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Antihypertensive Drug Therapy in Saskatchewan
Patterns of Use and Determinants in Hypertension
Chantal Bourgault, PhD;
Bruno Rainville, MSc;
Samy Suissa, PhD
Arch Intern Med. 2001;161:1873-1879.
ABSTRACT
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Background The benefits of continuous treatment of hypertension have been extensively
documented in randomized controlled trials. However, clinical trials may not
reflect actual drug use in the population.
Objective To examine the distribution and determinants of patterns of use of antihypertensive
agents in the first 5 years of hypertension treatment in Saskatchewan.
Methods Patterns of use and modifications to therapy were derived from a careful
examination of medication use in a cohort of 19 501 subjects aged 40
to 79 years, without recognized cardiac disease and initiating therapy with
an angiotensin-converting enzyme inhibitor, a calcium antagonist, or a ß-blocker
in Saskatchewan between 1990 and 1993.
Results Angiotensin-converting enzyme inhibitors (37.4%), followed by calcium
antagonists (27.5%) and ß-blockers (26.4%), were the most commonly prescribed
agents to initiate treatment in our study population. Patients with diabetes
were less likely to be dispensed a ß-blocker, as were younger and female
patients. Previous visits to a cardiologist decreased the likelihood of receiving
combination therapy or angiotensin-converting enzyme inhibitors but increased
that of using calcium antagonists. Apart from dose adjustment, 89% of study
subjects underwent at least 1 modification to their initial regimen, at a
median time of 134 days. After 1 year, only 33.8% of patients were still using
their initial drug. An early decrease in the proportion of patients continuing
to receive initial therapy was noted, especially among ß-blocker users.
Conclusions Erratic drug-taking behaviors were observed in this Saskatchewan population.
In addition, initial drug use does not seem to be in accordance with the stepped-care
approach to hypertension therapy recommended in the Canadian guidelines.
INTRODUCTION
SUBOPTIMAL treatment of uncomplicated hypertension constitutes a major
barrier to effective therapy. Early discontinuation and erratic drug use manifested
by frequent interruptions and switches to different treatment regimens have
been shown to be associated with the progression of cardiovascular and renal
diseases, and to increase the risk of a readmission to the hospital.1-8
Clinical guidelines on the management of hypertension are built on scientific
evidence obtained from randomized controlled trials that are not designed
for evidence gathering on actual drug use in the clinical practice. Several
attempts have been made to document the management of hypertension in the
general population. However, few studies have examined longitudinally the
patterns of antihypertensive drug use, including treatment interruptions and
modifications in treatment regimens.5-6,9-11
Several of these studies did not use a cohort of newly treated hypertensive
subjects but rather included patients at different times in the course of
their disease.6, 11 Indeed, patients
with established hypertension, compared with newly diagnosed subjects, may
present different characteristics, such as severity of hypertension and coexisting
conditions that may affect patterns of drug use. In addition, these studies
were restricted to no more than 1 year of follow-up5, 9-11
or included only continuous users or compliers.6
Recent publications by Caro et al12-15
focused on persistence with therapy in association with initial treatment
among single-drug users. Although the authors presented an interesting algorithm
to identify changes in treatment such as additions, switches, and deletions,
they only reported on persistence rates of antihypertensive therapy and did
not provide any insight as to the incidence or timing of such modifications
to therapy. Hence, despite these previous attempts, an important information
gap exists with regard to the patterns of use of antihypertensive agents in
the population, from treatment initiation onward.
In this study, we documented the management of uncomplicated hypertension
by examining the distribution and determinants of selected patterns of antihypertensive
drug use in Saskatchewan from treatment initiation onward during up to 7 years
of observation. More specifically, we examined the factors associated with
specific choices of initial therapy, the incidence and timing of treatment
modifications during the course of therapy, and their correlates.
PATIENTS AND METHODS
SOURCE OF DATA
Data were obtained from the Saskatchewan Health data files developed
in the context of the universal health insurance program provided to 95% of
all residents of this Canadian province. These data files provided drug-related
information (drug type and dispensing date), demographic data (date of birth,
sex, coverage initiation and termination dates, date of death, and receipt
of social assistance), and information concerning hospital admissions and
medical visits. Information on the indication for drug use was not available.
