Introduction
Open-access esophago-gastroduodenoscopy (OAE) allows the general practitioner (GP)
to refer patients for esophago-gastro-duodenoscopy without prior consultation of a
gastroenterologist. OAE was introduced to decrease waiting time for patients who require
urgent endoscopy, to decrease outpatient workload for gastroenterologists and to decrease
costs related to endoscopy by eliminating potentially unnecessary office-based consultations.
However, the introduction of OAE has resulted in an increase of the total number of
performed endoscopies, leading to waiting list for patients requiring urgent endoscopy,
whilst the frequency of clinically relevant findings has decreased [1]
[2]
[3]. In addition, although an esophago-gastro-duodenoscopy is relatively safe it is
associated with potential complications and causes discomfort [4]. Therefore, unnecessary OAEs should be avoided.
To optimize use of an open-access system, guidelines for appropriate referral to OAE
have been developed. Most studies of the diagnostic yields of OAE used American or
British guidelines to examine the appropriateness of the OAE indication. These guidelines
contain more indications than the Dutch College of General Practitioner guideline
(NHG guideline) “upper abdominal complaints” [5]
[6]
[7]
[8]. The performed studies about the yield of OAE showed widely ranging non-adherence
rates and also different rates of clinical relevant findings [3]
[4]
[8]
[9]
[10].
Some studies tried to identify subgroups which are at risk of malignant disease. It
was shown that age, male gender, smoking and alarm symptoms were independent predictors
of malignancy but their accuracy is controversial [11]
[12].
Due to the absence of studies wherein the Dutch NHG guideline is used, the uncertainty
about the diagnostic yield in the Netherlands and the vagueness about which subgroups
in the Netherlands have the largest a priori probability of malignancy. The aim of
this study was to assess the following questions; what is the appropriateness of referral
according to the NHG guideline ‘upper abdominal complaints’? What is the diagnostic
yield of OAE in the Netherlands? Which subgroups have the greatest yield of OAE? An
answer to these questions is even more important in the era of evidence-based medicine,
growing efficacy and cost-effectiveness. Furthermore, the capacity for endoscopic
examinations is limited and therefore the need to avoid unnecessary OAE is of paramount
importance.
Patients and methods
A retrospective chart review of all referrals for diagnostic OAE between October 2012
and October 2016 at the Northwest Clinics, location Alkmaar was performed. All patients
who underwent an OAE were included and patients younger than eighteen years or with
an incomplete endoscopy (not due to a stenosis) were excluded from further analysis.
The indications for OAE were collected from the referral letter. The NHG guideline
“upper abdominal complaints” was used to determine the appropriateness of the indication
for endoscopy ( [Table 1]). According to the guideline, reassurance was an appropriate indication for OAE,
although in this study it was classified as an inappropriate indication, because all
OAEs are performed for some sort of reassurance, for the patient or for the GP.
Table 1
Referral indications divided in 4 groups, of which the first three groups are considered
appropriate referral indications and the last group is considered inappropriate according
to the NHG guideline.
|
Referral indications
|
|
Alarm symptoms
|
Follow-up
|
Other referral indications according to the guideline
|
Referral indications not mentioned in the guideline
|
|
Dysphagia
|
Follow-up of gastric ulcer healing
|
Persistent or recurrent dyspepsia older than age 50 with a negative H. pylori status
|
Dyspepsia younger than age 50 without alarm symptoms
|
|
Unexplained weight loss
|
|
First-degree relative older than age 40 of a patient with familial gastric cancer
|
Persistent or recurrent dyspepsia older than age 50 with unknown H. pylori status
|
|
Gastrointestinal bleeding
|
|
|
Familial esophageal cancer
|
|
Anemia
|
|
|
Reassurance
|
|
Persistent vomiting
|
|
|
|
The referral indications were divided into 4 groups; alarm symptoms, follow-up, other
referral indications according to the guideline and referral indications not mentioned
in the guideline ( [Table 1]).The first 3 categories are considered appropriate and the last category is considered
inappropriate according to the NHG guideline.
Alarm symptoms were considered the most clinical relevant when present and patients
with any of these symptoms were classified in the category alarm symptoms, irrespective
of any other dyspeptic symptoms.
Referrals were screened by a gastroenterologist and they determined the time frame
during which the OAE was performed, but even in the absence of an appropriate indication
OAE was performed
The OAEs were performed by an experienced gastroenterologist or by a gastroenterologist
in training under the supervision of an experienced gastroenterologist. Endoscopic
findings were reported in a digital reporting system (Endobase©, Olympus, Zoeterwoude, The Netherlands) with, whenever possible, internationally
accepted terminology and definitions (Forrest classification for ulcer bleeding, Los
Angeles classification for erosive esophagitis and the Prague C & M classification
for a Barrett’s esophagus).
Endoscopic findings were classified into 3 categories; malignant, benign with clinical
relevance and benign without clinical relevance. A finding was considered clinically
relevant if there was impact on therapeutic decisions and prognosis, wherein it was
assumed that patients used a proton pump inhibitor (PPI) or an H2 receptor antagonist
(H2RA) in an adequate dose as described in the NHG guideline “upper abdominal complaints.”
Malignancies found during OAE were classified into the category malignant. To classify
the other diagnosis, the patient file was reviewed to examine whether the outcome
of the OAE changed the therapeutic decisions or prognosis. If that was the case patients
were classified into the category benign with clinical relevance.
When multiple endoscopic findings were present, patients were included for statistical
analysis in the most relevant group, wherein it was assumed that the group malignant
was the most relevant.
Besides the referral indication other variables which were possibly associated with
the outcome of the endoscopy were collected, such as: age, gender, treatment with
PPI or H2RA and Helicobacter pylori status.
