Influence of the incidence of ulcerative gastroduodenal bleeding on the effectiveness of treatment. Statistical surveillance

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OBJECTIVE

To study and to justify statistically the influence of the incidence of ulcerative gastroduodenal bleeding on the results of treatment.

MATERIAL AND METHODS

The results of treatment of 56.233 patients with ulcerative gastroduodenal bleeding in the Central Federal district have been analyzed throughout a 5-year follow-up period. Statistical analysis was performed in Microsoft Excel 2007 and Review Manager 5.3.

RESULTS

Overall in-hospital mortality (r=0.871) and surgical activity (r=0.725) depend on the number of patients with ulcerative bleeding. Active surgical approach was followed by overall in-hospital mortality 6.9%, moderate surgical approach — 5.3% (OR 1.3%, 95% CI 1.18—1.4, p<0.05).

CONCLUSION

The correlations between the number of patients with ulcerative bleeding and surgical activity, overall in-hospital and postoperative mortality were identified in a large sample.

Keywords:

peptic ulcer

ulcerative gastroduodenal bleeding

morbidity

treatment effectiveness

Authors:

V.P. Sazhin

Vishnevsky National Medical Research Center of Surgery;
Pavlov Ryazan State Medical University

ORCID: 0000-0001-9452-1656

A.G. Beburishvili

Volgograd State Medical University

S.I. Panin

Volgograd State Medical University

SPIN RSCI: 8303-5413
Scopus AuthorID: 57198338379
ORCID: 0000-0003-4086-2054

I.V. Sazhin

Pirogov Russian National Research Medical University

ORCID: 0000-0002-8073-6717

M.P. Postolov

Volgograd State Medical University;
Volgograd Regional Clinical Oncology Dispensary

Received:

29.02.2020

Accepted:

15.03.2020

List of references:

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Lebedev NV, Klimov AE, Petukhov VA. Repeated endoscopic hemostasis as an alternative to surgical treatment of patients with gastroduodenal ulcerative bleeding. Khirurgiya. Zhurnal im. N.I. Pirogova. 2016;6:52-56. (In Russ.). https://doi.org/10.17116/hirurgia2016652-56
Levine M, Beuhler MC, Pizon A, Cantrel FL, Spyres MB, LoVecchio F, Skolnik AB, Brooks D.E. Assessing Bleeding Risk in Patients. With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications. Ann Emerg Med. 2018;71(3):273-278. https://doi.org/10.1016/j.annemergmed.2017.08.046
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Nikitin VN, Klipach SG. «Difficult» Stump in Complicated Giant Penetrating Pyloroduodenal Ulcers. Novosti Khirurgii. 2017;25(6):574-582. (In Russ.). https://doi.org/10.18484/2305-0047.2017.6.574
Beburishvili AG, Fedorov AV, Sazhin VP, Panin SI, Zyubina EN Surgical treatment of ulcerative pyloroduodenal stenosis. Khirurgiya. Zhurnal im. NI Pirogova. 2019;4:94-99. (In Russ.). https://doi.org/10.17116/hirurgia201904194
Kubyshkin VA, Sazhin VP, Fedorov AV, Krivtsov TA, Sazhin IV. Organization and results of surgical care for ulcerative gastroduodenal bleeding in the hospitals of Central Federal District. Khirurgiya. Zhurnal im. N.I. Pirogova. 2017;2:4-9. (In Russ.). https://doi.org/10.17116/hirurgia201724-9
Kozek-Langenecker SA, Ahmed AB, Afshari A, Albaladejo P, Aldecoa C, Barauskas G, et al. Management of severe perioperative bleeding:guidelines from the European Society of Anaesthesiology: First update 2016. European Journal of Anaesthesiology. 2017;34(6):332-395. https://doi.org/10.1097/EJA.0000000000000630
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Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal haemorrhage. Gut. 1996;38:316-321. https://doi.org/10.1136/gut.38.3.316
Ermolov AS, Tveritneva LF, Teterin Y.S. Modern methods of endoscopic hemostasis in treating ulcerative gastroduodenal hemorrhage (literature review). Meditsinskii alfavit. 2017;3(29):41-46. (In Russ.).
Tarasov EE, Bagin VA, Nishnevich EV, Astafyeva MN, Rudnov VA, Prudkov MI. Epidemiology and risk factors of adverse outcome in nonvariceal upper gastrointestinal bleeding. Khirurgiya. Zhurnal im. N.I. Pirogova. 2019;5:31-37. (In Russ.). https://doi.org/10.17116/hirurgia201905131
Omel’yanovskii VV. Metodicheskie rekomendatsii po provedeniyu otsenki nauchnoi obosnovannosti vklyuchaemoi v klinicheskie rekomendatsii informatsii. M. 2019. (In Russ.).
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Background

