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The management of hypertension in primary care: updated guidance from NICE
Volume 17 Number 1
September 2006

Part 3 — A review and critique of the updated NICE guideline for drug treatment of hypertension

Why was there a need to update the NICE guideline?
How were the updated guidelines developed?
How do the changes for drug treatment compare with the 2004 guideline?
Why may some of the changes be contentious?
References

Summary  This Bulletin provides an update on the management of hypertension in primary care following publication of MeReC Briefing No. 29 on this topic in April 2005 and issue of the updated NICE clinical guideline CG034 in June 2006. The Bulletin is in several parts, each of which can be downloaded separately as printer-friendly documents: Part 1 — a quick 2 page summary of the key points Part 2 — a more detailed overview of the management of hypertension, including sections on risk assessment, measurement of blood pressure, treatment thresholds and targets, lifestyle interventions, and drug treatment Part 3 — a more detailed review and critique of the recent update to the NICE guidelines regarding the drug treatment of hypertension. Please insert the link to Part 3 in the above wording

In June 2006, NICE issued an updated drug treatment section of their hypertension guideline.⁶ Previous recommendations from the 2004 guideline¹⁹ for other aspects remain unchanged.

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Why was there a need to update the NICE guideline?

Expert opinions vary as to which antihypertensive drug or combination of antihypertensive drugs is most appropriate for the treatment of hypertension. This is evident in the disparity between the previous BHS² and NICE guidelines,¹⁹ and international guidelines.^9,21,22

In 2004, NICE and the BHS issued separate clinical guidelines for the management of hypertension, with different algorithms for antihypertensive drug treatment.^2,19 Whereas the NICE guideline recommended low-dose thiazide diuretics as the first-line choice for most people with uncomplicated hypertension,¹⁹ BHS recommended initial treatment with an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-II receptor antagonist (AIIRA) or ß-blocker or, alternatively, a calcium-channel blocker (CCB) or thiazide diuretic, depending on age and ethnicity (the AB/CD algorithm).² Having two ‘national’ guidelines resulted in considerable confusion among prescribers and was a major obstacle to full implementation of the NICE guideline. MeReC Briefing No. 29 issued in April 2005⁶¹ recommended that the NICE guideline should be followed, as the BHS guideline algorithm was not supported by evidence from long-term studies measuring important clinical outcomes and it did not consider cost-effectiveness.

In September 2005, results of the BP lowering arm of the ASCOT study were published.²⁶ There was extensive media hype and misreporting of this study at the time, with suggestions that there should be a change in practice from the ‘older’ drugs to first-line use of the ‘newer’ (and more costly) antihypertensives. ASCOT was a large prospective open-label RCT, with blinded endpoint assessment. It compared first-line treatment with a β-blocker, atenolol 50–100mg, (adding a diuretic, bendroflumethiazide, second-line if BP targets were not met) with a CCB, amlodipine 5–10mg, (adding an ACEI, perindopril, second-line if necessary). There was no significant difference in the primary endpoint (non-fatal myocardial infarction [MI] [including silent MI] and fatal coronary heart disease [CHD]) with the ‘newer’ drugs compared with the ‘older’ drugs (hazard ratio [HR] 0·90, 95% CI 0·79 to 1·02, P=0·1052). However, the trial was stopped early by the data safety monitoring board (after a median of 5.5 years), when interim analysis showed significant disadvantages in mortality for patients on the atenolol-based regimen, and this may have reduced the power of the study to detect a difference in this primary endpoint. There were significant differences in secondary outcome measures in favour of the CCB-based regimen compared with the β-blocker-based regimen, e.g. fatal and non-fatal stroke (HR 0·77, 95%CI 0·66 to 0·89, P=0·0003), total cardiovascular (CV) events and procedures (HR 0·84, 95%CI 0·78 to 0·90, P<0·0001), and all-cause mortality (HR 0·89, 95%CI 0·81 to 0·99, P=0·025).²⁶

A MeReC Extra article in November 2005⁶² pointed out that the β-blocker regimen chosen for the ASCOT study (50–100mg daily before the addition of a thiazide diuretic, whereas the BNF recommends that doses higher than 25–50mg daily are rarely necessary) was an unusual one these days, and the results were consistent with the more rapid reduction in BP observed in the patients who received amlodipine rather than atenolol first-line.⁶³

Although ASCOT questioned the choice of β-blockers as a first-line choice for many hypertensive patients, it provided no evidence to suggest that diuretics were an inappropriate first-line treatment, as recommended by NICE at the time.¹⁹ Nevertheless, the additional data provided by ASCOT was considered by NICE to be of sufficient merit to require a rapid re-evaluation of the evidence for drug treatment and consideration as to whether or not their guideline needed changing. The review was welcomed, particularly as it would be carried out in collaboration with the BHS who would endorse the guidelines, and unlike the BHS guideline² would consider both clinical effectiveness and the impact on costs within the NHS.

