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For peer review only
Use of non-steroidal anti-inflammatory drugs and proton pump inhibitors in correlation with incidence, recurrence
and fatality of peptic ulcer bleeding
Journal: BMJ Open
Manuscript ID: bmjopen-2012-002056
Article Type: Research
Date Submitted by the Author: 04-Sep-2012
Complete List of Authors: Lu, Yunxia Sverdén, Emma Ljung, Rickard; Karolinska Institutet, Söderlund, Claes Lagergren, Jesper; Karolinska Institutet,
<b>Primary Subject Heading</b>:
Epidemiology
Secondary Subject Heading: Gastroenterology and hepatology
Keywords: Peptic ulcer bleeding , Non-steroidal anti-inflammatory drugs, Propton Pump Inhibitors
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Use of non-steroidal
anti-inflammatory drugs and proton pump inhibitors
in correlation with incidence, recurrence and fatality of peptic ulcer
bleeding
Running head:
Drug use and peptic ulcer bleeding
Authors:
Yunxia Lu, M.D., Ph.D. 1, Emma Sverdén,M.D.
2, Rickard Ljung, MD, MPH, Ph.D.
1,3, Claes Söderlund,
M.D, Ph.D. 2, and Jesper Lagergren, M.D., Ph.D.
1, 4
Affiliations:
1 Upper Gastrointestinal Research, Department of Molecular Medicine and Surgery,
Karolinska Institutet, Stockholm, Sweden.
2 Section of Upper Gastrointestinal Surgery, Department of Surgery, Stockholm South
General Hospital, Sweden.
3 Centre for Epidemiology, The National Board of Health and Welfare, Stockholm, Sweden.
4 King´s College London, United Kingdom.
Corresponding author:
Yunxia Lu
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Address: Upper Gastrointestinal Research, 2nd
floor, Department of Molecular Medicine and
Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
E-mail: [email protected]
Tel: +46-(0)8-51772401
Fax: +46-(0)8-51776280
Key words: Peptic ulcer bleeding; NSAIDs; PPIs;
Word count: 1492 words.
Statement of Interests:
Authors' declaration of personal interests: None.
Declaration of funding interests: We thank the Swedish Research Council (SIMSAM) and
the Astrid and David Hagelén Foundation for supporting this study with research funding.
Contributorship Statement: LY: Study design, data collection, data analysis and manuscript writing.
ES: Results report and interpretation, manuscript writing.
RL: Data collection, data analysis and interpretation of results.
CS: Results report, results interpretation and manuscript writing.
JL: Study design, results interpretation and manuscript writing.
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Data Sharing Statement: Unpublished data from this study can be shown for reviewers if asked.
1) The decreased NSAID use was particularly evident in patients over 75 years of age.
2)We also analysed the trend of use of aspirin and H2 receptor antagonists which seems not very
relevant with trends of peptic ulcer bleeding.
3) The present study shows that the sales have decreased since 2004 with regard to both genders,
and this decrease is more obvious in women and in the population aged over 75.
4) Women in this study has the older mean age which might be associated with the results.
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Abstract
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors
(PPIs) are regarded as two types of drugs that respectively increase and decrease the risk of
peptic ulcer bleeding. However, their relation to occurrence, recurrence and fatality of
bleeding in the population level is not clear.
Study Objective: To clarify recent calendar time correlations between sales of NSAIDs and
PPIs and the occurrence of peptic ulcer bleeding, re-bleeding, and fatality in an ecological
study.
Design: A nationwide Swedish study was conducted in 2000–2008, during which trends in
sales of NSAIDs and PPIs were compared with hospitalization for peptic ulcer bleeding
episodes, recurrence of bleeding episodes within 60 days of hospitalization, and 30-day
fatality after admission for bleeding episodes.
Results: The time trend of peptic ulcer bleeding did not correlate with PPI use but did
correlate with NSAIDs in males (Rmale =0.6571, Pmale=0.05). Use of PPIs (inverse) and
NSAIDs correlated with re-bleeding in females (Rmale =−0.8754, P=0.002 and Rfemale =0.7161,
P=0.03, respectively), but not in males. An inverse correlation between PPI use and 30-day
fatality after bleeding was found (Rmale =−0.9392, Pmale=0.0002 and Rfemale =−0.8561,
Pfemale=0.003), and NSAID use was found to correlate with increased fatality after bleeding
((Rmale =0.7278, Pmale=0.03, Rfemale =0.7858, Pfemale=0.01).
Conclusion: The use of NSAIDs and PPIs correlates with recurrence of peptic ulcer bleeding
in female and fatality after peptic ulcer bleeding in both genders in the population level.
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Article Summary
Article focus:
Non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are two
types of drugs that are closely associated with opposite risk of peptic ulcer bleeding. Their
relation to occurrence, recurrence and fatality of bleeding in the population level is not clear.
Key message:
(1) The use of NSAIDs and PPIs (inversely) correlate with recurrence and fatality after peptic
ulcer bleeding on the population level;
(2) Women appeared to have a higher fatality of bleeding which might be associated with
older age and higher use of NSAIDs.
(3) The results highlight the need for careful consideration of the drug prescriptions to
patients with peptic ulcer bleeding.
Strengths and limitations:
(1) Drug use and peptic bleeding outcomes could not be linked with regard to individual
patients.
(2) Re-bleeding could only be identified on the basis of re-admission, which means we might
have lost information regarding re-bleeding that occurred within the same case of
hospitalization.
(3) It is difficult to find a suitable cut-off day for the definition of re-bleeding.
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Introduction
Bleeding is the most frequent and serious complication of peptic ulcer disease. Despite the
marked decrease in the occurrence of peptic ulcer disease during recent decades, paralleling
the decreasing prevalence of Helicobacter pylori infection, the incidence of peptic ulcer
bleeding has not changed significantly. On the contrary, several surveys have shown that the
incidence of peptic ulcer bleeding has increased among older people 1-4
. Re-bleeding and
fatality after peptic ulcer bleeding occur in 7-16% 2,5
and 3%-14%, respectively. These figures
might increase as a result of the increasing average age of many populations 1,2,6,7
. The high
risk of recurrence and fatality highlights the need to identify the best preventive measures
available. The established risk factors for peptic ulcer bleeding include Helicobacter pylori
infection and medications such as non-steroidal anti-inflammatory drugs (NSAIDs), while
proton pump inhibitors (PPIs) can prevent ulcer bleeding8. We aimed to examine how the use
of PPIs and NSAIDs correlates with the incidence, recurrence and fatality of peptic ulcer
bleeding in a population perspective.
Methods
Study design
This was a nationwide ecological study that addressed the correlation between relevant drug
sales and peptic ulcer bleeding in Sweden during the period 2000–2008. We used complete
Swedish nationwide registers to collect data on sales of NSAIDs and PPIs, hospitalization and
fatality after peptic ulcer bleeding. The average daily defined doses (DDDs) of NSAIDs and
PPIs were compared with the incidence, recurrence within 60 days after hospitalization for
bleeding, and 30-day fatality after admission for peptic ulcer bleeding, in Sweden. The
Regional Ethics Committee in Stockholm approved the study.
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Data collection
Definition of bleeding incidence
Aggregated data on drug sales in Sweden during the study period was available from the
Swedish Prescribed Drug Register. This register records all prescribed and collected
medications in the entire Swedish population of approximately 9 million inhabitants9. The
Prescribed Drug Register contains data on the age and sex of patients together with names of
prescribed drug substances according to the anatomical therapeutic chemical (ATC)
classification. All NSAIDs (ATC codes: M01A) and PPIs (ATC codes: A02BC and A02BD)
were used for this study.
