Download Combination therapy for HYPERTENSION

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Combination therapy for
HYPERTENSION
Mandi Schultz, BSc(Micro), BPharm
Abstract
Current blood pressure treatment guidelines call for a single drug to be tried first in people with Stage 1
hypertension, i.e. those with a systolic reading over 140 mmHg and a diastolic reading over 90 mmHg (but with
readings of less than 160 mmHg systolic and 100 mmHG diastolic). However, because of the pathophysiological
complexity underlying hypertension, many patients obtain better control of their blood pressure with a combination
of antihypertensives than with monotherapy. Various studies show that low-dose drug combination in the treatment
of hypertension allows for a greater reduction in blood pressure, often with fewer side effects, as well as providing
reduced cardiovascular morbidity and mortality.
pressure at the usual does it is unlikely to be more
successful at higher doses thereafter.
Introduction
Hypertension is a common and significant cardiovascular
risk factor, with the majority of hypertensive patients over the
age of 65 dying from a cardiovascular event such as a
myocardial infarct or stroke. It has been established that an
aggressive blood pressure lowering strategy achieving a
target of below 140 mmHg systolic and 90 mmHg diastolic,
results in the prevention of hypertension-induced stroke and
a significant reduction in hypertension-attributable ischaemic
heart disease. Reaching and maintaining these targets in the
majority of patients does however often present a clinical
challenge.
Currently, several drug classes can be utilised in the treatment of hypertension, namely thiazide diuretics, betablockers, calcium channel blockers (CCBs), angiotensinconverting enzyme (ACE) inhibitors, angiotensin II receptor
blockers (or ARBs), alpha blockers and centrally acting
agents. There are three important classes of antihypertensives for the management of patients without compelling
indications for a particular antihypertensive i.e. diuretics,
ACE-inhibitors and calcium channel blockers. Practice has
been to begin treatment with one of these agents as monotherapy at a low dose, depending on patient co-morbidities
and concurrent medication use. If this does not control blood
pressure adequately then the physician is usually faced with
three options, namely:
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Upward drug dose titration – in this case the patient
continues on the current monotherapy but the daily
dosage is increased. In most cases increasing the dose
leads to only a modest increase in blood pressure
response and often an increase in the incidence and/or
severity of side effects. If a drug fails to lower blood
•
A trial of sequential monotherapy until an effective agent
is found. Unfortunately, there is no simple and reliable
method to predict which agent will work for an individual
patient. This method usually requires a lengthy titration
period with a loss of patient confidence in the prescribing
physician. In many patients the ideal monotherapy may
never be found.
•
Combination therapy – the third option is to use more
than one drug either as multiple individual drugs or a
single-pill combination therapy.
In the past, the latter was not favoured and was labelled as
‘polypharmacy’. Rational drug combinations in single-pill
formulations have however been widely used in the treatment of other conditions such as Parkinson’s disease or
bacterial infection. The use of multiple drug classes has also
been widely accepted in the management of other chronic
conditions such as angina, which resulted in a renewed
interest in the use of low-dose combination therapy and
increased recognition that this approach offers efficacy and
tolerability with simplicity. Today, the most recent guidelines
on hypertension treatment acknowledge that most people
will require more than one drug to control blood pressure. In
fact, a common reason given for poor control of blood
pressure today is that many doctors still use monotherapy in
patients obviously in need of a combination therapy to
normalise their blood pressure.
Treatment guidelines worldwide have, for a long time, recommended using a thiazide diuretic alone as the initial drug
SA Pharmaceutical Journal – September 2009
REVIEW
therapy for high blood pressure, particularly in the elderly. It is
however common knowledge that thiazide diuretics deplete
potassium, which led researchers to investigate a suspected
link between potassium wastage and sudden cardiac death.
Studies showed a 40% reduction in total cardiac mortality
and in sudden cardiac death in elderly patients with hypertension taking a combination of thiazide diuretic and a
potassium-sparing drug compared with those receiving a
placebo. In South Africa, low dose thiazide diuretics alone
are however still regarded as the first line of treatment for
uncomplicated hypertension in many patients.
