European Heart Journal (1997) 18 {Supplement E), E9-E13
Adequate blood pressure control: perception and
reality
T. Morgan
Department of Physiology, University of Melbourne, Australia and Hypertension Clinic, Austin & Repatriation
Medical Centre, Heidelberg, Germany
Blood pressure should be controlled over 24 h to reduce or
prevent cardiac hypertrophy and reduce the prevalence
of sudden death, myocardial infarction and myocardial
ischaemia at the time of the morning rise in blood pressure.
Anti-hypertensive medication is usually given once-daily in
the morning and the dose is titrated on the basis of postdose (peak) blood pressure. This frequently leads to inadequate control prior to the next drug dose unless drugs with
appropriate pharmacokinetics or pharmacodynamics are
used. ACE inhibitors exhibit an Emax plasma concentration:blood pressure response relationship, and thus shortacting ACE inhibitors can exert an effect over 24 h if
titrated based on pre-dose (trough) blood pressure. However, when titrated in clinical practice on post-dose (peak)
blood pressure response, doses are used that are inadequate
to control blood pressure for 24 h. ACE inhibitors with
appropriate pharmacokinetics such as perindopril can control blood pressure when titrated at peak provided a dose is
used (4 or 8 mg) that is known to have a T:P close to 10.
Shorter-acting ACE inhibitors frequently give inadequate
control when titrated at peak.
Introduction
death'5 7]. This peak incidence correlates with the rise in
blood pressure that takes place at the time of arising and
awakening. There are increased incidence of sudden
death, increased incidence of myocardial infarction,
increased incidence of cerebrovascular accidents and
also increased frequency of silent coronary ischaemic
events'81. It is possible that neuro-humoral activation
that takes place at this time to cause the rise in blood
pressure may also have adverse effects on platelet function and on cardiac performance. However, it is possible
that the rise in blood pressure, which is rapid and acute,
is the cause of the increased frequency of these problems.
Hypertensive patients have a marked reduction in coronary artery flow reserve and coronary flow cannot
respond rapidly to changes required by increased
demand. When blood pressure rises acutely there is a
marked increase in cardiac workload and, in a person
whose coronary arteries cannot vasodilate to supply the
required oxygen and remove metabolites, this may cause
the onset of arrhythmia and sudden death. This is
particularly likely to occur in a person with increased
cardiovascular sympathetic activity. A second possibility
is that the acute rise in blood pressure may increase
the shear force. This increase in shear force, both in
coronary arteries and also possibly in cerebrovascular
Correspondence: Professor Trefor Morgan, Department of
Physiology, University of Melbourne, Parkville, Victoria 3052,
Australia.
0195-668Xy97/OE0009+05 S18.00/0
Key Words: ACE inhibitors, pharmacokinetics, pharmacodynamics, T:P, enalapril, perindopril.
1997 The European Society of Cardiology
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Most people would accept that blood pressure should be
controlled throughout the day. However, there is little
absolute proof that control throughout the 24-h period is
essential. Nonetheless, there are a number of studies
which demonstrate a closer association between endorgan damage and 24-h blood pressure than between
end-organ damage and clinic blood pressure. Likewise,
there is an association between the variability in blood
pressure over the 24-h period and end-organ damage''^3'.
A recent study has given preliminary evidence that the
best results are obtained when patients' blood pressure is
reduced at night-time as well as in the daytime, and this
reduction in night-time blood pressure is associated with
resolution of left ventricular hypertrophy; the best prognosis is in people who have good 24-h control and
resolution of hypertrophy'4'.
The reason for 24-h blood pressure control
relates predominantly to two aspects. First, between 6.00
and 10.00 am there is a peak incidence of cardiovascular
An understanding of the pharmacokinetics and pharmacodynamics of a drug, coupled with knowledge of the time the
drug was taken, together with the time of blood pressure
measurements, enables control to be achieved with oncedaily therapy even if the drug is titrated at peak response.
(Eur Heart J 1997; 18 (Suppl E): E9-E13)
E10
T. Morgan
arteries, may cause rupture of the vulnerable collar area
of unstable atherosclerotic plaques thereby precipitating
myocardial infarction, sudden death, silent ischaemia or
cerebrovascular accidents. Thus it would seem sensible
to control blood pressure at this time of the day.