Statistical analysis
Patients with appropriate indications were compared with those with an inappropriate
indication to assess the association between the appropriateness of the referral indication
and the presence of clinically relevant endoscopic diagnoses (malignant and benign
with clinical relevance). The extent of this association was calculated with univariate
logistic regression analysis.
Logistic regression analyses were performed on predictor variables with a P value < 0.2 in the univariate analysis, using a forward method procedure with a cut-off
P value of 0.05.
The ability of the NHG guideline to predict relevant endoscopic diagnoses was determined
by calculating the relative risk and positive and negative predictive value for each
separate referral indication and for all indications combined.
To find out which subgroup of patients has the highest risk of a upper gastrointestinal
malignancy a logistic regression analysis was performed, were tested for different
factors influencing the finding of a malignancy. The receiver operating characteristics
(ROC) curve with the area under the curve (AUC) was used to describe the performance
of these factors. The statistical difference between these AUCs of the dependent ROC
curves was calculated with the method of DeLong et al. using MedCalc (MedCalc Software,
Mariakerke, Belgium).
Internal validation of the prediction model for upper gastrointestinal malignancies
found by the logistic regression model was done by bootstrap resampling (1000 bootstrap
samples).
Nominal and ordinal variables were described as numbers with percentages. Continuous
variables were described as means with standard deviations in case of a normal distribution
and as median with interquartile range in case of a skewed distribution. Normality
was tested with Kolmogorov-Smirnov test. Independent Student’s t-tests were used to
analyze continuous outcome variables and logistic regression analyses were used for
dichotomous outcome variables. Differences were considered significant at a 5 % probability
level.
Statistical analyses were conducted using Statistical Package for Social Sciences
(SPSS®, IBM, New York, United States of America) version 20.
Results
Baseline characteristics
A total of 2006 OAEs were performed during the study period. Of these patients, 1088
were women (54.2 %) and 918 were men (45.8 %). The median (± IQR) age of the participants
was 60 ± 20 years (range 18 – 92 years). In total 1478 (73.7 %) used a PPI or H2RA
before the OAE was performed. The H. pylori status was known for 611 patients prior
to the OAE (30.5 %) of whom 6 patients tested positive (0.3 %). In 100 patients (4.9 %)
showed the biopsies, or the test done after the endoscopy that they were infected
with H. pylori. 979 patients had an unknown H. pylori status (48.8 %). Any form of
sedation with midazolam or alfentanil was used in 774 patients (38.6 %).
Referral indication
The indication for OAE was considered appropriate, according to the NHG guideline,
in 59.6 % of the cases (1195 patients). The main indication in this group was dysphagia
in 420 patients (35.1 %). The main inappropriate indication was dyspeptic symptoms
in 427 patients (52.7 %) older than 50 years without a H. pylori status. All referral
indications are summarized in [Table 2].
Table 2
Relative risk of finding a malignancy, a benign finding with clinical relevance and
a benign finding without clinical relevance for every referral indication. Wherein
patients with the referral indication are compared to patients without the referral
indication.
|
Outcome of endoscopy
|
|
Referral indication
|
N (%)
|
Malignant
|
Benign with clinical relevance
|
Benign without clinical relevance
|
|
|
n (%)
|
RR (95 % CI)
|
n (%)
|
RR (95 %CI)
|
n (%)
|
RR (95 %CI)
|
|
Indication according to the NHG guideline
|
1195 (59.6 %)
|
100 (5.0 %)
|
17.0 (6.3 – 45.91)[1]
|
264 (13.2 %)
|
1.44 (1.19 – 1.75)[1]
|
831 (41.4 %)
|
0.83 (0.79 – 0.87)[1]
|
|
Alarm symptoms overall
|
797 (39.7 %)
|
94 (4.7 %)
|
14.26 (7.48 – 27.20)[1]
|
200 (10.0 %)
|
1.61 (1.35 – 1.93)[1]
|
503 (25.0 %)
|
0.75 (0.71 – 0.80)[1]
|
|
Dysphagia
|
420 (20.9 %)
|
38 (1.9 %)
|