The accuracy of these data for use in a research setting has been documented.16-17
STUDY POPULATION
A cohort of 35 631 subjects initiating therapy with angiotensin-converting
enzyme inhibitors (ACEIs), ß-blockers, or calcium antagonists (CAs) between
January 1, 1990, and December 31, 1993, was first identified. Treatment initiation
was the date of the first dispensing of 1 or several of these agents. To ensure
that study subjects were initiating treatment, those dispensed any antihypertensive
agent (including diuretics,  -blockers, or centrally acting agents)
in the year preceding treatment initiation were excluded from the cohort.
Because incidence rates of hypertension are low in these age groups, we excluded
6881 subjects younger than 40 years. We also excluded 2793 subjects older
than 80 years because of short follow-up and the very high prevalence of comorbidity
in that group.
Several criteria were used to identify subjects for whom the most likely
indication for antihypertensive treatment was uncomplicated essential hypertension.
We first restricted the cohort to subjects without evidence of overt cardiovascular
disease as indicated by hospital admissions with heart disease as a discharge
diagnosis (International Classification of Diseases, Ninth
Revision, code 402, 404, 410-416, 420-429, or 745.4-746.9) in the year
preceding cohort entry. We also excluded subjects who, in the same period,
were pharmacologically treated for conditions for which antihypertensive medications
are also indicated. These conditions include migraine, hyperthyroidism, and
arrhythmia (for which ß-blockers are indicated), angina (ß-blockers
and CAs), and congestive heart failure (ACEIs and diuretics). Subjects who
used any cardiovascular agent (anticoagulants, loop diuretics, or other cardiac
agents) in the year before initiation of hypertension therapy were also excluded.
Overall, slightly more than 7000 subjects were excluded from the initial cohort
because of overt cardiovascular disease. An additional 89 users of thyroid
drugs and 969 subjects who used ergot preparations were excluded because of
the possible use of antihypertensive agents as an adjuvant to the treatment
of hyperthyroidism or migraine. We assumed the remaining subjects to be treated
for uncomplicated hypertension and followed them up until the earliest of
March 31, 1997, date of death, emigration from the province, or end of coverage
of the insurance plan.
ANTIHYPERTENSIVE DRUG USE
Patterns of use of the major antihypertensive drug classes were examined.
Both initial treatment and subsequent modifications to therapy were documented.
Initial Therapy
Initial treatment regimen was defined as the
first antihypertensive agent dispensed. Initial regimens were divided into
single-drug use (ACEI, ß-blocker, or CA only) or combination therapy,
defined as either the dispensing of more than 1 drug class or a fixed-combination
product containing drugs from different classes (eg, ACEI-diuretic combination)
(Table 1). Subjects initiating
therapy with diuretics were not included.
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Table 1. Antihypertensive Drug Classes Used at Treatment Initiation*
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Modifications to Therapy
Any change to the initial drug class was considered a modification to
therapy. A treatment interruption was defined as a failure to fill a prescription
for any of the studied agents in the 120 days after the filling date of the
last prescription, assumed to last 30 days. The 90-day cutoff point for drug
holidays was based on the ground that, with an 80% threshold for compliance,
2.5 months without using any antihypertensive drugs would be required during
a 1-year period for a patient to be considered not compliant enough to benefit
from therapy. When the last treatment regimen included more than 1 agent from
the same drug class, possible stockpiling of medications was considered by
treating them as sequential prescriptions and assuming continuing therapy,
providing the prescriptions were dispensed within 15 days of each other.
To differentiate between a switch and the addition of a second or third
drug, an algorithm similar to that used by Caro et al13
was constructed by using, for each prescription, information pertaining to
the subsequent dispensing dates. Two types of modifications to therapy were
considered: (1) switching from a therapeutic drug class to another (if at
least 1 agent belonging to a different therapeutic drug class was encountered
in the following trimester without renewal of the index one) and (2) adding
a second drug class (if at least 1 prescription that belonged to a different
therapeutic class was encountered in the following trimester in addition to
the index one). Dropping 1 or several drugs from treatment was not considered
in the algorithm. For a switch or a drug addition to occur, a gap of up to
119 days was allowed between 2 dispensing dates. Otherwise, the modification
was considered to be a treatment interruption if a new course of therapy occurred
before the end of follow-up and a discontinuation of therapy if not. Hence,
a subject discontinuing therapy did not use any antihypertensive agents until
the end of follow-up. Dosage adjustments were not considered to be modifications
to therapy.