ARB and calcium channel blockers
CCBs and ARBs interact synergistically. The CCB and the
ARB target two key effector pathways and as such provide
two different and complementary ways to reduce blood
pressure. Side effects, such as peripheral oedema experienced in CCB monotherapy, are significantly reduced with
combination therapy.
Blood pressure lowering combinations
Note: The combination of thiazide diuretics and calcium
channel blockers is controversial and usually less effective.
Black patients respond best to a diuretic combined with other
antihypertensive agents as the majority have low plasma
renin activities.
Thiazide diurectics and beta-blockers
The combination of a thiazide diuretic with a beta-blocker
should be discouraged especially where there is abdominal
obesity combined with hypertension, as both classes of
drugs have adverse metabolic consequences and increase
the risk of new diabetes. Furthermore, contrary to expectations, beta-blockers do not reduce cardiovascular mortality or
myocardial infarct mortality when given for hypertension.
Beta- with alpha-blockade
These include beta-blockers with alpha-blocking effects e.g.
carvedilol and labetalol.
In contrast to calcium channel blockers, beta-blockers
appear to offer little advantage on blood pressure when
combined with ACE inhibitors.
Potential advantages of combination therapy
Thiazide diuretics and ACE inhibitors/AII blockers (ARBs)
A powerful combination with efficacy at low doses. Efficacy
was demonstrated by Chysant in a large double-blind
placebo-controlled multicentre study, which showed that a
combination of 12.5 mg hydrochlorothiazide plus 10 mg
lisinopril gave a powerful antihypertensive effect whilst
having a low incidence of side effects. ACE inhibitors also
reduce the incidence of hypokalaemia in patients taking
thiazides. Combining ARBs with thiazides relies on the
same principles with the additional benefit of avoiding the
usual ACE inhibitor side effects such as cough and angioedema. Compared with ACE-inhibitors, ARBs provide
more effective blockade of the renin-angiotensin system.
•
•
•
•
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Calcium channel blockers and ACE inhibitors
Calcium channel blockers are potent vasodilators and
potentiate the action of ACE inhibitors resulting in a greater
reduction in blood pressure while reporting fewer side effects
than each individual treatment.
•
There may be enhancement of each drug’s antihypertensive effect, which may be synergistic, rather than simply
additive e.g. ACE inhibitors/ARBs and calcium channel
blockers.
Since the single-pill combination exerts its action through
different modes of action, there is potential for a smoother
onset and longer duration of action.
By keeping both drugs at low dose the incidence of side
effects from each is minimised.
In some cases the combination of the two drugs can offset
each other’s side effect profile to some degree e.g. the
hypokalaemia caused by thiazide diuretics can be
prevented by concurrent use of an ACE inhibitor.
Different mechanisms may exert different beneficial
effects beyond just the benefits of blood pressure
reduction e.g. trials have shown certain combination
therapies reduce renal damage and cardiac hypertrophy
more than monotherapy.
Combination therapies, particularly low dose therapies
Figure 1: Choosing drug combinations for newly diagnosed patients
Step 1
Younger than 55 years
55 years or older or black patients of any age
A (or B)*
C or D
Step 2
A (or B)* + C or D
Step 3
A (or B)* + C + D
Step 4
A + B+ C + D
OR
add an alpha blocker or low dose spirinolactone
* See page 28
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SA Pharmaceutical Journal – September 2009
REVIEW
•
can usually be taken once daily with improvement in
patient compliance.
Dose adjustments and titration is simpler with targets
more attainable resulting in fewer visits to the physician
and better therapy at a primary care level leading to an
overall reduction in the cost of treatment.
Choosing an effective combination therapy
The British Hypertension Society recommends the use of a
treatment algorithm to determine the logical use of combination therapy (Figure 1). The theory underpinning the use of
the algorithm is that hypertension can broadly be classified
as ‘high renin’ or ‘low renin’ and is therefore best treated
initially with one of two categories of antihypertensive drug –
those that inhibit the renin-angiotensin system, namely ACEinhibitors (A) and beta-blockers (B) and those that do not,
namely calcium channel blockers (C) and diuretics (D).