Patients with peptic ulcer bleeding were identified from the Swedish Patient Register, which
contains complete, nationwide data on all codes representing diagnoses and surgical
procedures relating to in-hospital care in Sweden since 1987. Codes representing peptic ulcer
bleeding according to the international classification of diseases (ICD) version 10 were used
(K25.0, K25.4, K26.0, K26.4, K27.0, K27.4, K28.0, K28.4, K92.0, K92.1, and K92.2). Since
the treatment of ulcer perforation is different from the treatment of ulcer bleeding, patients
with perforation were excluded. Re-admission for peptic ulcer bleeding within one day of
discharge was not regarded as a new case of bleeding. Re-bleeding was defined as an episode
of bleeding that occurred within 60-days after a previous bleeding. Fatality was defined as
any death occurring within 30 days of the date of admission for peptic ulcer bleeding. Death
dates were obtained from the Death of Cause Register and the Swedish Population Register.
The personal number, which is the unique identity for all the Swedish residents, was used to
link data among different registers.
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Statistical analyses
Average DDD and time trends regarding the use of PPIs and NSAIDs were calculated on the
basis of the average population for each year. DDD/TID was described as DDDs per thousand
inhabitants per day. A linear regression model was applied to test the statistical significance
of trends at the 5% level. Correlation analyses were performed between drug use and the
incidence, recurrence, and fatality of peptic ulcer bleeding. All analyses were gender-specific.
Figures were plotted to show the correlations between drug use and bleeding events. All
statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC).
Results
Trends of PPI and NSAID use
The use of PPIs increased during the study period, except for a temporary drop in 2003
(Figure 1). The use of NSAIDs increased until 2004, after which there was a decrease to a
level lower than in year 2000 (Figure 2). The decreased NSAID use was particularly evident
in patients over 75 years of age (data not shown). Women used more PPIs and NSAIDs than
men (Figures 1 and 2), and this difference was more obvious with regard to NSAIDs. We also
analysed the trend of use of aspirin and H2 receptor antagonists (data not shown) which seems
not very relevant with trends of peptic ulcer bleeding, then we focus on correlations of PPIs /
NSAIDs and peptic ulcer bleeding in this study.
Incidence, recurrence and fatality of peptic ulcer bleeding
The hospitalization rate for peptic ulcer bleeding was stable during the study period, while a
higher rate was observed in men than in women (Figure 1). The rate of recurrence of bleeding
was similar between the genders, although the recurrence rate in women showed a slightly
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decreasing trend (Figure 3). The 30-day fatality after peptic ulcer bleeding decreased during
the study period, especially in males (Figures 5 and 6). Furthermore, women showed a higher
fatality rate in different time periods (Figure 4).
PPIs and NSAIDs use and peptic ulcer bleeding
The trend of peptic ulcer bleeding did not correlate with the PPIs use in either gender (Figure
1; Rmale=-0.2274, Pmale=0.5562,Rfemale=-0.2398, Pfemale=0.5342), but it correlated marginally
with the trend of the use of NSAIDs in males only (Figure 2; Rmale =0.6571,Pmale=0.05,
Pfemale=0.2633, Rfemale =0.4177 ).
PPI and NSAID use and peptic ulcer re-bleeding
The time trends of re-bleeding did not correlate with the use of PPIs or NSAIDs in males
(Figures 3 and 4, Rmale =0.2227, Pmale=0.5647; Rfemale =0.023, Pfemale=0.9522), but the
decreased occurrence of re-bleeding in females correlated with the time trends of both PPI use
(Rmale =−0.8754, P=0.002) and NSAID use (Rfemale =0.7161,P=0.03).
PPI and NSAID use and 30-day fatality
There was an inverse correlation between PPI use and fatality in both genders (Rmale =−0.9392,
Pmale=0.0002, Rfemale =−0.8561, Pfemale=0.003) (Figure 5), and the NSAID use showed a close
correlation with fatality of bleeding in both genders (Rmale =0.7278, Pmale=0.03, Rfemale
=0.7858, Pfemale=0.01) (Figure 6).
Discussion
This study indicates that use of NSAIDs and PPIs (inversely) correlates with 30-day fatality
(both sexes) and recurrence (females) of peptic ulcer bleeding in the unselected population.
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Women appeared to have a higher fatality of bleeding which might be associated with age and
greater use of NSAIDs.
The main strength of this study is the nationwide, complete data collection regarding drug
sales, hospitalization for bleeding, and fatality. Since there is virtually no private care for
peptic ulcer bleeding in Sweden and since such bleeding usually requires hospitalization, the
incidence of bleeding and re-bleeding covered by this study should represent population-
based figures. There are, however, several weaknesses that should be acknowledged. Drug
use and peptic bleeding outcomes could not be linked with regard to individual patients. This
ecological design makes the interpretations more uncertain. Re-bleeding could only be
identified on the basis of re-admission, which means we might have lost information
regarding re-bleeding that occurred within the same case of hospitalization. On the other hand,
it is difficult to find a suitable cut-off day for the definition of re-bleeding. The definition of
fatality of bleeding was based on death within 30 days after discharge, since it is difficult to
assess if death actually results from bleeding.
NSAIDs constitute an established risk factor for peptic ulcer bleeding, but the use of these
medications at the population level is less well documented. A previous study reported that
the sales of NSAIDs in Sweden increased during the period 1978-2002.10
The present study
shows that the sales have decreased since 2004 with regard to both genders, and this decrease
is more obvious in women and in the population aged over 75 (data not shown). This decline
might contribute to the decreasing trend of peptic ulcer fatality and re-bleeding in women.
Similarly, the increased use of PPIs might contribute to these trends. The correlation between
use of PPIs and fatality indicates that PPIs might prevent deaths from bleeding. This relation
is more apparent in the male population, which shows a very interesting, coinciding pattern.
The different correlations of drug and bleeding fatality between men and women could
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attribute to the different use of PPIs and NSAIDs between the genders. Previous studies have
found that PPIs may help reduce peptic ulcer bleeding, re-bleeding and the need for surgery,
but not death 11-13
. It is difficult to differentiate the respective roles of PPIs and NSAIDs.
Nevertheless, the gastric mucosal protective effects of PPIs could be beneficial if NSAIDs are
used. Surprisingly, PPIs are used in only 10%–12% of patients admitted with a peptic ulcer
disease and using NSAIDs.14-16
The incidence of peptic ulcer bleeding is higher in men than in women, but few studies have
reported the gender distribution with regard to re-bleeding and death. One British case series
study suggested that women are at a higher risk of perforation or death than men 17
. The older
mean age in women was, however, an important factor in that study, and this is consistent
with our data (data not shown). The greater use of NSAIDs in women cannot be ignored. The
rapid decrease of NSAID use in women since 2004 might contribute to the significantly
decreased occurrence of re-bleeding and fatality in this group in which PPI use is increasing
continuously.
In conclusion, although the use of NSAIDs and PPIs in the general population does not seem
to mirror the incidence of peptic ulcer bleeding, such use correlates with re-bleeding and
fatality of peptic ulcer bleeding. Therefore, PPIs or other gastroprotective drugs should
probably be prescribed more often, when NSAID prescriptions are needed in patients with
known peptic ulcer disease.
References
1. Blatchford O, Davidson LA, Murray WR, Blatchford M, Pell J. Acute upper gastrointestinal
haemorrhage in west of Scotland: case ascertainment study. BMJ. Aug 30
1997;315(7107):510-514.