STATISTICAL ANALYSIS
Simple contingency tables for proportions were used to provide descriptive
data on the patterns of use of antihypertensive agents. Logistic regressions
were used to examine the correlates of initial treatment, with ß-blockers
as the reference. Time to the first modification to therapy was assessed by
means of multivariate Cox proportional hazards models, and the rates of modifications
to therapy were modeled by means of Poisson regression for rates accounting
for between-subject variation. Factors potentially associated with any of
these patterns of use included patient characteristics (age, sex, and social
assistance), physician visits and hospitalizations in the year preceding treatment
initiation, and drug markers for comorbid conditions during that same period
(nonsteroidal anti-inflammatory drugs, glucocorticoids, neurotropic [lithium
carbonate, benzodiazepines, antidepressants, and major tranquilizers] and
antilipemic agents, drugs used for respiratory illness, and antiulcer medications).
The year of treatment initiation and the duration of follow-up were also controlled
for to account for possible time trends in medication use. Diabetes and the
onset of heart failure or angina were also included as predictors of treatment
modifications, along with the drug class used at treatment initiation.
RESULTS
PATIENT CHARACTERISTICS
Study subjects were aged 60 years on average, and almost half of them
were male (Table 2). Slightly
more than 4% of them received social assistance at initiation of therapy.
Slightly more patients were included earlier during the study period (27%
in 1990 and 22% in 1993).
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Table 2. Characteristics of the Study Population at Treatment Initiation
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INITIAL ANTIHYPERTENSIVE THERAPY
Distribution of Antihypertensive Drugs at Treatment Initiation
Of the 4 treatment regimens under study, ACEIs were the most commonly
dispensed at treatment initiation (37.4%), followed by CAs (27.5%) and ß-blockers
(26.4%). Of the 1708 patients starting combination therapy (8.8%), 86.8% received
a diuretic in addition to 1 of the 3 main agents. Only 64 patients received
more than 2 different agents to initiate therapy.
Time Trends
Examination of the rates of use of these agents at treatment initiation
over time showed ACEI use to have significantly increased between 1990 and
1993 (P<.001 by  2 test). The use
of CAs and ß-blockers as single agents and prescription of multiple drug
therapy seemed more stable (Figure 1).
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Figure 1. Time trends in initial treatment
according to antihypertensive drug class. ACEI indicates angiotensin-converting
enzyme inhibitor; BBL, ß-blocker; and CA, calcium antagonist.
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Factors Associated With Initial Therapy
Men, older subjects, users of antidiabetic medications or respiratory
agents, and subjects who visited a cardiologist in the preceding year were
more likely to initiate therapy with an ACEI or a CA than with a ß-blocker
(Table 3). Later initiation of
therapy also increased the probability of being prescribed CAs, whereas previous
use of neurotropic agents was negatively associated with filling a first prescription
for CAs. However, previous use of antiulcer or neurotropic agents and previous
visits to a cardiologist were negatively associated with ACEI use at treatment
initiation relative to ß-blockers. Previous use of NSAIDs or neurotropic
or antiulcer agents, as well as previous visits to a cardiologist, decreased
the risk of starting antihypertensive treatment with multiple agents, whereas
respiratory illness and diabetes were positively associated with that initial
choice. Older age and male sex also increased the likelihood of using multiple
agents at treatment initiation compared with ß-blockers.
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Table 3. Baseline Characteristics of Study Subjects in Relation to
Initial Drug Class (vs ß-Blockers)*
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MODIFICATIONS TO THERAPY
Incidence of Modifications to Therapy
During the period of observation, 11.5% of study subjects had no treatment
modification or interruption. The overall rate of treatment modification was
58.1 per 100 subjects per year. Treatment interruptions and addition of 1
or several agents were the most frequent types of modification (30.1 and 27.9
per 100 subjects per year, respectively), whereas the rate of switching across
therapeutic classes was rather low (5 per 100 subjects per year). Predictors
of the frequency of switching or adding drugs belonging to another therapeutic
class were found to be older age, male sex, and overt heart failure or angina.
