 and the BHS.5 Of these, the NICE guideline advised step-wise treatment beginning with a thiazide diuretic (or beta-blocker in patients aged under 55 years), combined, if necessary, with a beta-blocker or an ACE inhibitor (in patients at risk of new-onset diabetes); calcium channel blockers were considered third-line drugs.6 By contrast, the BHS guideline recommended treatment based on the so-called AB/CD algorithm.5 This involved initial treatment with either an ACE inhibitor (or angiotensin-II receptor antagonist if an ACE inhibitor was not tolerated) (A) or beta-blocker (B) for white patients aged under 55 years, or a calcium channel blocker (C) or diuretic (D) for older white people or black people of any age.5 The updated NICE guideline follows the earlier BHS treatment recommendations, with the notable exception that beta-blockers are not recommended for first-line therapy.1 However, beta-blockers are still identified as an option for younger patients (aged under 55 years) who cannot take an ACE inhibitor or angiotensin-II receptor antagonist, women who may become pregnant, or patients with evidence of increased sympathetic drive, as well as a fourth-line option for patients with blood pressure inadequately controlled on the combination of an ACE inhibitor (or angiotensin-II receptor antagonist), a calcium channel blocker and a thiazide diuretic.
IMPACT OF THE UPDATED GUIDELINE
Analysis of a sample of GP patient records and national prescription data from England suggests that prescribing in primary care has changed in line with the updated NICE guideline.3 For instance, the proportion of patients with newly diagnosed hypertension and starting on an ACE inhibitor as monotherapy increased from 23% in April–June 2004 to 48% in January–March 2007; this was accompanied by increases for calcium channel blockers from 13% to 23% and for angiotensin-II receptor antagonists from 5% to 8%. For the same periods, the proportion of patients started on a thiazide diuretic fell from 41% to 18%, and for beta-blockers from 18% to 3%. These trends are consistent with changes in overall prescribing data for the community in England.3 The number of prescription items for a calcium channel blocker dispensed during the 12-month period to December 2007 increased by around 10% compared with the previous 12 months, to nearly 27 million. The numbers for ACE inhibitors and angiotensin-II receptor antagonists increased to around 34 million (13% increase) and 13 million (15% increase), respectively, while the numbers for thiazide diuretics and for beta-blockers both fell by around 2%, to around 21 million and 27 million, respectively.
WHAT UNDERLIES THE NICE GUIDELINE?
The updated NICE guideline was based on a reappraisal of evidence including four randomised controlled trials and an economic analysis that had not been available for the earlier guideline.1
The case against beta-blockers?
Key reasons for NICE’s advice against the use of beta-blockers as first-line therapy included evidence that, compared to the other main treatment options, these drugs (in particular atenolol) were less effective at preventing stroke, were more likely to cause new-onset diabetes, and were less cost-effective.1
A systematic review of randomised controlled trials that compared any combination of the main antihypertensive drugs was published as part of the NICE guideline.1 For the comparison between beta-blockers and calcium channel blockers, two studies (involving a total of 21,499 patients) were available, by far the larger of which was the Blood Pressure Lowering Arm of the Anglo-Scandinavian Cardio Outcomes Trial (ASCOT-BPLA;7 see box below). Meta-analysis of these two trials indicated that beta-blockers were less effective than calcium channel blockers in preventing stroke (relative risk [RR] 0.77, 95% CI 0.67 to 0.88). Another study, involving 9,103 patients showed that beta-blockers were also less effective than angiotensin-II receptor antagonists in preventing stroke (RR 0.75, 95% CI 0.63 to 0.88).1
ASCOT-BPLA was a randomised controlled trial involving 19,257 patients (mean age 63 years, 77% male, 95% white) with untreated high blood pressure (at least 160 mmHg systolic or 100 mmHg diastolic) or treated high blood pressure (at least 140 mmHg systolic or 90 mmHg diastolic), and at least three other risk factors for cardiovascular disease (e.g. diabetes, left-ventricular hypertrophy or other ECG abnormality).7 Patients received titrated therapy with either amlodipine 5–10 mg daily (plus perindopril 4–8 mg daily as required) or atenolol 50–100 mg daily (plus a combination of bendroflumethiazide 1.25–2.5 mg and potassium daily as required) to achieve a target blood pressure of below 140/90 mmHg (or below 130/80 mmHg for patients with diabetes). The trial was stopped prematurely because of a significant difference between treatments in the incidence of death and other secondary outcomes. At a median follow-up of 5.5 years, the two regimens did not differ in the incidence of non-fatal myocardial infarction plus fatal coronary heart disease (the combined primary endpoint; 8.2 per 1,000 patient years with amlodipine-based regimen vs. 9.1 per 100,00 with atenolol-based regimen, hazard ratio (HR) 0.90, 95% CI 0.79–1.02). On average, blood pressure values were 2.7/1.9 mmHg lower with the amlodipine-based regimen throughout the trial.
