Can J Cardiol Vol 23 No 10 August 2007783
Polytherapy with two or more antihypertensive drugs
to lower blood pressure in elderly Ontarians.
Room for improvement
Norman RC Campbell MD1, Finlay A McAlister MD MSc2, Minh Duong-Hua BSc3, Karen Tu MD MSc3,4,5
linical trials, meta-analyses (1,2) and guidelines (3-5) have
focused primarily on first-line therapy choices in recommending
particular drug classes for individuals with hypertension. As a result,
pharmacoepidemiological studies have also focused on monotherapy
treatment choices (6). However, large clinical trials have docu-
mented that to achieve currently recommended blood pressure tar-
gets, two or more drugs are required in most patients (7-10).
Although the Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure does not recommend particular drug combinations (3),
both British (11) and Canadian (12) guidelines recommend
combining drugs with different mechanisms of action as per the
Birmingham algorithm (13-15). The Birmingham algorithm advo-
cates the coprescribing of drug classes that are not only supported by
IN COLLABORATION WITH THE CANADIAN HYPERTENSION SOCIETY
©2007 Pulsus Group Inc. All rights reserved
NRC Campbell, FA McAlister, M Duong-Hua, K Tu.
Polytherapy with two or more antihypertensive drugs to lower
blood pressure in elderly Ontarians. Room for improvement. Can
J Cardiol 2007;23(10):783-787.
BACKGROUND: Although guidelines now recommend polytherapy
to achieve blood pressure targets, little is know about which antihy-
pertensive drugs are combined in clinical practice.
OBJECTIVE: To examine current practices for the coprescribing of
METHODS: A population-based cohort study was performed using
linked administrative databases on all Ontario residents 66 years of
age or older who were newly treated for hypertension between July 1,
1994, and March 31, 2002, and did not have diabetes or other rele-
vant comorbidities. All patients were followed for two years to deter-
mine which antihypertensives were prescribed concurrently.
RESULTS:Of the 166,018 patients in the described cohort, 1819 (1%)
were prescribed a combination therapy tablet as their first-line therapy.
The number of patients prescribed antihypertensive polytherapy with-
in the first two years of diagnosis increased from 2071 (21%) of the
9825 hypertensive patients starting treatment in the second half of
1994 to 2578 (37%) of the 6988 hypertensive patients beginning treat-
ment in the first quarter of 2002 (P<0.0001). Overall, 11,003 (27%) of
polytherapy prescriptions were for drugs without additive hypotensive
effects when combined and this proportion did not change over time.
CONCLUSIONS: Although there has been an increase in the use of
polytherapy in elderly hypertensive patients without comorbidities in
Ontario over the past decade, more than one-quarter of the two drugs
prescribed together have not been proven to have additive hypotensive
effects. Because this likely contributes to suboptimal blood pressure con-
trol rates, future guidelines and educational programs should devote
increased attention to the choice of optimal polytherapy combinations.
Key Words: Antihypertensive prescribing patterns; High blood
pressure; Hypertension; Polytherapy
Polychimiothérapie composée d’au moins deux
antihypertenseurs pour abaisser la pression
artérielle chez les personnes âgées en Ontario :
Place à l’amélioration
CONTEXTE : Bien que la polychimiothérapie soit recommandée dans les
lignes directrices pour faciliter l’atteinte des valeurs cibles de la pression
artérielle, on connaît peu de choses sur l’association des antihypertenseurs
BUT : L’étude avait pour but d’examiner la pratique actuelle en matière
d’emploi concomitant des antihypertenseurs.
MÉTHODE : Une étude de cohorte, fondée sur une population, a été
menée à partir du recoupement de plusieurs bases de données
administratives concernant toutes les personnes âgées d’au moins 66 ans,
demeurant en Ontario, nouvellement traitées pour de l’hypertension
artérielle entre le 1erjuillet 1994 et le 31 mars 2002 et non atteintes de
diabète ou d’autres maladies concomitantes, liées à la première affection.
Les patients ont été suivis pendant deux ans pour permettre de déterminer
quels antihypertenseurs étaient prescrits en association.
