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Additional file 2: Definitions of adverse events
Adverse event
Any sign or symptom whether or not related to the study drug; any clinically
significant laboratory abnormality; any abnormality detected on physical
examination. Investigators recorded adverse events reported by the patient, as well
as those observed based on examination.
Severity of adverse events
The severity of an adverse event is graded as:

Mild (causing no limitation of usual activities)

Moderate (causing some limitation of usual activities)

Severe (causing inability to carry out usual activities)
Serious adverse event
Any event causing significant hazard, contraindication, side effect, or precaution.
Including any event that is: fatal, life threatening, causes significant incapacity or
disability, causes or prolongs inpatient hospitalisation, a congenital anomaly or birth
defect, or is an important medical event.
Treatment-related adverse event
Adverse events were to be recorded regardless of whether they were thought to be
associated with the study or the drug under investigation. An adverse event was
considered to be related to use of a study drug if, in the opinion of the investigator,
there was a reasonable possibility that the event might have been caused by the
study drug. Relationship to study drug was recorded as none, uncertain, or probable.
Only those recorded as probable were regarded as treatment-related for this analysis.
GI tolerability
Adverse events could be mild (causing no limitation of usual activities), moderate
(causing some limitation of usual activities), or severe (causing inability to carry out
usual activities).
GI tolerability was a composite outcome of moderate or severe nausea, dyspepsia, or
abdominal pain and was used as such in a number of trials. For trials where that
information was not available, but where the individual reports of moderate or
severe adverse events were, the composite outcome was calculated for the trial.
Endoscopic ulcer
In those trials designed to detect ulcers by endoscopy, an ulcer was defined as any
break in the mucosa at least 3 mm in diameter with unequivocal depth.
Ulcers and bleeds
Gastric, duodenal, or gastroduodenal ulcer, or a haemorrhagic ulcer, or
gastrointestinal haemorrhage were reported as treatment-emergent events. While
some trials had independent adjudication panels, we took the results as reported in
the trial report, and not (so far was we know) as judged by a panel.
Hypertension
Hypertension included both new cases of hypertension, and aggravated
hypertension in patients with originally well-controlled hypertension. Hypertension
was not given a specific and uniform definition in the trials, except where it was a
primary outcome. For this analysis we took all reports of treatment-emergent
hypertension or aggravated hypertension.
Raised creatinine
Creatinine raised to 1.3 times the upper limit of normal for the laboratory or more
during treatment.
Oedema
Oedema at any body site (generalised, peripheral, facial) was analysed together.
Oedema was reported inconsistently, sometimes as just oedema, other times as
generalised oedema, and in other reports defined by localisation. We analysed
reports of unspecified oedema, generalised oedema, or the sum of specific oedema
reports.