Other systematic reviews support NICE’s analysis about beta-blockers.8, 9 In a meta-analysis of 13 randomised controlled trials (including ASCOT-BPLA) involving a total of 105,951 patients, the risk of stroke, but not myocardial infarction or all-cause mortality, was greater with beta-blockers than with other drugs (RR 1.16, 95% CI 1.04 to 1.30).8 However, the absolute difference in the incidence of stroke between treatments was small (3.18% with beta-blockers vs. 2.96% with other drugs) and was not adjusted for differences in blood pressure lowering between treatments. In a recent Cochrane review, beta-blockers reduced the risk of stroke compared with placebo or no treatment (four trials involving a total of 23,613 patients: 1.8% vs. 2.3% with placebo, RR 0.80, 95% CI 0.66 to 0.96).9 This represents one less stroke for every 200 patients treated with a beta-blocker for around 5 years.9 However, a beta-blocker was less likely than a calcium channel blocker to prevent stroke (three trials, a total of 44,167 patients: absolute difference 0.6%, RR 1.24, 95% CI 1.11 to 1.40) or an ACE inhibitor or angiotensin-II receptor antagonist (two trials, a total of 9,951 patients: absolute difference 1.5%, RR 1.30, 95% CI 1.11 to 1.53).9 For comparisons with diuretics, heterogeneity between trials prevented meta-analysis. This was possibly related to the type of beta-blocker used since there was a higher risk of stroke with the use of a non-selective beta-blocker (propranolol; RR 2.28, 95% CI 1.31 to 3.95) but no difference with cardioselective drugs (atenolol, metoprolol).9
Whether these differences in the incidence of stroke indicate a specific drug effect, as suggested by the authors of the ASCOT-BPLA study, is questionable.7,10 In that study, stroke (a secondary outcome) was less likely in patients treated with the amlodipine-based regimen than with the atenolol-based regimen (hazard ratio [HR] 0.77, 95% CI 0.66 to 0.89). However, subsequent analysis suggests that such a difference reflected the consistently lower blood pressure achieved in the amlodipine group11 and supports the view that the major effect on cardiovascular outcomes is achieved by blood pressure lowering rather than being dependent on the type of drug used.12,13
The risk of diabetes
A network meta-analysis* of 22 randomised trials (involving a total of 143,153 patients) that compared different blood pressure lowering therapies has assessed the risk of developing diabetes with such treatment.13 Compared with diuretics, angiotensin-II receptor antagonists were least likely to cause diabetes (odds ratio [OR] 0.57, 95% CI 0.46 to 0.72), followed by ACE inhibitors (OR 0.67, 95% CI 0.56 to 0.80) and calcium channel blockers (OR 0.75, 95% CI 0.62 to 0.90). There was no difference between diuretics and beta-blockers. However, these data have important limitations. In particular, very few long-term trials used incident diabetes as a prespecified endpoint, so efforts to detect diabetes varied between studies, as did the criteria and methods used for diagnosing diabetes.13
*A network meta-analysis is a statistical technique in which both direct and indirect comparisons are undertaken, even when two of the strategies have not been directly compared.