2.17 (1.48 – 3.19)[1]
|
113 (5.6 %)
|
1.55 (1.28 – 1.88)[1]
|
269 (13.4 %)
|
0.82 (0.76 – 0.88)[1]
|
|
Weight loss
|
104 (5.2 %)
|
10 (0.5 %)
|
1.95 (1.05 – 3.62)[1]
|
21 (1.0 %)
|
1.05 (0.71 – 1.55)
|
73 (3.7 %)
|
0.93 (0.82 – 1.05)
|
|
Gastrointestinal bleeding
|
92 (4.6 %)
|
4 (0.2 %)
|
0.83 (0.31 – 2.21)
|
22 (1.1 %)
|
1.25 (0.86 – 1.82)
|
66 (3.3 %)
|
0.95 (0.83 – 1.08)
|
|
Anaemia
|
31 (1.5 %)
|
2 (0.1 %)
|
1.25 (0.32 – 4.84)
|
9 (0.4 %)
|
1.51 (0.87 – 2.64)
|
20 (1 %)
|
0.85 (0.66 – 1.11)
|
|
Dysphagia and weight loss
|
121 (6.0 %)
|
34 (1.7 %)
|
7.57 (5.25 – 10.91)[1]
|
28 (1.4 %)
|
1.21 (0.86 – 1.70)
|
59 (2.9 %)
|
0.64 (0.54 – 0.78)[1]
|
|
Weight loss and gastrointestinal bleeding
|
12 (0.6 %)
|
1 (0.05 %)
|
1.61 (0.24 – 10.64)
|
4 (0.2 %)
|
1.73 (0.77 – 3.87)
|
7 (0.35 %)
|
0.77 (0.48 – 1.25)
|
|
Dyspepsia > 50 years of age, HP negative
|
383 (19.1 %)
|
6 (0.4 %)
|
0.26 (0.11 – 0.59)[1]
|
62 (3.5 %)
|
0.81 (0.63 – 1.03)
|
315 (15.2 %)
|
1.11 (1.05 – 1.18)[1]
|
|
Other
|
32 (1.6 %)
|
5 (0.25 %)
|
3.12 (1.36 – 7.13)[1]
|
5 (0.25 %)
|
0.81 (0.36 – 1.81)
|
22 (1.1 %)
|
0.91 (0.72 – 1.15)
|
|
Indication not according to the NHG guideline
|
811 (40.4 %)
|
4 (0.2 %)
|
0.06 (0.02 – 0.16)[1]
|
124 (6.2 %)
|
0.69 (0.57 – 0.84)[1]
|
683 (34.0 %)
|
1.21 (1.15 – 1.27)[1]
|
|
Dyspepsia < 50 years of age
|
373 (18.6 %)
|
0 (0 %)
|
0.02 (0.00 – 0.34)[1]
|
39 (1.9 %)
|
0.49 (0.36 – 0.67)[1]
|
334 (16.7 %)
|
1.24 (1.18 – 1.30)[1]
|
|
Dyspepsia > 50 years of age, HP unknown
|
427 (21.3 %)
|
4 (0.2 %)
|
0.15 (0.05 – 0.40)[1]
|
82 (4.2 %)
|
0.99 (0.80 – 1.23)
|
341 (16.9 %)
|
1.08 (1.02 – 1.14)[1]
|
|
Other
|
11 (0.5 %)
|
0 (0 %)
|
0.80 (0.05 – 12.08)
|
3 (0.1 %)
|
1.41 (0.54 – 3.73)
|
8 (0.4 %)
|
0.96 (0.67 – 1.38)
|
|
Total
|
2006 (100 %)
|
104 (5.2 %)
|
|
388 (19.3 %)
|
|
1514 (75.5 %)
|
|
Only the indications occurring with a frequency > 0.5 % were extensively reported
1
P < 0.05
Endoscopic finding
A malignancy in the upper gastrointestinal tract was detected in 104 examinations
(5.2 %) of which the majority was found to be an esophageal carcinoma (n = 82; 4.1 %).
An endoscopic finding classified as benign with clinic relevance was found in 388
patients (19.3 %), of these findings a Barrett’s esophagus accounted for 6.4 % (129
patients). A not clinically relevant finding and a normal examination occurred in
39.5 % and 36 % of the cases, respectively. All endoscopic findings are summarized
in [Table 3].
Table 3
Odds ratio of different endoscopic outcomes in OAEs performed for an appropriate referral
indication.
|
Outcome of OAE
|
Number of patients (%)
|
Appropriate referral indication, n (%)
|
Inappropriate referral indication, n(%)
|
OR
|
95 % CI
|
P value
|
|
Malignant
|
104 (5.2 %)
|
100 (5 %)
|
4 (0.2 %)
|
18.425
|
6.754 – 50.260
|
< 0.0001
|
|
Esophageal carcinoma
|
82 (4.1 %)
|
79 (3.9 %)
|
3 (0.2 %)
|
19.066
|
5.998 – 60.601
|
< 0.0001
|
|
Malignancies of the stomach
|
21 (1.05 %)
|
20 (1 %)
|
1 (0.05 %)
|
13.787
|
1.847 – 102.935
|
0.011
|
|
Malignant tumors of the duodenum
|
1 (0.05 %)
|
1 (0.05 %)
|
0 (0 %)
|
|
|
|
|
Benign with clinical relevance
|
388 (19.3 %)
|
264 (13.2 %)
|
124 (6.1 %)
|
1.571
|
1.242 – 1.987
|
< 0.0001
|
|
Reflux esophagitis grade A
|
12 (0.6 %)
|
5 (0.25 %)
|
7 (0.35 %)
|
0.483
|
0.153 – 1.526
|
0.215
|
|
Reflux esophagitis grade B
|
15 (0.7 %)
|
6 (0.28 %)
|
9 (0.42 %)
|
0.450
|
0.159 – 1.268
|
0.131
|
|
Reflux esophagitis grade C
|
37 (1.8 %)
|
23 (1.1 %)
|
14 (0.7 %)
|
1.117
|
0.571 – 2.184
|
0.746
|
|
Reflux esophagitis grade D
|
29 (1.4 %)
|
25 (1.2 %)
|
4 (0.2 %)
|
4.311
|
1.495 – 12.434
|
0.007
|
|
Barrett esophagus
|
129 (6.4 %)
|
73 (3.6 %)
|
56 (2.8 %)
|
0.877
|
0.612 – 1.258
|
0.476
|
|
Esophageal candidiasis
|
30 (1.6 %)
|
24 (1.3 %)
|
6 (0.3 %)
|
2.750
|
1.119 – 6.757
|
0.027
|
|
Hiatal hernia
|
22 (1.1 %)
|
19 (0.95 %)
|
3 (0.15 %)
|
4.351
|
1.283 – 14.753
|
0.018
|
|
Ulcus ventriculi
|
20 (1 %)
|
16 (0.8 %)
|
4 (0.2 %)
|
2.738
|
0.912 – 8.219
|
0.073
|
|
Gastritis
|
19 (0.9 %)
|
13 (0.6 %)
|
6 (0.3 %)
|
1.476
|
0.559 – 3.898
|
0.432
|
|
Ulcus duodeni
|
17 (0.8 %)
|
12 (0.6 %)
|
5 (0.2 %)
|
1.635
|
0.574 – 4.659
|
0.357
|
|
Other
|
58 (2.9 %)
|
48 (2.4 %)