RÉSULTATS : Au total, 166 018 patients ont été inclus dans la cohorte
en question; sur le nombre, 1819 (1 %) patients ont été soumis à la
polychimiothérapie orale comme traitement de première intention. Le
nombre de patients qui ont reçu une ordonnance de polychimiothérapie
antihypertensive au cours des deux années suivant la pose du diagnostic est
passé de 2071 (21 %) sur les 9825 hypertendus ayant commencé le
traitement au cours de la seconde moitié de 1994 à 2578 (37 %) sur les
6988 hypertendus ayant commencé le traitement au cours du premier
trimestre de 2002 (p < 0,0001). Sur l’ensemble des ordonnances de
polychimiothérapie, 11 003 (27 %) l’étaient pour des médicaments
dépourvus d’effet hypotenseur additif lorsqu’ils étaient employés en
association, et la proportion n’a pas changé au fil du temps.
CONCLUSIONS : Bien que le recours à la polychimiothérapie ait
augmenté chez les personnes âgées hypertendues, non atteintes de
maladies concomitantes, en Ontario, au cours de la dernière décennie, plus
du quart des traitements prescrits, composés de deux médicaments ne
produisaient pas d’effet hypotenseur additif avéré. Comme cela conduit
vraisemblablement à une maîtrise sous-optimale de la pression artérielle, il
faudrait que les futures lignes directrices et les nouveaux programmes de
formation comportent un volet sur le choix des médicaments susceptibles
d’association afin de composer une polychimiothérapie optimale.
1Departments of Medicine, and Pharmacology and Therapeutics, Libin Cardiovascular Institute, University of Calgary, Calgary; 2Division of
General Internal Medicine, University of Alberta, Edmonton, Alberta; 3Institute for Clinical Evaluative Sciences (ICES); 4University Health
Network – Toronto Western Hospital Family Medicine Centre; 5Department of Family and Community Medicine, University of Toronto,
Correspondence: Dr Karen Tu, c/o ICES, G108, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5. Telephone 416-480-4055 ext 3871,
fax 416-480-6048, e-mail email@example.com
Received for publication May 12, 2006. Accepted September 4, 2006
Campbell et al
Can J Cardiol Vol 23 No 10 August 2007784
a pathophysiological rationale, but that also have extensive clinical
evidence to support their additive hypotensive effects – not surpris-
ingly, all of these combinations are also available as combination
products, with both drugs in a single tablet (13,14,16-20). These
include thiazide diuretics with beta-blockers, angiotensin-converting
enzyme (ACE) inhibitors or angiotensin receptor blockers; beta-
blockers with calcium channel blockers; and calcium channel block-
ers with ACE inhibitors or angiotensin receptor blockers. For other
drug combinations, there is controversy over whether they have
additive hypotensive effects (21-33), and the combinations do not
have regulatory approval to be combined in a single tablet for the
purposes of blood pressure lowering (13,17-19). Both the British
Hypertension Society and the Canadian Hypertension Education
Program endorse the combining of two antihypertensive drugs with
proven additive hypotensive effect and advise against the use of
unproven drug combinations in the absence of compelling indica-
tions arising from comorbid conditions, such as heart failure (11,12).
Several clinical trials (34-36) and meta-analyses (37,38) have
documented that initial therapy of uncomplicated hypertension
with a beta-blocker results in less prevention of cardiovascular
events than is seen with other therapies. It remains controversial
whether this lower effectiveness is limited to elderly patients (39),
is explained merely by less blood pressure lowering effectiveness
with beta-blockers (which may be partially addressed by using a
higher dose) or whether the reduced effectiveness is also seen when
beta-blockers are used as second-line or ‘add-on’ therapy. The
extent to which beta-blockers are used as add-on therapy in hyper-
tension treatment in elderly patients is unknown. Recently, Wald
and Law (40) advocated the use of combination therapy in the
treatment of hypertension, and suggested that a polypill containing
fixed combinations of drugs may be the best option for cardiovas-
cular disease prevention in patients older than 55 years of age.
While this suggestion generated a storm of negative feedback on
the British Medical Journal’s rapid response Web site, one of the
potential advantages of a polypill – that antihypertensive drugs
combined in the polypill would be proven to have additive proper-
ties for blood pressure-lowering efficacy – was neglected by respon-
dents. Of course, the extent to which this may represent an
advantage of the polypill depends on how commonly physicians
prescribe antihypertensive drug combinations that are not additive
in their effects. Given the paucity of studies examining physician
prescribing practices when combining two (or more) antihyperten-
sive drugs in clinical practice, we designed the present study to
examine which drugs were coprescribed when polytherapy was used
in older individuals newly treated for hypertension.