A second problem is that the rise in blood
pressure that occurs at this time in the morning results
in an increase in the total 24 h cardiac workload. In
addition, however, the acute rise in blood pressure will
cause an increase in wall stress. This increase in wall
stress may activate the processes that lead to alterations
in the genetic control of muscle hypertrophy, thereby
precipitating left ventricular hypertrophy, even though
blood pressure may be relatively controlled through
much of the rest of the day'91.
If the question were asked, 'Have you controlled
your patient's blood pressure?', many people would say,
'Yes'. But, as I intend to show you, it is quite probable
that you have not controlled the blood pressure at this
particularly vulnerable part of the day.
Problem of clinic management
24-hour ambulatory blood pressure
measurement
Twenty-four hour ambulatory blood pressure measurement has given us significant insight into the variability
Eur Heart J, Vol. 18. Suppl E 1997
Once-a-day drug use
Many drugs are shown during their development to
control blood pressure 24 h after administration. This
relates to the design of drug trials. In particular the drug
is titrated on the basis of the blood pressure measured
prior to that day's dose. Thus blood pressure is titrated
on the basis of the trough blood pressures. However in
clinical practice this is usually not the case. If a person
takes their medication in the morning the titration may
be based on a blood pressure taken 2-4 h post-dose or
up to 12 h post-dose if the person is seen in the evening.
Rarely are the conditions of the clinical trials imitated,
in which the blood pressure is taken prior to that day's
dose of the drug. This means that during clinical trials a
dose of the drug is recommended to be used in order to
give 24 h blood pressure control, but frequently in
clinical practice that dose is not reached. Consequently,
in order to get drugs to work for 24 h or across the dose
interval, drugs were frequently titrated excessively, causing too large a fall of blood pressure at the time of peak
response, with associated symptoms. This led to the
development by the FDA of the trough:peak ratio'141.
However, such an excessive fall in blood pressure is not
usually a major problem in clinical practice because if
it falls excessively and the person develops postural
hypotensive symptoms the drug dose will be decreased
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Most blood pressure control is obtained by measuring
the blood pressure at a clinic or in the doctor's office.
Even a hypertensive patient who is attending regularly is
unlikely to be seen more than once a month. The blood
pressure may only be taken once and in good centres
taken three times. On the basis of these blood pressures
taken at a particular time of the day, one month or more
apart, we base our entire therapeutic strategy. It is
somewhat surprising that this has been so successful
because blood pressure is a highly variable parameter
with marked swings in the blood pressure associated
with stress, physical and sexual activity. Even when we
measure blood pressure at the clinic we rarely ask the
patient when they have taken their medication and
rarely do we correlate the blood pressure response with
the time of dosage. In the past many anti-hypertensive
drugs had relatively short half-lives and it was common
to give medication three or even four times a day.
However, as people with milder degrees of hypertension
have been treated, the importance of compliance and
convenience has dictated that medication should be
given twice or in most cases once a day. Whether once a
day is necessarily better than twice a day is marginal.
However most drugs are now developed for once-daily
use. The patient in general takes medication in the
morning and is seen at a variable time after that
medication is given. We rely on the blood pressure
measured at that time as an index of the 24 h control.
in control that is achieved over 24 h. However, it is not
feasible to undertake 24 h ambulatory blood pressure
monitors in every patient at every visit and, accordingly,
other strategies need to be implemented. As a minimum
one must know the time of drug administration and the
time of blood pressure recording. If the time of blood
pressure recording is close to the time of administration
we need to be suspicious that 24-h control may not be
achieved — unless we are using a drug in a dose that is
known to give 24-h blood pressure control. Twenty-four
hour ambulatory monitor recordings are used frequently
in the assessment of many drugs and a parameter that is
derived is the trough:peak ratio. The trough:peak ratio
measured using clinic blood pressure is relatively easy to
define and measure'10'. Using ambulatory blood pressure
measurements, estimation of trough:peak ratio has been
difficult and has created problems. Frequently the peak
effect is over-estimated and the trough effect is underestimated, leading to falsely low trough:peak ratios for a
wide variety of drugs'1''. Conversely, it is feasible that
clinic determinations may lead to falsely high trough:
peak ratios. However, drugs that are known to have half
lives of 48 h or drugs that are known to have consistent
blood level concentrations have been reported to have
trough:peak ratios as low as 0-5 and such a a finding
seems very unlikely'"'121. Nonetheless, the trough:peak
ratio, when it is determined, can give you an index of the
likelihood that a drug in a particular dose will work
for 24 h. The trough:peak ratio of a drug must be
assessed in the context of the pharmacokinetics and the
pharmacodynamics of the drug'131.