|
10 (0.5 %)
|
3.352
|
1.686 – 6.665
|
0.001
|
|
Benign without clinical relevance
|
1514 (75.5 %)
|
831 (41.4 %)
|
683 (34.1 %)
|
0.428
|
0.342 – 0.536
|
< 0.0001
|
|
Reflux esophagitis grade A
|
152 (7.6 %)
|
79 (3.9 %)
|
73 (3.7 %)
|
0.716
|
0.514 – 0.997
|
0.048
|
|
Reflux esophagitis grade B
|
94 (4.7 %)
|
47 (2.3 %)
|
47 (2.3 %)
|
0.666
|
0.440 – 1.007
|
0.054
|
|
Schatzki ring
|
42 (2.1 %)
|
38 (1.9 %)
|
4 (0.2 %)
|
6.626
|
2.356 – 18.638
|
< 0.0001
|
|
Hiatal hernia
|
236 (11.7 %)
|
128 (6.4 %)
|
108 (5.3 %)
|
0.781
|
0.594 – 1.026
|
0.076
|
|
Fundic gland polyposis
|
48 (2.4 %)
|
29 (1.4 %)
|
19 (1 %)
|
1.037
|
0.577 – 1.862
|
0.904
|
|
Gastritis
|
176 (8.7 %)
|
99 (4.9 %)
|
77 (3.8 %)
|
0.861
|
0.630 – 1.176
|
0.348
|
|
Duodenitis
|
40 (2.0 %)
|
22 (1.1 %)
|
18 (0.9 %)
|
0.826
|
0.440 – 1.550
|
0.552
|
|
Normal
|
722 (36.0 %)
|
385 (19.2 %)
|
337 (16.8 %)
|
0.669
|
0.556 – 0.804
|
< 0.0001
|
|
Other
|
4 (0.3 %)
|
4 (0.3 %)
|
0 (0 %)
|
|
|
|
|
Total
|
2006 (100 %)
|
1195 (59.6 %)
|
811 (40.4 %)
|
|
|
|
Only the outcomes occurring with a frequency > 0.5 % were extensively reported.
Diagnostic yield
The diagnostic yield was significantly higher for OAEs with a referral indication
according to the NHG guideline. Of the 492 patients with clinical relevant endoscopic
findings, 74 % had an appropriate referral indication (OR 2.337 [95 % CI 1.866 – 2.928];
P < 0.0001). Significant predictive variables for a clinical relevant finding at OAE
found by multinomial logistic regression analysis were a referral indication according
to the NHG guideline, age, male gender and a positive H. pylori status ([Table 4]). A sensitivity analysis with age divided in equal quartiles showed that the significance
of age as predictive variable is based on the last quartile (69 years and older) (P < 0.0001).
Table 4
Uni- and multivariate logistic regression analysis of possible predictors for a clinical
relevant endoscopy outcome.
|
Clinical relevant endoscopy outcome
|
|
Univariate analyse
|
Multivariate analyse
|
|
Possible predictors
|
OR
|
95 % CI
|
P value
|
OR
|
95 % CI
|
P value
|
|
Appropriate referral indication
|
2.337
|
1.866 – 2.928
|
< 0.0001
|
1.565
|
1.075 – 2.280
|
0.020
|
|
Age
|
1.037
|
1.029 – 1.045
|
< 0.0001
|
1.023
|
1.010 – 1.037
|
0.001
|
|
Gender
|
|
|
Reference
|
|
|
|
|
|
|
|
2.071
|
1.684 – 2.547
|
< 0.0001
|
1.785
|
1.306 – 2.438
|
< 0.0001
|
|
PPI or H2RA use
|
|
|
Reference
|
|
|
|
|
|
|
|
1.817
|
1.445 – 2.285
|
< 0.0001
|
1.292
|
0.877 – 1.903
|
0.195
|
|
HP status
|
|
|
Reference
|
|
|
|
|
|
|
|
2.724
|
1.786 – 4.154
|
< 0.0001
|
2.767
|
1.757 – 4.357
|
< 0.0001
|
|
Sedation
|
|
|
0.900
|
0.728 – 1.113
|
0.332
|
|
|
|
|
|
Reference
|
|
|
|
|
|
The diagnostic yield of finding a malignancy in the upper gastrointestinal tract was
also significantly higher in patients with an appropriate referral indication (OR
18.425 [95 % CI 6.754 – 50.260]; P < 0.0001). The relative risk of finding a malignancy in patients with alarm symptoms
was 14.26 ([Table 2]). Especially dysphagia, weight loss and dysphagia with weight loss combined were
associated with a malignancy diagnosed with endoscopy. In contrast, the appropriate
referral indication: ‘dyspepsia in patients > 50 years of age with a negative H. pylori
status’ had a low diagnostic yield of finding a malignancy. 4 patients above 50 years
of age with dyspeptic symptoms and an unknown H. pylori status had a malignancy ( [Table 2]). The characteristics of these 4 patients with malignant disease are shown in [Table 5].
Table 5
Details of the 4 patients with malignant disease without a referral indication according
to the guideline.
|
No
|
Gender
|
Age
|
Sedation
|
PPI or H2RA use
|
H. pylori status
|
Referral indication
|
Diagnosis
|
|
1
|
Woman
|
81
|
No
|
Yes
|
Unknown
|
Nausea
|
Esophageal carcinoma
|
|
2
|
Man
|
80
|
Unknown
|
Yes
|
Unknown
|
Epigastric pain
|
Esophageal carcinoma
|
|
3
|
Man
|
69
|
No
|
Yes
|
Unknown
|
Epigastric pain
|
Esophageal carcinoma
|
|
4
|
Woman
|
70
|
No
|
Yes
|
Negative
|
Cough
|
Malignancy of the stomach
|
The sensitivity, specificity, PPV and NPV for all referral indication are summarized
in [Table 6].