Also, the rates of such modifications to therapy were significantly higher
among subjects who started treatment with an ACEI (adjusted relative risk,
1.29; 95% confidence interval, 1.24-1.34), a CA (adjusted relative risk, 1.11;
95% confidence interval, 1.06-1.16), and combination therapy (adjusted relative
risk, 1.45; 95% confidence interval, 1.37-1.55), compared with ß-blockers.
Types of Modifications
Of the first episodes of treatment modification, the most common were
interrupting treatment (31.5%) and discontinuing therapy (22.6%) (Figure 2). Agents belonging to a different
drug class were added for 20.1% of the study subjects, whereas 14.3% switched
to another therapeutic drug class. Of those who added a drug to their initial
treatment regimen, 47.6% did not subsequently modify their treatment, whereas
20.9% underwent another drug addition or switch. Among those who switched
first, these figures were 24.4% and 36%, respectively. More than half of the
stoppers came back to their initial treatment after the interruption. For
6940 subjects (35.6%), the first modification was the only one to occur during
the entire period of observation.
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Figure 2. Types and frequency of the first
2 modifications to therapy.
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Summarizing the type and frequency of the first 2 treatment modifications
starting from initial treatment led to 8 different patterns of drug use (Table 4). Important differences exist with
regard to the types of modification across initial treatment arms. Patients
in whom the initial treatment was combination therapy were more likely than
others to keep on with their initial treatment regimen or to interrupt treatment
a first time and start a new course of therapy with a different drug class.
Subjects using ß-blockers at treatment initiation and, to a lesser extent,
CAs were more likely to discontinue therapy or to interrupt treatment a first
time and come back to their initial treatment thereafter. Patients using ACEIs
at treatment initiation and, to a lesser extent, those using CAs were more
likely to add or switch twice in a row or to add or switch first and interrupt
treatment thereafter. Stratification beyond the second modification to therapy
resulted in numbers too small to draw conclusions from.
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Table 4. Types and Frequency of the First 2 Modifications to Therapy,
According to Initial Drug Class*
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Timing and Predictors of the First Modification to Therapy
One year after starting treatment, only 33.8% of patients were still
using the drug they were dispensed at treatment initiation, ie, did not yet
undergo any modification to initial therapy. Overall, the median time to the
first treatment modification was 134 days. A rapid early decrease in the proportion
of patients continuing to receive initial therapy was shown (Figure 3; P<.001 [log-rank test]). The
first modification to therapy arose considerably later for patients who started
with combination therapy or ACEIs, with median times to the first modification
of 202 and 208 days, respectively. This compares with 75 days for patients
who initiated treatment with ß-blockers and 105 days for CAs. Timing
of treatment modifications also differed according to the type of the first
modification, with discontinuation of therapy and treatment interruptions
occurring earlier than drug switches and additions (not shown). Overall, 50%
of subjects discontinuing therapy did so within 37 days of initiation of therapy.
Median time for a treatment interruption was 86 days, whereas this figure
was 146 and 218 days for drug switches and additions, respectively.
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Figure 3. Cumulative proportion of patients
continuing to receive initial therapy, according to initial agent. ACEI indicates
angiotensin-converting enzyme inhibitor; BBL, ß-blocker; and CA, calcium
antagonist.
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Predictors of a first modification to therapy did not differ in a clinically
important way across modification types, all relative risks lying between
0.85 and 1.2. As a general rule, younger subjects were found to be more likely
to experience any type of modification to therapy, as were men. Patients initiating
therapy with a ß-blocker were also found to have higher rates of modifications
than others, even after statistical adjustment for other potential predictors.
Finally, subjects starting treatment with a combination therapy were less
likely to experience a modification to therapy.