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How were the updated guidelines developed?

The updated recommendations were developed by the NICE Guideline Development Group on the basis of a review of clinical and cost-effectiveness prepared by the National Collaborating Centre for Chronic Conditions.²⁰ The review focused specifically on the drug treatment of hypertension, and considered evidence from sufficiently powered RCTs published up until December 19th 2005. It excluded studies in specific patient groups that were unrepresentative of the general UK hypertensive population (e.g. children, people with diabetes), and where stroke, MI and mortality outcomes were not reported. It considered a wide range of outcomes, including mortality, stroke, MI, heart failure, new-onset diabetes, vascular procedures, unstable angina and study drug withdrawal. Four new studies were considered in the review, including ASCOT, and three studies previously reviewed were rejected because there was confounding use of either a β-blocker or a diuretic. As there was insufficient evidence to suggest any differences between drugs within a class, these were all considered as one entity. ACEIs and AIIRAs were also considered together for the same reason.²⁰

Each of the drug classes (based on the first drug used) were compared with each other, or no treatment, where possible, in a series of meta-analyses for each of the outcomes reported (except for vascular procedures, study drug withdrawal, and unstable angina). However, any apparent benefit of a specific drug class identified in the meta-analyses needs to be interpreted cautiously. In most cases, the meta-analysis only considered two or three trials (in some cases only one trial), thus results could be heavily influenced by results from a single trial. Secondary analyses considered data from subgroups of black patients, those with isolated systolic hypertension (ISH) and younger patients (less than 55 years). Study designs varied widely, and there were many confounding factors that were not allowed for, not least the choice of additional antihypertensive agents used to achieve BP control.²⁰

In addition to the evidence from RCTs, other factors were also considered in drawing up the recommendations. These included adverse event data, issues of patient concordance, and results of a health economic analysis comparing the cost-effectiveness of the main drug classes. The health economic analysis considered the effect of drugs to prevent CV events, i.e. non-fatal unstable angina, MI, heart failure, stroke, and CVD related deaths. The only adverse effects modelled were onset of diabetes and heart failure. In view of the difficulties in interpreting this evidence, consideration was also given to pathogenesis of hypertension and the mechanism of action of the different classes of drug used to lower BP, allowing for age and ethnicity. Where evidence was not definitive, recommendations took into account existing guidelines and expert opinion to formulate guidelines consistent with current good practice.²⁰

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How do the changes for drug treatment compare with the 2004 guideline?

The recommendations of the updated NICE guideline are summarised and compared to those of the 2004 guideline in Table 3. It should be noted that neither the 2006 nor the 2004 guidelines considered people with diabetes and do/did not apply to this group.

Clinical effectiveness

Meta-analyses of placebo-controlled trials (3 studies) identified that antihypertensive therapy significantly reduced the risk of MI (relative risk [RR] 0.75, 95%CI 0.62 to 0.91) or stroke (RR 0.64, 95%CI 0.52 to 0.78), although no significant effect on mortality was demonstrated (RR 0.88, 95%CI 0.77 to 1.01).²⁰

The meta-analyses of head-to-head RCTs of antihypertensives also found no significant differences between any of the classes of drugs with regard to mortality.²⁰ However, some statistically significant differences were found for other outcomes; these are summarised in Panel 5.

 
Interpreting the evidence on clinical effectiveness from these meta-analyses was difficult for a number of reasons. Suitable head-to-head studies were not identified with which to make comparisons for all of the drug classes (see footnote to Panel 5 ), and, where there were studies, they were few in number — in some cases there was just one. This meant that results could be heavily influenced by the results of a single large study, such as ALLHAT and ASCOT, and subject to the limitations associated with these. Furthermore, in most studies, additional drugs were given if the first-choice drug failed to control BP adequately. In ASCOT, for example, 78% were taking more than one antihypertensive at the end of the study.²⁶ Therefore, results could be heavily influenced by the choice of combination drugs used in an individual study.