Table 6
Sensitivity, specificity, positive and negative predictive value of every referral
indication for different endoscopic outcome categories.
|
Referral indication
|
Outcome of endoscopy
|
Sensitivity (95 % CI)
|
Specificity (95 % CI)
|
PPV (95 % CI)
|
NPV (95 % CI)
|
|
Indication according to the NHG guideline
|
Malignant
|
96.2 % (90.4 %-98.9 %)
|
42.4 % (40.2 %-44.7 %)
|
8.4 % (8.0 %-8.8 %)
|
99.5 % (98.7 %-99.8 %)
|
|
Benign with clinical relevance
|
68.0 % (63.2 %-72.7 %)
|
42.5 % (40.0 %-44.9 %)
|
22.1 % (20.8 %-23.5 %)
|
84.7 % (82.6 %-86.6 %)
|
|
Benign without clinical relevance
|
54.9 % (52.3 %-57.4 %)
|
26.0 % (22.2 %-30.1 %)
|
69.5 % (68.1 %-71.0 %)
|
15.8 % (13.8 %-18.0 %)
|
|
Alarm symptoms overall
|
Malignant
|
90.4 % (83.0 %-95.3 %)
|
63.0 % (60.8 %-65.2 %)
|
11.8 % (10.9 %-12.7 %)
|
99.2 % (98.5 %-99.5 %)
|
|
Benign with clinical relevance
|
51.6 % (46.5 %-56.6 %)
|
63.1 % (60.7 %-65.5 %)
|
25.1 % (23.0 %-27.3 %)
|
84.5 % (83.0 %-85.8 %)
|
|
Benign without clinical relevance
|
33.2 % (30.9 %-35.7 %)
|
40.2 % (35.9 %-44.7 %)
|
63.1 % (60.7 %-65.5 %)
|
16.4 % (14.9 %-18.0 %)
|
|
Dysphagia
|
Malignant
|
36.5 % (27.3 %-46.6 %)
|
79.9 % (78.0 %-81.7 %)
|
9.1 % (7.1 %-11.5 %)
|
95.8 % (95.2 %-96.4 %)
|
|
Benign with clinical relevance
|
29.1 % (24.6 %-33.9 %)
|
81.0 % (79.0 %-82.9 %)
|
26.9 % (23.4 %-30.7 %)
|
82.7 % (81.7 %-83.6 %)
|
|
Benign without clinical relevance
|
17.8 % (15.9 %-19.8 %)
|
69.3 % (65.0 %-73.4 %)
|
64.1 % (60.0 %-67.9 %)
|
21.5 % (20.5 %-22.6 %)
|
|
Weight loss
|
Malignant
|
9.6 % (4.7 %-17.0 %)
|
95.1 % (94.0 %-96.0 %)
|
9.6 % (5.4 %-16.5 %)
|
95.1 % (94.8 %-95.4 %)
|
|
Benign with clinical relevance
|
5.4 % (3.4 %-8.2 %)
|
94.9 % (93.7 %-95.9 %)
|
20.2 % (13.7 %-28.8 %)
|
80.7 % (80.3 %-81.1 %)
|
|
Benign without clinical relevance
|
4.8 % (3.8 %-6.0 %)
|
93.7 % (91.2 %-95.7 %)
|
70.2 % (61.0 %-78.0 %)
|
24.2 % (23.7 %-24.7 %)
|
|
Gastrointestinal bleeding
|
Malignant
|
3.9 % (1.1 %-9.6 %)
|
95.4 % (94.3 %-96.3 %)
|
4.4 % (1.7 %-10.8 %)
|
94.8 % (94.6 %-95.0 %)
|
|
Benign with clinical relevance
|
5.7 % (3.6 %-8.5 %)
|
95.7 % (94.6 %-96.6 %)
|
23.9 % (16.5 %-33.4 %)
|
80.9 % (80.5 %-81.3 %)
|
|
Benign without clinical relevance
|
4.4 % (3.4 %-5.5 %)
|
94.7 % (92.4 %-96.5 %)
|
71.7 % (62.0 %-79.8 %)
|
24.4 % (23.9 %-24.8 %)
|
|
Anemia
|
Malignant
|
1.9 % (0.2 %-6.8 %)
|
98.5 % (97.8 %-99.0 %)
|
6.5 % (1.6 %-22.2 %)
|
94.8 % (94.7 %-95.0 %)
|
|
Benign with clinical relevance
|
2.3 % (1.1 %-4.4 %)
|
98.6 % (98.0 %-99.2 %)
|
29.0 % (16.0 %-46.9 %)
|
80.8 % (80.6 %-81.1 %)
|
|
Benign without clinical relevance
|
1.3 % (0.8 %-2.0 %)
|
97.8 % (96.0 %-98.9 %)
|
64.5 % (46.7 %-79.0 %)
|
24.4 % (24.1 %-24.6 %)
|
|
Dysphagia and weight loss
|
Malignant
|
32.7 % (23.8 %-42.6 %)
|
95.4 % (94.4 %-96.3 %)
|
28.1 % (21.7 %-35.5 %)
|
96.3 % (95.8 %-96.7 %)
|
|
Benign with clinical relevance
|
7.2 % (4.9 %-10.3 %)
|
94.3 % (93.0 %-95.3 %)
|
23.1 % (16.7 %-31.2 %)
|
80.9 % (80.4 %-81.4 %)
|
|
Benign without clinical relevance
|
3.9 % (3.0 %-5.0 %)
|
87.4 % (84.1 %-90.2 %)
|
48.8 % (40.3 %-57.3 %)
|
22.8 % (22.2 %-23.4 %)
|
|
Weight loss and gastrointestinal bleeding
|
Malignant
|
1.0 % (0.02 %-5.2 %)
|
99.4 % (99.0 %-99.7 %)
|
8.3 % (1.2 %-41.1 %)
|
94.8 % (94.7 %-94.9 %)
|
|
Benign with clinical relevance
|
1.0 % (0.3 %-2.6 %)
|
99.5 % (99.0 %-99.8 %)
|
33.3 % (13.1 %-62.3 %)
|