• People who are younger than 55 and white tend to
have higher renin concentrations than people aged 55 or
older or the black population. A or B drugs are therefore
generally more effective as initial blood pressure lowering treatment in younger white patients than C or D drugs.
However C or D drugs are more effective first line agents
for older white patients or black people of any age. If two
drugs are required, logical combinations are (A or B) + (C
or D) drugs. Thereafter if blood pressure is still insufficiently controlled, the combination of (A or B) + C + D is
recommended. When hypertension remains resistant the
addition of an alpha-blocker or low dose spironolactone
may be effective.
* The algorithm shows B in brackets because of the fact that
beta-blockers are no longer considered routine since they do
not reduce cardiovascular mortality or myocardial infarct
mortality when given for hypertension. In addition the use of
a combination of thiazide diuretics and beta-blockers is now
discouraged in cases where patients have abdominal
obesity because of the risk of developing type 2 diabetes.
When fixed dose combinations replicate the desired treatment plan and there is no cost disadvantage to their use,
they represent a sensible way of reducing the number of
tablets required.
Evidence based combination therapy
Randomised controlled trials performed over the last 30
years have shown that many patients will require more than
one drug to reach the recommended level of blood pressure
control. A judicious approach to prescribing would therefore
suggest the use of low-dose combination products early in
the treatment plan.
A number of studies have shown that drug combinations can
significantly reduce blood pressure despite the fact that
many patients had been unable to achieve good blood
pressure control with monotherapy before entering the
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various trials. One such study called ACCOMPLISH which
stands for ‘Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension’
demonstrated that just six months of treatment with a drug
combination was enough to bring the blood pressure of 73%
of patients into an acceptable range. When compared with
the fact that current blood pressure control rates are only
30% in the United States, this reduction represents exceptional control. In addition a 20% relative reduction in heart
related events in patients taking a RAAS inhibitor/amlodipine combination versus patients taking a RAAS inhibitor/
thiazide combination were found which challenges the
current treatment guidelines recommending combination
with diuretics as the first choice.
Another study called STITCH (Simplified Treatment Intervention to Control Hypertension) involved just over 2000
patients with high blood pressure and suggests that the
majority of recently diagnosed patients might better be
served starting with a half tablet of a single pill combination
drug (e.g. an ACE inhibitor/diuretic or ARB/diuretic combination) than the regular starting dose of a single drug.
Studies have also shown the effects of combination hypertension therapy in patients with type 2 diabetes, such as the
CALM (Candesartan and Lisinopril in Microalbuminuria)
study which showed that each individual drug was effective
in reducing microalbuminuria but combined treatment was
even better, achieving a 50% reduction in albumin:creatine
ratio compared with 24% for candesartan alone and 39% for
lisinopril alone.
Conclusion
The majority of patients will require more than one drug to
control their hypertension. The use of low-dose combination
therapy is justifiable as a safe and effective approach to
initiating therapy. It allows maximisation of each constituent
drug’s mode of action while minimising or even offsetting
side effects. Blood pressure may be controlled more easily
and with fewer consultations and a shorter titration period.
Patient compliance should be optimised and the financial
burden of treating hypertension will be minimised. Rational
combinations at appropriate doses offer safety and efficacy
in the short term and with longer term treatment of hypertension. References:
1. Hobbs R, Irwin P, Rubner J. Evidence-based treatment of hypertension:
ARBs in Combination Therapy
2. Latest South African Hypertension Guidelines Released, South African
Pharmaceutical Journal, May 2006
3. ‘Less is More’ when it comes to treating high blood pressure – Science
Daily, March 25 2009.
4. Stanton T, Reid JL. Fixed dose combination therapy in the treatment of
hypertension. Journal of Human Hypertension 2002 16:75-78.
5. Two-drug Blood Pressure Therapy Dramatically Lowers Cardiovascular Risk –
Science Daily April 1, 2008
6. Williams B, Poulter NR, et al. British Hypertension Society Guidelines for
Hypertension Management 2004 (BHS-IV): Summary. BMJ 2004; 328: 634–
40.
SA Pharmaceutical Journal – September 2009