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At the heart of general practice since 1960

Contraceptive methods most frequently prescribed by GPs

new series

in the spotlight

The ASCOT results published last month plunged hypertension management into turmoil. NICE

pre-empted publication by announcing days before that it would be revising its guidance, but the process will take months. Joint ASCOT study leader Professor Peter Sever advises what GPs should do in the interim, while on page 49 Professor Gareth Beevers answers a GP's questions on hypertension

Statistics on the number of patients whose hypertension is controlled in the UK are disappointing. Less than 10 per cent are controlled to today's targets of <140mmhg systolic="" and=""><85mmhg diastolic="" and="" so="" there="" is="" a="" real="" urgency="" for="" nice="" and="" the="" british="" hypertension="" society="" (see="" timeline,="" page="">

Faced with present contrasting and conflicting recommendations, the failure to adopt guidelines and achieve target blood pressures will inevitably continue and contribute to high residual and unnecessary cardiovascular morbidity and mortality in patients with hypertension.

A short history of ASCOT

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was designed about 10 years ago to establish whether newer antihypertensive drugs – the calcium channel blockers (CCBs) and the angiotensin converting enzyme inhibitors (ACEIs) – in combination would confer advantages over older drugs (the ß-blockers and the thiazide diuretics) in preventing coronary heart disease and stroke events.

In addition, the opportunity was taken, by way of a factorial-designed trial, to see whether lipid lowering with a statin compared with placebo in hypertensives with normal or moderately elevated cholesterol levels (<6.5mmol )="" would="" confer="" additional="" benefits="" to="" blood="" pressure="" lowering.="">

In brief, in the blood pressure lowering arm of the trial, which was stopped prematurely owing to an excess of cardiovascular and all-cause mortality in the

ß-blocker/thiazide group, there were highly significant benefits on most cardiovascular endpoints of the amlodipine/ perindopril arm compared with the atenolol/thiazide arm.

Although the primary endpoint of non-

fatal myocardial infarction and fatal CHD was reduced by 10 per cent in the amlodipine/perindopril arm, this did not achieve statistical significance.

Most other coronary endpoints, however, were significantly reduced.

The failure to achieve a significant reduction in the primary endpoint is best explained by the combination of early stopping of the trial, the increasing use of statins in trial patients following the disclosure of the substantial benefits of atorvastatin to hypertensive patients after the report of the lipid-lowering arm of ASCOT, which closed early in 2003, and finally the increasing management of acute coronary syndromes with angioplasty/stents and CABG procedures, which reduced the number of myocardial infarcts and hence the number of primary endpoints in the trial.

To the cardiovascular benefits associated with the ‘newer' blood pressure treatment strategy we must add the highly significant reduction in the incidence of new-onset diabetes (30 per cent) in those assigned amlodipine/perindopril compared with the

ß-blocker/diuretic combination.

Key messages

First and most importantly, good control of blood pressure is paramount. In ASCOT, irrespective of the BP treatment arm to which patients were assigned, there were major benefits of blood pressure reduction.

At baseline prior to randomisation, in the trial, patients – most of whom were already on antihypertensive treatment (about 80 per cent) – were poorly controlled with average blood pressure 164/95mmHg.

Entry into the trial, followed by the application of strict algorithms involving dose titration of antihypertensive drugs and the use of add-on drugs to achieve the trial BP goals, was associated with a rapid reduction in cardiovascular event rates by more than a third (resulting from better blood pressure control). The key message is that the benefits of good blood pressure control will be greater than benefits of any particular antihypertensive regimen, particularly when blood pressure is poorly controlled.

Were ASCOT patients representative of hypertensives seen in everyday clinical practice? In a word – Yes. ASCOT was a primary prevention trial, ie all patients with prior myocardial infarction or current CHD were excluded. Entry criteria to the trial required the presence of three additional cardiovascular risk factors, but these included, for example, male sex, age >55 and history of smoking.

The annual CHD event rate in the trial of <1 per="" cent="" per="" annum="" characterises="" ascot="" patients="" as="" one="" of="" the="" lowest-risk="" cohorts="" compared="" with="" those="" recruited="" into="" other="">

recently reported trials in hypertension,

for example VALUE, ALLHAT, INSIGHT etc.

We therefore feel confident the ASCOT results can be appropriately applied to most patients seen in everyday practice. They were certainly not at high cardiovascular risk as implied by a recent commentary in The Lancet.