80.7 % (80.6 %-80.9 %)
|
|
Benign without clinical relevance
|
0.5 % (0.2 %-1.0 %)
|
99.0 % (97.6 %-99.7 %)
|
58.3 % (30.9 %-81.5 %)
|
24.4 % (24.3 %-24.6 %)
|
|
Dyspepsia > 50 years of age, HP negative
|
Malignant
|
5.8 % (2.2 %-12.1 %)
|
80.2 % (78.3 %-82.0 %)
|
1.6 % (0.7 %-3.4 %)
|
94.0 % (93.7 %-94.3 %)
|
|
Benign with clinical relevance
|
16.0 % (12.5 %-20.0 %)
|
80.2 % (78.1 %-82.1 %)
|
16.2 % (13.1 %-19.9 %)
|
79.9 % (79.1 %-80.7 %)
|
|
Benign without clinical relevance
|
20.8 % (18.8 %-22.9 %)
|
86.2 % (82.8 %-89.1 %)
|
82.3 % (78.4 %-85.5 %)
|
26.1 % (25.3 %-27.0 %)
|
|
Other
|
Malignant
|
4.8 % (1.6 %-10.9 %)
|
98.6 % (97.9 %-99.1 %)
|
15.6 % (6.8 %-32.0 %)
|
95.0 % (94.8 %-95.2 %)
|
|
Benign with clinical relevance
|
1.3 % (0.4 %-3.0 %)
|
98.3 % (97.6 %-98.9 %)
|
15.6 % (6.7 %-32.3 %)
|
80.6 % (80.4 %-80.8 %)
|
|
Benign without clinical relevance
|
1.5 % (0.9 %-2.2 %)
|
98.0 % (96.3 %-99.0 %)
|
68.8 % (51.2 %-82.2 %)
|
24.4 % (24.2 %-24.7 %)
|
|
Indication not according to the NHG guideline
|
Malignant
|
3.9 % (1.1 %-9.6 %)
|
57.6 % (55.3 %-59.8 %)
|
0.5 % (0.2 %-1.3 %)
|
91.6 % (91.2 %-92.0 %)
|
|
Benign with clinical relevance
|
32.0 % (27.3 %-36.9 %)
|
57.5 % (55.1 %-60.0 %)
|
15.3 % (13.4 %-17.4 %)
|
77.9 % (76.5 %-79.3 %)
|
|
Benign without clinical relevance
|
45.1 % (42.6 %-47.7 %)
|
74.0 % (69.9 %-77.8 %)
|
84.2 % (82.0 %-86.2 %)
|
30.5 % (29.0 %-32.0 %)
|
|
Dyspepsia < 50 years of age
|
Malignant
|
0 %
|
80.4 % (78.5 %-82.2 %)
|
0 %
|
93.6 % (93.5 %-93.8 %)
|
|
Benign with clinical relevance
|
10.1 % (7.3 %-13.5 %)
|
79.4 % (77.3 %-81.3 %)
|
10.5 % (7.9 %-13.8 %)
|
78.6 % (77.9 %-79.3 %)
|
|
Benign without clinical relevance
|
22.1 % (20.0 %-24.2 %)
|
92.1 % (89.3 %-94.3 %)
|
89.5 % (86.2 %-92.2 %)
|
27.7 % (27.0 %-28.5 %)
|
|
Dyspepsia > 50 years of age, HP unknown
|
Malignant
|
3.9 % (1.1 %-9.6 %)
|
77.8 % (75.8 %-79.6 %)
|
0.94 % (0.36 %-2.42 %)
|
93.7 % (93.4 %-93.9 %)
|
|
Benign with clinical relevance
|
21.1 % (17.2 %-25.5 %)
|
78.7 % (76.6 %-80.7 %)
|
19.2 % (16.1 %-22.7 %)
|
80.6 % (79.7 %-81.5 %)
|
|
Benign without clinical relevance
|
22.5 % (20.4 %-24.7 %)
|
82.5 % (78.9 %-85.8 %)
|
79.9 % (76.2 %-83.1 %)
|
25.7 % (24.8 %-26.7 %)
|
|
Other
|
Malignant
|
0 %
|
99.4 % (99.0 %-99.7 %)
|
0 %
|
94.8 % (94.8 %-94.8 %)
|
|
Benign with clinical relevance
|
0.8 % (0.2 %-2.2 %)
|
99.5 % (99.0 %-99.8 %)
|
27.3 % (9.1 %-58.5 %)
|
80.7 % (80.6 %-80.9 %)
|
|
Benign without clinical relevance
|
0.5 % (0.2 %-1.0 %)
|
99.4 % (98.2 %-99.9 %)
|
72.7 % (41.5 %-90.9 %)
|
24.5 % (24.4 %-24.7 %)
|
Only the indications occurring with a frequency > 0.5 % were extensively reported.
Besides the malignancies in the upper gastrointestinal tract, more frequently detected
findings with clinical relevance in appropriate OAEs were; reflux esophagitis grade
D, esophageal candidiasis and hiatal hernia ( [Table3]).
Risk-predictive model
To find out which subgroup of patients has the greatest risk of a malignancy in the
upper gastrointestinal tract a multinomial logistic regression analysis ([Table 7]) was performed, which showed that significant predictive variables for a malignant
finding at OAE were; male gender, alarm symptoms and age. A sensitivity analysis with
age divided in equal quartiles showed that the significance of age as predictive variable
is based on the last 2 quartiles (60 years and older) (P < 0.001).