Adequate blood pressure control
Plasma level
Figure 1 Graphical representation of a drug that has a
relatively linear relationship between plasma concentration and blood pressure response. Most flatten off
(
) at the higher concentrations. See text for details.
Pharmacokinetics
The pharmacokinetics of a drug provide information
about whether a drug will work across the dose interval.
If the half-life of the drug is greater than or equal to the
dose interval it is likely to have a relatively similar effect
at trough and peak. If the half-life is less than the dose
interval, and particularly if it is short, it is possible that
the drug can be given once-a-day, but this will depend
upon the pharmacodynamics of the drug.
Pharmacodynamics
Drugs, at the extremes, can be divided into two major
groups. In the first there is a relatively linear plasma
concentration:blood pressure response. This has been
seen particularly with the dihydropyridine calcium channel blocking drugs and some vasodilating drugs such as
prazosin, doxazosin, nitroprusside. With this type of
drug, increasing the plasma concentration (or the drug
dose) causes an additional fall in blood pressure (Fig. 1).
This has the following effect. The blood pressure fall
desired is represented by point A. If the drug is titrated
at the peak response time, that is 3-4 h post-dose, the
plasma concentration at point A is achieved at that time.
Prior to the next dose of the drug the plasma concentration will have fallen to B and the response may be
inadequate. However, if titrated prior to the next dose of
the drug, the desired response and plasma concentration
is reached at point A. With the next dose of the drug,
plasma concentration rises to C and the response is
excessive. This is the situation that the FDA guidelines
for trough:peak ratio were developed to prevent'141. The
extent to which the plasma concentration moves along
this line depends upon the half-life of the drug; if a drug
of this nature has a short half-life it basically cannot be
used unless there are some important pharmaceutical
modifications. With a drug of this nature the solution is
to use a drug with a long half-life, to use a specialized
form of pharmaceutical delivery of the drug so that
essentially a constant infusion is given over 24 h, or to
use a combination of the two. This has been done with
amlodipine'151, which has a half-life greater than 24 h,
with nifedipine GITS or OROS[16) which has a specialized delivery system giving a constant infusion of the
drug and constant blood levels over the 24 h, and with
felodipine[17] which has a moderately long half-life and
also delayed release, once again being effective over 24 h
of the day. With this class of drug the trough:peak ratio
is relatively independent of the dose, though the
responses may be so trivial at trough as to make the
value uncalculable.
Pharmacodynamics of drugs with E max
effect
The other type of effect is that where an E max is
demonstrated. This is seen particularly with the ACE
inhibitors (Fig. 2) for which there is the full response
over a relatively narrow plasma concentration. Then as
the plasma concentration increases there is no further
effect of the drug on blood pressure. In the case of the
ACE inhibitors this fall down the curve relates to the
rate at which the drug dissociates from the angiotensin
converting enzyme either in the tissues or in the plasma.
The top part of the curve, the plateau response, is when
the drug is not bound to the ACE enzyme. ACE
inhibitors typically have at least two components to
their half-life. They have a rapid phase related to the
elimination of free drug, usually by renal excretion. This
is sometimes complicated by conversion of the prodrug
to the active drug and the initial elimination phase
depends on both these factors. The terminal half-life
depends on dissociation from the enzyme.
An example of the E max effect is seen in a small
study with enalapril. Six patients known to respond to
monotherapy with enalapril were given placebo, 5, 10,
20 or 40 mg of enalapril and their blood pressure
measured 3 and 24 h later. Three hours after the medication the fall in blood pressure was similar with all
doses of enalapril (Table 1). There was a trend to a
slightly smaller fall with 5 mg. However, 24 h after
medication there was no significant fall with either 5 or
10 mg of enalapril. The fall at 24 h with 20 and 40 mg of
enalapril was 70% or more of the fall achieved at 3 h.