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2. van Leerdam ME, Vreeburg EM, Rauws EA, et al. Acute upper GI bleeding: did anything
change? Time trend analysis of incidence and outcome of acute upper GI bleeding between
1993/1994 and 2000. Am J Gastroenterol. Jul 2003;98(7):1494-1499.
3. Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage:
a population-based study. Am J Gastroenterol. Feb 1995;90(2):206-210.
4. Yavorski RT, Wong RK, Maydonovitch C, Battin LS, Furnia A, Amundson DE. Analysis of 3,294
cases of upper gastrointestinal bleeding in military medical facilities. Am J Gastroenterol. Apr
1995;90(4):568-573.
5. Vreeburg EM, Snel P, de Bruijne JW, Bartelsman JF, Rauws EA, Tytgat GN. Acute upper
gastrointestinal bleeding in the Amsterdam area: incidence, diagnosis, and clinical outcome.
Am J Gastroenterol. Feb 1997;92(2):236-243.
6. Paspatis GA, Matrella E, Kapsoritakis A, et al. An epidemiological study of acute upper
gastrointestinal bleeding in Crete, Greece. Eur J Gastroenterol Hepatol. Nov
2000;12(11):1215-1220.
7. Barkun A, Sabbah S, Enns R, et al. The Canadian Registry on Nonvariceal Upper
Gastrointestinal Bleeding and Endoscopy (RUGBE): Endoscopic hemostasis and proton pump
inhibition are associated with improved outcomes in a real-life setting. Am J Gastroenterol.
Jul 2004;99(7):1238-1246.
8. Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta-analysis of proton pump
inhibitor therapy in peptic ulcer bleeding. BMJ. Mar 12 2005;330(7491):568.
9. Wettermark B, Hammar N, Fored CM, et al. The new Swedish Prescribed Drug Register--
opportunities for pharmacoepidemiological research and experience from the first six
months. Pharmacoepidemiol Drug Saf. Jul 2007;16(7):726-735.
10. Hermansson M, Ekedahl A, Ranstam J, Zilling T. Decreasing incidence of peptic ulcer
complications after the introduction of the proton pump inhibitors, a study of the Swedish
population from 1974-2002. BMC Gastroenterol. 2009;9:25.
11. Leontiadis GI, Sharma VK, Howden CW. WITHDRAWN: Proton pump inhibitor treatment for
acute peptic ulcer bleeding. Cochrane Database Syst Rev.5:CD002094.
12. Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and
proton-pump inhibitors: a cohort study. Ann Intern Med. Mar 16;152(6):337-345.
13. Zed PJ, Loewen PS, Slavik RS, Marra CA. Meta-analysis of proton pump inhibitors in
treatment of bleeding peptic ulcers. Ann Pharmacother. Dec 2001;35(12):1528-1534.
14. Di Fiore F, Lecleire S, Merle V, et al. Changes in characteristics and outcome of acute upper
gastrointestinal haemorrhage: a comparison of epidemiology and practices between 1996
and 2000 in a multicentre French study. Eur J Gastroenterol Hepatol. Jun 2005;17(6):641-647.
15. Ohmann C, Imhof M, Ruppert C, et al. Time-trends in the epidemiology of peptic ulcer
bleeding. Scand J Gastroenterol. Aug 2005;40(8):914-920.
16. Johnell K, Fastbom J. Concomitant use of gastroprotective drugs among elderly NSAID/COX-2
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17. Smart HL, Langman MJ. Late outcome of bleeding gastric ulcers. Gut. Aug 1986;27(8):926-928.
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PPI: D
DD/T
IND
20
25
30
35
40
45
50
55
60
Calendar Year
2000 2001 2002 2003 2004 2005 2006 2007 2008
0
2
4
6
8
10
12
14
16
18
20
Figure 1a: PPIs and bleeding in men
Male_PPI
Male_bleeding
20
25
30
35
40
45
50
55
60
Calendar Year
2000 2001 2002 2003 2004 2005 2006 2007 2008
Hospitaliz
ation rate
,per 100,0
00
0
2
4
6
8
10
12
14
16
18
20
Figure 1b: PPIs and bleeding in women
Female_PPI
Female_bleeding
Figure 1. Use of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000
inhabitants per day and hospitalization rate for peptic ulcer bleeding (hospitalizations for
bleeding per 100,000 inhabitants) in Sweden in 2000–2008. Figure 1a and Figure 1b represent
males and females, respectively.
Figure 2. Use of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses
(DDD) per 1,000 inhabitants per day and hospitalization rate for peptic ulcer bleeding
(hospitalizations for bleeding per 100,000 inhabitants) in Sweden in 2000–2008. Figure 2a
and Figure 2b represent males and females, respectively.
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Figure 3. Use of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000
inhabitants per day and peptic ulcer re-bleeding rate within 60 days (number of re-bleeders
per 100 in-hospitalizations for bleeding) in Sweden in 2000–2008. Figure 3a and Figure 3b
represent males and females, respectively.
Figure 4. Use of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses
(DDD) per 1000 inhabitants per day and peptic ulcer re-bleeding rate within 60 days (number
of re-bleeders per 100 hospitalizations for bleeding) in Sweden in 2000–2008. Figure 4a and
Figure 4b represent males and females, respectively.
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Figure 5. Use of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000
inhabitants per day and 30-day fatality of peptic ulcer bleeding (number of deaths within 30
days per 100 hospitalizations for bleeding) in Sweden 2000–2008. Figure 5a and Figure 5b
represent males and females, respectively.
Figure 6. Use of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses
(DDDs) per 1000 inhabitants per day and 30-day fatality of peptic ulcer bleeding (number of
deaths within 30 days per 100 hospitalizations for bleeding) in Sweden in 2000–2008. Figure
6a and Figure 6b represent males and females, respectively.
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Use of non-steroidal anti-inflammatory drugs and proton pump inhibitors in correlation with incidence, recurrence
and fatality of peptic ulcer bleeding
Journal: BMJ Open
Manuscript ID: bmjopen-2012-002056.R1
Article Type: Research
Date Submitted by the Author: 31-Oct-2012
Complete List of Authors: Lu, Yunxia Sverdén, Emma Ljung, Rickard; Karolinska Institutet, Söderlund, Claes Lagergren, Jesper; Karolinska Institutet,
<b>Primary Subject Heading</b>:
Epidemiology
Secondary Subject Heading: Gastroenterology and hepatology
Keywords: Peptic ulcer bleeding , Non-steroidal anti-inflammatory drugs, Propton Pump Inhibitors
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1
Use of non-steroidal 1
anti-inflammatory drugs and proton pump inhibitors 2
in correlation with incidence, recurrence and fatality of peptic ulcer 3
bleeding: an ecological study 4
Running head: 5
Drug sales/use and peptic ulcer bleeding 6
7
Authors: 8
Yunxia Lu, M.D., Ph.D. 1, Emma Sverdén,M.D.
2, Rickard Ljung, MD, MPH, Ph.D.
1,3, Claes Söderlund, 9
M.D, Ph.D. 2, and Jesper Lagergren, M.D., Ph.D.
1, 4 10
11
Affiliations: 12
1 Upper Gastrointestinal Research, Department of Molecular Medicine and Surgery, 13
Karolinska Institutet, Stockholm, Sweden.
14
2 Section of Upper Gastrointestinal Surgery, Department of Surgery, Stockholm South 15
General Hospital, Sweden.