Table 7
Uni- and multivariate logistic regression of possible predictors for upper gastrointestinal
malignancy.
|
Malignancy of the upper gastrointestinal tract
|
|
Univariate analyse
|
Multivariate analyse
|
|
Possible predictors
|
OR
|
95 % CI
|
P value
|
OR
|
95 % CI
|
P value
|
|
Alarm symptoms
|
16.032
|
8.298 – 30.974
|
< 0.0001
|
10.488
|
5.276 – 20.849
|
< 0.0001
|
|
Age
|
1.071
|
1.052 – 1.090
|
< 0.0001
|
1.051
|
1.032 – 1.071
|
< 0.0001
|
|
Gender
|
|
|
Reference
|
|
|
|
|
|
|
|
4.481
|
2.796 – 7.183
|
< 0.0001
|
3.942
|
2.401 – 6.473
|
< 0.0001
|
|
PPI or H2RA use
|
|
|
Reference
|
|
|
|
|
|
|
|
1.828
|
1.193 – 2.802
|
0.006
|
0.769
|
0.484 – 1.221
|
0.266
|
|
HP status
|
|
|
Reference
|
|
|
|
|
|
|
|
0.825
|
0.191 – 3.569
|
0.797
|
|
|
|
|
Sedation
|
|
|
0.810
|
0.541 – 1.214
|
0.308
|
|
|
|
|
|
Reference
|
|
|
|
|
|
No malignancies were found in patients < 40 years of age while it was uncommon in
patients under 45 years of age, whereas in this patient group many OAEs were performed
([Fig. 1] and [Fig. 2]). In women under the age of 50 years no malignancies of the upper gastrointestinal
tract were detected ([Fig. 1] and [Fig. 2]).
Fig. 1 Number of OAEs performed in different age groups.
Fig. 2 Outcome of endoscopy in different age groups.
The ROC curve ([Fig. 3]) showed that age alone (AUC = 0.729 [95 % CI 0.687 – 0.771]) was significantly (P < 0.0001) less accurate in predicting a malignant finding than our risk prediction
model (age, male gender and alarm symptoms combined) (AUC = 0.868 [95 % CI 0.841 – 0.894]).
Also alarm symptoms alone (AUC = 0.767 [95 % CI 0.729 – 0.805]) was less accurate
in predicting a malignant finding than the combination of the 3 factors ([Fig. 3]).
Fig. 3 Receiver operating characteristic (ROC) curve comparing the accuracy of age alone
(AUC = 0.729), alarm symptoms alone (AUC = 0.767) and age, alarm symptoms and male
gender combined (AUC = 0.868) in predicting a malignant finding in OAE.
Internal validation of the predicting model with bootstrap resampling showed a corrected
AUC of 0.867.
Discussion
Since the introduction of OAE an increase in the number of performed endoscopies has
been reported, whilst the frequency of clinically relevant findings has decreased
[1]
[2]. This results in waiting lists leading to delayed endoscopy for those with a potential
malignant disease [3]. The appropriateness of the referral and the diagnostic yield of OAEs is, therefore,
an important issue. To our knowledge, this is the first surveys on the diagnostic
yield of OAEs in the Netherlands in which the NHG guideline "upper abdominal complaints”
was used.
The most prominent finding in our study was the high frequency of malignancies compared
to other studies. In our cohort a prevalence of 5.2 % was found, whilst in a meta-analysis
(57,363 patients) a prevalence of upper GI cancer of 0.8 % was found [13]. The high frequency of malignancies in our study cannot be explained by patient
selection and the prevalence of upper gastrointestinal cancers in the Netherlands
is comparable to other Western countries [14]. We speculate that the difference can be explained by the use of the brief NHG guideline
and the good primary health care services in the Netherlands.
In our study the rate of patients referred for OAE with an indication not according
to the NHG guideline was 40.4 %. In other studies the rate of inappropriate referrals
ranged from 11.7 % till 77.2 % [4]
[9]
[10]. The greater guideline compliance in some studies can possibly be explained by a
lecture series for the GPs prior to the data collection [8]. This gives the impression that educational programs dedicated to GPs can improve
the effectiveness of an open-access system. However, due to the use of different guideline
as benchmarks these data are not comparable with our results.
In the present study, the diagnostic yield of OAE was statistically significant higher
for endoscopies with a referral indication according to the NHG guideline (P < 0.0001). The sensitivity and specificity of the NHG guideline to detect a malignancy
was 96.2 % and 42.4 %. For detecting a clinically relevant finding it was 68.0 % and
42.5 %, respectively. These data are concordant with a meta-analysis which showed
an adjusted sensitivity and specificity of the ASGE guidelines for clinical relevant
findings of 85 % and 28 % [15]. Despite the relatively high sensitivity, the frequency of a clinical relevant finding
in patients with an inappropriate referral indication was 15.8 % in our study, which
is a low frequency compared to other studies (ranging from 23 % till 66 %) [16]
[17]
[18].
In our study only 4 (3.8 %) of the 104 malignancies would be missed by strict adherence
to the guideline, therewith substantially lower than the 8 % in the study of Rossi
et al. [19]. This can be explained by the high sensitivity (96.2 %) of the NHG guideline in
our study for detecting malignancies. But the fact remains that by strict adherence
to the guideline some malignancies could be missed. That is why some authors were
stating that the appropriateness criteria should not be the only factor in the decision-making
process [20]. That is the reason that the Dutch NHG guideline states that a GP might consider
to perform a OAE for reassurance.
In this study 20.8 % of the referral indication were classified as ‘inappropriate’
due to an unknown H. pylori status in patients with dyspepsia above the age of 50. Of
these patients 4 (0.2 %) had a malignant finding and 82 (4.0 %) a benign finding with
clinical relevance. Epidemiologic studies have shown that individuals infected with
H. pylori have an increased risk of gastric adenocarcinoma and an decreased risk of
esophageal adenocarcinoma [21]
[22]. However, dramatic increases in gastric and esophageal adenocarcinoma rates in several
Western countries parallel the declines in H. pylori infection rates [22]. Due to the retrospective nature of this study and the discrepancy in the literature
we could only speculate what the role of a H. pylori infection was in the observed
malignancies. If dyspepsia above the age of 50 is considered an appropriate indication
no malignancies would be missed, however, the cost effectiveness of OAE would rapidly
decrease. Before any changes in the NHG guideline are made, more prospective studies
are needed addressing the relationship between a H. pylori infection and a malignant
finding in OAE.