Eur Heart J, Vol. 18, Suppl E 1997
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at the expense of blood pressure control. The problem is
that in clinical practice the drug is titrated on the basis of
post-dose blood pressure in contrast to the clinical trials.
This leads to control of blood pressure at peak response
but inadequate control prior to the next dose.
Ell
E12
T. Morgan
Table 2 Effect of fixed dose of enalapril and perindopril
3 and 27 h post-dose in people known to respond to an
A CE inhibitor
Placebo
Enalapril
10 mg
Perindopril
4mg
168
168
150*
156*
151*
150*
95
95
80*
84*
0-67
0-73
80*
81*#
0-95
0-93
1
hn
HI
S
h
D
—
y
a,
CQ
/
Systolic BP
3h
27 h
Diastolic BP
3h
27 h
Systolic T:P
Diastolic T:P
F
-- 1
1
/
J
lUvvl/V
*/"<001 compared to placebo. #/><0-05 compared to enalapril.
IE
Plasma level
Figure 2 Graphical representation of a drug that has an
E m a x effect. ACE inhibitors are in this class of drug. The
movement along the plateau occurs when all ACE is bound
and represents free plasma concentration that has no
effect. The movement along the steep part of the curve is
due to ACE binding. See text for details.
Diastolic BP
Enalapril
dose
3h
24 h
0
5
10
20
40
100
91*
88*
86*
87*
103
100
96
91*#
89*#
E5 or P2
ElOor P4
E20 or P8
E40
No. of people on that (lose
Perindopril
Enalapril
Peak *
Troughf
Peak*
Trough!
15
12
3
0
0
2
20
8
7
18
5
3
20
7
T:P
*Reading taken 3-4 h post-dose.
Total number of patients, 30.
0-3
0-5
0-8
11
dose of the drug given twice a day has the same 24 h
profile and control pattern as four or more times that
amount of the drug given once a day because when given
once a day most of the effectiveness of the drug is wasted
as it is excreted and never binds to the enzyme.
This does have important correlation in clinical
practice because, if two ACE inhibitors are titrated close
to the time of peak effect (3 or 4 h post-dose), there may
be equal control with both at the time of peak effect but
poor control at trough effect. In one study we compared
4 mg of perindopril with 10 mg of enalapril. The fall at
peak was similar with both drugs, but the fall at trough
with perindopril was virtually the same as at peak, giving
a trough peak ratio close to 1-0, whilst the trough:peak
ratio with enalapril was about 0-5 (Table 2)1'8'.
We also evaluated this in a group of patients who
were known to have responded to ACE inhibitors as
monotherapy. We titrated them according to the blood
pressure 3—4 h post-dose with either enalapril or perindopril in a double-blind study. When control was
achieved with that dose of the drug, we further titrated
them to obtain control on the basis of blood pressure
24 h after drug administration. We then changed them
to the other drug and performed the same study. The
results of this are shown in Table 3. When enalapril was
•Different from placebo at /»<0-01. *#Different from 5 and 10 mg
at / > <005.
Thus the trough:peak ratio of enalapril depended on the
dose of the drug that was used.
The importance of this is as follows. If a drug is
titrated at the time of peak effect of the drug (i.e.
post-dose) the blood pressure response required at the
plasma concentration is point D (Fig. 2). Prior to the
next dose of the drug the plasma concentration will fall
to point E and the response may be inadequate. However, if titrated at the trough level of the drug once again
point D is reached. With the next dose of the drug
plasma concentration moves along the plateau part of
the curve and there is no excessive blood pressure fall
(point F). The rate of movement back along the plateau
part of the curve depends largely on the initial half-life
of the drug, while the movement from D to E depends
on the terminal half-life of the drug. This may explain
why, in a number of ACE inhibitors, a relatively low
Eur Heart J, Vol. 18, Suppl E 1997
Enalapril (E)
or perindopril (P)
dose (mg)
taken 24 h post-dose.
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Table 1 Diastolic blood pressure 3 and 24 h after
placebo or enalapril in a group of six patients known to
respond to enalapril
Table 3 Dose of enalapril or perindopril required to
achieve control of blood pressure when titrated on the
basis of readings 3-4 h or 24 h post-dose in patients known
to be controlled with A CE inhibitor monotherapy
Adequate blood pressure control
titrated on the basis of peak blood response, an ineffective dose of the drug for 24-h control was achieved.