16
3 Centre for Epidemiology, The National Board of Health and Welfare, Stockholm, Sweden. 17
4 King´s College London, United Kingdom. 18
Corresponding author: 19
Yunxia Lu 20
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2
Address: Upper Gastrointestinal Research, 2nd
floor, Department of Molecular Medicine and 1
Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden. 2
E-mail: [email protected] 3
Tel: +46-(0)8-51772401 4
Fax: +46-(0)8-51776280 5
6
Key words: Peptic ulcer bleeding; NSAIDs; PPIs; 7
Word count: 1492 words. 8
9
Statement of Interests: 10
Authors' declaration of personal interests: None. 11
Declaration of funding interests: We thank the Swedish Research Council (SIMSAM) and 12
the Astrid and David Hagelén Foundation for supporting this study with research funding. 13
14
15
16
17
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Abstract 1
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors 2
(PPIs) are regarded as two types of drugs that respectively increase and decrease the risk of 3
peptic ulcer bleeding. However, their relation to occurrence, recurrence and fatality of 4
bleeding in the population level is not clear. 5
Study Objective: To clarify recent calendar time correlations between sales of NSAIDs and 6
PPIs and the occurrence of peptic ulcer bleeding, re-bleeding, and fatality in an ecological 7
study. 8
Design: A nationwide Swedish study was conducted in 2000–2008, during which trends in 9
sales of NSAIDs and PPIs were compared with hospitalization for peptic ulcer bleeding 10
episodes, recurrence of bleeding episodes within 60 days of hospitalization, and 30-day 11
fatality after admission for bleeding episodes. 12
Results: The time trend of peptic ulcer bleeding did not correlate with PPI sales but did 13
correlate with NSAIDs in males (Rmale =0.6571, Pmale=0.05). Sales of PPIs (inverse) and 14
NSAIDs correlated with re-bleeding in females (Rmale =−0.8754, P=0.002 and Rfemale =0.7161, 15
P=0.03, respectively), but not in males. An inverse correlation between PPI sales and 30-day 16
fatality after bleeding was found (Rmale =−0.9392, Pmale=0.0002 and Rfemale =−0.8561, 17
Pfemale=0.003), and NSAID sales was found to correlate with increased fatality after bleeding 18
((Rmale =0.7278, Pmale=0.03, Rfemale =0.7858, Pfemale=0.01). 19
Conclusion: The sales of NSAIDs and PPIs correlates with recurrence of peptic ulcer 20
bleeding in female and fatality after peptic ulcer bleeding in both genders in the population 21
level. 22
23
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Article Summary 1
Article focus: 2
Non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are two 3
types of drugs that are closely associated with opposite risk of peptic ulcer bleeding. Their 4
relation to occurrence, recurrence and fatality of bleeding in the population level is not clear. 5
6
Key message: 7
(1) The sales of NSAIDs and PPIs (inversely) correlate with recurrence and fatality after 8
peptic ulcer bleeding on the population level; 9
(2) Women appeared to have a higher fatality of bleeding which might be associated with 10
older age and higher sales of NSAIDs. 11
(3) The results highlight the need for careful consideration of the drug prescriptions to 12
patients with peptic ulcer bleeding. 13
14
Strengths and limitations: 15
(1) Drug sales/use and peptic bleeding outcomes could not be linked with regard to individual 16
patients. 17
(2) Re-bleeding could only be identified on the basis of re-admission, which means we might 18
have lost information regarding re-bleeding that occurred within the same case of 19
hospitalization. 20
(3) It is difficult to find a suitable cut-off day for the definition of re-bleeding. 21
22
23
24
25
26
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Introduction 1
Bleeding is one of the most frequent and serious complications of peptic ulcer disease. 2
Despite the marked decrease in the occurrence of peptic ulcer disease during recent decades, 3
paralleling the decreasing prevalence of Helicobacter pylori infection, the incidence of peptic 4
ulcer bleeding has not changed apparently. On the contrary, several surveys have shown that 5
the incidence of peptic ulcer bleeding has increased among older people. 1-4
Re-bleeding and 6
fatality after peptic ulcer bleeding occur in 7-16% and 3%-14%, 2,5,6
respectively. These 7
figures might increase as a result of the increasing average age of many populations. 1,2,7,8
The 8
high risk of recurrence and fatality highlights the need to identify the best preventive 9
measures available. The established risk factors for peptic ulcer bleeding include Helicobacter 10
pylori infection and medications such as non-steroidal anti-inflammatory drugs (NSAIDs), 11
while proton pump inhibitors (PPIs) can prevent ulcer bleeding. 9We aimed to examine how 12
the sales of PPIs and NSAIDs correlates with the incidence, recurrence and fatality of peptic 13
ulcer bleeding in a population perspective. 14
Methods 15
Study design 16
This was a nationwide ecological study that addressed the correlation between relevant drug 17
sales and peptic ulcer bleeding in Sweden during the period 2000–2008. We used complete 18
Swedish nationwide registers to collect data on sales of NSAIDs and PPIs, hospitalization and 19
fatality after peptic ulcer bleeding. The average daily defined doses (DDDs) of NSAIDs and 20
PPIs were compared with the incidence, recurrence within 60 days after hospitalization for 21
bleeding, and 30-day fatality after admission for peptic ulcer bleeding, in Sweden. The 22
Regional Ethics Committee in Stockholm approved the study. 23
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Data collection 1
Definition of bleeding incidence 2
Aggregated data on drug sales in Sweden during the study period was available from the 3
Swedish Prescribed Drug Register. This register records all prescribed and collected 4
medications in the entire Swedish population of approximately 9 million inhabitants. 10
The 5
Prescribed Drug Register contains data on the age and sex of patients together with names of 6
prescribed drug substances according to the anatomical therapeutic chemical (ATC) 7
classification. All NSAIDs (ATC codes: M01A) and PPIs (ATC codes: A02BC and A02BD) 8
were used for this study. All NSAIDs with ATC codes of M01A were sold as prescriptions 9
drug except a few types of ibuprofen in Sweden. 10
Patients with peptic ulcer bleeding were identified from the Swedish Patient Register, which 11
contains complete, nationwide data on all codes representing diagnoses and surgical 12
procedures relating to in-hospital care in Sweden since 1987. Codes representing peptic ulcer 13
bleeding according to the international classification of diseases (ICD) version 10 were used 14
(K25.0, K25.4, K26.0, K26.4, K27.0, K27.4, K28.0, K28.4, K92.0, K92.1, and K92.2). Since 15
the treatment of ulcer perforation is different from the treatment of ulcer bleeding, patients 16
with perforation were excluded. Re-admission for peptic ulcer bleeding within one day of 17
discharge was not regarded as a new case of bleeding. Re-bleeding was defined as an episode 18
of bleeding that occurred within 60-days after a previous bleeding. Fatality was defined as 19
any death occurring within 30 days of the date of admission for peptic ulcer bleeding. Death 20
dates were obtained from the Death of Cause Register and the Swedish Population Register. 21
The personal number, which is the unique identity for all the Swedish residents, was used to 22
link data among different registers. 23
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Statistical analyses 1
Average DDD and time trends regarding the sales of PPIs and NSAIDs were calculated on the 2
basis of the average population for each year. DDD/TID was described as DDDs per thousand 3
inhabitants per day. A linear regression model was applied to test the statistical significance 4
of trends at the 5% level. Correlation analyses were performed between drug sales and the 5
incidence, recurrence, and fatality of peptic ulcer bleeding. All analyses were gender-specific. 6
