Irritable Bowel Syndrome and Gastroesophageal Reflux Disease in Primary Care: Is There a Link?

Abstract

Population-based studies have shown that gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS) coexist
more commonly than expected by chance. We aimed to investigate the relationship between GERD and IBS in primary care. The
General Practice Research Database was used to identify patients with a first diagnosis of GERD (n=6,421) or IBS (n=2,932). Patients were followed up for 12months after diagnosis to investigate the incidence of IBS among GERD patients
and GERD among IBS patients. The relative risk (RR) of developing IBS was 3.5 (95%CI: 2.3–5.4) in the GERD cohort compared
with the comparison cohort. The RR of developing GERD was 2.8 (95% CI: 1.7–4.9) in the IBS cohort compared with the comparison
cohort. A first diagnosis of either IBS or GERD significantly increases the risk of a subsequent diagnosis of the other condition.

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ORIGINAL ARTICLE
Irritable Bowel Syndrome and Gastroesophageal Reflux Disease
in Primary Care: Is There a Link?
Ana Ruigo ´mez Æ Æ Mari-Ann Wallander Æ Æ
Saga Johansson Æ Æ Luis Alberto Garcı ´a Rodrı ´guez
Received: 3 March 2008/Accepted: 16 July 2008/Published online: 22 August 2008
? Springer Science+Business Media, LLC 2008
Abstract
troesophageal reflux disease (GERD) and irritable bowel
syndrome (IBS) coexist more commonly than expected by
chance. We aimed to investigate the relationship between
GERD and IBS in primary care. The General Practice
Research Database was used to identify patients with a first
diagnosis of GERD (n = 6,421) or IBS (n = 2,932).
Patients were followed up for 12 months after diagnosis to
investigate the incidence of IBS among GERD patients and
GERD among IBS patients. The relative risk (RR) of
developing IBS was 3.5 (95% CI: 2.3–5.4) in the GERD
cohort compared with the comparison cohort. The RR of
developing GERD was 2.8 (95% CI: 1.7–4.9) in the IBS
cohort compared with the comparison cohort. A first
diagnosis of either IBS or GERD significantly increases the
risk of a subsequent diagnosis of the other condition.
Population-based studies have shown that gas-
Keywords
reflux ? Irritable bowel syndrome ? Primary health care
Database ? Epidemiology ? Gastroesophageal
Introduction
Irritable bowel syndrome (IBS) and gastroesophageal
reflux disease (GERD) are both common gastrointestinal
diseases. The Rome III criteria define IBS as ‘‘a functional
bowel disorder in which abdominal pain or discomfort is
associated with defecation or a change in bowel habit, and
with features of disordered defecation’’ [1]. A recent,
global, evidence-based consensus (the Montre ´al Defini-
tion) defines GERD as ‘‘a condition which develops when
the reflux of stomach contents causes troublesome symp-
toms and/or complications’’ [2]. IBS and GERD frequently
coexist in the same patients [3]. Population-based studies
have shown that GERD and IBS coexist more commonly
than would be expected by chance [4–9]. A small number
of clinic-based studies also support these findings [10–12].
However, little is known about the natural history of
these conditions and their temporal relationship to each
other.
Subjects with upper gastrointestinal symptoms can
interchange between IBS and dyspepsia in population-
based surveys, but a questionnaire-based diagnosis of
GERD appears to be more stable, with only a minority of
individuals changing their symptom profile to dyspepsia
and/or IBS, or vice versa, 7 years later [13]. In primary
care, a longitudinal study that looked at the natural history
of GERD showed that patients with a new diagnosis of
GERD were more likely to have an existing diagnosis of
IBS than individuals with no GERD diagnosis, but the
reverse relationship was not investigated [14].
The current study sought to explore further the rela-
tionship between IBS and GERD diagnosed in primary
care. We conducted two longitudinal cohort studies to
investigate this relationship in UK primary care using the
General Practice Research Database (GPRD).