Details of how four Ontario administrative databases were linked
(consisting of all hospital visits, outpatient physician visits, vital
statistics and complete prescribing data) to construct a cohort of
newly treated hypertensive individuals without comorbidities (and
the list of conditions and comorbidities for which patients were
excluded from the cohort) were published previously (6). In brief,
the present cohort consisted of all Ontario residents 66 years of age
or older who received a new prescription for an antihypertensive
agent between July 1, 1994, and March 31, 2002, and did not have
diabetes mellitus or another condition for which an antihyperten-
sive drug may be prescribed for a nonblood pressure-lowering indi-
cation (such as coronary disease, heart failure or renal dysfunction).
All patients were followed for two years after their initial antihy-
pertensive prescription to determine antihypertensive polytherapy.
Each prescription was assumed to last 100 days, and polytherapy
was defined as the addition of another antihypertensive drug class
within 100 days from the date of the last prescription for the initial
antihypertensive drug class prescribed. Combination agents that
consisted of drugs from two different subclasses were separated and
counted as one prescription in each respective subclass when
assessing polytherapy. Annual proportions of patients treated with
polytherapy were calculated and compared between years. χ2test-
ing was performed to assess for significant trends.
For the purposes of the present report, the focus was on five
major antihypertensive drug classes: thiazide and thiazide-like
diuretics (hereafter referred to as diuretics), beta-blockers, ACE
inhibitors, calcium channel blockers and angiotensin receptor
blockers. Appropriate drug combinations were defined as those
that have theoretical basis and/or randomized trial evidence of an
additive hypotensive effect. These include: diuretics with beta-
blockers, ACE inhibitors or angiotensin receptor blockers; beta-
blockers with calcium channel blockers; and calcium channel
blockers with ACE inhibitors or angiotensin receptor blockers.
Drug combinations defined as ‘not recommended’ do not have
additive hypotensive effects on a theoretical basis and do not have
conclusive trial evidence supporting an additive hypotensive
effect. These include: diuretics with calcium channel blockers;
beta-blockers with ACE inhibitors or angiotensin receptor block-
ers; and ACE inhibitors with angiotensin receptor blockers.
The cohort consisted of 166,018 newly treated elderly hyperten-
sive patients who did not have diabetes or other comorbidities
(such as heart failure or coronary disease) that would mandate
treatment with a particular antihypertensive drug class. Initial
monotherapy drug choices in this cohort were previously reported
(41) – the most common monotherapy prescriptions were for
ACE inhibitors (29% of all initial prescriptions) and diuretics
(40% of all initial prescriptions).
Of the 166,018 patients in the cohort, 1819 (1%) were pre-
scribed a combination therapy tablet as first-line therapy. Within
two years of initial therapy, the number of patients prescribed two
drug classes concurrently to control blood pressure increased from
1992 of all 9825 (20%) hypertensive patients first treated in 1994 to
2184 of the 6988 (31%) first treated in 2002 (P<0.0001) (Figure 1).
Approximately 73% (29,439) of the two-drug combinations were
compatible with the Birmingham algorithm and Canadian
Hypertension Education Program recommendations, and this pro-
portion did not change between 1994 and 2002 (P=0.45). Being
prescribed an appropriate combination of two drugs occurred with a
frequency that was greater than predicted by chance (29,439 [73%]
versus 60% predicted, P<0.0001). Overall, polytherapy within the
first two years of diagnosis increased from 21% of the 9825 hyper-
tensive patients starting treatment in the second half of 1994 to
37% of the 6988 hypertensive patients beginning treatment in the
first quarter of 2002 (P<0.0001); the use of three or more drugs at
the same time increased more than threefold (from 138 [2%] to
345 [6%], P<0.0001) between 1994 and 2002 (Figure 1).
Choice of second antihypertensive drug class for add-on therapy
The drug classes chosen as the add-on drug for patients being
treated with two antihypertensive drugs were stable over time; the
most frequent add-on drugs were diuretics (13,436 [39%]), ACE
inhibitors (8327 [24%]), calcium channel blockers (6388 [19%])
and beta-blockers (5779 [17%]).