Figures were plotted to show the correlations between drug sales and bleeding events. All 7
statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). 8
Results 9
Trends of PPI and NSAID sales 10
The sales of PPIs increased during the study period, except for a temporary drop in 2003 11
(Figure 1). The sales of NSAIDs increased until 2004, after which there was a decrease to a 12
level lower than in year 2000 (Figure 2). The decreased NSAID sales were particularly 13
evident in patients over 75 years of age (data not shown). Women bought more PPIs and 14
NSAIDs than men (Figures 1 and 2), and this difference was more obvious with regard to 15
NSAIDs. We also analysed the trend of sales of aspirin and H2 receptor antagonists (data not 16
shown) which seems not very relevant with trends of peptic ulcer bleeding, then we focus on 17
correlations of PPIs / NSAIDs and peptic ulcer bleeding in this study. 18
Incidence, recurrence and fatality of peptic ulcer bleeding 19
The hospitalization rate for peptic ulcer bleeding was stable during the study period, while a 20
higher rate was observed in men than in women (Figure 1). The rate of recurrence of bleeding 21
was similar between the genders, although the recurrence rate in women showed a slightly 22
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decreasing trend (Figure 3). The 30-day fatality after peptic ulcer bleeding decreased during 1
the study period, especially in males (Figures 5 and 6). Furthermore, women showed a higher 2
fatality rate in different time periods (Figure 4). 3
PPIs and NSAIDs sales and peptic ulcer bleeding 4
The trend of peptic ulcer bleeding did not correlate with the PPIs sales in either gender 5
(Figure 1; Rmale=-0.2274, Pmale=0.5562,Rfemale=-0.2398, Pfemale=0.5342), but it correlated 6
marginally with the trend of the sales of NSAIDs in males only (Figure 2; Rmale 7
=0.6571,Pmale=0.05, Pfemale=0.2633, Rfemale =0.4177 ). 8
PPI and NSAID sales and peptic ulcer re-bleeding 9
The time trends of re-bleeding did not correlate with the sales of PPIs or NSAIDs in males 10
(Figures 3 and 4, Rmale =0.2227, Pmale=0.5647; Rfemale =0.023, Pfemale=0.9522), but the 11
decreased occurrence of re-bleeding in females correlated with the time trends of both PPI 12
sales (Rmale =−0.8754, P=0.002) and NSAID sales (Rfemale =0.7161,P=0.03). 13
PPI and NSAID sales and 30-day fatality 14
There was an inverse correlation between PPI sales and fatality in both genders (Rmale 15
=−0.9392, Pmale=0.0002, Rfemale =−0.8561, Pfemale=0.003) (Figure 5), and the NSAID sales 16
showed a close correlation with fatality of bleeding in both genders (Rmale =0.7278, Pmale=0.03, 17
Rfemale =0.7858, Pfemale=0.01) (Figure 6). 18
Discussion 19
This study indicates that sales of NSAIDs and PPIs (inversely) correlates with 30-day fatality 20
(both sexes) and recurrence (females) of peptic ulcer bleeding in the unselected population. 21
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Women appeared to have a higher fatality of bleeding which might be associated with age and 1
greater sales/use of NSAIDs. 2
The main strength of this study is the nationwide, complete data collection regarding drug 3
sales, hospitalization for bleeding, and fatality. Since there is virtually no private care for 4
peptic ulcer bleeding in Sweden and since such bleeding usually requires hospitalization, the 5
incidence of bleeding and re-bleeding covered by this study should represent population-6
based figures. There are, however, several weaknesses that should be acknowledged. Drug 7
sales/use and peptic bleeding outcomes could not be linked with regard to individual patients. 8
This ecological design makes the interpretations more uncertain. Re-bleeding could only be 9
identified on the basis of re-admission, which means we might have lost information 10
regarding re-bleeding that occurred within the same case of hospitalization. On the other hand, 11
it is difficult to find a suitable cut-off day for the definition of re-bleeding. The definition of 12
fatality of bleeding was based on death within 30 days after discharge, since it is difficult to 13
assess if death actually results from bleeding. Furthermore, selection bias for PPIs users could 14
exist since PPIs were also prescribed for gastroesophageal reflux diseases. This might dilute 15
the correlation between PPIs and incidence of peptic ulcer bleeding. Nevertheless, we also 16
have studied correlation between PPIs /NSAIDs and re-bleeding, PPIs /NSAIDs and mortality 17
after bleeding diagnosis which may possibly further pinpoint the specific correlation between 18
PPIs/NSAIDs and peptic ulcer bleeding. In addition, a few types of ibuprofen as one of 19
NSAIDs were sold as over the counter drug which might lead to selection bias for NSAIDs in 20
this study. Since most of NSAIDs were prescribed drugs and actually few persons buy drugs 21
without prescriptions in Sweden due to the nationwide health care system, this selection bias 22
may be negligible. 23
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NSAIDs constitute an established risk factor for peptic ulcer bleeding, but the sales/use of 1
these medications at the population level is less well documented. A previous study reported 2
that the sales of NSAIDs in Sweden increased during the period 1978-2002.11
The present 3
study shows that the sales have decreased since 2004 with regard to both genders, and this 4
decrease is more obvious in women and in the population aged over 75 (data not shown). This 5
decline might contribute to the decreasing trend of peptic ulcer fatality and re-bleeding in 6
women. Similarly, the increased sales/use of PPIs might contribute to these trends. The 7
correlation between sales/use of PPIs and fatality indicates that PPIs might prevent deaths 8
from bleeding. This relation is more apparent in the male population, which shows a very 9
interesting, coinciding pattern. The different correlations of drug and bleeding fatality 10
between men and women could attribute to the different sales/use of PPIs and NSAIDs 11
between the genders. Previous studies have found that PPIs may help reduce peptic ulcer 12
bleeding, re-bleeding and the need for surgery, but not death. 12-14
It is difficult to differentiate 13
the respective roles of PPIs and NSAIDs. Nevertheless, the gastric mucosal protective effects 14
of PPIs could be beneficial if NSAIDs are used. Surprisingly, PPIs are used in only 10%–22% 15
of patients admitted with a peptic ulcer disease and using NSAIDs.15-17
Our recent study using 16
individual prescription data from Sweden revealed that less than 40% long-term NSAIDs 17
users (those prescribed NSADs for more than 180 days) were prescribed concomitantly 18
gastroprotective medication18
. Furthermore this study found that men took less 19
gastroprotective drugs compared to women despite that the concomitant antithrombotic 20
treatment was more common in men. On the other side, another German study found that 21
over-prescription of drugs might increase risk of adverse effect because of drug-drug 22
interactions19
. It may indicate that use of NSAIDs in high risk population, e.g. patients with 23
history of complicated peptic ulcer, elderly population with several concomitant prescriptions, 24
should be cautious and personalized regimen should be considered thoroughly. 25
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The incidence of peptic ulcer bleeding is higher in men than in women, but few studies have 1
reported the gender distribution with regard to re-bleeding and death. One British case series 2
study suggested that women are at a higher risk of perforation or death than men. 20
The older 3
mean age in women was, however, an important factor in that study, and this is consistent 4
with our data (data not shown). The greater sales/use of NSAIDs in women cannot be ignored. 5
The rapid decrease of NSAID sales/use in women since 2004 might contribute to the 6
significantly decreased occurrence of re-bleeding and fatality in this group in which PPI 7
sales/use is increasing continuously. 8
In conclusion, although the sales/use of NSAIDs and PPIs in the general population does not 9