A. Ruigo ´mez (&) ? L. A. G. Rodrı ´guez
Spanish Centre for Pharmacoepidemiological Research (CEIFE),
Almirante 28, 28, 28004 Madrid, Spain
e-mail: aruigomez@ceife.es
M.-A. Wallander ? S. Johansson
AstraZeneca R&D, Mo ¨lndal, Sweden
M.-A. Wallander
Department of Public Health and Caring Science, Uppsala
University, Uppsala, Sweden
S. Johansson
Institute of Medicine, Sahlgrenska Academy, Gothenburg
University, Gothenburg, Sweden
123
Dig Dis Sci (2009) 54:1079–1086
DOI 10.1007/s10620-008-0462-0

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Materials and Methods
Source Population and Study Design
The source population for our studies was derived from the
GPRD. The GPRD contains anonymized data entered by
approximately 1,500 primary care physicians (PCPs) in the
UK, and covers a population of over 3 million [15]. Basic
demographic details are recorded for each patient, as are
details of all drug prescriptions together with the indication
for the drug, referrals to hospital, hospitalizations, and
details of selected tests and their results. Information sub-
mitted to the GPRD is subject to a range of quality checks,
and practices that fail to meet the required standard are
removed from the database [16].
The source population for our studies consisted of all
individuals in the GPRD aged 20–79 years at the start of
the study who were enrolled with a PCP for at least 2 years,
had a computerized prescription history for at least 1 year,
were not pregnant and were free of cancer (Fig. 1).
A number of surveys have validated the quality of
informationrecordedintheGPRD[17,18].Wecarriedouta
validation exercise as part of a previous study looking at
GERD in the GPRD [14]. In this validation exercise, over
90%ofthequestionnairessenttophysicianswerecompleted
and returned, and 73% of GERD diagnoses were confirmed
as being the first ever by the PCP. The GERD cohort used in
the present study is derived from this validated GERD
cohort.
Study Cohorts and Case Assessment
Study 1: Risk of IBS Following a GERD Diagnosis
To evaluate the risk of IBS following a diagnosis of GERD
weusedstudygroups fromapreviousstudyinwhich wehad
identified a cohort of patients newly diagnosed with GERD
in 1996 [14]. For the present analysis we excluded from this
original cohort those patients who had a recorded diagnosis
of IBS prior to 1996. This resulted in a GERD cohort of
6,421 patients. A comparison cohort (n = 10,000), fre-
quency-matched by age and sex to the GERD cohort, was
randomly sampled from the source population. After
applyingthesamestudyexclusioncriteriaaswereappliedto
the GERD cohort, 9,387 individuals without a GERD
diagnosis at the study start date constituted the comparison
cohort for study 1 (Fig. 1). Both cohorts were followed for
1 year to identify new cases of IBS. Incidence rates of IBS
were computed according to age and sex among both the
GERD cohort and the comparison cohort. We estimated the
Fig. 1 Study population and
design. GERD,
gastroesophageal reflux disease;
IBS, irritable bowel syndrome
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relative risk (RR) of IBS associated with GERD using Cox
proportional hazard regression, adjusting for potential risk
factors.
A nested case–control analysis was performed within the
GERD cohort to evaluate the association between various
factors and the risk of IBS. This compared cases with an
IBS diagnosis (n = 96) with the remaining GERD patients
with no IBS diagnosis (n = 6,325) used as controls. The
date of IBS diagnosis was designated as the index date
among cases, and a random date during the 1-year follow-
up period was designated as the index date for the controls.
We estimated odds ratios (ORs) and 95% confidence
intervals (CIs) using logistic regression analysis.
Study 2: Risk of GERD Following a IBS Diagnosis
To evaluate the risk of GERD following an IBS diagnosis
we used the study group from another previous study in
which we had identified a cohort of patients aged 20–
79 years who were newly diagnosed with IBS in 1994 [19].
For the present analysis, we excluded from this original
cohort of IBS patients those who had a recorded diagnosis
of GERD prior to 1994. This resulted in an IBS cohort of
2,932 patients. A comparison cohort, frequency-matched
by age and sex to the IBS cohort, was randomly sampled
from the source population. After applying the same study
exclusion criteria as were applied to the IBS cohort, 4,968
individuals without an IBS diagnosis at the study start date
constituted the comparison cohort for study 2 (Fig. 1). Both
cohorts were followed for 1 year to identify new cases of
GERD. The incidence of GERD was computed according
to age and sex among both the IBS cohort and the com-
parison cohort. The RR of a GERD diagnosis among
patients with IBS was estimated using Cox regression
analysis adjusted for sex and age.