In patients with CHD there are clear mortality benefits for the use of β-blockers, regardless of hypertension status.⁶⁴ However, in patients with hypertension, reductions in CHD risk with β-blockers appear not to be significantly different from placebo.⁶⁵ The NICE Guideline Development group considered that β-blockers were less effective than the comparator drugs at reducing major CV events, notably stroke.²⁰

Only a few studies have been carried out comparing non-atenolol β-blockers in hypertension, and results of these are inconclusive because of the lack of clinical events.⁶⁵ The lack of any evidence for a difference in clinical effect between atenolol and other β-blockers in the treatment of hypertension means that it is unclear whether the use of an alternative β-blocker to atenolol would result in benefit or harm to patients. NICE recommend that all β-blockers are an inappropriate option for routine initial treatment of hypertension, unless there are compelling indications for their use (e.g. ischaemic heart disease).²⁰

NICE considered that the evidence was sufficient to show that diuretics and CCBs were the first-line drugs most likely to confer benefits in CV outcomes, except possibly when used in younger patients (<55 years). Diuretics and CCBs were considered an equal option for first-line use. Based on limited evidence of their superior initial blood lowering effect, NICE considered that ACEIs were a more appropriate first-line choice than diuretics or CCBs in younger people (<55 years).²⁰

Because of the increased risk of developing diabetes, routine use of a β-blocker and a thiazide diuretic in combination was not recommended in the updated NICE guideline. Assuming a 20% baseline risk of developing diabetes over the next 10 years, it has been estimated that the use of a combination of a thiazide diuretic and a β-blocker may lead to an additional four cases of diabetes per 1000 patient-years of treatment compared with alternative antihypertensive treatments.⁶⁶ Although the development of diabetes in patients prescribed β-blockers and/or thiazide diuretics has not been shown to translate into an increased risk of mortality or major CV events, the recommendation to avoid their use in combination seems appropriate in view of other drug options. 

Although many patients will require more than one drug to achieve adequate BP control, there is little evidence to guide practice with regard to which drugs should be used in combination. The recommendation to add an ACEI to a diuretic or CCB (or vice versa in younger patients) based on pathophysiological grounds seems reasonable.

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Economic analysis

The economic model considered the healthcare costs (as measured from an NHS and personal social services perspective) associated with a range of treatment effects (as estimated from meta-analyses).²⁰ Treatment effects included non-fatal CVD events (unstable angina, MI, heart failure and stroke) and CVD-related deaths. Other CVD events such as stable angina, peripheral vascular disease and transient ischaemic attacks were not modelled because of inconsistent reporting between trials. Diabetes and heart failure were the only adverse events modelled. Health outcomes (beneficial and harmful) were summarised in the form of quality-adjusted life-years (QALYs), where one QALY represents one year of healthy life.²⁰

The base case chosen for the model was that of a man or woman aged 65 years, with a 2% CVD risk, a 1.1% diabetes risk, and a 1% heart failure risk per year.  Although β-blockers were more effective than no intervention, they were less effective than thiazide diuretics and more costly, and were, therefore, ruled out as being the most cost-effective option (see Figure 3 ). ACEIs were also ruled out as being the most cost-effective, although the absolute differences in the costs and effectiveness of ACEIs compared with CCBs were small. This is because treating some patients with thiazide diuretics and the remainder with CCBs would be less expensive and more effective than treating all patients with ACEIs.²⁰

Thiazide diuretics were identified as the only intervention that was less costly and more effective than no intervention (both men and women). CCBs were slightly more effective than thiazide diuretics but considerably more costly (see Figure 3 ). The incremental cost-effectiveness ratio for CCBs when compared with diuretics was £12,000 to £13,000 per QALY gained. As this was considered affordable by the NHS, i.e. below a threshold of £20,000 to £30,000 per QALY gained, CCBs were considered more cost-effective than thiazide diuretics for the base case.²⁰

The health economic analysis was sensitive to many factors, not least the uncertainties surrounding the estimates of differences in efficacy of the drugs derived from the meta-analyses discussed above. Extreme case scenarios are presented in the economic analysis whereby diuretics, ACEIs, and β-blockers are all the most cost-effective option if upper or lower 95% confidence limit values for the magnitude of the treatment effects are used. Sensitivity analysis also identified that if the cost of CCB increased from £70 (as used in the base case model) to £105 per year (£8 per 28 days) then CCBs would no longer be cost-effective compared with diuretics.²⁰

The difference demonstrated in the cost-effectiveness between diuretics, ACEIs and CCBs depended largely on their ability to prevent diabetes and heart failure. The model predictions were sensitive to changes in the patient risks for these adverse events. For people at low risk of heart failure, CCBs were predicted to be the most cost-effective, whereas for people at high risk of heart failure, diuretics were the most cost-effective, provided that they did not have a high risk of diabetes. For people who were at high risk of diabetes and heart failure, ACEIs were the most cost-effective.²⁰ Unfortunately, predicting the level of risk for diabetes or heart failure during a routine consultation and, therefore, which drug is most appropriate for a particular patient on cost-effectiveness grounds, is inexact and likely to be impractical.

