CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 2, March/April 2010
120
AFRICA
Combination therapy in hypertension: new recommendations
The recent publication of the American
Hypertension Society (ASH) position
paper on combination therapy in the treat-
ment of hypertension is essential reading
for all physicians and for South African
medical aid funders.
1
As all agree that the goal of antihy-
pertensive therapy is to reduce the risk of
vascular events, it is essential that effec-
tive and easy-to-use antihypertensives
with outcomes data be used early in ther-
apy. Available data from clinical trials and
meta-analyses have shown that at least
75% of patients will require combination
therapy to achieve contemporary targets.
The increasing prevalence of obesity, the
metabolic syndrome and type 2 diabetes
is likely to increase this percentage even
higher, the position paper notes.
When choosing combination therapy,
the position paper points to the physi-
cian making a deliberate choice as to
which combination for which patient.
The physician needs to consider efficacy,
tolerability and adherence aspects when
prescribing combination therapy.
In efficacy terms, rational combina-
tion therapy is based on evidence that the
combination lowers blood pressure more
significantly than its individual compo-
nents.The blood pressure reduction should
be smooth and continuous, meeting phar-
macokinetic criteria for once-a-day usage.
Dose-dependent effects of the combina-
tion should be less than those induced by
higher dosage of the monotherapy.
Funders need to take note that
co-payment by the medical aid member
will reduce compliance and reduce the
protective effect of the antihypertensive
medication on future vascular events.
TheASH position paper identifies two-
drug combinations that meet the three
criteria outlined above (a single pill with
three or more drugs were not reviewed)
and these are regarded as preferred combi-
nations. Others that have less evidence to
support efficacy, safety or tolerance are
also identified.
RAAS inhibitor and diuretic
This combination is classified as preferred,
whether an ACE inhibitor or an angio-
tensin receptor blocker (ARB), is used
with a low-dose diuretic. Most combi-
nations contain hydrochlorothiazide,
but chlorthalidone is also identified as
the most-used diuretics in US outcomes
trials, although combinations with this
diuretic are not currently available.
RAAS inhibitor and calcium channel
blocker
The combination of an ACE inhibitor
or ARB with a calcium channel blocker
(CCB) results in fully additive blood
pressure reduction and improves toler-
ability. The ACCOMPLISH trial
2
(Avoiding Cardiovascular events through
COMbination therapy in patients living
with Systolic Hypertension) showed bene-
ficial cardiovascular outcomes of thisACE
inhibitor/CCB combination compared
with the ACE inhibitor/diuretic. Most of
the patients in this trial were diabetic, with
evidence of underlying ischaemic disease.
The position paper considers ARB/CCB
combinations equivalent to ACE inhibi-
tor/CCB combinations.
Renin inhibitor and ARBs
This combination, although without
outcome data, has achieved partially addi-
tive blood pressure reduction and is well
tolerated. In a study of maximumapproved
doses of valsartan and aliskiren,
3
a 30%
additional blood pressure response was
seen compared to monotherapy. The side-
effect profile matched that of placebo.
CCB and diuretics
This combination also results in partially
additive blood pressure reduction and
performed well in outcome studies.
4
It is
classified in the position paper as accept-
able, perhaps because it does not meet
the criteria of reduced side-effect profile
of the combination compared to the indi-
vidual drugs.
β
-blockers and diuretics
The position paper notes that there is
evidence, mainly with the first-generation
β
-blocker, atenolol, that
β
-blockers are
less effective than diuretics, ACE inhibi-
tors, ARBs and CCBs.
β
-blockers attenu-
ate the RAAS activation that accompa-
nies the use of thiazide diuretics, and
their combination results in fully additive
blood pressure reduction.
Addition of the diuretic improves the
efficacy of
β
-blockers in black patients
and others with low-renin hypertension.
5
These combinations are classed as accept-
able with known side effects, such as
increased risk of glucose intolerance,
fatigue and sexual dysfunction.
Thiazide diuretics and potassium-
sparing diuretics
The use of spironolactone/HCTZ in obese
patients is especially noted, as is the fact
that the combination should be used only
in people with relatively well-preserved
kidney function (eGFR
>
50 ml/min).
CCBs and
β
-blockers
The pharmacological effects of these
two drug classes are complementary and
result in additive blood-pressure reduc-
tion. The combination should be with a
dihydropyridine CCB and not a non-dihy-
dropyridine CCB such as verapamil or
diltiazen because of their additive effects
on heart rate and A–V conduction.
This position paper places ACE inhibi-
tors and ARBs, RAAS inhibitors and
β
-blockers, and the combination of
β
-blockers and centrally acting agents
in the category of lower efficacy. It
concludes that early use of a combination
reduces counter-regulatory responses of
monotherapy and brings blood pressure to
target in a shorter period of time.
J Aalbers, Special Assignments Editor
Gradman AH, Basile JN, Carter BL, Bakris
1.
GL, on behalf of the American Society of
Hypertension writing group.
JAm Soc Hypertens
2010;
4
(1): 42–50
Jamerson K, Weber MA, Bakris GL Dahlof
2.
B, Pitt B, Shi V,
et al
; for the ACCOMPLISH
trial investigators.
N Engl J Med
2008;
359
:
2417–2428.
Oparil S, Yarrows SA, Patel S,
3.
et al
.
Lancet
2007;
370
: 221–229.
Julius S, Kjeldsen SE, Weber M, Brunner HR,
4.
Ekman S, Hansson L,
et al
; for the VALUE trial
group.
Lancet
2004;
363
: 2022–2031.
Gradman AH. Drug combinations. In: Isso Jl
5.
(jun), Black HR, Sica DA, eds.
Hypertension
Primer
. 4th edn. Philadelphia PA: Lippincott,
Williams and Wilkins, 2008.
Take-home message
Use combination therapy routinely to achieve
•
•
blood pressure targets
Use only preferred or acceptable two-drug
•
•
combinations
Initiate combination therapy routinely in
•
•
patients who require
≥
20/10 mmHg blood
pressure reduction to achieve target blood
pressure
Initiate combination therapy in stage 1
•
•
patients (at the physician’s discretion), espe-
cially when the second agent will improve the
side-effect profile of initial therapy
Use combinations rather than separate indi-
•
•
vidual agents in circumstances where conven-
ience outweighs other considerations.