Disentangling the individual diabetogenic effects of beta-blockers and thiazide diuretics is not straightforward because in some large trials a combination of the two drugs classes was used from an early stage. Also, the extent to which the diabetogenic effects influence future vascular outcomes is not clear, since trials of antihypertensive therapies have generally lasted around 5 years and it is uncertain whether within this time the unwanted effect of antihypertensive therapies on blood glucose will have had time to affect cardiovascular outcomes. More recently, subgroup analysis from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) suggested that despite a slightly less favourable metabolic profile, there was no difference in cardiovascular outcomes between thiazide-based regimens and calcium channel blocker-based regimens in individuals with and without “metabolic syndrome”.14,15 Understanding of the relationship between glycaemic control and cardiovascular outcomes is further complicated by data from a randomised controlled trial that compared intensive-control of blood glucose (i.e. target HbA1c level below 6.0%) with standard control (i.e. target HbA1c level 7.0–7.5%) in 10,251 patients with type 2 diabetes: the incidence of all-cause mortality was higher in the intensive-treatment group.16
These points are important because it is possible that the cost-effectiveness analysis for beta-blockers may have been too heavily weighted against these drugs in its assumption that the diagnosis of diabetes automatically conferred a later risk of coronary heart disease equivalent to that with established coronary heart disease.
Why calcium channel blockers first line?
In contrast to its earlier guideline, NICE has recommended a calcium channel blocker or diuretic as preferred first-line treatment in patients aged over 55 years and black patients of any age.1,6 Its meta-analysis of trials indicated that calcium channel blockers were at least as effective as other hypertensive drugs in preventing cardiovascular outcomes.1 Key to the NICE recommendation was the economic analysis in the guideline.1 Scrutiny of the economic model shows diuretics as having the lowest cost but similar effectiveness to calcium channel blockers and, accordingly, a lower cost per quality adjusted life year (QALY) even than that for no intervention. However, NICE judged calcium channel blockers to be the “most cost-effective initial drug” on the basis of evidence of slightly greater efficacy and the fact that the greater cost associated with such therapy was considered affordable within NHS resources.1
Drug choice and age
Few studies have assessed the effect of blood pressure lowering therapies in younger patients and none of these has assessed the effect of such treatment on cardiovascular outcomes. However, the NICE guideline recommends use of an ACE inhibitor first line for patients aged under 55 years based on three small studies and an age-stratified analysis from a fourth study, which collectively suggest that these drugs reduce blood pressure more effectively in younger patients.1 However, we believe that such a recommendation may increase use of angiotensin-II receptor antagonists as an automatic choice in patients who have failed to tolerate an ACE inhibitor, without consideration of other effective but less expensive options. We are also concerned that such a recommendation may increase the inadvertent exposure of women who may be pregnant to ACE inhibitors or angiotensin-II receptor antagonists. Of note, a recently published meta-analysis of 31 randomised controlled trials (involving a total of 190,606 patients) shows no difference between age groups (i.e. less than 65 years or over 65 years) in the effects of blood-pressure lowering therapies.12 It might be argued that these age limits differ from those used in the NICE guideline and the difference in mean age between the older and younger patients included in the analysis was not large (around 15 years).12 However, even when the data was analysed with age used as a continuous variable, there was no evidence of an interaction between age and treatment effect.12 Therefore, it seems inappropriate to favour any one particular drug class.
Drug choice and ethnicity
ACE inhibitors appear to be less effective in reducing blood pressure among people of black African origin, an effect likely to be related to lower circulating renin concentrations in such individuals.1 Therefore, for black patients, NICE recommends that first-line therapy for all ages is a diuretic or a calcium channel blocker.1 This seems a reasonable and pragmatic application of the limited evidence (i.e. subgroups within larger trials).
COMPARISONS WITH OTHER GUIDELINES
National guidelines on elevated blood pressure published in Scotland, Europe and elsewhere differ from each other in their scope. For example, in New Zealand, national guidelines for blood pressure management form part of broader recommendations on cardiovascular risk management,18 while in Scotland, guidelines focus on the treatment of blood pressure in older people.19 Two guidelines (for Canada and Europe) have been published since the NICE update in 2006 and take account of trials considered in that update;20,21 updated USA guidelines are expected in early 2009.