A nested case–control analysis was performed within
the IBS cohort to evaluate the association of several factors
with the risk of GERD. This compared cases with a GERD
diagnosis (n = 44) with the remaining IBS patients with no
diagnosis of GERD (n = 2,888) used as controls. The date
of GERD diagnosis was used as the index date among
cases, and a random date during the follow-up period was
used as the index date for the controls. Logistic regression
analysis was used to compute ORs and 95% CIs.
For both studies, information was obtained on patient
demographics, morbidity and drug use recorded by the PCP
in the 12 months prior to diagnosis and the 12 months
following diagnosis. Current/recent drug use was defined
as a supply of the most recent prescription lasting until the
index date or ending in the previous 365 days. Past use was
defined as a prescription ending more than 365 days before
the index date. Non-use was defined as no recorded pre-
scription before the index date.
Results
Study 1: Risk of IBS Following GERD Diagnosis
During the 1-year follow-up period, 96 patients were
diagnosed with IBS in the GERD cohort (n = 6,421) cor-
responding to an incidence rate of IBS of 15.0 per 1,000
person-years (95% CI: 11.9–17.7). During the same period,
33 patients were diagnosed with IBS in the comparison
cohort (n = 9,387), representing an incidence rate of 3.5
per 1,000 person-years (95% CI: 2.5–4.9). Incidence of IBS
was found to be higher among females of all ages in both
study cohorts, particularly in the 30–49 years age group.
We observed a decreased incidence of IBS in individuals
aged 70 years or over in all groups except the female
comparison group (Fig. 2). Patients with incident GERD
were more than three times more likely to be diagnosed
with IBS during the follow-up period than age- and
sex-matched patients without GERD (RR: 3.5; 95% CI:
2.3–5.4).
Patients with GERD who visited their PCP more often
([10 visits in the year prior to diagnosis compared with 0–2
visits) were at a significantly increased risk of an IBS
diagnosis (OR: 2.0; 95% CI: 1.1–3.7). Among GERD
patients, a history of stress was also associated with an
increased risk of an IBS diagnosis (OR: 3.1; 95% CI:
1.2–7.9) (Table 1). Associations of IBS diagnosis with
female sex (OR: 1.6; 95% CI: 1.0–2.5), and referral/
hospitalization in the previous year (OR: 1.7; 95% CI:
1.0–2.8), were of borderline significance. A history of
painful conditions, sleep disorders, anxiety and depression
1 year prior to GERD diagnosis, and age, did not vary sig-
nificantlybetweensufferers withandwithoutIBS(Table 1).
Fig. 2 Incidence rates of irritable bowel syndrome (IBS) in patients
with gastroesophageal reflux disease (GERD) and in the comparison
cohort, by sex and age group
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Prescribed oral contraceptives and hormone replacement
therapy (HRT) were positively associated with a diagnosis
of IBS in patients with GERD (Table 2). Significant
associations were found with both current/recent use (in the
previous 365 days) of HRT (OR: 2.4; 95% CI: 1.3–4.6),
and current/recent and past use of oral contraceptives. We
found no evidence of an association between past use of
HRT and a diagnosis of IBS (OR: 1.6; 95% CI: 0.5–4.6).
Study 2: Risk of GERD Following IBS Diagnosis
Among the cohort of patients with IBS (n = 2,932), 44
were diagnosed with GERD during the follow-up period,
corresponding to an incidence rate of GERD of 15.0 per
1,000 person-years (95% CI: 11.2–20.1). Of the compari-
son cohort with no IBS diagnosis (n = 4,968), 22 were
diagnosed with GERD during the 1-year follow-up period.
This corresponds to an incidence rate of 4.4 per 1,000
person-years (95% CI: 2.9–6.7). There are no obvious age-
or sex-related trends in the incidence of GERD. The
apparently high incidence of GERD in females aged over
70 years newly diagnosed with IBS (Fig. 3) could be a
reflection of the small numbers of patients in this age
group. Patients with incident IBS were nearly three times
more likely to be diagnosed with GERD during the follow-
up period than patients without an IBS diagnosis (RR: 2.8;
95% CI: 1.7–4.9).