Currently, the main indications for stomach surgery in surgical hospitals are complications of peptic ulcer disease [1 — 4]. Advisability of surgery in patients with perforated ulcers and decompensated gastric outlet obstruction is obvious [5, 6]. Complex non-surgical treatment for ulcerative gastroduodenal bleeding has been promoted for the last several decades [7 — 9]. Management of some patients with ulcerative bleeding becomes less aggressive due to conservative treatment with dynamic gastroscopy and combined endoscopic hemostasis [10, 11]. Unfortunately, widespread availability of these approaches in the Russian Federation is constrained by insufficient material base of surgical services in various regions and surgical departments of many hospitals. No statistically confirmed data on conservative therapy in patients with ulcerative gastroduodenal bleeding inhibits the introduction of perspective treatment of these patients.

Objective. To study and substantiate the influence of gastroduodenal ulcerative bleeding rate on treatment outcomes.

Material and methods

We have performed a multiple-center trial based on the annual information of chief surgeons in 17 regions of the Central Federal District. In accordance with primary objective, we analyzed the effect of the incidence of ulcerative gastroduodenal bleeding on surgical activity, overall in-hospital and postoperative mortality. There were 56,233 patients with ulcerative gastroduodenal bleeding for a 5-year period (2014–2018) in the regions of the Central Federal District.

Statistical analysis was carried out using Microsoft Excel 2007 (correlation-regression analysis) and Review Manager 5.3 software packages (meta-analysis of mortality, calculation of odds ratio (OR), 95% confidence interval (95% CI)). The degree of correlation was determined using Chaddock scale. Considering the central limit theorem, we assumed normal distribution of the variables.

Results

Heterogeneity of data was high (I2 93%). Surgical activity ranged from 5.6% to 38.2% in various regions of the Central Federal District (mean 14.9%). Overall in-hospital mortality from ulcerative bleeding in the Central Federal District was 5.5%. According to meta-analysis based on random-effect model, postoperative mortality was 13.4% (1123 out of 8406) (Table 1). Overall in-hospital mortality was 4.1% after complex conservative treatment with gastroscopy and endoscopic hemostasis (1982 out of 47827) (OR 4.1, 95% CI 3.02-5.55, p <0.00001).

Table 1. Meta-analysis of mortality in the groups of surgery and conservative approach

Study or Subgroup	Operated on			Not operated		Odds Ratio	Odds Ratio
Study or Subgroup	Events	Total	Events	Total	Weight M-H (%)	Random, 95*CI	M-H, Random, 95% CI
Yaroslavl	42	214	117	1726	5,9	3,36 [2,28, 4,94]
Tula	38	276	87	1961	5,9	3,44 [2,30, 5,15]
Tver	33	157	115	2016	5,8	5,28 [3,50, 7,96]
Tambov	25	197	31	1972	5,4	9,10 [5,25, 15,77]
Smolensk	43	194	117	1857	5,9	4,24 [2,88, 6,24]
Ryazan	41	181	148	2437	5,9	4,53 [3,08, 6,66]
Orel	31	139	67	1362	5,7	5,55 [3,47, 8,87]
Moscow region	255	1629	284	9332	6,4	5,91 [4,95, 7,07]
Lipetsk	37	455	131	2271	5,9	1,45 [0,99, 2,11]
Kursk	58	280	59	1900	5,9	8,15 [5,53, 12,02]
Kostroma	13	122	33	779	5,0	2,70 [1,38, 5,28]
Kaluga	52	208	225	3488	6,0	4,83 [3,43, 6,80]
Ivanovo	124	459	107	1081	6,2	3,37 [2,53, 4,49]
Voronezh	26	410	54	2342	5,6	2,87 [1,77, 4,64]
Vladimir	88	570	135	6197	6,2	8,20 [6,17, 10,89]
Bryansk	97	660	107	3451	6,2	5,38 [4,03, 7,19]
Belgorod	115	2255	165	3655	6,3	1,14 [0,89, 1,45]
Total (95% CI)		8406		47827	100,0	4,10 [3,02, 5,65]
Total events	1123		1982
Heterogeneity: Tau2=0,37; Chi2=214,34, df=16 (p<0,00001); I²=93%
Test for overall effect: Z=9,07 (p<0,00001)
							Operated on	Not operated

According to pooled statistics in the Russian Federation, mean surgical activity for ulcerative gastroduodenal bleeding in 2017-2018 was 18.1%. All regions of the Central Federal District were divided into 2 groups. Surgical activity was high and exceeded the mean value (> 18.1%) only in 2 regions of the Central Federal District (Belgorod, Ivanovo). In other fifteen regions of the Central Federal District, surgical activity was moderate (<18.1%). Overall in-hospital mortality was 6.9% in active surgical approach and 5.3% in moderate surgical activity. Differences were significant (OR 1.3, 95% CI 1.18-1.4, p <0.05) (Fig. 1).

