Mortality study of 18 000 patients treated with omeprazole

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Mortality in omeprazole takers

Table 5 Observed and expected deaths from cancer of the oesophagus in successive years according to initial
oesophageal disease diagnosis in those cancer free at registration

O/E, observed/expected.

*Includes all diagnoses of the condition, irrespective of date of diagnosis.

causes, likewise showed no relationship with the intensity of
treatment. Clear histological diagnoses were available in 29 of
38 oesophageal cancer cases diagnosed after the study enrol-
ment date. Fifteen (83%) of 18 patients with adenocarcino-
mata had initial clinical diagnoses of oesophagitis, oesopha-
geal ulcer, stricture, and/or Barrett’s oesophagus. In contrast,
only five (45%) of 11 patients with squamous cancers had
such initial diagnoses (p=0.086, Fisher’s exact test).

DISCUSSION

By registering patients with the NHSCR, we systematically
collected information on the causes of death over four years in
nearly 18 000 patients prescribed omeprazole. Mortality was
significantly greater than population expectation in the first
year after registration, falling progressively to that expectation
by the fourth year. Increased mortality in the first year is
unlikely to reflect drug effects because it was detectable for a
wide variety of causes and was unrelated to the duration of
initial treatment. Furthermore, very similar patterns were
observed in our previous studies of cimetidine takers
conducted in the same way.^{5 6} We deduce therefore that
confounding by indication for treatment explains the general
patterns observed. Thus treatment of chest pain attributed to
reflux, but actually anginal in origin, could well explain
increased cardiovascular disease mortality. Use of omeprazole
in those perceived to be at high risk of ulcer complications is
also likely to explain raised risks of death from peptic ulcer
disease and musculoskeletal disease.⁸ This finding should not
be taken to imply that such treatment fails in its objectives:
there is strong evidence from controlled trials to indicate that
treatment is appropriate and successful.^9-11 In the same way,
increased mortality from musculoskeletal diseases seems
likely to reflect use of omeprazole in those perceived as at risk
of ulcer complications.¹² The increased mortality observed
from infectious and parasitic disease in the first two years of
observation lacks a plausible explanation but may represent
the play of chance in small numbers. PPI use is known to be
associated with an increased frequency of dysenteric infec-
tions but not with death from this cause.^{13 14} Persistently
increased mortality from chronic liver disease in our cohort
seems likely to represent deaths in patients with upper
gastrointestinal symptoms coincident liver disease, and
common epidemiological features in smoking and
drinking.^{15 16} Scrutiny of our cases revealed none where a
causal relationship with antisecretory treatment seemed
likely. Prescribing of omeprazole to attendees at general prac-
titioner surgeries with other main complaints, a form of Berk-
son’s bias,¹⁷ would be expected to lead to increases in mortality
from a broad range of complaints, particularly in the early
period after prescription, a phenomenon seen in our previous
studies of cimetidine.

Examination of the data for neoplastic diseases showed that
mortality increases were particularly high for gastric and
oesophageal cancer in the first year after registration. This
almost certainly represents confounding by indication rather
than an adverse drug effect, or masking of disease by
treatment. The patterns are similar to those seen with cimeti-
dine; no dose relationship was seen with treatment, and death
rates fell progressively with time. Persisting increases into the
fourth year were only seen for oesophageal cancer. The major-
ity of those dying with oesophageal cancer had initial
diagnoses suggesting severe oesophageal disease, namely Bar-
rett’s disease, stricture, ulcer, or oesophagitis. Observed
mortality was more than three times as great as expected in
these patients whereas it was not increased in those with ini-
tial diagnoses of hiatal hernia or reflux, or in those initially
considered to have disease outside the oesophagus as the rea-
son for omeprazole prescription. Patients with adenocarcino-
mata were six times as likely to have initial clinical diagnoses
suggesting severe underlying oesophageal disease as those
with squamous tumours. Observed mortality was more than
10 times as high in patients in whom Barrett’s disease had
been detected at some time in their clinical course whether or
not found at registration. However, findings of high propor-
tions of Barrett’s disease in this group may reflect the results
of differences in intensity of surveillance in those with and
without malignant disease.

Although in the long term follow up of approximately
10 000 patients prescribed cimetidine we found no evidence
that treatment was likely to cause gastric or other varieties of
gastrointestinal cancer,^4-6 it has recently been suggested that
histamine receptor antagonist treatment might predispose to
cardio-oesophageal adenocarcinoma .¹⁸ That claim was based
on comparing prior drug intake in cardio-oesophageal cancer
patients with that in individuals with myocardial infarction.
The nature of the control would seem to make sensible deduc-
tions about causation impossible. Our findings indicate
strongly that the nature of the underlying oesophageal disease
is the major, and probably sole, cause of the raised risk of
oesophageal cancer death in our omeprazole takers. This con-
clusion is reinforced by evidence that death rates were
unrelated to the number of omeprazole scripts received at
registration. This finding is consonant with findings that the
proportions of patients receiving acid suppressant therapy for
Barrett’s oesophagus, and oesophagitis without Barrett’s
disease, did not differ significantly.¹⁹ The data in our study
suggest strongly that underlying oesophageal disease explains
the increased risk of oesophageal cancer but it should be noted
that classification depended upon reports available to us in
practice case records, these not being produced to standard-
ised criteria. The actual strength of risk is therefore uncertain.
Systematic study has suggested that there may be publication
bias in the reporting of cancer risks in Barrett’s oesophagus.²⁰
Our data show, compared with the findings of others, rather
moderate increases in the risk of oesophageal cancer. Our set
has particular strengths. Firstly, patients for study were
selected prior to the outcomes being known. Secondly, the

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