COMMENT
This study represents one of the first attempts to describe the patterns
of use of antihypertensive agents in Saskatchewan, from treatment initiation
onward, during a long period of observation. Our study confirms that those
patterns are highly variable, with a high frequency of treatment interruptions
and modifications. First, it appears that ACEIs and CAs are increasingly used
as initial therapy. Second, we found that only 11.5% of study subjects continuously
used the agent with which they initiated treatment. Caro et al14
reported earlier that a surprisingly high number of patients discontinued
therapy early after treatment initiation. Our study confirms this finding.
In addition, we found this to be more of a problem among ß-blocker users,
who tend to stop using antihypertensive agents earlier and in a higher proportion.
It is also interesting to note that patients receiving combined therapy were
less likely to modify their treatment regimen.
Both US and Canadian guidelines on the treatment of hypertension advise
the use of either diuretics or ß-blockers as first-line agents, unless
there are special indications for the use of other drug classes.18-21
The high prevalence of treatment initiation with ACEIs and CAs in our study
suggests that either adherence to clinical guidelines in Saskatchewan is not
very high or our study did not succeed in identifying special indications
for the use of other drug classes. Despite efforts to include modifications
to therapy, treatment interruptions, and general adherence to treatment regimens
in effectiveness analyses, randomized controlled trials are hardly comparable
with what actually happens at the population level. Still, it is assumed that
the positive results of large-scale randomized controlled trials would be
translated into effective treatment regimens in clinical practice. Our study
shows that, because of the high prevalence of treatment modifications and
interruptions, this may not be the case.
Commercial influences may have contributed to decreasing the use of
older agents such as ß-blockers22-23
while contributing to the increased use of CAs and ACEIs at treatment initiation.
Characteristics of the patients such as age, sex, and the presence of risk
factors or markers of complicated hypertension should also influence hypertension
management.24 Such factors did indeed emerge
in our study as predictors or correlates of initial drug choice. Surprisingly,
however, none of them emerged as predictors of the rates of treatment modification.
We found that patients who started treatment with ß-blockers had
higher discontinuation rates that occurred earlier in time. One likely hypothesis
to explain this result is that patients with less severe hypertension or without
specific concomitant conditions were more likely to receive these agents,
which would be consistent with clinical guidelines. We may assume as well
that modifications to treatment regimens may be indicative of poor blood pressure
control, lack of tolerance of the drug, or the onset of concomitant conditions.
Failure to achieve blood pressure control or the presence of concomitant diseases
may prompt treating physicians to step up the treatment regimen by (1) prescribing
a higher dose of the same agent, (2) substituting a more potent medication,
or (3) adding another antihypertensive agent.18-21
Side effects of the drugs, although not documented in this study, are also
a possible reason for stopping treatment. Also, the use at that time of nonselective ß-blockers
as well as the formerly often used high starting doses may have resulted in
many such changes.
Patients initiating therapy with combination drugs are probably considerably
different from other patients with newly diagnosed hypertension. First, it
is contrary to every clinical guideline to initiate therapy with multiple
drugs. These atypical patients represent only 8.8% of our study population,
which would represent around 3.5% of all patients with newly diagnosed hypertension
if patients starting treatment with diuretics were included. We hypothesize
that they represent sicker patients, more prone to use health services (including
drugs) and consequently more compliant with therapy, which would explain the
lower incidence of modifications to therapy in that group.
Computerized databases of prescription claims offer major advantages
for drug use studies, including the possibility of documenting the entire
history of drug use. Records of dispensed medications offer the possibility
of investigating patterns and timing of drug exposure and assessing determinants
and consequences of different patterns of use. Also, the large number of study
subjects allows a detailed description of the frequency of these patterns
in the population.
The degree of detail with regard to drug dispensing and a 7-year period
of observation constitute 2 major strengths of this study. Modifications to
therapy are hard to measure with accuracy.25
Previous drug use studies and examination of drug-taking behaviors have mostly
focused on measures of compliance averaged over a short period (usually 12
months). Also, 22% of the study subjects modified their treatment regimens
for the first time after the first year of observation. Hence, limiting the
latter to 1 year would result in a considerable loss of information.