seem to mirror the incidence of peptic ulcer bleeding, such sales/use correlates with re-10
bleeding and fatality of peptic ulcer bleeding. This correlation seems more obvious in old 11
women which propose an intriguing issue for future study. The potential reduced risk of death 12
due to decreased use of NSAIDs (especially in old women) and increased use of PPIs 13
(especially in male population) warrant further investigation. 14
References 15
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west of Scotland: case ascertainment study. BMJ. Aug 30 1997;315(7107):510-514. 17
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15. Di Fiore F, Lecleire S, Merle V, et al. Changes in characteristics and outcome of acute upper 22
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16. Ohmann C, Imhof M, Ruppert C, et al. Time-trends in the epidemiology of peptic ulcer 25
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17. Johnell K, Fastbom J. Concomitant use of gastroprotective drugs among elderly NSAID/COX-2 27
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18. Ljung R, Lu Y, Lagergren J. High concomitant use of interacting drugs and low use of 30
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19. Ahrens D, Chenot JF, Behrens G, et al. Appropriateness of treatment recommendations for 33
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20. Smart HL, Langman MJ. Late outcome of bleeding gastric ulcers. Gut. Aug 1986;27(8):926-928. 36
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Figure 1. Sales of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000 1
inhabitants per day and hospitalization rate for peptic ulcer bleeding (hospitalizations for 2
bleeding per 100,000 inhabitants) in Sweden in 2000–2008. Figure 1a and Figure 1b represent 3
males and females, respectively. 4
5
Figure 2. Sales of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses 6
(DDD) per 1,000 inhabitants per day and hospitalization rate for peptic ulcer bleeding 7
(hospitalizations for bleeding per 100,000 inhabitants) in Sweden in 2000–2008. Figure 2a 8
and Figure 2b represent males and females, respectively. 9
10
Figure 3. Sales of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000 11
inhabitants per day and peptic ulcer re-bleeding rate within 60 days (number of re-bleeders 12
per 100 in-hospitalizations for bleeding) in Sweden in 2000–2008. Figure 3a and Figure 3b 13
represent males and females, respectively. 14
15
Figure 4. Sales of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses 16
(DDD) per 1000 inhabitants per day and peptic ulcer re-bleeding rate within 60 days (number 17
of re-bleeders per 100 hospitalizations for bleeding) in Sweden in 2000–2008. Figure 4a and 18
Figure 4b represent males and females, respectively. 19
20
Figure 5. Use of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000 21
inhabitants per day and 30-day fatality of peptic ulcer bleeding (number of deaths within 30 22
days per 100 hospitalizations for bleeding) in Sweden 2000–2008. Figure 5a and Figure 5b 23
represent males and females, respectively. 24
25
Figure 6. Sales of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses 26
(DDDs) per 1000 inhabitants per day and 30-day fatality of peptic ulcer bleeding (number of 27
deaths within 30 days per 100 hospitalizations for bleeding) in Sweden in 2000–2008. Figure 28
6a and Figure 6b represent males and females, respectively. 29
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Use of non-steroidal 1
anti-inflammatory drugs and proton pump inhibitors 2
in correlation with incidence, recurrence and fatality of peptic ulcer 3
bleeding: an ecological study 4
Running head: 5
Drug sales/use and peptic ulcer bleeding 6
7
Authors: 8
Yunxia Lu, M.D., Ph.D. 1, Emma Sverdén,M.D.
2, Rickard Ljung, MD, MPH, Ph.D.
1,3, Claes Söderlund, 9
M.D, Ph.D. 2, and Jesper Lagergren, M.D., Ph.D.
1, 4 10
11
Affiliations: 12
1 Upper Gastrointestinal Research, Department of Molecular Medicine and Surgery, 13
Karolinska Institutet, Stockholm, Sweden.
14
2 Section of Upper Gastrointestinal Surgery, Department of Surgery, Stockholm South 15
General Hospital, Sweden.
16
3 Centre for Epidemiology, The National Board of Health and Welfare, Stockholm, Sweden. 17
4 King´s College London, United Kingdom. 18
Corresponding author: 19
Yunxia Lu 20
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Address: Upper Gastrointestinal Research, 2nd
floor, Department of Molecular Medicine and 1
Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden. 2
E-mail: [email protected] 3
Tel: +46-(0)8-51772401 4
Fax: +46-(0)8-51776280 5
6
Key words: Peptic ulcer bleeding; NSAIDs; PPIs; 7
Word count: 1492 words. 8
9
Statement of Interests: 10
Authors' declaration of personal interests: None. 11
Declaration of funding interests: We thank the Swedish Research Council (SIMSAM) and 12
the Astrid and David Hagelén Foundation for supporting this study with research funding. 13
14
15
16
17
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Abstract 1
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors 2
(PPIs) are regarded as two types of drugs that respectively increase and decrease the risk of 3
peptic ulcer bleeding. However, their relation to occurrence, recurrence and fatality of 4
bleeding in the population level is not clear. 5
Study Objective: To clarify recent calendar time correlations between sales of NSAIDs and 6
PPIs and the occurrence of peptic ulcer bleeding, re-bleeding, and fatality in an ecological 7
study. 8
Design: A nationwide Swedish study was conducted in 2000–2008, during which trends in 9
sales of NSAIDs and PPIs were compared with hospitalization for peptic ulcer bleeding 10
episodes, recurrence of bleeding episodes within 60 days of hospitalization, and 30-day 11
fatality after admission for bleeding episodes. 12
Results: The time trend of peptic ulcer bleeding did not correlate with PPI sales but did 13
correlate with NSAIDs in males (Rmale =0.6571, Pmale=0.05). Sales of PPIs (inverse) and 14
NSAIDs correlated with re-bleeding in females (Rmale =−0.8754, P=0.002 and Rfemale =0.7161, 15
P=0.03, respectively), but not in males. An inverse correlation between PPI sales and 30-day 16
fatality after bleeding was found (Rmale =−0.9392, Pmale=0.0002 and Rfemale =−0.8561, 17
Pfemale=0.003), and NSAID sales was found to correlate with increased fatality after bleeding 18
((Rmale =0.7278, Pmale=0.03, Rfemale =0.7858, Pfemale=0.01). 19
Conclusion: The sales of NSAIDs and PPIs correlates with recurrence of peptic ulcer 20
bleeding in female and fatality after peptic ulcer bleeding in both genders in the population 21
level. 22
23
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Article Summary 1
Article focus: 2
Non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are two 3
types of drugs that are closely associated with opposite risk of peptic ulcer bleeding. Their 4
relation to occurrence, recurrence and fatality of bleeding in the population level is not clear. 5
6
Key message: 7
(1) The sales of NSAIDs and PPIs (inversely) correlate with recurrence and fatality after 8
peptic ulcer bleeding on the population level; 9
(2) Women appeared to have a higher fatality of bleeding which might be associated with 10
older age and higher sales of NSAIDs. 11
(3) The results highlight the need for careful consideration of the drug prescriptions to 12
patients with peptic ulcer bleeding. 13
14
Strengths and limitations: 15
(1) Drug sales/use and peptic bleeding outcomes could not be linked with regard to individual 16
patients. 17
(2) Re-bleeding could only be identified on the basis of re-admission, which means we might 18
have lost information regarding re-bleeding that occurred within the same case of 19
hospitalization. 20
(3) It is difficult to find a suitable cut-off day for the definition of re-bleeding. 21
22
23
24
25
26
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Introduction 1
Bleeding is one of the most frequent and serious complications of peptic ulcer disease. 2
Despite the marked decrease in the occurrence of peptic ulcer disease during recent decades, 3