Adverse-effect profiles of antihypertensive drugs differ considerably between drug classes. Unfortunately, no reliable estimates of the impact of adverse effects on the quality of life of patients prescribed different antihypertensives were identified. Diabetes and heart failure were the only adverse events considered in the model. Small differences in side-effect profiles of different drugs may change their relative cost-effectiveness.²⁰

It is not certain that the costs allocated in the model to the development of diabetes, would be realised in patients prescribed thiazide diuretics first-line. It is possible that the achievement of BP control may eliminate the expected increased risk from the development of diabetes should it occur.⁶⁷ The long-term follow-up of the SHEP study (14.3 years) suggests this is the case.⁶⁸ This study found that the use of chlortalidone was associated with a greater incidence of diabetes (fasting plasma glucose [FG]>7mmol/l) compared with placebo (13% vs. 9%, P<0.0001). However, those patients who developed diabetes on chlortalidone had no increase in CV outcomes and had a better prognosis than did those with pre-existing diabetes. The ALLHAT study, which dominated the meta-analysis comparing diuretics and CCBs, found that for those patients who were non-diabetic at baseline, the proportion of patients who developed a raised FG of >7mmol/l was 11.6% with chlortalidone and 9.8% with amlodipine at four years (P=0.04; number needed to harm [NNH] of 56). However, the raised FG did not appear to translate into any increase in CV events or mortality.²⁸

There may also be some uncertainty surrounding the costs associated with heart failure because of inconsistencies between studies of how it was defined — for this reason heart failure was not originally included in the NICE review prior to consultation. However, in the ALLHAT study, which provided most of the patients for the NICE meta-analyses, use of amlodipine was associated with a significantly greater 6-year rate of heart failure than chlortalidone for both total heart failures (10.2% vs. 7.7%, RR 1.38, 95%CI 1.25 to 1.52, P<0.001) and for heart failures that resulted in hospitalisation or death (8.4% vs. 6.5%, RR 1.35, 95%CI 1.21 to 1.50, P<0.001).²⁸

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Why may some of the changes be contentious?

The most contentious change from the previous NICE guideline relates to the use of CCBs, which were only considered a third-line option in the previous NICE guideline.¹⁹ They are now considered an equal alternative to thiazide diuretics as a first-line choice for patients who are black or aged 55 years or older. More recent trials with long-acting CCBs have largely allayed early fears over their use (see Part 2), and the economic analysis identified them as the most cost-effective option. However, because of the limitations of the economic analysis discussed above, it is uncertain whether the long-term cost benefits suggested (and in particular those related to the development of diabetes) would be realised and compensate for the increased drug acquisition cost. In view of their equal status in the guideline, prescribers may choose thiazide diuretics preferentially because of their lower acquisition cost unless there are good reasons to do otherwise.

The updated NICE recommendation that β-blockers are an inappropriate choice for first-line treatment of hypertension is less contentious, in view of the alternatives available, and is supported by other studies. A meta-analysis of 13 RCTs identified an increased risk of stroke with β-blockers compared with other drugs (RR 1.16, 95%CI 1.04 to 1.30), but no increased risk of MI or all-cause mortality.⁶⁵ Another review of five RCTs (n=17,671) found that atenolol was associated with a significant increase in the risk of all-cause mortality (RR 1.13, 95%CI 1.02 to 1.25) and stroke (RR 1.30, 95% CI 1.12 to 1.50) compared with other antihypertensive drugs.⁶⁹ However, these meta-analyses did not consider age-specific effects. A more recent age-specific meta-analysis demonstrated that β-blockers, when compared with other antihypertensives, significantly increased the risk of death, stroke or MI in trials of older patients (mean ages 60 to 76) (RR 1.06, 95%CI 1.01 to 1.10)⁷⁰, but there was no significant difference in trials that included younger patients (RR 0.97, 95%CI 0.88 to 1.07). The authors of this review considered β-blockers a suitable option for treating hypertension in younger people.

β-blockers are recommended by NICE as an appropriate first-line choice in patients where ACEIs/AIIRAs are contraindicated. However, the choice of ACEIs for patients under the age of 55 ahead of other drugs, including β-blockers and diuretics, is not supported by good clinical evidence, but by BP-lowering effects and pathophysiological mechanisms. More research in younger patients is clearly needed.⁷¹

There is also little clinical evidence to support NICE recommendations for the drugs to prescribe should the first-choice drug prove insufficient. These follow the A(B)/CD approach previously adopted in the BHS guidelines. Although this approach is based on sound pathophysiological grounds, it has yet to be validated in large outcome trials. Recommendations for drug treatment should BP fail to be controlled by a combination of three drugs (i.e. ACEI, CCB, and diuretic) are also not based on any hard evidence from clinical studies, but are based on a consensus opinion of the Guideline Development Group.

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