Change in polytherapy combinations
Overall, the ACE inhibitor plus diuretic combination was the
most frequently used two-drug combination in all years that were
Polytherapy with antihypertensive drugs
Can J Cardiol Vol 23 No 10 August 2007785
studied, increasing from 547 (29%) in the 1994 cohort to 766 (35%)
in the 2002 cohort (P<0.0001) (Figure 2). The use of diuretics
with beta-blockers declined over time from 281 (15%) to
236 (11%) (P<0.0001), as did the coprescribing of calcium chan-
nel blockers with beta-blockers, from 206 (11%) to 116 (5%)
(P<0.0001), as well as calcium channel blockers with ACE
inhibitors, from 341 (18%) to 255 (12%) (P<0.0001).
Of the nonrecommended two-drug combinations, the most fre-
quent in all years of the present study were calcium channel block-
ers with diuretics, which declined from 353 (18%) of all two-drug
coprescriptions in 1994 to 287 (13%) in 2002 (P<0.0001) and beta-
blockers with ACE inhibitors, which increased from 189 (10%) of
all coprescriptions in 1994 to 261 (12%) in 2002 (P<0.0001).
The overall use of beta-blockers in two-drug combination ther-
apy declined from 35% in 1994 to 30% in 2002 (P<0.0001). With
the exception of the ACE inhibitor plus beta-blocker combina-
tion, all combinations with a beta-blocker declined.
In patients with hypertension and no comorbidities, the reduc-
tion in clinical events is directly related to the reduction in
blood pressure (42). However, over one-quarter of all second
drugs added to treatment regimens for elderly hypertensive
patients in our study was for drugs that have not been proven to
provide additive effects to the first-line therapy prescribed for
those patients (4,11,12). This may result in suboptimal blood pres-
sure lowering in these patients and may contribute to the poor
blood pressure control rates reported in surveys from a variety of
countries (43). Furthermore, even in 2002, 28% of Ontario elderly
patients with uncomplicated hypertension received a two-drug
combination that included a beta-blocker. Although the role of
beta-blockers in combination therapy is currently unclear, the
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and other
trials have demonstrated that beta-blocker-based therapies do not
reduce cardiovascular events to the same extent as other thera-
peutic strategies, particularly in elderly patients with uncompli-
cated hypertension (34-36). It is important that almost 40% of
add-on therapy was with a diuretic, which is the least expensive
The main strength of our study is that the data reflect longitu-
dinal prescribing to the population of Ontario older than 65 years
of age who were newly prescribed antihypertensive therapy and
did not have diabetes or cardiovascular comorbidities. Our find-
ings are congruent with a recently published analysis of the
National Health and Nutrition Examination Survey (NHANES)
1988 to 1994 and NHANES 1999 to 2002 data demonstrating
that the use of polytherapy to treat hypertension in patients with-
out comorbidities is increasing in the United States (from 29% in
1988 to 36% in 2002) and that the most common two-drug com-
bination is an ACE inhibitor with a diuretic (44). While our data
confirmed the NHANES analyses in another geographic locale,
our study also extended the NHANES findings, because it was
longitudinal and enrolled only newly treated patients, while the
NHANES analyses were cross-sectional and included a mix of
new and chronic diagnoses. We were thus able to examine serial
prescriptions over time to determine the sequence with which
drugs were combined (proving that diuretics were the most fre-
quently added second-line agent) and the frequency with which
polytherapy was prescribed within the first two years of diagnosis.
The coprescription of calcium channel blockers with diuretics
was the most common nonrecommended polytherapy combination
used in our study cohort. Some may cite the Valsartan
Antihypertensive Long-term Use Evaluation (VALUE) trial (45) as
evidence in support of the combination of a calcium channel
blocker with a diuretic. However, it is important to note that
although patients randomly assigned to amlodipine followed by
hydrochlorothiazide in the VALUE trial had greater reduction in
blood pressure than patients randomly assigned to valsartan fol-
lowed by hydrochlorothiazide, the VALUE trial was not designed to
examine the additive hypotensive effects of the combinations.