However, the use of computerized records also carries some limitations,
a major one being the lack of information about the indication and the specific
directions for use of the prescribed agents. Despite the fact that drug markers
have been used previously with good correlations with the diagnosis of hypertension,26 antihypertensive agents may have been used in some
study subjects to treat other conditions. Also, the average duration of an
antihypertensive drug prescription in Saskatchewan had to be used as a proxy.
Finally, drug data represents dispensed medications, and actual drug-taking
behaviors remain unknown. We suggest, however, that the likelihood of a patient
not actually taking medications that have been filled continuously is probably
low.
An important limitation of our study pertains to the definition of the
source population. First, because our initial study proposal did not address
patterns of drug use in patients who started treatment with diuretics, those
were not included in the cohort. This considerably limits the applicability
of our study findings. On the basis of external sources,13
diuretic use at treatment initiation could represent 38% of all prescriptions
for an antihypertensive agent. However, providing that the reported prevalence
data are interpreted in relative rather than absolute terms in our study,
this should not be a major threat to the validity of the study. The results
would also have benefited from an age-stratified analysis to assess whether
the patterns of use of antihypertensive agents vary across age groups, especially
among the very elderly population. Unfortunately, our sample size was insufficient
to allow such an analysis. Also, drug dosage adjustments were not included
in our definition of a modification of therapy, and drug dropping was not
documented. This means that our reported rates of modification to therapy
are probably conservative. Finally, these results describe the use of prescribed
drugs in Saskatchewan between 1990 and 1997 and may not reflect actual drug
use in other settings or time frames.
Despite all the progress in the field of hypertension management, selecting
the most appropriate agent for the individual patient remains a challenge.
Guidelines are based on efficacy results obtained from randomized controlled
trials, which may not reflect the actual population that eventually uses these
agents. Also, the relative value of antihypertensive agents should not be
measured solely by their ability to lower blood pressure or by their beneficial
effect on intermediate variables. Evidence of their ability to deliver better
cardiovascular protection and to improve survival should be available for
the entire population of potential users, not only for highly selected groups
of subjects such as those participating in randomized controlled trials. Hence,
high degrees of variability in drug-taking behaviors should be taken into
account when drug effects are assessed at the population level, and adherence
to therapy should be strongly encouraged.
AUTHOR INFORMATION
Accepted for publication January 9, 2001.
This study was funded by a grant from the Fonds de la Recherche en Santé
du Québec. The data were acquired thanks to grants from Hoescht Marion
Roussel, Kansas City, Mo, and Zeneca Pharmaceuticals, Toronto, Canada. Dr
Bourgault is currently the recipient of a postdoctoral fellowship from the
Medical Research Council of Canada (ZH5-36754) at Yale University School of
Internal Medicine (New Haven, Conn) and was, at the time the study was conducted,
the recipient of doctoral fellowships from the National Health Research and
Development Program (6605-4498-47) and the Social Sciences and Humanities
Research Council (752 94 1767) of Canada. Dr Suissa is the recipient of a
Senior Scientist Award from the Medical Research Council (ZH2-32088) of Canada.
Presented at the 16th International Conference on Pharmacoepidemiology,
Barcelona, Spain, August 21, 2000.
This study used data provided by the Saskatchewan Department of Health.
The statements contained herein do not necessarily represent those of the
Saskatchewan government.
We gratefully acknowledge the assistance of Serge Benayoun, MSc, in
editing the first version of the manuscript. We also thank Mary McNutt of
the Saskatchewan Research Services, Population Health Branch, Regina, for
her expertise and assistance with the data. Although the study was funded
by Zeneca Pharmaceuticals, the authors of this research were fully independent
in conception, design, analysis, and interpretation.
Corresponding author and reprints: Samy Suissa, PhD, Division of
Clinical Epidemiology, Royal Victoria Hospital (MUHC), 687 Pine Ave W, Ross
4.29, Montreal, Quebec, Canada H3A 1A1.
From the Department of Epidemiology and Biostatistics, McGill University
(Drs Bourgault and Suissa), and Pharmacoepidemiology Research Unit, Division
of Clinical Epidemiology, Royal Victoria Hospital, McGill University Health
Centre (Drs Bourgault and Suissa and Mr Rainville), Montreal, Quebec.
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