When adjusted for all other variables measured, neither
age nor gender were associated with developing GERD in
patients newly diagnosed with IBS (Table 3). A history of
pain-related diagnoses (OR: 3.1; 95% CI: 1.4–6.9) or
cough (OR: 2.8; 95% CI: 1.1–7.6) was associated with a
greater risk of developing GERD in patients with a diag-
nosis of IBS. However, we found no evidence of an
association between stress, sleep disorders, anxiety,
depression, asthma or laryngitis and a diagnosis of GERD
(Table 3). The use of HRT or oral contraceptives prior to
IBS diagnosis did not affect the risk of developing GERD
in women after a first episode of IBS (data not shown).
Discussion
This longitudinal study of patients in UK primary care is
the first to investigate the temporal relationship between
new diagnoses of GERD and IBS in the general population.
The incidence of IBS in individuals with GERD, and
GERD in individuals with IBS, is substantially higher than
in individuals with neither disease; in both cases there is an
approximately threefold increase in the risk of developing
the other disease. This could suggest that there is a shared
Table 1 Characteristics of
patients with gastroesophageal
reflux disease (GERD) with and
without subsequent irritable
bowel syndrome (IBS)
diagnoses, and their association
with a diagnosis of IBS (Study
1)
aOdds ratio (OR) estimates
with 95% confidence intervals
(CI) were adjusted by age, sex,
smoking, body mass index,
alcohol use and healthcare
utilization using logistic
regression
bPainful conditions included
headache, neuralgia, menstrual
and inter-menstrual pain, female
genital pain, eye pain, earache,
nose pain, throat pain, mouth
pain, chest pain, respiratory
pain, abdominal pain, rectal
pain, urinary tract pain, penile
and testicular pain, skin pain,
breast pain, limb pain, muscular
and joint pain, neck pain and
generalized pain
GERD patients with
a subsequent IBS
diagnosis n = 96 (n [%])
GERD patients with
no IBS diagnosis
n = 6,325 (n [%])
ORa(95% CI)
Age (years)
20–29 10 (10.4)541 (8.6)1
30–49 38 (39.6) 2100 (33.2)0.9 (0.4–1.8)
50–6938 (39.6) 2682 (42.4)0.6 (0.3–1.3)
70–7910 (10.4)1002 (15.8)0.4 (0.2–1.0)
Gender
Male 37 (38.5) 3073 (48.6)1
Female59 (61.5) 3252 (51.4)1.6 (1.0–2.5)
Visits to primary care physician in the previous year
0–2 23 (24.0)1936 (30.6)1
3–10
[10
41 (42.7)3296 (52.1)0.9 (0.5–1.5)
32 (33.3)1093 (17.3) 2.0 (1.1–3.7)
Referral/hospitalization in the previous year
No 21 (21.9)5302 (83.8)1
Yes75 (78.1) 1023 (16.2)1.7 (1.0–2.8)
Morbidity in the year before GERD diagnosis
Painful conditionsb
52 (54.2) 3091 (48.9)0.9 (0.6–1.4)
Stress5 (5.2) 89 (1.4) 3.1 (1.2–7.9)
Sleep disorders8 (8.3) 221 (3.5) 2.0 (0.9–4.2)
Anxiety 11 (11.5)338 (5.3)1.6 (0.8–3.1)
Depression 29 (30.2) 1336 (21.1)1.2 (0.6–2.3)
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comorbidity profile or risk factor phenotype that predis-
poses some individuals to both these diseases. It has
previously been reported that GERD, IBS and functional
dyspepsia may share a common pathophysiological
mechanism such as visceral hypersensitivity, or peristalsis
or gastric motility impairment [3, 20]. Alternatively, there
could be a familial association between the three diseases
[20]. However, there is, as yet, insufficient evidence for
any pathophysiological mechanism that could explain the
association between GERD and IBS. Furthermore, we have
found no shared risk factors in this study that could explain
the observed relationship. This suggests that IBS and
GERD are more likely to be separate diseases in most
patients, rather than different manifestations of the same
condition.
Patients with GERD can be managed with acid-sup-
pressive drug therapy, but may differ in their response to
this treatment [3]. It has been suggested that the presence
of dyspepsia or IBS tends to decrease the response rate of
GERD patients to proton pump inhibitors [21]. This may
help to explain why many patients with GERD have
incomplete symptom relief with proton pump inhibitors,
and are therefore considered to be non-responders [22].