Indeed, the greatest reduction in blood pressure in the VALUE trial
was during a period in which patients were on initial monotherapy,
and the blood pressure differences between the study groups nar-
rowed during combination therapy (45). Other studies have refuted
the additive hypotensive effect of this combination (21,23,25,27-
29,32). Although edema is the most frequent adverse effect of cal-
cium channel blockers and the addition of a diuretic may reduce
this effect (46-50), it is important to remember that calcium chan-
nel blockers are natriuretic, and the mechanism of edema formation
is not related to retention of salt and water (48-51). It is likely that
primary care physicians are unaware of the evidence supporting
optimum drug combinations to lower blood pressure.
19941995 19961997 1998
3-drug polytherapy2-drug polytherapy monotherapy
Figure 1) Elderly hypertensive patients in Ontario prescribed
monotherapy versus polytherapy, 1994 to 2002. Note that data for
1994 and 2002 only contain information from the third and fourth
quarters and the first quarter, respectively
1994 199519961997 1998
Diuretic + ACE inhibitor
Diuretic + beta-blocker
Diuretic + angiotensin
blocker + ACE inhibitor
blocker + beta-blocker
blocker + angiotensin
Figure 2) Use of proven efficacious polytherapy combinations in eld-
erly hypertensive Ontarians, 1994 to 2002. Note that data from 1994
and 2002 only contain information from the third and fourth quarters
and the first quarter, respectively. ACE Angiotensin-converting
To avoid confounding by indications for specific antihyperten-
sive combinations, patients were excluded in our study for the fol-
lowing rationale: strong clinical trial evidence supporting the
combination of beta-blockers with ACE inhibitors in patients
who have had a myocardial infarction or have congestive heart
failure (52-54). By the same token, although the combination of
an ACE inhibitor with an angiotensin receptor blocker may have
clinical advantages in patients with renal disease and proteinuria
despite a less than additive hypotensive effect (55), patients with
renal disease or diabetes were also excluded from our study.
Although we reported antihypertensive prescribing practices in
a large, representative and population-based sample of all elderly
adults newly treated for hypertension in Canada’s most populated
province over the past decade, there are limitations to the use of
administrative databases. Principally, we do not have blood pressure
readings, the reasons why physicians chose to prescribe one drug
over another are not recorded in administrative data, and our sam-
ple includes only those patients who filled their prescription for
antihypertensive drugs. However, although these limitations would
be fatal flaws for any study attempting to extrapolate from these data
to report hypertension incidence or prevalence rates, these limita-
tions do not directly impact our question of interest: ie, which drugs
do physicians choose to combine when treating their hypertensive
patients? Indeed, our use of administrative data collected on all
Ontario residents allowed us to avoid the problems with small sam-
ples, selection bias and measurement bias, which commonly afflict
cohort studies. We also did not have all the information on the
duration of prescriptions, and it is possible that our assumption of
each prescription lasting 100 days may have led to an overestimate
of the number of polytherapy prescriptions. As well, administrative
data do not provide information on adherence rates, which if low,
can also lead to an overestimate of polytherapy antihypertensive
use. Nevertheless, the same methods were applied to each year
throughout the study, and it is reasonable to assume that prescrip-
tion duration and adherence did not change significantly through-
out the study period.
Although the use of polytherapy to treat hypertension has been
increasing over time, approximately one-quarter of antihyperten-
sive drug combinations prescribed by clinicians are suboptimal and
this proportion has remained stable over the past decade.
Furthermore, almost one-third of elderly patients receiving poly-
therapy are treated with combinations that include a beta-blocker,
although this has been declining slowly over time. To this point,
most guidelines and continuing medical education programs on
hypertension have focused on making the diagnosis and choosing
initial monotherapy. Our data suggest that future guidelines and
programs should emphasize appropriate polytherapy combinations
in an effort to optimize the control of blood pressure and the reduc-
tion in cardiovascular disease in elderly hypertensive individuals.
ACKNOWLEDGEMENTS: This research was supported by a
Grant-in-Aid from the Heart and Stroke Foundation of Ontario
Grant #NA 5459. KT is supported by a Canadian Institutes of
Health Research (CIHR) Short-Term Clinician Investigator
Award. FAM is supported by an Alberta Heritage Foundation for
Medical Research Population Health Scholar Award, a CIHR
New Investigator Award and the University of Alberta/Merck
Frosst/Aventis Chair in Patient Health Management.
Campbell et al
Can J Cardiol Vol 23 No 10 August 2007786
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