paralleling the decreasing prevalence of Helicobacter pylori infection, the incidence of peptic 4
ulcer bleeding has not changed apparently. On the contrary, several surveys have shown that 5
the incidence of peptic ulcer bleeding has increased among older people. 1-4
Re-bleeding and 6
fatality after peptic ulcer bleeding occur in 7-16% and 3%-14%, 2,5,6
respectively. These 7
figures might increase as a result of the increasing average age of many populations. 1,2,7,8
The 8
high risk of recurrence and fatality highlights the need to identify the best preventive 9
measures available. The established risk factors for peptic ulcer bleeding include Helicobacter 10
pylori infection and medications such as non-steroidal anti-inflammatory drugs (NSAIDs), 11
while proton pump inhibitors (PPIs) can prevent ulcer bleeding. 9We aimed to examine how 12
the sales of PPIs and NSAIDs correlates with the incidence, recurrence and fatality of peptic 13
ulcer bleeding in a population perspective. 14
Methods 15
Study design 16
This was a nationwide ecological study that addressed the correlation between relevant drug 17
sales and peptic ulcer bleeding in Sweden during the period 2000–2008. We used complete 18
Swedish nationwide registers to collect data on sales of NSAIDs and PPIs, hospitalization and 19
fatality after peptic ulcer bleeding. The average daily defined doses (DDDs) of NSAIDs and 20
PPIs were compared with the incidence, recurrence within 60 days after hospitalization for 21
bleeding, and 30-day fatality after admission for peptic ulcer bleeding, in Sweden. The 22
Regional Ethics Committee in Stockholm approved the study. 23
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Data collection 1
Definition of bleeding incidence 2
Aggregated data on drug sales in Sweden during the study period was available from the 3
Swedish Prescribed Drug Register. This register records all prescribed and collected 4
medications in the entire Swedish population of approximately 9 million inhabitants. 10
The 5
Prescribed Drug Register contains data on the age and sex of patients together with names of 6
prescribed drug substances according to the anatomical therapeutic chemical (ATC) 7
classification. All NSAIDs (ATC codes: M01A) and PPIs (ATC codes: A02BC and A02BD) 8
were used for this study. All NSAIDs with ATC codes of M01A were sold as prescriptions 9
drug except a few types of ibuprofen in Sweden. 10
Patients with peptic ulcer bleeding were identified from the Swedish Patient Register, which 11
contains complete, nationwide data on all codes representing diagnoses and surgical 12
procedures relating to in-hospital care in Sweden since 1987. Codes representing peptic ulcer 13
bleeding according to the international classification of diseases (ICD) version 10 were used 14
(K25.0, K25.4, K26.0, K26.4, K27.0, K27.4, K28.0, K28.4, K92.0, K92.1, and K92.2). Since 15
the treatment of ulcer perforation is different from the treatment of ulcer bleeding, patients 16
with perforation were excluded. Re-admission for peptic ulcer bleeding within one day of 17
discharge was not regarded as a new case of bleeding. Re-bleeding was defined as an episode 18
of bleeding that occurred within 60-days after a previous bleeding. Fatality was defined as 19
any death occurring within 30 days of the date of admission for peptic ulcer bleeding. Death 20
dates were obtained from the Death of Cause Register and the Swedish Population Register. 21
The personal number, which is the unique identity for all the Swedish residents, was used to 22
link data among different registers. 23
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Statistical analyses 1
Average DDD and time trends regarding the sales of PPIs and NSAIDs were calculated on the 2
basis of the average population for each year. DDD/TID was described as DDDs per thousand 3
inhabitants per day. A linear regression model was applied to test the statistical significance 4
of trends at the 5% level. Correlation analyses were performed between drug sales and the 5
incidence, recurrence, and fatality of peptic ulcer bleeding. All analyses were gender-specific. 6
Figures were plotted to show the correlations between drug sales and bleeding events. All 7
statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). 8
Results 9
Trends of PPI and NSAID sales 10
The sales of PPIs increased during the study period, except for a temporary drop in 2003 11
(Figure 1). The sales of NSAIDs increased until 2004, after which there was a decrease to a 12
level lower than in year 2000 (Figure 2). The decreased NSAID sales were particularly 13
evident in patients over 75 years of age (data not shown). Women bought more PPIs and 14
NSAIDs than men (Figures 1 and 2), and this difference was more obvious with regard to 15
NSAIDs. We also analysed the trend of sales of aspirin and H2 receptor antagonists (data not 16
shown) which seems not very relevant with trends of peptic ulcer bleeding, then we focus on 17
correlations of PPIs / NSAIDs and peptic ulcer bleeding in this study. 18
Incidence, recurrence and fatality of peptic ulcer bleeding 19
The hospitalization rate for peptic ulcer bleeding was stable during the study period, while a 20
higher rate was observed in men than in women (Figure 1). The rate of recurrence of bleeding 21
was similar between the genders, although the recurrence rate in women showed a slightly 22
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decreasing trend (Figure 3). The 30-day fatality after peptic ulcer bleeding decreased during 1
the study period, especially in males (Figures 5 and 6). Furthermore, women showed a higher 2
fatality rate in different time periods (Figure 4). 3
PPIs and NSAIDs sales and peptic ulcer bleeding 4
The trend of peptic ulcer bleeding did not correlate with the PPIs sales in either gender 5
(Figure 1; Rmale=-0.2274, Pmale=0.5562,Rfemale=-0.2398, Pfemale=0.5342), but it correlated 6
marginally with the trend of the sales of NSAIDs in males only (Figure 2; Rmale 7
=0.6571,Pmale=0.05, Pfemale=0.2633, Rfemale =0.4177 ). 8
PPI and NSAID sales and peptic ulcer re-bleeding 9
The time trends of re-bleeding did not correlate with the sales of PPIs or NSAIDs in males 10
(Figures 3 and 4, Rmale =0.2227, Pmale=0.5647; Rfemale =0.023, Pfemale=0.9522), but the 11
decreased occurrence of re-bleeding in females correlated with the time trends of both PPI 12
sales (Rmale =−0.8754, P=0.002) and NSAID sales (Rfemale =0.7161,P=0.03). 13
PPI and NSAID sales and 30-day fatality 14
There was an inverse correlation between PPI sales and fatality in both genders (Rmale 15
=−0.9392, Pmale=0.0002, Rfemale =−0.8561, Pfemale=0.003) (Figure 5), and the NSAID sales 16
showed a close correlation with fatality of bleeding in both genders (Rmale =0.7278, Pmale=0.03, 17
Rfemale =0.7858, Pfemale=0.01) (Figure 6). 18
Discussion 19
This study indicates that sales of NSAIDs and PPIs (inversely) correlates with 30-day fatality 20
(both sexes) and recurrence (females) of peptic ulcer bleeding in the unselected population. 21
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Women appeared to have a higher fatality of bleeding which might be associated with age and 1
greater sales/use of NSAIDs. 2
The main strength of this study is the nationwide, complete data collection regarding drug 3
sales, hospitalization for bleeding, and fatality. Since there is virtually no private care for 4
peptic ulcer bleeding in Sweden and since such bleeding usually requires hospitalization, the 5
incidence of bleeding and re-bleeding covered by this study should represent population-6
based figures. There are, however, several weaknesses that should be acknowledged. Drug 7
sales/use and peptic bleeding outcomes could not be linked with regard to individual patients. 8
This ecological design makes the interpretations more uncertain. Re-bleeding could only be 9
identified on the basis of re-admission, which means we might have lost information 10
regarding re-bleeding that occurred within the same case of hospitalization. On the other hand, 11
it is difficult to find a suitable cut-off day for the definition of re-bleeding. The definition of 12