IBS in Patients with GERD
Age did not have a significant effect on IBS occurrence in
patients with GERD in this study. Previous studies have
found that IBS occurs mostly in the young and middle-
aged, but this relationship is not always clear [23]. We did,
however, find support for two risk factors for IBS (female
sex and stress) that have been identified in previous studies
[19, 24–27]. The predominance of females among IBS
patients, and the associations with psychosocial factors
such as stress, has been attributed to differences in con-
sulting behaviour[28–30].
explanations may also underpin these observations. There
are physiological sex-related differences in the autonomic
and perceptual response to pain and stress [31, 32]. Psy-
chosocial factors, including total life stress, are associated
with gastrointestinal symptoms (including IBS) in the
community as well as in consulters and therefore may drive
pathophysiology [27]. Pain burden, rather than psychoso-
cial factors, was associated with healthcare seeking in the
community [33].
We have also found evidence supporting a link between
ovarian hormones and IBS. HRT use has previously been
associated with an increased risk of IBS in postmenopausal
women, similar to the increased risk in younger women
associated with endogenous oestrogenic activity [34].
Patterns of IBS symptoms are known to vary during the
menstrual cycle [35, 36], and ovarian hormones are known
However, physiological
Table 2 Use of ovarian hormone drugs in women with gastroesophageal reflux disease (GERD), and their association with a subsequent
diagnosis of irritable bowel syndrome (IBS) (Study 1)
GERD patients with a subsequent
IBS diagnosis n = 59 (n [%])
GERD patients with no IBS
diagnosis n = 3,252 (n [%])
ORa(95% CI)
Use of prescribed hormone replacement therapy before GERD diagnosisb
Non-use 38 (64.4) 2,483 (76.4)1
Current/recent use 17 (28.8) 550 (16.9)2.4 (1.3–4.6)
Past use
Use of oral contraceptives before GERD diagnosisb
4 (6.8)219 (6.7) 1.6 (0.5–4.6)
Non-use 37 (62.7) 2,807 (86.3)1
Current/recent use10 (16.9)235 (7.2) 3.6 (1.4–9.0)
Past use 12 (20.3)210 (6.5) 4.4 (1.9–10.0)
aOdds ratio (OR) estimates with 95% confidence intervals (CI) were adjusted by age, sex, smoking, body mass index, alcohol use and healthcare
utilization using logistic regression
bCurrent/recent use was defined as a supply of the most recent prescription lasting until the index date or ending in the previous 365 days. Past
use was defined as a prescription ending more than 365 days before the index date. Non-use (no recorded prescription before the index date) was
used as the reference category
Fig. 3 Incidence rates of gastroesophageal reflux disease (GERD) in
patients with irritable bowel syndrome (IBS) and in the comparison
cohort, by sex and age group
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to affect the gastrointestinal tract [37]. Furthermore, animal
studies have discovered potential physiological mecha-
nisms linking stress and ovarian hormone status with IBS
[38–40].
GERD in Patients with IBS
We found no association between age or sex and a diag-
nosis of GERD in patients with IBS. This tends to agree
with previous studies that have shown no association of
GERD with sex (excluding pregnant women), while the
associations with age are less clear [41].
We did find that several of the traditional risk factors for
GERD in the general population also appear to increase the
risk of GERD diagnosis in patients with IBS. In IBS
patients, a history of general pain or cough was associated
with a greater risk of developing GERD. Individuals from
the general population who have a history of painful con-
ditions have also been found to be at greater risk of a
diagnosis of GERD [14]. Pain affects quality of life and
this group may have had a more severe symptom burden
prompting consultation [24, 33, 42]. There is evidence that
constipation-predominant IBS (IBS-C) is associated with
more pain and upper gastrointestinal symptoms [43] and it
may be that these patients were disproportionately IBS-C
sufferers, or they may have had a heightened sensitivity to
pain. Chronic cough is now established as being associated
with GERD, although the causal relationship is unclear. In
the recently published Montre ´al Definition, reflux cough
syndrome is recognized as an established extra-esophageal
syndrome of GERD [2]. IBS has also been found to be