When perindopril was titrated there were a few patients
in whom the drug was not titrated to adequate levels but
overall, due to the flatter dose response, control was
obtained. Thus if perindopril 4 or 8 mg is used and
titrated close to the time of peak response, most of the
response measured will be present prior to the next dose
of the drug. With enalapril, the dose of that drug that is
required to achieve a similar type result is 20 or 40 mg
and frequently the drug is not titrated to those levels.
Suggested guidelines
In clinical practice where ambulatory monitoring
may not be readily available we would also suggest the
following. If you have controlled your patient's blood
pressure on the basis of measuring the blood pressure
post-dose, you should ask your patient to miss their
medication prior to their next visit. If the blood pressure
is still well-controlled the drug is working for 24 h or
longer. If it is poorly controlled the right drug in the
right dose may not have been used. Depending on when
you measure the blood pressure and when the patient
takes the drug, you need to determine whether control
has been achieved. The perception is frequently that
blood pressure has been controlled; the reality is that
control is inadequate and does not persist across the
dose interval.
References
[1] Frattola A, Parati G, Cuspidi C, Albini F, Mancia G.
Prognostic value of 24 hour blood pressure variability. J
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[2] Verdecchia P, Porcellati C, Schillaci G et at. Ambulatory
blood pressure: an independent predictor of prognosis in
essential hypertension. Hypertens 1994; 24: 793-801.
[3] Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH.
Relation of left ventricular mass and geometry to morbidity
and mortality in essential hypertension. Ann Int Med 1991;
114: 345-52.
[4] Muiesan ML, Salvetti M, Rizzoni D, Castellano M, Donato
F, Agabiti-Rosei E. Association of change in left ventricular
mass with prognosis during long term antihypertensive treatment. J Hypertens 1995; 13: 1091-5.
[5] Myers A, Dewar HA. Circumstances attending 100 deaths
from coronary artery disease with coroners' necropsies. Br
Heart J 1975; 37: 1133^3.
[6] Muller JE, Ludmer PL, Willich SN et al. Circadian variation
in the frequency of sudden cardiac death. Circulation 1987; 75:
131-8.
[7] Purcell H, Mulcahy D, Fox K. Circadian patterns of myocardial ischaemia and the effects of antianginal drugs.
Chronobiol Int 1991; 8: 309-20.
[8] Schraeder AP, Brysting B, Sogaard P, Lederballe-Pedersen O.
Silent myocardial ischaemia in untreated essential hypertension. Blood Pressure 1995; 4: 97-104.
[9] Marban E, Koretsune Y. Cell calcium, oncogenes, and hypertrophy. Hypertens 1990; 15: 652-8.
[10] Guntzel P, Kobrin 1, Pasquier C, Zimlichman R, Viskoper JR.
The effect of cilazapril, a new angiotensin converting enzyme
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[11] Zannad F, Matzinger A, Larche J. Trough/peak ratios of once
daily angiotensin converting enzyme inhibitors and calcium
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[13] Morgan T. Twenty four hour BP control — which is best,
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Eur Heart J, Vol. 18, Suppl E 1997
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To be certain that you have controlled the blood pressure of your patients for 24 h, it is probably important to
measure blood pressure over the complete, or at the end,
of the time interval. Measurement could be done by
ambulatory monitors but this is difficult. An alternative
approach is as follows. If the drugs considered have a
linear type of plasma level:blood pressure response you
should only use those drugs that have a half-life of 24 h
or longer, or alternatively, have a pharmaceutical modification to their delivery system so that they have a
relatively constant blood level over the 24 h of the day.
If the drug is of the type having an E max effect, like the
ACE inhibitors, the situation is more complex. It is
preferable to select a drug that has a relatively long
terminal half-life plus a reasonably long initial half-life.
If the drug has a relatively long terminal half-life but a
very short initial half-life this may not give effective 24-h
blood pressure control, even when used in relatively high
doses. The second principle is to use a drug in a dose
that has a similar effect at trough and peak response. If
a drug has a relatively wide dose range and does not
have a similar response at trough and peak, this drug
should probably only be used if it is titrated at trough,
i.e. pre-dose, as is done in clinical trials.
El3