Fig. 1. Overall in-hospital mortality in ulcerative gastroduodenal bleeding.

There was a reverse trend regarding postoperative mortality. This value was higher in regions with moderate surgical activity compared to regions with active surgical approach (15.5% vs. 8.8%) (Fig. 2). Differences were significant (OR 1.9, 95% CI 1.63-2.21, p <0.05).

Fig. 2. Postoperative mortality in ulcerative gastroduodenal bleeding.

Correlation-regression analysis was used to analyze the effect of independent variable X (incidence) on predicted variables Y (overall in-hospital mortality and surgical activity).

According to correlation analysis (Table 2) with Pearson’s test, there was a proportionality of changes in the number of patients with ulcerative gastroduodenal bleeding and overall in-hospital mortality. Correlation coefficient (r = 0.8705) confirmed strong correlation in accordance with Chaddock scale and made it possible to analyze the model of linear relationship between these statistical values.

Table 2. Correlation analysis

CFD regions	Sick (n) — X	Died (n) — Y	%
Belgorod	5 910	280	4,7
Bryansk	4 111	204	5,0
Vladimir	2 752	80	2,9
Voronezh	6 767	223	3,3
Ivanovo	1 540	231	15,0
Kaluga	3 696	277	7,5
Kostroma	901	46	5,1
Kursk	2 180	117	5,4
Lipetsk	2 726	168	6,2
Moscow region	10 961	539	4,9
Orel	1 501	98	6,5
Ryazan	2 618	189	7,2
Smolensk	2 051	160	7,8
Tambov	2 169	56	2,6
Tver	2 173	153	7,0
Tula	2 237	125	5,6
Yaroslavl	1 940	159	8,2
Total	56 233	3105	5,5
Pearson's correlation coefficient — r (PEARSON)			0,8705

According to regression statistics (Table 3, Fig. 3), r² coefficient determining the value of the established relationship between overall in-hospital mortality and morbidity is 0.7578.

Table 3. Regression analysis

Multiple R	0,870535703
R²	0,757832411
Standardized R²	0,741687905
Standard error	58,50907134
Sample	17

Fig. 3. Morbidity/overall in-hospital mortality regression analysis.

The proposed statistical model explains correlation of overall in-hospital mortality and incidence of ulcerative gastroduodenal bleeding by 75.8%. In 24.2% of cases, variation between these variables is determined by other random deviations.

Additional variance analysis determined positive (variable X1, coefficient = 0.04) correlation (higher morbidity results higher overall in-hospital mortality) and confirmed the fact that other factors also influence overall in-hospital mortality (Y-intersection, coefficient = 49). These factors of unfavorable outcome following bleeding management are comorbidities, initial severe blood loss, etc. [12]. Moreover, we found statistical significance of correlation between overall in-hospital mortality and morbidity (degrees of freedom — 15, expected t-criterion (6.851) was more than critical t-criterion (2.13), p <0.05)). In this case, the compromising factor of the constructed model of linear regression is mean approximation error that characterizes deviation of the calculated values from the actual ones (Ᾱ — 34.4%).

Pearson’s correlation test between surgical activity and incidence of ulcerative gastroduodenal bleeding confirmed strong correlation according to Chaddock scale (r = 0.725) (Table 4).

Table 4. Correlation between the incidence of ulcerative gastroduodenal bleeding and surgical activity

Surgical activity
CFD regions	Sick (n) — X	Surgeries (n) — Y	%
Belgorod	5910	2255	38,2
Bryansk	4111	660	16,1
Vladimir	2752	570	20,7
Voronezh	6767	410	6,1
Ivanovo	1540	459	29,8
Kaluga	3696	208	5,6
Kostroma	901	122	13,5
Kursk	2180	280	12,8
Lipetsk	2726	455	16,7
Moscow region	10 961	1629	14,9
Orel	1501	139	9,3
Ryazan	2618	181	6,9
Smolensk	2051	194	9,5
Tambov	2169	197	9,1
Tver	2173	157	7,2
Tula	2237	276	12,3
Yaroslavl	1940	214	11,0
Total	56 233	8406	14,9
Pearson's correlation coefficient — r (PEARSON)			0,725371

Linear regression model (Table 5, Fig. 4) showed that correlation of surgical activity and incidence of ulcerative gastroduodenal bleeding has a coefficient of determination r² = 0.526.

Table 5. Regression analysis

Multiple R	0,72537105
R²	0,52616316
Standardized R²	0,494574037
Standard error	410,7196095
Sample	17

Fig. 4. Morbidity/surgical activity regression analysis.