The current study showed that the PPV of alarm symptoms for detecting a malignancy
is considerably higher compared to other studies (11.8 % versus 5.9 %). Especially
patients with the alarm symptoms dysphagia and weight loss combined had a relatively
high PPV of 28.1 % ([Table 5]). The NPV is 99.2 % which is corresponding with a meta-analysis which showed a pooled
NPV for alarm symptoms of 99.4 % [23]. Our analysis showed that age, male gender and alarm symptoms are significant predictive
variables for upper gastrointestinal malignancies. The combination of these variables
resulted in an AUC of 0.868 for detecting upper GI malignancies, therewith higher
than a similar Finnish study (AUC = 0.72) [24]. Our risk-prediction model (age, alarm symptoms and male gender) gives the same
AUC as the risk-prediction model made by Khademi et al. (AUC = 0.85) which was based
on different independent variables (age, alarm symptoms and smoking) [25]. Due to missing data, we could not include cigarette smoking in our risk prediction
model, but this previous study suggests that our AUC could possibly become even higher
by including this variable. Our study suggests that in female patients without alarm
symptoms the age threshold for performing OAE could be safely raised compared to male
patients.
The aim of OAE is to ensure rapid detection of upper gastrointestinal malignancy and
to provide an effective way of managing patients without a malignancy. In our study,
there was no malignancy found in patients under the age of 40 years and more than
90 % of the patients with a malignancy had 1 or more alarm symptoms ([Fig. 2]). Our study is consistent with others who found that upper gastrointestinal cancer
was rare in patients under the age of 45 and all patients had alarm symptoms at presentation
[26]. In contradiction, 1 study showed that 0.3 % of the malignancies were detected in
patients under the age of 45 who presented with uncomplicated dyspepsia [27]. However, it is uncertain whether an earlier diagnosis would alter clinical outcome,
as studies showed that patients with a malignancy under the age of 55 years presented
with uncomplicated dyspepsia had lymph node metastasis at diagnosis [27]
[28]. The authors concluded that increasing the age limit of OAE to 55 years in patients
with uncomplicated dyspeptic symptoms would unlikely affect clinical consequences,
given the inoperable stage of the tumors in this younger patient group [27]
[28]. These and our results support the opinion that patients without alarm symptoms
under the age of 50 year can be treated without OAE, which is concordant with the
indications mentioned in the NHG guideline [24]. It even suggests that you can treat patients under the age of 40 without OAE, irrespectively
of alarm symptoms. This with a low risk of missing a curable malignancy of the upper
gastrointestinal tract. Important to notice is that this age threshold is only applicable
to the Dutch community because it is determined by local epidemiological factors (ethnic
background and prevalence of H. pylori).
In our study OAE is unnecessary (no clinical relevant finding) in 88.3 % of dyspeptic
patients under the age of 45, even 50 % had a normal endoscopy. Our results were consistent
with studies which found that OAE is unnecessary in approximately 75 % of young dyspeptics
[29]
[30]. Yet, in our study 16 % of the OAE are performed in this age group, in other studies
this number rises to even a third of all endoscopies [26]
[31]. A reduction of this number of unnecessary OAEs can be crucial to the cost effectiveness
of the open-access system. In addition, evidence suggest that most patients with reflux
symptoms are, regardless of the endoscopic findings, switched to acid suppressive
therapy [32]
[33]. This may suggest that the management of symptoms is hardly influenced by the OAE.
However, a normal endoscopy cannot simply be devalued, it may have changed the treatment
course of some patients. 1 study showed that 67 % of the normal endoscopies assisted
the caring physicians whether to continue with medication or to proceed with other
investigations, and to help reassure patients [34]. Furthermore, some studies demonstrated that a normal endoscopy led to a better
quality of life and patient satisfaction [17]
[35]. In contradiction, other studies showed that quality of life was only improved during
a short period after a negative endoscopy and there was no difference in experienced
quality of life between prompt endoscopy or empirical treatment with acid suppressive
therapy after 1 year [36]
[37].
Our retrospective study had certain limitations. Firstly, indications for OAE were
based on information provided by the GP, consequently, appropriateness of the indication
could be underestimated or overestimated. This is, nevertheless, always the case in
an open-access system. Secondly, because of the sometimes brief referral letter some
data were missing. For example, it is unclear how long in advance the acid inhibition
has been stopped and whether it has been stopped at all. This could, possibly, have
masked some organic disorders. We think, however, that clinical relevant findings
would still be detected by OAE, irrespectively of PPI use. Lastly, we did not include
histological analysis of normal mucosa, which could lead to a diagnosis of celiac
disease, and therefore clinical relevance.
Conclusion
In conclusion, we found a high rate of malignant findings and only 3.8 % of the malignancies
would be missed by strict adherence to the guideline. This indicates that the open-access
system in the Netherlands works well. Further improvement of the open-access system
can be achieved by streamlining of the referrals by the endoscopy unit by only accepting
appropriate indications for OAE. Our results even suggest that patients under the
age of 40 can be treated without OAE, irrespectively of alarm symptoms, with a very
low risk of missing a curable malignancy. We showed that a risk-prediction model based
on the variables age, alarm symptoms and male gender is a good predictor of malignant
finding. This suggests that gender should be adopted in guidelines besides age and
alarm symptoms which may lead to a different age cut-off point for performing OAEs
in men and women.