fatality of bleeding was based on death within 30 days after discharge, since it is difficult to 13
assess if death actually results from bleeding. Furthermore, selection bias for PPIs users could 14
exist since PPIs were also prescribed for gastroesophageal reflux diseases. This might dilute 15
the correlation between PPIs and incidence of peptic ulcer bleeding. Nevertheless, we also 16
have studied correlation between PPIs /NSAIDs and re-bleeding, PPIs /NSAIDs and mortality 17
after bleeding diagnosis which may possibly further pinpoint the specific correlation between 18
PPIs/NSAIDs and peptic ulcer bleeding. In addition, a few types of ibuprofen as one of 19
NSAIDs were sold as over the counter drug which might lead to selection bias for NSAIDs in 20
this study. Since most of NSAIDs were prescribed drugs and actually few persons buy drugs 21
without prescriptions in Sweden due to the nationwide health care system, this selection bias 22
may be negligible. 23
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NSAIDs constitute an established risk factor for peptic ulcer bleeding, but the sales/use of 1
these medications at the population level is less well documented. A previous study reported 2
that the sales of NSAIDs in Sweden increased during the period 1978-2002.11
The present 3
study shows that the sales have decreased since 2004 with regard to both genders, and this 4
decrease is more obvious in women and in the population aged over 75 (data not shown). This 5
decline might contribute to the decreasing trend of peptic ulcer fatality and re-bleeding in 6
women. Similarly, the increased sales/use of PPIs might contribute to these trends. The 7
correlation between sales/use of PPIs and fatality indicates that PPIs might prevent deaths 8
from bleeding. This relation is more apparent in the male population, which shows a very 9
interesting, coinciding pattern. The different correlations of drug and bleeding fatality 10
between men and women could attribute to the different sales/use of PPIs and NSAIDs 11
between the genders. Previous studies have found that PPIs may help reduce peptic ulcer 12
bleeding, re-bleeding and the need for surgery, but not death. 12-14
It is difficult to differentiate 13
the respective roles of PPIs and NSAIDs. Nevertheless, the gastric mucosal protective effects 14
of PPIs could be beneficial if NSAIDs are used. Surprisingly, PPIs are used in only 10%–22% 15
of patients admitted with a peptic ulcer disease and using NSAIDs.15-17
Our recent study using 16
individual prescription data from Sweden revealed that less than 40% long-term NSAIDs 17
users (those prescribed NSADs for more than 180 days) were prescribed concomitantly 18
gastroprotective medication18
. Furthermore this study found that men took less 19
gastroprotective drugs compared to women despite that the concomitant antithrombotic 20
treatment was more common in men. On the other side, another German study found that 21
over-prescription of drugs might increase risk of adverse effect because of drug-drug 22
interactions19
. It may indicate that use of NSAIDs in high risk population, e.g. patients with 23
history of complicated peptic ulcer, elderly population with several concomitant prescriptions, 24
should be cautious and personalized regimen should be considered thoroughly. 25
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The incidence of peptic ulcer bleeding is higher in men than in women, but few studies have 1
reported the gender distribution with regard to re-bleeding and death. One British case series 2
study suggested that women are at a higher risk of perforation or death than men. 20
The older 3
mean age in women was, however, an important factor in that study, and this is consistent 4
with our data (data not shown). The greater sales/use of NSAIDs in women cannot be ignored. 5
The rapid decrease of NSAID sales/use in women since 2004 might contribute to the 6
significantly decreased occurrence of re-bleeding and fatality in this group in which PPI 7
sales/use is increasing continuously. 8
In conclusion, although the sales/use of NSAIDs and PPIs in the general population does not 9
seem to mirror the incidence of peptic ulcer bleeding, such sales/use correlates with re-10
bleeding and fatality of peptic ulcer bleeding. This correlation seems more obvious in old 11
women which propose an intriguing issue for future study. The potential reduced risk of death 12
due to decreased use of NSAIDs (especially in old women) and increased use of PPIs 13
(especially in male population) warrant further investigation. 14
References 15
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16. Ohmann C, Imhof M, Ruppert C, et al. Time-trends in the epidemiology of peptic ulcer 25
bleeding. Scand J Gastroenterol. Aug 2005;40(8):914-920. 26
17. Johnell K, Fastbom J. Concomitant use of gastroprotective drugs among elderly NSAID/COX-2 27
selective inhibitor users: a nationwide register-based study. Clin Drug Investig. 28
2008;28(11):687-695. 29
18. Ljung R, Lu Y, Lagergren J. High concomitant use of interacting drugs and low use of 30
gastroprotective drugs among NSAID users in an unselected elderly population: a nationwide 31
register-based study. Drugs Aging. Jun 1 2011;28(6):469-476. 32
19. Ahrens D, Chenot JF, Behrens G, Grimmsmann T, Kochen MM. Appropriateness of treatment 33
recommendations for PPI in hospital discharge letters. European journal of clinical 34
pharmacology. Dec 2010;66(12):1265-1271. 35
20. Smart HL, Langman MJ. Late outcome of bleeding gastric ulcers. Gut. Aug 1986;27(8):926-928. 36
37
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PPI: D
DD/T
IND
20
25
30
35
40
45
50
55
60
Calendar Year
2000 2001 2002 2003 2004 2005 2006 2007 2008
0
2
4
6
8
10
12
14
16
18
20
Figure 1a: PPIs and bleeding in men
Male_PPI
Male_bleeding
20
25
30
35
40
45
50
55
60
Calendar Year
2000 2001 2002 2003 2004 2005 2006 2007 2008
Hospitaliz
ation rate
,per 100,0
00
0
2
4
6
8
10
12
14
16
18
20
Figure 1b: PPIs and bleeding in women
Female_PPI
Female_bleeding
1
Figure 1. Sales of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000 2
inhabitants per day and hospitalization rate for peptic ulcer bleeding (hospitalizations for 3
bleeding per 100,000 inhabitants) in Sweden in 2000–2008. Figure 1a and Figure 1b represent 4
males and females, respectively. 5
6
7
Figure 2. Sales of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses 8
(DDD) per 1,000 inhabitants per day and hospitalization rate for peptic ulcer bleeding 9
(hospitalizations for bleeding per 100,000 inhabitants) in Sweden in 2000–2008. Figure 2a 10
and Figure 2b represent males and females, respectively. 11
12
13
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1
Figure 3. Sales of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000 2
inhabitants per day and peptic ulcer re-bleeding rate within 60 days (number of re-bleeders 3
per 100 in-hospitalizations for bleeding) in Sweden in 2000–2008. Figure 3a and Figure 3b 4
represent males and females, respectively. 5
6
7
Figure 4. Sales of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses 8
(DDD) per 1000 inhabitants per day and peptic ulcer re-bleeding rate within 60 days (number 9
of re-bleeders per 100 hospitalizations for bleeding) in Sweden in 2000–2008. Figure 4a and 10
Figure 4b represent males and females, respectively. 11
12
13
14
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1
2
Figure 5. Use of proton pump inhibitors (PPIs) in daily defined doses (DDDs) per 1,000 3
inhabitants per day and 30-day fatality of peptic ulcer bleeding (number of deaths within 30 4
days per 100 hospitalizations for bleeding) in Sweden 2000–2008. Figure 5a and Figure 5b 5
represent males and females, respectively. 6
7
8
9
Figure 6. Sales of non-steroidal anti-inflammatory drugs (NSAIDs) in daily defined doses 10
(DDDs) per 1000 inhabitants per day and 30-day fatality of peptic ulcer bleeding (number of 11
deaths within 30 days per 100 hospitalizations for bleeding) in Sweden in 2000–2008. Figure 12
6a and Figure 6b represent males and females, respectively. 13
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