Thus, direct correlation of surgical activity and morbidity in correlation-regression analysis can be explained in about half of cases (52.6%). Other 47.4% of cases (unexplained variance) depend on other random factors. These "random" factors include unavailable gastroscopy and endoscopic hemostasis, insufficient knowledge and experience in endoscopic specialist and surgeon, unreasonably long surveillance of a patient, insufficient equipment of intensive care unit and others. It should be noted that this statistical value is significantly lower than the previously determined relationship between overall in-hospital mortality and incidence of ulcerative gastroduodenal bleeding (r² = 0.7578). In this case, the proportion of unexplained variance was 24.2%.

Further dispersion analysis revealed moderate positive (variable X1, coefficient = 0.16) influence (higher morbidity results higher surgical activity) and the effect of other unaccounted factors on surgical activity (Y-intersection, coefficient 60.38). We have also determined significance of correlation between surgical activity and incidence of ulcerative gastroduodenal bleeding (degrees of freedom — 15, expected t-criterion (4.081) > critical t-criterion (2.13), p <0.05) and deviation of the expected values from the actual ones according to mean approximation error (Ᾱ — 53.9%).

Discussion

The effectiveness of treatment is determined by achievement of the objective following a particular medical measure in wide clinical practice (A. Cochrane) (cited by V. V. Omelyanovskiy 2019) [13]. Analysis of mortality rates in large arrays of clinical data is necessary to obtain statistical power and minimize the likelihood of type II error followed by false negative conclusions. It is also necessary to take into account the heterogeneity of data obtained from various primary sources.

According to our data, overall in-hospital mortality among patients with ulcerative gastroduodenal bleeding in the Central Federal District is 5.5%. High surgical activity was followed by mortality 4.7 — 15% (mean 6.9%), less aggressive approaches — 2.6 — 8.2% (mean 5.3%).

Oscillations of postoperative mortality are even more common in patients with ulcerative gastroduodenal bleeding. In the regions of the Central Federal District, high surgical activity is followed by postoperative mortality within 5.1 — 27.0% (mean 8.8%), and in the regions with less aggressive surgical strategy — 6.3 — 25.0% (mean 15.5%). There were significant differences in overall in-hospital and postoperative mortality following high surgical strategy and moderate surgical activity. In accordance with this trend, early surgery should be preferred in case of limited possibilities of endoscopic hemostasis in patients with ulcerative gastroduodenal bleeding.

In chronological analysis, the tendency of greater mortality following low surgical activity in regions is not unambiguous. Oscillations of these indicators are different from year to year and vary in a wide range. For example, postoperative mortality was significantly higher (OR 1.33, 95% CI 1.01-1.77, p = 0.04) in moderate surgical activity (19.2%) compared to high activity (9.8%) in 2014-2017. However, this situation has significantly changed in 2018, and postoperative mortality became higher (OR 1.33, 95% CI 1.01-1.77, p <0.05) in active surgical approach (20.4%) compared to more conservative approach (16.1%).

In chronological analysis of clinical material, heterogeneity of data in primary sources (annual information of chief surgeons of the Central Federal District) was 93% (I2, Review Manager 5.3). This result confirms heterogeneity of primary database on mortality in patients with ulcerative gastroduodenal bleeding (especially for postoperative mortality). Multiple concomitant factors can determine such heterogeneity and multidirectional trends in overall in-hospital and, especially, postoperative mortality. The random influence of these factors requires additional assessment. Patient-related and disease-related prognostic factors include various demographic characteristics of patients, comorbidities, course of peptic ulcer disease, and severity of bleeding.

Treatment strategy is an essential factor in addition to type of surgery per se. In our large-scale analysis, overall mortality rate was higher among patients with active surgical strategy compared to endoscopic hemostasis and intensive therapy [14 — 16]. At the same time, there is a downside to this trend. Reduced number of stomach surgeries undoubtedly results a loss of experience in gastric surgery in general surgical hospitals. Therefore, impaired prognosis of surgical treatment may be expected if open correction of complications of peptic ulcer disease is required [17]. We cannot also exclude the influence of other special cofactors, such as insufficient equipment and experience for any variant of endoscopic hemostasis. Unreliability of primary basic information is an important factor too. According to primary database, annual surgical activity in one of the regions of the Central Federal District was 5 times higher than mean statistical value. The causes of such a high sporadic activity in certain regions of the Russian Federation also require a detailed study.

Conclusion

The correlations between the number of patients with ulcerative gastroduodenal bleeding and surgical activity, overall in-hospital and postoperative mortality were established on a large clinical material. In active surgical strategy, overall in-hospital mortality prevails over postoperative one. Conservative approach and endoscopic hemostasis are followed by a reverse trend.

The authors declare no conflicts of interest.