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VOLUME 9 NUMBER 2 • JUNE 2012
REPORT
SA JOURNAL OF DIABETES & VASCULAR DISEASE
Optimal combination therapy in hypertension
Prof Neil Poulter
T
hroughout the world, hypertension is the
single biggest contributor to death – killing
via cardiovascular disease. It’s therefore
imperative to treat it, and to get that treatment
right. Professor Neil Poulter, professor of Preventive
Cardiovascular Medicine, Imperial College London,
UK, expressed this view during his recent visit to South
Africa as a guest of Servier Laboratories.
In 2000, there were approximately one billion
hypertensives worldwide and it is projected that the
number will rise to 1.56 billion by 2025. ‘The problem
will continue to get worse’, said Prof Poulter. ‘As
populations develop, people age, adopt unhealthy
dietary habits, exercise less and drink more, which
lead to increased weight and predispose to high blood pressure.
Controlling blood pressure with medication is one of the most cost-
effective ways of reducing the premature, and largely preventable,
cardiovascular morbidity and mortality that results from this.’
There are more data on hypertension than in any other area
of medicine, according to Prof Poulter, and yet the various
guidelines on the subject are not in agreement. ‘Monotherapy
is usually inadequate, but whether you start with two drugs or
move from monotherapy to combination therapy, what should
you use? The 2007 ESH/ESC guidelines recommend starting with
thiazide diuretics, even though the data do not support their use.
The recommendation should be simply for diuretics.’ The 2009
guidelines streamlined matters by recommending one of the
following:
angiotensin converting enzyme inhibitor (ACEI) plus diuretic
•
angiotensin receptor blocker (ARB) plus diuretic
•
calcium channel blocker (CCB) plus diuretic
•
ACEI plus CCB
•
ARB plus CCB.
•
The first two and the last two are known colloquially in the UK as
‘A+D’ and ‘A+C’ strategies.
Reviewing the various A+D trials (LIFE, VALUE, PROGRESS, HYVET
and ADVANCE), Prof Poulter noted that more than one trial had
shown a benefit for this type of combination with regard to stroke
and coronary risk reduction. Both HYVET and ADVANCE trials also
showed benefits in respect of all-cause mortality, something not
often improved in hypertension trials.
Turning to A+C studies, and the ASCOT trial in particular,
Prof Poulter observed that the combination of amlodipine and
perindopril had shown superiority over a beta-blocker–thiazide
diuretic combination in terms of all-cause mortality. The trial was
therefore stopped early. ‘ACE inhibitors appear to have benefits
beyond blood pressure when it comes to coronary protection, and
CCBs appear to have benefits beyond blood pressure in relation to
stroke prevention. So the combination of an ACE inhibitor and a
CCB, as in ASCOT, might be expected to generate extra benefits
in both. Every cardiovascular risk factor apart from heart rate
was positively impacted on, and statistically highly
significantly so by amlodipine–perindopril.’
The latest novel finding to emerge from the ASCOT
trial was the role of blood pressure variability in
predicting patients’ stroke and coronary heart disease
(CHD) outcomes. ‘Does it matter more than average
blood pressure? Yes. How much blood pressure varied
was the most important factor. Nothing predicted
both stroke and CHD risk better than long-term blood
pressure variability, i.e. over several years’, said Prof
Poulter.
The discovery may well lead to what he describes
as a ‘sea change’ in how blood pressure should
be perceived. ‘We now know that intermittent
hypertension is more dangerous than constant hypertension, and
this has significant implications for how blood pressure should
be monitored, measured and treated. Mean blood pressure has a
minimal association with stroke and CHD outcomes, while visit-
to-visit variability is a powerful predictor of both.’ Perindopril-
amlodipine was shown to be superior to a beta-blocker-thiazide
diuretic in controlling blood pressure variability.
More recently, the ACCOMPLISH trial evaluated a single-pill
ACEI–CCB combination versus ACEI–low-dose thiazide. The primary
endpoint, a composite of cardiovascular events and cardiovascular
death, favoured the A+C combination. Yet the ACEI–thiazide
combination is probably the most commonly used combination of
antihypertensive worldwide.
In the context of the ASCOT and ACCOMPLISH trials, the NICE
2011 guidelines now recommend the following. As a first step, in
patients under 55 years, start with an A. In patients over 55 years
and/or of African/Caribbean descent, start with a C. The second
step is to combine them. Because this combination is believed to
be the best, it is now central to the guidelines, which no longer
advocate the use of thiazide diuretics.
Summarising the evidence for diuretics in hypertension trials, Prof
Poulter said that the diuretic of choice is not a thiazide. ‘There is no
evidence of benefit from low-dose thiazides and they were shown
to be inferior to other options in both ASCOT and ACCOMPLISH
trials. There is, however, some good evidence for higher-dose non-
thiazide diuretics such as chlorthalidone and indapamide.’
Turning his attention to what not to combine, he cited the
findings of the ONTARGET trial in which an ACEI-ARB combination
was shown to have no benefits in respect of cardiovascular events.
His feeling was that there was a disconnect between the benefits of
preventing proteinuria versus cardiovascular events.
Having established the superiority of A+C in general, and
perindopril-amlodipine specifically, Prof Poulter concluded that
despite unaccountable resistance to fixed-dose combination pills
in the UK, this was the way to go. ‘Compliance has been shown
to be 21% better with fixed-dose combinations, which makes
a single pill a no-brainer. If it can be done at no extra cost,
why not?’
PETER WAGENAAR
S Afr J Diabetes Vasc Dis
2012;
9
: 70