The Canadian Hypertension Education Programme 2008 guideline on hypertension include initial therapy with a thiazide diuretic; a beta-blocker (in patients younger than 60 years); an ACE inhibitor (except in black people); a long-acting calcium channel blocker; or an angiotensin-II receptor antagonist.20 The recommendations indicate that add-on drugs should be chosen from this list of first-line drugs when target blood pressures are not achieved with standard dose monotherapy.
The European Society of Hypertension/European Society of Cardiology 2007 guideline emphasises that the main benefits of antihypertensive therapies are due to the lowering of blood pressure per se rather than any unique activity of the drugs used.21 Consequently, thiazide diuretics, beta-blockers, calcium channel blockers, ACE inhibitors and angiotensin-II receptor antagonists are considered suitable for the initiation and maintenance of treatment in all age groups, either as monotherapy or, more often, in some combinations with each other. However, the guideline acknowledges that each class has specific properties, advantages and limitations that will influence its role in patients with compelling indications such as renal disease, diabetes, heart failure or cerebrovascular disease.
For uncomplicated hypertension, the Joint National Committee on high blood pressure 7 (JNC-7) guideline recommends first-line therapy with a thiazide diuretic.22 However, the guideline states that for many people, a combination of drugs, including a thiazide is required. All other main drug classes (beta-blockers, ACE inhibitors, calcium channel blockers, angiotensin-II receptor antagonists) are recommended as alternatives, with specific recommendations for patients with compelling indications such as diabetes, renal disease or heart failure.
The American Heart Association, in its guideline on treatment for hypertension in the prevention and management of ischaemic heart disease (published in 2007), supports the use of an ACE inhibitor (or angiotensin-II receptor antagonist), calcium channel blocker or diuretic (but not a beta-blocker) as first-line therapy for primary prevention of coronary artery disease in patients with hypertension.23
New zealand 2003
The New Zealand Guidelines Group recommendations for the assessment and management of cardiovascular risk, which include guidance on blood pressure management, state that all medicines that lower blood pressure have similar efficacy and all have the potential for unwanted effects; the choice of treatment, therefore, is said to depend on the medical history and individual contraindications for particular medicines.18 However, the guideline also states that diuretics are an appropriate first-line option in most people at increased cardiovascular risk.
The Scottish Intercollegiate Guidelines Network (SIGN) guideline on hypertension in older people was published in 2001, with no review considered necessary following consultation in 2005.19 The guideline recommends the use of a low-dose thiazide diuretic as first-line therapy, with a beta-blocker as an alternative; calcium channel blockers and ACE inhibitors are also recommended as alternatives, particularly where there are compelling indications such as isolated systolic hypertension and diabetes, respectively. In its clinical guideline for the risk estimation and the prevention of cardiovascular disease (published in 2007), SIGN included a summary of the updated NICE guideline on treatment for blood pressure.24 However, the SIGN guideline recommends that consideration should be given to using two or more drugs, in half to standard doses.19
In its updated guideline for the treatment of patients with hypertension, the National Institute for Health and Clinical Excellence (NICE) recommends first-line use of a thiazide diuretic or calcium channel blocker in patients aged over 55 years, and an ACE inhibitor (or angiotensin-II receptor antagonist) for those aged under 55 years. Beta-blockers are no longer recommended as a first-line option. Evidence suggests that primary care prescribing in the UK has changed in line with this advice.
While all of the main classes of antihypertensive drugs prevent major cardiovascular outcomes, evidence suggests that beta-blockers (typically atenolol) are less likely to prevent stroke. It therefore seems reasonable to avoid using this class of drugs first line unless otherwise indicated. Whether beta-blockers also increase the likelihood of developing diabetes is less clear.
Evidence to support use of a particular drug depending on a patient’s age is not compelling and current NICE advice may increase use of angiotensin-II receptor antagonists in patients who do not tolerate an ACE inhibitor, without further consideration of the benefits of much less expensive options. In keeping with the current evidence, we believe that thiazide diuretics remain a good first-line option for many people. On current evidence, we can see no reason to routinely use a calcium channel blocker in preference to a thiazide diuretic, which is often less expensive. However, we also recognise that, in many patients, treatment with more than one drug will often be necessary.
[M=meta-analysis; R=randomised controlled trial]