associated with chronic cough: a recent community survey
Table 3 Characteristics of patients with irritable bowel syndrome (IBS) with and without subsequent gastroesophageal reflux disease (GERD)
diagnoses, and their association with a diagnosis of GERD (Study 2)
IBS patients with a subsequent
GERD diagnosis n = 44 (n [%])
IBS patients with no diagnosis
of GERD n = 2,888 (n [%])
ORa(95% CI)
Age (years)
20–297 (15.9) 582 (20.2)1
30–49 18 (40.9) 1522 (52.7) 0.8 (0.3–2.1)
50–69 14 (31.9) 682 (23.6) 1.3 (0.5–3.4)
70–795 (11.4) 102 (3.5) 3.1 (0.9–10.3)
Sex
Male12 (27.3) 740 (25.6)1
Female 32 (72.7) 2148 (74.4)0.8 (0.4–1.7)
Visits to primary care physician in the previous year
0–2 6 (13.6) 599 (20.7)
3–10
[10
25 (56.8) 1883 (65.2) 1.3 (0.5–3.4)
13 (29.5)406 (14.1) 2.9 (1.0–8.6)
Referral/hospitalization in the previous year
No 17 (38.6)1394 (48.3)1
Yes27 (61.4) 1494 (51.7) 1.1 (0.6–2.2)
Morbidity in the year before IBS diagnosis
Painful conditionsb
34 (77.3)1470 (50.9) 3.1 (1.4–6.9)
Stress 1 (2.3) 71 (2.5)0.8 (0.1–6.2)
Sleep disorders 1 (2.3)56 (1.9) 0.9 (0.1–7.1)
Anxiety1 (2.3) 56 (1.9)0.9 (0.1–7.1)
Depression 2 (4.5)169 (5.9)0.5 (0.2–2.3)
Asthma2 (4.5)110 (3.8)0.9 (0.2–4.1)
Cough5 (11.4)136 (4.7)2.8 (1.1–7.6)
Laryngitis1 (2.3) 35 (1.2)1.8 (0.2–14.1)
aOdds ratio (OR) estimates with 95% confidence intervals (CI) were adjusted by age, sex, smoking, body mass index, alcohol use and healthcare
utilization using logistic regression
bPainful conditions included headache, neuralgia, menstrual and inter-menstrual pain, female genital pain, eye pain, earache, nose pain, throat
pain, mouth pain, chest pain, respiratory pain, abdominal pain, rectal pain, urinary tract pain, penile and testicular pain, skin pain, breast pain,
limb pain, muscular and joint pain, neck pain and generalized pain
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has shown that regurgitation and IBS were strong predic-
tors of chronic cough [44].
Strengths and Weaknesses
A key strength of this study is that in order to ensure data
quality, completeness, and comparability between our
various comparison groups, all study subjects were
required to have been registered with a PCP for at least
2 years, and to have at least 1 year of prescription history,
before contributing data to the study. Furthermore, to
control for possible confounding due to the higher PCP
consultation rate in certain individuals, all risk estimates
were adjusted for the number of PCP visits and health
contacts in the previous year.
This longitudinal study adds a temporal dimension to
our understanding of the relationship between GERD and
IBS. However, a potential limitation of the study is that
most patients with GERD or IBS do not consult their PCP
[45, 46]. In addition, the study was reliant on clinical
judgement to diagnose IBS and GERD rather than uniform
criteria as in a prospective study. Both conditions are dif-
ficult to diagnose and universally accepted definitions were
lacking at the time of the study. The guidelines used to
assign these diagnostic labels may have changed over time,
and where definitions or specific diagnostic criteria do
exist, PCPs may not apply them [2, 47–49]. Heartburn is
one of the primary symptoms included in the spectrum of
GERD. It is possible that a proportion of the patients
recorded as having GERD in this study actually had
functional heartburn, which can be more representative of
dyspepsia than gastroesophageal reflux symptoms. This
appears particularly likely in the case of IBS patients who
were subsequently diagnosed with GERD.
Clinical Implications of this Study
A first diagnosis of either IBS or GERD increased the risk
of a subsequent diagnosis of the other condition by a factor
of approximately three. This illustrates the importance of
considering IBS symptoms in GERD patients, and of
checking for GERD symptoms in patients with IBS. An
awareness of the comorbid occurrence of GERD and IBS
may result in better diagnosis and treatment of individuals
affected with both diseases.
Acknowledgments
sicians for their collaboration, and the Boston Collaborative Drug
Surveillance Program (BCDSP) for providing access to the GPRD.
We thank Dr. Catherine Hill, from Oxford PharmaGenesis, who
provided editing assistance funded by AstraZeneca.
We thank the participating primary care phy-
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