Implications for practice

Changing patients already on ß-blockers

If patients are currently well-controlled (<140 0mmhg)="" on="" any="" drug="" regimen,="" including="" use="" of="" ß-blockers="" with="" or="" without="" diuretics,="" and="" the="" drugs="" are="" well-tolerated,="" it="" is="" better,="" in="" my="" view,="" to="" continue="" present="" treatment,="" rather="" than="" run="" the="" risk="" of="" changing="" medication="" and="" losing="" control="" of="">

In patients currently receiving

ß-blockers and thiazides who are not adequately controlled (and that will be the majority!) a calcium channel blocker such as amlodipine or an ACE inhibitor, for example perindopril, should be added to existing treatment.

The BHS recommendation for an ‘A' drug (ACE inhibitor or ARB) in those aged <55 or="" a="" ‘c'="" drug="" (a="" calcium="" channel="" blocker)="" in="" those="" aged="">55 can be followed with the addition of the alternative drug, ie ‘C' or ‘A' respectively if required to reach goal.

With good BP control on the newer regimen, consideration may be given to the gradual withdrawal of the ß-blocker (halve the dose for one week and then stop) but

only in patients with no history of prior

myocardial infarction, current coronary heart disease, or history of cardiac failure where there remains substantial evidence for benefit of ß-blockers.

The untreated patient

For the untreated patient, for whom a decision needs to be made on first-choice drug, the application of the BHS A(B)C D seems appropriate, with the proviso that ß-blockers should only be used in the patients with established coronary heart disease.

The decision on first-line drug is dictated by age, eg <55 years="" on="" ‘a'="" drug="" and="">55 on ‘C or D' drug. Dose-up titration and add-on therapy should be followed according to the BHS guidelines – A + C or D or C or D + A.

Ethnic minority groups

Subgroup analysis of patients recruited in ASCOT confirms that the advantages of the new BP treatment strategy apply to all major subgroups, although too few patients from ethnic minority groups were enrolled to enable firm statements to be made regarding choice of optimal drugs in these patients.

The relatively poor BP responses to ACE inhibitors (and ß-blockers) in patients of African origin should persuade physicians to avoid these classes of drugs as first-line agents, and the high propensity to insulin resistance, the metabolic syndrome and diabetes in those of Asian origin should direct physicians to the A + C or C + A regimen in such patients.

Do antenolol results apply across the class?

To what extent the disadvantages of the ß-blocker-based regimen reported from ASCOT were due to atenolol, rather than the class of ß-blocker drugs, is of course unknown.

Subsequent analyses reported in the second Lancet paper suggest that on-treatment changes in the lipid profile, notably reduction in HDL cholesterol, presumably resulting from atenolol, could have contributed to the observed differences in CHD outcomes.

Such adverse metabolic effects on lipids are common to most ß-blockers, and only some of the most recent ß-blockers (on which there are no morbidity and mortality data), seem to exert less of an effect on lipid profile.

Until outcome data is available on these newer agents, recommendations based on ASCOT probably should apply to the class rather than the individual drug.

Add a statin?

The result of the lipid-lowering arm of

ASCOT, together with recent meta-analyses of lipid-lowering trials, provide an overwhelming evidence base for the benefits of statins in hypertensive patients.

Irrespective of baseline cholesterol levels, a relative risk reduction of about one-third of CHD events and in excess of one-quarter of stroke events will result from the addition of a statin to blood pressure-lowering therapy.

Peter Sever is professor of clinical pharmacology and therapeutics at Imperial College London, and honorary consultant physician at St Mary's Hospital, London

Timeline

Are the days numbered for use of B-blockers in hypertension?
2004
December - Bllod pressure arm of ASCOT trial stopped a year early after finding an ACE inhibitor plus calcium channel blocker had 'substantial benefits' over a B-blocker and diuretic
December - Life trial of more than 9,000 patients found risk of dying from stroke was 35% lower with ARB than a B-blocker
2005
March - More results from the ASCOT trial are unveiled at the American College of Cardiology meeting in Orlando showing that an ACE inhibitor and calcium channel blocker could cut all-cause mortality by 15% compared with a diuretic and B-blocker; NICE and BHS announce they are to hold a high level meeting to issue new guidance when results are published.
September
Formal release of ASCOT data prompts NICE to announce it will review its guidance in the light of the data.

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